Women and

Drugs:

A New Era

for Research

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration
Women and Drugs:

A New Era for Research

Editors:

Barbara A. Ray, Ph.D.

Division of Clinical Research

National Institute on Drug Abuse

Monique C. Braude, Ph.D.

Division of Preclinical Research

National institute on Drug Abuse

NIDA Research Monograph 65

1986

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National Institute on Drug Abuse

5600 Fishers Lane

Rockville, Maryland 20857

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

Washington, D.C. 20402
NIDA Research Monographs are prepared by the research divisions of the

National Institute on Drug Abuse and published by its Office of Science. The

primary objective of the series is to provide critical reviews of research problem

areas and techniques, the content of state-of-the-art conferences, and

integrative research reviews. Its dual publication emphasis is rapid and targeted

dissemination to the scientific and professional community.

Editorial Advisors

MARTIN W. ADLER, Ph.D.

Temple University School of Medicine

Philadelphia, Pennsylvania

SYDNEY ARCHER, Ph.D.

Rensselaer Polytechnic lnstitute

Troy, New York

RICHARD E. BELLEVILLE, Ph.D.

NB Associates. Health Sciences

RockviIle, Maryland

KARST J. BESTEMAN

Alcohol and Drug Problems Association

of North America

Washington, DC

GILBERT J. BOTVIN, Ph.D.

Cornell University Medical College

New York, New York

JOSEPH V. BRADY, Ph.D.

The Johns Hopkins University School of

Medicine

Baltimore, Maryland

THEODORE J. CICERO, Ph.D

Washington University School of

Medicine

St Louis, Missouri

SIDNEY COHEN, M.D.

Los Angeles, California

MARY L. JACOBSON

National Federation of Parents for

Drug Free Youth

Omaha, Nebraska

REESE T. JONES, M.D.

Langley Porter Neuropsychiatric lnstitute

San Francisco, Californla

DENISE KANDEL, Ph.D.

College of Physicians and Surgeons of

Columbia University

New York, New York

HERBERT KLEBER, M.D.

Yale University School of Medicine

New Haven, Connecticut

RICHARD RUSSO

New Jersey State Department of Health

Trenton, New Jersey

NIDA Research Monograph Series

CHARLES R. SCHUSTER, Ph.D.

Director, NIDA

JEAN PAUL SMITH, Ph.D.

Acting Associate Director for Science, NIDA

Acting Editor

Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857
Women and Drugs:

A New Era for Research
This monograph is based upon papers and discussion from the

technical review on research issues related to women which took

place on May 1 and 2, 1985, at Bethesda, Maryland. The review was

sponsored by the Division of Clinical Research of the National

Institute on Drug Abuse.

COPYRIGHT STATUS

All material in this volume except quoted passages from copyrighted

sources is in the public domain and may be used or reproduced

without permission from the Institute or the authors. Citation of

the source is appreciated.

The United States Government does not endorse or favor any specific

commercial product or company. Trade names or company names

appearing in this publication are used only because they are

considered essential in the context of the studies reported herein.

DHHS Publication No. (ADM)90-1447

Alcohol, Drug Abuse, and Mental Health Administration

Printed 1966, Reprinted 1967, 1990

NIDA Research Monographs are indexed in the Index Medicus. They

are selectively included in the coverage of American Statistics

Index, BioSciences Information Service, Chemical Abstracts, Current

Contents, Psychological Abstracts, and Psychopharmacology Abstracts.

iv
Preface

Barbara A. Ray and Monique C. Braude

The history of drug abuse research shares with other sciences a

relative paucity of knowledge about females in particular and

about gender effects in general. This bias in knowledge stems

from the tradition of using male subjects for animal and human

experiments and an unexamined assumption that gender is not an

important experimental variable.

The Public Health Service is now charged with correcting this

cumulated imbalance in knowledge, and the PHS Women's Task Force

has developed specific recommendations for achieving the goal,

including targets for the future of drug- and alcohol-related

research. The history and significance of the Task Force is here

described by Dr. Chatham, and mechanisms and guidelines for

correcting gaps in knowledge about new and marketed drugs are

referenced in Dr. Danello's overview of the Food and Drug

Administration and its role in drug-related research.

Among the culturally embedded but inaccurate assumptions about

gender is that reproductive functioning is somehow an entirely

female matter. Consideration must now be given to the possible

assault on both male and female gametes by drug and alcohol abuse.

Not only can the female ovum possibly be damaged by substance

abuse, but male sperm can likewise be damaged and subvert healthy

fetal development.

Another false assumption about gender is that sex differences are

relevant only to reproductive processes. Dr. Hamilton provides an

extensive and well-documented story of the many ways that gender

affects health, including the gonadal steroid influences on brain

neurochemical substrate. A host of new discoveries make it clear

that differences in brain structure and physiology exist that are

attributable to a masculine or feminine patterning of hormones

occurring at critical periods during development.

As the chapter by Dr. Baum makes quite clear, sex hormones are not

male or female, but interact at critical stages to produce profound differences in anatomy and behavior. Dr. Baum leads us

v
through an intricate trail of detection to show that, in the ferret. It is ultimately estrogen that permits the formation of a

male brain nucleus that then seems to permit sensitivity to testosterone, leading to characteristic male behavior. Although

Dr. Baum describes brain dimorphism in the ferret, an extensive

literature is emerging that strongly suggests that brain dimorphism exists between the human female and male.

For the purposes of scientific research, studying just women is as

meaningless as studying just men. Rather, gender as an experimental variable needs to become standard in studies of drug abuse and

drug effects. Dr. Mendelson shows us that the picture for women

and drug abuse changes markedly when nature and extent figures are

broken out for men and women separately. Looking only at how many

substance abusers are women, their problem seems small compared to

the numbers of men abusing drugs and alcohol. But among women

needing mental health support services, drug and alcohol abuse

problems rank second only to depressive illness. From a female

perspective, substance abuse appears as an important threat to

health.

Dr. Mello presents evidence indicating that women who suffer dysphoria associated with the menstrual cycle may self-medicate

during the dysphoric period. That the menstrual cycle involves

coordinated and repeated hormonal secretions in the central nervous system makes the female possibly a useful model for studying

drugs of abuse, as abused drugs typically act on central neural

events.

Going back to reanalyze epidemiologic data by gender, Dr. Clayton

uses NIDA's 1982 National Survey to show certain stable differences in drug use by gender as well as a trend toward convergence

in age-of-first-use for females and males. Dr. Clayton directs

our attention to the changing role of women in society and sees a

need to track how this may affect substance abuse patterns in the

future.

For the purpose of preventing drug abuse, it is important to

understand how societal, economic, and physiological pressures

differ for subpopulations. Several contributors address this

question. Dr. Gritz outlines the correlation between a post World

War II decision by cigarette manufacturers to target the female

consumer and a gradual increase in cigarette smoking by women,

beginning in their teens, at a time when men were decreasing their

smoking. Dr. Braude provides an overview of the many important

changes in biology and life circumstances that confront the older

woman, who composes approximately 60 percent of the elderly

population. Dr. Braude also points out the especially high risk

In this population of harmful effects resulting from the taking of

multiple medications that may have unknown and possibly dangerous

interactions. In a related chapter, Dr. Barry, drawing upon her

geriatric expertise, gives details of the changing response to

drugs that accompanies the aging process and how this differs for

men and women.

vi
Gender research is in its infancy and promises to challenge

accepted ideas as the accumulating data sort fact from fiction.

The NIDA conference on women and drugs and this monograph are one

step in the process of opening the scientific community to new

ideas and knowledge about gender as it relates to substance abuse.

vii

Contents

Page

Preface v

The PHS Task Force on Women's Health Issues

Lois Chatham 1

FDA's Perspective on Women and Drugs

Mary Ann Danello 9

An Overview of the Clinical Rationale for Advancing

Gender-Related Psychopharmacology and Drug Abuse Research

Jean A. Hamilton 14

Clinical Investigations of Drug Effects in Women

Jack H. Mendelson and Nancy K. Mello 21

Drug Use Patterns and Premenstrual Dysphoria

Nancy K. Mello 31

Gender Dimorphism in Brain

Michael Bawn 49

Drugs and Drug Interactions in the Elderly Woman

Monique C. Braude 58

Gender as a Factor in Treating the Elderly

Patricia P. Barry 65

Gender and the Teenage Smoker

Ellen R. Grits 70

Gender Differences in Drug Use: An Epidemiological

Perspective

Richard R. Clayton, Harwin L. Voss, Cynthia Robbins,

and William F. Skinner 80

List of NIDA Research Monographs 100

ix
The PHS Task Force on

Women’s Health Issues

Lois Chatham

I have been asked to convey to you the background and significance

of the Public Health Service (PHS) Task Force on Women's Health

Issues. As background I would like to discuss the reasons why a

task force is created. It is my impression that a task force

usually is created to work on a specific, well-defined problem or

subject--hence the term task force. The establishment of such a

work group provides visibility and enables the appointing official

to cut across organizational lines for the purpose of pooling

resources. The creation of a task force also usually implies

speedy action.

A task force frequently is created in response to some perceived

emergency or threat. The event may be a national or regional

emergency, such as an outbreak of Legionnaire's disease, the

eruption of Mt. St. Helen, the flooding of Johnstown, Pennsylvania, or, more recently, the outbreak of Acquired Immune

Deficiency Syndrome (AIDS). On the other hand, such a group may

be established in response to perceived political pressures such

as the concerns of the aging, the Vietnam veterans, the handicapped, or minority populations.

The PHS Task Force on Women's Health Issues obviously was not

created in response to an emergency health event. In fact,

women's overall health status, like the Nation's health, has

improved over the past decade. However, it also is apparent that

the treatment of many chronic diseases and devastating illnesses

has not improved significantly over the past decade.

Because the Task Force report was scheduled for submission to the

Assistant Secretary for Health in October prior to the 1984

Presidential election, many of us wondered if the Task Force had

been created in response to political pressure. However, this

concern proved unfounded. To the contrary, the Task Force was the

attempt of the Assistant Secretary for Health, Dr. Edward Brandt,

to direct the Public Health Service to reexamine its activities

for the purpose of significantly improving women's health.

1
To assess the significance of a task force, one must examine the

organizational placement of the unit and the stature of the members. One also must assess the resources allocated to the

activity. In this case, although no funds were provided, the

Office of the Assistant Secretary for Health assigned a staff

member to serve as Executive Secretary for the Task Force. It

also is significant that the Chairperson of the Task Force is the

highest ranking woman in the Public Health Service, namely, Ruth

Kirschstein, M.D., Director of the National Institute of General

Medical Sciences. Other Task Force members were appointed by the

respective PHS agency heads. All members, by virtue of organizational location or personal characteristics, were in a position to

speak for the agency they represented in matters of policy and

resources. This is essential to the effective operation of such a

unit.

A task force put together to work quickly on a single task faces

certain dangers. First, because of the singlemindedness of the

assignment, a task force may create organizational threats to

existing agencies that feel the work being performed lies within

their agency's scope of responsibility. Second, the task force

may make impractical or impossible recommendations because of

bureaucratic naivete. Third, the report may not be read by the

right people, or, if read, the recommendations may not be implemented. To increase the likelihood that the recommendations of

the task force would be used, all recommendations were carefully

analyzed for feasibility and appropriateness by the organizational

units expected to implement them.

In October, 1984, the Task Force Report was submitted to the

Assistant Secretary for Health, Dr. Edward Brandt. In November,

1984, Dr. Brandt issued a memorandum to all Health and Human

Services (HHS) agency heads, directing them to develop plans for

implementing the Task Force recommendations. To ensure continuity

and oversight of these plans, in December, 1984, the Assistant

Secretary for Health established the Coordinating Committee on

Women's Health Issues. Thus, in June, 1985, agency representatives reported for the first time to the Assistant Secretary for

Health on the progress being made to implement the Task Force

recommendations. These plans, in turn, will be reviewed by the

Coordinating Committee as the first step in providing a continuing

review of the implementation of the Task Force Report and Recommendations.

To give you an historical perspective, the following lists have

been developed. These outline the history of the Task Force.

They outline its areas of responsibility and the recommendations

it has made. The chronological sequence of events is outlined

below:

2
PHS TASK FORCE ON

WOMEN'S HEALTH ISSUES

1983

Summer

Dr. Edward Brandt, DHHS, Assistant Secretary for Health, appoints

Task Force.

PHS agencies assemble information on diseases/conditions:

Unique to women

More prevalent in women

More serious in women

Having different risk factors for women

Fall

Task Force establishes six committees.

1984

January-March

PHS Regional Offices hold public hearings.

April-August

Reports and recommendations are prepared and edited.

September

Executive Summary and Recommendations plans developed by PHS

agencies.

December

PHS Coordinating Committee on Women's Health Issues is

established.

1985

February

Volume I of Women's Health: Report of the Public Health Service

Task Force on Women's Health Issues published (USPHS 1985).

3
May

Volume II of Women's Health report published (USPHS 1985).

The members of the Task Force encompassed all PHS agencies, as

follows:

Office of Disease Prevention and Health Promotion (OPDHP)

Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA)

Centers for Disease Control (CDC)

Food and Drug Administration (FDA)

Office of Public Affairs (OPA)

National Institutes of Health (NIH)

Health Resources and Services Administration (HRSA)

These agencies have divergent responsibilities, all of which

address the broad mandate of the Public Health Service. For ease

in implementation, recommendations were grouped according to which

of the six PHS missions they most clearly addressed. The PHS

missions are:

I. Promoting a Safe and Healthful Physical and Social

Environment

II. Providing Services for the Prevention and Treatment of

Illness

III. Conducting Research and Evaluation

IV. Recruiting and Training of Health Care Personnel

V. Educating and Informing the Public and Disseminating

Research Information

VI. Designing Guidance for Legislative and Regulatory Measures

Similarly, for ease in accomplishing the task, subcommittees were

formed to write reports for the full Task Force. After much

thought, six subcommittees were formed as outlined below:

Social Factors Affecting Women's Health

Women's Physical Health and Well-Being

Health Concerns of Older Women

4
Issues Related to Alcohol and Drug Abuse and the Mental Health

5

of Women

Assessment of Women's Health Issues as Presented at Regional

Meetings

Inventory of Public Health Service Programs Related to Women's

Health

The first four are substantive in nature. The fifth subcommittee

report summarizes the recommendations made at the meetings held in

the PHS regional offices, and the sixth subcommittee report is a

repository of all relevant women's health activities and resources

identified during the life of the Task Force.

Since the Task Force was to address health issues of women in the

broadest sense, it became apparent that the Federal Government was

responsible for implementing only a portion of the recommendations. Indeed, if women's health issues were to be effectively

and efficiently addressed, the following sectors needed to be

involved:

The Public Health Service

Other Federal, State, and local government agencies

Private and voluntary organizations

Women themselves

Below, the recommendations are displayed within the six-part

mission of the Public Health Service.

I.

A.

B.

II.

A.

B.

PROMOTING A SAFE AND HEALTHFUL PHYSICAL AND SOCIAL

ENVIRONMENT

Use the law and regulations to ensure a safe, healthful

physical and social environment for all.

Encourage women to learn about health issues and take

personal and political action to Improve their health.

PROVIDING SERVICES FOR THE PREVENTION AND TREATMENT OF

ILLNESS

Make chronic disease management a priority for the Public

Health Service.

Increase access to health care for women who are

underinsured, elderly, or isolated.
III.

A.

B.

C.

D.

E.

IV.

A.

B.

V.

A.

8.

C.

VI.

A.

B.

CONDUCTING RESEARCH AND EVALUATION

Expand research on conditions that are unique to women or

that are more prevalent in women.

Use longitudinal research to assess the interaction of

behavioral, social, and biological factors.

Collect and analyze health data by age, sex, and race.

Study workplace hazards for women.

Study how culture and socialization affect women's and men's

health differently.

RECRUITING AND TRAINING OF HEALTH CARE PERSONNEL

Increase the number of women in key health positions in

services, research, administration, and education.

Address continuing education programs in health to women's

needs.

EDUCATING AND INFORMING THE PUBLIC AND DISSEMINATING

RESEARCH INFORMATION

Communicate the importance of a healthful lifestyle through

outreach programs.

Organize a group from television, films, publishing, and

advertising to examine the effects of media images on

women's health.

Disseminate, via the Public Health Service, up-to-date

research information.

DESIGNING GUIDANCE FOR LEGISLATIVE AND REGULATORY MEASURES

Encourage organizations interested in women's well-being to

keep informed, promote information exchange and education,

and advocate improved health conditions for women.

Use law and regulations to ensure a safe, healthful physical

and social environment for all.

Finally, the Task Force report consists of many recommendations

beyond the 16 displayed above. Since the purpose of this meeting

is to look at women's health as affected by drug and alcohol

abuse, some additional recommendations have been identified as a

useful framework for conceptualizing presentations and potential

recommendations which may come from this conference.

6
SPECIAL EFFORTS SHOULD BE MADE TO GAIN KNOWLEDGE ABOUT THOSE

DISEASES RELATED TO ALCOHOL AND DRUG ABUSE, AND ABOUT MENTAL

ILLNESSES OF IMPORTANCE TO WOMEN, BY THE INITIATION OF:

(1) Research to study depression in women when it occurs alone or

in conjunction with alcohol or drug abuse problems.

(2) Studies of the significant factors related to the onset,

continuation, and cessation of smoking, drinking, and drug

taking by women.

(3) Studies of the role of the family and of cultural attitudes

in the maintenance of mental health or the development of

mental illness, as well as in the use or misuse of alcohol,

drugs, and tobacco.

A SYSTEMATIC EFFORT MUST BE MADE TO ADDRESS ISSUES RELATING TO

GENDER BIAS IN RESEARCH AND CLINICAL PRACTICE THAT LEAD TO

INADEQUATE ATTENTION TO THE NEEDS OF WOMEN.

Ways to effect such change include:

(1) The issuance of a comprehensive Public Health Service policy

directing all operating units to review their research guidelines to ensure that sex differences are routinely studied,

wherever feasible. Such instructions should be included in

grant application kits.

(2) The requirement that postmarketing surveillance of all

prescription drugs should include reporting of the adverse

effects in women of drug interactions with alcohol, commonly

used psychotherapeutic drugs, and drugs commonly used in

relation to hormonal changes in women.

(3) The requirement that adequate numbers of women be included in

clinical trials of drugs that will be used by women, and that

results be separately reported by gender for all new drugs

that are to be recommended for use by women.

(4) The commissioning of an interdisciplinary panel of senior

scientists, including women, to review existing research and

research methodology to develop a comprehensive plan for

addressing any gender bias identified in research in general,

but in particular in alcohol, drug abuse, and mental health

research.

(5) The establishment of a task force to review mental health

issues related to women and to make recommendations for

change in the Fourth Revision of the Diagnostic and

Statistical Manual (DSM IV) of the American Psychiatric

Association (APA), in order to promote adequate diagnosis

and treatment of women with alcohol, drug abuse, and mental

health problems. Such a task force should work closely with

7
the APA Task Force on Nomenclature and Statistics. In

addition, a similar review mechanism should be established

for the International Classification of Diseases (ICD-10).

This summarizes the progress and significance of the PHS Task

Force on Women's Health Issues. I am confident that our meeting

and collaborative publication reflect an awareness that research

on drug and alcohol use by women is crucial to improving the

health status of women. With the impetus provided by the Task

Force Report, it is anticipated that the research community will

be stimulated to explore aspects of women's health previously

neglected.

REFERENCES

U.S. Public Health Service. Women's Health: Report of the

Public Health Service Task Force on Women's Health Issues,

Volume I. Supplement to Public Health Reports, 100(1):73-106,

January-February 1985.

U.S. Public Health Service. Women's Health: Report of the

Public Health Service Task Force on Women's Health Issues,

Volume II. DHHS Publication No. (PHS)85-50206, May 1985.

AUTHOR

Lois Chatham, Ph.D.

Director of Extramural Research

National Institute on Alcohol Abuse

and Alcoholism

Parklawn Building, Room 14C-10

5600 Fishers Lane

Rockville, MD 20857

8
FDA’s Perspective on Women

and Drugs

Mary Ann Danello

Many of you are probably familiar with the Food and Drug Administration's (FDA) requirements for new drug approval. However, for

the benefit of those who are not as familiar with this process,

let me give you a brief overview as well as some idea of when

women are included in these clinical trials.

The FDA provides guidance for investigators performing clinical

evaluations of new drugs in an Agency publication entitled,

"General Considerations for Clinical Evaluation of Drugs" (HEW

publication no. FDA-77-3040). The purpose of this publication is

to present acceptable current approaches to the study of investigational drugs in humans. The document, in part, contains recommendations for clinical studies, which are recognized as desirable

approaches to be used in arriving at conclusions concerning the

safety and effectiveness of a new drug, and includes the following

basic information:

A description of institutional review boards (IRBs) and

principles of informed consent

Clinical trial design and analysis considerations

Selection of subjects

Numbers of and randomization of patients

Study control

Patient compliance

Dosage considerations

Drug dynamic studies

In addition to that document, there are 25 clinical guidelines

available concerning the design of adequate and well-controlled

9
studies on different classes of drugs. These guidelines have been

developed largely or entirely by the FDA's advisory committees and

consultants.

The FDA's drug review and approval process involves two stages--

the investigational new drug application stage (IND) and the new

drug application stage (NDA). The IND process begins after animal

data on the drug have been collected and analyzed and the testing

in humans is ready to commence. Once an IND is submitted to the

FDA, and the Agency is satisfied that the study does not pose

unreasonable risks to human subjects, then the sponsor may begin

testing the drug in humans.

The testing of investigational drugs occurs in three phases:

PHASE 1

These are clinical pharmacologic studies which include the initial

introduction of the drug into humans and involve a range of about

20 to 80 persons in a trial. Phase 1 trials include early doseranging studies as well as determination of toxicity levels and

pharmacologic effects. Drug dynamic and metabolic studies are

also considered to be Phase 1 clinical pharmacologic studies in

whichever stage of the clinical investigation they are performed.

It is recommended that females who are pregnant, or are at risk of

becoming pregnant, should be excluded from early dose-ranging

studies.

PHASE 2

These clinical investigations consist of controlled clinical

trials designed to demonstrate effectiveness and relative safety

of the investigational drug. These studies are normally performed

on a limited number (100 to 200) of closely monitored patients.

Women may be included in Phase 2 clinical trials if adequate

information on relative safety and efficacy has been amassed and

certain animal experiments described in the FDA animal reproduction guidelines (Segment 1 for females and Segment 2) have been

completed. These experiments determine the teratogenic potential

of the investigational drug. There are instances in which women

of childbearing potential may receive investigational drugs in the

absence of adequate reproduction studies in animals. These

include: the use of the drug as a lifesaving or life-prolonging

measure; use of the drug which belongs to a class of drugs the

teratogenic potential of which has already been determined; use of

women who may have been institutionalized for a time period

adequate to establish a nonpregnant state.

PHASE 3

These clinical trials are expanded controlled and uncontrolled

trials. They are performed after the drug's effectiveness has

been established (to a certain degree) and are intended to gather

10
additional evidence of effectiveness for specific indications and

a more precise definition of drug-related adverse effects. Since

Phase 3 trials are large-scale trials, it is recommended that

women of childbearing age be included only if all three segments

of the FDA animal reproduction guidelines are completed to determine the teratogenic potential of the investigational drug. As

with Phase 2 trials, there are circumstances in which an investigational drug may be administered to women in the absence of

adequate reproduction studies in animals.

Data from the Phase 1, 2, and 3 studies, as well as additional

information (supplements, amendments, progress reports, and

reviews), are compiled by the sponsoring pharmaceutical firm and

comprise the NDA (New Drug Application). After these data have

been analyzed and assessed by the FDA to determine that the investigational drug is safe and effective for what it claims to do,

the drug can be approved for marketing. Following the marketing

of a drug, the drug's sponsor should submit to the FDA reports on

adverse reactions, data from additional studies, or manufacturing

information.

PHASE 4

These studies are clinical trials which are undertaken after the

new drug has been marketed. Included in this category are:

additional studies to elucidate the incidence of adverse reactions or to obtain more information on a pharmacologic effect;

large-scale, long-term morbidity or mortality studies;

clinical trials in a patient population not adequately studied

in the premarketing stage;

clinical trials for an indication for which the presumed drug,

once available, will be used; and

additional Phase 3-type trials to supplement premarketing data

where it has been deemed in the public interest to release a

drug for more widespread use prior to the acquisition of all

data normally obtained before marketing.

Subpopulations

While the Agency has developed separate guidelines for clinical

evaluation of drugs in infants and children and is in the process

of addressing some of the special problems of clinical evaluation

of drugs in the elderly, there are presently no similar guidelines

for women of childbearing potential. However, the "General Considerations" publication includes a brief section on the inclusion

of women of childbearing potential in studies of investigational

drugs.

11
The salient features of these general considerations are as

follows:

Women of childbearing potential should be excluded from the

earliest dose-ranging studies.

If adequate information on efficacy and relative safety data

are present (including certain animal reproduction studies),

women of childbearing potential may be included in Phase 2 and

Phase 3 trials.

Women of childbearing potential may receive Phase 2 or Phase 3

investigational drugs in the absence of adequate reproduction

studies in animals under certain circumstances (e.g., the drug

is lifesaving or life prolonging, or it belongs to a class of

drugs for which the animal teratogenic potential is known).

When an investigational drug for which there are no animal

reproduction data is used in women for the treatment of a

serious disease, the lack of animal data should be pointed out

and fully informed consent obtained.

Pregnancy tests should be performed prior to the introduction

of investigational drugs in women and they should be advised of

contraceptive measures.

For drugs that are absorbed systemically, transplacental passage of the drug and its secretion in milk should be assumed.

Fetal followup should be conducted in women who become pregnant

while on an investigational drug. Excretion of the drug or its

metabolites in the milk of lactating women should be determined, when feasible, prior to the use of the drug in nursing

mothers.

This is a brief overview of the FDA new drug approval process and

the avenues for testing drug effects on women and their offspring,

including the current considerations for the use of women in

clinical trials for investigational drugs. As you have seen,

women of childbearing age can be included in clinical trials, but

under a prescribed set of circumstances. Older women (i.e., postmenopausal) can also be included in clinical trials for investigational drugs according to draft Agency guidelines for testing

drugs in the elderly.

FOOTNOTE

1

Segments of FDA animal reproduction studies:

Segment 1 - Single generation studies to assess gonadal function,

estrous cycle, mating behavior, and early stages of

gestation

Segment 2 - Assessment of teratogenesis

12
Segment 3 - Effects of the investigational drug on the late fetal

development, labor, delivery, lactation, and health

of the newborn

AUTHOR

Mary Ann Danello, Ph.D.

Special Assistant to the Commissioner

Food and Drug Administration

HF5/Room 1490

5600 Fishers Lane

Rockville, MD 20857

13
An Overview of the Clinical

Rationale for Advancing

Gender-Related

Psychopharmacology and Drug

Abuse Research

Jean A. Hamilton

Gender correlates with naturally occurring patterns of drug use,

misuse, and abuse (Russo et al. 1985). In studying gender as a

variable in clinical pharmacology, we must move beyond overly

simplistic laboratory studies of single agents and recognize the

drug combinations that women actually use. For example, women

frequently combine the use of drugs--legal and illegal--with the

use of exogenous steroid hormones, i.e., oral contraceptives or

estrogens for postmenopausal replacement therapy. These combinations are sometimes used in conjunction with alcohol or cigarettes, which are known to affect endogenous hormones (MacMahon et

al. 1982; Sepkovic et al. 1984). Certain drugs have side effects

that are known to alter the menstrual cycle or other gender-related reproductive functioning (Mendelson and Mello, this volume).

Despite this evidence, which provides a clinical rationale for a

more gender-related pharmacology, investigators have too often

behaved as though these effects are trivial and do not merit systematic attention. That a gender-related blind spot may occur in

drug research is suggested, for example, by the relative neglect

of gender as a variable, even when there is evidence that gender

is related to the actual disease process (Raskin 1974; Kinney et

al. 1981; Hamilton and Parry 1983; Hamilton et al. 1984b).

One example of the biased attitudes that operate against the

appropriate recognition of gender as a research variable is the

preference for "basic" as opposed to "applied" advances in scientific knowledge. Clinical pharmacologists have behaved as

though gender-related drug effects, even if they occurred, would

be "only metabolic." Implicit in this belief is the assumption

that gender-related effects will not help to clarify the basic

mechanisms of drug action.

While this belief may have been tenable in the previous decade, it

runs counter to the most recent evidence. For example, the existence of gender-related differences in brain structures--and perhaps in localized functioning--could have consequences for the

14
effects of certain drugs on the brain (Baum, this volume). Moreover, there is increasing evidence that gonadal steroids affect

the ongoing neurochemical substrate underlying the mechanisms of

drug action in the brain (Murphy and Hamilton 1983; Hamilton and

Conrad, in press). While speculative, these trends in the data

now provide a basic science rationale for gender-related drug research, which reinforces the purely clinical argument.

In considering the implications for drug abuse research, I am

impressed that both prescription psychoactive drugs and drugs of

abuse are often used to alter the quality of our thinking and

experiences. As one example, for reasons that are not understood,

antidepressants are rarely drugs of abuse (while speculative, this

may be related to side effects, or to an effect of the initial

baseline in terms of mood), but alcohol, opiates, and stimulants

are likely to be used or abused in order to avoid dysphoria, if

not to actually self-medicate a clinically significant depression.

At least from the standpoint of regulating affect, this suggests a

certain degree of motivational overlap. In addition, several prescription psychoactive drugs share with drugs of abuse some of the

side effects on reproductive functioning. From the perspective of

these observations, I will briefly review some of the genderrelated data for two types of psychoactive drugs, antidepressants

and antipsychotics.

My purpose in this chapter is to highlight gaps in knowledge and

to identify several methodological requirements for advancing

gender-related psychopharmacology. Many of these observations

will have parallels for drug abuse research. I will further address some of the attitudinal and conceptual barriers to moving

gender-related methods into the mainstream of clinical psychopharmacology and drug abuse research.

GENDER-RELATED DATA FOR SELECTED PSYCHOACTIVE DRUGS

Antidepressants

About 10 years ago, Raskin (1974) reviewed the existing data and

concluded that: "Although twice as many women as men are treated

for depression, the depression literature suggests that it is the

men rather than the women who benefit most from antidepressant

drugs." When I attempted to update Raskin's review, I was

especially interested in the literature on MAO-inhibiting antidepressants, due to the suggestion of sex-related differences in

responsivity in the animal literature. But my review of the

existing clinical data on phenelzine, a nonspecific MAO-inhibiting

antidepressant, demonstrated important gaps in knowledge, since

only 3 out of 25 studies (12 percent) tabulated the data by either

gender or age (Hamilton et al. 1984). It is likely that other

gender-related effects might be observed in psychopharmacology,

but without the adequate inclusion and reporting of gender as a

research variable, it is impossible to know (Hamilton and

Hirschfeld 1984).

15
Also of interest with regard to possible abuse or misuse of stimulants is Gerner's (1983) observation that amphetamine may be more

effective as an antidepressant in females or the elderly than in

males. This example highlights the need to clarify gender-related

effects in order to maximize therapeutic responsivity and to minimize untoward side effects in subgroups that are defined by gender

and age.

Antipsychotics

As we reevaluate gender as a variable in psychopharmacology, the

literature on antipsychotics and tardive dyskinesia demonstrates

the need to clarify gender by age effects in the light of hormonal

effects. Tardive dyskinesia is a movement disorder that occurs in

association with the use of antipsychotic drugs. The well-known

gender difference in the distribution of this side effect (Tepper

and Haas 1979; Kane and Smith 1982) is confirmed even when controlling for age; that is, the female excess is not simply an

artifact of comparing older women with younger males, since it

persists in studies with a similar male-female age distribution,

and it has also been observed in younger age groups (Brandon et

al. 1971; Degkwitz and Wenzel 1967).

There does not appear to be a simple or trivial explanation for

the gender-related difference in tardive dyskinesia. For example,

the finding is probably not simply a function of gender differences in absolute dosage (Odejide 1980; Simpson et al. 1978; Yassa

et al. 1983), relative dosage, length of drug use, or polypharmacy

(Simpson et al. 1978). Future studies of possible gender and hormonal effects on neuroleptic blood levels (Stevens 1973), optimal

dosages required for control of symptoms (Chouinard et al. 1980;

Seeman 1983), and subtype of movement disorder can clarify the

observed gender-related effects.

At present, the evidence for a hormonal account of the genderrelated distribution of tardive dyskinesia is mixed, but there is

some literature suggesting an effect of menstrual status and of

circulating levels of gonadal hormones (Stevens 1973). For example, when the gonadal hormone, estrogen, is extremely high in

premenopausal women--as with oral contraceptive use (Barber et al.

1976) or during pregnancy--a choreiform movement disorder may

arise, perhaps from excess functioning of the brain neurotransmitter, dopamine (Gordon et al. 1980; Klawans et al. 1980).

With menopause, estrogens diminish gradually, often over the

course of years. Moderate levels of estrogen are thought to be

protective for tardive dyskinesia, partly through a presynaptic

mechanism (Klawans et al. 1980). Particularly for women who have

been on antipsychotic medication, the loss of the protective effect of estrogen at menopause may, in effect, "unmask" tardive

dyskinesia. Although there is not an increase in the prevalence

of tardive dyskinesia in the menopausal age group, the greatest

increase in the severity of tardive dyskinesia does occur in the

forties and fifties Smith and Baldessarini 1980).

16
Another investigational finding connecting tardive dyskinesia with

estrogen levels is that exogenous estrogens improve dyskinesia in

both animals (Gordon et al. 1980) and humans. For example, standard doses of Premarin (.625 mg/d) resulted in marked improvement

in a repeated on-off clinical trial involving two women

(Villeneuve et al. 1978; Bedard et al. 1977).

METHODOLOGICAL REQUIREMENTS FOR ADVANCING GENDER-RELATED

PSYCHOPHARMACOLOGY AND DRUG ABUSE RESEARCH

Both of these examples highlight the need to select subjects in a

way that will clarify, rather than obscure, possible gender by age

and hormonal status effects on drug responsivity and on drug use.

A further methodological guideline is for investigators to report

the exact statistical significance (p value) by gender, in order

to allow for subsequent combining of statistics for meta-analysis

of several clinical trials.

The example of neuroleptic-related tardive dyskinesia reminds us

to examine not only gender-related trends in therapeutic efficacy,

but also in the patterning of side effects. As detailed elsewhere

(Hamilton et al. 1984). investigators must control, or at least

describe carefully, gender-related effects on known pharmacokinetic variables, e.g., body composition and serum levels. The

menstrual cycle must also be recognized consistently as a potential source of variance in psychopharmacological studies (Shader

and Harmatz 1982; Mendelson and Mello, this volume).

Finally, we must address the fact that confounding variables may

also be gender-related. Such variables may include baseline

levels of severity, placebo versus spontaneous remission rates, or

side effects related to rates of dropping-out. As mentioned earlier, the complexity of people's lives must also receive recognition in psychopharmacology and drug abuse research; for example,

there are gender-related differences in cigarette smoking and

alcohol use, and these may interact with other variables pertinent

to our research. Only by greater attention to naturally occurring

patterns of drug use or abuse-- including the social ecology of

drug combination--will we begin to clarify the mechanisms for gender-related effects on drug responsivity and usage (Russo 1985).

ON BARRIERS TO MOVING GENDER-RELATED METHODS INTO THE MAINSTREAM

OF DRUG RESEARCH

The scientific rationale for gender-related drug research is simply to advance knowledge and to improve the quality of research

clinically, theoretically, and empirically. From a policy point

of view, however, there are several conceptual barriers to moving

gender-related research into the mainstream (Hamilton, in press).

For example, this area is likely to be trivialized as though it

pertains only to a special "subpopulation." There is also a persistent notion among basic pharmacologists that gender is such an

17
obvious, almost simple-minded variable, that its study will result

only in clinical applications, as opposed to the possibility that

it will provide windows on mechanisms of drug action.

The problem with these attitudes is one of perspective. If you

speak with front-line clinicians--or with the women who actually

suffer from the perhaps needless excess of tardive dyskinesia or

with their families--even rather simple "metabolic" factors seem

less trivial. Theoretically, in fact, the study of gender-related

effects may advance a new thread of basic research, aimed at

understanding drug-hormone interactions, as one example.

Finally, we need to understand better the connections between

seemingly simple-minded variables like a e, and profound concepts

like "development," or "evolution." As the variable age is to the

concept development, so the variable gender may stand in relation

to some as yet unknown, but perhaps groundbreaking, concept in

drug research.

In summary, the use of gender comparisons is based on the long empirical tradition of comparative methods in physiology and in

neuroscience (Bullock 1984). At its best, gender-comparative research will both sharpen our skills in assessing the mechanisms of

drug action, and improve clinical care--not just for a single subpopulation, but for all subgroups defined by gender, age, and hormonal status.

REFERENCES

Barber, P.V.; Arnold, A.G.; and Evans, G. Recurrent hormone dependent chorea: Effects of oestrogens and progestogens. Clin

Endocrinol 5:291-293. 1976.

Bedard, P.; Langelier. P.; and Villeneuve, A. Oestrogens and

extrapyramidal system. Lancet 2:1367, 1977.

Brandon, S.; McClelland, H.A.; and Protheroe, C. A study of

facial dyskinesia in a mental hospital population. Br J

Psychiatry 118: 71-184, 1971

Bullock, T.H. Comparative Neuroscience holds promise for quiet

revolutions. Science 225: 473-478. 1984

Chouinard, G.; Jones, B.D.; Annable, L.; and Ross-Chouinard, A.

Sex differences in tardive dyskinesia. Am J Psychiatry

137(4):50, 1980.

Degkwitz, R., and Wenzel, W. Persistent extrapyramidal side

effects after long-term application of neuroleptics.

Neuropsychopharmacol 129:608-615, 1967.

Gerner, R.H. Systematic treatment approach to depression and

treatment-resistant depression. Psychiatr Ann 13:37-49, 1983.

Gordon. J.H.; Borison, R.L.; and Diamond, B.I. Estrogen in

experimental tardive dyskinesia. Neurol 30:551-554, 1980.

18
Hamilton, J.A. Avoiding methodological and policy-making biases

in gender-related research. In: Report of the Public Health

Service Task Force on Women's Health. Vol. II. Washington,

DC: Supt. of Docs., U.S. Govt. Print. Off., in press.

Hamilton, J.A., and Conrad, C. Toward a developmental psychopharmacology: The physiological basis of age, gender and hormonal

effects on drug responsivity. In: Call, J., ed. Update,

Handbook of Child Psychiatry. New York: Basic Books, in press.

Hamilton, J.A., and Hirschfeld, R.M.A. An additional recommendation on reporting depression. Am J Psychiatry 141(9):1134-1135,

1984.

Hamilton, J.A., and Parry, B. Sex-related differences in clinical

drug response: Implications for women's health. J Am Med Wom

Assn 38(5):126-132, 1983.

Hamilton, J.A.; Alagna, S.W.; and Pinkel, S. Gender differences

in antidepressant and activating drug effects on selfperceptions. J Aff Dis 7:235-243, 1984b.

Hamilton, J.A.; Lloyd, C.; Alagna, S.W.; Phillips, K.; and Pinkel,

S. Gender, depressive subtypes, and gender-age effects on antidepressant-response: Hormonal hypotheses. Psychopharm Bull

20(3):475-480, 1984a.

Kane,J.M.,and Smith, J.M. Tardive dyskinesia. Prevalence and

risk factors, 1959 to 1979. Arch Gen Psychiatry 39:473-481,

1982.

Kinney, E.L.; Trautmann, J.; Gold, J.A.; Vesell. E.S.; and Zelis,

R. Underrepresentation of women in new drug trials. Ann Int

Med 95:495-499, 1981.

Klawans, H.L.; Goetz, C.G.; and Perlik, S. Tardive dyskinesia:

Review and update. Am J Psychiatry 137(8):900-908, 1980.

MacMahon, B.; Trichopoulos, D.; Cole, P.; and Brown, J. Cigarette

smoking and urinary estrogens. N Engl J Med 307:1062-1065,

1982.

Murphy, D.L., and Hamilton, J.A. Gender-related differences in

neuropharmacologic responsivity: Contributions from neuro-chemical and drug metabolism studies. Proceedings of the American

College of Neuropsychopharmacologists, San Juan, Puerto Rico,

1983. (Abstract)

Odejide, A.O. Prevalence of persistent abnormal involuntary movements among patients in a Nigerian long-stay psychiatric unit.

Int Pharmacopsychiat 15:292-300, 1980.

Raskin, A. Age-sex differences in response to antidepressant

drugs. J Nerv Ment Dis 159:120-130, 1974.

Russo, N.F. Developing a national agenda to address women's mental health needs. Washington, DC: American Psychological

Association, 1985. pp. 19-22.

Seeman, M.V. Interaction of sex, age, and neuroleptic dose.

Compr Psychiatry 24(2):125-128, 1983.

Sepkovic, D.W.; Haley, N.J.; and Wynder, E.L. Thyroid activity in

cigarette smokers. Arch Int Med 144:501-503, 1984.

Shader, R.I., and Harmatz, J.S. Premenstrual tension in biochemical and psychotropic drug assessment. Psychopharm Bull

18(3):113-120, 1982.

19
Simpson. G.M.; Varga, E.; Lee, J.H.; and Zoubok, B. Tardive

dyskinesia and psychotropic drug history. Psychopharmacol

58:117-124. 1978.

Smith, J.M., and Baldessarini, R.J. Changes in prevalence,

severity, and recovery in tardive dyskinesia with age. Arch Gen

Psychiatry 37:1368-1373, 1980.

Stevens, J.R. An anatomy of schizophrenia? Arch Gen Psychiatry

29:177-189, 1973.

Tepper, S.J., and Haas, J.R. Prevalence of tardive dyskinesia. J

Clin Psychiatry 40:508-516, 1979.

Villeneuve, A.; Langlier, P.; and Bedard, P. Estrogens, dopamine

and dyskinesias. Can Psychiatr Assn J 23(1):68-70, 1978.

Yassa, R.; Ananth, J.; Cordozo, S.; and Ally, J. Tardive dyskinesia in an outpatient population. Prevalence and predisposing factors. Can J Psychiatry 28:391-394, 1983.

AUTHOR

Jean A. Hamilton, M.D.

Institute for Research on

Women's Health, Inc.

1616 Eighteenth Street, N.W.

Suite 109 (B)

Washington, DC 20009

20
Clinical Investigations of

Drug Effects in Women

Jack H. Mendelson and Nancy K. Mello

INTRODUCTION

Because prevalence of drug abuse problems in men is generally

greater than for women in the United States (Cisin et al. 1983),

it is not surprising that most of our information about process

and outcome of drug dependence treatment has been obtained in

studies with male patients. However, recent data obtained in the

National Institute of Mental Health Epidemiologic Catchment Area

Survey revealed that drug abuse and dependence was the second most

commonly reported mental health disorder for women between the

ages of 18 and 24 (Regier et al. 1984; Eaton et al. 1984; Robins

et al. 1984; Myers et al. 1984). During 1984, 37 of the 137 patients admitted to the Drug Dependence Unit at the McLean Hospital

were women. The percentage (27 percent) of female patients admitted to McLean Hospital for treatment of drug dependence is consistent with a general impression that approximately one out of

four patients diagnosed as having drug abuse or dependence problems in the United States is a woman (Myers et al. 1984).

The role of gender factors in determining both safety and efficacy

of pharmacotherapy for drug dependence remains largely unexplored.

Since gender differences have been shown to influence a wide range

of pharmacologic therapies in medical practice (Vesell 1979), a

more intensive assessment of pharmacologic treatment for drug

dependence of women should be carried out.

PHARMCOLOGIC TREATMENT OF COCAINE ABUSE

In a recent review of current and experimental treatments for cocaine abuse, Kleber and Gawin (1984) note that there are many

problems associated with criteria currently used for the diagnosis

of cocaine abuse. The importance of antecedent or consequent psychiatric illness associated with cocaine abuse is not clear.

Kleber and Gawin (1984) as well as Gold (1983) have argued that

cocaine abusers may be more heterogeneous with respect to variations in drug self-administration behavior than other patients who

21
request treatment for substance abuse problems. Marked heterogeneity has also been observed with respect to dosage, drug selfadministration patterns, presence of intercurrent illness, and

other social, biologic, and psychologic factors that appear to

have an important role in initiating and perpetuating drug abuse

(Mendelson and Mello 1982).

Our recent studies with women who have significant polydrug abuse

problems strongly suggest that the appearance of heterogeneity

among persons who are substance abusers may be accounted for, in

part, by gender differences (Lex et al. 1984; Mendelson et al.

1985; Mendelson et al., submitted for publication). Thus, targeted studies with women patients who have a diagnosis of cocaine

abuse, or cocaine abuse associated with alcohol abuse and dependence, may assist in identifying more precisely specific factors

that may contribute to variance in biologic and behavioral indices

as well as provide a basis for more rational and therapeutic

interventions for drug abuse problems in women.

We have been able to locate only two reports of use of antidepressant medication for the treatment of cocaine abuse (Tennant

and Rawson 1983; Gawin and Kleber 1984). Both these studies were

"open trials" and did not utilize placebo control, double-blind

crossover procedures for determination of treatment efficacy.

However, the initial data obtained in these studies encourage more

rigorous and systematic assessment of antidepressant pharmacotherapy for cocaine abuse by women.

The first report of the use of the antidepressant drug desipramine

for treatment of cocaine dependence was presented by Drs. Tennant

and Rawson (1983) at the 44th Annual Scientific Meeting of the

Committee on Problems of Drug Dependence, in 1982. A summary

report of the outcome of this study was published in the National

Institute on Drug Abuse Research Monograph 43 in April, 1983

(Tennant and Rawson 1983). Drs. Tennant and Rawson stated that

the rationale for selecting desipramine for the treatment of cocaine abuse was based upon research reported in 1961 by Dr. Julius

Axelrod, which demonstrated that amphetamines and cocaine inhibit

the reuptake of norepinephrine (Axelrod et al. 1961). Subsequent

studies showed that desipramine had the greatest degree of selectivity for blockade of norepinephrine uptake by tricyclic antidepressants (Hollister 1978). These data suggested to Tennant and

Rawson (1983) that desipramine might be an effective drug for

treating patients with cocaine abuse.

Tennant and Rawson (1983) reported outcome data for 14 cocaine

abusers, including 4 women. Desipramine was administered on an

outpatient basis for a period of 7 to 52 days. Daily dosage of

desipramine ranged from 50 to 125 mg. Outcome data for this study

did not describe any gender differences; this was not surprising

since only 4 females out of a total of 14 patients participated in

the clinical trial. The general outcome results, however, were

encouraging since 28 percent of all patients reported total

22
abstinence from cocaine use 30 to 45 days following the initiation

of the study. Tennant and Rawson (1983) cautioned that

the study must not be over-interpreted due to its nonblind nature, the possibility of placebo effect, and

the inherent difficulty of controlling drug-dependent

research subjects. Further clarification of the role

of desipramine in the treatment of amphetamine and

cocaine dependence must await double-blind trials.

(Tennant and Rawson 1983, p. 354)

The second report describing an open pilot trial with desipramine

for the treatment of cocaine abuse was published by Gawin and

Kleber in the September 1984 issue of the Archives of General

Psychiatry (Gawin and Kleber 1984). In this study, six patients,

three males and three females, were administered desipramine in

doses of 200 mg/day and also received psychotherapy in individual

sessions once or twice weekly. Some patients also participated

in l-hour group therapy sessions and in family therapy group

meetings.

Gawin and Kleber reported that

administration of desipramine was associated with

abstinence from cocaine in all subjects so treated with

this sample, regardless of the diagnosis. It was also

associated with an anticraving effect whose time course

was similar to the delayed effects of tricyclic antidepressants in major depression and neuroreceptor

studies. (Gawin and Kleber 1984, p. 907)

Gawin and Kleber noted that any conclusions derived from the study

were limited because of the open nature of the trial and the lack

of double-blind placebo controls. Specific gender differences in

treatment responses and outcome were not described, although one

illustrative case report highlighted the efficacy of desipramine

pharmacotherapy for a 21-year-old female treated for cocaine freebase smoking.

In retrospect, it is surprising that there have not been more attempts to evaluate the efficacy of desipramine treatment for cocaine abuse. Kleber and Gawin have noted findings derived from

many basic and clinical neuroscience studies that would support

the rationale for this approach (Colpaert et al. 1979; Ellinwood

1977; Fischman et al. 1976; Kosman and Unna 1968; Smith and Wesson

1980; Wesson and Smith 1977). Additional support for the potential efficacy of desipramine in the treatment of cocaine abuse may

be inferred from recent studies that have shown that tricyclic

antidepressants interact with the ionic channel moiety of acetylcholine receptors at the motor endplate (Eldefrawi et al. 1981;

Shaker et al. 1981) and that cocaine inhibits sodium uptake into

PC12 cells by binding to the open channel form of the receptor

(Karpen et al. 1982). In studies of the receptor-associated ionic

23
channels involved in catecholamine release, Cena and his associates found that imipramine and cocaine inhibit noradrenalin release by selective inactivation of the acetylcholine receptor

ionophore (Cena et al. 1983). Cocaine and the tricyclic antidepressant desipramine may have a very similar mode of action on

nerve cell receptor sites and membrane ion channel function, which

regulate neuronal activity and behavior. Desipramine may act as a

pharmacologic substitute for cocaine by inhibiting norepinephrine

release via selective inactivation of the acetylcholine receptor

ionophore (Cena et al. 1983).

PHARMACOLOGIC TREATMENT OF OPIOID ABUSE AND

DEPENDENCE--NALTREXONE

During 1984, naltrexone was approved by the Food and Drug Administration (FDA) for use as an adjunctive pharmacotherapy for the

treatment of opioid dependence. FDA approval of naltrexone followed extensive clinical investigations that documented both the

safety and limited efficacy of naltrexone treatment for opioiddependent persons (Ginzberg 1984; Ginzberg and Glass 1984; Judson

et al. 1981; Julius and Renault 1976; Resnick et al. 1974; Tennant

et al. 1984; Washton et al. 1984).

A pioneering study of the effects of naltrexone on self-determined

patterns of heroin self-administration by heroin-dependent men was

initiated at the Harvard-McLean Alcohol and Drug Abuse Research

Center (Meyer et al. 1976a; Meyer et al. 1976b; Meyer and Mirin

1979). Naltrexone (75 mg/day) effectively reduced heroin use in

comparison to Glacebo controls (Meyer and Mirin 1979). The safety

of chronic naltrexone therapy was also evaluated in these studies

with particular emphasis on naltrexone effects on neuroendocrine

function (Mello et al. 1981; Mendelson et al. 1980; Ellingboe et

al. 1980).

The vast amount of data obtained concerning safety and efficacy of

naltrexone treatment has been attained in studies with men

(Ginzberg 1984; Ginzberg and Glass 1984; Judson et al. 1981;

Julius and Renault 1976: Resnick et al. 1974; Tennant et al. 1984:

Washton et al. 1984). Women were infrequently studied because the

largest number of opiate-dependent persons who received naltrexone

in protocol-based studies were primarily men with compromised

social and economic resources. In studies with more affluent persons (Washton et al. 1984; Tennant et al. 1984), women represented

one-quarter to one-third of the patients treated with naltrexone,

but data obtained in these studies did not describe any gender

similarities or differences for either the safety or efficacy of

naltrexone treatment. This may be especially important since it

has been shown that opioid antagonists are potent stimulators of

both luteinizing hormone (LH) and prolactin in women (Ropert et

al. 1981; Quigley and Yen 1980). Since naltrexone has been shown

to stimulate gonadotropin secretion in males (Mendelson et al.

1979), it is likely that women may develop abnormalities of

menstrual cycle and reproductive function as a consequence of

chronic naltrexone therapy.

24
Since buprenorphine is an oripavine derivative of etorphine (Lewis

1974), a potent opioid agonist, and diprenorphine, an opiate antagonist (Jasinski et al. 1982; Jasinski et al. 1983; Mello and

Mendelson 1980; Mello et al. 1982), buprenorphine combines the

characteristics of both opioid agonists and antagonists. However,

unlike opiate agonists, buprenorphine does not produce severe and

protracted withdrawal signs and symptoms in man (Mello and

Mendelson 1980; Mello et al. 1982; Jasinski et al. 1978). Buprenorphine is also safer than opiate agonists since its antagonistic

component appears to prevent lethal overdose even at approximately

10 times the analgesic therapeutic dose (Banks 1979). This

reduces the possibility of opiate overdose deaths observed with

methadone use (Kreek 1978). Buprenorphine is equivalent to naltrexone in the duration of opiate antagonist action (Martin et al.

1973). A sublingual preparation of buprenorphine further enhances

its potential clinical utility for the treatment of opioid dependence (Jasinski et al. 1984).

PHARMACOLOGIC TREATMENT OF OPIOID DEPENDENCE--BUPRENORPHINE

The effects of maintenance on buprenorphine, a mixed opioid

agonist-antagonist, or placebo on patterns of operant acquisition

of heroin and money were studied under double-blind conditions

(Mello and Mendelson 1980; Mello et al. 1982). Male volunteers

with histories of heroin abuse lived on a clinical research ward

for 40 days. After a 5-day drug-free period, buprenorphine or

placebo was given in gradually ascending doses (0.5 to 8 mg/day

SC) over 14 days. Subjects were maintained on 8 mg/day of buprenorphine for 10 days during which they could earn money ($1.50) or

heroin (7 or 13.5 mg/injection IV) by responding on a second order

schedule of reinforcement [FR 300 (Fl 1 sec:S)] for approximately

90 minutes. Buprenorphine-maintained subjects took significantly

less heroin than subjects maintained on placebo (p<.001). Of the

total amount of heroin available, buprenorphine-maintained subjects took only between 2 and 31 percent, whereas placebo-maintained subjects took between 93 and 100 percent. One subject

maintained on a somewhat smaller dose of 4 mg/day of buprenorphine

took 55 percent of the available heroin: Tolerance to the opiate

agonist-like somatic and sedative effects of buprenorphine developed gradually. Buprenorphine maintenance did not impair operant

performance for money, Placebo subjects also showed no impairment

of operant performance for heroin and money during heroin intoxication; they titrated operant work to acquire the desired amount

of heroin and then resumed working for money. There were no significant differences between the buprenorphine and the placebo

group in total operant points earned or total hours worked during

any phase of the study. These data indicate the effectiveness of

buprenorphine in suppressing heroin self-administration and illustrate the value of using direct measures of drug self-administration to evaluate new pharmacotherapies for the treatment of opiate

abuse.

25
Buprenorphine also suppressed plasma luteinizing hormone (LH) and

increased prolactin levels after 12 consecutive days of ascending

dose administration in comparison to drug-free control conditions

(Mendelson et al. 1982). During a subsequent 10-day period of buprenorphine maintenance at a dose of 8 mg SC, LH levels remained

suppressed and prolactin continued to be elevated. Tolerance to

buprenorphine effects on LH and prolactin levels did not occur

during chronic drug administration (Mendelson et al. 1982).

Buprenorphine-induced changes in plasma LH and prolactin after

chronic administration to human males were smaller than those observed with less potent opiate agonist drugs (Mendelson et al.

1982).

We have been unable to locate any reports of buprenorphine effects

on pituitary and gonadal hormones in females. Therefore, studies

for determining safety (in addition to efficacy) of buprenorphine

pharmacotherapy for opioid-dependent women should be conducted in

the near future.

REFERENCES

Axelrod, J.; Whitby, L.G.; and Hertiling, G. Effect of psychotropic drugs on the uptake of H3

-norepinephrine by tissues.

Science 133:183, 1961.

Banks, C.D. Overdose of buprenorphine: Case report. NZ Med J

89:255-256, 1979.

Cena, V.; Nicolas, G.P.; Sanchez-Garcia, P.; Kirpekar, S.M.; and

Garcia, A.G. Pharmacological dissection of receptor-associated

and voltage-sensitive ionic channels involved in catecholamine

release. Neuroscience 10:1455-1462, 1983.

Cisin, I.; Miller, J.; and Abelson, H. The National Household

Survey on Drug Abuse 1982. National Institute on Drug Abuse.

Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1983.

Colpaert, F.C.; Niemegeers, C.J.; and Janssen, P.A. Discriminative stimulus properties of cocaine: Neuropharmacological characteristics as derived from stimulus generalization experiments.

Pharmacol Biochem Behav 10:535-546, 1979.

Eaton, W.W.; Holzer, C.E., III; Von Korff, M.; Anthony, J.C.;

Helzer, J.E.; George, L.; Burnam, M.A.; Boyd, J.H.; Kessler,

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ACKNOWLEDGEMENTS

This research was supported, In part, by Grants DA 00064,

DA 00101, and DA 02905 from the National Institute on Drug Abuse.

AUTHORS

Jack H. Mendelson, M.D.

Alcohol and Drug Abuse

Research Center

McLean Hospital

115 Mill Street

Belmont, MA 02178

Nancy K. Mello, Ph.D.

Alcohol and Drug Abuse

Research Center

McLean Hospital

115 Mill Street

Belmont, MA 02178

30
Drug Use Patterns and

Premenstrual Dysphoria

Nancy K. Mello

The issue of how gender differences may affect drug use patterns

or the consequences of drug abuse has been largely ignored. There

appears to be an implicit assumption that information obtained

from men will be completely generalizable to women and that any

possible gender differences are of little consequence. In the

absence of data to the contrary, such attitudes are likely to

persist. Yet unless both women and men are studied, the prevalent

notion that gender differences are inconsequential cannot be

adequately tested. This essay will consider some possible implications of gender differences for our understanding of the proximal determinants and consequences of alcohol and drug abuse. The

intent is not to construct a bastian of militant feminism with a

mindless insistence on examination of women qua women--many fundamental biological processes are unlikely to be gender specific.

Rather the intent is to suggest some areas of investigation that

are relevant to the unique attributes of women and may present

special problems as well as special research opportunities for

studies of substance abuse.

The serious health risks associated with cigarette smoking,

alcohol and drug abuse are widely recognized, and educating women

about the health consequences of substance use has become an issue

of increasing concern. This technical review on women and drugs

initiated by the National Institute on Drug Abuse (NIDA) is an

important first step towards implementation of the recommendations

of the 1985 DHHS Task Force on Women's Health Issues concerning

substance abuse-related research. The Task Force urged that

special efforts should be made to gain knowledge about

those diseases related to alcohol and drug abuse, and

about mental illnesses of importance to women, by the

initiation of: (1) research to study depression in

women when it occurs alone or in conjunction with

alcohol or drug abuse problems; (2) studies of the

significant factors related to the onset, continuation

and cessation of smoking, drinking, and drug taking by

31
women; and (3) studies of the role of the family and of

cultural attitudes in the maintenance of mental health

or the development of mental illness, as well as in the

use or misuse of alcohol, drugs, and tobacco. (Report

of the Public Health Service Task Force on Women's

Health Issues 1985, p. 81)

The Task Force report and its implications are discussed more

fully elsewhere in this monograph (Chatham, this volume).

Increased Federal attention to the health problems of women generally, and the impact of substance abuse in particular, is an encouraging development. In 1978, the National Institute on Alcohol

Abuse and Alcoholism (NIAAA) was among the first to sanction the

notion that alcohol abuse problems may be different in men and

women in their first research monograph, "Alcoholism and Alcohol

Abuse Among Women: Research Issues" (NIAAA 1980). In 1984, the

NIAAA sponsored a second National research conference on women and

alcohol. Since 1980, several important books on alcohol and drug

abuse problems in women have been published (Wilsnack and Beckman

1984; Kalant 1980; Sandmaier 1980; Eddy and Ford 1980). Despite

evidence of progress in reversing the longstanding tendency to

assume that women are just like men, this attitude is deeply

imbedded in our culture. Its myopic adherents appear to be

afflicted with "the Adam's Rib syndrome!" A fundamentalist's

interpretation of genesis subscribes to the belief that Adam was

"formed from the dust of the ground" and Eve from one of his

ribs. Although this is not the dominant hypothesis in contemporary biomedical science, many people still behave as if this were

a guiding assumption. Calling attention to the possible importance of gender differences (except in reproductive biology) can

evoke reactions ranging from incredulity to indifference.

SUBSTANCE ABUSE: RISK AND RECURRENCE

Risk for development of substance abuse problems is influenced by

many interacting variables. The great diversity of individuals

with alcohol and drug abuse problems argues against a search for

constant etiological factors (Mello 1980; Mello 1983a). Trying to

analyze the events that maintain drug abuse behavior may be more

important than attempting to recapture the distant antecedents of

that behavior. We understand very little about the way in which

alcohol and drugs come to control behavior leading to their

repeated administration. Drinking and drug abuse problems may

develop for many reasons, but once established, there may be similarities in the way abuse patterns are maintained that transcend

the specific pharmacological properties of the drug (Mello 1983b).

A once common belief was that certain drugs inevitably led to

repetitive compulsive use, motivated in part by the avoidance of

withdrawal signs and symptoms. Yet direct observations of drug

users have not supported this notion. Alcohol-dependent men

alternated between drinking and abstinence, over periods of 30 to

32
60 days, despite the occurrence of withdrawal signs and symptoms

(Mello and Mendelson 1972; Mello and Mendelson 1978). Similar

cyclic patterns of alcohol self-administration were seen in rhesus

monkeys (Winger and Woods 1973). Occasional intermittent use of

heroin is also reported (Harding and Zinberg 1983). Given that

drugs are often used intermittently, it would be useful to

identify the proximal determinants of drug use and clarify the

extent to which these may differ in men and women.

Behavior is maintained by its consequences, but clinical research

has shown that the consequences of chronic alcohol and drug abuse

are considerably more complex and varied than was once believed.

Traditionally, the purported "positive" effects of intoxication

(mood elevation, rush, high, euphoria) have been considered as a

primary explanation for repeated drug abuse. Although intoxication may initially induce pleasant feeling states and diminish

feelings of anxiety and depression, chronic intoxication with

alcohol and opiates is often associated with increased anxiety and

depression (Mello 1983b). The elusive effects of chronic drug

intoxication may be reflected in microcosm in the acute effects of

drug intoxication. Biphasic changes in mood state appear to

parallel the ascending and descending phase of drug concentrations

in plasma. The transient positive changes in mood usually occur

during the rising phase of the drug concentration curve. Opiates

and cocaine may produce positive changes in feeling states within

seconds or minutes after intravenous administration. Alcohol may

produce similar effects within 30 to 90 minutes after drinking, as

the blood alcohol curve rises. But dysphoric changes in feelings

may occur after the heroin rush, after smoking cocaine paste, and

during the falling phase of the blood alcohol curve. Higher drug

doses are more likely to be associated with dysphoric changes in

subjective states. However, this generalization is qualified by

the fact that many nonpharmacological factors including expectancy, drug experience, and social context modulate the perceived

consequences of intoxication (Mello 1983b; Marlatt and Rohsenow

1980).

Naive users of alcohol, opiates, and nicotine often experience

dysphoria, nausea, vomiting, dizziness, and some impairment of

concentration and thinking. Although tolerance to the adverse

effects of initial drug use may develop, another possibility is

that the initial adverse drug reactions (dysphoria, nausea,

vomiting) will persist and become an integral part of the

reinforcing properties of subsequent drug use (Mello 1983b).

To the extent that dysphoric consequences are associated with

both acute and chronic intoxication, the explanatory value of

"euphoria" is diminished. One advantage of the term "reinforcement" is that it does not imply anything about the nature of the

reinforcing event. Rather reinforcement describes a functional

relationship between events and behavior. If occurrence of an

event increases behavior leading to that consequence, the event

can be defined as a reinforcer. If the removal of an event

33
increases behavior leading to it, the event can also be defined as

a reinforcer. However, if either the presentation or removal of

an event decreases behavior leading to it, the event can be

defined as a punisher (Morse and Kelleher 1977).

The maintenance of behavior by aversive or noxious events is not

unusual. There is considerable evidence that aversive consequences

such as electric shock will maintain shock self-administration

behavior in animals under certain conditions (Morse et al. 1977).

Opiate-dependent monkeys will work to produce injections of a

narcotic antagonist which, in turn, precipitate opiate abstinence

signs (Goldberg et al. 1972; Woods et al. 1975). Within this

context, the fact that the increased despondency and anxiety often

associated with chronic drug abuse are part of the complex that

maintains the drug use behavior is less surprising.

The challenge of analyzing the mercurial reinforcing effects of

drugs is further illustrated by patterns of polydrug use which

involve the concurrent use of substances with different pharmacological actions. Polydrug use of stimulants and depressants has

prompted the speculation that a change in state may be the critical reinforcing component of drug intoxication. The direction of

that change in state, up or down, may be far less important than

the change itself. Insofar as drugs are stimuli leading to some

change in subjective state, to think of drug self-administration

as a form of stimulus administration may be useful (Mello 1977;

Mello 1983b). It is possible that any drug which has definite

stimulus properties, i.e., behavioral effects for the user, is a

drug which has abuse potential (Mello 1983b).

Since expectancy is a powerful determinant of the perceived consequences of intoxication, "placebo effects" may be as salient in

maintaining behavior as actual consequences (Mendelson et al.

1984). Alcoholic men recalled only the anticipated positive

effects of a drinking experience and none of the dysphoric events

during a subsequent episode of sobriety (McGuire et al. 1966;

Tamerin et al. 1970). Anticipation of a positive intoxication

experience, aided by selective recall of past intoxication, is

likely to remain an important determinant of drug use. Intoxication is a common strategy for coping with problems of all types.

However, whether or not the periodic recurrence of certain definable problems reliably predicts episodes of drug use is unclear.

GENDER DIFFERENCES THAT MAY EFFECT DRUG USE PATTERNS

There is little question that the menstrual cycle uniquely differentiates women of childbearing age from men. Until very recently,

the psychological concomitants of phases of the menstrual cycle

and the impact on women's health and behavior have received very

little scientific attention. The emergence of the women's liberation movement in the early sixties was-accompanied by definitions

of social equality which often involved denial of sexual

differences: Attention to sexual differences was regarded as

34
perniciously sexist by some. This militant extremism has gradually evolved towards the recognition that there may be important

sexual differences which have significant consequences for women's

health, a position most recently exemplified in the 1985 Task

Force on Women's Health Issues. Indeed it could be argued that

the time-honored tradition of assuming that sex-related differences are unimportant reflects a profound sexism with more potentially adverse implications for women than objective examination

of these differences.

The menstrual cycle is controlled by a complex interaction between

hypothalamic, pituitary, and ovarian hormones. The synthesis and

secretion of hypothalamic and pituitary hormones is regulated by

the central nervous system and modulated by the ovarian steroid

hormones. Hypothalamic LHRH (luteinizing hormone-releasing

hormone) stimulates the production and release of pituitary

gonadotropins, LH (luteinizing hormone) and FSH (follicle-stimulating hormone). Changes in the levels of pituitary gonadotropins

and ovarian steroid hormones (estrogens and progesterone) define

the successive phases of the menstrual cycle (Knobil 1980; Wilson

and Foster 1985). A schematic diagram of the hypothalamicpituitary-gonadal interrelationships appears in figure 1.

The menstrual cycle is usually divided into two phases which correspond to the development of the ovarian follicle and ovulation

(the follicular phase) and transformation of the follicle into a

corpus luteum (the luteal phase). The onset of menses defines the

beginning of a menstrual cycle and the beginning of the follicular

phase. During the follicular phase, FSH and LH stimulate maturation of the ovarian follicle and secretion of estrogen, an ovarian

steroid hormone. As the follicle matures, there is a rapid increase in estrogen secretion with a surge of estrogen at midcycle.

This estrogen surge is followed by a surge in LH and FSH which

triggers ovulation, i.e., release of the ovum from the ovarian

follicle into the fallopian tube. After ovulation, the ovarian

follicle is transformed into the corpus luteum which produces

progesterone, another ovarian steroid hormone. The corpus luteum

continues to synthesize and secrete progesterone for approximately

13 days unless fertilization of the ovum and pregnancy occurs.

Increased progesterone levels prepare the uterus for implantation

of the ovum by inducing uterine glandular and vascular proliferation. If pregnancy does not occur, the endometrial lining of

the uterus is sloughed off during the process of menstruation.

Demise of the corpus luteum marks the end of a menstrual cycle.

The average menstrual cycle lasts for 28 days (+ 4 days). The

follicular phase includes menses, which usually last 3 to 5 days,

and the period of follicular development, 7 to 10 days. Variations in the length of the follicular phase account for variations

in length of the normal menstrual cycle. The 2 days before and

after ovulation are usually designated as the periovulatory phase.

35
FIGURE 1. A schematic diagram of the interrelationships between

the hypothalamus, the anterior pituitary, and the

ovary

NOTE: Hypothalamic secretion of LHRH Is responsible for maintaining the tonic

secretion of LH and FSH by the pituitary. Gonadotropin (LH and FSH) stimulation of the ovary leads to follicular development and the secretion of

estrogens. When circulating estrogen levels reach 200 to 300 pg/ml, the

pituitary releases a surge of LH and FSH which causes the ovarian follicle

to rupture and release its ovum. The follicle Is then luteinized and

secretes progesterone. The feedback relationships between hypothalamic

LHRH, the pituitary gonadotropins, and ovarian steroid hormones are shown

by the arrows. The contribution of the central nervous system to

hypothalamic regulation is indicated by the suprahypothalamlc brain.

36
The length of the luteal phase is quite consistent from cycle to

cycle, varying between 13 and 15 days. The midluteal phase, when

progesterone levels are highest, usually occurs about 8 days after

ovulation. The end of the luteal phase, 3 to 5 days before menstruation, is commonly referred to as the premenstruum. However,

definitions of the premenstruum vary, and symptoms usually associated with the premenstruum can occur as early as 13 days prior

to the onset of menstruation (Halbreich et al. 1982).

There is abundant clinical evidence that dysphoric mood states are

correlated with the premenstrual phases of the menstrual cycle. A

syndrome often referred to as "premenstrual tension" is characterized by increased anxiety, depression, tension, irritability,

sleep disturbances, lethargy, impaired concentration, headaches,

constipation, bloating, backaches, breast tenderness, weight

changes, and changes in sexual feeling and activity (Moos 1969;

Smith 1975; Steiner and Carroll 1977; Wilcoxon et al. 1976).

Although the premenstruum is most commonly associated with dysphoria and lability of affect, menstruation and the periovulatory

phase may also be associated with increased anxiety and depression. These symptoms may not occur in all women at every cycle,

and all are not specific to women or to the menstrual cycle

process. However, the periodic recurrence of this constellation

of symptoms in concert with phases of the menstrual cycle has been

implicated in an exacerbation of psychotic disorders, especially

depression (Smith 1975; Steiner and Carroll 1977), as well as increased abuse of alcohol (Podolsky 1963; Belfer and Shader 1976;

Belfer et al. 1971). It should be emphasized that premenstrual

tension often occurs in normal women, independently of a concomitant depressive disorder (Steiner et al. 1980; Haskett et al.

1980).

The existence of a premenstrual tension syndrome has been challenged on ideological as well as methodological grounds (Wilcoxon

et al. 1976; Rubinow and Roy-Byrne 1984). For example, it has

been argued that women experience discomfort because they have

been taught that they should feel premenstrual tension and anxiety

(Ruble 1977). The influence of social expectancy on reports of

menstrual-cycle-related symptoms has often been emphasized

(AuBuchon and Calhoun 1985). At the other end of the spectrum are

those who postulate that the cyclic changes in pituitary gonadotropins and ovarian steroid hormones, which define the phases of

the menstrual cycle, may contribute to changes in affective states

(Bardwick 1974; Steiner and Carroll 1977; Reid and Yen 1981), but

the pathophysiology of the premenstrual tension syndrome is not

understood (Vaitukaitis 1984; Rubinow and Roy-Byrne 1984). These

discrepant views point to the obvious conclusion that the premenstrual tension syndrome is multiply determined, and simplistic,

single-factor explanations are unlikely to adequately account for

the syndrome. How subjective changes in feeling states are influenced by expectancy or modulated by concurrent changes in pituitary and gonadal hormone secretory patterns is unknown; however,

it is generally agreed that these dysphoric changes in feeling

37
states are not necessarily associated with dysmenorrhea (Smith

1975; Moos 1969).

An association between mood fluctuations and menstrual cycle

phases has been consistently established despite a wide diversity

of methods and subjects. One recent study examined changes in

mood and physical symptoms in women in treatment for severe premenstrual tension and compared them with women with a history of

premenstrual tension and with asymptomatic women (Sanders et al.

1983). Phases of the menstrual cycle were defined by measurement

of pituitary and gonadal hormones. All women showed similar

changes in mood and physical states as a function of cycle phase.

Feelings of well-being were greatest during the late follicular

phase and declined during the luteal phase. Self-ratings of depression, irritability, and physical complaints began to increase

during the early luteal phase and were maximal at the premenstruum. The magnitude of these changes was greatest in the

groups that reported premenstrual tension. Women in treatment for

premenstrual tension reported intense negative experiences often

beginning early in the luteal phase and increasing significantly

at the premenstruum (Sanders et al. 1983).

Since some women do experience anxiety and dysphoria in association with the late luteal (premenstrual) phase of the menstrual

cycle, it is tempting to postulate that these may be accompanied

by various forms of self-medication behavior including increased

use and abuse of alcohol and other drugs. A schematic diagram

illustrating this hypothesis appears in figure 2. Recurrent menstrual cycles are shown at the top of the figure, and the onset of

premenstrual dysphoria is shown as a dark bar in the second row.

The hypothesis that menstrual cycle mood changes may be associated

with increased alcohol and drug use is shown in the third and

fourth rows.

ALCOHOL USE AND MENSTRUAL CYCLE PHASE

The evidence relating to this hypothesis is somewhat sparse, but

provocative. Podolsky (1963) was one of the first to state this

hypothesis explicitly on the basis of clinical observations of

seven female patients with alcohol problems. Each patient reported that she drank most heavily during the premenstrual period,

and each patient suffered from severe premenstrual tension.

Podolsky (1963) concluded that

in general, such women drink in order to alleviate the

symptoms of premenstrual tension. The tempo of drinking is increased during the premenstruum. Alcohol is

utilized partly to relieve tension, but for the most

part to allow acting out and verbalization of passivity

demands. (Podolsky 1963, p. 818)

The clinical impression that alcohol use is related to premenstrual tension was confirmed by Belfer and coworkers in 1971.

38
FIGURE 2. Schematic diagram of possible association between menstrual cycle, mood changes, and drug/alcohol intake

Self-reports of the relation of premenstrual tension and/or menopause to drinking patterns were obtained from 34 alcoholic women

and 10 nonalcoholic women who accompanied their alcoholic husbands

to an alcohol clinic. Over half of the alcoholic women related

drinking to the menstrual cycle, especially to the premenstrual

period. Belfer and coworkers (1971) commented that

this association was made in the absence of obvious

disturbances in sexual or menstrual function and in

lieu of any difference in the scores of women who

experienced maximal versus minimal task interference,

physical discomfort or psychological discomfort during

their menstrual cycle. (Belfer et al. 1971, p. 543)

MARIJUANA USE AND MENSTRUAL CYCLE PHASE

Marijuana is probably the most frequently used illicit drug in

this country today (Clayton 1984) and marijuana use among women

appears to be increasing (Abelson et al. 1977; Smart 1983). The

possible effects of chronic marijuana use on pulmonary and

39
reproductive function is an issue of continuing concern (Fehr and

Kalant 1983; Marijuana and Health 1982; Braude and Ludford 1984).

In the context of a series of studies designed to examine marijuana effects on female reproductive function and behavior, we

examined the extent to which marijuana acquisition and use

patterns covaried with specific phases of the menstrual cycle

(Mello and Mendelson 1985). Twenty-one young women (average age

26.7 ± 1.15 years) who reported smoking marijuana for an average

of 8.1 (± 0.89) years gave informed consent for participation in

clinical research studies. Each woman was in good health as

determined by clinical and laboratory examinations. Women were

studied in groups of three or four and lived on a clinical research ward for 35 days. A 7-day drug-free baseline was followed

by 21 days of marijuana availability and a postmarijuana drug-free

period of 7 days. Operant techniques were used to provide an

objective and quantitative measure of performance for two alternative reinforcers, marijuana and money. Women could work for money

throughout the study and for marijuana during the period of

marijuana availability by pressing a button on a simple operant

manipulandum. Women could earn either one marijuana cigarette

(1 gm containing approximately 1.83 percent delta-9-THC) or 50

cents by 30 minutes of operant work on a second-order FR 300

(FI 1 sec: [S]) schedule of reinforcement. A fixed ratio (FR) of

300 responses on the fixed interval (FI) 1-second component of the

schedule was required to earn a single purchase point. The FI 1-

second schedule specified that only the first response after

1 second had elapsed was recorded as an effective response by the

programming circuitry. Approximately 5 minutes of operant performance was required to earn 300 effective responses, or one

purchase point on the FI 1-second schedule. Six purchase points

were required to buy one marijuana cigarette or to earn 50 cents

upon completion of the study.

Since subjects were studied in groups, scheduling admissions to

coincide with any specific phase of the menstrual cycle was not

possible. However, the period of marijuana availability extended

over most of a complete menstrual cycle in 7 women and coincided

with the premenstruum, defined as 3 days immediately before

menstruation, in 15 women. Five of these fifteen women increased

marijuana use during the premenstruum; five women decreased marijuana use during the premenstruum; and five women showed no change

in marijuana use during the premenstruum.

Examination of scores on the Premenstrual Assessment Form (PAF)

(Halbreich et al. 1982) showed a striking concordance between

premenstrual dysphoria and marijuana use during the premenstruum.

Women who increased marijuana use at the premenstruum reported

significantly greater depression, anxiety, mood lability, anger,

irritability, and impaired social functioning (p<.O5) than women

whose marijuana use decreased or stayed the same. Severity of

premenstrual dysphoria appeared to be more important in differentiating the three groups of women than physical discomfort

associated with the premenstruum. Although women who increased

40
marijuana use reported greater physical discomfort, pain, nausea,

dizziness, and general malaise than the other two groups, with the

exception of signs of water retention, these differences were not

statistically significant. These data suggest that the dysphoric

component of premenstrual tension is probably more closely associated with increased drug use than dysmenorrhea (Mello and

Mendelson 1985).

An association between increased use of marijuana and alcohol and

premenstrual dysphoria lends support to the notion that depression

and anxiety associated with the premenstruum may be one proximal

determinant of episodic increases in drug use by women. However,

the experience of premenstrual dysphoria appears to be a critical

factor, since recent studies indicate that drug use does not covary with menstrual cycle phase in women who do not report premenstrual dysphoria. Daily marijuana use did not covary with

menstrual cycle phase in 30 women who reported no significant

increase in Moos Menstrual Distress Questionnaire (MDQ) factors

reflecting negative affect, decreased concentration, behavior

change, or arousal (Griffin et al. 1985). Women completed daily

diaries reporting drug use and MDQ (Form T) scores for three

consecutive menstrual cycles, and 2,715 of a possible 2,741

diaries were returned. The group reported smoking an average of

1.4 (± 2.0) marijuana cigarettes per day, and individuals smoked

between 7.3 (± 3.8) and 0.1 (± 0.4) marijuana cigarettes per day

(Griffin et al. 1985). Both marijuana and alcohol use increased

on weekends, and day of the week predicted drug use more reliably

than any other variable in this sample. Neither unusual life

events nor sexual activity were associated with concurrent alcohol

and marijuana use (Lex et al. 1985).

The lack of significant variation of these MDQ factors across

phases of the menstrual cycle was surprising since these female

marijuana users were similar to the Moos normative sample in age,

education, and menstrual cycle characteristics (Moos 1969).

However, Moos' normative sample differed from women studied by

Griffin and coworkers (1985) in that 9.7 percent were pregnant

during standardization of the MDQ and over half were currently

using a contraceptive pill.

DO DRUG EFFECTS DIFFER AT DIFFERENT PHASES OF THE MENSTRUAL CYCLE?

An issue related to the question of whether or not menstrual cycle

phases affect drug self-administration is whether drug effects

remain constant across the menstrual cycle. The literature concerning changes in the effects of alcohol in women at different

phases of the menstrual cycle is conflicting and inconsistent

(Mello 1980). According to reports in 1976, women develop higher

blood alcohol levels at the premenstruum than during menstruation

or at midcycle after equivalent doses of alcohol (Jones and Jones

1976a; Jones and Jones 1976b). Women absorbed alcohol more rapidly and developed significantly higher blood alcohol levels at the

premenstrual period (80 mg/dl) than during menstruation or cycle

41
days 13 through 18 (64 and 68 mg/dl). Three women were studied

daily throughout a single menstrual cycle and given a moderate

dose of alcohol (0.66 ml/kg) at the same time each morning. There

was considerable variation in blood alcohol levels, but the highest peak blood alcohol levels occurred during the premenstruum and

at the periovulatory phase of the menstrual cycle (Jones and Jones

1976b). The investigators hypothesized that these data might be

related to more rapid alcohol absorption (Jones and Jones 1976a;

Jones and Jones 1976b). These data were surprising since increased water retention associated with the premenstruum would be

more likely to result in lower blood alcohol levels after a fixed

alcohol dose than at other times during the menstrual cycle. The

degree of water retention in relation to the total body waterlipid pool would determine alcohol dilution in body water

compartments.

Recent clinical studies have not confirmed reports that blood

alcohol levels vary with menstrual cycle phase. Peak blood

alcohol levels did not differ at the premenstruum, menstruation,

and cycle days 12 to 15 in 9 women given sufficient alcohol to

produce peak blood alcohol levels of 103 mg/dl (Hay et al. 1984).

One limitation of these clinical studies was that menstrual cycle

phase was defined by calendar estimates and subsequent verification of predicted cycle phase was not reported. Changes in

pituitary and gonadal hormone levels that define each menstrual

cycle phase were not measured. A number of variables which might

influence alcohol absorption and metabolism, such as drinking

frequency, recency of alcohol consumption, other drug use, nutritional status, and hours of fasting, usually were not reported,

and only a relatively low dose of alcohol was studied.

We reexamined the question of whether or not blood alcohol levels

after a standard dose of alcohol vary as a function of menstrual

cycle phase in female macaque monkeys (Mello et al. 1984).

Monkeys were studied at four phases of the menstrual cycle: the

premenstruum, menstruation, the periovulatory phase, and the midluteal phase. Calendar estimates of menstrual cycle phase were

confirmed by radioimmunoassay of LH and estradiol. Ascending and

peak blood alcohol levels after low (1.5 g/kg), moderate (2.5

g/kg), and high (3.5 g/kg) doses of alcohol were measured. The

average peak blood alcohol levels after nasogastric intubation of

low, moderate, and high doses of alcohol averaged 139 mg/dl, 238

mg/dl, and 335 mg/dl. There were no differences in peak blood

alcohol levels at the premenstruum, menstruation, the periovulatory phase, or the midluteal phase of the menstrual cycle

after a standard dose of alcohol. The only difference as a function of menstrual cycle phase was the rate of increase in blood

alcohol curve after a low dose of alcohol. Blood alcohol levels

were significantly higher 30 minutes after alcohol administration

during the premenstruum than during menstruation or the midluteal

phase (p<0.02). However, at higher alcohol doses, no significant

42
differences were observed in the rate of increase in blood alcohol

levels as a function of menstrual cycle phase (Mello et al. 1984).

Recent studies of the acute effects of marijuana on subjective

mood reports and pulse rate also showed no differences as a function of menstrual cycle phase (Lex et al. 1984). Twenty-eight

women volunteered to live on a clinical research ward for 4 consecutive days. On the second and fourth days following admission,

women were given marijuana (one 1-gm cigarette containing approximately 1.8 percent delta-9-THC) or marijuana placebo under doubleblind conditions. Ten women were studied during the follicular

phase of the menstrual cycle and nine during the luteal phase.

While five subjects were studied during the ovulatory phase of the

menstrual cycle, the brief duration of the periovulatory phase

precluded their serving as their own controls, so a separate control group of four women were compared. Marijuana produced significant increases in ratings of intoxication within 15 minutes

after smoking, whereas placebo marijuana cigarettes did not. However, there were no significant differences as a function of

menstrual cycle phase in subjective level of intoxication or the

time course or degree of elevation in pulse rate following marijuana. Marijuana did not alter factor scores on the POMS (Profile

of Mood States) for friendliness, anger, fatigue, depression,

tension, vigor, or elation. However, the confusion score (which

includes feeling more confused, unable to concentrate, muddled,

bewildered, forgetful, uncertain about things, and unable to be

efficient) did increase after marijuana but not after placebo

smoking. Confusion was somewhat more pronounced in subjects

studied during the follicular phase (Lex et al. 1984).

In contrast to the relative lack of effects of menstrual cycle

phase on subjective and physiological reactions to marijuana,

there was a significant influence of history of marijuana smoking.

Intermittent marijuana smokers (five or less times each week) had

significantly higher pulse rates, subjective levels of intoxication, and POMS confusion scores than subjects with a past history

of regular marijuana use defined as six or more times each week.

Marijuana-induced changes in pulse rate, intoxication, and confusion persisted longer in subjects with a history of intermittent

marijuana smoking (Lex et al. 1984).

These studies suggest that the effects of alcohol and marijuana

remain relatively constant across the menstrual cycle. Since

there appears to be no compelling evidence that alcohol and drug

effects become more salient at any particular menstrual cycle

phase, any changes in drug use which are consistently correlated

with a specific phase of the menstrual cycle probably cannot be

attributed to cycle-related changes in drug effects.

SEX DIFFERENCES AND ALCOHOL EFFECTS

Alcohol is unique among abused drugs in that it is distributed

throughout body water and its concentration is affected by body

43
habitus (Kalant 1971). Men and women differ in total body water,

and there are reports that women develop higher blood alcohol levels than men after an equivalent dose of alcohol (Jones and Jones

1976a; Jones and Jones 1976b; Dubowski 1976). Acute alcohol doses

of 0.33, 0.66, and 1.32 ml/kg each produced higher blood alcohol

levels in women than in male controls (Jones and Jones 1976a;

Jones and Jones 1976b). These findings were interpreted to indicate that since women have less water per body unit than males,

and since alcohol is distributed throughout the body water, the

same dose of alcohol should result in higher peak blood alcohol

levels in females than in males. However, this view has recently

been challenged in studies of the acute effects of alcohol in men

and women when data were adjusted statistically for total body

water, estimated anthropometrically, or measured directly by 3Hwater dilution (Sutker et al. 1983; Marshall et al. 1983). The

most recent data illustrate the differential effects of the method

used to calculate the alcohol dose (Goist and Sutker 1985). Blood

alcohol levels in 12 men and 12 women (tested at the premenstrual

phase of the menstrual cycle) were compared following acute alcohol administration. When alcohol doses were equated for body

weight, women reached significantly higher peak blood alcohol concentrations than men. However, when equivalent alcohol doses were

based on total body water, there were no significant sex differences. Self-reported levels of intoxication at peak blood alcohol

levels did not differ as a function of either alcohol dose determination or sex (Goist and Sutker 1985).

Detailed comparisons of the effects of other drugs as a function

of sex are not currently available. However, it seems unlikely

that the effects of drugs administered intravenously or via inhalation would differ appreciably as a function of sex.

CONCLUSIONS

The effects of drugs do not appear to differ as a function of

phase of the menstrual cycle. In women who do not experience premenstrual dysphoria, there appears to be no consistent relationship between drug use and menstrual cycle phase. However, there

is some evidence that women who do have premenstrual dysphoria may

increase alcohol and/or marijuana use at the premenstruum. These

data suggest that premenstrual dysphoria may be one proximal determinant of increased drug use by women. Insofar as the periodic

recurrence of premenstrual dysphoria covaries with changes in drug

use, this may be one factor that differentiates drug use patterns

in men and women. Further studies will be necessary to evaluate

this hypothesis and examine the generality of the apparent covariance between alcohol and drug use and premenstrual dysphoria.

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ACKNOWLEDGEMENTS

Preparation of this review was supported, in part, by Grant

#DA00101 from the National Institute on Drug Abuse, and Grants

AA04368 and AA06252 from the National Institute on Alcohol Abuse

and Alcoholism, ADAMHA.

AUTHOR

Nancy K. Mello

Alcohol and Drug Abuse Research Center

Harvard Medical School-McLean Hospital

115 Mill Street

Belmont, MA (12178

48
Gender Dimorphism in Brain

Michael Baum

The classic research of Jost (1950) and, more recently, of Wilson

et al. (1981) established that androgen, secreted by the mammalian

testes during fetal development, plays a crucial role in organizing the internal and external genital structures that are characteristic of the male. In the absence of this androgenic stimulation, individuals of either genetic sex develop phenotypically

feminine internal and external genitalia. Knowing these facts,

Young and his coworkers (Phoenix et al. 1959) provided the first

indirect evidence that perinatal exposure of the male to testicular hormones permanently alters the structure of the mammalian

brain. Working with guinea pigs, these workers found that prenatal administration of testosterone (T) to pregnant animals

caused two types of change in the reproductive behavior of the female offspring. First, it defeminized their behavior, i.e., reduced their capacity to display feminine coital behaviors after

adult treatment with ovarian steroids. Second, it masculinized

their behavior, i.e., augmented their ability to display masculine

coital patterns of behavior after adult treatment with T. Subsequently, these findings were repeated and extended in a wide variety of mammalian species (Baum 1979).

Further research, carried out in several nonprimate mammalian species, showed that perinatal exposure to testicular androgens also

defeminizes the ability of the hypothalamic-pituitary axis to mediate estrogen-induced surges in luteinizing hormone (LH), which

is characteristic of females around the time of ovulation (Neill

1972).

Although most investigators assumed that both these behavioral and

neuroendocrine consequences of perinatal androgen exposure reflected a permanent, structural change in the CNS, it was only in

1971 that the first direct demonstration of such a structural

change was published. Raisman and Field (1971) used electron microscopy to analyze synaptic connectivity in the dorso-lateral

portion of the rat preoptic area (POA). They reported that, in

females, preoptic dendrites receive a higher proportion of affer49
ent inputs onto dendritic spines than in males. Furthermore, neonatal treatment with T created the male phenotype in genetic females (Raisman and Field 1973).

This first finding of a sex dimorphism in neural connectivitywas

followed by a report (Nottebohm and Arnold 1976) that the forebrain nuclei that control singing in song birds are larger in

males (which typically sing) than in females (which sing considerably less than males). These first efforts laid the groundwork

for numerous subsequent studies that have firmly established that,

in several vertebrate classes, testicular hormones act in the male

during species-specific, critical periods of development to alter

the morphology of certain brain regions.

Raisman and Field (1971; 1973) originally directed their attention

to the rat preoptic area (POA) because earlier research had

implicated this area in the control of both reproductive behavior

and the estrogenic regulation of LH secretion, two functions that

were known to be sexually dimorphic. These workers used a tedious, quantitative analysis of synaptic connectivity to demonstrate

a neural dimorphism. More recent work with the rat (Gorski et al.

1978), and subsequently with the guinea pig (Hines et al. 1985),

gerbil (Commins and Yahr 1984a), and human (Swaab and Fliers 1985)

has shown that nuclei exist in the male POA that are significantly

larger, i.e., contain more neurons, than in the female. Along a

similar line, my coworkers and I (Tobet et al., in press) recently

found that, in the male ferret, a bilateral nucleus exists in the

dorsal portion of the POA/anterior hypothalamus (POA/AH) which is

not present in females (figure 1). This dorsal nucleus (dn) of

the POA/AH consists primarily of neurons with large cell bodies.

The somal areas of these neurons increased significantly in

response to adult exposure to T or either of the two primary neural metabolites of T, estradiol (E) and dihydrotestosterone (DHT),

but not to progesterone (Tobet et al., in press).

Adult exposure of gonadectomized female ferrets to these gonadal

steroids failed to organize a male-like dnPOA/AH, nor did these

treatments affect somal areas in cells located in the dorsal portion of the female POA/AH. Whereas adult exposure to sex steroids

failed to create a dnPOA/AH in female ferrets, prenatal exposure

to T, achieved by administerin T pellets to pregnant ferrets over

the last 11 days of gestation (total gestation is 42 days), created a male-like dnPOA/AH in genetic females. Neonatal castration

of male ferrets failed to block the normal development of a

dnPOA/AH.

Taken together, these data show that the final quarter of gestation constitutes the critical period for the formation of this

sexually dimorphic structure in the male ferret diencephalon.

A large body of literature (Callard et al. 1984) shows that, during perinatal development, androgen is readily converted into

estrogen in subcortical brain regions of all vertebrate species

50
FIGURE 1. Photomicrographs of sequential 60-micron-thick coronal

sections through the preoptic/anterior hypothalamic

area (POA/AH) of one gonadectomized adult female (A,

B, and C) and one male (D, E, and F) ferret

NOTE: Sections were stained with thionin. One bilateral nucleus can be seen in

the ventral POA/AH of males and females (straight arrows), whereas in males

a second more dorsal bilateral nucleus is also discernible (curved

arrows). Magnification approx. 30x. AC- anterior commissure: OC- optic

chiasm; V- third ventricle; acn- suprachiasmatic nucleus.

studied to date. The ferret is no exception to this rule. High

levels of aromatase activity (the enzyme complex responsible for

conversion of androgen to estrogen) are present in the AH/POA,

hypothalamus, and temporal lobe of perinatal ferrets of both sexes

(Tobet et al. 1985). Also, neural receptors for estrogen were

isolated in these same brain regions 5 days prior to birth (earlier ages were not assessed), suggesting that the intraneuronal

receptors for E are available prenatally to mediate biological

actions of any estrogen present (Vito et al. 1985). These observations, together with the finding (Erskine and Baum 1982) that

51
plasma concentrations of T are significantly higher in males than

in female ferrets prenatally, led us to ask whether the ability of

T to create a dnPOA/AH in ferrets when given experimentally to fetal females, or when secreted endogenously in fetal males, depends

on the formation and action of estrogenic metabolites of this

testicular androgen. The answer is, quite unambiguously, yes.

Tobet (1985) found that administration of the steroid, 1,4,6-androstatriene-3,17-dione (ATD) to pregnant ferrets almost completely inhibited the synthesis of estrogen from androgenic precursor

in fetal hypothalamus. Thus, adding ATD administration to other

methods for eliminating estrogens from the fetal environment of

the male ferret may block development of the dnPOA/AH. Male ferrets whose mothers were ovariectomized and given progesterone (to

sustain pregnancy) plus ATD over days 30 to 41 of gestation lacked

a dnPOA/AH in adulthood. Prenatal administration of a high dosage

of E, together with ATD, reversed this inhibition, and promoted

the development of a dnPOA/AH. Furthermore, prenatal exposure to

an androgen receptor antagonist, flutamide, failed to attenuate

the development of a dnPOA/AH in other males.

These findings show that local neural formation of E from T during

embryonic development is required for the normal development of

one sexually dimorphic feature of the dorsal POA/AH. In the rat

the medial nucleus of the POA/AH is larger in males than in females (Gorski et al. 1978), and some evidence suggests that this

size difference results from the action of estrogen perinatally in

the male (Dohler et al. 1984). Although more species need to be

studied, prior to proposing a universal role for estrogenic metabolites of T in creating CNS sex dimorphisms, strong data for two

mammalian orders, rodentia (rat) and carnivora (ferret), point in

this direction.

To date, there is only limited evidence linking the existence of

morphologic dimorphisms of the POA/AH to sex differences in neuroendocrine or behavioral function. The best example of such a link

exists in the gerbil, where lesions of the sexually dimorphic nucleus of the POA/AH in males caused severe deficits in scent marking and masculine coital behaviors (Commins and Yahr 1984b). To

date, such studies have not been successful in the rat (Arendash

and Gorski 1983). That is, although workers have long known that

the rat POA contributes to the control of both masculine and feminine sexual behavior in males and females? respectively, and to

the control of LH secretion in females, discrete manipulations of

the sexually dimorphic area of the POA/AH have not caused consistent changes in any of these functions.

There is. however, suggestive evidence in the ferret that the estrogen-dependent dnPOA/AH may contribute to the normal process of

coital masculinization in the male. Behavioral studies were carried out using the same ferrets that had been used in our anatomical study (Tobet 1985). All animals were castrated on postnatal

day 5, and later in adulthood were given T propionate daily, prior

52
to being tested with sexually receptive females. Compared with a

group of control males that were castrated on postnatal day 114,

males that were castrated on postnatal day 5, and whose mothers

were sham-operated (ovariectomized) and sham-implanted (progesterone plus ATD), displayed significantly lower levels of neck grip,

mount, and pelvic thrusting behavior (coital behaviors displayed

by the male ferret). However, males derived from mothers that had

been ovariectomized and given progesterone plus ATD over gestational days 30 to 41 displayed even lower levels of these masculine coital behaviors than either control males or males whose

mothers had received flutamide during gestation. Thus, we hypothesize that prenatal exposure to estrogenic metabolites of T

leads to the development in males of a dnPOA/AH, which in turn

promotes the sensitivity of the neonatal CNS to the behavioral,

masculinizing action of T itself.

At present, no evidence exists showing whether, in humans, prenatal exposure of the developing male POA to estrogen promotes the

development of the recently described sexual dimorphism of the

POA/AH (Swaab and Fliers 1985). A recent study (Ehrhardt et al.

1985) has, however, shown that prenatal exposure of women to the

synthetic estrogen, diethylstilbestrol (which in past years was

given to pregnant mothers as an anti-abortion agent) did cause a

small, yet statistically significant, increment in the incidence

of homo- or bisexual orientation, as compared with either sibling

or clinical control groups. Much more work remains to be carried

out on both the behavioral and anatomical facets of human sexual

differentiation. However, the available evidence is in general

agreement with the results of experiments conducted using several

different nonhuman mammalian species, including the ferret.

How do the above data concerning hormonally determined sex dimorphisms in brain morphology as well as in behavioral potential

relate to the issue of gender and drug abuse? They may relate in

at least two ways. First, the response of male and female patients to a therapeutic drug or to a drug of abuse may differ as a

result of sexually dimorphic differences in brain structure. To

date, most research along this line has been limited to elucidating sex differences that can be attributed to the action of sex

steroids (ovarian steroids in the female/testicular steroids in

the male) in either the liver (Gustafsson et al. 1980) or the

brain (Decker et al. 1982). However, in neither animal models nor

in man has much attention been paid to the possible contribution

of sexually dimorphic neural structures or connectivity per se as

keys to gender differences in drug action.

As more information becomes available concerning the existence of

sex dimorphisms in brain structure, I expect more studies will be

directed specifically to assessing possible consequences for drug

action. A second possible interaction between drugs and gender

dimorphisms in the brain concerns the possible effect of drugs

consumed by the mother on the development of normal sex dimorphisms in brain structures. To my knowledge, nobody has shown di53
rectly that prenatal or perinatal exposure to any drug can influence the development of sexually dimorphic neuronal structures.

However, much data concerning the effects of several drugs of

abuse on neuroendocrine and behavioral parameters strongly suggests that perinatal drug exposure may ultimately affect behavior

by altering the development of sexually dimorphic neural features.

A brief, selective review follows of studies in which perinatal

exposure to drugs of abuse affected neuroendocrine function or behavioral development in animals. Administration of tetrahydrocannabinol to pregnant mice caused a significant reduction in plasma

T in fetal male offspring; this deficit in T was associated with a

long-term reduction in masculine coital ability (Dalterio and

Bartke 1978; Dalterio and Bartke 1981). Similar reductions in fetal testicular secretion of T were observed in male rats born of

mothers given phenobarbitol at the end of gestation (Gupta et al.

1982). Neonatal administration of pentobarbitol to male hamsters

caused permanent deficits in masculine coital capacity (Clemens et

al. 1979). Likewise, administration of morphine to pregnant rats

late in gestation caused reductions in plasma T in fetal males

that were associated with long-term deficits in masculine coital

potential (Ward et al. 1983). By contrast, no such behavioral effect was obtained in male offspring derived from rats in which

morphine treatment was stopped just prior to the onset of the gestational age of sexual differentiation, e.g., gestational day 18

(Vathy et al. 1985). In another study (Lumia et al. 1985) chronic

ingestion of ethyl alcohol by pregnant rats caused significant

increments in the ability of male offspring to display feminine

sexual behavior in response to adult treatment with ovarian hormones (i.e., ethanol attenuated the normal process of coital defeminization) without affecting masculine coital potential.

Similar effects were recently reported in the male offspring of

pregnant rats treated with nicotine (Rodriguez-Sierra 1985).

None of these reported effects of various drugs of abuse on the

reproductive behavioral capacity of offspring have as yet been

linked directly to changes in the brain structure. In several instances, however, the effects of fetal exposure of drugs of abuse

on later behavior have been linked, particularly in the male, to

reductions in circulating levels of T. Such results, along with

the knowledge that prenatal exposure either to T itself or to estrogenic metabolites of T may contribute importantly to brain sexual differentiation in males of several mammalian orders, raises

the question of whether drug abuse in pregnant women may disrupt

the normal course of brain sexual differentiation in their male

fetuses. More basic studies on the hormonal regulation of brain

and behavioral sex determination, coupled with studies on the possible effects of perinatal drug exposure on this process, are

needed to answer this question.

54
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the sexually dimorphic nucleus of the preoptic area or other

medial preoptic regions on the sexual behavior of male rats.

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Baum, M.J. Differentiation of coital behavior in mammals: A comparative analysis. Neurosci Biobehav Rev 3:265-284, 1979.

Becker, J.B.; Robinson, T.E.; and Lorenz, K.A. Sex differences

and estrous cycle variations in amphetamine-elicited rotational

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Callard, G.V. Aromatization in brain and pituitary: An evolutionary perspective. In: Celotti, F.; Naftolin, F.; and

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Clemens, L.G.; Popham, T.V.; and Ruppert, P.H. Neonatal treatment

of hamsters with barbiturate alters adult sexual behavior. Dev

Psychobiol 12:49-59, 1979.

Commins, D., and Yahr, P. Adult testosterone levels influence the

morphology of a sexually dimorphic area in the Mongolian gerbil.

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Commins, D., and Yahr, P. Lesions of the sexually dimorphic area

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193, 1984b.

Dalterio, S., and Bartke, A. Perinatal exposure to cannabinoids

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Dalterio, S., and Bartke, A. Fetal testosterone in mice: Effect

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Dohler, K.D.; Srivastava, S.S.; Shryne, L.E.; Jarzab, B.; Sipos,

A.; and Gorski, R.A. Differentiation of the sexually dimorphic

nucleus of the preoptic area of the rat brain is inhibited by

postnatal treatment with an estrogen antagonist. Neuroendocrinology 38:297-301, 1984.

Ehrhardt, A.A.; Meyer-Bahlburg, H.F.L.; Rosen, L.R.; Feldman,

J.F.; Veridiano, N.P; Zimmerman, I.; and McEwen, B.S. Sexual

orientation after prenatal exposure to exogenous estrogen. Arch

Sex Behav 14:57-78, 1985.

Erskine, M.S., and Baum, M.J. Plasma concentrations of testosterone and dihydrotestosterone during perinatal development in male

and female ferrets. Endocrinology 111:767-772, 1982.

Gorski, R.A.; Gordon, J.H.; Shryne, J.E.; and Southam, A.M. Evidence for a morphological sex difference within the medial preoptic area of the rat brain. Brain Res 148:333-346, 1978.

Gupta, C.; Yaffe, S.J.; and Shapiro, B.H. Prenatal exposure to

phenobarbitol permanently decreases testosterone and causes reproductive dysfunction. Science 216:640-642, 1982.

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Gustaffson, J.A.; Mode, A.; Norstedt, G.; Hokfelt, T.;

Sonnenschein, C.; Enroth, P.; and Skett, P. The hypothalamopituitarv-liver axis: A new system in control of hepatic steroid and drug metabolism. In: Litwack, G., ed. Biochemical

Actions of Hormones. Vol. 7. New York: Academic Press,

1980. pp. 47-89

Hines, M.; Davis, F.C.; Coquelin, A.; Goy, R.W.; and Gorski,

R.A. Sexually dimorphic regions in the medial preoptic area and

the bed nucleus of the stria terminalis of the guinea pig

brain: A description and an investigation of their relationship

to gonadal steroids in adulthood. J Neurosci 5:40-47, 1985.

Jost, A. Recherches sur le controle de l'organogenese sexuelle du

lapin et remarques sur certaines malformations de l'appareil

genital humain. Gynec et Obstr (Paris) 49:44-60, 1950.

Lumia, A.; Kleber, P.; Van der Woude, S.; Flynn, J.; and Broide,

J. Prenatal exposure to alcohol facilitates feminine sexual responsivity without disrupting masculine sexual behavior in male

rats. Paper presented at the Conference of Reproductive Behavior, Asilomar, CA, June, 1985.

Neill, J.D. Sexual differences in the hypothalamic regulation of

prolactin secretion. Endocrinology 90:1154-1159, 1972.

Nottebohm, F., and Arnold, A.P. Sexual dimorphism in vocal control areas of the songbird brain. Science 194:211-213, 1976.

Phoenix, C.H.; Goy, R.W.; Gerall, A.A.; and Young, W.C. Organizing action of prenatally administered testosterone propionate on

the tissues mediating mating behavior in the female guinea

pig. Endocrinology 65: 369-382, 1959.

area of the rat. Science 173:731-733, 1971.

Raisman, G., and Field, P.M. Sexual dimorphism in the preoptic

Raisman, G., and Field, P.M. Sexual dimorphism in the neuropil of

the preoptic area of the rat and its dependence on neonatal androgen. Brain Res 54:1-29, 1973.

Rodriguez-Sierra, J. Prenatal nicotine exposure feminizes male

rats at adulthood. Paper presented at the Conference on Reproductive Behavior, Asilomar, CA. June, 1985.

Swaab, D.F.; and Fliers, E. A sexually dimorphic nucleus in the

human brain. Science 228:1112-1114, 1985.

Tobet, S.A. A sexual dimorphism in the preoptic/anterior hypothalamic area of ferrets: Hormonal determinants and functional

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Tobet, S.A.; Shim, J.H.; Osiecki, S.T.; Baum, M.J.; and Canick,

J.A. Androgen aromatization and 5-alpha reduction in ferret

brain during perinatal development: Effects of sex and testosterone manipulation. Endocrinology 116:1869-1877, 1985.

Tobet, S.A.; Zahniser, D.J.; and Baum, M.J. Sexual dimorphism in

the preoptic/anterior hypothalamic area of ferrets: Effects of

adult exposure to sex steroids. Brain Res, in press.

Vathy, I.U.; Etgen, A.M.; and Barfield, R.J. Effects of prenatal

exposure to morphine on the development of sexual behavior in

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Vito, C.C.; Baum, Bloom, C.; and Fox, T.O. Androgen and estrogen receptors in perinatal ferret brain. J Neurosci

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ACKNOWLEDGEMENTS

The author is the recipient of Research Scientist Development

Award MH 000392. The author's research is supported by Grant HD

13634, awarded by the National Institutes of Health.

AUTHOR

Michael J. Baum, Ph.D.

Associate Professor

Department of Biology

Boston University

2 Cummington St.

Boston, MA 02215

57
Drugs and Drug Interactions in

the Elderly Woman

Monique C. Braude

Although the elderly are commonly assumed not to be users of illicit drugs, they are generally recognized as having a high level

of use of legal drugs. In fact, when speaking of the elderly, it

seems more appropriate to speak of drug misuse than of drug abuse

(Glantz 1982). To avoid confusion, definitions of the terms drug

misuse and drug abuse will be those adopted by the Federal

Strategy Council on Drug Abuse in 1979.

Drug abuse is the nontherapeutic use of any psychoactive substance, including alcohol, in such a manner as to adversely affect

some aspects of the user's life. The substance may be obtained

from any number of sources: by prescription, from a friend, overthe-counter, or through the illicit market. The use pattern may

be occasional or habitual. Drug misuse is the inappropriate use

of drugs intended for therapeutic purposes. This includes inappropriate prescribing or use of drugs resulting from inadequate

knowledge of the drug's effects, by either the physician or the

patient; it also includes self-medication by the patient in a

manner inconsistent with the label information.

One difference between men's and women's use/misuse is owing to a

higher proportion of women (60 percent) among the U.S. population

aged 65 years and older. Because of the longer life expectancy of

women, the problems of the elderly are increasingly those of

women. Future growth of the older population is expected to be

substantial and, by the year 2000, the Census Bureau projects a

population of 19 million older women versus 12.7 million older

men. In spite of this fact, research has failed to explore adequately the unique health problems of the older woman.

RISK OF ADVERSE EFFECTS DUE TO DRUG INTERACTIONS

Of major concern is the elderly woman at especially high risk for

harmful effects from drug interactions. In Hecht's review of

medicine and tie elderly (1983), the author pointed out the

following facts. The elderly--those 65 and over--constitute at

58
present about 11 percent of the total population, yet they take

about 25 percent of all drugs dispensed in the United States, both

prescription and over-the-counter (OTC). It is the rare older

patient who needs only one or two prescription drugs. For most,

polypharmacy is the rule rather than the exception. A University

of Florida College of Pharmacy survey reported, in 1980, that

elderly patients took an average of eight different drugs a

month. Other studies have shown that older patients may be getting as many as 14 to 18 different drugs in the course of a year.

Nursing home patients have been reported to take as many as 20 to

30 drugs.

The reason the elderly take so many drugs is not hard to understand. They are more likely than other age groups to have one or

more chronic illnesses, including heart disease, high blood pressure, diabetes and arthritis. Few such diseases can be treated

with just one drug. Medication for chronic ills usually must be

taken over long periods, frequently for the rest of the patient's

life.

Elderly women have been prescribed drugs such as estrogens to

replace diminished hormones after menopause and to prevent later

years' osteoporosis. They also use sedatives, hypnotics, antianxiety drugs, antihypertensive medication, vitamins, analgesics,

diuretics, laxatives, and tranquilizers at a rate of two and a

half times that of elderly men.

The very fact that the elderly must take so many medications increases their chance of experiencing adverse reactions--a chance

three times greater than that of the younger patient. Such reactions may be severe enough to require hospitalization. The reactions elderly patients may experience include stupor, confusion or

paradoxical overstimulation from sedatives, intestinal bleeding

from aspirin, lowered blood pressure from antipsychotics such as

chlorpromazine, and fainting following use of antidepressants,

diuretics, sedatives, tranquilizers, and some high blood pressure

medications.

Taking so many drugs also increases the potential for harmful drug

interactions. One drug can alter the effect of another, for

instance, by speeding up or slowing down its metabolism in the

liver, so that two similar drugs taken together may produce an

effect that is greater than expected, or the drugs may counteract

one another. Women, according to Hamilton and Parry (1983), and

as supported by data from the Drug Abuse Warning Network (DAWN),

have more adverse drug reactions than men and, especially after

menopause, may be more vulnerable to tardive dyskinesia, a disorder associated with use of psychoactive drugs.

The young as well as the old patient can experience adverse drug

reactions, but the problem is compounded in the elderly by the

very process of growing old. With age, there are physiological

changes that can affect the way in which drugs behave in the body

59
(Barry, this volume). In addition, such factors as diet, alcohol

consumption, disease, weather conditions (such as high heat and

humidity), malnutrition, and even bed rest can alter the movement

of drugs through the body.

The potentiation of psychoactive drug effects by alcohol may represent an additional danger for older women. Although generally

less recognized than for men, use of alcohol by older women to

combat depression or feelings of inadequacy or loneliness exists,

and can interfere with the drugs that they are taking for medical

purposes. As the environmental stresses (such as loss of spouse,

family and friends, income, employment, decreased physical beauty,

mobility, health, stamina, valued roles at home and in the neighborhood, independence, self-esteem) increase in later years, women

whose habitual coping responses to stress involved drinking or

drug taking may be particularly vulnerable in old age. Most of

the psychoactive drugs taken by the elderly woman to combat

depression, for instance, are potentiated by alcohol, resulting in

overdose incidents.

CHANGES IN DRUG DISPOSITION WITH AGE

The elderly woman may also be at risk due to changes in drug disposition, which may be the result of changes in absorption, distribution, metabolism, or elimination occurring with age. Drugs

usually enter the body by mouth or by injection. How well drugs

will produce their effect depends first on how well they are absorbed. While there is no clear evidence that age alone affects

absorption, it has been suggested that decreased absorption might

occur as a result of physiological changes such as decreased gastric acidity, or a reduction in peristaltic activity that changes

the time it takes food to leave the stomach, or a decreased

intestinal blood flow.

Where age does make a difference is in drug distribution, the process by which drugs are delivered to various sites in the body.

Drug distribution in the elderly is altered in part because of

changes in the body's composition. The total body water and lean

body mass--essentially muscle and bone--decrease, while the proportion of fat increases, even though there is no increase in

total weight. This means that drugs normally distributed in lean

body tissue, such as digoxin, will end up at higher concentrations

in the bloodstream. On the other hand, barbiturates (Nembutal and

others), phenothiazines (Thorazine and others), and diazepam

(Valium) are stored in fatty tissue. The increased fat in the

elderly can serve as a reservoir for these drugs and prolong their

"working" time.

Drug distribution can also be altered by age-related changes.

Plasma proteins in the blood aid in transporting many drugs from

the intestines throughout the body. A certain percentage of the

drug is always bound to the protein. Only the unbound, or free,

portion of the drug can work. Thus, binding is important in

60
determining how much drug will be available to produce the desired

effect. With age, there is a decline in the amount of albumin,

one of the blood proteins. Some drugs are highly bound to albumin,

including the epilepsy drug Dilantin, Valium, and blood-thinning

drugs (Dicumarol). A reduction in albumin will result in an

increased amount of active drug, so what would normally be a

therapeutic dose of the drug may prove to be a toxic one. Still

other problems may develop because drugs compete for these binding

sites. When one drug is blocked at the binding site by a second

drug, the amount of the first drug that is freely circulating

increases, as does the potential for toxicity. For example,

phenylbutazone, salicylates, and sufonamides can displace

tolbutamide (a drug for treating diabetes), leading to

hypoglycemia.

Metabolism also changes with age. Drug metabolism rates in the

elderly are one-half to two-thirds the rates of middle-aged and

younger patients. Metabolism takes place primarily in the liver,

where drugs are changed into water-soluble form so that they can

be excreted. One drug may stimulate the metabolism of another,

thus decreasing its effectiveness. Phenobarbital has this effect

on anticlotting drugs. On the other hand, the antibiotic chloramphenicol slows the metabolism of these drugs, thereby increasing

the magnitude and duration of their effects. The capability of

the liver to perform this vital function depends on the blood flow

to that organ. In the elderly, this blood flow is decreased.

Drugs ingested orally, including beta blockers, narcotics,

nitrates, hydralazine, and tricyclic antidepressants pass through

the liver before they reach the general circulation. Because of

the reduced blood flow, smaller amounts of these drugs are metabolized and excreted. Consequently, the amount that enters the

elderly person's system is higher than it should be.

Finally, the body's processes for eliminating drugs can be impaired in the elderly because of changes that occur in the aging

kidney, changes that are more dramatic than those in any other

organ. The kidneys become smaller, as blood flow and filtering

capacity decrease. Such kidney impairment retards the elimination

of water-soluble drugs such as digoxin, certain antibiotics,

chlorpropamide, and hypotensive agents, leaving the elderly

patient more prone to adverse drug reactions.

INCREASED SENSITIVITY TO DRUGS IN THE ELDERLY

As if this weren't enough, the elderly appear to be more sensitive

to certain drugs. For instance, they seem to be more affected by

anticholinergic drugs. These drugs can cause confusion, disorientation, hallucinations, and delirium, as well as blurred vision,

dry mouth, palpitations, and constipation in the elderly. Among

anticholinergics are medications for spastic colon, drugs used for

treatment of Parkinson's disease, some antihistamines, tricyclic

antidepressants, and drugs to control irregular heartbeats. Older

patients may experience fainting and dizzy spells from drugs such

61
as antidepressants, which don't usually produce such effects in

younger patients. Older women also seem to be more sensitive to

diazepam, thus requiring smaller doses than younger patients.

Nonprescription, or over-the-counter (OTC), drugs have a prominent

place in the medicine cabinets of most elderly people. Analgesics

(painkillers), antacids, cough and cold preparations, and laxatives are among the OTC drug products most frequently used by

older people. While many people don't think of these as drugs,

OTC drug products can be the cause of adverse side effects in

older patients. Aspirin, for instance, can increase the effect of

blood thinners, and decrease sodium and chloride excretion--a matter of concern to those with congestive heart failure. Chronic

use of aspirin may lead to iron deficiency anemia. Antacids can

interfere with the absorption of some drugs, such as the antibiotic tetracycline, while chronic use of laxatives can lead to

electrolyte and water balance disturbances.

While many elderly people may have some vitamin deficiencies,

treatment with megadoses of vitamins is generally not recommended.

One reason for avoiding them is the side effects of such doses.

Too much vitamin C may raise uric acid levels and trigger gout in

those disposed to this painful disease. Vitamin C can also cause

false readings on urine tests essential to control diabetes. Too

much vitamin A can be the cause of fatigue, malaise and lethargy.

It would seem that the best way to avoid adverse reactions in

older patients is simply to reduce the amount and number of drugs

they take. However, prescribing for the elderly, like life

itself, is not simple. The changes that come with age often are

gradual, and patients, being individuals, do not necessarily age

at the same rate. Drug manufacturers, for the most part, do not

test their products in elderly patients, and there are no easy,

clear guidelines to determine how much or little of a drug a particular patient will need. To solve some of these problems, the

Food and Drug Administration, encouraged by the American Association of Retired Persons and the National Institute on Aging, is

looking into the development of guidelines for geriatric testing

of drugs.

One should not forget that, since older women suffer from multiple

chronic illnesses and are users of multiple drugs, nutrition

becomes a major health concern for this population, as these illnesses and concomitant drug use often interfere with the ability

to eat and absorb foods needed for good nutrition.

CONCLUSIONS AND RECOMMENDATIONS

A comprehensive strategy will be necessary to respond to the growing crisis of resource shortages in the face of expanding numbers

of older women, and a clear policy is needed regarding the health

issues of older women. All relevant agencies at the State and

Federal level should include this topic as a research priority.

62
The strategy needs to conceptualize aging women to include middle

and later life, and needs to address the double jeopardy of agism

and sexism. To be most effective, a strategy will require an

integrated approach to the multiple factors influencing the health

of elderly women and will respond to high-risk subgroups of older

women. Solutions that strengthen informal caring are both costeffective and practical; these can be integrated with formal resources.

The planning and implementation of a strategy to address the

health issues of aging women will require research, education, resource coordination, legislation, advocacy, and insurance. The

initiative now begun must continue to define areas of need and to

distinguish the needs of the very elderly woman, whose risks are

immediate and linked to long-term care, from those of the woman

who is chronologically old but functioning at a high level, at

least until she experiences health and economic deficits. It

should also reflect the needs of the middle-aged woman dealing

with life transitions and managing dependent people, and those of

the younger woman with an old age to plan for.

A response to the health needs of older women requires continuity

that incorporates a futuristic orientation with the imperatives of

the present. To plan an effective current and future strategy,

broad priorities must be matched with a comprehensive research

agenda and educational efforts. A comprehensive research agenda

would address the normal aging process as well as the pathological

models. Furthermore, biomedical, applied health care, social

science, and clinical intervention research are all part of this

research agenda. To date, all types of research have neglected to

design studies that compare older men with women, younger with

older women, and subgroups of older women with each other. In

studies where such data have been collected, information related

to older women's concerns is either only partially analyzed or not

readily accessible in published form.

The field is wide open to the creative investigator. New analytical procedures may need to be discovered and applied to produce

reliable data about the interaction of age and gender variables.

Health survey research, program design, and outcome studies need

to be increased in number and scope.

Significant educational advances have been made in medical,

nursing, social work, and other key professions as they shift

toward more gerontological and geriatric content, but much of the

curriculum is devoid of gender-related information. Clinical

training often fails to reduce myths and stereotypes held by

practitioners about older women. The focus of education can

transcend the narrow pathological/disease perspective and move

toward an understanding of function and dysfunction within an

environmental perspective. With this understanding, economic

resources in support of gerontological and geriatric education can

be distributed effectively among the relevant disciplines, to

63
improve training and continuing education, so that the older woman

is better served.

REFERENCES

Glantz, M. Predictions of elderly drug abuse. In: Peterson, D.,

and Whittington, F., eds. Druqs, Alcohol and Aging. Dubuque,

Iowa: Kendall Hunt Publishing Co., 1982. pp. 117-126.

Hamilton, J., and Parry, B. Sex-related differences in clinical

drug response: Implications for women's health. J Am Med Wom

Assoc 38:126-132, 1983.

Hecht, A. Medicine and the elderly. FDA Consumer, September

1983. pp. 20-21.

AUTHOR

Monique C. Braude, Ph.D.

Senior Research Pharmacologist

Division of Preclinical Research

National Institute on Drug Abuse

Room lOA-31, Parklawn Building

5600 Fishers Lane

Rockville, MD 20857

64
Gender as a Factor in

Treating the Elderly

Patricia P. Barry

THE ELDERLY

Chronologic age alone does not account for the increased incidence

of drug toxicity with advancing years. Elderly persons have more

disease, often severe and of long duration, requiring more medications. In addition, factors such as nutrition, mental status,

functional capacity, and use of alcohol and cigarettes are important. In these respects, as in many others, the elderly comprise

a heterogeneous group that must be carefully evaluated, on an

individual basis, in the treatment of illness.

Several problems are common in the clinical practice of geriatrics. The elderly often are afflicted with multiple diseases.

Heart disease. cancer, chronic lung disease, and Alzheimer's

disease, which are major causes of death in the elderly, may also

lead to chronic ill health. Additionally, functional impairment

due to arthritis, impaired vision and hearing, and depression may

limit the elderly person's ability to attend to personal needs, or

to maintain mobility and adequate nutrition. The clinician must

also consider the management of such common diseases as diabetes

and hypertension in the treatment plan.

PHYSIOLOGIC CHANGES

Biological changes of aging have been recognized as important factors to be considered in planning drug therapy. Gastrointestinal

changes, such as increased gastric pH, increased gastric emptying

time (Stevenson et al. 1979). and decreased active transport

(Bender 1968). have been noted in clinical studies. In the renal

system, function declines in many elderly patients, even in the

absence of renal disease. Such parameters as glomerular filtration, as well as tubular secretion and absorption, may be reduced

as much as 35 percent (Rowe et al. 1976). Due to decreased endogenous production of creatinine (Vestal 1978). serum creatinine,

which is a measure used to indicate kidney function, may not reflect the decrease in creatinine clearance, which may be as much

65
as 10 ml/min/decade (Kampmann et al. 1974). Cockcroft and Gault

(1976) developed a useful formula for calculating estimated

creatinine clearance in the elderly:

Creatinine Clearance = (140-age) body weight

72 x serum creatinine

The hepatic changes in the elderly are not usually reflected by

abnormalities in the standard liver function tests. Not only can

the production of albumin decrease, but reduced hepatic blood flow

may be a major determinant of the prolonged metabolism of many

drugs (Geokas and Haverbach 1969). Microsomal enzyme activity,

especially hydroxylation (a Phase I reaction) is often reduced in

the elderly (Greenblatt et al. 1982). Body composition alterations in the elderly include a reduction in lean body mass (Forbes

and Reina 1970) and total body water (Novak 1972), and an increase

in adipose tissue mass, which may be even more significant in

elderly women than in elderly men (Greenblatt et al. 1982).

ALTERED PHARMACOKINETICS

The changes noted may affect the pharmacokinetics of many medications in the elderly patient. Absorption, reviewed by Stevenson

et al. (1979), has not been shown to significantly decrease in

most elderly persons. The drugs so far studied, however, are

among those known to have good absorption properties in the general population, and it is possible that drugs known to be poorly

absorbed will show decreased absorption by the elderly.

Drug distribution is influenced by the volume of distribution and

the extent of protein binding. Drugs that are lipid soluble may

have an increased volume of distribution in the elderly, due to

the increased proportion of adipose tissue, especially in women.

The volume of distribution for water-soluble drugs is contracted

in many elderly, resulting in higher plasma levels. Finally,

drugs that are extensively bound to albumin may have increased

levels of unbound drug in the elderly, if the serum albumin is

decreased.

Clearance is primarily a function of the liver and kidney, and is

dependent upon blood flow to these organs. In elderly patients

with diminished perfusion, therefore, clearance may be reduced due

to decreased renal elimination and hepatic metabolism.

Both volume of distribution and clearance of a drug will affect

the serum half life by the following relationship:

t 1/2 = 0.693 x Volume of distribution

clearance

Persons with increased volume of distribution or decreased

clearance, or both, will have increased serum half life (t l/2)

and greater susceptibility to drug toxicity (Greenblatt et al.

1982).

66
DRUG PROBLEMS

In several studies of compliance reviewed by Vestal (1978), the

elderly were found to have serious difficulties. Error frequencies ranged from 25 to 50 percent, and were often due to lack of

understanding of drug regimens. Vestal also noted that the

incidence of drug reactions is higher in the elderly, ranging from

15 to 24 percent in hospital settings. Drugs that may cause

problems include digoxin, diuretics, antihypertensives, anticoagulants, bronchodilators, analgesics, sedative-hypnotics, antidepressants, and antipsychotics. Drug toxicity may be manifested by

confusion, sedation, hypotension, fluid and/or electrolyte disturbances, cardiac arrhythmias, anorexia, urinary retention, and many

other common complaints.

GENDER DIFFERENCES

Greenblatt et al. (1982) noted that the body proportion of adipose

tissue increases with age, from 18 to 36 percent in men and from

33 to 48 percent in women. Women have a larger volume of distribution of lipid-soluble drugs, and a smaller volume of distribution for water soluble drugs. Decreased protein binding in women

has been noted in some studies, but data are conflicting (Wilson

1984). However, diminished activity of hepatic oxidative enzymes,

resulting in decreased drug clearance has been found to be more

significant in elderly men than in elderly women (Greenblatt et

al. 1982).

DRUG STUDIES

Sex-related differences have been studied by Greenblatt and coworkers, and reported for diazepam, desmethyldiazepam (an active

metabolite), oxazepam, and temazepam; half-life of these drugs is

consistently longer in women (Wilson 1984). Gender differences in

oxidation are important in the metabolism of these drugs; for

oxazepam and temazepam, the clearance rate is higher in men

(Greenblatt et al. 1980a, Divoll et al. 1981); for diazepam and

desmethyldiazepam it is lower in men (Greenblatt et al. 1980b;

Ochs et al. 1981; Allen et al. 1980). The increased half-life of

the latter drugs in women is apparently related to their greater

volume of distribution for these lipid-soluble drugs.

Other drugs in which gender differences have been observed include

heparin, which has greater adverse effects in women (Greenblatt et

al. 1982), and imipramine, which is less protein-bound in women

(Kristensen 1983). Goble (1975) has extensively reviewed a number

of drugs for sex-related differences in response or side effects.

TREATMENT CONSIDERATIONS

Elderly women differ in other important respects from elderly

men. They are more likely to be widowed, live alone, or reside in

an institution; many have reduced income. (Elderly men more often

67
reside with their spouses, and often have the assistance of veterans' benefits.) Medical problems such as osteoporosis and urinary

incontinence are more common in women, in addition to the obvious

importance of medical problems specific to women, such as cancer

of the breast, ovary, and uterus.

In the field of geriatric medicine, considerable attention has

been directed to the problems associated with prescription drug

use and misuse. Little attention has been directed to the

specific considerations of elderly women, despite the fact that

our population becomes increasingly female with age. Most drug

studies comparing women with men have considered only younger

women and have emphasized such factors as pregnancy, menstruation,

and the use of oral contraceptives, despite the fact that women

today live one-third of their lives after menopause. Future

research must therefore address the physiologic, pharmacologic and

socioeconomic factors that contribute to gender differences in our

elderly population.

REFERENCES

Allen, M.D.; Greenblatt, D.J.; Harmatz, J.S.; and Shader, R.I.

Desmethyl diazepam kinetics in the elderly after oral prazepam. Clin Pharmacol Ther 28:196-202. 1980.

Bender, A.D. Effect of age on intestinal absorption: Implications of drug absorption in the elderly. J Am Geriatr Soc

16:1331-1339, 1968

Cockcroft, D.W., and Gault, M.H. Prediction of creatinine

clearnace from serum creatinine. Nephron 16:31-41, 1976.

Divoll, M.; Greenblatt. D.J.; Harmatz, J.S.; and Shader, R.I.

Effect of age and gender on disposition of temazepam. J Pharm

Sci 70:1104-1107, 1981.

Forbes, G.B., and Reina, J.C. Adult lean body mass declines with

age: Some longitudinal observations. Metabolism 19:653-663,

1970.

Geokos, M.D., and Haverbach. B.J. The aging gastrointestinal

tract. Am J Surg 117:881-892, 1969.

Goble, F.C. Sex as a factor in metabolism, toxicity and efficacy

of pharmacodynamic and chemotherapeutic agents. In: Garattini

et al., eds. Advances in Pharmacology and Chemotherapy Vol.

13. New York: Academic Press, 1975. pp. 174-252.

Greenblatt, D.J.; Allen, M.D.; Hirmatz; J.S.; and Shader, R.I.

Diazepam disposition determinants. Clin Pharmacol Ther 27:301-

302, 1980a.

Greenblatt, D.J.; Divoll, M.; Harmatz, J.S.; and Shader, R.I.

Oxazepam kinetics: Effects of age and sex. J Pharmacol Exp

Ther 215:86-91, 1980b.

Greenblatt, D.J.; Sellers, E.M.; and Shader, R.I. Drug

disposition in old age. N Engl J Med 306:1081-1088, 1982.

Kampmann, J.; Siersbaek-Nielsen, K.; Kristensen, M.; and Molholm

Hansen, J. Rapid evaluation of creatinine clearance. Acta Med

Scand 196:517-520, 1974.

68
Kristensen, C.B. Imipramine serum protein binding in healthy

subjects. Clin Pharmacol Ther 34:689-694, 1983.

Novak, L.P. Aging, total body potassium, fat free mass and cell

mass in males and females between the ages of 18 and 85. J

Geronotol 27:438-443, 1972.

Ochs, H.R.; Greenblatt, D.J.; Divoll, M.; Abernethy, D.R.;

Feyerabend, H.; and Dingler, H.J. Diazepam kinetics in relation

to age and sex. Pharmacology 23:24-30, 1981.

Rowe, J.W.; Andres, R.; Tobin, J.D.; Norris, A.H.; and Shock,

N.W. The effect of age on creatinine clearance a man: A

cross-sectional and longitudinal study. J Geronotol 31:155-163,

1976.

Stevenson, I.H.; Salem, S.A.M.; and Shepard, I.M.M. Studies on

drug metabolism and absorption in the elderly. In: Crooks, J.

and Stevenson, I.H., eds. Drugs and the Elderly. Baltimore:

University Park Press, 1979. pp.51-63.

Vestal, R.E. Drug use in the elderly: A review of problems and

special considerations. Drugs 16:358-382, 1978.

Wilson, K. Sex-related differences in drug disposition in man.

Clin Pharmacokinet 9:189-202, 1984.

AUTHOR

Patricia P. Barry, M.D.

Geriatric Section

Department of Medicine and

Home Medical Service

Boston University Medical Center

Boston, Massachusetts

69
Gender and the Teenage Smoker

Ellen R. Gritz

INTRODUCTION

Cigarette smoking is no longer a behavior that is considered normative for men but socially disapproved for women, thus undertaken

in secret, or openly as a symbol of risque or avante guarde feminism. As a result of sweeping changes in social forces during

this century, cigarette smoking became an acceptable behavior for

both males and females. We are thus witnessing the "disinhibition" of a problem, the emergence of a problem-in-waiting.

Women's smoking prevalence increased from 18.1 percent in 1935 to

33.3 percent in 1965 and has since decreased to 29.5 percent in

1983; in comparison, men's smoking prevalence decreased rather

steadily from 52.5 percent in 1935 to 34.8 percent in 1983 (USDHHS

1980; NCHS, in press). The mean age of initiation of smoking

among successive birth cohorts of women smokers from 1900 to 1960

has dropped to approximately the same mean age as men (USDHHS

1980). Interestingly, these great changes in women's smoking behavior have been paralleled by an unrivalled direct-appeal campaign by cigarette advertisers, which began in the mid- to late

1920’s (Howe 1984).

The trend data describing women's smoking prevalence are not new,

so why should it suddenly be considered the disinhibition of a

problem? What is news in 1985 is the actualization of a National

tragedy that was totally preventable--the emergence of lung cancer

as the number one cause of cancer mortality among women, surpassing breast cancer (American Cancer Society 1985). In 1985, it is

predicted that 38,600 women will die of lung cancer versus 38,400

of breast cancer. Lung cancer has become a major problem for women as a result of the dramatic increase in women's smoking just

described. A disease that virtually did not exist in this country

at the turn of the century is now killing more men and women annually than any other form of cancer (American Cancer Society 1985).

The charge of this paper, however, is to concentrate on adolescent

smoking and to speculate on some of the psychosocial factors which

may promote smoking in teenage girls.

70
TRENDS IN CIGARETTE SMOKING AMONG ADOLESCENTS

Lagging behind, but paralleling changes in the smoking patterns of

adult women, have been widespread changes in teenage smoking.

However, "equality" in smoking behavior had been reached in adolescents prior to adults. National survey data show that gender

differences in teenage cigarette smoking have virtually disappeared, and that female smoking now exceeds that of males for

most analyses (Johnston et al. 1985; NIE 1979; Clayton, this

volume). A series of cigarette smoking surveys among 12- to 18-

year-olds was conducted by the National Clearinghouse for Smoking

and Health and the National Institute of Education between 1968

and 1979 (NIE 1979). While a greater percentage of boys (14.7

percent) than girls (8.4 percent) smoked at the time of the 1968

survey, smoking prevalence increased steadily among girls until

the 1979 survey, when the first evidence of a decline appeared.

Smoking among boys began to decrease beginning with the 1972

survey. By 1979, the prevalence of smoking was higher among girls

(12.7 percent ) than among boys (10.7 percent). Although a

National survey of smoking behavior in the 12- to 18-year-old age

group has not been conducted since 1979, one is planned by the

Office on Smoking and Health (Shopland, personal communication).

A second source of National data describing teenage smoking patterns comes from the Monitoring the Future project, a survey of

drug use among high school seniors, conducted annually since 1975

by investigators at the University of Michigan Institute for

Social Research and sponsored by the National Institute on Drug

Abuse (Johnston et al. 1985). Between 1977 and 1980, the prevalence of cigarette smoking fell by nearly one-third and then leveled off for several years. The most recent survey showed the

prevalence of daily use among high school seniors to be 18.7 percent in 1984--a reduction of 2.5 percent from the 21.2 percent

prevalence in 1983 and a resumption of the downward trend

(Johnston et al. 1985).

Gender-specific data revealed a higher prevalence of smoking among

girls at levels of occasional smoking--one or more cigarettes per

month (F=31.9 percent, M=25.9 percent) and one or more cigarettes

per day (F=20.5 percent, M=16.0 percent). However, this gender

difference decreased as consumption levels increased to one-half

pack or more per day (F=12.8 percent, M=11.0 percent) and one pack

or more per day (F=6.2 percent, M=6.6 percent), until approximate

parity was reached at the latter consumption level, characteristic

of adult smoking behavior. Figure 1 shows temporal trends by sex

in daily cigarette smoking for any daily use and for one-half pack

or more per day, and simultaneously displays temporal trends in

daily use of marijuana and alcohol (Johnston et al. 1985). The

trends for the three drugs are obviously quite different, with

only cigarettes showing the reversal of the higher prevalence from

males to females.

71
FIGURE 1. Trends in 30-day prevalence of daily use of marijuana,

alcohol, and cigarettes, by sex

NOTE: Daily use for alcohol and marijuana is defined as use on 20 or more occasions In the past 3O days. Daily use of cigarettes is defined as smoking

one or more cigarettes per day in the past 30 days.

SOURCE: Johnston e+

 al. Use of licit and illicit drugs by America’s high school

students, 1975-1904. DHHS Pub. No. (ADM) 05-1394, 1985.

THE DEVELOPMENT OF SMOKING BEHAVIOR

Adolescent females have been characterized by cognitive and emotional immaturity, hypersensitivity to peer rejection, vulnerability to impulsive behavior, and difficulty in acquiring a positive

body image (Freedman 1984). The combination of these four dimensions makes the teenage female exquisitely vulnerable to the seductive allure of smoking. Developmental models of the initiation

of smoking behavior, such as that of Flay et al. (1983), set out

factors predisposing to cigarette smoking; these may be biological, environmental, and/or psychological.

In the preparation or anticipation stage, family influences predominate. Thus, watching parents or older siblings smoke facilitates the development of a positive attitude toward smoking in the

cognitively and emotionally immature girl and teaches her how,

when, and where smoking is appropriate. The presence of smoking

in the home will accustom her to the smell and sight of cigarettes

and will also expose her passively to some of the health damaging

effects of cigarette smoke, as well as teaching her to imitate the

physical actions of smoking, if she is so inclined. As evidence

72
for this family influence, data show a fivefold increase in likelihood (20.3 percent versus 4.1 percent) that an adolescent girl

will smoke if she is in a household in which one or both parents

or an older sibling smoke compared to a household in which none of

these persons smoke (NIE 1979).

During the period of initiation, trying the first cigarette, peers

become most important. This is a period of social transition and

of movement to a school more distant from home, a time where

hypersensitivity to peer rejection may lead a young girl to accept

the offer of a cigarette all too easily from a valued set of

friends. Fifty percent of all first cigarettes are smoked with a

friend (Bewley et al. 1974; Friedman et al. 1985; Palmer 1970),

and almost 75 percent of all first cigarettes are smoked with

another teenager (Biglan et al. 1983). Friedman et al. (1985) reported that 60 percent of all first-cigarette experiences or pressures to smoke occurred in the teenager's own home or in that of a

friend, suggesting acceptance (or ease of sneak experimentation)

in the two main social settings for this age group. Indeed, parents were even present in 7 percent of the first-cigarette incidents reported in that study. Teenage smokers stick together, as

do nonsmokers, and initial experiences occur most frequently with

persons of the same sex (Friedman et al. 1985; NIE 1979). Lifestyle choices are beginning to be made at this time, and may

include a variety of behaviors and value orientations into which

the image of a smoker fits (Wang-McCarthy and Gritz 1982).

The period of learning and becoming, experimental smoking, is

operationally defined as smoking less than one cigarette per week.

In this period of social reinforcement, the formation of a selfimage is occurring. Thus, impulsive behaviors like smoking and

experimentation with alcohol and sex may occur when socially

prompted. The image of a smoker, described by both personality

and physical attributes, can become highly valued and identified

with; teenage girls may see smoking as a way to acquire such an

image. McCarthy and Gritz (1984) demonstrated that the closer the

ideal self-image of a smoker was to her/his description of a model

in a cigarette advertisement, the more likely that adolescent intended to be a smoker (Barton et al. 1982; Chassin et al. 1981).

In this stage of the model as well as in the following stage, the

physical image of the female smoker portrayed in advertisements

may wield substantial power. Also in this and the following

stage, the smoker learns to regulate the nicotine dose of a

cigarette, to become accustomed to its mood-altering and other

pharmacologic effects, and to begin a pattern of conditioned reinforcement from smoking.

The final stage in the developmental model of smoking, habituation, is achieved when the adolescent is smoking at least one

cigarette weekly. National surveys use this level to define

regular smoking in the age group 12 to 18 years (NIE 1979).

Dependence can begin to develop about this time. Skilled, by this

stage, in techniques of inhalation and nicotine/dose regulation,

73
the teenage girl may especially learn to use cigarettes as a legal

and sanctioned means of weight control, also highly valued during

this period.

VULNERABILITIES FOR ADOLESCENT FEMALES: WEIGHT MD ADVERTISING

Using the developmental model for smoking for a teenage girl, it

becomes easier to see how standards of slenderness and weight loss

may be related to smoking and how cigarette advertising may capitalize on these and other descriptions of female beauty.

Feminine beauty has been equated with ultraslimness for a generation (Freedman 1984). Obsession with reducing body weight and the

existence of serious eating disorders is increasingly prevalent

among teenage girls and women today (Wooley and Wooley 1984; Yager

1985). Almost 20 years ago, Dwyer et al. (1967) reported that by

the end of high school 60 percent of girls had already been on a

serious diet and half that number were dieting at any one time

(compared to 24 percent and 6 percent, respectively, for boys).

Current data from the NIDA High School Senior Survey (Johnston et

al. 1985) show an astounding use of nonprescription diet pills

among female high school seniors: ever used, but not in past

year--43 percent (versus 15 percent for boys); used in the past

year, not in past month--27 percent (versus 9 percent for boys);

used in past month, less than daily--l4 percent (versus 5 percent

for boys); and used daily in the past month--l.9 percent (versus

0.3 percent for boys). Interestingly, in the Glamour Magazine

survey of 33,000 women, 50 percent of respondents reported using

diet pills sometimes or often (Wooley and Wooley 1984). Analysis

of the NIDA teenage data for concurrent use of reducing pills and

cigarettes has not been reported, but an association might be predicted. Teenagers who smoke are more likely to have tried other

substances such as alcohol and marijuana, and to engage in problem

behaviors. The gateway theory of substance use predicts the order

in which licit and illicit drugs are introduced, and analyses have

been performed on continuation and discontinuation patterns

(Jessor and Jessor 1977; Kandel 1978; Kandel and Logan 1984;

O'Malley et al. 1984).

A recently published study (Charlton 1984) of smoking behaviors

and beliefs conducted on 16,000 British children and adolescents

revealed several fascinating relationships between beliefs about

cigarette smoking and weight control:

Across all respondents, the proportion agreeing that "smoking

keeps your weight down" rose steadily from 16.6 percent in

never smokers to 42.2 percent in the heaviest smokers (more

than six cigarettes per week).

This increase was more pronounced in girls than boys, and,

among regular smokers (at least one cigarette per week) at all

ages, girls were more likely than boys to agree that smoking

controls weight.

74
Concurrent with the advent of puberty, the belief among regular

smokers that smoking controls weight takes a sharp increase,

from 5.0 percent among 9- to 11-year-old girls to 35.7 percent

in 12-year-old females. This belief rises steadily to a peak

of 52.9 percent among 16-year-olds, the age at which a sharp

drop in the percentage of males agreeing (29.0 percent) occurs.

The authors note that among the various belief questions on the

survey, only the question of weight control mirrors the postpubertal rise in girls' smoking so closely. Comparable data

for the United States are greatly needed, and could possibly be

collected, along with the type of information in the NIDA High

School Senior Surveys.

Cigarette smoking provides a lifestyle crutch with a physiological

basis to facilitate weight control. Stimulation of the gastrointestinal tract by nicotine results in increased tone and motor

activity of the bowel (Gilman et al. 1980). Anecdotally, smoking

a cigarette is said to suppress appetite; thus, smoking serves as

a means of delaying eating or reducing consumption. Cigarettes

are also often used to mark the end of a meal and frequently

accompany coffee and alcohol consumption (McKennell and Thomas

1967 ). Thus, the ritual aspects of smoking and eating/drinking

may come to represent social competence to an adolescent girl,

along with an image of physical attractiveness.

This brings us to the putative role of cigarette advertising in

female smoking, a highly debated influence with regard to the initiation of smoking. Pictorial advertising portrays smoking as

fun, sophisticated, sexually adventurous, and involving risk taking (FTC 1981; FTC 1985; Yankelovich et al. 1977). At the very

least, we can say that cigarette advertising provides an indirect

Influence on smoking onset by supporting the image of smoking as a

symbol of maturity, autonomy, and attractiveness.

These admired traits, and those mentioned above, form part of the

myth surrounding the social benefits of smoking (Chapman and

Fitzgerald 1982). Girls learn far earlier than puberty that

beauty is a primary dimension of femininity; by adolescence, the

cultivation of attractiveness has become a major task (Freedman

1984). Girls also grow up surrounded by omnipresent models of

beautiful women on billboards, television, in movies and magazines, which are capable of influencing their evaluation of the

importance of beauty for attaining popularity. Combined with the

fact that early adolescence marks the highest degree of anxiety

and greatest dissatisfaction with body image (Freedman 1984), the

allure of cigarette ads targeted at women can be immense. Every

psychosocial attribute and culturally relevant message valued in

this age group can be found in cigarette ads which feature, in

addition to those attributes mentioned earlier, athletics, dress,

favorite activities, feminism, and very frequently, extreme

slenderness.

75
The most recent Federal Trade Commission Report to Congress Pursuant to the Federal Cigarette Labeling and Advertising Act (Federal

Trade Commission 1985) contains an analysis of cigarette advertising practices and expenditures for the years 1982-1983. In those

years, ads directed primarily toward females featured glamorous

and elegant women, and a "luxury brand" was introduced. The FTC

Report summarizes the advertising approach as follows: "The cigarette marketers placed increasing emphasis on linking a particular

brand with health, wealth, luxury, and achievement."

To note that cigarette manufacturers spent a total of $2.65 billion in 1983, compared to $1.2 billion in 1980, may serve to

illustrate the degree of environmental flooding that is possible

with a media campaign. The three forms of media on which the

greatest amounts of money were spent for advertising in 1983 were

magazines, newspapers, and outdoor displays, in decreasing order.

Public entertainment or special events, including sports, musical,

and other cultural events, received increased sponsorship. This

included such sporting events as Team America Pro Soccer, the

Western Rodeo series, Ski Days, the Virginia Slims Tennis Tournaments, and the Raleigh Children's Cancer Classic Celebrity golf

Tournament. Cigarette advertising and giveaways, such as T-shirts

with a brand logo, were frequently prominent at such events.

Examples of cultural events sponsored in whole or part by the

cigarette industry were the Kool Jazz Festival and the New York

City Opera Company's National tour. Obviously, many of these

events are attended by adolescents, who may even come to associate

such attractions with particular brand images.

Recently, Warner (1985) has written convincingly regarding media

self-censorship on the known relation between smoking and health.

He cites several sources of self-censorship, the primary one being

the fear of publishers that advertising will be withdrawn and thus

substantial revenues lost if the health effects of smoking are

openly addressed. Additionally, advertisements for antismoking

products and services may be rejected by publishers for fear of

offending the tobacco advertisers. Warner states, "Evidence...

strongly suggests that the public is fed a media diet deficient in

news, comment, and commercial promotion relating to the adverse

consequences of smoking."

With specific regard to women's magazines, Whelan et al. (1981)

reported that only eight feature articles on smoking or quitting

were published in the 12 years between 1967 and 1979 in 10 leading

magazines that carried cigarette advertising. Twice as many (16)

such articles appeared during the same time period in two women's

magazines that do not carry cigarette advertising. Compared to

the dangers of smoking, far greater attention was given to other

women's health issues, such as contraception, stress, mental

health, and nutrition, in the magazines that accept cigarette advertising than in those that do not. Thus, there is a very clear

source of bias in the amount of information about health issues, in

general, and about smoking in particular, that an adolescent

76
female will encounter if she reads women's or other magazines

which accept cigarette advertising. The female adolescent must

somehow overcome this source of misinformation if she is to avoid

habitual use of tobacco and increased risk of cancer.

DIRECTIONS FOR FUTURE HEALTH EDUCATION

To make nonsmoking appealing and counter the extremely sophisticated images presented by cigarette advertisers constitutes a

major task for researchers and educators from the fields of school

and public health, the medical professions, and health psychology

(Gritz 1984; Howe 1984). Prevention programs often do not address

the lifestyle choices and values of those adolescent girls most

likely to take up smoking--those who are disinterested in school,

not college-bound, who are precocious in social and sexual behaviors, and who may especially value the images peddled by advertisements (NIE 1979; Yankelovich et al. 1977). In addition, the

health risks to fetus and mother associated with smoking in pregnancy, especially low birth weight, are important to remember

since low birth weight is a major problem for teenage mothers

(USDHHS 1980; USDHHS 1981). Parental smoking also elevates risk

of respiratory disease in infants (USDHHS 1980). Thus, the teenage female smoker may be at risk for immediate as well as future

health consequences. We need to learn to "market" nonsmoking to

this population of young women in ways they will find attractive.

using role models they adulate. In light of the worrisome prevalence trends of the mid-1980's. this may be our foremost undertaking in smoking prevention for women.

FOOTNOTES

1. Report to Congress: Pursuant to the Federal Cigarette

Labeling and Advertising Act, for the Years 1982-1983.

Washington DC: Federal Trade Commission, 1985. p. 7.

2. Warner, K.E. Cigarette advertising and media coverage of

smoking and health. N Engl J Med 312(6):384-388, 1985.

p. 387.

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HMSO. 1967. 308 pp.

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and Advertising Act, for the Years 1982-1983. Washington, DC:

Federal Trade Commission, 1985. 50 pp.

Shopland, D. Personal communication. Acting Director, Office on

Smoking and Health, June, 1985.

Staff Report on the Cigarette Advertising Investiqation.

Washington, DC: Federal Trade Commission, 1981. 210 pp.

Teenage Smoking, Immediate and Long-Term Patterns. Rockville, MD:

Department of Health, Education, and Welfare, National Institute

of Education, 1979. 259 PP.

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Health, Office on Smoking and Health. Rockville, MD: 1980.

359 pp.

Warner, K.E. Cigarette advertising and media coverage of smoking

and health. N Engl J Med 312(6):384-388, 1985.

Whelan, E.M.; Sheridan, M.J.; Meister, K.A.; and Mosher, B.A.

Analysis of coverage of tobacco hazards in women's magazines. J

Public Health Policy 2:28-35, 1981.

Wong-McCarthy, W.J., and Gritz, E.R. Preventing regular teenage

cigarette smoking. Pediatr Ann 11(8):683-689, 1982.

Wooley, W., and Wooley, S. Feeling fat in a thin society: 33,000

Women tell how they feel about their bodies. Glamour Magazine.

February, 1984. pp. 198-252.

Yager, J. Introduction to section IV, eating disorders. Ann Rev

Amer Psychiat Assn 4:401-405, 1985.

Yankelovich, Skelly, and White, Inc. A Study of Cigarette Smoking

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ACKNOWLEDGEMENTS

This work was supported by PHS Grant No. 1-P50 CA36 409 awarded by

the National Cancer Institute, DHHS.

AUTHOR

Ellen R. Gritz, Ph.D.

Director

Division of Cancer Control

Jonsson Comprehensive Cancer Center

10920 Wilshire Boulevard, Suite 1106

Los Angeles, CA 90024

79
Gender Differences in

Drug Use: An Epidemiological

Perspective

Richard R. Clayton, Harwin L. Voss, Cynthia Robbins,

and William F. Skinner

The purpose of this paper is to

differences in drug use. This

of what is known about drug use

provide a broad overview of gender

is a formidable task because much

is based on studies of males.

Further, drug use is a heterogeneous phenomenon, involving a variety of drugs having effects that vary with circumstance. Specifically, this paper will examine:

the prevalence of use of several drugs by men and women in

different age groups (youth, 12 to 17 years old; young adults,

18 to 25 years old; mid-adults, 26 to 34 years old; and older

adults, 35 years old or older);

the use of psychotherapeutics medically and nonmedically, by

sex and age group; and

differences in age at onset of use of various drugs, by sex and

age.

The findings are based on data obtained in the 1982 National

Survey on Drug Abuse through personal interviews with 5,624

individuals 12 years old or older. Before examining these

specific issues, however, we will review the broader societal

context within which drug use and abuse by women has become a

topic of major concern for public health professionals.

THE SOCIETAL CONTEXT OF PUBLIC HEALTH ISSUES

Some social issues are, by nature, temporary, being prominent for

a period of time until the public turns its attention to other

concerns. During the early 196Os, under the banner of civil

rights, the twin issues of poverty and discrimination were prominent. During the late 1960s and early 1970s, the war in Vietnam

was the major issue. As historians describe the past they often

label eras by the issues that dominated the public's attention.

Thus, references to the "civil rights" era and the "Vietnam' era

invoke images that link us as individuals to forces at the

societal level that influenced our lives.

80
Other social issues are, by nature, lingering or perhaps permanent, remaining prominent over longer periods of time and sustaining the public's attention. One such issue is drug abuse,

which has been of growing public concern for almost two decades

since the epidemic of marijuana use emerged in the mid-1960s

(O'Donnell et al. 1976). One reason drug abuse has continued

salience may be that the "drug scene" appears as constantly In

flux. New drugs emerge, such as PCP and MDMA, or old drugs take

fashion, such as cocaine, and a new epidemic threatens the public

health.

Issues of public health and policy often link together, as new

issues are seen in the context of matters already of public-policy

concern. This has been the case for women's issues, ignored until

quite recently. The existence of a conference focused on gender

differences in drug use and abuse is one example of this linking

of issues.

This linkage is timely. In the past, drug abuse research has

focused too often exclusively on men, on only one class of drugs,

such as opiates. or on one type of user, such as addicts. One

cannot understand drug use and abuse in the United States by

studying only male opiate addicts, just as one cannot understand

alcohol abuse and problem drinking by studying only skid row alcoholics. In view of this, the mistakes of the past should not be

continued by focusing exclusively on drug use and abuse among

women, but rather both genders should be studied at the same time

to reveal differences and similarities. More can be learned by

studying gender as a variable, by comparing the patterns of drug

use of men and women, than by studying either sex alone. While a

few research questions are gender-unique in the drug field, for

Instance, the influence of drugs on the neuronal and hormonal

processes In the menstrual cycle (Mello, this volume), the majority of important questions about women's drug use and abuse are

best addressed from a comparative perspective, using gender as an

experimental variable.

BASIC ASSUMPTIONS

In addition to the assumption that a comparative approach offers

a promising way to examine drug use and abuse by women, several

additional assumptions underlie this paper.

First, production of knowledge takes time. The two national

institutes dedicated to the study of substance abuse, alcohol and

drug abuse, have been in existence for only 10 years. Instead of

chastising ourselves for how little is known about gender differences in drug use, a more constructive approach would be to note

how much has been learned in such a short time.

Second, while the differences between men and women have been of

interest to poets, novelists, and philosophers for many years,

only recently have social scientists devoted serious attention to

81
gender differences. The reason sex differences have been ignored

is simple. For most of human history the lives of men and women

were essentially on separate paths. There was a man's world and a

woman's world. Obviously, this situation has changed markedly in

the past 20 to 30 years. As options have expanded for both sexes,

men and women are doing things now that never would have occurred

in the past. There is considerable diversity in the behavioral

options available for both sexes and considerable overlap in those

options.

Finally, disciplinary disputes within the field of drug abuse

appear to be dissipating, and the various disciplines now acknowledge the relevance of fields besides their own. Sociologists, for

example, recognize that once the variables they consider to be

relevant have been measured, a substantial amount of variance in

drug use is left unexplained. The unexplained variance may be

accounted for by independent variables favored by other disciplines. This recognition accounts, in part, for the ascendance of

gender differences in drug use as important for public policy. By

focusing exclusively on men or women, information is lost about

gender as an independent variable affecting the dependent variable, drug use. Variance cannot be attributed to a constant.

EPIDEMIOLOGY AS AN ORGANIZING FRAMEWORK

The organizing conceptual framework for this paper is provided by

epidemiology, of which there are at least three types: classical,

psychiatric, and social. Classical epidemiology derives from a

medical orientation and has usually been employed to trace the

course of a disease through a population. Excellent examples of

the application of classical epidemiology in the study of drug

abuse are the investigations of De Alarcon (1969). Levengood et

al. (1973), and Hughes et al. (1971) on the spread of heroin

through communities.

Psychiatric epidemiology involves an application of classical

(medical) techniques of tracing the spread of a phenomenon through

a population, but adds diagnostic confirmational criteria to

validate and further describe the particular phenomenon under

study. For example, it may be important in studying drug use to

confirm whether a drug was taken medically or illicitly. As

Robins (1984) notes, what distinguishes drug abuse from infectious

diseases as the focus of epidemiological research is "the willingness of the host to participate, at least at first."

Social epidemiology, in this paper, is the conceptual framework

for examining gender differences in drug use. Social epidemiology

is generally survey-based and is focused on a large geopolitical

area rather than a single community. The principal functions of

such studies are to provide a description. not only of the extent

of the problem, but also its nature. The components as well as

the size of the problem are measured to detect new aspects of the

problem and to chart changes or trends. Social epidemiological

82
studies of drug use provide a picture of who is using what, at

what frequency, and with what acute consequences. Social epidemiology is more useful for generating than testing hypotheses. One

of the most useful functions of social epidemiological studies of

drug use is to evaluate the accuracy of cornnonsense perceptions of

the scope and nature of a social problem such as drug use.

LIFETIME PREVALENCE OF DRUG USE

Drug use is complex and difficult to study. The least precise,

but most frequently measured dimension of drug involvement is

lifetime prevalence, the use of one or more drugs over the course

of a person's life. The data in table 1 are of this kind and

show, by both gender and age group, the epidemic of drug use that

occurred in the United States beginning in the mid-1960s, the

epidemic related to the passage of the so-called "baby boom generation." Two of the age groups (18 to 25 and 26 to 34 years old)

roughly correspond to the baby boom birth cohorts, or persons born

in the years 1948 through 1964.

On the basis of earlier research, it would be hypothesized that

the lifetime prevalence of use of illicit substances will be

higher among males than females, while the prevalence of medical

use of psychotherapeutics will be higher among females than males

(Mellinger and Balter 1981; Yamaguchi and Kandel 1984).

Further, the prevalence rates for use of illicit drugs would be

expected to be higher for individuals in the two baby boom age

groups than for persons younger or older. Among youth, lower

rates would be anticipated because initiation of drug use is

developmental in character, building from one to several drugs

and from infrequent to more frequent use. Lower rates would be

expected among older individuals because they had entered adult

roles when the drug epidemic of the 1960s and 1970s began. On the

other hand, Mellinger and Balter (1981) suggest that the probability of using psychotherapeutic drugs increases with age, so that

the prevalence rates for these drugs might be expected to be highest in the oldest age category.

Checking these assumptions against the 1982 survey data, we find

agreement with expectations, with some exceptions. In table 1, 32

comparisons of males and females with respect to the use of illicit drugs can be made. The males, as expected, have the higher

prevalence rate except for categories of prescribed drugs, regardless of age group. Furthermore, the rates for use of illicit

drugs are higher in the two baby boom age groups, regardless of

gender, also as expected.

The instances in which the hypotheses are not supported are in the

use of prescription psychotherapeutics among youth, where in three

of the four comparisons, males have slightly higher rates of use

of prescription sedatives, stimulants, and analgesics. Females,

however, show higher use of prescribed tranquilizers in most

83
TABLE 1. Lifetime prevalence of various drugs by age group and

gender: 1982 Rational Survey on Drug Abuse

a. Youth, 12 to 17 years old in 1982, were born in 1965-70.

b. Young Adults, 18 to 25 years old in 1982, were born In 1957-64.

c. Mid-Adults, 26 to 34 years old in 1982, were born in 1948-56.

d. Older Adults, 35 years old or over in 1982, were born prior to 1948.

categories, as expected. If one allows for reasonable margins of

error, male and female youth do not differ in terms of lifetime

use of these four classes of drugs.

Contrary to expectations, the highest rates for psychotherapeutics

are not uniformly found among the respondents in the oldest age

group. It should be noted that the lifetime prevalence rates for

some of the psychotherapeutics are quite high. For example,

almost one-half of the females who are 35 or older have used tranquilizers medically, and 50 percent of these women have used analgesics medically. Further, the rates are somewhat higher among

the women 18 to 25 and 26 to 34. While it would be inappropriate

to interpret these data as evidence of abuse of these drugs, such

high prevalence rates show that a substantial proportion of women

age 35 and older are "at risk" for progression toward abusive

patterns of use. It is, therefore, important to examine the frequency or extent to which these four classes of drugs are used by

men and women, as well as how they are used (e.g., nonmedically

only, medically only, both medically and nonmedically).

84
FREQUENCY OF USE

There is little consensus regarding what constitutes frequent or

abusive use of drugs and, as one might expect, the criteria vary

by class of drug. Because the literature offers few guidelines,

an arbitrary decision was made to classify "more frequent" users

according to the following definitions:

for cigarettes, if they smoked a pack or more each day during

the preceding 30 days;

for marijuana, if they smoked during 10 or more days of the

past 30 days;

for alcohol, if they drank on 10 or more days of the past 30

days;

for cocaine, if they used on 5 or more days of the past 30

days.

The data shown in table 2 reveal that patterned differences by sex

exist when these criteria are applied. Almost three times as many

adult men as women report using marijuana on 10 or more days

during the preceding month. The ratio for alcohol use on 10 or

more of the past 30 days is about 2.7 to 1. Thus, gender differences in drug use exist and are in the expected direction for this

sample, whether the measure is lifetime prevalence or more

frequent use of licit and illicit drugs.

MEDICAL AND NONMEDICAL USE OF PSYCHOTHERAPEUTICS

Some classes of drugs serve legitimate medical functions and are

obtained primarily through prescriptions. These drugs can also be

used nonmedically, or in ways inconsistent with the physician's

instructions despite being obtained from a pharmacy. Persons who

obtain drugs other than by means of a prescription are nonmedical

users by definition, but it is also possible to misuse a properly

prescribed drug, which is to use it nonmedically. In the 1982

National Survey, questions were posed that dealt with the medical

and nonmedical use of sedatives, tranquilizers, stimulants, and

analgesics.

The data shown in table 3 provide evidence concerning gender differences in the use of psychotherapeutic drugs by age group. A

word of caution is necessary before these data are discussed. The

figures are percentages of those who have "ever used" the particular substances, not percentages of the total sample. With this

caveat in mind, the data in adjacent columns can be used to address important hypotheses about gender differences in drug use.

85
TABLE 2. Recent, more frequent use of cigarettes, alcohol,

marijuana, and cocaine, by age group and gender: 1982

National Survey on Drug Abuse

a. Youth, 12 to 17 years old in 1982, were born in 1965-70.

b. Young Adults, 18 to 25 years old in 1982, were born in 1957-64.

c. Mid-Adults, 26 to 34 years old in 1982, were born In 1948-56.

d. Older Adults, 35 years old or over in 1982, were born prior to 1948.

As predicted, women are generally more likely than men to report

medical use of psychotherapeutics except for youthful and older

respondents, where the gender difference is reversed or smaller.

Of the 16 comparisons, the only reversed gender difference is in

use of stimulants by youth, 29 percent of males compared to 17

percent of females, but small or near zero gender differences

appear for youth and older adults. It should be noted again that

these percentages refer only to those who have ever used stimulants, not to all youth.

Forgetting prescribed medical use for now to look at gender differences in nonmedical use of psychotherapeutics (table 3), we

86
TABLE 3. Percent of "ever users" of four classes of psychotherapeutics who report use nonmedically only, only by

prescription, and both medically and nonmedically by

age group and gender: 1982 National Survey on Drug

Abuse

a. Youth, 12 to 17 years old in 1982, were born in 1965-70.

b. Young Adults, 18 to 25 years old in 1982, were born in 1957-64.

c. Mid-Adults, 26 to 34 years old in 1982, were born in 1948-56.

d. Older Adults, 35 years old or over in 1982, were born prior to 1948.

find males predominating, as expected, except in three instances--

sedatives, stimulants, and analgesics among youth. but the significance of these exceptions has not been determined.

The expectation that males will be more likely than females to

report using these drugs both medically and nonmedically is supported by the data. Of 16 possible comparisons, two are exceptions to this expectation. Both exceptions occur for stimulants

87
for young and mid-adults and involve substantial differences

between males and females. Among young adults, only 1 percent of

the males who have used stimulants report having used both medically and nonmedically in comparison with 12 percent of the

females. Among mid-adults, 10 percent of males and 20 percent of

females use stimulants both medically and nonmedically.

Overall, these data confirm expectations based on the existing

literature concerning gender differences in the use of the psychotherapeutics. It is also apparent that persons in the older age

groups, particularly the oldest group, are most likely to have

used these drugs only in a medical context (see table 3). The exceptions to the expected patterns cluster in one class of drugs,

the stimulants. There is evidence from the survey of high school

seniors that the proportion of females using stimulants nonmedically for weight control has increased substantially during the

past 10 years (Johnston et al. 1985). This may account, at least

partially, for the high proportion of young females who report

that they used stimulants only nonmedically.

CONSEQUENCES OF USE OF PSYCHOTHERAPEUTICS

There is a commonsense but untested assumption that use of psychotherapeutics by women is related to role-related stress. Stated

differently, women are said to use these drugs in a quasi-medical

way to cope with or to alleviate stress. In the 1982 National

Survey on Drug Abuse, the respondents were asked if they had ever

experienced the following consequences as a result of using the

psychotherapeutic drugs: depression, argumentativeness, automobile accident, trouble at school, trouble at work, or a medical

emergency. In analyzing these data, the psychotherapeutics were

combined into three mutually exclusive categories: nonmedical

use, medical use, and both medical and nonmedical use. The questions had been posed with respect to specific drugs, but our

interest was in respondents experience of the consequence, regardless of the specific psychotherapeutic drug producing it. Age

was ignored because the number of positive responses was too small

for a meaningful analysis by age.

Looking at table 4, it is clear that respondents rarely attribute

adverse consequences to the use of psychotherapeutics. The most

prevalent consequence is depression, but it is reported by only

5.9 percent of the males and 7.1 percent of the females who had

ever used the psychotherapeutics. Respondents who used psychotherapeutic drugs both medically and nonmedically were more likely

to report depression and argumentativeness than subjects who used

drugs only medically or only nonmedically. There do not seem to

88
TABLE 4. Consequences attributed to use of psychotherapeutic

drugs (sedatives, tranquilizers, stimulants,

analgesics) by, type of use and gender: 1982 National

Survey on Drug Abuse

be differences between males and females, except for depression in

respondents who report only nonmedical use of psychotherapeutics.

Few people, however, reported any adverse consequences, and the

sample is too small for reliably measuring small differences.

AGE AT INITIATION OF DRUG USE

Although concern has been expressed that children are initiating

drug use at younger and younger ages, little research has focused

directly on age at onset. Virtually nothing is known about gender

difference in age at onset for abused drugs, including whether or

not it has changed over the years.

In the 1982 National Survey, respondents were asked to specify the

age of first use of various drugs. In presenting the data, a

decision was made to exclude persons between the ages of 12 and 19

because the usual age at onset for the "gateway drugs"--

cigarettes, alcohol, and marijuana--is presumed to occur during

the teens. By starting with persons who have already passed

89
through the period during which they are "most at risk," we avoid

the problem of confounding due to differential periods at risk.

Adjacent birth cohorts (e.g., 20 to 21, 22 to 23) were combined to

avoid the problem of small sample size in certain cells of the

table. It was decided not to present age at onset for age groups

in which less than 10 percent of respondents used the drug.

Finally, medians rather than means are presented because they are

less sensitive to outliers.

These data are relevant to important issues and questions of

public policy:

Is the age at onset of drug use decreasing? If so, for what

drugs?

Have the differences between males and females in age at onset

of drug use changed?

From an epidemiological perspective, is there evidence of an

age, period, or cohort effect with regard to age at onset of

drug use?

The data in tables 5 and 6 show, by gender, the median age at

onset of use, both medical and nonmedical, of a number of drugs

and drug classes--cigarettes, alcohol, marijuana, cocaine, sedatives, tranquilizers , stimulants, and analgesics. The ages shown

in these tables reflect midpoints--one-half of the subjects who

report use of that particular drug first used it earlier than the

age shown, while the other half used it later.

Cigarette and Alcohol Use

In every comparison between men and women for cigarettes and

alcohol, the median age at onset of use is higher for women than

it is for men (figure 1). The median age at onset for cigarettes

appears to be rising for males, the average median age being 13.6

for young respondents (12-19) compared to 12.8 for older respondents (58-65). The trend for women is the opposite, with the average median age being 14.5 for young respondents and 16.6 for older

respondents. It is important to note that although a greater

change occurred among women, the net result is a convergence in

the median age at onset of cigarette use for males and females.

This convergence depends on both women and men changing age at

first use (cigarettes) and in opposite directions.

9 0
TABLE 5. Median age at first use of various drugs: 1982 National Survey on Drug Abuse (males)
TABLE 5. Median age at first use of various drugs: 1982 National Survey on Drug Abuse (females)
FIGURE 1. Median age of onset of cigarettes for males and females

For alcohol, males show no change in their age at first use

(figure 2). For males, initial use of alcohol is a developmental

or age-specific phenomenon. For women, median age at first use of

alcohol has dropped an average of almost 2 years from the oldest

to the youngest four age groups. This suggests an influence of

era, a cohort effect, for females beginning to consume alcohol in

this society.

93
FIGURE 2. Median age of onset of alcohol for males and females

Marijuana and Cocaine

Three findings are apparent from examining the data for marijuana

in tables 5 and 6. First, men in only one age group have less

than 10 percent of respondents reporting marijuana use compared to

four such age groups for women. Second, for both men and women,

the median age at first use of marijuana is related to when the

respondents were born, with younger age groups starting use earlier than older respondents. This suggests either a cohort or a

period effect for marijuana use. Third, there is little difference by gender in the median age at onset of marijuana use. For

example, for each of the cohorts born between 1949-50 and 1961-62,

there Is less than a l-year difference between males and females

in onset of marijuana use.

94
For cocaine, also, there is a cohort or a period effect, with the

younger respondents using the drug earlier than the older age

groups. For females there are seven age groups in which less than

10 percent of the respondents report use of cocaine, while for

males there are four. The trend is toward younger men and women

starting use of cocaine. A separate analysis of data from the

1982 National Survey focusing explicitly on cocaine suggests that

an epidemic (i.e., period effect) of cocaine use occurred during

the late 1970s and early 1980s. In fact, 47 percent of the

respondents in the 1982 survey who had ever used cocaine used it

first in 1979, 1980, or 1981 (Clayton 1985).

Nonmedical Use of the Psychotherapeutics

Psychotherapeutics can be used medically or nonmedically, and

several conclusions may be drawn from the data regarding nonmedical use of these drugs. First, young females are the ones

likely to use these drugs nonmedically, whereas older males use

them nonmedically. For example, In only 1 of the 16 age groups

(22 to 23) do more than 10 percent of the female respondents re

port having used analgesics nonmedically. Only women in the five

youngest age groups contain more than 10 percent of respondents

reporting nonmedical use of sedatives and tranquilizers. For

tranquilizers, more than 10 percent report use in the three youngest age groups. Among these age groups, the median ages at onset

do not differ greatly. For stimulants, 9 of the 16 age groups

contain 10 percent or more women reporting nonmedical use, and

there is little difference in the age at onset in these groups.

Nonmedical use of the psychotherapeutics is more prevalent among

men, and, for each of the four psychotherapeutics, the median age

at onset is similar for the age groups of 20 to 21 through 30 to

31. It appears that age at onset of nonmedical use of psychotherapeutics represents a developmental phenomenon for males or a

societal trend away from recreational use of psychotherapeutics.

Among females, nonmedical use is not sufficiently prevalent to

justify a generalization.

Medical Use of the Psychotherapeutics

The clearest gender difference in medical use of psychotherapeutics is for stimulants. Among males, only 1 of the 16 age

groups has a prevalence above 10 percent. In contrast, females'

medical use of the stimulants is not a rare occurrence. The

median age at onset of stimulant prescriptions is essentially the

same for every age group from 20 to 21 through 30 to 31. This

finding is consistent with the notion that women in these age

groups use stimulants for dieting purposes. The reasons for use

of drugs are, however, not available from the 1982 survey data.

Looking now at medical use of sedatives, use is less prevalent

among males than females, just as it is for stimulants. For both

95
males and females, the median age at onset is lower for younger

age groups.

The same trend appears for medical use of tranquilizers and analgesics. Males and females show an earlier median age at onset for

the younger age groups. The age at onset for medical use of all

these drugs seems to be declining.

Onset of drug use is not exclusively an adolescent phenomenon, as

can be seen from the data presented in tables 5 and 6. For example, a substantial proportion (21.9 percent) of persons ever using

marijuana or cocaine first used after the age of 20. For males,

the percent starting at age 20 or later is 21.5; for females, it

is 22.8. Thus, the percentage of persons waiting until adulthood

to try these drugs does not differ significantly by gender. These

findings are not consistent with the widely held assumption that

reaching the age of 20 without having used these drugs assures a

future probability of initiation close to zero.

What accounts for this unexpected finding that runs counter to one

of the most commonly held assumptions in the drug abuse field?

Several possible answers exist. First, most data about when drug

use begins comes from samples of adolescents. The annual surveys

of high school seniors, for instance, is based on a sample aged 18

or under. To examine differences in age at onset, a full range of

ages must be studied. To our knowledge, the data pertaining to

age at onset gathered in the series of national surveys sponsored

by NIDA have yet to be analyzed. Second, an era effect may be

confused with a cohort effect. That is, a temporary epidemic of

drug use, in which the median age at onset of drug use differs

between age groups but is similar within age groups, can add to

evidence for adult initiation of drug use. This is in contrast to

a long-term cohort effect, whereby younger age groups show a longterm or permanent trend to use at an earlier age. One must examine the years in which new users appear in order to separate these

possibilities. It is possible that women will lag behind men by

an average of a year or more when the data are more closely

analyzed.

DISCUSSION

Patterns of drug use by gender, as analyzed here, confirm some

popular opinions. For example, measured in terms of lifetime

prevalence, rates of drug use are higher among males than females. In addition, males report more frequent and extensive use

of cigarettes, alcohol, marijuana, and cocaine than do females.

For the psychotherapeutic drugs, men are more likely to obtain

them nonmedically, while women are more likely to obtain these

drugs through medical channels. Median age at onset for older

women was at a later age than for men of comparable age.

96
Notable among the younger cohorts is an apparent convergence

between the sexes in the age at initiation of drug use. Specifically, the median age at onset of cigarette use has Increased

among men and decreased among women, eliminating any gender difference for respondents 33 or younger. For alcohol, males show a

stable median age at onset across a wide range of birth years.

Females, however, show a decreasing median age at onset that is

almost 2 years lower in the youngest cohorts than in the oldest

cohorts. The pattern of drug use of men and women is becoming

more similar according to these results, which comes as no great

surprise. The explanation of this convergence, however, remains

to be found.

Disconfirming a widely held belief that a person who does not

begin using marijuana during adolescence will not start after age

20, the data show that 22 percent of the respondents in the 1982

National Survey started using marijuana after age 20. No gender

differences show in the percentage of respondents who started to

use marijuana after 20, suggesting a period or era effect when

using the drug may have been the fashion. Although lifetime prevalence of marijuana use is sufficiently high in persons under 20

that one might suspect the rate was approaching maximum, over 20

percent of males and females begin use at a later age. For

cocaine, the figure is more striking, with almost 50 percent of

lifetime users starting after age 20. As with marijuana, males

and females show no differences in percent initiating cocaine use

after age 20. The important implication of this finding is that

prevention programs aimed only at the young miss a sizable portion

of the population at risk.

From the perspective of public policy, gender differences exist

for use of several drugs and should be considered in the development of prevention and treatment strategies. Treating the "drug

abuser," with little effort to tailor the program to the characteristics of the clients, is known to be inefficient in treating

patients with different psychiatric diagnoses. To the extent that

the gender variable determines patterns of drug use and abuse, it

is reasonable to expect that efficient treatment will attend to

these differences. The data reported in this paper show that men

and women do differ in both how they obtain and how they use

psychotherapeutic drugs.

The Federal research agenda for studying gender as a variable

affecting drug use and abuse can easily be accommodated and is an

important topic for public policy. Some of the gender effects in

substance abuse that require attention are:

the use of stimulants by women, particularly younger women, to

lose weight, and the relationship of such use to anorexia and

bulemia;

97
the near and long-term effects of drugs on the reproductive

process, including male reproductive biology, and the

implications for the public health of future generations;

the factors that account for higher levels of physician visits

and prescriptions for women compared to men;

the effects of women's changing role and increasing presence in

the labor force on "patterns" of drug use and abuse; and

the possible link between divorce and substance use.

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Room, R.G.W. Young Men and Drugs--A Nationwide Survey.

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Robins, L.N. The natural history of adolescent drug use. Am J

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98
ACKNOWLEDGEMENT

York on this paper was completed under the auspices of Contract

No. 271-84-7301 from the National Institute on Drug Abuse.

AUTHORS

Richard R. Clayton, Ph.D.

Professor

Department of Sociology

University of Kentucky

Lexington, KY 40506

Harwin L. Voss, Ph.D.

Professor

Department of Sociology

University of Kentucky

Lexington, KY 40506

Cynthia Robbins, Ph.D.

Assistant Professor

Department of Sociology

University of Kentucky

Lexington, KY 40506

William F. Skinner, Ph.D.

Assistant Professor

Department of Sociology

University of Kentucky

Lexington, KY 40506

99
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66 GENETIC AND BIOLOGICAL MARKERS IN DRUG ABUSE AND ALCOHOLISM.

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67 PROBLEMS OF DRUG DEPENDENCE, 1985. PROCEEDINGS OF THE 47TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. NCDAI out of stock

GPO Stock #017-024-01292-1 $18

68 STRATEGIES FOR RESEARCH ON THE INTERACTIONS OF DRUGS OF ABUSE.

Monique C. Braude, Ph.D., and Harold M. Ginzburg, M.D..J.D.,M.P.H.,

eds.

GPO Stock #017-024-01296-3 $6.50 NCDAI out of stock

69 OPIOID PEPTIDES: MEDICINAL CHEMISTRY. Rao S. Rapaka, Ph.D.;

Gene Barnett, Ph.D.; and Richard L. Hawks, Ph.D., eds.

GPO Stock #017-024-1297-1 $11

70 OPIOID PEPTIDES: MOLECULAR PHARMACOLOGY, BIOSYNTHESIS, AND

ANALYSIS. Rao S. Rapaka. Ph.D., and Richard L. Hawks, Ph.D., eds.

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71 OPIATE RECEPTOR SUBTYPES AND BRAIN FUNCTION. Roger M. Brown,

Ph.D.; Doris H. Clouet, Ph.D.; and David P. Friedman, Ph.D., eds.

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72 RELAPSE AND RECOVERY IN DRUG ABUSE. Frank M. Tims, Ph.D., and

Carl G. Leukefeld, D.S.W., eds.

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73 URINE TESTING FOR DRUGS OF ABUSE. Richard L. Hawks, Ph.D., and

C. Nora Chiang, Ph.D.. eds.

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74 NEUROBIOLOGY OF BEHAVIORAL CONTROL IN DRUG ABUSE. Stephen I.

Szara, M.D., D.Sc.. ed.

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75 PROGRESS IN OPIOID RESEARCH. PROCEEDINGS OF THE 1986 INTERNATIONAL NARCOTICS RESEARCH CONFERENCE. John W. Holaday, Ph.D.;

Ping-Yee Law, Ph.D.; and Albert Her-z. M.D., eds.

GPO Stock #017-024-01315-3 $21

76 PROBLEMS OF DRUG DEPENDENCE, 1986. PROCEEDINGS OF THE 48TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

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IN PRESS

77 ADOLESCENT DRUG ABUSE: ANALYSES OF TREATMENT RESEARCH.

Elizabeth R. Rahdert, Ph.D. and John Grabowski, Ph.D., eds.

U.S. GOVERNMENT PRINTING OFFICE: 1990-276-211/21013

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DHHS Publication No. (ADM)90-1447

Alcohol, Drug Abuse, and Mental Health Administration

Printed 1986. Reprinted 1987, 1990