Marijuana

Research Findings: 1980

Editor:

Robert C. Petersen, Ph.D.

NIDA Research Monograph 31

June 1980

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National Institute on Drug Abuse

Division of Research

5600 Fishers Lane

Rockville, Maryland 20857

For sale by the Superintendent of Documents, U.S. Government Printing Office

Washington, D.C. 20402
The NIDA Research Monograph series is prepared by the Division of Research

of the National Institute on Drug Abuse. Its primary objective is to provide

critical reviews of research problem areas and techniques, the content of

state-of-the-art conferences, integrative research reviews and significant

original research. Its dual publication emphasis is rapid and targeted

dissemination to the scientific and professional community.

Editorial Advisory Board

Avram Goldstein, M.D.

Addiction Research Foundation

Palo Alto, California

Jerome Jaffe, M.D.

College of Physicians and Surgeons

Columbia University, New York

Reese T. Jones, M.D.

Langley Porter Neuropsychiatric lnstitute

University of California

San Francisco, California

William McGlothlin, Ph.D.

Department of Psychology. UCLA

Los Angeles, California

Jack Mendelson, M.D.

Alcohol and Drug Abuse Research Center

Harvard Medical School

McLean Hospital

Belmont, Massachusetts

Helen Nowlis, Ph.D.

Office of Drug Education. DHHS

Washington, D.C.

Lee Robins, Ph.D.

Washington University School of Medicine

St Louis, Missouri

NIDA Research Monograph series

William Pollin, M.D.

DIRECTOR, NIDA

Marvin Snyder, Ph.D.

DIRECTOR, DIVISION OF RESEARCH, NIDA

Robert C. Petersen, Ph.D.

EDITOR-IN-CHIEF

Eleanor W. Waldrop

MANAGING EDITOR

Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857
Marijuana

Research Findings: 1980
The U. S. Government does not endorse or favor any specific

commercial product or commodity. Trade or proprietary names

appearing in this publication are used only because they are

considered essential in the context of the studies reported

herein.

Library of Congress catalog card number 80-600104

DHHS publication number (ADM) 80-1001

Printed 1980

NIDA Research Monographs are indexed in the Index Medicus.

They are selectively included in the coverage of Biosciences

Information Service, Chemical Abstracts, Current Contents,

Psychological Abstracts, and Psychopharmacology Abstracts.

iv
Foreword

1980 marks the 10th anniversary of the Marijuana and Health

Reporting Act, which called for annual reports to the Congress

on the health consequences of marijuana use. The letter of transmittal accompanying the first Marihuana and Health report expressed the conviction that the reports would "prove to be valuable tools in the public education and debate concerning the

health impact of this widely discussed drug" and that they

would "stimulate additional research concerning marihuana in

those areas which need further attention." The widespread use

of the reports which have been issued in succeeding years suggests

that they have fulfilled these expectations.

In 1976, in addition to the mandated report for Congress and

the public, the National Institute on Drug Abuse published a

monograph intended for readers who wanted to pursue the subject

in greater depth. NIDA Research Monograph 14, Marihuana Research

which that year's Marihuana and Health report was based. More

Findings: 1976, presented the scientific background papers upon

recent developments now call for the publication of another monograph, to bring the record up to date for those with a serious

interest in discovering the present extent and limits of knowledge

of marijuana chemistry and metabolism and its effects on human

health. Now, as then, extensive reference listings make the

original sources accessible to the reader.

For Marijuana Research Findings: 1980, research reports through

late 1979 reviewed by eight scientists/authors, and care

has been taken that the reporting and interpretation of data

are balanced and unbiased. The new monograph appears at a

time when major changes in marijuana use have been occurring.

Today, street marijuana is used by larger numbers of young people,

beginning at earlier ages, more frequently, and often in much

higher potency than it was 10 or even 5 years ago. There is

widespread and justified concern over the effects of this use

v
and a desire for authoritative answers to questions about it.

The pendulum of public opinion, which in the early and mid

seventies appeared to swing in favor of reducing penalties for

possession and use of marijuana, has reversed its direction.

Cne sign of this is the growing numbers of parents who are

banding together to find ways of discouraging marijuana use by

their children.

We hope that the findings presented in this monograph, while

intended primarily for those with a scientific interest, will

also benefit legislators, judges, health professionals, educators,

parents, and others who are often asked to make decisions or

give advice based on the most reliable information available.

Despite advances in research, our knowledge of the acute and

long term effects of marijuana is still limited, and much as we

may wish for quick, definitive answers to our questions, the

accumulation of solid facts can occur only gradually. The full

picture may become clear only after many more years of study--

and, unfortunately, of continuing marijuana use. To that end,

however, the National Institute on Drug Abuse will continue to

support investigations that promise to broaden our understanding

of the implications of marijuana use for the health of our

citizens.

William Pollin, M.D.

Director

National Institute on Drug Abuse

vi
Contents

FOREWORD

William Pollin

MARIJUANA AND HEALTH: 1980

Robert C. Petersen

Executive Summary

Introduction

Nature and Extent of Marijuana Use in the

United States

Addendum: 1979 National Survey--A Marijuana Update

Human Effects

Therapeutic Aspects

Effects of Marijuana in Combination With Alcohol

and Other Drugs

The Hazards of Marijuana Versus Other Recreational

Drugs

Future Directions

References

HUMAN EFFFCTS: AN OVERVIEW

Reese T. Jones

Introduction

The Drug: Botany and Chemistry

Assay Techniques

Dose Considerations

General Psychological Effects in Humans

Psychological Effects

Physiological Effects

Cardiovascular Effects

Respiratory and Pulmonary Effects

Neurological Effects

Cannabis and Psychopathology

Amotivation

Tolerance and Dependence

References

CHEMISTRY AND METABOLISM

Carlton E. Turner

Summary

The Drug Marijuana

Synthetic Progress

Chemistry of Marijuana Smoke

Metabolism

References

v

1

2

5

6

10

12

33

37

40

40

43

54

55

59

59

62

63

64

65

66

67

71

73

74

76

81

83

86

87

88

91

vii
ACUTE EFFECTS OF MARIJUANA ON HUMAN MEMORY AND

COGNITION

Douglas P. Ferraro

Cognitive Tasks 98

Memory Tasks 102

Marijuana-Intoxicated Free Recall Following

Nondrug Learning 103

Marijuana-Intoxicated Free Recall Following

Marijuana-Intoxicated Learning 105

Nondrug Free Recall Following Marijuana-Intoxicated

Learning 109

Recognition Memory 110

References 111

EFFECTS OF MARIJUANA ON NEUROENDOCRINE FUNCTION 120

Carol Grace Smith

Evidence for the Effect of Marijuana on HypothalamicPituitary Function 121

Effects of THC on Gonadotropin Secretion 121

Effects of THC on Prolactin Secretion 123

Effects of THC on Thyrotropin (TSH) Secretion 124

Effects of THC on Corticotropin (ACTH) Secretion 124

Evidence for the Role of Hypothalamic Neurotransmitters in the Mechanism of Action of Marijuana Effects

on Hypothalamic-Pituitary Function 125

Role in Gonadotropin Secretion 126

Role in Prolactin Secretion 127

Role in Thyrotropin Secretion 128

Role in Corticotropin Secretion 129

Effect of Marijuana or THC on Neurotransmitters 129

References 132

THE EFFECT OF MARIJUANA ON REPRODUCTION AND

DEVELOPMENT

Jack Harclerode

Effect of Marijuana on the Male 137

Human Males 141

Summary 142

Effect of Marijuana on the Female Reproductive System 142

Human Females 145

Summary 145

Effect on Adrenal Cortical Hormones 145

Humans 147

Effect on Prostaglandins 147

Effect on Pregnancy 148

Effect on Lactation 148

Effect on Development

Effect on Reproductive Behavior

149

151

Human 152

Summary 153

References 154

viii
EFFECTS OF CANNABIS IN COMBINATION WITH ETHANOL

AND OTHER DRUGS

Albert J. Siemens

Introduction

Interactions Between Cannabis and Ethanol

Interactions Between Cannabis and Sedatives,,

Hypnotics and Opiates

Interactions Between Cannabis and Stimulants

Interactions of Cannabis and Nonpsychoactive Drugs

Interactions of THC and Other Cannabinoids

Interactions of THC With Modifiers of Neurotransmitters

Marijuana in Combination With Other Drugs:

Unresolved Issues

References

THERAPEUTIC ASPECTS

Sidney Cohen

Open Angle Glaucoma

Asthma

167

168

173

180

183

184

184

185

185

199

201

202

Anorexia, Nausea and Vomiting in Cancer Chemotherapy,

Irradiation and Anorexia Nervosa 204

Epilepsy 207

Retardation of Tumor Growth 208

Antibiotic Action 209

Antianxiety and Sleep-Inducing Effects 209

Muscle Relaxant 210

Preanesthetic 210

Pain 211

Depression 212

Alcoholism and Drug Dependence 212

Summary

References

213

215

LIST OF NIDA RESEARCH MONOGRAPHS 222

i x

Marijuana and Health: 1980

The first chapter of this volume, with the exception of the

addendum on pages 10-11, is a reprint of the text of the eighth

Marijuana and Health report, which was presented to the U. S.

Congress in February 1980. Its annual publication provides to

political decisionmakers and others a summary of current marijuana

research. The more general distribution of this report has

served a further function as a source of information on marijuana's

effects for an interested and concerned public.

Preparation of the eighth Marijuana and Health report was made

possible by contribution of preliminary project reports and

other data from members of the scientific community. The

report is based on the technical reviews of various aspects

of these findings, which follow the first chapter. Dr. Robert C.

Petersen, Assistant Director of the Division of Research, National

Institute on Drug Abuse, wrote the report and had primary responsibility for its overall preparation. In addition, members

of the Division of Research staff offered many helpful suggestions.

1
EXECUTIVE SUMMARY

In this eighth edition of the Marijuana and Health Report several

areas of recent developments in marijuana research are highlighted

together with a summary of the scientific research accumulated

through the end of 1979 concerning the drug's possible health implications.

Nature and Extent of Use

By contrast with a decade ago, marijuana use now often begins at

a much earlier age and is more likely to be frequent rather than

experimental use. The most significant increases noted in the

1977 National Survey of drug use were in marijuana use by 12-to

17-year-olds. Other, more recent sources of data are generally

consistent. Among high school seniors, for example, daily use

nearly doubled from the Class of 1975 to those of 1978 and 1979

(from 5.8 percent to 10.7 and 10.3 percent for each of these

classes). Moreover the percentage of each of these senior

classes which began use in the ninth grade or earlier has also

nearly doubled (from 16.9 percent of the Class of 1975 to 30.4

percent of the 1979 class). Despite these increases in use, most

members of all age groups surveyed continue to disapprove of regular marijuana use and to advocate continued prohibition.

Chemistry

"Street" marijuana has increased markedly in potency over the

past five years. Confiscated materials in 1975 rarely exceeded one percent THC content. By 1979 samples as high as five

percent THC content were common. "Hash oil," a marijuana extract

unavailable a decade ago, has been found to have a THC content

as high as 28 percent, with more typical samples analyzed by

University of Mississippi chemists ranging from fifteen to twenty percent THC.

Considerable progress has been made in developing simpler laboratory techniques for detecting marijuana use by examining body

fluids. Methods are now being field tested which will probably

be commercially available by mid 1980 which can be used for such

purposes as detection of driving under the influence of marijuana.

Acute Effects

A review of marijuana's acute effects on intellectual functioning

done for this year's report indicates the data is generally consistent: marijuana intoxication interferes with immediate memory

2
and a wide range of intellectual tasks in a manner that might be

expected to impair classroom learning among student users. There

is also good evidence that marijuana interferes with driving

skills and is a significant factor in erratic driving.

Long Term Effects

While much remains to be learned about the chronic effects of

marijuana, there are converging lines of evidence with respect to

its pulmonary effects. Both animal and human experiments suggest

that marijuana impairs lung function to a greater extent than

tobacco cigarettes do. While there is as yet no direct evidence

that it can play a causal role in lung cancer, it is known that,

like tobacco smoke residuals, the "tar" from marijuana is tumorproducing when applied to the skin of test animals. One known

cancer-producing chemical, benzopyrene, has been reported to be

70 percent more abundant in marijuana smoke than in tobacco smoke.

Following exposure to marijuana smoke the lung's defense systems

against bacterial invasion have been shown to be impaired.

Although the evidence is by no means definitive, several kinds of

animal and human research have suggested that heavy marijuana use

may impair reproductive functioning. Such impairment may include

diminished sperm count and motility in males and possible interference with fertility in females. Such preliminary findings may

have greater significance for the marginally fertile. Given the

many unknowns concerning the effects of marijuana on fetal development, the use of marijuana during pregnancy should continue

to be strongly discouraged.

Other questions of possible marijuana effects continue to be unresolved. Evidence concerning an effect on the body's principal

defense against disease, the immune response, remains contradictory. While some human studies have found laboratory evidence of

impairment, others have not, and the clinical significance of such

findings is still in doubt. There have been no large-scale epidemiological studies to determine whether or not chronic marijuana

users suffer from infections and other diseases to a greater extent

than do nonusers of similar life style. Evidence concerning

possible effects on chromosomes is also contradictory and its

clinical significance questionable.

Psychopathological Effects

There have been few new developments in this area. An acute

panic anxiety reaction is the most common adverse psychological

reaction to use, especially when unexpectedly strong material is

consumed. A number of clinicians have cautioned against use of

marijuana by those with a history of serious psychological problems or who have previously had drug-precipitated emotional

disturbances (so-called "bad trips"). While more serious psychiatric problems such as a cannabis-related psychosis have been

reported in countries with a long tradition of use, such reactions

3
do not appear common here. Concern has been expressed that availability of much stronger varieties of cannabis may result in more

serious problems than in the past.

While there have been a number of overseas studies of the impact.

of chronic marijuana use on intellectual functioning, most of

which have reported some impairment, the quality of such studies

is highly variable and the question also remains in doubt. Studies

of American users have not generally reported such impairment,

although the American experience has been limited to relatively

highly motivated college populations using smaller amounts of cannabis for shorter periods of time. Since user populations in the

United States are generally younger than those overseas, the

question of possible impact on younger users is an important one

which remains to be studied.

Therapeutic Uses

Overall, marijuana, THC and related drugs have shown definite

promise in treating the nausea and vomiting which often accompany

cancer chemotherapy. While thus far they have not proven to be

invariably superior to other medication, they may be enduringly

useful with patients for whom other drugs are relatively ineffective.

A second therapeutic application which has received wide publicity is the use of THC or marijuana in reducing the vision-destroying intraocular pressure in open-angle glaucoma. Initial trials

with oral THC found the drug to be of variable success, although

when used with other standard drugs better results were achieved.

An eye drop preparation has been developed which in initial human

trials produced eye irritation and was not consistently effective.

Additional studies are in progress.

It should once again be emphasized that although marijuana, THC

and related drugs have shown some therapeutic promise, much work

remains to be done and that any pharmaceuticals developed will

be chemically related but not identical to the constituents of

the natural material. Such compounds would be chosen to minimize

undesirable side effects and to provide a better-focused therapeutic effect. Like any other new medication, chemically related

materials must be carefully tested for toxicity and for therapeutic effectiveness.

4
INTRODUCTION

This edition of Marijuana and Health represents the eighth in a

series of annual reports from the Secretary of Health, Education,

and Welfare to the Congress and the American people as required by

Title V of Public Law 91-296. The seventh edition dated 1977,

which included research findings available to the end of 1977, was

released last year. This edition has been dated 1980 so as to reduce the confusion concerning the date of actual release. In order

to make it as current as possible, research reports have been included virtually to the end of 1979. Although it is not yet

possible to be definitive in our answers to many of the health questions that marijuana use raises, the report once again tries to answer the central question as it can best be answered at this time:

"What are the health implications of marijuana use for Americans?"

While all of us would wish for greater certainty in this area, such

certainty is not yet possible. The American marijuana experience

has been of brief duration. It is comparatively recently that significant numbers of individuals have been using the more potent

cannabis now available on a daily basis. As our experience with

tobacco and alcohol demonstrates, it frequently requires many years

of use by large numbers for long range effects of a drug to become

apparent. While there are cultures in which cannabis use has been

traditional for many years, the drug is often used differently,

and traditional users rarely include women or the very young. Perhaps the most disquieting development in our society has been the

rapid increase in younger users, under age eighteen. Use is beginning earlier and earlier and is often on a daily basis. Even

those who regard occasional use by well integrated, healthy adults

as unlikely to pose serious public health problems agree that

use, especially frequent use, by children and adolescents can be

seriously disruptive,

Research developments since issuance of the seventh report last

year include additional information on the possible effects on reproduction and pulmonary function. Despite our increasing knowledge,

much remains to be learned about the effects of chronic use. Unfortunately, our present limited knowledge is often interpreted as

indicating that marijuana is "safe." More accurately, there are

many areas in which we simply do not know the parameters of risk.

We do know that even acute use poses hazards in driving and other

complex behavior and definitely interferes with memory and intellectual functioning while "high." As use comes to involve both

younger and older persons it becomes increasingly important that

we be able to specify more precisely the kinds and degree of public

health risk which present and anticipated levels of cannabis use

pose. This report summarizing our present knowledge is another

step in achieving a better understanding of marijuana's public

health implications.

5
NATURE AND EXTENT OF MARIJUANA USE IN THE UNITED STATES

Although a comprehensive updated picture of national trends in

marijuana use since the last 1977 National Survey on Drug Abuse will

not be available until the 1979 Survev results have been tabulated

and analyzed in mid-1980, a review of previous years and of more

limited recent findings indicates a generally consistent upward

trend in use.* There are indicators that the increase is greatest

among younger users (under 18). For example, the most notable

changes in the 1977 National Survey from its predecessor in 1976

were a 25 percent increase in the total of those between ages 12

and 17 who had ever used marijuana and a nearly 30 percent increase

in the number of that age group who were currently using marijuana

(i.e., who had used it in the month preceding the Survey). By contrast, current use in the over-18 population did not increase significantly. Nearly three out of ten (28.2 percent) of 12-to l7-yearolds in 1977 reported having tried marijuana at some point in their

lives; nearly one in six (16.1 percent) were current users (1).

Young adulthood--from age 18 to 25--represents the peak period for

marijuana use. Three out of five in that age group reported having

ever used marijuana in the most recent National Survey; over one in

four (27.7 percent) 18-to 25-year-olds was currently using in 1977.

Use continues to be correlated with age. This is true whether we

are talking about those who have ever used the drug or about current

use. For example, among children between ages 12 and 13, eight percent have had some experience with marijuana, a figure which climbs

to 29 percent for 14-and 15-year-olds and to 47 percent for those

ages 16 and 17. The 22-to 25-year-old group reports the peak level

of use--with 62 percent indicating ever having done so. The percentage who have used is 44 percent in the 26-34-year-old group and

only 7 percent of those over 35 report any past use. Similar

trends are to be found in current use (i.e., use in the month preceding the Survey). While 4 percent of the 12-and 13-year-olds

report current use, the peak years for such use are between 18 and

21. Three out of ten (31 percent) of those between 18 and 2l were

current users in the 1977 Survey (I).

Although the percentages of females who had either tried marijuana

or were currently using it have generally increased in the course

of the five national surveys to date, female use has tended to lag

behind that of males. Interestingly enough, among 12-to 17-yearolds, the percentage of girls and boys who had ever used remained

nearly equal in the three Surveys conducted in 1971, 1972, and 1974.

However, by 1976 the percentage of males who had used in this age

group was significantly greater than that of females (26 percent

for males and 19 percent for females). In 1977, a still greater

difference in cannabis use by the two sexes developed in the 12 to

17 age group (33 percent of males had used at some point compared

with 23 percent for females). While boys' use in the 12 to 17

group increased significantly between 1976 and 1977, use by girls

did not. Among those over 18, by contrast, prevalence of male use

*see ADDENDUM, pages 10-11

6
in all five survey years has been consistently higher, about twice

that of females up until the 1977 survey in which the gap narrowed.

This survey indicates 30 percent of males over 18 had ever used

marijuana as compared with 19 percent of females. However, the

percentage of females over 18 who had ever used increased statistically significantly between 1976 and 1977 while that of males did

not. When one examines current use, generally similar trends are

present--male use predominates by a ratio of about two to one among

those over 18, while in the 12 to 17 age group the difference is

smaller. Half again more boys than girls ages 12 to 17 were currently using in 1977, unchanged from the 1976 findings (1).

Racial differences are of some interest although the broad statistical breakdown into "white" and "other races" categories precludes

more detailed analysis. Among the 12 to 17 age group, white use

for most survey years has slightly exceeded that of other races

whether we are talking about those who have ever used or about those

currently using. In 1977, use by whites 12 to 17 significantly increased both in the "ever used" and "current use" categories (from

22 percent to 29 percent ever having used and from 12 percent to

17 percent for current use). Among those over 18 the percentages

of whites and of other races who have ever tried marijuana were

nearly equal in 1977 (24 percent of whites had used compared to 27

percent of other races) in contrast to previous years in which

"other races" use by the over-18 group tended to be greater than

that of whites. Among current users in the 12-to 17-year age group,

whites consistently predominate over "other races" for all survey

years. Among those over 18, current use by whites and other races

was approximately equal for all survey years including that of

1977 (eight percent of each group in the current survey).

In earlier national surveys adults with college training were considerably more likely to have used marijuana than were adults who

had not gone beyond high school graduation. These differences have

narrowed in recent years. For example, the percentage of college

graduates who had ever used marijuana at the time of the 1977 Survey

was 28 percent, compared to 26 percent of the high school graduates.

In terms of the four geographical regions into which the National

Survey results are divided (Northeast, Northcentral, South, and

West), the only area to note a statistically significant increase

in marijuana use between 1976 and 1977 was the Northeast. There a

significant increase was found in the number of 12- to 17-year-olds

who reported having used marijuana. By contrast with previous survey years, marijuana use in 1977 in the Northeast approximately

equalled that in the West. This was true both for lifetime prevalence and for current use. Other areas of the country had lower

levels of use.

If one takes the percentages of cannabis users noted in the 1977

Survey and extrapolates to the general population, 43 million

7

323-754 0 - 80 - 2
Americans had tried marijuana as of spring 1977, and about 16 million were currently using the drug (i.e., had smoked it in the

month previous to the 1977 Survey).

Although more recent national statistics for the general population

are not yet available, there are some additional data on the drug

attitudes and behavior of American youth who are at a pivotal

point of transition to adult life--their senior year in high school.

Since 1975, a representative nationwide sample of high school seniors

has been queried. Because of the large sample involved, this survey

is a particularly reliable source of information on drug using

trends, sensitive to even small changes. It is also a source of

information on student attitudes and beliefs about drugs, which may

be useful in anticipating future drug trends. While statistically

significant increases (i.e., increases likely to reflect actual behavior changes rather than survey artifacts) in marijuana use were

noted in each of the years through 1978, data for the senior class

of 1979 indicate a leveling off of marijuana use, although at fairly

high levels. The percentage of each of the five senior classes

from 1975 to 1979 who had tried marijuana steadily increased from

47.3 percent in 1975 to 60.4 percent of the Class of 1979. Indeed,

the percentage of 1979 high school seniors with marijuana experience

is equal to that of the National Survey's peak-using group, the 18-

to 25-year-olds. The increase in use between the classes of 1978

and 1979 was the smallest annual increment to date, less than one

percent (2,3).

Daily use rates which rose from six percent in 1975 to 9.1 percent

in 1977, reaching a peak level of 10.7 percent in the Class of

1978, were 10.3 percent in 1979. While use within the 30 days

prior to each of the surveys rose from a little over a quarter of

the seniors of the Class of 1975 to 37.1 percent of the Class of

1978, it leveled off at 36.5 percent in the 1979 senior class. Thus,

this study suggests that the proportion of high school seniors using

marijuana has remained stable for the past two years (2,3).

A disturbing trend continues to be the tendency toward initial

marijuana use at younger ages. For example, 16.9 percent of the

Class of 1975 had used the drug prior to the tenth grade, but the

corresponding percentages in the 1976, 1977, and 1978 classes were

22.3, 25.2, and 28.2 percent. In the most recent senior high school

class studied, the 1979 group, 30.4 percent had used prior to the

tenth grade. Thus, the percentage of seniors who first used in the

ninth grade or earlier has nearly doubled over the past five years

(2,3).

Although overall the use of alcohol and tobacco continues to exceed

that of marijuana, daily use of marijuana among high school seniors

in the Class of 1978, for example, (10.7 percent) was nearly double

that for alcohol (5.7 percent daily use) and exceeded only by daily

cigarette smoking (27.5 percent). Daily use of marijuana has been

about twice as frequent among males as females. However, at less

8
frequent levels of marijuana use, the sexes do not differ markedly

in the percentages using (2,3).

Nationwide statistics may obscure considerable local variation. For

example, in Maryland and Maine, where druq surveys were conducted in

1978, higher levels of daily or nearly daily use of marijuana were

found than among high school seniors nationwide (10.7 percent of

seniors nationally). In Maryland, use "daily or several times a

week" was reported by a quarter (25.3 percent) of the twelfth graders

(4). In Maine, nearly one in six high school students reported daily

marijuana use, four times as many as used alcohol daily (four percent) (5).

Summary--Nature and Extent of Marijuana Use

Although national data representative of the general population subsequent to 1977 are not available at this time, several trends are

noteworthy. Among high school seniors use may be plateauing, although at fairly high levels--over a third of the seniors in recent

years--report use in the month preceding the surveys. About one in

ten reported daily use in the 1979 senior class. The percentages

of seniors using marijuana prior to the tenth grade has steadily increased since 1975, nearly doubling in that five year period.

Current Attitudes and Beliefs About Marijuana

Both the National Survey and the high school senior survey include

questions dealing with respondents' attitudes and beliefs about

drugs in addition to asking about actual behavior. Such attitudes

and beliefs are, of course, subject to change in response to new information and do not necessarily reflect objective reality. Nevertheless, they are of considerable interest in enabling us to better

understand user assumptions and present behavior, and they may be

to some extent predictive of future behavior.

Despite the general assumption of widespread acceptance of marijuana

in our society it is noteworthy that youth (12-17), young adults

(18-25), and older adult groups (26+) all contain substantial proportions advocating either that marijuana continue to be illegal or our

present laws be made still stricter. Seventy-four percent of youth

and 79 percent of older adults take this tack. Even among the peakusing 18-25 year-old group, 40 percent support in about equal proportions the position that marijuana continue to be illegal (20 percent) or that ideally the laws be made still stricter (also 20

percent of the group). Similarly two-thirds of high school seniors

disapprove of regular use.

Respondents in the National Survey were also asked to indicate

which of a list of drugs each regarded as "addictive," ("that is,

anybody who uses it regularly becomes physically and psychologically

dependent on it and can't get along without it"). Alcohol and heroin

were classified as "addictive" by four out of five or more respondents

9
in the 12- to 17-, the 18- to 25-, and the over-26 age groups,

Tobacco was also typically classified as "addictive," with the percentage so designating it increasing with age (youth: 62.4 percent;

young adults: 78.6 percent, and older adults: 83.1 percent).

Marijuana, by contrast, was seen as "addictive" by less than half

of youth and young adults (47.3 percent and 43.7 percent respectively),

but was so classified by over three out of five (63.6 percent) older

(26+) adults.

The percentage of high school seniors who disapprove of regular

marijuana use has remained fairly constant at just over two-thirds

in senior classes from 1975 to 1978 (1975 = 71.9 percent; 1976 =

69.5 percent; 1977 = 65.5 percent; and 1978 = 67.5 percent). A

similar percentage to those disapproving of regular marijuana use

objects to taking one or two alcoholic drinks each day and to smoking one or more packs of cigarettes daily. A little less than half

of the classes of 1976 to 1978 disapproved of occasional marijuana

use; about a third objected to even trying it. Although nearly

half (or more) of the seniors disapproved of even occasional marijuana use, they did not associate "great risk" with use. The percentage who believe there is great risk of some form of harm even

from regular use of marijuana has steadily decreased. While 43.3

percent of the Class of 1975 placed regular use in the "great risk"

category, the percentage of those in the 1978 Class who so described

it had decreased to 34.9 percent. Only 15 percent in the Class of

1975 saw "great risk" in trying marijuana once or twice, and that

has decreased to nearly half (8.1 percent) in the Class of 1978.

While three out of five seniors in the Classes from 1975 to 1978

continued to feel people should be legally prohibited from smoking

marijuana in public, the percentage who believe that use in private

should be legally prohibited has steadily decreased (from a third

of the Class of 1975 to a quarter of the Class of 1978). While two

out of five 1977 and 1978 seniors believe that cigarette smoking

should be legally prohibited in public, only a quarter believe that

marijuana smoking should be illegal in private.

ADDENDUM

The 1979 National Survey--A Marijuana Use Update

At the time of completion of the Eighth Marijuana and Health Report

(late 1979), the 1979 National Household Survey has not yet been

completed. The following addendum is a brief summary of this most

recent National Survey, which was released on June 20, 1980.

As has been consistently true since the National Survey was first

conducted in 1972, marijuana use is highly correlated with age.

This past year (1979), 8 percent of 12- and 13-year-olds reported

some experience with the drug, but by ages 14 and 15 the percentage

who had used it increased to 32 percent. A simple majority--51

10
percent--had used it by ages 16 and 17. Peak use was found among

18- to 25-year-olds, a group in which over two-thirds (68 percent)

had tried the drug at some time in their lives. Taking the 12-

to 17-year-old group as a whole, the percentage that had ever used

marijuana had more than doubled since 1972--from 14 percent to 31

percent. Among young adults (18- to 25-year-olds) the increase

was smaller--from 48 percent in 1972 to 68 percent in 1979 (a

significant increase from 60 percent in 1977).

Current use--defined as use within the month preceding the survey--

is also markedly age related. For youth (12 to 17) and young

adults (18 to 25), about half as many currently use marijuana as

have ever used. Thus 16.7 percent of youth currently use marijuana,

a figure unchanged from the 1977 survey, but also more than double

the 7 percent of this age group that reported then current use

in 1972. Thirty-five percent of young adults were currently using

by late 1979, a figure nearly a third larger than that of 1977.

Until this past year's survey, current use was consistently between

25 and 28 percent for all survey years from 1972 to 1977.

For older age groups, that is, those over 26, both lifetime prevalence and current use are markedly lower than for younger persons.

Nearly 20 percent (19.6 percent) of older adults had ever used

marijuana by 1979, compared to the 7.4 percent who had had marijuana experience in 1972. Current use by this age group has risen

from 2.5 percent in 1972 to 6.0 percent this past year (1979). The

percentage of older adults reporting current use has nearly

doubled since 1977 (from 3.3 to 6 percent).

As the figures indicate, while there have been marked changes in

all age groups since 1972, statistically significant changes

(i.e., changes not likely to be the result of chance) between

1977 and 1979 were confined to the young adult and older age

groups. Youthful use was unchanged from 1977.

This year's survey, for the first time, included questions about

perceived hazards of marijuana use. It is noteworthy that only

5 percent of the peak-using 18- to 25-year-old group saw the drug

as having "no bad effects." Perceived adverse consequences range

from performance and health impairment to possible psychological

effects and the increased likelihood of using stronger drugs,

Nearly three quarters (72.2 percent) of young adults believed

that being high causes impaired driving performance. One in

eight young adults felt it would not. These observations on

perceived hazards should serve as a useful baseline for future

comparisons.

11
HUMAN EFFECTS

Chemistry and Metabolism of Cannabis

Although the chemistry and metabolism of marijuana (i.e., the ways

in which the drug is broken down and chemically transformed in the

body) are technical topics not easily translated into everyday

language, they are important. For example, contrary to popular

belief, the plant material is quite complex, containing at least

421 individual compounds. Sixty-one of the chemicals which have

been identified in the plant--the cannabinoids--are specific to

cannabis. Ten are now routinely quantified in identifying cannabis

samples. When smoked, some of the chemicals contained are further

transformed by burning (pyrolysis) into still other compounds (6).

Plant material differs widely in the amount of the principal psychoactive ingredient--delta-9-tetrahydrocannabinol (THC, for short)--

contained, as well as in the proportions of other chemicals.

Although the effects of cannabinoids other than delta-9-THC have

been studied, much remains to be learned about their effects, both

singly and in interaction with one another. While, for many practical purposes, the percentage of delta-9-THC is a useful guide

to the psychoactivity of a drug sample, other chemical ingredients

may ultimately prove to be-important in modifying THC's effects

as well as because of their own impact on the body. A good deal

of valuable basic research has been done on THC, but it should be

emphasized that it is only one ingredient of the natural material:

Thus, some of the research on THC may be only partially relevant

to the effects of the plant material itself. In addition, the

ratios of the different cannabinoids found in cannabis change in

response to the passage of time and storage conditions. Plants

which have been specifically cultivated for their psychoactivity

contain much more delta-9-THC than do those grown for fiber. Most

of the cannabis qrowing wild in the United States derives from

plants which were originally cultivated for their fiber, rather

than drug content, so that they could be used in making rope and

other nondrug products. Thus the THC content of this wild cannabis

in the United States rarely exceeds one percent THC.

Although there has been no representative random sampling of illicit

marijuana that can provide an accurate indication of changes over

time, there is evidence that material now sold is significantly

higher in THC content than was true only a few years ago. Chemists

at the University of Mississippi who have been analyzing confiscated

samples of cannabis for several years have found increases on the

order of ten times in potency since 1974. Mexican "brick" (i.e.,

compressed kilogram quantities of marijuana) samples studied in

1974 averaged about a fifth of one percent delta-9-THC. Mexican

samples analyzed thus far in 1979 have averaged nearly two percent.

Other cannabis samples, probably of Colombian origin, which were

analyzed in 1979 have averaged over four percent THC content. Hash

oil, a concentrated liquid marijuana extract not available on the

street up until a few years ago has been found to have THC levels

12
ranging from nearly eleven percent to twenty-eight percent. Such

stronger materials are more likely to lead to higher levels of

intoxication and to possibly adverse consequences.

As knowledge of cannabis chemistry and metabolism has increased and

the role of various metabolites becomes more important, there has

been a corresponding need to synthesize supplies of these substances.

Research availability of these materials enables us to tease out

their effects from those of other constituents. In the past year

several improved methods for synthesizing metabolites have been

developed. The ability to synthesize marijuana components and

metabolites in research quantities has accelerated work on the

detection of marijuana in body fluids, as well as permitted studying

the drug's metabolism. By radioactively labelling the substances

involved, it is possible to trace their passage through the body.

The chemistry of marijuana smoke has commanded considerable attention in recent years. Some 150 compounds have been identified in

the smoke itself (7). One of them, benzopyrene, known to be carcinogenic, is 70 percent more abundant in marijuana smoke than in

tobacco smoke (7). There is also evidence that more "tar" is found

in marijuana cigarettes than in high tar tobacco cigarettes (8).

The metabolism of marijuana is only partially understood. Over

35 metabolites of delta-9-THC have thus far been identified along

with several dozen metabolites of other marijuana constituents.

Ability to identify and trace the pathways of these chemicals in

the body provides vital information concerning how they are stored

and eventually eliminated. Such information is useful in helping

determine the possible sites of action for long term effects of

marijuana.

Detection and quantification of cannabinoids and their metabolites

in body fluids continues to be an important problem. Sophisticated

laboratory techniques are available for the precise measurement of

cannabinoid levels in blood and other biological samples. More

routine and simpler techniques have also been developed recently

and are currently undergoing field testing. When this is completed

and the techniques become generally available (probably by mid 1980),

they will be useful for such purposes as the routine laboratory

detection of marijuana-intoxicated automobile drivers, screening

individuals for current marijuana use in treatment programs, etc.

The earlier, more elaborate techniques have been important for

research purposes as well as to provide the necessary standards

by which the results of more rapid and convenient techniques can

be evaluated.

A good beginning has been made in understanding marijuana chemistry

and metabolism. It has enabled researchers to demonstrate that

marijuana constituents cross the placental barrier and as a result

may affect fetal development (9). The presence of cannabinoids in

mother's milk also raises the question of possible impact on the

13
infant of the marijuana-using mother (10). Greater understanding

of the chemistry of marijuana has also raised the possibility

(cf., Therapeutic Aspects) that one or more of the synthesized

components of cannabis in its original or chemically modified

form may come to have therapeutic usefulness. Finally, our

increased awareness of marijuana's chemical complexity and the

ways in which components other than delta-9-THC modify the drug's

effects may shed light on the common street belief that different

types of marijuana have different effects not wholly related to

their THC content.

14
Acute Effects of Marijuana

Although much recent interest has been focused on the possible

long term, chronic effects of marijuana, it is important to

recognize that some of the drug's acute effects on intellectual

and psychomotor performance have definite practical significance.

This includes the likelihood of impaired learning ability when

marijuana is used by students during the school day, as well as

adverse effects on driving and other complex psychomotor performance.

Effects of the marijuana "high" on various aspects of psychological performance were systematically observed as early as

the 1930s and, of course, more subjective accounts of marijuana's

effects exist that long antedate scientific description (11, 12).

These earlier clinical descriptions have generally been verified

by more systematic research investigation.

A wide range of impairment of intellectual performance was

initially found. It included such tasks as digit symbol substitution (a timed task in which the individual substitutes a

series of symbols for numbers) (13),choice-reaction time (a

reaction-time task in which the response depends on rapidly

discriminating between choices) (14), the ability to repeat in

forward and backward order a succession of digits (15), and to

mentally make a succession of repeated subtractions (16). Many

other task performances, including concept formation (17), reading

comprehension (18), and speech have also been found to be impaired to a greater or lesser extent (19).

Generally, such impairment has been found to be related to several

kinds of variables, including the dose of drug, the level of

motivation, the individual's tolerance to marijuana, and the

complexity and familiarity of the task being performed. More

familiar, less demanding tasks are less interfered with than those

involving new material and more difficult task requirements. A

common denominator to impairment of functioning is the effects

of marijuana on short term memory. Marijuana appears to interfere with the transfer of material from immediate to longer term

memory storage. (20)

When marijuana is smoked, the ability to recall material learned

while "high" is typically impaired. This impairment occurs with

a wide variety of verbal, as well as graphic, material. The

body of research evidence accumulated to date indicates that

marijuana intoxication has a detrimental effect on memory functioning, in that material learned while "high" is significantly

less well recalled than that learned in a nondrugged state. This

is especially true when the task involves recalling the learned

material rather than simply its recognition.

15
There are now dozens of experimental studies which have been

conducted, all of which are generally consistent. While marijuana's acute effects on memory and cognition vary with the task

and amounts used, they are almost invariably detrimental.

Although there have been no studies directly assessing the impact of marijuana intoxication on classroom learning the similarities with laboratory experiments which have been done make

it virtually certain that the drug interferes with classroom

performance as well. Since there is now evidence that substantial numbers of high school students are using marijuana during

the course of the school day, it is likely that its use is having

a detrimental effect on their classroom functioning and knowledge

acquisition.

Acute Marijuana Intoxication and Complex Psychomotor Performance

in Driving and Flying

There is good evidence that marijuana use at typical social

levels definitely impairs driving ability and related skills.

Studies indicating impairment of driving skills include: laboratory

assessment of driving-related skills (22), driver-simulator

studies (23), test-course performance (24), actual street-driver

performance (25) and, as previously reported, a study conducted

for the National Highway Traffic Safety Administration of drivers

involved in fatal accidents (26).

As use becomes increasingly common and socially acceptable and

as the risk of arrest for simple possession decreases, more users

are likely to risk driving while high. In limited surveys, from

60 percent to 80 percent of marijuana users questioned indicated

that they sometimes drive while high.

Marijuana use in combination with alcohol is also quite common

and the risk of the two drugs in combination may well be greater

than that posed by either substance alone.

A study of drivers involved in fatal accidents in the greater

Boston area was conducted by the Boston University Accident Investigation Team. They found that marijuana smokers were overrepresented in fatal highway accidents as compared to a control

group of nonusers of similar age and sex (26).

A more recent study, conducted by the California State Department

of Justice, found that of nearly 1,800 blood samples taken from

drivers arrested for driving while intoxicated, sixteen percent

were positive for marijuana. Where no alcohol was present in

the blood sample (about ten percent of the samples) the incidence

of marijuana detected rose to twenty-four percent (27). Additional

studies of motorist impairment related to marijuana use are being

conducted.

16
There are, therefore, several converging lines of evidence that

driving performance is impaired when under the influence of

marijuana, viz.: users' subjective assessments of their driving

skills while high, measures of driving-related performance, a

limited study of actual highway fatalities and a study of individuals arrested for driving while intoxicated.

The parameters of impairment for the average driver under various

dosages of marijuana cannot yet be adequately specified. It is

important to develop reliable standards for what constitutes

driving under the influence of cannabis so as to discourage

potentially dangerous driving. At present it is clearly desirable to discourage driving while "high" and to make drivers

aware that it is a significant risk.

While there have been no recent studies, previous research

findings indicate that experienced pilots undergo marked deterioration in performance under flight simulator test conditions while

"high"(28). Thus, flying while marijuana-intoxicated is clearly

dangerous.

A continuing danger common to both driving and flying is that

some of the perceptual or other performance decrements resulting

from marijuana use may persist for some time (possibly several

hours) beyond the period of subjective intoxication. Under such

circumstances, the individual may attempt to fly or drive without realizing that his or her ability to do so is still impaired

although he or she no longer feels "high."

Pulmonary Effects

Because marijuana is typically smoked, its possible adverse

effects on the lung and pulmonary function have long been of

concern both here and abroad. It is noteworthy that one of the

earliest attempts to assess the health and social implications

of cannabis use, the Report of the Indian Hemp Drugs Commission

of 1893-94, includes observations about its pulmonary effects

that are surprisingly similar to more contemporary observations.

For example, this report mentions a possible value in the treatment of asthma because of the drug's "pulmonary sedative"

qualities. However, it goes on to say that "long continued

smoking...doubtless results in the deposition of finely divided

carbonaceous matter in the lung tissues, and the presence of

other irritating substances in the smoke ultimately causes

local irritation of the bronchial mucous membrane, leading to

increased secretion, and resulting in the condition which is

described as chronic bronchitis in ganja smokers." ("Ganja" is

the Indian term for a type of smoked cannabis preparation intermediate in potency between that of marijuana and hashish.)

The report makes still another observation strikingly descriptive

of present day marijuana use, viz.: “In ganja smoking...the

17
inspiratory act is far greater and more prolonged, a larger

volume of smoke entering the lungs than in cigarette smoking" (29).

Such deep inhalation of marijuana may well offset the typically

smaller amounts smoked as compared to cigarette smoking. One

indication of this is to be found in a study comparing marijuana

and cigarette smokers which found that smoking less than one

"joint" per day decreases vital capacity--the amount of air the

lungs can expel following a deep breath--as much as smoking sixteen cigarettes per day (30). Although the ratio found needs to be

confirmed by more extensive research, it suggests that the mode

of marijuana inhalation and the way in which it is consumed may

result in disproportionately adverse pulmonary effects as compared to modern cigarettes. Part of this difference may be

accounted for by the fact that present day cigarettes are filtered

and have significantly lower levels of "tar" than was true in

the past. Marijuana "joints" are unfiltered and virtually

entirely consumed. Moreover, under conditions of ready availability there is some evidence that the number of "joints" consumed may approach that of tobacco cigarettes (as high as ten

per day) (31).

Thus far there is no direct evidence that smoking marijuana is

correlated with lung cancer. The American experience has been

too brief for this to be a likely outcome. Nevertheless, there

is good reason for concern about the possibility of pulmonary

cancer resulting from extended use over several decades. Like

tobacco smoke residuals--so-called "tar"--cannabis residuals

when applied to the skin of experimental animals have been

shown to be tumor-producing (32). Analysis of marijuana smoke

has also found evidence that it contains larger amounts of

cancer-producing hydrocarbons. For example, benzopyrene, a

known cancer-producing chemical found in tobacco smoke, has been

reported to be 70 percent more abundant in marijuana smoke (33).

Cilia which assist in moving inhaled dust and other small foreign

particles from the lungs have been found to be adversely affected

by marijuana smoke. Following exposure to marijuana smoke,

anti-bacterial defense systems in the lung have been shown to

be less effective against staphylococcus aureus, a bacterium

causing a serious form of pneumonia (34).

While similar effects have not yet been demonstrated in humans,

it would be surprising if they did not occur and they may be

expected to be dose related. The greater the amount and frequency of use, the greater the likelihood of adverse pulmonary

(and other) consequences.

Serious effects on the lungs have been found in rats exposed to

marijuana smoke in quantities producing blood cannabinoid levels

similar to those of human daily users. The animals were made

to inhale smoke in a specially constructed apparatus at daily

18
intervals for periods corresponding to an eighth to one-half

their normal life span. Extensive lung inflammation and degenerative changes were found, similar to but more severe than those

produced by exposure to tobacco smoke. The authors conclude

that in addition to the irritating effects of smoke, the cannabinoids, chemicals specific to marijuana, "may have a direct

undesirable effect on pulmonary function" (35).

There have been several clinical studies of human users which

have reported such symptoms as laryngitis, cough, hoarseness,

bronchitis, and cellular change in chronic marijuana and hashish

smokers which resemble those of heavy tobacco smokers (36,37,38).

In one of these, a study of American soldiers stationed in

Europe, these symptoms were serious enough for the chronic hashish

users involved to seek medical treatment (38). While studies of

small numbers of chronic cannabis users in Jamaica, Greece, and

Costa Rica did not find evidence of lung pathology, this may have

been because traditional users in those countries do not inhale

cannabis smoke as deeply and retain it in their lungs as do

American users (39,40,41).

From the total body of clinical and experimental evidence accumulated to date, it appears likely that daily use of marijuana

leads to lung damage similar to that resulting from heavy

cigarette smoking. Since marijuana users often smoke both tobacco and marijuana, the effects of the combination require

additional study.

19
Reproductive Effects of Marijuana

Effects on reproduction have been attributed to marijuana as far

back as the earliest cannabis commission's scientific report, that

of the Indian Hemp Drugs Commission of 1894. While commenting on

a sexual "stimulant" effect similar to that of alcohol, the Report

also describes cannabis as "used by ascetics in this country

(i.e., India) with the ostensible object of destroying sexual

appetite" (42). Quite apart from the drug's psychologically related reproductive effects, there have been numerous experiments

with animals detailing effects on organs, processes, and hormone

levels related to reproduction. At doses generally much higher

than those used by humans, the evidence is consistent--cannabis

causes decreases in the weight of organs such as testes and

ovaries, as well as altering various hormone levels that are involved in reproduction and lactation. Some more recent studies

have examined the effects in animals of drug doses more clearly

comparable to heavy use in humans. There have also been a few

experiments in which researchers have attempted to study human

reproductive effects directly.

With respect to human males, some have found a decrease in levels

of serum testosterone correlated with heavy marijuana use, although several others have not. One explanation for this apparent

discrepancy in experimental findings is that after smoking marijuana the temporarily depressed levels of testosterone may rapidly

return to more usual levels. Depending on the time schedule in

which sampling is done, the effect may be missed. Even when

testosterone decreases have been found, the levels have been within

normal limits. Whether more persistent chronic use of marijuana

might result in permanently depressed levels of serum testosterone

is not known at this time.

Two studies of the semen of male chronic users have found abnormalities in sperm count, motility and in the structural characteristics of the sperm examined (44,45). In one of these, the semen

of 16 healthy young males smoking marijuana under controlled

conditions was studied (44). The levels of use while "high"--eight

to twenty "joints" per day--were comparable to those of other very

heavy users in the general population. Decreases in sperm count

and motility were found, together with evidences of structural

abnormality in the user's sperm. A second study of Greek chronic

users also found structural abnormalities in sperm that were

associated with heavy use (45). While the clinical implications

of these animal and human findings are by no means certain, decreased fertility might well result, especially in those of

already marginal fertility. In the more controlled laboratory

study there was an apparent gradual return to normal functioning

when marijuana use was discontinued (44). To date (late 1979),

there have been no published reports of abnormal offspring of

fathers which have been related to their marijuana use. Whether

or not alterations in reproductive function might have greater

20
significance for the developing child or adolescent is not known

at this time, although this is a concern since the younger user is

probably more vulnerable.

When we turn to the question of marijuana's effects on the female

reproductive system, there is some recent animal experimentation

with doses comparable to those in actual societal use that suggests

possible adverse consequences. Results to date are, however, far

from definitive. One study, using THC at levels which the authors

describe as "equivalent to moderately heavy marijuana usage in the

United States," found that the rate of "reproductive loss" in THCtreated female rhesus monkeys was about four times greater than

that in drug-free controls. The majority of these losses represented deaths, abortions, or resorptions of the fetus. No clear

pattern of fetal abnormality was evident. The authors conclude

that their experimental results "raise the possibility that exposure of the human female to marijuana in amounts in relatively

common use may be associated with an increased risk of reproductive

loss" (46).

A study of female "street users"--women using marijuana on their

own and of unknown potency--has also raised questions about the

possible reproductive effects of cannabis on women. In this

research 26 women in their twenties who used marijuana three times

a week or more for six months or more were compared to a nonusing

group of women of similar age. The experimental group had a significantly higher frequency of abnormal menstrual cycles in which

they failed to ovulate (i.e., produce a ripened egg) or showed

possible evidence of a shortened period of potential fertility--

shortened luteal phase of the menstrual cycle. Lowered prolactin

levels--a hormone important after childbirth in producing adequate

mother's milk--were also found, suggesting that nursing might be

impaired in marijuana-using women following childbirth (47). While

such findings are of considerable interest, they must be regarded

as preliminary. The drug-using women also used larger amounts of

alcohol than did the controls, which may have contributed to the

result, and there may have been other differences in lifestyle

which contributed to the experimental outcome. Nevertheless, both

animal and human data raise the distinct possibility that fertility

may be impaired in heavy marijuana users as a result of their use.

Studies which have been done in countries of more traditional

cannabis use are of little value in clarifying this question since

male use overwhelmingly predominates among traditional users.

Experiments with radioactively labelled THC (enabling its progress

through the body to be traced) clearly indicate that the drug

appears in the milk of nursing monkey mothers and in their offspring when the drug is administered to the mothers (48). There

is also good evidence that THC and other cannabinoids pass through

the placental barrier, reaching the fetus during uterine development where they tend to concentrate in the fetus' fatty tissue

21
(including the brain) (49). While pre- and postnatal changes related to maternal use have usually only been found with larger

doses in animals and have not been reported in humans, the distinct possibility that marijuana use during pregnancy might result in abnormal fetal development makes its use during pregnancy

very unwise.

While much remains to be learned about the possible effects of

marijuana on reproduction, several points are reasonably clear.

Marijuana at higher doses has a range of effects relevant to reproduction in animals. These appear to result from a variety of

mechanisms, including the drug's effects on adrenal function and

hormone production in testes and ovaries. More recently, at dose

levels that might be encountered in the heavy, regular user,

possible adverse consequences for fertility in both males and

females have been identified. Such effects may be of greater

importance for the marginally fertile or the developing adolescent

than for the mature, healthy adult. Finally, given the many unknowns concerning possible effects on the human fetus, use of

marijuana during pregnancy should be especially discouraged.

Cardiovascular Effects

Although cardiovascular effects of marijuana have been investigated

extensively, such research in humans has been largely restricted

to healthy young male volunteers in whom the effects appear to be

limited in duration and generally benign. One such study examined

the short range effects of smoking one to three marijuana cigarettes on 21 male experienced smokers participating in a 94-day inhospital study of heavy marijuana smoking. They found, as have

others, a significant increase in heart rate after smoking although

not as clearly dose related as previous findings. They attribute

the lack of a clear dose relation to tolerance that developed for

the cardiovascular effects of the drug as a result of chronic use.

The changes they found in heart functioning were secondary to

temporarily increased heart rate and appeared to be free of

adverse consequences (50). As previous editions of this report

emphasize, however, there is evidence that in patients with

already impaired heart function use of marijuana may precipitate

chest pain (angina pectoris) more rapidly and following less effort

than tobacco cigarettes (51). This possible difference in the

response to marijuana in heart disease patients may prove to be of

considerable practical significance if use expands to include

older populations or if presently young adult users continue to

use cannabis as they progress through middle life. Despite the

limited evidence to date, a warning to heart patients and others

who may have impaired cardiac function not to use marijuana,

continues to be justified.

22
Marijuana and the Immune Response

Because of the importance of the body's natural defenses against

illness, principally the immune response, in preserving the health

of the individual, reports of impairment of this vital function

must continue to be carefully considered. There have been contradictory reports of impairment of this response in humans (52,

53,54,55,56). The animal data, using generally higher doses, have

consistently indicated a definite suppression of the test animals'

immune responses (51,58). In humans, even when there have been

indications of a diminished response, it has not been found in

all users and the clinical implications are in doubt. As yet,

there has been no epidemiological research undertaken to determine

whether marijuana smokers suffer from infections and other diseases

to a greater extent than others of similar lifestyle who do not

use the drug. For the present, this important question must be

regarded as unresolved and the evidence far from clear cut.

Chromosome Abnormalities

There is no new evidence in this area. While there were early

reports of increases in chromosomal breaks and abnormalities in

human cell cultures, more recent results have been inconclusive.

The three positive studies in humans that have been reported have

decided limitations (50,60,61). All were retrospective--i.e.,

studies of those already using marijuana who were compared to

nonusers. Such variables as differences in lifestyle, exposure to

viral infections and possible use of other drugs, all known to

affect chromosome integrity, could not be reliably assessed. In

two of the studies, the aberrations observed were found only in a

minority of the users.

Three other studies done prospectively (i.e., before and after use)

have been reported (62,63,64). All are negative, but the results

could have been influenced by the fact that all the subjects had

at least some prior experience with marijuana. It is possible

that the baseline levels of chromosome deficits may have been

elevated by earlier casual marijuana use, thus masking a drugrelated effect.

A team investigating the effect of marijuana smoke on human lung

cells in laboratory culture has found an increase in the number of

cells containing an abnormal number of chromosomes (65). Another

investigator who previously reported a high proportion of cells

in marijuana smokers with reduced numbers of chromosomes has more

recently reported that the addition of delta-9-THC (the principal

psychoactive ingredient of marijuana) to human white blood cell

cultures also resulted in an increased frequency of cells with

abnormally low chromosome numbers (66). The implications of these

findings continue to be uncertain.

23

323-754 0 - 80 - 3
Overall, there continues to be no convincing evidence that marijuana

use causes clinically significant chromosome damage. However, it

should be emphasized this year as last that the limitations of

the research to date preclude definitive conclusions.

Alterations in Cell Metabolism

The implications of laboratory findings on the inhibition of DNA,

RNA, and protein synthesis (all of which are basically related to

cellular reproduction and metabolism) are still unknown. Adding

delta-9-THC to various types of human and animal cell cultures

has been found to inhibit DNA, RNA, and protein synthesis. No

effect on DNA repair synthesis was found although the uptake of

the chemical precursors within the cells was reduced by half (67).

The possibility that cannabis, or one or more of its chemical

ingredients, differentially affects the cell metabolism and reproduction of cancer cells in animals was raised by earlier

reported research. One aspect of the mechanism by which this may

occur is an inhibition of DNA metabolism in abnormal cells but

not in normal cells.

If this preferential inhibition of DNA synthesis in animal tumors

also occurs in humans, marijuana might prove of value as an anticancer drug. It should, however, once again be stressed that

there is no evidence to date that cannabis or any of its synthesized or naturally occurring constituents is of value in inhibiting

human cancer growth. If animal findings of a depressed cell

immunity response which is also related to cell metabolism are

substantiated in humans, cannabis, its synthesized components or

chemically related drugs might prove useful in preventing organ

rejection in human organ transplant surgery.

Brain Damage Research

A British research report, which originally appeared in 1971,

attributed brain atrophy to cannabis use in a group of young male

users. In the original study, 10 patients, with histories of

from 3-11 years of marijuana use, were examined by air encephalography, a neurological technique used to detect gross brain

changes. The authors concluded that their findings suggested that

regular use of cannabis may produce brain atrophy (68). This

research was faulted on several grounds: all of the patients had

used other drugs, making the causal connection with marijuana use

questionable; and the appropriateness of the comparison group and

diagnostic technique was questionable. The potential seriousness

of the original observations justifies a brief review of several

subsequent studies bearing on the original British observations.

In a study of chronic Greek users, a different technique (echoencephalography) was employed to determine whether brain atrophy

24
might be present in heavy users. The findings from the Greek

study were negative; that is, users were not found to differ from

nonusers in evidence of gross brain pathology (69).

Two studies were subsequently conducted in Missouri and

Massachusetts (70,71). They examined two samples of young men

with histories of heavy cannabis smoking using computerized transaxial tomography (CTT), a brain scanning technique for visualizing

the anatomy of the brain. In both studies, the resulting brain

scans were read by experienced neuroradiologists independent of

the drug histories. In neither was there any evidence of cerebral

atrophy. As was emphasized last year, however, several additional

points should be stressed. Neither study rules out the possibility

that more subtle and lasting changes of brain function may occur

as a result of heavy and continued marijuana smoking. It is

entirely possible to have impairment of brain function from toxic

or other causes that is not apparent on gross examination of the

brain in the living organism. Nevertheless, virtually all

studies completed to date (late 1979) show no evidence of chronically impaired neuropsychologic test performance in humans at dose

levels experimentally studied.

A researcher who used electrodes implanted deep within the brains

of monkeys instead of more conventional scalp recording techniques

has found persistent changes related to chronic use (72). This

same investigator has reported that rhesus monkeys administered

marijuana smoke from one joint daily for five days per week for

six months show persistent microscopic changes in brain cellular

structure following this treatment (73). While both these experiments demonstrate the possibility that more subtle changes in

brain functioning or structure may occur as a result of marijuana

smoking in animals, the implications of these changes for subsequent human or animal behavior are at present unknown. Other

studies, using more conventional EEG techniques to measure brain

electrical activity, have found changes temporarily associated

with acute use, but no evidence of persistently abnormal EEG

findings related to chronic cannabis use (74,75).

25
Psychopathology

Although this has been discussed in previous editions of this

report, and there is little new evidence since the seventh edition, a reiteration of what is known may be useful to those

unfamiliar with the area. The most common adverse psychological

reaction of marijuana-use represents an exaggeration of the more

usual marijuana response in which the individual loses perspective (i.e., the realization that what she or he is experiencing

is a transient drug-induced distortion of reality) and becomes

acutely anxious. This reaction appears to be more common in

relatively inexperienced users although unexpectedly higher

doses of the drug (e.g., a higher potency variety of marijuana)

can cause such a response even in the more experienced user.

The symptoms generally respond to authoritative assurance and

diminish in a few hours as the immediate effects of acute intoxication recede.

Transient mild paranoid feelings are common in users and it has

been suggested that those who are characterized by more paranoid

defense mechanisms are less likely to experience other acute

adverse reactions. It has been repeatedly emphasized that

reactions of users are very much influenced by the set and

setting of use. Set refers to the pre-existing expectations the

individual has regarding use; by setting is meant the physical

environment during use. It is generally conceded that anxiety

and mild paranoid reactions are more likely if the user is

initially anxious about the experience and/or the circumstances

of use are anxiety producing. Additional research support for

this clinical impression is found in a field survey which used

a questionnaire to measure acute adverse drug reaction. Preliminary work has found that, in a college population, those who

are more hypochondriacal, and who feel less in control of their

own lives and more at the mercy of external events are more

likely to have adverse reactions to marijuana and other psychoactive drugs (79).

An acute brain syndrome associated with cannabis intoxication

including such features as clouding of mental processes, disorientation, confusion, and marked memory impairment has been

reported (80). It is thought to be dose-related (much more likely

at unusually high doses) and to be determined more by the size

of the dose than by pre-existing personality. This set of acute

symptoms has not been frequently reported in the United States,

possibly because until recently very strong cannabis materials

were less readily available here than in some overseas locations.

Acute brain syndrome also diminishes as the toxic effects of the

drug wear off.

Descriptions of a specific cannabis psychosis are to be found

principally in the Eastern literature from cultures where use

26
is typically more frequent and at much higher doses than those

generally consumed in the United States (81). It continues to be

difficult to interpret such reports because the diagnosis of mental

illness is partly dependent upon sociocultural factors. In

addition, the diagnostic picture is frequently complicated by

use of other drugs and earlier evidence of psychopathology not

necessarily associated with drug use. While the overseas studies

conducted under United States auspices in Jamaica, Greece, and

Costa Rica did not find such adverse consequences, the small

size of the user samples studied, together with the probable

rarity of the disorder, would have made its detection unlikely.

One clinical study in India has contrasted the features of a

paranoid psychosis arising in the course of long ten cannabis

use with that of paranoid schizophrenia. Twenty-five consecutive patients admitted with each diagnosis were compared. The

cannabis users, reportedly, had used the drug for 5 or more

years in amounts up to several grams per day in gradually

increasing quantities. Those diagnosed as having a cannabis

psychosis were characterized by the authors as showing more

bizarre behavior, more violence and panic. an absence of schizophrenic thinking and greater insight into their illness.

Patients with the cannabis-related disorder recovered rapidly

upon being hospitalized and being treated with a major tranquilizer 82).

In this and other clinical studies. it is often difficult to

distinguish the role of cannabis from that of pre-existing

psychological problems or other environmental precipitants in

marijuana-related psychological difficulties. Frequently, heavy

marijuana users are also those, who have had emotional problems

prior to use.

Some further indication of this is to be found in a paper reporting on four cases of well documented schizophrenia in which the

use of marijuana is believed to have led to an exacerbation of

psychotic symptoms in patients whose psychoses were in at least

partial remission prior to use. The author concludes that "While

marijuana can perhaps be safely used by many persons, this is not

so with the schizophrenic." He urges that schizophrenics be

alerted to the special hazards he feels marijuana poses for them

in the same way other patients would routinely be alerted to

possible hazardous interactions between their illness and substances they might use (83).

In a detailed review of the relationship between cannabis and

violence the author concludes that while marijuana probably does

not precipitate violent behavior in the majority of users,

nevertheless there may be some individuals with a prior history

of poor impulse control or special circumstances of stress which

combined with pre-existing personality may make use inadvisable.

27
It is not clear, however, he points out, whether it is specifically marijuana which might have the undesirable effect of

releasing violence or any of a variety of other drugs including

alcohol 84).

Based on his experience with some five thousand drug-related

psychoses encountered while medical director of many youth

festivals, one author has summarized his clinical experience

including that with marijuana users. In his experience, serious

adverse reactions to marijuana are rare, but he offers several

sources of concern about its widespread and indiscriminate use.

Specifically, he feels that the possibly unexpectedly high

potency of some of the cannabis preparations may pose a hazard

for those used to weaker materials. Although he believes it to

be very rare, he thinks that it is possible to have a psychotic

reaction to marijuana. He also believes that persistent psychiatric symptoms after psychotic drug experiences are more common

than is generally believed, as many as 5 to 10 percent of those

cases which he was able to follow up. While some patients reporting "flashbacks" had their initial "bad trip" on drugs other

than marijuana, the flashback recreation of the disturbing aspects

of the original experience frequently occurred following alcohol

or marijuana use. He concludes by advising that "Those with a

history of emotional disturbances and especially 'bad trips'

(i.e.. previous drug precipitated emotional disturbances) should

avoid intoxicants including alcohol and marijuana." Finally.

this author advises that present emergency room and psychiatric

hospital procedures should be altered to make the situation less

judgmental, less frightening and coercive, more compassionate

and more acceptable to youth, with more homelike and reassuring

surroundings (85).

Marijuana flashbacks--spontaneous recurrences of feelings and

perceptions similar to those produced by the drug itself--have

been reported. A survey of United States Army users found that

flashbacks occurred in both frequent and infrequent users and

were not necessarily related to a history of LSD use. Such

occurrences may range from the quite vivid recreation of a drugrelated experience to a mild evocation of a previous incident.

The origin of such experiences is uncertain but those who have

had them typically appear to require little or no treatment (86).

One source of information about possible adverse reaction to

drugs, including marijuana, is the federally sponsored Drug

Abuse Warning Network (DAWN). This is a nationwide reporting

system which provides information about the frequency with which

various drugs in common use are implicated in patient contacts

with such facilities as hospital emergency rooms.

28
During a 1-year period beginning in May 1976 and ending in April

1977, marijuana ranked thirteenth among the drugs mentioned in

drug-related emergency room contacts. But during the year 1978,

the most recent year for which complete data are available,

marijuana had risen to sixth place. While such figures are not

always easy to interpret, they do suggest that marijuana is not

an uncommon factor in causing individuals to seek help and that

its importance may be rising, possibly because of an increase in

the number using the drug or because of the increased availability

of stronger materials more likely to precipitate adverse reactions.

Effects of Chronic Use on Intellectual Functioning

The question of whether or not enduring effects on memory and

other aspects of intellectual functioning occur as a result of

chronic use is a difficult one to answer. While three more

carefully controlled studies of heavy users in Jamaica, Greece,

and Costa Rica failed to find evidence of this, several caveats

should be mentioned. The numbers studied were small, the testing

procedures with the populations studied may have been insensitive

to drug-induced decrements, if any, and even the mode of drug

use may have differed from American use. Overall, the majority

of studies have suggested impairment does occur. Unfortunately,

the quality of studies in this area leaves much to be desired.

Thus the issue still remains in significant doubt, especially

with reference to American users.

A retrospective study of an Egyptian prison population of cannabis users compared 850 chronic users with 839 noncannabis-using

controls, using a number of tests of psychological functioning.

Users were reported to be slower in their psychomotor performance

and to show impaired visual coordination and memory for designs.

These performance deficiencies were found to be more common in

younger, better educated users from urban backgrounds than in

older, illiterate users from rural areas (87,88). This study has

been sharply criticized for alleged sampling and psychometric

deficiencies and equally sharply defended by its author (89,90).

Despite the apparent disagreement on many points, there was

agreement on the desirabflity of replicating the work and possibly.

doing further analysis of the original data. The large samples

employed, despite some of the methodological deficiencies, might

well make the original Egyptian study more sensitive to modest

differences between smoker and nonsmoker groups which smaller

studies may well have missed. At present the information available does not permit a conclusive judgment of the adequacy of

the study's findings particularly if the data were subjected to

more elaborate analysis designed to take some of the criticisms

leveled against the study into account.

29
A study of chronic cannabis users in Northern India has been

published based primarily on a comparison of 11 male users (out

of a larger sample of 23, in turn chosen from 139 long term

cannabis users) with 11 male nonusers who were matched in terms

of age, occupation, and marital status. Users had all used

cannabis equivalent to about 50 mg THC per day (about the

equivalent of 5 to 10 "joints" of typical 1 to 2 percent THC

content marijuana) for 5 years or more. They were given physical

examinations including various laboratory tests of blood and

urine as well as chest X-rays, electrocardiogram (EKG), and

electroencephalogram (EEG). Subjects were also given a range of

psychological tests of intelligence, memory, and other intellectual functions sometimes impaired in the brain-damaged.

The physical examinations including all but one of the

laboratory tests (for uric acid blood levels which were found to

be somewhat elevated in users) were normal for both users and

controls. On the psychological tests, however, users did significantly less well than did nonusers on: two measures of intelligence (9 to 11 I.Q. points lower for users), a measure of memory,

a task requiring reproduction from memory of geometric figures,

a test of combined cognitive psychomotor speed, and a test of

time perception (91).

Unfortunately, several questions of methodology which might have

had an influence on these findings are not clear from the report.

Twenty-three users more carefully examined were selected from a

larger sample of 139 long-term heavy cannabis users and of these

only 11 were then matched with 11 nonusers. It is not clear whether

the basis for selection of the initial 23 was random or whether

some non-random criteria were used such as ready availability, willingness to be further tested, need for possible inducements

to participate, etc. The authors themselves raise the question

whether the impairments found in user functioning were caused by

drug use or if the impairments detected existed prior to such

use. They argue for the desirability of doing a prospective

study if the question of cannabis-related impairment of function

is ultimately to be resolved. The possibility that other aspects of lifestyle such as inadequate diet might have played a

role cannot be dismissed as a factor in the poorer performance

of the users. Since users were from among the poorer groups in

the society, the cost of their cannabis might well significantly

reduce the amounts available for food purchases. At present,

the results must be regarded as provocative and should be more

carefully explored.

American studies comparing college student users with nonusers

have found little in the way of evidence of intellectual performance decrement associated with cannabis use at least as such

performance is measured by college grades. As was pointed out

in previous reports, the higher levels of motivation of students

30
in the schools studied, the rather modest levels of use compared

with that overseas and the possibility that those whose performance was impaired by marijuana use had dropped out earlier,

all limit broader interpretation of these more limited findings.

Tolerance and Dependence

Tolerance to cannabis--i.e., a diminished response to a given

repeated drug dose--is now well substantiated. Tolerance

development was originally suspected because experienced overseas

users were able to use large quantities of the drug that would

have been toxic to United States users accustomed to smaller

amounts of the drug. Carefully conducted studies with known doses

of marijuana or THC leave little question that tolerance develops

with prolonged use.

Several more detailed reviews of tolerance development to the

behavioral and physiological effects of marijuana in both animals

and humans have been published (92,93,94). A report detailing

tolerance development of 30 young adult subjects in a 94-day

closed experimental ward environment has also been published which

stresses tolerance to both the effects on heart rate and the subjective "high "(95). The practical implications of this work are

that experienced, frequent users of marijuana experience less

pronounced physiological and psychological changes at a constant

level of use than would less experienced users. This is in some

contrast with the original impression that users had a "reverse

tolerance"--i.e., a greater sensitivity to marijuana upon repeated use. The latter impression probably derived from the relatively low dose, infrequent use that characterized some of the

earlier observations. Under those conditions neophyte users may

have become more aware of marijuana's subjective effects with repeated use partly as a result of social learning of what was to

be expected from the experience and thus subjectively believed

that its effects were enhanced. Since marijuana's metabolites

(the transformation products which result as marijuana is

metabolized) are also persistent in body fat, it is also possible

that repeated low dosage use released some of the previously

stored material, enhancing the effects. Whatever the ultimate

explanation of these earlier impressions, under conditions of

heavier, more regular use, tolerance now appears to be well

established.

When one turns to the question of "cannabis dependence" the term

has often been used in an imprecise way with meanings ranging

from a vague desire to continue use, if available, to the manifestation of physical withdrawal symptoms following its discontinuance. If "dependence" is defined as experiencing definite

physical symptoms following withdrawal of the drug, there is now

experimental evidence that such symptoms can occur at least under

conditions of extremely heavy research ward administration that

31
are atypical of social marijuana use in the United States. The

changes noted after drug withdrawal under these experimental conditions include one or more of the following symptoms: irritability, restlessness, decreased appetite, sleep disturbance,

sweating, tremor, nausea, vomiting, and diarrhea (96,97). Some of

these symptoms were experienced in a similar research study by

users who selected their own smoked marijuana doses (98). Such a

"withdrawal syndrome" has thus far been reported clinically in

only one formal research report.

32
THERAPEUTIC ASPECTS

A "fringe benefit" of the past decade’s marijuana research has been

a renewed interest in its potential as a therapeutic agent. As

earlier editions of these reports have indicated, cannabis has a

very ancient history of use for the treatment of an unusually wide

range of human ills. Almost from the dawn of history, cannabis has

been used in many parts of the world as a pharmaceutical preparation. As recently as 1937, tinctures of cannabis were still listed

in the United States Pharmacopoeia and presumably used therapeutically

in the United States. One limitation of these earlier preparations

was the extreme variability of drug potency--ranging from inert or

nearly so to unexpectedly potent.

Renewed interest in the potential usefulness of cannabis or of some

synthetically related drug has led to experimentation with these

drugs for a wide range of symptoms and disorders. Although several

of these applications have shown promise, much remains to be learned

about even the most promising applications.

Control of Nausea in Cancer Chemotherapy

Use of marijuana, THC, or related drugs for the treatment of the

extreme nausea and vomiting which often accompany cancer chemotherapy is probably the single most promising application of these

drugs. While by no means invariably effective, they are sometimes

valuable when other standard antinausea drugs are not. One of the

earlier studies done in 1970 found that THC-treated cancer chemotherapy patients showed improved appetite and diminished weight

loss (99). A subsequent study done in Boston found that when compared with a placebo--that is, an inert substance--in a doubleblind study in which neither patients nor physicians knew which

drug was being administered, THC had an antiemetic effect in seven

out of ten patients. The placebo-treated patients showed no improvement (100). In one recent study of 15 patients receiving methotrexate

for their bone cancer, THC or placebo was randomly assigned. Fourteen of the 15 patients showed improvement following the use of THC.

The amount of reduction in nausea and vomiting was closely related

to the dose of THC given. At the highest THC dose employed, in

6 percent of the treatment sessions, patients experienced nausea

and/or vomiting, compared to 44 percent when half the dosage was

used. Such adverse symptoms were found in 72 percent of the sessions

in which the pharmacologically inert placebo was employed. In a

second phase of the same experiment, four patients who had shown

excellent therapeutic response in the first phase were again treated

with THC, but this time much less favorable results were achieved.

The reasons for this are unclear, although the authors suggest the

possibility that these patients developed a tolerance to the effect

during the first phase of the experiment (101). Other studies have

attempted to compare marijuana-related drugs to other standard antinausea medication to determine their relative effectiveness. Nabilone,

a drug chemically related to marijuana constituents, was compared to

33
prochlorperazine, a standard antinausea drug, in a series of 113

patients receiving cancer chemotherapy. Eighty percent responded

to nabilone, compared to 32 percent who responded to prochlorperazine (102). Use of this experimental drug has, however, since been

suspended because of toxic effects observed in dogs.

A partial analysis of the response of the first 66 patients of a

series of 200 receiving prochlorperazine and THC in an experimental

design in which each patient received trials of both found that

equal numbers--25--preferred each, 12 had no preference, and four

patients did not respond to the question. Sleepiness was the most

common side effect of both drugs (103).

Overall, marijuana, THC, and related drugs show promise for treating

the nausea and vomiting which are common side effects of chemotherapy,

Although thus far, THC and marijuana do not appear to be invariably

superior to other medication, they may be useful with patients for

whom other drugs are relatively ineffective.

Glaucoma

A second treatment application which has received wide publicity in

the mass media is to reduce the vision-destroying intraocular pressure which occurs in open-angle glaucoma. This use is based on the

original observation, both in normal young men and in test animals,

that such pressure reductions occur (104). Initial trials with oral

THC alone found the drug to be of variable success. When used as a

supplemental drug with other standard intraocular-pressure-reducing

drugs, greater success was achieved. Because of the desirability

of developing a more convenient dosage form with fewer side effects,

an eye-drop preparation has been tried. Although it showed initial

promise in reducing intraocular pressure in rabbits, it produced

eye irritation and was ineffective in humans in one trial. Additional human testing is planned.

A recent study employing smoked marijuana with 16 glaucoma patients,

eight of whom were hypertensive and eight of whom were not, found

that the hypertensive patients showed a significantly greater drop

in eye pressure than did those with normal blood pressure (105).

At present, marijuana-related drugs have been shown capable of

reducing intraocular pressure in people with glaucoma, alone and

in combination with more conventional anti-glaucoma medications.

However, the long-term safety and efficacy of marijuana-related

drugs administered chronically to glaucoma patients has not been

established, nor is there any data from long-term controlled studies

to demonstrate whether these preparations can actually preserve

visual function in such individuals.

As with other clinical applications, a synthesized drug with fewer

of the side effects found with the natural material may ultimately

be more useful. Continued clinical trials to determine the most

useful combinations with other drugs could be desirable.

34
Other Therapeutic Uses

A variety of other clinical uses of marijuana have been suggested

or experimentally employed. While marijuana's ability to dilate

the lung's air passages (bronchodilation) has been thought to have

promise in treating asthmatics, the drug's lung-irritating properties seem to have offset this potential benefit. Aerosol preparations for inhalation have shown some promise, but have produced

lung irritation and may not be commercially feasible (106). Despite

these problems, a marijuana-related drug may still prove to be of

limited usefulness since its different mechanism of action from

that of conventional drugs may make it useful with some patients

with whom other drugs are ineffective.

The paradox that THC and marijuana have both convulsant and anticonvulsant properties has led both to concern about the implications

of marijuana use by epileptics and to speculation about its possible

value in controlling seizures. In animal experimentation, these

drugs have reduced as well as increased seizure activity, depending

on how the experiment was conducted. As in the treatment of glaucoma, the possibility that one or more of marijuana's constituents

may be useful in combination with other standard antiseizure medication exists, although its usefulness, if any, appears limited at

this time. Although a small survey of youthful epileptics did not

disclose any particular effect of cannabis use upon their seizure

patterns, our present limited knowledge and the possibility that

marijuana might adversely affect these patients suggests that

caution be exercised in use (107).

While there have been some clinical reports of marijuana reducing

muscular spasticity in paraplegics and patients with multiple

sclerosis, such work is still in an early stage, and a definite

usefulness has not yet been found on a more systematic basis (108).

Still other applications of marijuana in the treatment of depression,

pain, and of alcoholism and drug dependence have been variously considered. Although these applications have not been adequately

explored, there is little evidence that they are likely to prove

useful at this time.

While marijuana and/or its synthesized constituents have shown some

promise as therapeutic agents, it should again be emphasized that

additional work is necessary before such agents become generally

approved as standard medications, even for limited purposes.

If consistently useful medical applications for marijuana are found,

it is quite likely that the product or products resulting will be

chemically related to but not identical to the natural material's

constituents.

35
Whether or not cannabis, one of its synthesized constituents, or

a chemically related compound once again finds a place in modern

medicine depends on several considerations. One problem is that

pharmaceutically desirable effects may not be persistently useful

for the chronic disorders. Tolerance undoubtedly develops for a

number of the effects of the natural material. This may also be

true for new chemically related compounds. Like any other new

medication, chemically related materials must be carefully tested

for toxicity and for therapeutic effectiveness. This process is

time-consuming and many new pharmaceuticals showing initial promise

are ultimately discarded as unanticipated drawbacks and limitations

to their use arise.

36
EFFECTS OF MARIJUANA IN COMBINATION WITH ALCOHOL AND OTHER DRUGS

Since marijuana is so commonly used in combination with alcohol and

other drugs, the combined effects of these drugs has potentially

important implications. Given the extremely wide range of possible

doses and interactions, it is not surprising that our present

knowledge is still quite limited. This is true even of the most

commonly used combination, alcohol and marijuana.

A related issue is the extent to which marijuana use might displace

alcohol use were both drugs equally available. Although some

marijuana users in the 1960s were ideologically opposed to alcohol,

it now appears that use of both has generally increased. While

it is not possible to be certain what would occur under conditions

of equal availability, there is no indication that increased

marijuana use among teenagers and young adults has resulted in a

decrease in alcohol use. In fact, several researchers have noted

a positive correlation between heavy marijuana use and that of

alcohol; that is, those using marijuana heavily were more likely

to use alcohol than those who either did not use it or used it

less frequently. One large scale longitudinal study of children

from elementary school to high school age has found that the early

use of alcohol (and tobacco) is more common in those who also

begin marijuana use early or use it more regularly and heavily (109).

In one study of marijuana use in young men conducted in a closed

experimental ward setting, marijuana smoking increased regardless

of the availability of alcohol, although, conversely, alcohol use

decreased when marijuana was available (110). Thus the larger

question of what would happen in American culture were marijuana

more freely available cannot readily be answered. It might well

depend on the kinds of informal social attitudes and controls

which developed among users.

Animal studies of the behavioral effects of the alcohol-cannabis

(or THC-alcohol) combination have generally found that the combined

effect is greater than that of either alone (111). For example,

the duration of alcohol-induced sleep increased as much as threefold when rats or mice also received a marijuana extract or THC

prior to being given alcohol (112, 113, 114, 116). Animals receiving

THC in doses that ordinarily did not interfere with their ability

to remain on a moving belt showed increased alcohol-related impairment of their performance (117). When animals have been simultaneously administered both drugs, conditioned avoidance (i.e., a

learned avoidance of a noxious stimulus), general activity level,

heart rate, and body temperature have been more affected than when

either was used alone (118).

The limited human research to date is generally consistent with

the results of animal research. Experiments at alcohol levels

within the range commonly used socially showed that performance

reductions from combined use are greater than those from the use

37
of either alone. Such decrements have been detected in reasoning,

manual dexterity, and standing steadiness (119,120). Although the

effects after 40 minutes were greater than either drug separately,

2 hours and 40 minutes later some of the changes were less than

those of THC alone. This apparently antagonistic action under some

circumstances may result from the different rate at which the two

drugs are metabolized. In more recent experiments, when alcohol

was given one hour after THC, the effects of the drugs were clearly

additive. Combined use reduced reaction time, cognitive performance, standing steadiness, and psychomotor coordination more than

that of either alone (121).

In measuring glare recovery--the time it takes for light adaptation

after exposure to bright light--it was only slightly greater for

the combination than for either alone (122).

The authors of a research paper dealing with the side effects of

alcohol and marijuana caution that the use of the two simultaneously

may be dangerous for those with cardiac disorders. In a study of

seven healthy male volunteers aged 20 to 29, they found that four

of the seven developed intense nausea and vomiting when they smoked

a marijuana cigarette after drinking a moderate amount of alcohol.

The doses of alcohol involved (1 gm ethanol/kg. of body weight or

about 57 cc. of pure alcohol for an average man weighing 154 lbs.)

represented about the equivalent of three drinks containing one and

a half ounces each of 90 proof liquor. All four men were markedly

incapacitated during the height of the adverse effects, although

they recovered in three to four hours. The fact that not all seven

subjects were equally affected illustrates large individual differences in response. One subject, for example, experienced a marked

drop in heart rate under the influence of the drugs--from 150 to

36 beats per minute. When the experiment was repeated with half

the amount of alcohol originally used, no adverse effects occurred.

The volunteers acknowledged that similar adverse consequences had

sometimes occurred when they had used the drug recreationally (123).

Taking the total of animal and human research simultaneous use of

both alcohol and marijuana typically has more profound effects

than the use of either alone. However, the magnitude and duration

of the effect may vary depending on the dosages of the two drugs

involved, the type of effect measured, and the time intervals

involved in administering the drugs. As with either drug alone,

there are also undoubtedly individual differences in response to

the drugs in combination,

Animal research has raised the question of a possible cross tolerance

between alcohol and marijuana. By this is meant regular administration of one drug may result in a decreased response to another drug,

even though the other has not been given. A recent experiment has

found that when both alcohol and THC were administered to rats,

they developed tolerance to alcohol much more quickly than when

38
they received only alcohol (124). In humans the question of cross

tolerance has not yet been resolved. While there is some evidence

that the performance of male heavy marijuana users is less affected

by drinking four to five ounces of 100 proof alcohol than is that

of nonusers, a later study of performance under similar conditions

found the trend to be statistically insignificant (that is, the

difference found may well have been the result of chance rather

than due to prior marijuana use) (125).

There have been few human studies of the interactive effects of

marijuana with drugs other than alcohol. However, limited evidence

suggests that such interactions may be significant. A study in

which high doses of THC were given to young adult males

indicates that chronic marijuana use may affect the persistence

of barbiturates in the body as well as their rate of absorption (126).

Only limited studies of combined use of amphetamines and marijuana

in humans have thus far been done. One study found that simultaneous use resulted in an increase in the intensity and duration

of the subjective "high" greater than use of either alone produced (127).

The possibility that absorption, distribution, and the metabolism

of therapeutic drugs might be modified by marijuana use has been

raised. In rats, aspirin has been found to decrease the rate of

disappearance of THC in their blood as well as to increase the THC

brain levels (128). Since there are many therapeutic drugs in widespread use which are used in many different forms and dosages,

much work remains to be done.

39

323-754 0 - 80 - 4
THE HAZARDS OF MARIJUANA VERSUS OTHER RECREATIONAL DRUGS

A question that frequently arises is how hazardous is marijuana

as compared to alcohol and tobacco. As appealing as such a comparison is, it is also misleading on several grounds. Any comparison of alcohol and tobacco use and that of marijuana compares

drugs with great differences in social acceptability, period of

use, and degree of availability. The hazards of alcohol and

tobacco are reasonably well known and the social and public health

costs quite high. For example, fully 10 percent of alcohol users

have been described as having an alcohol problem, and alcohol has

been implicated in half the automotive fatalities in the United

States. The health costs of alcohol in terms of cirrhosis,

mental illness, crime, and industrial accidents can also be

documented. A similar analysis can be done for tobacco. By contrast, marijuana has only recently become a popular substance; it

remains illegal and most use is not habitual at present. Moreover,

unlike cigarettes and alcohol, for which the health hazards can be

reasonably well specified, much less is known about the implications of marijuana use.

Any consideration of the hazard a drug poses must take into account

not only its present use, but also use that might be reasonably

expected in the future. At present, this involves many imponderables such as the parameters of risk for various groups in our

society at different levels of use, the likely circumstances of

use, effects on user functioning and motivation of heavier use

patterns, degree of use restriction possible, combined use with

other drugs--to name but a few. As the history of the introduction

of alcohol demonstrates, it is very difficult to anticipate the

problems which will arise in a given society in advance. Thus,

any attempt to compare the health impact of marijuana with that

of alcohol and tobacco at current levels of use is certain to

minimize the hazards of marijuana. But any comparison at levels

of anticipated use involves many assumptions that are at best

dubious and at worst may be dangerouly misleading. Such a comparison seems, therefore, useless and undesirable until such time

as the parameters of risk are better specified than they can be

at present.

FUTURE DIRECTIONS

The past decade's priority emphasis on Federal marijuana research

has brought about an impressive increase in our knowledge concerning cannabis and its effects. Our understanding of the basic

chemistry of marijuana, its mode of action in the body, and some

of the acute and chronic effects of the drug have all expanded

rapidly. Nevertheless, there are still many areas in which our

knowledge continues to be modest. For example, we know little

about the implications of use by girls and women both for their

own health and for possible offspring. Since nearly half of the

40
American users are females of childbearing age, this is an important area for further research.

As marijuana use has come to include much younger ages--a decade

ago use was largely restricted to young adults, now significant

numbers use it in their early teens--the need to understand the

implications of use by this group has also become imperative.

Unfortunately, teasing out the effects of marijuana from that of

both other drugs and other aspects of lifestyle is not always

easy. Heavier users of marijuana at any age are more likely than

nonusers or light users to take other drugs as well. As we have

seen, "street" marijuana can also vary in potency from inert or

nearly so to material with high THC content, which is very

psychoactive.

While carefully controlled animal experimentation in which factors

as disparate as genetic and learning history can be specified is

very useful, there are important differences between animals and

humans. While marijuana, for example, slows heart action in most

animals, in humans it accelerates it. And, while significant

progress has been made through special apparatus to induce animals

to smoke the material, it is not easy to replicate typical conditions of human use.

The National Institute on Drug Abuse (NIDA), the agency within the

Department of Health, Education and Welfare* which has principal responsibility for marijuana research, makes repeated use of

non-government scientists serving as consultants to assist in

determining new directions for research. One of the central

questions that has been considered is the desirability of conducting large-scale, long-term epidemiological studies analogous to

those which were done to determine the effects of cigarette smoking.

Because the level of marijuana use for most of the population has

been modest and because the potency of the material has been so

variable, this approach is unlikely to produce results in proportion to its high cost. Instead, the Institute has elected to support a large variety of smaller studies focusing on some of the

already identified specific effects as well as exploring implications of use in high risk groups.

Following the recommendations of its consultants, NIDA is particularly concerned with studying the implications of use during periods

of likely maximum sensitivity. These include childhood, adolescence,

and prenatal development. The study of groups receiving standardized health care is being investigated to determine cost-effective

means of doing larger scale studies likely to detect effects in

children, adolescents, and young adults. Development of standardized

data collection methods which will enable researchers to effectively

pool data from several sources is also being pursued. This enables

us to detect use implications employing samples larger than are

available in any single study. Such standardized methods also make

it possible to compare data from different sources.

* Now the Department of Health and Human Services (1980)

4 1
Because of the increasing importance of multiple drug use patterns,

the implications of that type of use are also being studied. While

simultaneous use of alcohol and marijuana is the most common pattern, many users use the drug with other licit and illicit drugs.

Such patterns of use and their implications must be explored.

It is unlikely that any single approach will be sufficient.

Methods as diversified as the study of the impact of marijuana's

constituents on cell membrane metabolism to psychosocial research

on changing patterns of use are all essential to developing a

well-rounded picture of the implications of marijuana use. It is

also unlikely that any single piece of research will provide the

definitive answers to our concerns about marijuana's effects. As

with other drugs, it is probable that our understanding will increase gradually and that the effects of the drug will not be

uniform, but will vary significantly depending upon the age,

mental and physical health of the user, and the individual differences in vulnerability to the drug's effects.

Finally, given the marked increase in use by children and adolescents, it is important that we develop more effective means of

discouraging use. While some progress has been made in this area,

much more needs to be learned about individuals and groups at high

risk of becoming seriously involved with marijuana use. Through

an improved understanding of the factors which play a role in

individual vulnerability we may ultimately be better able to

"target" prevention efforts toward those most likely to suffer

serious adverse consequences rather than at a more general

population.

An important step in the ongoing process of exploring the implications of cannabis use and the best ways of coping with it is an

independent review of the marijuana area being sponsored by the

Department to be conducted in 1980. This review will provide a

fresh look at our present knowledge and possible future directions

of effort. It will encompass research into the physiological

effects of marijuana use as well as behavioral research into such

use-related problems as intervention strategies to help adolescents resist peer pressure. A report is expected to be produced

in about one year.

42
REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

Abelson, H.I., Fishburne, P.M., and Cisin, I. National Survey

on Drug Abuse: 1977. National Institute on Drug Abuse, 1977.

Johnston, L.D., Bachman, J.G., and O'Malley, P.M. Drugs and

the Class of '78: Behaviors, Attitudes, and Recent National

Trends. Rockville, Md: National Institute on Drug Abuse,

1979.

Johnston, L.D. Personal communication. 1979.

Maryland Department of Health and Mental Hygiene Drug Abuse

Administration. 1978 Survey of Drug Abuse Among Adolescents -

General Report. Annapolis, Maryland. March 23, 1979.

State of Maine, Department of Human Services, Office of Alcoholism and Drug Abuse Prevention. An Evaluation of the Decriminalization of Marijuana in Maine - 1978. Augusta, Maine. January 5, 1979.

Turner, C.E. Chemistry and metabolism of marijuana. In:

Petersen, R.C. (ed.). Marijuana Research Findings: 1980.

Washington, D.C.: U.S. Government Printing Office, in press.

Lee, M.L., Novotny, M., and Bartle, K.D. Gas chromatography/

mass spectrometric and nuclear magnetic resonance spectrometric

studies on carcinogenic polynuclear aromatic hydrocarbons in

tobacco and marijuana smoke-condensate. Anal Chem, 48(2):

405-416, 1976.

Turner, C.E. See reference 6.

Vardaris, R.M.; Weisz, D.J.; Fazel, A.; and Rawitch, A.B. Chronic administration of delta-9-tetrahydrocannabinol to pregnant

rats: studies of pup behavior and placental transfer. Pharmacol

Biochem Behav 4:249-254, 1976.

Chao, F.-C.; Green, D.E.; Forrest, I.S.; Kaplan, J.N.; WinshipBall, A.; and Braude, M. The passage of 14C-delta9

-tetrahydrocannabinol into the milk of lactating squirrel monkeys. Res

Commun Chem Pathol Pharmacol, 15(2):303-317, 1976.

Bromberg, W. Marijuana intoxication. Am J Psychiatry, 91:

303-330, 1934.

Gautier, T. The hashish-eaters' club (1844). In: Haining, P.

(ed.). The Hashish Club - An Anthology of Drug Literature.

London: Peter Owen, Ltd., 1975.

43
13. Weil, A.T., Zinberg, N.E., and Nelsen, J.M. Clinical and

psychological effects of marijuana in man. Science, 162:

1234-1242, 1968.

14. Clark, L.D. and Naskashima, E.N. Experimental studies of marijuana. Am J Psychiatry, 125:379-384, 1968.

15. Melges, F.T.; Tinklenberg, J.R.; Hollister, L.E.; and Gillespie,

H.K. Marijuana and the temporal span of awareness. Arch Gen

Psychiatry, 24:564-567, 1971.

16. Manno, J.; Kiplinger, G.F.; Haine, S.E.; Bennett, I.F.; and

Forney, R.B. Comparative effects of smoking marijuana or placebo on human motor and mental performance. Clin Pharmacol

Ther, 11:808-815, 1970.

17. Klonoff, H., Low, M., and Marcus, A. Neuropsychological effects

of marijuana. Can Med Assoc J, 108:150-156, 1973.

18. Clark, L.D., Hughes, R., and Nakashima, E.N. Behavioral effects

of marijuana: Experimental studies. Arch Gen Psych, 23:193-

198, 1970.

19. Tart, C.T. On Being Stoned, A Psychological Study of Marijuana

Intoxication, Palo Alto: Science and Behavior Books, 1971.

20. Tinklenberg, J.R. and Darley, C.F. Psychological and cognitive

effects of cannabis. In: Cornell, P.H. and Dorn, N. (eds.).

Cannabis and Man. New York: Churchill Livingstone, 1975.

21. Ferraro, D.P. Acute effects of marijuana on human memory and

cognition. In: Petersen, R.C. (ed.). Marijuana Research

Findings: 1980. Washington, D.C.: U.S. Government Printing

Office, in press.

22. Moskowitz, H., McGlothlin, W., and Hulbert, S. The effects of

marijuana dosage on driver performance. Contract No. DOT-HS150-2-236; University of California; Los Angeles, California;

1973.

23. Moskowitz, H. Marihuana and driving. Accident Analysis and

Prevention, 8(1):21-26, 1976.

24. Klonoff, H. Effects of marijuana on driving in a restricted

area and on city streets: Driving performance and physiological changes. In: Miller, L.L. (ed.). Marijuana: Effects on

Human Behavior. New York: Academic Press, 1974. pp. 359-397.

25. Klonoff, H. Marijuana and driving in real-life situations.

Science, 186:317-324, 1974.

26. Sterling-Smith, R.S. A special study of drivers most responsible in fatal accidents. Summary for Management Report; Contract No. DOT-HS-310-3-595; April, 1976.

44
27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

Reeve, V.C. Incidence of marijuana in a California impaired

driver population. State of California; Department of Justice, Division of Law Enforcement Investigative Services

Branch; Sacramento; 1979.

Janowsky, D.S.; Meacham, M.P.; Blaine, J.D.; Schorr, M.; and

Bozzetti, L.P. Marijuana effects on simulated flying ability.

Am J Psychiatry, 133(4):383-388, 1976.

Marijuana. Report of the Indian Hemp Drug Commission, 1893-

1894. (Reprinted by Thomas Jefferson Publishing Co., Silver

Spring, Md., 1969.)

Tashkin, D.P., Calvarese, B., and Simmons, M. Respiratory

status of 75 chronic marijuana smokers: Comparison with

matched controls. UCLA School of Medicine, Los Angeles, California. Abstract in: Am Rev Resp Dis, 117:(4-Part 2)261, 1978.

Cohen, S.; Lessin, P.J.; Hahn, P.M.; and Tyrrell, E.D. A

94-day cannabis study. In: Braude, M.C. and Szara, S. (eds.).

Pharmacology of Medicine. New York: Raven Press, 1976.

pp. 621-626.

Hoffmann, D.; Brunnemann, K.D.; Gori, G.B.; and Wynder, E.L.

On the carcinogenicity of marihuana smoke. Res Adv Phytochem,

9:63-81, 1975.

Novotny, M., Lee, M.C., and Bartle, K.D. A possible chemical

basis for the higher mutagenicity of marihuana smoke as compared to tobacco smoke. Experientia, 32(3):280-282, 1976.

Huber, G.L.; Simmons, G.A.; McCarthy, C.R.; Cutting, M.B.;

Laguarda, R.; and Perefra, W. Depressant effect of marihuana

smoke on antibactericidal activity of pulmonary alveolar macrophages. Chest, 68:769-773, 1975.

Rosenkrantz, H. and Fleischman, R.W. Effects of cannabis on

lungs. In: Nahas, G.G. and Paton, W.D.M. (eds.). Marihuana:

Biological Effects. New York: Pergamon Press, 1979. pp. 279-300.

Chopra, G.S. Studies on psycho-clinical aspects of long-term

marihuana use in 124 cases. Int J Addict, 8:1015-1026, 1973.

Henderson, R.L., Tennant, F.S., and Guerry, R. Respiratory

manifestations of hashish smoking. Arch Otolaryng, 95:248-

251, 1972.

Tennant, F.S.; Preble, M.; Prendergast, T.J.; and Ventry, P.

Medical manifestations associated with Hashish. J Amer Med

Assoc, 216:1965-1969, 1971.

Coggins, W.J. Costa Rica Cannabis Project: An interim report

on the medical aspects. In: Braude, M.C. and Szara, S. (eds.).

Pharmacology of Marihuana. New York: Raven Press. 1976.

pp. 667-670.

45
40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

Rubin, V. and Comitas, L. Ganja in Jamaica: The Effects of

Marihuana. New York: Anchor/Doubleday, 1976.

Stefanis, C., Boulougouris, J., and Liakos, A. Clinical and

psychophysiological effects of cannabis on long-term users.

In: Braude, M.C. and Szara, S. (eds.). Pharmacology of Marihuana. New York: Raven Press, 1976. pp. 659-665.

Marijuana. Report of the Indian Hemp Commission. See reference

29.

Harclerode, J. The effect of marijuana on reproduction and development. In: Petersen, R.C. (ed.). Marijuana Research Findings: 1980. Washington, D.C.: U.S. Government Printing Office.

in press.

Hembree, W.C., Nahas, G.G., and Huang, H.F.S. Changes in human

spermatozoa associated with high dose marihuana smoking. In:

Nahas, G.G. and Paton, W.D.M. (eds.). Marihuana: Biological

Effects. New York: Pergamon Press, 1979. pp. 429-439.

Issidorides, M.R. Observations in chronic hashish users: nuclear aberrations in blood and sperm and abnormal acrosomes in

spermatozoa. In: Nahas, G.G. and Paton, W.D.M. (eds.). Marihuana: Biological Effects. New York: Pergamon Press, 1979.

pp. 377-388.

Sassenrath, E.N., Chapman, L.F., and Goo, G.P. Reproduction

in Rhesus monkeys chronically exposed to delta-9-THC. In:

Nahas, G.G. and Paton, W.D.M. (eds.). Marihuana: Biological

Effects. New York: Pergamon Press, 1979. pp. 501-512.

Bauman, J.E.; Kolodny, R.L.; Dornbush, R.L.; and Webster, S.K.

Endocrine effects of human female chronic marihuana use. In

press.

Chao, R.-C.; Green, D.E.; Forrest, I.S.; plan, J.N.; WinshipBall, A.; and Braude, M. The passage of 14C-delta9

-tetrahydrocannabinol into the milk of lactating squirrel monkeys. Res

Commun Chem Pathol Pharmacol, 15(2):303-317, 1976.

Vardaris, R.M.; Weisz, D.J.; Fazel, A.; and Rawitch, A.B. Chronic administration of delta-9-tetrahydrocannabinol to pregnant

rats: studies of pup behavior and placental transfer. Pharmacol Biochem Behav, 4:249-254, 1976.

Nowlan, R. and Cohen, S. Tolerance to marihuana: heart rate

and subjective "high." Clin Pharmacol Ther, 22(5):550-555, 1977.

Prakash, R. and Aronow, W.S. Effects of marihuana in coronary

disease. Reply. Clin Pharmacol Ther, 19(1):94-95, 1976.

Nahas, G.G.; Suciu-Foca, N.; Armand, J.P.; and Morishima, A.

Inhibition of cellular mediated immunity in marijuana, smokers.

Science, 183:419-420, 1974.

46
53. Gupta, S., Grieco, M., and Cushman, P. Impairment of rosetteforming T-lymphocytes in chronic marihuana smokers. N Eng J

Med, 291:874-877, 1974.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

Silverstein, M.D. and Lessin, P.J. Normal skin test response

in chronic marijuana users. Science, 186:740-742, 1974.

Petersen, B.H., Graham, J., and Lemberger, L. Marihuana, tetrahydrocannabinol and T-cell function. Life Sciences, 19:395-

400, 1976.

Cushman, P. and Khurana, R. A controlled cycle of tetrahydrocannabinol smoking: T and B cell rosette formation. Life

Sciences, 20:971-980, 1977.

Rosenkrantz, H. The immune response and marihuana. In: Nahas,

G.G. (ed.). Marihuana: Chemistry, Biochemistry and Cellular

Effects. New York: Springer-Verlag, 1976.

Zimmerman, S.; Zimmerman, A.M.; Cameron, I.L.; Laurence, H.L.

Delta-9-tetrahydrocannabinol, cannabidiol, and cannabinol effects on the immune response of mice. Pharmacology, 15:10-23,

1977.

Herha, J. and Obe, G. Chromosomal damage in chronic users of

cannabis. Pharmakopsychiatric, 7:328-337; 1974.

Kumar, S. and Kunwar, K.B. Chromosome abnormalities in cannabis

addicts. J Assoc Physicians India, 19:193-195, 1972.

Stenchever, M.A., Kunysz, T.J., and Allen, M.A. Chromosome

breakage in users of marihuana. Am J Obstet Gynecol, 118:106-

113, 1974.

Matsuyama, S.S.; Jarvik, L.F.; Fu, T.K.; and Yen, F.S. Chromosome studies before and after supervised marfhuana smoking. In:

Braude, M.C. and Szara, S. (eds.). Pharmacology of Marihuana.

New York: Raven Press, 1976. pp. 723-729.

Matsuyama, S.S.; Yen, F.S.; Jarvik, L.F.; Sparkes, R.S.; Fu,

T.K.; Fisher, H.; Reccius, N.; and Frank, I.M. In vivo marihuana exposure and human lymphocyte chromosomes. Mutation

Research, 1977.

Nichols, W.W.; Miller, R.C.; Heneen, W.; Bradt, C.; Hollister,

L.; and Kanter, S. Cytogenetic studies on human subjects receiving marfhuana and delta-9-tetrahydrocannabinol. Mutation

Research, 26:413-417, 1974.

Leuchtenberger, C. and Leuchtenberger, R. Correlated cytological and cytochemical studies of the effects of fresh smoke from

marihuana cigarettes on growth and DNA metabolism of animal

and human lung cultures. In: Braude, M.C. and Szara, S. (eds.).

Pharmacology of Marihuana. New York: Raven Press, 1976. pp.

595-612.

47
66. Morishima, A.; Henrich, R.T.; Jayaraman, J.; and Nahas, G.G.

Hypoploid metaphases in cultured lymphocytes of marihuana

smokers. In: Nahas, G.G. and Paton, W.D.M. (eds.). Marihuana: Biological Effects. New York: Pergamon Press, 1979.

pp. 371-376.

67. Blevins, R.D. and Regan, J.D. Delta-9-tetrahydrocannabinol:

Effect on macromolecular synthesis in human and other mammalian

cells. Archives of Toxicology, 35:127-135, 1976.

68. Campbell, A.M.G.; Evans, M.; Thompson, J.L.G.; and Williams,

M.R. Cerebral atrophy in young cannabis smokers. Lancet,

1219, 1971.

69. Fink, M.; Volavka, J.; Panagiotopoulos, C.P.; and Stefanis,

C. Quantitative EEG studies of marihuana, delta-9-THC, and

hashish in man. In: Braude, M.C. and Szara, S. (eds.). Pharmacology of Marihuana. New York: Raven Press, 1976. pp.

383-392.

70. Co, B.T.; Goodwin, D.W.; Gado, M.; Mikhael, M.; and Hill, S.Y.

Absence of cerebral atrophy in chronic cannabis users. JAMA

237(12):1229-1230, 1977.

71. Kuehnle, J.; Mendelson, J.H.; Davis, D.R.; and New, P.F.J.

Computed tomographic examination of heavy marihuana smokers.

JAMA, 237(12):1231-1232, 1977.

72. Heath, R.G. Marihuana and delta-9-tetrahydrocannabinol: Acute

and chronic effects on brain function of monkevs. In: Braude,

M.C. and Szara, S. (eds.). Pharmacology of Marihuana. New

York: Raven Press, 1976. pp. 345-356.

73. Heath, R.G.; Fitzjarrell, A.T.; Garey, R.E.; and Myers, W.A.

Chronic marihuana smoking: Its effect on function and structure of the primate brain. In: Nahas, G.G. and Paton, W.D.M.

(eds.). Marihuana: Biological Effects. New York: Pergamon

Press, 1979. pp. 713-730.

74. Fink, M.; Volavka, J.; Panagiotopoulos, C.P.; and Stefanis, C.

Quantitative EEG studies of marihuana, delta-9-THC, and hashish

in man. In: Braude, M.C. and Szara, S. (eds.). Pharmacology

of Marihuana. New York: Raven Press, 1976. pp. 383-392.

75. Klonoff, H. and Low, M.D. Psychological and neurophysiological

effects of marihuana in man: An interaction model. In: Miller,

L.L. (ed.). Marihuana: Effects on Human Behavior. New York:

Academic Press, 1974. pp. 359-397.

76. Halikas, J.A. Marihuana use and psychiatric illness. In:

Miller, L.L. (ed.). Marihuana: Effects on Human Behavior.

New York: Academic Press, 1974. pp.265-302.

48
77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

Meyer, R.E. Psychiatric consequences of marihuana use: The

state of the evidence. In: Tinklenberg, J.R. (ed.). Marihuana and Health Hazards: Methodologic Issues in Current

Research. New York: Academic Press, 1975. pp. 133-152.

Naditch, M.P. Acute adverse reactions to psychoactive drugs,

drug usage and psychopathology. J Abnorm Psychol, 83(4):

394-403, 1974.

Naditch, M.P. Progress Report to NIDA, 1976.

Meyer, R.E. Psychiatric consequences of marihuana use: The

state of the evidence. In: Tinklenberg, J.R. (ed.). Marihuana and Health Hazards: Methodologic Issues in Current Research. New York: Academic Press, 1975. pp. 133-152.

Halikas, J.A. Marihuana use and psychiatric illness. In:

Miller, L.L. (ed.). Marihuana: Effects on Human Behavior.

New York: Academic Press, 1974. pp. 265-302.

Thacore, V.R. and Shukla, S.R.P. Cannabis psychosis and paranoid schizophrenia. Arch Gen Psych, 33(3):383-386, 1976.

Treffert, D.A. Marihuana use in schizophrenia: a clear hazard.

Amer J Psych, 135:10, October 10, 1978.

Abel, E.L. The relationship between cannabis and violence: a

review. Psychol Bull, 84:193-211, 1977.

Abruzzi, W. Drug-induced psychosis. Int J Addict, 121(l):

183-193, 1977.

Stanton, M.D., Mintz, J., and Franklin, R.M. Drug flashbacks,

1976.

Some additional findings. Int J Addict, 11(1):53-69,

Soueif, M.I. Chronic cannabis users: Further analysis of objective test results. Bull Narc, 27(4):1-26, 1975.

Soueif, M.I. Some determinants of psychological deficits associated with chronic cannabis consumption. Bull Narc, 28(l):

25-42, 1976.

Fletcher, J.M. and Satz, P. A methodological commentary on

the Egyptian study of chronic hashish use. Bull Narc, 29(2):

29-34, 1977.

Soueif, M.I. The Egyptian study of chronic cannabis use: a

reply to Fletcher and Satz. Bull Narc, 29(2):35-43, 1977.

Wig, N.N. and Varma, V.K. Patterns of long-term heavy cannabis

use in North India and its effects on cognitive functions: a

preliminary report. Drug and Alcohol Dependence, 2:211-219,

1977.

49
92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

Fried, P.A. Behavioral and electroencephalographic correlates

of the chronic use of marihuana - a review. Bull Narc, 29(2):

29-34, 1977.

Jones, R.T. and Benowitz, N. The 30-day trip--Clinical studies

of cannabis tolerance and dependence. In: Braude, M.C. and

Szara, S. (eds.). Pharmacology of Marihuana. New York:

Raven Press, 1976. pp. 627-642.

Karler, R. Toxicological and pharmacological effects (of

marihuana). In: Petersen, R.C. (ed.). NIDA Research Monograph 14, Marihuana Research Findings: 1976. Washington, D.C.:

U.S. Government Printing Office, Stock No. 017-024-00622-0,

1977. pp. 55-66.

Nowlan, R. and Cohen, S. Tolerance to marihuana: heart rate

and subjective "high." Clin Pharmacol Ther, 22(5):550-556,

1977.

Jones, R. Human effects. In: Petersen, R.C. (ed.). NIDA

Research Monograph 14, Marihuana Research Findings: 1976.

Washington, D.C.: U.S. Government Printing Office, Stock

No. 017-024-00622-0, 1977. pp. 128-178.

Jones, R.T. and Benowitz, N. The 30-day trip--Clinical studies

of cannabis tolerance and dependence. In: Braude, M.C. and

Szara, S. (eds.); Pharmacology of Marihuana. New York: Raven

Press, 1976. pp. 627-642.

Mendelson, J.H., Rossi, A.M., and Meyer, R.E. (eds.). The

Use of Marihuana, a Psychological and Physiological Inquiry.

New York: Plenum Press, 1974.

Regelson, W.; Butler, J.R.; Schultz, J.; Kirk, T.; Peck, L.;

Green, M.L.; and Zakis, O. Delta-9-THC as an effective antidepressant and appetite stimulating agent in advanced cancer

patients. In: Braude, M.C. and Szara, S. (eds.). Pharmacology of Marijuana. New York: Raven Press, 1976.

Sallan, S.E., Zinberg, N.E., and Frei, E. Antiemetic effect of

delta-9-THC in patients receiving cancer chemotherapy. New Eng

J Med 293:795-797, 1975.

Chang, A.E.; Shiling, D.J.; Stillman, R.C.; Goldberg, N.H.;

Seipp, C.A.; Barofsky, I.; Simmon, R.M.; and Rosenberg, S.A.

Evaluation of antiemetic effects of delta-9-THC during adjuvant chemotherapy in patients receiving high dose therapy.

Annals of Int Med, to be published, 1979.

Herman, T.S.; Einhorn, L.H.; Jones, S.E.; Nagy, C.; Chester,

A.B.; Dean, J.C.; Furnas, B.; Williams, S.D.; Leigh, S.A.;

Dorr, R.T.; and Moon, T.E. Superiority of nabilone over pro50
chlorperazine as an antiemetic in patients receiving cancer

chemotherapy. New Eng J Med, 300:1295-1297, 1979.

103. Ungerleider, J.T. and Andrysiak, T. Effect of inhaled delta9-THC in reduction of nausea and vomiting associated with

bone marrow transplant and chemotherapy. Personal communication, 1979.

104. Hepler, R.S. and Frank, I.M. Marihuana smoking and intraocular pressure. JAMA , 217:1392, 1971.

105. Crawford, W.J. and Merritt, J.C. Effects of tetrahydrocannabinol on arterial and intraocular hypertension. Int J Clin

Pharmacol & Biopharm, 17:191-196, 1979.

106. Tashkin, D.P.; Calverese, B.M.; Simmons, M.S.; and Shapiro,

B.J. Respiratory status of 74 habitual marijuana smokers.

Presented at the annual meeting of the American Thoracic Society, Boston, 1978.

107. Feeney, D.M., Spiker, M., and Weiss, G.K. Marihuana and epilepsy: Activation of symptoms by delta-9-THC. In: Cohen,

S. and Stillman, R.C. (eds.). The Therapeutic Potential of

Marijuana. New York: Plenum Press, 1976.

108. Petro, D.J. and Ellenberger, C. Marijuana (cannabis sativa)

as a therapeutic agent in patients with muscle spasms or

spasticity: Case reports and literature review. Presented

at the American Academy of Neurology Meeting, Chicago, 1979.

109. Smith, G.M. and Fogg, C.P. High school performance and behavior before and after initiation of illicit drug use. Fed Proc,

35(3):564, 1976.

110. Mello, N.K.; Mendelson, J.H.; Kuehnle, J.C.; and Sellers, M.L.

Human polydrug use: marijuana and alcohol. J Pharmacol Exp

Ther, 207:922-934, 1978.

111. Siemens, A.J. Effects of cannanis in combination with ethanol

and other drugs. In: Petersen, R.C. (ed.). Marijuana Research

Findings: 1980. Washington, D.C.: U.S. Government Printing

Office, in press.

112. Siemens, A.J.; Kalant, H.; Khanna, J.M.; Marshman, J.; and

Ho, G. Effect of cannabis on pentobarbital-induced sleeping

time and pentobarbital metabolism in the rat. Biochem Pharmacol, 23:477-488, 1974.

114. Phillips, R.N.; Neel, M.A.; Brown, D.J.; and Forney, R.B. Enhancement of caffeine or methamphetamine stimulation in mice

with aqueous-suspended delta-9-tetrahydrocannabinol. Pharmacologist, 13:297, 1971.

5 1
115. Sofia, R.D. and Knobloch, L.C. The interaction of delta-gtetrahydrocannabinol pretreatment with various sedativehypnotic drugs. Psychopharmacologia (Berl), 30:185-194, 1973.

116. Siemens, A.J. and Khanna, J.M. Acute metabolic interactions

between ethanol and cannabis. Alcoholism. Clin Exp Res, 1:

343-348, 1977.

117. Kalant, H. and LeBlanc, A.E. Effect of acute and chronic pretreatment with delta-1-tetrahydrocannabinol on motor impairment by ethanol in the rat. Can J Physiol Pharmacol, 52:

291-297, 1974.

118. Pryor, G.T.; Larsen, F.F.; Carr, J.D.; Braude, M.C. Interactions of delta-9-tetrahydrocannabinol with phenobarbital,

ethanol and chlordiazepoxide. Pharmacol Biochem Behav 7:

331-345, 1977.

119. Chesher, G.B.; Franks, H.M.; Hensley, V.R.; Hensley, W.J.;

Jackson, D.M.; Starmer, G.A.; and Teo, R.K.C. The interaction

of ethanol and delta-9-tetrahydrocannabinol in man. Effects

on perceptual, cognitive and motor functions. Med J Aust 2:

159-163, 1976.

120. Chesher, G.B.; Franks, H.M.; Jackson, D.M.; Starmer, G.A.;

and Teo, R.K.C. Ethanol and delta-9-tetrahydrocannabinol.

Interactive effects on human perceptual, cognitive and motor

functions. Med J Aust, 1:478-481, 1977.

121. Belgrave, B.E.; Bird, K.D.; Chesher, G.B.; Jackson, D.M.; Lubbe, K.E.; Starmer, G.A.; and Teo, R.K.C. The effect of (-)

trans-delta-9-tetrahydrocannabinol, alone and in combination

with ethanol, on human performance. Psychopharmacology, 62:

53-60, 1979.

122. Brown, B.; Adams, A.J.; Haegerstrom-Portnoy, G.; Jones, R.T.;

and Flom, M.C. Pupil size after use of marijuana and alcohol.

Am J Opthalmol, 83:350-354, 1977.

123. Sulkowski, A. and Vachon, L. Side effects of simultaneous

alcohol and marihuana use. Amer J Psych, 134(6):691-692,

1977.

124. Siemens, A.J., George, P., and McConnell, J.E. Influence of

non-psychoactive drugs on delta-9-tetrahydrocannabinol disposition. Fed Proc, 38:591, 1979.

125. Jones, R.T. and Stone, G.C. Psychological studies of marijuana

and alcohol in man. Psychopharmacologia (Berl), 18:108-117,

1970.

126. Benowitz, N.L. and Jones, R.T. Effects of delta-9-tetrahydrocannabinol on drug distribution and metabolism. Clin Pharmacol

Ther, 22:259-268, 1977.

52
127. Evans, M.A.; Harbison, R.D.; Brown, D.J.; and Forney, R.B.

Stimulant actions of delta-9-tetrahydrocannabinol in mice.

Psychopharmacology, 50:245-250, 1976.

128. Siemens, A.J., George, P., and McConnell, J.E. Influence

of non-psychoactive drugs on delta-9-tetrahydrocannabinol

disposition. Fed Proc, 38:591, 1979.

GPO 866 591

53
Human Effects: An Overview

Reese T. Jones, M.D.

INTRODUCTION

Each year it becomes more difficult to write a reasonably brief

review of the effects of cannabis on humans. Since the early

1960's cannabis research literature has grown rapidly. Increased

research activity is a consequence of both increased public

interest and increased support for cannabis research In 1951

the United Nations Division of Narcotic Drugs, Geneva, had

approximately 1,000 publications in its cannabis files. Their

bibliography issued in 1965 included 1,860 titles. In 1968 the

Addiction Research Foundation in Toronto, Canada, published a bibliography containing almost 2,000 publications (Kalant et al 1968).

The Foundation currently has about 5,000 articles on cannabis in

its archives. Over 1,000 are directly relevant to human health

consequences, many of the others have indirect implications. As

a result, a review such as this must be selective.

Because the review is selective, it is more apt to reflect the

author's biases. One of the interesting things about the cannabis research literature, particularly that dealing with human

effects, is that personal views and bias often seem to cloud the

judgment of otherwise reasonable scientists. A nonscientist may

well puzzle over what appear to be contradictory opinions and

results from research studies, particularly when the research is

reviewed by others. However, careful study of the original

literature often suggests relatively little disagreement over the

facts, that is, the findings and the data. The area of greatest

disagreement and controversy involves interpretation of these

findings and speculation about long range health consequences.

This is not unique to cannabis research. It occurs in many areas

of medicine.

This large and rapidly growing literature demonstrates that all

relevant information on all effects of cannabis will probably

never be available. Because of the nature of science, usually

facts change as experience accumulates. As more people use any

54
drug for more time, as analytic instruments become more sensitive, and as researchers ask more focused questions, new facts

appear and the significance of older facts is continually revised

(Edwards 1974). For those who believe that our knowledge of

cannabis effects is unreasonably modest, a review of progress or

lack of progress in determining the full spectrum of effects of

such drugs as tobacco or alcohol or of many therapeutic drugs

will give a sense of perspective. Such a review should induce

some humility and make one aware of the imperfections of the

scientific process in predicting the ultimate consequences of

widespread and relatively uncontrolled use of a drug.

For interested readers who desire an entree into the cannabis

scientific literature, a number of review articles, books, and

proceedings of meetings have been published in recent years which

cover in great detail aspects of cannabis (Harris, Dewey and

Razdan 1977; Harris 1978; Nahas 1979; Graham 1976; Fried 1977).

Some reviews discuss research findings in the context of making

political-social decisions (Edwards 1974). Others emphasize

adverse effects of cannabis (Nahas 1979), or legal versus health

issues (Brecher1975), or the chemistry of cannabis (Harris,

Dewey and Razdan 1977). The reports issued by two national

commissions (the Canadian and the United States) along with the

eight annual reports on "Marijuana and Health" that have been

presented to the U.S. Congress by the Secretary of Health, Education, and Welfare provide some historical perspective concerning

issues and earlier data.

THE DRUG: BOTANY AND CHEMISTRY

Cannabis sativa, the plant from which marijuana and hashish are

derived, has been cultivated for at least 5,000 years, spreading

originally from Central Asia to all temperate and tropical areas

of the world. As with any plant material, the pharmacology and

chemistry are necessarily more complicated than those of pure

drugs. Among plants, cannabis sativa is more variable than most,

due to its genetic plasticity. The plant has been cultivated for

fiber, oil, or its psychoactive resin. Fiber strains have lower

concentrations of the psychoactive substance delta-9-tetrahydrocannabinol(THC) than those cultivated for drug content. The

fiber type commonly contains less than .5 percent THC; the drug

type may contain as high as 4 or 5 percent THC. Thus, when

considering expected effects of using marijuana, immediate distinctions must be made regarding the plant's characteristics. Is

it a fiber strain or a drug-rich strain?

In addition to THC, the major source of psychoactivity, there are

over 400 other chemicals in this plant. About 60 of these are

called cannabinoids, found only in cannabis sativa. There is

increasing evidence that these other natural cannabinoids such as

cannabidiol (CBD), cannabinol (CBN), cannabickcmene and cannabicyclol, although they have little or no psychoactive effect, do

have biological activity.

55

323-754 0 80 5
THC is most concentrated in the upper small leaves, bracts, and

flowering tops of the plant. To make marijuana cigarettes, the

leaves and flowering tops are finely chopped, rolled in cigarette

paper, and smoked much like a deeply inhaled tobacco cigarette.

Although the size of a marijuana cigarette varies in the United

States, a 0.5 to 1 gram cigarette containing 1 to 2 percent THC

(5 to 20 mg) is fairly typical.

Hashish, the concentrated plant resin, may contain up to 12

percent THC. "Hash oil," which is easily extracted from cannabis

plant material using a variety of solvents, can contain up to 60

percent THC. The oil is customarily added to plant material to

enhance its pharmacologic potency, or it can be used in baked

gods or otherwise eaten.

Thus, when considering the possible human effects of cannabis,

distinctions must depend partially on THC content. The dose of

any drug is a very basic and necessary bit of information in

understanding its pharmacology and effects. With marijuana,

doses vary widely, based initially on the concentration of THC

in the plant. As will be discussed in other sections, this

beginning dose may be complexly modified so as to determine the

final ingested dose. Uncertainty as to dose is but one factor

that makes it difficult to answer questions and make predictions

regarding long term cannabis effects.

Cannabis preparations can also be eaten, or drunk in mixtures of

resin and water or milk, a form known as bhang in India. The

pharmacology of such dosage forms has not been researched. In

North America, cannabis is probably eaten most often in cookies

or other baked goods. No exact figures are available, however,

as to what percentage of users consume what form. Because THC is

virtually insoluble in water at room temperature, the fatty

substances in baked goods in bhang may be necessary for a

pharmacologically active dose.

The mix of cannabinoids in the plant is probably controlled more

by the type of seed than by soil or climatic conditions, but

after a few generations this my change. The success of illicit

growers in producing high THC content plant material in a variety

of locations illustrates the plasticity and adaptability of both

the plant and those who grow it.

Compared to many other psychoactive drugs, the chemistry of the

cannabinoids is complex (Harris, Dewey and Razdan 1977). The

amount of THC absorbed by an individual, of course, depends on

the method of administration. After absorption, because THC is

so fat soluble, it leaves the bloodstream very rapidly. Initial,

plasma THC concentrations of about 100 nanogram per milliliter

decrease with in an hour after smoking to 5 to 10 nanograms per

milliliter of blood, even though the obvious signs and symptoms

of intoxication last 2 or 3 hours. The THC in the blood is

rapidly changed to 11-hydroxy-THC, a metabolite that is also

psychoactive, and to at least 20 other known metabolic products

56
that are either relatively inactive or have unknown activity.

This metabolism mostly occurs in the liver (Lemberger and Rubin

1978).

Only in the last few years have there been reliable methods for

assaying the levels of THC and its metabolites in bodily fluids

and tissues (Willette 1976). Some earlier studies depended on

measurement of radioactivity in blood and tissues after the

administration of a radioactive dose of THC. The data from those

studies perhaps has been overinterpreted, and the more precise

metabolic studies are still underway. Species differences in

metabolism complicate our understanding of this important aspect

of a drug's pharmacology. Rats, for example, metabolize cannabinoids far more rapidly than do humans, thus partially accounting for the need to administer larger doses to rats to get what

seem to be human equivalents of drug effects.

THC leaves the blood rapidly, not only because it is metabolized

but also because of its efficient uptake by tissues. An understanding of the pharmacologic properties of THC is necessarily

complex because of its complicated pharmacokinetic behavior: that

is, its apparent entry into multiple body compartments, THC's

multiple metabolites, the formation of both active and inactive

metabolites, and the tendency for THC and metabolites to bind

tightly to proteins in the blood and to remain for long periods

of time in fatty tissues (Harris, Dewey and Razdan 1977). While

stored in body fats, THC and its metabolites are slowly released

back into the bloodstream. Thus, 5 days after a single injection

of THC, 20 percent of the THC remains stored, while 20 percent of

its metabolites remain in the blood. Complete elimination of a

single dose can take 30 days. After the passage of about 6

hours, the step that limits the rate of elimination of unchanged

THC in the blood is not its metabolism but rather the very slow

return to the plasma of THC that has been sequestered in the

tissues. As more sensitive analytic techniques are developed,

one might predict the measurement of even slower rates of plasma

decline of THC in humans. Measurable levels of THC in the blood

of chronic users can be detected for up to 6 days after their

last marijuana cigarette. The terminal half-life for THC, that

is, the time it takes for half of the amount to be eliminated

from the blood, was reported to be 56 hours in subjects who had

never had cannabis and 28 hours in those who had used it chronically (Lemberger et al. 1971a, 197lb). More recent studies using

slightly different analytic techniques suggest a terminal halflife of about 19 hours in frequent users (Hunt and Jones 1980).

Another possible source of the uncertainty as to half-life is a

confusion between THC and THC metabolites, since the metabolites

seem to have a much longer half-life -- in the range of 50 hours.

No matter what the precise clearance rate, there is general

agreement that THC and its metabolites are cleared from the body

more slowly than some other psychoactive drugs. Thus, there is

the theoretical possibility of accumulating biologically active

metabolites. Increased toxicity may result, like that of chronic

57
exposure, because the drug is sequestered in the body even when

it is used intermittently (for example, every few days).

In studies where repeated doses of THC or marijuana were given

(Hollister and Reaven 1974; Mendelson et al. 1974; Jones et al.

1976), there did not appear to be any significant accumulation of

drug or metabolites, at least as judged by behavioral and physiologic measures. This would suggest that the biological activity

of metabolites is not obvious, but it does not rule out the

possibility, of course. Biochemical studies have not yet been

done.

Given the slow clearance of cannabinoids, one might predict that

repeated administration of marijuana at intervals of less than 8

to 10 days should result in accumulation of THC or its metabolites in the tissues. This would be impossible to measure from

levels in the blood. One explanation for the lack of such human

data is that tissue biopsies are more difficult to obtain from

humans than from experimental animals. The body's storage capacity for THC and other cannabinoids is enormous. Thus, what is

termed by pharmacologists as a steady state level, where elimination is equal to absorption, would be reached only after about

4 weeks of daily or more frequent administration.

Elimination of the THC metabolites is largely through the feces.

Relatively little is eliminated in the urine. Both urinary and

fecal metabolites, of course, can be detected for weeks, and

there is some recycling through the enterohepatic circulation.

The very strong protein binding of THC in the blood and the low

level of drug free in the plasma means that the uptake by the

tissues of THC and metabolites will be limited mainly by blood

flow. Thus, it is not surprising that tissues with high blood

flow (for example, lung, liver, kidney, and spleen) take up the

drug so quickly. Testes and ovaries also take up the drug

rapidly. However, one must be careful not to conclude that

because an organ takes up the cannabinoids quickly they necessarily have any action there. Hair follicles, for example, have

considerable affinity. Despite some understanding of the halflife of THC and metabolites in the blood, the lifetime in the

human brain and other relevant tissues is unknown. Regional

levels of THC and THC metabolites may be far more important in

terms of predicting toxicity than blood levels are. Accumulation

of THC itself in human body fat has not been demonstrated.

Drugs that are slowly cleared are not necessarily inherently more

toxic than drugs that are rapidly cleared. However, slow clearance may make for cumulative toxicity (assuming that some of the

metabolites have biological activity). Many useful therapeutic

drugs are cleared slowly from the body; for example, many benzodiazepines. Therapeutic drugs having this characteristic sometimes cause problems when their dosage schedules are not properly

regulated. Thus, slow elimination and the possibility of drug

accumulation become even more significant with a drug such as

58
marijuana which is administered in doses and on a dosage schedule

controlled by the individual user and by custom rather than as

recommended and monitored by a physician.

ASSAY TECHNIQUES

Much effort has gone into developing practical assay techniques

to determine cannabinoid and cannabinoid metabolite levels in

humans (Willette 1976). Such techniques are needed not only for

research purposes, but also for law enforcement and medical

diagnostic purposes. The very low level of THC in the blood and

the even lower levels of its numerous metabolites makes quantifying and identifying cannabinoids in bodily fluids a far more

complicated undertaking, compared, for example, to assessing

alcohol blood levels. The only completely accurate and sensitive

method is mass spectrometry combined with either high pressure

gas or liquid chromatography. While these are superb techniques

in the research laboratory, they are too slow and costly for more

general use. Although not fully developed because of the problem

of crossreacting cannabinoids, immunoassay is also a promising

technique, particularly for determining total cannabinoid levels,

THC, or the 11-hydroxy metabolites, which seem to be the most

psychoactive ones identified thus far.

Although the pharmacokinetics of THC are becoming better understood, simple techniques for identifying THC levels in the body

and predicting driving impairment or other abnormal behavior are

still far from the stage of any practical application. There are

theoretical reasons why such a technique will never be practical,

at least in terms of using blood levels to predict driving

impairment or abnormal behavior. For example, the very rapid

disappearance of THC from the bloodstream is severely limiting.

That is, the levels of psychoactive drug one is really interested

in are not blood levels but rather brain or other tissue levels

not easily accessible to a convenient assay. This is quite

different from alcohol, in which blood levels do reflect brain

levels. Also, the very low levels that one must measure, the low

levels eliminated in urine, and the prolonged period of elimination all make it difficult to correlate a given level of THC

metabolites measured in the urine with specific behavioral or

physiological abnormalities. These analytic and theoretical

complexities have been extensively discussed in a recent monograph (Willette 1976).

DOSE CONSIDERATIONS

The ease with which the ingested dose of THC in smoked marijuana

can be controlled is one of cannabis' most attractive attributes

to the user. It is also a complication in health-related

research. The very wide marijuana potency range has already been

emphasized. Because of varied smoking techniques, the range of

actual ingested doses per experience or per unit time is equally

broad. In free access studies, the amount that humans will

voluntarily consume is enormous. While in general surveys one or

59
two marijuana cigarettes a week is a common dose, in free access

chronic studies 20 or more marijuana cigarettes per day may be

consumed (Babor et al. 1975). Volunteers in the free access

studies as well as "street users" may use upwards of 200 micrograms per kilogram per day.

To accurately predict or to measure long term health consequences

of drug ingestion, it is necessary to identify populations using

known dosage levels. Such data are difficult, if not impossible,

to obtain from large populations of marijuana users. Similar

problems are encountered in detemining the health consequences

of tobacco use. Even in that situation, with the advantage of

commercially produced, relatively standard cigarettes, there is

considerable dosage variability, depending on brand, amount of

inhalation, puff frequency, etc.

In North America, smoking appears to be the most common way to

consume marijuana. A little less than half the THC in a marijuana cigarette is delivered to the lungs in the smoke (Lemberger

and Rubin 1976). Lung absorption and transport to the brain are

quite rapid, with THC probably reaching the brain within about 14

seconds of inhalation. This very efficient and very rapid

delivery of a smoked drug to the brain may be important in determining the positive reinforcing characteristics of marijuana and

other smoked material such as tobacco. For many marijuana users,

the rapid onset of intoxication makes smoking it far more attractive than consuming it orally. THC has been estimated to be 3 to

5 times more potent when inhaled than when ingested. This also

undoubtedly makes smoking the preferred route. Smoking is even

more efficient than intravenous injections for efficient delivery

of a drug to the brain. To avoid confusion when interpreting

scientific data from various studies, some of which involve oral

administration, some smoking, and some intravenous administration

of THC or other cannabinoids, one must keep these dose efficiency

differences in mind.

A marijuana cigarette containing 2 percent THC would deliver

slightly less than 10 milligrams of THC to the lungs where must

is probably absorbed. But to reach an equivalent state of

intoxication when taken orally, from 30 to 50 milligrams of THC

would have to be consumed. The slower absorption via the oral

route and the resulting slower onset of intoxication make comparisons imprecise, since the time course of the intoxication is so

different. As the user is just beginning to become intoxicated

from an oral dose, a person who simultaneously smoked it instead

is becoming less intoxicated.

Although used in laboratory experiments, the intravenous route of

THC administration is rarely used illicitly. The few case

reports of intravenously administered marijuana describe injections of various crude plant extracts. The results reflect a

generalized toxicity from the foreign material, bacteria, etc.,

rather than THC effects as such. When given intravenously in 1

or 2 milligram intravenous doses, THC produces effects similar to

60
smoking marijuana, containing about 20 milligram of THC. Should

intravenous THC become available on the illicit market, one might

anticipate more acute behavioral and physical toxicity because of

the great potency when administered by that route.

The actual dose delivered with each puff on a marijuana cigarette

is partially determined by the acummulation of THC in the "butt"

or roach as the cigarette is smoked down. Thus, in a group of

marijuana smokers sharing a cigarette, the last person taking a

puff on the joint receives considerably more THC than does the

first. The relatively low incidence of intoxication levels

greater than the user anticipates suggests that reasonably efficient titration of level of intoxication is common, probably

because of the extremely short time between a puff and its

psychological and physiological consequences. The experience

from laboratory experiments suggests that some adverse psychological reactions are more often the result of encountering

marijuana stronger than previously experienced than of the

presence of adulterants (Jones1973). Oral ingestion poses more

dose control problem because of the user's inability to control

the level of intoxication after the dose has been ingested.

In recent years them have been attempts to determine doses of

alcohol that could be used with acceptable levels of toxicity.

Although open to some dispute, such levels can be specified.

While that would be a reasonable goal for cannabis as well (that

is, the specification of a certain dose of THC per unit time

resulting in certain expected effects and not resulting in toxicity), at present there is insufficient scientific data to allow

such a specification or prediction.

Even the precise specification of what is a high, moderate, or

low dose, or what heavy frequent use or intermittent use is, has

not been well established in North American studies. Most laboratory investigators use marijuana cigarettes containing from 10

to 20 milligrams of THC. This is determined as much by the

availability of standardized marijuana cigarettes from the

National Institute on Drug Abuse as on any more rational basis.

Very little systematic data has been published from well-defined

marijuana user groups that would help one decide that 20 milligram is indeed a "large" and 10 milligrams a "modest" dose.

Things are even more unsettled when it comes to specifying oral

doses. A tremendous range of oral doses has been administered in

experimental studies, with some investigators routinely giving 50

milligram oral doses with the implication that those are "realistic." Other studies are often referred to as "high dose

studies," although doses of only 10 to 30 milligrams were administered orally.

One can conclude from the literature that approximately a 30

milligram oral dose is needed to produce easily measurable

physiologic and subjective effects. Intravenously, most investigators have administered 1 to about 3 milligram per 70 kilograms of body weight, though no systematic dose effect studies

6 1
have been done with the intravenous route.

The problem of specifying dose is compounded by the fact that THC

disappears from the bloodstream rapidly and is also rapidly

metabolized. Thus, one might expect that the effects from a

given dose would last for only a short time unless the metabolites themselves are active. In most human laboratory studies

this, in fact, seem to be the case. Most measurable effects

tend to disappear 3 to 6 hours after a dose of marijuana, or THC

(Harris 1978). Since in the usual social situation repeated

doses are used, the issue arises how often a repeated dose should

be given in the laboratory to mimic the social setting. A best

guess based on incomplete data would suggest that repeat dosing

every 3 to 4 hours is probably realistic. Thus, whatever the

reinforcing attributes of marijuana, the dose needs to be repeated every 3 to 4 hours to produce acceptable levels of continued

intoxication. Of course, most users dose themselves with cannabis less often. Compared to our knowledge of alcohol, tobacco,

or almost any therapeutic drug, we are still woefully ignorant of

cannabis dosage considerations.

GENERAL PSYCHOLOGICAL EFFECTS IN HUMANS

Although this review emphasizes recent research findings, a book

first published in 1845 by Moreau still provides one of the more

vivid and detailed descriptions of the psychological effects of

cannabis (Moreau 1973). More recent research activity really has

extended the descriptions in that book and, to some extent, only

adds a better understanding of the dose-effect relationships

reflected in Moreau's descriptions. In that early study Moreau

considered the need for dose differences and for control groups,

as well as to take into account individual suggestibility and

setting in greater detail than in some contemporary psychopharmacologic studies. In the book, Hashish and Mental Illness, he

wrote, "By its mode of action on the mental faculties, hashish

gives everyone who submits to its strange influence the power of

studying on himself, the moral disturbances of mental illness, or

at least the principal intellectual disorders from which all

kinds of mental disturbances originate." Moreau deliberately

used cannabis to produce psychotic or psychotic-like symptoms in

normal people. He was probably orally administering cannabis

doses containing 50 to 100 milligrams of THC, while most, of our

current North American users are describing the effects of only 1

to 10 milligrams.

Moreau described dose-related phases of cannabis intoxication.

The initial feeling of "happiness" or euphoria was mixed with

excitement and a dissociation of ideas. This was quickly

followed by an altered sense of time and space relationships, a

subjective enhancement of senses, particularly hearing, and, with

higher doses, the appearance of delusions, labile emotions,

particularly anxiety, decreased impulse control and, at the

highest doses, profound sensory illusions and hallucinations.

62
Many current users of marijuana in the United States may argue

that the sense of well-being or euphoria, the relaxation, drowsiness, mild perceptual changes and altered time sense that follow

the smoking of a marijuana cigarette are not what Moreau was

describing. One explanation for these differences is the dose

taken. The brief and relatively mild "high" that follows the

smoking of 10 to 20 milligrams of THC can be altered by many

nonpharmacological variables. Prior drug experience, expectations, the setting, and other enviromental factors, as well as

user's personality can all shape the experience both qualitatively and quantitatively. Interpretation of many physiologic

findings is complicated by the initial and relatively brief

period of stimulation, autonomic arousal and sympathetic activity

followed by a longer period of 2 to 3 hours of a drowsy, relaxed,

often dream-like state with decreased sympathetic activity. A

similar pattern occurs in or out of the laboratory, thus supporting the validity of much of the laboratory data.

Because of exposure to a wide range of plant material and because

of the cultural labeling (almost like advertising) of much of the

marijuana experience, many marijuana users are particularly

subject to the effects of nonpharmacologic variables that alter

the intoxication. A number of studies suggest that experienced

marijuana users are more subject to "placebo reactions"; that is,

a degree of intoxication disproportionate to the THC content of

the material, particularly if they are exposed to low potency

marijuana. This is presumably a result of experience and practice at recognizing minimal physiologic cues together with the

smell, taste and other sensations associated with smoking a

marijuana cigarette (Jones 1971).

A misinterpretation of this finding may be the simplest explanation of so-called "reverse tolerance." Reverse tolerance refers

to an apparently increased sensitivity to cannabis in the experienced user and a lack of sensitivity in the novice. Although it

is conceivable that metabolic considerations cause this, a more

parsimonious explanation is that with very mild threshold levels

of intoxication, practice, recognition and set influence the

subjective intoxication more than at higher levels. Given

sufficiently potent plant material, it is well established that

even the first-time novice smoker will experience all the characteristics of the expected marijuana intoxication, although in

some instances the interpretation of the pleasantness of that

state may be altered.

PSYCHOLOGICAL EFFECTS

The most striking acute effects of cannabis are alterations in

cognition, thinking, sensation and psychomotor functions. Many

of these are reviewed in more detail elsewhere in this volume.

These psychological effects are more predictable, and, depending

on dose, of greater magnitude than most of the physiologic

effects that will be discussed later.

63
Although users report subjective feelings of enhanced sensory

acuity, sensitivity, and interpersonal closeness, in fact, as

measured in the laboratory and observed in the real world,

generally there are either no effects or an impairment of performance, sensation, and behavior. For the most part, the degree

of impairment is dose-related. In studies where psychological

effects were not readily measured, generally low doses of the

drug or subjects with high levels of tolerance appear to have

beenused. When large doses of marijuana in any dosage form are

combined with testing at the time of peak intoxication, it is

possible to show dramatic alterations very reliably.

PHYSIOLOGICAL EFFECTS

As with psychological effects, observed physiological effects

depend on dose and all the other factors already discussed. Some

years ago it was not uncommon for reviewers to comment on the

preponderance of psychological effects and the relative paucity

of physiologic effects from a given dose of cannabis. This, of

course, is only true if one is talking about relatively low doses

of THC. At moderate to high doses, many physiologic systems are

altered. Whether the alterations indicate adverse or potentially

dangerous effects is a far more complicated question to answer.

As with many, if not all, drugs, acute effects (that is, effects

following a single dose) are not necessarily similar to chronic

effects (that is, effects following repeated use, sometimes for

many years). It is around "chronic effects" that marijuana

"experts" most disagree, with resulting confusion to the nonspecialist.

If proper attention is paid to dose, setting, route of administration, etc., there is fair consistency from laboratory to

laboratory as to many physiologic effects. It is the long-term

biological significance of many of these effects that is debated.

Given very sensitive, sophisticated and refined test procedures

and instruments, a research scientist is now able to detect very

subtle and formerly unmeasurable effects on many bodily systems.

Thus, the most difficult task in judging cannabis research findings is to decide whether a measurable effect has biological or

practical health significance. Such decisions are particularly a

problem for those in social policymaking or public health positions (Edwards 1974). In addition, incompletely understood

factors such as past history of cannabis exposure, variations in

genetic background of the user, current or prior use of other

drugs, and metabolic differences, all partially determine the

magnitude and spectrum of physiologic drug effects.

Even in therapeutic drug administration, where careful monitoring

of effects is possible, surprising, unpredicted and not well

understood effects sometimes develop only after years of exposure.

For example, consider the cardiovascular effects associated with

tobacco stoking or consider the occurrence of vaginal carcinoma

in the offspring of mothers treated with diethylstilbestrol,

64
where a 20-year lag may pass between exposure to the drug and the

disease, or consider the appearance of increased carcinoma of the

breast in women treated with reserpine, a cardiovascular drug

used for treating hypertension (AMA article current).

What follows is not an exhaustive listing of all effects. Some

are mentioned because of their obvious health implications.

Others are mentioned just because they are interesting. Many

other effects of cannabis are disscused in more detail in a

number of review articles (Stimmel 1979; Harris, Dewey and

Razdan 1977; Fried 1977).

Cardiovascular Effects

Cardiovascular effects are among those most easily measured

(Stimel 1979). Increased heart rate proportional to dose of THC

is one of the more reliable consequences of ingesting marijuana.

During the early phase of cannabis intoxication, heart rate can

increase up to 160 beats per minute or more, along with decreases

in standing (that is, orthostatic) blood pressure. Myocardial

contractility is probably unaffected, though the myocardial

oxygen demand, coupled with decreased myocardial oxygen delivery,

produces problems in people with coronary artery disease. These

problems range from a decrease in exercise performance before the

onset of angina to the theoretical possibility of myocardial

infarction in predisposed individuals.

Even with easily measured cardiovascular phenomena, there are

inconsistencies in reports of various research groups; for

example, regarding blood pressure. These can generally be reconciled by a careful reading of the reports, as they usually

reflect differing experimental procedures, doses, techniques of

measurement, etc. For example, blood pressure has been reported

to be increased, decreased, or unchanged after the smoking of

marijuana. More often than not, if the subject was in a standing

position when blood pressure was measured, it was decreased; in a

sitting position, it was unchanged; and in a prone or supine

position, slightly increased. Lack of attention to things like

body position can needlessly confuse the uninitiated reader of

such research reports.

To predict chronic from acute effects is problematic. The long

term administration of oral THC, for example, can result in a

decrease in heart rate and a persistent mild lowering of blood

pressure, with the initial orthostatic hypotension disappearing,

probably became of a marked expansion in plasma volume (Benowitz

and Jones 1975). While these changes in themselves may be of no

particular biological or functional significance, after years of

drug exposure they could be associated with lasting health consequences. The lessons learned from chronic tobacco use are worth

considering. It was only after many years of use by millions of

people that cardiovascular disease associated with tobacco use

was recognized. Even now the exact mechanisms are scientifically

debatable. Assuming that smoking cannabis has some similarity to

6 5
smoking tobacco (in fact, THC seems to have far more profound

effects on the cardiovascular system than does nicotine), one may

assume that long term chronic effects will be different from the

more commonly reported and easily studied acute ones. The many

problems in measurement of the results of chronic exposure to

marijuana are discussed in a later section.

Respiratory and Pulmonary Effects

Like tobacco, marijuana is commonly smoked. It would be surprising if there were not some effects from repeated inhaling of

combustion products. When tobacco is smoked, approximately 70

percent or more of the total particulate matter in the smoke is

retained in the lung (Huber et al. 1976). There is reason to

assume that with marijuana, because of deeper inhalation, a still

greater percentage is retained. Smoke is a mixture of tiny

particles suspended in gas, mostly carbon monoxide. These solid

particles carbine to form a residue called "tar." Cannabis

produces more tar than an equivalent weight of tobacco and is

smoked in a way that would facilitate tar deposition in the lung.

Alveolar macrophages that play a role in clearing debris from the

lung appear to have their bacteria-inactivating activity impaired

when exposed cannabis smoke. Early reports that cannabis

improved lung functionby increasing the diameter of air passages

received much publicity. Subsequent data indicate that chronic

use has different effects from those found in heavy cigarette

smokers. Significant worsening of pulmonary function was evident

after only 6 to 8 weeks of smoking a few marijuana cigarettes

daily in an experimental situation (Tashkin et al. 1976a, 1976b).

A similar pattern of change was noted in an earlier study where

volunteers smoked cannabis while living on a research ward (Mendelson et al. 1974). Chronic exposure to marijuana smoke appears

to impair many of the lung's defense mechanisms and to produce

cellular changes in lung tissue that may be precancerous (Leuchtenberger et al. 1976). This is one area of research in which

the test tube and laboratory data are consistent with clinical

experience. The cellular changes noted in laboratory studies and

the changes in laboratory pulmonary function tests are consistent

with clinical observations that cannabis users often have laryngitis, pharyngitis, bronchitis, asthma-like conditions, cough,

hoarseness, and dry throat after periods of frequent use.

Although the acute administration of THC or marijuana produces

bronchodilatation (that is, an increase in airway diameter),

chronic use produces obstructive airway disease of the sort that

is often seen in cigarette smokers, Cellular changes often

termed precancerous have been found in the bronchial biopsies of

heavy smokers of hashish and tobacco in their early twenties.

Such changes are ordinarily seen in tobacco smokers only after

the age of 40. The pattern suggests either a potentiation of

tobacco-related changes with marijuana smoking or a result of

increased tar inhalation from combined use (Tennant et al. 1979).

66
The biological and the health significance of similar tobaccorelated cellular and functional changes was in dispute for some

years and still remains a topic of dispute by some scientists. A

long period of observation of a sizeable group of chronic cannabis smokers will be needed to establish the health implications

of such pulmonary changes. In North America most cannabis users

do not have the high level of exposure of cigarette smokers; thus

making for a longer period of incubation before any pathology

becomes clinically apparent. The increase in cannabis smoking

by very young people might provide the necessary period of years

of exposure. The limitations of interpreting the absence of

serious pulmonary disease in the few chronic studies undertaken

thus far will be discussed later.

NEUROLOGICAL EFFECTS

As with any psychoactive drug, there is no question that cannabis

produces neurological effects. What are called psychoactive

effects are, of course, neurologic effects as well. Cannabis

clearly alters brain function. The perceptual, cognitive, and

mood changes, the memory alteration, the alterations in time

sense, alterations in behavior, and other effects sought by the

user of cannabis and predictably apart of the acute intoxication

are presumably a result of changes in nervous system activity.

Some might even argue that such altered, usually impaired, brain

function is prima facie evidence of temporary brain and nervous

system damage, at least during the few hours of acute intoxication after a dose of marijuana. As with drugs deliberately

ingested to produce intoxication, that viewpoint is not usually

shared by their users. The more important health issue is

whether the neurological alterations last only for the few hours

during the period of acute intoxication or whether they persist

or become cumulative over longer periods of time. The scientific

data on this issue is not consistent.

There are various techniques for measuring neurological effects.

Subjective and behavioral changes are perhaps the most sensitive.

Electrical, biochemical, radiographic or cellular anatomic alterations are other approaches. All of these have been used to

study marijuana-related changes. Some techniques can only be

used in animal or test tube studies and their human implications

judged only by inference.

Acute cannabis intoxication includes not only the pleasant state

of relaxation, euphoria, and sought-after sensory alterations,

but also impairs judgments of distance and time, memory for

recent events, ability to learn new information, and physical

coordination. At slightly higher doses the acute intoxication

includes tremor, transient muscular rigidity, or myoclonic muscle

activity. The subjective feelings of muscular "weakness" or

stiffness can be measured objectively. Low doses produce no

changes in tendon reflexes, but high doses cause hyperexcitability of knee jerks with clonus (Tassinari et al. 1976). At

even higher doses a full blown acute brain syndrome is possible.

67
As is often the case with psychoactive drugs, the scalp-recorded

EEG; changes at ordinarily used doses are minimal and brief

(Klonoff et al. 1973). They tend to resemble those associated with

drowsiness and relaxation. Modest increases in alpha activity

and slowing of alpha frequency are the most commonly observed

changes. Cannabis has no unique qualities as measured by scalp

EEGs. There are no published reports of scalp EEG; changes that

would indicate any specific gross central nervous system abnormalities following the smoking of cannabis. The occasional

reports of convulsions associated with marijuana use have not

been corroborated by the EEG changes incontrolled laboratory

studies, though, of course, the latter studies usually involve

lower doses given to healthy volunteers not prone to seizures.

Although scalp EEG changes are minimal, marked alterations in

electrical activity have been recorded from electrodes implanted

in deep brain structures, particularly in the septal and amygdala

areas (Heath et al. 1979). These areas are involved in regulation of emotion and memory. The functional significance of such

acute changes is not entirely understood, though similar electrical activity has been noted in some patients with schizophrenia or epilepsy. Normal people have not had electrodes

implanted in such areas, of course. Similar EEG changes are seen

in the brains of monkeys exposed to marijuana smoke or given THC

intravenously. Exposure to the smoke from the equivalent of

about 3 marijuana cigarettes per day produced the electrical

changes after 2 to 3 months of daily administration. After 3 to

6 months exposure, the electrical abnormalities persisted for up

to 8 months. Anatomic changes at the brain synapses were apparent in electron microscopic studies, suggesting long-lasting

changes related to the THC exposure.

Perhaps one of the more important observations from these studies

was that throughout this experiment scalp EEGs of the monkeys

were not altered, despite the changes in deeper brain structures.

This indicates that the measurementtechniques used in human

subjects may sometimes miss changes that would be made apparent

by the use of more sensitive measurement techniques. Although

the behavioral significance of these lasting neurological changes

is yet to be determined (Jones 1975), they provide clear-cut

evidence of THC-induced alterations in brain function and structure that could plausibly occur in human users.

Sleep EEG; recordings are often more sensitive indicators of drug

effects than are EEG recorded in a waking state. Loss of rapid

eye movement sleep appears to be a predictable effect of cannabis (Feinberg et al. 1976). Total sleep time increases, although

tolerance develops to this effect. Unlike the situation with

other drugs, stage four or slow wave sleep is relatively unaffected. When cannabis use is stopped after a period of prolonged

administration, rapid eye movement sleep stages and eye movements

show a rebound above baseline measures like that seen with a

variety of sedative hypnotic drugs. In contrast to the relatively small changes in waking EEGs, the sleep EEG changes are

68
fairly large.

A number of studies of cannabis or THC effects on sensory evoked

potentials recorded from scalp electrodes have demonstrated

changes consistent with alterations in brain function (Herning

et al. 1979). However, the pattern of change varies with dose

and measurement technique, and between laboratories. The biological or functional significance of these alterations remains

obscure. Although there was some hope that these evoked potential techniques might provide direct measures of attention

deployment or motivation, it appears that, like so many neurophysiologic measures, their interpretation is far more complicated than was originally assumed (Jones 1975).

An earlier study done in England, which reported enlarged brain

ventricles consistent with the presence of cerebral atrophy in a

group of ten young marijuana users, stands alone as indicating

anatanic changes in human marijuana users (Campbell et al. 1971);

Recent studies in this country, in Missouri and Boston, examined

equally small groups of marijuana users aud nonusers for evidence

of brain atrophy using computerized transaxial tomography (CAT),

a relatively new brain scanning technique for visualizing brain

anatomy (Co et al. 1977; Kuehnle et al. 1977). These studies

found no evidence for brain anatomic changes in the marijuanasmoking groups. Such findings are reassuring in that they demonstrate the possibility of regularly consuming fairly large

amounts of marijuana without obvious evidence of cerebral atrophy.

However, the results demonstrate one of the recurring problem in

interpreting many marijuana effects. The earlier Campbell study

that reported changes consistent with brain atrophy used a different measurement technique, pneumoencephalography, rather than

tomography. An important difference in the earlier study was

that the population of marijuana users were mostly sick people,

neurologically impaired or with neurological symptoms. In the

more recent studies finding no evidence of brain damage, the

subjects were preselected as healthy, normal marijuana users. A

populationof abnormal, neurologically impaired, marijuana users

might show evidence of brain abnormality while a group of healthy

and normal users would not.

It is possible to demonstrate organic toxicity from alcohol or

not to demonstrate it, depending on the sample of alcohol users.

The sampling or selection process is a general problem that

confuses simple interpretation of many studies of chronic cannabis users. Depending on the sampling techniques, the populations

of research subjects who finally appear in the laboratory may

represent selected subgroups who are relatively more resistant or

less resistant to marijuana-induced changes (assuming there are

such changes of course). None of the three X-ray studies just

mentioned either confirms or totally rules out the possibility

that subtle changes in brain function may follow marijuana smoking. With many psychoactive drugs it is quite possible to have

severe impairment of brain function that is not apparent on gross

69
examination, microscopic examination, or by any physical testing

of brain tissue.

One indirect but sensitive measure of neurological alterations is

change in mental and psychomotor perfomance. In previous

reviews and in other sections of this monograph the many studies

reporting impaired functioning on cognitive and performance tasks

while intoxicated have been discussed. The magnitude and character of these alterations are generally dose-related. Interactions between dose and task difficulty, practice, motivation,

and setting are as complex with cannabis as with any other

psychoactive drug. Performance on complex taks requiring vigilance and optimal nervous system functioning, such as driving,

flying, instrument operation, etc., are altered, whether in a

laboratory setting or outside. Since survey data indicates more

cannabis users are now driving while cannabis intoxicated than

was true a few years ago, this drug-induced impairment assumes

great public health significance. The great weight of evidence

is that cannabis does have detrimental effects on such complex

psychomotor-cognitive performance.

A major area of controversy among scientists is the issue of

impaired neurological functioning beyond the period of acute

intoxication. Many survey and laboratory studies comparing user

and nonuser populations have reported no differences in cognitive, intellectual, or perceptual function between these two

groups (Grant et al. 1973). Such results are reassuring only to

the extent that they demonstrate that impairments are not inevitable. In science, particularly when dealing with drug effects,

it is impossible to prove the absence of something or to prove

that something will not happen. Many of the studies reporting no

neurological differences between users and nonusers have compared

very selected people using 1, 2, or 3 marijuana cigarettes per

week to those using none (Grant et al. l973). It may well be

that lasting impairment will be evident only at a greater dosage

level or that the marijuana use interacts with some other unrecognized factor to produce lasting effects. The impairment will

thus be missed in such limited studies. On the other hand, when

deleterious, possibly marijuana-related, effects on function have

been noted in groups of cannabis users, it is very difficult to

determine whether the cannabis use caused the impairment, or was

simply associated with it, or followed it. For example, in one

of the few longitudinal studies of college students examining the

relationship between cannabis use and psychosocial adaptation and

academic performance (Brill and Christy 1974), the users and

nonusers did not differ on grade point average or educational

achievement, but the marijuana users dropped out of college more

often and seemed to have more difficulty in deciding on career

goals. Fewer of them planned to seek advanced academic degrees.

They considered themselves to have poorer academic adjustment.

It is impossible to decide whether these attributes were simply

associated with marijuana use or caused by it. In fact, some

would argue that such differences do not reflect impairments nor

should they be considered harmful.

7 0
Studies done oveseas comparing chronic cannabis users with

nonusers not infrequently report slower psychomotor performance,

poorer perceptual motor coordination and memory in the user group

(Soueif 1975). Other studies comparing cannabis users and nonusers in Jamaica (Rubin and Comitas 1975), Costa Rica (Coggins

et al. 1976), and Greece (Stefanis et al. 1976) concluded there

were no long-lasting neuropsychological impairments. Sampling

problems and difficulties in interpreting psychological test

performance in illiterate, rural, older, and less intelligent

subjects make any simple interpretation of the findings from

abroad inherently controverisal. It is an area where the total

weight of evidence must be considered as well as such things as

scientific design, control groups, etc. If one considers neurochemical data from test tubes, animal data, clinical case reports,

survey data, controlled laboratory data, and semicontrolled field

studies, the weight of the evidence so far is that lasting neuropsychological impairments are possibly but not inevitably associated with some undetermined level of heavy, prolonged cannabis

use. However, the many factor that would determine the appearance of clinically evident cannabis-induced neuropsychological

changes in any given user are so complex as to make any simple

pronouncement of risk almost meaningless.

CANNABIS AND PSYCHOPATHOLOGY

The evidence for cannabis as a specific cause of psychoses or

other mental illness is confusing. A variety of psychiatric

disorders are associated with cannabis use, but whether the

psychopathology preceded use, is a consequence of it or coincident with it is still open to question and likely to remain so,

as it has for LSD, amphetamine, PCP, alcohol, and many other

drugs. Past reviews have pointed out many of the methodological

and theoretical shortcomings of published work and no definitive

new studies have been done (jones 1975; Meyer 1975). Use of

cannabis, like so many other psychoactive drugs, probably can

precede, result from, or occur coincidentally with psychopathology, depending on the person, the culture, and many other

variables.

The acute anxiety reaction that may occur during marijuana intoxication remains the most common adverse psychological reaction

(Halikas 1974; Meyer 1975). This reaction, which usually starts

off with an exaggeration of normal cannabis effects, can range

from mild anxiety and restlessness to panic with paranoid delusions, to a full-blown acute toxic psychosis with loss of contact

with reality, delusions, hallucinations, and agitated and inappropriate behavior. The reaction is more likely to occur in

inexperienced users or in the user who unknowingly consumes more

potent cannabis material than is anticipated. Preexisting psychological difficulties may also contribute. The symptoms usually

diminish over a few hours and are somewhat alleviated by reassurance, a quiet environment, and generally supportive atmosphere.

71
These acute reactions seem to occur most frequently in individuals who are under stress, depressed, or have a history of

schizophrenia. The relationship to schizophrenia is becoming

clearer as more case reports are published (Treffert 1978;

Thacore and Shukla 1976). Patients with schizophrenia, or perhaps patients who have the genotype for schizophrenia, may be

more prone to develop schizophrenic-like psychoses after consuming only modest amounts of cannabis. The clinical signs and

symptoms resemble schizophrenia. The usual treatments for

schizophrenia appear to be effective, and thus it is not surprising that the literature reflects some uncertainty as to whether

case reports are really discussing schizophrenia or a cannabisinduced psychosis. Since schizophrenia is not a rare disease, if

there is a special vulnerability of such people for adverse

cannabis psychological reactions, this has obvious implications.

The descriptions of long-lasting cannabis psychosis are drawn

1argely from Middle Eastern and Asian cultures where cannabis use

is more frequent and at higher dosage levels than is typical for

the United States. The cannabis psychosis often lasts for 1 to 6

weeks or longer. Some authors distinguish its symptoms from

those of paranoid schizophrenia. The patient said to be suffering from cannabis psychosis shows more bizarre behavior, more

violence and panic, and a relative absence of schizophrenic

thought disorder. Such patients tend to relapse when cannabis

use is resumed. As is often the case with clinical reports,

studies describing cannabis psychosis rarely present data in a

way that would withstand rigorous scientific scrutiny. A number

of reports finding no evidence of links between cannabis use and

psychoses unfortunately have the same methodologic problem as

studies claiming drug-related associations, making it very difficult to draw unequivocal conclusions.

The studies of chronic marijuana users in Jamaica, Greece, and

Costa Rica failed to document the existence of such psychoses.

However, these studies used very small, select samples; in their

selection process they could have missed the relatively rare

occurence of such a psychosis. In addition, these retrospective

studies used recruiting procedures that would tend to screen out

subjects with a high likelihood of psychosis.

Psychopathology is an area of cannabis research where there is a

need to depend on so-called "clinical" studies. Such data are

necessarily inexact, only partially controlled, and heavily

dependent on the hunches, wisdom, and good judgment of clinical

investigators. Many of the reported cases may ultimately reflect

interacting nutritional, genetic, or coincident disease factors

that are more important than the simple use of cannabis in determining the onset of a cannabis psychosis. Because of the obvious

difficulties in experimentally producing such states in human

subjects, however, it may well be that such imprecise clinical

data is all that can be obtained.

72
Marijuana flashbacks, that is, spontaneous recurrences of the

feelings and perceptual state similar to that produced by the

drug, are still occasionally reported (Brown and Stickold 1976).

Their etiology is still unexplained. Either medical investigators have ceased reporting flashback experiences or they have

become uncommon.

Relatively little new information is available on the relationship between cannabis and violence. An extensive review of that

issue has recently been published (Abel 1977). Most commissions

and review groups that have specifically studied the relationship

between cannabis and violence have concluded that the use of

marijuana is not a major cause of aggression. There is little

new that would change that conclusion. However, as Abel points

out, such conclusions are based on "typical" or average marijuana

users and tend to underemphasize individuals who may be at some

special risk and who may react atypically and violently as a

consequence of their marijuana use. It might be the rare individual, perhaps someone with a prior history of violent behavior

and impulse control problems, in whom cannabis might reduce

control even further and lead to violent behavior. In laboratory

studies and in many surveys, such people maybe screened out by

the selection process. This may be yet another area where clearcut human data must depend on clinical reports and the slow

accumulation of clinical experience rather than on experimental

studies. The literature from animal studies suggests that with

proper combinations of stress and environmental conditions,

cannabis can produce aggressive behavior. Scattered case reports

(Thacore and Shulka 1976; Treffert 1978) describe explosive,

agitated, and violent behavior in some patients. A more complicated issue is whether such behavior is a specific consequence of

marijuana or due to the combined use of marijuana and other drugs

such as alcohol and possibly to other unrecognized factors.

Aggressive behavior is not a common consequence of marijuana use

in this country, however.

AMOTIVATION

Apathy, a lack of concern over the future, and loss of motivation

have been described in populations of cannabis users. The term

is deceptively simple but is difficult to operationally define.

In laboratory studies, in some respects subjects seem activated

during the acute phase of intoxication, but in others they work

very hard at the assigned experimental tasks. In chronic studies

of people living on research wards, some types of work output

decreased as the level of intoxication increased (Mendelson

etal. 1976a, l976b; Miles etal. 1974). To ascribe these changes

simply to changes in motivation, however, ignores the complexity

of drug effects, even in a relatively simple experimental environment. Artificial work conditions and artificial tasks make

generalizations imprecise. In the studies of chronic users in

Greece, Jamaica and Costa Rica, work output of marijuana users

did not appear to be lower than that of nonusers. Particularly

in the Greek study, however, the employment histories of the

73
cannabis users were such that one might suspect some level of

amotivation. Uncontrolled clinical reports from areas of the

world where cannabis is readily available continue to report

decreased work output and initiative in chronic cannabis users

(Sharma 1975). Similarly, uncontrolled reports from observations

of users in this country suggest a similar pattern.

TOLERANCE AND DEPENDENCE

Tolerance, that is, a diminished response to a repeated cannabis

dose, is clearly associated with repeated use (Fried 1977). The

magnitude of the tolerance and the rapidity with which it develops depend on the size and frequency of the repeated dose, just

as with opiates, alcohol, barbiturates, and virtually any other

psychoactive drug. The pharmacokinetics of THC are complex

enough so that simple predictions as to the characteristics of

tolerance are not possible. If one assumes that THC is cleared

rapidly; that is, if one focuses on the rapid or alpha phase of

clearance, then the prediction would be that frequent doses of

THC are necessary to clearly demonstrate tolerance. If one

focuses on the terminal half-life of THC and metabolites, a

period of time which can be 50 hours or more, then less frequent

administration should be necessary to produce tolerance. It

appears now, both in animals and in humans, that tolerance

develops quite rapidly to many of the effects of THC. The more

frequent the administration and the higher the dose the more

rapidly it develops, but even subjects smoking as little as one

marijuana cigarette per day in a laboratory experiment demonstrate tolerance on some behavioral and physiologic dimensions

when they are carefully measured. As with many other drugs,

tolerance does not develop to all THC effects. Some of the more

prominent effects, for example the "high" and the tachycardia,

show tolerance far more rapidly than such effects as the reddening of the conjunctival blood vessels or weight gain. Most of

the tolerance seems to be lost rapidly, but this rate may vary

with the sensitivity of the measures used.

In outpatient studies where frequent and infrequent users or

other populations with differing drug histories are compared,

marked tolerance is less obvious, if evident at all. However,

with sensitive and reliable measures, even infrequent outpatient

use produces some tolerance (Borg and Gershon 1975; Cohen and

Rickles 1974). Drug-seeking behavior in experimental studies is

not clearly related to the degree of tolerance (Babor et al.

1975), but in free access studies with smoked marijuana material

research subjects do tend gradually to increase their dosage over

a 2 or 3 week period. Just how many cigarettes per day are

smoked seem to be governed by many other pharmacologic and nonpharmacologic factors in addition to tolerance.

With many drugs, the development of tolerance is associated with

dependence, that is, the appearance of withdrawal signs and

symptoms following discontinuation of drug use. In those instances where definite cannabis tolerance develops in humans,

74
mild physical dependence seems to be associated. Healthy volunteers given in divided doses the oral equivalent of several

marijuana cigarettes a day so as to maintain constant blood

levels of THC show within hours after the last dose of THC,

irritability, restlessness, decreased appetite, sleep disturbance, sweating, tremor, nausea, vomiting and diarrhea (Jones

et al. 1976). These signs and symptoms are reversed by small

doses of marijuana and possibly by other sedative hypnotic drugs.

Such dramatic psychologic and physiologic changes have not been

commonly observed in other chronic administration studies in the

United States involving smoked material. Less intense and fewer

symptoms, but still including restlessness, sleep disturbance,

loss of appetite, mild nausea, and general irritability, were

evident in subjects who had on an average smoked five marijuana

cigarettes per day for a 64-day period (Nowlan and Cohen 1977).

Although the investigators did not conclude that dependence was

present, restlessness, anorexia, and a sudden weight loss were

described in one group of inpatient volunteer subjects at the end

of a 21-day smoking period (Mendelson et al. 1974;. Greenberg

et al. 1976).

In the group of Greek hashish users that was studied in some

detail, irritability, anxiety, and unpredictable emotional outbursts followed when they failed to obtain hashish each day.

This was replaced by a relaxed and drowsy state after the smoking

of hashish (Stefanis et al. 1976b). Such symptoms have not been

commonly reported in nonexperimental studies in this country,

though one German study described withdrawal symptoms in nonlaboratory cannabis users (Kielholz and Ladewig 1970). The

detailed studies of marijuana users in Costa Rica and in Jamaica

did not describe withdrawal symptoms in those user populations

(Coggins et al. 1976; Rubin and Comitas 1975).

The most important question regarding dependence is the clinical

significance of drug dependence particularly as manifested by a

mild transient withdrawal syndrome of the sort that can, under

some circumstances, be produced by cannabis. The relationship

between withdrawal symptoms and drug-seeking behavior is not a

simple one (Jones and Benowitz 1976). There is much to suggest

that dependence and drug-seeking behavior are not necessarily

associated. Drug-seeking behavior is shaped by a multitude of

social, economic, psychological, and other factors. For example,

if we better understood the role of the relatively mild symptoms

of withdrawal from tobacco as a determinant of tobacco-seeking

behavior, and if we understood why the relatively mild withdrawl

syndrome associated with low potency doses of illicit heroin

generally available in the United States should be associated

with heroin-seeking behavior, then we could better answer the

question about the significance of a mild abstinence syndrome

following frequent cannibis use. Of course, the information to

answer such questions about any of these drugs does not exist.

In the past, medical researchers have had little success in

predicting dependence liability of drugs that become available

for widespread, relatively uncontrolled use.

75
REFERENCES

Abel, E.L. The relationship between cannabis and violence: A

review. Psychol Bull, 84(2):193-211, 1977.

Babor, T.F., Mendelson, J.H., Greenberg, I., and Kuehnle, J.C.

Marijuana consumption and tolerance to physiological and subjective effects. Arch Gen Psych, 32(12):1548-1552, 1975.

Benowitz, N.L. and Jones, R.T. Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. Clin Pharmacol

Ther, 18(3): 287-297, 1975.

Borg, J. and Gershon, S. Dose effects of smoked marijuana on

human cognitive and motor function. Psychopharmacologia, 42:

211-218, 1975.

Brecher, E.M. Marijuana: The health questions. Consumer

Reports, 40:143-149, 1975.

Brill, N.Q. and Christie, R.L. Marijuana use and psychosocial

adaptation. Arch Gen Psych, 31(5):713-719, 1974.

Brown, A. and Stickgold, A. Marijuana flashback phenanena. J

Psychedelic Drugs, 8(4):275-283, 1976.

Campbell, A.M.G., Evans, M., Thomson, J.L.G., and Williams, M.J.

Cerebral atrophy in young cannabis smokers. Lancet, ii(7736):

1219-1225, 1971.

Co, B.T., Goodwin, D.W., Gado, M., Mikhael, M., and Hill, S.Y.

Absence of cerebral atrophy in chronic cannabis users. JAMA,

237(12):1229-1230, 1977.

Coggins, W.J., Swenson, E.W., Dawson, W.W., Fernandez-Salas, A.,

Hernandez-Bolanos, J., Jiminez-Antillon, C.F., Solano, J.R.,

Vinocour, R., and Faerron-Valdez, F. Health status of chronic

heavy cannabis users. Ann NY Acad Sci, 282:148-161, 1976.

Cohen, M.J. and Rickles, W.H., Jr. Performance on a verbal

learning task by subjects of heavy past marijuana usage. Psychopharmacologia, 37(4):323-330, 1974.

Edwards, G. Cannabis and the criteria for legalization of a

currently prohibited recreational drug: Groundwork for a debate.

Acta Psychiat Scandinavica, 251(Suppl):1-62, 1974.

Feinberg, I., Jones, R., Walker, J., Cavness, C., and Floyd, T.

Effects of marijuana extract and tetrahydrocannabinol on electroencephalographic sleep patterns. Clin Pharmacol Ther, 19(6):

782-794, 1976.

7 6
Fried, P.A. Behavioral and electroencephalographic correlates of

the chronic use of marijuana. A review. Behav Biol 21(2): 163-

196, 1977.

Graham, J.D.P. Cannabis and health. In: Graham, J.D.P., ed.

Cannabis and Health. London: Academic Press, Inc, 1976. pp.

271-230.

Grant, I., Rochford, J., Fleming, T., and Stunkard, A. A neuropsychological assessment of the effects of moderate marijuana

use. J Nerv Ment Dis, 156(4):278-280, 1973.

Greenberg, I., Kuehnle, J., Mendelson, J.H., and Bernstein, J.G.

Effects of marijuana use on body weight and caloric intake in

humans. Psychopharmacology, 49(1):79-84, 1976.

Halikas, J.A. Marijuana use and psychiatric illness. In:

Miller, L.L., ed. Marijuana: Effects on Human Behavior. New

York: Academic Press, Inc, 1974. pp. 265-302.

Harris, L.S. Cannabis: A review of progress. In: Lipton,

M.A., DiMascio, A., and Killam, K.F., eds. Psychopharmacology:

A Generation of Progress. New York: Raven Press, 1978. pp.

1565-1574.

Harris, L.S., Dewey, W.L., and Razdan, R.K. Cannabis. Its

chemistry, pharmacology and toxicology. In: Martin, W.R., ed.

Drug Addiction II. Amphetamine, Psychotogen, and Marijuana

Dependence. New York: Springer-Verlag, 1977. pp. 371-429.

Heath, R.G., Fitzjarrell, A.T., Garey, R.E., and Myers, W.A.

Chronic marijuana smoking: Its effect on function and structure

of the primate brain. In: Nahas, G.G. and Paton, W.D.M., eds.

Advances in the Biosciences, Vol. 22 and 23. Marihuana: BioReproduction and Brain. Oxfrod: Pergamon Press, 1979. pp.

logical Effects. Analysis, Metabolism, Cellular Responses,

713-730.

Herning, R.I., Jones, R.T., and Peltzman, D.J. Changes in human

event related potentials with prolonged delta-9-tetrahydrocannabinol (THC) use. Electroenceph Clin Neurophysiol, 47(5):556-570,

1979.

Hollister, L.E. and Reaven, G.M. Delta-9-tetrahydrocannabinol

and glucose tolerance. Clin Pharmacol Ther, 16(2):297-302, 1974.

Huber, G., O'Connell, D., McCarthy, C., Pereira, W., Mahajan, V.,

and Mullane, J. Toxicologic pharmacology of tetrahydrocannabinol

(THC) and marijuana (MJ) smoke components. Clin Res, 24(3):A255,

1976.

Hunt, C.A. and Jones, R.T. Tolerance and disposition of tetrahydrocannabinol in man. J Pharmacol Exp Ther, in press, 1980.

7 7
Jones, R.T. and Benowitz, N. The 30 day trip - clinical studies

of cannabis tolerance and dependence. In: Braude. M.C., and

Szara, S., eds. Pharmacology of Marihuana. Vol. 2. New York:

Raven Press, 1976. pp. 627-642:

Jones, R.T., Benowitz, N., and Bachman, J. Clinical studies of

cannabis tolerance and dependence. Ann NY Acad Sci, 282:221-239,

1976.

Jones, R.T. Effects of marijuana on the mind. In: Tinklenberg,

J.R., ed. Marijuana and Health Hazards. New York: Academic

Press, Inc., 1975. pp. 115-120.

Jones, R.T. Drug models of schizophrenia - cannabis. In: Cole,

J.O., Freedman, A.M., and Friedhoff, A.J., eds. Psychopathology

and Psychopharmacology. Baltimore: Johns Hopkins Press, 1973.

pp. 115-120.

Jones, R.T. Marijuana-induced "high": influence of expectation,

setting and previous drug experience. Pharmacological Reviews,

23: 359-369, 1971.

Kalant, O.J. and Kalant, H. Marijuana and its effects: an

assesment of current knowledge. Addictions, 15(1):1-7, 1968.

Kielholz, P. and Ladewig, D. Drug addiction, especially hashish,

in young people. Dtsch Med Wochenschr, 95(3):101-105, 1970.

Klonoff, H., Low, M., and Marcus, A. Neuropsychological effects

of marijuana. Can Med Assoc J, 108(3):150-156, and 165, 1973.

Kuehnle, J., Mendelson, J.H., Davis, K.R., and New, P.F.J.

Computed tomographic examination of heavy marijuana smokers.

JAMA, 237(13):1231-1232, 1977.

Lemberger, L. and Rubin, A. Cannabis: the role of metabolism in

the development of tolerance. Drug Metab Rev, 8(1):59-63, 1978.

Lemberger, L. and Rubin, A. Physiolcgical Disposition of Drugs

of Abuse. New York: Spectrum Publications, Inc., 1976.

Lemberger, L., Axelrod, J., and Kopin, I.J. Metabolism and

disposition of tetrahydrocannabinols in naive subjects and

chronic marijuana users. Ann NY Acad Sci, 191:142-154, 1971a.

Lemberger, L., Tamarkin, N.R., Axelrod, J., and Kopin, I.

Delta-9-tetrahydrocannabinol: metabolism and disposition in

long-term marijuana smokers. Science, 173(3991):72-74, 1971b.

Leuchtenberger, C., Leuchtenberger, R., Zbinden, J., and Schleh,

E. Cytological and cytochemical effects of whole smoke and of

the gas vapor phase from marijuana cigarettes on growth and DNA

metabolism of cultured mammalian cells. In: Nahas, G.G., ed.
Marihuana: Chemistry, Biochemistry, and Cellular Effects.

New York: Springer-Verlag, 1976. pp. 243-256.

Mendelson, J.H., Kuehnle, J.C., Greenberg, I., and Mello, N.K.

The effects of marijuana use on human operant behavior: individual data. In: Braude, M.C., and Szara, S., eds. Pharmacology

of Marihuana. Vol. 2. New York: Raven Press, 1976a. pp.

643-653.

Mendelson, J.H., Keuhnle, J.C., Greenberg, I., and Mello, N.K.

Operant acquisition of marijuana in man. J Pharmacol Exp Ther,

198(1):42-53, 1976b.

Mendelson, J.H., Rossi, A.M., and Meyer, R.E., eds. The Use of

Marihuana. A Psychological and Physiological Inquiry. New York:

Plenum Press, 1974. 202 pp.

Meyer, R.E. Psychiatric consequences of marijuana use: the

state of the evidence. In: Tinklenberg, J.R., ed. Marijuana

and Health Hazards. New York: Academic Press, Inc., 1975. pp.

133-152.

Miles, C.G., Congreve, G.R.S., Gibbins, R.J., Marshman, J.,

Devenyi, P., and Hicks, R.C. An experimental study of the

effects of daily cannabis smoking on behavior patterns. Acta

Pharmacol Toxicol, 34(l), Suppl:43 pp, 1974.

Moreau, J.J. Hashish and Mental Illness. New York: Raven

Press, 1973.

Nahas, G.G. Current status of marijuana research. JAMA, 242(25):

2775-2778, 1979.

Nowlan, R. and Cohen, S. Tolerance to marijuana. Heart rate and

subjective "high." Clin Pharmacol Ther, 22(5):550-556, 1977.

Rubin, V. and Comitas, L. The clinical studies. In: Rubin, V.

1975. pp. 81-87.

and Comitas, L., eds. Ganja in Jamaica. The Hague: Mouton,

Sharma, B.P. Cannabis and its users in Nepal. Brit J Psych,

127:550-552, 1975.

Soueif, M.I. Chronic cannabis takers: some temperamental characteristics. Drug Alc Depend, 1(2):125-154, 1975.

Stefanis, C., Boulougouris, J., and Liakos, A. Clinical and

physiological effects of cannabis in long-term users. In:

Brande, M.C., and Szara, S., eds. Pharmacology of Marihuana.

Vol. 2. New York: Raven Press, 1976a. pp. 659-665.

Stefanis, C., Liakos, A., and Boulougmris, J.C. Incidence of

mental illness in hashish users and controls. Ann NY Acad Sci,

282:113-120, 1976b.

79
Stimmel, B. Marijuana. In: Stimmel, B., ed. Cardiovascular

Effects of Mood-Altering Drugs. New York: Raven Press, 1979.

pp. 167-178.

Tashkin, D.P., Shapiro, B.J., Ramanna, L., Taplin, G.V., Lee,

Y.E., and Harper, C.E. Chronic effects of heavy marijuana

smoking on pulmonary function in healthy young males. In:

Braude, MC., and Szara, S., eds. Pharmacology of Marihuana.

New York: Raven Press, 1976a. pp. 291-295.

Tashkin, D.P., Shapiro, B.J., Lee, Y.E., and Harper, C.E. Subacute effects of heavy marijuana smoking on pulmonary function in

healthy men. N Engl J Med, 294(3):125-129, 1976b.

Tassinari, C.A., Amrosetto, G., Peraita-Adrados, M.R., and

Gastaut, H. The neuropsychiatric syndrome of delta-9-tetrahydrocannabinol and cannabis intoxication in naive subjects: a clinical and polygraphic study during wakefulness and sleep. In:

Braude, MC., and Szara, S., eds. Pharmacology of Marihuana.

New York: Raven Press, 1976. pp. 357-375.

Tennant, F.S., Guerry, M.C., and Henderson, R.L. Histopathologic

and clinical abnormalities of the respiratory system in chronic

hashish smokers. Paper presented at the National Drug Abuse

Conference, New Orleans, August 26-31, 1979.

Thacore, V.R. and Shulka, S.R.P. Cannabis psychosis and paranoid

schizophrenia. Arch Gen Psych 33(3):383-386, 1976.

Treffert, D.A. Marijuana use in schizophrenia: a clear hazard.

Amer J Psych, 135(10):1213-1215, 1978.

Willette, R.E., ed. Cannabinoid Assays in Humans. National

Institute on Drug Abuse Research Monograph 7. Washington, D.C.:

Superintendent of Documents, U. S. Government Printing Office,

1976,

AUTHOR

Reese T. Jones, M. D.

Professor of Psychiatry

Langley Porter Psychiatric Institute

University of California, San Francisco

San Francisco, California 94143

80
Chemistry and Metabolism

Carlton E. Turner, Ph.D.

SUMMARY

Marijuana is not a simple drug. It is a complex mixture of over

400 individual chemicals. In some cases, pharmacological data on

pure Δ

9

-THC, referred to as the "most active" compound in marijuana,

may be irrelevant, since some marijuana contains very little Δ

9

-THC.

(−)−Δ9

-Trans-tetrahydrocannabinol is only one of 61 cannabinoids

known to occur in the Cannabis plant. Cannabinoids are chemicals

indigenous to the Cannabis plant and are found in all crude drugs

derived from it, i.e., marijuana, hashish, sinsemilla, etc.

Marijuana chemistry is, therefore, not synthetic cannabinoid chemistry nor the chemistry of analogs and homologues of cannabinoids.

Marijuana chemistry is the chemistry of: 1) all classes and subclasses of chemicals found in Cannabis and their interactions; 2)

pyrolysis of these individual chemicals and classes when smoked to

produce tars and other compounds; 3) absorption of chemicals and

distribution of these chemicals in systems of the body; and 4) subsequent reactions of these chemicals during metabolism, storage,

and elimination from the body.

Much progress has been made in identifying and quantitating cannabinoids found in marijuana. Today ten cannabinoids are routinely

quantitated. Pharmacologists can now design studies with marijuana

of better known composition.

Although analytical data can routinely account for ten cannabinoids,

no method exists to routinely quantitate the other 411 constituents

found in Cannabis, and no method has been developed to fill the

forensic need for determining sample origin. Reports indicate certain analytical tools and methods can identify the origin of

Cannabis; however, dynamic fluctuation of cannabinoids and the

existence of three basic types of Cannabis plants have prevented any

positive identification. Nevertheless, progress in the chemical

classification of marijuana has been made.

8 1
Refinement of procedures and techniques continues to be noteworthy

in the identification of unknown components in marijuana. Gas,

thin layer, column, high pressure liquid, and plasma chromatography

are being used, but X-ray methods are playing a significant role in

understanding the crystal and molecular structures of known and

unknown cannabinoids. These structural data enable scientists to

develop a more accurate understanding of the nature and distribution of cannabinoids at the cellular level.

The chemistry and pharmacology of individual cannabinoids play a

role in understanding marijuana. Recent findings suggest the

interactions between cannabinoids and other components along with

the cellular action of cannabinoids may be very significant. These

factors may explain why the percent of Δ

9

-THC in a marijuana sample

is not an absolute indication of potency. The interaction between

cannabinol and Δ

9

-THC has been known for some time. Recently the

decomposition of Δ

9

-THC to the less psychotropic cannabinol has

been elucidated. Compounds of the cannabitriol type are intermediates in this process and may have pharmacological actions that

mimic Δ

9

-THC or other cannabinoids. Two other classes of compounds

indigenous to Cannabis have recently been discovered. Cannabisativine type alkaloids of the spermidine class and cannabispiran, a

spiro-compound, have been found. Several of the spiro-compounds

have been identified from different Cannabis samples and two cannabisativine type alkaloids have been found.

Synthetic cannabinoids and improvements in synthetic procedures

continue to be of major interest. With these advances many new

analogs have been synthesized and are being tested for their pharmacological profiles. Cannabichromene, one of the four major cannabinoids, has been synthesized in quantity. The use of microorganisms to produce metabolites is promising.

Metabolic studies are significant. No major breakthrough has

occurred in this area but some progress has been made. Gas chromatography-mass spectrometry, radioimmunological assays, electron capture gas chromatography and thin layer chromatography remain the

methods of choice for metabolic studies. None of these methods

solves the problem of determining levels of intoxication in humans.

Radiolabeled compounds are being used in studies on total distribution of cannabinoids in animal models.

Constituents found in marijuana smoke are being investigated. Considerable pyrolysis work has been done on cannabidiol and many

pyrolytic products have been identified.

Chemical interactions between constituents of marijuana and/or their

metabolites and other drugs may create toxic reactions. Progress

has been slow in this area. The chemical changes in brain chemistry

caused by marijuana constituents continue to be investigated as does

the therapeutic potential of cannabinoids and analogs.

8 2
In the future marijuana chemical and metabolic research will, by

necessity of ongoing programs and unanswered questions, be focused

on providing a constant supply of standard marijuana of known

composition, and a program to provide synthetic cannabinoids, their

metabolites, and analogs.

THE DRUG MARIJUANA

Continued research into the synthetic chemistry and pharmacology

of individual cannabinoids has clouded the natural chemistry of

preparations from the Cannabis plant. The chemistry of (-)-Δ

9

-

trans-tetrahydrocannabinol (Δ9-THC) is not the chemistry of marijuana, and the pharmacology of Δ

9

-THC is not the pharmacology of

marijuana, although Δ

9

-THC is referred to as "synthetic marijuana."

Marijuana chemistry is complex and cannot be simplified or extrapolated to any one or two "active compounds." As early as 1974 this

fact was recognized (UN Doc 1974), and it was recommended that all

research reports on marijuana list a minimum of three cannabinoids:

1) Δ

9

-THC, 2) cannabinol (CBN), 3) cannabidiol (CBD). Cannabinoids

are compounds indigenous to the Cannabis plant and therefore, to

all crude drugs prepared from this plant. Prior to 1964 only three

cannabinoids were known to exist even though prominent chemists

had attempted to elucidate "active principles" since the 1870's

(Preobraschensky 1876). Today 61 cannabinoids are known.

Since 1964 many procedures to produce synthetic Δ

9

-THC, other cannabinoids, and their respective homologues and analogs have been

developed (Waller et al. 1976, Pitt et al. 1979). However, the

chemistry of marijuana and other crude drugs from Cannabis was not

well defined, and consequently not adequately understood. This

progress report is designed to bring the reader up to date on natural

marijuana chemistry and will, therefore, review the complex crude

drugs prepared from Cannabis, i.e., marijuana, hashish, sinsemilla,

dagga, etc.

The chemistry of marijuana can best be understood by breaking all

known constituents of the Cannabis plant down into classes of chemicals. The total number of constituents known from Cannabis is

421 (Turner, Elsohly, and Boeren 1980) (Table 1).

Table 1. Chemical Constituents of Cannabis Preparations

1. Cannabinoids: 61 nown

a. Cannabigerol (CBG) type: 6 known

b. Cannabichromene (CBC) type: 4 known

c. Cannabidiol (CBD) type: 7 known

d. Δ 9-Tetrahydrocannabinol (Δ 9-THC) type: 9 known

e. Δ 8-Tetrahydrocannabinol (Δ 8-THC) type: 2 known

f. Cannabicyclol (CBL) type: 3 known

g. Cannabielsoin (CBE) type: 3 known

h. Cannabinol (CBN) type: 6 known

i. Cannabinodiol (CBND) type: 2 known

8 3
Table 1. Continued.

j. Cannabitriol (CBT) type: 6 known

k. Miscellaneous types: 9 known

l. Other cannabinoids: 4 known

2. Nitrogenous compounds: 20 known

a. Quarternary bases: 5 known

b. Amides: 1 known

c. Amines: 12 known

d. Spennidine alkaloids: 2 known

3. Amino acids: 18 known

4. Proteins, glycoproteins, and enzymes: 9 known

5. Sugars and related compounds: 34 known

a. Monosaccharides: 13 known

b. Disaccharides: 2 known

c. Polysaccharides: 5 known

d. Cyclitols: 12 known

e. Aminosugars: 2 known

6. Hydrocarbons: 50 known

7. Simple alcohols: 7 known

8 . Simple aldehydes: 12 known

9. Simple ketones: 13 known

10. Simple acids: 20 known

11. Fatty acids: 12 known

12. Simple esters and lactones: 13 known

13. Steroids: 11 known

14. Terpenes: 103 known

a. Monoterpenes: 58 known

b. Sesquiterpenes: 38 known

c. Diterpenes: 1 known

d. Triterpenes: 2 known

e. Miscellaneous compounds of terpenoid origin: 4 known

15. Noncannabinoid phenols: 16 known

16. Flavanoid glycosides: 19 known

17. Vitamins: 1 known

18. Pigments: 2 known

Not only is the chemistry of marijuana complex because of the

large number of chemical constituents, it is compounded by three

distinctly different Cannabis chemovariants: each producing a

distinctly different marijuana. The three types are fiber, intermediate, and drug. Cannabidiol is the major cannabinoid found in

fiber type; the percent by dry weight of cannabidiol is equal to

or greater than Δ

9

-THC in intermediate Cannabis; and Δ

9

-THC is the

major cannabinoid in the drug type with CBD being absent or present

in trace amounts. Cannabichromene is always present in drug types.

Ratios of cannabinoids vary hourly, daily, etc.; thus there are

dynamic changes over time (Turner et al. 1979).

To understand Cannabis chemistry it is best to observe analyses

of several samples of crude drugs from Cannabis available on the

street, from NIDA and from the UN (Table 2)

8 4
Table 2. Cannabinoid Analyses

Cannabis Prep CBDV1Δ 9-THCV CBL CBD CBC Δ 8-THC Δ 9-THC CBN

Sinsemilla2(Fiber) 0.07 0.02 0.03 4.68 0.47 0.09 0.21 0.06

Sinsemilla(Inter.) t

3

0.08 9.01 3.69 0.61 0.07 3.58 0.21

Sinsemilla(Drug) -

4

0.15 0.02 0.02 0.20 - 6.28 0.22

Hashish (UN Stand.) 0.03 0.03 0.03 2.89 0.38 0.22 2.22 2.50

NIDA5 (Cig 1) 0.01 t t t 0.12 0.09 0.84 0.30

(Cig 2) - 0.02 0.02 0.02 0.18 0.15 1.86 0.13

1CBDV=cannabidivarin; Δ9

-THCV=(-)- Δ

9

-trans-tetrahydrocannabivarin;

CBL=cannabicyclol; CBD=cannabidiol; CBC=cannabichromene; Δ

8

-THC=

(-)-Δ 8-trans-tetrahydrocannabinol; Δ 9

-THC=(-)- Δ 9-trans-tetrahydrocannabinol and CBN=cannabinol. Cannabigerol (CBC) and cannabigerol

monomethylether (CBGM) were excluded but are routinely included in

all analyses.

2

Sinsemilla-a crude drug from the flowering tops of female Cannabis

plants that have not been pollinated: "Seedless marijuana." Same

as Dagga from the Republic of South Africa. These samples were

grown in Calif.

3

t=trace (less than 0.009%).

4

absent

5

Standard NIDA Mexican marijuana cigarette from Cannabis grown in

Mississippi.

The preparations listed in Table 2, with the exception of hashish,

are dry forms of Cannabis commonly called marijuana and illustrate

the fact that the chemistry of marijuana is not just the chemistry

of Δ

9

-THC, but at a minimum? a combination of cannabinoids. For

example, observe the cannabinoid ratios in the three types of

Sinsemilla listed. Moreover, Δ

9

-THC is not the only psychomimetically active compound: Δ

8

-THC, Δ

9

-THC, and CBN are active (Holister 1974, Perez-Reyes et al. 1973). Kinetic interactions have been

reported to occur among cannabinoids since the early 1970's

(Karniol and Carlini 1972, Borgen and Davis 1974, Siemens, Kalant and

deNie 1976). Therefore, other cannabinoids play a role yet to be

determined in the pharmacology of marijuana.

Recently a new subclass of cannabinoids called cannabitriols were

discovered. Chan, Magnus, and Watson (1976) provided the first of

these compounds: (-)-cannabitriol. Elsohly, El-Feraly, and Turner

(1977), Elsohly et al. (1978), and Boeren, Elsohly, and Turner

(1979) quickly confirmed this work and found four additional cannabitriols. Boeren, Elsohly, and Turner (1979) determined the

85
stereochemistry of one compound, cannabiripsol, and determined the

presence of other "cannabitriols." These compounds may be of

pharmacological significance since they decompose to CBN and are

produced when Δ

9

-THC decomposes to CBN (Turner and Elsohly 1979).

For many years it was believed that alkaloids were responsible for

the biological activity found in Cannabis preparations (Preobraschensky 1876, Humphrey 1902). Until recently no alkaloids

of significance were found in marijuana. El-Feraly and Turner

(1975) reported the structure of hordenine and Lotter et al. (1975)

reported the finding of a spermidine class alkaloid: cannabisativine. In 1978 Elsohly et al. found anhydrocannabisativine.

These three alkaloids are present in marijuana produced from many

variants of Cannabis (Elsohly and Turner 1977). Pharmacological

studies on cannabisativine and anhydrocannabisativine have not

been carried out. These compounds are unique and believed to be

indigenous to Cannabis.

Discovery of a new class of spiro-compounds in marijuana (Ottersen

et al. 1976, Bercht et al. 1976, Boeren et al. 1977, Kettenes and

Salemink 1978, Shoyama and Nishioka 1978, Crombie, Crombie, and

Jamieson 1979) may solve some of the inconsistencies reported in

hormonal research with marijuana since compounds of the spiro

type have exhibited estrogenic properties (Bailey et al. 1976).

Moreover these compounds may be more abundant in marijuana than

previously thought (El-Feraly et al. 1977).

Burstein et al. (1976) reported that eugenol and p-vinylphenol

may contribute to the overall activity of marijuana. Both of

these compounds are noncannabinoid phenols as are the spiro-compounds. In research programs using only synthetic cannabinoids,

these compounds are excluded.

The contribution of X-ray crystallography to research in the field

of marijuana chemistry has been demonstrated by Ottersen et al.

(1976, 1977a,b); Jones et al. (1977); and El-Feraly et al. (1977).

Structural data obtained by X-ray methods will allow more investigation into the possible structural correlations with other

classes of drugs. These correlations are presently underway with

anticonvulsant drugs (Jones et al. 1977).

Synthetic Progress

Synthetic production of new analogs of naturally occurring cannabinoids continues at a rapid pace. Handrick et al. (1977) synthesized

the cis isomers of cannabidiols and Uliss et al. (1979) reported

a procedure to convert cis cannabinoid isomers to trans. The synthesis of novel cannabinoids (Uliss et al. 1977a,b) along with

other synthetic procedures reported (Handrick et al. 1979) provide

new approaches to the synthesis of metabolites and some elusive

cannabinoids (Boeren, Elsohly and Turner 1979).

8 6
Microbiological oxidation of the pentyl side chain to provide a

series of metabolites was a significant accomplishment. Refinements

of this method (Robertson et al. 1978) combined with synthetic programs as described by Pitt et al. (1979) and Ohlsson et al. (1979)

provide a route to side chain metabolites.

Another significant development since the last report was the synthesis of a C-glucuronide of Δ

8

-THC. C-glucuronides may be very

significant in determining the nature of water soluble conjugates

(Yagen, Levy, and Mechoulam 1977). These conjugates are of particular interest since Harvey, Martin, and Paton (1977) reported

the identification of 0-glucuronides of seven cannabinoids.

With the synthesis of CBC by Elsohly, Boeren, and Turner (1978a)

it is now possible to study CRC and its influence on the pharmacology of other cannabinoids. Cannabichromene is one of the four

major naturally occurring cannabinoids. Pharmacological studies

were previously restricted because of an insufficient supply.

Further work on the separation and quantitation of CRC and CBD

(Fifth Marihuana Health Report 1975, Sixth Marihuana Health Report

1976) was carried out and again confirmed that CBC is a major

cannabinoid (Coutts and Jones 1979). The report by Coutts and

Jones (1979) also has important forensic significance since all

extracts of suspected Cannabis preparations found to be positive

using 1) microscopic-examination of the material, 2) modified

Duquenois-Levine color reaction, and 3) a thin layer chromatographic examination of the extracts were confirmed in blind

experiments using GC-mass spectral data.

Chemistry of Marijuana Smoke

Marijuana chemistry is the chemistry of smoke from natural marijuana

or special products prepared by coating placebo marijuana with

individual synthetic cannabinoids. Research programs may use both

products whereas users consume natural material. In this connection, Mikes and Waser (1971) suggested that the cannabinoid composition of marijuana smoke may differ from the leaf analysis.

Reports on the amount of Δ

9

-THC available in marijuana smoke have

been inconsistent (Truitt 1971, Manno et al. 1970); however, smoking

conditions normally employed by the marijuana user may provide up

to 62 percent of the original Δ

9

-THC in the smoke (Fehr Land

Kalant 1972). Also, more tar will be produced from a marijuana

cigarette than from a tobacco cigarette deliberately chosen to

produce high tar levels. Many variables affect the amount of

drug (cannabinoids) available to the user via the smoking method

(UN Doc 1975). Lee, Novotny and Bartle (1976) identified 150 compounds in marijuana smoke using a capillary GC column. Further

work on the acidic fraction of marijuana smoke was done by

Maskarinec, Alexander, and Novotny (1976). Novotny, Lee and Bartle

(1976) concluded that benzopyrene, a known carcinogen found in

tobacco smoke, was 70 percent more abundant in marijuana smoke.

Pyrolysis of cannabinoids or nonpolar higher terpenes abundant in

marijuana (Turner et al. 1979) was thought to be the source of the

elevated amounts of polynuclear aromatic hydrocarbons found in

87

323-754 0 - 80 - 7
marijuana smoke. Hoffman et al. (1975) provided a detailed comparison between marijuana and tobacco smoke.

Some of the products formed in the pyrolysis of pure CBD have been

isolated and characterized (Küppers et al. 1975, Spronck and

Salemink 1978, Luteyn, Spronck and Salemink 1978). The pyrolysis

of pure CBD produced many new cannabinoid-like compounds. Rosenkrantz and Hayden (1979) found marked changes in animal testicular

tissue during acute and subacute inhalation of Turkish marijuana,

CBC, and CBD. These findings are indicative of variation in smoke

content. Moreover, in a one-year study Fleischman, Baker and

Rosenkrantz (1979) found focal granulomatous inflammation and

cholesterol-like clefs in rats exposed to marijuana smoke. These

two studies illustrate the variable results obtained when smoke

from different types of marijuana and synthetic cannabinoids is

delivered to research subjects. A striking finding by Rosenkrantz

and Hayden (1979) was that Turkish marijuana smoke was more lethal

than placebo impregnated with 10 percent CBC or CBD which was more

lethal than 9 percent Δ

9

-THC on placebo. Using standard Mexican

marijuana, Zwillich et al. (1978) found marijuana had stimulatory

effects on metabolic rate, ventilation, and the ventilatory response

to CO2.

Current analytical data on cannabinoids in marijuana is sufficient

but an adequate understanding of the chemical composition of marijuana smoke and interactions of the cannabinoids within smoke is

lacking. Progress in impregnating and preventing the decomposition of synthetic cannabinoids on placebo produced from natural

marijuana will contribute to the ultimate understanding of marijuana chemistry and pharmacology.

Metabolism

Progress has been made in understanding mechanisms for distribution, storage, and disposition of cannabinoids and their metabolites.

This progress is the key to illuminating the short and long term

effects of marijuana and individual cannabinoids on the body.

Initial metabolism of cannabinoids in marijuana smoke takes place

in the lungs, whereas initial cannabinoid metabolism of orally consumed marijuana takes place in the liver. Since different enzymes

are involved, different initial metabolites are produced. Major

lung metabolites are usually side chain hydroxylated metabolites

whereas major liver metabolites are usually hydroxylated derivatives of the cyclohexene ring system. There are over 35 metabolites

of Δ

9

-THC, 22 metabolites of CBD, and 22 metabolites of CBN known.

Considerable species variation exists (Harvey, Martin and Paton

1978, Yisak et al. 1978, Harvey and Paton 1978). These metabolites

were formed by in vivo and in vitro metabolism and were found in

feces, plasma, urine and homogenized tissues and organs.

We now know several of the biotransformation pathways for Δ

9

-THC.

These include allylic and aliphatic hydroxylations; oxidation of

methyl groups to acids, aldehydes, and ketones; conjugations with

88
fatty acids or ß-glucuronic acid; epoxidation of double bonds; and

reduction of the terpene double bond.

Many of these metabolites are "psychoactive," but most are not.

This does not mean, however, that these "cannabinoids" will not have

biological activity. Recent findings on the nonspecific membrane

binding properties of Δ

9

-THC (Roth and Williams 1979), the interaction of cannabinoids with model membranes (Tamir, Lichtenberg, and

Mechoulam 1978), and the complex pharmacokinetics of distribution,

storage, and disposition of cannabinoids and metabolites (Garrett

1978) strongly suggest biological activity.

Data shows that cannabinoids and their metabolites are distributed

throughout the body. Recent experiments using radiolabeled Δ

9

-THC

in rats by Schou et al. (1977) have demonstrated that 11-hydroxyΔ

9

-THC penetrates the blood-brain barrier more readily than Δ

9

-THC.

Possibly the affinity of 11-hydroxy-Δ

9

-THC for plasma albumin

accounts for this. Δ

9

-THC is bound to lipoprotein.

Progress in finding and isolating new metabolites (Harvey, Martin

and Paton 1978, Yisak et al. 1978, Harvey and Paton 1978) has been

significant. These advances provide much information on how metabolites are stored and disposed of by the body. Synthesis of these

individual metabolites and subsequent toxicological testing can

add much to accurately define the long term effects of marijuana.

Determination of cannabinoids and metabolites in biological fluid

can be accomplished by the following principal methods: 1) gas

chromatography-mass spectrometry, 2) thin layer chromatography,

3) high pressure liquid chromatography, 4) radioimmunoassay (RIA),

and 5) gas chromatography. Of these, the gas chromatography-mass

spectrometry method provides the most specific and sensitive assays

for cannabinoids in biological fluids (Agurell, Lindgren and Ohlsson

1978). Both chemical and electron impact ionization methods are

used. Fentiman, Foltz and Foltz (1978) have provided a manual and

Rosenthal et al. (1978) have compared the methods for quantitating

Δ

9

-THC in biological media. Foltz (1978) also discussed the use

of gas chromatography chemical ionization in the quantitative

analysis of Δ

9

-THC. Pirl, Papa and Spikes (1979) have used this

method to detect Δ

9

-THC in postmortem blood samples.

Thin layer and high pressure liquid chromatography have been used

to detect and separate cannabinoids and metabolites but recently,

Kanter, Hollister and Loeffler (1978) developed a method to quantitate Δ

9

-THC by combining thin layer and high pressure liquid

chromatography. Maximum sensitivity at 215 mm is about 30 times

greater than at 280 mm.

Radioimmunoassay, in general, lacks the specificity and precision

of other methods, but it does offer certain advantages due to

cross activity between Δ

9

-THC and its metabolites and other cannabinoids. A recent report by Gross and Soares (1978) illustrated

a RIA method for determining Δ

9

-THC in plasma which gave levels

corresponding to intoxication.

8 9
Ahomogenous enzyme immunoassay (EMIT) for cannabinoids in urine

has been used (Rodgers et al. 1978) and may prove useful in rapid

screening programs.

Progress has been slow in the quantitation of pure Δ

9

-THC and its

metabolites in biological systems. Moreover, when marijuana is

used no practical method has been developed as a forensic tool for

determining levels of intoxication based on detectable cannabinoids

and metabolites.

Our knowledge of how pure Δ

9

-THC and its metabolites, as well as

the crude drug marijuana, affect certain systems of the body is

constantly increasing. It is known that the cannabinoids

affect brain amine levels (Johnson and Dewey 1978); platelet monoamine oxidase activity (Stillman et al. 1978); and ultrastructural

changes in neurons (Myers and Heath 1979). The cannabinoids interact with ethanol (Siemens and Khanna 1977, Siemens and Doyle 1979,

Belgrave et al. 1979); cross the placental barrier (Vardaris et al.

1976); cross the blood-brain barrier (Schou et al. 1977); and, are

transferred from the milk of lactating animals to nursing pups

(Chao et al. 1976). These diverse examples illustrate the complex

ways in which pure Δ

9

-THC and marijuana affect body chemistry and

metabolism. A comprehensive understanding of "marijuana chemistry"

is just beginning. The future of marijuana chemical and metabolic

research will continue to focus on a "standard" supply of the crude

drug marijuana and studies of synthetic metabolites.

The broad spectrum of biological activity found in marijuana and

its components may provide chemical leads for developing therapeutic drugs. However, current knowledge on the chemistry of

marijuana precludes the use of this crude drug.

90
REFERENCES

Chemistry and Metabolism

Agurell, S., J. -E. Lindgren, and A. Ohlsson. Symposium on marihuana, Reims, France. 22-23 July, 1978. In press.

Bailey, D. J., N. S. Doggett, L. Y. Ng, and T. Qazi. Potentiation

of the estrogenic activity of silbestrol by spiro(cyclohexane-1,2'-

indan)-1',4-dione. J Med Chem 19(3):438-439, 1976.

Belgrave, B. E., K. D. Bird, G. B. Chester, D. M. Jackson, K. E.

Lubbe, G. A. Starmer, and R. V. C. Teo. The effect of (-)-transΔ

9

-tetrahydrocannabinol, alone and in combination with ethanol, on

human performance. Psychopharmacology, 62:53-60, 1979.

Bercht, C. A. L., J. P. C. M. van Dongen, W. Heenna, R. J. J. CH.

Lousberg, and F. J. E. M. Küppers. Cannabispirone and cannabispirenone, two naturally occurring Spiro-compounds. Tetrahedron,

32:2939-2943, 1976.

Boeren, E. G., M. A. Elsohly and C. E. Turner. Cannabiripsol: a

novel Cannabis constituent. Experientia, accepted for publication,

1979.

Boeren, E. G., M. A. Elsohly, C. E. Turner, and C. A. Salemink.

ß-Cannabispiranol: a new noncannabinoid phenol from Cannabis

sativa L. Experientia, 33:848, 1977.

Borgen, L. A., and W. M. Davis. Cannabidiol interaction with

Δ

9

-tetrahydrocannabinol. Res Commun Chem Pathol Pharmacol, 7(4):

663-670, 1974.

Burstein, S., P. Taylor, F. S. El-Feraly, and C. E. Turner. Prostaglandins and Cannabis-V. Identification of p-vinylphenol as a

potent inhibitor of prostaglandin synthesis. Biochem Pharmacol,

25:2003-2004, 1976.

Chao, F. -C., D. E. Green, I. S. Forrest, J. N. Kaplan, A. WinshipBall, and M. Braude. The passage of 14C-Δ

9

-tetrahydrocannabinol

into the milk of lactating squirrel monkeys. Res Commun Chem

Pathol Pharmacol, 15(2)303-317, 1976.

Chan, W. R., K. E. Magnus, and H. A. Watson. The structure of cannabitrol. Experientia, 32:283, 1976.

Coutts, R. T., and G. R. Jones. A comparative analysis of Cannabis

material. J Forensic Sci, 24(2):291-302, 1979.

Crombie, L., W. M. L. Crombie, and S. V. Jamieson. Isolation of

cannabispiradienone and cannabidihydrophenanthrene. Biosynthetic

relationships between the spirans and dihydrostilbenes of Thailand

Cannabis. Tetrahedron Letters, 7:661, 1979.

91
Elsohly, M. A., E. G. Boeren, and C. E. Turner. Constituents of

Cannabis sativa L. An improved method for the synthesis of dlcannabichromene. J Heterocyclic Chem, 15:699, 1978a.

Elsohly, M. A., E. G. Boeren, and C. E. Turner. (±)9,10-dihydroxyΔ

6a(10a)-tetrahydrocannabinol and (±)8,9-dihydroxy-Δ6a(10a )-tetrahydrocannabinol: two new cannabinoids from Cannabis sativa L.

Experientia, 34:1127-1128, 1978b.

Elsohly, M. A., F. S. El-Feraly, and C. E. Turner. Isolation and

characterization of (+)-cannabitriol and (-)-10-ethoxy-9-hydroxyΔ

6a(l0a) -tetrahydrocannabil: two new cannabinoids from Cannabis

sativa L. extract. Lloydia, 40(3):275-280, 1977.

Elsohly, M. A., C. E. Turner, C. H. Phoebe, Jr., J. E. Knapp, P.

L. Schiff, Jr., and D. J. Slatkin. Anhydrocannabisativine, a new

alkaloid from Cannabis sativa L. J Pharm Sci, 67(1):124, 1978.

Elsohly, M. A. and C. E. Turner. Screening of Cannabis grown from

seed of various geographical origins for the alkaloids hordenine,

cannabisativine and anhydrocannabisativine. U N Secretariat ST/

SOA/SER.S/54, 1977.

Elsohly, M. A. and C. E. Turner. A review of nitrogen containing

compounds from Cannabis sativa L. Pharmaceutisch Weekblad III,

1976.

El-Feraly, F. S., M. A. Elsohly, E. G. Boeren, C. E. Turner, T.

Ottersen, and A. Aasen. Crystal and molecular structure of cannabispiran and its correlation to dehydrocannabispiran. Tetrahedron, 33:2373-2378, 1977.

El-Feraly, F. S. and C. E. Turner. Alkaloids of Cannabis sativa

leaves. Phytochemistry, 14:2304, 1975.

Fehr, K. O'Brien, and H. Kalant. Analysis of Cannabis smoke obtained

under different combustion conditions. Canad J Physiol Pharmacol,

50(8):761-767, 1972.

Fentiman, A. F., R. B. Foltz, and R. L. Foltz. Manual for quantitation of Δ

9

-tetrahydrocannabinol in biological media by gas

chromatography/mass spectrometry. Report to NIDA, Battelle Columbus

Laboratories, King Ave., Columbus, Ohio, 43201, 1978.

Fleischman, R. W., J. R. Baker, and H. Rosenkrantz. Pulmonary pathologic changes in rats exposed to marihuana smoke for 1 year.

Toxicol Appl_Pharmacol, 47:557-566, 1979.

Foltz, R. C. Quantitative analysis of abused drugs in physiological

fluids by gas chromatography/chemical ionization mass spectrometry.

In: de Leenheer, Rancucci, and van Peteghen. Quantitative Mass

Spectrometry in Life Sciencs II. Amsterdam, Holland, Elsevie

Scientific, 1978. pp. 39-62.

92
Garrett, E. R. Symposium on marijuana, Reims, France, 22-23 July,

1978. In press.

Gross, S. J. and J. R. Soares. Validated direct blood Δ

9

-THC radioimmune quantitation. J Anal Toxicol, 2:98-100, 1978.

Handrick, G. R., R. K. Razdan, D. B. Uliss, H. C. Dalzell and E.

Boger. Hashish. Synthesis of (±)-Δ

1

- and Δ

6

-3,4-cis-cannabidiols

and their isomerization by acid catalysis. J Org Chem, 42:2563-

2568, 1977.

Handrick, G. R., D. B. Uliss, H. C. Dalzell, and R. K. Razdan.

Hashish. Synthesis of (-)-Δ

9

-tetrahydrocannabinol (THC) and its

biologically potent metabolite 3

1

-hydroxy-Δ

9

-THC. Tetrahedron

Letters, 8:681-684, 1979.

Harvey, D. J., B. R. Martin, , and W. D. M. Paton. Identification of

metabolites of Δ

1

- and Δ

1(6) -tetrahydrocannabinol containing a

reduced double bond. J Pharm Pharmacol, 29:495-497, 1978.

Harvey, D. J., B. R. Martin, and W. D. M. Paton. Identification

of glucuronides as invivo liver conjugates of 7 cannabinoids and

some of their hydroxy acid metabolites. Res Commun Chem

Pathol Pharmacol, 16(2):265-279, 1977.

Harvey, D. J. and W. D. M. Paton. Identification of six substituted 4"-hydroxy-metabolites of Δ

1

-tetrahydrocannabinol in mouse

liver. Res Commun Chem Pathol Pharmacol, 21:435-436, 1978.

Hoffman, D., K. D. Brunnemann, G. B. Goria, and E. L. Wynder. On

the carcinogenicity of marijuana smoke. Recent Advances in PhytoChem, 9:63-81, 1975.

Hollister, L. E. Structure-activity relationships in man of Cannabis constituents, and homologs and metabolites of Δ

9

-tetrahydrocannabinol. Pharmacology, 11:3, 1974.

Humphrey, J. The chemistry of Cannabis indica. Pharm J, 14:392,

Johnson, K. M., and W. C. Dewey. The effect of Δ

9

-tetrahydrocannabinol on the conversion of [

3H]tryptophan to 5-[3H]-hydroxytriptamine in the mouse brain. J Pharmacol Exper Therapeu, 207:140-

150, 1978.

Jones, P. G., L. Falvello, 0. Kennard, and G. M. Sheddrick. Cannabidiol. Acta Cryst, B33:3211-3214, 1977.

Kanter, S. L., L. E. Hollister, and K. O. Loeffler. Marihuana

metabolites in the urine of man. VIII. Identification and quantitation of Δ

9

-tetrahydrocannabinol by thin layer chromatography and

high pressure liquid chromatography. J Chromatog, 150:233-237,

1978.

93
Karniol, I. G. and E. A. Carlini. The content of (-)-Δ

9

-transtetrahydrocannabinol (Δ9

-THC) does not explain all biological

activity of some Brazilian marihuana samples. J Pharm Pharmacol,

24:833-835, 1972.

Kettenes-van den Bosch, J. J., and C. A. Salemink. Cannabis XIX.

Oxygenated 1,2-diphenylethanes from marihuana. J Royal Netherlands

Chem Soc 97:7, 1978.

Küppers, F. J. E. M., C. A. L. Bercht, C. A. Salemink, R. J. J.

CH. Lousberg, J. K. Terlouw, and W. Heerma. Cannabis XIV. Pyrolysis

of cannabidiol-analysis of the volatile constituents. J Chromatog,

108:375-379, 1975.

Lee, M. L., M. Novotny, and K. D. Bartle. Gas chromatography/mass

spectrometric and nuclear magnetic resonance spectrometric studies

on carcinogenic polynuclear aromatic hydrocarbons in tobacco and

marihuana smoke condensate. Anal Chem, 48(2):405-416, 1976.

Lewis, G. S., and C. E. Turner. Constituents of Cannabis sativa L.

XIII. Stability of dosage form prepared by impregnating synthetic

(-)-Δ

9

-trans-tetrahydrocannabinol on placebo Cannabis plant material.

J Pharm Sci 67(6):876, 1978.

Lotter, H. L., D. J. Abraham, C. E. Turner, J. E. Knapp, P. L.

Schiff, Jr., and D. J. Slatkin. Cannabisativine, a new alkaloid

from Cannabis sativa L. root. Tetrahedron Letters, 33:2815-2818,

1975.

Luteyn, J. M., H. J. W. Spronck, and C. A. Salemink. Cannabis

XVIII. Isolation and synthesis of olivetol derivatives formed in

the pyrolysis of cannabidiol. J Royal Netherlands Chem Soc, 97:

187-190, 1978.

Manno, J. E., G. F. Kiplinger, S.E. Haine, I.F. Bennet, and R. B.

Forney. Comparative effects of smoking marihuana or placebo on

human motor performance. Clin Pharmacol Ther, 11:808-815, 1970.

Marihuana and Health, Fifth Annual Report to Congress from the Secretary or Health Education, and Welfare, 1975. DHEW Pub. No.(ADM)

76-314. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off. 1976.

Marihuana and Health, Sixth Annual Report to Congress from the Secretary of Health, Education,and Welfare, 1976. DHEW Pub. No.(ADM)

77-443. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off. 1977.

Maskarinec, M. P., G. Alexander, and M. Novotny. Analysis of the

acidic fraction of marihuana smoke condensate by capillary gas

chromatography-mass spectrometry. J Chromatogr, 126:559-568, 1976.

Mikes, F. and P. G. Waser. Marihuana components: effects of

smoking Δ

9

-tetrahydrocannabinol. Science, 172:1158-1159, 1971.

94
Myers, W. A. III, and R. G. Heath. Cannabis sativa: ultrastructural

changes in organelles of neurons in brain septal region of monkeys.

J Neuro Sci, 4:9-17, 1979.

Novotny, M., M. C. Lee, and K. D. Bartle. A possible chemical

basis for the higher mutagenicity of marihuana smoke as compared

to tobacco smoke. Experientia, 32(3):280-282, 1976.

Ohlsson, A., S. Agurell, K. Leander, J. Dahmén, H. Edery, G. Porath,

S. Levy, and R. Mechoulam. Synthesis and psychotropic activity of

side-chain hydroxylated Δ

6

-tetrahydrocannabinol metabolites. Acta

Pharmaceutica Succica, 16:21-33, 1979.

Ottersen, T., A. Aasen, F. S. El-Feraly, and C. E. Turner. X-ray

structure of cannabispiran: a novel Cannabis constituent. J Chem

Soc Chem Commun, 580-581, 1976.

Ottersen, T., E. Rosenqvist, C. E. Turner, and F. S. El-Feraly.

The crystal and molecular structure of cannabinol. Acta Chemica

Scandinavica B, 31:781-787, 1977a.

Ottersen, T., E. Rosenqvist, C. E. Turner, and F. S. El-Feraly.

The crystal and molecular structure of cannabidiol. Acta Chemica

Scandinavica B, 31:807-812, 1977b.

Perez-Reyes, M., M. C. Timmons, K. H. Davis, and M. E. Wall. A

comparison of the pharmacological activity in man of intravenously

administered Δ

9

-tetrahydrocannabinol, cannabinol, and cannabidiol.

Experientia, 29:1368, 1973.

Pirl, J. N., V. M. Papa, and J. J. Spikes. The detection of delta9-tetrahydrocannabinol in postmortem blood samples. J Anal Toxicol,

3:129-132, 1979.

Pitt, C. G., H. H. Seltzman, Y. Sayed, C. E. Twine, Jr., and D. L.

Williams. General synthesis of side chain derivatives of cannabinoids. J Org Chem, 44(5):677-683, 1979.

Preobraschensky, W. Cannabineae. Jahresber Pharmacog Toxicol,

4:98, 1876.

Robertson, L. W., S. W. Koh, S. R. Huff, R. K. Malhotra, and A.

Ghosh. Microbiological oxidation of the pentyl side chain of

cannabinoids. Experientia, 34:1020-1021, 1978.

Rodgers, R., C. P. Crowl, W. M. Eimstad, M. W. Hu, J. K. Kam, R.

C. Ronald, G. L. Rawley, E. F. Ullman. Homogenous enzyme immunoassay for cannabinoids in urine. Clin Chem, 24:95-100, 1978.

Rosenkrantz, H., and D. W. Hayden. Acute and subacute inhalation

toxicity of Turkish marihuana, cannabichromene, and cannabidiol

in rats. Toxicol Appl Pharmacol, 48:375-386, 1979.

Rosenthal, P., T. H. Harvey, J. T. Bursy, D. Brine, and M. E. Wall.

Comparison of gas chromatography mass spectrometry methods for the

determination of Δ

9

-THC in plasma. Biomed Mass Spectr, 5:312-316,

1978.

95
Roth, S.H., and P.J. Williams. The non-specific membrane binding

properties of Δ

9

-tetrahydrocannabinol and the effects of various

solubilizers. J Pharm Sci, 31:224-230, 1979.

Schou, J., L. D. Prockop, G. Dalhstrom, and C. Rohde. Penetration

of delta-9-tetrahydrocannabinol and 11-OH-delta-9-tetrahydrocannabinol through the blood-brain barrier. Acta Pharmacol et Toxicol,

41:33-38, 1977.

Shoyama, Y., and I. Nishioka. Cannabis XIII. Two new spriocompounds,

cannabispirol and acetyl cannabispirol. Chem Pharm Bull, 26(12):

3641, 1978.

Siemens, A. J. and D. C. Doyle. Cross-tolerance between Δ

9

-tetrahydrocannabinol and ethanol: the role of drug disposition.

Pharmacol Biochem Behav, 10:49-55, 1979.

Siemens, A. J., and J.M. Khanna. Acute metabolic interactions

between ethanol and Cannabis. Alcoholism Clin Exper Res, 1:343-

348, 1977.

Siemens, A. J., H. Kalant, and J. C. deNie. Metabolic interactions between Δ

9

-tetrahydrocannabinol and other cannabinoids in

rats. In: Braude, M. C., and Szara S., eds. The Pharmacology of

Marihuana. Raven Press, New York, 1976. pp. 77-92.

Spronck, H. J. W., and C. A. Salemink. Cannabis XVII. Pyrolysis

of cannabidiol. Structure elucidation of two pyrolytic conversion

products. J Royal Netherlands Chem Soc, 97:185, 1978.

Stillman, R. C., R. J. Wyatt, D. L. Murphy, and F. P. Rauscher.

Low platelet monoamine oxidase activity and chronic marihuana use.

Life Sci, 23:1577-1582, 1978.

Tamir, I., D. Lichtenberg, and R. Mechoulam. Interaction of cannabinoids with model membranes-NMR studies. In: Pullman B.

Nuclear Magnetic Resonance Spectroscopy in Molecular Biology.

Dordrecht, Holland: D. Reidel, 1978. pp.405-422.

Truitt, E. G., Jr. Biologic disposition of tetrahydrocannabinols.

Pharmacol Rev, 23:273-278, 1971.

Turner, C. E. and M. A. Elsohly. Constituents of Cannabis sativa

L. XVI. A possible decomposition pathway of Δ

9

-tetrahydrocannabinol

to cannabinol. J Heterocyclic Chem, accepted, 1979.

Turner, C. E., M. A. Elsohly, and E. G. Boeren. A review of the

chemical constituents of Cannabis sativa L. Lloydia, 43 (2), 1980.

Turner, C. E., M. A. Elsohly, P. C. Cheng, and G. Lewis. Constituents of Cannabis sativa L. XIV: intrinsic problems in classifying

Cannabis based on a single cannabinoid analysis. J Natural Products, 42(3):317-319, 1979.

96
Uliss, D. B., G. R. Handrick, H. C. Dalzell, and R. K. Razdan. The

conversion of 3,4-cis- to 3,4-trans-cannabinoids. Tetrahedron,

34:1885-1888, 1979.

Uliss, D. B., G. R. Handrick, H. C. Dalzell, and R. K. Razdan. A

terpenic synthon for Δ

1

-cannabinoids. J Am Chem Soc, 100(9):

2929-2930, 1978.

Uliss, D. B., G. R. Handrick, H. C. Dalzell, and R. K. Razdan. A

novel cannabinoid containing a 1,8-cineol moiety. Experientia,

33:577, 1977a.

Uliss, D. B., R. K. Razdan, H. C. Dalzell, and G. R. Handrick.

Synthesis of racemic and optically active Δ

1

- and Δ

6

-3,4-cis-tetrahydrocannabinols. Tetrahedron, 33:2055-2059, 1977b.

United Nations Division of Narcotic Drugs. The Chemistry of Cannabis and its components. MNAR/9/1974-GE, 74-11502, 1974.

United Nations Division of Narcotic Drugs. The Chemistry of Cannabis smoke. MNAR/6/1975-GE, 75-5104, 1935.

Vardaris, R. M., D. J. Weisz, A. Fazel, and A. B. Rawitch. Chronic

administration of delta-9-tetrahydrocannabinol to pregnant rats:

studies of pup behavior and placental transfer. Pharmacol Biochem

Behav, 4:249-254, 1976.

Waller, C.W., J.J. Johnson, J. Buelke, and C.E. Turner. Marihuana:

An Annotated Bibliography. Macmillan Information, New York: 1976.

pp. 560.

Yagen, B., S. Levy, R. Mechoulam. Synthesis and enzymatic fornation of a C-glucuronide of Δ

6

-tetrahydrocannabinol. J Am Chem

Soc, 99:6444-6446, 1977.

Yisak, W., S. Agurell, J. E. Lindgren, and M. Widman. In vivo

metabolites of cannabinol identified as fatty acid conjugates.

J Pharm Pharmac, 30:462-463, 1978.

Zwillich, G. W., R. Doekel, S. Hammill, and J. V. Weil. The

effects of smoked marihuana on metabolism and respiratory control.

Amer Rev Resp Dis, 118:885-891, 1978.

AUTHOR

Carlton E. Turner, Ph.D.

The University of Mississippi

Research Institute of Pharmaceutical Sciences

School of Pharmacy

9 7
Acute Effects of Marijuana on

Human Memory and Cognition

Douglas P. Ferraro, Ph.D.

A person who smokes or ingests marijuana will generally exhibit an

impairment in memory and cognitive functions, such as attending,

speaking, thinking, problem solving, and forming concepts. These

marijuana-induced impairments in psychological functioning are

apparently quite robust as they were easily identified by early

clinical investigators of the psychological syndrome of marijuana

intoxication (Ames 1958; Bromberg 1934; Halpern 1944; Williams

et al. 1946). These early clinical accounts have been remarkably

well verified by subsequent psychological descriptions of marijuana

intoxication in man (e.g., Tart 1971).

Wikler (1974) has noted that the most obvious feature which permeates

all descriptive accounts of acute marijuana intoxication is the

difficulty the observer has in understanding what the intoxicated

person is saying. Speech is fragmented, thought patterns are disjointed, and the speaker quite often forgets what is being thought

or what was recently said. On this basis, Weil and Zinberg

(1969) hypothesized that the acute effects of marijuana on speech

are due primarily to a drug-induced impairment of the user's

memory.

COGNITIVE TASKS

Early laboratory investigations of the effects of marijuana on

cognitive functioning in man also indirectly suggest that many of

the cognitive deficits produced by marijuana can be attributed to

memory failures. These early experiments established empirically

that marijuana can impair performance on a wide variety of cognitive tasks including: digit-symbol substitution (Weil, Zinberg and

Nelsen 1968), choice reaction time (Clark and Nakashima 1968),

digit span and goal directed serial alternation (Melges et al.

1970a, 1970b, 1971) serial subtraction (Manno et al. 1970), time

estimation (Jones and Stone 1970), production of time intervals

(Tinklenberg, Roth and Kopell 1976), spatial location (Clark and

Nakashima 1968), concept formation (Klonoff, Low and Marcus 1973),

98
abstraction (Pearl, Domino and Rennick 1973), attention (Dittrich,

Battig and Von Zeppelin 1973, Casswell and Marks 1973b) and

reading comprehension (Clark, Hughes and Nakashima 1970).

The inference that a drug-induced memory disruption occurs in these

experiments is drawn from the requirements of the cognitive tasks

themselves. For instance, under the digit span task, the subject

is presented with a number of digits and then is immediately asked

to recall them in order. Under the serial subtraction task, the

subject is given some starting number and then is asked to subtract

some constant number, such as seven, until zero is reached. In

other words, at any given moment in time the subject needs to remember what the current number is and to perform, from memory,

previously learned arithmetic operations. Likewise, the goal

directed serial alternation task requires the subject to hold a

number in memory and to perform cognitive functions directed

toward a remembered goal. It seems apparent that one could infer

that marijuana impairs memory directly from marijuana-induced

performance decrements under these cognitive tasks.

The inference that memory impairment mediates marijuana-induced

performance decrements on cognitive tasks is less direct in the

case of cognitive tasks involving, for example, concept formation,

abstraction, or reading comprehension. Nevertheless, in each of

these latter cases the inference is appropriate since each involves

the acquisition of some cognitive behavior, and the process of

acquisition may be viewed cognitively as consisting of memory processes and retrieval processes. A possible exception to this interpretation is any cognitive task that involves the fundamental

process of attention (DeLong and Levy 1973, 1974). It should be

noted, however, that there are several considerations which have

served to mitigate the inference, drawn from cognitive task performance, that marijuana impairs memory or that memory impairment

mediates marijuana-induced impairments in cognition.

The primary consideration is that subsequent research

did not always empirically confirm the earlier findings of marijuanainduced performance decrements on these same cognitive tasks. For

example, in selected experiments, marijuana did not affect performance on such cognitive tasks as: digit-symbol substitution (Hollister

and Gillespie 1970), choice and concept formation (Peters et al.

1976), reaction time (Rossi, Kuehnle and Mendelson 1977; Kvalseth

1977), digit span (Waskow et al. 1970; Rafaelsen et al. 1973),

goal directed serial alternation (Tinklenberg et al. 1972), serial

subtraction (Melges et al. 1970a), time production (Jones and Stone

1970; Tinklenberg et al. 1976), card sorting (Beautrais and Marks

1976), and attention (Sulkowski, Vachon and Rich 1977, Vachon and

Sulkowski 1976; Vachon, Sulkowski and Rich 1974).

Comprehensive reviews of the experimental literature pertaining to

marijuana’s effects on cognitive tasks of the types discussed herein

are available elsewhere (see especially: Abel 1975; Braude and

Szara 1976; DeLong and Levy 1974; Jones 1976; Miller 1974;

1976). A general perusal of these earlier reviews indicates that

99
marijuana most often impairs cognitive functioning. Additionally,

evidence favors interpreting these marijuana-induced impairments in

cognitive functioning in terms of memory disruption although, as

noted above, the data are too equivocal to be definitive in this

regard.

It is well established that most drug effects on memory and cognition depend upon a host of pharmacological and extrapharamcological

factors. Marijuana is similar to other psychoactive drugs in this

regard. Indeed, part of the above-described discrepancy in experimental findings regarding marijuana's effects on performance under

cognitive tasks may be accounted for in terms of such factors.

Furthermore, the early reported finding that marijuana's cognitive

effects are not consistently present within a subject but instead

tend to wax and wane across the duration of a single drug intoxication may be similarly explained (e.g., Clark and Nakashima 1968;

Tinklenberg et al. 1970; Rafaelsen et al. 1973).

With respect to pharmacological factors? for example, the adverse

effects of marijuana on cognitive functions including concept

formation, convergent and divergent thinking, goal direction,

attention, choice, and decisionmaking have been shown to be directly dependent upon the magnitude of the drug dose (Borg and Gershon

1975; Klonoff, Low and Marcus 1973; Klonoff and Low 1974; Schaefer,

Gunn and Dubowski 1977), although performance on some cognitive

tasks may paradoxically improve at low drug doses (Weckowicz et al.

1975). Further pharmacologically, propranolol pretreatment can

block a marijuana-produced impairment of performance on a digitsymbol substitution task (Sulkowski et al. 1977), but no drug

interactions are found between marijuana and cannabidiol (Dalton

et al. 1976) or marijuana and dextroamphetamine (Evans et al.

1976) on cognitive behavior. Neither cannabidiol or dextroamphetamine alters marijuana's effects on cognitive performance when administered simultaneously with marijuana. On the other hand, drug

combinations involving marijuana and alcohol produce additive effects

at first (Belgrave el al. 1979) and later may produce a possible

antagonism in that cognitive functions may eventually be less impaired under an alcohol-marijuana combination than under marijuana

alone (Chesher et al. 1977).

With respect to behavioral factors that have been shown to alter

marijuana's effects on cognition, Casswell (1975) has shown that

monetary incentive can attenuate marijuana's adverse effects on goal

directedness, choice, and memory. However, other experiments have

questioned the efficacy of monetary reward in modulating marijuana's

effects (Galanter et al. 1973) or have shown that motivational

factors may reduce drug effect on some tasks (e.g., time

estimation) but not on others (e.g., memory - cf. Cappell and

Pliner 1973; 1974). Peeke, Jones and Stone have shown that prior

practice on a cognitive task can eliminate the marijuana-produced

impairment on that task. In this latter context, Beautris and

Marks (1976) and Miller et al. (1977c) have disagreed in suggesting

that training in a nondrug state confers no advantage to the marijuana user when subsequently drugged. Still other research (Cohen

100
and Stillman 1976; Rafaelsen et al. 1973) has shown that marijuana's cognitive effects are directly related to the difficulty or

the complexity of the cognitive task.

Cappell and Pliner (1974) have reviewed the evidence that relates

amount of prior marijuana usage to marijuana's effects on cognition.

This review leaves no doubt that a prior history of marijuana use

can mitigate the drug's effects on cognitive performance. Indeed,

Cohen and Rickles (1974) and Cohen, Rickles and Naliboff (1975) have

proposed the construct of "cognitive tolerance" in order to account

for the fact that the very cognitive impairments which are produced

by marijuana in infrequent marijuana smokers (Rickles et al. 1973)

are not manifested by individuals who smoke marijuana frequently.

Individual differences and psychologically dynamic factors have also

been shown to modulate marijuana's effects on cognition. For example,

Linton, Kuechenmeister and White (1976) suggest that a person's

individual preference for marijuana is the most potent determinant

of the individual's response on cognitive tasks. Furthermore, the

effects of marijuana intoxication on cognition are related to the

individual user's extent of depersonalization (Melges et al. 1970),

cognitive style (Harshman, Crawford and Hecht 1976; Weckowicz et

al. 1975), and personality (Miller et al. 1978b).

Last, but by no means least, there is no gainsaying that the cognitive set of the marijuana user and the physical and social setting

in which the marijuana is consumed have considerable influence over

the subjective and cognitive effects of the drug (cf. Cappell and

Pliner, 1974; Jones 1976). In one of the more recent studies of

this sort, for example, it was found that the smoker's cognitive

expectancy and verbal labelling determine the level of intoxication

to marijuana (Pihl, Segal and Shea 1978).

To summarize briefly up to this point, marijuana clearly impairs

speaking, thinking, attending and other cognitive functions. One

possible interpretation of some of these drug-induced impairments

is that marijuana acts primarily to disrupt memory, and it is through

this behavioral mechanism of action that marijuana causes cognitive

dysfunction. The evidence favoring this interpretation, which can

be drawn from experiments using cognitive tasks, is inferential and

sometimes equivocal. Some of the variability between experimental

outcomes, which pertains to marijuana's effects on cognition, may

be attributed to pharmacological and extrapharmacological factors,

although this is not always so readily done (cf. Abel 1975, Miller

1976).

There is one other source of variance which complicates the interpretation of marijuana's effects on cognitive task performance.

This complication stems from the different dependent variables

used to measure performance on these tasks. Taking the abovedescribed serial subtraction task as an example, different

dependent variables are possible. Specifically, these dependent

variables are: time to complete the task, number of errors

made in completing it, and a combination of completion time and

101
number of errors. Interestingly, the majority of studies that have

observed marijuana-induced impairments on the serial subtration task

have given equal weight to time and errors as dependent variables

(Casswell and Marks 1973a, Manno et al. 1970), whereas when errors

alone are considered, no impairment may be observed (Pearl, Domino,

Rennick 1973; Rafaelsen et al. 1973).

The issue of which dependent variable is appropriate to measure

cognitive performance on these tasks is exacerbated when the tasks

are assumed to represent, or to be isomorphic with, different memory

functions (Melges et al. 1970a). For example, if the serial subtraction task involves only long-term memory, or both long-term

and short-term memory, then the question arises as to which dependent variable should be taken to represent which memory function

(Rafaelsen et al. 1973).

Taken together, the variability in experimental outcomes, the unidentified pharmacological and extrapharmacological determinants of

performance, the confusion regarding appropriate dependent

variable(s), and the lack of an adequate theoretical framework under

which to interpret the existing marijuana research on cognitive tasks

have led researchers, particularly those interested in marijuana's

effects on memory, to pursue alternate research paradigms. By and

large, psychopharmacological researchers have now adopted the

conventional methodologies used by experimental psychologists to

study memory and the corresponding theoretical frameworks (e.g.,

Atkinson and Shiffrin 1968; Kintsch 1970) in order more directly

to study the effects of marijuana on memory.

MEMORY TASKS

The procedures that have been used experimentally to study marijuana's

effects directly on memory have not been as multifarious as those

used to study marijuana's effects on cogniticm. Indeed, the procedures used to study marijuana's effects on memorial functioning can

be dichotomized between those procedures involving free recall and

those involving recognition memory.

Under the free recall procedure, subjects are first presented with

verbal or pictorial material to be learned. Subsequently, the subjects are asked to recall the previously presented material in the

absence of that material. The procedure is called free recall because there are no strictures placed on the subject as to the method

or order of recalling the material. The recall phase can occur

immediately after learning (immediate free recall) or after an

intervening period of time (delayed free recall). Of course, either

original learning, or subsequent recall, or both learning and recall

(or neither one) can occur under marijuana intoxication.

There are two typically used measures of free recall performance.

One measure is the overall amount or percentage of original material

that is correctly reproduced. The other is the serial position

curve, which is a graphical representation of the amount of material

102
recalled plotted as a function of the material's serial or&r of

presentation during learning. That is, the serial position curve

provides an answer to the question of whether the amount of material

freely recalled depends upon the order in which the material was

presented during learning. Under typical, nondrug, immediate freerecall conditions, the serial position curve has a U-shape; the best

recall occurs for material that had been presented first (primacy

effect) and last (recency effect).

The recognition memory procedure differs from the free recall procedure in that during the recall phase following original learning,

the subject must identify the previously presented material from an

array of old and new material. That is, rather than reproduce the

previously presented material, the subject is asked to recognize

which of the material presented during the recall phase was previously presented during the learning phase, and which was not.

Obviously, recognition memory may be tested immediately after learning or following a delay, and it may be tested in a drug or nondrug

state. The usual dependent variable under this procedure is some

measure of the total amount of material correctly recognized.

However, it has often been found useful to analyze the errors of

recognition into those instances where the subject failed to recognize previously presented material (misses) and those instances

where the subject purported to recognize material that had not been

previously presented (false alarms).

For ease of exposition, the ensuing review of the empirical literature pertaining to marijuana's acute effects on human memory will

deal separately with free recall and recognition memory. It will

be noted, however, that in some experiments these two memory procedures have been used in the same subject following a common learning experience (with the free recall procedure usually preceding

the recognition memory procedure). Similarly, the free recall data

will be arbitrarily divided between those situations where the

original material was learned in a nondrug (or placebo) state and

where original learning occurred in a marijuana-intoxicated state,

even though in some experiments subjects have served as their own

drug or nondrug controls. For other reviews of marijuana's effects

on memory, the reader should consult the following: Abel 1975;

Darley and Tinklenberg 1974; Miller 1976; and Tinklenberg and

Darley 1975, 1976.

Marijuana-Intoxicated Free Recall Following Nondrug Learning

The incisive question that the experiments reviewed in this section

were designed to answer is "Does marijuana cause you to forget

things you otherwise know?" Stated more functionally the question

is, "If an individual learns simple verbal material when not drugged,

what acute effect will marijuana have on the subsequent free recall

of that material?" The extant literature is unequivocal in its

answer to the latter question; marijuana has no effect on the free

recall of simple verbal material learned in a drug-free state. This

answer was indirectly suggested by the earlier research using cognitive tasks such as serial subtraction and goal directed serial

103
alternation (e.g., Melges et al. 1970a). However, the first direct

answer using an explicit memory task was provided by Abel (1971b,

1971c).

In Abel’s free recall experiments, subjects were first presented

with several lists of words in a nondrug state. Twenty-five minutes

after one-half of the subjects had smoked marijuana, all subjects

were given a delayed free recall test. No differences in recall

were obtained between drugged and nondrugged subjects. Abel’s

(1971b, 1971c) experiments contained some possible confoundings,

and used marijuana that was not analyzed for Δ-9-THC content.

Nevertheless, this research has stood the test of replication.

Using a well controlled methodology, Darley et al. (1973b) and

Dombush (1974) have directly replicated the finding that delayed

free recall of word lists learned in the nondrug state is not altered

by marijuana smoking or by oral ingestion of Δ-9-THC. Still

further, Darley et al. (1974) have found that neither fixed rehearsal

or free rehearsal of word lists during nondrugged learning differentially favors the marijuana or placebo group during subsequent delayed free recall of the lists. Finally, Pickles et al. (1973)

found that no significant marijuana-induced impairment in delayed

free recall of word responses occurs after prior nondrug learning

of a list of verbal paired associates.

Several other experiments have investigated the effects of marijuana

on the recall of verbal material that was previously learned outside

of the experimental situation. For example, Darley et al. (1977)

assessed the free recall of commonly known facts by college students.

The recall of the nonexperimentally presented information was not

affected by marijuana. The same conclusion was reached by Stillman

et al. (1974) who investigated the recall of preexperimentally

formed word associations (cf. Hill and Goodwin (1976) for a conflicting finding).

Delayed free recall of material learned in the nondrug state is not

as impervious to marijuana when the experimenter imposes a structure

on the material during original learning. For example, marijuana

significantly impairs the free recall of word lists that are presented as categorized groups of words during original learning

(Domino, Rennick and Pearl 1976; Pearl, Domino and Rennick 1973;

Eich et al. 1975; Stillman et al. 1976; Weingartner, Murphy and

Stillman 1978). Interestingly, in these experiments the marijuanainduced memory impairment is alleviated or eliminated if during

recall the subject is presented with retrieval cues in the form of

appropriate category names.

A second way to impose structure experimentally on material is to

sequence or order it during learning and to require that it subsequently be recalled in order. The delayed recall of ordered material

is impaired by the administration of marijuana prior to the recall

period. This drug effect on sequential recall has been found for

ordered arrangements of pictures, geometric objects , and meaningless

strings of words (Hill et al. 1973; Stillman et al. 1974; Weingartner, Murphy and Stillman 1978).

104
It should be noted that in these latter two general instances where

structure was added to the material, the recall procedure used was

not actually free-recall. That is, when retrieval cues are presented during recall, or when material is required to be recalled

in a particular sequence, the recall is not free in the sense of

being unaided or unrestricted. Thus, it is possible to offer a

reasonably consistent and general summary of the free recall literature following learning in a nondrug state. Specifically, when

compared to a person who learns material and later recalls it in a

nondrug state (ND-ND), a person who learns material in a nondrug

state but later recalls it in a marijuana drug state (ND-D) exhibits

no difference in memory function.

Marijuana-Intoxicated Free Recall Following

Marijuana-Intoxicated Learning

The literature reviewed in this section may also be introduced by

an empirical question. To wit, "Can a person under the influence

of marijuana recall material, which was learned when intoxicated,

as well as can a person who does not use marijuana during either

learning or recall?" More succinctly, the relevant comparison is

between learning and free recall in a marijuana drug state (D-D),

and learning and free recall in a nondrug state (ND-ND). As a

preview to the relevant literature that follows, it may be stated

that in this instance, the marijuana user has a distinct disadvantage.

The initial experiment in this area was again done by Abel (1970).

Subjects first smoked either a placebo or marijuana of unknown

Δ-9-THC content, and then read some narrative material. Fifteen

minutes later the placebo and drug subjects were asked to recall

freely what they had recently read. Marijuana had no effect on

total verbal output; the marijuana subjects produced as many total

words as did the nondrug subjects. However, marijuana significantly

decreased the smoker's ability to reproduce the narrative correctly

either in terms of words or meaning. In a direct followup to this

experiment, Abel (1971a) obtained precisely the same findings when

the narrative was read to the subjects rather than having the subjects read the narrative to themselves.

Additional support for the finding that narrative material, which

is heard and then later recalled freely, is not remembered as well

under the influence of marijuana was provided by Drew et al. (1972)

and Miller and Drew (1972). These latter workers made explicit what

was first noticed by Abel (1970), namely that marijuana-intoxicated

recall of narrative material is typified by distorted intrusions,

that is, by the introduction of new and unrelated material that was

not contained in the original narrative.

The marijuana-induced impairment in free recall memory observed in

these experiments is dose related (Miller and Cornett 1978), but

it is by no means specific to the narrative material used. Indeed,

under comparable drug and free recall procedures, it has been repeatedly found that the recall of widely varying verbal and

105
pictorial materials is generally diminished by marijuana intoxication. The generalization that learning and recall suffer with marijuana use applies to materials as diverse as: anagrams (Abel

1971a), auditory consonant trigrams (Dornbush, Fink and Freedman

1971), digits (Galanter et al. 1973), words (Abel, 1971b ; Darley

et al. 1973b), word associations (Hill et al. 1973), categorized

word lists (Pearl, Domino and Rennick 1973), geometric figures

(Miller, Cornett and Nallan 1978), pictures (Miller et al. 1977d),

and prose (Miller et al. 1977a).

As was the case for narrative material, marijuana-induced disruptions in free recall of other verbal material, such as a word list,

are characterized by intrusions of material external to the word

list or to the learning situation more generally (e.g., Miller et

al. 1976; 1977c; Pfefferbaum et al. 1977). Miller and coworkers

have further analyzed these marijuana-engendered intrusions of new

material and have found that the increase in intrusions is not dose

related (Miller and Cornett 1978), nor is it significantly correlated with total recall (Miller et al. 1977c ) or with cognitive

style (Miller, Cornett and Nallan 1978). In a related vein, marijuana increases the descriptive novelty of ambiguous stimuli (Roth

et al. 1975) but it does not enhance measures of object description (Tinklenberg et al. 1978). On balance, then, it appears that

marijuana-induced intrusions do not represent creative or associational thinking.

When material is both learned and recalled under marijuana, as it

was in the above-cited experiments in this section, it is not necessarily the case that drug-induced impairments in the free recall

of material implicate a memory dysfunction per se. Indeed, it is

conceivable that instead marijuana blocks the perception or sensory

registration of the presented material in such a way that no material

is ever made available to the marijuana user for later recall. It

has been clearly demonstrated, however, that marijuana does not

affect the sensory registration of presented information in this

manner.

One way this has been demonstrated has been to compare the free

recall of material immediately after presentation of the material

(0 sec delay) with recall following a delay of a few (4-6) seconds

(Dombush, Fink and Freeman 1971; Galanter et al. 1973). Under

marijuana intoxication, a few seconds can make a difference; immediate recall is not impaired while short-delay recall is depressed.

Obviously, the material must have registered in the sensorium to

be recalled at all, even immediately, although it is apparently not

available from memory after a few seconds.

A similar argument may be made based upon the serial position recall

curves that have been obtained in experiments investigating the

recall of word lists. When marijuana impairs free recall of word

lists, the obtained serial position recall curve necessarily differs

from that obtained in the nondrug state. In some experiments,

particularly but not necessarily if free recall is delayed somewhat,

the serial position curve obtained in the drug state will have the

106
same shape as that obtained in the nondrug state; but it will be

depressed throughout (e.g., Galanter et al. 1973; Miller et al.

1977a; 1977c). In other experiments, the drug state serial position

curve will be depressed at all serial input positions except for

the very last positions, that is, except for the few words that were

presented last during learning. For these most recently presented

words, the drug and nondrug serial position recall curves are not

different (Abel 1971b; Darley et al. 1973b; Darley and Tinklenberg

1974). Taken all together, these experiments again suggest that

marijuana does not interfere with the sensory registration of material, but it does somehow impair memorial registration (see also

Darley et al. (1973a) for further supporting data obtained with a

different experimental memory procedure).

Some of the research that has investigated the acute effects of

marijuana on recall of material learned in the drug state has gone

beyond the since identification and description of marijuana’s

acute effects to investigate the influence of various behavioral

factors on the marijuana-induced memory impairment. Among the

behavioral factors that have been investigated to date are ones

that might reasonably be expected to influence free recall of material when a person is in the nondrug state. Specifically, recent

experiments have studied the roles of practice, rehearsal, organization, and retrieval cues on free recall, mostly of word lists, in

the marijuana drug state.

The experiments that have investigated the effects of practice on

marijuana-intoxicated free recall have done so within an experimental

session rather than between experimental sessions as had been done

previously with cognitive tasks (e.g., Peeke, Jones and Stone 1976).

In the first of these memory experiments (Miller et al. 1977c),

marijuana-intoxicated and placebo subjects were presented with 20

word lists, with an immediate free recall memory test being given

after each list. The practice component in this experiment was

contained in the fact that the same word list was used as lists

numbered one, six, eleven, and sixteen. Practice on the word lists

did not attenuate the effects of marijuana on free recall; performance under marijuana was consistently inferior to performance under

placebo conditions for all word lists. A similar conclusion regarding the ineffectiveness of practice in attenuating marijuanainduced free recall deficits may be drawn from a study by Miller,

Cornett and McFarland (1978). These researchers used a technique

of restricted reminding in which, following an initial immediate

free-recall test of a 30-word list, only those words not recalled

were presented again, and again until the word was recalled once.

Thus, in subsequent learning trials the subject would be presented

with only previously unrecalled words, although the subject was

asked to recall the entire list during each memory test. Repeated

practice on previously unrecalled words did not alleviate the marijuana suppression of total recall.

Manipulating the subject’s rehearsal of words during list presentation also does not erase the deficits in immediate recall evidenced

by marijuana-intoxicated subjects. No matter whether the marijuana107
intoxicated individual is asked to rehearse the presentation of a

word freely and covertly (Darley et al. 1974; Darley and Tinklenberg 1974), overtly by repeating the word (Darley et al. 1974;

Pfefferbaum et al. 1977), or overtly by speaking aloud freeasociates to the word (Pfefferbaum et al. 1977), the marijuana

effect remains consistently in evidence.

When a marijuana-intoxicated person is asked freely to recall recently presented pictures and words, the subjective organization

of the material recalled does not differ from the subjective organization imposed upon the material by a nonintoxicated person

(Miller et al. 1977d). However, if the experimenter imposes an

organization on the material, say by presenting categorized lists

of words and, perhaps, category names, then the marijuana-intoxicated person will organize the material less during free recall and

will recall fewer total words than will the nonintoxicated person.

For example, Pearl, Domino and Rennick (1973) found that marijuanaintoxicated subjects less often recall items from the same category

together, and Eich et al. (1975) found that they recall fewer

categories all together.

Cueing the subject during the recall of categorized lists by providing the subject with appropriate category names has the effect

of erasing marijuana-placebo recall differences (Stillman et al.,

1976; Weingartner, Murphy and Stillman 1978). However, cueing is

not a generally effective method of overcoming a marijuana-induced

impairment of memory. For example, Miller et al. (1976) found that

cues representative of to-be-remembered words were only mildly

effective in reversing the recall deficit in marijuana-intoxicated

subjects. In a second experiment dealing with cued recall, Miller

et al. (1977a) used questions concerning facts and events in a

narrative as retrieval cues for the prose material. No relative

cued recall advantage was found in marijuana subjects as compared

to nondrug control subjects.

By way of summarizing this section, it may be said that when a

person uses marijuana, the person's ability to freely recall events

experienced in a marijuana state will be compromised. This druginduced impairment is pervasive in that it occurs with a wide

variety of verbal and pictoral material, and it is resistant to

amelioration, in that it is generally insensitive to practice,

rehearsal, or cueing. The problem clearly involves memorial

functioning in the marijuana smoker inasmuch as indices of sensory

registration show that the to-be-remembered material is initially

available to the marijuana smoker. Additionally, the marijuanaimpaired recall of material is sometimes characterized by a lack

of cognitive organization, and frequently involves the intrusion of

inappropriate memories.

Finally, in considering the preceding two sections on free recall

memory together, it is appropriate to emphasize the importance of

the drug state during original learning. If a person learns in a

nondrug state, later marijuana usage will have no effect, or only

a minimally detrimental effect, on the recall of the learned

108
material. Apparently, a change in marijuana drug state between

acquisition and recall (specifically, nondrug to drug) is not

sufficient in and of itself to produce substantially reliable

effects on memory. On the other hand, if a person learns under the

influence of marijuana and continues to use marijuana, the recall

of prior events will be seriously curtailed in comparison to the

memory of the nonuser of marijuana. This summarization gives rise

to one additional empirical question regarding free recall memory

and marijuana usage: "If a person learns material under the influence of mariajuana, will the subsequent recall of this material

depend upon the person's drug state at the time of recall?" In

other words, "Will the person remember better if marijuana intoxicated, or will the person have better recall if not under the influence of marijuana?"

Nondrug Free Recall Following

Marijuana-Intoxicated Learning

The issue here is one of state dependency, that is, whether material

learned in the marijuana state is better recalled in the same marijuana state (state dependence) or given a change to a nondrug state.

Before proceeding to discuss the literature pertaining to free recall

memory and state dependency, it should be noted that marijuana generally does not produce a wide ranging state dependency on cognitive and memory tasks.

For instance, no disadvantage is afforded the nonintoxicated person in performing a wide variety of cognitive tasks that were

originally learned while intoxicated, including: visual concept

formation and tactile form discrimination (Klonoff, Low and Marcus

1973), reaction time (Peeke, Jones and Stone 1976), and card

sorting (Beautrais and Marks 1976). Likewise, marijuana-intoxicated recall is not better than nondrug recall, after original

learning in the marijuana state, using a variety of memory procedures including: cued recall (Eich et al. 1975; Stillman et al.,

1976; Weingartner, Murphy and Stillman 1978), recognition memory

(Darley et al. 1973b, 1974), and tactile and auditory memory

(Klonoff, Low and Marcus 1973).

With respect to free recall procedures, there are a number of studies

that suggest that marijuana-intoxicated learning is not state dependent, material learned in the marijuana state is not better

recalled in the marijuana state than when not under the influence

of the drug. No state dependency has been found in free recall of

a variety of materials including: word lists (Stillman et al., 1974),

paired associates (Rickles et al. 1973), free associates (Hill and

Goodwin 1976), pictures (Klonoff, Low and Marcus 1973), and prose

(Miller et al. 1977a). Indeed, there exists in the literature only

one report of state-dependent memory using a free recall procedure

(Darley et al. 1974). In this latter experiment, delayed free

recall of word lists learned under marijuana was better in the drug

than in the nondrug state.

There are two general experimental procedures that tend to yield

109
state-dependent recall of material originally learned under marijuana. Interestingly, these are the same two procedures for which

a drug-induced recall impairment was obtained following nondrug

learning. Recall of material in the same drug (or same nondrug)

state seems to be consistently better than recall of material in a

changed state when the material has been organized by categories

(e.g., Weingartner, Murphy and Stillman 1978) or by sequential

order (e.g., Hill et al. 1973) during learning.

Overall then, marijuana does not often produce state dependent

performance on cognitive and memory tasks. What state dependency

there is for marijuana seems to be task dependent and somehow related to the organization of the material to be remembered.

More generally summarized, it appears that when considering the free

recall of learned material there are no advantages, and some distinct disadvantages, for the marijuana user. To begin with, in no

memory experiment using a free recall procedure has marijuana ever

been reported to enhance the user's memory of material learned in

thenondrug state. The weight of the evidence supports the same

conclusion for material learned in the drug state. Indeed, as

compared to the learning and free recall of material while nondrugged, marijuana intoxication has a generalized detrimental

effect on memory just as it does on cognition.

Recognition Memory

Many theories about the processes of memory contend that free recall

and recognition memory tasks measure different hypothetical memory

functions (e.g., Kintsch 1970; McCormack 1972). Be that as it

may, there is no denying that the two memory tasks are operationally

quite different. Procedurally, free recall involves the reproduction of previously experienced material, while recognition memory

involves the identification of previously experienced material that

is presented within the context of new material. As compared to the

investigation of marijuana's acute effects on free recall, there

has been much less research done on the effects of marijuana on

recognition memory. Nevertheless, what research has been done

tends to support the generalization that the person who becomes

intoxicated with marijuana risks the possibility of an impaired

memory. As might be expected from the free recall data, marijuana's

acute effects on recognition memory depend, to some extent, upon

the drug condition present at the time of original learning and

again later during the recognition test. However, in no instance

has it been found that marijuana facilitates recognition memory.

Beginning with the situation in which subjects are presented with

verbal material in a nondrug state and then are later asked to

recognize the material in either a nondrug or marijuana-intoxicated

state, the literature is quite consistent in showing that drug and

nondrug subjects do not differ in terms of the number of items

correctly identified. Apparently marijuana does not impair one's

ability to recognize correctly material that was previously experienced in a nondrug state (e.g., Abel 1971b; 1971c; Darley et al.

110
1973b; 1974; Miller et al., 1977b). This lack of an effect on

recognition memory holds across a range of marijuana doses miller

and Cornett, 1978), and for material experienced both within and

outside the experimental situation (Darley et al. 1977).

There is one drug-related effect which is sometimes reported in

the recognition memory context and that pertains to the occurrence

of false alarm errors, that is, to the erroneous positive identification of material which, in fact, had not been previously presented. (False alarms in recognition memory bear a conceptual

similarity to erroneous intrusions in free recall). When recognition memory of material previously experienced in a nondrug state

is tested in the marijuana-intoxicated person, an increase in false

alarms is sometimes (Abel 1971b , 1971c; Dornbush 1974), but not

always (Miller et al. 1977b; Miller and Cornett 1978), observed.

Recognition memory for material originally experienced while marijuana intoxicated has been studied systematically in only four experiments, all of which used word lists. In one of these experiments (Dornbush 1974), subjects were exposed to the word lists in

either a nondrug or marijuana state and then were tested for recognition memory in the marijuana state. The initial drug exposure

produced a small decrease in subsequent recognition memory, which

was typified by an increase in false alarms.

The remaining three experiments compared recognition memory between subjects who were always in the marijuana-intoxicated state

with those who were not drugged during either the initial presentation of the material or the later recognition memort test. The

data here are somewhat equivocal. A drug-induced impairment was

found in one experiment (Darley et al. 1973b ) but not in the

other two (Darley et al. 1974; Miller et al. 1977).

Quite obviously, marijuana-induced memory impairments are not as

intensive under a recognition memory procedure as they are under a

free recall procedure. However, as suggested at the outset of this

section, the recognition memory data are well in accord with the

data reviewed for cognitive tasks and for the free recall of

material from memory. Marijuana’s acute effects on memory and

cognition are sometimes small, but where there are effects, large

or small, they are seemingly always detrimental to the marijuana

user.

REFERENCES

Abel, E.L. Marijuana and memory. Nature, 227: 1151-1152, 1970.

Abel, E.L. Effects of marijuana on the solution of anagrams,

memory and appetite. Nature, 231: 260-261, 1971a.

Abel, E.L. Marijuana and memory: Acquisition or retrieval?

Science, 173: 1038-1040, 1971b.

111
Abel, E.L. Retrieval of information after use of marijuana.

Nature, 231: 58, 1971c.

Abel, E.L. Marijuana, learning and memory. International Review

of Neurobiology, 18: 329-356, 1975.

Ames, F. A clinical and metabolic study of acute intoxication with

cannabis sativa and its role in the model psychoses. Journal of

Mental Science, 104: 972-999, 1958.

Atkinson, R.C., and Shiffrin, R.M. Human memory: A proposed system

and its control processes. In: Spence, K.W., and Spence, J.T., eds.

The Psychology of Learning and Motivation: Advances in Research and

Theory. Vol. II. New York: Academic Press, 1968. pp. 89-195.

Beautrais, A.L., and Marks, D.F. A test of state dependency effects

in marijuana intoxication for the learning of psychomotor tasks.

Psychopharmacologia, 46: 37-40, 1976.

Belgrave, B.E., Bird, K.D., Chesher, G.B., Jackson, D.M., Lubbe, K.E.

Starmer, G.A., and Teo, R.K. The effect of (-) trans-delta-9-

tetrahydrocanna binol, alone and in combination with ethanol, on

human performance. Psychopharmacology, 62: 53-60, 1979.

Borg, J., and Gershon, S. Dose effects of smoked marijuana on human

cognitive and motor functions. Psychopharmacologia, 42: 211-218,

1975.

Braude, M.C., and Szara, S., eds. The Pharmacology of Marijuana.

New York: Raven Press, 1976.

Bromberg, W. Marijuana intoxication. American Journal of Psychiatry, 91: 303-330, 1934.

Cappell, H.D., and Pliner, P.C. Volitional control of marijuana

intoxication: A study of the ability to "come down" on command.

Journal of Abnormal Psychology, 82: 428-434, 1973.

Cappell, H.D., and Pliner, P.C. Cannabis intoxication: The role of

pharmacological and psychological variables. In: Miller, L.L., ed.

Marijuana: Effects on Human Behavior. New York: Academic Press,

1974. pp. 233-264.

Casswell, S. Cannabis intoxication: Effects of monetary incentive

on performance, a controlled investigation of behavioral tolerance

in moderate users of cannabis. Perceptual and Motor Skills, 41:

423-434, 1975.

Casswell, S., and Marks, D. Cannabis and temporal disintegration

in experienced and naive subjects. Science, 179: 803-805, 1973a.

Casswell, S., and Marks, D. Cannabis induced impairment of performance of a divided attention task. Nature, 241: 60-61, 1973b.

112
Chesher, G.B., Franks, H.M., Jackson, D.M., Starmer, G.A., and

Teo, R.K. Ethanol and delta-9-tetrahydrocannabinol interactive

effects on human perceptual, cognitive and motor functions. II.

Medical Journal of Australia, 1: 478-481, 1977.

Clark, L.D., Hughes, R., and Nakashima, E.N. Behavioral effects of

marijuana: Experimental studies. Archives of General Psychiatry,

23: 193-198, 1970.

Clark, L. D., and Naskashima, E.N. Experimental studies of marijuana. American Journal of Psychiatry, 125: 379-384, 1968.

Cohen, M.J., and Rickles, Jr., W.H. Performance on a verbal

learning task by subjects of heavy past marijuana usage. Psychopharmacologia, 37: 323-330, 1974.

Cohen, M.J., Rickles, W.H., and Naliboff, B.D. Marijuana influenced changes in GSR activation peaking during paired-associate

learning. Pharmacology, Biochemistry and Behavior, 3: 195-200, 1975.

Cohen, S., and Stillman, R.C., eds. The Therapeutic Potential of

Marijuana. New York: Plenum, 1976.

Dalton, W.S., Martz, R., Lemberger, L., Rodda, B.E., and Forney,

R.B. Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. Clinical Pharmacology and Therapeutics, 19: 300-309, 1976.

Darley, C.F., and Tinklenberg, J.R. Marijuana and memory. In:

Miller, L.L., ed. Marijuana: Effects on Human Behavior. New York:

Academic Press, 1974. pp. 73-102.

Darley, C.F., Tinklenberg, J.R., Hollister, T.E., and Atkinson,

R.C. Marijuana and retrieval from short-term memory, Psychopharmacologia, 29: 231-238, 1973a.

Darley, C.F., Tinklenberg, J.R., Roth, W.T., and Atkinson, R.C.

The nature of storage deficits and state-dependent retrieval under

marijuana. Psychopharmacologia, 37: 139-149, 1974.

Darley, C.F., Tinklenberg, J.R., Roth, W.T., Hollister, L.E., and

Atkinson, R.C. Influence of marijuana on storage and retrieval

processes in memory. Memory and Cognition, 1: 196-200, 1973b.

Darley, C.F., Tinkleberg, J.R., Roth, W.T., Vernon, S., and Kopell,

B.S. Marijuana effects on long-term memory assessment and retrieval.

Psycopharmacology, 52: 239-241, 1977.

DeLong, F.L., and Levy, B.I. Cognitive effects of marijuana described in terms of a model of attention. Psychological Reports,

33: 907-916, 1973.

DeLong, F.L., and Levy, B.I. A model of attention describing the

cognitive effects of marijuana. In: Miller, L.L., ed. Marijuana:

Effects on Human Behavior. New York: Academic Press, 1974. pp. 103-120.

113
Dittrich, A., Battig, K., and von Zeppelin, I. Effects of (-)

delta-9-trans-tetrahydrocannabinol (Δ -9-THC) on memory, attention

and subjective state: A double blind study. Psychopharmacologia,

33: 369-376, 1973.

Domino, E.F., Rennick, P., and Pearl, J.H. Short-term neuropsychopharmacological effects of marijuana smoking in experienced male

users. In: Braude, M.C., and Szara, S., eds. The Pharmacology of

Marijuana, Vol. I. New York: Raven Press, 1976. pp. 393-412.

Dornbush, R.L. Marijuana and memory: Effects of smoking on storage.

Transactions of the New York Academy of Science, 36: 94-100, 1974.

Dombush, R.L., Fink, M., and Freedman, A.M. Marijuana, memory and

perception. American Journal of Psychiatry, 128: 194-197, 1971.

Drew, W.G., Kiplinger, G.F., Miller, L.L., and Marx, M. Effects of

propranolol on marijuana-induced cognitive dysfunctioning.

Clinical Pharmacology and Therapeutics, 13: 526-533; 1972.

Eich, J.E., Weingartner, H., Stillman, R.C., and Gillin, J.D.

State dependent accessibility of retrieval cues in the retention

of a categorized list. Journal of Verbal Learning and Verbal Behavior, 14: 408-417, 1975.

Evans, M.A., Martz, R., Rodda, B.E., Lemberger, L., and Forney, R.B.

Effects of marijuana-dextroamphetamine combination. Clinical

Pharmacology and Therapeutics, 20: 350-358, 1976.

Galanter, M., Weingartner, H., Vaughan, T.B., Roth, W.T., and Wyatt,

R.J. Delta-9-trans-tetrahydrocannabinol and natural marijuana.

Archives of General Psychiatry, 28: 278-281, 1973.

Halpem, F. Psychological study. In: Mayor LaGuardia's Committee

on Marijuana. The Marijuana Problem in the City of New York --

Sociological, Medical, Psychological, and Pharmacological Studies.

Lancaster: Jacques Cattell, 1944.

Harshman, R.A., Crawford, H.F., Hecht, E. Marijuana, cognitive

style and lateralized hemispheric functions. In: Cohen, S., and

Stillman, R.C., eds. The Therapeutic Potential of Marijuana. New

York: Plenum, 1976. pp. 205-254.

Hill, S.Y., and Goodwin, D.W. Stimulant effects of marijuana on

three neuropsychological systems. In: Cohen, S., and Stillman, R.C.,

eds. The Therapeutic Potential of Marijuana. New York: Plenum,

1976. pp. 139-152.

Hill, S.Y., Schwin, R., Powell, B., and Goodwin, D.W. State-dependent effects of marijuana on human memory. Nature, 243: 241-242,

1973.

Hollister, L.E., and Gillespie, H.K. Marijuana, ethanol, and dextroamphetamine: Mood and mental function alterations. Archives of

114
General Psychiatry, 23: 199-203, 1970.

Jones, R. Human Effects. In: Petersen, R.C., ed. Marijuana Research Findings: 1976. National Institutes on Drug Abuse Research

Monograph 14 DHEW Pub No. (ADM)77-501. Washington, D. C.: Superintendent of Documents, U.S. Government Printing Office, 1976.

pp. 128-178.

Jones, R.T., and Stone, G.C. Psychological studies of marijuana

and alcohol in man. Psychopharmacologia, 18: 108-117, 1970.

Kintsch, W. Models for free recall and recognition. In: Norman,

D.A., ed. Models of Human Memory. New York: Academic Press, 1970.

Klonoff, H., and Low, M.D. Psychological and neurophysiological

effects of marijuana in man: An interaction model. In: Miller, L.L.,

ed. Marijuana: Effects on Human Behavior. New York: Academic

Press, 1974. pp. 121-157.

Klonoff, H., Low, M., and Marcus, A. Neuropsychological effects of

marijuana. Canadian Medical Association Journal, 108: 150-156, 1973.

Kvalseth, T.O. Effects of marijuana on human reaction time and

motor control. Perceptual and Motor Skills, 45: 935-939, 1977.

Linton, P.H., Kuechenmeister, C.A., and White, H.B. Drug preference

and response to marijuana and alcohol. Research Communications in

Psychology, Psychiatry and Behavior, 1: 629-643, 1976.

Manno, J., Kiplinger, G.F., Haine, S.E., Bennett, I.F., and Forney,

R.B. Comparative effects of smoking marijuana or placebo on human

motor and mental performance. Clinical Pharmacology and Therapeutics, 11: 808-815, 1970.

McCormack, P.D. Recognition memory: How complex a retrieval system?

Canadian Journal of Psychology, 26: 19-41, 1972.

Melges, F.T., Tinklenberg, J.R., Hollister, L.E., and Gillespie,

H.K. Marijuana and temporal disintegration. Science, 168: 1118-

1120, 1970a.

Melges, F.T., Tinklenberg, J.R., Hollister, L.E., and Gillespie,

H.K. Temporal disintegration and depersonalization during marijuana intoxication. Archives of General Psychiatry, 23: 204-210,

1970b.

Melges, F.T., Tinklenberg, J.R., Hollister, L.E., and Gillespie, H.K.

Marijuana and the temporal span of awareness. Archives of General

Psychiatry, 24: 564-567, 1971.

Miller, L.L., ed. Marijuana: Effects on Human Behavior. New York:

Academic Press, 1974.

Miller, L.L. Marijuana and human cognition: A review of laboratory

115
investigations. In: Cohen, S., and Stillman, R.C., eds. The

Therapeutic Potential of Marijuana. New York: Plenum, 1976

pp. 271-292.

Miller, L.L., and Cornett, T.L. Marijuana: Dose effects on pulse

rate, subjective estimates of intoxication, free recall and recognition memory. Pharmacology, Biochemistry and Behavior, 9: 573-

577, 1978.

Miller, L.L., Cornett, T., Brightwell, D., McFarland, D., Drew,

W.G., and Wikler, A. Marijuana and memory impairment: The effect

of retrieval cues on free recall. Pharmacology, Biochemistry and

Behavior, 5: 639-643, 1976.

Miller, L.L., Cornett, T.L., Brightwell, D.R., McFarland, D.J.,

Drew, W.G., and Wikler, A. Marijuana: Effects on storage and retrieval of prose material. Psychopharmacology, 51: 311-316, 1977a .

Miller, L., Cornett, T., Drew, W., McFarland, D., Brightwell, D.,

and Wikler, A. Marijuana: Dose-response effects on pulse rate,

subjective estimates of potency, pleasantness, and recognition

memory. Pharmacology, 15: 268-275, 1977b.

Miller, L., Cornett, T., and McFarland, D. Marijuana: An analysis

of storage and retrieval deficits in memory with the technique of

restricted reminding. Pharmacology, Biochemistry and Behavior,

8: 327-332, 1978.

Miller, L., Cornett, T., and Nallan, G. Marijuana: Effect on nonverbal free recall as a function of field dependence. Psychopharmacology, 58: 297-301, 1978.

Miller, L.L., and Drew, W.G. Effects of marijuana on recall of

narrative material and Stroop colour-word performance. Nature,

237: 172-173, 1972.

Miller, L.L., McFarland, D., Cornett, T.L., and Brightwell, D.

Marijuana and memory impairment: Effect on free recall and recognition memory. Pharmacology, Biochemistry and Behavior. 7: 99-

103, 1977c.

Miller, L.L., McFarland, D.J., Cornett, T.L., Brightwell, D.R., and

Wikler, A. Marijuana: Effects of free recall and subjective organization of pictures and words. Psychopharmacology, 55: 257-262,

1977d.

Pearl, J.H., Domino, E.F., and Rennick, P. Short-term effects of

marijuana smoking on cognitive behavior in experienced male users.

Psychopharmacologia, 31: 13-24, 1973.

Peeke, S.C., Jones, R.T., and Stone, G.C. Effects of practice on

marijuana-induced changes in reaction time. Psychophamacologia,

48: 159-163, 1976.

116
Peters, B.A., Lewis, E.G., Dustman, R.E., Straight, R.C., and Beck,

E.C. Sensory, perceptual, motor and cognitive functioning and subjective reports following oral administration of Δ-9-tetrahydrocannabinol. Psychopharmacology, 47: 141-148, 1976.

Pfefferbaum, A., Darley, C.F., Tinklenberg, J.R., Roth, W.T., and

Kopell, B.S. Marijuana and memory intrusions, The Journal of

Nervous and Mental Disease, 165: 381-386, 1977.

Pihl, R.O., Segal, Z., and Shea, D. Negative expectancy as a mediating variable in marijuana intoxication. Journal of Clinical

Psychology, 34: 978-982, 1978.

Rafaelsen, L., Christrup, H., Beck, P., and Rafaelsen, O.J. Effects

of cannabis and alcohol on psychological tests. Nature, 242:

117-118, 1973.

Rickles, Jr., W.H., Cohen, M.J., Whitaker, C.A., and McIntyre, K.E.

Marijuana induced state-dependent verbal learning. Psychopharmacologia, 30: 349-354, 1973.

Rossi, A.M., Kuehnle, J.C., and Mendelson, J.H. Effects of marijuana on reaction time and short-term memory in human volunteers.

Pharmacology, Biochemistry and Behavior, 1: 73-77, 1977.

Roth, W.T., Rosenbloom, M.J., Darley, C.F., Tinklenberg, J.R.,

and Kopell, B.S. Marijuana effects on TAT form and content.

Psychopharmacologia, 43: 261-266, 1975.

Schaefer, C.F., Gunn, C.G., and Dubowski, K.M. Dose-related heartrate, perceptual, and decisional changes in man following marijuana

smoking. Perceptual and Motor Skills, 44: 3-16, 1977.

Stillman, R., Eich, J.E., Weingartner, H., and Wyatt, R.J. Marijuana-induced state-dependent amnesia and its reversal by cueing.

In: Braude, M.C., and Szara, S., eds. The Pharmacology of Marijuana, Vol. I. New York: Raven Press, 1976. pp. 453-456.

Stillman, R.C., Weingartner, H., Wyatt, R.J., Gillin, C., and Eich,

J. State-dependent (dissociative) effects of marijuana on human

memory. Archives of General Psychiatry, 31: 81-85, 1974.

Sulkowski, A., Vachon, L., and Rich, Jr., E.S. Propranolol effects

on acute marijuana intoxication in man. Psychopharmacology, 52:

47-53, 1977.

Tart, C.T. On Being Stoned, A Psychological Study of Marijuana

Intoxication. Palo Alto: Science and Behavior Books, 197l.

Tinklenberg, J.R., and Darley, C.F. Psychological and cognitive

effects of cannabis. In: Cornell, P.H., and Dorn, N., eds.

Cannabis and Man. New York: Churchill Livingstone, 1975.

Tinklenberg, J.R., and Darley, C.F. A model of marijuana's cognitive

117
effects. In: Braude, M.C., and Szara, S., eds. The Pharmacology

of Marijuana, Vol. I. New York: Raven Press, 1976. pp. 429-439.

Tinklenberg, J.R., Darley, C.F., Roth, W.T., Pfefferbaum, A., and

Kopell, B.S. Marijuana effects on associations to novel stimuli.

The Journal of Nervous and Mental Disease, 166: 362-364, 1978.

Tinklenberg, J.R., Kopell, B.S., Melges, F.T., and Hollister, L.E.

Marijuana and alcohol: Time production and memory functions.

Archives of General Psychiatry, 27: 812-815, 1972.

Tinklenberg, J.R., Melges, F.T., Hollister, L.E., and Gillespie,

H.K. Marijuana and immediate memory. Nature, 226: 1171-1172, 1970.

Tinklenberg, J.R., Roth, W.T., and Kopell, B.S. Marijuana and

ethanol: Differential effects on time perception, heart rate, and

subjective response. Psychopharmacology, 49: 275-279, 1976.

Vachon, L., and Sulkowski, A. Attention, learning and speed in

psychomotor performance after marijuana smoking. In: Braude, M.C.,

and Szara, S., eds. The Pharmacology of Marijuana, Vol. I. New

York: Raven Press, 1976. pp. 449-452.

Vachon, L., Sulkowski, A., and Rich, E. Marijuana effects on

learning, attention and time estimation. Psychopharmacologia, 39:

1-11, 1974.

Waskow, I.E., Olsson, J.E., Salzman, C., and Katz, M.M. Psychological effects of tetrahydrocannabinol. Archives of General Psychiatry, 22: 97-107, 1970.

Weckowicz, T.E., Fedora, O., Mason, J:, Radstaak, D., Bay, F.S., and

Yonge, K.A. Effect of marijuana on divergent and convergent production cognitive tests. Journal of Abnormal Psychology, 84: 386-

398, 1975.

Weil, A.T., and Zinberg, N.E. Acute effects of marijuana on speech.

Nature, 222: 434-437, 1969.

Weil, A.T., Zinberg, N.E., and Nelsen, J.M. Clinical and psychological effects of marijuana in man. Science, 162: 1234-1242, 1968.

Weingartner, H., Murphy, D., and Stillman, R.C. Drug and mood

state-specific encoding and retrieval of experience. In: Petersen,

R.C., ed. The International Challenge of Drug Abuse. National

Institute on Drug Abuse Research Monograph 19. DHEW Pub. No. (ADM)

78-654. Washington, D.C.: Superintendent of Documents, U.S.

Government Printing Office, 1978. pp. 210-223.

Wikler, A. The marijuana controversy. In: Miller, L.L., ed.

Marijuana: Effects on Human Behavior. New York: Academic Press,

1974. pp. 25-45.

Williams, E.G., Himmelsbach, C.K., Wikler, A., Ruble, D.C., and

118
Llody, B.J. Studies on marijuana and pyrahexyl compound. Public

Health Reports, 61: 1059-1083, 1946.

AUTHOR

Douglas P. Ferraro, Ph.D.

Department of Psychology

University of New Mexico

Albuquerque, New Mexico 87131

119
Effects of Marijuana on

Neuroendocrine Function

Carol Grace Smith, Ph.D.

One of the major problems of studying the effects of drugs on

neuroendocrine systems relates to an incomplete understanding of

mechanisms of neuroendocrine regulation. In general, a neuroendocrine system consists of neural cells which secrete a chemical

substance (neurohormone) that exerts its effect on other cells

within the body. These target cells may be other nerves or

somatic cells. Thus, the neurohormones are often placed into two

classes. One class consists of those secretions that are known

to be involved in neural function, such as the neurotransmitters.

The second class consists of those secretions that are involved

in somatic cell function, such as the hypothalamic hormones that

regulate anterior pituitary function. The mechanisms that control neuroendocrine activity are thought to be forms of negative

or positive feedback, similar to the feedback systems that control the peripheral endocrine glands.

Most of the newer studies of the effects of marijuana on neuroendocrine regulation have examined the effects of the drug on the

hypothalamic-pituitary axis. These studies have resulted in part

because of the observed effects of marijuana on the peripheral

endocrine organs that are regulated by the hypothalamic-pituitary

axis. For example, the reproductive consequences of prolonged

marijuana use include both 1) alterations in reproductive hormones (Smith et al. 1979) and 2) effects on spermatogenesis

(Hembree et al. 1976) or ovulation (Smith et al. 1979). Since

both of these reproductive processes are controlled by the hormones from the anterior pituitary gland, and since marijuana is a

neuroactive drug, it seemed reasonable to assume that the hypothalamic-pituitary axis was the site of action for the reproductive effects of marijuana.

In attempting to describe a mechanism for the hypothalamic-pituitary effects of marijuana, it becomes apparent that the study of

the effects of marijuana on central nervous system neurotransmitters is also important. These neurotransmitters are located

along the nervous pathways that regulate the hypothalamic-pituitary axis and, at a cellular level, the effect of marijuana may

120
be mediated by the drug's effect on these neurotransmitters.

Thus, in order to summarize these studies on the effects of

marijuana on neuroendocrine regulation, this review will be

divided into two parts: 1) evidence for the effects of marijuana

on hypothalamic-pituitary function and 2) studies on the role of

neurotransmitters in the mechanism of action of marijuana effects

on hypothalamic-pituitary function.

EVIDENCE FOR THE EFFECT OF MARIJUANA ON

HYPOTHALAMIC-PITUITARY FUNCTION

Effects of THC on Gonadotropin Secretion

Since the initial report by Harks in 1973 of the inhibitory

effect of tetrahydrocannabinol (THC) on luteinizing hormone (LH)

levels in ovariectomized rats, a number of studies have appeared

which confirm this observation and attempt to describe the mechanism. Studies in the ovariectomised rhesus monkey have defined

the dose-response relationship of the effect (Besch et al. 1977).

In these studies, THC (0.6 - 5.0 mg/kg) or vehicle (3 percent

polysorbate 80 [Tween 80] in saline) was given to ovariectomized

monkeys by an intramuscular injection. The result was a prompt

and significant decrease in LH levels (average 50 - 80 percent

decrease) that lasted for 12 - 24 hours depending upon the dose

level of THC. These results are in agreement with studies in

ovariectomized rats (Tyrey 1978) which showed a suppression in

episodic LH secretion following THC administration. In both the

monkey and rat studies, the magnitude of the decreases appeared

not to be directly related to the dose of THC; but the duration

of the responses was shown to be related to the dose, with larger

doses of THC producing longer lasting depressions in gonadotropin

levels. The suppression of LH secretion appeared to be complete,

but the effect was completely reversible.

A comparison of the effects of the various doses of THC on the

levels of LH and the levels of follicle stimulating hormone (FSH)

in ovariectomized monkeys showed no great differences between the

two gonadotropins (Smith et al. 1979). For example, the average

maximum decrease in LH and FSH following the 5.0 mg/kg dose of

THC was 68 percent and 56 percent respectively. Comparison of

the time course of the effects on gonadotropin levels in individual monkeys showed that the maximum decrease in hormone levels

occurred at generally the same times for LH and FSH.

It is important to note, at this point, that these studies have

examined the effect of Δ

9

-tetrahydrocannabinol on pituitary

hormone levels. One study has compared the effects of THC and

other marijuana derivatives, including the crude alcohol extract

of marijuana (CME) containing 25 to 30 percent THC (Smith et al.

1979). THC and CME were administered to ovariectomixed monkeys

at equivalent dose levels (based on total amount of THC). The

decreases in both LH and FSH levels were equivalent in response

to equal doses of THC and CME. That is, the 4.16 mg/kg dose of

CME produced an average 40.8 percent inhibition of LH levels that

121
lasted for 6 hours. The equivalent dose of THC (1.25 mg/kg)

produced an average 35.9 percent decrease in LH that also lasted

for 6 hours. Other cannabis derivatives that were examined for

effects on pituitary hormones included cannabidiol (CBD) and

cannabinol (CBN). Neither CBD nor CBN had any statistically

significant effect on gonadotropin levels at dose levels up to 10

mg/kg.

The comparison of the inhibition of gonadotropins produced by

THC, marijuana extract and the other cannabis derivatives indicates that the inhibitory action of marijuana on gonadotropin

levels is produced by THC, and that the other cannabis derivatives contained in marijuana do not contribute to the effect.

This is particularly evident because the relative doses of CBN

and CBD used in this study were much larger than would be contained in the doses of marijuana extract. In addition, these

results suggest, but do not prove, that the inhibitory effect of

cannabis derivatives on gonadotropins is related to their psychoactivity. Further studies need to be done with other psychoactive cannabinoids and with cannabis derivatives devoid of psychoactive properties. It should also be noted that while certain

cannabis derivatives may not contribute significantly to the

endocrine changes caused by marijuana, they may have other direct

effects on spermatogenesis, ovulation, and other reproductive

functions.

The pharmacological site of action of a single dose of THC on

gonadotropin levels was investigated in ovariectomized monkeys

(Smith et al. 1979). Synthetic gonadotropin releasing factor

(GnRH) was administered to the monkeys 6 hours after the administration of 2.5 mg/kg of THC. This dose of THC produces a

statistically significant depression in gonadotropins that lasts

for at least 12 hours. GnRH administration resulted in a stimulation of the blood levels of both LH and FSH. The increase in

LH and FSH levels was statistically significant at 30, 60, 90,

and 120 minutes after the GnRH administration. The stimulation

of LH and FSH levels measured after GnRH could be considered as a

reversal of the effect of THC since all of the stimulated gonadotropin levels were within the 95 percent confidence interval

established for each monkey's control values. The response to

releasing hormone in ovariectomised rats was the same as the

response in monkeys (Tyrey 1978). Further, the suppression of

ovulation in rats (Nir et al., 1973) and in rabbits (Asch et al.

1979) caused by THC can be reversed by the administration of

GnRH. These results show that the pituitary gland can respond to

hypothalamic releasing hormones by releasing gonadotropins in the

presence of THC. This indicates a hypothalamic site of action

for THC, and while the exact mechanism of the inhibitory effect

of THC on gonadotropin secretion remains unknown, the involvement

of hypothalamic neuroendocrine processes seems very likely.

In summary, the effect of single doses of THC on pituitary gonadotropins is a significant inhibition that lasts 12 to 24 hours

depending upon the dose of THC administered. The effect appears

122
to be mediated at the level of the hypothalamus. Little is known

about the effects of short-term or chronic administration of THC

on these hormones and the possible development of tolerance. The

weight of current evidence (described elsewhere in this volume)

clearly indicates that the effect of THC on gonadotropins is

sufficient to produce disruption of the reproductive process in

both males and females.

Effects of THC on Prolactin Secretion

While there are a number of drugs, including narcotics (Tolis et

al. 1975). phenothiazine tranquilizers (Frantz 1973), and sex

steroids (Robyn and Vekeman 1973), that will inhibit LH and FSH

levels, these drugs have a stimulatory effect on prolactin

levels. The effect of THC on prolactin levels has been quite

controversial with studies reporting either increases or decreases in man (Lemberger and Rubin 1975), rats (Daley et al. 1974),

and mice (Raine et al. 1978).

Studies in male and female rhesus monkeys have shown that the

acute effect of THC on prolactin levels is a significant, but

short-lived inhibition (Asch et al. 1979). THC (2.5 mg/kg) or

vehicle (3 percent Tween 80 in saline) was administered to the

monkeys, and blood was drawn at 30, 60, 90, 120 and 180 minutes

after injection. While vehicle administration produced no consistent change in prolactin levels, THC produced a prompt and

significant decrease in prolactin level. The decrease in prolactin levels was significant for both male and female monkeys

(average 84 percent decrease) at all of the time intervals from

30 to 180 minutes. The site of action of the inhibitory effect

of THC on prolactin was determined by using thyrotropin releasing

hormone (TRH). TRH administration stimulates the release of

prolactin from the pituitary by a direct action on the pituitary

gland. The results indicated that the effect of THC on prolactin

levels is mediated by a hypothalamic site of action, since the

administration of TRH at 30 minutes after THC injection reverses

the inhibitory effect on prolactin levels. Kramer and Ben-David

(1974) have shown that the inhibitory action of THC on prolactin

secretion in the rat can be abolished by cyprohepatidine (a

serotinin antagonist) or perphenazine and pimozine (dopamine

antagonists). While the exact mechanism remains unclear, the

evidence now shows that the acute effect of THC on prolactin is

inhibition. The mechanism most likely involves an effect of THC

on hypothalamic, neuroendocrine control of prolactin secretion.

A study of the effects of short-term administration of THC on

prolactin levels indicates a very different type of response. In

this study, THC was administered to normal rhesus monkeys during

the luteal phase of their menstrual cycles (Smith et al. 1979).

Daily administration of THC (2.5 mg/kg) had no effect on serum

progesterone levels or on the length of the luteal phase. However, after discontinuation of the THC administration, the next

cycle period was marked by an absence of normal estrogens, gonadotropins, and progesterone. Notably, the prolactin levels

recorded during the posttreatment period were 4 to 5 times

123
greater than prolactin levels in normal ovulatory cycles. Thus,

while the acute effect of THC on prolactin levels is a prompt and

significant decrease, the short-term effect appears to be chronically elevated prolactin levels associated with the production

of anovulatory cycles. Whether this elevation in prolactin

levels is a direct effect of THC on the hypothalamic-pituitary

control of prolactin or a secondary effect of the disruptive

effect of THC on the menstrual cycle remains to be determined.

Effects of THC on Thyrotropin (TSH) Secretion

In 1965, Miras first reported that administration of cannabis

resin to rats depressed the uptake of radioactive iodine into the

thyroid gland. This inhibitory effect could have been due to a

direct effect of the cannabis resin on thyroid gland function or

due to a secondary effect of the cannabis resin on the hypothalamus or pituitary function. Later studies confirmed the inhibitory effect of marijuana on thyroid function and identified the

hypothalamus as the site of action (Lomax 1970). In these studies, the injection of marijuana distillate extract inhibited the

release of radioiodine from the thyroid gland in rats. The

administration of thyroid stimulating hormone (TSH) resulted in

the reversal of the inhibitory effect of the drug, suggesting

that reduced TSH secretion was the primary cause of the thyroid

inhibition produced by marijuana. Further evidence of a hypothalamic site of action comes from studies in which bilateral

electrolytic lesions in the region of the medial mammillary

nuclei of the hypothalamus prevented the decrease in pituitarythyroid activity induced by marijuana (Lomax and George 1966).

These investigators compared the effect of marijuana to the

effect of morphine on pituitary-thyroid function, and they postulated that the effect of both drugs may be either inhibition of

hypothalamic neurons responsible for thyrotropin releasing factor

(TRF) secretion or the stimulation of specific inhibitory centers

in the hypothalamus.

Effects of THC on Corticotropin (ACTH) Secretion

Contrary to the effect of THC on gonadotropins, prolactin, and

thyrotropin, the apparent effect of THC on corticotropin, and

hence, adrenal cortical activity, is activation. Dewey et al.

(1970) demonstrated this activation of adrenal function in laboratory rats by measuring depletion of ascorbic acid from the

adrenal gland, indicating increased hormonal activity by the

adrenal gland. Kubena et al. (1971) reported an increase in

plasma corticosterone levels after THC administration. The

elevation of plasma corticosterone levels was found at 45 minutes

after a dose of THC as low as 2.0 mg/kg. The effect of a single

dose of THC lasted less than 8 hours, but the effect was still

present at 45 minutes after daily administration of THC for 8

days. This elevation in adrenal cortical hormone was attributed

to hypothalamic-pituitary site of action, because the increase in

plasma corticosterone was completely blocked in hypophysectomized

rats or after pretreatment with anesthetic doses of pentobarbital

124
and morphine. Additional findings in THC-treated rats (Barry et

al. 1973) show that the elevation in adrenal steroids is associated with hyperglycemia at 45 minutes after drug administration

and increased sodium retention and potassium excretion measured

in the urine at 6 hours after drug administration. The diuresis

continued during the 8 days of short term drug administration in

these studies. The hyperglycemia and diuresis produced in these

animals by THC treatment are the metabolic consequences of pituitary-adrenal activation and elevations in adrenal steroids.

These metabolic changes are similar to such responses elicited by

the effects of stress on pituitary-adrenal activation in animals.

The pharmacological effects of THC treatment on pituitary-adrenal

function are similar to those reported for intoxicating doses of

ethyl alcohol (Ellis 1966). Several other CNS depressant drugs

can cause pituitary-adrenal activation after a single dose (Marks

and Bhattacharya 1970), indicating that CNS depression or sedation may be an important component of the effect of such drugs.

Unlike the effects of THC and alcohol, the effects of other CNS

drugs tend to disappear with repeated drug administrations,

indicating the possible development of tolerance to the effects

of certain CNS depressant drugs.

In order to attain a full understanding of the effects of drugs

on pituitary-adrenal function, both physiological changes and

psychological changes must be considered. Pituitary-adrenal

activation can be measured as a nonspecific effect of various

types of stress. This activation is mediated by the hypothalamic-pituitary axis by an increase in the secretion of ACTH (corticotropin). Certainly, conscious recognition of the CNS depressant effects of drugs could be considered a stress. Hollister

et al. (1970) measured adrenal hormone levels in human volunteers

after an oral dose of THC up to 1 mg/kg. Increases in hormone

levels were detected only in individuals in which a severe anxiety reaction occurred.

The idea that pituitary-adrenal activation may be a nonspecific

stress reaction to CNS depression is further supported by the

paradoxical effect of certain CNS drugs (e.g. pentobarbital and

morphine) at high doses. At sufficiently high doses, these drugs

actually block the pituitary-adrenal activation caused by THC

(Barry et al. 1973). Thus, the pituitary-adrenal activation in

response to lower doses of certain CNS depressants and in response

to THC or alcohol could reflect a normal compensatory mechanism

to counteract the stress of the depressant effect on functions of

the CNS. Further studies are necessary to fully define the

effects of THC on pituitary-adrenal function and to describe the

hypothalamic-pituitary action that apparently results in an

increased adrenal activity in response to THC administration.

EVIDENCE FOR THE ROLE OF HYPOTHALAMIC NEUROTRANSMITTERS

IN THE MECHANISMS OF ACTION OF MARIJUANA EFFECTS

ON HYPOTHALAMIC-PITUITARY FUNCTION

125
Hypothalamic biogenic amines have been demonstrated to exert an

important influence on the secretion of pituitary hormones.

These transmitters probably act by altering release of hypothalamic releasing factors or release-inhibiting factors from nerve

terminals in the median eminence of the hypothalamus into the

pituitary portal vessels. Alterations in levels of dopamine

(DA), serotonin (5-HT), and norepinephrine have been observed to

influence the release of pituitary hormones and may in fact be

the physiological modulators of these hormones. Several studies

have also indicated a possible role for the recently discovered

endogenous opiate peptides (EOP's) in the hypothalamic control of

pituitary hormones.

Before discussing the evidence for effects of THC or marijuana on

these hypothalamic modulators, it is necessary briefly to review

the evidence for the roles of these substances in the control of

pituitary hormones. A number of methods have been used to investigate the mechanisms and physiological significance of neurotransmitter-hormone interactions. However, those methods currently available all have limitations. For example, treatment of

animals with drugs affects transmitter levels in the whole brain,

making it very difficult to distinguish between direct effects on

the hypothalamus and secondary effects mediated at other brain

levels. Even direct infusion of drugs or transmitters into the

brain's ventricles or into the hypothalamus is likely to result

in greater than normal physiological concentrations of the transmitters in the hypothalamus and/or cerebrospinal fluid (CSF),

resulting in artifacts.

In addition to methodological considerations, it should be remembered that each pituitary hormone can be controlled by several

factors such as negative feedback by peripheral hormones, circadian rhythms in hormones, and stress-induced alterations in

hormone secretion. Several of these factors may regulate levels

of a single pituitary hormone but may operate through alterations

in more than one hypothalamic neurotransmitter. Thus, methodological limitations and the complex nature of the neuroendocrine

systems make conclusions about the physiological controlling

mechanisms tentative at best.

Role of Hypothalamic Neurotransmitters

in Gonadotropin Secretion

It has been known for several, decades that the secretions of the

anterior pituitary gland are regulated by substances generated by

the hypothalamus. The best evidence for this came from the

demonstration of the existence of a factor in the hypothalamus

that causes the release of the gonadotropin, luteinizing hormone

(LH), from the anterior pituitary gland (McCann et al. 1960).

This releasing factor actually brings about the release of both

the gonadotropins LH and FSH (follicle stimulating hormone), so

it is also referred to a gonadotropin releasing hormone (GnRH).

It is now recognized that all of the effects of the hypothalamus

on the release of both FSH and LH can be explained by variations

126
in dose, time course, and steroid hormone interactions at the

pituitary level with a single releasing factor, GnRH. The mechanisms behind basal or tonic levels of secretion of gonadotropins,

the generation of gonadotropin surges, or even the timing of the

onset of puberty are not well understood.

There is considerable evidence in experimental animals that the

hypothalamic neurons that release GnRH are regulated by biogenic

amines. For example, dopamine and norepinephrine content in the

hypothalamus change with different stages of the estrous cycle in

the rat, and dopamine can stimulate GnRH release when incubated

with hypothalamic fragments in vitro (Schneider and McCann 1969).

Little is known, however, about the role of biogenic amines in LH

or FSH control in primates. Primates and rodents differ in the

development of the cyclic LH release mechanism, in that androgen

levels early in life suppress this response in the rodent but not

in the primate. In the rhesus monkey, both the tonic and episodic secretory mechanisms appear to be localized within the medial

basal hypothalamus (Knobil 1974), while in rodents, neural pathways that arise elsewhere in the brain impinge upon the GnRH

system. These differences may help explain the differing susceptibility of gonadotropins in primates and rodents to pharmacological manipulation. In general, it can be said that the neuropharmacological studies in primates indicate that norepinephrine,

and perhaps dopamine, may be involved in GnRH release. Adrenergic and dopaminergic agonists probably enhance the release of

GnRH, and adrenergic and dopaminergic antagonists probably inhibit

the release of GnRH. More studies need to be done in primates

and humans before the exact role of these transmitters can be

defined.

Role of Hypothalamic Neurotransmitters in Prolactin Secretion

Of the hypothalamic mechanisms for the control of pituitary hormones, the mechanisms for the control of prolactin have been most

extensively studied. Prolactin secretion is probably controlled

by two systems: a prolactin inhibitory factor (PIF) and one or

more prolactin releasing factors. Current evidence indicates

that dopamine is the inhibitory substance of hypothalamic origin

that controls prolactin secretion (Bishop et al. 1972). Drugs

that are classified as dopamine anatagonists (pimozide and haloperidol) cause the release of prolactin (MacLeod and Lehmeyer

1974). Infusion of dopamine (Meites et al. 1972) or administration of a drug that increases production of dopamine (such as

L-dopa) inhibits prolactin release (Noel et al. 1973). Apomorphine, a drug that interacts with dopamine receptors, mimics the

inhibitory effect of dopamine on prolactin release (Anden et al.

1967). Thus it is thought that the dopamine that is released in

the hypothalamus is transported to the pituitary and inhibits the

release of prolactin.

The existence of a prolactin releasing factor or factors is less

well established. Serotonin (5-HT), in contrast to dopamine, has

been shown to produce an increase in prolactin release (Meites et

127
al. 1972); whereas, methylsergide and cyproheptadine (serotonin

receptor blockers) decrease prolactin release. In addition,

morphine and the endogenous opiate peptides (EOP’s) stimulate the

release of prolactin (DuPont et al. 1979). This stimulatory

effect of morphine and the EOP’s is thought to be mediated by

interaction with specific receptors, since the narcotic receptor

blocking drug, naloxone, blocks the effect of narcotics and EOP’s

on prolactin release. At least part of the stimulatory hypothalamic influence on prolactin appears to be mediated by thyrotropin

releasing hormone (TRH), the hypothalamic peptide that stimulates

thyrotropin stimulating hormone (TSH) secretion, and thereby

stimulates thyroid gland function. TRH has been shown to stimulate prolactin secretion both in vivo (Jacobs et al. 1973) and in

vitro (Labrie et al. 1979). The question remains as to which of

these prolactin stimulatory factors is the physiological trigger

for prolactin release. Rapidly accumulating evidence suggests

that dopamine, rather than these other substances, may be the

primary or perhaps the only hypothalamic substance controlling

prolactin release. These studies indicate doubt in the existence

of a prolactin releasing factor. The inhibitory effects of

serotonin antagonists, for example, can be shown in pituitary

cell culture studies to be due to their partial dopamine agonist

activity (Labrie et al. 1979). The stimulatory effect of morphine

and the EOP’s on prolactin release has also been shown to involve

interference with hypothalamic dopamine activity. Thus, while

serotonin and EOP's may be involved in stimulation of prolactin

release, it now appears that the control of prolactin levels is

directly mediated by increasing dopamine activity (resulting in

prolactin inhibition) or decreasing dopamine activity (resulting

in prolactin secretion).

Role of Hypothalamic Neurotransmitters in Thyrotropin Secretion

Only a few experimental studies have been reported that have

investigated the role of hypothalamic neurotransmitters in the

control of the secretion of TRH thyrotropin releasing hormone.

Both dopamine and norepinephrine have been shown to release TRH

from mouse hypothalamic tissue in vitro, but dopamine was ineffective when conversion of dopamine to norepinephrine was blocked

(Grimm and Reichlin 1973). Serotonin inhibited the TRH release,

and acetylcholine analogues had no effect on TRH release. The

suggestion that serotonin pathways inhibit TRH release is further

supported by the observation that injection of 5-hydroxytryptophan (a precursor that increases hypothalamic content of serotonin) inhibits peripheral TSH levels. The exact role of hypothalamic transmitters in the control of thyroid function in

response to other factors, including cold and stress, has not

been fully defined; it now appears that adrenergic pathways are

involved in enhancement of the release of TRH, and serotonergic

pathways may be responsible for the inhibitory effects on TRH

release. TRH apparently has a direct effect on pituitary TSH

release, since these transmitters do not alter the pituitary

response to TRH.

128
Role of Hypothalamic Neurotransmitters in Corticotropin Secretion

The hypothalamic region that controls ACTH release apparently

involves a large part of the basal hypothalamus. In addition to

the excitatory control, there may be an inhibitory control that

is thought to be in the posterior hypothalamus, close to the

mammillary bodies. Thus, adrenal response to negative feedback

control, to diurnal rhythm and to stress is thought to be mediated by changes in ACTH release from the pituitary. The analysis

of the role of hypothalamic neurotransmitters in the CRF (corticotropin releasing factor) control of ACTH has proven to be the

most difficult of all of the hypothalamic-pituitary systems.

This is because both excitatory and inhibitory pathways appear to

exert an influence on ACTH, and several transmitters, including

catecholamines, serotonin, and acetyl choline, appear to have

important effects on ACTH (viz. Hiroshige and Abe 1973). In man,

evidence for the role of catecholamines in ACTH regulation suggests a dual role, with alpha-adrenergic agonists enhancing ACTH

release and beta-adrenergic agonists inhibiting ACTH release.

However, current evidence for this role of catecholamines in ACTH

is not yet conclusive. Serotonin has been implicated in the

inhibitory control of ACTH release. Serotonin antagonists interfere with stimulated ACTH release but apparently do not alter

basal secretion of ACTH. Serotonin may be responsible for the

diurnal variation in adrenal hormone. A cholinergic component

has also been suggested in ACTH regulation. Studies in rodents

indicate that acetylcholine may be involved in the activation of

the adrenal system after stressful stimuli.

It has been very difficult to describe the role of hypothalamic

neurotransmitters in the CRF-ACTH control of adrenal functions.

The studies that have been described here have examined the

effects of neurotransmitters on ACTH rather than CRF. Although

CRF was the first releasing factor recognized, its identity is

still unknown. In addition, the many physiological and pathological factors that impinge on the hypothalamic-pituitary regulation of adrenal function make the studies that are necessary to

understand the process difficult indeed.

Effect of Marijuana or THC on Neurotransmitters

In several studies, the site of action of the effects of marijuana and THC on hypothalamic-pituitary function has been shown to

be at the level of the hypothalamus. In general, it has been

shown that the pituitary responds to exogenous releasing factors

in the presence of the drugs. This inhibitory effect on hypothalamic-pituitary function is not unique to cannabis derivatives

but is a property shared by several CNS depressant drugs including narcotics, some tranquilizers and some sedatives. Certain of

the cannabis effects, however, are unique, especially the inhibition of prolactin secretion. Virtually every other drug that

inhibits LH and FSH levels (including narcotics and sex steroids), stimulates prolactin release. THC inhibits LH, FSH, and

prolactin. The hypothalamic-pituitary activity of the cannabis

129
derivatives also appears to be somewhat associated with the

psychoactivity or neuroactivity of the compounds. Among the

other CNS depressant drugs, this may not be true. It appears

certain that the hypothalamic-pituitary effects of marijuana are

somehow related to the effects of the drug on hypothalamic neurotransmitters.

Some neuropharmacological studies have examined the role of hypothalamic neurotransmitters in the neuroendocrine effects of THC.

Marks (1973) studied the involvement of a hypothalamic cholinergic mechanism by using oxotremorine, a cholinergic muscarinic

agonist, in combination with THC. He concluded that the effect

of THC on LH levels was not related to its effect on the cholinergic system. Studies by Kramer and Ben-David (1974) indicate

that both serotonin and dopamine disruption may be involved in

the inhibitory effect of THC on prolactin. However, experiments

that study the combined effects of THC with agonists or antagonists of the various neurotransmitters are particularly difficult

to interpret. While some studies have examined the effects of

marijuana or THC on transmitter function in various areas of the

brain, very few have specifically addressed the effects of the

drugs on hypothalamic neurotransmitters (Constantinidis and Miras

1974).

Because of the important role of biogenic amines, especially

dopamine, and norepinephrine, in the regulation of hypothalamic

releasing factors, it has been postulated that the effects of THC

on these transmitters may be important. Several studies have

shown that THC can alter levels of biogenic amines in the CNS

(Fuxe and Jansson 1972; Truitt and Anderson 1972; and Welch et

al. 1971). This effect on these transmitters appears to be

mediated by an effect of THC on the reuptake of dopamine, norepinephrine , and serotonin into nerve endings in the brain (Howes

and Osgood 1974; Hershkowitz et al. 1977). This effect of THC

apparently results in an increase in serotonin levels in certain

areas of the brain (Sofia et al. 1971) and a decreased content of

catecholamines in certain areas of the brain (Holtzman et al.

1969). It is not clear, however, whether THC acts directly on

transmitter levels or even on transmitter uptake or whether its

effects are mediated by secondary effects on neuronal activity.

THC has also been shown to alter cholinergic activity in certain

brain areas. Studies on the turnover rate of acetylcholine in

the rat hippocampus indicate that THC (but not the nonpsychoactive

cannabidiol) decreases cholinergic activity (Revuelta et al.

1979). This effect of THC appears to be secondary to an increase

in the activity of GABA (gamma-aminobutyric acid), another important central transmitter. The effect of THC on central cholinergic pathways is probably important in the psychoactive effects

of THC. Its role in the disruption of hypothalamic-pituitary

function is not known.

The effects of THC on certain metabolic processes and subcellular

structures in the rat brain have also been studied (Jakubovic and

130
McGeer 1972). These studies showed that THC, but not the nonpsychoactive cannabinoids, decrease protein and nucleic acid synthesis in the infant rat brain. Studies of the subcellular

distribution of THC indicate that these metabolic effects may be

related to the preferential binding of THC to mitochondrial and

microsomal fractions in brain cells.

Certain cell membrane processes have been reported to respond

specifically to psychoactive cannabinoids (Greenberg et al.

1978). The plasma membrane-bound enzyme, LPC-acyltransferase,

which is thought to be responsible for regulating the proportion

of saturated fatty acids in the plasma membrane, is inhibited by

the psychoactive cannabinoids only. The inhibition of this

enzyme in synaptosomes from mouse brain may be responsible for

the effects of marijuana on neurotransmitter uptake mechanisms.

Morphological changes in the ultrastructure of the synaptic cleft

region in rhesus monkey brain has also been reported in response

to marijuana exposure or THC treatment (Harper et al. 1977).

These changes consisted of 1) appearance of opaque granular

material in the synaptic cleft region;. 2) widening of the synaptic cleft; and 3) synaptic vesicle clumping. These ultrastructural changes were consistent with lasting EEG changes produced

in the monkey by marijuana or THC. They were observed in various

areas of the brain, with the most profound effects in the septal

region, the hippocampus, and the amygdala (Heath et al. 1979).

The impact of morphological changes on the neural effects of THC

or marijuana remains to be shown.

131
REFERENCES

Anden, N.E., Rubenson, A., Fuxe, L., and Hökfelt. T. Evidence

for dopamine receptor stimulation by apomorphine. J Pharm

Pharmacol, 19:627, 1967.

Asch, R.H., Fernandez, E.O., Smith, C.G., and Pauerstein, C.

J. Blockage of the ovulatory reflex in the rabbit with delta-9-

tetrahydrocannabinol. Fertil Steril 31:331, 1979.

Barry, H., Kubena, R.K., and Perhach, J.L. Pituitary - adrenal activation and related responses to Δ'-tetra-hydrocannabinol. In: Zimmerman, E., Gispen, W.H., Marks, B.H., and

de Weid, D., eds. Progress in Brain Research - Drug Effects on

Neuroendocrine Regulation. Vol 10. Amsterdam: Elsevier, 1973,

p. 323.

Besch, N.F., Smith, C.G., Besch, P.K., and Kaufman, R.H.

The effect of marihuana (delta-9-tetrahydrocannabinol) on the

secretion of luteinizing hormone in the ovariectomized Rhesus

monkey. Am J Obstet Gynecol, 128:635, 1977.

Bishop, W., Fawcett, C.P., Krulich, L., and McCann, S.M.

Acute and chronic effects of hypothalamic lesions on the release

of FSH, LH and prolactin in intact and castrated cats. Endocrinology, 91:643, 1972.

Constantinidis, J., and Miras, C.J. Effects of hashish smoke

sublimate on hypothalamic noradrenaline studied by the fluoresence method. Psychopharmacologia (Berl.), 22:80, 1974.

Daley, J.D., Branda, L.A., and Rosenfeld, J. Increase of

serum prolactin in male rats by (minus)-trans-delta-9-tetrahydrocannabinol. J Endocrinol, 63:415, 1974.

Dewey, W.L., Peng, T.C., and Harris, L.S. The effect of

1-trans-delta-9-tetrahydrocannabinol on the hypothalamic -

hypophyseal-adrenal axis of cats. Eur J Pharmacol, 12:382,

1970.

DuPont, O., Cusan, L., Ferland, L., Lemay, A., and Labrie, F.

Evidence for a role of endorphins in the control of prolactin

secretion. In: Cullu, R., Barbeau, A., Buehanne, J. R., and

Rochefort, J., eds. Central Nervous System Effects of Hypothalamic Hormones and other Peptides. New York: Raven Press, 1979,

p. 283.

Ellis, B.W. Effects of ethanol on plasma corticosterone

levels. J Pharmacol Exp Ther, 153:121, 1966.

Frantz, A.G. Catecholamines and the control of prolactin secretion in humans. In: Zimmerman, B., Gispen, W. H., Marks, B.

H ., and de Wied, D., eds. Progress in Brain Research. Vol. 10.

Amsterdam: Elsevier, 1973, p. 311.

132
Fuxe, K., and Jansson, G. Effect of tetrahydrocannabinol on

central monoamine neurons. Acta Pharm Suec 8:695, 1972.

Greenberg, J.H., Mellors, A., and McGowan, J.C. Molar volumes

relationships and the specific inhibition of a synaptosomal

enzyme by psychoactive cannabinoids. J Med Chem, 21:1208,

1978.

Grimm, Y., and Reichlin, S. Thyrotropin-releasing hormone (TRH):

Neurotransmitter regulation of secretion by mouse hypothalamic

tissue in vitro. Endocrinology, 93:626, 1973.

Harper, J.W., Heath, R.G., and Myers, W.A. Effects of cannabis sativa on ultrastructure of the synapse in monkey brain.

J Neurosci Res 3:87, 1977.

Heath, R.G. Fitzjarrell, A.T., Garey, R.E., and Myers, W.A.

Chronic marijuana smoking: Its effect on function and structure of the primate brain. In: Nahas. G.G., and Patton. W.

J.D., eds. Marijuana: Biological Effects. Oxford: Pergamon

Press, 1979, p. 713.

Hembree, W.C., Zeidenberg, P., and Nahas, G.G. Marijuana's

effect on human aonadal function. In: Nahas. G.G., ed.

Marijuana - Chemistry, Biochemistry, and Cellular Effects. New

York: Springer-Verlag, 1976, p. 521.

Hershkowitz, H., Goldman, R., and Raz, A. Effect of cannabinoids on neurotransmitter uptake, ATPase activity and morphology

of mouse brain synaptosomes. Biochem Pharmacol, 26:1327, 1977.

Hiroshige, T., and Abe, K. Role of biogenic amines in the regulation of ACTH secretion. In: Yagi, K., and Yoshida, S.,

eds. Neuroendocrine Control. New York: John Wiley and Sons,

1973, p. 205.

Hollister, L.E., Moore, F., Kanter, S., and Noble., Δ

1

-tetrahydrocannabinol, synhexyl, and marijuana extract administered

orally in man: Catecholamine excretion, plasma cortisol levels

and platelet serotonin content. Psychopharmacologia, 17:354,

1970.

Holtzman, D., Lovell, R.A., Jaffe, J.H., and Freedman, D.K.

1-delta-9-tetrahydrocannabinol: Neurochemical and behavioral

effects in the mouse Science, 163:1464, 1969.

Howes, J., and Osgood, P. The effect of delta-9-tetrahydrocannabinol on the uptake and release of 14C-dopamine from crude

striatal synaptosoma preparations. Neuropharmacology, 13:

1109, 1974.

Jacobs, L.S., Snyder, P.J., Utiger, R.D., and Daughaday, W.

H. Prolactin response to thyrotropin-releasing hormone in

normal subjects. J Clin Endocrinol Metab, 36:1069, 1973.

133
Jakubovic, A., and McGeer, P.L. Inhibition of rat brain protein and nucleic acid synthesis by cannabinoids in vitro.

Canad J Biochem 50:654, 1972.

Knobil, E. On the control of gonadotropin secretion in the

Rhesus monkey. Recent Prog Horm Res, 30:1, 1974.

Kramer, J., and Ben-David, M. Suppression of prolactin secretion

by acute administration of delta-9-THC in rats. Proc Soc Exp

Biol Med, 147:482, 1974.

Kubena, R.K., Perhach, L., and Herbert, H. Corticosterone

elevation mediated centrally by Δ'-tetrahydrocannabinol. Eur J

Pharmacol, 14:89, 1971.

Labrie, F., Beulieu, M., Ferland, L., Raymond, V., Di Paolo,

T., Caron, M. G., Veilleux, R., Denizeau, F., Euvard, C.,

Raynaud, J. P., and Baissier, J. R. Control of prolactin

secretion at the pituitary level: A model for postsynaptic

dopaminergic systems. In: Collu, R., Barbeau, A., Ducharme,

J. R., and Rochefort, J., eds Central Nervous System Effects

of Hypothalamic Hormones and Other Peptides. New York: Raven

Press, 1979, p. 207.

Lemberger, L., and Rubin, A. The physiologic disposition of

marijuana in man. Life Sci, 17:1637, 1975.

Lomax, P. The effect of marijuana on pituitary-thyroid activity

in the rat. Agents and Actions, 1:5, 1970.

Lomax, P., and George, R. Thyroid activity following administration of morphine in rats with hypothalamic lesions. Brain

Research, 2:361, 1966.

MacLeod, R. M., and Lehmeyer, J.E. Restoration of prolactin

synthesis and release by the administration of monoaminergic

blocking agents to pituitary tumor-bearing rats. Cancer Res,

34: 345, 1974.

Marks, B.H. Δ'-THC and luteinizing hormone secretion. In:

Zimmerman, E., Gispen, W. H., Marks, B. H., and deWied, D.,

eds. Progress in Brain Research - Drug Effects on Neuroendocrine

Regulation. Vol. 10. Amsterdam: Elsevier, 1973, p. 331.

Marks, B. H., and Bhattacharya,, A. N. Psychopharmacological

effects and pituitary - adrenal activity. In: de Wied, D.,

and Wenner, W.H., eds. Progress in Brain Research - Pituitary,

Adrenal, and the brain. Vol 32. Amsterdam: Elsievier, 1970, p.

57.

McCann, S. M., Taleisnik, S., and Friedman, H. M. LH-releasing

activity in the hypothalamic extracts. Proc Soc Biol Med

104:432, 1960.

134
Heites, J., Lu, K.H., Wuttke, W., Welsch, C.W., Nagasawa, H.,

and Quadri, S.K. Recent studies on functions in rats. Recent

Prog Horm Res, 28:471, 1972.

Miras, C.J. Some aspects of cannabis action. In: Wolstenholme,

G. W., and Knight, J., eds. Hashish: Its Chemistry and Pharmacology. Boston: Little, Brown and Co., 1965, p. 37.

Nir, I., Aylon, D., Tsafriri, A., Cordova, T., and Lindner, H.

R. Suppression of the cyclic surge of luteinizing hormone

secretion and of ovulation in the rat by Δ'-tetrahydrocannabinol.

Nature, London, 243:470, 1973.

Noel, G.L., Suh, H.K., and Frantz, A. G. L-dopa suppression

of TRH-stimulated prolactin release in man. J Clin Endocrinol

Metab, 36:1255, 1973.

Raine, J. M., Wing, D.R., and Paton, W.D. The effects of

delta-1-tetrahydrocannabinol on mammary gland growth, enzyme

activity and plasma prolactin levels in the mouse. Eur J

Pharmacol, 51:11, 1978.

Revuelta, A. V., Cheney. D.L., Wood, P.L., and Costa, E.

GABAergic mediation in the inhibition of hippocampal acetylcholine turnover rate elicited by Δ

9

-tetrahydrocannabinol.

Neuropharmacology, 18:519, 1979.

Robyn, C., and Vekeman, M. Influence of low dose oestrogen on

circulating prolactin, LH, and FSH levels in post menopausal

women. Acta Endocrinol, 83:9, 1973.

Schneider, H.P. G., and McCann, S.M. Possible role of dopamine

as transmitter to promote discharge of LH-releasing factor.

Endocrinology, 85:121, 1976.

Smith, C. G., Ruppert, M.J., and Besch, N.F., Comparison of

the effects of marijuana extract and Δ-9-tetrahydrocannabinol

on gonadotropin 1evels in the Rhesus monkey. Pharmacologist.

21: 204, 1979.

Smith, C. G., Ruppert, M. J., Asch, R. H., and Siler-Khodar, T.

M. Effects of tetrahydrocannabinol on prolactin levels in

Rhesus monkey. Presented at the NIDA Conference on Genetic,

Perinatal, and Developmental Effects of Abused Substances,

20-22 March 1979, Airlie, Virginia.

Smith, C. G., Smith, M. T., Besch, N. F., Smith, R. G., and

Asch, R. H. Effect of Δ-9-tetrahydrocannabinol (THC) on female

reproductive function. In: Nahas, G. G., and Patton, W. D. M.,

eds. Marijuana - Biological Effects. Oxford: Pergamon, 1979, p.

449.

135

323-754 0 - 80 - 10
Sofia, R. D., Dixit, B. W., and Barry, H. The effect of delta1-tetrahydrocannabinol on serotonin metabolism in the rat

brain. Life Sci, 10:425, 1971.

Tolis, G., Hickey, J., and Guyda, H., Effects of morphine on

serum growth hormone, cortisol, prolactin, and thyroid stimulating hormone in man. J Clin Endocrinol Metab 41:797, 1975.

Truitt, E. B., Jr., and Anderson, S. H. Biogenic amine alterations produced in the brain by tetrahydrocannabinol and their

metabolites. Ann NY Acad Sci, 191:68, 1972.

Tyrey, L. Δ-9-tetrahydrocannabinol suppression of episodic

luteinizing hormone secretion in ovariectomized rat. Endocrinology, 102:1808, 1978.

Welch, R. L., Welch, A. S., Mensina, F. S., and Berger, H. J.

Rapid depletion of adrenal epinephrine and elevation of telencephalic serotonin by (-)-trans-delta-tetrahydrocannabinol in

mice. Res Commun Chem Pathol Pharmacol, 4:382, 1971.

AUTHOR

Carol Grace Smith, Ph.D.

Associate Professor

Uniformed Services University

of the Health Sciences

Bethesda, Maryland 20014

136
The Effect of Marijuana on

Reproduction and Development

Jack Harclerode, Ph.D.

In the years since the effects of marijuana upon reproduction

were first reported much research effort has been directed initially to document the changes that occur, and, more recently, to

attempt to explain the physiological and pharmacological reasons

for these changes. It is now generally agreed that marijuana

exerts significant effects on all phases of reproduction and development, on members of both sexes and in all species studied So

far. The list of species studied includes rats (Collu et al.

1975, Collu 1976), mice (Dixit et al. 1974), rhesus monkeys

(Smith et al. 1976), dogs (Dixit et al. 1977), pigeons (Vyas

and Singh 1976), and humans (Cohen 1976, Kolodny et al. 1976).

The effects of marijuana are observed in all phases of reproductive physiology, including decreases in the weight and functions

of organs associated with reproduction and decreases in hormones

that control development of the fetus. These changes may be

caused indirectly by the alteration of circulating hormones in

blood, directly by an effect of the physiologically active ingredients in marijuana on the reproductive structures, or by a combination of both direct and indirect action.

THE EFFECT OF MARIJUANA ON THE MALE

Bat and mouse testes respond to delta-9-tetrahydrocannabinol (Δ9-THC) or Crude Marijuana Extract (CME) with a slight decrease in

organ weight. This organ is sensitive to THC over many different

dosages, given in several different vehicles via several different

routes (Bloch et al. 1978, have summarized these). Most of these

studies report the effect on testes of young rats and mice, while

a few report cannabinoid effects on adult testes weight. Fujimoto

et al. (1978) showed that adult rats treated with CME (15 and 75

mg/kg, orally) for 77 days at very high dosages had a significant

reduction in ventral prostate, seminal vesicle, and epididymal

weight, as well as a decrease in the plasma testosterone levels.

The semen of these rats contained smaller numbers of sperm in the

epididymis as well as a decreased fructose content (an energy

source for sperm) indicating that there were qualitative changes

in the semen. Treatment of rats for only 5 days produced none of

137
these changes. Thirty days after cessation of CME treatment,

there appeared to be a return to control levels of organ weights

and testicular function.

There are other reports indicating that the quality of sperm is

affected by cannabinoids; for the semen of mice treated with THC

(5 and 10 mg/kg, i.p.; 5 days) or cannabidiol (CBD) (10 and 25

mg/kg, i.p.; 5 days) had an increase in the number of abnormal

sperm (oligospermia) (Zimmerman et al. 1979a), as well as an increase in the number of ring and chain translocations (Zimmerman

et al. 1979b). Rats similarly treated with marijuana smoke

(Δ-9-THC content .4 to 3 mg/kg) for 75 days had a higher number

of abnormal sperm in their semen, including some which showed

a separation of the sperm head and the sperm tail, as well as

a decrease in epididymal sperm count (Huang et al. 1979).

Recent research has been concerned with clarifying the biochemical

and hormonal mechanisms responsible for the morphological changes

described above. Attention has also been focused on whether Δ-9-

THC has its effect directly on testicular cells themselves or

whether the effects observed are due to an indirect action.

It is possible that much of the decreases in male reproductive

function documented here could be produced by the action of cannabinoids on the hypothalamus to inhibit release of Luteinizing

Hormone Releasing Factor (LHRF) or on the pituitary to inhibit release of the gonadotropins Luteinizing Hormone (LH) and Follicle

Stimulating Hormone (FSH). In fact, there is evidence that Δ-9-

THC (5 mg, i.m., twice weekly for 6 weeks) does depress LH in male

rats, which presumably is responsible for the lowered testosterone

levels observed in the plasma (Symons et al. 1976). When the

animals treated with Δ-9-THC were given exogenous LHRF, the Δ-9-

THC-injected animals secreted less LH than vehicle-injected control animals. This fact indicated that the pituitary was able to

respond to LHRF, but in a sluggish manner (Symons et al. 1976).

Also, when ovariectomized rhesus monkeys, whose LH and FSH were

suppressed by Δ-9-THC (5 mg/kg, i.m., acute) were provided with

LHRF exogenously, they responded with a prompt release of gonadotropins. This evidence suggested that THC had its action primarily on central neural mechanisms to inhibit LHRF release (Smith

et al. 1976). Several other studies point to cannabinoid suppression of LHRF release as a major cause of both the observed

decreased LH and gonadal hormone secretion. These studies are

discussed in this chapter under The Effects of Marijuana on the

Female Reproductive System.

Other arguments for an indirect action of THC on testicular function are that rats injected with Δ-9-THC (2 mg/kg, i.p.; 9 days)

or cannabidiol (CBD) (2 mg/kg, i.p.; 9 days) had a decrease in

both microsomal cytochrome P-450 from Leydig cells of the testes,

an enzyme which is involved in biosynthesis of testosterone, and

γ -glutamyl transpeptidase, a marker protein for Sertoli cells

in the seminiferous tubules of the testes (Schwarz et al. 1977).

When exogenous LH, FSH, or LH and FSH together were supplied

to THC-treated animals, the testes were able to be

138
restored to control levels of cytochrome P-450 and γ- glutamyl

transpeptidase, indicating that the testes were able to respond in

a normal way when gonadotropins were present (Harclerode et al.

1979).

Among the evidence presented for a direct effect of cannabinoids

on reproductive tissues is the observation that Δ-9-THC, when incubated with testicular cells grown in cell culture or in cultures

of testicular slices, was able to depress certain functions seen

in normal intact testicular cells. Protein synthesis is one function that has been shown to be depressed by Δ-9-THC and one which

could explain decreased organ size as well as the decrease in

spermatogenesis already reported (Jakubovic and McGeer 1977).

Also, decapsulated mouse testes grown in culture were less able

to release testosterone to the incubation medium with added Δ-9-

THC or CBN (12.5 to 25 μg/ml) than were control testes (Dalterio

et al. 1977).

The Leydig cells of the testes, which are responsible for testosterone biosynthesis, are less able to synthesize testosterone when

treated with Δ-9-THC in culture (Dalterio et al. 1978). Apparently this occurs due to the effect of Δ-9-THC (3.2 to 32 μM) to

either decrease the release of precursor cholesterol from ester

storage, or inhibit the conversion of cholesterol to pregnenalone

(Burstein et al . 1978a, Burstein et al. 1979). Burstein and

Hunter (1978) have pointed out that cannabinoids could have

direct effects on cell membranes, thereby altering the rate at

which materials enter or leave the cell. Also, Purohit et al.

(1979) showed Δ-9-THC (10 mg/kg, s.c.) and CBN (10 mg/kg, s.c.)

blocked the stimulatory effect of testosterone and dihydroxytestosterone on ventral prostate and seminal vesicle weights in

rats.

It was reported that both Δ- 9-THC (2 mg/kg/day, i.p.) and CBD (2

mg/kg/day, i.p.) cause depression of an esterase isozyme located

in the Leydig cells of the rat testis after 10 days of treatment

(Goldstein et al. 1977). Hubbard et al. (1979) showed that cultured rat Leydig cells with Δ-9-THC (16 μM) added had reduced

cholesterol esterase activity. This enzyme hydrolyzes the

cholesteryl esters of oleic, arachidonic, and palmitic acids.

Jakubovic and his coworkers have shown that low levels of Δ-9-

THC (.05 μg/ml) may directly inhibit protein synthesis and testosterone production of Leydig cells grown in cultures stimulated

by Human Chorionic-Gonadotropin (HCG) or cyclic andenosine monophosphate (AMP). Since the effect was not observed in nonhormonally

stimulated cells, it is possible that the cannabinoids affect the

way in which Leydig cells respond to hormones such as LH (Jakubovic

et al. 1979a, 1979b; Dalterio et al. 1978).

In view of the relative insolubility of Δ-9-THC in water, the

question arises as to how much Δ-9-THC is actually present in the

incubation medium of these in vitro systems. Moreover, the

effects observed in vitro may not be observed in vivo, since no

139
attempt has been made to show that the levels of cannabinoid in

the testicular blood supply reach the level approaching that of

the culture media. There is also the question of whether the

intact testes accumulate Δ-9-THC to the concentration used in

these in vitro experimental systems.

The liver appears to be affected directly by cannabinoids, for rat

liver microsomes were reported by Chan and Tse (1978) to exhibit

a competitive inhibition at the 5-α-reduction step, which is involved in the metabolism of testosterone when incubated with

either Δ-9-THC (25 μM or Δ-8-THC (50 μM). These liver microsomes contain enzymes which are responsible for the metabolism

and inactivation of many hormones and drugs including the cannabinoids in vivo. Moreover, the livers from rats treated chronically (10 days) with Δ-9-THC (2 or 10 mg/kg each, i.p.) had

microsomes with increased steroid hydroxylation activity (List

et al. 1977). The enzymatic changes in these liver microsomes

could, in effect, decrease serum testosterone levels by increasing

metabolism and excretion of testosterone from the blood. Thus,

Δ-9-THC could depress the already lowered testosterone levels

found in the blood due to decreased testosterone synthesis.

Prolactin is another hormone affected by cannabinoid treatment

which is related to reproductive activity. Adult rats treated

with Δ-9-THC (2-10 mg/kg, i.p.) had a decrease in serum prolactin

levels 30 minutes after a single injection, which returned to normal about four hours later (Kramer and Ben-David 1974, Bromley

and Zimmerman 1976). In contrast, younger rats (36-day-old)

responded with increased serum prolactin levels 24 hours after an

injection of Δ-9-THC (16 mg/kg, i.p.) (Daley et al. 1974), and

Collu (1976) observed increased prolactin levels in the pituitary

of 23-day-old rats when Δ-9-THC was administered intraventricularly. Hughes et al. (1979) report that Δ-9-THC (1 mg/kg, i.v.)

did not influence serum prolactin levels in ovariectomized rats

with established ectopic-pituitary autografts. This suggests Δ-9-

THC indirectly affects prolactin secretion through other central

nervous structures rather than having a direct action on the

pituitary.

C.G. Smith et al. (1979a ) have shown that the administration of a

single dose (2.5 mg/kg, i.p.) of Δ-9-THC suppressed serum prolactin levels in both ovariectomized and adult male rhesus monkeys.

The maximal effect (84 percent in females and 74 percent in males)

was obtained between 30 and 90 minutes after drug administration.

The inhibitory action of THC on serum prolactin levels was reversed by TRH administration, which suggests an hypothalamic site

of action for THC. Interestingly, the administration of daily

doses of THC in female rhesus monkeys during the luteal phase of

the normal menstrual cycle produced an absence of ovulation which

was associated with elevated prolactin levels during the subsequent cycle period.

140
Human Males

In humans, marijuana is consumed by smoking. This route of administration allows investigators to study the effect of the

chemical components found in marijuana after absorption of the

smoke by the lungs, its normal route of absorption, and after

normal biotransformation in the human body of all of the absorbed

constituents in marijuana, In terms of endocrine effects, the

human male appears to respond to marijuana in much the same way

rats and mice do. Acute marijuana smoking decreased both LH and

testosterone levels in the blood, an effect which lasted for up

to three hours, whereas no change was detected in FSH levels

(Cohen 1976, Kolodny et al. 1975, Kolodny et al. 1976, Jones 1977).

Some studies that examined the chronic effects of marijuana in the

male found conflicting results. However, this area of research is

controversial since an earlier report had shown that marijuana

smoking decreased blood levels of testosterone but had no effect

on LH, FSH, or prolactin (Kolodny et al. 1974), although some

workers were unable to find any change in plasma testosterone concentration (Coggins et al, 1976, Mendelson et al. 1974, Mendelson 1976, Nahas 1976). The differences between the findings

of these studies may have been caused by differences in experimental design of the different investigators. For instance, after

smoking marijuana, hormone levels in the plasma appear to return

to normal fairly rapidly. Studies which sampled hormones in the

blood after this time interval may have been missing the effective

period. Also, the dosage of marijuana used and the length of administration appear to have important effects on hormonal levels

that control testicular function.

Hembree et al. (1979) examined the semen of 16 healthy, chronic

marijuana smokers under controlled research ward settings (8-20

cigarettes/day, for 5 to 6 weeks, 2 percent Δ-9-THC). Semen from

these men had decreased sperm count and concentration of sperm as

well as a decrease in sperm motility. Moreover, there was an increase in the number of sperm which had abnormal morphology (oligospermia) as well as an increase in the number of sperm which had

aberrations of the nucleus. The aberrations seen in sperm are

viewed as being an effect of marijuana on spermatogenesis although

some effects could be due to changes in the sperm as they pass

through the epididymus or due to failure of complete sperm maturation. It is interesting to note, however, that once marijuana

treatment was stopped there was a gradual return to apparent normal gonadal activity.

Issidorides (1979), using the same population of 47 chronic Greek

hashish users and 40 matched controls from a previous study

(Stefanis and Issidorides 1976), reported on sperm aberrations

in ejaculated semen. The most prevalent abnormality was that a

spongy, fuzzy, disorganized layer of acrosomal substance covered

what appeared to be normal sperm heads. Also, some sperm had incomplete condensation of chromatin in sperm heads of normal size,

but with no acrosomes. Some sperm exhibited morphology of arrested maturation which correlated well with their low protamine

content.

141
Summary

In summary, marijuana affects male reproductive function in all

species studied. This is observed as a decrease in organ weight

and organ function after both short- and long-term treatment.

The mechanism by which this occurs seems to be due to the effect

of the active ingredients in marijuana to depress release of LHRF

with the subsequent depression of the gonadotropins. This lack

of gonadotropin stimulation of Leydig cells is probably responsible for the observed decreased testosterone production. Many

of the changes seen in decreased weight of the testes and associated reproductive organs are probably caused by the decreased

testosterone production. Apparently when gonadotropins are administered along with THC, the testis is able to overcome the

defects observed with THC treatment, indicating that the testis

is able to respond when gonadotropins are present.

Cannabinoids appear to alter the quality of the semen as observed

in decreases in several important constituents of semen as well as

the appearance of decreased numbers of sperm and sperm with abnormal morphology, an observation seen in both lower animals and

in man. The effects of marijuana on male reproductive function

appear to be reversible and recovery occurs after cessation of

treatment.

THE EFFECT OF MARIJUANA ON THE FEMALE REPRODUCTIVE SYSTEM

The effects of cannabinoids on the reproductive system of the female have been examined less intensively than in males. Although

most research reports deal largely with the effects on rats and

mice, there is some recent work which reports effects of cannabinoids on rhesus monkeys and humans.

There is a similarity in the biological action of Δ-9-THC and

estrogens in both males and females, for a number of common physiological processes are affected by both substances (Solomon et al.,

1976; Rawitch et al. 1977). It has been shown that both alter

prolactin secretion, depress the weights of testes, seminal

vesicles, and prostate, depress release of LH from the pituitary,

inhibit spermatogenesis and stimulate mammary gland development.

Indeed, there are reports of breast development (gynecomastia) in

male heavy marijuana users (Harmon and Aliapoulios 1972). Moreover, mammary tissue of rats treated with Δ-9-THC (1 mg/kg 5 days/

week, s.c.) was stimulated, to develop (Harmon and Aliapoulios

1974).

The organs that comprise the reproductive tract in nonpregnant

females are affected by cannabinoids in several different ways.

Uteri of mice treated with cannabis extract (1 mg/day for 64

days) showed decrease in weight, glycogen content, and RNA content

(Dixit et al. 1975; Chakravarty et al. 1975a ). Since these effects are opposite from what estrogen causes in the uterus, Δ-9-

THC may be acting to cause depressed estrogen secretion. Although

one report showed that Δ-9-THC (50 mg/kg for 28-180 days, orally)

142
did not cause a change in the weight or the morphology of the

ovaries or uteri of intact adult rats (Rosenkrantz et al. 1975),

others report a weak estrogenic effect in ovariectomized adult

females (2.5 mg/kg Δ-9-THC). Solomon et al. (1976) described

uterine weight gain and cytological changes upon Δ-9-THC administration of about two-thirds of the effect caused by injecting 2

μg estradiol. They later showed the uterine weight gain was associated with hypertrophy and hyperplasia of the uterus and increased

stratification of vaginal epithelium (Solomon et al. 1977), and

believe the "uterotropic" effect of Δ-9-THC to be a direct estrogenic action on uterine tissue.

Fujimoto et al. (1979) were unable to duplicate the uterotropic

effect reported by Solomon et al. (1976, 1977) in Fisher rats

using oral doses of either Δ-9-THC (1-5-25 mg/kg) or CME (3-15-75

mg/kg) administered for 72 days. In fact, the higher doses caused

a decrease in both uterine and ovarian weight as well as producing

an indication that the rats had a prolonged diestrus. Thirty

days after cessation of treatment both uteri and ovaries regained

about 90 percent of the control weight. C.G. Smith et al. (1979b )

also found no direct estrogenic or antiestrogenic effect in rhesus

monkeys that were administered Δ-9-THC (2.5 mg/kg, i.m.) for short

terms. There was no stimulatory effect on the histology of the

uterus or vagina; they found that THC did not bind to rat and

monkey uterus cytosols, nor did THC, CBD, or marijuana compete

with estrogen for estrogen receptors in these tissues.

If cannabinoids are estrogenic they would be expected to compete

with estradiol for binding sites in the cytosol of uterus and

other estrogen target tissues. The competition, if it does exist,

is very weak and is of questionable specificity (Rawitch et al.

1977). Shoemaker and Harmon (1977) reported a high affinity

binding of Δ-9-THC and 11-hydroxy-Δ-9-THC on uterine and mammary

gland cytosol, as well as competitive binding with estradiol

binding sites. In contrast, Okey and Bondy (1978) found no competition of Δ-9-THC for binding sites in mouse mammary or uterine

cytosols. Also, R.G Smith et al. (1979), using cytosol prepared

from uteri of rhesus monkeys and humans, showed that Δ-9-THC did

not compete with estradiol for estradiol receptors. Instead,

radioactive Δ-9-THC bound to macromolecules in the uterine cytosol

in the rhesus monkey but was not displaced by estradiol, progesterone, diethylstilbesterol, THC, cortisol, or 5-α-dihydroxytestosterone. They concluded that inhibition by Δ-9-THC of gonadotropin and steroid levels in primates was not caused by THC's interaction with intracellular steroid hormone receptors. Further,

Stanely et al, (1979) found that human term placenta lacked both

progesterone and estrogen receptors but did contain an androgen

receptor in the cytosol. THC was unable to displace androgens

from this binding substance.

This evidence and a number of other arguments have been expressed

against considering Δ-9-THC as an estrogen. These are (1) lack of

a dosage response relationship, (2) the very large amount of Δ-9-

THC that was needed to cause the estrogenic response, and (3) in

143
some of the processes that are stimulated by estradiol, Δ-9-THC

may be antagonistic.

Cannabinoids also affect the ovary, for studies have shown an

atrophy in ovarian function, including a decrease in ovarian

weight and changes in rat vaginal smears which indicated a complete halt of the ovarian cycle (Dixit et al. 1975). Other

changes included inhibition of luteinization and corpus luteum

degeneration along with a decrease in uterine RNA, protein and

glycogen content. The authors suggest that cannabis may be antiestrogenic. In contrast, two Macaque monkeys which were maintained on Δ-9-THC (2.4 mg/kg/day, in diet) for up to a year still

exhibited a normal menstrual cycle (Sassenrath and Chapman 1975).

At least some of the changes that occur in the female reproductive

tract caused by cannabinoids can partially be explained by their

depressive action on LH secretion with the subsequent reduction of

estrogen secretion by the ovary. Marks (1972) showed that Δ-9-THC

(1-3-10 mg/kg, i.v.) produced a decrease in LH secretion in ovariectomized rats. Δ-9-THC (2 mg/rat, i.p.) was able to prevent the

surge of LH into the blood from the pituitary of ovulating rats

that occurs just prior to ovulation (Nir et al. 1973). This inhibition may be a direct effect on the ovary, since LH given concurrently with a blocking dose of sodium pentobarbital after Δ-9-THC

administration was not as effective in causing ovulation. Most workers demonstrate a depression with Δ-9-THC of serum LH levels in both

ovariectomized and normally cycling rats, and there also are

reports that serum prolactin levels are decreased in both sexes

(Chakravarty et al. 1975b). Kashi et al. (1977) showed that Δ9-THC depressed the proestrous rise in LH, FSH, and prolactin

that occurs in the rat and delayed ovulation 24 hours. LHRF, when

administered, was able to reverse these effects. Similar effects

were obtained by Ayalon et al. (1977) and Tyrey (1978 a,b). The rabbit also responds in this way, for Asch et al. (1979) showed that

Δ- 9-THC (2.5-5.0 mg/kg, i.m.) was able to block the ovulatory reflex and halt ovulation, but that LHRF was able to produce ovulation in Δ-9-THC-treated rabbits. The rhesus monkey responded to

a single injection of D-9-THC (5.0 to .625 mg/kg, i.m.) with a

dramatic decrease in plasma LH and FSH that lasted until about 12

hours after injection (Besch et al. 1977), and return of the hormones in the plasma to normal base levels after this time was

fairly rapid. The rhesus monkey responds to LHRF similarly to

rabbits and rats; a single dose of Δ-9-THC (5.0 to .625 mg/kg, i.m.)

decreased serum levels of LH and FSH in ovariectomized rhesus monkey, but LHRF was able to produce release of LH and FSH in the D9-THC treated animals (Smith, C. G., et al. 1979b ). It is interesting to note that greater dosages of THC produced longer hormonal suppression, but the magnitude of the effect was not related

to the quantity of Δ-9-THC administered.

C. G. Smith et al. (1979a) also showed that rhesus monkeys which

received Δ-9-THC each day of the normal menstrual cycle did not

ovulate during subsequent cycles. An elevated prolactin level

probably caused this lack of ovulation.

144
Human Females

Bauman et al. (in press) report that chronic smoking of marijuana

(at least three times per week for the preceding 6 months) increased the number of menstrual cycles where no ovulation occurred

or menstrual cycles marked by inadequate luteal phase in the human

female. This alteration was also marked by lower prolactin and

lower progesterone levels, but higher testosterone levels in the

blood. This study raises some important questions about the effect of marijuana on the human menstrual cycle, since, if confirmed by future studies, marijuana might contribute to female

infertility. Nursing and normal lactation may also be impaired

by the lowered prolactin levels in the blood, The study itself,

however, should be repeated in a research ward setting similar to

that used for males by Hembree et al. (1979). Such a study could

control for amount of marijuana consumed (and with a known Δ-9-

THC content), variations in diet and environment, and differences

in lifestyle between the two groups of females.

Summary

In summary, the major depressive effect of cannabinoids on the female reproductive tract (as well as in the male) would appear to

be due to their inhibition of LHRF release with subsequent depression of LH release. It is probable that many of the changes in

female reproductive physiology that are observed after cannabinoid

treatment are due to lack of LH stimulation of estrogen production

by the ovary. It is possible that some of the effects of cannabinoids may be due to direct action of the active ingredients in

marijuana on the female reproductive structures. More work is

needed to explore this possibility. Moreover, the responses observed may not be identical when Δ-9-THC is used and when other

cannabinoid and noncannabinoid constituents found in marijuana

smoke are used.

THE EFFECT OF MARIJUANA ON ADRENAL CORTICAL HORMONES

The adrenal cortex secretes honmnes that have important effects

on the reproductive system. In rats and mice, acute treatment

with cannabinoids generally produces a prompt rise in corticosteroid levels in plasma which is also accompanied by a decrease

in the level of ascorbic acid found in the adrenal glands. A

wide range of dosages (2-20 mg) of Δ-9-THC is effective in producing this rise (Bloch et al. 1978, summarize these), apparently

by direct action on the hypothalamus and pituitary gland to increase adrenocorticotropic hormone (ACTH) (Mäier and Maitre 1975).

In this way cannabinoids act like stressors and effectively block

the negative feedback of elevated plasma corticosterone on the

hypothalamus (Drew and Slagel 1973). Maier and Maitre (1975)

have shown that hypophysectomy, which removes the source of ACTH

production, also abolished the adrenocortical response to Δ-9-THC.

Moreover, pentobarbital (Mitra et al. 1977) and dexamethasone

(Kokka and Garcia 1974), two agents which are known to block ACTH

secretion, also prevent the adrenocortical response to Δ-9-THC.

145
Since cannabinoids are thought to interact at the level of the

brain and pituitary, several investigators have examined the uptake of radioactive Δ-9-THC by various brain structures. There

was some slight uptake of the radioactive compound by the medulla,

preoptic areas, hypothalamus, and pituitary; however, the amount

was not greater than in other brain structures (Erdmann et al. 1976,

Martin et al. 1976). Uptake of radioactive corticosterone by the

hypothalamus and thalamus was reduced if rats were pretreated

with Δ-9-THC at a high dose (9 mg/kg, i.p.) but smaller doses (3

mg/kg, i.p.) increased corticosterone uptake (Drew and Slagel

1973). These results are in apparent contradiction to a recent

study by Johnson et al. (1978), who examined the effect of 11-

hydroxy-Δ-9-THC (11-OH-Δ-9-THC), Δ-9-THC, and cannabinol (CBN) on

mouse brain uptake of radioactive corticosterone. Higher doses

of the cannabinoids (30 and 100 mg/kg) increased 3H-corticosterone uptake by whole brain. Pretreatment with Δ-9-THC (3, 10,

100 mg/kg, s.c.) increased the affinity of the hippocampus for 3Hcorticosterone, but decreased its concentration in hypothalamus,

midbrain, pons and medulla, The differences between the results

of this study and those of Drew and Slagel (1973) are probably due

to differences in experimental design and differences in species

used.

Injection of Δ-9-THC directly into the ventricles of the rat brain

led to anincrease in general activity of cells in the adrenal and

pituitary, and also caused an increased corticosterone production

(Collu 1976). Chronic treatment in rats and mice with Δ-9-THC

led to increased adrenal weight, which appeared to be reversible

(Dixit et al. 1974). The adrenal was still able to respond to

Δ-9-THC with a plasma corticosterone rise even after two months

of cannabinoid treatment (Barry et al. 1972). Also, Jacobs et

al. (1979) showed that Δ-9-THC (5 mg/kg, i.p.) does not prevent the

release of corticosterone in stressed (electric shock) rats. The

adrenal cortical response to cannabinoids seems to be confined to

rodents, for rabbits (Maier and Maitre 1975; Thompson et al.

1975), monkeys (Sassenrath and Chapman 1975; Thompson et al.

1975), and guinea pigs (Huy et al. 1975) apparently do not respond to cannabinoids with increased adrenal cortical activity.

In addition to the direct action of cannabinoids on adrenal cortical function through their effect on hypothalamus and thalamus,

and subsequent pituitary ACTH production, cannabinoids can exert

a direct suppressive effect on adrenocortical activity. When

mouse adrenocortical cells were grown in tissue culture with

added Δ-9-THC, CBN, or CBD (10-6 to 10-4 M each cannabinoid), the

cells were unable to respond when ACTH was added to the culture

medium (Carchman et al. 1976; Warner et al. 1977). This lack

of responsiveness was selective and not due to a change in the

viability of the cells. Moreover, the cannabinoids seemed to

affect the formation of steroid hormones at a biochemical step

somewhere between cyclic AMP and pregnenolone production (Warner)

et al. 1977. Burstein et al. (1978a) showed that Δ-9-THC (3.2

and 16 μM) added to incubation medium containing homogenized rat

adrenal inhibited cholesterol esterase activity similarly to its

146
action in Leydig cells. The finding of a direct action on adrenocortical cells is important since the adrenal cortex, especially

the lipids and the mitochondria, may selectively retain Δ-9-THC

(Bloch et al, 1978), thereby maintaining higher concentrations

of cannabinoids in the adrenal cortex after the level in the

plasma has decreased.

Humans

Several studies have examined the effect of cannabinoids on adrenal

cortical activity and function in humans (Kolodny et al., 1974;

Hollister et al. 1970). In contrast to the way in which the rat

adrenal gland responds to Δ-9-THC, no changes were reported for

humans. Cruickshank (1976) found no difference in excretion of

major urinary metabolites of cortisol between marijuana smokers

(1-24 cigarettes/day, Δ-9-THC content .07-10.3 percent) and controls. Perez-Reyes (1976) examined the way marijuana

smoking affects the adrenal cortical response to a synthetic corticotropin in frequent marijuana users compared to nonusers. He

concluded that frequent use of marijuana did not alter the capacity

of the adrenal cortex to respond to synthetic corticotropin stimulation.

THE EFFECT OF MARIJUANA ON PROSTAGLANDINS

Some of the actions that cannabinoids exert on reproductive processes are possibly induced by changes in prostaglandin synthesis

in the reproductive organs. Prostaglandins are substances which

regulate functions of many organs throughout the body. In the

female reproductive tract, they allow the ovaries to respond to

gonadotropic hormones, are active during parturition, and produce

normal contractility and motility of the uterus and oviducts.

They are also important in the male, where they affect contractility and mobility of the vas deferens and epididymis. In both

the male and female they are necessary for the proper tone of the

circulatory system that is associated with all of these reproductive structures.

It was postulated by Howes and Osgood (1976) that cannabinoids may

affect reproductive structures by altering the way in which prostaglandins are synthesized in these tissues and organs. Certainly

LH secretion, the maturation of follicles in the ovary, reduced

sperm counts and reduced uterine contractility are affected by

changes in concentration of prostaglandins in these tissues, and

cannabinoids are known to depress these same reproductive processes. It is possible, then, that cannabinoids may have their

depressive effects on some reproductive functions by inhibiting

prostaglandin synthesis and there is some experimental evidence

to justify these claims. Burstein and Raz (1972) and Burstein et

al. (1973) showed that several cannabinoids inhibited prostaglandin

synthesis in microsomal preparations from the seminal vesicles of

cows. Moreover, Burstein et al. (1975, 1976) showed that other

constituents in marijuana (alkaloids, aromatic alkaloids and acids,

turpenes) might be more potent in reducing prostaglandin synthesis

than Δ-8- and Δ-9-THC, CBD, or CBN.

147
THE EFFECT OF MARIJUANA ON PREGNANCY

An early study showed that very high doses (1-4 g) of Δ-9-THC

caused a prolonged gestation in rats even though the birth weights

were normal (Borgen et al. 1971). Since then, other investigators have shown that rats treated daily with Δ-9-THC (25 to 200

mg/kg/day) throughout pregnancy did not have the same weight gain

as normal pregnant rats (Pace et al. 1971; Banerjee et al. 1975).

Nonpregnant rats showed a decreased rate of growth which was correlated with decreased food consumption (Bartova and Birmingham

1976; Rosenkrantz et al. 1975; Rosenkrantz and Braude 1976). It

would appear that moderate and low doses of cannabinoids (5 mg/kg/

day) were ineffective in changing either length of gestation, viability of the mother, or amount of weight that was gained during

pregnancy (Wright et al. 1976; Pace et al. 1971).

Unlike rats, mice did not seem to be influenced by consumption of

Δ-9-THC with respect to pregnancy and fertility (Legator et al.

1976; Mantilla-Plata et al 1975). Fertility, mating, and pregnancy in chimpanzees were not affected by Δ-9-THC (1 and 2.1 mg/kg/

day) intake (Grilly et al. 1974).

It is important that the corpora lutea of pregnant mice concentrate radioactive Δ-9-THC, which indicates an affinity of this

structure for Δ-9-THC either through binding to proteins in the

corpus luteum or merely to the solubility of Δ-9-THC in the lipids

of the corpus luteum (Freudenthal et al. 1972; Kennedy and

Waddell 1972).

THE EFFECT OF MARIJUANA ON LACTATION

Milk production in pregnant and lactating animals treated with

cannabinoids was inhibited. Δ-9-THC (1.2 gm/day, day 10-16 of

pregnancy, s.c.) given to pregnant rats decreased the amount of

milk produced by the mother after the pups are born. This depression was observed as a decrease in the amount of milk reaching the

newborn pups, which resulted in increased neonatal mortality

(Borgen et al. 1971; Pace et al. 1971). It is possible that

Δ-9-THC suppressed the production of prolactin as well as having

a direct effect on the mammary glands themselves to lower milk

synthesis or to a combination of both lowered prolactin and the

direct effect. Moreover, mammary tissue is effective in concentrating Δ-9-THC from the blood and, as such, mammary tissue may

serve as a reservoir which may actually prolong transmission of

Δ-9-THC to the young (Jakubovic et al. 1973). Raine et al. (1978)

showed decreased prolactin and decreased mammary gland growth in

mice treated from Day 13 of pregnancy with Δ-9-THC (25 mg/kg, s.c.).

Lower doses (CME; .5 to 5 mg THC/kg content, p.o.; or 5 mg/kg, i.v.

or i.p.) did not affect lactation (Wright et al. 1976; Maker et

al. 1974). Radioactive Δ-9-THC administered to lactating squirrel

monkeys appeared in the milk and in the suckling infants (Chao et

al. 1976).

148
THE EFFECT OF MARIJUANA ON DEVELOPMENT

Radioactive Δ-9-THC was able to leave the maternal circulation

and pass the placenta to accumulate inside the fetuses of pregnant

rats and mice (Pace et al. 1971). Martin et al. (1977) found

radioactive Δ-9-THC (.05 mg/kg) was concentrated in the brain of

the dog fetus 20 minutes after injection into the mother. The

distribution in the fetus was similar to the distribution found

in the mother, although the uptake was only one-third that of the

mother. Loss of Δ-9-THC from the fetus and placenta was slower

than that found in the mother, which may tend to prolong fetal

exposure to Δ-9-THC (Mantilla-Plata and Harbison 1976a ,b). Moreover, because of its high lipid solubility, Δ-9-THC accumulates

in the adipose tissues of the mother and the fetus (Harbison and

Mantilla-Plata 1972). The net effect of this would allow concentration of Δ-9-THC from the circulation and then slower release of

it over a prolonged period of time back to the circulation

(Mantilla-Plata and Harbison 1976a ).

The ultimate effect of the constituents in marijuana upon development and growth of the fetus seems to depend upon the stage of development at which the fetus is exposed to the chemicals. In

general, if the fetus is exposed to teratogens during the early

part of gestation at a time when the internal organs are undergoing

development, there may be organ malformation or fetal toxicity.

If exposure to drugs occurs during the latter stages of pregnancy

after the organs have been formed, there may be growth retardation

in the fetus. In mice, rats, and rabbits Δ-9-THC or CME at very

high doses (30-50 mg/kg/day) producedanincrease in the number of

fetal and embryonic mortalities if given in the first half of gestation. These mortalities were observed as an increased incidence

of resorptions of the fetus, as well as a decrease in the number

of pups born (Mantilla-Plata et al, 1973; Joneja, 1976, 1977;

Fleischman et al. 1975; Banerjee et al, 1975). Harbison et al.

(1977) found no fetal anomalies with pregnant mice treated with

Δ-9-THC (50-200 mg/kg, i.p.); however, they found an increase in

in utero deaths with decrease in body weight of the surviving

fetuses. Fried (1976) showed increased resorptions of rat fetuses

from mothers exposed to marijuana smoke (estimated 3.3 mg Δ-9-THC)

from Day 1 to Day 19 of gestation. Moreover, the pups that were

born had smaller birth weights and were less active (Fried and

Charlebois, in press). Rosenkrantz (1979) found that oral doses

of Δ-9-THC (in mice, 5-50 mg/kg; in rats, 12.5-50 mg/kg) produced

embryo toxicity if given after Day 6 of gestation. Cozens et al.

(1979) found marijuana extract (1 mg/kg/day, orally) reduced body

weight of maternal and fetal rabbits, with only minor changes in

the fetus.

If cannabinoids were given later in pregnancy, they did not produce fetal toxicity (Fleischman et al, 1975; Joneja 1976; Haley

et al. 1973; Wright et al. 1976). Some studies showed Δ-9-THC

(150 mg/kg) decreased survival of mouse fetuses (Day 8-10 of gestation) (Mantilla-Plata et al. 1975; Mantilla-Plata and Harbison

1976a).

149
Sassenrath et al. (1979) reported that a group of female rhesus

monkeys which had received Δ-9-THC (2.4 mg/kg daily, orally) over

a five-year period had no decrease in the number of conceptions,

but there was an increase in reproductive loss at all stages of

development and a reduced birth weight of male infants.

The growth of the fetus was similarly affected by large amounts of

CME or Δ-9-THC in mice, rats, rabbits, and hamsters. The same

doses that caused increased resorptions resulted in retardation of

growth and reduced survival of the fetus (Harbison et al. 1977;

Joneja 1977; Mantilla-Plata and Harbison 1976a; Banerjee et al.

1975).

Matsuyama and Jarvik (1977) reviewed the early research that reported a teratogenic effect of cannabinoids. Much of the conflict

between these reports was ascribed to several variables, including

differences in the species or strain used, the route and time of

administration of the cannabinoids, as well as the dosage of cannabinoidused. Bloch et al. (1978) evaluated these early conflicting

reports and found evidence of a clear teratogenic response in mice

(Mantilla-Plata et al. 1973, 1975; Mantilla-Plata and Harbison

1976a and b; Harbison et al. 1977; Joneja 1976; and Kostellow et al.

1978). The most frequently described developmental lesion was cleft

palate and exencephaly. In all of these studies, doses of several

hundred mg/kg of body weight were needed to produce congenital defects. Also, agents which affected Δ-9-THC metabolism when given

simultaneously with it enhanced activity of Δ-9-THC to interfere

with palate closure. Harbison et al. (1977) showed that large doses

of Δ-9-THC (50 or 200 mg/kg, i.p.) given to mice led to cleft

palate formation if given in combination with certain other drugs

such as phenobarbital.

Although an early study by Persaud and Ellington (1968) showed

malformation in rat fetuses whose mothers were treated with cannabis resin (4.2 mg/kg/day, i.p.) given between Day 1 and Day 6 of

gestation, several other studies were unable to demonstrate a

teratogenic action of CME or Δ-9-THC (Banerjee et al. 1975;

Uyeno 1975; Wright et al. 1976). For example, Wright et al.

(1976) found no evidence of teratogenic activity when pregnant

rats were treated orally with Δ-9-THC or CME containing Δ-9-THC

equivalent doses of 5-50 mg/kg on gestation Days 6-15. Nor were

there any changes over control animals in average number of pups

delivered, pup survival, nor on lactation.

Other investigators have shown congenital defects on dental development in rats (Δ-9-THC, 3.3-20 mg/kg/day), including incisor

eruption (Fried 1976), and mandibular and maxillary asymmetry

(Siegel et al., 1977). Large doses of Δ-9-THC (125-500 mg/kg,

i.g.) given to pregnant hamsters produced only minor defects in

the fetus (Joneja 1977).

Only two reports exist which examined teratogenic effects on primates. Of two fetuses born to Macaques treated with Δ-9-THC (2.4

mg/kg, orally) for a year; one was hyperactive but otherwise normal, and the other died shortly after birth and was hydrocephalic

150
(Sassenrath and Chapman 1975). Chimpanzees who were exposed to

marijuana smoke prior to mating had eight normal offspring (Grilly

et al. 1974).

In view of the relatively large amount of cannabinoids that are

needed to produce developmental anomalies in lower animals, it is

doubtful that the cannabinoids by themselves are teratogenic. It

is possible, however, that they may facilitate the teratogenicity

of known teratogens by lowering the threshold at which they have

their effect.

THE EFFECT OF MARIJUANA ON REPRODUCTIVE BEHAVIOR

There are not many reports in the research literature which examine the effect of marijuana and its constituents on reproductive

behavior. Reproductive behavior is fairly complex and comprises

many different components. Most of the reports are concerned with

mating and have not examined very intensively sexual behaviors

other than mating. Acute studies of male rats treated with Δ-9-

THC (8.3 and 16.6 mg/kg, acute) report an increase in the length

of times until the first mount, ejaculation, and longer postejaculation intervals, as well as a significant decrease in the

number of males achieving, intromission (Corcoran et al. 1974).

Mice also showed a decreased number of mounts which were of

shorter duration, as well as a depression of the investigative behavior exhibited by the male prior to sexual activity (Cutler et

al. 1975a,b). Chronic cannabinoid (2 percent resin in diet) administration in rats caused significantly lower reproductive activity than controls and, also, no differences were observed in

mating behavior of either males or females (Miras 1965).

These kinds of studies have been criticized by Bloch et al. (1978)

for lack of adequate experimental controls, since no attempt was

made to evaluate the depressant effects of marijuana on general

motor activity and feeding behavior, and low doses of Δ-9-THC

might possibly be behavioral stimulants. In some cases the quantification used to analyze reproductive behavior could have been

improved, and many times the degree of female receptivity was not

constant. When crude marijuana extract was used, no attempt was

made to determine what parts of behavior were affected by the

various constituents of cannabis.

Very little work has been reported on female behavior. However,

Sassenrath and Chapman (1975) reported that chronic treatment with

Δ-9-THC (2 mg/kg/day, in diet) presumably produced an irritable rejection in a single female Macaque toward its infant.

If marijuana is to have an effect on sexual behavior, one would

assume a direct action of the constituents in marijuana on those

brain structures which serve to elicit sexual behavior. The two

principal areas in the brain which elicit and regulate reproductive behavior are the preoptic and hypothalamic areas. Certainly

sex hormones are concentrated in these areas and reproductive behavior can be elicited by either electrical or hormonal stimulation

151

323-754 0 - 80 - 11
of these areas. If they are destroyed by lesions, reproductive

behavior is abolished. Also, cannabinoids may affect sexual behavior by altering the sex hormones circulating in the blood which

elicit sexual behavior by their action on central nervous targets

by cannabinoids' effect on other brain structures to depress LHRF

release.

A series of experiments were reported which examined the uptake of

radioactive Δ-9-THC in different regions of the brain of rats.

These studies are not numerous, nor are they very definitive.

Some report no difference in concentration between different

regions of the rat brain (Layman and Milton 1971), whereas others

report a significant uptake between regions of the brain but by

areas not directly concerned with reproductive behavior (Martin

et al. 1976; McIsaac et al. 1971; Erdmann et al. 1976). A possible exception, however, was the lateral hypothalamus (Shannon

and Fried 1972; Erdmann et al, 1976), where there is reasonable

evidence to indicate that it may be involved in reproductive

behavior.

Two other areas associated with reproductive behavior are the

amygdyla and portions of the limbic structure, Three reports show

there is heavy accumulation of radioactive Δ-9-THC in amygdyloid

nuclei (McIsaac et al. 1971; Shannon and Fried 1972; Martin et

al. 1976). However, the exact nuclei are not specified and may

be ones which are not involved in regulating reproductive behavior.

One thing is clear: there is altered electrographic activity in

the amygdyla after administration of cannabinoids in both cats

(Hockman et al. 1971; Miller and Brew 1974) and monkeys (Heath

1976). Similarly, altered electrographic activity was reported

in the ventromedial nucleus of the cat, an area located in the

hypothalamus that may also be involved in reproductive behavior

(Myers 1974; Pfaff et al. 1974).

Human

Most of the reports on the effect of marijuana on human sexual behavior are based on subjective self-reports. Several of these report an increase in sexual stimulation, by noting that sexual desire and sexual performance were prolonged in both males and females. However, it is interesting to note that in some countries,

such as India, cannabis is used as a sexual depressant (Chopra and

Chopra 1957; Chopra 1969). An early experiment by Hollister et

al. (1968) reported stimulation of sexual thoughts after cannabis

administration. Indeed, a large number of experienced marijuana

users report an increase in sexual pleasure after marijuana use

(Tart 1971; Berke and Hernton 1974; Traub 1977), and, in contrast to alcohol, marijuana use was reported to decrease sexually

assaultive behavior (Tinklenberg et al. 1974). Acute use of cannabinoids at lower doses apparently enhances sex drive; however,

high doses lead to depression of sexual desire and even impotence,

possibly due to the decreased plasma testosterone levels,

Bloch et al. (1978) have pointed out that many of the reported

152
effects may not be due to the effect of cannabis directly but may

reflect the lifestyle of the marijuana user which tends to be sensation-seeking and risk-taking. Moreover, there may be a placebo

reaction involved. One cannot dismiss the possibility of a secondary effect of marijuana to increase vasodilation in the genitals

caused by reduction of sympathetic tone. The appreciation of

sexual performance might also be affected by an altered perception

of time. Moreover, heightened appreciation of sexual activity may

be caused by the effect of marijuana to delay ejaculation as well

as to perceive tactile stimulation more intensely.

SUMMARY

This review has pointed out the fact that cannabinoids have significant depressive actions on reproduction and development. In

the male, cannabinoids produce decreased organ weights and functional levels of the organs associated with reproduction. These

changes may be due to the direct action of cannabinoids to depress

testosterone production in the Leydig cells of the testes, or

through inhibition of LH and FSH release by the pituitary. One of

the primary targets of cannabinoids is on central nervous structures, such as the hypothalamus, to shut down production of LHRF.

There is evidence that the testes of animals treated with cannabinoids responded in a normal fashion when LH and FSH were provided exogenously; moreover, the pituitary was shown to respond

in a normal fashion when exogenous LHRF was provided. Rats, mice

and humans treated with cannabinoids had decreased numbers of

sperm with an increase in percent of abnormal sperm in their semen.

After cessation of cannabinoid treatment, both rodents and humans

returned to normal levels of reproductive function fairly rapidly.

Females similarly responded to cannabinoids with a decrease in the

function of organs associated with reproduction. The uterus

showed changes in weight and morphology, while the ovary had irregular cycles or a complete cessation of cycling. These changes

were probably caused by lowered estrogen production in the ovary

caused by the cannabinoids' action to depress gonadotropin release from the pituitary. As inthemale, the primary target of

cannabinoids would appear to be their action on central nervous

structures to shut down release of LHRF. Certainly, when exogenous LHRF was provided, the pituitary was able to release gonadotropins. It seems at this point that the estrogenic action of

cannabinoids previously reported is controversial since recent

evidence shows a lack of highly specific binding to the cytosol

receptors for estradiol.

Cannabinoids also may have an action on reproduction through a

variety of other mechanisms including: (1) their ability to

stimulate adrenal cortical hormones, an action that is probably

due to the cannabinoids' effect on central nervous structures to

cause release of ACTH from the pituitary, since agents which block the

release of ACTH also prevent the cannabinoid response; (2) cannabinoids may have a direct effect on both male and female reproductive organs to either alter hormone production or to alter the

153
response of the reproductive organs to hormones; (3) cannabinoids

may alter prostaglandin synthesis in reproductive organs, thus

affecting reproductive function.

High doses of cannabinoids appear to inhibit reproductive behavior,

at least in rodents, while lower doses may facilitate reproductive

behavior, possibly through their action on other physiological systems, to alter time perception, delay ejaculation, and alter perception of tactile stimulation during the sex act.

Cannabinoids also decrease prolactin secretion and release in both

male and female. This depression has been shown in nursing females to cause a decrease in milk production and lactation. Cannabinoids may have a direct action on the mammary tissues themselves to decrease milk production.

REFERENCES

Asch, R.H., Fernandez, E.O., Smith, C.G., and Pauerstein, C.J.

Precoital single doses of delta-9-tetrahydrocannabinol block

ovulation in the rabbit. Fertil Steril, 31(3):331-334, 1979.

Ayalon, D., Nir, I., Cordova, T., Bauminger, S., Puder, M., Naor,

Z., Kashi, R., Zor, U., Harell, A., and Lindner, H.R. Acute

effect of Δ

1

-tetrahydrocannabinol on the hypothalamo-pituitaryovarian axis in the rat. Neuroendocrinology, 23:31-42, 1977.

Banerjee, B.N., Galbreath, C., and Sofia, R.D. Teratologic

evaluation of synthetic delta-9-tetrahydrocannabinol in rats.

Teratology, 11(1):99-101, 1975.

Barry, H., III, Kubena, R.K., and Perhach, J.L., Jr. Pituitaryadrenal activation and related responses to Δ

1

-tetrahydrocannabinol. Prog Brain Res, 39:323-330, 1972.

Bartova, A., and Birmingham, M.K. Effect of delta-9-tetrahydrocannabinol on mitochondrial NADH-oxidase activity. J Biol Chem,

251:5002-5006, 1976.

Bauman, J.E., Kolodny, R.C., Dornbush, R.L., and Webster, S.K.

Endocrine effects of human female chronic marihuana use. In

press.

Berke, J., and Hernton, C. The Cannabis Experience: an interpretive study of the effects of marijuana and hashish. London:

Peter Owen, 1974. 228 pp.

154
Besch, N.F., Smith, C.G., Besch, P.K., and Kaufman, R.H. The

effect of marihuana (delta-9-tetrahydrocannabinol) on the secretion of luteinizing hormone in the ovariectomized rhesus monkey,

Am J Obstet Gynecol, 128(6):635-642, 1977.

Bloch, E., Thysen, B., Morrill, G.A., Gardner, E., and Fujimoto,

G. Effects of cannabinoids on reproduction and development.

Vitam Horm 36:203-258, 1978.

Borgen, L.A., Davis, W.M., and Pace, H.B. Effects of synthetic

Δ-9-tetrahydrocannabinol on pregnancy and offspring in the rat.

Toxicol Appl Pharmacol, 20(4):480-486, 1971.

Bromley, B., and Zimmerman, E. Divergent release of prolactin

and corticosterone following Δ-9-tetrahydrocannabinol injection

in male rats. Fed Proc Fed Am Soc Exp Biol, 35:220, 1976.

Burstein, S., and Hunter, S.A. Prostaglandins and cannabis--VI.

Release of arachidonic acid from HeLa cells by Δ-1-tetrahydrocannabinol and other cannabinoids. Biochem Pharmacol, 27:1275-1280,

1978.

Burstein, S., Hunter, S.A., and Shoupe, T.S. Inhibition of

cholesterol esterases by Δ-1-tetrahydrocannabinol. Life Sci, 23:

979-982, 1978a.

Burstein, S., Hunter, S.A., and Shoupe, T.S. Site of inhibition

of Leydig cell testosterone synthesis by Δ-1-tetrahydrocannabinol.

Mol Pharmacol, 15(3):633-640, 1979.

Burstein, S., Hunter, S.A., Shoupe, T.S., and Taylor, P. Cannabinoid inhibition of testosterone synthesis by mouse Leydig cells.

Res Commun Chem Pathol Pharmacol, 19(3):557-560, 1978b.

Burstein, S., Levin, E., and Varanelli, C. Prostaglandins and

cannabis. II. Inhibition of biosynthesis by the naturally

occurring cannabinoids. Biochem Pharmacol, 22(22):2905-2910,

1973.

Burstein, S., and Raz, A. Inhibition of prostaglandin E2 biosynthesis by delta-1-tetrahydrocannabinol. Prostaglandins 2(5):

369-374, 1972.

Burstein, S., Taylor, P., El-Feraly, F.S., and Turner, C. Prostaglandins and cannabis--V. Identification of p-vinylphenol as a

potent inhibitor of prostaglandin synthesis. Biochem Pharmacol,

25(17):2003-2004, 1976.

Burstein, S., Varanelli, C., and Slade, L.T. Prostaglandins and

cannabis--III. Inhibition of biosynthesis by essential oil components of marihuana. Biochem Pharmacol, 24(9):1053-1054, 1975.

155
Carchman, R.A., Warner, W., White, A.C., and Harris, L.S. Cannabinoids and neoplastic growth. In: Nahas, G.G. ed. Marihuana:

Chemistry, Biochemistry and Cellular Effects. New York: SpringerVerlag, 1976. pp. 329-345.

Chakravarty, I., Sengupta, D., Bhattacharyya, P., and Ghosh, J.J.

Effect of treatment with cannabis extract on the water and glycogen contents of the uterus in normal and estradiol-treated prepubertal rats. Toxicol Appl Pharmacol 34(3):513-516, 1975a .

Chakravarty, I., Sheth, A.R., and Ghosh, J.J. Effect of acute

delta-9-tetrahydrocannabinol treatment on serum luteinizing hormone and prolactin levels in adult female rats. Fertil Steril

26(9):947-948, 1975b .

Chan, M.Y., and Tse, A. The effect of cannabinoids (Δ9

-THC and Δ

8

-

THC) on hepatic microsomal metabolism of testosterone in vitro.

Biochem Pharmacol, 27:1725-1728, 1978.

Chao, F.C., Green, D.E., Forrest, I.S., Kaplan, J.N., Winship-Ball,

A., and Braude, M. The passage of 14C-delta-9-tetrahydrocannabinol into the milk of lactating squirrel monkeys. Res Commun

Chem Pathol Pharmacol, 15(2):303-317, 1976.

Chopra, G.S. Man and marijuana. Int J Addict, 4:215, 1969.

Chopra, I.C., and Chopra, R.N. The use of cannabis drugs in

India. Bull Narc, 9:4-29, 1957.

Coggins, W.J., Swenson, E.W., Dawson, W.W., Fernandez-Salas, A.,

Hernandez-Bolanos, J., Jiminez-Antillon, C.F., Solano, J.R.,

Vinocour, R., and Faerron-Valdez, F. Health status of chronic

heavy cannabis users. Ann NY Acad Sci, 282:148-161, 1976.

Cohen, S. The 94-day cannabis study. Ann NY Acad Sci, 282:211-

220, 1976.

Collu, R. Endocrine effects of chronic intraventricular administration of Δ-9-tetrahydrocannabinol to prepuberal and adult male

rats. Life Sci, 18:223-230, 1976.

Collu, R., Letarte, J., Leboeuf, G., and Ducharme, J.R. Endocrine effects of chronic administration of psychoactive drugs to

prepuberal male rats. I: Δ-9-tetrahydrocannabinol. Life Sci,

16:533-542, 1975.

Corcoran, M.E., Amit, Z., Mallsbury, C.W., and Daykin, S. Reduction in copulatory behavior of male rats following hashish injections. Res Commun Chem Pathol Pharmacol, 7:779-782, 1974.

Cozens, D.D., Clark, R., Palmer, A.K., and Harvey, D.J. The effect

of a crude marihuana extract on embryonic and foetal development of

the rabbit. In: Nahas, G.G., and Paton, W.D.M., eds. Marihuana:

Biological Effects. New York: Pergamon Press, 1979. pp. 469-477.

156
Cruickshank, E.K. Physical assessment of 30 chronic cannabis

users and 30 matched controls. In: Dombush, R.L., Freedman,

A.M., and Fink, M., eds. Chronic Cannabis Use. New York Acad

Sci, 1976. pp. 162-167.

Cutler, M.G., Mackintosh, J.H., and Chance, M.R.A. Effects of

cannabis resin on social behaviour in the laboratory mouse.

Psychopharmacologia, 41:271-276, 1975a.

Cutler, M.G., Mackintosh, J.H., and Chance, M.R.A. Cannabis resin

and sexual behavior in the laboratory mouse. Psychopharmacologia,

45:129-131, 1975b.

Daley, J.D., Branda, L.A., Rosenfeld, J., and Younglai, E.V. Increase of serum prolactin in male rats by (-)-trans-delta-9-tetrahydrocannabinol. J Endocrinol, 63:415-416, 1974.

Dalterio, S., Bartke, A., and Burstein, S. Cannabinoids inhibit

testosterone secretion by mouse testes in vitro. Science, 196:

1472-1473, 1977.

Dalterio, S., Bartke, A., Roberson, C., Watson, D., and Burstein,

S. Direct and pituitary-mediated effects of Δ-9-THC and cannabinol

on the testis. Pharmacol Biochem Behav 8:673-678, 1978.

Dixit, V.P., Arya, M., and Lohiya, N.K. The effect of chronically

administered cannabis extract on the female genital tract of mice

and rats. Endokrinologie, 66(3):365-368, 1975.

Dixit, V.P., Crupta, C.L., and Agrawal, M. Testicular degeneration

and necrosis induced by chronic administration of cannabis extract

in dogs. Endokrinologie, 69:299-305, 1977.

Dixit, V.P., Sharma V.N., and Lohiya, N.K. The effect of chronically administered cannabis extract on the testicular function of

mice. Eur J Pharmacol, 26:111-114, 1974.

Drew, W.G., and Slagel, D.E. Δ-9-THC: selective impairment of

corticosterone uptake by limbic structures of the rat. Neuropharmacology, 12:909-914, 1973.

Erdmann, G., Just, W.W., Thel, S., Werner, G., and Wiechmann, M.

Comparative autoradiographic and metabolic study of Δ-8- and Δ-9-

tetrahydrocannabinol in the brain of the marmoset Callithrix

jacchus. Psychopharmacology, 47:53-58, 1976 .

Fleischman, R.W., Hayden, D.W., Rosenkrantz, H., and Braude, M.C.

Teratologic evaluation of delta-9-tetrahydrocannabinol in mice,

including a review of the literature. Teratology, 12(1):47-50,

1975.

Freudenthal, R.I., Martin, J., and Wall, M.E. Distribution of

delta-9-tetrahydrocannabinol in the mouse. Br J Pharmacol, 44(2):

244-249, 1972.

157
Fried, P.A. Short- and long-term effects of prenatal cannabis

inhalation upon rat offspring. Psychopharmacology, 50:285-291,

1976.

Fried, P.A., and Charlebois, A. Effects upon rat offspring following cannabis inhalation before and/or after mating. Can J

Psychol. In press.

Fujimoto, G.I., Kostellow, A.B., Rosenbaum, R., Morrill, G.A., and

Bloch, E. Effects of cannabinoids on reproductive organs in the

female Fischer rat. In: Nahas, G.G., and Paton, W.D.M., eds.

Marijuana: Biological Effects. New York: Pergamon Press, 1979.

Fujimoto, G.I., Rosenbaum, R.M., Ziegler, D., Rettura, G., and

Morrill, G.A. Effect of marihuana extract given orally on male

rat reproduction and gonads. Proc 60th Ann Meet Endocr Soc 1978.

Abstract #597, p. 373.

Goldstein, H., Harclerode, J., and Nyquist, S.E. Effects of

chronic administration of delta-9-tetrahydrocannabinol and cannabidiol on rat testicular esterase isozymes. Life Sci, 20(6):951-

954, 1977.

Grilly, D.M., Ferraro, D.P., and Braude, M.C. Observations on the

reproductive activity of chimpanzees following long-term exposure

to marihuana. Pharmacology, 11:304-307, 1974.

Haley, S.L., Wright, P.L., Plank, J.B., Keplinger, M.L., Braude,

M.C., and Calandra, J.C. The effect of natural and synthetic

delta-9-tetrahydrocannabinol on fetal development. Toxicol Appl

Pharmacol, 25:450, 1973.

Harbison, R.D., and Mantilla-Plata, B. Prenatal toxicity, maternal distribution and placental transfer of tetrahydrocannabinol.

J Pharmacol Exp Ther, 180(2):446-453, 1972.

Harbison, R.D., Mantilla-Plata, B., and Lubin, D.J. Alteration of

delta-9-tetrahydrocannabinol-induced teratogenicity by stimulation

and inhibition of its metabolism, J Pharmacol Exp Ther, 202:455-

465, 1977.

Harclerode, J., Nyquist, S.E,, Nazar, B., and Lowe, D. Effects of

cannabis on sex hormones and testicular enzymes of the rodent.

In: Nahas, G.G., and Paton, W.D.M., eds. Marihuana: Biological

Effects. New York: Pergamon Press, 1979. pp. 395-405.

Harmon, J., and Aliapoulios, M.A. Gynecomastia in marihuana users.

N Engl J Med, 287:936, 1972.

Harmon, J.W., and Aliapoulios, M.A. Marijuana-induced gynecomastia:

clinical and laboratory experience. Surg Forum, 25:423-425, 1974.

158
Heath, R.G. Marihuana and Δ-9-tetrahydrocannabinol: Acute and

chronic effects on brain function of monkeys. In: Braude, M.C.,

and Szara, S., eds. Pharmacology of Marihuana. New York: Raven

Press, 1976. pp. 345-356.

Hembree, W.C., Nahas, G.G., and Huang, H.F.S. Changes in human

spermatozoa associated with high dose marihuana smoking. In:

Nahas, G.G., and Paton, W.D.M., eds. Marihuana: Biological

Effects. New York: Pergamon Press, 1979. pp. 429-439.

Hockman, C.H., Perrin, R.G., and Kalant, H. Electroencephalographic and behavioral alterations produced by delta-1-THC.

Science, 172:968-970, 1971.

Hollister, L.E., Moore, F., Kantor, S., and Noble, E. Delta-ltetrahydrocannabinol, synhexyl and marijuana extract administered

orally in man: catecholamine excretion, plasma cortisol levels

and platelet serotonin content. Psychopharmacologia, 17:354-360,

1970.

Hollister, L.E., Richards, R.K., and Gillespie, H.K. Comparison

of tetrahydrocannabinol and synhexyl in man. Clin Pharmacol Ther,

9:783-791, 1968.

Howes, J.F., and Osgood, P.F. Cannabinoids and inhibition of

prostaglandin synthesis. In: Nahas, G.G., ed. Marihuana:

Chemistry, Biochemistry, and Cellular Effects. New York:

Springer-Verlag, 1976. pp. 415-424.

Huang, H.F.S., Nahas, G.G., and Hembree, W.C. Effects of marihuana inhalation on spermatogenesis of the rat, In: Nahas, G.G.,

and Paton, W.D.M., eds. Marihuana: Biological Effects. New York:

Pergamon Press, 1979. pp. 419-427,

Hubbard, C.D., Burstein, S., Hunter, S.A., and Shoupe, T.S.

Inhibition of cholesterol esterase by cannabinoids. Fed Proc Am

Soc Exp Biol, 38(3):510, 1979.

Hughes, C.L., Tyrey, L., and Everett,, J.W. Serum prolactin levels

in rats bearing pituitary autografts following administration of

delta-9-tetrahydrocannabinol. Proc 61st Ann Meet Endocr Soc

1979. Abstract #864, p. 288.

Huy, N.D., Gailis, L., Cote, G., and Roy, P.E. Effects of chronic

administration of delta-9-transtetrahydrocannabinol (delta-9-THC)

in guinea-pigs. Int J Clin Pharmacol, 12:284-289, 1975.

Issidorides, M.R. Observations in chronic hashish users: nuclear

aberrations in blood and sperm and abnormal acrosomes in spermatozoa. In: Nahas, G.G., and Paton, W.D.M., eds. Marihuana: Biological Effects. New York: Pergamon Press, 1979. pp. 377-388.

159
Jacobs, J.A., Dellarco, A.J., Manfredi, R.A., and Harclerode, J.

The effects of delta-9-tetrahydrocannabinol, cannabidiol, and

shock on plasma corticosterone concentrations in rats. J Pharm

Pharmacol, 31:341-342, 1979.

Jakubovic, A., Hattori, T., and McGeer, P.L. Radioactivity in

suckled rats after giving 14-C-tetrahydrocannabinol to the mother.

Eur J Pharmacol, 22(2):221-223, 1973.

Jakubovic, A., and McGeer, P.L. Biochemical changes in rat testicular cells in vitro produced by cannabinoids and alcohol: metabolism and incorporation of labeled glucose, amino acids, and

nucleic acid precursors. Toxicol Appl Pharmacol, 41(3):473-486,

1977.

Jakubovic, A., McGeer, E.G., and McGeer, P.L. Biochemical alterations induced by cannabinoids in the Leydig cells of the rat testis in vitro: effects on testosterone and protein synthesis. In:

Nahas, G.G., and Paton, W.D.M., eds. Marihuana: Biological Effects.

New York: Pergamon Press, 1979a. pp. 251-264.

Jakubovic, A., McGeer, E.G., and McGeer, P.L. Effects of cannabinoids on testosterone and protein synthesis in rat testis Leydig

cells in vitro. J Mol Cell Endocrinol, 1979b .

Johnson, K.M., Dewey, W.L., Ritter, K.S., and Beckner, J.S. Cannabinoid effects on plasma corticosterone and uptake of 3H-corticosterone by mouse brain. Eur J Pharmacol, 47:303-310, 1978.

Joneja, M.G. A study of teratological effects of intravenous,

subcutaneous, and intragastric administration of delta-9-tetrahydrocannabinol in mice. Toxicol Appl Pharmacol 36(1):151-162,

1976.

Joneja, M.G. Effects of delta-9-tetrahydrocannabinol on hamster

fetuses. J Toxicol Environ Health, 2(5):1031-1040, 1977.

Jones, R. Human effects. In: Petersen, R.C., ed. Marihuana

Research Findings.National Institute on Drug Abuse Research

Monograph 14. DHEW Pub. No. (ADM) 78-501. Washington, D.C.

Superintendent of Documents, U. S. Government Printing Office,

1977. pp. 128-178.

Kashi, R., Zor, U., Harell, A., and Lindner, H.R. Acute effect of

delta-1-tetrahydrocannabinol on the hypothalamo-pituitary-ovarian

axis in the rat. Neuroendocrinology, 23(1):31-42, 1977.

Kennedy, J.S., and Waddell, W.J. Whole-body autoradiography of

the pregnant mouse after administration of 14C-Δ

9

-THC. Toxicol

Appl Pharmacol, 22(2):252-258, 1972.

Kokka, N., and Garcia, J.F. Effects of delta-9-THC on growth hormone and ACTH secretion in rats. Life Sci, 15:329-338, 1974.

160
Kolodny, R.C., Lessin, P.J., Toro, G., Masters, W.H., and Cohen,

S. Depression of plasma testosterone with acute marihuana administration. In: Braude, M.C., and Szara, S., eds. Pharmacology

Marihuana. New York: Raven press, 1976. pp. 217-225.

Kolodny, R.C., Masters, W.H., Kolodner, R.M., and Toro, G. Depression of plasma testosterone levels after chronic intensive

marihuana use. N Engl J Med, 290(16):872-874, 1974.

Kolodny, R.C., Toro, G., and Masters, W.H. Letter to the editor

in response to Schaefer, Gunn and Dubowski. N Engl J Med, 292:

868, 1975.

Kostellow, A.B., Bloch, E., Morrill, G.A., and Fujimoto, G.I.

Effect of cannabinoids on estrous cycle, reproductive capacity,

and fetal development in A/J mice. Fed Proc Fed Am Soc Exp Biol,

37:858, 1978.

Kramer, J., and Ben-David, M. Suppression of prolactin secretion

by acute administration of Δ-9-THC in rats. Proc Soc Exp Biol

Med 147:482-484, 1974.

Layman, J.M., and Milton, A.S. Distribution of tritium labelled

delta-1-tetrahydrocannabinol in the rat brain following intraperitoneal administration. Br J Pharmacol, 42:308-310, 1971.

Legator, M.S., Weber, E., Conner, J., and Staeckel, M. Failure to

detect mutagenic effects of Δ-9-tetrahydrocannabinol in the dominant lethal test, host-mediated assay, blood-urine studies, and

cytogenetic evaluation with mice. In: Braude, M.C., and Szara,

S., eds. Pharmacology of Marihuana. New York: Raven Press, 1976.

List, A., Nazar, B., Nyquist, S., and Harclerode, J. The effects

of delta-9-tetrahydrocannabinol and cannabidiol on the metabolism

of gonadal steroids in the rat. Drug Metab Dispos, 5(3):286-272,

1977.

Maier, R., and L. Maitre. Steroidogenic and lipolytic effects of

cannabinols in the rat and the rabbit. Biochem Pharmacol, 24:

1695-1699, 1975.

Maker, H.S., Khan, M.A., and Lehrer, G.M. The effect of selfregulated delta-9-tetrahydrocannabinol consumption on pregnant

mice and offspring. Fed Proc Fed Am Soc Exp Biol, 33:540, 1974.

Mantilla-Plata, B., Clewe, G.L., and Harbison, R.D. Teratogenic

and mutagenic studies of delta-9-tetrahydrocannabinol in mice.

Fed Proc Fed Am Soc Exp Biol, 32:746, 1973.

Mantilla-Plata, B., Clewe, G.L., and Harbison, R.D. Delta-9-

tetrahydrocannabinol-induced changes in prenatal growth and development of mice. Toxicol Appl Pharmacol, 33(2):333-340, 1975.

161
Mantilla-Plata, B., and Harbison, R.D. Influence of alteration

of tetrahydrocannabinol metabolism on tetrahydrocannabinol-induced

teratogenesis. In: Braude, M.C., and Szara, S., eds. Pharmacology of Marihuana. New York: Raven Press, 1976a. pp. 733-742.

Mantilla-Plata, B., and Harbison, R.D. Alteration of delta-9-

tetrahydrocannabinol-induced prenatal toxicity by phenobarbital

and SKF-525A. In: Nahas, G.G., ed. Marihuana: Chemistry, Biochemistry and Cellular Effects. New York: Springer-Verlag, 1976b.

pp. 469-480.

Marks, B.H. Δ-1-tetrahydrocannabinol and luteinizing hormone

secretion. Prog Brain Res, 39:331-338, 1972.

Martin, B.R., Dewey, W.L., Harris, L.S., and Beckner, J.S. 3H-Δ9-tetrahydrocannabinol tissue and subcellular distribution in the

central nervous system and tissue distribution in peripheral

organs of tolerant and nontolerant dogs. J Pharmacol and Exp

Ther, 196:128-144, 1976.

Martin, B.R., Dewey, W.L., Harris, L.S., and Beckner, J.S. 3Hdelta-9-tetrahydrocannabinol distribution in pregnant dogs and

their fetuses. Res Commun Chem Pathol Pharmacol, 17(3):457-470,

1977.

Matsuyama, S., and Jarvik, L. Effects of marijuana on the genetic

and immune systems. In: Petersen, R.C., ed. Marihuana Research

Findings. National Institute on Drug Abuse Research Monograph 14.

DHEW Pub. No. (ADM)78-501. Washington, D. C.: Superintendent of

Documents, U.S. Government Printing Office, 1977. pp. 179-193.

McIsaac, W.M., Fritchie, G.E., Idanpaan-Heikkila, J.E., Ho, B.T.,

and Englert, L.F. Distribution of marihuana in monkey brain and

concomitant behavioral effects. Nature (London), 230:593-594,

1971.

Mendelson, J.H. Marihuana use. Biological and behavioral aspects.

Postgrad Med, 60(5):111-115, 1976.

Mendelson, J.H., Kuehnle, J., Ellingboe, J., and Babor, T.F.

Plasma testosterone levels before, during and after chronic marihuana smoking. N Engl J Med, 291(20):1051-1055, 1974.

Miller, L.L., and Drew, W.G. Cannabis: Review of behavioral

effects in animals. Psychol Bull, 81(7):401-417, 1974.

Miras, C.J. Some aspects of cannabis action. In: Wolstenholme,

G.E.W., and Knight, J., eds. Hashish: its chemistry and pharmacology, CIBA Found. Study group 21. Boston: Little, Brown,

1965. pp. 37-52.

Mitra, G., Poddar, M.K., and Ghosh, J.J. Interaction of Δ-9-

tetrahydrocannabinol with reserpine, phenobarbital, and LSD-25 on

plasma and adrenal corticosterone. Toxicol Appl Pharmacol, 42:

505-512, 1977.

162
Myers, R.D. Handbook of drug and chemical stimulation of the

brain: behavioral, pharmacological and physiological aspects,

New York: Van Nostrand-Reinhold, 1974. 759 pp.

Nahas, G.G. Marijuana: Chemistry, Biochemistry and Cellular

Efffects. New York: Springer-Verlag, 1976. 556 pp.

Nir, I., Ayalon, D., Tsafriri, A., Cordova, T., and Lindner, H.R.

Letter: Suppression of the cyclic surge of luteinizing hormone

secretion and of ovulation in the rat by Δ-1-tetrahydrocannabinol.

Nature, 24(100):470-471, 1973;

Okey, B., and Bondy, P. Δ-9-tetrahydrocannabinol and 17ß-estradiol bind to different macromolecules in estrogen target tissues.

Science, 200:312-314, 1978.

Pace, H.B., Davis, W.M. and Borgen, L.A. Teratogenesis and

marijuana. Ann NY Acad Sci, 191:123-131, 1971.

Perez-Reyes, M. Clinical study of frequent marijuana use: adrenal

cortical reserve metabolism of a contraceptive agent and development of tolerance. Ann NY Acad Sci, 282:168-179. 1976.

Persaud, T.V.N., and Ellington, A.C. Teratogenic activity of

cannabis resin. Lancet, 2:406-407, 1968.

Pfaff, D.W., Diakow, C., Zigmond, R.E., and Kow, L.M. Neural and

hormonal determinants of female mating behavior in rats. In:

Schmitt, F.O., and Worden, F.G., eds. The Neurosciences: Third

Study Program. Massachusetts: MIT Press, 1974. pp. 621-646.

Purohit, V., Singh, H.H., and Ahluwalia, B.S. Evidence that the

effects of methadone and marihuana on male reproductive organs are

mediated at different sites in rats. Biol Reprod, 20:1039-1044,

1979.

Raine, J.M., Wing, D.R., and Paton, W.D.M. The effects of delta1-tetrahydrocannabinol on mammary gland growth, enzyme activity

and plasma prolactin levels in the mouse. Eur J Pharmacol, 51:11-

17, 1978.

Rawitch, A.B., Schultz, G.S., Ebner, K.E., and Vardaris, R.M.

Competition of delta-9-tetrahydrocannabinol with estrogen in rat

uterine estrogen receptor binding. Science, 197(4309): 1189-1191,

1977.

Rosenkrantz, H. Effects of cannabis on fetal development of

rodents. In: Nahas, G.G., and Paton, W.D.M., eds Marihuana:

Biological Effects. New York: Pergamon Press, 1979. pp. 479-499.

Rosenkrantz, H., and Braude, M.C. Comparative chronic toxicities

of Δ-9-tetrahydrocannabinol administered orally or by inhalation

in rat. In: Braude, M.C., and Szara, S., eds. Pharmacology of

Marihuana. New York: Raven Press, 1976. pp. 571-584.

163
Rosenkrantz, H., Sprague, R.A., Fleischman, R.W., and Braude, M.C.

Oral Δ-9-tetrahydrocannabinol toxicity in rats treated for periods

up to six months. Toxicol Appl Pharmacol, 32:399-417, 1975.

Sassenrath, E.N., and Chapman, L.F. Tetrahydrocannabinol-induced

manifestations of the "marihuana syndrome" in group-living macaques.

Fed Proc Fed Am Soc Exp Biol, 34(8):1666-1670, 1975.

Sassenrath, E.N., Chapman, L.F., and Goo, G.P. Reproduction in

rhesus monkeys chronically exposed to moderate amounts of delta-gtetrahydrocannabinol. In: Nahas, G.G., and Paton, W.D.M., eds.

Marihuana: Biological Effects. New York: Pergamon Press, 1979.

pp. 501-512.

Schwarz, S., Harclerode, J., and Nyquist, S.E. Effects of delta9-tetrahydrocannabinol administration on marker proteins of rat

testicular cells. Life Sci, 22:7-14, 1977.

Shannon, M.E., and Fried, P.A. The macro- and microdistribution

and polymorphic electroencephalographic effects of delta-9-tetrahydrocannabinol in the rat. Psychopharmacologia, 27:141-156, 1972.

Shoemaker, R.H., and Harmon, J.W. Suggested mechanism for the demasculinizing effect of marijuana. Fed Proc Fed Am Soc Exp Biol,

36(3):345, 1977.

Siegel, P., Siegel, M.I., Krimmer, E.C., Doyle, W.J., and Barry,

H., III. Fluctuating dental asymmetry as an indicator of the

stressful prenatal effects of delta-9-tetrahydrocannabinol in the

laboratory rat. Toxicol Appl Pharmacol, 42:339-344, 1977.

Smith, C.G., Moore, C.E., Besch,N.F., and Besch,P.K. The effect of

marijuana (delta-9-tetrahydrocannabinol) on the secretion of sex

hormones in the mature male rhesus monkey. Clin Chem, 22(7):1120,

1976.

Smith, C.G., Ruppert, M.J., Asch, R.H., and Siler-Khodr, T. The

effects of tetrahydrocannabinol on prolactin in the rhesus monkey.

Paper presented at the NIDA Conference on Genetic, Perinatal, and

Developmental Effects of Abused Substances, Airlie, Virginia,

March, 1979a.

Smith, C.G., Smith, M.T., Besch, N.F., Smith, R.G., and Asch, R.H.

Effect of D-9-tetrahydrocannabinol (THC) on female reproductive

function. In: Nahas, G.G., and Paton, W.D.M., eds. Marihuana:

Biological Effects. New York: Pergamon Press, 1979b. pp. 449-467.

Smith, R.G., Besch, N.F., Besch, P.K., and Smith, C.G. Inhibition

of gonadotropin by delta-9-tetrahydrocannabinol: mediation by

steroid receptors? Science, 204:325-327, 1979.

Solomon, J., Cocchia, M.A., and DiMartino, R. Effect of delta-9-

tetrahydrocannabinol on uterine and vaginal cytology of ovariectomized rats. Science, 195:875-877, 1977.

164
Solomon, J., Cocchia, M.A., Gray, R., Shattuck, D., and Vossmer, A.

Uterotrophic effect of delta-9-tetrahydrocannabinol in ovariectomized rats. Science, 192(4239):559-561, 1976.

Stanely, R.L., Milwidsky, A., Besch, P.K., Smith, R.G., Besch,

N.F., and Smith, C.G. Effect of Δ-9-tetrahydrocannabinol on

steroid binding and aromatase activity in the human term placenta:

preliminary report. Paper presented at the NIDA Conference on

Genetic, Perinatal and Developmental Effects of Abused Substances,

Air-lie, Virginia, March, 1979.

Stefanis, C.N., and Issidorides, M.R. Cellular effects of chronic

cannabis use in man. In: Nahas, G.G., ed. Marihuana: Chemistry

Biochemistry, and Cellular Effects. New York: Springer-Verlag,

1976. pp. 533-550.

Symons, A.M., Teale, J.D., and Marks, V. Proceedings: Effect of

delta-9-tetrahydrocannabinol on the hypothalamic-pituitary-gonadal

system in the maturing male rat. J Endocrinol, 68(3):43P-44P,

1976.

Tart, C.T. In: On Being Stoned: A Pyschological Study of Marihuana

Intoxication. Palo Alto, California: Science and Behavior Books,

1971. 333 pp.

Thompson, G.R., Rosenkrantz, H., Fleischman, R.W., and Braude, M.C.

Effects of Δ-9-tetrahydrocannabinol administered subcutaneously

to rabbits for 28 days. Toxicology, 4:41-51, 1975.

Tinklenberg, J.R., Murphy, P.L., Murphy, P., Darley, C.F., Roth,

W.T., and Kopell, B.S. Drug involvement in criminal assaults by

adolescents. Arch Gen Psychiatry, 30:685-689, 1974.

Traub, S.H. Perceptions of marihuana and its effects--comparison

of users and nonusers. Br J Addict, 72:67-74, 1977.

Tyrey, L. Δ -9-tetrahydrocannabinol suppression of episodic

luteinizing hormone secretion in the ovariectomized rat.

Endocrinology, 102(6):1808-1814, 1978a.

Tyrey, L. Transient suppression of serum LH in the rat following

acute exposure to low levels of delta-9-tetrahydrocannabinol.

Proc 60th Ann Meet Endocr Soc 1978b. Abstract #725, p. 440.

Uyeno, E.T. Δ-9-tetrahydrocannabinol administered to pregnant

rats. Pharmacology, 17:181, 1975.

Vyas, D.K., and Singh, R. Effect of cannabis and opium on the

testis of the pigeon Columba livia Gmelin. Indian J Exp Biol,

14(1):22-25, 1976.

Warner, W., Harris, L.S., and Carchman, R.A. Inhibition of corticosteroidogenesis by delta-9-tetrahydrocannabinol. Endocrinology,

101:1815-1820, 1977.

165
Wright, P.L., Smith, S.H., Keplinger, M.L., Calandra, J.C., and

Braude, M.C. Reproductive and teratologic studies with delta-9-

tetrahydrocannabinol and crude marijuana extract. Toxicol Appl

Pharmacol 38:223-235, 1976.

Zimmerman, A.M., Bruce, W.R., and Zimmerman, S. Effects of cannabinoids on sperm morphology. Pharmacology, 18(3):143-148, 1979a .

Zimmerman, A.M., Zimmerman, S., and Raj, A.Y. Effects of cannabinoids on spermatogenesis in mice. In: Nahas, G.G., and Paton,

W.D.M., eds. Marihuana: Biological Effects. New York: Pergamon

Press, 1979b. pp. 407-418.

AUTHOR

Jack Harclerode, Ph.D.

Department of Biology

Bucknell University

Lewisburg, Pennsylvania 17837

166
Effects of Cannabis in Combination

With Ethanol and Other Drugs

Albert J. Siemens, Ph.D

INTRODUCTION

It has become progressively more evident in recent years that

many people who use cannabis (marijuana and hashish) also may

ingest a large number of other drugs in a wide range of combinations, frequencies, and sequences. Studies clearly reveal

that individuals who regularly smoke marijuana may also use

alcoholic beverages, barbiturates, amphetamines, hallucinogens

and opiates (McGlothlin, Jamison, and Rosenblatt 1970; Carlin

and Post 1971; Grupp 1972; Whitehead, Smart, and La Forest 1972;

Fisher and Brickman 1973; Hochhauser 1977; Sample 1977). Virtually all surveys have revealed that marijuana and alcohol

(ethanol) are the most common drug combination, whereas the use

of opiates in conjunction with marijuana is comparatively rare.

Although McGlothlin, Jamison, and Rosenblatt (1970), Fisher and

Brickman (1973), and Tec (1973) observed a positive relationship

between heavy marijuana and alcohol use in a variety of populations, Mello et al. (1978) determined that the simultaneous

availability of alcohol and marijuana in a clinical research

ward did not result in an increase in the use of both drugs by

male volunteers. In the latter study, alcohol use decreased

when marijuana was available and marijuana smoking increased

irrespective of the availability of alcohol. How representative

these findings are of the general population is unknown.

The observation that marijuana users do consume other chemical

substances has prompted numerous investigators to examine, in

experimental animals and man, the consequences of using a

variety of drugs in conjunction with cannabis or Δ

9

-tetrahydrocannabinol (THC), the major psychoactive constituent of cannabis.

This review will deal with the interaction of cannabis and its

constituents with a wide range of drugs, with some emphasis

being placed on investigations concerning marijuana and alcohol

in view of the popularity of these two drugs in our society.

167

323-754 0 - 80 - 12
INTERACTIONS BETWEEN CANNABIS AND ETHANOL

Correlates of Acute Cannabis/Ethanol Treatment in Animals

Studies with animal models have established that the acute depressant effects of a combination of marijuana and ethanol doses

are greater than those produced by either drug alone. Administration of a marijuana extract, containing a 10 mg/kg dose of THC

(Siemens and Kalant 1974); or THC alone, 8.5-40 mg/kg (Forney

and Kiplinger 1971; Phillips, Brown, and Forney 1971; Sofia and

Knobloch 1973; Siemens and Khanna 1977) to rats or mice 30-60

minutes before injection of a hypnotic dose of ethanol increased

the duration of the loss of righting reflex (sleep) up to 3-fold.

Similar results were obtained with Δ

8

-THC (Friedman and Gershon

1974), a cannabinoid which is generally present in marijuana at

less than 5% of the Δ

9

-THC concentration (Waller 1971). However,

cannabidiol (CBD), which is found in marijuana in variable concentrations depending upon its geographical source (Jenkins and

Patterson 1973; Chiesa, Rondina, and Coussio 1973; Holley,

Hadley, and Turner 1975), did not modify ethanol-induced sleep

in the rat (Siemens and Khanna 1977). Moreover, CBD, 24 mg/kg,

did not alter the influence of THC, 6 or 12 mg/kg, on ethanol

sleeping time,

The impairing effects of subhypnotic doses of ethanol were also

enhanced by THC. Kalant and LeBlanc (1974) reported that THC,

at doses (3-15 mg/kg) which alone did not influence the motor

performance of rats on a moving belt, increased ethanol-induced

impairment in a biphasic manner. In the lower THC dose range,

the magntidue of impairment gradually increased, but at higher

doses the enhancement became less marked. Thus, at higher doses

THC may have exerted a stimulatory effect.

Esplin and Capek (1976), who compared THC and ethanol alone and

in combination for anticonvulsant activity in mice in a maximal

electroshock seizure test, found that the effects of the two

drugs were additive. Furthermore, Pryor et al. (1977a) determined

that treatment of rats with THC, 2.5-10.0 mg/kg, in conjunction

with ethanol, 2.0 g/kg, impaired rotarod performance and a conditioned avoidance response, reduced photocell-monitored activity,

and depressed the heart rate and body temperature to a greater

extent than either drug alone.

It has been established that at doses administered in the cited

studies, THC does not inhibit the disappearance of ethanol from

the blood (Kalant and LeBlanc 1974; Friedman and Gershon 1974;

Siemens and Khanna 1977) or vice versa (Siemens and Khanna 1977).

Accordingly, the behavioral and pharmacological interactions

which have been observed are probably mediated centrally.

Correlates of Acute Cannabis/Ethanol Doses in Man

Consistent with the results of animal studies, the concurrent use

168
of cannabis and ethanol by humans at doses encountered socially

can produce more marked effects than either drug alone. Ingestion

of ethanol, 0.5-0.6 g/kg, by young, healthy, male volunteers 30

minutes before smoking marijuana (THC, 0.04-0.07 mg/kg) (Manno et

al. 1971), or oral ingestion of THC, 0.14-0.21 mg/kg, simultaneously

with the alcohol dose (Chesher et al. 1976; Chesher et al. 1977)

resulted in greater impairment of perceptual, cognitive and motor

functions than caused by either drug, depending upon the time of

measurement. In the smoking study the peak brain levels of THC

and ethanol will probably have coincided shortly after the end

of the smoking period (Isbell et al. 1967; Lemberger et al. 1972;

Kalant 1971), thus permitting a measure of the maximal effects

of the drug combination at that time (Manno et al. 1971). However, following oral ingestion, maximum ethanol brain levels will

have been reached in advance of the THC peak since absorption of

the cannabinoid is relatively slow from the gastrointestinal

tract (Lemberger et al. 1972; Perez-Reyes et al. 1973). Nonetheless, an additive interaction between THC and ethanol on tests

of numerical reasoning, manual dexterity and standing steadiness

(eyes open) was already detected at 40 minutes after the oral

drug doses. Later in the experiment (160 minutes), the effects

of the drug combination on standing steadiness (eyes closed) and

responses to visual and auditory stimuli (Vienna Determination

Apparatus) were less than produced by THC alone (Chesher et al.

1976; Chesher et al. 1977). This apparent antagonism between

the two drugs has not been explained, but it is possible that

ethanol reduced the amount of THC available to the brain after

oral administration as has been demonstrated in the rat (Siemens

and Khanna 1977). If so, subjects ingesting only THC might be

expected to be more impaired than those taking the drug combination, as the ethanol disappeared in the later stages of the experiment.

In a subsequent study with male and female students, Belgrave et

al. (1979a) increased the oral THC dose to 0.32 mg/kg and administered ethanol, 0.54 g/kg, one hour later, thus correcting in

part for the anticipated differences in the pharmacokinetics of

the two drugs, The effects of the drug combination on reaction

speed, cognitive performance, standing steadiness and psychomotor

coordination were additive with no indication of antagonism. In

contrast, CBD, 0.32 mg/kg orally, did not modify the impairing

effect of ethanol on these measures (Belgrave et al. 1979b ).

Marijuana and ethanol not only modify mental and psychomotor

performance but also influence physiological parameters. For

example, the concurrent use of THC and alcohol produced a greater

increase in pulse rate and conjunctival reddening than either

drug (Manno et al. 1971; Information Canada 1972). It has also

been observed that eye movements, quantitated by electro-oculographic recordings of saccades, smooth pursuit and optokinetic

nystagmus, which were impaired at blood ethanol levels of 0.05

and 0.1% in college students, were further reduced, albeit not

169
significantly, upon smoking a marijuana cigarette containing THC,

0.1 mg/kg (Baloh et al. 1979). In contrast, antagonism between

the two drugs has been reported on pupil size and glare recovery

in young male subjects. Even though a marijuana cigarette (THC,

15 mg) significantly reduced pupil diameter, and ethanol, 0.56

g/kg, was without effect when administered alone, pupil size was

not changed significantly when both drugs were used simultaneously

(Brown et al. 1977). Furthermore, the time required for light

adaptation upon intense light exposure (glare recovery) was only

slightly greater following the simultaneous use of marijuana

(THC, 15 mg) and alcohol, 0.56 g/kg, compared to each drug individually despite the fact that recovery was delayed about 2

hours by either drug. That the drug combination did not produce

a greater effect on eye function could have been partially due

to the slight, yet significantly lower peak blood ethanol concentration when the subjects smoked marijuana in conjunction

with the alcohol than when the beverage was taken alone (Adams

et al. 1978).

The subjective effects of THC-ethanol combinations also appear

variable. Some human subjects have suggested that marijuana

antagonized the effects of alcohol (Manno et al. 1971), while

other subjective ratings have indicated that the influence of

the drug combination either did not differ (Information Canada

1972) or was greater than the effect of the individual drugs

(Manno et al. 1971; Chesher et al. 1976). Indeed Sulkowski and

Vachon (1977) observed "intense psychological distress" in association with severe nausea, vomiting, tachycardia, variations in

blood pressure, skin pallor, and profuse cold sweating in four

of seven male volunteers who consumed ethanol, 1 g/kg, followed

one hour later by a marijuana cigarette (THC, 18 mg). The adverse

reaction did not occur, however, when the ethanol dose was reduced to 0.5 g/kg.

Thus a variety of measures have demonstrated that the concomitant

use of cannabis and ethanol may have more profound effects than

either agent alone. The magnitude and duration of the effects

appear to be related to the parameters measured, drug doses, and

the time course of action of each drug. As noted above, some

signs of antagonism between the two drugs could possibly be

accounted for by reductions in either ethanol or THC brain levels

(Siemens and Khanna 1977; Benowitz and Jones 1977; Adams et al.

1978). However, the increases in drug effects are not related

to elevated blood ethanol levels (Information Canada 1972;

Benowitz and Jones 1977; Chesher et al. 1977; Baloh et al. 1979;

Belgrave et al. 1979a).

Correlates of Chronic Cannabis/Ethanol Treatment in Animals

Since tolerance develops to the depressant effects of THC

(McMillan, Dewey, and Harris 1971; Information Canada 1972;

Paton and Pertwee 1972; Jones, Benowitz, and Bachman 1976)

and ethanol (Kalant, LeBlanc, and Gibbins 1971; Mendelson 1971;

Smith 1977) on the central nervous system in animals and man, a

170
number of investigators have questioned whether cross-tolerance

between the two drugs could occur. Indeed, rats made tolerant

to THC exhibited cross-tolerance to ethanol as determined by

conditioned avoidance (Newman et al. 1972), lever pressing

(Newman, Lutz, and Domino 1974) and rotarod (Siemens, 1978;

Siemens and Doyle 1979) tasks. Similar conclusions were drawn

from a study with mice on the basis of rotarod performance

(Sprague and Craigmill 1974). In contrast, Kalant and LeBlanc

(1974) were unable to demonstrate cross-tolerance to ethanol

in THC-tolerant rats on a moving belt test. The reasons for the

conflicting results are not clear but could be related to drug

doses, duration of chronic drug treatment and the measured used.

Although Newman et al. (1972) and Sprague and Craigmill (1976)

reported that ethanol-tolerant rats and mice were also tolerant

to challenge doses of THC, Siemens and Doyle (1979) failed to

detect complete cross-tolerance to THC in rats on rotarod and

conditioned avoidance tasks, respectively. That cross-tolerance

was not entirely reciprocal suggests that the nature or characteristics of the impairing effects of the two drugs may not

be identical. This possibility is supported by the observation

that THC could not be substituted for ethanol in a drug discrimination test in gerbils (Järbe 1977).

Other studies have examined pharmacological interactions between

challenge doses of THC and ethanol after subacute treatment (6-

14 days) of rats with a marijuana extract (THC, 10 mg/kg/day)

(Siemens and Kalant 1974) or pure THC, 10 mg/kg/day (Pryor et

al. 1977a). The combined effects of THC and ethanol on sleeping

time (Siemens and Kalant 1974), conditioned avoidance responding,

photocell-monitored activity, rotarod performance, heart rate and

body temperature (Pryor et al. 1977a ) were greater before than

after the subacute treatments. The decrease in the interactive

effects of the drugs at the doses studied was attributed, for

most measures, to the development of tolerance to THC rather

than a cross-tolerance to ethanol (Pryor et al. 1977a) .

In a most recent experiment (Siemens et al, 1979), the simultaneous administration of THC, 6-10 mg/kg, and ethanol, 2-4 g/

kg, to rats twice daily in gradually increasing doses resulted

in an increased rate and magnitude of ethanol tolerance and

physical dependence development. Complete ethanol tolerance

was established within 12-16 days in animals receiving both

drugs, whereas only minimal ethanol tolerance or cross-tolerance

was detected in ethanol- or THC-treated rats, respectively, at

this time. The number of animals exhibiting signs of physical

dependence as well as the magnitude of these signs, quantitated

according to Goldstein and Pal (1971), were much greater in the

THC plus ethanol group compared to all other groups of animals.

A variety of sedatives, hypnotics and minor tranquilizers which

show cross-tolerance to ethanol in animals and man are effective

171
in counteracting signs of ethanol dependence (Kalant, LeBlanc,

and Gibbins 1971; Smith 1977). Correlatively, treatment of

ethanol-dependent mice with THC at doses of 1.5-2.0 mg/kg i.v.

(Blum et al. 1975) and 10-40 mg/kg i.p. (Sprague and Craigmill

1978) respectively reduced handling-induced convulsions and

suppressed the enhanced responsiveness of the animals to electric

foot shock during ethanol abstinence. Nabilone, a synthetic

derivative of THC, similarly decreased the response to foot shock

(Sprague and Craigmill 1978), indicating that marijuana or related drugs may be beneficial in the treatment of alcohol withdrawal. It should be noted, however, that at higher THC doses,

handling-induced convulsions were intensified in ethanol-dependent

mice (Blum et al. 1975; Kralik, Ho, and Matthews 1976; Sprague

and Craigmill 1978). This phenomenon may have been related to

the convulsant action of THC in mice irrespective of ethanol

(Sprague and Craigmill 1978).

It is generally accepted that drug tolerance or cross-tolerance

may be of functional or dispositional origin (Kalant, LeBlanc,

and Gibbins 1971). Functional tolerance is characterized by a

decrease in the apparent sensitivity of the central nervous system

to a drug, whereas dispositional tolerance involves a decrease in

the amount of drug available to its sites of action in the brain,

resulting from an increase in the rate of drug metabolism or

elimination, or a change in drug distribution. Sprague and

Craigmill (1976) and Siemens and Doyle (1979) have demonstrated

that cross-tolerance between THC and ethanol is not dispositional

in mice and rats, respectively, implying that the phenomenon is

functionally mediated.

Correlates of Chronic Cannabis/Ethanol Use in Man

The definitive demonstration of cross-tolerance between THC and

ethanol in rodents supports the clinical observation (Jones and

Stone 1970) that heavy marijuana users, males who used marijuana

regularly for a year or more, apparently showed less behavioral

and motor impairment than expected after consuming the equivalent

of four to five ounces of 100 proof alcohol. Similarly, MacAvoy

and Marks (1975) observed that experienced marijuana users were

less impaired than nonusers at a blood ethanol level of 96 mg/

100 ml as determined by divided attention performance. Although

a similar trend was noted in a repetition of this study, the

cross-tolerance between the two drugs was not statistically

significant. Thus although the issue of cross-tolerance between

the two drugs in man has been entertained, the problem has not

been fully resolved.

Cannabis has been tried in alcoholism treatment with varying

degrees of success. According to Thompson and Proctor (1953),

pyrahexyl, an analog of THC, reduced withdrawal signs including

restlessness, irritability and sleep disturbances in 84% of the

70 alcoholics treated. Although Rosenberg, Gerrein, and Schnell

(1978) concluded that making marijuana available to alcoholics

172
did not induce alcoholics to enter or remain in treatment, Mikuriya

(1970) described a measure of success in substituting marijuana

for alcohol in one female alcoholic. Since the clinical experience

in treating various forms and stages of alcohol abuse and alcoholism with marijuana or THC is still limited, it is premature to

draw a final conclusion on the benefits of cannabis in this area.

INTERACTIONS BETWEEN CANNABIS AND SEDATIVES, HYPNOTICS AND OPIATES

Acute Interactions of Cannabis and CNS Depressants in Animals

Numerous investigators, employing a variety of pharmacological

parameters, have provided definitive evidence that cannabis

enhances the depressant effects of sedatives and hypnotics on the

central nervous system (CNS). Marijuana extracts prolonged sleep

induced by barbiturates in rats (Loewe 1944; Bose, Saifi, and

Bhagwat 1964; Siemens et al. 1974) and mice (Paton and Pertwee

1972; Chesher, Jackson, and Starmer 1974). Correlatively, the

dose of thiopental required to induce anesthesia in rabbits was

significantly reduced by pretreatment with a cannabis extract

(Paton and Temple 1972).

The THC content in the marijuana extracts was responsible, at

least in part, for the modification of barbiturate hypnosis.

THC doses, 0.6-80.0 mg/kg, which do not produce severe impairment

alone, significantly prolonged drug-induced sleep in a dose-dependent manner when administered to mice or rats shortly before

or after (30-60 minutes) injection of hexobarbital (Garriott et

al. 1967; Bating et al. 1972; Sofia and Knobloch 1973; Fernandes,

Kluwe, and Coper 1974), pentobarbital (Kubena and Barry 1970;

Paton and Pertwee 1972; Chesher, Jackson, and Starmer 1974;

Frizza et al. 1977), barbital (Kubena and Barry 1970; Sofia and

Barry 1970; Sofia and Barry 1973) or thiopental (Frizza et al.

1977). A number of studies with mice and rats have further

demonstrated that THC, 0.6-40.0 mg/kg, also prolonged sleep

induced by nonbarbiturate sedative/hypnotics including ethanol

(Phillips, Brown, and Forney 1971; Sofia and Knobloch 1973;

Siemens and Kalant 1974; Kalant and LeBlanc 1974; Siemens and

Khanna 1977), zoxazolamine (Sofia and Barry 1973), ethchlorvynol,

meprobamate, ethinamate, glutethimide, chloral hydrate, paraldehyde (Sofia and Knobloch 1973), methaqualone (Sofia and Knobloch,

1973; Stone, McCoy, and Forney 1976), ketamine, the steroidal

anesthetic CT-1341 (Sofia and Knobloch 1974a), and phencyclidine

(PCP) (Murray and Craigmill 1976). Furthermore, THC, 0.5-2.0 mg/

kg, produced a dose-dependent decrease in the minimum alveolar

anesthetic concentration for halothane in dogs (Stoelting et al.

1973) and cyclopropane in rats (Vitez et al. 1973).

THC not only augments anesthesia but also modifies the cardiovascular effects of anesthetics. For example, the heart rate and

blood pressure of conscious dogs were slightly decreased by THC,

1 mg/kg i.v., but pentobarbital, 35 mg/kg, (Cavero et al. 1972)

urethane, 1 g/kg, or chloralose, 100 mg/kg (Jandhyala and

Buckley 1977), markedly potentiated the depression of these

parameters. Although THC also reduced the heart rate in

173
morphine-sedated dogs, 3 mg/kg, the cannabinoid produced

significant tachycardia in animals treated with the combination of morphine plus chloralose (Jandhyala and Buckley 1977).

Furthermore, THC decreased the cardiac output and pulmonary blood

flow in association with increases in pulmonary vascular resistance, pulmonary arterial pressure and right ventricular stroke

volume in dogs under pentobarbital anesthesia (Jandhyala, Malloy,

and Buckley 1976; Jandhyala and Hamed 1978). In contrast, THC,

administered to dogs anaesthetized with morphine plus chloralose,

increased heart rate and cardiac output and decreased pulmonary

vascular resistance, pulmonary arterial pressure and right ventricular stroke work. The mechanisms for these effects have

not been fully elucidated although a number of hypotheses have

been presented (Jandhyala and Hamed 1978).

In addition to enhancing the depressant effects of drugs at their

hypnotic or anesthetic dose levels, THC augments responses to

much lower, yet behaviorally effective doses. Pryor et al.

(1977a, 1977b) evaluated dose-response interactions of THC,

2.5-10 mg/kg, with phenobarbital, 10-40 mg/kg, chlordiazepoxide

(Librium), 2.5-10 mg/kg, ethanol, 0.5-2.0 g/kg, and PCP, 1.25-5

mg/kg, on measures of conditioned avoidance, rotarod performance,

photocell activity, heart rate, and body temperature in rats.

Most measures showed that the combination of THC with either of

the four drugs at their highest doses produced a greater depressant effect than any individual compound. At 1.25 and 2.5 mg/kg

doses of PCP, the enhancement was apparently more than additive

(Pryor et al. 1977b). Similar results were obtained on measures

of schedule-controlled behavior (Murray and Craigmill 1976;

Pryor et al. 1977b). When administered alone, PCP markedly increased photocell and open field locomotion, an effect which

was almost entirely antagonized by THC doses which alone had

little influence on these behaviors (Pryor et al. 1977b). Stone

and Forney (1978) have also reported that THC partially antagonized the stimulatory effect of PCP on photocell activity in

mice.

Cannabinoids such as Δ

8

-THC, cannabidiol (CDB), cannabinol (CBN)

and cannabigerol (CBG), which are commonly present in cannabis

in addition to Δ

9

-THC (Jenkins and Pattersen 1973; Chiesa,

Rondina, and Coussio 1973; Holley, Hadley, and Turner 1975),

have also been evaluated for potential interactions with depressant agents. Rating et al. (1972) reported that Δ

8

-THC, 5 mg/kg,

increased the duration of hexobarbital-induced sleep almost twofold in rats. Chesher, Jackson, and Starmer (1974) also observed

that Δ

8

-THC and Δ

9

-THC, 10 mg/kg, were equivalently effective in

prolonging the pentobarbital-induced sleep in mice. Furthermore,

CBD, 10-80 mg/kg, caused a dose-dependent prolongation of pentobarbital and hexobarbital sleeping time in mice and rats, the

effect being greater than produced by THC (Loewe 1944; Paton

and Pertwee 1972; Chesher, Jackson and Starmer 1974; Siemens et

al. 1974; Fernandes, Kluwe, and Coper 1974; Coldwell et al. 1974;

Frizza et al. 1977). In contrast, studies in mice showed that

THC was more effective than CBD in prolonging the methaqualone

174
loss of righting reflex (Stone, McCoy and Forney 1976) and,

moreover, CBD appeared to antagonize ether anesthesia (Malor,

Jackson, and Chesher 1975).

Whereas CBG, 20 mg/kg, antagonized pentobarbital sleep in rats,

CBN, 5-80 mg/kg, did not appear to be effective in altering

ketamine, pentobarbital, thiopental, propanidid in anesthesia

(Frizza et al. 1977). However, CBN did prolong ether anesthesia

(Malor, Jackson, and Chesher 1975).

In view of the contrasting influences that the different cannabinoids may exert, it is not surprising that complex interactions

occurred when more than one cannabinoid was administered in

conjunction with anesthetics. For example, the effects of CBD

plus THC in prolonging pentobarbital sleep in mice were apparently

additive, (Chesher, Jackson, and Starmer 1974) or potentiative

(Frizza et al, 1977), while CBN reduced the effectiveness of

either THC alone (Krantz, Berger, and Welch 1971) or the combination of CBD and THC (Chesher, Jackson, and Starmer 1974).

Although CBD reversed ether anesthesia, it did not counteract

the THC-induced enhancement of the anesthetic effect (Malor,

Jackson, and Chesher, 1975). Other, as yet, unexplained interactions between groups of cannabinoids and various anesthetics

have also been reported (Frizza et al. 1977). It is likely

that the ultimate interactions which may occur are related to

factors such as cannabinoid and other drug doses, mechanisms

of drug action, pharmacokinetics, and animal species.

Mechanisms of Acute Cannabis/Depressant Interactions

Considerable emphasis has been placed on the assessment of

mechanisms which might be involved in the interactions between

THC and CNS depressant agents. To determine whether interactions between THC and depressants reflect the summation of

two independent drug actions or, alternatively, are due to a

common mechanism of action, gerbils (Järbe, Johansson, and

Henricksson 1975) and pigeons (Järbe and Ohlin 1979) were

studied for their ability to discriminate between the effects

of THC and pentobarbital. Although THC and pentobarbital

both exhibited depressant effects, the cue properties of THC

were not equivalent to those of pentobarbital in gerbils or

pigeons. THC administration in conjunction with pentobarbital

increased the barbiturate-appropriate responses in gerbils

(Järbe, Johansson, and Henricksson 1975), but the opposite was

observed in pigeons (Järbe and Ohlin 1979). Unfortunately, a

firm conclusion cannot be drawn from these disparate results,

but the observation that the two drugs were not interchangeable

in either animal species supports the hypothesis that THC and

barbiturates have different mechanisms of action, which may be

complementary in drug interactions.

Numerous other investigators have evaluated the relationships

between observed behavioral interactions and changes in the

175
disposition of THC or the interacting agent. Since the duration

of action of barbital and thiopental is not dependent on the

rate of drug metabolism, the enhancement of the depressant

effects of these barbiturates by THC is likely mediated by a

mechanism within the central nervous system. This conclusion

is consistent with the observation that both a marijuana extract

(Chesher, Jackson, and Starmer 1974) and THC alone (Malor, Jackson,

and Chesher 1975) prolonged anesthesia induced by ether, a drug

which is also not dependent on metabolism for elimination.

Sofia and Barry (1970), observing that SKF 525-A, a known inhibitor

of hepatic drug metabolism, augmented the THC-mediated prolongation

of barbital sleeping time, concluded that unchanged THC rather

than its metabolites was likely responsible for the functional

interaction with the barbiturate. This conclusion was supported

by the studies showing that SKF 525-A did inhibit THC metabolism

in vitro (Burstein and Kupfer 1971; Dingell et al. 1973; Siemens

et al. 1975) and in vivo (Gill and Jones 1972; Estevez, Englert,

and Ho 1974; Siemens, Kalant, and deNie 1976).

Even though interactions of THC with some hypnotics appear to

originate primarily in the brain, the cannabinoid and other

drugs which are metabolized by the hepatic mixed function oxidase

system may mutually inhibit one another's metabolism, thereby

prolonging and perhaps intensifying pharmacological effects.

Indeed, THC at high doses, 20-40 mg/kg, slightly reduced the

rate of hexobarbital disappearance from the blood and brain

(Fernandes, Kluwe and Coper 1974) and slowed the urinary excretion of pentobarbital in rats (Coldwell et al. 1974). However,

lower doses of THC, 10 mg/kg, which also prolonged hexobarbital

sleep, did not change the tissue concentrations of hexobarbital

(Rating et al. 1972), again implying that the central nervous

system is the major mediator of THC-barbiturate interactions.

Pryor et al. (1977b ) similarly concluded that behavioral interactions between THC and PCP in the rat were not related to

changes in brain or plasma drug levels. However, this conclusion

remains conjectural since the radioassay which was used did not

differentiate between unchanged PCP and its metabolites.

The influence of THC on the distribution, metabolism and elimination of many of the other depressant drugs which have been

referred to above has not been established. Moreover, only a

few studies have examined the influence of psychoactive drugs

on the disposition of THC in the rat. Hepatic THC metabolism

was inhibited in vitro to varying extents by high concentrations

(10-4-10-3 M) of the barbiturates, hexobarbital (Burstein and

Kupfer 1971), pentobarbital and phenobarbital (Siemens et al.

1975), and the tricyclic antidepressants, desipramine, nortriptyline and iprindole (Dingell et al. 1973). Inhibition of THC

metabolism in vitro by meprobamate and morphine was minimal.

Consistent with the observation that high concentrations of

drugs were required to inhibit THC metabolism in vitro, pentobarbital and phenobarbital, at behaviorally effective doses,

176
did not modify the biliary excretion of THC (Siemens et al.

1975). Although these results show that THC metabolism can be

altered by psychoactive drugs, it is doubtful that this is a

major mechanism of interaction at drug doses which have been

used in behavioral studies.

CBD, in contrast to THC, does not primarily interact with other

drugs at the brain locus, but rather modifies the action of

drugs by inhibiting their hepatic metabolism. Upon observing

that CBD inhibited phenazone metabolism in vitro, Paton and

Pertwee (1972) predicted that CBD prolonged pentobarbitalinduced sleep in mice by inhibition of the metabolism of the

barbiturate. This prediction was supported by Siemens et al.

(1974) and Coldwell et al. (1974) who showed that the magnitude

of the prolongation of pentobarbital sleep in the rat was

directly related to the inhibition of pentobarbital metabolism

in vivo. Interactions between CBD and hexobarbital were similarly

attributed to the inhibition of barbiturate metabolism (Fernandes

et al. 1973; Fernandes, Kluwe, and Coper 1974). The inhibition

of pentobarbital and hexobarbital metabolism was detectable

for at least 63 (Siemens et al. 1974) and 48 hours (Fernandes

et al. 1973), respectively, following single acute doses of CBD.

This long-lasting effect has been attributed to the slow disappearance of CBD metabolites from the liver (Karler et al.

1979; Siemens, Walczak, and Buckley 1980). CBD is clearly a more

Potent inhibitor of drug metabolism in vivo and in vitro than

either THC or CBN (Paton and Pertwee 1972; Fernandes et al.

1973; Siemens et al. 1974).

Correlates of Chronic Doses of Cannabis/CNS Depressants in Animals

Chronic studies of interaction between THC and CNS depressants,

including opiates, have centered upon aspects of cross-tolerance

and cross-dependence as previously described for ethanol. Using

a measure of shock avoidance behavior in rats, Newman, Lutz,

and Domino (1974) determined that the development of tolerance

to repeated daily doses of THC resulted in a dose-dependent crosstolerance to pentobarbital but not to chlorpromazine. Although

the effects of THC and chlorpromazine could have been perceived

by the animals as being different in nature, it is possible that

the challenge doses of chlorpromazine were simply too high.

Pryor et al. (1977a) observed that THC tolerance in rats was

accompanied by an attenuation of the depressant effects of a

combination of THC and phenobarbital challenge doses on some,

but not all behavioral measures which were used. The depressant

influence of concurrent challenge doses of THC and chlordiazepoxide was also partially reduced on some behavioral and physiological measures in THC-tolerant animals. Conversely, subacute

treatment (6 days) of animals with phenobarbital resulted in

partial tolerance development to the barbiturate, and in a slight

reduction in the interactive effects between THC and phenobarbital.

Subacute treatment with chlordiazepoxide, however, did not result

177
in tolerance to the tranquilizer or to combinations of THC and

chlordiazepoxide. Tolerance to the interactive effects of THC

and PCP on behavioral and physiological measures was also demonstrated in THC-tolerant rats (Pryor et al. 1977b). However,

subacute treatment with PCP resulted in an enhancement of the

behavioral effects of concurrent challenge doses of THC plus

PCP, suggesting that PCP had cumulative effects.

Bloom and Dewey (1978) have determined that THC-tolerant rats

were cross-tolerant to morphine on a measure of hypothermia

and that morphine-tolerant animals were cross-tolerant to the

antinociceptive effect of THC. The fact that the cross-tolerance

was not symmetrical on these two measures supports the argument.

that the drugs act by different mechanisms.

The mechanisms responsible for cross-tolerance development between

THC and the various depressant agents have not been elucidated

explicitly, but may have functional as well as dispositional

components. Although there is little evidence that THC alone

induces the metabolism of other drugs (Dewey, Kennedy, and Howes

1970; Kupfer, Levin, and Burstein 1973; Marcotte et al. 1975),

substances such as phenobarbital (Wall 1971; Siemens and Kalant

1974), DDT (Kupfer, Levin, and Burstein 1973), 3-methylcholanthrene (Nakazawa and Costa 1971) and marijuana smoke (Lemberger

et al. 1971) can stimulate the metabolism of THC.

As may be expected on the basis of cross-tolerance observations,

THC has been shown to be effective in counteracting some signs of

physical dependence on CNS depressants. Gildea and Bourn (1977)

determined that THC antagonized withdrawal convulsions in barbital-dependent rats in a dose-related manner. THC also attenuated some of the behavioral and physiological signs of naloxoneprecipitated abstinence in morphine-dependent rats (Hine et al.

1975a; Zaluzny et al. 1979), guinea pigs (Frederickson, Hewes,

and Aiken 1976), and mice (Bhargava 1976; Bhargava 1978).

Indeed Zaluzny et al. (1979) have concluded that THC was of

similar potency to morphine in suppressing the naloxone-precipitated withdrawal in rats.

It is of further interest that CBD and CBN (Hine, Torrelio,

and Gershon 1975), at doses which did not modify the withdrawal

reactions alone, further augmented the THC attenuation of the

abstinence signs in rats. Although Δ

8

-THC also counteracted

withdrawal signs in rats (Hine et al. 1975b) it was not effective

in mice, a discrepancy which may be related to differences in

the duration of action of the two THC isomers in the different

animal species (Bhargava 1978).

In contrast to the apparent THC-mediated antagonism of morphine

withdrawal, Carlini and Gonzalez (1972) observed that THC

enhanced aggressive behavior in morphine-dependent rats. Moreover, Deikel and Carder (1976) have reported that the cannabinoid

did not counteract naloxone-precipitated withdrawal in methadone178
dependent rats. The latter authors have argued that studies by

Hine et al. (1975a) were not adequately controlled and, furthermore, that the antagonistic effects of THC may be related to

nonspecific sedative effects (Carder 1975).

The mechanism for the antagonism of morphine abstinence by THC

has not been defined, but Zaluzny et al. (1979) have recently

concluded that the phenomenon is not solely dependent on the

availability of opiate or dopamine receptors in the brain, and

that sedation alone, as previously reported by Frederickson,

Hewes, and Aiken (1976), cannot account for the effect.

Interactions of Cannabis and CNS Depressants in Man

Studies of interactions between the cannabinoids of cannabis and

CNS depressant drugs, other than ethanol, have been much more

limited in man than in experimental animals. Nevertheless, a

variety of interactions in man have been documented. Dalton et

al. (1975), who administered secobarbital, 150 mg/70 kg orally,

to young males 50 minutes before a marijuana cigarette (THC,

25 μg/kg), found that the magnitude of the depressant effect of

the drug combination on measures of standing steadiness and

psychomotor and mental performance represented “additivity of

the component effects.” In addition, the subjective effects of

the drug combination were greater than produced by either drug

alone. Similarly, Johnstone et al. (1975) and Smith and Kulp

(1976), reported that injection of THC, 27-130 μg/kg i.v.,

shortly after pentobarbital, 100 mg/70 kg i.v., induced more

profound subjective effects, including hallucinations and severe

anxiety, than caused by either drug. The slight stimulant and

depressant effects of pentobarbital and THC, respectively, on

ventilation were mutually antagonized by the drug combination.

Pentobarbital in conjunction with THC increased the heart rate and

cardiac index and decreased total peripheral resistance.

Johnstone et al. (1975) also observed that THC caused a doserelated enhancement of the sedation and ventilatory depression

induced by oxymorphone, 1 mg/70 kg i.v. Although oxymorphone

had no influence on cardiovascular parameters, the concurrent

injection of THC, 134 μg/kg, increased the heart rate and cardiac

index and decreased peripheral resistance. THC also augmented

CNS and ventilatory depression caused by diazepam, 5-20 mg/70

kg i.v. However, diazepam apparently counteracted the THCmediated increase in heart rate and cardiac index. (Smith and

Kulp 1976). These studies by Johnstone et al. (1975) and

Smith and Kulp (1976) are of significant interest, but it is

difficult to assess the magnitude of the interactive effects

between THC and the other drugs because the pharmacological

effects of THC alone which have been used for comparison were

based on a separate experiment (Malit et al. 1975).

In contrast to the effects of THC, inhalation of CBD, 150 or

500 μg/kg, in marijuana smoke, immediately before an oral dose

of secobarbital, 150 mg/70 kg, did not produce responses greater

179
than caused by the barbiturate alone (Dalton et al. 1975). In

addition, CBD did not alter the pharmacokinetics of secobarbital

in the blood. It is possible that the absence of an interactive

effect between CBD and secobarbital was related to the order of

drug administration as discussed for THC and ethanol above.

The observation by Benowitz and Jones (1977) that treatment of

young males with THC, 60-180 mg/day, for 14 days increased the

half-lives of pentobarbital and antipyrine in the plasma and

reduced the rate of absorption of the barbiturate, indicates that

chronic marijuana use could alter the effects of drugs in man.

Furthermore, after THC administration was terminated, the metabolic

clearance of pentobarbital was increased, suggesting that a

metabolic cross-tolerance between the two drugs could occur.

Although studies of potential interactions between cannabis

and CNS depressants are not abundant, the evidence obtained to

date reveals that significant interactive effects are possible.

The findings indicate that caution should be exercised in the use

of cannabis in conjunction with other agents and that additional,

well-designed studies in man are imperative.

INTERACTIONS BETWEEN CANNABIS AND STIMULANTS

Interactions of Cannabis and Stimulants in Animals

Considerable attention has also been directed toward the examination of potential interactions between THC and stimulants in

rodents. THC (Garriott et al. 1967; Phillips et al. 1971;

Craigmill, Canafax, and Curtiss 1974) and two synthetic derivatives of THC (Daginnanjian and Boyd 1962) enhanced the amphetamine-induced stimulation of motor activity in mice. Although

the results of various studies agree qualitatively, quantitative

differences are apparent. For example, Garriott et al. (1967)

noted that THC, 25 mg/kg, increased d-amphetamine, 4 mg/kg, -

stimulated motor activity for up to 3 days in aggregated mice,

whereas Craigmill, Canafax, and Curtiss (1974) reported a very

transient (10 minutes) increase in activity after the administration of THC, 18 mg/kg, and d-amphetamine, 5 mg/kg. Evans et al.

(1976) found that the influence of THC on methamphetamine-stimulated motor activity in mice was dependent upon whether the

animals were aggregated or isolated. In aggregated mice, a

maximum augmentation of methamphetamine stimulation was produced

by a 15 mg/kg dose of THC, with higher and lower doses having

less effect. However, in isolated mice, THC consistently

antagonized methamphetamine stimulation.

THC, in a dose-related fashion, antagonized the stimulant action

of d-amphetamine (Hattendorf et al. 1977; Pryor et al. 1978)

and methamphetamine (Kubena and Barry 1970) in rats, independent

of aggregation. Furthermore, THC counteracted the effects of

amphetamine on conditioned avoidance responding. Conversely,

Grunfeld and Edery (1969) demonstrated that dl-amphetamine

reversed a THC-mediated cataleptoid response in rats.

180
Interactive effects between THC and amphetamine on other

measures in the rat are more variable. Whereas Hattendorf et

al. (1977) found that THC antagonized hyperthermia induced by

amphetamine, Pryor et al. (1978) reported that amphetamine

tended to enhance THC-induced hypothermia and bradycardia. In

addition, THC prolonged amphetamine-related stereotypy (Hattendorf

et al. 1977), a finding which may be consistent with the observation by Waters and Glick (1973) that the combination of THC

and amphetamine caused a circling behavior in rats. Some stereotypic effects, however, were reduced by THC in a study by Gough

and Olley (1975).

Variable results have also been obtained in determinations of

THC's effect on the toxicity of amphetamines in mice and rats.

Early studies by Garattini (1965) and Salustiano, Hoshino, and

Carlini (1966) indicated that marijuana or THC had little or no

effect on amphetamine lethality in mice. However, Howes (1973a)

and Blum et al. (1977) have shown that higher THC doses increase,

and lower doses decrease, amphetamine toxicity in aggregated mice.

Opposing evidence of Evans et al. (1976) revealed that low doses

of THC administered to grouped mice enhanced, but high doses

decreased, the toxicity of methamphetamine. In isolated mice no

change in lethality was detected. Studies with rats showed an

antagonistic effect of THC on amphetamine toxicity (Kubena and

Barry 1970).

According to Willinsky, DeCarlos, and Longo (1973) and Consroe,

Jones, and Aikins (1975), THC enhanced some of the excitatory

effects of d-amphetamine and methamphetamine, respectively,

in rabbits. Moreover, the combination of THC and methamphetamine caused stereotypic behavior in this species. However,

methamphetamine antagonized THC-induced increases in cortical

electrogenesis and depression of behavioral activity. Thus

both synergism and antagonism between THC and amphetamines

have been described.

Other stimulants which have been evaluated in experimental

animals for potential pharmacological interactions with THC

include cocaine, nicotine, caffeine, apomorphine, phenitrone,

and pemoline. As observed for methamphetamine, Consroe, Jones

and Laird (1976) noted that acute doses of cocaine, caffeine

and apomrphine all reversed the THC-induced depression of

behavioral activity in rabbits. In agreement with this finding,

Pryor et al. (1978) reported that cocaine tended to antagonize

THC's depression of photocell activity and rotarod performance

in rats. However, nicotine further decreased rotarod performance and augmented THC-mediated bradycardia and hypothermia

(Pryor et al. 1978).

Daily treatment of rats with THC for 6-8 days resulted in

tolerance development to the cannabinoid and, consequently,

the interactions with amphetamine (Hattendorf et al. 1977),

cocaine and nicotine were no longer detectable (Pryor et al.

181
1978). In contrast, subacute treatment of rats with amphetamine,

cocaine or nicotine did not result in tolerance to the stimulant

effects of these drugs or a change in their interaction with THC

(Pryor et al. 1978).

Phenitrone (Kudrin and Davydova 1968; Spaulding et al. 1972) and

pemoline (Howes 1973b) were studied as potential antagonists to

THC intoxication. In direct contradiction of the report by Kudrin

and Davydova (1968) that phenitrone blocked hashish intoxication

in dogs, Spaulding et al. (1972) determined that the drug did not

antagonize THC activity in dogs and pigeons, or hypothermia in

mice. Although phenitrone was not confirmed as a THC antagonist,

Howes (1973b) showed that pemoline counteracted the THC-induced

depression of motor activity and perception of noxious stimuli

in mice. Unlike amphetamine, there was no indication of an enhanced stimulatory effect. Whether pemoline would be a good

antagonist of THC affects in other species is not known.

Mechanisms of Cannabis/Stimulant Interactions

The mechanisms for the interactions between THC and stimulants

have not been fully clarified, but could involve alterations in

cholinergic (Consroe 1973) and/or catecholaminergic neurotransmission (Waters and Glick 1973; Howes and Osgood 1974; Consroe,

Jones, and Laird 1976; Hattendorf et al. 1977) or changes in

drug distribution and disposition. Craigmill, Canafax, and

Curtiss (1974) reported that THC either decreased or had no

effect on amphetamine brain levels. This suggests that the observed potentiation of amphetamine effects in the study was at

least not due to an increase in drug level. Unfortunately, the

peak potentiative effect had already occurred when the drug

level was determined, precluding a firm conclusion. Other studies

have demonstrated that THC reduced the rate of disappearance of

unchanged amphetamine from the blood of rats (Siemens 1977).

Evans et al. (1976) and Pryor et al. (1978), in assessing the

effects of THC on the disappearance of radiolabelled stimulants

from the plasma of mice and rats, measured levels of total radioactivity only. Thus despite the finding that THC did not modify

these levels, it is not known whether the parent compounds or

specific metabolites were altered. Similarly, although amphetamine and nicotine altered the plasma levels of total radioactivity

derived from 14C-THC, a conclusion regarding changes in unchanged

THC or its active metabolites is not possible. It has been reported, however, that amphetamine inhibited the hepatic metabolism

of THC in vitro (Siemens et al. 1975). A determination of the

significance of the latter findings in relation to behavioral

interactions between THC and amphetamine remains to be carried

out.

Interactions of Cannabis with Amphetamine and Propranolol in Man

The results of animal studies are quite variable and cannot be

182
extrapolated directly to the human experience, but they have

revealed that the potential for interactions exists. However,

Zalcman et al. (1973) who administered an oral dose of d-amphetamine, 200 μg/kg, to marijuana users immediately preceding a

marijuana cigarette (THC, 200 μg/kg) did not detect any significant interaction between the drugs on measures of blood pressure,

respiratory rate, pupil size, conjunctival injection, cognitive

performance or subjective effects. Similarly, Forney et al.

(1976) were unable to obtain evidence of an interactive effect

between marijuana (THC, 25 μg/kg) and d-amphetamine, 140 μg/kg,

which was taken orally 1.5 hours before the cigarette, on

measures of cardiovascular function, psychomotor performance

and subjective response. Nonetheless, when the marijuana, THC

dose was increased to 50 μg/kg, the drug combination produced

an additive increase on systolic blood pressure and a greater

than additive increase in the intensity and duration of the

subjective "high" (Evans et al. 1976). Thus although extensive

studies of potential interactions between cannabis and stimulants have not been accomplished in man, the reports to date

indicate that interactions may occur depending upon drug doses

and the time intervals between ingestions.

Propranolol, a beta adrenergic blocking agent which is devoid

of CNS action at the doses used (Dunleavy, MacLean, and Oswald

1971), has been examined for its effectiveness in antagonizing

THC-induced impairment of mental functions and tachycardia. In

an experiment reported by Drew et al. (1972), young males took

4 oral doses of propranolol, 40 mg, every 6 hours, followed 2

hours after the last dose by a marijuana cigarette (THC, 25 μg/

kg). The investigators failed to observe any antagonism of

the cognitive dysfunction produced by marijuana alone. In

contrast, Sulkowski, Vachon, and Rich (1977) reported that a

single dose of propranolol, 120 mg, given one hour before a

marijuana cigarette (THC, 140 μg/kg) blocked marijuana-related

learning impairment as well as the subjective depressant effect,

but did not alter the "high" rating. Furthermore, propranolol

antagonized the THC-induced tachycardia, elevation in blood

pressure and eye reddening in agreement with an earlier study

by Beaconsfield, Ginsburg, and Rainsbury (1972). The discrepancy between the latter studies and that of Drew et al.

(1972) is likely a factor of drug doses. This and related

evidence suggest that THC may act, at least in part, by

modifying neurotransmitter function. A further evaluation

of this area is not within the scope of this review.

INTERACTIONS OF CANNABIS AND NONPSYCHOACTIVE DRUGS

Little is known regarding pharmacological interactions between

cannabis and nonpsychoactive drugs. The widespread use of

cannabis and the frequent use of prescription and nonprescription drugs for a wide range of medical reasons raises the

possibility that people may use marijuana concurrently with a

183 323-754 0 - 80 - 13
nonpsychoactive therapeutic agent. Depending upon the chemical

nature and dose of the drug, the cannabinoids in marijuana

could modify its absorption, distribution, metabolism and elimination, and vice versa. Siemens, George and McConnell (1979) ,

in considering this possibility, determined that aspirin significantly decreased the rate of disappearance of THC from the blood

of rats, and, moreover, increased the levels of THC in the brain.

This finding may account for the potentiating effect of aspirin

on the behavioral depression caused by THC in rats (Pryor et al.

1976; G.I. Pryor, SRI International, unpublished observation).

Furthermore, phenylbutazone also increased THC levels in the

brain and liver, whereas dicumarol was without effect (Siemens,

George, and McConnell 1979). Further work in this area is

expected.

INTERACTIONS OF THC AND OTHER CANNABINOIDS

As already implied above, it is imperative that the full complement of cannabinoids which are normally present in cannabis must

be evaluated individually for their interactions with other drugs

to develop a comprehensive understanding of the consequences of

concurrent cannabis-drug use. Such an evaluation, however, is

complicated by the fact that the various cannabinoids in cannabis

also interact. A review of cannabinoid interactions is beyond

the scope of this review. It suffices to point out that some

of the pharmacological effects of THC in conjunction with other

cannabinoids have been shown to be significantly different from

those of THC alone in animals (Karniol and Carlini 1973; Borgen

and Davis 1974; Fernandes et al. 1974) and man (Isbell et al.

1967; Karniol and Carlini 1972; Galanter et al. 1973; Kamiol

et al. 1974; Lemberger et al. 1976). These interactions are

likely associated, at least partially, with an inhibition of

THC metabolism by cannabinoids such as CBD (Jones and Pertwee

1972; Siemens, Kalant, and de Nie 1976).

INTERACTIONS OF THC WITH MODIFIERS OF NEUROTRANSMITTERS

Many experiments which were designed to determine the mechanisms

of action of THC in the central nervous system have depended

upon the chemical manipulation of neurotransmitter levels, turnover and function. Thus these studies involve interactions

between THC, neurochemical agonists or antagonists, and specific

neurotransmitters. Since these interactions are also beyond the

domain of this review, the reader is referred to reports by

Sofia and Knobloch (1974b), Hollister (1976), Consroe, Jones

and Laird (1976) and Ho and Johnson (1976) for an introduction

to the subject.

184
USE OF MARIJUANA IN COMBINATION WITH OTHER DRUGS:

UNRESOLVED ISSUES

Despite the extensive efforts which have been made to evaluate

the consequences of using marijuana in combination with other

drugs, many important questions remain unanswered. Although a

variety of significant interactions have been described on the

basis of animal models, demonstration of interactive effects in

man has been limited. Human studies involving the acute administration of marijuana and other drugs have not evaluated fully

the relationships between potential marijuana-drug interactions

and the wide range of drug doses and sequences of drug ingestion

which are encountered socially. The absence of a drug interaction

at one particular dose combination does not ensure that an interactive effect will not occur at other doses.

Furthermore, information is scarce on the consequences of the

chronic human use of marijuana together with other agents.

Even though studies addressing the latter concern may be precluded in man on ethical and other grounds, experiments with a

variety of animal species would provide results which could be

rationally extrapolated to humans. At present, it may be presumptuous to predict effects in humans on the basis of chronic

experiments which have been restricted almost exclusively to

rodent models.

Two other areas which require further attention in both man and

animals include an assessment of the efficacy of treating alcohol and other drug dependencies with marijuana or THC, and the

determination of potential interactions between cannabis and

nonpsychoactive drugs. These are not the only areas of concern which remain, but they are indicative of the wide variety

of issues which still must be addressed in dealing with the

problem of marijuana use in combination with other drugs.

REFERENCES

Adams, A.J., Brown, B., Haegerstrom-Portnoy, G., Flom, M.C. and

Jones, R.T. Marijuana, alcohol, and combined drug effects on

the time course of glare recovery. Psychopharmacology, 56:

81-86, 1978.

Baloh, R.W., Sharma, S., Moskowitz, H. and Griffith, R. Effect

of alcohol and marijuana on eye movements. Aviat Space Environ

Med, 50: 18-23, 1979.

Beaconsfield, P., Ginsburg, J., Rainsbury, R. Marijuana smoking.

Cardiovascular effects in man and possible mechanisms. N Engl J

Med, 287: 209-212, 1972.

185
Belgrave, B.E., Bird, K.D., Chesher, G.B., Jackson, D.M., Lubbe,

K.E., Stanner, G.A. and Teo, R.K.C. The effect of (-)trans-Δ

9

-

tetrahydrocannabinol, alone and in combination with ethanol, on

human performance. Psychopharmacology, 62: 53-60, 1979a.

Belgrave, B.E., Bird, K.D., Chesher, G.B., Jackson, D.M., Lubbe,

K.E., Starmer, G.A. and Teo, R.K.C. The effect of cannabidiol,

alone and in combination with ethanol, on human performance.

Psychopharmacology, 64: 243-246, 1979b.

Benowitz, N.L. and Jones, R.T. Effects of delta-9-tetrahydrocannabinol on drug distribution and metabolism. Clin Pharmacol

Ther, 22: 259-268, 1977.

Bhargava, H.N. Inhibition of naloxone-induced withdrawal in

morphine dependent mice by 1-trans-Δ

9

-tetrahydrocannabinol.

Eur J Pharmacol, 36: 259-262, 1976.

Bhargava, H.N. Time course of the effects of naturally occurring

cannabinoids on morphine abstinence syndrome. Pharmacol Biochem

Behav, 8: 7-11, 1978.

Bloom, A.S. and Dewey, W.L. A comparison of some pharmacological

actions of morphine and Δ

9

-tetrahydrocannabinol in the mouse.

Psychopharmacology, 57: 243-248, 1978.

Blum, K., Briggs, A.H., Feinglass, S.J., Domey, R. and Wallace, J.E.

Effects of D

9

-tetrahydrocannabinol (Δ9-THC) on amphetamine-aggregate

toxicity in mice. Curr Ther Res 21: 242-244, 1977.

Blum, K., Hudson, K.C., Friedman, R.N. and Wallace, J.E. Tetrahydrocannabinol : inhibition of alcohol-induced withdrawal symptoms

in mice. In: Singh, J.M. and Lal, H., eds. Drug Addiction.

Vol. III. Neurobiology and Influences on Behavior. New York:

Stratton Intercontinental Medical Book Corporation, 1975. pp.

39-53.

Borgen, L.A. and Davis, W.M. Cannabidiol interaction with Δ

9

-

tetrahydrocannabinol. Res Commun Chem Pathol Pharmacol, 7:

633-670, 1974.

Bose, B.C., Saifi, A.Q. and Bhagwat, A.W. Effect of Cannabis

indica on hexobarbital sleeping time and tissue respiration of

rat brain. Arch Int Pharmacodyn, 141: 520-524, 1963.

Brown, B., Adams, A.J., Haegerstrom-Portnoy, G., Jones, R.T.

and Flom, M.C. Pupil size after use of marijuana and alcohol.

Am J Ophthalmol, 83: 350-354, 1977.

Burstein, S.H. and Kupfer, D. Hydroxylation of trans-Δ

1

-tetrahydrocannabinol by hepatic microsomal oxygenase. Ann N.Y. Acad

Sci, 191: 61-67, 1971.

186
Carder, B. Blockade of morphine abstinence by Δ

9

-tetrahydrocannabinol. Science, 190: 590, 1975.

Carlin, A.S. and Post, R.D. Patterns of drug use among marijuana

smokers. JAMA, 218: 867-868, 1971.

Carlini, E.A. and Gonzalez, C. Aggressive behaviour induced by

marijuana compounds and amphetamine in rats previously made

dependent on morphine. Experientia, 28: 542-544, 1972.

Cavern, I., Kubena, R.K., Dziak, J., Buckley, J.P. and Jandhyala,

B.S. Certain observations on interrelationships between

respiratory and cardiovascular effects of (-)-Δ

9

-trans-tetrahydrocannabinol. Res Commun Chem Pathol Pharmacol, 3: 483-

492, 1972.

Chesher, G.B., Franks, H.M., Hensley, V.R., Hensley, W.J.,

Jackson, D.M., Starmer, G.A. and Teo, R.K.C. The interaction

of ethanol and Δ

9

-tetrahydrocannabinol in man. Effects on

perceptual, cognitive and motor functions. Med J Aust, 2:

159-163, 1976.

Chesher, G.B., Franks, H.M., Jackson, D.M., Starmer, G.A.

and Teo, R.K.C. Ethanol and Δ

9

-tetrahydrocannabinol. Interactive effects on human perceptual, cognitive and motor

functions. Med J Aust, 1: 478-481, 1977.

Chesher, G.B., Jackson, D.M. and Starmer, G.A. Interaction of

cannabis and general anesthetic agents in mice. Br J Pharmacol,

50: 593-599, 1974.

Chiesa, E.P., Rondina, R.V.D. and Coussio, J.D. Chemical

composition and potential activity of Argentine marijuana.

J Pharm Pharmacol, 25: 953-956, 1973.

Coldwell, B.B., Bailey, K., Paul, C.J. and Anderson, G.

Interaction of cannabinoids with pentobarbital in rats.

Toxicol Appl Pharmacol, 29: 59-69, 1974.

Consroe, P.F. Effects of Δ

9

-tetrahydrocannabinol on a cholinergic-induced activation of the electroencephalogram in the

rabbit. Res Commun Chem Pathol Pharmacol, 5: 705-712, 1973.

Consroe, P.F., Jones, B.C. and Akins, F. Δ

9

-Tetrahydrocannabinol-methamphetamine interaction in the rabbit. Neuropharmacology, 14: 377-383, 1975.

Consroe, P., Jones, B. and Laird, H. EEG and behavioral effects

of Δ

9

-tetrahydrocannabinol in combination with stimulant drugs

in rabbits. Psychopharmacology, 50: 47-52, 1976.

Craigmill, A.L., Canafax, D.M. and Curtiss, F.R. The interaction of Δ

9

-tetrahydrocannabinol and d-amphetamine in aggregated

mice. Res Commun Chem Pathol Pharmacol, 9: 229-241, 1974.

187
Dagirmanjian, R. and Boyd, E.S. Some pharmacological effects

of two tetrahyrocannabinols. J Pharmacol Exp Ther, 135: 25-

33, 1962.

Dalton, W.S., Martz, R., Lemberger, L., Rodda, B.E. and Forney,

R.B. Effects of marijuana combined with secobarbital. Clin

Pharmacol Ther, 18: 298-304, 1975.

Dalton, W.S., Martz, R., Rodda, B.E., Lemberger, L. and Forney,

R.B. Influence of cannabidiol in secobarbital effects and

plasma kinetics. Clin Pharmacol Ther, 20: 695-700, 1976.

Deikel, S.M. and Carder, B. Attentuation of precipitated

abstinence in methadone-dependent rats by Δ

9

-THC. Psychopharmacol Commun, 2: 61-65, 1976.

Dewey, W.L., Kennedy, J.S. and Howes, J.F. Some autonomic,

gastrointestinal and metabolic effects of two constituents

of marijuana. Fed Proc, 29: 650, 1970.

Dingell, J.V., Miller, K.W., Heath, E.C. and Klausner, H.A.

The intracellular localization of Δ

9

-tetrahydrocannabinol in

liver and its effects on drug metabolism in vitro. Biochem

Pharmacol, 22: 949-958, 1973.

Drew, W.G., Kiplinger, G.F., Miller, L.L. and Marx, M.

Effects of propranolol on marijuana-induced cognitive

dysfunctioning. Clin Pharmacol Ther, 13: 526-533, 1972.

Dunleavy, D.L.F., Maclean, A.W. and Oswald, I. Debrisoquine,

guanethidine, propranolol and human sleep. Psychopharmacologia (Berl), 21: 101-110, 1971.

Esplin, B. and Capek, R. Quantitative characterization of

THC and ethanol interaction. Res Commun Chem Pathol Pharmacol,

15: 199-202, 1976.

Estevez, V.S., Englert, L.F. and Ho, B.T. Effect of SKF-525-A

on the metabolism of (-)- Δ

9

-tetrahydrocannabinol in the rat

brain and liver. Res Commun Chem Pathol Pharmacol, 8:

389-392, 1974.

Evans, M.A., Harbison, R.D., Brown, D.J. and Forney, R.B.

Stimulant actions of Δ

9

-tetrahydrocannabinol in mice. Psychopharmacology, 50: 245-250, 1976.

Evans, M.A., Martz, R., Rodda, B.E., Lemberger, L. and Forney,

R.B. Effects of marijuana-dextroamphetamine combination. Clin

Pharmacol Ther, 20: 350-358, 1976.

Fernandes, M., Kluwe, S. and Coper, H. Cannabinoids and hexobarbital induced loss of righting reflexes. Naunyn-Schmiedeberg's

Arch Pharmacol, 283: 431-435, 1974.

188
Fernandes, M., Warning, N., Christ, W. and Hill, R. Interactions

of several cannabinoids with the hepatic drug metabolizing system.

Biochem Pharmacol, 22: 2981-2987, 1973.

Fisher, G. and Brickman, H.R. Multiple drug use of marijuana

users. Dis Nerv Syst, 34: 40-43, 1973.

Forney, R.B. and Kiplinger, G.F. Toxicology and pharmacology

of marijuana. Ann N.Y. Acad Sci 191: 74-82, 1971.

Forney, R.B., Martz, R., Lemberger, L. and Rodda, B. The

combined effect of marijuana and dextroamphetamine. Ann N.Y.

Acad Sci, 281: 162-170, 1976.

Frederickson, R.C.A., Hewes, C.R. and Aiken, J.W. Correlation

between the in vivo and in vitro expression of opiate withdrawal

precipitated by naloxone : their antagonism by -(-)- Δ

9

-tetrahydrocannabinol. J Pharmacol Exp Ther, 199: 375-384, 1976.

Freidman, E. and Gershon, S. Effect of Δ

8

-THC on alcoholinduced sleeping time in the rat. Psychopharmacologia (Berl),

39: 193-198, 1974.

Frizza, J., Chesher, G.B., Jackson, D.M., Malor, R. and Starmer,

G.A. The effect of Δ

9

-tetrahydrocannabinol, cannabidiol, and

cannabinol on the anaesthesia induced by various anaesthetic

agents in mice. Psychopharmacology, 55: 103-107, 1977.

Galanter, M., Weingartner, H., Vaughan, T.B., Roth, W.T. and

Wyatt, R.J. Δ

9

-Tetrahydrocannabinol and natural marijuana.

Arch Gen Psychiatry, 28: 278-281, 1973.

Garattini, S. Effects of a cannabis extract on gross behavior.

In: G.E.W. Wolstenholme and J. Knight, eds. Hashish : Its

Chemistry and Pharmacology, Boston: Little, Brown and Company,

1965. pp. 70-77.

Garriott, J.C., King, L.J., Forney, R.B. and Hughes, F.W.

Effects of some tetrahydrocannabinols on hexobarbital sleeping

time and amphetamine induced hyperactivity in mice. Life Sci,

6: 2119-2128, 1967.

Gildea, M.L. and Bourn, W.M. The effect of delta-9-tetrahydrocannabinol on barbiturate withdrawal convulsions in the rat.

Life Sci, 21: 829-832, 1977.

Gill, E.W. and Jones, G. Brain levels of Δ

1

-THC and its metabolites

in mice - correlation with behaviour and the effect of the metabolic

inhibitors SKF 525-A and piperonyl butoxide. Biochem Pharmacol,

21: 2237-2248, 1972.

Goldstein, D.B. and Pal, N. Alcohol dependence produced in mice

by inhalation of ethanol: grading the withdrawal reaction.

Science, 172: 288-290, 1971.

189
Gough, A.L. and Olley, J.E. Cannabis and amphetamine-induced

stereotypy in rats. J Pharm Pharmacol, 27: 62-63, 1975.

Grunfeld, Y. and Edery, H. Psychopharmacological activity of the

active constituents of hashish and some related cannabinoids.

Psychopharmacologia (Berl), 14: 200-210, 1969.

Grupp, S.E. Multiple drug use in a sample of experienced marijuana

smokers. Int J Addict 7: 481-491, 1972.

Hattendorf, C.H., Hattendorf, M., Coper, H. and Fernandes, M.

Interaction between Δ

9

-tetrahydrocannabinol and d-amphetamine.

Psychopharmacology, 54: 177-182, 1977.

Hine, B., Friedman, E., Torrelio, M. and Gershon, S. Morphinedependent rats: blockade of precipitated abstinence by tetrahydrocannabinol. Science, 187: 443-445, 1975a.

Hine, B., Friedman, E., Torrelio, M. and Gershon, S. Tetrahydrocannabinol-attenuated abstinence and induced rotation in morphine

dependent rats: possible involvement of dopamine. Neuropharmacology, 14: 607-610, 1975b .

Hine, B., Torrelio, M. and Gershon, S. Differential effect of

cannabinol and cannabidiol on THC-induced responses during

abstinence in morphine-dependent rats. Res Commun Chem Pathol

1975.

Ho, B.T. and Johnson, K.M. Sites of neurochemical action of

Δ

9

-tetrahydrocannabinol : interaction with reserpine. In:

Nahas, G.B., ed. Marihuana. New York : Springer-Verlag, 1976.

pp. 367-382.

Hochhauser, M. Alcohol and marijuana consumption among undergraduate polydrug users. Am J Drug Alcohol Abuse, 4: 65-76, 1977.

Holley, J.H., Hadley, K.W. and Turner, C.E. Constituents of

Cannabis sativa L. XI: Cannabidiol and cannabichromene in

samples of known geographical origin. J Pharm Sci 64:

892-895, 1975.

Hollister, L.E. Interactions of Δ

9

-tetrahydrocannabinol with

other drugs. In: Vesell, E.S. and Braude, M.C., eds. Interactions of Drugs of Abuse. New York: The New York Academy of

Sciences, 1976. pp. 212-218.

Howes, J.F. The effect of Δ

9

-tetrahydrocannabinol on amphetamine induced lethality in aggregated mice. Res Commun Chem

Pathol Pharmacol, 6: 895-900, 1973a.

Howes, J.F. Antagonism of the effects of Δ

9

-tetrahydrocannabinol by pemoline (CylertR

). Res Commun Chem Pathol

Pharmacol, 6: 901-908, 1973b.

190
Howes, J.F and Osgood, P. The effect of Δ

9

-tetrahydrocannabinol

on the uptake and release of 14C-dopamine from crude striatal

synaptosomal preparations. Neuropharmacology, 13: 1109-1114, 1974.

Information Canada, Preliminary summary of commission cannabis

and alcohol experiments. In: A Report of the commission of

Inquiry into the Non-Medical Use of Drugs. LeDain, G., Chairman, Ottawa, Canda, 1972. pp. 131-144.

Isbell, H., Gorodetzky, C.W., Jasinski, D., Claussen, U.,

Spulak, F.V. and Korte, F. Effects of Δ

9

-trans-tetrahydrocannabinol in man. Psychopharmacologia (Berl), 11: 184-188,

1967.

Jandhyala, B.S. and Buckley, J.P. Influence of several anesthetic agents on the effects of D

9

-tetrahydrocannabinol on the

heart rate and blood pressure of the mongrel dog. Eur J

Pharmacol, 44: 9-16, 1977.

Jandhyala, B.S. and Hamed, A.T. Pulmonary and systemic hemodynamic effects of Δ

9

-tetrahydrocannabinol in conscious and

morphine-chloralose-anesthetized dogs: anesthetic influence on

drug action. Eur J Pharmacol, 53: 63-68, 1978.

Jandhyala, B.S., Malloy, K.P. and Buckley, J.P. Effects of

acute administration of Δ

9

-tetrahydrocannabinol on pulmonary

hemodynamics of anesthetized dogs. Eur J Pharmacol, 38:

183-188, 1976.

Järbe, T.U.C. Alcohol-discrimination in gerbils : interactions

with bemegride, DH-524, amphetamine, and Δ

9

-THC. Arch Int

Pharmacodyn, 227: 118-129, 1977.

Järbe, T.U.C., Johansson, J.O. and Henricksson, B.G. Δ

9

-tetrahydrocannabinol and pentobarbital as discriminative cues in the

mongolian gerbil (Meriones unguiculatus). Pharmacol Biochem

Behav, 3: 403-410, 1975.

Järbe, T.U.C. and Ohlin, G.C. Discriminative Effects of Combinations of Δ

9

-tetrahydrocannabinol and pentobarbital in pigeons.

Psychopharmacology, 63: 233-239, 1979.

Jenkins, R.W. and Patterson, D.A. The relationship between

chemical composition and geographical origin of cannabis.

Forensic Sci, 2: 59-66, 1973.

Johnstone, R.E., Lief, P.L., Kulp, R.A. and Smith, T.C. Combination of Δ

9

-tetrahydrocannabinol with oxymorphone or pentobarbital. Anesthesiology, 42: 674-684, 1975.

Jones, R.T., Benowitz, N. and Bachman, J. Clinical studies of

cannabis tolerance and dependence. Ann N.Y. Acad Sci, 282:

221-239, 1976,

191
Jones, G. and Pertwee, R.G. A metabolic interaction in vivo

between cannabidiol and Δ

1

-tetrahydrocannabinol. Br J Pharmacol,

45: 375-377, 1972.

Jones, R.T. and Stone, G.C. Psychological studies of marijuana

and alcohol in man. Psychopharmacoiogia (Berl), 18: 108-117,

1970.

Kalant, H. Absorption, distribution and elimination of ethanol:

effects on biological membranes; In: Kissin, B. and Begleiter, H.,

eds. The Biology of Alcoholism, I. Biochemistry. New York:

Plenum Press, 1971. pp. 1-62.

Kalant, H. and LeBlanc, A.E. Effect of acute and chronic pretreatment with Δ

1

-tetrahydrocannabinol on motor impairment by

ethanol in the rat. Can J Physiol Pharmacol, 52: 291-297,

1974.

Kalant, H., LeBlanc, A.E. and Gibbins, R.J. Tolerance to, and

dependence on, some non-opiate psychotropic drugs. Pharmacol

Rev, 23: 135-191, 1971.

Karler, R., Sangdee, P., Turkanis, S.A. and Borys, H.K. The

pharmacokinetic fate of cannabidiol and its relationship to

barbiturate sleep time. Biochem Pharmacol, 28: 777-784, 1979.

Karniol, I.G. and Carlini, E.A. The content of Δ

9

-tetrahydrocannabinol (D9

-THC) trends does not explain all biological activity

of some Brazilian marijuana samples. J Pharm Pharmacol, 24:

833-835, 1972.

Karniol, I.G. and Carlini, E.A. Pharmacological interaction

between cannabidiol and Δ

9

-tetrahydrocannabinol. Psychopharmacologia (Berl), 33: 53-70, 1973.

Kamiol, I.G., Shirakawa, I., Kasinski, N., Pfeferman, A. and

Carlini, E.A. Cannabidiol interferes with the effects of Δ

9

-

tetrahydrocannabinol in man. Eur J Pharmacol, 28: 172-177,

1974.

Kralik, P.M., Ho, B.T. and Matthews, H.R. Effect of Δ

9

-THC on

ethanol withdrawal in mice. Experientia, 32: 723-725, 1976.

Krantz, J.C., Berger, H.J. and Welch, B.L. Blockade of (-)-transΔ

9

-tetrahydrocannabinol depressant effect by cannabinol in mice.

Am J Pharm, 143: 149-152, 1971.

Kubena, R.K. and Barry, H. Interactions of Δ

1

-tetrahydrocannabinol

with barbiturates and methamphetamine. J Pharmacol Exp Ther,

173: 94-100, 1970.

Kudrin, A.N. and Davydova, O.N. Elimination of hashish intoxication

with phenitrone in dogs. Farmakol J Toksikol, 31: 549, 1968.

192
Kupfer, D., Levin, E. and Burstein, S.H. Studies on the effects

of Δ

1

-tetrahydrocannabinol (Δ1-THC) and DDT on the hepatic microsomal metabolism of Δ

9

-THC and other compounds in the rat. Chem

Biol Interact, 6: 59-66, 1973.

Lemberger, L., Dalton, B., Martz, R., Rodda, B. and Forney, R.

Clinical studies on the interaction of psychopharmacologic agents

with marijuana. In: Vesell, E.S. and Braude, M.C., eds. Interactions of Drugs of Abuse. 1976. New York : The New York Academy

of Sciences. pp. 219-228.

Lemberger, L., Tamarkin, N.R. and Axelrod, J. and Kopin, I.J.

Delta-9-tetrahydrocannabinol : metabolism and disposition in

long-term marijuana smokers. Science, 173: 72-74, 1971.

Lemberger, L., Weiss, J.L., Watanabe, A.M., Galanter, I.M., Wyatt,

R.J. and Cardon, P.V. Delta-9-tetrahydrocannabinol. Temporal

correlation of the psychologic effects and blood levels after various

routes of administration. N Engl J Med, 286: 685-688, 1972.

Loewe, S. Studies on the pharmacology of marijuana. In: The

Marijuana Problems In City of New York, by the Mayor's Committee

on Marijuana. Lancaster, Pennsylvania: The Jaques Cattell Press,

1944. pp. 149-212.

Macavoy, M.G. and Marks, D.F. Divided attention performance of

cannabis users and non-users following cannabis and alcohol.

Psychopharmacologia (Berl), 44: 147-152, 1975.

Malit, L.A., Johnstone, R.E., Bourke, D.I., Kulp, R.A., Klein, V.

and Smith, T.C. Intravenous delta-9-tetrahydrocannabinol.

Anesthesiology, 42: 666-673, 1975.

Malor, R., Jackson, D.M. and Chesher, G.B. The effect of Δ

9

-

tetrahydrocannabinol, cannabidiol and cannabinol on ether

anaesthesia in mice. J Pharm Pharmacol, 27: 610-612, 1975.

Manno, J.E., Kiplinger, G.F., Scholz, N. and Forney, R.B.

The influence of alcohol and marijuana on motor and mental

performance. Clin Pharmacol Ther, 12: 202-211, 1971.

Marcotte, J., Skelton, F.S., Cote, M.G. and Witschi, H.

Induction of aryl hydrocarbon hydroxylase in rat lung by

marijuana smoke. Toxicol Appl Pharmacol, 33: 231-245, 1975.

McGlothlin, W., Jamison, K. and Rosenblatt, S. Marijuana and

the use of other drugs. Nature, 228: 1227-1228, 1970.

McMillan, D.W., Dewey, W.L. and Harris, L.S. Characteristics

of tetrahydrocannabinol tolerance. Ann N.Y. Acad Sci, 191:

83-99, 1971.

Mello, N.K., Mendelson, J.H., Kuehnle, J.C. and Sellers, M.L.

Human polydrug use : marijuana and alcohol. J Pharmacol Exp

Ther, 207: 922-934, 1978.

193
Mendelson, J.H. Biochemical mechanism of alcohol addiction.

In: Kissin, B. and Begleiter, H., eds. The Biology of Alcoholism.

Vol. 1. New York : Plenum Press. 1971. pp. 513-544.

Mikuriya, T.H. Cannabis substitution : an adjunctive therapeutic

tool in the treatment of alcoholism. Med Times, 98: 187-191,

1970.

Murray, T.F. and Craigmill, A.L. Interactions between Δ

9

-tetrahydrocannabinol and phencyclidine in rats and mice. Proc West

Pharmacol Soc, 19: 362-368, 1976.

Nakazawa, K. and Costa, E. Metabolism of Δ

9

-tetrahydrocannabinol

by lung and liver homogenates of rats treated with methylcholanthrene. Nature, 234: 48-49, 1971.

Newman, L.M., Lutz, M.P. and Domino, E.F. Δ

9

-Tetrahydrocannabinol

and some CNS depressants : evidence for cross-tolerance in the

rat. Arch Int Pharmacodyn Ther, 207: 254-259, 1974.

Newman, L.M., Lutz, M.P., Gould, M.H. and Domino, E.F. Δ

9

-Tetrahydrocannabinol and ethyl alcohol: evidence for cross-tolerance

in the rat. Science, 175: 1022-1023, 1972.

Paton, W.D.M. and Pertwee, R.G. Effect of cannabis and certain

of its constituents on pentobarbitone sleeping time and phenazone

metabolism. Br J Pharmacol, 44: 250-261, 1972.

Paton, W.D.M. and Temple, D.M. Effects of chronic and acute

cannabis treatment upon thiopentone anaesthesia in rabbits.

Br J Pharmacol Chemother, 44: 346P-347P, 1972.

Perez-Reyes, M., Lipton, M.A., Timmons, M.C., Wall, M.E.,

Brine, D.R. and Davis, K.H. Pharmacology of orally administered

Δ

9

-tetrahydrocannabinol. Clin Pharmacol Ther, 14: 48-55, 1973.

Phillips, R.N., Brown, D.J. and Forney, R.B. Enhancement of

depressant properties of alcohol or barbiturate in combination

with aqueous suspended Δ

9

-tetrahydrocannabinol in rats. J

Forensic Sci, 16: 152-161, 1971.

Phillips, R.N., Neel, M.A., Brown, D.J. and Forney, R.B.

Enhancement of caffeine or methamphetamine stimulation in mice

with aqueous-suspended Δ

9

-tetrahydrocannabinol. Pharmacologist,

13: 297, 1971.

Pryor, G.T., Husain, S., Larsen, F., McKenzie, C.E., Carr, J.D.

and Braude, M.C. Interactions between Δ

9

-tetrahydrocannabinol

and phencyclidine hydrochloride in rats. Pharmacol Biochem

Behav, 6: 123-136, 1977b.

194
Pryor, G.T., Husain, S. and Mitoma, C. Acute and subacute interactions between Δ

9

-tetrahydrocannabinol and other drugs in the

rat. In: Vesell, E.S. and Braude, M.D., eds. Interactions of

Drugs of Abuse. New York: The New York Academy of Sciences.

1976. pp. 171-189.

Pryor, G.T., Larsen, F.F., Carr, J.D., Braude, M.C. Interactions

of Δ

9

-tetrahydrocannabinol with phenobarbital, ethanol and chlordiazepoxide. Pharmacol Biochem Behav, 7: 331-345, 1977a.

Pryor, G.T., Larsen, F.F., Husain, S. and Braude, M.C. Interactions of Δ

9

-tetrahydrocannabinol with d-amphetamine, cocaine,

and nicotine in rats. Pharmacol Biochem Behav, 8: 295-318, 1978.

Rating, D., Broennann, I., Honecker, H., Kluwe, S. and Coper, H.

Effect of subchronic treament with (-)-Δ

8

-trans-tetrahydrocannabinol (Δ8

-THC) on food intake, body temperature, hexobarbital sleeping time and hexobarbital elimination in rats. Psychopharmacologia (Berl), 27: 349-357, 1972.

Rosenberg, C.M., Gerrein, J.R. and Schnell, C. Cannabis in the

treatment of alcoholism. J Stud Alcohol, 39: 1955-1958, 1978.

Salustiano, J., Hoshino, K. and Carlini, E.A. Effects of

cannabis sativa and chlorpromazine on mice as measured by two

methods used for evaluation of tranquilizing agents. Med

Pharmacol Exp, 15: 153-162, 1966.

Sample, C.J. Concept of polydrug use. In: Richards, L.G. and

Blevens, L.B., eds. The Epidemiology of Drug Abuse: Current

Issues. National Institute on Drug Abuse Research Monograph

10. DHEW Pub. No. (AIM)77-432. Washington, D.C.: Superintendent

of Documents, U.S. Government Printing Office, 1977. pp. 19-31.

Siemens, A.J. Effects of Δ

9

-tetrahydrocannabinol on the disposition of d-amphetamine in the rat. Life Sci, 20: 1891-

1904, 1977.

Siemens, A.J. Cross-tolerance between ethanol and Δ

9

-tetrahydrocannabinol: the contribution of changes in drug disposition.

Fed Proc, 37: 318, 1978.

Siemens, A.J., Chang, T.B., Doyle, O.L. and George, P. Influence

of Δ

9

-tetrahydrocannabinol (THC) on development of ethanol tolerance and dependence. Pharmacologist, 21: 205, 1979.

Siemens, A.J., DeNie, L., Kalant, H. and Khanna, J.M. Effects

of various psychoactive drugs on the metabolism of Δ

1

-tetrahydrocannabinol by rats in vitro and in vivo. Eur J Pharmacol,

31: 136-147, 1975.

Siemens, A.J. and Doyle, O.L. Cross-tolerance between Δ

9

-tetrahydrocannabinol and ethanol : the role of drug disposition.

Pharmacol Biochem Behav, 10: 49-55, 1979.

195

323-754 0 - 80- 14
Siemens, A.J., George, P. and McConnell, J.E. Influence of

non-psychoactive drugs on Δ

9

-tetrahydrocannabinol disposition.

Fed Proc, 38: 591, 1979.

Siemens, A.J. and Kalant, H. Metabolism of Δ

1

-tetrahydrocannabinol

by rats tolerant to cannabis. Can J Physiol Pharmacol, 52:1154-

1166, 1974.

Siemens, A.J., Kalant, H. and DeNie, J.C. Metabolic interactions

between Δ

9

-tetrahydrocannabinol and other cannabinoids in rats.

In: Braude, M.C. and Szara, S. eds. The Pharmacology of Marihuana

New York : Raven Press, 1976. pp. 77-92.

Siemens, A.J., Kalant, H., Khanna, J.M., Marshman, J. and Ho, G.

Effect of cannabis on pentobarbital-induced sleeping time and

pentobarbital metabolism in the rat. Biochem Pharmacol, 23:

477-488, 1974.

Siemens, A.J., and Khanna, J.M. Acute metabolic interactions between

ethanol and cannabis. Alcoholism. Clin Exp Res, 1: 343-348, 1977.

Siemens, A.J., Walczak, D. and Buckley, F.E. Characterization

of the blood disappearance and tissue distribution of 3Hcannabidiol. Biochem Pharmacol, 29:462-464, 1980.

Smith, C.M. The pharmacology of sedative/hypnotics, alcohol,

and anesthetics : sites and mechanisms of action. In: Martin,

W.R., ed. Drug Addiction, Vol. 1, New York: Springer-Verlag.

1977. pp. 413-587.

Smith, T.C. and Kulp, R.A. Respiratory and cardiovascular

effects of delta-9-tetrahydrocannabinol alone and in combination

with oxymorphone, pentobarbital, and diazepam. In: Cohen, S.

and Stillman, R.G. eds. The Therapeutic Potential of Marijuana.

New York : Plenum Medical Boo Company. 1976. pp. 123-13 .

Sofia, R.D. and Barry, H. Depressant effect of Δ

1

-tetrahydrocannabinol enhanced by inhibition of its metabolism. Eur J

Pharmacol, 13: 134-137, 1970.

Sofia, R.D. and Barry, H. Interactions of chronic and acute Δ

1

-

tetrahydrocannabinol pretreatment with zoxazolamine and barbiturates. Res Commun Chem Pathol Pharmacol. 5: 91-98, 1973.

Sofia, R.D. and Knobloch, L.C. The interaction of Δ

9

-tetrahydrocannabinol pretreatment with various sedative-hypnotic drugs.

Psychopharmacologia (Berl), 30: 185-194, 1973.

Sofia, R.D. and Knobloch, L.C. The effect of Δ

9

-tetrahydrocannabinol pretreatment on ketamine thiopental or CT-1341 -

induced loss of righting reflex in mice. Arch Int Pharmacodyn

Ther, 207: 270-281, 1974a.

196
Sofia, R.D. and Knobloch, L.C. Influence of acute pretreatment

with Δ

9

-tetrahydrocannabinol on the LD50 of various substances

that alter neurohumoral transmission. Toxicol Appl Pharmacol,

28: 227-234, 1974b.

Spaulding, T.C., Ford, R.D., Dewey, W.L., McMillan, D.E. and

Harris, L.S. Some pharmacological effects of phenitrone and

its interaction with Δ

9

-THC. Eur J Pharmacol, 19: 310-317,

1972.

Sprague, G.L. and Craigmill, A.L. Ethanol and delta-9-tetrahydrocannabinol: mechanism for cross-tolerance in mice.

Pharmacol Biochem Behav, 5: 409-415, 1976.

Sprague, G.L. and Craigmill, A.L. Effects of two cannabinoids

upon abstinence signs in ethanol-dependent mice. Pharmacol

Biochem Behav, 9: 11-15, 1978

Stoelting, R.K., Martz, R.C., Gartner, J., Creasser, C.,

Brown, D.J. and Forney, R.B. Effects of delta-9-tetrahydrocannabinol on halothane MAC in dogs. Anesthesiology, 38: 521-

524, 1973.

Stone, C.J. and Forney, R.B. The effects of cannabidiol or

delta-9-tetrahydrocannabinol on phencyclidine-induced activity

in mice. Toxicol Lett, 1: 331-335, 1978.

Stone, C.J., McCoy, D.J. and Forney, R.B. Combined effect of

methaqualone and two cannabinoids. J Forensic Sci, 21: 108-

111, 1976.

Sulkowski, A. and Vachon, L. Side effects of simultaneous

alcohol and marijuana use. Am J Psychiatry, 134: 691-692,

1977.

Sulkowski, A., Vachon, L. and Rich, E.S. Propranolol effects

on acute marijuana intoxication in man. Psychopharmacology,

52: 47-53, 1977.

Tec, N. A clarification of the relationship between alcohol

and marijuana. Br J Addict, 68: 191-195, 1973.

Thompson, L.J. and Proctor, R.C. The use of pyrahexyl in

the treatment of alcoholics and drug withdrawal conditions.

N Carolina Med J 14: 520-523, 1953.

Vitez, T.S., Way, W.L., Miller, R.D. and Eger, E.I. Effects

of delta-9-tetrahydrocannabinol on cyclopropane MAC in the rat.

Anesthesiology, 38: 525-527, 1973.

Wall, M.E. The in vitro and in vivo metabolism of tetrahydrocannabinol (THC). Ann N.Y. Acad Sci, 191: 23-39, 1971.

Waller, C.W.. Chemistry of Marijuana. Pharmacol Rev, 23:

265-271, 1971.

197
Waters, D.H. and Glick, S.D. Asymmetrical effect of Δ

9

-

tetrahydrocannabinol (THC) on striatal dopamine and behavior.

Res Commun Chem Pathol Pharmacol, 6: 775-778, 1973.

Whitehead, P.C., Smart, R.G. and La Forest, L. Multiple drug

use among marijuana smokers in Eastern Canada. Int J Addict,

7: 179-190, 1972.

Willinsky, M.D., DeCarlos, S. and Longo, V.G. EEG and behavioral

effects of natural, synthetic and biosynthetic cannabinoids.

Psychopharmacologia (Berl), 31: 365-374, 1973.

Zalcman, S., Liskow, B., Cadoret, R. and Goodwin, D. Marijuana

and amphetamine : the question of interaction. Am J Psychiatry,

130: 707-708, 1973.

Zaluzny, S.G., Chesher, G.B., Jackson, D.M. and Malor, R. The

attenuation by Δ

9

-tetrahydrocannabinol and morphine of the

quasi-morphine withdrawal syndrome in rats. Psychopharmacology,

61: 207-216, 1979.

AUTHOR

Albert J. Siemens, Ph.D., Research Institute on Alcoholism

1021 Main Street, Buffalo, N.Y. 14203 and Department of

Biochemical Pharmacology, State University of New York at

Buffalo, Amherst, N.Y. 14260.

198
Therapeutic Aspects

Sidney Cohen, M.D., D.Sc.

A review of the therapeutic capabilities of cannabis and of

delta-9-THC has been published in NIDA Research Monograph 14:

Marihuana Research Findings: 1976 (NIDA 1977). Another volume,

The Therapeutic Potential of Marijuana (Cohen and Stillman 1976),

presented similar information in greater detail.* That material

will be only briefly summarized here, while the investigations

from the subsequent years will be given more extensive coverage.

It may be appropriate to begin with a quotation from the Introduction to The Therapeutic Potential of Marijuana (Cohen 1976):

"The constitutents of Indian Hemp have unusual chemical configurations, and these are coming under scientific scrutiny

after millenia of trial and error traditional usage. The possible

therapeutic utility of cannabis seems to derive from two general

pharmacologic activities: its mood-altering properties and its

physiologic actions. In the first instance the euphoriant,

relaxed state is exploited in attempts to treat tension, depression and other noxious affects. In the second instance the

subjective psychic symptoms are unnecessary: in fact, they often

become undesired side effects. Rather, it is the bronchopulmonary,

cardiovascular, or opthalmic physiology that merits attention.

"Cannabis is a controversial plant these days. It evokes the

widest spectrum of emotional reactions of adoration to

revulsion that I have ever witnessed in response to a weed.

We must be aware of the debate if only because it makes our

findings more newsworthy than they are. Of course, we are deeply

*A recent review article is that of Bhargava (1978b).

199
interested in any report of adverse effects about cannabis because

it relates to our current and future work with the agent. But

beyond that, we cannot allow the extreme value judgments from

either polar group to affect our studies. There is an appropriate

Latin epigram whose author I do not remember. Translated it goes:

"Nothing is of itself good or evil, only the manner of usage makes

it so."

The most noteworthy recent activity on therapeutic use has occurred

in the legislative arena, not the medical. More than a dozen

States have passed legislation and others are considering statutes

permitting the use of marijuana or delta-9-THC for clinical research trials. These are being proposed for the management of

the anorexia, nausea, and vomiting connected with cancer chemotherapy or for glaucoma, or both. A very few States have active

programs in being at this time. The cannabis or delta-9-THC is

being supplied by the NIDA: alternatively, confiscated material

might be used. Recently the Federal Government has refused to

reclassify cannabis or delta-9-THC from Schedule I (no medical

usefulness, high potential for abuse) to Schedule II (medical

usefulness, high abuse potential). However, new hearings are

underway.

The initiatives of various States to make cannabis or its active

ingredients available for clinical trial raise certain questions.

How much will be learned from such research? Hopefully, each

patient will be carefully studied, and the cannabinoids compared

with the previously prescribed medications. Combinations of the

cannabinoids with the conventional medications should also be

considered, but undesired drug interactions would be a possibility.

Since most of the patients with glaucoma and malignancies are

in the older age groups, the effects of the cardioacceleratory

property of cannabis will have to be taken into account (Nowlan and

Cohen 1978). Furthermore, the cannabinoids used in treatment

are intoxicating, and in many older people, sometimes anxietyprovoking. Questions of driving vehicles and operating other

machinery will certainly arise following the use of these drugs

if they are not carefully prescribed and supervised.

Another regulatory change has been the decision to permit women

to serve as research subjects or patients under restricted

conditions. Until recently, cannabis could not be legally

administered to females who were capable of becoming pregnant

because its teratologic risk had not been definitely assessed.

It still has not, but the lack of information on the cannabisinduced endocrine changes that take place in females is considered

more risky than excluding women from carefully safeguarded

studies.

It may be worthwhile to deal with the therapeutic potential of

cannabis by examining each of the various indications for its

clinical use. Clearly, some of the reports are quite preliminary

while others appear to have been satisfactorily substantiated.

200
It is evident that cannabis itself will hardly become officially

accepted by the Food and Drug Administration. It contains over

400 identified chemical entities, the great majority of which

are unnecessary or even undesirable for any therapeutic activity.

What is much more likely is that delta-9-THC, cannabidiol or some

synthetic variant will turn out to be the approved drug for

specific therapeutic purposes.

Open Angle Glaucoma

Since the demonstration in 1971 (Hepler and Frank) that smoked

marijuana significantly reduces intraocular pressure (IOP) in

normal human subjects, the finding has been amply confirmed by

others (Green 1979; Cuendet et al. 1976). Animal studies have also

supported the observation. A number of investigations involving

glaucoma patients have shown that ocular hypertension decreases

of about 20 to 40 percent lasting 4-5 hours are measurable in the

majority of those treated with smoked marijuana. Oral THC is also

effective although activity is delayed, less reliable and more

prolonged.

Oral delta-9-THC has been used in 10 to 20 mg doses in 15 glaucoma

patients. (Hepler et al. 1976) When given alone, the drug

was variably successful. When administered as a supplement to

previously insufficiently effective medical treatment to eight

patients, it was effective in five and partially effective in

one. The psychic side effects were minor. Green et al. (1976)

have attempted to explain the mechanism of action as a beta

adrenergic stimulation by delta-9-THC that dilates the efferent

blood vessels of the anterior uvea. Alpha adrenergic stimulation

may also participate in the effect by reducing capillary pressure

in the afferent vessels of the ciliary process. Those effects

might be modulated through an inhibition of prostaglandin

synthetase (Burstein 1976).

A logical extension of the work with chronic open angle glaucoma has

been the development of delta-9-THC eye drops in a light mineral oil

base. Their use in rabbits demonstrated an ocular hypotensive effect (Green 1978a), but their preliminary use in humans was found to

be associated with irritation of the superficial ocular structures.

Furthermore, there is some question whether the molecular configuration of delta-9-THC is small enough to diffuse readily into the

uveal tract. A number of investigators have reported reduction in

ocular hypertension with the topical administration of delta-9-THC

(Green 1978a,b). In fact, Green (1976) also mentions a lesser effect on the untreated eye, indicating systemic absorption. Welltolerated opthalmic drops (perhaps by decreasing the plasma concentration of delta-9-THC) would circumvent the issue of psychoactivity

and tachycardia. Systemic absorption of the eye drops is insufficient to produce the well-known psychophysiological effects.

Another line of investigation is the use of ocular hypotensive

cannabinoids with little or no central effects, such as delta-8-

THC and 8-11-hydroxy-delta-8-THC. Work with these in glaucoma

201
remains at a preliminary level. Actually, delta-8-THC is at

least as efficacious as the delta-9 analogue, and it is less

psychoactive; therefore, it may be preferable as an antiglaucoma preparation. Nabilone, a synthetic analogue, also

produces few psychic effects and reduces the average IOP by 35,

percent in glaucoma patients in oral doses of 0.5 mg. Topical

nabilone will induce an equivalent ocular hypotension in the

rabbit, but the eye drop preparation has been found irritating

in humans. Except for its use as an opthalmic topical preparation nabilone is not being actively investigated because some

dogs developed seizures and some humans manifested neurotoxicity.

Another important question remains only partially resolved.

Does tolerance develop to the IOP-reducing effect? During the

initial testing with smoked marijuana tolerance did not appear

to occur. A ceiling effect was noted, however, in that the

smoking of more than one cigarette (containing 19 mg of delta9-THC) did not result in an additional decrease in eyeball

pressure (Hepler et al. 1976). In a subsequent study, when large

amounts of oral delta-9-THC were used, additional ingestion or

smoking failed to cause a fall in pressure. It appears that

tolerance to the intraocular hypotensive effect of the cannabinoids will depend (as in other instances of tolerance) upon

the dose-time exposure. In the small amounts necessary to produce decreases in eyeball pressure, especially in topical preparations, it is not likely that tolerance will be a problem.

No tolerance was detected after one year's ocular instillation

of SP 106, a synthetic cannabinoid. (Green et al. 1977).

Crawford and Merritt (1979) compared eight normotensive and

eight hypertensive glaucoma patients under conditions involving the smoking of 900 mg placebo cigarettes and of a similar

cigarette containing 2.8 percent of delta-9-THC. In addition to

the increase in heart rate they found a hypotensive effect, more

significant in the systemic hypertensives. Although all the

patients had a drop in their intraocular pressure, the hypertensive glaucoma patients had a significantly greater fall in

eyeball pressure than the normotensive patients. The substantial

decreases (p = 0.01) in sitting systolic and diastolic blood

pressures produced by delta-9-THC in hypertensives has not been

reported previously in humans.

Although formal studies have not yet been conducted on the

issue, it appears from clinical notations that the effective

cannabinoids show an additive effect when they are given with

conventional anti-glaucoma medications like pilocarpine and

acetazolamide (Diamox). This line of investigation might provide

important clinical data in the future.

Asthma

The investigative pursuit of cannabis as a therapeutic tool

for bronchospastic disorders has been slowed because of the

confirmation that pulmonary complications are associated with

202
excessive chronic smoking, It is quite clear that the acute

smoking of marihuana produces bronchodilation (Tashkir et al.

1974). However, consistent smoking may narrow the larger airways by about 20 percent (Tashkin, et al. 1978). This effect is

secondary to the irritant effects of the coal tars that can

produce chronic bronchitis in heavy smokers. Whether the

bronchitis can evolve into obstructive lung disease (emphysema

or fibrosis) remains undetermined experimentally.

Delta-9-THC is the major bronchodilator in cannabis, but it is a

tracheobronchial irritant when smoked. Swallowed delta-9-THC

has an antiasthmatic action, but it is delayed and unreliable

due to variable absorption from the gastrointestinal tract.

Tashkin. et al. (1977) developed a Freon aerosol spray that was

successful in producing bronchodilation in nonasthmatic subjects

comparable to equivalent smoked dosages. Interestingly, 5 mg of

aerosolized preparation provided a bronchodilation that was 80

percent of the 20 mg aerosolized dose. However, when used in

patients with asthma, the procedure was not considered satisfactory because some of them complained of severe bronchial

irritation. Two of five asthmatic patients developed bronchospasm rather than dilation. Delta-9-THC is so water insoluble

that much of the aerosol appears to precipitate out in the

upper airway and reaches the bronchioles through the systemic

circulation rather than topically.

Vachon et al. (1976) provided a preliminary report of three

asthmatics and two normal controls given either delta-9-THC

in propylene glycol or the vehicle alone in a microaerosol

spray. A significant and prolonged bronchodilation occurred

without adverse side effects. When compared to an isoproterenol

Medihaler, the latter produced a more rapid but shorter-acting

effect on airway conductance. By using a dose of 0.5 mg of

delta-9-THC, most of the systemic effects could be avoided.

Problems remain, including the need to refrigerate the solution,

whether microsprays are commercially feasible, and whether

severe asthmatic attacks can be controlled by a delta-9-THC preparation. Williams et al. (1976) reported significant airway

dilation in all 10 asthmatic patients using 0.2 mg of an

aerosolized delta-9-THC preparation.

Another discouraging aspect of using cannabis for lung disorders

is the finding that the smoke, like tobacco, contains carcinogens,

co-carcinogens and cilia-toxic components (Cottrell et al. 1973,

Hoffmann et al. 1975, Busch et al. 1979). As with tobacco,

skin tumors have been produced on mouse skin using coal tars

from cannabis. Pulmonary macrophage inhibition after exposure

of rats to marijuana smoke has been found (Huber et al. 1978).

Intrapulmonary bacterial inactivation to staphylococcus aureus

occurred in a dose-dependent manner. The cytotoxin in marijuana

is not delta-9-THC but other constituents of the smoke. Impairment of the pulmonary defense system may be clinically significant

by decreasing resistance to bacterial pulmonary infections.

203
Oral delta-9-THC offers no advantages over available antiasthmatic

preparations, especially in the light of the cardiac-accelerating

and sometimes unpleasant psychic effects of cannabis. Whether

an effective aerosol spray of THC can be developed in the future

is undeterminable.

In a published letter, Shapiro et al. (1977) make the

case for further studies of the cannabinoids for asthma. Despite

its obvious disadvantages (tachycardia, mood alterations, impaired

behavioral performance, bronchial irritation by the smoked

material) there is a compelling reason to continue to study this

group of drugs. They seem to have a novel mechanism of action,

for it appears that delta-9-THC is neither a beta-adrenergic

agonist in the bronchi, an antimuscarinic agent, or a phosphodiesterase inhibitor, as most antiasthmatic drugs are. Finding

the mechanism of action may open up possibilities for new treatments

of bronchospastic diseases. Other cannabinoids, natural or synthetic, may turn out to be effective and with fewer side effects than

delta-9-THC.

Anorexia, Nausea and Vomiting in Cancer Chemotherapy, Irradiation

and Anorexia Nervosa

Animal studies have both confirmed and not sustained the impression that the cannabinoids are antiemetics. Nabilone, the

synthetic cannabis derivative, was tested against a number of

emetic agents including antineoplastic drugs in unanesthetized

cats (Borison et al. 1978). Nabilone provided pronounced

protection against vomiting, in contrast to prochlorperazine

(Compazine) which showed no antiemetic effect against meclorethamine and against apomorphine (McCarthy and Borison 1977).

Utilizing the dog and apomorphine-induced emesis (Shannon et al.

1978), delta-9-THC, chlorpromazine (Thorazine), the vehicle,

or saline was given intravenously 30 minutes prior to the

apomorphine infusion. Delta-9-THC had no effect upon the emetic

dose of apomorphine, whereas chlorpromazine reduced it by 75

percent. Furthermore, delta-9-THC prolonged the total period of

emesis and chlorpromazine reduced its duration. A number of

mechanisms exist in controlling emesis, so that conflicting results

may be expected.

Although antiemetic agents exist--thiethylperazine (Torecan),

prochlorperazine, trimethobenzamide (Tigan), etc.--their effectiveness in controlling nausea and emesis caused by the presentday cancer therapeutic agents is variable. A number of

studies involving smoked marijuana or oral delta-9-THC have

been completed, and 22 are either underway or not yet published.

In addition, chemotherapy patients have been known to use their

own marijuana to deal with the chemotherapy treatments.

Regelson et al. (1976) in a comparison between delta-9-THC and

204
a placebo believed that the principal benefits to their cancer

chemotherapy patients were improved appetite and the lack of an

unexpected weight loss. Appetite enhancement and the lack of

it have been mentioned in a few preclinical and clinical studies.

Sedation, which in this group may or may not be desirable,

occurred frequently. In a double-blind, crossover comparison

of delta-9-THC 10 mg/sq meter body surface, Sallan et al. (1975)

found an antiemetic effect in 70 percent of 22 patients during the

drug course and in none during the placebo course. They believe

that the antiemetic effect paralleled the subjective mood elevation.

Butler and Regelson (1976) reported a nonsignificant difference

between the placebo and delta-9-THC, although those who improved

on placebos were all from the medication-first group. Delta-9-THC

0.15 to 0.3 mg/kg daily was given in three doses, the first prior

to chemotherapy.

In a very preliminary analysis of their data in which prochlorperazine 10 mg, delta-9-THC 15 mg and both together were compared, Stevens and Goodwin (1979) indicate that "delta-9-THC

may be of limited benefit when compared to prochlorperazine."

The National Cancer Institute protocol (Chang et al. 1979)

compared 10 mg delta-9-THC/meter2 with a placebo in 15 osteogenic sarcoma patients receiving high dose methotrexate (250 mg/

kg) therapy. The chemotherapy was given every three weeks for

18 months. During Phase I each patient received either a

placebo or delta-9-THC in randomized fashion. When an oral dose

was not retained, delta-9-THC (17.4 mg) cigarettes or

placebo cigarettes were substituted. The dosages were given

five times beginning two hours prior to the methotrexate infusion.

Delta-9-THC produced a reduction of nausea and vomiting in

14 of 15 patients as compared to the placebo periods. Fiftythree percent had more than an 80 percent reduction in vomiting,

volume of emesis, and degree and duration of nausea. It was found

that when plasma concentrations of delta-9-THC were 0 ng/ml (the

placebo patients) nausea and/or vomiting occurred in 72 percent

of the time periods. Concentrations of less than 5.0 ng/ml

were associated with 44 percent, 5.0 to 10.0 ng/ml with 21 percent and 10.0 ng/ml with 6 percent of nausea and/or vomiting.

Therefore blood levels are an important variable in the therapeutic efficiency of the drug. Only five dysphoric reactions

of a total of 281 delta-9-THC drug doses were recorded. It

should be remembered that these were hospitalized patients who

did not need to ambulate. Sedation was a common side effect

(80 percent). Feelings of "high" correlated with favorable

results, probably because both co-varied with higher plasma

levels of the active drug.

In Phase II four excellent responders to delta-9-THC were given

subsequent courses of the drug. The results in all four were

noted to be only fair. Two fair responders sustained no benefit

from subsequent courses of delta-9-THC. The authors speculate

about drug tolerance, but this is unlikely when delta-9-THC is

given in short courses at tri-weekly intervals.

205
Appetite stimulation was not a significant finding. In addition

to the methotrexate patients, five additional patients receiving

adriamycin and cytoxan were also studied. Of these, two were

fair responders and three were nonresponders to the delta-9-

THC. This brings up the question of a variable antiemetic effect

depending on the cytotoxic drug given.

Herman et al. (1979) did two double-blind studies comparing

nabilone with prochlorperazine. Of 113 patients receiving anticancer chemotherapy, 80 percent responded to nabilone and 32

percent to prochlorperazine. Complete relief of symptoms

occurred in only nine nabilone patients and no prochlorperazine

patients. Both nausea and vomiting were less with nabilone,

and the patients indicated a strong preference for it. Side

effects, consisting of somnolence, dry mouth and dizziness,

occurred twice as frequently with nabilone. Three patients on

nabilone hallucinated and one became symptomatically hypotensive.

In a partial analysis of their first 66 patients in a 200-

patient controlled crossover study of delta-9-THC vs prochlorperazine for the anorexia, nausea and vomiting following cancer

chemotherapy, Ungerleider and Andrysiak (l979b) found that 25

patients preferred each of the two drugs, with 12 expressing no

preference. Four patients did not respond to that item in the

questionnaire. Drowsiness was the major side effect, with 20

patients on the cannabinoid and 15 on prochlorperazine mentioning

that symptom.

Davies et al. (1974) report on what may be the first study of

delta-9-THC during irradiation therapy for cancer. The problems

of nausea and vomiting are not markedly dissimilar to cancer chemotherapy. Ten mg of delta-9-THC or an identical placebo was

given prior to radiotherapy for seven days. No difference in

appetite was noted between the two courses. The authors were

more concerned about the drug's psychic effects than upon nausea.

On rating scales the active drug produced more fatigue and

confusion and less elation or vigor than the placebo,

Another first use of cannabinoids is a single case report from

Ungerleider and Andrysiak (1979a). A woman with an inoperable

cancer of the pancreas was treated with autologous bone marrow

transplantation and high dose mitomycin. She had been treated

with prochlorperazine 25 mg orally and secobarbital 75 mg

intravenously with continued nausea, retching, anorexia and

vomiting. After being placed on marijuana cigarettes containing

18 mg of delta-9-THC, she obtained good to excellent relief on

an average of 1/2 of a cigarette whenever she felt nauseated.

Special devices were necessary to provide sterile marijuana smoke

in this case because such a patient has no resistance to

infection.

206
In the first trial of delta-9-THC for primary anorexia nervosa,

Gross et al. (1980) did a controlled study on 11 patients comparing delta-9-THC with diazepam. In addition, during the fourweek crossover study, a behavior modification program was included. No significant changes in caloric intake, weight, the

Situational Discomfort Scale scores, depression or anxiety were

found between the two drugs. Delta-9-THC provided significantly

higher scores for somatization, interpersonal sensitivity and

sleep disturbance with the obsessive-compulsive behavior score

approaching statistical significance (p = 0.082). It would

appear that any appetite-enhancing property of delta-9-THC can

hardly be expected to influence so profound a psychophysiological

disturbance as anorexia nervosa.

Epilepsy

The major effort to determine the anticonvulsant and epileptogenic

effects of various cannabinoids has used a variety of animal

species. In general, antiseizure activity has been demonstrated

to electrically-induced, audiogenic and pentylenetetrazol (Metrazol) seizures (Consroe et al. 1975). The anticonvulsant profile

resembles that of phenytoin (Dilantin) more than that of phenobarbital. Antiepileptic effects were recently obtained in amygdaloid-kindled rats with delta-8-THC and delta-9-THC (Corcoran

et al. 1978). Both isomers acutely suppressed kindled seizures,

but consistent effects were obtained only with subtoxic doses.

Repeated dosages of the cannabinoids resulted in tolerance

development to the anticonvulsant action.

The hope that delta-9-THC might play a role in certain seizure

disorders has been tempered by the reports of its convulsant

properties in some animal species. EEG patterns of convulsivelike activity have been reported in rodents, dogs, cats, rabbits

and monkeys (Feeney 1977). In addition, behavioral convulsions

have been reported on occasion in rats, dogs and monkeys at

high doses. Martin and Consroe(1976) present evidence that a

strain of New Zealand white rabbits exhibit behavioral convulsions

at intravenous doses of 0.05 mg/kg of delta-9-THC, an extremely

low dose. Delta-8-THC, SP-111A, cannabinol and 11-hydroxy-delta9-THC also produced convulsive episodes, but cannabidiol did

not. Tolerance to the development of seizures occurred over

a period of 4 to 10 days. After a week without exposure to the

cannabinoids, sensitivity to behavioral seizures was reinstituted.

Feeney (1977) has obtained comparable results in two other species:

in the naturally epileptic beagle dog and in cats with focal

epilepsy induced by injections of alumina cream. He has also

reported temporal lobe seizures and myoclonus in dogs given a

single oral dose of 5 mg/kg. The fact that delta-9-THC has both

convulsant and anticonvulsant effects is unique.

Cannabidiol (CBD), essentially devoid of psychoactivity, is at

least as effective as delta-9-THC as an antiseizure drug

(Karler and Turkanis 1976). It apparently does not precipitate

207
convulsions in animals. However, there is a single case report

of an increased epileptiform EEG pattern in a human epileptic

after the administration of a relatively large intravenous dose

of the drug (Perez-Reyes and Wingfield 1974). Nevertheless, CBD

is a cannabinoid of minimal toxicity and proven anticonvulsive

activity in animals; therefore trials in humans are definitely

indicated. In a preliminary controlled study of 15 patients

with generalized epilepsy secondary to a temporal lobe focus,

who were poorly controlled on their current medication, Cunha

et al. (1979) added 200-300 mg of CBD or a placebo to their

current antiepileptic drugs for a period of 41⁄2, months. Mild

sedation was the only side effect noted in the CBD group. Three

CBD patients showed complete improvement, two partial improvement, two minor improvement, and one was unchanged. Of the

placebo patients, one improved markedly and seven were unchanged.

It was concluded that CBD can assist certain seizure patients

in improving when it is combined with their customary medicine.

Whether CBD alone in larger doses could have produced a

beneficial effect is unknown.

A third of youthful epileptic patients smoke marijuana, usually

without mentioning this to their physicians. In a small survey

of these individuals, they reported no particular effect of

their cannabis use upon their seizure patterns (Feeney et al.

1976).

Insofar as synthetic analogues are concerned, Mechoulam and

Carlini (1978) prepared a series of oxygenated CBD derivatives.

They found that both the 6-oxo-CBD diacetate congener and CBD

effectively protected mice from transcorneal electroshock

convulsions.

Those analogues of dimethylheptylpyran which are soluble, well

absorbed orally, and produce no psychotoxicity or tachycardia

showed significant anticonvulsant activity against the standard

seizure-inducing techniques in mice and rats at least equal to

phenytoin. Short term tolerance to the antiseizure effect did

not develop. On the other hand marked tolerance to the antiepileptic activity of delta-9-THC over prolonged exposure has

been suggested by Karler and Turkanis (1976).

Retardation of Tumor Growth

In mice inoculated with Lewis lung adenocarcinoma (Harris et al.

1976) a variable reduction in tumor size ranging from 25 to 82

percent depending on dose and duration of treatment with oral

delta-9-THC, delta-8-THC and cannabinol was found. Survival

time increased 25-34 percent compared to a 50 percent increase

in survival with cyclophosphamide. L1210 murine leukemia was

not inhibited by delta-9-THC. Replicating the inhibition of

specific neoplasms in vitro, Harris et al. (1976) concluded

that certain cannabinoids possess some antineoplastic capability.

This may occur because these compounds interfere with RNA and

208
DNA synthesis. White et al. (1976) found that delta-9-THC inhibits

replication after thymidine uptake and attributed this to the

extreme lipophilia of delta-9-THC, and therefore its effects on the

cell membrane. Cannabidiol may have a growth-enhancing effect

on Lewis lung adenocarcinoma.

In itself, delta-9-THC cannot be considered an effective antitumor agent despite an attractive differential in inhibition of

tritiated thymidine into DNA between Lewis lung tumor cells and

bone marrow cells (Harris et al. 1976). The possibility

remains that certain cannabinoids may prove to be useful as

adjuncts to other chemotherapeutic agents. The impression that

delta-9-THC and delta-8-THC are inferior to known antineoplastic

drugs is reinforced by the equivocal findings of Friedman (1977)

who did not find inhibition of thymidine- 3

H incorporation

DNA, leucine-3H uptake into protein, or cytidine-3H into RNA

into

in his in vivo Lewis lung carcinoma study.

Antibiotic Action

A number of clinical investigations utilizing cannabis lotions

and ointments as topical antibacterial agents were carried out

at the Palacky University in Olomouc, Czechoslavakia (Krejci

1961). A variety of conditions were successfully treated including herpes labialis and otitis media. Cannabis irrigations

sometimes outperformed tetracycline. A few osteomyelitic

fistulas were healed with cannabis irrigations. In two cases of

second degree burns, an analgesic effect is mentioned in addition

to healing of the skin. More recently, it was found that delta9-THC and cannabinol (CBN) were bacteriostatic or bacteriocidal

against staphyllococci and streptococci in vitro (Van Klingerin and

ten Ham 1976). When horse serum was introduced into the broth

cultures, the antibacterial activity was essentially eliminated.

Presumably, binding of the CBN and delta-9-THC to plasma proteins could have accounted for the inactivation. They were ineffective against Gram-negative organisms.

Even in these days of effective synthetic antibiotics, a role

might possibly be found for topical cannabis preparations if

further studies corroborate the Czechoslovakian work.

Antianxiety and Sleep-Inducing Effects

Like other sedatives, cannabis prolongs barbiturate sleeping time,

reduces REM sleep periods and may increase Stage IV sleep

(Freemon 1974). REM rebound could occur after abrupt discontinuance of the drug. When used as an hypnotic, Neu et al. (1976)

found that it decreased sleep latency with fewer awakenings.

Doses of 10, 20 or 30 mg of delta-9-THC tended to produce hangover effects in some subjects. In a second study utilizing 5, 10

and 15 mg of delta-9-THC, 500 mg of chloral hydrate or a placebo,

no particular differences in sleep latency or duration were

observed among the various drug schedules.

209
Cannabis users occasionally relate that the prime reason that

they use the drug is to relax, unwind or decrease tensions. A

few find it helpful in falling asleep. The sedative effect

occurs most frequently; however, anxiety and dysphoria are also

reported. This is especially true when intravenous delta-9-THC

is taken, but it is also seen during oral ingestion and smoking.

Somnolence is also listed as a side effect in many of the

research studies in which sedation is not desired.

Muscle Relaxant

Only individual case reports are available to suggest a muscle

relaxant effect of cannabis, and animal models for neuromuscular

spasm have been only infrequently used (Passatore et al. 1975).

A significant decrease of both twitch and tetanic contractions

of the gastrocnemius muscle of adult mice following supermaximal stimulation of the sciatic nerve after chronic delta-9-

THC treatment has been demonstrated.

When 10 paraplegics were questioned (Dunn and Davis 1974) about

the effects of their marijuana use upon their symptoms, four

reported a decrease in phantom pain sensations, five mentioned

a decrease in muscle spasticity, with three noting no improvement and two not having significant spasticity. The results of

smoking also had an inconsistent effect upon bladder spasms.

Fourteen patients with either lower motor neurone lesions due

to spinal cord trauma or multiple sclerosis were said to have

a reduced muscle spasticity in connection with their cannabis

use (Petro and Ellenberger 1979). Neurological examinations

before and after cannabis smoking showed evidence of decreased

clonus and muscle spasticity.

Preanesthetic

The possibility that delta-9-THC could be employed as a preanesthetic agent has been fairly well explored (Smith & Kulp

1976). The consensus is that the drug has no important role

to play for this therapeutic application. Problems of syncopal

hypotension, respiratory depression and excessive, serious

sedation when delta-9-THC is combined with other preoperative

medications make for unacceptable adverse reactions. Most of

the investigators have reported serious anxiety when delta-9-

THC is given intravenously, which it must be for preoperative

purposes. The dysphoric response under these conditions may

represent a combination of setting, set and the effects of

rapid onset of the autonomic and psychic symptoms of delta-9-

THC. These problems in addition to the cardiac accelerating

property make it an undesirable medication to use prior to

surgery.

210
Pain

The folk use of cannabis includes numerous references to its

pain-allaying qualities. It was traditionally given for toothache, dysmenorrhea, difficult childbirth, neuralgia and rheumatism in those lands where it grew wild.

Preclinical tests in general confirm an analgesic property by

demonstrating an elevation of pain thresholds and an attenuation

of the escape response to painful stimuli (Parker and Dubas 1973).

Delta-9-THC was found to be equipotent to morphine in some tests

(hot plate, acetic acid writhing), but not in others (paw

pressure) (Sofia et al. 1975).

Some nondefinitive human studies have been done. Milstein et

al. (1975) reported an increased pain tolerance, but only in

the preferred hand. There was a trend for experienced smokers

to have elevated pain thresholds as compared to inexperienced

smokers although this variable did not achieve significance.

Hill et al. (1974) recorded a double-blind study of smoke from

a placebo vs. smoke containing 12 mg of delta-9-THC. Delta-9-

THC was found to decrease pain tolerance and heighten pain

sensitivity in response to electrical skin stimulation.

Raft and associates (1977) gave intravenous diazepam (0.157 mg/

kg), delta-9-THC (0.22 mg/kg) and (0.44 mg/kg) and a placebo

to ten students undergoing elective removal of all four

impacted third molars. Lidocaine was used as a local anesthetic.

In addition, measurements of experimental pain were employed:

a strain gauge algometer and an electrocutaneous stimulus to

the skin. Pain detection thresholds (discomfort) were elevated

with the high dose of delta-9-THC, but pain tolerance (unbearable pain) was less than after diazepam and placebo. Delta-9-

THC was not considered to be a true analgesic for either experimental or surgical pain. Instead, it was believed to alter

pain responsivity on the basis of the emotion evoked (anxiety

or euphoria) and a disruption of sensory interpretive capacities.

Similarly, Cooler and Gregg (1976) were unable to demonstrate

an analgesic effect of delta-9-THC in human volunteers as

measured by periosteal pressure stimulation or by cutaneous pain

thresholds utilizing intravenous doses of 1.5 and 3 mg of delta9-THC, 10 mg of diazepam or a placebo.

Cancer patients requiring analgesics were treated with either

a placebo or delta-9-THC, 10 or 20 mg orally, by Noyes et al.

(1975). It was concluded from the study that delta-9-THC was

a mild analgesic. In a dose of 20 mg it was prohibitively

sedating and intoxicating. The 10 mg dose only rarely presented

such problems. Blurred vision and impaired thinking were also

recorded. Appetite stimulation, mood elevation and feelings of

relaxation were occasionally noted.

211

323-754 0 - 80 - 15
Butler and Regelson (1976) in a broad study of delta-9-THC effects

on advanced cancer patients found no appreciable anti-pain

response to 0.15 and 0.3 mg/kg of delta-9-THC as compared to a

placebo.

It was found that much of the analgesic effect of delta-9-THC

was in its 11-hydroxy metabolite (Wilson and May 1974). The 9-

nor derivative that cannot form 11-hydroxy compounds in vivo does

not possess analgetic action. Synthesis of 9-nor-9-ß-hydroxyhexahydrocannabinol proved it to be a potent analgesic approximately equivalent to morphine. Harris (1976) attempted to reverse the 9-nor-9-ß-hydroxyhexahydrocannibinol antinociceptive

effect with naloxone and was not able completely to reverse its

activity. Nor could cross tolerance between this compound and

morphine be demonstrated.

Depression

Cannabis has been used for melancholia in many cultures in which

it is a folk medicine. Pyrahexyl (Synhexyl) was used by

physicians during the 1950s for depression: in fact, Parker and

Wrigley's (1950) study may have been the first in which a

double-blind design was used with a cannabinoid. The results

of this study were negative. Nor did Kotin et al. (1973) find

any difference from a placebo in his one-week study using 0.3

mg/kg of delta-9-THC in depressed patients. Many antidepressant

drugs require longer periods of time before their therapeutic

effect becomes discernible.

The studies performed for the amelioration of nausea and vomiting

in cancer patients may be able to make a contribution to the

question of an antidepressant action. Regelson et al. (1976)

found that delta-9-THC acted as a mood elevator and tranquilizer

as measured by the Zung test. Decisive studies of unipolar

and bipolar depressions utilizing delta-9-THC have not yet

been done.

Alcoholism and Drug Dependence

The use of marijuana as a reward for certain alcoholics to stay

on disulfiram (Antabuse) has been suggested by Rosenberg et al;

(1978). No drug interaction appears to occur between the two

substances. However cannabis alone or in combination with

disulfiram was not particularly effective in inducing

alcoholics to enter or remain in treatment. Some evidence exists

that cannabis and alcohol produce cross tolerance.

After making rats morphine dependent by implanting pellets,

Hine et al. (1975a,b) injected them with delta-9-THC, 1,2,5 or 10

mg/kg daily. Naloxone 4 mg/kg was then injected and attenuation

of the abstinence syndrome in two of the nine rated abstinence

symptoms was noted. The authors believe that a trial of delta9-THC in opiate detoxification is justified. This study was

212
partially replicated by Bhargava (1976) in mice with delta-9-,

delta-8, and 11-hydroxy-delta-8-THC. Carder (1975) points out

that in the Hine study mentioned above, the effects of delta-9-

THC and CBD in suppressing only two of nine naloxone-precipitated morphine abstinence symptoms is not impressive. It could be

accounted for by the nonspecific depressant activity of the

cannabinoids.

Ten morphine-dependent rats were injected with delta-9-THC

twice daily in increasing doses for five weeks, reaching 40 mg/

kg during the last three weeks (Bhargava 1978a,b). Ten morphinedependent controls received the vehicle. On the 22nd and 31st

days naloxone precipitated an abstinence syndrome, as did

cessation of the delta-9-THC on day 35. The most common abstinence signs noted were tooth chattering, defecation, urination,

dyspnea and complete palpebral closure. In the delta-9-THC

group infrequent tremors, chewing and eating of objects, escape

behavior, sniffing, biting of fingers and increased locomotor

activity were observed. These symptoms peaked 48 hours after

withdrawal.

The value of finding a new detoxification agent to ameliorate

opiate withdrawal is not an important clinical need. A more

important issue is whether the psychoactive cannabinoids

interpose at the endorphin binding sites. This point is not yet

settled.

SUMMARY

Twelve categories of symptoms or of disease states have been

considered in relation to a potential ameliorative effect by

cannabis or one of its derivatives. To sumnarize the state of

the art insofar as the cannabinoids' role as therapeutic agents

is concerned is difficult, but an overall impression will be

attempted here.

Not only the effectiveness of the drug, but also the need for

new treatment products will be considered in the evaluation.

1. Glaucoma. An acceptable topical preparation will

benefit certain patients not helped by the conventional medications. It will have to contain less than 0.5 percent of delta-9-

THC. A superior synthetic analogue may be found.

2. Asthma. Elucidating the mechanism of action of the

cannabinoids be more important than attempting to produce

a non-irritating aerosol.

3. Antiemetic. It appears that cannabis has definite, but

not invariable antinauseant and antiemetic capabilities. It is

at least comparable to our standard antiemetics, and may offer

relief to those who are currently not benefitted by them.

213
Combinations of cannabis plus the standard drugs used for

vomiting should be tried in future studies.

4 . Epilepsy. Cannabidiol deserves further clinical

trials in humans as an anticonvulsant alone or with established

antiseizure drugs.

5. Tumor Growth Inhibition. Although, of interest, it

does not appear that the cannabinoids will make a contribution

in this area. What may be of concern is that tumor growth

inhibitors are invariably cellular toxins to normal cells

depending on the dosage since they interfere with cellular

metabolism. Therefore delta-9-THC should be studied further

for a possible cytotoxic effect in dosage levels used by

humans.

6. Topical Antibiotics. The earlier Czechoslovakian work

requires confirmation utilizing double-blind procedures and

appropriate controls.

7. Antianxiety and Insomnia. While the cannabinoids seem

to have sedative-hypnotic activity, they are inconstant and

not comparable to existing medications for that purpose. Sometimes paradoxical anxiety and panic states intervene.

8. Muscle Relaxant. Although the work is quite preliminary,

the effort to determine whether cannabis or its derivatives can

make a contribution to the management of musculospastic disorders

should continue.

9. Preanesthetic. It does not appear that the cannabinoids

have any future for this indication.

10. Pain. Unless new synthetic compounds are found, it is

difficult to believe that the available cannabinoids can compete

with current analgesics.

11. Depression. This indication has not been convincingly

investigated, and no conclusions can be drawn.

12. Alcoholism and Drug Dependence. It is not likely,

from the work available that the cannabis group will make a

substantial impact on the treatment of the alcoholic or the

drug-dependent person.

214
REFERENCES

Therapeutic Aspects

Bhargava, H.N. Inhibition of naloxone-induced withdrawals in

morphine dependent mice by 1-trans-delta-9-tetrahydrocannabinol. European Journal of Pharmacology, 36: 258-

262 (1976).

Bhargava, H.N. Time course of the effects of naturally occurring

cannabinoids on morphine abstinence syndrome. Pharmacology Biochemistry and Behavior, 8:7-11, (1978a).

Bhargava, H.N. Potential therapeutic applications of naturally

occurring and synthetic cannabinoids. General

Pharmacology, 9:195-213 (19786).

Borison, H.L. McCarthy, L.E. and London, S.W. Cannabinoids and

emesis. New England Journal of Medicine, 298: 1480-

1481 (1978).

Boyd, E.S. and Merritt, D.A. Effects of a tetrahydrocannabinol

derivative on some motor systems in the cat. Archives

of International Pharmacodynamics, 153:1-12 (1965).

Burstein, S. Prostaglandins and cannabis: IV. a biochemical

basis for therapeutic application. In: The Therapeutic

Potential of Marijuana. Cohen, S. and Stillman, R.C.

(eds.) New York: Plenum, 1976.

Busch, F.W., Seid, D.A. and Wei, E.T. Mutagenic activity of

marijuana smoke condensates. Cancer Letters, 6:319-

324 (1979).

Butler, J.R. and Regelson, W. Treatment effects of delta-9-

THC in an advanced cancer population. In: Cohen, S.

and Stillman, R.C. (eds.), The Therapeutic Potential of

Marijuana. New York; Plenum, 1976.

Carder, B. Blockade of morphine abstinence by delta-9-tetrahydrocannabinol. Science, 190:590 (1975).

Chang, A.E., Shiling, D.J., Stillman, R.C., Goldberg, N.H.,

Seipp, C.A., Barofsky, I., Simmon, R.M. and Rosenberg,

S.A. Evaluation of antiemetic effects of delta-9-THC

during adjuvant chemotherapy in patients receiving

high dose therapy. Annals of Internal Medicine, to be

published, 1979.

Cohen, S. and Stillman, R.C. (eds.) The Therapeutic Potential

of Marijuana. New York: Plenum, 1976.

215
Cohen, S. Introduction. In Cohen, S. and Stillman, R.C. (eds.)

The Therapeutic Potential of Marijuana. New York:

Plenum, 1976.

Consroe, P.F., Wood, G.C. and Buchsbaum, H. Anticonvulsant

nature of marihuana smoking. Journal of the American

Medical Association, 234: 306-307 (1975).

Cooler, P. and Gregg, J.M. The effect of delta-9-tetrahydrocannabinol on intraocular pressure. In: Cohen, S

and Stillman, R.C. (eds.), The Therapeutic Potential

of Marihuana, New York: Plenum, 1976.

Corcoran, M.E., McCaughran, J.A., Jr., and Wade, J.A. Antiepileptic and prophylactic effects of tetrahydrocannabinols in amygdaloid kindled rats. Epilepsia,

19: 47-55 (1978).

Cottrell, J.C., Sohn, S.S., and Vogel, W.H. Toxic effects of

marijuana tar on mouse skin. Archives of Environmental

Health, 26: 277-278 (1973).

Crawford, W.J. and Merritt, J.C. Effects of tetrahydrocannabinol

on arterial and intraocular hypertension. International

Journal of Clinical Pharmacology and Biopharmacy, 17:

191-196 (1979).

Cuendet, J.F., Shapiro, D., Calanca, A. Faggioni, R. and Ducrey,

N. The action of delta-9-THC on ocular tension. Opthalmologica, (Basel) 172:122-127 (1976).

Cunha, J.M., Carlini, E.A., Pereira, A.E., Romos, O.L., Pimentel,

C., Gogliardi, R., Sanvito, W.L., Lander, N. and

Mechoulam, R. Chronic administration of cannabidiol

to healthy volunteers and epileptic patients. To be

published (1979).

Davies, B.H. Weatherstone, R.M., Graham, J.D.P. and Griffiths,

R.D. A pilot study of orally administered delta-1-

trans-tetrahydrocannibinol in the management of patients

undergoing radiotherapy for carcinoma of the bronchus.

British Journal of Clinical Pharmacology, 1:301-306

(1974).

Dunn, D. and Davis R. The perceived effects of marihuana in

spinal cord injuries. Paraglegia, 12:175 (1974).

Feeney, D.M., Spiker, M. and Weiss, G.K. Marihuana and epilepsy:

Activation of symptoms by delta-9-THC. In: Cohen, S.

and Stillman, R.C. (eds.), The Therapeutic Potential

of Marijuana, New York: Plenum; 1976.

216
Feeney, D.M. Marijuana and epilepsy. Science, 197:1301-1302

(1977).

Feinberg, I., Jones, R., Walker, J., Cavness, C. and Floyd, T.

Effects of marijuana extract and tetrahydrocannabinol

on EEG sleep patterns. Clinical and Pharmacological

Therapeutics, 19:782-794 (1976).

Freemon, F.R. The effect of delta-9-tetrahydrocannabinol on

sleep. Psychopharmacologia, 35: 39-44 (1974).

Friedman, M.A. In vivo effects of cannabinoids on macromolecular biosynthesis in Lewis lung carcinomas.

Cancer Biochemistry and Biophysics, 2:51-54 (1977).

Green, K., Kim, K. and Bowman, K. Ocular effects of delta-9-

tetrahydrocannabinol. In: Cohen, S. and Stillman, R.

C. (eds.). The Therapeutic Potential of Marijuana,

New York: Plenum, 1976.

Green, K., Kim, K, Wynn, H. and Shimp, R.G. Intraocular

pressure, organ weights and the chronic use of

cannabinoid derivates in rabbits for one year.

Experimental Eye Research, 25: 465-471 (1977).

Green, K. The ocular effects of cannabinoids. In: Zadunaisky,

J.A. and Davison, H. (eds.) Current Topics in Eye

Research, New York; Academic, 1978a.

Green, K. Is there a scientific basis to the legislation of

marijuana as a medicament? Journal of Psychedelic

Drugs. 10:207-210 (1978b).

Green, K. The Ocular Effects of Cannabinoids, Vol. 1, Current

Topics in Eye Research, New York: Academic, 1979.

Gross, H.A., Ebert, M., Goldberg, S., Kay, W., Caine, E.,

Faden, V., Hawks, R. and Zinberg, N. A trial of delta9-THC in primary anorexia nervosa. To be presented

at the annual meeting of the American Psychiatric

Association, San Francisco, 1980.

Harris, L.S. Analgesic and antitumor potential of the cannabinoids. In: Cohen, S. and Stillman, R.C. (eds.).

The Therapeutic Potential of Marijuana, New York:

Plenum, 1976.

Harris, L.S., Munson, A.E. and Carchman, R.A. Antitumor

properties of cannabinoids. In: Braude, M.C. and

Szara, S (eds.) The Pharmacology of Marijuana, New

York: Raven, 1976.

217
Hepler, R.S. and Frank, I.M. Marijuana smoking and intraocular

pressure. Journal of the American Medical Association,

217:1392 (1971).

Hepler, K.S., Frank, I.M. and Petrus, R. Ocular effects of

marijuana smoking. In: Braude, M.C and Szara, S (Eds.)

Pharmacology of Marijuana, New York: Raven, 1976.

Herman, T.S., Einhom, L.H., Jones, S.E., Nagy, C., Chester, A.

B., Dean, J.C., Furnas, B., Williams, S.D., Leigh,

S.A., Dorr, R.T. and Moon, T.E. Superiority of

nabilone over prochlorperazine as an antiemetic

in patients receiving cancer chemotherapy. New England

Journal of Medicine, 300:1295-1297 (1979).

Hill, S.Y., Schwin, R., Goodwin, D.W. and Powell, B.J.

Marijuana and pain. Journal of Pharmacology and

Experimental Therapeutics, 188:415-418 (1974).

Hine, B., Friedman, E., Torrelio, M. and Gershon, S. Morphine

dependent rats: Blockade of precipitated abstinence

by tetrahydrocannabinol. Science, 187:443-446 (1975).

Hine, B., Tarredio, M. and Gershon, B. Interaction between

cannabidiol and delta-9-THC during abstinence in

morphine dependent rats. Life Sciences, 17:851-857

(1975).

Hoffmann, D., Brunnemann, K.D., Gori, G.B. and Wynder, E.L.

On the carcinogenicity of marijuana smoke. Recent

Advances in Phytochemistry, 9:63-81 (1975).

Huber, G.L., Pochay, V.E., Pereira, W., Shea, J.W., Hinds, W.C.

First, M.W. and Somberger, G.C. Marijuana, THC and

pulmonary antibacterial defenses. Presented at the

Seventh International Congress of Pharmacology,

Reims, France, 1978.

Karler, R. and Turkanis, S.A. The antiepileptic potential of

the cannabinoids, In: Cohen, S. and Stillman, R.C.

(eds.), The Therapeutic Potential of Marijuana.

New York: Plenum, 1976.

Kaymakalan, S., Ayhan, I.H. and Tulunay, F.C. Naloxone induced

or post withdrawal abstinence signs in delta-9-THC

tolerant rats. Turkei Psychopharmacology. 55:243-249,

(1977).

Kotin, J., Post, R.M. and Goodwin, F.K. Delta-9-tetrahydrocannabinol in depressed patients. Archives of General

Psychiatry, 28: 345-348 (1973).

218
Krejci, Z. To the problem of substances with antibacterial

action: Cannabis effect. Casopis Lekaru

Ceskych, 43: 1351-1354 (1961).

Marihuana Research Findings: 1976. National Institute on Drug

Abuse Research Monograph 14. DHEW Pub. No. (ADM) 77-

501. Washington, D.C.: Supt. of Documents, U.S. Government Printing Office, 1977.

Martin, P and Consroe, P. Cannabinoid induced behavioral

convulsions in rabbits. Science, 194:965-967 (1976).

McCarthy, L.E. and Borison, H.L. Antiemetic activity of

nabilone, a cannabinol derivative, reversed by

naloxone in awake cats, Pharmacologist 19:230 (1977).

Mechoulam, R. and Carlini, E.A. Towards drugs derived from

cannabis. Naturwissenshaften, 65:174-179 (1978).

Milstein, S.L., Mac Cannell, K., Karr, G. and Clark, S.

Marijuana-produced changes in pain tolerance. Experienced and non-experienced subjects. International

Pharmacopsychiatry, 10:177-182 (1975).

Nowlan, R. and Cohen, S. Tolerance to marijuana: Heart rate

and subjective high. Journal of Pharmacology and

Experimental Therapeutics, 208: 223-241 (1978).

Noyes, R., Brunk, S.F., Baram, D.A. and Canter, A. Analgesic

effect of delta-9-THC. Journal of Clinical Pharmacology, 15:139-143 (1975).

Neu, C., Di Mascio, A, and Zwilling, G. Hypnotic properties of

THC: Experimental comparison of THC with chloral

hydrate and placebo. In: Cohen, S. and Stillman, R.C.

(eds.) The Therapeutic Potential of Marijuana.

New York: Plenum, 1976.

Parker, C.S. and Dubas, T.C. Automatic determination of the pain

threshold to electroshock and the effects of delta-9-

THC. International Journal of Clinical Pharmacology,

Therapy and Toxicology, 7:75-81 (1973).

Parker, C.S. and Wrigley, F. Synthetic cannabis preparations

in psychiatry: Synhexyl. Journal of Mental Science,

96:276-279 (1950).

Passatore, M., Casoni, R.P., Chiarotti, M. and Guisti, G.V.

Effect of THC on the supramaximal stimulation of the

mouse sciatic nerve. Acta Medica Roma, 13:427-431

(1975).

Perez-Reyes, M. and Wingfield, M. Cannabidiol and electroencephalographic epileptic activity. Journal of the

American Medical Association, 230: 1635 (1974).

219
Petro, D. J. and Ellenberger, C. Marijuana (cannabis sativa)

as a therapeutic agent in patients with muscle

spasms or spasticity: Case reports and literature

review. Presented at the American Academy of

Neurology meeting, Chicago, 1979.

Raft, D., Gregg, J., Ghia, J. and Harris, L. Effects of

intravenous tetrahydrocannabinol on experimental and

surgical pain. Clinical Pharmacology and Therapeutics,

21:26-33 (1977).

Regelson, W., Butler, J.R., Schultz, J., Kirk, T., Peck, L.,

Green, M.L. and Zakis, 0. Delta-9-THC as an effective

antidepressant and appetite stimulating agent in

advanced cancer patients. In: Braude, M.C. and

Szara, S. (eds.), Pharmacology of Marijuana. New York:

Raven, 1976.

Rosenberg, C.M., Gerrein, J.R. and Schnell, C. Cannabis in

the treatment of alcoholism. Journal of Studies in

Alcohol, 39:1955-1958 (1978).

Sallan, S.E., Zinberg, N.E. and Frei, E. Antiemetic effect

of delta-9-THC in patients receiving cancer chemotherapy.

New England Journal of Medicine, 293:795-797 (1975).

Shannon, H.E., Martin, W.R. and Silcox, D. Lack of antiemetic

effects of delta-9-tetrahydrocannabinol in apomorphine

induced emesis in the dog. Life Sciences, 23: 49-53

(1978).

Shapiro, B.J., Tashkin, D.P and Vachon, L. Tetrahydrocannabinol

as a bronchodilator. Why bother? Chest, 71:558-559

(1977).

Smith, T.C. and Kulp, R.A. Respiratory and cardiovascular

effects of delta-9-THC alone and in combination with

oxymorphine, pentobarbital and diazepam. In: Cohen,

S. and Stillman, R.C. (eds.), The Therapeutic Potential

of Marijuana, New York: Plenum; 1976.

Sofia, R.D., Vassar, H.B. and Knobloch, L.C. Comparative

analgesic activity of various naturally occurring

cannabinoids in mice and rats. Psychopharmacologia,

40: 285-295 (1975).

Sterns, R.L. and Goodwin, W. Antiemetic trials in patients

receiving cancer chemotherapy. Preliminary report,

1979.

Stevens, R.L. and Goodwin, W. Personal communication, 1979.

Tashkin, D.P., Shapiro, B.J. and Frank, I.M. Acute effects

of smoked marijuana and oral delta-9-THC on specific

airway conductance in asthmatic subjects. American

Review of Respiratory Disease, 109:420-428 (1974).

220
Tashkin, D.P., Shapiro, B.J., Reiss, S., Olsen, J.L. and

Lodger, J.W. Bronchial effects of'aerosolized delta9-tetrahydrocannabinol. In: Cohen, S. and Stillman,

R.C. (eds.), The Therapeutic Potential of Marijuana.

New York: Plenum, 1976.

Tashkin, D.P., Reiss, S., Shapiro, B.J., Calverse, B., Olsen,

J.L and Lodge, J.W. Bronchial effects of aerosolized

delta-9-THC in healthy and asthmatic subjects. American

Review of Respiratory Disease, 115:57-65 (1977).

Tashkin, D.P., Calverese, B.M., Simmons, M.S. and Shapiro, B.

J. Respiratory status of 74 habitual marijuana

smokers. Presented at the annual meeting of the

American Thoracic Society, Boston, 1978.

Ungerleider, J.T. and Andrysiak, T. Effect of inhaled delta-gTHC in reduction of nausea and vomiting associated

with bone marrow transplant and chemotherapy.

Personal communication, 1979a.

Ungerleider, J.T. and Andrysiak, T. A comparison of prochorperazine and delta-9-THC for the nausea and vomiting

of cancer chemotherapy patients. Personal communication, 1979b.

Vachon, L., Robins, A., and Gaensler, E.A. Airways response to

aerosolized delta-9-tetrahydrocannabinol: Preliminary

Report, In: Cohen, S and Stillman, R.C. (eds.). The

Therapeutic Potential of Marijuana. New York: Plenum,

1976.

van Klingerin, B. and ten Ham, M. Antibacterial activity of

delta-9-tetrahydrocannabinol and cannabidiol. Antonie

van Leeuwenhoek, 42: 9-12 (1976).

Wilson, R.S. and May, E.L. 9-nor-delta-8-tetrahydrocannabinol:

A cannabinoid of metabolic interest. J Med Chem 17:

475-476 (1974).

White, A., Munson, J., Munson, A. and Carchman, R. Effects

of delta-9-THC in Lewis lung adenocarcinoma cells in

tissue culture. Journal of the National Cancer Institute.

56:155-658 (1976).

Williams, S.J., Hartley, J.P. and Graham, J.D. Bronchodilator

effect of tetrahydrocannabinol administered by aerosol

of asthmatic patients. Thorax, 31:720-723 (1977).

AUTHOR

Sidney Cohen, M.D., D.Sc.

Clinical Professor of Psychiatry

Neuropsychiatric Institute, School of Medicine

University of California at Los Angeles

Los Angeles, California 90024

221
monograph series

While limited supplies last, single copies of the monographs may

be obtained free of charge from the National Clearinghouse for Drug

Abuse Information (NCDAI). Please contact NCDAI also for information about availability of coming issues and other publications of

the National Institute on Drug Abuse relevant to drug abuse research.

Additional copies may be purchased from the U.S. Government Printing

Office (GPO) and/or the National Technical Information Service (NTIS)

as indicated. NTIS prices are for paper copy. Microfiche copies,

at $3.50, are also available from NTIS. Prices from either source

are subject to change.

Addresses are:

NCDAI

National Clearinghouse for Drug Abuse Information

Room 10A-56

5600 Fishers Lane

Rockville, Maryland 20857

GPO

Superintendent of Documents

U.S. Government Printing Office

Washington, D.C. 20402

NTIS

National Technical Information

Service

U.S. Department of Commerce

Springfield, Virginia 22161

1 FINDINGS OF DRUG ABUSE RESEARCH. Not available from NCDAI.

Vol. 1: GPO out of stock NTIS PB-#272 867/AS $22

Vol. 2: GPO out of stock NTIS PB #272 868/AS $20

2 OPERATIONAL DEFINITIONS IN SOCIO-BEHAVIORAL DRUG USE RESEARCH

1975. Jack Elinson, Ph.D., and David Nurco, Ph.D., eds. Not

available from NCDAI.

GPO out of stock NTIS PB #246 338/AS $11

3 AMINERGIC HYPOTHESES OF BEHAVIOR: REALITY OR CLICHE? Bruce J.

Bernard, Ph.D., ed.

GPO Stock #017-024-00486-3 $2.25 NTIS PB #246 687/AS $11

222
4 NARCOTIC ANTAGONISTS: THE SEARCH FOR LONG-ACTING PREPARATIONS.

Robert Willette, Ph.D., ed.

GPO Stock #017-024-00488-0 $1.10 NTIS PB #247 096/AS $6

5 YOUNG MEN AND DRUGS: A NATIONWIDE SURVEY. John A. O'Donnell,

Ph.D., et al.

GPO Stock #017-024-00511-8 $2.25 NTIS PB #247 446/AS $11

6 EFFECTS OF LABELING THE "DRUG ABUSER": AN INQUIRY. Jay R.

Williams, Ph.D.

GPO Stock #017-024-00512-6 $1.05 NTIS PB #249 092/AS $6

7 CANNABINOID ASSAYS IN HUMANS. Robert Willette, Ph.D., ed.

GPO Stock #017-024-00510-0 $1.95 NTIS PB #251 905/AS $10

8 Rx: 3x/WEEK LAAM - ALTERNATIVE TO METHADONE. Jack Blaine, M.D.,

and Pierre Renault, M.D., eds.

Not available from GPO NTIS PB #253 763/AS $10

9 NARCOTIC ANTAGONISTS: NALTREXONE PROGRESS REPORT. Demetrios

Julius, M.D., and Pierre Renault, M.D., eds.

GPO Stock #017-024-00521-5 $2.55 NTIS PB #255 833/AS $12

10 EPIDEMIOLOGY OF DRUG ABUSE: CURRENT ISSUES. Louise G. Richards,

Ph.D., and Louise B. Blevens, eds. Examines methodological issues

in surveys and data collection. Not available from NCDAI.

GPO Stock #017-024-00571-1 $2.60 NTIS PB #266 691/AS $13

11 DRUGS AND DRIVING. Robert Willette, Ph.D., ed. Review research

on effects of drugs on psychomotor performance, focusing on measures

of impairment by different drugs at various levels.

GPO Stock #017-024-00576-2 $1.70 NTIS PB #269 602/AS $11

12 PSYCHODYNAMICS OF DRUG DEPENDENCE. Jack D. Blaine, M.D., and

Demetrios A. Julius, M.D., eds. Theoretical and clinical papers concerned with the intrapsychic determinants of drug addiction.

GPO Stock #017-024-00642-4 $2.75 NTIS PB #276 084/AS $12

13 COCAINE: 1977. Robert C. Petersen, Ph.D., and Richard C. Stillman, M.D., eds. Reports the extent and limits of current knowledge

about cocaine, its use and misuse.

GPO Stock #017-024-00592-4 $3 NTIS PB #269 175/AS $13

14 MARIHUANA RESEARCH FINDINGS: 1976. Robert C. Petersen, Ph.D.,

ed. Technical papers on which the 6th Marihuana and Health report

to Congress was based.

GPO Stock #017-024-00622-0 $3 NTIS PB $271 279/AS $15

15 REVIEW OF INHALANT S: EUPHORIA TO DYSFUNCTION. Charles Wm. Sharp,

Ph.D., and Mary Lee Brehm, Ph.D., eds. Review of inhalant abuse,

including an extensive bibliography.

GPO Stock #017-024-00650-5 $4.25 NTIS PB #275 798/AS $19

223
16 THE EPIDEMIOLOGY OF HEROIN AND OTHER NARCOTICS. Joan Dunne

Rittenhouse, Ph.D., ed. Task Force report on research technologies

and implications for studying heroin-narcotic use.

GPO Stock #017-024-00690-4 $3.50 NTIS PB #276 357/AS $14

17 RESEARCH ON SMOKING BEHAVIOR. Murray E. Jarvik, M.D., Ph.D.,

al., eds. Includes epidemiology, etiology, consequences of use, and approaches to behavioral change. From a NIDA-supported UCLA conference.

GPO Stock #017-024Y00694-7 $4.50 NTIS PB #276 353/AS $20

18 BEHAVIORAL TOLERANCE: RESEARCH AND TREATMENT IMPLICATIONS.

Norman A. Krasnegor, Ph.D., ed. Theoretical and empirical studies

of nonpharmacologic factors in development of drug tolerance.

GPO Stock #017-024-00699-8 $2.75 NTIS PB #276 337/AS $11

19 THE INTERNATIONAL CHALLENGE OF DRUG ABUSE. Robert C. Petersen,

Ph.D., ed. Papers from the VI World Congress of Psychiatry which

deal with drug issues of particular interest worldwide.

GPO Stock #017-024-00822-2 $4.50 NTIS PB #293 807/AS $19

20 SELF-ADMINISTRATION OF ABUSED SUBSTANCES: METHODS FOR STUDY.

Norman A. Krasnegor, Ph.D., ed. Techniques used to study basic

processes underlying abuse of drugs, ethanol, food, and tobacco.

Not available from GPO NTIS PB #288 471/AS $15

21 PHENCYCLIDINE (PCP) ABUSE: AN APPRAISAL. Robert C. Petersen,

Ph.D., and Richard C. Stillman, M.D., eds. Pioneering volume for

clinicians and researchers assessing what is known about the problem of PCP abuse.

GPO Stock #017-024-00785-4 $4.25 NTIS PB #288 472/AS $17

22 QUASAR: QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS OF ANALGESICS, NARCOTIC ANTAGONISTS, AND HALLUCINOGENS. Gene Barnett, Ph.D.;

Milan Trsic, Ph.D.; and Robert Willette, Ph.D.; eds. Reports from

an interdisciplinary conference on the molecular nature of drugreceptor interactions.

GPO Stock #017-024-00786-2 $5.25 NTIS PB #292 265/AS $24

23 CIGARETTE SMOKING AS A DEPENDENCE PROCESS. Norman A. Krasnegor,

Ph.D., ed. Discusses factors involved in the onset, maintenance,

and cessation of the cigarette smoking habit. Includes an agenda

for future research.

GPO Stock #017-024-00895-8 $4.50 NTIS PB #297 721/AS $13

24 SYNTHETIC ESTIMATES FOR SMALL AREAS: STATISTICAL WORKSHOP PAPERS

AND DISCUSSION. Joseph Steinberg, ed. Papers from a workshop cosponsored by NIDA and the National Center for Health Statistics on

a class of statistical approaches that yield needed estimates of

data for States and local areas.

GPO Stock #017-024-00911-3 $5 NTIS PB #299 009/AS $16

224
25 BEHAVIORAL ANALYSIS AND TREATMENT OF SUBSTANCE ABUSE. Norman A.

Krasnegor, Ph.D., ed. Papers present commonalities and implications

for treatment of dependency on drugs, ethanol, food, and tobacco.

GPO Stock #017-024-00939-3 $4.50 NTIS PB #80-112428 $15

26 THE BEHAVIORAL ASPECTS OF SMOKING. Norman A. Krasnegor, Ph.D.,

ed. Reprint of the behavioral section of the 1979 Report of the

Surgeon General on Smoking and Health, with an introduction by

the editor.

GPO Stock #017-024-00947-4 $4.25 NTIS PB #80-118755 $12

27 PROBLEMS OF DRUG DEPENDENCE, 1979: PROCEEDINGS OF THE 41ST ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG DEPENDENCB, INC. Louis S. Harris, Ph.D., ed. Comprehensive assemblage

of ongoing research on drug abuse, addiction, and new compounds.

GPO Stock #017-024-00981-4 $8 NTIS PB #80-175482 $25

28 NARCOTIC ANTAGONISTS: NALTREXONE PHARMACOCHEMISTRY AND SUSTAINEDRELEASE PREPARATIONS (DRUG DEVELOPMENT VOLUME V). Gene Barnett,

Ph.D., and Robert Willette, Ph.D., eds. Papers report research on

inserted sustained-release and long-acting drug devices, and on

possible use with the narcotic antagonist naltrexone.

In Preparation

29 DRUG ABUSE DEATHS IN NINE CITIES: A SURVEY REPORT. Louis A.

Gottschalk, M.D., et al. Epidemiologic study providing data on

drug-involved deaths and procedures for their investigations.

GPO Stock #017-024-00982-2 $4.25 NTIS PB #80-178882 $12

30 THEORIES ON DRUG ABUSE: SELECTED CONTEMPORARY PERSPECTIVES. Dan J.

Lettieri, Ph.D.; Mollie Sayers; and Helen Wallenstein, eds. Volume

presents summaries of the major contemporary theories of drug abuse

by each of 43 reading theorists. Not available from NTIS.

In Press

225

U.S. GOVERNMENT PRINTING OFFICE : 1980 0 - 323-754