DRUGS and DRIVING

EDITOR

ROBERT E. WILLETTE, PH.D.

DIVISION OF RESEARCH

NATIONAL INSTITUTE

ON DRUG ABUSE

MARCH 1977

NIDA RESEARCH MONOGRAPH 11

DEPARTMENT OF

HEALTH, EDUCATION. AND WELFARE

PUBLIC HEALTH SERVICE

Alcohol, Drug Abuse, and

Mental Health Administration

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

Washington, D.C. 20402 - Price $1.70 (paper cover)

Stock No. 017-024-00576-2
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 ciritcal 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 lnstutute

University of California

San Francisco, California

William McGlothlin, Ph.D.

Department of Psychology, UCLA

Los Angeles, California

Jack Mendelson, M.D.

AIcohol and Drug Abuse Research Center

Harvard Medical School

McLean Hospital

Belmont, Massachusetts

Helen Nowlis, Ph.D.

Office of Drug Education, DHEW

Washington, D.C.

Lee Robins, Ph.D.

Washington University School of Medicine

St. Louis, Missouri

NIDA Research Monograph series

Robert DuPont, M.D.

DIRECTOR, NIDA

William Pollin, M.D.

DIRECTOR, DlVlSlON OF RESEARCH, NIDA

Robert C. Petersen, Ph.D.

EDITOR-IN-CHIEF

Eunice L. Corfman, M.A.

EDITOR

Rockwell Building 11400 Rockville Pike Rockville, Maryland, 20852
ACKNOWLEDGMENT

A complementary volume to this, entitled Drugs and Driving:

A Research Review (contract MT-HS-4-00994) will be available

through the National Technical Information Service. In addition,

the reader should be aware of an ongoing DOT National Highway Traffic

Safety Administration project (State of Knowledge and Information

in Alcohol/Druge and Highway Safety; DOT-HS-S-01217) that is

critically evaluating existing research pertaining to drug related

accident risk, and is preparing a comprehensive outline of the

additional research required to assess fully the magnitude and

extent of the drug/highway safety problem. The final report

wiil be available towards the end of the year.

NIDA is grateful for the contribution of DOT observers at the

conference. The conference summary in this monograph is an

initial probe to identify key areas for future research attention

where present findings remain uncertain and sometimes controversial.

The conference summary should not be taken as representing DOT

policy or interpretations.
Thanks are due the people of Research Triangle Institute,

who capably organized and coordinated the panel conference,

held August 20, 1976 at Rockville, Maryland, under NIDA

contract 271-75-1016, from which the papers of this monograph

are derived.

NIDA Research Monographs are indexed in the INDEX MEDICUS.

DHEW publication number (ADM) 77-438

Library of Congress catalog card number 77-70426

i v
FOREWORD

It is now fashionable to recognize the negative effects of the

rapid growth of technology in the 20th century. Nowhere is the

negative side of this revolution more striking than in the area

of drugs and driving. The world is now on wheels. High-speed

vehicles are in the hands of virtually everyone over the age of

16. Impaired driving dramatically raises the risks we each face

daily--not only the risks inherent in our own driving performance

but those which result from the performance of other drivers.

Not only has technology let us get behind the wheels of cars,

it has also opened a treasure chest of old and new mind-altering

chemicals. Only in recent years have we begun to grasp the significant role played by alcohol in highway safety. Within the last

decade the drug use epidemic has added a complex array of other

drugs which influence driving ability. For example, the National

Institute on Drug Abuse surveyed the Nation’s 1976 high school

graduating class finding that just over 8 percent reported daily

marihuana use--compared to 5.9 percent who reported daily alcohol

use. We know that marihuana intoxication produces severe deterioration in driving performance. We are left to guess at the impact

of marihuana use on highway safety--and our best guesses are

frightening.

No less of a concern is the problem of prescription drug use and

the problem of multiple simultaneous drug use.

This monograph presents a critical review of the available literature relating drug use to driving and other complex human performance.

It offers recommendations for the future.

Adequate studies are scarce. Part of the problem is establishing

measures of driving skills and relating these skills to the use of

different types of drugs, at various dosage levels, at differing

periods of time after drug administration, and in a wide variety of

settings. The characteristics of the driving drug user--which change

with time, often over very short time periods--also vastly complicate

the issue. Even determining how many accidents are drug-related is

difficult. When the concept of “cause” is introduced, the problem is

made even more difficult.

It is now a matter of urgency to know the implications of drug use

for traffic safety and accident risk. Once a body of knowledge is

assembled, we can begin to consider proposing preventive or legal

responses. Towards that end we must isolate a few specific driving

components that are acceptable indicators of driving skill and measure

the impairment produced by different drugs at various levels.

v
The first challenge in highway safety is to measure impairment.

Then we must get impaired drivers off the highways. One major

cause of impairment is drug use--including alcohol use. The drug

user--and we now know he is "us”--is responsible for his behavior,

including his driving and his drug use. Once having detected

impairment of driving, the sanctions imposed could surely be

tailored to fit the causes of the impairment. But the critical

first question is detecting impairment.

Robert L. DuPont, M.D.

Director

National Institute on Drug Abuse

v i
PREFACE

Research into the relationship between drugs and driving highlights a complex policy question raised by extensive government

supported biomedical research efforts. How does one translate

incomplete knowledge into appropriate policy decisions, where

action or inaction can mean the difference of thousands of lives

and hundreds of thousands of serious and maiming accidents? A

related question is: How does one avoid an unnecessary tug of

war between the need to expand knowledge, on the one hand, and

the need for serious inquiry concerning the potential application

of available but incomplete data on the other?

Thus, we know that alcohol plays a role in roughly half of all

our fatal car crashes - 47,000 deaths in 1976. It plays a role

in a fourth to a third of all serious accidents - 1.8 million.

Apart from the pain and suffering of the individuals and families

involved, the economic costs are astonishing - $25.1 billion.

Though the situation with drugs other than alcohol is not as

clearcut, there are disturbing straws in the wind. A recent study

of 300 Boston area fatal car accidents indicates that 39% involved

driver use of alcohol or a combination of alcohol and other drugs.

An additional 9% involved other drugs (marihuana, barbiturates,

etc.) without alcohol. Of the total drivers, 16% admitted to being

under the influence of marihuana at the time of the crash. In other

limited surveys from 60 to 80% of marihuana users indicated they

sometimes drive while cannabis intoxicated. To some significant

but as yet quantitatively uncertain degree, widely used drugs other

than alcohol contribute to the toll levelled by alcohol.

Given these circumstances, some proportion of our current research

efforts should be directed towards further elucidation of the mechanism of action of such impairment and its precise degree of impact,

And some should be directed to policy research issues which systematically and empirically evaluate alternative options for applying

present incomplete knowledge to reduce the unnecessary consequences

of driving under the influence of various psychoactive drugs.

We are not aware of any simple formula for determining these proportions. However, it is our strong conviction after reviewing current

efforts along both of these dimensions that two conclusions are clear:

a) it is essential to maintain a balanced, vigorous program of research along both of these avenues, and b) presently it is the second

area, the area of policy research, which is grossly deficient and

needs to be substantially strengthened and reinforced,

vii
We need to be more certain, for example, of varying consequences and

differential levels of success of different approaches to regulating

driving under the influence of drugs. "Hardline” laws in the form of

high fines and long prison terms are not necessarily effective, particularly if judges and juries therefore refuse to convict. A more

effective approach appears to be engendering two kinds of awareness

in the public, of the real danger and cost of intoxicated driving,

and of a reasonable certainty that violators will be caught for it.

Sustained public education, large numbers of arrests and a justified

public fear of arrest appear to reduce crashes.

At the recent Seventh International Conference on Alcohol, Drug and

Traffic Safety, in Melbourne, Dr. H. Klette (“Politics and Drunken

Driving-The Swedish Experience”) reported that Sweden, in an effort

growing over a number of years, now has few drivers on the road with

BACs (blood alcohol concentrations) from 0 to 0.08 and one tenth as

many drivers at high BACs as we do. Sweden’s experience suggests that

strictly enforced laws can greatly decrease the number of social

drinkers who drink and drive. Experience from the Netherlands, somewhat like Britain’s, suggests two rules that, combined, can effectively

reduce the number of crashes and high BACs on the road. Dr. P.C.

Noordzij (“The Introduction of a 0.05 Limit in the Netherlands,

Effect on Drinking and Driving”) reported for the Netherlands a decrease of about 10% in crashes and 25% in high BACs on the road with

these two rules in effect. The first rule is that driving at BACs

over 0.05 is itself illegal, rather than, as with most of our laws,

merely presumptive evidence of impairment (at>0.10). The second is

that a screening breath test can be required of any driver, rather

than, as with most of our laws, only if there is “reason to believe”

the driver has been drinking. In our own country the “systematic

programs” of the Alcohol Safety Action Project suggest that the

integration of public education, increased arrests, court capacity

and treatment programs may contribute to reducing the number of

crashes. Two caveats are relevant. Large scale random testing of

drivers on the road is expensive and may be a civil liberties infringement we would be reluctant to accept. Secondly, the measures

described do not substantially affect two groups who are overrepresented among drivers in car crashes, the young and the problem

drinker. The latter needs much stronger motivations, legal sanctions

and treatment to stop drinking and driving.

Policy research, the systematic and intensive effort to study the

consequences of regulatory approaches and develop new ones, is an

area we hope to strengthen substantially, in conjunction with related

agencies such as the National Institute for Alcohol Abuse and

Alcoholism and the Department of Transportation. In the meantime,

the less dramatic but equally essential efforts to study the other

component parts of the jigsaw puzzle continue as a major responsibility.

viii
For drugs other than alcohol, such policy questions are equally

relevant, but more basic research questions must still be answered.

This volume undertakes to do this. Thus, its emphasis is propaedeutic and prospective. The first two chapters outline recommendations and research directions. But the ultimate objective is the

same. Too many people die or are maimed in these avoidable car

accidents. This is uncalled for and unacceptable. Drug research

needs to determine how many of these are due to which drugs at

what dose levels and time elapse from intake. It needs to develop

accurate and appropriate quantitative assay techniques, perhaps

roadside tests, for these drugs, and justifiable behavioral tests

for driving impairment. As this volume indicates, none of these

tasks is easy.

William Pollin, M.D.

Director

Division of Research, NIDA

ix
PANEL PARTICIPANTS

Robert Forney, Ph.D.

Department of Toxicology

Indiana University School of Medicine

1100 West Michigan Street

Indianapolis, Indiana

Markku Linnoila, M.D.

Department of Pharmacology

Siltavulrenpenger 10

SR-00170 Helsinki 17

Finland

Morton F. Mason, Ph.D.

University of Texas

Southwestern Medical School

5323 Harry Harry Hines Boulevard

Dallas, Texas 75235

Arthur McBay, Ph.D.

Chief Toxicologist

Medical Examiner's Office

901 Preclinical Education Building

University of North Carolina

Chapel Hill, North Carolina 27514

Herbert Moskowitz, Ph.D.

Southern California Research Institute

2033 Pontius Avenue

Los Angeles, California 90025

Satanand Sharma, Ph.D.

Southern California Research Institute

2033 Pontius Avenue

Los Angeles, California 90025

x
PANEL PARTICIPANTS (continued)

Reginald Smart, Ph.D.

Associate Director

Addiction Research Foundation of Ontario

33 Russell Street

Toronto, Ontario, Canada M5S 2S1

Jane H. Speaker, Ph.D.

Philadelphia City and County Medical

Examiner's Office

321 University Avenue

Philadelphia, Pennsylvania 19104

Maxine Stitzer, Ph.D.

Psychiatry D5 West

Baltimore City Hospitals

4940 Eastern Avenue

Baltimore, Maryland 21224

National Institute on Drug Abuse

Robert E. Willette, Ph.D.

Division of Research

Jack Blaine, M.D.,

Division of Research

Norman A. Krasnegor, Ph.D.

Division of Research

U.S. Department of Transportation

National Highway Traffic Safety Administration

Office of Driver and Pedestrian Research

Observers

Fred W. Benjamin, Ph.D., D.M.D.

Lee Summers, Ph.D.

Marvin Levy, Ph.D.

x i

CONTENTS

FOREWORD

PREFACE

PANEL PARTICIPANTS

CHAPTER I INTRODUCTION

CHAPTER II SYNOPSIS OF PANEL REVIEW

CHAPTER III SUMMARY OF POSITION PAPERS

CHAPTER IV DRUG IMPAIRMENT REVIEWS

Anesthetics Markku Linnoila, M.D.

Tranquilizers (Foreign)

Tranquilizers (General) Jane H. Speaker, Ph.D. 39

Tranquilizers (Minor)

Opiates

Morton F. Mason, Ph.D. 44

Sedatives Satanand Sharma, Ph.D.

Stimulants Robert Forney, Ph.D.

61

73

v

vii

x

1

3

14

18

19

Hallucinogens (General)

Marihuana

Herbert Moskowitz, Ph.D. 77

Marihuana

Other Drugs

Other Drugs (General)

Other Drugs

BIBLIOGRAPHY

List of Monographs

Arthur McBay, Ph.D.

Reginald Smart, Ph.D.

Maxine Stitzer, Ph.D.

91

100

113

125

136

xiii

CHAPTER I

INTRODUCTION

Evidence has been accumulating that licit and illicit drug use

causes impairment of driving and other complex human performance.

This use is believed responsible for accidents and deaths from

traffic collisions. Some studies have shown a correlation between

drug dose and performance decrements. Assays measuring the

presence of drugs in fatally injured drivers have suggested drug

use as a significant factor in many of these deaths. Although

alcohol alone and combined with other drugs predominates, a

high rate of marihuana use among drivers indicates it could be

a factor in traffic accident and fatalities.

Primarily for these reasons, the National Institute on Drug Abuse

(NIDA) undertook to sponsor a critical review of this research

literature, to see how much we know and we still need to know.

This was directed specifically to drug effects and is intended to

complement earlier surveys and reports published by the U.S.

Department of Transportation (DOT).

Illicit, prescription and over-the-counter drugs are included in

this review. Some alcohol studies are covered, with strong

emphasis on studies of alcohol in combination with other drugs.

The critical analysis concentrates on the type of performance

functions tested or measured, and methodological approaches used.

Detection techniques are also included.

The review was conducted by a panel of nationally recognized experts on the behavioral effects of drug usage. Each expert on the

panel prepared an individual summary review and critique of a

portion of the literature. The summary reviews are organized by

drug clusters, selected according to the World Health Organization’s designation and grouping. References for the studies

selected by the panelists for review are included at the end of

each individual review.

Chapter II is a synopsis of the issues and recommendations

developed by participants at the Rockville conference at NIDA.

Participants included panel members and staff representatives

from NIDA and DOT.

1
Chapter III consists of a summary of position papers prepared by

the panelists to guide discussion of issues identified through the

individual reviews. This discussion took place at a conference

sponsored by NIDA on August 20, 1976, at Rockville, Maryland. Its

purpose was to integrate these many complicated issues into

coherent working order.

Chapter IV presents the individual papers of panel members.

Since some drug clusters were much larger than others, the

panelists divided the larger clusters and some took more than one

of the smaller ones. Moreover, there are between-individual reviews variations in approach and degree of detail, variations we

elected to preserve on the whole, in deference to the panelists’

individual judgment. Nevertheless, the papers read in more or

less serial and uniform order.

The task the panelists undertook in writing reviews and critiques

is not so very different in kind from journal review articles that

are published periodically to keep an audience up to date on what

is happening in a given research area. Thus, Dr. Linnoila reviews

the literature on anesthetics and impaired performance, and with

Drs. Jane Speaker and Morton Mason considers tranquilizer effects

on performance. Dr. Mason also covers the opiates. Dr. Sharma

considers’the sedatives and Dr. Forney the stimulants. Dr.

Moskowitz reviews the hallucinogens and with Dr. McBay, marihuana.

Other psychotropic drugs, including antianxiety, muscle-relaxant

and antihistamine drugs, singly and in combination with ethanol,

are reviewed by Drs. McBay, Smart and Stitzer. There is some

overlap of the same drug in more than one cluster, but this was

preferred to leaving some studies unreviewed simply from incongruence with our drug categories.

But there was a second more unusual and still somewhat novel task

asked of the panelists in coming together for the conference.

They were asked collectively to do a second-order review of the.

entire topic of drug-induced driving impairment and on the basis

of the individual research reviews they had just completed, pool

their judgment in order to focus on what questions now most need

answering and what priorities should be adopted for further

research. This task calls on research scientists to use their

expertise with a broader perspective and more general judgment

than is customary, but in a very specific way. It was no easy

task, and the documents of chapters II and III are the result.

This is certainly not the last chapter on issues related to

assessing the problem of drug effects on driving. It represents

an attempt to provide a continuing review and evaluation of our

growing knowledge. We hope that it will aid and guide future

efforts.

Robert Willette, Ph.D.

Division of Research

National Institute on Drug Abuse

2
CHAPTER II

SYNOPSlS

A. INTRODUCTION

This synopsis is organized into four major sections. The introductory section summarizes opening remarks to the panel by Dr.

Willette and Dr. DuPont. The second section summarizes the “stateof-the-art” of current investigations presented by representatives

of NIDA and the National Highway Traffic Safety Administration

(NHTSA) of the U.S. Department of Transportation (DOT). The third

section defines the issues raised by the panel. The fourth and

concluding section contains recommendations developed by the panel

for future governmental initiatives.

Dr. Willette directed the panelists to focus discussion on the

effects of drugs on complex human behavior, particularly driving.

He stipulated the need for an action plan based on the participants’ review of the state-of-the-art in drugs and driving and

recommendations for alternatives to be pursued by the government in

this area.

Dr. DuPont presented some general information to the group. Three

national data systems were briefly described: (1) the National

Drug Abuse Treatment Systems (NDATS), which generate quarterly

reports on the approximately 25,000 admissions that are made to

drug programs ‘each year; (2) the Drug Abuse Warning Network (DAWN) ,

which concentrates on data from emergency rooms and medical examiners and reports on a monthly basis; and (3) annual national

surveys, such as the 3-year followup survey of high school seniors.

Based on these data, Dr. DuPont expressed the need for public

awareness of the dangers of driving under the influence of alcohol,

marihuana, or a combination of the two, especially among the

adolescent population. The mandate to the participants was to

review the subject of drugs and their influence on human performance, and to specify the knowledge base of the impact of drugs on

driving, from which alternative courses of action could be determined.

3

231-545 O - 77 - 2
B . PREVIOUS AND CURRENT NIDA-DOT RESEARCH

Studies sponsored by DOT have involved mainly alcohol and marihuana and have tested visual search, decisionmaking and risk-taking

with respect to driving behavior. Lane-shifting frequency and

pedal-to-brake time are being evaluated as possible criteria by

DOT researchers as measures of driving performance. However, it is

difficult to correlate performance on visual search behavior

and risk-taking decisions with various drugs.

DOT studies that focus on specific drugs include drugs that improve

driving performance in general as well as prescribed medication

taken to alleviate certain health conditions of drivers. Ramifications of such cases for punitive legislative action are included

within the scope of these studies. Among the ramifications are:

(1) DOT studies have shown no deterioration of driving performance

of subjects on methadone maintenance compared to a nonmethadone

using control group. However, these findings may be due to the

fact that the subjects had been in treatment for 6 weeks and had

developed tolerance to the effects of methadone. (2) Studies of

heroin users indicate that these individuals drove better than

similar controls, but this finding might be attributable to overcompensation based on the users’ fear of being stopped by police.

There have been no studies that have concentrated entirely on

amphetamine usage, due partly to the lack of adequate detection

assay techniques. There are no reliable studies of the effects of

previous amphetamine use on subsequent driving performance. Most

studies of this drug have relied on self-reporting and driving

records and the results indicate that amphetamine users are slightly more accident-prone than users of other drugs. However, these

studies are not well controlled and therefore are not necessarily

reliable indicators of the influence of this drug on driving performance.

Studies on the involvement of drugs in fatally injured drivers are

going to be continued. Up to 2,000 samples have been obtained over

the past 2 years and analyzed for 60 drugs. Attempts have been

made to analyze samples from matching controls, but failure to

obtain adequate cooperation from living drivers continues to

hamper interpretation of data from these studies.

Most studies of the relationships of drugs and driving must overcome problems of assessing the presence of drugs in the body. The

most sensitive measures of the presence of drugs are still only

obtainable from laboratory assays since there are as yet no portable means of detection. NIDA and DOT are developing instrumentation for the detection and quantification of marihuana from

blood, breath and saliva. This instrumentation may hold some

promise for roadside testing in the future. The possibility of

obtaining samples immediately after a collision at the scene of

the accident or traffic stop and analyzing them later in the

laboratory is also being explored.

4
At the present time NIDA is sponsoring research, partly in collaboration with DOT, to detect marihuana consumption through measures of the concentration of THC (the active ingredient of marihuana) in body fluids such as saliva. These tests show, however,

that marihuana is not easily detected after 1 hour. Several tests

are being developed using immunoassay analysis, mass spectroscopy,

and gas chromatography. However, the overriding question of

whether and how the levels of drugs in the body correlate with performance needs to be determined and is being actively investigated.

At the present time NIDA, in collaboration with DOT, is involved in

a 3-year pharmacokinetic study of nine drugs and their effects on

basic behavior. The objective is to study, in simulated realistic

settings, basic behavioral measures while determining drug levels

in body fluids. Once these correlations of behavioral measures to

drug levels are considered established, other findings will become

more meaningful and may help establish some basic methodological

procedures for future research. Multiple approaches are being used

to determine the relationships between the time of drug taking and

driving, dose levels, and drug typology.

Other NIDA-sponsored efforts are being carried out with cannabinoids (detecting THC and derivatives via mass spectroscopy),

diazepam, methadone, amphetamines, benzadrine, cocaine and its

metabolites, PCP, LSD, and other drugs. Almost all of these efforts deal with plasma assays. One of the goals of these efforts

is the development of a handbook and procedural manual to increase

familiarity and use of mass spectroscopy methods. Plasma assay

studies are also being conducted by other institutions under contract to NIDA and DOT. Similarly, proficiency testing regulations

for urinalysis and toxicology laboratories are being developed to

increase the accuracy and reliability of assays for drug presence.

C. ISSUES

The panel identified four major categories of issues: epidemiology, laboratory studies, assay development, and legal questions.

The substance of each category provided the context within which

recommendations for future studies were developed.

1. Epidemiology

Current epidemiological studies of drugs and driving are frequently

characterized by poor sampling procedures and result in making

inappropriate inferences to the population of interest. For example, only limited data are available on the differences in drug

use or abuse between the accident population and the total driving

population. The sample design of studies in which observations are

restricted to fatally injured drivers in hospital emergency rooms

leads to over-reporting of alcohol consumption from accident records,

if these consumption patterns are assumed to be indicative of those

of the total driving population. For another example, the sample

5
design of a study with observations restricted primarily to accidents that occur in the evening fails to detect the number of

accidents attributable to the use of tranquilizers by the middleaged female population, which does most of its driving during the

day. In addition, users of illicit drugs, especially opiates,

constitute a difficult population to study because of problems of

locating them by conventional survey methods.

Epidemiological studies are also frequently characterized by the

lack of an appropriate control group. For example, epidemiological

studies with individuals on methadone maintenance have shown that,

because tolerance develops rapidly from the time dosage is established, methadone maintenance shows little effect on task performance . Some of these studies included the use of control groups

such as drug abstainers and hospital patients. However, these may

not be the most appropriate controls. Differences observed between

these groups and individuals on methadone maintenance may be due to

different lifestyles or environmental conditions--such as those

found in hospitals compared to the methadone subculture--rather

than simply to drug conditions.

Procedures for collecting data for these studies are sometimes

inappropriate. For example, these studies frequently use selfreport data. Heavy drinkers usually tend to underreport both the

quantity and frequency of drinking patterns. In addition, selfreport data are sometimes characterized by only “yes” and “no”

responses that fail to provide details of drinking episodes. Data

obtained through studies that develop records contained in systematic drinking diaries were suggested as a potentially more

accurate and successful technique for data collection.

A final shortcoming of epidemiological studies is often the failure

to include appropriate qualifications in the analyses of study

results. The factors of race, sex, and ethnicity may be important

to consider in these analyses, since different groups display

varying levels of ethanol tolerance. Other important variables for

research consideration include age, duration of drug effect, and

fatigue level of the subject. The importance of including sex as a

variable in these analyses is underscored by the facts that previous studies have indicated that the driving performance for

females is impaired at lower blood concentration levels than it is

for males and that visual vigilance among females is impaired

significantly by alcohol more quickly than among males.

2. Laboratory Studies

Experimental studies of the relationships between drug usage and

performance decrements, conducted primarily in a laboratory setting, are also frequently characterized by problems of poor subject

selection. Anxiety levels in laboratory subjects, generated by

concern about experimental procedures, have a direct influence on

changes in performance, as previous studies have indicated that the

6
degree of drug-induced impairment may be directly related to the

level of anxiety in the subject.

Further, restrictions concerning the use of female subjects in

the childbearing age group in experimental drug studies are an

additional factor that limits selection of subjects for this

type of study. These restrictions may constitute an impediment

in developing tests for male-female differences in drug response.

More specific operational definitions of performance decrements

in the laboratory setting should be developed. With respect to

driving performance, a clear specification of how vigilance

should be operationally defined should be prepared. One example

indication of vigilance is the frequency of checking side and

rear-view mirrors in a simulated driving situation within the

laboratory.

A clear specification of hypotheses suitable for testing in a

laboratory setting is needed. This need is important in assessing the relationship between the degree of drug-caused impairment and time of drug ingestion. For example, there are no

systematic studies of the relationships between the use of sedatives and changes in performance skills over a period of 10 to

14 hours after ingestion. Hypotheses should be carefully developed and tested to determine whether performance capacity

could be decreased by aftereffects, even when performance levels

initially increase, as is the case with stimulants. Further,

initial improvement in performance could decrease or change to

impairment with chronic use of drugs.

Polydrug use introduces additional complications in developing

and testing these hypotheses. These include the fact that the

kind as well as the degree of impairment caused by a combination

of drugs may differ markedly from that caused by either drug

alone. The respective impairments are not necessarily additive.

Reliable evidence of the effects of drug and alcohol use on

human performance is not presently available from laboratory

studies. In laboratory studies of some 2,000 subjects at different drug levels, the pharmacokinetics of drug use were found

to be different from alcohol and differed from each other, since

these drugs have different kinds of distribution throughout the

body, metabolize differently, and reach equilibrium levels at

different rates. Thus, less straightforward correlations and

greater variation can be expected for the results of studies of

drugs other than alcohol, with the consequence that the results

of these studies are difficult to interpret. These problems can

be addressed by developing statistically valid experimental

designs that include these intervening variables so that the

relationships between different drugs and human performance will

become clearer. In addition, awareness of impairment from drug use

may induce overcompensation that actually improves performance

(over controls) and this factor should be studied.

7
The most realistic information on the effects of drugs on complex human performance is acquired through analyses of druginfluenced subjects in actual performance situations, such as

driving. But studies of this type are rarely possible and the

very complexity of a performance such as driving makes results

difficult to assess. Thus, it is desirable that the experimental

studies conducted in more controlled laboratory settings test a

broad range of less complex behavioral responses that can be

related to responses involved in realistic performance situations.

These studies should include an assessment of the effects of

different dosage levels of various types and combinations of

drugs. However, the usefulness of the results of these experimental studies will continue to be somewhat limited until specific

behavioral responses studied in the laboratory can be plausibly

linked and correlated to complex performance in the real world.

3. Drug Assays

There are major differences in the methods required to detect

and measure the presence of alcohol and drugs in the body.

There is a strong need for the development of improved detection

techniques, given the current analytical capabilities of most

laboratories. Since only a few drugs are found in high concentrations in the blood, these techniques should be developed for

breath as well as for other body fluids. These detection tests

are particularly important for use among individuals involved in

accidents and should be developed for use in autopsies as well

as among nonfatalities.

Increased emphasis is needed on the study of threshold effects,

controlled for body weight and drug concentration. The determination of the relationship between drug levels and blood

concentrations has significant implications for the legal problem

of adjudicating accident liability. Currently, chemical analysis alone cannot be used reliably for legal action, since

individual variations in tolerance and thresholds for performance

decrements differ widely.

The reliability and suitability of urinalysis as an appropriate

detection technique to be used in establishing the effects of

drug use on performance are as yet unknown but concentration

studies might be helpful, even when conducted with dead subjects.

However, the results of these studies should be interpreted with

caution. For instance, methadone has been shown to be present

in urine up to a week after intake and propoxyphene up to 18

hours, presumably far too long a time period for these substances

to affect performance.

4. Legal

Efforts should concentrate on determining the effects of each

drug’s use on performance and the role of various intervening

variables such as body weight, sex, age, dosage, time since

8
ingestion, etc., in this relationship, rather than on addressing

legal issues with respect to the effects of drugs on performance,

particularly driving performance. The problem of impaired

driving caused by the influence of drugs should be taken one

step at a time, beginning with a determination of the actual

effects of various drugs on behavioral reactions and then investigating the relation of these impaired reactions to actual

driving behavior. This phased approach is particularly appropriate in view of the nature of the relationship of the

dosage of certain drugs to performance, since small amounts of

ethanol or stimulants may improve performance while increased

dosages, depending on body weight, may be detrimental.

Although various law enforcement measures have not been notably

successful in reducing the effects of alcohol on driving behavior, they should be reexamined to determine if they might be

useful in the case of other drug abuse. At a minimum, the

medical profession should be encouraged to develop effective

standards for prescribing drugs and increase public awareness of

the possible detrimental effects of drugs on driving performance.

D. RECOMMENDATIONS

Recommendations were developed in three major categories: (1)

drug categories to be studied, (2) methodological issues, and

(3) prevention strategies.

Panel members reached a consensus concerning these recommendations. They were able to place priorities on the drug categories

to which future studies should be directed, but did not do so

for methodological issues or prevention strategies. Therefore,

the materials in the final two subsections only summarize the

recommendations of the panel members.

1. Drug Categories

a. The first level of priority for further study is alcohol.

Alcohol causes the greatest problems in impairment of complex

human performance, due to its frequency and quantity of use.

Studies of the detrimental effects of alcohol on human performance should focus on blood alcohol concentration levels of 0.10

percent and greater. The primary goals of studies within this

priority category should be to determine with greater precision

the frequency and quantity of use by people engaged in complex

performance, to assess the frequency of use of alcohol by these

individuals as against that of marihuana and cigarettes, and to

determine how much the impairment caused varies with the frequency and quantity of use. In addition, the effects of alcohol

in combination with other drugs should be assessed more thoroughly.

(However, unlike the Panelists, DOT spokesmen felt that levels below

0.10 should receive greater attention, since legal definitions at

these levels are still vague).

9
b. The second level of priority for study is cannabis and

diazepam (Valium) and their derivatives. The panel members

agreed that because of differing patterns of usage, studies of

cannabis and its derivatives should be restricted primarily to

younger members of the population while studies of diazepam and

its analogs should be restricted primarily to older members of

the population. The primary goals of studies within this priority category should be to determine the frequency of use of

these drugs by people engaged in complex performance, to obtain

more complete laboratory evidence of the drugs’ behavioral

effects, to assess the degree of impairment caused and/or directly related to drug intake, to determine the relationship

between this impairment and the traffic accident probability,

and to develop improved techniques for detecting and recording

concentration levels of these drugs in various body fluids.

c. The third level of priority of drugs for study is sedatives

and hypnotics. As in the case of the two higher priority

categories, a principal goal of studies of drugs in this category is to determine more precisely the relationship between

their use and the impairment of complex human performance.

Other goals of studies of these drugs include the development of

more accurate and realistic assays for detecting the presence

and level of these drugs in the body, and improved techniques

for detecting changes in the use of drugs in this priority

category--for example, by comparing information on sales and

prescription figures for these drugs to levels of abuse among

the population.

2. Methodological Issues

Panel members suggested a number of methodological topics that

should be the focus of future studies, but did not rank them. A

summary of these methodological topics is provided in the following paragraphs.

a. Epidemiological Studies. A major focus of future research.

should continue to be epidemiological studies. But the usefulness of these in the past has been limited because. the target

populations are recent imbibers of various types of drugs in

different amounts who have had driving accidents (or shown other

evidence of performance decrements). An adequate “fix” on these

populations is hard to come by without assays for detecting drug

concentration levels. Drug concentration levels have been

obtained from studies involving alcohol and also for certain

other drugs. Current DOT epidemiological studies have obtained

data from both fatal and living drivers and drug concentrations

for drugs such as those falling under the heading barbiturates.

Methods for detecting marihuana -concentrations in urine, plasma,

saliva and breath are now being developed.

Research topics include: (1) establishing correlations between

people exhibiting drug-induced performance decrements and

10
accident probabilities, (2) cost-benefit analyses of various

countermeasures such as public education to alert and perhaps

mitigate performance decrements, (3) analyses of the relationships between multiple drug use and accident probabilities, and

(4) comparing the nature and severity of accidents to types of

drug use. Future epidemiological studies should use information

from appropriately designed samples to avoid improper generalization from small sample sizes or inadvertant over/underrepresentation of a particular population.

Increased emphasis should be placed on studies of injuries in an

industrial setting, since detrimental effects of drugs on job

performance may be as serious a problem as on driving performance. Studies currently underway to assess the extent of drug

use in industrial settings could be expanded to include an

assessment of the relationship between drug use and performance

decrements.

An important source of data for future studies may be hospitals.

In the future, better accident data may be collected from emergency rooms (ER) and medical centers since accident victims are

being brought more frequently to these facilities where better

medical care is available. Investigators might achieve better

cooperation from ER personnel for these studies by stressing

their importance in the overall strategy to assess the relationship between the use of drugs and alcohol and accidents and

injuries that require hospitalization.

But epidemiological studies that rely on data collected in a

hospital setting present problems. These include the need to

obtain data from an appropriate control group, the difficulty in

establishing causality in an accident investigation, and the

previously cited problem of potential overrepresentation of drug

users among accident victims.

b. Laboratory Studies. Two principal reasons dictate continued emphasis on laboratory studies. First, most reliable available information on drug-induced performance decrements has been

obtained from laboratory studies. Second, studies should focus

on the causal relationship between changes in body chemistry

that occur as a result of drug ingestion and changes in specific

behavioral components rather than on trying to link drug use

directly to changes in complex performance such as driving and

flying. Laboratory studies are obviously an appropriate approach for assessing these chemical-behavioral component relationships. Furthermore, “real life” actual performance studies

will always be characterized by difficulties in establishing the

causal relationships between drug usage and performance decrements, due to the presence of large numbers of noncontrollable

intervening factors.

Future laboratory studies should include development of a battery

of psychomotor tests to detect the presence of certain side

11
effects of drug use, such as changes in risk-taking, and the

development of procedures to assess the magnitude of these side

effects.

c. Drug Assays. Improved techniques for drug assays are

needed because frequently the reliability of the assay report is

uncertain and laboratory procedures are not controlled. In

addition, relatively few laboratories in the United States are

capable of producing reliable results for a sufficiently wide

spectrum of drug assays. Of these laboratories, an even smaller

number are aware of and have implemented rigorous quality control

procedures.

A battery of tests to measure impairment as a function of dose

is needed. So also are improved analytical methods of measuring

blood concentration levels. Development of each of these measures

is needed to specify more precisely the possibly nonlinear

relationships between levels of drug concentration in the blood

and the degree of impairment.

Drug assays should establish lethal levels of drugs such as

barbiturates and aid in the selection of appropriate countermeasures and prevention strategies. Countermeasures are frequently conceived in terms of punitive legislative initiatives

that are often relatively ineffective in altering drug utilization. An alternative countermeasure might be a decision to

issue warnings of detrimental side effects of usage.

3 . Prevention Strategies

In order to provide a basis for an overall drug prevention

strategy, studies of unnecessary usage of tranquilizing drugs in

the United States should be undertaken. These studies should

include a followup of persons found to be using these drugs

unnecessarily, to determine the effects of withdrawal from

drugs. Methodologies for conducting these types of studies are

currently underway in Canada and should be relatively easily

transferred to similar studies in the United States.

law enforcement officials should be educated to focus more on

erratic driving behavior itself rather than on the causes of

such behavior. Drivers should be arrested for “driving erratically” rather than for "under the influence,” as present detection methods for the presence of drugs in the body are not

sufficiently developed for determining the causal relationship

between drug use and erratic driving behavior.

Other prevention strategies are expanded labeling and education

programs. The former would provide information on drug labels

concerning the length of a safe time span from drug intake to

safe driving. The education program should focus on individuals

who frequently dispense drugs, such as doctors and pharmacists,

12
and should provide them with information concerning the detrimental effects of drug usage on human performance. At present,

drug companies are including warning messages on packages of a

large number of drugs, with the consequence that the information

content of these messages may be extremely low. This problem

can be overcome by defining a certain level of risk associated

with the drug use that warrants the development of warning

labels. These levels of risk can be derived from the recommended

epidemiological and laboratory studies and from the drug assays.

13
CHAPTER III

SUMMARY OF POSITION PAPERS

In the course of considering the many issues surrounding the

identification and definition of the effects of drugs on driving

performance, several problem areas and unanswered questions have

been identified. They fall into six major categories: epidemiology, experimental design and performance measures, the relationship of drug levels to performance (pharmacokinetics), subject

variables, drug selection, and legal and prevention concerns.

Epidemiology

At best, any epidemiology study presents difficulties and the

driving area is particularly complicated. At present, it is felt

that insufficient information is available to confirm that a

drugs-and-driving problem exists. Common sense suggests some risk

is likely. Studies in the past have concentrated on fatally

injured drivers and greater attention must be placed on nonfatal

accidents, accident-involved pedestrians and passengers. We know

relatively little about how often drug users get into accidents,

what type of accidents they get into, and how often and where

these accidents occur. There is a strong need to pinpoint

populations at risk and establish the magnitude of the increased

risk to them from driving under the influence of drugs. And

finally, there is a significant lack of information about the relationship between drug levels and accident frequency.

In an effort to minimize the need for carrying out the costly and

difficult epidemiology studies, numerous laboratory or experimental studies have been conducted to identify drugs that can

impair driving performance. The experimental design of these

performance measures are exceedingly important and often fall

short of producing the desired result. Several observations and

suggestions are in order.

1. Good driving performance should be measured objectively

and numerical values assigned to various driving behavior

components. Measuring effects of drugs on particular

components rather than on some vague general competence

called “good driving” would provide a more meaningful test.

14
2.

3.

4.

5.

6.

Drugs may alter performance but other variables such as

physical state of the driver, road conditions, vehicle

condition, may be more important determinants of performance failure. These factors should be taken into

account.

Tests should be developed which would assess the likelihood that people drive or operate machinery after taking

drugs. This would help establish the size of the problem.

One should compare simulator performance with real performance to establish the validity of the former in

predicting the latter.

Subjects should be tested under actual driving conditions

with validated real performance tests and also under

simulator conditions with behavioral tests of driving

skills having a face-valid relation to real performance

tests. Such test results would help link these levels of

testing so that eventually a few simple psychomotor tests:

might be acceptable, valid indicators of real driving

competence.

Dose-effect functions of a drug should be compared on

several behavioral tasks which tap components of “real”

driving performance to establish a profile. Once such

sensitivity profiles are established, the ability of

various behavioral tasks to predict performance tasks

could be determined. This approach would establish

predictive potential and behavioral mechanisms

necessary for driving skills.

Experimental Design and Performance Measures

Attention should be paid to the following facts: Drug-performance

level relationships are inadequately defined because drivers

differ in their skills prior to taking drugs; some drivers may be

tolerant to drugs from chronic use; drivers may be able to compensate for drug effects when motivated. baseline standards

should be established against which subjects can be measured and

evaluated. More emphasis must be placed upon tests of perception.

Visual tests, in particular vigilance tasks, are essential to

include in any battery of performance tests. Specific types of

studies should include tests of vigilance performance, drugs

interaction studies using sedatives, tolerance-behavioral impairment and cross-tolerance behavioral impairment studies. Length

of training is important since some drugs may improve skills of

(inexperienced) subjects while these same drugs may produce

deterioration in experienced subjects. Motivation must be considered and controlled in any studies conducted.

15
Dose response studies are more useful than single dose for singledrug studies. Further, these should be administered under blind

and double-blind conditions in a crossover design to assess contributions of suggestibility to drug impairment.

Many believe that the best studies are derived from measured

driving performance conducted in closed driving courses. Possibly two or three simple, rapid, controlled laboratory measures

can be agreed upon as relevant indicators of driving performance

to acquire valid data for public policy purposes. Others believe that although used for safety, closed courses are inadequate for testing drug effects because driving skill interacts

with a variety of vehicles, road and environmental factors which

produce more natural driving situations. Simulators also are

only part-task devices, since only some of the necessary skills

are measured. Thus, the contention is, rather than attempt to

measure total driving performance inadequately by closed courses

or simulators , it is more useful to break up the notion of driving performance into plausible indicator behaviors and then

measure them for drug impairment.

It has been difficult to establish a representative sample of

required behaviors involved in driving performance, demonstrated

by the low correlation between driving test evaluation and accident histories. The tasks selected in a testing program should

be specified in terms of the behavioral demands made on the

subject and this should be the basis of comparison between tasks.

The selection of tasks to examine could be skills most highly

correlated with driver performance and those performance skills

whose lack is most frequently reported as the basis for accidents by groups performing intensive onsite investigations of

auto accidents. Systematic determination of what behaviors are

affected by a drug is the necessary direction for the field to

take.

The Relationship of Drug Levels to Performance

There is a serious question whether definite, dangerous performance decrements due to drugs can be identified to set legally

unacceptable drug levels for drivers as has been done for alcohol.

Efforts towards answers to this question have long been stymied by

the lack of suitable analytical methods for the determination of

drug levels, either in the laboratory or especially at the roadside. This lack of a device comparable to the breathalyzer for

drugs has hampered the necessary acquisition of such information.

Now, as methodology has been developed, work is proceeding towards

studying the pharmacokinetics, that is the relationship between

drug levels, time and effects, of a variety of drugs. Some problem

issues remain. The experimental design of such studies must take

into account the duration of action of these drugs and the influence of many factors, including the presence of other drugs and

disease states, both on the levels of the drug and its effects.

16
Subject Variables

As epidemiological studies will by necessity cover a wide range of

subjects or victims, it is necessary to include a variety of

subjects in any set of controlled studies. Too often such studies

are carried out on healthy volunteers? whereas a large percentage

of drug users, taking drugs on prescription or over-the-counter,

are in various disease states. It is important to determine if

such people drive better with drugs that might impair normal

subjects. Studies should include older subjects, females, and less

experienced, or perhaps younger drivers. Large sample sizes are

necessary to measure individual differences.

Drug Selection

Sufficient data exist to narrow down the selection of the most

likely candidates of drugs warranting concentrated attention. Some

obvious choices are dictated by such factors as basic pharmacology,

frequency and volume of consumption, and known incidence in driving

accidents. Marihuana in younger people and diazepam and other

sedative drugs such as flurazepam in older people are prime

targets. Several other examples of widely prescribed drugs with

CNS depressant actions, such as propoxyphene, codeine, antihistamines, barbiturates and tranquilizers are also suspect.

Legal and Prevention Concerns

A cycle of information flow and decision making occurs in balancing

the direction of research initiatives with prevention strategies

or countermeasures. Consideration of which prevention approaches

are most likely to succeed and which have poor previous records is

important in making research priorities. Likewise, information

from research studies is essential in establishing the validity of

any countermeasure taken. For example, laws (driving under the

incluence, drunken driving) prescribing legal sanctions for

driving/alcohol levels have at best only somewhat lowered the death

rate from drunken drivers. It is problematic whether establishing

similar levels for drugs would do better, even if this complex

determination could be made. Enforcement of such limits would

also depend on availability of roadside techniques, Education

campaigns aimed at users and prescribing physicians have often

proved unsuccessful. Before serious consideration is given to

such measures as invalidating a driver's lisence for “driving

under the influence of an impairing drug”, or setting any level

of drug use as legally impermissible, it would be necessary to,

assess the drug’s socially acceptable risk/benefit. In order to

do this the actual risks would have to be defined and that returns

us to GO.

17
CHAPTER IV

DRUG lMPAlRMENT REVIEWS

18
ANESTHETlCS AND FOREIGN TRANQUlLlZERS

Markku Linnoila, M.D.

SUMMARIES

STUDY: Doenicke, A., J. Kugler, M. Laub. Evaluation of Recovery

"Street Fitness” by E.E.G. and Psychodiagnostic Tests After

Anaesthesia. Can. Anaes. Soc. J., 14:567-583. 1967. (This study

has been conducted in West Germany, but the address of the authors

is not indicated in the reference.)

Subjects: The total number of subjects is not evident but it must

be above 200. Eighty-one subjects completed the psychomotor test

battery. Demographic data on the subjects and descriptions of

their health or drug use prior to the study are not given. They

are, however, described as healthy volunteers.

Method: This is an experimental study conducted in a clinical

laboratory. The drugs administered as a single dose were thiobutabarbital (500 mg), methohexital (150 mg), and propanidid and

C1-581 in doses which are not reported. Some subjects received

repeated anesthesia but their number is not reported, nor is the

order of or the interval between the anesthesias. Some subjects

also received halothane, diethylether, or nitrous oxide after

propanidid. Halothane was administered for 15 minutes. None of

the concentrations of the inhalation anesthetics are reported in

the text.

EEG was continuously recorded for 12 or 24 hours from the time of

anesthesia. Several psychomotor tests, such as Track tracer,

Chapuis’ labyrinth, down counting, simple and choice reaction time

and accuracy, and mental concentration ability tests were administered to the subjects up to 8 hours after anesthesia. No description of the exact test times can be found in the text. From

figure 8, one can conclude that the tests were probably given at 1,

2, and 4 hours after anesthesia. No statements concerning preexperimental training of the subjects are available. Certain cardiac

and circulatory functions were continuously recorded during the

experiment. Their exact nature, however, is not specified in the

text.

treatments

Drugs: Some subjects received alcohol in addition to the above

. The dose was calculated to induce a blood alcohol

concentration of 0.08 percent. Additional subject groups of unknown size received propanidid (7 mg/kg) or methohexital (2 mg/kg)

19

231-545 O - 11 - 3
in combination with alcohol. The exact time of the alcohol administration remains unclear, even though in the legend for figure 14

a statement can be found that alcohol was administered “one-half

hour before beginning test.”

Dependent variables: Scores of the psychomotor tests and manually

scored EEG’s were the dependent variables. However, it remains

obscure to the reader how the results of the psychomotor tests were

really scored. Even though there are statistically significant

differences among the results of the psychomotor tests after different treatments, no statement is made how these were obtained.

In 20 subjects, the blood barbiturate levels were measured as well.

However, no correlations between the blood levels and performance

effects of the drugs have been computed.

Results: The authors sum up their results by stating that drowsiness lasting for 12 hours was observed after barbiturates or ether

anesthesia, but not after propanidid and halothane. This was

confirmed by both psychodiagnostic tests and FEG. The authors

suggest that after propanidid, street fitness should be regained

within 2 hours. They stress the importance of the simultaneous

measurement of psychodiagnostic and psychophysiological variables

in the evaluation of street fitness after anesthesia.

Comment: This report concerns one of the first large-scale human

experimental studies investigating the “hangover” effects after

anesthesia. The writing is regrettably fussy and in many respects

obscure, as indicated above. It is therefore, impossible for the

reader to evaluate the conclusions of the authors based on the text

per se. However, a comparison of these conclusions with more

recent experiments reveals that they are valid. The necessity of

recording EEG in measuring late sedation and its concomitants after

anesthesia has not been confirmed in later experiments.

STUDY: Schuel, H. , C. Shienle, G. Reinhardt. Vergleichende Untersuchungen Uber die Strassen Verkehrstauglichkeit Nach Kurznarkosen

und Unter Alkoholeinfluss. Anaesthesist, 17:131-134, 1968.

Site: Department of Dental Surgery and Department of Forensic

Medicine, University of Erlanger, Nurnberg, West Germany.

Subjects: The 78 subjects were dental patients aged between 17 and

58 years, and healthy except for their dental problems. They were

divided into the experimental groups without selection; this is an

obvious drawback, taking into account their wide age distribution.

No statements are available concerning the sex distribution of the

subjects.

Method: The present study can be classified as a controlled clinical experiment as to the administration of the drugs. However, no

statements are made concerning the quality of the operations and

their distribution among the experimental groups. If their painfulness varied among groups, as one is led to believe, uncontrolling this variable among groups could reduce the reliability of the

20
results. The psychomotor tests included Mierke’s Determinationsgerat, Tachistoscope, Fallstab, as well as an attention test, a

combined tapping-coordination test, and a projective personality

test. The recorded variables included cumulative reaction times,

accuracy of reactions in a choice reaction test, speed of comprehension, concentration ability, eye-hand coordination, and certain

personality characteristics. BAL was measured according to the

Widmark method. The tests were repeated 30, 45, 60, 90, 120, and

240 minutes after the anesthesia, and 30, 90, and 150 minutes after

the ingestion of alcohol.

Dosage: Atropin (0.5 mg, intramuscularly) was used as a premedication 30 minutes before the anesthesia. Propanidid (500 mg) ,

which was repeated in 10 patients, and thiobarbital (0.8 to 1.0 g)

were the anesthetics investigated.

Dependent variables: The variables mentioned above were measured,

but no statistical treatments were computed to correlate the drug

effects with BAL or to compare the effects of the drugs with each

other.

Results: After propanidid (500 mg), driving skills were regained

in 60 minutes. The effect of thiobarbital lasted for a longer

period of time; however, this period has not been defined. The

effect of alcohol has been used as control for the late sedation

after anesthesia.

Conclusions: The authors conclude that driving for 4 hours after

propanidid should be prohibited. They recommend this period because of the lack of knowledge of other potentially harmful postoperative effects of propanidid.

Comment: The subject material has not been well controlled, and

therefore the results are somewhat questionable. The followup

period after anesthesia is much too short. That is why the authors

are unable to demonstrate the period required to abstain from

driving after thiobarbital. The results from the group ingesting

alcohol are of little benefit. No comparisons of the sensitivities

of the different tests in detecting the late sedation after anesthesia have been made. On the other hand, the results concerning

the length of the late sedation after propanidid agree well with

literature.

STUDY: Healy, T.E.J., H. Lautch, N. Hall, P.J. Tomlin, M.D.

Vickers. Interdisciplinary Study of Diazepam Sedation for Outpatient Dentistry. Brit. Med. J., 3:13-17, 1970.

Site: Department of Clinical Investigation and Research, Dudley

Road Hospital, Birmingham 18, Great Britain.

total of 54 courses of treatment. Their ages ranged from 15 to 54

Subjects: Forty-four anxious dental patients were subjected to a

years. Before the tests, the patients completed the Eysenck

21
personality inventory. They were observed to resemble the original

group of Eysenck’s neurotic subjects as to their anxiety.

Method: This study can be characterized as a partially controlled

clinical experiment. The duration of the operation and presumably

its painfulness, as well, varied from patient to patient. This

must have increased the variability of the results. Body sway,

auditory flutter fusion, visual reaction time, memory functions,

and coordination in the form of writing and manual dexterity were

measured between 45 and 165 minutes after anesthesia. The measurements were repeated eight times, except for the handwriting and

memory tests, which were measured only three times, at 60 and 90

minutes after anesthesia and a week later. Several vital functions

and blood chemistry were monitored during and immediately after the

anesthesia, but these measurements are not important to the present

topic.

Dosage: Diazepam (0.2 mg/kg) was administered intravenously. This

sedation was supplemented with 2% lidocaine plus adrenaline

(1/80,000) locally to the site of operation. The dose of the local

anesthetic was not standardized but adjusted according to the

individual needs. These doses must have varied considerably, since

the duration of the operations was anywhere from 5 to 115 minutes.

Dependent variables: The maximum body sway during 15 seconds after

a 5-second adjustment period was recorded. Reaction times were

recorded with an accuracy of 1/100 second. Elements of discrimination, decisionmaking, and coordination were required in the choice

reaction task. The auditory flutter-fusion frequency threshold was

taken to be the pulsation rate at which the sound seemed continuous

as the frequency was increased. At each test time, six practice

stimuli were given in the choice reaction task and three practice

runs were allowed in the flutter-fusion task.

Results: Body sway and reaction time measurements returned to

normal within 2 hours, and it took 2.5 hours for the flutter-fusion

performance to return to normality in all patients. Manual dexterity was regained within 90 minutes in all patients and no retrograde amnesia was observed after diazepam. All patients experienced anterograde amnesia; for visual stimuli, it lasted for an

average of 15 minutes, and for verbal stimuli, for 25 minutes.

Comment: In the discussion the authors mention one patient who

needed a higher dose of diazepam for equivalent sedation. In such

cases, they recommend that a longer time be allowed for the recovery of the patient before driving or controlling machinery.

Critique: Nothing is mentioned about the length of training of the

subjects on the apparatuses. Therefore, the short recovery periods

observed after diazepam may include a significant learning effect.

By the time of this experiment, the recurrence of sedation several

hours after diazepam was not known and no measurements were conducted later than 165 minutes after the drug. The wide age range

of the subjects as well as the varying lengths of operations and

22
doses of local anesthetic render the results of this study hard to

interpret. It appears that due to the factors mentioned above, the

estimated recovery periods after diazepam sedation are too short.

STUDY: Hannington-Kiff, J.G. Measurement of Recovery From Gutpatient General Anesthesia With a Simple Ocular Test. Brit. Med.

J., 3:132-135, 1970.

Site: Department of Anaesthetics, Farnham Group of Hospitals,

Farnham, Great Britain.

Subjects: Sixty-five of 80 dental patients who were able to cooperate in using the test apparatus participated in the study. The

age of the subjects varied considerably, from 5 to 64 years. Care

was taken to keep the female/male ratio constant between the experimental groups receiving different treatments. No other demographic data of the subjects are available. No statements concerning the general health of the patients were made.

Method: The study can be classified as a controlled clinical

experiment. Methohexital, propanidid, and thiopental were given

intravenously. Anesthesia was maintained by NO2 or halothane

inhalation. Halothane (0.5 to 1.0%) was administered to subjects

who needed a deeper anesthesia than that obtained with NO2. The

operation times varied very little--between 3 to 11 minutes. The

only test used was Maddox wing, which measures mainly the muscle

tone of the medial rectal extraocular muscles. It is pointed out

in the introduction that Maddox wing, when used as in the present

experiment, is not very sensitive to the changes in accomodative

power induced by general anesthesia.

Dosage: The patients received methohexital (1.2 mg/kg), propanidid

4.0 mg/kg), or thiopental (3.6 mg/kg) . No premeditation was

given. One group of patients received an entirely inhalational

anesthetic which consisted of a 2:1 mixture of NO2 and oxygen with

the addition of halothane (1-2%).

Results: In the measurements that were repeated every 5 minutes

for a minute period, it became evident that a full recovery

appeared in 50 percent of the patients 4.5 minutes after the cessation of the operation in the halothane group, 12.5 minutes after

the operation in the methohexital group, and 16.3 minutes after the

operation in the propanidid group. However, 30 minutes postoperatively extraocular imbalance was still present in 30 percent of

patients after methohexital, 30 percent after propanidid, and 70

percent after thiopental.

Comment: The experimental method measures only one aspect of the

drug-induced late impairment after anesthesia--muscle relaxation.

Even though this method is a very sensitive indicator of the ability of drugs to induce muscle relaxation, it is inadequate in

assessing late sedation after anesthesia. The time of ocular

imbalance is much shorter than the time necessary for recovery when

23
skills such as eye-hand coordination and choice reaction performance are measured. The large age variation of the subjects should

have enabled the author to compute correlation between drug effects

and age. However, this opportunity was not taken.

STUDY: Baird, E.S. and D.M. Hailey. Delayed Recovery From a

Sedative: Correlation of the Plasma Levels of Diazepam With Clinical Effects After Oral and Intravenous Administration. Brit. J.

Anaesth., 44:803-808. 1972.

Site: Royal Dental Hospital of London, London WC2, Great Britain.

Subjecfs Healthy male volunteers, aged between 30 to 23 years,

participated in the experiments. In part one, 29 subjects were

used; in part two, 5 subjects received a high dose of diazepam.

Method: The experiment can be classified as a controlled clinical

experiment. Single doses of diazepam were used. Seven subjects

received diazepam orally, and venous blood samples were taken at

intervals of 0.25, 0.50, 1.0, 1.5, 2.0, and 2.5 hours after drug

administration. Twenty-two subjects received diazepam intravenously. Venous blood samples were collected 3, 5, 10, 15, 30, and

60 minutes after drug administration. The subjects were followed

clinically and they were asked to report their drowsiness to the

investigators. In this part, the benzodiazepines were analyzed

after hydrolysis. In the second part the volunteers received

diazepam intravenously and venous blood samples were drawn for 48

hours. This time the glc-procedure for the analysis was a direct

one without hydrolysis of the agents. Again the subjects were

asked to report feeling drowsy during the experiment.

Dosage: In part one, the oral dose of diazepam was 10 mg, and the

intravenous ones were 10 and 20 mg. In the second part, the intravenous dose of diazepam was again 20 mg.

Dependent variables: The investigators were interested in the

plasma diazepam, and N-desmethyldiazepam concentrations as a function of time after drug administration. They assessed the relationship between the feeling of drowsiness, the plasma levels of

diazepam, and N-desmethyldiazepam as well.

Results:

observed.

A late increase in the plasma diazepam concentration was

In four out of five subjects, the plasma diazepam concentration increased about 6 hours after the drug administration.

Plasma N-desmethyldiazepam levels increased throughout the experiment. The subjects showing an increased plasma diazepam concentration at 6 hours reported an increased feeling of drowsiness as

well.

Conclusions: The authors discuss the role of a possible enterohepatic cycle of diazepam in the late drowsiness and elevation of

plasma diazepam concentrations after intravenously diazepam.

24
Comment: No objective measurements were used to quantitate possible impairments of performance concomitant to the subjective

feeling of drowsiness. Therefore, no conclusions concerning the

importance of this finding to driving and controlling machinery

can be made. Since this study, it has become evident that no significant enterohepatic cycling of diazepam occurs in man.

STUDY: Dixon, R.A. and J.A. Thornton. Tests of Recovery From

Anaesthesia and Sedation: Intravenous Diazepam in Dentistry.

Brit. J. Anaesth., 45:207-215. 1973.

Site: Departments of Community Medicine and Anaesthesiology, the

University of Sheffield, S10 2TN, Great Britain.

Subjects: Seventy-eight dental patients received diazepam, and 70

control patients received only local anesthesia. No data concerning the ages and the state of general health of the subjects are

available.

Method: Two paper and pencil tests were administered to the subjects, one 5 and the other 25 minutes after the patient left the

chair. The order of the tests was alternated from patient to

patient. The tests were the deletion of p’s test and the maze

test. In the deletion of p’s test, the subjects had to delete all

p’s from a foolscap (16'' x 13'') sheet containing 58 lines, each

with 38 closely spaced letters of the alphabet. They had to work

systematically from left to right down the page. In the maze test,

the patients traced around a number of adjacent mazes printed on a

single sheet of foolscap. The subjects were allotted to the

treatment groups and to the groups taking the tests in the different orders, so that the types of dental treatments, sex, and the

time from the administration of the local anesthetic to leaving the

dental chair were balanced between them.

Dosage: Patients were given diazepam at a rate of 5 mg/min until

signs of sedation followed. The mean use was 0.23 mg/kg (range

0.12 to 0.32 mg/kg).

Dependent variables: The number of lines completed in 180 seconds

and the number of errors were counted in the deletion of p’s test.

The number of mazes completed and the number of errors, i. e. , the

number of times the line drawn with pencil touched a “hedge” during the 60 second experimental period, were recorded.

Results: The exact way of conducting the statistical analysis is

not indicated in the text. The patients receiving diazepam were

significantly unrecovered, i.e., their performances were substantially impaired at both test times. No effects of the local anesthetics were documented by the tests. By appropriately combining

the results of the two tests, the authors claim an accuracy of 82

percent in detecting psychomotor impairment after diazepam sedation.

25
Conclusions: The authors conclude that patients receiving intravenous diazepam in the same dose range they used should not drive

for 24 hours after the operation.

Comment: The times of measurement are too close to the actual

operation. The tests should have been administered several times

during a much longer period in order to test their real reliability. They appear not to be very sensitive, since they do not

demonstrate any effect of the local anesthetic used. In later

studies, such an effect has been demonstrated to occur within the

first hour after the administration of these agents.

STUDY: Trieger, N., W.J. Loskota, A. W. Jacobs, M.G. Newman.

Nitrous Oxide - A Study of Physiological and Psychomotor Effects.

J. A. D. A., 82: 142-150. 1971.

Site: Division of Oral Surgery, School of Dentistry, University

of California at Los Angeles.

Subjects: Twenty white male UCLA dental students volunteered for

the study. No other data concerning the subjects are available.

Method: This experiment is a controlled clinical study. The

subjects received three different combinations of NO2 and oxygen

in a fixed order with the highest NO2 concentration in the middle.

An interim period of 7 days was allowed between each administration. Psychomotor tests were performed according to the following

schedule: a test after 1 minute of 100% 02, a test after 1 minute

of NO2 and O2 at the prescribed concentration, two tests at 2-

minute intervals immediately thereafter, a test 30 seconds after

the anesthetic had been discontinued and while the subject

breathed 100% 02, and two tests at 2-minute intervals immediately

thereafter, with the subjects breathing only room air.

The psychomotor test was a modification of a drawing test from the

Bender Motor Gestalt Test. It consists of a series of dots spaced

approximately 1 mm apart in a geometric figure that, when drawn,

measures psychomotor function and coordination.

Several physiological parameters and possible alterations in the

pain threshold were also measured during the experimental sessions

as well. However, their relevance to the present problem is

minor.

Dosage: Doses of 25, 50, and 75% NO2 in combination with 02 were

given. The anesthetic was administered for 6 minutes, with an

administration of 100% 02 immediately preceding and following the

anesthetic.

Dependent variables: The number of dots missed and the deviations

of the pencil line from a straight one were counted and added to

give a single score.

26
Results: At the highest dose of NO2, many students were unresponsive to verbal commands. In each instance, however, a complete

psychomotor recovery was achieved within 5 minutes, as measured by

the above-mentioned test. With the lower concentrations of NO2, a

complete recovery became evident within 3 minutes.

Conclusions: The authors note that local anesthesia in addition

to NO2 has to be used for dental procedures.

Comment: The conclusions of the authors concerning psychomotor

recovery after NO2 intake are based on results obtained in healthy

young volunteers. In addition, only one test of eye-hand coordination was used. One must therefore be more careful in generalizing the results than the authors are, particularly, since later

studies have shown that NO2 may indeed have longer after effects

on psychomotor skills than those mentioned above.

STUDY: Tetsch, P., E. Esser, A. Stumborg. Verkehrsmedizinische

Probleme bei Operativen Eingriffen in Lokalanaesthesie Unter BReceptorenblockade. Anaesthesist, 22:251-254. 1973.

Site: Abteilung fur fur Mund- und Keiferchirurgie, der Westf.

Wilhelms-Dniversitgt, Miinster, West Germany.

Subjects: One hundred and fifty-nine dental patients were divided

unevenly in five experimental groups. No other data concerning

the patients are available.

Method: This study can be classified as a partially controlled

clinical experiment. The test apparatus was a choice reaction

machine delivering alternatively three different visual stimuli

(lights with different colors), and a sound. The subjects had to

respond to the stimuli by pressing a lever, one for each type of

stimulus, as soon as possible after the stimulus appeared. The

total number of stimuli in every experiment was 30. Only reaction

times were recorded. The subjects were trained on the apparatuses

in order to reach a stable pretest performance. Whether the

allocation was random does not appear in the text. The first

group received a local anesthetic, the second group received a

local anesthetic and a beta-receptor blocking drug (Betadrenol R),

the third group received the beta-receptor blocking agent 20

minutes before the local anesthetic, the fourth group received 10

mg of diazepam orally as premedication, and the fifth group received .5 mg atropin intramuscularly 30 minutes before the operation. The choice reaction test was completed twice, 10 and 30

minutes after the operation.

0.05% solution and that of the beta-receptor blocking drug was 1.5

Dosage: The average dose of the local anesthetic was 3 ml of

mg.

Dependent variables: The dependent variable was the average

reaction time in the choice reaction test. The students’ t-test

was used for the statistical treatment of the data.

27
Results: The average choice reaction times were shorter in all

groups receiving premeditation. In all groups, the test completed

immediately before the medications for the operation demonstrated

prolonged reaction times. This was interpreted to be due to the

stress caused by awareness’of the operation.

Conclusions: The authors discuss the euphoria-inducing effect of

diazepam, and stress this as an extra risk factor in traffic.

However, no such effect was demonstrated in the experiment.

Comment: There is a considerable variation in the average choice

reaction times between the groups; this leads one to believe that

there were considerable differences among the groups of subjects.

Since a shortening of choice reaction times was demonstrated after

diazepam as a clear central effect of the drug, and because it is

known that such effects are often accompanied by impairments

(e.g., in coordination), one should be more cautious drawing

conclusions than were the authors. The conclusions should not be

based on results of a single psychomotor test. The lack of data

concerning the number of mistakes in the choice reaction test is

suspicious.

STUDY: Korttila, K. Outpatient Anaesthesia in Finland: Drugs

Used and Postoperative Care of Patients. Ann. Chir. Gyn. Fenn.,

64. 1975.

Site: Department of Anaesthesia, University Central Hospital,

Haartmaninkatu 4, SF-00290 Helsinki 29, Finland.

Method: In this study, the author mailed a questionnaire concerning the drugs used in outpatient anesthesia to the physicians

responsible for their administration in 126 medical facilities in

Finland. Eighty-one of them responded. The time of hospital stay

and the time the patients were advised not to drive after anesthesia were reported as well.

Results: Drugs most commonly used were diazepam, propanidid,

thiopental, N02, diazepam plus meperidine, halothane, divinyl

ether, diethyl ether, methohexital, and droperidol, in that order.

The intravenous dose ranges for propanidid, thiopental, diazepam,

and methohexitone were 200-1,500, 125-1,000, 3-35, and 75-200 mg,

respectively. The ranges of the time the subjects were not allowed to drive after the same drugs were 2-27, 10-24, 6-24, and 6-

36 hours, respectively.

Conclusions: The author concludes that the highest doses of the

intravenous agents propanidid and thiopental, in particular, are

dangerous. According to him, droperidol should not be used at all

due to the very later recovery it causes and the common extrapyramidal symptoms after it. The rapidity of recovery after propanidid or halothane with NO2 has not been generally appreciated.

Comment: There are no attempts in the article to compare the

length of the recommended recovery periods with the doses of

28
anaesthetics used in different hospitals. It is not apparent

whether high doses were associated with prolonged times of recommended avoidance of driving and vice versa.

STUDIES: 1. Korttila, K. Psychomotor Skills Related to Driving

After IntraMuscular Lidocaine. Acta Anaesth. Stand., 18:290-206.

1974.

2. Korttila, K., S. Hakkinen, M. Linnoila. Side Effects and

Skills Related to Driving After Intramuscular Administration of

Bupivacaine and Etidocaine. Acta Anaesth. Stand., 19:384-391.

1975.

Site: Department of Anaesthesia and Pharmacology, University of

Helsinki, Helsinki, Finland, and Department of Industrial Psychology, Institute of Technology, Espoc, Finland.

These two experimental, clinical studies are reviewed together

because the methodology in them is essentially the same, and the

main problem in both is the effect of intramuscularly administered

local anaesthetics on psychomotor skills related to driving.

Subjects: Thirty healthy student volunteers, 20 to 25 years of

age, participated in study number 1. The subjects were of normal

weight as to their height, ± 10 percent (according to Home Economics Research Report, No 10, ARS, USDA). The three experimental

groups were controlled as to their sex distribution as well. None

of the subjects had a history of mental illness. They had not

been on drugs for at least a month prior to the study. There were

24 males and 6 females in the whole group. Eleven subjects, nine

men and two women sharing the characteristics of the subjects

described above, participated in study number 2.

Method: A choice reaction test with three different coloured

visual and two sound stimuli was used in these controlled clinical

experiments. The total number of stimuli was 32. Two foot pedals

were used for responding to the visual stimuli, and a button was

pressed when responding to the sound stimuli. Total duration of

this test was about 1 minute. Two tracking tasks were used to

measure eye-hand coordination. In these tasks, the subjects had

to keep a black dot on an illuminated track by means of a steering

wheel. The track was driven once at a fixed speed and the subjects were allowed once to adjust their speed by means of an

accelerator pedal. In an attention test, the subjects had to

follow simultaneously four dials with revolving pointers. Every

time a pointer in any dial passed a sign at the periphery of a

dial the subject had to respond by pressing a key with his or her

finger . There were four keys, one for every dial. The keys were

in front of the sitting subject on a handrest in the same order as

the respective dials. Two of the dials were in the center of the

visual field, and two of them were symmetrically positioned in its

periphery.

degrees.

The visual angel needed for the task was about 110

29
Critical flicker fusion was used in study number 2. Artificial

pupillae and a stable background illumination were used to eliminate the effect of drugs on ocular parameters that would interfere

with the results. The frequency of flickering of a 3-mm-diameter

red light source was increased gradually. The subjects had to

report when they saw a continuous red light. The position of the

subject’s head was standardized at a distance of 90 cm from the

light source. Threshold for discrimination, sensitivity to brightness, and visual discrimination ability in bright counterlight

were recorded as well.

The subjects were trained for an hour on the tests before the

experiments. The drugs were administered intramuscularly, double

blind, and measures were taken not to inject intravenously or

subcutaneously. Study number 1 was not crossover, whereas study

number 2 was crossover and the design was balanced with a Latin

square. One hour before the injection, the subjects were tested

to produce the base line results. Additional tests were conducted

15, 80, and 170 minutes after the injection in study number 1, and

30, 120 and 240 minutes after the injection in study number 2.

Immediately after the tests, venous blood samples were drawn for

the measurement of the drug concentrations in plasma.

Dosage: In study number 1, 10 subjects received placebo, 10

received 200 mg of lidocaine, and 10 were given 500 mg of lidocaine

with adrenaline. In study number 2, every subject received placebo,

etidocaine (2.6 mg/kg) , and bupivacaine (1.3 mg/kg) at l-week

intervals. The order of the treatments was randomized.

Dependent variables: Average cumulative reaction times and number

of mistakes were recorded in the reaction test. Number of deviations from the track, and the length of these deviations as percentages of the total track length were recorded in the coordination tests. In coordination test II, which was driven at the free

speed, the driving time was recorded as well. In the attention

test, the numbers of correct responses were individually recorded

for every dial during the lo-minute test period. The numbers

during the first, fifth, and tenth minute were separately analyzed

in order to detect possible deterioration of attention as a

function of time. The two-way analysis of variance, student’s ttest, and Fisher exact probability test were computed for the data

analysis. Additivity and within-cell variances were checked

before the analysis.

Results: Lidocaine prolonged reaction times at 25 minutes after

its injections, whereas lidocaine and adrenaline improved attention 90 minutes after injection. No correlation was found between

the blood concentrations of lidocaine and its effects. The author

suggests that driving should not be allowed for 1 to 1.5 hours

after local anesthesia with lidocaine. In study number 2, bupivacaine significantly impaired coordination and flicker fusion

during the whole observation period, whereas etiodocaine impaired

flicker fusion discrimination only, The authors conclude that

driving should not be allowed for at least 2 hours after local

30
anesthesia with these agents. Again no clear correlation between

the drug levels and performance was found.

Conclusions: The study number 1, the author concludes that the

effect of lidocaine is mainly due to the parent compound and not

due to its metabolites. The author discusses the generalizability

of the results and point out that the effects of the drugs are

probably most deleterious in patients who are old or who have

liver disease.

Comment: In study number 2, the time of followup was too short;

it should have been 8 hours at least. No dose response relationships were investigated. These studies, like a majority of those

available concerning recovery after anesthesia, did not measure

vigilance performance. Vigilance has recently been demonstrated

to be very sensitive toward the effects of alcohol, and it may

prove to be a good measure of late sedation, as well.

COMMENT: ANESTHETICS

The rapid increase of hospital expenses taking place in all western

countries has forced the expansion of outpatient services. This

trend has imposed new requirements on the methods used for anesthesia and sedation. Hospitals should use anesthetics which lack

cardiovascular side effects and which allow for a rapid recovery

after the medical procedure is over (1,2,3). This is of particular importance in countries such as the United States, where

personal cars provide the most convenient transportation for local

travel. Cur knowledge concerning the recovery of psychomotor

skills related to driving after anesthesia is increasing, but we

are still far from the goal of being able to predict the duration

of the aftereffects of an anesthetic on an individual patient.

There are several methods to choose for outpatient anesthesia,

depending on the type of operation or procedure and the habits and

preferences of the anesthetist. Local anesthetics can be suggested

for outpatient use whenever possible. Lidocaine in high doses

does not impair psychomotor performance for more than 2 hours (4),

and combining the anesthetic with epinephrine can reduce the

adverse psychomotor effects of the drug by slowing its absorption

from the site of injection (4). Prilocaine has an even lower

central-nervous-system toxicity than lidocaine (5). On the other

hand, the more potent and toxic local anesthetics etidocaine and

bupivacaine have adverse effects on skills related to driving for

2 hours at least (6). However, local anesthetics cannot be used

in certain outpatient procedures as the only means of anesthesia,

and overtly anxious patients generally need some kind of sedation

in addition to the local anesthesia.

To reduce the side effects of anesthetics and the doses of these

drugs, premeditations are often used. Atropine alone has been

recommended as a premeditation for outpatient anesthesia (7), but

intramuscular diazepam has its supporters as well (8). Atropine

does not have prolonged adverse effects (9), but diazepam can

31
delay recovery (10). Narcotic analgesics cannot be recommended

for outpatient practice because they delay recovery (11,12).

Intravenous sedation and anesthesia with such agents as diazepam,

lorazepam, thiopental, methohexital, and other ultra-short-acting

barbiturates produce delayed recovery, and the patients should

generally be advised not to drive for 24 hours after taking the

drugs (13,14,15). Young subjects (under 30 years) are generally

able to drive 10 hours after taking diazepam (16). Alphadione

impairs psychomotor skills for a shorter time (about 6 hours) than

the above-mentioned agents, and the shortest recovery period after

any intravenous anesthetic is that after propanidid (about 3

hours) (17).

The inhalation anesthetics--NO2 and halothane, in particular--have

not been thoroughly examined, but there is a widely accepted

opinion that these agents do not cause a delayed recovery. This

concept, however, may have to be modified, because during prolonged

operations the amount of halothane accumulating in the body is

substantial and both agents may induce adverse psychomotor effects

in the personnel of operating theaters, who are exposed to low

concentrations of these gases for prolonged periods of time (18,19).

Diethylether can produce delayed recovery (20).

The above conclusions have been extracted from the most recent

literature concerning outpatient anesthesia and driving, and they

are based on the most reliable information that is available.

Even though the recommendations are much more specific than those

given in a review I wrote in 1974 concerning the same topic (21),

there are still important aspects of outpatient anesthesia which

have not been addressed in the studies published so far.

It is hard to determine what are equivipotent doses of different

anesthetics, and, therefore, the comparisons between drugs are

somewhat unreliable. when producing dose-response relationships

concerning recovery periods after anesthesia, a generally accepted

method should be used for testing analgesia during the anesthesia

and amnesia after the procedure. This would guarantee that drugs

doses of equal anesthetic power would be compared with each other.

so far, very few studies concerning recovery have tested the depth

of the anesthesia and the duration of amnesia.

A conspicuous feature of many studies in the field is that subjective feelings of drowsiness last longer than does actual impairment of skills, as measured by objective testing. Such a discrepancy is suggestive of inappropriate choice of variables in

studies using only one or a few restricted variables to measure

recovery. However, the subjective feeling of drowsiness lasting

for a very long time can often be substantiated by EEG changes

after anesthesia (20).

Because even complicated test batteries sometimes show results at

variance with the EEG findings and with subjective feelings of

performance, we may, as mentioned above, have overlooked in the

32
past certain important variables in choosing our test methods.

One such variable may be visual vigilance, which has not been

tested in studies concerning recovery after anesthesia. Dr. C. W.

Erwin and I have recently demonstrated that ethanol has, against

former belief, a profound deleterious effect on visual vigilance

(22). Since ethanol has effects similar to general anesthetics,

this finding suggests that visual vigilance should be tested in

investigating recovery after anesthesia.

Another psychological function impaired by ethanol and not investigated after anesthesia is iconic memory (23), which may have a

significant role in dense traffic. Decisionmaking and problem

solving are also specific psychological functions that can be

adversely affected by anesthetics and which have not been investigated.

The subjects in the studies concerning outpatient anesthesia have

generally been either healthy volunteers or patients. Studies

using healthy volunteers have generally controlled the background

of the subjects fairly well, but the subjects have usually been

students, which limits generalizing the data. Old and sick persons

are probably more sensitive to the anesthetics than young and

healthy ones. This sensitivity can be due both to central and

peripheral factors such as increased end-organ sensitivity (24)

and to delayed metabolism of the agents (25). Another factor that

is excluded in the studies using healthy volunteers is postoperative pain. Pain of moderate intensity can antagonize the effects

of ethanol (26). Therefore, a mild postoperative pain may, by

increasing arousal, antagonize the delayed effects of an anesthetic. A severe pain, on the other hand, may per se impair driving

ability and require additional medication. This additional medication, which in the case of outpatients is often ethanol, can

increase the late, deleterious effects of anesthetics. our knowledge concerning the combined effects of anesthetics, analgesics,

and ethanol is fragmentary.

Since anxious patients may need higher than usual doses of anesthetics, their recovery might be longer than usual. However, the

relationship between the anxiety of the patients and their recovery after anesthesia has not been systematically investigated.

To minimize the late effects of anesthesia, the anesthetists at

the moment can use the lowest possible doses of the anesthetics

for any particular operation. A fast injection rate of, for

example, diazepam and the barbiturates causes a deeper anesthesia

or amnesia than a slow one (27) and enables the use of low doses.

Even the risk of thrombophlebitides associated with a fast injection rate of diazepam may be avoided after the development of a

new vehicle for the drugs (28).

In a thorough review concerning recovery of skills after minor

outpatient anesthesia (29), Dr. K. Korttila recommnended the

following topics for future research:

33
1. Driving skills after taking inhalation agents should be thoroughly examined.

2. The effect of age on recovery from anesthesia should be

evaluated.

3. Dose-response relationships after use of the most common drugs

should be investigated.

4. Simple clinical tests having a correlation with the recovery

of skills related to driving should be developed.

5. Well-controlled studies using patients of different ages

should be undertaken.

These recommendations are valid, and combined with the suggestions

provided above, should form a basis for the future studies.

COMMENT: TRANQUILIZERS

In this short review, the term tranquilizer is used for three

classes of drugs: neuroleptics, antidepressants, and anxiolytics.

Including the antidepressants under the term tranquilizer may seem

controversial, but in the medical practice they are often used in

the treatment of neurotic outpatients for indications similar to

neuroleptics and anxiolytics.

From the epidemiological point of view, the role of tranquilizers

in traffic is obscure at the moment (1). I have earlier pointed

out in two reviews (1,2) that studies concerning the influence of

tranquilizers on the numbers of fatal accidents do not demonstrate

a clear overrepresentation of users of these drugs among the

participants. However, the only hospital study available so far

(which concerns the prevalence of diazepam, the most commonly used

anxiolytic, among participants in personal injury accidents)

demonstrates a clear overrepresentation of the drug users.

This seemingly controversial result may eventually appear quite

logical when attention is paid to the populations represented in

the two types of studies as related to the population of drug

users. Participants in fatal accidents are mostly young males,

who seldom use tranquilizers--at least for therapeutic purposes--

whereas participants in personal injury accidents are more often

from other groups of drivers. The fatal accidents often take

place late on weekend nights, whereas the personal injury accidents

are more evenly distributed throughout the week and often happen

during the early hours of the evening. Tranquilizers are used

mainly by elderly and middle-aged persons. Females use tranquilizers more often than males. As drivers, these persons are relatively seldom on the roads during the times when most fatal accidents occur. They may also be at a smaller risk of speeding and

of driving under the influence of alcohol, two common features in

fatal accidents.

Conclusions from the data above may not be very reliable, however,

since the studies concerning the fatal accidents have mainly been

conducted in the United States, and the hospital study was conducted

in Oslo, Norway. Therefore, there is an obvious need for a series

of epidemiological studies concerning the role of tranquilizers in

34
personal injury and property damage accidents, Such a series of

studies should in an optimum case be conducted in several countries

at the same time and under the guidelines of an international

organization such as OECD or IDBRA. This would enable the comparison between different countries of the consumption statistics of

these drugs as related to their role in traffic accidents. These

figures also would reveal some aspects of the prescription habits

of the physicians in these countries and, if used correctly, could

modify these habits later on. After all, tranquilizers are prescription medications, and their use is under the control of the

medical profession. If tranquilizers have a significant role in

property damage and personal injury accidents, this role can be

diminished only through a fruitful cooperation with the medical

profession.

Most recent laboratory studies concerning tranquilizers and driving

have been discussed by Dr. I. Saario in the summary of his M.D.

thesis (3). Different kinds of impairments of psychomotor skills

have been observed after use of the different classes of tranquilizers. This is as expected, when the pharmacology of the diverse

drugs classified as tranquilizers is taken into account. Laboratory studies have indicated that the relationship between the

levels of the drugs in biological specimens (such as blood, plasma,

or urine) and their effects is much more complicated than that

between blood alcohol levels and their effects. This is because

most of the tranquilizers have multiple active metabolites, which

may have a role in their adverse effects. The development of

tolerance to the effects of tranquilizers is much stronger than

that toward alcohol. The phannacokinetics of the tranquilizers

are also much more complicated than those of alcohol. Structurally,

closely related tranquilizers may have major differences in their

pharmacokinetics, depending on factors such as water solubility,

pKa, etc.

Taking into account the above discussion, it seems hard to develop

legislation concerning tranquilizers and driving which would be

equivalent to the present drinking and driving laws in the United

States; i.e., any legal limits of plasma tranquilizer concentrations are extremely hard to define. What can be done in the

future concerning tranquilizers and driving? The role of tranquilizers in traffic accidents has to be established, as suggested

above. If a significant role is found, then studies should be

directed in the following manner.

1. Controlled laboratory studies should be conducted to study the

influence of the following factors on the effect of tranquilizers

on psychomotor skills: age, sex, personality, and mental illness.

The psychomotor skills measured should include choice reaction,

coordination, divided attention, vigilance, and memory functions,

as well as information sampling.

2. Best possible correlations between the pharmacokinetics of the

drugs and their metabolites and psychomotor performance should be

searched. In this context, a very important variable has turned

out to be the duration of treatment.

35
3. Simple clinical tests for the measurement of skills related to

driving should be developed.

4. Tests concerning the effects of drugs on skills related to

driving should be included in the premarketing testing of tranquilizers and certain other drugs that are going to be used mainly for

the treatment of outpatients.

5. Use of tranquilizers should be limited to those patients who

really need them. Present consumption statistics suggest that

many relatively healthy persons use tranquilizers; fewer of these

people should take them.

6. Since we have recently demonstrated a fairly strong statedependent effect of diazepam (4), training the drug users in how

to manage in traffic under the influence of the tranquilizers may

become a useful means of reducing the possible accident risk

caused by these drugs.

REFERENCES: ANESTHESIA

1. Baird, E.S., G.D. Flowerdew: Intravenous Diazepam in Conservative Dentistry. Brit. Dent. J., 128:111-116, 1970.

2. Cohen, D.D., J.B. Dillon: Anaesthesia for Outpatient Surgery.

J. Amer. Med. Ass., 196. 1966.

3. Wilkinson, B.M.: Driving Ability and Reaction Times Following Intravenous Anaesthesia. New Z. Dent. J., 61. 1965.

4. Korttila, K.: Psychomotor Skills Related to Driving After

Intramuscular Lidocaine. Acta Anaesth. Stand., 18:290-296, 1974.

5. Eriksson, E.: Prilocaine. An Experimental Study in Man of a

New Local Anaesthetic With Special Regards to Efficacy, Toxicity

and Excretion. Acta Chir Stand., Suppl. No. 358.

6. Korttila, K., S. Häkkinen, M. Linnoila: Side Effects and

Skills Related to Driving After Intramuscular Administration of

Bupivacaine and Etidocaine. Acta Anaesth. Stand., in press.

7. Lennartz, H.: Die Allgemeinnarkose bei Ambulanten Patienten.

Chirurgie, 43. 1972.

8. Duncan, A.W., A.B. Marshall: Diazepam Premeditation and

Awareness During General Anaesthesia for Bronchoscopy and Larnygoscopy. Brit. J. Anaesth., 45. 1973.

9. Linnoila, M.: Effects of Drugs on Psychomotor Skills Related

to Driving: Anticholinergics and Alcohol, Eur. J. Clin. Pharmacol.,

6:107-112, 1973.

10. Baird, E.S., D.M. Hailey: Plasma Levels of Diazepam and Its

Major Metabolite Following Intramuscular Administration. Brit. J.

Anaesth., 45:546-550, 1973.

36
11. Walton, J.G., J.W. Thompson: Pharmacology for the Dental

Practitioner 11. - Relief of Pain: Narcotic Analgesics and Premedication. Brit. Dent. J., 127. 1969.

12. Korttila, K., M. Linnoila: Psychomotor Skills Related to

Driving After Intramuscular Administration of Diazepam and Meperidine. Anaesthesiol. 42:685-691, 1975.

13. Korttila, K., M. Linnoila: Skills Related to Driving After

Intravenous Diazepam, Flunitrazepam or Droperidol. Brit. J.

Anaesth., 46:961-969. 1974.

14. Dundee, I.: Prolonged Amnesic Effect of Lorazepam, presentation to the International Anaesthesist Meeting, Mexico City, 1976.

15. Elliot, C.R.J., R. Green, T.H. Howells: Recovery After

Intravenous Barbiturate Anaesthesia. Comparative Study of Recovery from Methohexitone and Thiopentone. Lancet, 2:68-70, 1962.

16. Korttila, K., M. Linnoila: Recovery and Skills Related to

Driving After Intravenous Sedation: Dose-Response Relationship

With Diazepam. Brit. J. Anaesth., 47:457-463. 1975.

17. Korttila, K., M. Linnoila, P. Ertama, P., S. Häkkinen:

Recovery and Simulated Driving After Intravenous Anesthesia With

Thiopental, Methohexital, Propanidid, or Alphadione. Anestheisol.,

43:283-291, 1975.

18. Fedorova, O.: personal communication.

19. Korttila, K., M. Linnoila, H. Hänninen: in preparation.

20. Doenicke, A., J. Kugler, M. Laub: Evaluation of Recovery and

“Street Finess" by E.E.G. and Psychodiagnostic Tests After Anaesthesia. Can. Anaes. Soc J., 14:567-583. 1967.

21. Linnoila, M.: Effect of Drugs and Alcohol on Psychomotor

Skills Related to Driving. Ann. Clin. Res., 6:7-18. 1974.

22. Linnoila, M., C.W. Erwin, P. Logue, D. Gentry: GenderRelated Effect of Alcohol on Performance and Mood. J. Stud. Alc.

Submitted.

23. Moskowitz, H.: personal communication.

24. Linnoila, M., M. Viukari: Efficacy and Side Effects of

Nitrazepam and Thioridazine as Sleeping Aids in Hospitalized

Psychogeriatric patients. Brit. J. Psychiatr. In press.

25. Klotz, V., G.R. Avant, A. Hoyumpa: The Effects of Age and

Liver Disease on the Disposition and Elimination of Diazepam in

Adult Man. J. Clin. Invest., 55:347-359, 1975.

37
26. Frankenstein, M.: Factors Antagonizing Effects of Alcohol.

Presentation to the 6th International Meeting on Alcohol, Drugs,

and Driving, Toronto. 1974.

27. Korttila, K., M.J. Mattila, M. Linnoila: Prolonged Recovery

After Diazepam Sedation: The Influence of Food, Charcoal Ingestion and Injection Rate on the Effects of Intravenous Diazepam.

Brit. J. Anaesth.. In press.

28. Korttila, K., A. Sothman, P. Andersson: Polyethylene Glycol

as a Solvent for Diazepam: Bioavailability and Clinical Effects

After Intramuscular and Rectal Administration, and Precipitation

from Intravenous Solutions. Acta Pharmacol. et Toxicol., 39:104-

117. 1976.

29. Korttila, K.: Recovery and Skills Related to Driving After

Minor Outpatient Anaesthesia. M.D. thesis, University of Helsinki,

Helsinki, Finland. 1975.

REFERENCES: TRANQUILIZERS

1. Linnoila, M.: Effect of Drugs and Alcohol on Psychomotor

Skills Related to Driving. Ann. Clin. Res. 7:6-18, 1974.

2. Linnoila M.: Tranquillizers and Driving. Act. Anal. Prev.,

8:15-19, 1976.

3. Saario, I.: Effect of Hypnotics or Psychotropic Drugs and

Alcohol on Psychomotor Skills. M.D. thesis, University of Helsinki,

Helsinki, Finland. 1976.

4. Liljequist, R., M. Linnoila, M.H. Mattila, T. Seppälä:

State Dependent Effects of Diazepam on Memory and Psychomotor

Performance. In preparation.

38
GENERAL TRANQUILIZERS

Jane H. Speaker, Ph.D.

SUMMARY

Current methodology for determining plasma levels of diazepam and

its active metabolites employs electron-capture gas chromatography

and can measure 1- to 10-ng quantities (2,15).

When a group of people are administered diazepam at a particular

dose, there is a wide range of plasma concentrations of diazepam

(2,3,6,7,12,15). This range, in 13 subjects administered 15 mg of

oral diazepam daily for a week or more, is 16 to 400 ng/ml (6,15).

Garattini et al. (3) found a range of 10 to 250 ng/ml in 27 subjects given a single 15-mg oral dose. A half-life of 38 to 92

minutes has been measured by this group in five female subjects.

Kleijn et al. (7) calculated a half-life of 20 to 42 hours after 10

mg three times a day, about 0.5 mg/kg/day orally in five subjects.

This great variability in plasma concentration is a major problem

in interpreting drug effects on human performance. Perhaps the

factors that influence plasma concentration curves can be identified and controlled. With seven subjects, Linnoila et al. (11)

showed that ingestion of food increases plasma levels of diazepam

6,7, and 8 hours after intravenous administration of 0.3 mg of

diazepam per kg. They suggest that enterohepatic recycling of

diazepam is occurring. Kleijn et al. (7) had also suggested this

mechanism.

The influence of ethanol on diazepam plasma levels was also studied. In both the Linnoila et al. study (12) and that of Haffner et

al. (5) diazepam levels were higher when alcohol was also given.

By contrast, Linnoila et al. (12) did not see significant alterations in chlordiazepoxide or thioridazine plasma concentrations

after ethanol ingestion.

When diazepam dosage was administered on a body weight basis, great

plasma concentration variations were still usually encountered

(5,12,14). However, Linnoila et al. (11) found much closer agreement in the levels of their seven subjects when both body weight

and food intake were controlled. Unfortunately, the individual

values are not presented in this article, but their standard error

appears from the table to be about ± 20 for values between 300 and

400 ng/ml.

39
The sampling time is important. The peak after oral absorption

occurs 0.5 to 3 hours after administration (2).

Kanto et al. (6) suggest several reasons for believing that diazepam may induce its own metabolism to desmethyldiazepam in man.

They point to the appearance, of high levels of the N-desmethyl

metabolite in the plasma of chronic diazepam users after a single

diazepam dose and to the very low levels seen in control subjects

given the same dose. They also demonstrated a marked drop in the

N-desmethyl metabolite plasma response to a diazepam dose after

abstinence from diazepam in a chronic user. They present evidence

that patients who have been taking diazepam for periods of months

or years have lower plasma levels than those who have been on

diazepam a few weeks, and show in a series of eight patients that

after 1 to 6 weeks on 15 mg/day orally, there is a fall in plasma

diazepam levels. Enzyme induction cannot explain the great variations seen in plasma diazepam levels because the N-desmethyl metabolite concentrations vary as much or more than the diazepam levels

and generally are higher when diazepam levels are higher and lower

when diazepam levels are lower (6,7,15).

Diazepam binds to protein (7). Relatively little diazepam can be

recovered from hemolyzed red blood cells (15). The proportion of a

diazepam dose bound to tissue may be a critical factor in the

variability of plasma levels. Interestingly, Zingales (15) finds

low levels of the N-desmethyl metabolite in erythrocytes after

cessation of diazepam administration and at a time when there is no

longer a measurable plasma level of diazepam or its metabolites.

As with diazepam, a given dose of chlorpromazine produces a wide

range of plasma levels (1). Ingestion of food may alter the

chlorpromazine plasma concentration. Fasting may result in rapid

attainment of high plasma levels when chlorpromazine is subsequently

administered orally. Since this effect is not always obtained, the

authors suggest that residual food from a previous meal may be

interfering with rapid absorption of the drug. Curry et al. (3)

also present evidence for phenobarbital induction of increased

metabolism of chlorpromazine. They found, in addition, that only

about 1 percent of a l-g oral chlorpromazine dose was excreted in

urine and feces. This study covers many ideas and presents a

number of kinds of measurement. It suffers from a lack of numbers

of subjects . In most cases the plasma levels represent measurements on only a single individual.

Cordon (4) reports that diazepam can produce the classic effects of

addiction: tolerance, phychic dependence, and physical dependence.

He presents only one case, but that is sufficient to demonstrate

the matter.

Kleinknecht and Donaldson (8) review 23 articles which present data

on the effects of diazepam on cognitive and psychomotor performance. They organize the many tests employed into groups according

to the attributes they believe the tests to measure. They suggest

that there is need to control and/or analyze for age, sex,

40
personality (e.g., introversion vs. extroversion), and subject

population (e.g., student vs. mental patient). Three of the articles reviewed by Kleinknecht and Donaldson are represented in the’

present summary (5,9,14). Two additional articles dealing with the

effects of tranquilizers and ethanol on simulated driving performance are added to the present survey (10,13).

Haffner et al. (5), Mørland et al. (14), Linnoila (10), and Loomis

(13) have shown that diazepam (5,10,14), chlordiazepoxide (10),

thioridazine (10), haloperidole (10), flupenthixole (10), chlorpromazine (13), secobarbital (13), and meprobamate (13) in therapeutic

doses can impair human performance in complex tests like simulated

driving. Similarly, alcohol can impair this performance. When

tranquilizers and ethanol are administered to the same subject,

complex performance is impaired to a greater degree (10,13,14).

When separate elements of a complex task are looked at individually

or tests for less complex behavior are administered, there is less

consistency in the data (5,9,10,14). With ethanol and diazepam,

performance on some elements of simulated driving was improved over

that with placebo and lower doses of the same agent (10).

Lawton and Cahn (9) found only slight impairment with diazepam on

three of five less complex psychomotor tests. Their oral dosage

regimen was 5 mg three times a day for 3 days prior to testing and

5 mg just before testing on the morning of the fourth day. The 20

subjects also took 3 ounces of 100-proof vodka in grape juice or

pure grape juice just before testing. Alcohol did not impair

performance on these tests nor did it further increase the effect

of diazepam. No drug concentrations were reported. The blood

ethanol concentrations varied widely, from 68 to a surprising 140

mg/100 ml, and the change in concentration in 3 hours exceeded 60

mg/100 ml in every case. The average change was 82 mg/100 ml or

over 27 mg/100 ml/hour, far too high to be consistent with values

of 15 to 20 mg/100 ml/hour usually reported. There seems to have

been a problem with the method of analysis, although other possibilities include improper storage before analysis and wide variations in sampling times.

COMMENT

It is difficult to interpret the relation of diazepam plasma levels

to behavioral responses because of the great variation in concentrations achieved with any particular dose. Food and alcohol

intake patterns contribute to the variation.

There are some problems with the entire group of five behavioral

studies (5,9,10,13,14). All the subjects were healthy young males.

No attempt was made to identify individuals suffering from anxiety.

There seems to be great difficulty in designing or selecting tests

for the mental and psychomotor elements of complex tasks. For

instance, critical flicker-fusion frequency tests are very sensitive to diazepam effects, but the relationship of the test performance of complex human tasks is not obvious, In addition, either no

41
plasma levels of the tranquilizers were measured (9,10,13) or

large variations were reported among the subjects (5,14).

However, these are careful studies. Haffner et al. (5) and Mørland

et al. (14) presented a large range of mental and psychomotor

tests, and their use of two diazepam dose levels permits delineation of the threshold for drug effects. All of the papers reviewed

here report the use of placebos, and in all but one (10), ethanol

blood levels were measured. Different subjects were used for each

test (10,13) or a randomized rotation procedure was used with at

least a week between testing procedures (5,9,14).

REFERENCES

1. Curry, S.H., J.M. Davis, D.S. Janowsky, J.H.C. Marshall:

Factors Affecting Chlorpromazine Plasma Levels in Psychiatric

Patients. Archives of General Psychiatry, 2:209-215, 1970.

2. DeSilva, J.A.F., I. Bekersky, C.V. Puglisi, M.A. Brooks, R.E.

Weinfeld: Determination of 1,4-Benzodiazepines and -Diazepin-2-

Ones in Blood by Electron-Capture Gas-Liquid Chromatography.

Analytical Chemistry, 48:10-19, 1976.

3. Garattini, S., F. Marcucci, P.L. Morselli, E. Mussini: The

Significance of Measuring Blood Levels of Benzodiazepines. In:

Biological Effects of Drugs in Relation to Their Plasma Concentrations. D.S. Davies and B.N.C. Prichard, eds., University Park

Press, Baltimore, 1973, pp. 211-225.

4. Gordon, E.B.: Addiction to Diazepam (Valium). British Medical

Journal, 1:112, 1967.

5. Haffner, J.F.W., J. Mørland, J. Setekleiv, C.E. Strømsaether,

A. Danielsen, P.T. Frivik, F. Dybing: Mental and Psychomotor

Effects of Diazepam and Ethanol. Acta Pharmacol. et Toxicol.,

32:161-178, 1973.

6. Kanto, J., E. Iisalo, V. Lehtinen, J. Salminen: The Concentrations of Diazepam and Its Metabolites in the Plasma After an Acute

and Chronic Administration. Psychopharmacologia, 36:123-131.

1974.

7. Kleijn, E. van der, J.M. van Rossum, E.T.J.M. Muskens, N.V.M.

Rijntjes. Pharmacokinetics of Diazepam in Dogs, Mice, and Humans.

Acta Pharmacol. et Toxicol. 21 (Suppl. #3):109-127, 1971.

8. Kleinknecht, R.A. and D. Donaldson: A Review of the Effects of

Diazepam on Cognitive and Psychomotor Performance. J. Nerv. Ment.

Dis., 161:399-414, 1975.

9. Lawton, M.P. and B. Cahn: The Effects of Diazepam (Valium) and

Alcohol on Psychomotor Performance. J. Nerv. Ment. Dis., 136:550-

554. 1963.

42
10. Linnoila, M.: Effects of Diazepam, Chlordiazepoxide, Thioridazine, Haloperidole, Flupenthixole and Alcohol on Psychomotor

Skills Related to Driving. Annales Medicinae Experimentalis et

Biologiae Fenniae, 51:125-132, 1973.

11. Linnoila, M., K. Korttila, M.J. Mattila: The Effect of Food

and Repeated Injections on Diazepam Serum Levels. Acta Pharmacol.

et Toxicol, 36:181-186. 1975.

12. Linnoila, M., S. Otterstrom, and M. Anttila: Serum Chlordiazepoxide, Diazepam and Thioridazine Concentrations After the Simultaneous Ingestion of Alcohol or Placebo Drink. Annals of Clinical

Research, 6:4-6. 1974.

13. Loomis, T.A.: Effects of Alcohol on Persons Using Tranquilizers. In: Alcohol and Road Traffic, Proceedings of Third International Conference on Alcohol and Road Traffic, J.D.J. Harvard,

ed., London, Sept. 3-7, 1962, British Medical Association, 1-4,

1963.

14. Mørland, J., J. Setekleiv, J.F.W. Haffner, C.E. Strømsaether,

A. Danielsen, and G. Holst Wethe: Combined Effects of Diazepam and

Ethanol on Mental and Psychomotor Functions. Acta Pharmacol. et

Toxicol., 34:5-15. 1974.

15. Zingales, I.A.: Diazepam Metabolism During Chronic Medication.

Unbound Fraction in Plasma, Erythrocytes and Urine: J. Chromatogr.,

75:55-78. 1973.

43
OPIATES

MINOR TRANQUILIZERS

Morton F. Mason, Ph.D.

SUMMARIES AND COMMENTS

STUDY: Gordon, N.B. Reaction Times of Methadone-Treated Heroin

Addicts . Psychopharmacologia, 16:337-344. 1970.

Site: Rockefeller University and Yeshiva University, New York

City, New York.

Subjects: The subjects were divided into six groups. Groups 1

and 3 both had been maintained for at least 1 year on methadone

for the treatment of heroin addiction. Group 1 had 18 males whose

average age was 32.5 years; group 3 had 9 females whose average

age was 33.5 years. Group 2 consisted of 20 unpaid male volunteers

who did not use drugs; they averaged 32.5 years. The participants

in groups 4 and 5 had recently withdrawn from narcotic drugs. The

20 males in group 4 averaged 31.5 years and had withdrawn 14 days

earlier. The 19 males in group 5 averaged 30 years and had withdrawn 4 days earlier. Group 6 consisted of 9 females whose average

age was 23 years. They were paid volunteers from the nonprofessional

hospital staff, and did not use drugs.

Method: Measurements were taken under controlled laboratory

conditions; urines were tested (details were not given) for drugs

to assure conformity to group. Variations of reaction time were

tested in a button-pressing situation: (a) simple reaction time

(one of six stimuli); (b) multiple discrimination/multiple response

(one of six stimuli for one of six responses); (c) multiple discrimination/single response (one of six discrimination presented in

random spatial and temporal order, with single response). A

diagram of the instrument used was provided. The digit 1 readout

was sequestered from the subject and a noise level was introduced

to obscure instrumental sounds which might be used by the subject

to his advantage.

Dosage: Subject group 1 (males) received 100 mg of methadone per

subject per day for a year or more. Subject group 5 was composed

of females, who also received 100 mg of methadone per subject per

day for a year or more. The other subject groups received no

drugs: group 2 had males who were not drug users; group 3 had

persons withdrawn from drugs for 14 days; group 4 had males withdrawn from drugs 4 days prior to testing; and group 6 had females

44
who were not drug users--paid volunteers from nonprofessional

hospital staff.

Results: The subjects receiving methadone had shorter reaction

times an did the others to the tests administered. 'Ihe results

were statistically significant except in the cases of the 4-day

and 14-day detoxified groups.

Comment: The findings would be much more significant if, following

the original observations, closed- and/or open-course driving tests

had been made along with simulator tests such as tracking, tests

involving divided attention, etc.

STUDY: Kiplinger, G.F., G. Sokol, and B.E. Rodda. Effect of

Combined Alcohol and Propoxyphene on Human Performance.

Int. Pharmacodyn., 212:175-180. 1974.

Arch.

Site: Lilly Laboratory for Clinical Research, Marion County

General Hospital and Indiana University School of Medicine,

Indianapolis, Indiana.

Subjects: Eight medical and graduate students and others participated and were paid for their services. Essentially no information

was provided regarding sex, age, size, driving history, and their

general state of health and lifestyle was self-assessed.

Method: Subjects were asked to refrain from taking CNS-affectant

drugs (except for tobacco) for 24 hours prior to testing. The

purpose of the tests was explained to them and they fasted for

6 hours prior to drug administration. Combinations of alcohol,

propoxyphene, and control placebos were administered in four

treatment sequences that followed a randomized block design; each

subject received all treatments in the course of the experiments.

Testers used double-blind technique under controlled laboratory

conditions. Parameters of measurement included: (a) four pursuit

meter patterns (as described by Forney et al.); (b) four conditions

of standing stability (described by Shipley and Harley); and nine

verbal tests (using DAF measurements also described by Forney et

al.).

Dosage: Mixed in an iced pineapple-grapefruit beverage, alcohol

was given at 15 ml ethanol per 50 lb body weight, a dose designed

to produce a concentration of about 0.05% v/v in 60 minutes when

30 minutes was taken for ingestion. The alcohol placebo was iced

beverage alone. Subjects received propoxyphene as a 65-mg capsule,

its placebo being starch and talc. The capsule was swallowed at

the start of each experiment so that the peak plasma concentration

could be expected to occur during the experimental period.

Results: The data were statistically evaluated. Very little

difference was found between the modest impairing effects of

ethanol and those of propoxyphene at the doses given. Dosage with

both drugs produced moderate additive impairments. There was no

evidence for interaction.

45
Comment: It would have helped to have studied doses considered

"abuse" quantities. Also, closed-course driving might have yielded

more evidence of significant impairments.

STUDY: Linnoila, M., and M.J. Mattila: Drug Interaction on

Psychomotor Skills Related to Driving: Diazepam and Alcohol.

Europ. J. Clin. Pharmacol., 5:186-194. 1973.

Site: Department of Pharmacology, University of Helsinki,

Helsinki, Finland.

Subjects: The four hundred volunteers (371 males, 29 females)

were comprised of medical students, technical students, and cadets.

A brief history was taken to exclude subjects suffering from

diseases or taking drugs. (Caffeine and tobacco were not specifically mentioned as being exclusionary, but coffee and "drugs" were

stated as excluded "during the tests.") The mean age of the

subjects was 22 years (S.D. = 2.8 years). The subjects were

divided into 20 groups of 20 subjects each which were similar in

sex, age, weight, educational level, and district of residence.

Driving experience was not mentioned. Results of only 10 of the

test groups are reported in this article.

Method: The research was experimental, under controlled laboratory

conditions, using double-blind technique. Coding was changed

daily, and 10 subjects were tested each day. Before any administration of drugs and drink, the subjects were instructed in the

test procedures and apparatus by the same person in the same way.

Each subject was tested 30, 90, and 150 minutes after taking

capsules.

The groups tested were as follows:

No drug, no drink

Placebo + capsule + placebo drink

Diazepam(5 mg) + placebo drink

Diazepam(10 mg) + placebo drink

Placebo capsule + alcohol(0.5 g/kg)

Placebo capsule + alcohol(0.8 g/kg)

Diazepam(5 mg) + alcohol(0.5 g/kg)

Diazepam(10 mg) + alcohol(0.5 g/kg)

Diazepam(5 mg) + alcohol(0.8 g/kg)

Diazepam(10 mg) + alcohol(0.8 g/kg)

Zero group

Placebo group

D5 group

D10 group

A5 group

A8 group

D5 A5 group

D10 A5 group

D5 A8 group

D10 A8 group

Several parameters of measurement were employed, one being a

commercially available choice reaction testing instrument. Subject

reacted to three different light stimuli by pushing one or both of

two foot pedals. They also had to push a button responding to a

low pitched sound and not react to a higher pitched sound. The

test totaled 36 stimuli normally requiring 54 seconds. Cumulative

reaction time was recorded along with incorrect responses.

A commercially available coordination tester was used twice in

each test, (I) at a fixed speed and (II) at an optimum speed

46
chosen by the subject. The test was a tracking task to keep a

black ball on a track by means of a steering wheel. Coordination

test I lasted 30 seconds; test II lasted 30 to 80 seconds depending on the subject. A cumulative mistake percentage of total

track length was calculated for I. The driving time was recorded

in II.

Subjective examinations included: (a) subjects grading their own

performances on scale of 1 (very good) to 5 (very bad); and (b)

subject statements of what treatment they believed they had

received.

In another test, blood alcohol levels were determined by ADA and

Widmark methods for 20 medical students not used in tests, after

they ingested 0.5 g/kg alcohol (10 students) and 0.8 g/kg (10

students) . Five of both groups also took 10 mg of diazepam and

the other five received placebos.

The results for all tests were adequately evaluated statistically.

Dosage: Diazepam was administered in 5-mg capsules, with lactose

capsules as placebos. Alcohol, a bitters solution containing 28

percent alcohol, was blended w/v with one-third volume of water,

using nonalcoholic bitters as placebo. The amounts were adjusted

to 0.5 g and 0.8 g/kg, and drinks were cooled to 8° to 10° C.

Results: The zero and placebo groups estimated their performances

as slightly lower than normal. Psychomotor variables of the

placebo group were slightly impaired compared to the zero group.

Group A5 psychomotor variables were slightly improved compared to

those of the zero group, but only the reaction time at 30 minutes

was statistically significant. At 30 minutes, the A8 group reaction

times were also slightly shorter than those for the zero group and

statistically significant. The driving times of the A8 group were

longer than those for the zero group.

Subjects in the A5 group considered their performances good, but

actually were found to be slightly (but not significantly) impaired,

except for a moderate prolongation of driving time. No significant

difference was found between the D5 and A5 groups. The D10 group

believed their performance was improved and they actually were

slightly improved, although driving time was prolonged at 30 and

90 minutes. No significant difference was found between the D10

and A8 groups.

The D5 A5 group showed slight impairment in coordination test I

and increased driving time compared to the zero group, and they

were more impaired than the A5 or A8 groups. Subjects in the D10

A5 group were more impaired than those in the A5 group. ‘Ihe

difference was greater between the D10 A5 and A8 groups, and the

D10 A5 group members were more impaired than those in the D10 group.

The D5 A8 group was more impaired than either the zero group or

the A8 group. Likewise the D5 A8 group was more impaired than the

47
D10 group. The D10 A8 group was also more impaired than the zero

group or the A8 group. Comparison of D10 A8 with D10 showed

greater impairment by the former group.

The discussion of these complex combinations of results indicated

with diazepam alone, psychomotor test performances were somewhat

improved after either 5- or long doses. Slight improvements were

also noted after alcohol ingestion in the amounts given. Combinations of both drugs impaired psychomotor performance. It was

also concluded (on the basis of unpublished data obtained by the

authors) that alcohol accelerates the absorption of diazepam.

In a discussion of the relation of the findings to "real world"

driving, the authors stated that coordination test I most strongly

correlated with actual driving. Subjects in this test did not

show improvement after single drug administration, and furthermore

were the first to show impairment after taking drug combinations.

It is likely that in "real world" driving, too, improvement does

not occur after such single drug doses, and that psychomotor skills

while driving would be impaired by the interaction of combined

drugs, as they were in test I.

Comment: The detailed presentation and accompanying discussion

indicates the complexities involved in studying the effects of

alcohol and other drugs on driving, and their interactions. In

this paper, minor impairments by combinations of diazepam and

alcohol at modest dosages are demonstrated. Single drug effects

showing improvement rather than impairment with 5- and 10-mg

dosages are shown and then essentially discounted by the authors.

From a medicolegal standpoint, initial studies involving obvious

abuse-dosages of drugs would be of much greater value.

STUDY: Landauer, A.A., G. Milner, and J. Patman. Alcohol and

Amitriptyline Effects on Skills Belated to Driving Behavior,

Science, 163:1467-1468. 1969.

Site: Department of Psychology, University of Western Australia,

Nedlands, Western Australia and Mental Health Services of Western

Australia, Claremont Hospital, Claremont, Western Australia.

Subjects: The subjects were healthy medical students (18 men, 3

women) with a mean age 22.1 years (S.D. = 1.15). None of the

subjects were taking any medication and none had a recent illness.

They were divided into three groups of six men and one woman each.

Method: Testing was performed under controlled laboratory conditions, double-blind. It began 2 hours after the second issue of

tablets (see Dosage). After completion of first series of tests,

subjects drank their preferred beverage over a period of 30 to

45 minutes in amounts calculated to bring their blood alcohol

concentrations to 0.08% w/v. Fifteen minutes later, a Breathalyzer test was administered and the performance tests were

repeated. After a meal, the subjects were medically examined,

48
filled out a questionnaire, and were taken home. All data were

statistically evaluated by analysis of variances.

Parameters of measurement included a simulated driving test, a dot

tracking test, and a pursuit rotor test. The simulated driving

test employed the Gibbs variant of tracking, in which the subject

is required, by means of a steering wheel, to move a pointer in

line with one of five horizontal lights that flash on for 1.27

seconds in random order. The test lasts 12 minutes but only the

last 150 seconds are scored, making it a good measure of fatigue.

A one-way screen separates the subject from the recorder and

observer. The proportion of errors to total recorded responses

made is used to score the test.

In the dot tracking test, a continuous line must be drawn between

dots arranged in an irregular spiral pattern. Scoring is based

on number of dots tracked accurately. The pursuit rotor test

allows 2 seconds for practice, then gives 10 trials of 10 seconds

duration each, with a 28-second interval between trials. Responses

are electrically recorded and scored on the basis of time on the

target.

on the night before the test and on the morning of next day prior

Dosage: Group A received amitriptyline (0.8 mg/kg) in tablet form

to testing--i.e., at a 12- to 15-hour interval. Group B received

a placebo at night and amitriptyline the next morning; and group

C was given placebo tablets both the night before and the morning

of testing.

Results: For simulated driving, when subjects were sober, there

was no difference in performance among the three groups. With

alcohol, there was no increase in errors by the double placebo

group (group C) but errors were increased in groups A and B, which

received amitriptyline. For dot tracking, essentially the same

results were obtained. The improvement with practice was overcome

by the presence of amitriptyline. There were similar decrements

in performance in the presence of amitriptyline in the pursuit

rotor task.

Comment: It had earlier been found that after several days on

medication, driving skills were not significantly further decreased

by interaction of amitriptyline with alcohol. Hazardous interaction may occur, however, during the first 2 days of medication

with amitriptyline.

It would have been useful to have studied the interaction of the

drugs at abuse dosages with alcohol; i.e., those leading to blood

concentrations of 0.10 to 0.25% w/v.

STUDY: Clayton, A.B., T.A. Betts, and G.M. Mackay. A Study

of the Effects of Certain Tranquilizers and Small Amounts of

Alcohol on Driving Performance. European J. Toxicol., 5:254-257.

1972.

49
Site: Departments of Transportation, Environmental Planning, and

Psychiatry, University of Birmingham, United Kingdom.

Subjects: The 50 males and 50 females were mostly students, the

mean age being 28.1 years. Their driving experience varied, and

none normally took prescribed psychotropic medications.

Method: Subjects performed closed-course driving-tests under

controlled conditions. They were generally tested in groups of

six, using a fixed routine.

On Wednesday afternoon, subjects practiced for 1 hour on all

driving tests at the driving site. They then received two unmarked bottles--one containg five drug tablets, the other five

placebo tablets--along with directions of how and when to take

them. (Both bottles used by the control group contained placebos.)

One bottle was to be used first--one tablet Friday evening; three

on Saturday (at intervals); and the fifth Sunday morning. Random

double-blind administration techniques were used. On Sunday

morning, subjects performed three runs on test 1, three runs on

test 2, and five runs on test 3 (all described below). They

received an objective assessment rating and answered a subjective

questionnaire derived from Reisby and Theilgaard. After this

they were given ethanol (0.5 g/kg) in flavored sugar base, to be

drunk within 10 minutes. One hour later, the BAC was determined

with a Breathalyzer and the testing procedures were repeated.

The following Wednesday, another practice session was held. From

Friday to Sunday, subjects took the drugs in the second bottle,

whereupon the testing cycle was repeated. Methods of scoring were

accurately described.

Subjects drove a Ford 'Escort Saloon,"' 2.98 meters long, Test 1

involved driving the vehicle around posts 5.97 meters apart in a

straight line and then reversing back around the posts to the

starting point. Test 2 required parking between two boards 5.97

meters apart and getting as close to the curb as possible, Test

3 measured gap estimation. Subjects were required to estimate a

minimum distance between sets of posts through which they could

drive and then to drive through the chosen gap.

Dosage: The drugs were administered in amounts approximately

equal to the usual clinical doses: chlordiazepoxide, a benzodiazepine, 10 mg; amobarbital, a barbiturate, 30 mg; trifluoperazine, a phenothiazine, 2 mg; haloperidol, a butyrophenone, 0.5

mg; and alcohol, when given, 0.5 g/kg.

Results: Except for haloperidol, the drugs did affect driving

performance. An analysis of results was done using a split-plot

analysis of variance for each drug group for male and female

subjects separately. Little evidence of alcohol-drug interaction

was obtained, probably because of the low concentration of alcohol

and chronic administration of drugs.

50
Some differences between men and women were found in tests in which

skills were affected. The impairments were statistically significant, but were not detected by the subject or by objective clinical

assessment. Physicians are advised to warn patients of these

driving dangers, especially during early stages of medication.

Comment: This report is hard to follow, but its design seems

acceptible. Insufficient information on statistical data analysis

is supplied. Essentially, we are left with the statement that the

ratio of significant results to nonsignificant results exceeded

1:20, and that all drugs (even haloperidol) showed at least one

significant effect.

The work would have been much more useful if further data with

much higher alcohol concentrations had been obtained.

STUDY: Betts, T.A., A.B. Clayton, and G.M. Mackay. Effects

of Four Commonly Used Tranquilizers on Low Speed Driving Performance Tests. Brit. Med. J., 4:580-584. 1972.

Site: Departments of Psychiatry and Transportation and Environmental Planning, University of Birmingham, Birmingham, United

Kingdom.

the first 13 of whom were used in a pilot study testing vehicle

Subjects: There was a total of 113 volunteers, mostly students,

handling techniques. They ranged in age from 18 to 30 years,

and were free from medical or psychiatric problems. All had

valid drivers licenses. Further information regarding driving

experience was obtained during the testing.

Method: The 100 nonpilot subjects (50 men, 50 women) were divided

into five groups for testing and data analysis: (1) chlordiazepoxide vs. placebo; (2) haliperidol vs. placebo; (3) amobarbital

vs. placebo; (4) trifluoperazine vs. placebo; and (5) placebo vs.

placebo.

The subjects were tested in groups of six every 2 weeks, with

double-blind, randomized administrations. The fixed test procedure was to have the subjects who would be tested during a given

fortnight come to a closed-course driving site on Wednesday

afternoon. They were given (1) a visual screening test; (2) an

Eysenck Personality Inventory; (3) a biographical and driving

history questionnaire giving age, occupation, driving experience,

mileage, accidents, convictions, and car ownerships; (4) a

subjective feeling questionnaire, and (5) an objective assessment.

Then, after a few minutes driving the vehicle to be used, they

were given an instruction sheet and had a practice session: test

1, 6 runs; test 2, 4 runs; test 3, 3 runs; test 1, 6 runs (see

below). At that point each subject was given two bottles containing the appropriate drugs, with instruction on how and when to

take them.

51

231-545 O - 77 - 5
They returned to the driving site on Sunday morning, and after

completing a subjective questionnaire and having an objective

assessment, they completed the driving test: test 1, 3 runs;

test 2, 3 runs; test 3, 5 runs. They were then given alcohol in

a flavored sugar base, 0.5 g/kg. An hour later, they completed

the subjective feeling questionnaire, again took the objective

assessment test, and were tested on a Breathalyzer, whereupon the

three driving tests were repeated.

The following Wednesday the original procedure was repeated, the

second bottle of drugs was taken as directed, and on Sunday the

rest of the entire procedure was repeated.

For the three road tests, subjects used a Ford Escort Saloon, 13

ft 0.6 in. long. Test 1 involved driving a zigzag course between

five posts set one and one-half times the length of the car and

then, in reverse, returning to original starting position. For

test 2, subjects parked between two boards set across a curb at

a distance from each other of one and one-half times the length

of the car. Only three movements were permitted: forward, backward toward the curb, and forward to line up parallel with the

curb. Test 3 was a gap estimation test. A gap created by movable

posts was adjusted upon instruction from the driver to the minimum

gap through which he thought he could drive the car.

Scoring of the measurements was adequately described, and the

results were statistically evaluated. When alcohol was administered, the mean blood alcohol concentration achieved was close

to 0.05% w/v.

Dosage: Each of four drugs--chlordiazepoxide, 10 mg; amobarbitol,

30 mg; trifluoperazine, 2 mg; and haloperidol, 0.5 mg--was given

five times over a 36-hour period. All drugs and placebos were

prepared as similar white tablets.

Results: All drugs except haloperidol significantly impaired

response to one or more of the driving tests to a 5 percent

significance level. There was no certain evidence for interaction

with alcohol, perhaps because of the low blood alcohol concentrations reached. Objective assessment showed haloperidol had a

significant depressing effect, whereas amobarbital caused a slight

euphoria. In evaluating themselves, the subjects felt that none

of the drugs had any effect. With alcohol, the subject taking

haloperidol felt "'worse," whereas those taking amobarbital had a

subjective stimulating feeling.

Comment: The measurements made in tests 1, 2, and 3 are more

relevant to real-world driving than are the frequently reported

tests under controlled laboratory conditions. It would seem

preferable to have made tests with subjects taking the drugs at

true "abuse" levels, and when alcohol was administered to have

some groups attain common "real-world" blood alcohol concentrations of the order of 0.1 to 0.25% w/v.

52
STUDY: Patman, J., A.A. Landauer, and G. Milner. The Combined

Effect of Alcohol and Amitriptyline on Skills Similar to Motor Car

Driving. Medical J. of Australia, 2:946-949. 1969.

Site: Department of Psychology, University of Western Australia

and Claremont Hospital, Nedlands, Western Australia.

Subjects: Subjects were healthy volunteers over 21 years of age--

12 men and 12 women whose mean age was 26.0 (S.D. about 6.0). They

did not show histories of illnesses and were not on medication.

Method: Measurements were taken under controlled laboratory conditions, using double-blind techniques; results were evaluated by

statistical analysis of variance. The subjects were divided into

four equal groups and the individuals completed a battery of psychomotor tests on three consecutive mornings. Groups 1 and 2 were

given the active drug and groups 3 and 4 received a placebo. The

effects of alcohol were tested by giving groups 1 and 3 alcohol

at the second testing session (fourth day of drug administration)

and placebo alcohol at the third session (fifth day of drug

administration). Groups 2 and 4 received their placebo alcohol

at the second testing session and alcohol at the third testing

session. The testing sessions for each subject were on the third,

fourth, and fifth days of medication. Testing sessions involving

alcohol were given to half the subjects on the fourth day and the

other half on the fifth day.

The tasks consisted of a short clerical test (ACER, 1967); a dot

tracking test; a pursuit rotor test; and a simulated driving

test. The latter three are described in the other Landauer et al.

study reviewed earlier in this report.

The tablets for groups 1 and 2 were amitriptyline; those for groups

Dosage: Each subject received tablets every day for five days.

3 and 4 were placebo. On day 1, the dosage was two tablets.

Subjects each received four tablets, spaced, on days 2, 3, and 4.

On day 5, the dosage was again two tablets. In addition, each

group was given both alcohol and placebo: group 1 - alcohol on

day 4, placebo on day 5; group 2 - placebo on day 4, alcohol on

day 5; group 3 - alcohol on day 4, placebo on day 5; and group 4 -

placebo on day 4, alcohol on day 5.

Results: Amitriptyline caused no effects on performance. Some

decrement of performance was found due to alcohol in the pursuit

rotor and simulated driving tests. No evidence for interaction

with amitriptyline was found.

Comment: The findings support earlier ones that impairment from

Interaction of alcohol with amitriptyline is more apt to be

observed during the first 2 days of administration, and that the

impairment decreases with time. It would have been worthwhile

to have had data in which the alcohol and drug doses were increased

to "abuse" quantities, to see if their interaction persisted.

53
STUDY: Seppala, T., M. Linnoila, E. Elonen, M.J. Matilla, and

M.Maki. Effect of Tricyclic Antidepressants and Alcohol on

Psychomotor Skills Related to Driving. Clin. Phann. Therap.,

17:515-522. 1975.

Site: Department of Pharmacology, University of Helsinki,

Helsinki, Finland.

Subjects: The 40 student volunteers were of normal weight, 20 to

25 years old. All used alcohol occasionally; none had a history

of mental disorder.

Method: The experiments were laboratory controlled, with doubleblind cross over arrangements. Test groups were co&d as follows.

For trial I--dosage daily for 2 weeks:

Placebo drug, placebo drink

Placebo drug, alcohol

Amitriptyline, placebo drink

Amitriptyline, alcohol

Doxepin, placebo drink

Doxepin, alcohol

For trial II--dosage daily for 2 weeks:

Placebo drug, placebo drink

Placebo drug, alcohol

Chlorimipramine, placebo drink

Chlorimipramine, alcohol

Nortriptyline, placebo drink

Nortriptyline, alcohol

P Group

A Group

AMI group

AMI-A group

D group

D-A group.

P group

A group

CIP group

CIP-A group

N group

N-A group.

Testing sessions were on the 7th and 14th days of treatment.

Measurement parameters consisted of: (1) subjective assessments;

(2) psychomotor tests at 30, 90, and 150 minutes after ingestion

of the drug and beverage; (3) a tyramine pressor test initially

and on 14th day of every treatment; (4) a choice reaction test;

(5) two coordination tests; and (6) an attention test (not

described). Measurements (1), (4), and (5) were the same as

those described in the Linnoila and Mattila study reviewed earlier

in this report.

Dosage: Gelatin capsules, lactose placebo, amitriptyline, doxepin,

and nortriptyline, 10 mg each, were administered three times per

day for 7 days. The doses of chlorimipramine were 10 mg three

tiües per day for 7 days and 25 mg three times a day for the next

7 days.

Alcohol was administered in an alcoholic bitters solution (placebo

being bitters without alcohol) before psychomotor testing, at a

dose of 0.5 g alcohol/kg body wt.

54
Results: The tyramine test showed a decreased response with time,

indicating an antityramine effect from antidepressants. None of

the drugs alone importantly impaired psychomotor skills. When

combined with alcohol, doxepin and amitriptyline exhibited some

interaction, but no clear-cut interaction was demonstrated with

nortriptyline or chlorimpramine.

Comment: The results do not seem to support the statement in the

abstract that doxepin and amitriptyline, at the dosages given in

combination with 0.5 g/kg alcohol, may be especially dangerous in

driving. The effects actually appear to be slight. It would help

if tests were also made at abuse dosages of the drugs, and

especially with abuse concentrations of alcohol. In the United

States, persons charged with driving while intoxicated rarely have

blood alcohol concentrations indicating that their alcohol dosage

had been on the order of 0.5 g/kg.

STUDY: Huffman, W.J., A.E. Florio, J.L. Payne, and F.E. Bays.

The Influence of Two Selected Tranquilizers on Driving Skills.

Amer. J. Psychiatry, 119:885-886. 1963.

Site: Department of Health and Safety Education, University of

nois, Urbana, Illinois.

Subjects: Twenty-five young adults participated--15 men, with a

mean age of 22.5 years, and 10 women, whose mean age was 20.5 years.

They had normal health histories, possessed valid drivers licenses,

and were familiarized with the test procedures.

Method: This study consisted of a controlled laboratory experiment

and three driving tests, all double blind and counterbalanced in

design. Each subject served as his own control. Hydroxyphenamate

("Listica”) and meprobamate were compared with a placebo. For

Phase I, subjects were tested after “normal” doses of the two drugs

vs. placebos. Phase II occurred when, after about a month, the

subjects were again tested, this time with double the dosage of

drugs.

Sixteen measurements were made on each subject on six separate

occasions: the first two after placebo; the third after hydroxyphenamate, 200 mg; the fourth after hydroxyphenamate, 400 mg; the

fifth after meprobamate, 400 mg; and the sixth after meprobamate,

800 mg.

Subjects were tested for (1) reaction time; (2) hand steadiness;

(3) visual acuity (both eyes); (4) acuity, right eye; (5) acuity,

left eye; (6) stereo (depth) perception; (7) color perception;

(8) vertical deviation; (9) lateral deviation; (10) near visual

acuity, both eyes; (11) near acuity, right eye; (12) near acuity,

left eye; (13) near lateral deviation; (14) reaction time distance;

(15) braking distance; and (16) total stopping distance. The last

three tests involved use of an automobile. Data significance was

assessed by means of t tests.

55
Dosage: The Phase I dosage was 200 mg of hydroxyphenamate and

400 mg of meprobamate; for Phase II, dosages doubled. The tablets

were administered 1 hour before testing and tests were completed

by 2 hours. (No interaction with alcohol was studied.)

Results: The 96 tests showed five significant effects. In Phase

I, visual acuity of the right eye improved after hydroxyphenamate

compared to placebo; visual acuity in the left eye improved after

hydroxyphenamate compared to meprobamate. In Phase II, reaction

time increased after meprobamate compared to placebo. Acuity

(both eyes) diminished after hydroxyphenamate compared to placebo,

and near acuity (both eyes) diminished after meprobamate compared

with placebo.

Comment: The data seem clear-cut and are very simply presented,

as compared to many other reports. The relevance of the 16

measurements to real-world driving, however, is questionable. In

any event, one would surmise that in other tests of the effects

of these two drugs at the two dosages given, there would not be

much impairment.

STUDY: Landauer, A.A., and G. Milner. Desipramine and Imipramine

Alone and Together with Alcohol in Relation to Driving Safety.

Pharmacopsychiatric Neuropsychopharmakologia, 4:265-275. 1971.

Site: Department of Psychology, University of Western Australia,

and Mental Health Services of Western Australia.

Subjects: Twenty-seven medical students served as paid experimental subjects. Their mean age was 23.1 years (S.D. = 1.5), and

mean weight was 73.7 kg (S.D. = 8.7).

Method: In this controlled laboratory study, the subjects were

randomly divided into three groups of nine each. The three groups

received either imipramine, desipramine, or placebo, the drugs

being administered in tablet form, one at night before the experiment and the second on the morning of the experimental day--i.e.,

at a 12- to 14-hour interval. Alcohol was diluted with lime

juice, syrup, and water and had to be drunk in less than 15 minutes

Subjects were required not to drink alcoholic beverages on the day

before the test. On test day, after a light breakfast, a medical

examination, and the second tablet dose, they were asked to

complete a questionnaire rating themselves on their present state,

and on anything felt or experienced since taking the first tablet.

When 25 minutes had elapsed (for absorption) they were given motor

skill tests in random order.

These tasks consisted of a tapping test, a dot tracking test, a

pursuit rotor test, and a driving simulator test. Both the tests

and methods of scoring them are described in the study by Patman

et al. reviewed earlier in this report. When the test battery

was completed, alcohol (or placebo) was given and then 30 minutes

after stopping drinking a Breathalyzer test was administered.

56
The same test battery and Breathalyzer test were repeated. After

having a meal and remaining under observation until appearing

entirely sober, the subjects filled out a second questionnaire,

rating themselves on their recent intoxication and on symptoms.

A medical examination was performed and they were taken to their

houses, with a warning not to drink or drive for 24 hours.

Dosage: Imipramine, desipramine, and placebo each took the form

of one tablet, 0.8 mg/kg body weight. Alcohol and placebo alcohol

doses were 0.8 ml/kg body weight, prepared as described above.

Results: All data except the present rotor test were scored before

the drug key was known. The mean blood alcohol level attained was

0.074% w/v (S.D. = 0.009% w/v). The results were statistically

evaluated by analysis of variance.

Only the first questionnaire showed any significant differences.

The placebo group members rated themselves higher on having a stuffy

nose and on frequency of headaches (P < 0.05).

The laboratory tests failed to show any significant impairments

at the dosages given of either imipramine or desipramine and there

was no evidence for interaction of these drugs with alcohol.

Alcohol at 0.07% w/v blood alcohol content significantly impaired

performance of most tests, but improved the "transformed scores”

(see original article) of the driving simulator test.

Comment: The findings are another example of alcohol being the

at impairing agent when drug dosages close to “therapeutic”

quantities are taken with alcohol. This is more clearly seen in

these experiments because the dose of alcohol used produced a

mean blood alcohol content of 0.07%, a concentration at which

most people begin to be objectively affected in the eyes of a

careful observer.

The paper does not confine itself to simply reporting the hard

data, but also contains useful discussion of review material on

drugs and driving, the chemistry and pharmacology of tricyclic

antidepressants, previous work on antidepressant-alcohol interaction, clinical trials of desipramine and imipramine, stimulant

effects of antidepressants, and methodological difficulties

encountered in studies of alcohol-drug interactions in humans.

STUDY: Linnoila, M., I. Saario, and M. Maki. Effect of Treatment

With Diazenam or Lithium and Alcohol on Psychomotor Skills Related

to Driving: European J. of Clinical Pharm., 7:337-342. 1974.

Site: Department of Pharmacology, University of Helsinki, Helsinki,

Finland.

All used alcohol occasionally, none was obese, took drugs, or had

Subjects: Twenty male students, 20 to 23 years old, volunteered.

any psychiatric disorders.

57
Method: The double-blind, crossover, 2-week studies under controlled laboratory conditions measured the subacute effects of diazepam

alone and in combination with alcohol, and those of lithium alone and

in combination with alcohol. The test groups were coded as follows:

Placebo drug, placebo drink P group

Diazepam, placebo drink D group

Lithium, placebo drink L group

Placebo drug, alcohol A5 group

Diazepam, alcohol DA5 group

Lithium, alcohol LA5 group.

Testing took place on 7th and 14th days of the treatments. Effects

of learning were excluded by allocating subjects at random according to Latin square design. Subjects were trained on apparatus

used before the experiments. Each testing period consisted of

three sets of tests 30, 90, and 150 minutes after administration

of the drug or drink. At each session, half the subjects received

alcohol and half, the placebo drink. Changeover of the drinks was

done between each session.

Measurements: The subjects assessed their own performance by

completing a rating scale that included guessing of the present

treatment modality. Psychomotor tests included a choice reaction

test, two coordination tests, and an attention test. Blood

samples taken at the end of each session were analyzed for lithium

(serum, by flame photometry); for diazepam and N-desmethyldiazepam

(serum, by electron capture gas chromatography); and for alcohol

(blood, method not stated). Test results were treated by a modification (by Fischer) of the analysis of variance using two- and

three-factor designs. The attention test results were also

examined by the student's t-test. The three-factor analysis

revealed no significant differences among any treatments at the

7th and 14th days; hence, the two-factor analysis was used for

presentation.

Subjective assessments: The P and L groups considered themselves

normal on the 7th day but impaired on the 14th day during the 15-

minute test. Alcohol produced slight subjective impairment at

30 and 90 minutes. Diazepam had no effect. The combined effects

of alcohol and diazepam or lithium caused subjective impression

of impairment, especially on the 14th day.

On the 7th day, 30 percent of the P group and on 14th day, 50

percent of P group thought they had received a tranquilizer.

More than 80 percent of the D group thought their treatment was

with a tranquilizer. On the 7th day, 30 percent of the A5 group

thought their drink was a placebo and 70 percent of the P group

thought they had received alcohol. At the end of the trial (14

days), estimates were 90 percent correct.

Psychomotor measurements: For the choice reaction test, there was

no difference between the P and A5 groups. The D group had shorter

58
reaction times and fewer mistakes. The DA5 group was impaired

compared to the P group, especially at 30 minutes. Lithium prolonged reaction time and increased mistakes. The LA5 group showed

short reaction time and accurate responses at all times.

In coordination test I, alcohol increased the number of mistakes.

D subjects had only a slightly increased mistake percentage compared to the P group. The DA5 group had the largest number of

mistakes but their percentage of mistakes was of the same order

as that for the A5 group. These mistakes increased from 30 to 150

minutes. L subjects had an increased number of mistakes but a low

mistake percentage, whereas the LA5 group had a small number of

mistakes but an increased mistake percentage.

For coordination test II, the P group had shorter driving times and

lower mistake percentages than other groups but their mistake

numbers were high. The A5 group showed a lower number of mistakes

but an increased mistake percentage and prolonged driving time

compared to the P group. At 30 minutes, the results of the P and

D groups were similar but at 90 and 150 minutes the mistake percentage of group D increased and their driving time was prolonged.

The mistake percentage and driving times were increased in the

DA5 group at 30 minutes compared to the P group, but thereafter

the DA5 group decreased its mistake percentage and increased its

speed. Lithium increased the mistake percentage and prolonged

driving times at 150 minutes. The LA5 group showed impairment at

every test time compared to the P group.

In the attention test, several groups showed some impairment after

alcohol ingestion compared to the P group. The D group did not,

but the DA5 group showed impairment at 30 and 90 minutes, the

LA5 group showed impairment at 30 minutes, and the L group was

generally impaired compared to the P group.

The blood alcohol concentrations of the tested subjects ranged

from 0.40 to 0.60 mg/ml, with the highest values being at 90

minutes.

Dosage: Five mg of diazepam were administered three times daily

in gelatin capsules; and lithium carbonate tablets were given with

dosage adjusted to produce serum concentrations of 0.75 meq/l.

Placebos were administered as capsules or tablets identical in

appearance to the real items. Alcohol was given in bitters at a

dose of 0.5 g/kg; the placebo bitters had the same volume.

Results: The experiments show very little effect of diazepam

alone at the chronic dosage given. Alcohol alone caused only a

small amount of impairment. The combination of alcohol and diazepam

enhanced impairment; interaction may therefore be presumed. Lithium

alone caused some impairment, especially in information retrieval,

and when combined with alcohol produced a slight antagonism of

effects.

59
Comment: The information is useful but it would be very helpful

if experiments with real-world abuse doses of the drugs and

alcohol were undertaken first, to be followed by such work as

reported here, where the results are quantitatively unimpressive

and of uncertain significance with respect to real-world complex

performance.

60
SEDATIVES

Satanand Sharma, Ph.D.

SUMMARY AND COMMENTS

An assessment of the relationship between sedatives and driving

accidents requires the survey of literature dealing with: (1) the

effects of sedatives on actual driving behaviors, (2) the epidemiological studies of sedatives and traffic accidents, and (3) the

physiological, psychological, and behavioral effects of sedatives

on factors related to driving.

Only a few studies have tested the effects of sedatives either in

a simulator or in the field. Loomis and West (1) tested eight

subjects in a driving simulator from 1 to 6 hours after they were

given various drugs. The simulator consisted of an automobile

steering wheel and brake accelerator pedals arranged as in a standard automobile. The steering wheel operated a model car placed on

a moving belt 150 ft. long and 30 in. wide with an opaque l-in.

strip running down it lengthwise, which simulated the road bed.

The strip was shifted randomly, moving smoothly from side to side

as the belt advanced. Accelerator and brake pedals actuated and

controlled the rate of belt movement, and the steering wheel controlled the position of the model car. A light source placed 14

in. above the car was capable of producing an amber, red, or green

light. The subject was required to keep the car centered on the

road bed and to respond to the lights by depressing the accelerator

pedal when the green light appeared, releasing the pedal when an

amber light appeared, and depressing the brake pedal to stop the

belt when a red light appeared.

Response measures included braking time following the appearance

of a red light, time required to release foot pressure on the

accelerator pedal at the appearance of an amber light, and a steering score, which measured the cumulative time during which the car

was not “centered on the road.”

The experimenters describe the procedure as follows. ‘Tests were

performed at 1 (trial #1) and 2 (trial #2) hours after the administration of the drug. At 24 to 3 hours after the initial medication, standard lunch ... was consumed. One hour later the driving test was conducted following which the second dose of medication was taken by mouth ... The five drugs were: placebo (comstarch) 200mgm; secobarbital sodium 100mgm; chlorpromazine

hydrochloride (Thorazine) 50mgm; meprobamate (Equanil) 400mgm; and

61
phenaglycodol (Ultran) 300mgm.” It is not clear from this description whether the drug amounts cited were the sum of the first and

second doses or whether this amount was given at each of the two

drug administration times.

Secobarbital, chlorpromazine, and meprobamate produced impairment

on the tests. The decrease under secobarbital was the largest,

with a 115.6 percent decrement apparent at the fifth hour after initial drug administration. However, it is not clear whether this

occurred after 200 mg (a high dose) or after 100 mg of secobarbital.

The Loomis-West simulator represents a part-task simulator in that

it measures only some of the tasks related to driving. The simulator does represent some of the demands of driving in that it requires the subject to perform multiple acts simultaneously.

Another study which was carried out on a closed course was conducted by Betts et al. (2). They examined the effects of 150 mg sodium

amytal on three vehicle-handling tasks. These were a weaving test,

a parking test, and a gap estimation test requiring subjects to

estimate the gap between two traffic cones through which they could

drive. Fifty men and 50 women served as subjects. The results

indicated that the male subjects increased their failures in gap

estimations under the barbiturate, and the women decreased their

distances from the curb in the parking test, but increased their

successes in gap estimations. The qualitative difference in performance between men and women on the gap estimation may indicate

a heightened risk-taking attitude in men and a lowered risk-taking

attitude in women under the drug condition.

This is a typical closed-course study designed to determine the effects of drugs on driving behavior. The results are suggestive of

impairment in certain areas, but they cannot be extended to real

world driving situations. The closed course lacks all of the environmental stimuli which place demands on driving. Closed courses

are necessary for conducting safe tests, but they reduce the

validity of the results.

Flying simulators have also been used to determine the effects of

sedatives on complex behavioral tasks. One such study is by Harper

and Kidera (3) . The authors tested 30 pilots in a twin turbojet

flight simulator. The measures included the following parameters:

(1) airspeed, (2) altitude, and (3) ILS glide slope and localizer

indicator. In addition, an observer scored the subject on “procedures and techniques.” The subjects also filled out a questionnaire which was designed to measure feelings of alertness, fatigue,

and quality and soundness of sleep the previous night.

The 30 subjects were divided into three groups, with each group

receiving one of the three treatments: (1) placebo, (2) glutethimide (500 mg), or (3) flurazepam (30 mg) . The subjects were trained

for 4 hours, and then 1% hours of performance data were recorded

as a baseline. These data were compared to those obtained after

the subjects were given the dosages for two consecutive nights.

62
The tests were given approximately 12 hours after the second dose.

The simulator observations were presented only as improvement,

decrement, or no change, as compared to the baseline data. No

quantitative scores were provided. Six of the ten subjects under

glutethimide and four of the subjects under flurazepam showed decrements. No subjects showed no change, and five showed improvement. The results from the subjective questionnaire for glutethimide indicated seven subjects to be feeling worse than they did

when their baselines were recorded. Three under placebo reported

their feelings to be worse than their baseline days. The flight

data were scored in the same way as the simulator observer data.

Four subjects under glutethimide, three under flurazepam, and four

under placebo showed ‘decrement” performance in their final

approach.

The authors’ summary statement is, “Using flight recorder data as

the objective measurement, flurazepam (30 mg) and glutethimide

(500 mg), after two nights’ dosage, had no apparent effect on flight

performance twelve hours after use.” This is based largely on the

lack of differences between the drug and placebo groups. However,

this conclusion may be unwarranted since the study does suffer from

some methodological problems. The apparent lack of quantification

does not indicate what the various degrees of impairment were in

the different groups; and the use of the simulator observer and the

subjective rating scale does not allow a clear-cut determination of

the drugs’ performance effects per se.

Two other studies with flying simulators which did not contain

these shortcomings were conducted by McKenzie and Elliott (4) and

Hartman and McKenzie (5) . In the first study, subjects were tested

under 200 mg secobarbital on a flying simulator. The simulator

required division of attention and placed multiple monitoring demands on the subject. This is analogous to the driving situation,

in which it is necessary to keep the car centered in a lane and

simultaneously monitor other environmental signals that may occur.

This simulator, therefore, did require use of some skills necessary

for driving. It consisted of a cockpit-like console with stick,

rudder, and throttle controls. A panel containing four instruments

for airspeed, turn, bank, and engine rpm was mounted in front of

the subject. The dial needles were programmed to run independently,

but simultaneously. The subjects were required to monitor the

dials and use the controls to keep the needles in the center position.

The testing occurred 10 hours after ingestion of the drug and

lasted for 12 additional hours, with 15-second rest periods following each minute of operation. The results clearly indicated that

multiple tracking was degraded 10 hours after ingestion and performance impairment continued to show for the remaining 12 hours.

It is interesting to note that the impairment lasted well beyond

the peak pharmacological effect of the drug. From this study it

is apparent that the behavioral impairment does not linearly follow

63

231-545 O - 77- 6
the blood levels of secobarbital. In assessing the effects of

drugs on driving behavior, it is valuable to keep this in mind.

The second study, by Hartman and McKenzie, used a similar flying

simulator and tested four subjects 10 hours after drug administration. The test lasted for 4 hours and was performed under 200 mg,

100 mg, or placebo doses. Performance was degraded under the high

dose, but not the low dose. One interesting aspect of the study

was the enhancement of performance under placebo. This was accompanied by the subjects' subjective reports to the effect that they

slept as well after receiving placebos as after receiving 200 mg

secobarbital. This indicates a strong placebo effect and raises

questions regarding the reliability of subjective reports.

It is important to note that the impairment was sustained for 14

hours after drug administration. These residual or "hangover"

effects are important for driving. If impairment is exerted for

a considerable period of time, then the likelihood of involvement

in accidents is increased, even though the blood levels of the

drug may not be high. The hangover effect is also evident in other

studies.

One example of this hangover effect is a study by Walters and Lader

(6). They administered 100 and 200 mg of sodium butabarbitone and

5 and 10 mg of nitrazepam to 10 subjects in a balanced double-blind

design. The tests included EEG recordings at rest and also during

an auditory reaction time task, a key-tapping rate test, a digit

symbol substitution task, and a subjective ratings test for alertness. Testing took place 12 hours after drug administration. The

results showed that "many tests were affected significantly by the

drugs." This indicates that drug effects are demonstrable for

extended periods of time. As the authors stated," ... we must

remain aware that, although these hypnotics lessen the distress of

insomniac patients, psychological impairment and electrophysiological changes are inevitably left the next morning. Indeed, it is

unrealistic to expect any adequate hypnotic drug to be devoid of

pharmacological effects on wakening." These residual effects are

factors which must be faced in research related to drugs and

driving.

While the above simulator studies are important in yielding information regarding the effects of drugs, the extension of the results

to the real world has to be done with caution. A simulator only

partially taps the demands of operating a real vehicle in real

situations. The differences between drug effects on simulator

performance and on flying an airplane are shown in the study by

Billings et al. (7).

In this experiment, five highly experienced pilots were tested under 0, 100, and 200 mg secobarbital, both in a Cessna Model 172 airplane and in a Link-Singer GAT-1 simulator. Before testing, each

subject was permitted "to familiarize himself with the vehicle and

to practice instrument approaches until he was satisfied with his

performance." On test days, the pilots conducted two instrument

64
flights after ingesting the secobarbital. After the flights,

duplicate studies were performed on the same pilots under similar

conditions using the simulator. The responses recorded were

tracking performance in two axes and airspeed control. The average

decrement at the 100- and 200-mg doses, as compared to the placebo,

were 17 percent and 26 percent in the simulator and 2 percent and

14 percent in the airplane. The manual control decrement at the

100-mg dose in the airplane was not different from placebo. At the

higher dose level, little difference was observed for tracking in

the first flight, but significant differences were observed in the

second flight. The differences were significant for both flights

at both doses in the simulator. The paper does not state clearly

at what time interval after the administration of the drug the

testing took place.

fied.

Also, the total time of testing is not speciIt appears that testing may have taken place immediately

after administration, in which case the peak pharmacological effects

may not have been reached during testing.

However, it is clear from the results that there are differences in

performance between the simulator and the airplane. ‘This study

serves as a reminder that a simulator--and this may be true of most

Simulators--is not an airplane. ‘Flying’ it demands a different

strategy than that utilized in flying the airplane for which it is

a surrogate, and proficiency in the one vehicle does not imply

equal proficiency in the other.” A similar statement can be extended to driving and driving simulators.

The literature on epidemiological evidence which implicates sedatives with driving accident involvement is scant. It deals largely

with coroners’ reports, and published materials generally only indicate the number of driving fatalities which have occurred under

the drug’s influence or report the number of persons with drugs

present while they were driving.

A typical study dealing with sedatives is one by Gupta and Kofoed

(8) , in which they assayed urine and blood samples from persons

cited for driving while under the influence of drugs. They report

the number of persons showing the presence of barbiturates and no

alcohol. (For 1964, 18 such cases were cited in Ontario, Canada.)

There are a number of problems in using such data to implicate

sedatives in causing driving accidents. The numbers of drivers

apprehended under drugs do not indicate the nature of the relationship between the drugs and accident involvement. To determine

this, it is essential to know (1) the number of drivers involved

in accidents under the influence of sedatives and (2) the number

of individuals who drive under sedatives in the location where the

accident took place at the same time of day, but who are not involved in accidents. Only a comparison of the accident-involved

drivers and the at-risk population will yield an index that implicates sedatives in causing driving accidents. Such studies are

available for alcohol, but are sorely lacking for sedatives. Further, the Gupta and Kofoed study did not indicate what the drug

blood levels were. It is important to know what the relationship

65
is between drug levels and apprehension or accident involvement.

It has been mentioned earlier that impairment under barbiturates is

sustained for long periods of time. Thus, it is important to relate the residual effects of the drugs to driving accident causation. The existing epidemiological studies on sedatives suffer from

many methodological problems, ranging from the populations sampled

to the lack of quantitative data on drugs in body fluids.

The data from studies of the effects of sedatives on driving-related

skills also provide information regarding drug involvement in traffic accidents. Such behavioral studies can focus on various aspects

of driving skills. Driving itself is a complex task requiring

acquisition of information, processing of information, and the

execution of responses based on that information. These stages

require the performance of such tasks as monitoring the environment

for signals; tracking, or keeping the car on the road; and responding to the stimuli by braking, accelerating, or steering. There

are a number of papers which deal with aspects of these drivingrelated skills.

Drugs could affect sensory mechanisms, which in turn could produce

deleterious effects on driving behavior. There is a lack of literature on the effects of sedatives on visual functions. However,

there are a number of papers dealing with the effect of sedatives

on oculomotor functions, such as the one by Holzman et al. (9).

They examined the effects of single doses of chlorpromazine (0.667

and 1.33 mg/kg body weight), Valium (0.071, 0.142, and 0.284 mg/kg

body weight), and secobarbital (100 mg) on smooth-pursuit eye tracking. Five male subjects (four for the barbiturate) were required

to follow a pendulum that moved with a frequency of 0.4 Hz. The

horizontal eye movements were measured by silver-silver chloride

skin electrodes applied to the outer canthus of each eye and recorded on a dynograph. The scoring procedure required two scorers

to independently classify the tracking as qualitatively "normal" or

"deviant." One quantification of the scores was the number of

times the eyes stopped their pursuit of the target.

The results showed that only secobarbital disrupted eye-tracking

performance. Two of the four subjects under the barbiturate replaced their ocular pursuit with saccades. One of the subjects who

showed no qualitative disruption of his tracking pattern was given

the higher dose of 130 mg of secobarbital. This dose was found to

produce eye-tracking disruption which lasted 24 hours.

These results are suggestive of disruption of higher order processes. However, the study does contain some methodological problems.

The number of subjects is too small to allow generalizations about

the results. Also, the qualitative measures relied on the judgment

of scorers, and even the quantitative measures used in the study

are inadequate for describing the deviation of eye movements from

smooth pursuit. Manual inspection of the data is, of course, timeconsuming and limits the size of the study.

66
There are several studies dealing with the effects of sedatives on

vigilance behavior. Vigilance is important in the operation of

machinery or automobiles. Any unchanging environment can produce

impairment in skills performance. Kop iva et al. (10) tested 90

professional drivers under 150 mg/70 kg body weight pentobarbital.

Auditory signals were presented to the subjects at irregular intervals via earphones, such that the signals differed in spatial location (left, right, and midline) . The subjects were asked to ignore

the midline stimuli (50 percent of the presentations) and to depress

a button when the other two kinds of stimuli occurred. Each subject “was also informed that the course of physiological functions

after drug application permits to determine . . . whether the drug

has any effect or not and that this information would be transmitted to him by a light signal in time, so that he would be prepared to counteract any disturbing effect of the drug.” Pentobarbital increased the number of misses, and the cue did not affect

performance, but false alarms increased with the cue condition under

this drug. The authors noted that this may be related to a shift

in discrimination criteria. However, due to the lack of signal

detection analyses, it is not clear whether the poorer performance

under the drug is related to set or criterion shifts. It is nevertheless clear that pentobarbital affects signal detectability.

Psychomotor performance under sedatives has been studied by various

investigators. One such study is by Goodnow et al. (11). They

tested 30 male subjects on placebo and 100 mg pentobarbital, using

a crossover design. The test battery contained a number of tests

including: (1) tapping speed, using a telegraph key; (2) auditory

reaction time, in which the subject was required to depress a key at

the presentation of an auditory stimulus; (3) naming of opposites,

in which the time required to name the opposite of a common word

was recorded; and (4) memory for digits, which was simply measurement of backward digit span. the pentobarbital degraded performance

on all four of the tests 4 hours after administration. There was a

trend toward poorer performance (not statistically significant) 14

hours after the drug dose.

This study represents a sound experiment, in that the design controlled for many sources of variance. Learning effects were controlled by performing the statistical analyses on the differences

between the before and after tests for the placebo and drug treatments.

As has been mentioned earlier, driving is essentially a dual-task

function, requiring the detection of environmental signals and

tracking to keep the car on the road. Two examples of papers on

tracking under sedatives are those by Borland and Nicholson (12)

and Shroeder et al. (13).

Borland and Nicholson tested seven subjects under placebo and 200,

300, and 400 mg of heptabarbitone on a tracking task. This required subjects to position a spot inside a randomly moving circle

displayed on an oscilloscope. An error signal proportional to the

distance between the spot and the center of the circle controlled

67
the difficulty of the task by modulating the mean amplitude of the

movement of the circle. Each trial lasted 10 minutes with only the

last 500 seconds used as the performance measure. Each subject was

trained until a plateau level was reached. Predrug trials were run,

and post-drug trials were run at various intervals after administration. The various drug doses were administered in random order.

The results showed that heptabarbitone produced decrements in performance at 10 hours after the 200-mg dose, at 10- and 13-hour intervals after the 300-mg dose, and at 10-, 13-, 16- and 19-hour

intervals after the 400-mg dose. The performance impairment was

dose related. It is interesting to note that blood levels of

heptabarbitone did not correlate with individual performance.

The study by Schroeder et al. tested the effect of placebo, secobarbital (100 mg) and d-amphetamine (10 mg) on tracking performance.

Ten subjects were tested in each of the drug groups. The tracking

performance was tested under two conditions: (1) while the subject

sat stationary and (2) while the subject underwent angular motion.

The tracking test consisted of an aircraft localizer/glide-slope

indicator with the vertical needle being deflected to the right or

left of center by a sinusoidal forcing function. The subject was

required to keep the needle in the center by compensatory movements

of a joy stick. After the subjects were trained on the task, there

was a predrug test, and three post-drug sessions were conducted at

1, 2, and 4 hours after administration of the drugs. The response

measures included tracking errors under both static and dynamic

conditions and the number of nystagmic eye movements during the

dynamic condition. During the static condition, secobarbital did

not affect tracking scores. Amphetamine was found to improve scores

over control for the 2- and 4-hour post-drug sessions. During

angular acceleration, secobarbital produced more tracking errors and

increased vestibular nystagmus as compared to both the control and

amphetamine groups for all post-drug sessions.

Both of the above studies give examples of deleterious effects of

sedatives on tracking performance. The second study did not demonstrate any effects under the stationary condition, but it would be

worthwhile to examine the effects of the drug at more delayed intervals after drug administration.

Since alcohol is to a large extent consumed in conjunction with

other drugs, it is important to evaluate the combined effects of

sedatives and alcohol on driving skills performance.

Examples of this kind of investigation are presented in papers by

Sellers et al. (14) and by Mould et al. (15). In the first study,

Sellers et al. tested the effects of placebo, alcohol, and chloral

hydrate, singly and in combination, on changes in heart rate,

arterial pressure, skin temperature, simple and complex reaction

times, a tracking task, and a vigilance task. Five male subjects

were tested under the following drug conditions: (1) placebo;

(2) alcohol (0.5 g/kg body weight); (3) alcohol (0.5 mg/kg body

weight) given 1⁄2 hour after chloral hydrate (15 mg/kg body weight);

68
(4) chloral hydrate (15 mg/kg body weight); and (5) alcohol (0.5

g/kg body weight) after prior treatment with chloral hydrate (15

mg/kg body weight) for 7 days, with the last sedative dose being

given 12 hours before alcohol.

Compared to the control conditions, alcohol was found to increase

heart rate between 4 and 1 hour after administration. Chloral

hydrate combined with alcohol increased the cardiac rate at 1⁄2 hour

after administration more than did alcohol given alone or chloral

hydrate given alone. Chloral hydrate followed by alcohol caused

greater increases in skin temperatures than the other treatments.

There was no drug effect on the reaction time tasks. Alcohol was

found to degrade the tracking and vigilance tasks, but chloral

hydrate given alone had no effect on these tasks. The decrement

was pronounced (and larger than for alcohol alone) when chloral

hydrate was given in combination with alcohol on both the tracking

and vigilance tasks.

There are a number of methodological problems with this study. For

example, the size of the sample is too small and the specifics of

the experimental design are not clear. However, it is clear that

alcohol and chloral hydrate in combination do cause greater performance deficits than does either substance taken alone.

Mould et al. tested six subjects on the effects of glutethimide

(250 mg) alone and in combination with alcohol on reaction time,

tracking, and a finger-tapping task. Glutethimide alone was found

to affect all the behavioral tests. Glutethimide consumed simultaneously with 100 ml of vodka was found to increase the reaction

time responses, but did not affect the other tests (nor did alcohol

alone). This is in contrast to the previous study, where chloral

hydrate in combination with alcohol had no effect on reaction time

tests, but did affect the tracking task.

One interesting finding was that, when chloral hydrate and alcohol

were given simultaneously, blood alcohol concentration was significantly higher (11 percent) at 105, 135, and 165 minutes after drug

administration than when the alcohol was ingested alone. In contrast, a second experiment which was part of the same study tested

phenobarbital (60 mg) given in combination with alcohol (50 ml

vodka). A decrease in the blood alcohol concentration was shown at

30 and 90 minutes after administration. This study also suffers

from the use of a small sample size and an ambiguous experimental

design.

An example of a study which investigated the effects of drugs in

combination (other than alcohol) on behavioral performance is one

conducted by Dalton et al. (16). They tested 12 subjects under

marihuana (25 mg THC/kg body weight) and secobarbital (150 mg/70 kg

body weight), alone and in combination, on a complex tracking task,

a stability test, a tapping test, and mental performance tests.

Marihuana alone was found to impair stability of stance and performance on the tracking and mental performance tests, but did not

affect the tapping task. Secobarbital degraded performance on all

69
the tests, except the stability of stance test. The combination of

secobarbital and marihuana evidenced performance deficits on the

pursuit, stability, and mental performance tests beyond those

experienced under either drug alone, suggesting additivity of the

component effects.

This study is an example of degraded performance when drugs are

used in combination; it suggests a need to explore this area further.

Finally, the history of drug-taking can have differential effects

under sedatives. Metabolic rates are known to be accelerated for

certain drugs by other drugs (e.g., tolbutamide by alcohol) and

other types of physiological changes may be induced by the use of

some drugs which could modify the effects of yet other drugs. A

study by Raft et al. (17) provides an example of the differences in

responses to sedatives between light and heavy alcohol drinkers.

They tested 12 heavy drinkers and 12 light drinkers, either under

placebo or 200 mg of pentobarbital. One hour after drug administration, the experimenter subjectively evaluated the subjects' impairment of memory, concentration, and "physiological signs," including

nystagmus. The heavy alcohol drinkers were found to be "resistant"

to the effects of pentobarbital. The "low alcohol users exhibited

significantly more signs of intoxication then did high alcohol

users."

The authors did not report the blood pentobarbital levels at the

time of evaluation. The results, of course, have to be interpreted

cautiously, since they are subjective impressions and not objective

data. However, they are suggestive of behavioral tolerance buildup

caused by the use of other drugs. Whether such tolerance lowers

impairment under sedatives is left to further study. There is

clearly a need for more research in this area.

It is clear from the above examples of research on sedatives that

there are several areas dealing with sedatives and driving that

require further investigation. These include: (1) the epidemiological evidence of relationship between sedative use and driving

accident involvement; (2) the extended duration of action of sedatives; (3) vigilance performance under sedatives; (4) the interaction of sedatives and other drugs, including alcohol; and (5)

physiological and behavioral tolerance buildup to sedatives as well

as cross-tolerance between sedatives and other drugs.

There are many methodological problems inherent in epidemiological

data collection for sedatives and driving. In addition, simulator

and closed-course studies yield little data which provide information about either accident causation or mechanisms of sedative

actions leading to driving accidents. The one area which clearly

will provide much information about sedative use and driving is

research dealing with the behavioral mechanisms affected by sedatives. It is suggested that further studies be performed which

would systematically investigate the behavioral impairment

experienced under sedatives.

70
REFERENCES

1. Loomis, T.A. and T.C. West: Comparative Sedative Effects of

a Barbiturate and Some Tranquilizer Drugs on Normal Subjects.

Journal of Pharmacology and Experimental Therapeutics, 122:525-531.

1958.

2. Betts, T.A., A.B. Clayton, G.M. MacKay: Effects of Four

Commonly-Used Tranquilizers on Low-Speed Driving Performance Tests.

British Medical Journal, 4:580-584. December 1972.

3. Harper, C.R. and G.J. Kidera: Aviator Performance and the Use

of Hypnotic Drugs. Aerospace Medicine, 43(2):197-199. 1972.

4. McKenzie, R.E. and L.L. Elliott: Effects of Secobarbital and

D-Amphetamine on Performance During a Simulated Air Mission.

Aerospace Medicine, 36:774-779. 1965.

5. Hartman, B.O. and Maj. R.E. McKenzie: Hangover Effect of

Secobarbital on Simulated Pilotage Performance. Aerospace Medicine,

37:1121-1124. 1966.

6. Walters, A.J. and M.H. Lader: Hangover Effect of Hypnotics in

Man. Nature, 229:637-638. 1972.

7. Billings, C.E., R.J. Gerke, R.L. Wick, Jr.: Comparisons of

Pilot Performance in Simulated and Actual Flight. Aviation, Space

and Environmental Medicine. March 1975.

8. Gupta, R.C. and J. Kofoed: Toxicological Statistics for

Barbiturates, Other Sedatives, and Tranquillizers in Ontario: A

Ten-Year Survey. Canadian Medical Association Journal, 94:863-865.

April 16, 1966.

peutics, 102(1):55-61. 1951.

9. Holzman, P.S., D.L. Levy, E.H. Uhlenhuth, L.R. Proctor, D.X.

Freedman: Smooth-Pursuit Eye Movements, and Diazepam, CPZ, and

Secobarbital. Psychopharmacologia, 44:111-115. 1975.

10. Kop iva, K., E. Frantík, M. Horváth: Pentobarbital Effect on

Performance in Monotonous Conditions Not Prevented by Compensatory

Effect. Activ. Nerv. Sup. (Praha), 16:3. 1974.

11. Goodnow, R.E., H.K. Beecher, M.A.B. Brazier, F. Mosteller,

R. Tagiuri: Physiological Performance Following a Hypnotic Dose

of a Barbiturate. Journal of Pharmacology and Experimental Thera12. Borland, R.G. and A.N. Nicholson: Human Performance After a

Barbiturate (Heptabarbitone). British Journal of Clinical Pharmacology, 1:209-215. 1974.

13. Schroeder, D.J., H.E. Collins and G.W. Elam: Effects of

Secobarbital and D-Amphetamine on Tracking Performance During

Angular Acceleration. Ergonomics, 17(5):613-621. 1974.

71
14. Sellers, E.M., G. Carr, J.G. Bernstein, et al.: Interaction

of Chloral Hydrate and Ethanol in Man. Clinical Pharmacology and

Therapeutics, 13:50-58. 1972.

15. Mould, G.P., S.H. Curry, T.B. Binns: Interaction of Glutethimide and Phenobarbitone With Ethanol in Man. Journal of Pharm.

Pharmac., 24:894-899. 1972.

16. Dalton, W.S., R. Martz, L. Lemberger, B.E. Rodda, R.B. Forney:

Effects of Marihuana Combined With Secobarbital. Clinical Pharmacology and Therapeutics, 18(3):298-304. 1975.

17. Raft, D., R. Gomez, J.A. Ewing. The Pentobarbital Test Dose

for Depressant Drug Dependence. Journal of Nervous and Mental

Disease, 159(5):366-370. 1974.

72
STIMULANTS

Robert Forney, Ph.D.

SUMMARY

Leake (1) philosophizes concerning the sleepy driver and his involvement in traffic accidents. He suggests that physicians should

take an active interest in their patients’ driving habits, warning

about the effects of drug and alcohol use.

Many disease states may complicate driving prowess. Drugs--e.g.,

caffeine, amphetamine--may be used to combat fatigue. No definitive data are presented. The suggestions and discussion are interesting but not novel.

Rutenfranz and Jansen (2) studied the effects of caffeine or Pervitin (methamphetamine) using two subjects (age or sex not reported)

and a driving simulator.

g/kg. Either 0.2 g of caffeine or 9 mg methamphetamine were inThe alcohol dose was either 0.5 g or 1.0

jected. Either alcohol dose deteriorated performance. Methamphetamine reversed this effect with the low dose of alcohol and

partially with the high dose. The subjects claimed not to feel the

alcohol effect when their blood concentration was 0.06 percent.

Caffeine also reversed the alcohol effect but was less potent.

The study was poorly controlled, and too few subjects were used.

The results have not been confirmed by others.

Kraft (3) has reviewed a series of case histories to emphasize the

possibility of central stimulating drug involvement in driving

performance. The driving errors were not documented as having been

influenced by drugs, but that possibility was raised, considering

the pharmacological properties of commonly used drugs. The fact

that alcohol disappearance was not altered by this class of compounds is not surprising. The paper serves to reemphasize the

problem but offers no solution.

Hurst (4) has studied the effect of d-amphetamine on risk taking

based on the observation that it is a mood elevator. Heightened

optimism contributes to self-confidence and increased risk taking.

Little data had been published to indicate that amphetamines had

behavioral or judgmental effects. Studies bearing on this possibility were so structured as to be insensitive to mood changes.

Gambling was chosen as the test measure.

tiary inmates were the subjects.

Twenty-nine male penitenThe dose of d-amphetamine was 10

73
mg. Risk taking increased with drug treatment. The change was not

dramatic and the subjects were very special. The dose of d-amphetamine was modest, especially for nonprescription use.

Wilson et al. (5) studied the combined effect of ethanol (1.2 g/kg)

and amphetamine (15 mg/kg) on performance using 32 medical and

pharmacy students, sex presumed to be male but not stated. No

difference was shown between ethanol-amphetamine and ethanollactose on performance of balance, skipping, Minnesota manipulation,

Purdue Peg board, Maudsley Personality Inventory, pursuit rotor, or

digit span. During testing, blood alcohol values ranged from 0.06

to 0.08 percent (Breathalyzer). Minor changes were noted with

other test parameters. No placebo controls were used. The testing

devices were likely insensitive. No dramatic data were obtained.

No information to relate amphetamine and/or amphetamine-ethanol use

in driving was provided.

Laties and Weiss (6) summarized published information relative to

the effect of amphetamines on enhancing performance. The work was

a 5-year update of a previous analysis of the question. They

reaffirmed that amphetamines do improve performance on a wide

variety of tasks. They suggest that greater improvement can be

achieved by manipulating the variables controlling the tasks.

Introducing an element of variety may increase attention to and

interest in performance, but how this could be utilized in a driving situation was not discussed. Any device to increase driver

motivation and/or attention has great potential for good. Suggestions for such an innovation were not made but should be considered.

Livingood et al. (7) have studied the effects of d-amphetamine (15

mg), caffeine citrate (500 mg) and high temperature (125.6” F) on

human performance. Twenty-four young males were subjects. Strength task data, heart rate, rectal temperature, and evaporating

water loss were observed, although the data are considered irrelevant to driving performance. Improvement in mental performance was

noted in subjects dosed with amphetamine and in a high-temperature

area. The improvement, however, was at a low level of significance

which would be unimportant in driving skills.

Hurst et al. (8) studied the effect of amphetamines on judgment and

decisionmaking by evaluating published studies (including their

own, reviewed here) which have shown that drugs improve mood and

lessen fatigue. Increased risk taking may be a reflection of these

effects. The complicated explanation of the results obtained in the

experiments reviewed has little relevance to a driving situation

and adds nothing of importance.

Hurst (9) further examined the effects of amphetamines upon judgments and decisions. At this time he reported that, despite published data to the contrary, the belief that amphetamine affected

judgment was widely held. Either d-amphetamine or diamphetamine

in doses of 15 mg/kg was given to 93 students of mixed sex. A

mathematical reasonsing test with self-appraisal and a reward for

good performance was given. Performance was not affected.

74
Positive self-appraisal was effected by either drug treatment, with

d-amphetamine, as expected, being more potent. Improved selfappraisal may be a reflection of mood elevation. Whether impaired

performance in a motor car would attend this was not discussed and

is certainly not apparent.

Hurst et al. (10) have investigated the effect of ethanol and damphetamine upon mood and volition. Seventy male subjects were

used. The parameters of risk taking (gambling), verbal production

on an assigned subject, and mood were measured. Even the authors

did not suggest what significance verbal production changes would

or did mean. The increase in confidence with alcohol or amphetamine was not expected. The modest increase in mood or risk taking

may be attributed to the modest doses of either drug (15 mg damphetmine, 45 g ethyl alcohol). Nothing definitive or applicable

to the problem of these drug combinations in drivers was presented.

Wagner (11) responded to a question-and-answer section of the

medical journal concerning elderly people who doze when driving.

He suggested that a medical condition may be responsible and recommmended caffeine or amphetamine for mild stimulation. No data are

presented and the medical opinion is not helpful.

Bye et al. (12) have compared the effects of 1-benzylpiperazine, a

compound having some activity similar to dexamphetamine in mice and

rats, with dexamphetamine on human performance. Two groups of

normal subjects were tested; the first group had 9 men and 3 women

and the second had 7 men and 5 women. The age range was 21 to

46 in group 1 and 21 to 47 for group 2. Significant improvement

(p < 0.05) occurred in an auditory vigilance test after either

drug. In the short-duration tests (i.e., tapping rate, hand steadiness, and arithmetic) significant changes were not seen. The

conclusions of-the study are interesting but have little relevance

to performance in motor vehicle operation. A relationship may

exist between improved auditory signal detecting and automobile

driving; the authors unfortunately did not discuss it.

Frank et al. (13) measured the effect of caffeine (300 mg/kg) alone

and in combination with ethanol (75 mg/kg) on 68 students of both

sexes. Tests measured cognitive, perceptual, and motor functions.

The battery consisted of standing steadiness, simple and complex

reaction time, manual dexterity, numerical reasoning, perceptual

speed, and verbal fluency. A placebo control was used. The peak

plasma ethanol concentration of 92 ± 4 mg percent was not altered

by caffeine. Caffeine did not antagonize the ethanol-induced

performance decrement except in reaction time tests, in which

caffeine antagonized complex reaction time impairment induced by

ethanol. The authors agree that no clear pattern of ethanol antagonism occurred with the doses of caffeine used. The suggested

hazard of a driver feeling more alert with caffeine after drinking

yet having a performance decrement is a conjecture unsupported by

their data. The evidence is that ordinary amounts of caffeine do

not practically antidote ethanol-induced impairment.

75

231-545 O - 77 - 9
REFERENCES

1. Leake, C.D. : The Amphetamines and the Sleepy Driver. Ohio Text

State Medical Journal (Columbus), 53(2):176-178. 1957.

2 Rutenfranz, J. and G. Jansen: The Compensation of the Alcohol

Effect by Caffeine and Pervitin in a Psychomotor Performance.

Internationale Zeitschrift für Angewandte Physiologie Einschliesslich Arbeitsphysiologie (Berlin), 18:62-81. 1959 .

3. Kraft, H.G.: Performance in Traffic Under the Influence of

Central Stimulation Drugs. Arzneimittelforschung (Aulendorf),

12(11):1071-1074. 1962.

4. Hurst, P.M.: The Effects of d-Amphetamine on Risk Taking.

Psychophannacologia, 3:283-290. 1962.

5. Wilson, L., J.D. Taylor, C.W. Nash, D.F. Camerson: The Combined Effects of Ethanol and Amphetamine Sulfate on Performance on

Human Subjects. Canad. Med. Ass. J., 94:478-484. 1966.

6. Laties, V.G. and B. Weiss: Performance Enhancement by the

Amphetamines: New Appraisal. Neuropsychopharm., 5:800-808. 1966.

7. Livingood, B.W., C.S. Blyth, W.H. Peacock, R.B. Lindsay:

Effects of d-Amphetamine Sulfate, Caffeine and High Temperature on

Human Performance. Res. Quart., 2:64-71. 1967.

8. Hurst, P.M., M.F. Weidner, R. Radlow: The Effects of Amphetamines Upon Judgments and Decision. Psychophannacologia, 11:397-

404. 1967.

9. Hurst, P.M. Judgment Distortion by Amphetamines: Some Moderating Influences. Psychopharmacology of the Normal Human, ch. VI,

W.O. Evans and N.S. Kline, eds., Chas. C. Thomas, Springfield,

Illinois. 1969.

10. Hurst, P.M., R. Radlow, N.C. Chubb, S.K. Bagley: Effects of

Alcohol and d-Amphetamine Upon Mood and Volition. Psychol. Reports,

24:975-987. 1969.

11. Wagner, H.J.: Sleep for Seconds in Elderly Automobile Drivers.

Dtsch. Med. Wachenschr., 97:882. 1972.

12. Bye, C., A.D. Munro-Foure, A.W. Peck, P.A. Young: A Comparison of the Effects of 1-Benzylpiperazine and Dexamphetamine on

Human Performance Tests. Europ. J. Clin. Pharmacol., 6:163-169.

1973.

13. Franks, H.M., H. Hagedorn, U.R. Hensley, G.A. Starmer: The

Effects of Caffeine on Human Performance, Alone and in Combination

With Ethanol. Psychopharmacologia, 45:177-181. 1975.

76
MARIHUANA

GENERAL HALLUCINOGENS

Herbert Moskowitz, Ph.D.

SUMMARY: MARIHUANA

The following group of studies involving the administration of

either marihuana or a hallucinogenic drug has been concerned

primarily with the conclusions that one can derive from possible

changes in the dependent behavioral methodological issues in drugs

studies attempting to examine skills performance.

The experimental literature on marihuana offers an excellent survey

of the techniques commonly used to investigate the effects of drugs

on skills performance. These range from studies done with actual

cars in real driving situations to laboratory studies of components

of behavior assumed to be important for driving.

The experiment with perhaps the most face validity for a real

driving situation was performed by Klonoff (1). He utilized 64

subjects, some studied in a closed driving course and some studied

while on the streets of Vancouver. Active treatments were dosages

of 4.9 and 8.4 mg delta-9 THC administered by smoking. The subjects on the closed course went through a slalom, two tunnels of

different widths, a funnel, a stop-and-back-up maneuver, a corner,

an emergency stop, and a risk-taking situation involving gap

estimation.

Scoring was generally unambiguous, being based on the number of

cones hit, except for risk taking. Scoring for the traffic driving

situation, however, was less definitive as it involved subjective

estimations of performance by examiners from the State Department

of Motor Vehicles. No evidence was given for the reliability of

these subjective judgments, and this may be the source of the large

variability found in performance under marihuana. Some subjects

exhibited improved performance. In the 11 scales of subjective

judgments, such as cooperation, attitude, irritability, care while

driving, speed, confidence, tension, judgments, etc., that were

used in the study, only 3 appeared to be significantly affected--

judgment, care while driving, and concentration. The objective

scores on the closed course revealed no significant impairment at

the low dose, but did at the high dose, on all but the backup and

corner tasks.

If one can accept the validity of the subjective measures used by

the traffic examiners in the open traffic driving situations,

77
their scoring suggests that marihuana impairs some aspects of

driving skills which might be examined in a more objective experimental situation. The subjective variables themselves give little

insight into the nature of the pharmacological actions which might

be affecting driving. Clearly, the closed course situation with

its more objective measurements provides greater certainty that

marihuana had impaired driving skills performance. The study

attempts to determine whether the skills utilized in driving are

affected by the use of a particular drug. The variables (e.g.,

number of cones hit, etc.) have not been related to any behavioral

variables; therefore, the nature of the deficit produced by

marihuana cannot be understood.

Typical of the simulator studies performed under the influence of

marihuana is a study by Rafaelsen et al. (2). Subjects in the

simulator performed two major behavioral tasks--tracking and

responding to various signals. The tracking task required following a simple outline of a road, which moved in a circular track;

the recognition task required responding with the brake to. stoplight signals and with the accelerator to start-light signals.

Speed and number of gear changes were also recorded in this manual

transmission-equipped car. Marihuana was orally administered in

doses of 8, 12, and 16 mg delta-9 TMC.

The two larger marihuana doses primarily affected the speed of

responding to signals, either from the start or stop lights. At

no dose level was the frequency of gear changes or the mean speed

affected. In comparison with road driving, the simulator has more

objective measures for components of driving.

This study suggests that marihuana has a greater effect on sensory

or perceptual aspects of car control than upon motor aspects.

While deficits occurred in the latency of responses to signals,

none appeared in tasks involving motor responses, such as gear

changes or speed. In comparing two methodologies of actual car

driving versus simulator studies, the one advantage of the simulator has been its ability thus far to differentiate aspects of

behavior more clearly than has been possible by actually driving

cars. This is not a theoretical necessity, but merely a consequence of the limited range of responses that have been available

in most instrumented cars. It should be noted, though, that the

Department of Transportation has recently developed an instrumented

car with considerable capacities for analysis of tracking behavior.

Another example of the manner in which simulators have been employed to examine specific behavioral characteristics is their use

in studying the effect of marihuana on risk taking. Dott (3) used

the closed-loop simulator built by the U.S. Public Health Service

in Providence, Rhode Island, to develop a passing-task situation.

This simulator uses a single-beam optical projection system with

model cars on two belts. The two belts represent two road lanes,

and can be moved at different speeds relative to each other. In

the study, the subject was required to pass a car in his lane

before a car approached in the opposite direction in the other

78
lane, which was to be used for passing. The study was complicated

by a requirement for aborting the passing maneuver or, conversely,

for attempting a rapid completion when various light signals were

presented.

Twelve subjects were examined under two active treatments and one

placebo treatment, the active treatments being 11-1/4 and 22-1/2

mg delta-9 THC. The results indicated that subjects made fewer

attempts to pass under marihuana. When the warning signal

occurred, the subjects were placed under stress for a quick decision to pass or not to pass. Despite a reward for successful

passing, the subjects under marihuana were more likely to abort

the attempt to pass and thus adopt a more conservative set of

behaviors., Objectively, there were no differences in the paths

traversed under the different doses and treatments for the passing

maneuver. The author thus concluded that marihuana produced a

decreased willingness to take a risk.

The only negative finding regarding the effect of marihuana was

that the length of time necessary to decide whether to pass when

an opportunity to do so was presented increased under marihuana.

An interesting aspect of the latter finding was that the passing

situation was presented under two conditions. One condition was

not considered to be an emergency and one was presented as an

emergency with a warning signal demanding a rapid response. The

increased decision time only occurred when it was a nonemergency

situation. If a warning signal occurred, there was no difference

in decision time from that when not under marihuana. Apparently,

the stress of the situation helped compensate for part of the

negative effect of marihuana upon decisionmaking. Methodologically,

this study of drug effects with a simulator had the advantage that

its design permitted a separate examination of a risk-taking

behavioral function. Rather than merely producing a yes-no

comment on whether marihuana was or was not impairing, it was able

to examine drug effects on a behavioral function.

Most marihuana research has taken place in behavioral laboratories,

where attempts have been made to isolate specific behavioral

functions for further analysis. Typical of such studies is one by

Manno et al. (4). The authors examined what they called motor

performance, utilizing the pursuit tracking test at four levels of

difficulty, a delayed auditory feedback task, and a variety of other

psychological and subjective measures. The 12 subjects were given

doses of either 0, 2-1/2, or 5 mg delta-9 THC. Pursuit tracking

involves two stimuli, typically two dots or bars on an oscilloscope

screen. One of the stimuli is under the influence of a forcing

function, and the other is controlled by the subject. The subject's

task is to track the first dot with his dot so as to minimize the

distance, or error, between them. The differences between the

four pursuit tracking conditions in this situation would be directly related to the forcing function's complexity.

Both marihuana doses seriously impaired performance on the tracking

test, with no difference between the two dose levels. Since

79
tracking is an important component of driving, this is clearly an

important finding. The finding is limited only by (1) its inability

at this time to relate the difficulty level of the tracking task

in the laboratory to that of the tracking task in an actual

driving situation, and (2) its inability to determine what behavioral

functions are involved in performing a tracking task.

Manno et al. also examined performance on delayed auditory feedback, which is described as a measure of mental performance. This

skill was also impaired by marihuana. However, no comment will be

made on this measure, as it is not clear how it relates to skills

performance. This study also examined the effects of alcohol, and

alcohol and marihuana in combination, on these behavioral variables.

There was a clear additive effect of greater impairment. This

suggests a need for further investigation of the interaction between

drugs and alcohol, since they are frequently used together.

As it became clear that tracking tests were sensitive to the influence of marihuana, other investigators utilized tracking tasks to

evaluate the influence of marihuana upon further behavioral variables. For example, Roth et al. (5) examined the effect of marihuana on tracking performance using a paced contour tracking test.

This is a pursuit tracking task in which the subject has a momentby-moment preview of the demands of the task, and is closely akin

to the tracking demands of real driving, in which we can see the

road ahead. The study examined two issues--whether marihuana

would be sensitive to such a pursuit tracking task, and whether

taking samples of tracking performance at 15-sec time intervals

would produce evidence that marihuana effects fluctuate during

short time periods. Nineteen subjects received placebos and 18

subjects received oral doses of 20 mg of delta-9 THC.

No evidence was found which suggests that marihuana effects fluctuate in short time periods. However, tracking task performance

was significantly impaired by marihuana, although the deficit did

not appear proportionately as great as that found in the Manno

et al. study perviously cited. This could be due to the differences

in the forcing functions rather than the differences in the type

of pursuit tracking tasks used in the two studies.

One of the difficulties in interpreting these studies is that it

is not clear which behavioral characteristics are important for

tracking performance. There is evidence that both perceptual and

central cognitive aspects, as well as motor skills, are important

in tracking. In recent years there has been considerable interest

in a more analytical evaluation of the nature of tracking performance, and among engineers attempts have been made to apply

linear mathematical models, known as describing functions, to

describe the human operator. These techniques will become

increasingly important as soon as there is greater agreement on

the meaning of the various elements of those linear differential

equations? in terms of behavioral characteristics. There is a

growing literature designed to elucidate precisely this issue.

80
An example of this methodology in drug research is a study by

Reid et al. (6) , which examines alcohol and marihuana effects on

compensatory tracking using a spectral analysis of tracking

responses. Three subjects received the low dose of 21 mg delta-9

THC/kg body weight, and three subjects received the high dose of

88 mg delta-9 THC/kg body weight. While alcohol affected several

parameters of the tracking describing function, only the high dose

of marihuana had any effect, a small increase in the random error

term in the describing function. Unpublished work from other

laboratories suggests that there is a greater effect than that

demonstrated in this study, possibly because the forcing function

selected was inadequately difficult. The study does have merit,

however, in that it indicates a method of examining tracking

performance in which changes in tracking performance can be broken

down into components related to the behavioral aspects affected

by the drug.

Such an analytical method is more satisfactory than using the pursuit rotor task, as in the study by Weil et al. (7). Using doses

of 4.5 and 18 mg delta-9 THC, Weil et al. found that naive subjects

were significantly affected at both doses on the pursuit rotor

tracking test, but that chronic users were not. While the study

is valuable in demonstrating a tolerance effect, which should be

taken into account when evaluating other performance skills under

the effects of marihuana, the pursuit rotor has failed to demonstrate that it utilizes behavioral components that are characteristic of tracking tasks in industry or driving. It also fails to

indicate which behavioral components are involved in this task so

that we can at least make some statements regarding the nature of

marihuana’s effect on significant psychological variables.

Drug researchers often select response variables for which interpretations in terms of skills performance are unknown. For

attempting to assess drug effects in relationship to industry or

to driving, it is important that the response variables be appropriate.

In a study by Milstein et al. (8), several variables were examined

under the influence of marihuana: these included a hand-maze test ,

moving a stylus in a vertical or horizontal groove, and tests of

the speed of finger and toe tapping. This study compared the

performance on these variables of 16 experienced male and female

marihuana users with the performance of 16 subjects who had never

taken marihuana. All subjects in this crossover design received

7.8 mg delta-9 THC by smoking. There were significant decrements

in the vertical and horizontal groove task, the maze, and hand

steadiness, although there were no effects on the finger tapping

and toe tapping.

The authors found that the decrement in performance on the maze and

hand steadiness test was significantly greater for the experienced

smokers than the inexperienced smokers. This contradicts the

report by Weil et al. as well as other data in the literature.

Perhaps the difference is that most prior reports have dealt with

81
heavy users vs. infrequent users. ‘Ihis study seems to be comparing

moderate users with naive subjects who had never previously used

the substance. While the data may have merit in showing the differential effect in terms of usage, it would appear to have limited

value for documenting the effects of marihuana on more complex

skills performance.

Casswell and Marks (9) provide an example of the examination of

marihuana’s effects on a more complex function which a variety of

studies have shown to be highly important for skills performance.

The ability referred to is the simultaneous performance of two

tasks, or division of attention. In recent years, research in

skills performance has emphasized the importance of higher cognitive skills, with the ability to divide attention as a prime

example. Driving is intrinsically a situation in which one is

required to divide attention between a tracking task and a search

and recognition task for environmental dangers.

In the Casswell and Marks study, 10 naive subjects and 10 experienced subjects were compared at doses of 0, 3.3, and 6.3 mg delta-9

THC. Subjects were required to indicate whenever a break occurred

in the sequence of light flashes appearing at the center of a

visual arc. They were also asked to detect the random flashing of

a series of lights on the periphery of the visual arc. Under both

doses of marihuana, there were clear deficits in the perception of

changes for both central and peripheral lights. While the differences between the naive and the experienced users were not statistically significant, the trend appeared to be for a greater

decrement in the naive users.

As noted earlier, this study is important because it involved a

response variable which is important for driving skills. The

major criticism of the study, which is unrelated to the previous

point, is that a deficit shown in tests that measure division of

attention can be due to (1) interference with the specific skill

of performing divided attention, (2) to impairment of continuous

attention, or (3) to a decrement in the ability to monitor the

situation due to sensory input failure. Because there were no

controls for the variables required for dividing attention, we are

unable to pinpoint the nature of the reason for the deficit in

division of attention. However, as mentioned above, it is noteworthy that this study selected a variable shown to be of great

significance for driving.

An increasing number of studies are being published which are

designed to examine in greater detail the nature of deficits in

variables already known to be impaired by marihuana. One example

is the study by Dittrich et al. (10), in which 17 subjects were

examined after an orally administered dose of 15 mg delta-9 THC

to determine aspects of marihuana’s effects on memory, attention,

and subjective states.

The essence of the study was the correlation between the effects

of marihuana on an attention test and on a memory test, both

82
presented to subjects in the same session. Testing showed impairment of both attention and memory, and the decrement in attention

was found to be correlated with the decrease in input into longterm memory storage. These results emphasized the importance of

the role of attention as a variable influenced by the drug in

explaining some of the other effects of marihuana on performance.

While the variable examined here, memory, is probably not of great

importance in driving and other skilled performance situations, the

attempt to examine the relationship among more complex variables

in order to understand the nature of the deficit makes the study

valuable.

In addition to complex cognitive variables, skills performance is

affected by changes in simple sensory input functions such as the

thresholds for detection of auditory and visual signals. One early

study on sensory skills under marihuana was published by Caldwell

et al. (11). They examined auditory and visual thresholds in 20

experienced subjects before and after smoking marihuana. The

amount of marihuana administered was not calibrated, but was determined by the subjects’ reporting the point at which they experienced

a "high.” Marihuana had no effect on the visual brightness test,

on the auditory frequency threshold test, or on differences between

frequencies. There was a small effect on detection of differences

between auditory intensity thresholds. In general, the evidence

suggested that marihuana had little effect on auditory and visual

thresholds.

The importance of studying simple sensory phenomena in the laboratory is twofold. On the one hand, it is clear that such simple

sensory functions are of importance for driving and the performance

of other skills, and on the other, it is necessary if we are to

find the locus of the perceptual performance impairment under

marihuana that has been exhibited in experiments involving more

complex response tasks.

Users of marihuana have often reported the subjective, emotional

influences it has on their feelings and, potentially, their

behavior. These aspects of the effects of marihuana have been

elusive in laboratory examination as compared to sensory, perceptual, or motor skills effects. It is important that these behavioral

elements be examined, however, since they could affect the likelihood of accidents as much as deficits in visual or motor skills

could.

Subjective elements are frequently examined for drug influence by

self-reported scales filled out before and after a drug is

administered. The study by Waskow et al. (12) is typical of this

method. In this case, the chief measure was the Subjective Drug

Effects Questionnaire (SDEQ), which examines changes in thinking,

feeling, perception, and somatic areas influenced by drugs. Sixteen subjects received a dose of 20 mg of delta-9 THC and were

compared with 16 subjects who received a placebo. Half the subjects

under each drug treatment performed while music was being played.

83
This was designed to examine the influence of variables that are

typically met in a social context.

In addition to the subjects rating themselves, observers rate the

subjects on a standard observation form based on the Clyde Mood

Scale. The main effect shown by the Mood Scale was that subjects

under THC appeared more sleepy and less lucid to observers. The

prime result on the subjective self-report scale was that subjects

under marihuana felt that their thinking was fuzzy, their movements

slow, and that they were losing their sense of time. They also

reported perceptual changes, such as blurred eyesight and seeing

images with eyes closed. Subjects reported feeling sleepy and

“high,” and also reported a fair amount of somatic discomfort with

feelings of body heaviness and unsteadiness, and experiences of

impaired cognition.

Some studies have indicated a discrepancy between subjective reports

and objective performance changes; because of this, self-reports

are often difficult to interpret. They can provide important clues

as to marihuana’s effects, but may not be completely accurate. In

the study by Moskowitz and McGlothlin (13) on auditory signal

detection, subjects receiving placebo treatments, for example,

reported a “high” and various changes appeared on the Subjective

Drug Effects Questionnaire, but there was no change in performance

on the objective detection task.

An examination of social influences on drug effects was performed

by Jones (14) in which 9 mg of delta-9 THC were administered to

subjects who smoked in social group settings of four individuals,

and also to subjects who smoked in a solitary setting. The

response measure was again the Subjective Drug Effects Questionnaire (SDEQ) , and the findings were similar to those in the paper

by Katz et al. However, the subjects who used the marihuana in a

group setting reported far greater perceptual and thought changes

than those in the solitary setting, and also perceived the

experience as far more euphoric with far fewer elements of dysphoria.

Clearly, as far as the “high” is concerned, the "drug effect” is

much greater in a social setting. This finding for marihuana is

similar to reports for narcotics. It indicates that the environment in which the drug is used strongly affects the subjective

experience. In none of these studies, however, is there a

comparison between subjective and objective measures.

A study by Pliner et al. (15) presents an interesting attempt to

get around the problem of basing one’s conclusions on individual

self-reports. In this case, videotapes were made of subjects’

behavior at two similar parties--one in which they were served

alcohol and one in which they were served marihuana--with experimenter-participants leading the conversation to similar topics.

The videotapes were edited to remove all references to the substances being utilized, and then presented to observers who had

no prior knowledge of the drug used. These observers were asked

to rate the behavior they observed on a series of Mood Scales,

84
the Nowlis-Green Mood Adjective Check List, and several semantic

differential scales. The tapes were observed by individuals who

were merely asked to describe how the behavior of the individuals

they were viewing fell on the various Mood Scales. Since the

situation was that of a party, the quantities of drugs used were

determined by the subjects . On an average, the marihuana subjects

smoked three cigarettes, each containing 8 mg delta-9 THC. Examination of the Mood Scale indicated that the groups intoxicated on

marihuana were rated as appearing less active and more fatigued than

subjects in the alcohol study group. Subjects under the influence

of alcohol were rated as more tenacious, excitable, dissonant,

tense, unfriendly, anxious, and aggressive than subjects on marihuana.

This study lends support to subjective self-reports of behavior

changes made by individuals under the influence of marihuana.

Observers were able to detect such changes without being aware of

the drug’s presence. This experiment would have been even more

illuminating if subjects had also been examined. However, as a

step toward describing highly complex patterns of social interaction

which may in turn influence skills impairment under drugs, the study

represents a step forward in methodology.

To summarize the situation with regard to marihuana, it is clear

from the study examined, plus others, that the preponderance of

evidence indicates that marihuana does impair skills performance,

perceptual processes, attention, and tracking behavior. All

important components of driving and skills performance were thus

clearly affected.

The behavioral sites of marihuana’s pharmacological action are less

clear. That is, we do not how which behavioral mechanisms or

functions are being affected to cause the decrements in the

behavioral responses we are measuring.

While most studies on sensation of thresholds (e.g., the preceding

discussion by Caldwell et al.) have found no evidence for impairment, a recent study by Hill et al. (16) found that marihuana

decreased the pain threshold. The study used 20 subjects in the

marihuana group and 6 in the placebo group. Subjects received

approximately 12 mg delta-9 THC. Subjects under the influence

of marihuana exhibited increased sensitivity, that is, lower

thresholds, to electrical stimulation applied to the subjects’

fingers. This was true for both painful and nonpainful stimulation.

These results for electrical stimulation are at variance with

results from the majority of studies on sensory thresholds for

visual and auditory sensations. It would have been better to have

a design which separated out such factors as the set or criterion

effects from the actual sensitivity effects.

If signal detection theory had been utilized in the experimental

design and in analysis of the results, we would have been able to

determine whether marihuana affected sensitivity per se or whether

bias was changed. Certainly, these results raise questions with

regard to what is the proper pharmacological category into which

85
marihuana should be placed. At minimum, they make clear that we

still lack knowledge about the nature of the behavioral mechanisms

affected by marihuana.

SUMMARY: HALLUCINOGENS

The Marihuana studies reviewed above have illustrated the wide

range of techniques which have been applied to examine the effects

of that drug on skills performance. Unfortunately, few such studies are available for the hallucinogens. While a large number of

papers were examined on hallucinogens, the overwhelming majority of

them were concerned with subjective reports of subjective states.

One of the better examples of these was the one done by Katz et al.

(17). Twenty-four subjects were administered 50 μg of LSD and their

responses to a series of rating scales, such as the Clyde Mood Scale

and the Subjective Drug Effects Questionnaire, a picture rating

scale, and a verbal and vocal behavior scale, were recorded. The

subjects were compared with other subjects receiving 15 mg of

amphetamine, 50 mg of chlorpromazine, or placebo treatment. It

should be noted that the subjects were studied in prison, since

there might well be an interaction between the nature of the environment and the drug.

Subjects under the influence of LSD reported the occurrence of very

strong emotional reactions, without any apparent stimulation from

the outside. They also reported feeling unable to control their

emotions and thoughts, feeling detached from the real world, perceiving the real world as having an unreal quality and, finally,

feeling generally suspicious about their perceptions. Such reports,

while suggesting possible difficulties while driving, certainly

would make it hard to predict how the drug would influence actual

performance.

Woody (18) reported on three cases of patients who had experienced

episodes of visual disturbance while driving. Subjects were active

hallucinogenic drug abusers, although none, had taken any of the

substances within the preceding 10 hours. The episodes appeared to

have been flashbacks, which can be described as either hallucinations or prolonged after-images. What is important is the fact that

the subjects reported reacting to these visual disturbances as

though they were real, either by stopping the car immediately or by

driving off the road.

The experimental studies that we found on the effects of hallucinogens using objective measures were not performed on measures that

could be easily related to skills performance. Thus, for example,

there is the study by Hebbard and Fischer (19) which examined the

effects of psilocybin, LSD, and mescaline, as compared to the

effects of alcohol, on small, involuntary eye movements. The eye

movements concerned are those microsaccades which occur while trying to maintain a fixation on a small target.

a physiological nystagmus that was studied.

Essentially, it was

In all cases, the

three hallucinogenic drugs, plus alcohol, increased both the fre86
quency and amplitude of these involuntary eye movements. The

oscillographic records of these eye movements were very similar for

the three hallucinogenic drugs, i.e., a microsaccade would occur

with a rapid transition to a new point which was held steady, and

then another saccade would occur very rapidly to another maintained

position.

These records appear as a series of square waves. Alcohol showed

a series of saw-toothed patterns in which, after the saccade had

occurred, there was an extensive continued drift of position. The

records indicate that the ocular motor control system is differentially affected by hallucinogenic drugs and alcohol. This particular measure of ocular motor control has no apparent relationship

to the subject's performance. The major conclusion one can offer

after examining a considerable number of papers (not reported)

discussing hallucinogenic drugs, is the surprising lack of research

examining objective skills performance under hallucinogenic drugs.

COMMENT

Many researchers have set their sights upon determining whether a

particular skill is affected by a drug, whereas others have been

concerned with how that skill is affected, i.e., what behavioral

mechanisms are specifically influenced by the drug to produce the

skills decrement. I suggest that, in general, the second view is

the better for both theoretical and practical reasons.

Certainly only by determining which behavioral mechanisms are

affected by specific drugs will we be capable in the long run of

understanding the relationship between the alterations in physiology

produced by drugs and behavioral changes. Also, only by determining the specific behaviors affected by a drug will we be in a position to specify possible countermeasures to the safety-reducing side

effects. Many therapeutic drugs will remain in use despite their

effects on skills performance. By understanding what behaviors

they influence, we could possibly suggest effective countermeasures.

In addition to examining behaviors which suggest the nature of the

drug effect rather than studying merely whether behavior is

affected, one must face a major empirical problem with behavioral

studies that aim solely to determine whether a particular skill is

affected. This problem is that for few skills are we in a position

to say that any study has obtained a representative sample of the

behaviors required for that skill.

While it would be desirable to have a behavioral test which represents all the major requirements of driving, no such test currently

exists. The behavioral demands are quite diverse, complex, and

inadequately specified.

It might be thought that one could sample the necessary skills by

placing subjects under drugs in an actual car on the road. Such an

approach is inadequate, since the potential for danger from drug

87
use involves an interaction with a host of vehicle, road, and environmental factors which cannot be easily sampled in a short time

span. Moreover, for safety, actual vehicle examination of driving

behavior usually takes place on closed courses. These are quite

unreal in the environmental demands they make on the subject.

It might be thought that a driving simulator could adequately sample

the demands of driving. However, all existing and currently conceivable simulators are essentially part-task simulators. Some

subsample of the total demands of driving is examined, with the

demand character of the simulator and resulting dependent experimental measures being determined by the theoretical position of the

simulator developer.

Moreover, many of the more complex simulators have difficulty

specifying the nature of the behavioral demands placed upon the

subjects driving them. It is better to test subjects on clearly

specified behavioral skills involved in driving rather than to use

devices with face validity but with little evidence to specify the

nature of the behavioral demands involved.

Since any current testing program can only examine some subset of

all the behavioral demands of driving, it is important that the

tasks selected for testing be adequately specified in terms of their

behavioral demands upon the subject. If this is done, information

acquired can be compared with what is currently known and with

knowledge that will be acquired in the future about the behavioral

aspects of driving.

The selection of which performance tasks to examine could initially

be based on literature from two sources: (1) skills tasks performance most highly correlated with adequacy in job (such as

driver) performance and (2) those performance skills tasks most

frequently reported, by their absence, as the basis of accidents by

groups performing intensive on-site investigations of driving accidents. It is interesting to note that both sources of information

suggest the same factors as being of prime importance in complex

skills performance.

Correlations with long-term safety records and examinations of the

immediate proximal causes of accidents suggest that the most important behavioral factors involved in accidents are perception, attention, and information processing.

The above areas to investigate are a good place to begin due to

their obvious importance for skills performance. However, this is

not completely adequate, since a particular drug could produce a

deficit in a behavior normally assumed to have little correlation

with skills performance because of its small variation range in

normal adults. For instance, the range of visual acuity in the

driving public is little correlated with driving accidents, but a

drug which reduced acuity to 20/600 might well produce greater

probabilities of accidents. Therefore, beyond the behaviors most

highly correlated with skills performance, an adequate survey of

88
the possible effects of drugs on safety must examine functions

which appear to show only small correlations with skills performance but which a logical analysis of the skills suggests are

necessary component capabilities.

The above discussion has concerned which behavioral variables to

investigate. An equally important issue is the nature of the

experimental design and data analysis. In this regard, it is

important to use the latest analytical psychological techniques

which fractionate the behavioral area into psychologically significant variables. Thus, for example, one can investigate perception with classical techniques or using signal detection theory,

a technique by which one can separate out changes in perception

caused by sensitivity changes from those caused by changes in subject's criterion. Similarly analysis of tracking can utilize the

newer techniques of describing functions which attempt to fractionate changes in tracking behavior into elements primarily related to

such factors as basic reaction time, attitudes, and sensitivity.

To summarize, the study of the relationship between drugs and

skills performance requires an understanding of how drugs affect

various behavior components which are required skills performance. Attempting to determine if any particular skill situation

is liable to drug impairment is empirically difficult with any

single test and may well be misleading. For the long run development of the field of behavioral drug studies as well as for the

empirical needs of determining the potential hazards associated

with a drug, systematic determination of what behaviors are

affected by a drug are necessary.

REFERENCES

1. Klonoff, H.: Marijuana and Driving in Real-Life Situations.

Science, 186:317-324. 1974.

2. Rafaelsen, O.L., P. Bech, J. Christiansen, H. Christrup,

J. Nyboe, L. Rafaelsen: Cannabis and Alcohol: Effects on Simulated

Car Driving. Science, 179:920-923. 1973.

3. Dott, A.B.: Effect of Marihuana on Risk Acceptance in a

Simulated Passing Task. Public Health Service Report ICRL-RR-71-3,

DHEW Publication No. HSM-72-10010, Washington, D.C. 1972.

4. Manno, J.E., G.F. Kiplinger, N. Scholz, R.B. Fomey: The

Influence of Alcohol and Marihuana on Motor and Mental Performance.

Clin. Pharmacol. Therapeutics, 12:650-657. 1971.

5. Roth, W.T., J.R. Tinklenberg, C.A. Hitaker, C.F. Darley,

B.S. Kopell, L.E. Hollister: The Effect of Marihuana on Tracking

Task Performance. Psychopharmacologia, 33:259-265. 1973.

6. Reid, L.D., M.K.F. Ibrahim, R.D. Miller, H.W. Hansteen.

The Influence of Alcohol and Marijuana on a Manual Tracking Task.

89
Society of Automotive Engineers Congress, Technical Paper No.

730092, Detroit, Michigan, January 1973.

7. Weil, A.T., N.E. Zinberg, J.M. Nelsen: Clinical and

Psychological Effects of Marijuana in Man.

1968.

Science, 162:1234-1242.

8. Milstein, S., K. MacCannel, G. Karr, S. Clark: MarijuanaProduced Impairment in Coordination. Journal of Nervous and Mental

Diseases, 161:26-31. 1975.

9. Casswell, S. and D. Marks: Cannabis Induced Impairment of

Performance of a Divided Attention Task. Nature, 241:60-61. 1973.

10. Dittrich, A., K. Battig, I. von Zeppelin: Effects of (-)Delta9 Transtetraphydrocannabinol (Delta-9 THC) on Memory, Attention and

Subjective States. Psychopharmacologia, 33:369-376. 1973.

11. Caldwell, D.F., S.A. Myers, E.F. Domino, P.E. Mirriam:

Auditory and Visual Threshold Effects of Marihuana in Man.

Motor Skills, 29:755-759. 1969.

Perc.

12. Waskow, I., J. Olsson, C. Sulzman, M. Katz: Psychological

Effects on Tetrahydrocannabinol. Archives of General Psychiatry,

22:97-107. 1970.

13. Moskowitz, H. and W. McGlothlin: Effects of Marihuana on

Auditory Signal Detection. Psychopharmacologia, 40:137-145. 1974.

14. Jones, R.: Tetrahydrocannabinol and the Marihuana-Induced

Social "High," or the Effects of the Mind on Marihuana. Annals New

York Academy of Sciences, 191:155-165. 1971.

15. Pliner, P., H. Cappell, C.G. Miles: Observer Judgements of

Intoxicated Behavior During Social Interaction: A Comparison of

Alcohol and Marihuana. Drug Addiction: Vol. 2, Clinical and Sociolegal Aspects, J.M. Singh, L.G. Miller, and H. Lal, eds., Future,

Mt. Kisco, New York. 1972.

16. Hill, S.Y., R. Schwin, D.A. Goodwin, B.J. Powell: Marihuana

and Pain. J. Pharmacol. Exper. Therapeutics, 188:415-418. 1974.

17. Katz, M., M. Waskow, J. Olsson: Characterizing the Psychological State Produced by LSD. Journal of Abnormal Psychology, 73:

1-14. 1968.

18. Woody, G.: Visual Disturbances Experienced by Hallucinogenic

Drug Abusers While Driving. American J. of Psychiatry, 127:683-686.

1970.

19. Hebbard, F. and K. Fischer: Effect of Psilocybin, LSD and

Mescaline on Small Involuntary Eye Movements. Psychopharmacologia,

9:146-156. 1966.

90
MARIHUANA

OTHER DRUGS

Arthur McBay, Ph.D.

SUMMARY: MARIHUANA

Marihuana has been smoked by 30 million Americans and it is estimated that 13 million smoke it rather frequently. Many must operate motor vehicles following the smoking of the drug. It has not

been established that marihuana causes hazardous changes in driving

ability. Until marihuana concentrations in drivers responsible for

crashes are compared with marihuana concentrations in drivers not

responsible for crashes, other less satisfactory studies will have

to be used to shed some light on the potential problem.

Studies have examined the effects of marihuana on sensory-perceptual skills.

Moskowitz, Sharma, and Schapero (1) compared the effects of marihuana and alcohol on visual fun tions. Their 12 male subjects

smoked marihuana cigarettes which allegedly delivered 0 or 200 μg

of THC per kg. It was found that marihuana produced a significant

decrement in peripheral signal detection under all conditions of

central visual information processing, including the condition

where no central information processing is required. A similar

study on subjects who were given up to 0.8 g of alcohol per kg

revealed that there was significant impairment of peripheral

vision when central vision transmits material requiring information

processing by the brain but not when central vision does not require information processing by the brain. The subjects who smoked

marihuana showed significant increases in apparent movement of

light (autokinesis) whereas the alcohol-influenced subjects did

not. Neither drug impaired light adaptation or visual acuity.

Both drugs produced an impairment of ocular motor control.

Moskowitz, Shanna, and McGlothlin (2) reported that marihuana

impaired detection of peripheral light stimuli and that the decrement was linearly related to dose. This report is similar to that

of the preceding report except that the marihuana smoked was

alleged to deliver 0, 50, 100, or 200 μg of THC per kg.

Moskowitz and McGlothlin (3) studied the effects of marihuana on

auditory signal detection. Their 23 male subjects each smoked

marihuana cigarettes containing 0, 50, 100, or 200 μg of THC per

kg. Their data indicated that marihuana produced significant

decrements in auditory signal detection under concentrated and

91

231-545 O - 77 - 8
divided attention conditions. Alcohol at a dose of 0.69 g/kg

produced impairment under conditions of divided attention but not

when attention was concentrated. They concluded that alcohol

impairment appeared to be related to the requirement that information be processed from two simultaneous sources. They also concluded that marihuana impairs single as well as two-source information processing and that the degree of impairment by marihuana is

greater under more complex demands of divided attention.

Moskowitz, Shea, and burns (4) examined the effect of marihuana on

the psychological refractory period by measuring the reaction times

to an auditory stimulus and a subsequent visual stimulus. Their 12

male subjects each smoked two marihuana cigarettes such that their

dose levels were 0, 100, or 200 μg of THC per kg. They found that

the reaction time to an auditory stimulus was delayed by the 100-

and 200-μg doses, essentially the same amount, and that the reaction time to the visual stimulus was delayed approximately twice as

much by the larger dose as compared to the smaller dose.

Another attempt at testing the deterioration of driving performance

was through the use of the driving simulator. Moskowitz, Hulbert,

and McGlothlin (5) reported on the effects of marihuana on simulated driving performance. Their subjects, 24 male college volunteers, smoked marihuana cigarettes which allegedly delivered doses

of 0, 50, 100, or 200 μg of THC per kg. Marihuana smoking did not

create significant deviations from the norm in car control and

tracking aspects of the driving simulator.

The authors conclude that the data provide no evidence that marihuana significantly affects car control performance as measured by

the driving simulator. There was not a statistically significant

within-subject increase in reaction time as the marihuana dose was

increased. The data did indicate a statistically significant doserelated impairment of reaction times to the subsidiary tasks of

responses to light signals.

Rafaelsen and others (6) tested the effects of marihuana and alcohol on simulated car driving. Their subjects were eight volunteers

from the Danish Civil Defense Corps. Cannabis resin was baked in

small brown cakes each of which contained 0, 8, 12, or 16 mg of

THC. The cakes were eaten. Drinks with alcohol were prepared by

mixing 70 g of 96% ethanol with fruit juice. When ingested, blood

alcohol concentrations of about 0.10 percent resulted. Fruit juice

with no alcohol was used as a placebo. Alternating between ethanol, various strengths of cannabis, and placebos, each subject was

allowed to serve as his own control. Cannabis in doses which

contained 12 and 16 mg of THC and alcohol significantly increased

brake time. Only cannabis in doses which contained 16 mg of THC

significantly increased start time. The number of gear changes

increased with alcohol and decreased with cannabis. Pulse rates

increased with alcohol and cannabis. Neither drug affected the

actual mean speed.

92
Crancer and others (7) studied the effects of marihuana and alcohol

on simulated driving performance. Their subjects, 7 females and 29

males, each smoked two marijuana cigarettes which weighed a total

of 1.7 g of 1.3% THC. The subjects ingested enough 95% alcohol in

orange or tomato juice to produce 0.10 percent blood alcohol concentration. Following smoking marihuana, pulse rates increased and

there was an increase in speedometer errors but there were no

significant deviations from the norm in accelerator, brake, signal,

steering, and total errors. The same subjects under the influence

of alcohol accumulated significantly more accelerator, brake,

signal, speedometer, and total errors than under control conditions.

There were significant increases in steering errors. No increase

in impairment was noted because of inexperience with marihuana or

when marihuana dosage was increased. About half the subjects

showed improvement in individual error scores following marihuana

smoking.

In 1972, Dott (8) tested the effect of marihuana on risk acceptance

in a simulated passing task. His 12 male subjects each smoked two

marihuana cigarettes which allegedly delivered 0, 11.25, or 22.5 mg

of THC. The mean plasma concentration was about 70 ng of THC per

ml for samples taken following the 11.25- and 22.5-mg THC doses.

Risk-taking behavior was measured by attempts, completed passes,

and accidents. It appears that the subject under the influence of

marihuana was less likely to accept the increased risk of attempting to complete the passes that were more hazardous. Marihuana did

not significantly affect the number of attempted passes or the

number of accidents; nor did it significantly affect the emergency

decision-reaction time or the decision-reaction time or the lateral

control of the vehicle. The drug did prolong the decision-reaction

time during the nonabort of the passing situation. In a prior

study, 16 subjects whose mean alcohol concentration was 0.09 percent attempted and completed more passes and had more accidents

than those who smoked marihuana. Alcohol also affected the lateral

position of the vehicle and the tracking range during passes;

marihuana did not.

Klonoff (9) examined the effects of marihuana on driving in reallife situations. The marihuana was administered by having 64

volunteers smoke cigarettes containing 0, 4.9, or 8.4 mg of THC.

Smoking was standardized and a double-blind procedure was used.

Duel-control automobiles with an observer in the front seat were

operated on a driving course and on downtown streets during peak

traffic. Eleven behavioral components were used as measures of

driving skills. Marihuana impeded learning; the rate of decline

was dose related. Braking distance was not specifically affected.

The results indicated a significant deterioration of performance by

some subjects and improvement by others on the driving course and

on city streets. The deterioration was greater than the improvement following marihuana usage. The deterioration was also greater

following high marihuana usage than after low marihuana usage, and

during street driving than in course driving. Marihuana appeared

to significantly affect judgment, care, and concentration. The

ambivalent effects of the drug on driving became apparent when no

93
significant change was found in 21 to 43 percent of the subjects

and when 14 to 32 percent showed significant improvement after

smoking marihuana .

Moskowitz in 1976 (10) reported on the effects of alcohol and

marihuana on visual search behavior when viewing driving scenes.

In the alcohol experiment, 27 male heavy drinkers were given enough

alcohol to produce blood alcohol concentrations of 0.0, 0.075, or

0.15 percent. Blood alcohol concentrations were measured. Significant changes in visual search behavior including increased dwell

duration, decreased dwell frequency, and increased pursuit duration

and frequency were found in those under the influence of alcohol.

The authors conclude that a person under the influence of alcohol

can examine fewer events or examine the same event fewer times. He

tends to pursue moving objects more often and for a longer time,

further limiting the opportunity for simultaneously concentrating

on different events.

In the marihuana experiment, 10 male social marihuana users smoked

cigarettes containing mixtures of detoxified marihuana and marihuana containing 2.45% THC to give doses of 0, 50, or 200 μg of

THC per kg. Not a single visual search or subsidiary task measure

was affected to any degree by this rather heavy marihuana treatment.

Janowsky (11) reported on the effects of marihuana on simulated

flying ability. Their subjects, 10 certified pilots, smoked a

placebo and marihuana in pipes. The marihuana which contained 2.1%

THC was presumably administered in a dose of 0.09 mg of THC per kg,

using randomized double-blind crossover design. Average data for

the entire group of pilots were presented rather than data for

individual performance, which changed considerably from pilot to

pilot and from variable to variable. The results indicate that

when experienced pilots smoked marihuana in doses used “socially,”

significant deterioration occurs in simulated instrument flying

ability within 30 minutes.

and is gone within 4 hours.

The effect probably peaks for 2 hours

It appears that marihuana affects

short-term memory and sense of time. It also appears to create

alterations in concentration and attending behavior, generating

concentration on one variable to the exclusion of others.

SUMMARY: OTHER DRUGS - DRIVING

Korttila and Linnoila (12) tested skills related to driving after

intravenous diazepam, flunitrazepam, and droperidol. Their subjects, 62 students whose skills related to driving and the ability

to discriminate the fusion of flickering light, were measured

double blind. Intravenous injections of diazepam (0.3 mg/kg),

flunitrazepam (0.03 mg/kg), and droperidol (5 mg) were given alone

or in combination with pethidine (1 mg/kg) or fentenyl (0.2 mg).

The doses of diazapam and flunitrazepam were halved in those subjects given pethidine but the dose of droperidol was the same with

and without fentanyl.

benzodiazepines.

Droperidol proved more deleterious than the

Flicker fusion discrimination and coordination

94
was impaired for up to 10 hours by flunitrazepam and up to 6 hours

by diazepam. The doses of narcotic analgesics did not enhance the

effects of other drugs. The authors were helpful by including

blood concentrations of diazepam and flunitrazepam. They concluded

that patients should not drive or operate machinery for 10 hours

after injection of diazepam and 24 hours after flunitrazepam and

droperidol.

Korttila and Linnoila (13) studied the recovery and skills related

to driving after intravenous injection of diazepam. Their 34

subjects, whose skills related to driving, the ability to discriminate the fusion of flickering light, and hand and foot proprioception, were measured double blind.

harmful to coordination.

The effects of diazepam were not

Coordinative skills were significantly

impaired for up to 2.6 and 8 hours by 0.15 mg/kg, 0.30 mg/kg, and

0.45 mg/kg of diazepam, respectively. Blood concentrations of

diazepam were given. The authors concluded that patients should

not drive or operate machinery for 6 hours after 0.15 mg/kg of

intravenous diazepam or 10 hours after 0.30 and 0.45 mg/kg.

Korttila and Linnoila (14) examined skills related to driving after

intramuscular injection of diazepam and meperidine. Their 11

subjects, whose skills again related to driving and the ability to

discriminate the fusion of flickering light, were measured double

blind, crossover fashion. The drugs were used in doses of 10 mg

for diazepam and 75 mg for meperidine. Diazepam significantly

impaired the coordinative and reactive skills for as long as 5

hours. Meperidine impaired reactive skills for up to 3 hours and

flicker-fusion discrimination and coordinative skills for up to 12

hours. The authors concluded that patients should not drive or

operate machinery for 7 hours after receiving meperidine intramuscularly. Serum concentrations of the drugs are given.

Korttila, Linnoila, and others (15) reported on recovery and simulated driving after intravenous anesthesia with thiopental, methohexital, propanidid, and alphadione. Skills of their 40 subjects

were tested using a driving simulator. The intravenous anesthesia

used was thiopental (6 mg/kg), methohexital (2 mg/kg), propanidid

(6.6 mg/kg), or alphadione (μl/kg). Driving performances were

significantly deteriorated for 6 hours after thiopental, for 8

hours after methohexital, and for 6 hours after alphadione. Propanidid produced no impairment of driving skills.

Finkle (16) studied 2,500 cases in which drugs were involved in

drinking drivers. The subjects were 2,559 of the 10,436 drivers

arrested in Santa Clara County, California, during the years 1966,

1967, and 1968. The 2,559 cases in which drug involvement was

reported were determined by the arresting officer questioning the

driver, or by chemical analysis. It appears that some of the drugs

were discovered because the police officers requested the analyses.

Others were found because of drug analyses undertaken on subjects

who had blood alcohol concentrations of less than 0.15 percent and

who were exhibiting overt signs of intoxication. Seven hundred

drug analyses were performed; 159 (22 percent) were positive. It

95
appears that there were 213 occurrences of 24 different drugs. One

hundred and sixty occurrences were in subjects whose blood contained

0.10 percent alcohol or less, and it appears that the deterioration

of performance in these cases were attributed to the various drugs.

No mention is made as to whether some subjects had more than one

drug or whether the concentration of the drug was considered sufficient to influence the operator. In any event, 160 represents

1.5 percent of the 10,436 drivers arrested. Three-fourths of the

drugs involved were barbiturates. Data in this study thus reveal

that a relatively small percentage of operators were detected whose

driving appeared affected by drugs other than alcohol.

Garriott and Latman (17) reported on the detection of drugs in

arrests for “driving under the influence.” Since some of their

data cover the last half of 1973 and all of 1974, and other data

cover all of 1973 and 1974, this summary will deal only with 1974

data. In 1974, there were 6,047 driving under the influence

arrests and 71 driving under the influence of drugs arrests in

Dallas County, Texas. Drug-related arrests amounted to 1 percent

of the total. In 13 of the 71 cases, alcohol was the only drug

found. Alcohol concentrations of 0.10 percent or more were found

in six cases where more than one drug was found. Neither alcohol

nor any other drug was found in seven more cases. It appears that

the drug charge was substantiated by scientific evidence in 45 (63

percent) of the cases. The principal drugs detected were barbiturates, methaqualone, and diazepam. No comments were made about

what concentrations of these drugs are thought to effect the driver.

COMMENT: MARIHUANA

The studies of Moskowitz were based on visual and auditory stimuli

and reaction times. Standardized marihuana cigarettes were smoked

but no blood determinations were made. Blood concentration studies

have revealed that tetrahydrocannibinol peaks in about 10 minutes

after smoking and drops rapidly to about 5 percent of this concentration in an hour. The activities of any metabolites have not

been firmly established. It would be interesting to know if any

individual subjects were not affected by marihuana or whether some

improved. His results were averaged. Moskowitz also used a driving simulator to study the effects of the drug. The above comments

apply to this study also.

Rafaelsen used a driving simulator but he administered marihuana

orally from baked cakes containing the drug. Crancer also used a

driving simulator but his subjects smoked. In both these studies,

no blood determinations are reported.

Dott used a rather sophisticated driving simulator. His subjects

smoked marihuana, and plasma concentrations of THC were reported.

Marihuana appeared to improve performance in a risk-taking passing

situation.

Klonoff allowed drivers to smoke marihuana and drive on a course

and on city streets. The ambivalence of the effects of marihuana

96
was demonstrated by those whose driving performance did not significantly change and those who had a significant improvement. No

blood determinations were made.

Janowsky allowed pilots to smoke marihuana and tested their ability

to fly a simulator. He averaged data because individual performance varied considerably. No blood determinations were made.

The effects of marihuana as determined by these studies are subtle.

Complex testing would be required to detect deviations from skills

from normal. The drug appears to affect the sensory-perceptual

skills, judgment, and performance. Performance decrement appears

when the subject is faced with unexpected and random events where

constant attention is needed or where information must be stored

and retrieved. The loss of motor control of vehicles is unlikely.

There appears to be no effect on depth perception, visual brightness threshold, adaptation to darkness, and visual acuity. Marihuana seems to make subjects less aggressive and less likely to

take a risk.

It is realized that the quantitation of THC in blood is a relatively recent practice, for which data are not readily available.

Until performance is related to blood concentrations or until blood

concentrations of accident-free drivers are compared with those who

have accidents, it will not be possible to claim that performance

is sufficiently affected to cause crashes and deaths. It will not

be possible to justifiably charge a person with driving under the

influence of marihuana until it can be shown that marihuana use, in

itself, has a detrimental effect on driving. At the present time

there is no evidence that marihuana is a significant public safety

problem or is about to become one. The effects of marihuana reported in these studies are such that it is highly unlikely that a

person driving erratically and recklessly would do so because of

the influence of the drug.

People should be advised not to operate a motor vehicle or other

machinery following the ingestion of any drug which could possibly

cause any deterioration of performance. The effects of marihuana

on driving should be compared with those of alcohol, barbiturates,

aspirin, propoxyphene, caffeine, tobacco, and other drugs. The

average operator can relate to some of these.

COMMENT: OTHER DRUGS

Korttila and Linnoila commented on the effects on driving of some

drugs which may be used intravenously or intramuscularly on some

ambulatory patients. The drugs were diazepam, flunitrazepam,

droperidol, meperidine, thiopental, methohexital, propanidid, and

alphadione. Blood concentrations for most of these were given.

The authors’ warnings about not driving for various times after the

administration of these drugs are helpful.

Fincle’s study reaffirmed the few studies made of drugs and actual

driving. These studies in general have shown that drugs other than

97
alcohol are found in less than 5 percent of the cases. Of the

drugs that were found, some have been shown to cause no deterioration in performance or to be present in concentrations too small to

cause deterioration.

REFERENCES

1. Moskowitz, H., S. Shanna, M. Schapero: A Comparison of the

Effects of Marihuana and Alcohol on Visual Functions. In: Current

Research in Marihuana, Academic Press, New York, 1972, pp. 129-150.

2. Moskowitz, H., S. Sharma, W. McGlothlin: Effect of Marihuana

on Peripheral Vision as a Function of the Information Processing

Demands in Central Vision. Percep. Motor Skills, 35:875-882.

1972.

3. Moskowitz, H. and W. McGlothlin: Effects of Marihuana on

Auditory Signal Detection. Psychopharmacologia, 40:137-145. 1974.

4. Moskowitz, H., R. Shea, M. Burns: Effects of Marihuana on the

Psychological Refractory Period. Percep. Motor Skills, 38:959-962.

1974.

5. Moskowitz, H., S. Hulbert, W. McGlothlin: Marihuana: Effects

on Simulated Driving Performance. Accid. Anal. Prev., 8:45-50.

1976.

6. Rafaelsen, O.J., P. Bech, J. Christiansen, H. Christrup, J.

Nyboe, L. Rafaelsen: Cannabis and Alcohol: Effects on Simulated

Car Driving. Science, 179:920-923. 1973.

7. Crancer, A., J.M. Dille, J.C. Delay, J.E. Wallace, M.D. Haykins:

Comparison of the Effects of Marihuana and Alcohol on Simulated

Driving Performance. Science, 164:851-854. 1969.

8. Dott, A.B.: Effect of Marihuana on Risk Acceptance in a

Simulated Passing Task. Public Health Service Report ICRL-RR-71-3,

DHEW Publication No. HSM-72-10010, Washington, D.C., 1972.

9. Klonoff, H.: Marihuana and Driving in Real-Life Situations.

Science, 186:317-324. 1974.

10. Moskowitz, H., K. Zeidman, S. Sharma: Visual Search Behavior

While Viewing Driving Scenes Under the Influence of Alcohol and

Marihuana. From a prepublication copy of Human Factors, 1976. (In

press).

11. Janowsky, D.S., M.P. Meacham, J.D. Blaine, M. Schoor, and L.P.

Bozzetti: Marihuana Effects on Simulated Flying Ability. Am. J.

Psychiatry, 133:384-388. 1976.

12. Korttila, K. and M. Linnoila: Skills Related to Driving After

Intravenous Diazepam, Flunitrazepam, or Droperidol. Brit. J.

Anesth., 46.961-969. 1974.

98
13. Korttila, K. and M. Linnoila: Recovery and Skills Related to

Driving after Intravenous Sedation: Dose-Response Relationship

With Diazepam. Brit. J. Anesth., 47:457-463. 1975.

14. Korttila, K. and M. Linnoila: Psychomotor Skills Related to

Driving After Intramuscular Administration of Diazepam and Meperidine. Anesthesiology, 42:685-691. 1975.

15. Korttila, K., M. Linnoila, P. Ertama, and S. Hakkinen: Recovery and Simulated Driving After Intravenous Anesthesia With

Thiopental, Methohexital, Propanidid, or Alphadione. Anesthesiology, 43:283-291. 1975.

16. Finkle, B.: Drugs in Drinking Drivers: A Study of 2,500

Cases. J. Safety Res., 1:179-183. 1969.

17. Garriott, J.C. and N. Latman: Drug Detection in Cases of

“Driving Under the Influence.” J. Forensic Sci., 21:398-415.

1976.

99
OTHER DRUGS - GENERAL

Reginald Smart, Ph.D.

SUMMARY

Milner (1) reported on a study made in Perth, West Australia,

of adults attending eight general practitioners, two psychiatrists,

and two psychiatric hospital departments. There were 564 patients

attending psychiatrists and 4,020 seeing general practitioners.

Questions were asked about demographic characteristics, drugs

prescribed, driving, and drinking.

It was found that 57 percent of the male and 35 percent of the

female patients given psychotropic drugs "might" also drink and

drive. Phenothiazines and other tranquilizers were prescribed

for 45 percent of the patients, sedatives were next most common,

followed by antianxiety preparations (Librium, Valium). A negligible

amount of amphetamines and MAO inhibitors were prescribed. More

than one drug was prescribed for 33 percent of patients. Of those

given psychotropics, 85 percent of the men drank, 66 percent were

licensed to drive, and 57 percent were at risk of drinking and

driving while on a psychotropic. For women, the figures were

71 percent, 42 percent, and 35 percent, respectively.

It was concluded that:

1. A large proportion of patients drink alcohol and are licensed

to drive.

2. As psychotropics are long acting, dangerous driving behavior

may result from their use.

3. Warnings should be given to patients on such drugs.

The paper presented data only for conclusion 1.

Crancer and Quiring (2) studied the driving records of 628 persons

in the State of Washington. They were sampled from the Seattle

Police Department records and the entire list of active narcotic

users in King County as supplied by the U.S. Bureau of Narcotics.

Each was placed into one of three groups: (1) narcotic users,

except marihuana (n = 198); (2) dangerous drug (amphetamines,

barbiturates, and hallucinogens) users (n = 270); and (3) marihuana

users (n = 160). Of these, 51 percent were licensed at some time

in the previous 6 years. Only 302 were checked for traffic records, as they were currently licensed in and residents of King

County. A comparison was made to 687,228 currently licensed drivers

of the same age and sex.

100
The results indicated that:

1. All groups of illegal drug users had higher accident and

violation rates than the corresponding general population

group (29 percent higher overall).

2. Few illegal drug users had clear records, i.e., no accident

or violation.

3. Illegal drug users had higher rates of certain violations,

i.e., reckless driving, negligent driving, hit-and-run, and

defective equipment but lower rates of speeding, failure to

stop, and failure to yield.

4. The narcotics group (but not the others) had a slightly

higher percentage of injury accidents than expected.

The conclusions that arrests for illegal drug use would be valuable

in predicting driving performance seems only partly justified

as it is not clear that all illegal drug users had been arrested,

nor that a comparison was made between those arrested and those

not arrested. Also, no data were obtained on driving exposure

(e.g., miles driven)--drug users could have higher citation rates

because of greater exposure.

Finkle (3) studied 10,436 routine drinking-driver arrests in Santa

Clara County, California. The basic data were from the chemical

testing of blood and urine samples. Detailed interviews were

apparently not conducted.

The results indicated that about 25 percent had a drug involvement,

as determined by the arresting officer or a chemical analysis.

In total, 273 different drugs were encountered on 2,688 occasions.

The most common were tranquilizers (n = 518), analgesics (n =

315), and stimulants (n = 309). In 1,406 cases or 13 percent

of the total, there were "dangerous" drugs, i.e., those requiring

a prescription. About 60 percent of drug cases involved drivers

with 0 to 0.05 percent blood alcohol content (BAC), 10 percent

with 0.05 to 0.10 percent BAC, 23 percent with 0.10 to 0.15 percent BAC, and 7 percent with more than 0.15 percent BAC.

A total of 700 drug analyses were done on drivers with blood alcohol

levels in excess of .15 percent. Of these, 22 percent were positive.

Only 6 percent of cases positive for drugs were negative for alcohol.

About 75 percent of those involved with drugs were males in their

twenties and forties. Female drug positives tended to be in their

forties. The results were useful in the administration of justice

in that the district attorney issued complaints in 77 percent

of cases with drugs detected by analysis, chiefly for driving

under the influence of alcohol and drugs.

Apparently this study did not involve a search for illicit drugs

such as narcotics, hallucinogens, or cannabis, and the prevalence

figures relate to prescription and over-the-counter drugs. The

study is a good one, considering its aims, methods, and conclusions.

101
Kielholz (4) made a study of 1,030 hospitalized persons injured

in traffic accidents in seven areas in Switzerland. Apparently,

not all were drivers, and the ages were also uncertain. In all,

35.2 percent had some alcohol in their blood, and 21.1 percent

had .08 percent or more. The highest percentage under the influence were bicyclists (43.1 percent) and motorcyclists (43.8

percent), followed by motorists (39.7 percent) and pedestrians

or codrivers (25.8 percent). Reference is made to an earlier

study made by the same author in which the ratio of alcohol to

medication was 8:1. Apparently drug analyses were not done for

the 1,030 hospitalized persons.

Brief reference is made to a study with 320 Basle policemen showing

that at a BAC of .08 percent and over, a 130 percent increase

in numbers of severe driving faults could be observed.

It is concluded that the main danger of psychotropics is that

they intensify the effects of alcohol rather than exerting a

direct influence on the driving capacity of a person. No data

are presented to support these conclusions.

By way of critique, it should be noted that the study would not

include persons killed in accidents or given injuries too minor

to require a hospital stay. It is uncertain how these deletions

would affect the results.

A preliminary study of traffic deaths in Puerto Rico was reported

by Kay (5). Some 262, or 48.5 percent of the total of 540, were

studied for blood alcohol levels primarily because they occurred

within 25 miles of San Juan. The data show an increase in fatalities

from 1960 (n = 346) to 1968 (n = 545) and a slight decline (n = 540)

in 1969. The proportion of males to females also declined

in 1969. The ratio of pedestrians to drivers was 2:1.

Blood alcohol content was determined in 179 cases for which death

occurred soon after the accident: Of the analyzed cases, 48.6

percent were positive for alcohol; of these, 48.3 percent had

a blood alcohol level of 0.15 percent or more. Among pedestrians,

45.3 percent of samples analyzed were positive, with most at 0.15

percent or more; 46.0 percent of passenger deaths were positive

(only 20 percent with 0.15 percent or more). However, 66.7 percent

of driver samples were positive.

Drug analyses were done in a few cases, but the number is uncertain.

In 1969, there were three cases of carbon monoxide poisoning

among drivers (5 percent or more) and 12 cases positive for drugs

(6 morphine, 2 barbiturates, 3 tranquilizers, and 1 salicylates).

It was concluded that both alcohol and morphine are a serious

problem. However, it should be noted that this study involved

only fatalities around Puerto Rico and that the number of drug

analyses is not certain. Details are not given on how many drug

samples were analyzed, what methods were used, what body fluids

102
were studied, or what drugs could be detected. The conclusion

about morphine appears weak.

Woodhouse (6) studied laboratory analyses of body fluids for fatally

injured drivers. Cooperation was requested from alcohol safety

action programs, coroners, and medical examiners in 57 areas in

the United States. A total of 1,731 kits were sent out and 710

specimen collection kits supposedly containing fluids from fatally

injured drivers were obtained from December 1971 to September

1973. Kits were expected to obtain samples of urine, blood, bile,

and alcohol washings from the face and hands. However, 11 were

not from drivers. Of the kits received, 79.3 percent furnished

alcohol washes; 56.5 percent urine, blood, and bile; 74 percent

urine; 97.6 percent blood; and 75.3 percent bile.

The analyses used were thin-layer chromatography followed by gas

chromatographic confirmation of the positives. If any doubt

existed, mass spectrometric analysis was also done. A large

number of sedatives and hypnotics (including alcohol), tranquilizers,

analgesics, stimulants, antidepressants, antihistamines, narcotics,

and hallucinogens (e.g., cannabis, MDA) were screened. Information

on the type of accident and fault for the driver was also obtained.

The results were that:

1. Only alcohol among all drugs was significantly involved in

the at-fault category of accidents;

2. Forty-seven percent of drivers were legally drunk, 15.2

percent gave evidence of drug use, and 38 percent gave

evidence of marihuana use.

3. Alcohol is the only drug for which time of day is a significant

influence.

4. Regional variations were unimportant.

5. The groups of tranquilizers, antihistamines, and stimulants

were not large enough for meaningful analysis.

Several limitations of a very serious nature make the interpretations

of the results impossible. The results for cannabis suggested

that the analytic tests were unreliable. Drugs may be in the

system for days after their impairing effects have worn off. The

sampling methods used resulted in an accidental sample of an uncertain nature in relation to all fatally injured drivers.

The aim in the study by Moser et al. (7) was to determine whether

drug use is related to rates of traffic accidents and convictions.

The data were driving history and demographic factors for 1,889

arrestees in six large cities in the United States. Those excluded

were Federal prisoners, military prisoners, and persons arrested

for drunkenness, for driving while intoxicated, for gambling,

for traffic violations, and for certain minor administrative

crimes (contempt of court, bail forfeiture, etc.). Narcotics

violators were included in three cities and excluded in three.

Driving records were obtained for 46 percent from State authorities, and interviews concerning drug use were held (for about

103
50 percent). The major comparisons made were between drug users

and nonusers, and among various types of users in terms of driving

histories. Some (about 50 percent) arrestees also provided urine

samples for drug analyses. The driving history and drug interview data relate to 865 drivers.

The major results were:

1. Pates of accidents and violations were higher among heavy

and moderate psychedelic drug users and among occasional

tranquilizer and cocaine users than among nonusers.

2. Users of psychedelics were the only group to have more

accidents and convictions than nonusers of drugs.

3. When all drug users and nonusers are compared, the nonusers

consistently have more accidents and violations than the

users.

4. The above results are supported by the urinalyses in that

those having no drugs jn their systems had higher conviction

and accident rates than those who had positive urinalyses.

Several limitations are pointed out for this study, the main one

being that the sample population is "arrestees" rather than a

random sample of drug users. Also the lack of significant differences

could be in part due to the lack of exposure information, e.g.,

miles driven, drug use while driving, etc.

Kapur (8) reported laboratory analyses of drugs found in patients

suspected of drug use and seen at several university hospitals

in Toronto and other hospitals in Ontario. The data were the

results of thin-layer chromatography, gas-liquid chromatography,

and calorimetric analyses for the following drugs: amphetamines,

barbiturates, codeine, most alcohols, the common tranquilizers,

PCP, quinine, and salicylates. Over the 9-month period of October

1972 to June 1973, 1,560 cases were studied. The drugs found

analytically were compared to those expected by clinic physicians.

The major results were:

1. Nine hundred and thirty-eight cases or 60.1 percent were

positive for one or more drugs.

2. The most common drugs were alcohol (44.6 percent) and

barbiturates (39.5 percent), alone or in combination with

other drugs.

3. Physician suspicions for barbiturates were correct 61 percent

of the time, for alcohol 71.8 percent, meprobamate 80 percent,

methyprylon 94.1 percent. Suspicions for most other drugs

tended to be mostly unfounded.

4. Positive tests for drugs such as sedative hypnotics were often

found to be missed by physicians.

The author tentatively concludes that the patterns of drugs seen in

emergency rooms are very similar to those seen in drinking-driver

cases. No comparative data are given to support this conclusion.

104
The paper by Waller (9) contains a review of material on drugs

and highway crashes and some newly presented results from one

of the author's earlier papers (New Engl. J. Med., 1965).

The general argument in the review is that psychoactive drugs

other than alcohol are so widely used as to be expected to cause

driving problems. A large amount of anecdotal and epidemiological

work suggests that some accidents are due to drug impairment.

However, except for amphetamines, these effects are not marked.

Several types of drug users do present problems, but not necessarily

because of their drug use. One would be psychopathic persons

who repeatedly have problems with authority, concerning driving

laws as in other situations. The second category would be problem

drinkers whose elevated risk is mostly due to their drinking.

A third would be prescription drug and cannabis users who do not

have an increased risk of accidents.

In the author's previous study, he indicated that drug users had

higher rates of convictions for driving offenses. However, it

was not pointed out that their contacts with the police and community

service agencies began when they were very young. Most were known

to the motor vehicle authorities before they began using drugs.

They had patterns of "wide ranging antisocial acts" with high

citation rates but low accident rates. It is suggested therefore

that drug use was incidental to the high citation rates and that

the citations are more a matter of lifestyle and personality than

a result of drug effects.

In critique, it might be pointed out that this is a valuable insight

which would have been more valuable if more data had been given.

A table showing the proportions of drug users, by type of drug

(known and not known to driving authorities), would have made

the conclusion stronger.

The aim of the study by Wangel (10) was to determine whether

drivers who consume ordinary therapeutic doses of drugs get more

intoxicated by alcohol than other drivers not on drugs but with

the same blood alcohol level (BAL). The data were drawn from

interviews and alcohol analyses performed by a forensic laboratory

in Denmark. The study is one of comparative records and interviews.

'Ihe data came from more than 6,000 cases" where there was complete

medico-legal examination of persons involved in accidents (where

concussion, drug addiction, or stupor was not present). The cases

were divided into two groups:

1. An alcohol-free group having a BAL of less than 0.15 promille,

consisting of 1,191 males and 35 females; 119 males and 5

women had consumed drugs in the past 24 hours.

2. The alcohol group with BAL > 0.15 promille, consisting of

4,805 males and 436 females; 770 males and 13 females had

consumed drugs in the past 24 hours.

105
The drug-user group was divided further into users of analgesics,

hypnotics, "pharmacological" drugs (meprobamate), all drugs in

common, and those who do not remember their drug.

The results were:

1. Consumers of drugs and nonconsumers of drugs had the same

blood alcohol level.

2. The most common tranquilizer used was meprobamate, but it did

not potentiate the consumption of alcohol.

3. Consumption of drugs was higher in the group having alcohol

in the blood.

A number of methodological questions arise with this study. I t

is uncertain whether only drivers or all accident victims were

included. There is not much information on the interview which

was given nor on whether the reports of drug use (except for

alcohol) were supplemented with laboratory analyses.

Another report by Waller (11) discusses 2,672 consecutive

persons with known medical problems whose driving licenses were

under review in California. Review was usually because of a

medical report or court record. It is emphasized that the results

pertain only to persons with medical problems that are known

to licensing authorities and not to all medical conditions. A

comparison sample of 922 California drivers was also chosen.

The data used were demographic data and driving records for the

previous 3 years. The drivers with medical conditions were divided

into seven groups: epilepsy, cardiovascular disease, diabetes,

alcoholism, drug usage, mental illness, and "miscellaneous." Those

not in the alcoholism or drug use groups most closely represented

the comparison population--the former were more often in lower

class occupations. Data on driving exposure in terms of miles

driven were also obtained.

The results were:

1. All categories of drivers with medical problems had higher

than expected accident rates except for drug users.

2. All categories of drivers with medical problems had higher

than expected violation rates except for the cardiovascular

group.

3. On license review, the largest proportions of revocations

were for drivers in the drug use, epilepsy, and alcoholism

groups (all over 50 percent).

4. Initial reports to license authorities were usually made by

law enforcement officials for those in the alcoholism and drug

use categories and by self or medical agencies in the others.

The tentative conclusion respecting drug use is that the high

violation rates are a "reflection of social rebellion" rather

than a direct drug effect. It would have been useful had this

study differentiated "drug users" as to type, e.g., narcotic users,

prescription drug users, etc.

106
Waller and Goo (12) made a further study of some of the data in

an earlier paper (New England J. Med., 1965) by the first author.

Driving and health records were searched for 2,160 persons known

to the California Department of Motor Vehicles and with organic

and psychosocial disorders. The study is a comparative records

study. The conditions were diabetes, epilepsy, cardiovascular

disease, alcoholism, mental illness, illegal drug use, and a

miscellaneous category. A comparison group of 922 California

drivers not known to have medical conditions was also obtained.

The data used were demographic characteristics, driving records

for the previous 3 years, and exposure in terms of miles driven.

This study examines the number and types of crashes and citations

for each medical group.

The major results were:

1.

2.

3.

4.

5.

Twenty-eight percent of drivers with organic conditions, 27

percent of the psychosocial group, and 19 percent of the

comparison group had crashes; the comparable figures for

violations are 51, 63, and 38 percent.

All medical groups had higher than expected proportions of

crashes involving weaving, running off the road, and being

on the wrong side when not passing.

Drivers with medical conditions, especially alcoholism, more

often committed driving errors prior to accidents than

expected.

Drivers in the alcoholism and drug use groups more often had

crashes attributable to high speed and passing (alcoholism

only significant) than expected.

Drivers in the alcoholism and drug use group had more citations

for driving while license was suspended, improper equipment,

and other nonmoving violations.

Conclusions are acceptable, except that it is not clear that they

apply only to medical conditions serious enough to attract attention

sufficient to have their licenses reviewed. Drivers with similar

medical conditions but not attracting attention may have lower

crash and citation rates.

Rees (13) reports a survey taken to determine the proportion of

motorists taking psychotropic drugs in a rural area of Wales.

The number of people driving was determined by asking police officers.

Of the 4,088 people over 17 years of age who lived in the area,

59.8 percent of men and 16.4 percent of women "drove a motor

car." Of those, 3.4 percent had been taking sedative, tranquilizing,

or antidepressant drugs for at least 3 months in the past 5 years.

Most were taking them for psychiatric rather than somatic reasons.

These data were gathered from the records of physicians. About

3 percent of the male drivers and 5 percent of the female drivers

were taking psychotropic drugs while driving. About 2.3 percent

were currently taking psychotropic drugs.

107

231-545 O - 77 - 9
Braunstein et al. (14) studied the role of alcohol and drugs in

traffic fatalities in Suffolk County, New York. Conclusions

are also made about the laws governing alcoholic drivers.

Apparently, analyses to screen drugs were performed on 188 consecutive

driver fatalities during 1965 and 1966. (It is uncertain whether

or not the 188 includes 34 persons who died long after their

accidents.) In addition to the screening tests, interviews were

held with "several" patrolmen concerning their views about drinkingdriving laws. Analyses were made, for "acidic, basic, and neutral

drugs, which include the total spectrum of drugs which could impair

normal driving." The study was nonexperimental and examined

autopsy data. Thin-layer and gas chromatographic analyses were

used.

The major results were that all drugs other than alcohol were

rarely found in fatally injured drivers. Only three of the autopsied

drivers had sedatives in their blood (barbiturates and Dilantin)

and a few had salicylates and chloroquine derivatives. However,

83 had "significant" blood and brain alcohol levels (i.e., 0.04

percent or above). Blood alcohol levels were highest in those

aged 20 to 50.

The main conclusions were that:

1. Drugs other than alcohol have played a minor role in fatal

accident causation.

2. Alcohol is a major causual factor in driver fatalities.

3. Patrolmen felt that the dririking-driving laws were cumbersome,

resulted in time-consuming paperwork, and were not helpful in

preventing accidents.

4. Mandatory loss of license should be imposed on anyone found

driving while intoxicated.

By way of critique, it is possible to question the empirical

basis for all of the conclusions. It is unclear exactly what

drugs were screened for. and some drugs could not be accurately

screemed at that time (e.g., cannabis, amphetamines). It was

concluded that alcohol is a maior causal factor in fatalities

but no data on the causal role of alcohol are presented--only

data on alcohol tests in fatally injured drivers. The study

of patrolmen is small and briefly reported. The evidence that

mandatory license suspension would work is not given.

Miller (15) developed and used several batteries of tests for

assessing drug effects at the University of Michigan, Ann Arbor.

The tests included the American Automobile Associations' Auto

Trainer, a Whipple steadiness test (hand steadiness), and the

Ortho-rater for testing visual acuity and depth perception, as

well as self-ratings and ratings of others.

The author conducted experimental studies of various drugs on

normal subjects and a variety of psychiatric, arthritic, and

108
neurological patients. The conditions for the first study were:

(1) twice the normal dose of meprobamate, (2) dexedrine, (3)

meprobamate plus alcohol, (4) alcohol alone, and (5) placebo.

No behavioral effects were found except for some unsteadiness

with alcohol. A more extensive battery of tests (51 behavioral

measures) also found no reliable effects with normal subjects.

Four groups of six patients each showed some improved thinking

under benactyzine, especially in obsessive-compulsives.

Chronic administration of meprobamate and 'Tranquil" (a triplebromide) were studied with 24 anxiety neurotics and 12 normal

subjects. Behavioral measures, self-ratings, and other ratings

were used, Meprobamate in doses of 1,600 mg daily and double

the usual clinical dose slowed reaction times but improved time

estimations. Emylacamate in 800-mg doses (twice as high as usual)

slowed reaction time and increased feelings of calmness.

Twenty-eight psychiatric, arthritic, and neurological patients

received the battery on the 12th and 14th day after starting

daily (three times) administration of carisoprodal (Soma). There

were no significant differences between drug and placebo periods.

twenty-four normal males received 20 mg of chlordiazepoxide (Librium)

or matching placebos. Under the drug, (1) judgment scores indicating

an increase in speed and decrease in accuracy deteriorated, (2)

visual acuity decreased, and (3) lateral phoria scores for near

and far vision decreased.

Brief reference was made to other studies but details were not

sufficient. It was concluded that:

1. Tests of behavioral toxicity should be used to evaluate new

compounds.

2. There is no evidence to show how much behavioral toxicity on

laboratory tests would be significant for driving.

3. Most of the tranquilizers tested "appear not to have serious

behavioral toxicity" for normals.

4. Patients on drugs should be restricted from driving.

Conclusion 3. seems not justified by the data presented for Librium,

as significant behavioral toxicity was found for normal subjects.

COMMENT

The impression gained from reviewing the 15 articles selected

is that few firm conclusions can be made about the contribution

of drug use to driving risk. Although a number of epidemiological

studies have been done, the methods used are still fairly primitive.

There is a considerable amount of dependence on self-report estimates

of drug use after driving and accidents. The technology to utilize

body fluids in assessing even the contribution of drugs to fatalities

is still uncertain. Controversy still exists about whether various

types of drug users have or do not have elevated accident and

109
violation rates. Many studies do not contain sufficient detail

on the populations studied or the laboratory tests done.

Too many papers depend upon blood or body fluid analyses of drivers

in accidents, without being able to state how the drug-fluid level

relates to the actual accident. Several papers (e.g., Kaye,

Kielholz, and Finkle) indicate that drugs occur among drivers

who were involved in accidents or fatally injured. However,

it is not clear that the use of these drugs contributed to the

accident. Many of the drugs could have been taken many hours

or days prior to the accident, long after the clinical effects

have worn off. We are not sure that a fatally injured driver

had his accident or fatality because of, or despite, his drug

use.

Little information seems to exist on the frequency of drug use

in various driving populations, i.e., those not in accidents.

We have indications from Rees' paper and others that many drivers

drive after drug use and after alcohol and drug use. However,

we are not sure what the actual risk is. There appears to be

no study of the level of drugs in the body fluids of drivers

in general. This makes it very difficult to be sure that the

levels found in accident and fatality populations are any different

than levels occurring in the nonaccident population. This is

a considerable weakness in the epidemiological research performed

so far, and one which should soon be remedied.

Another weakness in much of the research is that few studies

seem to be directly concerned with drug use and driving. Many

(e.g., Kielholz, Braunstein et al., Wangel, Milner) seem most

oriented toward drinking and driving. The question of drugs

and driving is of minor interest and does not receive equal attention

to that afforded alcohol. Although probably justified in terms

of known extent of the problem, this situation is likely to contain

a self-fulfilling prophecy.

A major difficulty surrounds the problem of whether drug users

of different types have more accidents and charges. Some interesting

studies (Moser et al., Crancer and Quiring) do not include any

exposure information. That is, we have no information on car

ownership, miles driven, etc., which would allow a real comparison of drug users and nonusers. Only Wailer's study seems to

include this, suggesting that users do not have higher than expected

accident rates, but do have high violation rates. This is supported

by the Crancer and Quiring study but not by Moser et al. However,

the difficulties in comparing the samples used are considerable.

It is difficult to find any clear replication studies where two

investigators have used similar populations and similar methodologies.

Naturally, then, it is difficult to find more than unexplainable

inconsistency.

By way of strengths, the studies by Waller and by Finkle should

be mentioned. Of all of those reviewed, they are the most convincing.

110
They involve large samples, clearly defined and up-to-date methodologies,

and careful conclusions. It would be worthwhile repeating Finkle's

studies with more modern analytic methods and Waller's with a

different (large) sample of drug users. Both approaches and methodologies

could be copied in other studies.

Other strengths in the papers are somewhat difficult to find,

except those of a general nature. It is clear that a beginning

has been made studying some problems of drugs and driving. We

have information on the frequency of prescription drug use (in

some populations); prescription drug use and driving; and drug

use, drinking, and driving. This is probably sufficient to indicate

the need for warnings to patients and physicians, as Milner suggests.

However, it is not sufficient to generate the need or support

for detailed, sophisticated countermeasure programs. It is also

clear from several papers that the major "drugs and driving" problem

may be only an aspect of the "drinking-driving" problem. That

is, that drivers who have been drinking are most likely to have

been using drugs as well.

REFERENCES

1. Milner, G.: Drinking and Driving in 753 General Practice and

Psychiatric Patients on Psychotropic Drugs. British Journal of

Psychiatry, 115:99-100. 1969.

2. Crancer, A. and D.L. Quiring: Driving Records of Persons

Arrested for Illegal Drug Use. State of Washington, Department

of Motor Vehicles, Report 011, May 1968.

3. Finkle, B.S.: Drugs in Drinking Drivers: A Study of 2,500

Cases. Journal of Safety Research, 1:179-183. 1969.

4. Kielholz, P.: Alcohol, Drugs and Driving Behaviour in

Switzerland. Proceedings of the 6th International Conference on

Alcohol, Drugs and Driving, Toronto, 1974, pp. 395-7.

5. Kaye, S.: Blood Alcohol Levels and Fatal Traffic Accidents

in Puerto Rico. United States Department of Transportation,

April 1, 1970.

6. Woodhouse, E.J.: The Incidence of Drugs in Fatally Injured

Drivers. U.S. Department of Transportation, DOT-HS-119-1-627,

Washington, 1974.

7. Moser, B.A., L.D. Bressler, R.B. Williams: Collection

Analysis and Interpretation of Data on Relationship Between Drugs

and Driving. U.S. Department of Transportation, DOT-HS 022-1-023,

Washington, 1972.

111
8. Kapur, B.M.: Patterns of Drug Abuse and Their Relationship

to Traffic Accidents. In Alcohol, Drugs and Traffic Safety

Proceedings of the 6th International Conference, S. Israelstam and

S. Lambert, eds., Toronto, 1975.

9. Waller, J.A.: Drugs and Highway Crashes: Can We Separate

Fact From Fancy? J.A.M.A., 215:1477-1482. 1971.

10. Wangel, J.: Alcohol, Road Traffic and Drugs in Denmark, 1960.

Proceedings of 3rd International Conference on Alcohol and Road

Traffic, 1962, pp. 162-165.

11. Waller, J.A.: Chronic Medical Conditions and Traffic Safety:

Review of the California Experience. New England Journal of

Medicine, 273:1413-1420. 1965.

12. Waller, J.A. and J.T. Goo: Highway Crash and Citation

Patterns and Chronic Medical Conditions. Journal of Safety

Research, 1:13-27. 1969.

13. Rees W.D.: Psychotropic Drugs and the Motorist. Practitioner,

196:704-6: 1966.

14. Braunstein, P.W., S.B. Weinberg, L. Dal Cortivo: The

Drunk and Drugged Driver Versus the Law. Journal of Trauma,

8:83-90. 1968.

15. Miller, J.G.: Objective Measurements of the Effects of Drugs

on Driver Behaviour. J.A.M.A., 179:940-943. 1962.

112
OTHER DRUGS

Maxine Stitzer, Ph.D.

SUMMARY

This review will summarize a limited number of experimental studies

concerning effects of tranquilizers, muscle relaxants, and antihistamine drugs, as well as combinations of these drugs with

ethanol, on human performance related to driving. The first group

of studies utilized batteries of psychological and/or psychomotor

tests to assess drug effects, while the second group used driving

simulators. Procedures and results of each study will be summarized, and this will be followed by a general critique of methodologies which have been used along with suggestions for improved

methodologies.

Drug Effects on Human Psychomotor Performance

Idestrom and Cadenius (1) studied effects of acute oral doses of

amobarbital (150, 300, and 450 mg), chlordiazapoxide (20 and 40

mg) , a piperazine phenothiazine, dipiperon (20 and 40 mg) , and

placebo on a battery of tests which included choice reaction time

(visual), tapping speed, critical flicker fusion, hand coordination, standing steadiness, and auditory discrimination. Twentyone male students about 20 years old participated in the testing.

Each subject received all drug treatments in a random order under

double-blind conditions. Tests were conducted at an unspecified

time following drug administration (less than 1-1/2 hours), and

performance compared with scores on a predrug test. There was no

pretraining on the tasks and no indication is given as to whether

performance changed over time.

In the original group of subjects, only the critical flicker fusion

test was significantly affected by drugs (amobarbital, 150 mg;

chlordiazepoxide, 40 mg; and dipiperon, 20 and 40 mg). Tapping

speed was also reduced by 150 mg of amobarbital, but the 300-mg

dose had no effects. In a subgroup of 15 students who received 450

mg amobarbital, significant effects of the 150-mg dose were no

longer apparent. However, the high dose produced significant impairment on most (7 out of 10) tests.

This study has several good methodological features. Multiple drug

doses were employed and orderly dose-effect relations were observed

on most tests even though drug-produced changes did not generally

reach statistical significance. Subjects were used as their own

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controls, and the use of a range of doses of amobarbital showed

that the tests employed were at least sensitive to a high dose of

sedative drug. The critical flicker-fusion test stood out as being

sensitive to small doses of drug, and indicated that both dipiperon

and chlordiazepoxide may affect visual processes. The pretreatment

time, however, may have been too short to see peak effects of benzodiazepines or phenothiazines.

Heimann, Reed, and Witt (2) studied effects of acute oral doses of

perphenazine (10 mg), imipramine (75 mg), opipramol (75 mg), and

placebo on heart rate, blood pressure, facial movements. eve movements and eye fixation (via videotape-analysis), and a battery of

psychological tests including pattern recognition, cancellation,

word fluency, digit span, arm-hand steadiness, complex visualauditory discrimination, and eye-hand coordination (copying a

geometric pattern). Twenty medical and graduate students 20 to 25

years old were tested. Each subject was exposed to all treatment

conditions in randomized order under double-blind conditions.

Tests were conducted 1, 3, and 5 hours after drug ingestion.

Neither perphenazine nor opipramol has any significant objective

effects on performance at the doses given. Imipramine significantly increased mean arterial blood pressure and produced subjective reports of discomfort, but altered only one performance

measure. Inclusion of an independent physiological measure provided independent evidence that an effective dosage of imipramine

was used, and strengthens the conclusion that the drug produced no

behavioral impairment at this dose on the tests employed. Higher

doses, however, might have revealed behavioral effects. In view of

the lack of drug effects reported, no conclusion can be drawn about

the sensitivity of the behavioral tests employed.

Hughes and Fomey (3) at the Indiana University School of Medicine

studied the effects of chronic doses of several antihistamine

compounds--diphenhydramine (50 mg), clemizole (40 mg), tripelennamine (50 mg), and placebo--as well as ethanol (45 mg/150 lb) and

combinations of each antihistamine with ethanol. These investigators employed a battery of reading and numerical calculation

problems, all performed under delayed auditory feedback (a technique which is supposed to produce “stress” and enhance sensitivity

of the tests). They also use a pursuit-tracking task in which the

subject must superimpose a black spot upon a wave pattern generated

on an oscilliscope screen.

In the chronic dosing regimen, four drug doses were ingested prior

to testing, two the previous day (noon and bedtime) and two on the

day of testing (at breakfast and 1 hour prior to testing). Sixteen

medical and graduate students 21 to 29 years old participated.

Each subject was exposed to all eight treatment conditions in

random order under double-blind procedure. No pretraining was

given to the subjects and there is no indication of whether performance was stable. Eight out of 13 variables measured showed a

significant main effect of drug treatment. This was due to the

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ethanol treatment (at a dose which produced blood alcohol levels of

about 50 mg percent).

Ethanol alone or combined with an antihistamine generally produced

some impairment on the behavioral tests, although these effects

were not significantly different from placebo effects, as judged by

the criterion of the Tukey "W" post-test. Antihistamines alone had

no discernable effects on performance, although subjects generally

identified antihistamine treatment as a depressant drug. There

were no noticeable additive effects of antihistamines plus ethanol.

Subjective reports provide independent evidence that effective

doses of antihistamines were employed, although higher doses of

these drugs may have revealed behavioral effects.

In another study using identical procedures, Hughes, Fomey, and

Richards (4) studied effects of chronic doses of chlordiazepoxide

(15 mg/day) and diazepam (6 mg/day) alone and in combination with

acute doses of ethanol (45 mg/150 lb). Sixteen medical and graduate students participated as subjects. Drugs were administered in

three divided doses for 2 days prior to testing and tests were

conducted 1 hour after the last dose (5 mg chlordiazepoxide and 2

mg diazepam) . Drugs alone had no discernable effects on performance; the greatest impairment was seen in treatments that included

ethanol. No additive effects of tranquilizers with ethanol were

notable, although diazepam plus alcohol did have a somewhat greater

effect on performance than ethanol alone on 3 out of 13 tests. In

this study, significant F tests were seen on only 5 out of 13

variables, and impairment by ethanol was more marginal than in the

previous study. Doses of tranquilizers used were very low; the

students could not identify subjective effects of the tranquilizers. Higher doses may have revealed behavioral effects.

Linnoila and his coworkers in the University of Helsinki in Finland

have completed a series of studies concerning effects of drugs and

drug combinations on motor skills related to driving. These

studies used a group design in which each subject was exposed to

only one drug treatment. There was high fall validity in the

relationship between the behavioral tests employed and the skills

used in driving performance. In a complex visual and auditory

choice reaction test, subjects pushed an appropriate combination of

foot pedals in response to three stimuli and also pressed a button

in response to presentation of a masked target tone. The researchers recorded cumulative reaction time to a fixed number of stimuli

as well as the number of errors. In the coordination test, subjects tried to keep a black dot superimposed on a moving track by

turning a steering wheel. A 30-second test was run under fixed

speed and an additional test under subject-controlled speed. In

the self-controlled test, both the percent of time off the track

and average speed were measured.

In one study (5), Linnoila looked at acute effects of oral doses of

two antihistamine compounds--meclastine (1.5 and 3 mg) and diphenhydramine (25 and 50 mg)--and of a muscle relaxant, chlormezanone

(200 and 400 mg), and placebo. Each drug was studied alone and in

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the choice reaction time and coordination tests, in combination

with ethanol (0.5 g/kg). Three hundred medical and technical

students and cadets with an average age of 22 years were tested;

there were 15 groups of 20 subjects each. Each subject was exposed

to a single drug combination and one group received no drug treatment. Tests were conducted at 30, 90, and 150 minutes following

drug ingestion. No pretraining was given on the tasks, and marked

practice effects were apparent for most measures. When taken

alone, none of the drugs had any effect on performance. However,

ethanol combined with both doses of diphenhydramine and with the

high dose of meclastine slowed driving speed at 30 minutes after

drug ingestion in the subject-controlled coordination test, and

ethanol plus diphenhydramine (50 mg) impaired performance in the

fixed-speed coordination test. These results are suggestive of an

interaction between ethanol and diphenhydramine, but results are

difficult to interpret because of inappropriate statistical procedures (multiple t-tests were used and drug groups were compared

with the no-drug group rather than with the group receiving placebo) and also because of the unstable baseline, which was showing

practice effects over time.

Saario, Linnoila, and Maki (6) studied effects on psychomotor

skills related to driving of (1) chronic doses of a sedative compound, PLP (6- (4-methyl-1-piperazinyl) morphanthridine) (10 mg) ,

nitrazepam (10 mg) , and placebo of (2) acute doses of ethanol (0.5

g/kg), and of (3) the combinations of each drug with ethanol. They

used the previously described coordination and reaction time tests

plus a complex visual signal detection attention test. Subjects

were 17 male and 3 female students 20 to 25 years old. Under the

chronic dosing regimen, a single dose of drug was taken each night

between 10 and 11 p.m. for 14 days. Testing was carried out on

days 7 and 14, one test with ethanol and the other with a placebo

drink. Three testing trials were then conducted at 30, 90, and 150

minutes after administration of the drink. Each subject was exposed to all treatment conditions in a random order under doubleblind conditions. In this study, subjects were trained prior to

testing and reached a stable level of performance on the coordination tests (but not on the attention test).

Subjects felt that alcohol impaired their performance and that

impairment was enhanced by the sedative drugs. Although there are

not statistical analyses presented to indicate significance of

individual treatment effects, nitrazepam plus alcohol produced the

most noticeable average impairment on all four tests, especially at

30 minutes after the drink. Also, nitrazepam alone increased

driving time in the subject-controlled coordination test. Serum

levels of nitrazepam and PLP, which were analyzed on days 1, 7, and

14 of treatment, indicated that nitrazepam but not PLP was present

in the blood at the time of testing. This objective confirmation

of the presence of drug plus the orderliness of the time course

data lends credence to the observation of a drug interaction between nitrazepam and ethanol.

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Franks et al. (7) studied the effects of ethanol (0.75 g/kg), caffeine (300 mg/70 kg), and placebo, as well as the combined effects

of ethanol and caffeine, on a variety of psychological and psychomotor tests including standing steadiness, manual dexterity, numerical reasoning, perceptual speed, verbal fluency, and reaction

time (visual, auditory, and complex). They tested 68 male and female university students 20 to 28 years old. Each subject was

exposed only to one drug treatment and was given a single predrug

run on the test battery. Tests were conducted 40, 100, and 160

minutes after the start of drug intake (it took 20 minutes to

consume the ethanol drink). Ethanol (at plasma levels of .72 to

.92 mg/100 ml) produced marked impairment on virtually all the

performance tests, while caffeine alone had only nonsignificant

effects on a few tests (e.g., impaired standing steadiness, and

improved performance on perceptual speed and complex reaction time

tests). Caffeine antagonized ethanol-induced performance deficits

on the complex reaction time test (significant at 40 and 160

minutes) and on the visual and auditory reaction time tests at 160

minutes after ingestion. Caffeine did not antagonize ethanol

effects on any other measures.

Effects of Drug on Driving Simulator Performance

Loomis and West (8) studied acute effects of two divided oral doses

of secobarbital (100 mg), chlorpromazine (50 mg), meprobamate (400

mg) , and phenglycodol (300 mg). Doses were administered about 4 to

4-1/2 hours apart. Four-minute tests on the driving simulator were

conducted at 1 and 2 hours following each drug ingestion. Eight

male subjects 23 to 40 years old and weighing 150 to 185 pounds

participated. Reaction time measures were obtained from eight

presentations of an amber light (time to release of a gas pedal)

and a red light (time to switch closure under a brake pedal). Red

and yellow lights were scheduled to appear regularly every 12

seconds during the 4-minute test. An additional measure was the

cumulative time when the auto was not centered over the roadbed.

Speed on the road was always controlled by the subjects. Participants were pretrained to a criterion performance on the driving

test. Each received all treatments in the same sequence under

double-blind conditions.

Secobarbital produced a clear decrement in performance on all three

measures in all individual subjects. Effects were most marked at 1

hour after the first dose and 1 and 2 hours after the second dose.

Chlorpromazine produced performance decrements only after the

second dose (possibly a cumulative effect). Meprobamate had small

equivocal effects on two out of five test runs, while phenglycolol

had no effect on performance. An important feature of this study

is the demonstration of clear behavioral effects of acute doses of

secobarbital on stable baselines of performance in all individual

subjects. This indicates that the driving simulator used is sensitive to drug effects and provides a comparison for the relative

extent of impairment produced by other drugs.

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Miller and his associates at the University of Michigan conducted

a series of studies concerning drug effects on both driving simulator performance and on a battery of tests which included measurements of visual acuity and phoria (8 tests, 30 variables measured).

In the driving simulator test, subjects were required to keep a

simulator car centered on a roadbed and to apply the brake following six irregularly spaced presentations of a red light. Three

trials were run, one at a fixed low speed of the roadbed, one at

a fixed high speed, and the third with speed controlled by the

subjects. Accuracy (time in contact with the center of the roadbed) and reaction time scores were obtained for each trial.

Uhr, Pollard, and Miller (9) studied effects of chronic doses of

meprobamate (1,600 mg); five Tranquil tablets (active ingredients:

sodium bromide, 0.485 mg; potassium bromide, 0.97 g; and ammonium

bromide, 0.164 g); and placebo on the driving simulator performance and the test battery. The subjects were 32 volunteers, from

21 to 41 years old. Fifteen were men, 17 women; 23 had been diagnosed as anxiety neurotics and 9 were normal. Drugs were ingested

for 21 consecutive days and testing was conducted at the end of

that period. Each subject was exposed to all treatment conditions

in mixed order under double-blind conditions. Subjects were given

one practice session on the test battery, which was conducted

under the influence of a 15-mg dose of phenobarbital, but no information is given as to whether performance was stable.

Out of the entire test battery, including driving performance, only

two measures showed significant drug effects. Reaction time

scores in the high-speed driving test were shorter for both drugs

than for placebo treatment, and estimates of 20-sec time intervals

were more accurate (longer) under meprobamate than under placebo.

Those tested were not able to report any subjective effects of the

drug treatments. There were no procedures used to verify that subjects had ingested the drugs in the proper quantities and at the

specified times. This could be important in view of the relative

lack of either objective or subjective drug effects.

In another experiment, Uhr and Miller (10) administered acute oral

doses of the muscle relaxants emylcamate (400 and 800 mg) and

meprobamate (800 mg), and of placebo4to 49 prisoner subjects 1

hour prior to the test battery. The highest doses of both drugs

produced a significant slowing of reaction times, and meprobamate

reduced driving accuracy (significant only for the fast-speed

test). More studies using drugs or drug doses with clear behavioral activity would be needed to establish the sensitivity of

this driving simulator test battery.

Linnoila and Hakkinen (11) studied effects of acute oral doses of

diazepam (10 mg), codeine (25 mg), ethanol (0.5 g/kg), and placebo,

as well as combinations of drugs and ethanol, on simulated driving

performance. Seventy professional drivers from the Finnish army,

19 to 22 years old, participated as subjects. They were divided

into groups of 10; each group received a single drug-drink combination, and one group received no drug treatment. Subjects were

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trained on the driving simulator until they felt comfortable.

Tests were 40 minutes long and were conducted 30 minutes after drug

ingestion. The simulated driving program was very complicated and

involved following instructions for turns and stops as well as

reacting to "emergency" situations, such as cars pulling out onto

the road. Driving speed was controlled by the subjects. Frequency

measures were obtained for driving off the road, steering wheel

reversals, for the number of collisions and neglected instructions,

and for the use of brakes, the clutch, the gearshift, and turn

signals.

Some of these measures seemed to be sensitive to drug effects.

There were more neglected instructions and more collisions under

all drugs than under placebo. In addition, 6 out of 10 subjects

drove off the road at least once under diazepam plus alcohol, while

only one did so under alcohol alone and none under diazepam alone

or placebo. (Three drove off the road under codeine and three

under codeine plus alcohol.) The diazepam plus alcohol group also

has the slowest average driving speed.

Statistical significance of the results cannot be evaluated since

the drug groups were compared with the no drug treatment group

rather than with the placebo group, and the placebo group did have

some performance changes that were in the same direction as the

drug groups. In addition, groups were relatively small and variability was large. Results do indicate that some measures on this

driving simulator test may be sensitive to drug effects and that an

ethanol-diazepam combination may produce more impairment than

either drug alone, although the pretreatment time was probably too

short to see peak effects of benzodiazepines.

It is important to determine the effects of drugs on driving performance in real driving situations for at least two reasons:

first, to see whether results from laboratory experiments are

predictive of drug effects in real driving situations, and second,

to suggest priorities about what drugs to study more extensively in

the laboratory. Since experimental studies of drug effects on

driving performance in wholly naturalistic situations are generally

not feasible, information must be obtained from correlational

analyses of drug ingestion and automobile accident rates.

Smart, Schmidt, and Bateman (12) at the Addiction Research Foundation in Toronto interviewed 30 psychoactive drug users who were

involved in psychiatric treatment, had been diagnosed as drugdependent, and who had held a driver's license for some time during

the previous 6 years. Interviews covered driving history (miles

driven, numbers and types of accidents) as well as drug use over 6

years preceding the interview. Those accident reports which were

verified against state records indicated some underreporting of

accidents. Obtained accident frequencies for each individual subject were compared with expected frequencies for that subject.

Expected frequencies were corrected for age, sex, and exposure

(miles driven).

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Thirteen out of 30 subjects reported one or more accidents and this

overall accident rate was higher than the overall expected rate for

the group. Accident rates which were higher than expected rates

were associated with dependence on certain drugs and drug combinations and not with others. Subjects reporting mixed addiction to

alcohol and barbiturates (N=7), tranquilizers alone (N=2), and

amphetamines mixed with alcohol, barbiturates, and tranquilizers

(N=3) had accident rates only slightly higher than expected. Subjects reporting addiction involving amphetamines alone or amphetamines mixed with barbiturates and tranquilizers (N=5) as well as

subjects reporting addiction to alcohol plus tranquilizers (N=3)

had accident rates much higher than expected, while subjects reporting dependence on barbiturates alone (N=6), barbiturates and

tranquilizers (N=2) or alcohol, barbiturates, and tranquilizers

(N=2) had accident rates lower than expected. Most subjects who

reported using drugs within 12 hours prior to their accidents were

in the group whose addictions involved amphetamines (6 out of 8

reported such use).

In normal humans who are not drug dependent, barbiturates generally

impair psychomotor performance, while amphetamines do not impair

and may enhance performance. Thus, we might predict that barbiturates but not amphetamines would be related to higher than

expected accident rates. This study found the opposite relationship. This suggests that drug effects on driving performance could

be different in drug-tolerant than in nontolerant individuals.

Alternatively, drugs could influence driving performance by some

means other than direct effects on psychomotor skills related to

driving. Amphetamines, for example, are known to alter judgment

about performance capabilities. Another interesting possibility is

that drugs affect accident rates by altering the probability that

people will engage in driving in the first place. Amphetamines,

which energize activity, and were related to higher than expected

accident rates, might increase the likelihood that people will

drive, while barbiturates, which are primarily sedating, and were

related to lower than expected accident rates, might actually

reduce the probability that people will drive after using drugs.

This study at least suggests that more driving research needs to be

focused on effects of stimulants and on drug effects in drugdependent or drug-tolerant individuals.

CONCLUSIONS AND COMMENTS

Three of the studies reviewed found that acute doses of barbiturates (1,8) and alcohol (7) dramatically impaired human psychomotor

performance. No other drugs or drug combinations in any of the

studies reviewed here had effects of comparable magnitude. Some

alteration of performance was reported for acute doses of chlordiazepoxide (40 mg) and dipiperon (20 and 40 mg) on a critical

flicker-fusion test (1), and for 50 mg of chlorpromazine (8), 800

mg of emalcymate, and 800 mg of meprobamate (10) on simulated

driving performance. Additive interactions of drugs with moderate

120
were suggested for acute doses of 50 mg of diphenhydramine (5), and

of 10 mg of diazepam (11), and for chronic doses of 10 mg of nitrazepam (6).

Drug treatments which had no significant effects on psychomotor

performance or driving simulator tests included acute doses of 300

mg of amobarbital and 20 mg of chlordiazepoxide (1); 10 mg of

perphenazine, 75 mg of imipramine, and 75 mg of opipramol (2); 400

mg of meprobamate and 300 mg of phenglycolol (8); 10 mg of diazepam

and 25 mg of codeine (11); 200 and 400 mg of chlormezanone (5); and

caffeine (7). Other treatments producing no effect were chronic

doses of 1,600 mg of meprobamate and Tranquil (9); 10 mg of PLP and

nitrazepam (6); 15 mg/day of chlordiazepoxide and 6 mg/day of

diazepam (4); as well as acute and chronic doses of several antihistamines including 50 mg of diphenhydramine, 1.5 and 3 mg of

meclastine, and 50 mg of tripelenamine (3,5).

Drug treatments showing no additive interaction with ethanol included chronic doses of 50 mg of diphenhydramine, 40 mg of clemizole, 50 mg of tripelenamine (3); 15 mg/day of chlordiazepoxide and

6 mg/day of diazepam (4); and acute doses of 15 mg of meclastine,

of 200 and 400 mg chlormezanone (5), and of 25 mg of codeine (11);

and chronic doses of 10 mg of PLP (6).

The finding that a particular drug has no effect on performance in

a particular situation does not mean that the drug is behaviorally

inert. Drug doses could be inadequate (i.e., at the low end of the

dose-effect curve); drug absorption time could be too short; investigators could have failed to verify that chronic dosing procedures were followed by subjects; or behavioral tests could be

insensitive to drug effects. These possibilities must be eliminated before a meaningful conclusion can be drawn about the lack of

a drug effect. These methodological problems are discussed in the

summaries of individual articles when they apply. Below is a more

general discussion of the important methodological considerations

which must be made for a meaningful analysis of drug effects on

human performance.

Testing a Range of Drug Doses

Only a few studies in the present review utilized more than one

dose of drug (1,5,10). Studying a range of drug doses (establishing dose-effect relationships) is very important for several

reasons. First, drugs may affect performance differently at

different doses--enhancing performance at one dose range, and

depressing or impairing performance at another range. Second,

people can differ dramatically in their sensitivity to a drug,

whether because of drug history (tolerance), differences in drug

absorption and metabolism rates, or other unknown factors. Testing

a range of dosages would reveal functional relationships between

drug dose and performance measures and would lead to a dose-profile

of behavioral toxicity. Finally, people ingest drugs over a wide

range of dosages depending on the context and intent of drug intake,

121
from low dosages taken for therapeutic intent to extremely high

dosages taken for recreational intent.

If only a single drug dose is studied, it is important to include

some independent physiological (2), biochemical (6), subjective

(3), or behavioral measure which indicates that an active drug dose

was employed. This is especially important if the drug turns out

to have no effect on the behavior variables under investigation.

Determining the Time-Course of Drug Effect

It is a good idea, if possible, to conduct behavioral tests for

several hours after ingestion of acute drug doses (2,7,8,11). Time

course data can provide valuable information about the onset and

dissipation of drug effects. It is also important to consider the

time course of drug effects in chronic dosing studies, where some

investigators have controlled the time between testing and the last

drug ingestion (3,4,11), while others have not (9). Finally, time

course must be considered in drug interaction studies, where absorption time for the two drugs may be quite different (11). If the

intent is to conduct behavioral tests at the time of peak effect of

each drug, then pretreatment times must be adjusted accordingly.

Establishing Sensitivity of Behavioral Tests

In order to obtain meaningful information about drug effects on

performance measures, it is crucial to demonstrate that behavioral

tests used are sensitive to drug effects. This can be done by

studying a range of drug dosages, including high doses with clear

behavioral activity or, when this is not feasible, by including a

standard drug such as a barbiturate at doses that produce some

behavioral effects (1,8). The finding that a particular drug at

a particular dosage has no effect on a particular set of performance measures does not mean that the drug is behaviorally inert,

since the finding could as well mean that behavioral tests employed are insensitive to drug effects. Increasing the number of

tests in a battery or increasing the number of variables measured

does not necessarily increase the sensitivity of behavioral tests,

since performance of individual subjects on a number of sequentially administered tests will probably not be independent.

Studying Drug Effects on Stable Baselines of Performance

Several studies reviewed gave no pretraining to subjects on behavioral tests or gave insufficient training such that marked practice effects could be seen in the data (5). Studying drug effects

on a stable baseline of performance has at least two advantages.

First, it decreases variability of performance measures and makes

it much more likely that drug effects will be detected. Second,

since driving is a highly practiced skill, it makes the laboratory

test situation more naturalistic.

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Advantages of Using a Within-Subject Design

Individuals may differ in their sensitivity to drugs as well as in

their baseline levels of stable control performance. Group designs

will reveal the proportion of subjects in a population who have

substantial behavioral effects at a given drug dose, but may mask

more subtle, though equally important, effects of drugs in individual subjects. Within-subject experimental designs eliminate

intersubject variability by repeatedly observing drug effects on

stable behavioral baselines in single individuals. This technique

will reveal functional relationships between drug dose and performance changes; the consistency of these relationships can then

be evaluated across individuals. A within-subject design maximizes

the sensitivity of experimental procedures and makes it likely that

subtle behavioral effects of drugs will be detected. It might be

advisable to conduct more studies which make a detailed analysis of

single drugs or single drug combinations over a range of doses in

individual subjects rather than attempting to screen single doses

of many drugs from different pharmacological classes within a

single study, as has so often been the case.

Establishing the Validity of Behavioral Tests

The validity of behavioral tests as predictors of drug effects on

driving performance can only be established empirically be correlating drug effects on performance tests with drug effects in

natural driving situations. It should be stressed that behavioral

test situations need not have "face validity" to be sensitive and

valid indicators of drug effects on driving performance. Conversely, behavioral tests such as driving simulators, which do have face

validity, may not be empirically valid indicators of drug effects

on driving performance. Much more information is needed about the

relationship between psychoactive drug ingestion and accident rates

(12) to establish the validity of laboratory tests.

It is clearly important to specify effects of drugs on driving performance since both automobile driving and drug ingestion are

ubiquitous practices among large portions of the populations of

industrialized societies. This is a formidable task since it involves as a preliminary step the specification and development of

human performance tests which are sensitive to drug effects and

which are valid predictors of drug effects in real driving situations. Specification of sensitive and valid performance tests must

then be followed by studies involving multiple dosage testing, preferably using within-subject experimental design of a wide variety

of commonly used drugs and drug combinations.

REFERENCES

1. Idestom, C., and B. Cadenius: Chlordiazapoxide, Dipiperon and

Amobarbital: Dose Effect Studies on Human Beings. Psychopharmacologia, 4:235-246. 1963.

123

321-545 O - 77 - 10
2. Heimann, H., C.F. Reed, and P.N. Witt: Some Observations

Suggesting Preservation of Skilled Motor Acts Despite Drug-Induced

Stress. Psychopharmacologia, 13:287-298. 1968.

3. Hugues, F.W., and R.B. Forney: Comparative Effect of Three

Antihistaminics and Ethanol on Mental and Motor Performance.

Clinical Pharmacology and Therapeutics, 5:414-421. 1964.

4. Hughes, F.W., R.B. Forney, and A.B. Richards: Comparative

Effect in Human Subjects of Chlordiazepoxide, Diazepam, and Placebo

on Mental and Physical Performance. Clinical Pharmacology and

Therapeutics. 6:139-145. 1965.

5. Linnoila, M.: Effects of Antihistamines, Chlormezanone and

Alcohol on Psychomotor Skills Related to Driving. European Journal

of Clinical Pharmacology, 2:247-254. 1973.

6. Saario, I., M. Linnoila, and M. Maki: Interaction of Drugs

with Alcohol on Human Psychomotor Skills Related to Driving: Effect

of Sleep Deprivation or Two Weeks' Treatment With Hypnotics. The

Journal of Clinical Pharmacology, 15:52-59. 1975.

7. Franks, H.M., H. Hagedorn, V.R. Hensley, W.J. Hensley, and

G.A. Starmer: The Effect of Caffeine on Human Performance, Alone

and in Combination With Ethanol. Psychopharmacologia, 45:177-181.

1975.

8. Loomis, T.A., and T.C. West: Comparative Sedative Effects

of a Barbiturate and Some Tranquilizer Drugs on Normal Subjects.

Journal of Pharmacology and Experimental Therapeutics, 122:525-531.

1958.

9. Uhr, L., J.C. Pollard, and J.G. Miller. Behavioral Effects

of Chronic Administration of Psychoactive Drugs to Anxious Patients.

Psychopharmacologia, 1:150-168. 1959.

10. Uhr, L., and J.G. Miller: Behavioral Toxicity of Emylcamate

(Straitran). American Journal of Medical Science, 240:197-203.

1960.

11. Linnoila, M., and S. Hakkinen: Effects of Diazepam and Codeine,

Alone and in Combination With Alcohol, on Simulated Driving.

Clinical Pharmacology and Therapeutics, 15:368-373. 1974.

12. Smart, R.G., W. Schmidt, and K. Bateman: Psychoactive Drugs

and Traffic Accidents. Journal of Safety Research, 1:67-73. 1969.

124
BIBLIOGRAPHY

The following supplemental bibliography was

compiled from a computer search of recent

literature by the National Clearing House

for Drug Abuse Information.

125
DRUGS AND DRIVING

(General)

Barnes, T.H., compiler. Drug use and driving. Toronto: Addiction

Research Foundation, 1974, 106 pp.

Benson, Roy. 'Drug abuse in industry'. In: Scher, Jordan M., ed.

Drug Abuse in Industry: Growing Corporate Dilemma. Springfield,

Illinois: Charles C. Thomas, 1973, pp. 55-58.

Curry, A.S. Reliability and significance of results of alcohol

and drug analyses. In: Israelstam, Stephen, and Lambert,

Sylvia, eds. Proceedings of the Sixth International Conference on Alcohol. Drugs. and Traffic Safety. Toronto.

September 8-13, 1974. Toronto: Addiction Research Foundation of Ontario, 1975, pp. 469-481.

Finkle, Bryan S. 'Will the real drugged driver please stand up?'

an analytical toxicology assessment of drugs and driving.

In: Israelstsm, Stephen and Lambert, Sylvia, eds. Proceedings

of the Sixth International Conference on Alcohol, Drugs. and

Traffic Safety. Toronto. September 8-13. 1974. Toronto:

Addiction Research Foundation of Ontario, 1975, pp. 607-611.

Frankenhaeuser, Marianne. Drug effects on emotions: relevance

to driving accidents. In: Israelstam, Stephen, and Lambert,

Sylvia, eds. Proceedings of the Sixth International Conference on Alcohol. Drugs. and Traffic Safety. Toronto.

September 8-13, 1974. Toronto: Addiction Research Foundation

of Ontario, 1975, pp. 259-270.

Israelstam, Stephen, and Lambert, Sylvia, eds. Alcohol, drugs,

and traffic safety. Proceedings of the Sixth International

Conference on Alcohol, Drugs, and Traffic Safety, Toronto,

September 8-13, 1974. Toronto: Addiction Research Foundation

of Ontario, 1975.

Kielholz, P., and Hobi, V. The influence of psychopharmaca on

the aptitude to drive. Therapeutische Umschau (Revue

Therapeutique) (Bern), 31(9):606-613, September 1974.

Perrine, M.W., ed. Alcohol, Drugs and Driving. Springfield,

Virginia: National Technical Information Service, March 1974,

380 pp.

Perrine, M.W. Alcohol, drugs and driving: relative priorities for

basic and applied research. In: Israelstam, Stephen, and Lambert,

Sylvia, eds. Proceedings of the Sixth International Conference on

Alcohol, Drugs. and Traffic Safetv. Toronto. September 8-13 1974.

Toronto: Addiction Research Foundation of Ontario, 1975, pp. 107-128.

126
Drugs and Driving - General (Cont'd)

Wilde, G.J.S. Evaluation of effectiveness of public education and

information programmes related to alcohol, drugs and traffic

safety. In: Israelstam, Stephen, and Lambert, Sylvia, eds.

Proceedings of the Sixth International Conference on Alcohol,

Drugs, and Traffic Safety. Toronto, September 8-13. 1974.

Toronto: Addiction Research Foundation of Ontario, 1975,

pp. 813-823.

Zeller, Anchard F. Joint committee on aviation pathology: IX.

Alcohol and other drugs in aircraft accidents. Aviation,

Space, and Environmental Medicine. 46(10):1271-1274, October 1975.

127
DRUGS AND DRIVING

(Alcohol and Other Drugs - Combined Effects)

Bo, O.; Haffner, J.F.W.; Langard, O.; Trumpy, J.H.; Bredesen, J.E.;

and Lunde, P.K.M. Ethanol and diazepam as causative agents

in road traffic accidents. In: Israelstam, Stephen,

and Lambert, Sylvia, eds. Proceedinns of the Sixth International Conference on Alcohol, Drugs, and Traffic Safety.

Toronto, September 8-13. 1974. Toronto: Addiction Research

Foundation of Ontario, 1975, pp. 439-448.

Finkle, Bryan S. 'Will the real drugged driver please stand up?'

An analytical toxicology assessment of drugs and driving.

In: Israelstam, Stephen, and Lambert, Sylvia, eds.

Proceedings of the Sixth International Conference on Alcohol,

Drugs, and Traffic Safety. Toronto. September 8-13. 1974.

Toronto: Addiction Research Foundation of Ontario, 1975,

pp. 607-611.

Frankenhaeuser, Marianne. Drug effects on emotions: relevance

to driving accidents. In: Israelstam, Stephen, and Lambert,

Sylvia, Eds. Proceedinns of the Sixth International Conference

on Alcohol, Drugs. and Traffic Safety. Toronto. September 8-13,

1974. Toronto: Addiction Research Foundation of Ontario, 1975,

pp. 259-270.

Israelstam, Stephen, and Lambert, Sylvia, eds. Alcohol, drugs,

and traffic safety. Proceedings of the Sixth International

Conference on Alcohol. Drugs, and Traffic Safetv. Toronto.

September 8-13, 1974. Toronto: Addiction Research Foundation

of Ontario, 1975.

Kielholz, P., and Hobi, V. The influence of psychopharmaca on the

aptitude to drive. Therapeutische Umschau (Revue Therapeutique)

(Bern), 31(9):606-613, September 1974.

Kielholz, P. Alcohol, drugs, and driving behaviour in Switzerland.

In: Israelstam, Stephen, and Lambert, Sylvia, eds. Proceedings

of the Sixth International Conference on Alcohol, Drugs, andTraffic Safety, Toronto, September 8-13, 1974. Toronto:

Addiction Research Foundation of Ontario, 1975, pp. 395-397.

Landauer, Ali A.; Pocock, Derek A.; and Prott, F.W. The effect

of medazepam and alcohol on cognitive and motor skills used

in car driving. Psychopharmacologia (Berlin), 37(2):159-168,

June 21, 1974.

128
Drugs and Driving - Alcohol and Other Drugs - Combined Effects

Linnoila, M.; Saario, I.; and Maki, M. Effect of treatment with

diazepam or lithium and alcohol on psychomotor skills related

to driving. European Journal of Clinical Pharmacology (Berlin),

7(5):337-342, August 23, 1974.

Moller, M.R.; Witzmann, K.H.; and Tausch, D. Report on the

determination of the combined intake of alcohol and pharmaceuticals. Beitraege Zur Gerichtlichen Medizin (Vienna),

31:259-266, 1973.

Perrine, M.W., ed. Alcohol, Drugs and Driving. Springfield,

Virginia: National Technical Information Service, March

1974, 380 pp.

Perrine, M.W. Alcohol, drugs and driving: relative priorities

for basic and applied research. In: Israelstam, Stephen,

and Lambert, Sylvia, eds. Proceedinns of the Sixth International

Conference on Alcohol. Drugs. and Traffic Safety.

September 8-13. 1974. Toronto: Addiction Research Foundation

of Ontario, 1975, pp. 107-128.

Schroeder, Stephen R.; Ewing, John A.; and Allen, John A. Combined

effects of alcohol with methapyrilene and chlordiazepoxide on

driver eye movements and errors. Journal of Safety Research,

6(2):89-93, June 1974.

Smiley, A.; LeBlanc, A.E.; French, I.W.; and Burford, R. The

combined effects of alcohol and common psychoactive drugs:

II. Field studies with an instrumented automobile. In:

Israelstam, Stephen, and Lambert, Sylvia, eds. Proceedings

of the Sixth International Conference on Alcohol. Drugs and

Traffic Safetv. Toronto, September 8-l3. 1974. Toronto:

Addiction Research Foundation of Ontario, 1975, pp. 433-438.

129
DRUGS AND DRIVING

(Epidemiology)

Bureau of Motor Carrier Safety, Federal Highway Administration,

U.S. Department of Transportation. Physical Condition Report

of Commercial Drivers Involved in Accidents for Year 1971.

Federal Highway Administration, U.S. Washington, D.C. 20590,

December 1973.

Eash, Zaneta, and Reed, Patricia. Driving records of Oregon

methadon patients. In: Blachly, P.H., ed. Methadon.

Proceedings of the Methadon Workshop, March 27-28, 1971,

Portland, Oregon. Corvallis, Oregon: Continuing Education

Publications, 1971, pp. 26-27.

Kapur, B.M. Patterns of drug abuse and their relationship to

traffic accidents. In: Israelstam, Stephen, and Lambert,

Sylvia, eds. Proceedings of the Sixth International Conference

on Alcohol. Drugs. and Traffic Safety, Toronto. September 8-13.

1974. Toronto: Addiction Research Foundation of Ontario, 1975,

pp. 69-72.

Kaye, Sidney. Sudden drop in alcohol and drug related traffic

deaths in Puerto Rico--1974. Asociacion Medica de Puerto

Rico, Boletin (Santurce), 67(12):369-371, December 1975.

Silverstone, T. Drugs and driving. British Journal of Clinical

Pharmacology (London), 1(6):451-454, December 1974.

Sterling-Smith, Robert S. Alcohol, marijuana and other drug

patterns among operators involved in fatal motor vehicle

accidents. In: Israelstam, Stephen, and Lambert, Sylvia, eds.

Proceedings of the Sixth International Conference on Alcohol,

Drugs. and Traffic Safetv. Toronto. September 8-13, 1974.

Toronto: Addiction Research Foundation of Ontario, 1975,

pp. 93-105.

Turk, Robert F.; McBay, Arthur J.; Hudson, Page; and Bullaboy,

Marilyn M. Involvement of alcohol, carbon monoxide and other

drugs in traffic fatalities. In: Israelstam, Stephen, and

Lambert, Sylvia, eds. Proceedings of the Sixth International

Conference on Alcohol, Drugs and Traffic Safety. Toronto.

September 8-13, 1974. Toronto: Addiction Research Foundation

of Ontario, 1975, pp. 597-606.

Waller, Julian A. Epidemiologic issues about alcohol, other drugs

and highway safety. In: Israelstam, Stephen, and Lambert, Sylvia,

eds. Proceedings of the Sixth International Conference on

Alcohol, Drugs, and Traffic Safety. Toronto. September 8-13,

1974. Toronto: Addiction Research Foundation of Ontario, 1975,

pp. 3-11.

130
Drugs and Driving - Epidemiology (Cont'd)

Woodhouse, E.J.; Adams, R.A.; Huerner, J.; and Reich, S. The

incidence of drugs in fatally injured drivers. Final report.

Journal of Safety Research, 6(1):42, March 1974.

131
DRUGS AND DRIVING

(Marihuana)

Cress, C. Raymond. The marijuana arguments. Medical Arts and

Sciences; 28(1):34-38, March 1974.

Dott, Andrew B. Effect of marijuana on aggression and risk

acceptance in an automotive simulator. Clinical Toxicoloev

7(3):289, 1974.

Ellingstad, V.S.; McFarling, L.H.; and Struckman, D.L. Alcohol.

Marijuana and Risk Taking. Virginia: National Technical

Information Service, January 1974, 74 pp.

Is the whole country going to pot? National Drug Reporter,

5(11):3, November 1975.

Jones, Reese. Human effects. In: National Institute

on Drug Abuse. Marihuana and Health

5th Annual Report to Congress from Secretary of Health,

Education, and Welfare, 1975. Washington, D.C.: U.S.

Gov't. Printing Office, 1976, pp. 78-106.

Miller, Loren L., ed. Marihuana: Effects on Human Behavior.

New York: Academic Press, 1974, 406 pp.

Moskowits, Herbert. Marihuana and driving. Accident Analysis

and Prevention, 8(1):21-26, 1976.

Moskowitz, H.; McGlothlin, W.; and Hulbert, S. The Effect of

Marihuana Dosage on Driver Performance, Prepared for U.S.

Department of Transportation. Springfield, Virginia: National

Technical Information Service, 1973, 53 pp.

Moskowitz, Herbert; Hulbert, Slade; and McGlothlin, William H.

Marihuana: Effects on simulated driving performance. Accident

Analysis and Prevention. 8(1):45-50, 1976.

National Organization for the Reform of Marijuana Laws. NORML

Statements of Position and Policy. National Organization

for the Reform of Marijuana Laws, 2317 M Street, N.W.,

Washington, D.C. 20037, December 5, 1975.

Nicholas, James L. Drug Use and Highwav Safety: A Review of

the Literature. Prepared for U.S. Department of Transportation.

Stevens Point, Wisconsin: University of Wisconsin, 1971, 110 pp.

132
Drugs and Driving - Marihuana (Cont'd)

Pot can harm, but does prison help? U.S. News and World Report,

77(23):80, December 2, 1974.

Rafaelsen, Lise; Christrup, Henriette; Beth, Per; and Rafaelsen,

Ole J. Effects of cannabis and alcohol on psychological

tests. Nature (London), 242(5393):117-118, March 9, 1973.

Rouse, Beatrice A., and Ewing, John A. Marijuana and other drug

use by women college students: associated risk taking and

coping activities. American Journal of Psvchiatry, 130(4):

486-491, April 1973.

Science and Marijuana. Merchandiser (Mt. Joy, Pennsylvania),

February 12, 1975.

Teale, Derrick, and Marks, Vincent. A fatal motor-car accident

and cannabis use: investigation by radioimmunoassay.

Lancet (London), 1(7965):884-885, April 24, 1976.

133
DRUGS AND DRIVING

(Sedatives)

Aschoff, Jurgen C.; Becker, Wolfgang; and Weinert, Dieter.

Computer-electronystagmography: a useful tool in evaluating

influence of psychopharmacological drugs on traffic safety.

In: Israelstam, Stephen, and Lambert, Sylvia, eds. Proceedings

of the Sixth International Conference on Alcohol. Drugs. and

Traffic Safety, Toronto. September 8-13. 1974. Toronto:

Addiction Research Foundation of Ontario, 1975, pp. 319-327.

Berry, P.A.; and Grubb, D.J. Effects of oxypertine and chlordiazepoxide on human motor co-ordination. Journal of International

Medical Research (North Hampton, England), 2(3):177-188, 1974.

Dureman, I., and Norrman, B. Clinical and Experimental Comparison

of Diazepam, chlorazepate and placebo. Psychopharmacologia

(Berlin), 40(4):279-284, March 10, 1975.

Fuller, George S. Drugs: a rising traffic enforcement dilemma.

Police Chief, 42(1):26, 80, January 1975.

Kaye, Sidney. Alcohol, drugs, and carbon monoxide in traffic

fatalities. In: Israelstam, Stephen, and Lambert, Sylvia,

eds. Proceedings of the Sixth International Conference on

Alcohol, Drugs, and Traffic Safety. Toronto. September 8-13.

1974. Toronto: Addiction Research Foundation of Ontario,

1975, pp. 85-92.

Kopriva, K.; Frantik, E.; and Rorvath, M. Effects of monotony

and of pentobarbital in monotonous conditions: correlation

with personality traits. Activitas Nervosa Superior (Prague),

17(1):45-48, 1975.

LeBlanc, A.E., and Wilson, A. Drug after effects and traffic

safety. In: Israelstam, Stephen, and Lambert, Sylvia, eds.

Proceedings of the Sixth International Conference on Alcohol,

Drugs, and Traffic Safety, Toronto, September 8-13, 1974.

Toronto: Addiction Research Foundation of Ontario, 1975,

pp. 449-452.

Pekkanen, John. The tranquilizer war: controlling librium and

valium. New Republic, 173(3):17-19, July 19, 1975.

Thompson, L.J.; Toulson, P.K.; and Ragg, K.E. Effects of oxprenolol

and diazepam on psychomotor performance. New Zealand Medical

Journal (Dunedin), 82(546):138, August 27, 1975.

134
DRUGS AND DRIVING

(Search and Seizure)

Caruso, David A. After United States v. Robinson: effect

on New York law. Albany Law Review, 39(4):895-912, 1975.

DHSS supports marijuana law changes. Wisconsin Mental Hygiene

Review. 10(1):2, January-February 1976.

Forfeiture--Iowa. State v. one certain conveyance, 1971 Honda

350, etc., 211 N.W.2D 297 (Iowa 1973). Contemporary Drug

Problems, 3(1):172, Spring 1974.

Forfeiture of automobile--Utah. State v. one porsche, 526

P.2D 917 Utah Sup. Ct. (1974). Contemporary Drug Problems,

4(2):245, Summer 1975.

Rose, Michael Edward. The automobile presumption in the New

York narcotics law., Fordham Law Review, 42:761-769, 1974.

Search and Seizure--New York. People v. Chestnut, 43 App. Div.

2D 260 (3D Dept. 1974). Contemporary Drug Problems, 3(1):173,

Spring 1974.

Stickgold, Arthur. Dope scoreboard: thou shalt not get caught.

Los Angeles Free Press, 12(11):27, March 14, 1975.

Vehicle search given ok. Gazette (Phoenix, Arizona), January 31, 1975.

135
monograph series

1 FINDINGS OF DRUG ABUSE

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An annotated bibliography of

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mural grant research 1967-74

Vol. 1, pp. 384; Vol. 2, pp. 377

2 OPERATIONAL DFINITIONS IN

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RESEARCH 1975

Editors: Jack Elinson, Ph.D. and

David Nurco, Ph.D.

Task Force articles proposing

consensual definitions of concepts and terms used in psychosocial research to achieve operational comparability. pp. 167

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BEHAVIOR: REALITY OR CLICHE?

Editor: Bruce J. Bernard, Ph.D.

Articles examining the relation

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range of animal and human

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Author: Jay R. Williams, Ph.D.

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