ii

Introduction

About NIDA

The National Institute on Drug Abuse (NIDA) supports most of the world’s research on drug abuse and addiction. 

NIDA-funded research enables scientists to apply the most advanced techniques available to the study of every aspect of 

drug abuse, including:

•	 genetic, behavioral, and social determinants of vulnerability and response to drugs;

•	 short- and long-term effects of drugs on the brain, behavior, and addiction;

•	 other health and social impacts of drug abuse, including infectious diseases and economic costs;

•	 development and testing of medication and behavioral treatments for abuse and addiction; and

•	 development and research on effective messages to deter young people, in particular, from abusing drugs.

About NIDA Notes

This publication is a compilation of a sampling of articles focused specifically on Women and Sex/Gender Differences 

research reprinted from NIDA’s research newsletter, NIDA Notes. Published six times per year, NIDA Notes reports 

on important highlights from NIDA-sponsored research in a format that specialists and lay readers alike can read and put 

to use. Selections such as those contained herein are intended to remind regular NIDA Notes readers and inform other 

readers of important research discoveries during the periods they cover.

For more information

To subscribe to NIDA Notes and for further information on NIDA’s drug abuse and addiction research, please visit 

www.drugabuse.gov. For more information on NIDA’s Women and Sex/Gender Differences Research Program, please 

visit www.drugabuse.gov/WHGD/WHGDHome.html, which includes a comprehensive list of publications and videos 

specific to this important research area.
Prenatal Nicotine Exposure May Damage Receptors 

That Influence Auditory Processing 

(V22-3; April 2009)...................................................... 1

Brain Activity Differs in Cocaine Abusers According to 

Gender (V22-3; April 2009) ......................................... 3

Nicotine Dependence Is Linked With Mental Disorders 

in Pregnant Women (V22-2; December 2008)............. 4

Reducing Postpartum Drug Use 

(V22-2; December 2008).............................................. 5

Behavioral Problems Related to Maternal Smoking 

During Pregnancy Manifest Early in Childhood 

(V21-6; June 2008)....................................................... 6

Methamphetamine Restricts Fetal Growth, Increases 

Lethargy in Newborns (V21-6; June 2008)................... 9

Study Links Anabolic Steroids to Brain Changes in 

Adolescent Female Mice (V21-4; October 2007)........ 10

Adolescent Inhalant Use Is Stable Overall, but Rising

Among Girls (V21-4; October 2007).......................... 12

Studies Focus on Acculturation and Hispanic Youth 

(V21-2; February 2007).............................................. 13

Drugs Affect Men’s and Women’s Brains Differently 

(V20-6; June 2006)..................................................... 14

Community-Based Treatment Benefits 

Methamphetamine Abusers (V20-5; April 2006)........ 17

Studies Identify Factors Surrounding Rise in 

Abuse of Prescription Drugs by College Students 

(V20-4; March 2006).................................................. 19

Weighing Nicotine Replacement 

(V20-4; March 2006).................................................. 21

Disulfiram May Work for Men, but Not Women 

(V20-2; August 2005)................................................. 22

ATHENA Program Reduces Substance Abuse 

by Girls on High School Sports Teams 

(V20-1; August 2005)................................................. 23

Smoking Exposure In Utero Increases Risk of 

Later Addiction (V19-4; December 2004) .................. 25

Men and Women May Process Cocaine Cues 

Differently (V19-4; December 2004).......................... 27

Conference Provides Overview of Consequences of

Prenatal Drug Exposure (V19-3; September 2004)..... 29

Researchers Adapt HIV Risk Prevention Program for 

African-American Women (V19-1; April 2004).......... 30

The Neurobehavioral Legacy of Prenatal Tobacco 

Exposure (V18-6; February 2004)............................... 33

Gender and Ethnic Patterns in Drug Use Among 

High School Seniors (V18-2; August 2003)................ 36

Joint Treatment of PTSD and Cocaine Abuse

May Reduce Severity of Both Disorders 

(V18-1; June 2003)..................................................... 38

New Animal Model Simulates Human Exposure, 

Confirms Harm From Prenatal Cocaine 

(V18-1; June 2003)..................................................... 40

Substance-Abusing Adolescents Show Ethnic and 

Gender Differences in Psychiatric Disorders 

(V18-1; June 2003)..................................................... 42

Animal Studies Show Sex Differences in Impact 

of Efforts To Reduce Drug Seeking 

(V17-6; March 2003) .................................................. 45

Study Finds Significant Mental Deficits in 

Toddlers Exposed to Cocaine Before Birth 

(V17-5; January 2003)................................................ 47

Women and Smoking: Sensory Factors, Attitudes 

About Weight, Phase of Menstrual Cycle All Key To 

Quitting (V17-4; November 2002)............................. 49

Timing Quit Date May Help Women Smokers 

(V17-4; November 2002) ........................................... 51

Prenatal Exposure to Ecstasy May Impair Memory 

and Cognition (V17-3; October 2002)....................... 52

In Drug Abuse, Gender Matters 

(V17-2; May 2002)..................................................... 54

Prenatal Exposure to Methamphetamine Increases 

Vulnerability to the Drug’s Neurotoxic Effects in 

Adult Male Mice (V17-2; May 2002)......................... 56

High-Risk Sex Is Main Factor in HIV Infection 

for Men and Women Who Inject Drugs 

(V17-2; May 2002)..................................................... 58

Cocaine’s Effects on Cerebral Blood Flow Differ 

Between Men and Women (V17-2; May 2002).......... 60

Childhood Sex Abuse Increases Risk for Drug 

Dependence in Adult Women 

(V17-1; April 2002).................................................... 62

iii

Table of Contents
Biochemical Brain Abnormality Found in 

School-Age Children Prenatally Exposed to Cocaine 

(V16-4; October 2001)............................................... 64

Adolescents, Women, and Whites More 

Vulnerable Than Others to Becoming Nicotine

Dependent (V16-2; May 2001) .................................. 66

Maternal Smoking During Pregnancy Associated 

With Negative Toddler Behavior and Early Smoking 

Experimentation (V16-1; March 2001) ...................... 67

Women and Smokeless Tobacco Use 

(V16-1; March 2001).................................................. 69

Drug Abuse and Conduct Disorder Linked to 

Maternal Smoking During Pregnancy 

(V15-5; October 2000) .............................................. 70

Boys and Girls Encounter Different Drug Offers,

Use Different Refusal Strategies 

(V15-4; September 2000) ........................................... 71

Gender Differences in Drug Abuse Risks and 

Treatment (V15-4; September 2000).......................... 72

NIDA Initiative Targets Increasing Teen Use of 

Anabolic Steroids (V15-3; July 2000) ......................... 73

Marijuana-Like Compound in Womb May 

Influence Early Pregnancy (V15-1; March 2000)........ 75

UCLA Study Looks at Women in Treatment 

(V14-6; March 2000).................................................. 76

Female Rats Progress Quickly to Drug Abuse 

(V14-6; March 2000).................................................. 76

Support Group Improves Outcomes for

Pregnant Drug Users (V14-4; November 1999) ......... 77

Twin Studies Help Define the Role of Genes in 

Vulnerability to Drug Abuse 

(V14-4; November 1999) ........................................... 78

Gender Differences in Progression to AIDS 

(V14-3; September 1999) ........................................... 80

Study Shows How Genes Can Help Protect 

From Addiction (V13-6; March 1999) ....................... 81

Men and Women in Drug Abuse Treatment 

Relapse at Different Rates and for Different 

Reasons (V13-4; November 1998).............................. 82

Researchers Find Gender Differences In 

How Drug Abusers Respond To HIV 

Prevention Strategies (V13-4; November 1998).......... 84

Gender Affects Relationships Between 

Drug Abuse and Psychiatric Disorders 

(V12-4; July/August 1997) ......................................... 85

Women’s Dependence on Smoking Affected By 

Something in Addition to Nicotine 

(V12-3; May/June 1997) ............................................ 87

Cocaine Affects Men and Women Differently, NIDA 

Study Shows (V11-1; January/February 1996) ............ 89

Daughters of Mothers Who Smoked During 

Pregnancy are More Likely to Smoke, 

Study Says (V10-5; September/October 1995) ........... 91

Early Childhood Behavior and Temperament 

Predict Later Substance Use 

(V10-1; January/February 1995)................................. 93

iv
Research Findings

Volume XX, Number X (Month Year)

1

Prenatal Nicotine Exposure May Damage Receptors That Influence 

Auditory Processing

Tests correlate biochemical abnormality with deficits in rats’ responses to sounds.

By NIDA Notes Staff

Research Findings

Volume 22, Number 3 (April 2009)

Some children of women who smoked 

during pregnancy experience subtle difficulties processing auditory information; for example, they may have more

than average problems recognizing 

slightly garbled words or understanding speech in a noisy environment. 

A recent series of animal experiments 

indicates that the cause of the problem is not in the ear but in the brain: 

Nicotine exposure during development damages a set of receptors in the 

brain’s auditory processing center.

Hearing Versus Heeding 

The NIDA-funded experiments first 

demonstrated a deficit in sound processing in rats that had been exposed 

to nicotine at a developmental stage 

corresponding to that of a human fetus 

in the third trimester of gestation. Dr. 

Raju Metherate and colleagues at the 

University of California, Irvine, began 

by injecting rat pups with nicotine twice daily for 5 days 

(postnatal days 8 to 12). The injections produced nicotine

blood levels approximating those of smokers, and presumably of pregnant smokers’ fetuses. A group of same-aged 

control rats received injections of saline.

When the rats were 2 months old, a researcher trained 

them to escape an electrical shock by crossing from one 

chamber of an experimental box to another. The next 

day, a 5-second tone preceded each shock. All the animals 

immediately turned their heads toward the tone, indicating that they had heard it. Over 4 days, the rats had the

opportunity to learn that the tone signaled an impending 

shock.

By the end of the training, all but one of the 12 control 

animals had learned the lesson well enough to routinely 

avoid the shock by crossing into the safe chamber during 

the tone. These animals moved to the safe chamber more 

rapidly as time went on, and eventually, many went into 

the safe chamber as soon as the tone began. Just 6 of the

11 rats exposed to nicotine, however, learned to associate 

the tone with the shock, and they responded more 

slowly than the control animals. The remaining 5 

nicotine-exposed rats moved to the safe chamber only 

after receiving the shock.

A Less Responsive Cortex

The UC-Irvine researchers’ next experiment linked the 

nicotine-exposed rats’ poorer responses to warning tones 

to a difference in the animals’ brains.

The auditory cortex is the brain’s primary area for interpreting sounds. Normally, nicotine amplifies the cortex’s 

responsiveness to auditory inputs. Researchers measure 

this effect by comparing electrical activity levels in the cortex before and after an injection of the drug.

Using this protocol when their rats were 2 to 3 months of 

age, Dr. Metherate’s team documented smaller increases 

in cortical activity levels, on average, in the animals with 

early exposure to nicotine than in the control animals. 

Among adult rats not exposed to nicotine as pups, a 

1
2

stronger auditory cortex response to nicotine at 2 to 3 

months of age correlated with faster and more accurate 

learning to associate sound with electrical shocks. These 

observations may provide a hint why rats’ early nicotine 

exposure leads to later difficulty using warning tones.

Underdeveloped Receptors

The researchers next investigated the underlying mechanism for their nicotine-exposed rats’ diminished cortical 

responsiveness. The findings indicated that nicotine exposure during early development prevents a key receptor in 

the brain’s acetylcholine signaling system from achieving 

full functionality.

Nicotine binds to the same receptors as acetylcholine, a 

chemical that neurons in the auditory cortex and elsewhere use to transmit electrical excitation to neighboring neurons. “When nicotine or acetylcholine binds to a 

receptor on the surface of a nerve cell, the binding process 

sets off chemical reactions inside the cell that help the cell 

function properly and fulfill its special physiological role,” 

Dr. Metherate says.

The researchers measured electrical activity in the auditory 

cortex before and after injecting 2- to 3-month-old rats 

with mecamylamine, a compound that shuts down the 

nicotinic acetylcholine (nACh) receptors. The injection 

markedly reduced electrical activity in normal rats but 

made little difference in the rats that had been exposed 

to nicotine shortly after birth. This finding indicates that 

their nACh receptors were ineffective.

“Somehow, early nicotine exposure disconnects the receptors from the inside of the cell,” Dr. Metherate says. 

“Acetylcholine and nicotine bind to the cell surface, but 

no chemical reactions take place in the interior.”

A Clue and a Caution

Because human and rat brains process sounds similarly, 

the UC-Irvine findings may relate to the problems that 

people prenatally exposed to nicotine have interpreting 

sounds, and the experimental results may provide a clue to 

effective treatments as well. “If we can figure out how to 

reconnect the receptors to the activity inside the cells, we 

may be able to reverse these auditory-cognitive deficits in 

children, adolescents, or even adults,” Dr. Metherate says.

He adds that nACh receptors also play a role in the development of other parts of the brain, including cortical areas 

that process vision and touch. So, prenatal nicotine exposure may undermine brain activity in those areas as well.

“Even though Dr. Metherate’s rats were exposed to nicotine for only 5 days, the damage to their brains was longlasting,” says Dr. Thomas Aigner of NIDA’s Division 

of Basic Neuroscience and Behavioral Research. “This is 

important information for women who think that smoking only intermittently during pregnancy is safe for the 

fetus. If they smoke during a critical period of brain development, in this case a few days into the third trimester, it 

looks as though the nicotine exposure can produce serious 

and long-lasting damage.”

Sources

•	 Liang, K., et al. Neonatal nicotine exposure impairs

nicotinic enhancement of central auditory processing 

and auditory learning in adult rats. European Journal 

of Neuroscience 24(3):857-866, 2006.

•	 Liang, K., et al. Nicotinic modulation of tone-evoked

responses in auditory cortex reflects the strength of 

prior auditory learning. Neurobiology of Learning and 

Memory 90(1):138-146, 2008.
Research Findings

Volume XX, Number X (Month Year)

3

Brain Activity Differs in Cocaine Abusers According to Gender

Volume 22, Number 3 (April 2009)

Cocaine abusers have reduced neural activity in the orbitofrontal cortex (OFC), a brain region that mediates decisionmaking. NIDA-funded researchers have discovered 

that gender determines where in the OFC the dampening

occurs.

Dr. Bryon Adinoff and colleagues at the University of 

Texas Southwestern Medical Center and the Veterans 

Affairs North Texas Health Care System measured OFC

neural activity, as indicated by blood flow, of 35 people 

who had used cocaine for 12 years, on average, but had 

been abstinent for 2 to 4 weeks. They compared the 

results with measurements from 37 people who had never

used the drug. The researchers found that the OFC contributed a smaller portion of total brain activity in cocaine 

abusers than in nonabusers. However, the relative deficit 

was in the lateral OFC in men and in the medial OFC in

women.

“One can hypothesize that sex differences in regional

blood flow may give rise to contrasting behavioral 

responses,” says Dr. Adinoff. Such differences might arise 

because the areas most affected in each gender support 

different behaviors. For example, brain scans of people 

who do not use drugs have suggested that the lateral OFC

is active when people refrain from doing something that 

they anticipate will have a bad outcome. In contrast, the 

medial OFC engages when people take action to try to

achieve a desired result.

The depressed neural activity in the lateral OFC among

men who abuse cocaine may lead to problems putting 

the brakes on behaviors with bad outcomes and so hinder 

their ability to abstain, says Dr. Adinoff. The less active 

medial area in women may reflect a blunted drug reward, 

he adds.

While his findings are likely to be relevant for individuals in early abstinence, Dr. Adinoff notes that they may 

not apply to individuals in later stages of recovery. “The 

participants in our study had only been abstinent 2 to 

4 weeks,” he says. “Scientists need to examine whether 

the depressed neural activity we observed among cocaine 

abusers recovers with long-term abstinence.”

“Future research might examine whether regional differences influence treatment strategies and recovery success,” 

notes Dr. Harold Gordon of NIDA’s Division of Clinical 

Neuroscience and Behavioral Research.

Dr. Adinoff concurs, suggesting that through understanding these differences, treatment providers may eventually 

be able to tailor gender-specific therapies that promote 

abstinence.

Source 

•	 Adinoff, B., et al. Sex differences in medial and lateral

orbitofrontal cortex hypoperfusion in cocaine-dependent men and women. Gender Medicine 3(3):206-

222, 2006.

3
Research Findings

Volume 22, Number 2 (December 2008)

4

Nicotine Dependence is Linked With Mental Disorders in 

Pregnant Women
Reducing Postpartum Drug Use

Research Findings

Volume 22, Number 2 (December 2008)

In a recent clinical trial, a 20-minute computerized intervention reduced new mothers’

drug abuse in the first 4 months postpartum. The computer software program, which 

was developed by Dr. Steven J. Ondersma and colleagues at Wayne State University in

Detroit and Virginia Commonwealth University in Richmond, was administered in an 

urban obstetric hospital soon after each woman gave birth. The program features an animated narrator who asks questions, addresses ambivalence, provides feedback, and offers 

options. The intervention also included vouchers for an initial session of drug treatment 

and an easy-to-read brochure, mailed to the women after they took their babies home, that 

discussed infant and maternal health and briefly addressed drug abuse. The researchers 

estimated that the intervention had a “small to moderate” beneficial effect in their study 

population—107 mostly poor women who abused drugs. At a 4-month followup, those

who received the intervention reported using cocaine, amphetamine, and opiates less frequently than before the birth, while the comparison group reported slightly increased abuse of these drugs. No definitive 

differences were observed between the two groups regarding marijuana use.

Source

•	 American Journal of Preventive Medicine 32(3):231-238, 2007.

5
Research Findings

Volume XX, Number X (Month Year)

6

Behavioral Problems Related to Maternal Smoking During 

Pregnancy Manifest Early in Childhood

Researchers find probable precursors of adolescent conduct disorders in the behavior of toddlers and 

schoolchildren.

By NIDA Notes Staff

Research Findings

Volume 21, Number 6 (June 2008)

Many studies have established that a pregnant woman’s 

smoking raises her child’s risk of disruptive behavior disorders and of delinquency in the teen and young adult years, 

but its behavioral effects in early life have been been difficult to trace. Now, however, NIDA-funded researchers have 

revealed associations between a child’s in utero exposure to 

smoking and specific patterns of aberrant behavior as a toddler, at school age, and as a teen. The researchers propose 

that these patterns form a continuum, united by an underlying theme of disrupted social information processing.

An Early Start to Disruptive Behavior 

In an initial study, Dr. Lauren Wakschlag of the Institute 

for Juvenile Research at the University of Illinois at

Chicago and her colleagues, Dr. Rolf Loeber of the 

University of Pittsburgh and Dr. Kate Pickett of The 

University of York in England, analyzed disruptive behavior patterns in first graders and subsequent problems that 

have been associated with later delinquency. Data were 

derived from the first-grade cohort of the Pittsburgh 

Youth Study (PYS), a community sample of boys at risk 

for delinquency who were followed over several decades 

under the direction of Dr. Loeber.

The researchers concentrated on 448 boys, who were

roughly age 7 when the PYS study began. One hundred

and sixty-six boys in this group had mothers who smoked 

during pregnancy. These boys developed the antisocial 

behavior pattern known as oppositional defiant disorder (ODD) at more than double the rate of the rest (see

graph). Children with ODD demonstrate defiant, disobedient, and hostile behavior towards authority figures that 

persists for at least 6 months, and they are touchy, easily 

angered, and resentful. ODD is often considered a developmental precursor of conduct disorder (CD), a condition 

in older children and adolescents characterized by persistent antisocial behaviors such as lying, truancy, vandalism, 

and aggression.

Boys whose mothers smoked while pregnant did not 

have a higher incidence of attention deficit hyperactivity 

disorder (ADHD) without ODD than the nonexposed

boys. However, the incidence of co-occurring ODD and

ADHD—a combination that often results in chronic 

disruptive behavior problems—was nearly twice as high 

in the exposed group as in the nonexposed group. As 

the boys entered and traversed their teens, delinquent 

behavior began earlier and was more severe in the exposed 

group.

“All the children with ODD in the PYS study were diagnosed in first grade, meaning the disorder developed in 

the first 5 or 6 years of life. This provides evidence of a 

coherent developmental pathway from prenatal exposure 

to cigarettes to a subsequent sequence of conduct problems,” Dr. Wakschlag says. “While previous research 

established a link between prenatal exposure to cigarettes 

6
7

and CD in older children, this study is the first to establish connections to ODD and to do so as early as first

grade.”

Toddlers With Troubles

To look for exposure-related behavioral abnormalities at 

even younger ages, Dr. Wakschlag’s team conducted the 

Family Health and Development Project (FHDP), in collaboration with colleagues from the University of Illinois, 

The University of York, the National Institute of Mental 

Health, and the University of Massachusetts-Boston. The 

researchers recruited 96 expectant mothers, age 18 and

older, at several clinics. The women were predominantly 

white and working class. Along with the women’s selfreports, the researchers collected biological data, such 

as measurements of the nicotine metabolite cotinine in 

urine samples, to assess fetal exposure to maternal smoking. These measurements, taken three times during pregnancy, indicated that 47 percent of the women smoked

throughout their pregnancies. Ninety-three infants and 

their mothers completed the study’s developmental phase, 

which lasted until the babies were 24 months old.

The babies were evaluated every 6 months. At the 12-, 

18-, and 24-month evaluations, each mother filled out the

Infant-Toddler Social Emotional Assessment (ITSEA). 

During 20-minute laboratory observations of the toddlers

and their mothers interacting at 24 months, the researchers rated specific components of the toddlers’ behavior 

using codes from the Disruptive Behavior Diagnostic 

Observation Schedule.

The results indicated that toddlers whose mothers had 

smoked during pregnancy demonstrated a high and 

escalating pattern of disruptive behavior from 12 to 24 

months, whereas nonexposed toddlers exhibited a relatively stable pattern. A mother’s smoking during pregnancy increased the likelihood of the observed atypical 

trajectory of behavior independent of several associated 

risk factors, including parental antisocial behavior, quality 

of parenting, and postnatal exposure to tobacco smoke. 

At 24 months, toddlers whose mothers had smoked while 

pregnant were more than 11 times as likely as nonexposed 

peers to exhibit clinically significant patterns of disruptive 

behavior, shown on the ITSEA.

To more precisely determine the nature of the boys’ 

behavior problems, the researchers examined four components of disruptive behavior, each of which is considered a 

precursor to disruptive behavior patterns seen at later ages:

•	 Aggressive/destructive behavior, including threatening, hitting, and throwing or smashing toys;

•	 Dysregulated negative affect, characterized by

persistent, uncontrolled outbursts of anger with loud 

yelling, intense crying, and temper tantrums;

•	 Stubborn defiance, marked by obstructive behavior

that persists after the mother has increased expressions 

of support for her child and has tried several strategies 

to change her child’s behavior; and

•	 Low social competence, where the child misses social

cues and exhibits low social interest or concern. 

These four behaviors, while viewed as normal in toddlers, 

are considered precursors to clinical problems if they are 

severe or pervasive.

The children whose mothers had smoked during pregnancy displayed lower social competence than other children and significantly higher levels of aggressive/destructive behavior and stubborn defiance. They were not more 

likely to exhibit dysregulated negative affect.

“Dr. Wakschlag has teased out some components of disruptive behavior problems when they first emerge between 

18 and 24 months of age,” says Dr. Nicolette Borek of

NIDA’s Division of Clinical Neuroscience and Behavioral 

Research. “This gives us a way to identify at-risk children 

early and raises interesting questions about the role of 

brain development in later-stage behavioral issues.”

On to Adolescence 

Dr. Wakschlag and colleagues have hypothesized that the 

resistant, hostile, and unresponsive patterns of behavior 

demonstrated in FHDP, PYS, and similar studies may 

reflect disruptions in social-information processing that 

resulted from prenatal exposure to cigarette smoke. To 

test this hypothesis, the team is conducting the NIDAfunded East Boston Family Study (EBFS), which includes 

272 adolescents and is a followup to the Maternal-Infant

Smoking Study of East Boston (MISSEB). Dr. Wakschlag 

and her colleagues are also examining the influence of 

genetic makeup on exposure-related disruptive behavior 

among these young people. The researchers are using 

maternal exposure data originally collected by MISSEB 

but applying more sophisticated methods to measure prenatal exposure to cigarette smoke. These new techniques, 

which combine maternal self-report and biological data, 

were developed from FHDP-derived data by Dr. Vanja 

Dukic at the University of Chicago in collaboration with 

Dr. Neal Benowitz of the University of California, San 

Francisco and Dr. Wakschlag.

“Maternal self-reports are affected by memory lapses and 

social pressure not to smoke, and biological methods can 

be inaccurate because the smoke-derived chemicals have 

a short half-life and rates of metabolism differ among 

individuals,” says Dr. Wakschlag. “In addition, we know 

that smoking levels fluctuate throughout a pregnancy. The 

new technique incorporates the unique information from 

both of these methods to provide a more precise estimate 

of prenatal exposure to cigarettes.”
8

Sources

•	 Wakschlag, L.S., et al. A developmental framework

for distinguishing disruptive behavior from normative 

misbehavior in preschool children. Journal of Child 

Psychology and Psychiatry and Allied Disciplines 48(10;

Special Issue on Preschool Psychopathology):976-987,

2007.

•	 Wakschlag, L.S., et al. Is prenatal smoking associated

with a developmental pattern of conduct problems in 

young boys? Journal of the American Academy of Child 

and Adolescent Psychiatry 45(4):461-467, 2006.

•	 Wakschlag, L.S., et al. Elucidating early mechanisms

of developmental psychopathology: The case of prenatal smoking and disruptive behavior. Child 

Development 77(4):893-906, 2006.
Methamphetamine Restricts Fetal Growth, Increases Lethargy 

in Newborns

Research Findings

Volume 21, Number 6 (June 2008)

A NIDA-funded study 

found that newborns whose 

mothers abused methamphetamine during pregnancy showed higher rates 

of growth restriction compared with unexposed newborns. Dr. Barry M. Lester 

and colleagues at Brown 

Medical School and other 

institutions analyzed data 

from 1,618 mother-infant pairs, 84 of whom were methexposed. The meth-exposed newborns weighed 3,174

grams (7 pounds), on average, versus 3,381 grams (nearly

7.5 pounds) for unexposed newborns. The meth-exposed

newborns also had a lower gestational age at birth (38.7

weeks versus 39.2 weeks). Although most infants were full

term, methamphetamine infants were 3.5 times as likely 

to be small for gestational age—a finding that suggests 

fetal growth restriction.

In a followup with 166 infants from the study, the 

researchers assessed the newborns’ behavioral capabilities 

within the first 5 days of life. The 74 meth-exposed newborns showed greater lethargy and were more difficult to 

awaken than the 92 unexposed newborns. Once aroused,

however, meth-exposed newborns also showed a sign of 

physiological distress—difficulty maintaining normal, regular breathing. The differences held when the researchers 

took into account factors known to affect fetal growth, 

including maternal smoking and other drug abuse and 

socioeconomic status. In addition, higher concentrations 

of methamphetamine in samples of the babies’ stool were 

related to increased central nervous system stress. 

9
Study Links Anabolic Steroids to Brain Changes in Adolescent 

Female Mice

Research Findings

Volume 21, Number 4 (October 2007)

Anabolic androgenic steroid (AAS) 

abuse, once largely limited to elite athletes, has spread to a wider population 

that includes adolescents along with 

adults, and girls as well as boys. While 

the psychological and behavioral 

consequences of AAS use presumably reflect its impact on a number of 

brain areas, a NIDA-funded study at 

Dartmouth Medical School has identified one neurobiological effect that has 

potentially important implications for 

the emotional stability and well-being 

of adolescent girls in particular.

Principal investigator Dr. Leslie 

Henderson and colleagues studied the 

effect of the AAS, 17a-methyltestosterone (17a-MeT), on the activity of 

the neurotransmitter gamma-aminobutyric acid (GABA) 

in adolescent mice. Loosely speaking, GABA acts as a 

calming agent throughout the nervous system: It dampens activity of the neurons to which they are connected. 

Specifically, the researchers focused on the steroid’s 

impact on GABA functioning in the medial preoptic area 

(MPOA) of the basal forebrain, a region that participates

in the regulation of sexual behavior, anxiety, and aggression. They found that in female, but not male, animals 

the AAS interfered with GABA transmission in the area. 

Theoretically, this effect would reduce GABA’s inhibitory 

influence and thus potentially contribute to the excessive 

emotions and behaviors seen in AAS abuse. Various studies have linked increased anxiety and aggression, and both 

increased and decreased libido to AAS use.

“The GABA system isn’t the only target for the effects of 

AAS, but it is likely an important one,” Dr. Henderson 

says. “Going into the experiment, we assumed we’d see an 

anabolic steroid effect on the GABA system in the MPOA

and expected there would be differences between males 

and females.” This area of the brain, particularly the cluster of neurons within it called the medial preoptic nucleus 

(MPN), is structurally different in the sexes.

Drug Targets Receptors

The researchers injected mice with a solution of 17aMeT in sesame oil, in doses (7.5 mg/kg/d) that would

correspond to those taken by humans who are abusing 

the drug heavily. They injected a control group of mice 

with the sesame oil vehicle alone. The researchers examined brain tissue from half the mice in each group after 3 

weeks of treatment and from the other half after 6 weeks. 

They focused on the subunits that make up GABA type 

A receptors (GABAA) in cells of the MPN and on the way 

that AAS exposure affected the function of these receptors. 

Each receptor contains five of these subunits, proteins 

that determine the receptor’s sensitivity to drugs and 

hormones.

To test how the reduction in a2 subunit production 

might affect GABAA receptor function, the researchers measured the amplitude and frequency of inhibitory 

postsynaptic currents (IPSCs)—a measure of the receptor’s efficacy in inhibiting the activity of neurons—in the 

MPN. Here, too, they found sex-based differences that 

were magnified by AAS. In untreated mice, the IPSCs 

were smaller in amplitude in females than in males. 

Female mice that received 3 to 4 weeks of AAS displayed 

smaller and less frequent currents than controls, suggesting that exposure to the drug had reduced GABAA receptor function, thereby widening the gender gap. There was 

no comparable change in males.

The researchers concentrated on the a2 subunit family, 

which earlier studies had shown that 17a-MeT alters. 

Before treatment, levels of messenger RNA (mRNA) for 

the a2 subunit were lower in female than in male mice in 

cells of the MPN. After 6 weeks, a2 subunit mRNA—an 

10

Effects on Relative Levels of GABA Receptor mRNA The researchers measured the effects induced by anabolic 

androgenic steriods (AAS) on GABAA receptor subunit mRNA levels for male and female mice treated with 17a-MeT for 3 

(blue) or 6 (purple) weeks. Six weeks of AAS exposure decreased the amount of one the a subunits of the receptor a2 

only in female mice. No significant effects were observed in the treated male mice.
11

indicator of the quantity of the subunit being produced—

had declined by 37 percent in female mice treated with

the AAS compared with controls, but was essentially 

unchanged in males. When the researchers measured the 

actual protein that makes up the a2 subunit in female 

mice, they found a small but significant reduction (8 percent) in the number of neurons containing a2 protein.

Chronic exposure to the AAS augmented gender differences in both the structure and function of certain GABA 

receptors, Dr. Henderson says. “Overall, the effect was

to decrease GABA transmission in the MPN of female, 

but not male, adolescent mice. This would presumably 

increase the level of activity or change the pattern of activity in postsynaptic neurons of the female mice.”

A Closer Look

How do these neurobiological changes contribute to the 

behavioral manifestations of AAS abuse? “It could be that 

an AAS that promotes aggression in males would promote 

it more in females, or have different effects on the expression of sexual behaviors, but this is something we are 

just beginning to explore,” Dr. Henderson says. “What’s 

more, there are 60 to 100 AAS, and their neurobiological

effects are unlikely to be uniform. In time, we may be able 

to start parsing out whether certain commonly abused steroids are likely to amplify aggression and libido in women 

or in men while others affect both genders equally.”

Dr. Henderson notes that alterations in GABAA receptor 

function could have other important effects as well. “The 

GABAA receptor is a major target of many drugs, including alcohol and benzodiazepines. Changing the subunit 

composition could alter the brain’s sensitivity to these 

chemicals.”

“Although this is a basic research study, its potential translation to humans, even if speculative, is striking,” says Dr. 

Pushpa Thadani, formerly of NIDA’s Division of Basic 

Neuroscience and Behavioral Research. “It demonstrates 

that AAS exposure in the adolescent period produces 

gender-specific changes at the molecular level that may be 

correlated with known behavioral outcomes.”

Although applying findings from this and similar studies 

in actual interventions remains a distant goal, “these studies advance our understanding of the actions of AAS on 

the brain and behavior, which can empower us to better 

educate the lay public on the harmful effects associated 

with abuse,” Dr. Thadani says. “The research is still in its 

infancy,” she observes. Other studies, now under way, are

seeking to clarify the links between aggression in female 

mice and AAS-associated neurobiological changes. “When 

these findings are available, we’ll probably be in a better 

position to translate this information into the 

human arena.”

Source

•	 Penatti, C.A.A., et al. Sex-specific effects of chronic

anabolic androgenic steroid treatment on GABAA

receptor expression and function in adolescent mice. 

Neuroscience 135(2):533-543, 2005.
Adolescent Inhalant Use Is Stable Overall, but Rising Among Girls

Research Findings

Volume 21, Number 4 (October 2007)

Almost 5 percent of girls between the ages of 12 and 17

used an inhalant to get high in 2005, an increase from

4.1 percent in 2002, according to a new report. Overall,

inhalant use by boys and girls in this age group remained 

stable over the 4-year period, at an average annual rate of 

4.5 percent, or an estimated 1.1 million adolescents.

The report, “Patterns and Trends in Inhalant Use by 

Adolescent Males and Females: 2002-2005,” is based on

an analysis of the 2002-2005 National Household Survey

on Drug Use and Health, an annual survey sponsored 

by the Substance Abuse and Mental Health Services 

Administration (SAMHSA). SAMHSA, NIDA, and other 

federal agencies released the report at a March 15 press 

conference to kick off the 15th National Inhalants and 

Poisons Awareness Week, March 18-25.

“Young people who turn to inhalants may be completely 

unaware of the serious health risks,” said NIDA Deputy 

Director Dr. Timothy P. Condon. “We know that inhalant abuse can start early, with research suggesting that 

even preadolescent children seek them out because they 

are easy to obtain. NIDA research also indicates that those 

who begin using inhalants at an early age are more likely 

to become dependent on them—and long-term inhalant 

abusers are among the most difficult drug abuse patients 

to treat.”

The report is available at www.drugabusestatistics.samhsa.

gov/2k7/inhalants/inhalants.pdf.

12
Studies Focus on Acculturation and Hispanic Youth 

Research Findings

Volume 21, Number 2 (February 2007)

U.S.-Born Hispanic 

Women Have More 

Drug Problems Than 

Immigrants: Among 

19-to 21-year-old

Hispanic women in 

South Florida, those 

born in the United States 

face a higher risk of drug 

addiction than immigrants, according 

to a recent study by 

Dr. R. Jay Turner and

colleagues. The U.S.-

born women reported more acculturation, measured as 

preference for English over Spanish, and greater exposure 

to stressful events, both of which were associated with 

increased risk for addiction. The gap in acculturation 

between the two groups accounted for 40 percent of the

risk difference; a high score on either acculturation or

stress exposure was associated with a nearly three-fold 

increase in the odds of addiction, compared with low 

scores on those measures (evaluated at one standard deviation above and below average). The investigators speculate 

that cultural influences help protect foreign-born Hispanic 

young women from stress. Native-born and immigrant 

young men reported similar levels of stress exposure and 

had similar rates of addiction.

Source

•	 Drug and Alcohol Dependence 83(1):79-89, 2006.

Latino Parent Training: Men and women who completed a parent-training program adapted for Latino culture 

reported improvements in effective parenting practices 

and their children’s (aged 13 years, on average) behavior 

compared with those who did not receive the intervention. Children whose parents received the program also 

reported that they were less likely to abuse tobacco, marijuana, and other drugs in the future. The parents also said 

their children’s behavior improved.

Drs. Charles R. Martinez and J. Mark Eddy of the

Oregon Social Learning Center randomly assigned 73

Spanish-speaking Latino parents (90 percent were of

Mexican heritage) to participate in Nuestras Familias: 

Andando Entre Culturas (Our Families: Moving Between

Cultures) or to receive no intervention. During each of 12 

weekly 2.5-hour sessions, participants in the intervention 

group discussed developing effective family communication, bridging cultures, being positive, and encouraging 

success using appropriate discipline and limit setting, and 

practiced parenting techniques in role-play.

Source

•	 Journal of Consulting and Clinical Psychology

73(5):841-851, 2005.

13
14

Drugs Affect Men’s and Women’s Brains Differently

Gender appears to influence biological responses to nicotine, cocaine, and alcohol.

By Carl Sherman, NIDA NOTES Contributing Writer

Research Findings

Volume 20, Number 6 (June 2006)

Two recent NIDA-funded studies cast new light on men’s 

and women’s different responses to nicotine, cocaine, 

and alcohol. Dr. Steven G. Potkin and colleagues at the 

University of California (UC), Irvine, demonstrated 

that various brain regions are more strongly activated in 

women than in men while they perform certain tasks, 

and that nicotine equalizes the response. Dr. Elinore F. 

McCance-Katz and colleagues at the Medical College of 

Virginia found that women registered greater feelings of 

physical and mental well-being than men after receiving 

cocaine and had higher heart rates after drinking alcohol.

Brain Effects of Nicotine

Men and women abuse the same drugs, but not always in 

the same ways. When women smoke cigarettes, they take 

shorter and fewer puffs and experience improvements in 

mood that men do not. Women generally are less successful in quitting. To the UC Irvine study team, these behavioral and experiential differences suggested that nicotine 

might affect men’s and women’s brains differently.

Using positron emission tomography (PET), the researchers tracked brain metabolism in 42 women and 

77 men (55 smokers and 64 nonsmokers) while they performed two tasks. In the Continuous Performance Task 

(CPT), a test of vigilance, the study participant watched 

a series of numbers flashed on a screen and pressed a button when certain figures appeared. The objective of the 

Bushman Competition and Retaliation Task (BCRT) was 

to provoke an aggressive response: The participant and 

an unseen opponent (actually a computer) competed in 

a test of reaction time, with the loser receiving a blast of 

noise whose volume and duration were determined by the 

winner. When the participant lost, which was always the 

case in early rounds, he or she was shown the noise level 

that his or her opponent had set; when participants finally

won, they could choose how loud and long to blast the 

opponent back. Participants performed each task once 

with a placebo patch and once with a transdermal 

nicotine patch.

When smokers performed the CPT wearing the placebo 

patch, women’s brain metabolism was significantly higher 

than men’s, particularly in the cortical and subcortical prefrontal systems—areas associated with choice, attention, 

executive function, mood, and memory. These differences 

largely disappeared when participants wore the nicotine 

patch: Brain metabolism increased for men and decreased 

for women. Among nonsmokers, there was little difference 

in brain activity in men and women while performing the 

CPT, either with the nicotine patch or with placebo.

With the BCRT, in contrast, it was among nonsmokers that the male-female difference was most marked: 

PET Scans Reveal Differences in 

Metabolic Activity 

Reprinted from International Journal of Neuropsychopharmacology, Vol. 8(1): 511-528, Fallon, J.H., et al.: “Gender: A major determinant of brain response to nicotine,” © 2005. Reprinted with the permission of Cambridge University Press.

Red indicates brain areas where metabolic activity was higher in 

women than in men during the Continuous Performance Test and 

Bushman Competition and Retaliation Task. Exposure to nicotine 

greatly reduced the size of these areas, suggesting the drug’s ability to 

neutralize gender differences in task-driven brain activity.
Women’s brain activity 

was higher in virtually all 

regions when the task was 

performed with placebo, 

but both sexes exhibited 

equal activity with nicotine. 

The gender disparity was 

smaller among smokers, 

and this, too, disappeared 

when they wore the nicotine patch.

“Some effects of nicotine 

on brain metabolism was 

not due to the effects of 

chronic smoking, but 

rather a fundamental biological difference between 

men and women in their 

response to nicotine,” Dr. 

Potkin says. “Everyone 

knew that there were differences in male and female 

smoking behavior and 

smoking rates, but assumed 

they were just cultural. 

Based on our findings, a 

more likely explanation is 

an interplay of cultural and 

biological differences. That 

provides an interesting starting point for devising gender 

specific interventions.”

Effects of Alcohol, Cocaine, and Both Combined

Dr. McCance-Katz’s study took as a starting point the 

observation that people frequently consume alcohol and 

cocaine simultaneously. “We wanted to understand why 

that might be and whether responses differed in men and 

women,” says Dr. McCance-Katz.

In the double-blind study, nine men and eight women who 

were addicted to both cocaine and alcohol participated in 

three experiments performed on successive days. During 

the first, they received four 1 mg/kg intranasal doses of 

cocaine at 30-minute intervals, and two oral doses of

alcohol 1 hour apart, in amounts calculated to maintain 

plasma alcohol concentrations of approximately 100 mg/

dL; in the second, cocaine along with alcohol placebo;

and in the third, alcohol along with cocaine placebo. The 

protocol was designed to approximate how cocaine and 

alcohol might be used together during a day-long binge, 

Dr. McCance-Katz says. The researchers monitored the 

participants’ psychological and physiological status over an 

8-hour period during and after the administration of

the drugs.

By most measures, the men’s and women’s responses 

did not differ significantly. The researchers did note that 

women’s hearts beat significantly faster than men’s when 

given alcohol alone. Although men and women reported 

similar ratings of “rush,” “any high,” “cocaine high,” 

“sad,” “depressed,” “nervous,” or “paranoid” after taking 

cocaine, women consistently scored higher than men on 

“feel good”—a rating of combined mental and physical 

well-being—throughout an observation period starting 

with their first dose of cocaine and lasting until 6.5 hours 

after the last. On a scale from 0 to 100, the women’s

scores ranged from 36 to 54, whereas the men’s ranged 

from a much lower 20 to 34, thus showing no overlap

in scores. Gender differences in subjective response to 

cocaine and alcohol combined, or to alcohol alone, did 

not attain significance.

“We were a little surprised that women rated their wellbeing higher [after taking cocaine],” Dr. McCance-Katz 

says. In previous studies that involved single, somewhat 

larger doses, women had reported greater anxiety than 

men when they consumed cocaine. Although it is impossible to predict exactly how feelings of well-being might 

influence use of the drug, they could well increase the 

risk of toxicity, says Dr. McCance-Katz. “If you have a 

strong sense of good mental and physical well-being, you 

might not be attuned to the internal stimuli that signal 

15

“Feel Good” Ratings Differ by Gender

Women consistently rated their overall well-being higher than men after ingesting four 1 mg/kg doses of 

cocaine at half-hour intervals. The differences persisted long after the last dose.
the need to stop.” Coupled with the fact that cocaine is 

the illicit drug most often cited by medical examiners in 

autopsies of female decedents, the finding underlines the 

importance of bringing more women into treatment and 

conducting further studies to explore which modalities are 

effective for women, she says.

Dr. Cora Lee Wetherington, Women and Gender 

Research Coordinator at NIDA, observes that Dr. 

McCance-Katz’s findings echo animal research showing 

that female rats exhibit higher levels of motivation for 

cocaine self-administration than male rats and may be 

particularly sensitive to the drug’s reinforcing effects. 

“The results of all these studies attest to the importance 

of not taking a unisex approach to the analysis of data,” 

comments Dr. Wetherington. “Otherwise, you could

come up with averaged findings that don’t apply to men 

or women.”

Dr. Jamie Biswas, Chief of the Medications Research

Grants Branch at NIDA, says that larger studies should 

explore why substances of abuse appear to elicit a greater 

perception of well-being among women. Future research 

might include women in diverse locales and situations and 

directly address whether they are more easily addicted or 

harder to treat than men. 

Sources

•	 Fallon, J.H., et al. Gender: A major determinant of

brain response to nicotine. International Journal of 

Neuropsychopharmacology 8(1):17–26, 2005.

•	 McCance-Katz, E.F., et al. Gender effects following

repeated administration of cocaine and alcohol in 

humans. Substance Use & Misuse 40(4):511–528,

2005.

16
17

Community-Based Treatment Benefits Methamphetamine Abusers 

A large California study finds favorable effects for inpatients and outpatients; women’s gains are larger.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 20, Number 5 (April 2006)

Methamphetamine abusers can achieve long-term abstinence with the help of standard community-based drug 

abuse treatment. Nine months after beginning therapy, 

87 percent of patients treated for heavy or long-term

methamphetamine abuse in California 

outpatient and residential programs 

were abstinent from all drugs, according to a NIDA-supported analysis. “In 

the public dialogue, and even among 

professionals in the field, one sometimes hears that meth abuse is ‘not 

treatable.’ But that view is not borne 

out by recent clinical trials or our 

study, which shows that communitybased treatment reduces drug abuse 

and other problems,” says lead investigator Dr. Yih-Ing Hser.

Dr. Hser and colleagues at the University of California, 

Los Angeles analyzed data from the California Treatment 

Outcome Project (CalTOP), an ongoing study that has

followed the progress of adult substance abusers treated 

at 43 outpatient and residential programs throughout the 

State since April 2000. The researchers focused on 1,073

patients who reported that methamphetamine abuse was 

their primary drug problem (572) or that they had abused

the stimulant regularly for at least 1 year before beginning treatment (501). Most were in their 30s or younger,

White or Latino, unemployed, and on public assistance;

most had an arrest history. They had abused methamphetamine for about 9 years, on average, and nearly onequarter (22 percent) reported injecting drugs at least once. 

Although 64 percent had children aged 18 or younger,

one-third of parents did not live with their children in the 

month before beginning treatment. One parent in five

reported that a child protection court had ordered that his 

or her children live with someone else, and 6.3 percent 

had their parental rights terminated by the State.

The patients received the addiction treatment services routinely provided by each program. These usually included 

group therapy, with an average of 69 drug-related and 51

alcohol-related sessions during the first 3 months of treatment. On average, the patients also received 22 sessions

on dealing with mental health symptoms and 13 addressing psychosocial problems, including family, parenting, 

and employment.

More than 60 percent of the patients completed 3 months

of treatment. Among all the patients in the study—those 

who finished 3 months and those who did not—the average reported frequency of methamphetamine abuse fell 

from 2.7 to 0.5 days per month from the start of treatment to 9 months later. The portion who were abstinent

from all drugs rose from 55 percent to 87 percent in the

same interval, and 68 percent were abstinent and also

not incarcerated. Patients improved in all areas—drug 

and alcohol 

abuse; mental health 

symptoms;

and employment, family, and legal 

problems—

except one: 

men’s medical problems. 

Dr. Thomas 

Hilton of 

NIDA’s 

Division of 

Epidemiology, 

Services and 

Prevention 

Research says 

these findings should 

reassure 

professionals 

working in the 

80

70

60

50

40

30

20

10

0

n Before Treatment n 9-Month Followup

Percent reporting problem in past month

 Any Drug Criminal Depression

 Abuse Activity

45

13

63

51

42

30

Abusers Achieve Gains 

With Treatment

Nine months after methamphetamine abusers 

began addiction treatment, they had reduced 

past-month drug abuse and criminal activity, 

and fewer reported depression.

“Because methamphetamine abusers respond to 

treatment, getting them into therapy is a top priority. For women, there is added urgency to help them 

avoid exposing the children they may bear to the 

consequences of prenatal drug exposure.”
18

addiction, social services, and criminal justice fields that current therapies work for these troubled patients. 

“Dr. Hser’s findings suggest that 

treatments available in the community help meth abusers reduce drug 

abuse and start to get their lives back 

on track, echoing prior research,” he 

says.

Women’s Experiences

Dr. Hser’s findings confirm gender 

differences seen in other studies: 

Women began treatment with more 

severe psychosocial problems than 

men (see chart, right) and benefited 

more. Although treatment retention 

levels were similar for the two sexes, 

the women made greater gains in the 

areas of family relationships and medical problems, while achieving similar 

improvements in all other areas at 

the 9-month followup. The women’s

better outcomes may have resulted in 

part from more intensive services 

(see chart below); as well, Dr. Hser

says that many women in the study 

had a powerful motivator—family. 

“Many were trying to maintain or 

regain custody of their children by 

demonstrating improvement during 

treatment. Others had ‘hit bottom,’

saw how drug abuse was hurting their 

families, and decided to make a 

change,” she says.

“Because methamphetamine abusers respond to treatment, 

getting them into therapy is a top priority. For women, 

there is added urgency to help them avoid exposing the 

children they 

may bear to the 

consequences of 

prenatal drug 

exposure,” says 

Dr. Hser.

Dr. Hser and 

her colleagues 

continue to 

analyze CalTOP

data, aiming to 

determine the 

longer-term 

impact of therapy and identify 

ways programs 

can improve 

outcomes. “Enhancing psychiatric, parenting, and 

employment services would better match patients’ needs, 

and my team plans to study the relationship between help 

for these problems and longer-term outcomes,” says Dr. 

Hser. They also plan to investigate whether women-only 

treatment is more effective for pregnant methamphetamine abusers than mixed-gender programs.

 “The field needs more research following meth abusers 

over time to get a picture of the long-term outcomes 

of treatment, relapse episodes, and whether these patients 

require additional support to sustain gains made during 

therapy,” says Dr. Hilton. “Because the availability of 

community health and social services varies across 

States, we cannot generalize the findings from one 

State, such as California. We need data from across the 

country,” he adds. 

Source

•	 Hser, Y.-I.; Evans, E.; and Huang, Y.-C. Treatment

outcomes among women and men methamphetamine 

abusers in California. Journal of Substance Abuse 

Treatment 28(1):77-85, 2005. 

Men, Women Experience Different Problems 

Family and Social Circumstances

Women, % 

(n=567)

Men, % 

(n=506)

Total, % 

(N=1,073)

Children living with someone else by court order 29.3 9.9 20.1

Parental rights terminated 10.1 2.2 6.3

Family abused substances 21.7 10.5 16.4

Physically abused (past month) 5.5 1.8 3.7

Sexually abused (past month) 2.5 0.6 1.6

Employed 23.8 43.9 33.3

On public assistance 63.1 37.0 50.8

Criminal Justice System Involvement

On parole 4.4 12.7 8.3

On probation 32.3 37.6 34.8

Ever arrested 76.7 88.3 82.2

Arrest in past year 36.7 45.1 40.6

Criminal activity (past month) 55.2 71.7 63.0

Psychiatric Symptoms (Past Month)

Serious depression 38.8 29.8 34.6

Difficulties with understanding, 

concentrating, remembering 36.2 26.5 31.6

Suicidal thoughts 11.3 6.3 9.0

Prescribed psychiatric medicine 21.3 15.4 18.6

Women beginning treatment for methamphetamine abuse reported more psychosocial 

problems, while men reported more crime and criminal justice involvement.

Women Receive More 

Services in Some Areas

Services

Women 

(No. of 

interventions†)

Men 

(No. of 

interventions 

†

)

Employment* 4.6 2.3

Family‡ 6.5 4.6

Mental Health‡ 23.6 19.9

Parenting* 4.2 1.7

†Includes counseling sessions, medical appointments, and 

prescriptions. * Outpatients. ‡Outpatient and residential.

For some problems, women received more 

services than men during the first 3 

months of treatment.
19

Studies Identify Factors Surrounding Rise in Abuse of Prescription 

Drugs by College Students

By Lori Whitten, NIDA NOTES Staff Writer

Research Findings

Volume 20, Number 4 (March 2006)

Prescription drug abuse among 

students in U.S. colleges and universities has been rising for several 

years. The 2004 Monitoring the

Future (MTF) Survey of College 

Students and Adults—the most 

recent data available—estimated 

that 7.4 percent of college students

used the painkiller hydrocodone 

(Vicodin) without a prescription 

in that year, up from 6.9 percent

in 2002, with similar increases for

other opioid medications, stimulants, and sedatives. Three new 

NIDA-funded studies reveal which 

students and campuses have the 

highest rates of abuse and connect such abuse to other unhealthy 

behaviors. According to the research, 

rates of collegiate prescription stimulant abuse are highest among men, 

Whites, fraternity/sorority members, 

and at schools in the Northeast.

Stimulant Abuse Nationwide

Dr. Sean Esteban McCabe and colleagues at the 

University of Michigan and Harvard University analyzed 

the answers from the Harvard School of Public Health 

College Alcohol Study, which in 2001 surveyed 10,904

randomly selected students enrolled at 119 colleges across

the United States. Overall, 4 percent of the respondents

reported having taken a stimulant medication without a 

prescription at least once during the previous year. Men 

were twice as likely as women (5.8 percent versus 2.9

percent) to have abused methylphenidate (Ritalin), 

dextroamphetamine (Dexedrine), and amphetamine/ 

dextroamphetamine (Adderall). Stimulant medication 

abuse was also more prevalent among students who were:

•	 White (4.9 percent versus 1.6 percent for AfricanAmericans and 1.3 percent for Asians);

•	 Members of fraternities or sororities (8.6 percent

versus 3.5 percent for nonmembers); and

•	 Earning lower grades (5.2 percent for grade point

average of B or lower versus 3.3 percent for B+ or 

higher).

Students who abused prescription stimulants reported 

higher levels of cigarette smoking; heavy drinking; risky

driving; and abuse of marijuana, MDMA (Ecstasy), and

cocaine. Compared with other survey respondents, for 

example, they were 20 times as likely to report past-year

cocaine abuse and 5 times as likely to report driving after 

heavy drinking.

The campus prevalence of past-year stimulant abuse 

ranged from 0 percent at 20 colleges—including the three

historically African-American institutions included in the 

survey—to 25 percent. The prevalence was 10 percent or

higher at 12 colleges. Students attending colleges in the 

Northeast, schools with more competitive admission 

standards, and noncommuter schools reported higher 

rates of abuse.

One University’s Painkiller Picture 

At a large Midwestern university, about 9 percent of

9,161 undergraduates surveyed had taken a prescription

pain medication without a doctor’s order at least once 

during the past year; 16 percent reported such abuse in

their lifetime. Of the latter, 54 percent said they had

obtained the drugs from peers, while 17 percent said their

source was a family member. Dr. McCabe and colleagues 

16.9 

46.3 

Percent Reporting Abuse 

0 

10 

20 

30 

40 

50 

60 

70 

80 

Women Men 

Obtained 

from peers 

Obtained 

from family 

Nonabusers 

of painkillers 

50.1 

42.1 

50.7 

74.3 

80.1 

Two-week 

binge drinking

0 

10 

20 

30 

40 

50 

60 

70 

80 

Obtained 

from peers 

Obtained 

from family 

Nonabusers 

of painkillers 

Past-month 

marijuana abuse

14.6 16.9 16.8 21.1 

48.2 

61.7 

Binge Drinking, Marijuana Abuse Are Elevated Among 

Students Who Obtain Painkillers From Peers

At one university, students who obtained prescription painkillers from peers reported higher 

levels of binge drinking and marijuana abuse than nonabusers or those who received 

painkillers from family.
20

at the University of Michigan Substance Abuse Research 

Center found that students who obtained medications 

from peers were more likely to smoke and drink heavily 

and to have abused other substances—including marijuana, cocaine, and other illegal drugs—

than those who obtained them from 

family members.

The researchers found that exposure 

to prescription pain medication early 

in life increased the likelihood of 

abuse in college. Women who had 

received prescriptions for pain relievers in elementary school were more 

than four times as likely as those with 

no prescribed use to report abuse in 

the past year. Men with early prescribed use were twice as likely as 

those without to report such abuse. 

In addition:

•	 Women students were more likely

to be prescribed pain medication, 

while men were more likely to be 

approached to sell or give away 

prescribed medication.

•	 More men obtained the drugs

from peers while more women 

obtained them from family 

members. 

•	 Past-year prescription painkiller

abuse was higher among fraternity 

members than nonmembers 

(17 percent versus 9 percent) and among sorority

members compared with nonmembers (9.6 percent

versus 8.6 percent).

“Students abuse prescription drugs to get high, to selfmedicate for pain episodes, to help concentrate during 

exam time, and to try to relieve stress. Regardless of the 

motivation, people need to know the risks of abuse and 

the dangers of mixing drugs,” says Dr. Lynda Erinoff, formerly of NIDA’s Division of Epidemiology, Services and 

Prevention Research. Most people assume that if a medication is available on the market, it must be safe—even if 

it has not been prescribed for them, says Dr. Erinoff, “but 

a drug or dose that a doctor orders for one person is not 

necessarily appropriate for another, and prescription abusers are potentially taking a serious risk.” NIDA continues 

to work with doctors and pharmacists and to link prevention specialists with researchers focusing on the problem. 

“Educating the public remains a critical challenge,” says 

Dr. Erinoff.

Membership Matters

Based on responses from more than 5,000 young people

who participated in the MTF when they were high school 

seniors in 1988 to 1997, and also when they were in college, Dr. McCabe and his Michigan 

colleagues found that active members of 

college fraternities or sororities engage 

in more heavy episodic, or “binge,” 

drinking, cigarette smoking, and 

marijuana abuse than nonmembers.

The students who joined fraternities or 

sororities in college were the same ones 

who reported the highest levels of substance abuse in high school. Moreover, 

cigarette smoking, binge drinking, 

and drug abuse increased for all survey 

participants as they progressed through 

college. Fraternity and sorority members showed greater elevations in binge 

drinking and marijuana abuse over time 

compared with nonmembers. The picture that emerges is of students who are 

already heavy drinkers when they come 

to college selecting fraternities and 

sororities with a reputation for “partying” and then, as members, further 

increasing their drinking in an environment that supports the behavior. 

“It’s important for each student to 

explore, perhaps with counseling, a 

possible mismatch between his or her 

college environment and individual 

needs. Some students benefit from settings that emphasize socialization outside of the party scene; these might

include group living arrangements based on shared academic or extracurricular interests,” Dr. McCabe says. 

Sources

• McCabe, S.E., et al. Non-medical use of prescription

stimulants among US college students: Prevalence 

and correlates from a national survey. Addiction

100(1):96-106, 2005.

• McCabe, S.E., et al. Selection and socialization effects

of fraternities and sororities on US college student 

substance use: A multi-cohort national longitudinal 

study. Addiction 100(4):512-524, 2005.

• McCabe, S.E.; Teter, C.J.; and Boyd, C.J. Illicit use of

prescription pain medication among college students. 

Drug and Alcohol Dependence 77(1):37-47, 2005.

Stimulant Abuse Varies by 

Campus Characteristics

Students enrolled in the most selective colleges 

reported relatively high levels of past-year 

stimulant abuse, as did those attending schools 

in the Northeast. Residential schools reported 

higher rates than commuter colleges.

Selected 

Characteristics

Past-year Stimulant 

Abuse Rates, %

Admission criteria

 More competitive 5.9

 Competitive 4.5

 Less competitive 1.3

Geographical region

 Northeast 6.3

 South 4.6

 West 3.2

 North Central 2.8

Commuter status

 Noncommuter school 4.6

 Commuter school 1.2
Weighing Nicotine Replacement

Research Findings

Volume 20, Number 4 (March 2006)

Postmenopausal women using the nicotine patch gained less weight during their first 2 

weeks of abstinence from smoking than women on placebo, even though they consumed 

more total calories and fat and had the same level of physical activity. In one of the first 

studies to address the challenges older women face when they try to quit smoking, Dr. 

Sharon Allen and colleagues at the University of Minnesota also found that the simultaneous use of hormone replacement therapy by participants did not affect the results. 

One-third of women over age 45 smoke, and researchers are looking for strategies to help

them quit. Fear of weight gain can be a serious barrier to quitting, particularly during the 

menopausal period when women typically gain a few pounds. 

Source

•	Addictive Behaviors 30(7):1273-1280, 2005.

21
Disulfiram May Work for Men, but Not Women

Research Findings

Researchers studying disulfiram, an “old” medication for 

alcoholism that has emerged as a potential “new” treatment for cocaine abuse, have found a possible sex difference in treatment response: Cocaine-addicted men who 

were treated with the medication had better outcomes 

than those who were not, whereas women showed no significant difference in outcome. 

Dr. Kathleen Carroll of Yale University School of 

Medicine and her colleagues have conducted several studies on the medication’s effects on cocaine abuse and have 

moved on to the next step—determining which types 

of patients benefit from the treatment. There were not 

enough women in their recent study (see “Disulfiram 

Reduces Cocaine Abuse, NIDA Notes, Vol. 20, No. 2”)

to analyze sex differences, so the investigators combined 

data from two of their other treatment studies to compare men’s and women’s responses to disulfiram. “We 

know that men and women react to cocaine differently. 

For example, women progress more quickly to cocaine 

addiction than men. Sex differences in treatment response 

seemed likely,” says Ms. Charla Nich, lead investigator of 

the study. 

In one study, the investigators treated alcohol- and 

cocaine-addicted patients with disulfiram and various 

behavioral therapies; in the second, they tested disulfiram

in opioid- and cocaine-addicted patients under treatment 

with methadone. Altogether, 191 patients participated in

the studies, which, when combined, had enough women 

(36 percent) to permit a valid comparison. 

Both studies found that patient groups taking disulfiram 

reduced cocaine abuse compared with groups receiving 

placebo. But when the investigators combined and reanalyzed the data, they found that only the men in the groups 

responded to the medication. The reanalysis indicated that 

men treated with disulfiram produced a higher percentage of drug-free urine specimens than men in the placebo 

groups (49 versus 30 percent). Among women, however,

the percentage of drug-free specimens was not significantly 

different with disulfiram or placebo (38 versus 39 percent).

“Our data don’t conclusively prove a sex difference in the

response to disulfiram,” says Ms. Nich. “For that, we need 

studies that directly compare men and women taking the 

medication.” NIDA’s Dr. Dorynne Czechowicz agrees 

that researchers should follow up on these intriguing 

preliminary findings, which “highlight the importance of 

paying attention to sex differences in medication development and other drug abuse research.” 

Source

•	 Nich, C., et al. Sex differences in cocaine-dependent

individuals’ response to disulfiram treatment. 

Addictive Behaviors 29(6):1123-1128, 2004.

22

Volume 20, Number 2 (August 2005)
Research Findings

Volume 20, Number 1 (August 2005)

23

ATHENA Program Reduces Substance Abuse by 

Girls on High School Sports Teams

By Patrick Zickler, NIDA NOTES Staff Writer 

High school girl athletes who participated in a recently 

evaluated NIDA-supported nutritional and behavioral 

guidance program were less likely than nonparticipating 

peers to engage in substance abuse and other high-risk 

behaviors. Girls on teams that used ATHENA (Athletes 

Targeting Healthy Exercise and Nutrition Alternatives) 

were less likely than girls on teams that received only 

printed information to use diet pills or so-called performance-enhancing substances such as steroids, amphetamines, and muscle-building supplements. The ATHENA 

team members also were less likely to be sexually active 

and more likely to wear seat belts, and they experienced 

fewer injuries during the sports season.

In the ATHENA program, developed at the Oregon

Health & Science University in Portland by Drs. Diane 

Elliot and Linn Goldberg, 

selected team leaders 

receive a 90-minute orientation and then conduct 

discussion and activity 

sessions during scheduled 

team practices. Each team 

leader works with a squad 

of approximately six teammates, following a manual that 

is much like a playbook, with scripts for eight 45-minute 

sessions dealing with the harmful consequences of substance abuse and other unhealthy behaviors and the 

beneficial effects of good diet and exercise. Along with 

providing information, the workbook engages the girls in 

activities such as critiquing magazine advertising and other 

media influences on 

self-image; classifying

various foods according 

to carbohydrate, fat, 

and protein content;

and determining the 

best balance of dietary 

fuels for athletic training and competition. 

Each ATHENA athlete 

uses a pocket-sized 

nutrition and training 

guide to monitor diet 

and exercise. Coaches 

and other staff members receive an orientation to assist the team 

leaders as timekeepers 

and facilitators for 

the sessions.

To evaluate ATHENA, 

the researchers recruited 40 girls’ sports

teams in 18 public high

schools in northwest 

Oregon and southwest

Washington. Teams 

from half the schools 

followed the ATHENA 

program. The other 

ATHENA’s Impact on Behavior and Nutrition

High-school girls who participated in the ATHENA curriculum were less likely to engage in drug abuse or 

other unhealthy behaviors than were girls given printed information about drugs and nutrition.

Control Group Experimental Group

Before 

Intervention

After 

Intervention

Before 

Intervention

After 

Intervention

 Nutrition, Exercise Abilities, and Beliefs*

 Tracking protein intake 2.11 2.03 2.16 2.54

 Eating more protein in the last 2 months 3.95 3.92 4.19 5.10

 Knowing how to lift weights to improve strength 5.48 5.61 5.15 5.92

 Self-rating of skill in strength training 5.48 5.61 5.15 5.92

 Believing that nutrition affects sport performance 5.75 5.64 6.06 6.01

Additional Health-Influencing Behaviors

 Rode in a car with an alcohol-consuming driver** 0.44 0.42 0.41 0.26

 Knowing how to turn down unhealthy weight-loss 

 behaviors* 5.80 5.77 5.91 6.14

 No. of sport injuries so could not train in the last 

 3 months 0.32 0.36 0.32 0.26

Intentions Toward Future Disordered Eating 

 Behaviors and Drug Use*

 Diet pill use 1.74 1.79 1.87 1.62

 Vomiting to lose weight 1.66 1.76 1.62 1.57

 Tobacco use 1.56 1.79 1.55 1.58

 Creatine (muscle-building supplement) use 1.87 1.77 1.72 1.51

 Data are significant differences expressed as the mean.

 *Scored using a seven-item agreement scale ranging from 1 (strongly disagree) to 7 (strongly agree).

 **Scored 0 to 4 for times occurred with 0 indicating none; 1, once; 2, two or three times; 3, four or five times; or 4, six or more times.
24

teams received printed information about eating disorders, 

substance abuse, and sports nutrition, but did not take 

part in discussion or group activities. Before the first practice of their sports season and again within 2 weeks after 

the season ended, each girl filled out a questionnaire about 

her eating patterns; nutritional awareness; use of diet pills,

amphetamines, anabolic steroids, and muscle-building 

supplements; and other health-related behaviors.

Preseason survey results were essentially the same for girls 

on ATHENA teams and those in the control group, but 

in postseason surveys the ATHENA participants reported 

significant decreases in risky behaviors. According to Dr. 

Elliot, the control athletes were three times more likely to 

begin using diet pills and almost twice as likely to begin 

using other body-shaping substances, including amphetamines, anabolic steroids, and muscle-building supplements, during the season. The use of diet pills went up 

among control girls, while it fell to approximately half its 

preseason level among ATHENA girls. ATHENA athletes 

also were more likely to use seatbelts and less likely to ride 

in a car with a driver who had been drinking, to believe 

claims in advertising, or to agree with the statement that 

men find thin women most attractive.

Adolescent girls experience social and cultural pressure 

about body image, and they look to each other for role 

models more than they follow the guidance offered in 

classrooms, research has shown. The competitive environment of athletic programs may compound the pressure, 

leading to disordered eating and the use of body-shaping 

substances such as steroids, diuretics, laxatives, and even 

tobacco, Dr. Elliot says. However, the athletic environment can exert positive peer pressure also. The researchers 

modeled ATHENA’s use of sports teams as a forum to 

promote healthy lifestyles on a similar program they developed for male high school athletes (see “Like ATHENA, 

ATLAS Targets High School Athletes”). “We found 

that the team-based approach used in ATLAS [Athletes 

Training and Learning to Avoid Steroids] produced 

greater positive change than did a more conventional 

classroom-style approach,” Dr. Elliot says.

“Two features of the ATHENA program are striking,” 

says Dr. Larry Seitz of NIDA’s Division of Epidemiology, 

Services and Prevention Research. “One is the peer-based

rather than classroom-based approach, and the other is the 

effect on a wide spectrum of linked behaviors, from vomiting to induce weight loss to believing nutritional claims 

in advertising. Improvements like these can help young 

female athletes make healthier choices throughout life, not 

just during the sport season.”

The Oregon Health & Science University Sports

Medicine Web site, www.ohsu.edu/hpsm/index.html, provides more information about ATHENA and ATLAS.

Source

•	 Elliot, D.L., et al. Preventing substance use and disordered eating: Initial outcomes of the ATHENA program. Archives of Pediatric and Adolescent Medicine

158(11):1043-1049, 2004.

Like ATHENA, ATLAS Targets High School Athletes 

ATLAS (Athletes Training and Learning To Avoid Steroids), the result of 5 years of 

NIDA-supported development, is a program for male high school athletes to help reduce 

use of anabolic steroids and other sport supplements, alcohol, and other drugs. ATLAS 

emphasizes the immediate impact of alcohol and other drugs on athletic performance 

and conditioning rather than potential and abstract long-term effects. An evaluation of 

the program in 15 high schools showed that, compared with a control group, 1 year after 

completion of the program, ATLAS-trained students had:

• Half the incidence of new use of anabolic steroids 

and less intention to use the drugs in the future; 

• Less use of alcohol, marijuana, amphetamines, and narcotics; 

• Less use of “athletic enhancing” supplements; 

• Less likelihood of engaging in hazardous substance abuse 

behaviors such as drinking and driving; 

• Reduced substance abuse risk factors; and

• Improved substance abuse protective factors.
Research Findings

Volume 19, Number 4 (December 2004)

25

Smoking Exposure In Utero Increases Risk of Later Addiction

By Arnold Mann, NIDA NOTES Contributing Writer

An expectant mother’s smoking during pregnancy does 

not increase the likelihood that her child will later try 

smoking or become a regular smoker. Her pack-a-day 

smoking, however, doubles the risk that if her child does 

become a smoker, he or she will become addicted to 

tobacco, according to the first study to examine rates of 

tobacco addiction in adults who were prenatally exposed.

The study was led by Dr. Stephen L. Buka of the Harvard 

School of Public Health in Boston and cosponsored by 

the National Cancer Institute, the National Institute of 

Mental Health, the Robert Wood Johnson Foundation,

and NIDA. Dr. Buka, together with Drs. Edmond D. 

Shenassa and Raymond Niaura, both of Brown Medical 

School in Providence, Rhode Island, collected data from 

1,248 individuals aged 17 to 39. All the study subjects’

mothers had participated in the Providence cohort of the 

National Collaborative Perinatal Project (NCPP) between 

1959 and 1966. As part of the NCPP, pregnant women

provided information about their smoking and gave blood 

samples for measuring nicotine levels.

Among the men and women in the new study, 62 percent had smoked regularly and 45 percent met the medical criteria for tobacco dependence at some time in their 

lives. The criteria, as defined by DSM-III (Diagnostic 

and Statistical Manual of Mental Disorders, Revision III), 

include persistent, unsuccessful attempts to quit or control 

smoking, continued use despite smoking-related problems, 

and smoking to reduce withdrawal symptoms. Thirtyeight percent were born to mothers who did not smoke, 

25.6 percent to mothers who smoked less than a pack a 

day, and 36.4 percent to mothers who smoked a pack or 

more per day at some point during pregnancy.

Among children who had smoked at least once, those 

whose mothers smoked up to a pack a day during pregnancy had a 20 percent higher, and those whose mothers

smoked a pack a day or more had a 60 percent higher

odds of having at some time been addicted to tobacco, 

compared with those whose mothers had not smoked. 

Among children who had at some time in their lives 

smoked daily for a month or more, those exposed in utero

to a mother’s pack-a-day smoking had double the odds of 

progressing to addiction.

“The evidence from this study, which reinforces the findings of experimental research with animals, is compelling,” says Dr. Buka. “Early exposure to tobacco during 

pregnancy apparently affects the individual’s response to 

cigarettes in later adolescence and adulthood.”

The researchers’ statistical analyses indicated that the associations between maternal smoking during pregnancy and 

offspring’s future smoking were independent of socioeconomic status, maternal age at pregnancy, offspring 

sex, and offspring age at the time of the interview. What’s 

left, then, is a biological factor. “The most likely hypothesis is that the toxins in cigarettes cross the placental barrier and interact with the genes that control cell differentiation, permanently altering cells’ responsiveness in ways 

that increase vulnerability to tobacco addiction,” Dr. 

Buka says.

0.0

0.5

1.0

1.5

2.0

1-19 cigs/day 20+ cigs/day

Progress 

(reg. add.)

Nicotine

Addicted

Regular

Smoker

Ever 

Smoked

Odds* of Children Smoking

Children’s Smoking Level as Adults

Maternal Tobacco Smoking Level

0.8 0.8

1.1

1.2

1.1

1.6

1.1

2.0

* Odds ratio, calculated by dividing the odds of the children in the maternal 

 smoking group by the odds of those with nonsmoking mothers.

Heavier Maternal Smoking During 

Pregnancy Increased Children’s Odds of 

Nicotine Addiction as Adults

Children of women who smoked at least 20 cigarettes a day during 

pregnancy were more likely to become addicted to nicotine or progress from regular smoking to nicotine addiction as adults compared 

with children of women who smoked fewer than 20 cigarettes a 

day. Children of heavier smokers were no more likely to try smoking or to smoke regularly than children of lighter smokers.
26

The cross-generational impetus to tobacco addiction 

documented by the study is a serious national health concern. Almost half of women who smoke continue to do so 

when they become pregnant, says Dr. Buka. The smoking mothers-to-be constitute about 12 percent of women 

who give birth—a national potential for 500,000 prenatal

exposures every year. 

The researchers also collected information about the study 

participants’ marijuana abuse and found no tie to prenatal 

nicotine exposure. This suggests, the investigators say, that 

the “pathophysiological pathway” that promotes vulnerability to tobacco addiction among offspring differs from 

the pathway that leads to marijuana addiction. 

The study confirms the need for energetic efforts to deter 

women from smoking, especially during pregnancy, says 

Dr. Kevin Conway, deputy chief of NIDA’s Epidemiology 

Research Branch. Preventing smoking by pregnant women 

will improve nicotine addiction rates of the next generation. “This study highlights opportunities for physicians 

to intervene with mothers who smoke, for the health of 

themselves and their children,” says Dr. Conway.

“Healthy-baby prenatal visits, labor and delivery, and 

postnatal-care visits are golden opportunities for providers to offer assistance to quit smoking and prevent relapse, 

thereby reducing the risk of children’s progression to 

nicotine addiction,” says study coauthor Dr. Niaura. 

“Health care providers must take advantage of every 

opportunity to ask, advise, and assist patients in efforts 

to quit smoking.” 

Source

• Buka, S.L.; Shenassa, E.D.; and Niaura, R. Elevated

risk of tobacco dependence among offspring of mothers who smoked during pregnancy: A 30-year prospective study. American Journal of Psychiatry

160(11):1978-1984, 2003.

0.0

0.5

1.0

1.5

2.0

1-19 cigs/day 20+ cigs/day

Mar. Progress 

(reg. add.)

Marijuana 

Addicted

Regular 

Smoker

Ever 

Smoked

Odds* of Children Using Marijuana

Children’s Marijuana Use Level as Adults

Maternal Tobacco Smoking Level

1.3

1.1

1.3

1.2 1.1

1.0

1.1 1.1

* Odds ratio, calculated by dividing the odds of the children in the maternal 

 smoking group by the odds of those with nonsmoking mothers.

Maternal Tobacco Smoking During 

Pregnancy Did Not Affect Children’s 

Odds of Marijuana Use as Adults

The finding that in utero exposure to tobacco did not affect 

later marijuana use indicates that the two drugs have different 

physiological pathways.
Men and Women May Process Cocaine Cues Differently

By Lori Whitten, NIDA NOTES Staff Writer 

Research Findings

Volume 19, Number 4 (December 2004)

Some aspects of cocaine addiction and 

recovery are different for men and 

women—including the reasons for seeking drug rehabilitation, response to 

treatment, and vulnerability to relapse. 

Women are more likely to seek cocaine 

abuse treatment in response to cooccurring depression, remain abstinent 

after treatment, and relapse in response 

to interpersonal problems and negative 

feelings. Cocaine-addicted women also 

demonstrate greater craving than men in 

response to drug cues. In the first brain 

imaging study of cocaine craving by 

cocaine-addicted women, NIDA-funded 

researchers have made observations 

that, if borne out in larger studies, 

may point to neurological sources of 

these differences.

Dr. Clinton Kilts and colleagues at the 

Emory School of Medicine in Atlanta 

used positron emission tomography 

(PET) to measure drug-craving-related 

changes in regional cerebral blood 

flow—a correlate of neural activity—in 

eight cocaine-addicted African-American 

women aged 35 to 46. The women had 

abstained from cocaine use for 1 to 14 

days and reported frequent periods of 

cocaine craving in the 30 days preceding

the study. While lying in the PET scanner, each woman listened to a 1-minute 

recording of a script describing her personal experiences of acquiring the drug and anticipating 

sensations associated with taking cocaine. Each patient’s 

script was derived from her own answers to an autobiographical questionnaire and narrated in the first person:

“...I start thinking about how good it’s going to feel to 

take that first hit...with my eyes wide open I take my 

lighter out of my pocket, put it to the stem, and get ready 

to take that first, good blast....”

The researchers injected each woman with a radiotracer 

and took pictures of the blood flow in her brain as she 

listened to the script and relived the scene in her mind. 

After each brain scan, the women rated the urge to use 

cocaine, vividness of the mental image, and their 

emotions. They repeated this process twice.

The women also underwent imaging in three control situations: resting, listening to a script of a personal experience in nature, and listening to a script designed to provoke anger. The researchers verified that the mental imagery of the cocaine-related script induced a greater urge to 

use cocaine than the nature or anger script. By comparing 

the brain scans produced in response to the different 

scripts, the researchers were able to evaluate cerebral blood 

flow while the women were craving cocaine versus when 

they were relaxed and not thinking of the drug. The procedure also distinguished changes related to craving from 

27

Selected Key Brain Regions Affected by Cue-Induced 

Cocaine Craving in Cocaine-Addicted People 

(Cocaine-use imagery compared with neutral imagery)

Brain Region Putative Role in Behavior Activity Changes During Cocaine Craiving

Men Women

Right nucleus 

accumbens

Processes anticipated and attained 

rewards—probably 

contributes to the expectation 

of pleasure during craving

Increased activity Increased activity

Amygdala

Generates and regulates emotional 

responses; assesses the positive or 

negative value of experiences and 

forms associations between experiences and emotional consequences

Increased activity Decreased activity

Dorsal 

anterior 

cingulate 

cortex

Monitors competing options, inhibits goal-inappropriate behavior, and 

plans movements related to obtaining rewards; activity 

influenced by past experiences—

possibly provides cognitive control 

of drug-seeking behavior 

Increased activity

Increased activity, 

greater than that 

of men

Ventral anterior 

cingulate 

cortex

Regulates emotional response 

to cocaine cues; activation may 

precede craving onset

Increased activity Increased activity, less 

than that of men

Frontal 

cortex

Monitors relationship of drug 

cue to drug availability; provides 

inhibition or control over actions; 

activity influenced by past 

experiences—possibly counterregulates emotional input

Increased activity

Increased activity, 

greater than that 

of men
those that might simply reflect strong general emotional reactions (as in the angerinducing script). To examine possible sex 

differences in the neural representation 

of cocaine craving, the investigators compared the findings in women with results 

from eight cocaine-addicted men of 

similar ages and backgrounds who experienced the same process.

In both men and women, cue-induced 

cocaine craving activated several brain 

areas involved in determining a cue’s 

reward value and controlling rewardrelated behaviors, including the right 

nucleus accumbens—a structure that 

seems to produce the expectation of 

pleasure during drug craving (see table, 

“Selected Key Brain Regions Affected 

by Cue-Induced Cocaine Craving in 

Cocaine-Addicted People”). “These 

common activations suggest that both 

sexes may process cocaine-use memories—mental images that are associated 

with strong emotions—as cues that guide 

reward-based decisionmaking,” says Dr. 

Kilts. However, men and women also 

showed some dissimilar neural responses 

to cocaine cues. Most notably, activity of 

the amygdala—a structure that assesses 

whether an experience is pleasurable or 

aversive and connects the experience 

with its consequences—fell in women 

during cocaine craving. “This finding 

is notable because our study and others 

have shown cue-induced amygdala activation in men,” says Dr. Kilts. “Reduced 

neural responses in the amygdala may 

result from greater activation of the 

frontal cortex in women. The frontal 

cortex inhibits the activity of structures 

involved in emotional responding to 

drug cues, and our observations were consistent with previously reported sex differences in frontal cortical areas.”

“As a field, we need more and better controlled studies of 

sex differences in factors that cause relapse,” says Dr. Kilts. 

Combining imaging technologies in the same study—for 

example, PET with magnetoencephalography—would 

improve the localization of neural activity. “We could better define the neural responses that occur before, during, 

and after drug cues—illuminating the temporal sequence 

of the craving experience in men and women,” he says.

“This research reveals that men and women differ in a 

critical brain area in their responses to cocaine craving,” 

says Dr. Steven Grant of NIDA’s Division of Clinical 

Neuroscience, Development, and Behavioral Treatments. 

“Differences in the amygdala may indicate that male and 

female abusers crave the drug for different reasons or hope 

to achieve different results from taking the drug. Imaging 

studies that examine gender differences in specific behavioral aspects of drug craving will provide insight on how 

to tailor treatment programs to meet the needs of men 

and women.”

Source

•	 Kilts, C.D.; Gross, R.E.; Ely, T.D.; and Drexler,

K.P.G. The neural correlates of cue-induced craving 

in cocaine-dependent women. American Journal of 

Psychiatry 161(2):223-241, 2004.

28

Brain Response Differs in Men and Women 

During Cue-Induced Craving

These PET scans show differences in blood flow between a neutral state and a cocainecraving state. White areas indicate an increase in blood flow. Most notable is the decrease 

in blood flow in the women’s amygdala (top right panel) during craving; men show an 

increase in blood flow during craving (bottom right panel).
Conference Provides Overview of Consequences of 

Prenatal Drug Exposure

By Patrick Zickler, NIDA NOTES Staff Writer 

Research Findings

Volume 19, Number 3 (September 2004)

On March 23 and 24, NIDA-supported investigators met

in Bethesda, Maryland, to discuss long-term consequences 

of prenatal exposure to drugs. The conference, “Long 

Term Follow-up of Prenatal Drug Exposure: Advances, 

Challenges, and Opportunities,” was cosponsored by

the National Institute of Child Health and Human 

Development (NICHD) and the National Institute of 

Health’s Office of Research on Women’s Health. The

meeting brought together more than 100 researchers

involved in studying the impact of prenatal exposure to 

drugs on children. Conference participants described 

recent findings and discussed research techniques and 

technology that can make the most effective use of the 

research cohorts recruited in the past two decades.

“NIDA has long recognized the importance of studies 

that can follow the development of children from before 

birth through adolescence and early adulthood,” said 

Dr. Vincent Smeriglio of NIDA’s Division of Clinical 

Neuroscience, Development, and Behavioral Treatment. 

“For example, NIDA supports the Ottawa Prenatal

Prospective Study, which began in 1978 and has examined the impact of prenatal tobacco and marijuana use on 

offspring who are now in their early twenties,” continued 

Dr. Smeriglio. “Other research projects, such as those

designed to examine the effects of 

MDMA [Ecstasy] 

and methamphetamine over similarly long developmental periods, 

are just getting 

under way.” In 

all, NIDA’s prenatal drug research 

involves 24 studies and thousands 

of prenatally 

exposed offspring 

(see “Summary of 

Current Prenatal Studies”). 

The largest longitudinal study of prenatal drug exposures 

is the Maternal Lifestyle Study (MLS), an interagency collaboration cosupported by NICHD. “This study involves 

more than 1,300 children who now are entering adolescence,” observed NICHD Director Dr. Duane Alexander. 

“MLS has allowed us to look at the effects of prenatal 

cocaine exposure as well as the longer term effects of a 

postnatal environment involving drug 

abuse. The study has made significant 

contributions to the field of developmental science, and following these 

children even longer will help us 

assess more fully the impact of drugs 

on development.” 

 “To move forward in every aspect 

of prevention and treatment, we 

must build on our knowledge of 

what impact drugs have on development and on vulnerability,” said 

NIDA Director Dr. Nora Volkow. 

“That is why the focus of the 

research we’re discussing at these 

meetings is so important. It is crucial to study the effects of drugs at 

the earliest stages of brain development, while the fetus is still in the 

womb.” 

29

Summary of Current Prenatal Studies

Studies Total Sample 

(Range in Study Size) Current Age Range

Cocaine 

14 studies

5,936 

(224-1,388) 1 month to 16 years

Tobacco

5 studies

1,108 

(100-413)

Newborn to 

24 years

Opiates

1 study 100 14 years (at final evaluation)

Marijuana

2 studies

719 

(155-564) 18 to 24 years

Methamphetamine

1 study 508 Newborn to 

12 months

MDMA (Ecstasy)

1 study 150 Newborn to 24 months
Research Findings

Volume 19, Number 1 (April 2004)

30

Researchers Adapt HIV Risk Prevention Program for 

African-American Women

By Jill Schlabig Williams, NIDA NOTES Contributing Writer

The HIV/AIDS epidemic has taken a disproportionate 

toll on racial and ethnic minority populations, especially 

women. In its surveillance report on the number of 

Americans living with HIV/AIDS in 2002, the Centers

for Disease Control and Prevention estimates that among 

women with HIV/AIDS, non-Hispanic African-American 

women outnumbered non-Hispanic white women by 

three to one—a racial disparity not found among men.

African-American drug-using women were addressed 

in two recent studies by NIDA-funded researchers 

in Atlanta. Dr. Claire E. Sterk of Emory University, 

Dr. Kirk W. Elifson of Georgia State University, and colleagues developed and tested gender-tailored, culturally 

specific adaptations of a standard NIDA HIV prevention 

intervention. They found that female African-American 

injecting drug users (IDUs) and crack cocaine users who 

received either of two targeted 4-week prevention programs reduced their risk behaviors related to drug taking 

and sex more 

than did 

women who 

received the 

standard intervention.

“These studies 

are examples 

of research 

that is responsive to community needs,” says Dr. Dionne Jones of NIDA’s Center

on AIDS and Other Medical Consequences of Drug

Abuse. “When it comes to designing a prevention program, it’s not one-size-fits-all. You have to consider social 

context, be culturally sensitive and appropriate, and tailor 

your message to the group.”

The researchers’ goal was to develop culturally appropriate 

programs grounded in the reality 

of the daily lives of women most at 

risk and the difficulties they face in 

their individual, social, family, and 

sexual relations and activities. “We 

worked hard to develop interventions with input from this target 

population, deliver the interventions in a setting where they feel 

comfortable, and involve them in 

planning, implementing, and 

evaluating the interventions,” 

says Dr. Sterk.

Over 1 year, using one-on-one

interviews and small focus groups, 

the researchers sought to define 

the key issues in the women’s 

lives and identify ways to address 

those issues, including such factors as gender dynamics, economic 

stressors, gender-specific norms 

and values, and power and control. 

Two interventions came out of 

this research phase. One, a motivation intervention, was designed to 

motivate the participants to change 

African-American drug-using women in three intervention groups reduced behaviors that 

heightened their risk of HIV infection. However, women receiving the culturally specific, gendertailored motivation and negotiation interventions generally reported greater reductions in risky 

behaviors after their participation than women in the NIDA standard intervention. 

Behavior in 

Past 30 days

NIDA Standard 

Intervention Group

Motivation 

Intervention Group

Negotiation 

Intervention Group

 Baseline Six-Month 

 Followup

 Baseline Six-Month 

 Followup

 Baseline Six-Month 

 Followup

Number of days 

injected powder 

cocaine

8.2 3.1 6.4 0.1 4.7 0.2

Number of days 

injected heroin 16.4 8.9 12.7 1.5 9.8 3.2

Percentage who 

traded sex for drugs 70.4 40.7 50.0 20.0 42.9 10.0

Mean number of 

days crack used 17.7 12.9 18.2 15.6 18.7 13.8

Percentage who had 

vaginal sex with 

one or more paying 

partners

43.9 24.6 34.3 19.2 30.8 20.5

Injecting Drug Users Crack Cocaine Users

Tailored Interventions Build on NIDA Intervention To Help 

Drug-Using Women Reduce HIV Risk
31

their behavior. The other, a negotiation intervention, 

recognized that women may fear verbal or physical abuse 

if they propose safer sex or safer needle use and thus 

sought to strengthen their negotiation and conflictresolution skills.

“Our goal in the motivation intervention was to reduce

risk based on what’s realistic in the context of the participant’s life,” explains Dr. Sterk. “We worked with the 

women to set short- and long-term goals, celebrate successes, analyze failures, and identify and overcome barriers.” The negotiation intervention recognizes that many of 

the women’s challenges dealt with the need to resolve conflict and that negotiation skills are key to reducing risk.

Once the interventions were ready, more than 300

African-American women ages 18 to 59 years—68 IDUs

and 265 crack cocaine users—were enrolled in the studies. All were HIV-negative and heterosexually active. The 

women were randomly assigned to one of the three 

interventions. The NIDA standard intervention was 

delivered in two one-on-one sessions; the motivation and

negotiation interventions each involved four one-on-one 

sessions. (See textbox, below, for descriptions of each 

intervention.) At the 6-month followup, both IDUs and 

crack cocaine users in all three groups reported lower 

levels of drug-using behavior and risky sexual behaviors 

than they had reported before receiving the interventions. 

Reductions were greater among women who received 

the tailored interventions.

Injecting Drug Users. The motivation and negotiation 

interventions were equally effective in reducing the incidence of needle and injection-works sharing. At 6 months, 

there was no sharing of drug injection paraphernalia in 

these groups; in the standard intervention group, 13 percent reported sharing needles and 18 percent reported

sharing injection works. Although women in all intervention groups reduced their number of injections over time, 

only those in the tailored interventions reported statistically significant decreases. Participants in the motivation 

intervention were most likely to attend drug treatment, 

whereas women in the negotiation intervention reported 

more changes in their sexual behavior than did women in 

other interventions.

Crack Cocaine Users. All three interventions were associated with a drop in crack use in the 30 days preceeding followup. About 40 percent of the women in each

group reported no use during that period. Among those 

still abusing crack at followup, women in the motivation 

intervention were more likely to have reduced their use of 

crack in risky settings, such as outside or in a crack house, 

hotel room, or car. Women in the standard and motivation intervention groups significantly decreased the number of paying partners for vaginal sex and the frequency 

of sex with paying partners.

Dr. Sterk suggests that the study’s results show it may 

be optimal to create an intervention that combines 

skills taught in both the negotiation and motivation 

Protocols for Standard, Motivation, and Negotiation Interventions

All interventions include discussion of the local HIV epidemic, sex and drug-related risk behaviors, safer sex and 

drug use, and HIV risk-reduction strategies. The two tailored interventions also include a discussion of the impact of 

race and gender on HIV risk and protective behaviors. 

The NIDA standard intervention is an HIV/AIDS education program that was developed in the early 1990s. It

builds on standard HIV testing and counseling developed by CDC and adds discussion of the principles of HIV 

prevention for drug users and their sex partners. The intervention involves testing, counseling, and educating participants through use of cue cards on such topics as the definition of HIV/AIDS, who is at risk, and ways to reduce 

risk. Also offered are demonstrations on condom use and equipment-bleaching techniques for IDUs. Referrals to 

counseling and other services are provided.

The motivation intervention follows the format of the standard intervention for the first session but ends with asking participants to consider what they are motivated to change in their lives. During the second session, this list is 

reviewed and short- and long-term goals are set. The third and fourth sessions involve discussion of experiences with 

behavior change, including the woman’s sense of control and feelings of ambivalence about behavior change. Riskreduction messages tailored to the participant’s level of readiness to change are also delivered in the fourth session.

The negotiation/conflict-resolution intervention also follows the NIDA standard intervention for the first session, 

but it ends with a discussion of intended behavior changes. The second session reviews the list of possible behavior 

changes and the level of control the participant believes she has and introduces general communication skills and 

strategies to develop assertiveness. Short-term goals are set for strengthening communication, gaining control, and 

developing assertiveness. Negotiation and conflict-resolution strategies are introduced during the third session and 

tailored to the individual during the final session.
32

interventions. While participants in the negotiation intervention were generally more successful at reducing sexual 

risk behaviors, including decreasing the number of paying 

partners and increasing condom use with steady partners, 

participants in the motivation intervention had more success at changing drug-use behaviors.

Efforts were also made to assist program participants in 

their lives outside of the program, with success extending 

well beyond the study’s parameters, notes Dr. Sterk. “A 

lot of the women who received the one-on-one support 

available through the tailored interventions said the program served as a re-entry into society. For example, they 

were encouraged to obtain a photo ID. Many reported 

that this simple act made them feel more connected to 

society again, part of the larger world.” Program graduates 

returned to school, earned their GED, found jobs, joined 

the project to become counselors or interviewers, and 

stopped using drugs.

“Over and over, researchers are finding that we need to

take a more holistic approach to intervention programs,” 

says NIDA’s Dr. Jones. “We can’t just focus on drugs and

sex. We must look at the big picture. It involves childcare, education, employment, housing, and job training. 

Community stakeholders need to develop programs 

that address multiple needs.”

The project maintained a high retention rate—96 percent of the women enrolled in the studies completed the 

6-month followup interview. Dr. Sterk attributes this 

success to the fact that the project was grounded in the 

community and to the value of involving community 

consultants—residents, both former drug users and others, who played key roles in recruiting, interviewing, and 

counseling participants.

In future research, Dr. Sterk intends to examine the 

cost-effectiveness of various intervention formats. “It 

appears that individual sessions may be more desirable 

and cost-effective,” she predicts. Dr. Sterk would like to 

continue the research, assessing the long-term effects of 

specific interventions. She wants to develop an intervention that focuses on women’s households, targeting both 

the woman and her main partner, and she is interested in 

capacity-building—translating her research into other settings and training people to develop similar programs in 

more communities.

Sources

•	 Sterk, C.E.; Theall, K.P.; and Elifson, K.W.

Effectiveness of a risk reduction intervention among 

African American women who use crack cocaine. 

AIDS Education and Prevention 15(1):15-32, 2003.

•	 Sterk, C.E.; Theall, K.P.; Elifson, K.W.; and Kidder,

D. HIV risk reduction among African-American 

women who inject drugs: A randomized controlled 

trial. AIDS and Behavior 7(1):73-86, 2003.

Principles That Guide Format, Content of Interventions

The interventions used by Dr. Sterk and her colleagues in this study are firmly based in theoretical research. The 

researchers conducted a series of one-on-one interviews and focus groups with the target population. These interviews yielded the following key principles that guided both the format and the content of the interventions.

• Offer counseling sessions on an individual basis. “It was very clear that women wanted to start with oneon-one sessions,” says Dr. Sterk. “HIV risk behaviors involve so many private, personal issues—previous abuse 

experiences, actions to support their drug habits, things they’d never before discussed. They found it easier to 

discuss these experiences with one person, not a group.”

• Adopt a holistic approach. Along with this research project, a clothing fair was conducted and clothes made 

available to program participants. Food for breakfast was provided; daycare was close by; and ongoing services,

such as help preparing for job interviews, were provided. 

• Make programs community-based. The project was headquartered in a house in the community, which was 

key to participants’ convenience and comfort. Researchers also found it important for the women to link participation in this project to local social and health services, including local drug treatment, daycare centers, health 

services, and other community-based organizations. Community consultants played a key role in the project. 

• Address women’s multiple social roles in the intervention. Participants insisted that they didn’t want to be 

labeled simply as drug users. Instead, they wanted the social context of their daily lives to be addressed, including their roles as mothers and steady partners.
Research Findings

Volume 18, Number 6 (February 2004)

33

The Neurobehavioral Legacy of Prenatal Tobacco Exposure

By Jill Schlabig Williams, NIDA NOTES Contributing Writer 

More than 17 percent of pregnant women between the

ages of 15 and 44 smoke, according to the 2002 National

Survey on Drug Use and Health. Much is known about 

the adverse effects of smoking during pregnancy: Cigarette 

smoke reduces blood flow through the placenta by as 

much as 38 percent, and pregnant smokers are more than

twice as likely as nonsmokers to have an infant with low 

birthweight. New research by NIDA-funded investigators 

now provides the first evidence of toxic effects of prenatal 

exposure to tobacco smoke on newborn neurobehavior. This finding begins to fill in our picture of how the 

adverse neurological effects of prenatal exposure manifest 

from the earliest days of life to later observed effects, 

including lower IQ and increased risk of developing attention-deficit/hyperactivity disorder.

Drs. Barry M. Lester and Karen L. Law and their colleagues at Brown Medical School in Providence, Rhode 

Island, used the Neonatal Intensive Care Unit Network 

Neurobehavioral Scale (NNNS) to document the effects 

of maternal smoking on 1- to 2-day-old infants. The 

researchers found significant differences in short-term 

neurobehavioral status in tobacco-exposed newborns 

compared with unexposed newborns and noted that neurobehavioral impact worsened as the mothers’ smoking 

levels rose.

“This study offers the first solid evidence of a doseresponse relationship between maternal smoking during 

pregnancy and newborn neurobehavior,” says Dr. Lester. 

“Babies born to mothers who smoked while pregnant are 

stressed, which could affect their development.”

“Focusing on newborn neurobehavioral outcomes is 

important,” comments Dr. Vincent Smeriglio, Chair of 

NIDA’s Child and Adolescent Work Group. “It invites 

us to think about the continuity of consequences, as we 

NNNS Tobacco-Exposed Non-Exposed Measure Description, Number of Items,

Category Infants (N=27) Infants (N=29) and Range

Handling 0.57 0.44 Mean number of strategies used to maintain 

infant’s alert state (8 items, 0-1)

Excitability 3.08 1.91 Sum of items measuring excitable behavior 

(15 items, 0-15)

Hypertonicity 0.37 0.00 Sum of items measuring excess muscle 

rigidity response (10 items, 0-10)

Total Stress/Abstinence 0.12 0.05 Mean number of observed stress/abstinence 

(Withdrawal) 

signs (50 items, 0-1)

 Central Nervous System Stress 0.16 0.09 Subscale of total stress/abstinence score 

(range 0-1)

Gastrointestinal Stress 0.16 0.02 Subscale of total stress/abstinence score 

(range 0-1)

 Visual Stress 0.11 0.01 Subscale of total stress/abstinence score 

(range 0-1)

Tobacco-Exposed Infants Exhibit Significant Neurobehavioral Effects

The NICU Network Neurobehavioral Scale (NNNS), developed with NIDA funding to study prenatal drug exposure, was used to assess the 

effects of prenatal nicotine exposure on 56 newborns within 48 hours of birth. Infants prenatally exposed to tobacco were highly aroused and 

reactive, with more rigid muscles than non-exposed infants. Tobacco-exposed infants also scored higher on a checklist of 50 items that serve 

as markers of stress or drug withdrawal in high-risk babies, with significant results evident for central nervous system, gastrointestinal, and 

visual stress. Data shown are adjusted scores; statistical analyses controlled for parity, 5-minute Apgar score, and birthweight.
34

see these very early behavioral differences in prenatally 

exposed children and consider them in light of effects in 

older children” (see below, “Cognitive Deficits Persist Into 

Early Adolescence for Children of Smoking Mothers”). 

“This research is providing an important piece of the 

puzzle linking prenatal exposure to cigarette smoke and 

long-term behavioral outcomes,” Dr. Smeriglio says.

The researchers conducted their study with 56 new mothers, ages 18 to 35, and their newborns at a Providence

hospital. Recruited shortly after they had given birth, the 

mothers—27 smokers and 29 nonsmokers—had not used

any illegal drugs during their pregnancy and consumed 

fewer than four alcoholic drinks per month. Mothers who 

smoked reported smoking fewer than seven cigarettes per 

day, with tobacco use confirmed by measuring saliva levels of cotinine, the primary metabolite of nicotine. Only

healthy newborns whose weights were appropriate to their 

gestational ages were included in the study; the researchers controlled for birthweight so the effects they found 

on neurobehavior could not be attributed to the effects of 

maternal smoking on birthweight.

A certified examiner who was unaware of the mother’s 

smoking status administered the NNNS to each newborn 

within 48 hours of birth. The test examines an infant’s

Cognitive Deficits Persist Into Early Adolescence 

for Children of Smoking Mothers

Teenage children of mothers who smoked during pregnancy perform more poorly on tests of general intelligence 

and on tasks requiring auditory memory than do children who were not exposed to cigarette smoke before birth, 

according to NIDA-supported researchers at Carleton University in Ottawa, Canada. Dr. Peter Fried and his colleagues, who have followed the development of children born to smoking mothers as part of the Ottawa Prenatal

Prospective Study, previously reported poorer cognitive abilities in children of smokers when the children were ages 

5 to 6 and 9 to 12. “The results we see now that the children are 13- to 16-year-olds continue to suggest that exposure to cigarettes before birth has negative impact on general IQ and on auditory memory. And the effects are doserelated: The deficits are more severe in children of heavy smokers,” Dr. Fried says.

The scientists administered a battery of tests to 145 13- to 16-year-olds (78 boys, 67 girls) whose mothers smoked

heavily (more than a pack per day), lightly (less than a pack per day), or not at all during their pregnancies. The 

tests included measures of general achievement (reading and language skills), visual memory (identifying a missing 

number from a random sequence of numbers from 1 to 10), auditory memory (repeating tape-recorded sentences of

increasing length and complexity), and general intelligence (IQ scores). In some tests there were no significant differences among the children. In tests of general intelligence and auditory memory, however, children born to smokers 

had lower scores than did children of nonsmokers, and children born to heavy smokers had poorer scores than children of light smokers. For example, in the general intelligence test, for which scores from 99 to 109 are considered

“normal,” children of nonsmokers had an average score of 113.4; of light smokers, 109.8; and of heavy smokers,

105.2.

In some areas of cognitive function, the gap in test results between exposed and unexposed children has narrowed 

as the children have grown, observes Dr. Fried. This improvement is most notable in tests that measure achievement rather than innate ability. For instance, although measured IQ remains lower for exposed children, their scores 

on reading and language skills are equivalent to those of unexposed children. “This comparative improvement in 

achievement is associated most strongly with the educational level of the parents. Achievement tests are in many 

ways a measure of formal learning acquired at home and in school. It appears that family and environmental factors 

that support learning can help moderate the negative effects seen in measures of ability,” Dr. Fried explains. 

“The improvements found in this most recent evaluation of these children are encouraging,” says Dr. Vincent 

Smeriglio, chair of NIDA’s Child and Adolescent Work Group. “Nonetheless, the continued finding of poorer 

performance as the exposed children enter adolescence underscores the damage that appears to be done by smoking 

during pregnancy. These kids may be catching up in some ways, but they started out with a serious disadvantage.”

Source

•	 Fried, P.A.; Watkinson, B.; Gray, R. Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicology and Teratolgy 25(4):427-436, 2003.
35

neurological state, considering muscle tone, reflexes, and 

integrity of the central nervous system (CNS); behavior,

including attention, arousal, and excitability; and a checklist of 50 items shown by previous research to be markers

of stress or—in high-risk babies—of drug withdrawal. 

Dose-response effects were determined by evaluating the 

relationship between measures of maternal smoking (cotinine and self-report) and NNNS scores.

“Infants exposed to tobacco in the womb showed statistically significant differences that suggest toxic effects of 

prenatal tobacco exposure on the newborn neurological 

system,” says Dr. Lester. The tobacco-exposed infants 

were highly aroused and reactive as indicated by the 

higher excitability and handling scores, and their muscles 

were more rigid. They also showed signs of stress and 

drug withdrawal consistent with what has been reported 

in infants exposed to other drugs. When the total stress/

abstinence scores were broken down into subscales, 

exposed infants showed significant CNS, gastrointestinal, 

and visual effects. Further, infants prenatally exposed to 

tobacco required more handling to keep them in a quiet 

and alert state.

“These infants’ higher scores in such areas as excitability and arousal reflect that nicotine is a stimulant,” says 

Dr. Lester. The researchers also found consistent doseresponse relationships for both the cotinine bioassay 

results and the self-reports of number of cigarettes smoked 

per day. “These results indicate that greater exposure to 

tobacco smoke is related to increasingly negative neurobehavioral effects,” he adds, “and that these children may be 

at increased risk for future neurobehavioral problems.”

Dr. Lester is currently designing a larger, multisite study 

focusing on the neurobehavioral effects of prenatal exposure to cigarette smoke. Future research will attempt to 

pinpoint which components of tobacco are responsible for 

the known neuro-behavioral effects; determine whether

those effects are long-term; clarify whether newborns

experience nicotine withdrawal; and separate the effects

of prenatal exposure from those of postnatal exposure 

through second-hand smoke or breastfeeding.

With valid information on the potential neurobehavioral effects of prenatal tobacco exposure, more pregnant 

women may be swayed to quit smoking, notes Dr. Lester. 

“The smoking effects observed in our study underscore 

the importance of smoking cessation programs, particularly for women of childbearing age,” he says.

Source

• Law, K.L.; Stroud, L.R.; LaGasse, L.L.; Niaura, R.;

Liu, J.; Lester, B. Smoking during pregnancy and

newborn neurobehavior. Pediatrics 111(6):1318-1323,

2003.
Gender and Ethnic Patterns in Drug Use Among High 

School Seniors

Research Findings

Volume 18, Number 2 (August 2003)

Although rates of marijuana, alcohol, and tobacco use by 12th-grade 

boys and girls declined over the 

25-year period ending in 2000,

the “gender gap” in use of these 

drugs remained largely unchanged. 

According to data compiled by 

the annual Monitoring the Future 

(MTF) survey, senior girls were 77

percent as likely as boys (compared 

with 78 percent in 1976) to have

reported using marijuana in the past 

month. Girls in the 12th-grade class 

of 2000 were 64 percent as likely

(up from 54 percent in 1976) to

have had five or more drinks in a 

row during the past 2 weeks, and 

girls and boys were equally likely to 

be daily smokers.

Ethnic differences in drug use— 

for boys as well as girls—are much 

wider than are gender differences. 

A recently published review of 

MTF data reveals that these ethnic 

differences are significant and have 

persisted since MTF began collecting drug use data in 1976. Key

substance use patterns among ethnic groups and gender differences 

within those groups are presented 

below.

Smoking

Daily smoking declined among all ethnic groups between 

1976 and 1990, then leveled off before beginning to

increase modestly between 1996 and 2000. Among ethnic groups, Native Americans were most likely to smoke 

and African Americans least likely. Within ethnic groups, 

African-American girls were less likely than boys to be 

daily smokers. 

Alcohol

Girls were less likely than boys to report heavy alcohol use 

(five or more drinks in a row within the past 2 weeks), 

and the prevalence for girls and boys over the 25-year 

period ending in 2000 generally decreased. Among ethnic

groups, Native Americans were most likely to report 

heavy drinking; Asian-American and African-American

12th-graders reported the lowest prevalence. No significant gender differences in alcohol use emerged within 

ethnic groups.

36

Substance Use Among High School Seniors, 1976-2000*

12th-Grade Females 12th-Grade Males ‘76-’80 81-’85 ‘86-’90 ‘91-’95 ‘96-’00 ‘76-’80 ‘81-’85 ‘86-’90 ‘91-’95 ‘96-’00

Daily Cigarette Smoking

 White 28.8 23.6 22.6 22.2 27.2 24.4 18.6 19.2 22.3 26.3

 Black 20.8 12.2 5.8 3.4 5.1 21.9 10.8 7.7 6.5 10.9

 Mexican American 15.6 13.2 8.4 9.3 11.0 19.1 13.2 11.8 12.6 15.1

 Puerto Rican/** 15.2 17.9 22.5 23.4

 Other Latin American 10.8 9.8 8.9 15.3

 Asian American 13.3 10.2 8.0 8.6 10.1 14.5 11.5 10.8 12.9 14.3

 Native American 49.8 39.8 30.5 34.2 34.2 38.7 30.8 25.7 32.4 24.7

Heavy Alcohol Use Within Past 2 Weeks

 White 32.1 34.1 30.8 24.6 28.0 53.4 52.9 46.8 39.7 42.4

 Black 12.1 11.1 8.6 7.6 8.3 27.5 24.8 22.9 19.9 18.0

 Mexican American 25.0 26.8 21.4 19.6 23.4 52.0 48.3 44.1 38.8 40.6

 Puerto Rican/** 16.2 18.0 34.2 27.0

 Other Latin American 15.5 19.4 26.7 32.6

 Asian American 14.7 11.4 9.0 8.2 11.1 28.4 22.4 19.4 15.2 18.9

 Native American 40.9 38.3 30.8 26.9 32.5 62.8 57.6 46.8 46.2 41.5

Marijuana Use Within Past 30 Days

 White 30.8 24.6 17.9 15.0 20.8 40.4 31.6 22.5 19.7 26.0

 Black 22.1 20.1 7.2 6.8 12.7 36.6 29.2 14.6 15.9 26.6

 Mexican American 25.9 21.2 11.7 10.5 18.7 39.8 36.9 19.5 19.9 29.3

 Puerto Rican/** 10.8 20.7 26.4 26.7

 Other Latin American 11.0 12.9 13.7 19.6

 Asian American 18.3 13.8 5.2 5.1 9.1 31.2 13.0 9.8 9.0 16.0

 Native American 44.7 30.3 19.7 21.5 32.0 50.9 36.1 26.6 25.5 27.2

*Percentage prevalence shown as the mean for each 5-year span.

**Beginning in 1990, the data distinguish between Puerto Rican and Other Latin American.

18.0 15.0 12.4 18.7 13.7 12.4

21.9 18.5 13.0 36.6 34.6 30.3

19.5 14.4 8.7 34.7 22.7 17.2
Marijuana

Overall, 12th-grade boys in all ethnic groups were somewhat more likely than girls to have used marijuana within 

the past 30 days. Prevalence rates for girls and boys

declined between 1976 and 1990, held steady until 1995,

and increased between 1996 and 2000. Among ethnic

groups, Native Americans were most likely and Asian 

Americans least likely to have used marijuana within the 

past month. 

Source

• Wallace, J.M., et al. Gender and ethnic differences in

smoking, drinking and illicit drug use among 

American 8th, 10th and 12th grade students, 1976-

2000. Addiction 98(2):225-234, 2003.

37
Joint Treatment of PTSD and Cocaine Abuse May Reduce Severity 

of Both Disorders

By Robert Mathias, NIDA NOTES Staff Writer

Research Findings

Volume 18, Number 1 (June 2003)

Many individuals who abuse cocaine, alcohol, and other 

substances also suffer from posttraumatic stress disorder 

(PTSD) related to life-threatening or other traumatic 

events they have experienced or witnessed. Individuals 

with PTSD suffer recurring flashbacks, anxiety, and other 

symptoms that can impede substance abuse treatment. 

Similarly, substance abuse can make PTSD symptoms 

worse. Thus, integrated treatment is recommended as 

the way to treat patients with both disorders. Yet until 

recently, the most effective nonpharmacological treatment 

for PTSD, known as exposure therapy, was considered too 

risky to use with cocaine-dependent patients. The therapy 

seeks to desensitize patients to the distressing emotional 

effects of the trauma that triggered their PTSD by requiring them to repeatedly and graphically describe it.

“Researchers and clinicians have been reluctant to use 

exposure therapy with cocaine-dependent patients,” 

says Dr. Kathleen Brady of the Medical University of 

South Carolina in Charleston. “Drug abuse patients were 

thought to be likely to turn to alcohol and drugs to cope 

with the emotional demands placed on them by recounting the fear-inducing experience.”

A preliminary study led by Dr. Brady suggests that the 

belief that exposure therapy would do these patients more 

harm than good may not be merited. In the study, instead 

of triggering emotional distress and relapse to substance 

abuse, treatment that combined exposure therapy for 

PTSD with substance abuse counseling produced substantial improvement in both disorders.

Thirty-nine cocaine-dependent individuals with PTSD, 

32 of them women, participated in the outpatient study. 

The majority of participants had developed PTSD following such severe traumatic experiences as rape (74 percent),

aggravated assault (89 percent), and other physical assault

(95 percent). Individuals who feel intense fear and helplessness or horror during such terrifying events can later 

develop distressing symptoms that can impair their ability 

to live and work normally.

PTSD symptoms fall into three general categories: “intrusions,” such as flashbacks or nightmares in which the 

person reexperiences the traumatic event; “hyperarousal”

or anxiety, which can be marked by extreme vigilance and 

jumpiness, difficulty sleeping or concentrating, and 

irritability; and “avoidance” of people, activities, and

situations that might trigger memories of the incident. 

When symptoms persist for more than 3 months, PTSD 

is considered chronic. Chronic sufferers often have additional psychiatric disorders. An estimated 30 to 60 percent

of individuals with substance abuse disorders have PTSD, 

according to studies cited by Dr. Brady.

The study used a psychotherapy developed by Dr. Brady 

and her colleagues that combines counseling for drug 

abuse with exposure therapy for PTSD. “We wanted to 

evaluate whether cocaine-dependent PTSD patients could 

38

Combination Psychotherapy Reduces Posttraumatic 

Stress Disorder (PTSD) Symptoms and Cocaine Use

Fifteen cocaine-dependent patients with PTSD who completed a 

psychotherapy that addressed both disorders significantly reduced 

cocaine use and had fewer and less intense PTSD 

symptoms, as assessed by physicians.
safely tolerate the therapy and whether it would be effective in reducing the severity of their PTSD symptoms 

and cocaine use,” Dr. Brady says. The combined therapy 

consists of 16 90-minute individual sessions. In the first

3 weeks, patients participate in two counseling sessions a 

week that concentrate solely on their drug abuse problems 

and developing relapse prevention skills. “The therapy 

in those first sessions gives people a chance to experience 

some sobriety and provides them the coping techniques 

and strategies they will need to deal with high-risk situations and the urges to use drugs they may experience 

when they get into the exposure therapy,” Dr. Brady says.

Once patients start to feel comfortable sharing their feelings with the therapist and are willing to engage in exposure therapy, a technique called imaginal exposure is used 

to address their PTSD symptoms. In imaginal sessions, 

patients describe in detail the circumstances and feelings 

they experienced during the traumatic event that triggered their disorder. They also develop a list of situations 

or places they have been avoiding because they associate 

them with the event. Between sessions, patients carry out 

assignments in which they gradually expose themselves 

to similar situations that are safe but fear-inducing. If, 

for example, they were abducted from a parking lot and 

assaulted, they may have become fearful of any parking 

lot or areas with cars in them. Assignments could involve 

going to such areas, first with a friend, then by themselves 

in the middle of the day. 

“We are trying to get at the irrational fears and inappropriate avoidance of situations that are interfering with 

their lives,” Dr. Brady says. “By talking about their experience over and over in the imaginal sessions, they are basically reliving it. The point of the exposure is to desensitize 

them to the trauma, thereby reducing the fear, anxiety, 

and emotion from the memory itself. By the end of successful therapy, patients are able to go through their entire 

traumatic scenario and feel much less distressed because 

they are able to separate irrational fears from simply thinking about the event.”

The goal of the therapy is that the intrusion, arousal, and 

avoidance symptoms all recede. The exposure has done 

its job when someone can go through his or her detailed 

recalling of the event and score no higher than 5 on a 

20-point scale that measures how much distress they are

feeling, says Dr. Brady. 

Fifteen of the 39 study participants completed the combined therapy, attending at least 10 of the 16 sessions,

including a minimum of 3 exposure therapy sessions. 

Assessments by both patients and clinicians indicated that 

those who completed treatment experienced significant 

reductions in all three PTSD symptom categories and in 

cocaine use from study entry to treatment completion.

Using a self-administered Impact of Events Scale, patients 

reported a 53-percent reduction in “intrusion” symptoms and a 27-percent reduction in inappropriate avoidance behaviors. Over the same period, clinicians using a

30-item structured clinical interview tallied a 66-percent

reduction in “intrusions,” a 70-percent reduction in

“avoidances,” and a 47-percent reduction in hyperarousal

symptoms. By the end of treatment, completers also had 

reduced cocaine use by 60 percent and reported experiencing significantly fewer substance-related problems. 

Followup assessments indicated that treatment completers 

had maintained these improvements in both PTSD symptoms and cocaine use 6 months after treatment ended. 

In contrast, no differences emerged in any PTSD or 

substance-abuse-related scores at treatment completion or 

6 months later among noncompleters. 

“This study provides promising preliminary evidence 

that exposure therapy can be used safely and effectively 

in treating PTSD in some cocaine-dependent individuals 

without increasing the risk of relapse,” says Dr. Brady. 

The improvements in PTSD symptoms were comparable 

to those reported by other studies that used exposure 

therapies to treat patients with no substance abuse disorder. Dropout rates, though high, also were similar to those 

in previous studies that used other psychotherapies to treat 

cocaine-dependent patients.

Nevertheless, the small number of patients in the study 

and the high dropout rates underscore the need for randomized controlled studies to replicate these results, Dr. 

Brady cautions. Such studies also could provide information that would help to identify patients who are likely to 

benefit from this treatment, as well as those who might 

need different approaches.

Source

•	 Brady, K.T., et al. Exposure therapy in the treatment

of PTSD among cocaine-dependent individuals: 

Preliminary findings. Journal of Substance Abuse 

Treatment 21(1):47–54, 2001.

39
New Animal Model Simulates Human Exposure, Confirms Harm 

From Prenatal Cocaine

By Kimberly Martin, NIDA NOTES Contributing Writer 

Research Findings

Volume 18, Number 1 (June 2003)

Research has shown that some children exposed in the 

womb to cocaine may have memory and attention deficits 

that hinder their ability to learn. These children also may 

have difficulties completing complex tasks or tests that 

involve distractions, and they tend to perform poorly on 

visual recognition memory and attention tasks.

Now, Dr. Bret Morrow and his colleagues at Yale 

University have demonstrated in rats that prenatal exposure to cocaine may cause long-term changes in an area 

of the brain responsible for short-term memory. Previous 

animal studies have reported negative effects of cocaine 

on cognitive performance, but doubts persisted about the 

applicability of study results to humans. The new findings 

help allay those doubts, which are based partly on differences in how people use cocaine and in how cocaine was 

administered to rats in earlier experiments. By designing 

an experiment that closely simulates the way humans use 

cocaine, the Yale team has enhanced the applicability of 

cognitive impairment in rats prenatally exposed to cocaine 

to that observed in children.

“To more closely replicate the way human fetuses are 

exposed to cocaine, we administered the drug to the pregnant rats intravenously. This enabled us to use dosages 

similar to those taken by people. Also, the way cocaine is 

absorbed and metabolized when it is administered intravenously is much closer to what we see in humans,” says 

Dr. Morrow. “Additionally, tests commonly used in rat 

studies to assess cognitive deficits—maze and swimming 

tests—rely on artificial manipulation of the animal’s 

environment, such as food restriction, reward, or stress. 

Our test, a two-object recognition task that relied on

the rat’s own motivation to complete the task, is comparable to one used with human infants to assess shortterm memory.”

Cocaine was administered to pregnant rats twice a day 

for 11 days before they gave birth. At ages equivalent to 

human adolescence and adulthood, the male offspring 

were placed in a cage with two identical objects, allowed 

to explore the objects, then removed from the cage. After 

delays of 20 minutes, 1 hour, and 24 hours, the rats were

returned to the cage with one of the former objects and 

a new object. The time a rat spent actively exploring the 

new and former objects was recorded. If he spent more 

time exploring the new object, the rat was considered to 

remember the former object. To count as “exploring” 

time, the rat had to be actively exploring the object, with 

his nose within about 2 cm of the object.

“The rats that were not exposed to cocaine spent more 

time exploring the novel object than the familiar object 

after 20-minute and 1-hour delays, but not after 24

hours,” says Dr. Morrow. “We interpreted this behavior 

as memory of the familiar object from the previous exposure. The rats that were prenatally exposed to cocaine did 

not demonstrate a preference for the novel object over the 

familiar object at any time. This behavior was interpreted 

as their having no memory of the familiar object. These 

findings indicate that in the rat model, prenatal exposure 

to cocaine may result in long-lasting deficits in shortterm memory.”

In a separate study, the researchers found that adolescent 

rats prenatally exposed to cocaine as described above had 

40

This rat is exploring an object during the two-object recognition task. He was previously exposed to one object, whereas the 

other is new. The rat was considered to remember the former 

object if he spent more time exploring the new one. Rats exposed 

to cocaine before birth did not demonstrate a preference for the 

new object, indicating no memory of the familiar object.

Two-Object Recognition Test Mimics Test 

Used with Infants

Photo credit: Dorothy Cameron, the Johns Hopkins University Bloomberg School of Public Health.
long-term changes in the frontal cortex. They showed 

excess activation of neurons in the prefrontal cortex, the 

brain area governing short-term memory. Activation was 

measured by the concentration of Fos, a protein produced 

by excited neurons. “Fos activation during development 

can change the way a neuron responds in the future; in

other words, it undergoes a long-term adaptation,” says 

Dr. Morrow. “In some cases, this may indicate important 

adaptations that help the animal meet new challenges. 

However, in cocaine-exposed animals, we believe that the 

excessive Fos activation may lead to deficits in attention 

and memory.”

“This type of animal model is valuable in guiding research 

into the possible mechanisms and consequences of exposure to drugs of abuse during human development,” says 

Dr. Laurence Stanford of NIDA’s Division of Treatment 

Research and Development. “Animal models allow us 

to reduce the number of variables and confounding factors that are present when pregnant women abuse drugs. 

Research with children strongly suggests a significant dose 

effect, with the severity and presence of deficits linked to 

the extent of exposure. Maternal health may also play a 

role in the effects of prenatal drug exposure. For example, 

the appetite-suppressing effects of cocaine and resulting 

nutritional deficits can contribute to growth retardation 

in the womb. For the purposes of reducing the number of 

variables, and thus attempting to isolate the effects of 

prenatal cocaine exposure, this research is a valuable 

experiment.”

“This animal model may prove valuable not only for 

probing neurological and cognitive deficits caused by 

prenatal cocaine exposure, but also for testing potential 

therapies,” says Dr. Susan Volman of NIDA’s Division of 

Neuroscience and Behavioral Research.

Sources

•	 Morrow, B.A., et al. Prenatal cocaine exposure disrupts nonspatial, short-term memory in adolescent 

and adult male rats. Behavioral Brain Research 129

(1-2):217–223, 2002.

•	 Morrow, B.A., et al. Male rats exposed to cocaine in

utero demonstrate elevated expression of Fos in the 

prefrontal cortex in response to environment. 

Neuropsychopharmacology 26(3):275–285, 2002.

41
Substance-Abusing Adolescents Show Ethnic and Gender 

Differences in Psychiatric Disorders

By Kimberly Martin, NIDA NOTES Contributing Writer 

Research Findings

Volume 18, Number 1 (June 2003)

NIDA researchers have found that the patterns of cooccurring psychiatric disorders in adolescent substance 

abusers differ between ethnic groups and between boys 

and girls. This information may help clinicians be particularly alert to symptoms of the most common psychiatric 

disorders when interviewing patients from each group. 

Eventually, it may aid in the development of tailored 

screening, assessment, and treatment interventions for 

different groups.

Ethnic Differences

Dr. Michael Robbins and colleagues from Florida’s 

University of Miami found high rates of psychiatric disorders among Hispanic and African-American adolescent 

substance abusers referred for outpatient therapy. Their 

study distinguished externalizing disorders—characterized 

by lack of self-control and acting-out behaviors, recurring patterns of aggression, and behaviors that prevent 

the development and maintenance of relationships—from 

internalizing disorders, typified by sadness, withdrawal, 

avoidance of interaction with others, and loss of interest 

in activities.

“Studies have consistently documented high rates of psychiatric disorders among adolescent substance abusers. 

They also have found that certain co-occurring disorders 

are associated with certain treatment outcomes. For example, depression or attention-deficit/hyperactivity disorder 

(ADHD) may contribute to early dropout and poor treatment outcomes,” says Dr. Robbins. “Therefore, treating 

substance abuse alone may 

not be enough. Treatment 

providers need to address the 

constellation of emotional 

and behavioral problems presented by each individual.”

The researchers recruited 

167 Hispanic and AfricanAmerican 12- to 17-year-olds

referred for outpatient treatment for substance abuse 

between October 1997 and

March 2000. Participants’

substance use was assessed 

before treatment with the 

Adolescent Drug Abuse 

Diagnosis, a standard assessment tool that provides 

information on the frequency 

of use of alcohol, marijuana, 

cocaine, and other drugs during the preceding month. 

The youths also completed 

the Diagnostic Interview 

Schedule for Children—

Predictive Scales, a questionnaire that screens for nine psychiatric disorders, including social phobias, panic, anxiety, 

major depression, ADHD, oppositional defiant disorder 

(ODD), and conduct disorders (CD).

Dr. Robbins and colleagues found that Hispanic and 

African-American youths were similar in the drugs they 

used and their overall prevalence of co-occurring psychiatric disorders. More than 80 percent of the participants

reported using marijuana, and about 17 percent and 35

percent reported using cocaine and alcohol, respectively. 

42

Externalizing Behaviors

•	 Recurring patterns of aggression

•	 Excessive arguing

•	 Use of physical or verbal coercion

•	 Noncompliance with reasonable

requests 

•	 Persistent pattern of tantrums

•	 Persistent pattern of lying or stealing

•	 Lack of self-control, acting-out

behavior 

•	 Behaviors that prevent development or maintenance of relationships 

Internalizing Behaviors

•	 Sad affect, depression, feelings of

worthlessness 

•	 Auditory or visual hallucinations

•	 Constant repetition of certain

thoughts, ideas, or situations 

•	 Repetitive and useless actions

•	 Frequent crying, atypical affect

•	 Severe headaches or other somatic

problems 

•	 Talk of suicide

•	 Decreased interest in activities

•	 Restricted activity levels

•	 Withdrawal, avoidance of interactions, lack of personal care

Typical Behaviors in Adolescent Psychiatric Disorders
Overall, 87 percent of the youths reported symptoms of

at least one co-occurring psychiatric disorder. Of these,

about 19 percent reported symptoms for only one disorder, while more than 54 percent reported symptoms of 

three or more disorders.

Hispanic youths had significantly more symptoms of 

externalizing psychiatric disorders, such as ADHD and 

ODD, than did African-American youths. More than 78

percent of Hispanics reported symptoms of at least one 

externalizing disorder, compared with about 65 percent 

of African-American youths. However, about twice as 

many African-American adolescents reported symptoms 

for agoraphobia, an internalizing psychiatric disorder 

that finds the sufferer severely anxious about going outside the home. The researchers note, though, that the 

high rates of symptoms associated with agoraphobia may 

instead reflect legitimate fears about being in very dangerous public settings.

“Our findings suggest that substance abuse among

Hispanic youths may occur more often within a larger 

context of problem behaviors,” says Dr. Robbins. “In 

addition to enhancing Hispanic youths’ emotional and 

behavioral functioning, interventions need to address 

problems with their families, schools, peer group, and 

other areas where co-occurring externalizing behaviors 

often have severe and profound consequences.”

Dr. Robbins observes that his findings may be relevant 

primarily to youths referred for outpatient treatment, 

rather than all Hispanic and African-American substanceabusing youths. “We believe substance abuse among 

African-American youths may be related to problem 

behaviors as well. Our sample drew from community

outpatient referrals. Further research is warranted to determine if there is a basic difference between ethnic groups in 

the constellation of behavior problem symptoms or if our 

numbers reflect a bias in the way youths are referred 

to outpatient treatment. African-American youths may 

be more likely to be referred 

to other types of treatment 

providers or sent to jail or 

detention.”

Gender Differences

Dr. William Latimer and colleagues at the Johns Hopkins

University, Bloomberg 

School of Public Health, in 

Baltimore, and the University 

of Minnesota, Twin Cities, 

Minneapolis, examined gender 

differences in rates of co-occurring psychiatric disorders in 

substance-abusing adolescents. 

They found that more male 

teenage substance abusers also 

had disruptive disorders, whereas females had higher rates of 

depression.

“Gender may be useful in helping clinicians who assess youths 

referred to drug treatment by 

signaling the likely presence of 

certain psychiatric disorders for 

males and females. However, 

clinicians should not rule out 

the possibility of a disorder 

based on the patient’s gender.” says Dr. Latimer. “For 

example, although co-occurring 

disruptive disorders are more 

common among males than 

females, this shouldn’t obscure 

43

Co-Occurring Psychiatric Disorders Vary by Ethnicity and Gender 

in Adolescent Substance Abusers (by Percent)

Psychiatric Disorder0

Attention-deficit/hyperactivity 

disorder

Oppositional defiant disorder

Conduct disorder

Any disruptive behavior disorder

Agoraphobia

Major depressive disorder

Any mood disorder

African 

Americana

N=77

20.8%

41.6

53.6

NAc

40.3

26.0

NAc

Hispanica

N=90

41.4%

60.5

56.6

NAc

19.5

33.3

NAc

Femaleb

N=34

23.5%

26.5

47.1

76.5

NAc

44.1

50.0

Maleb

N=101

45.5%

18.8

72.3

94.1

NAc

16.8

36.6

Externalizing Behaviors

Internalizing Behaviors

a Robbins et al., Journal of the American Academy of Child and Adolescent Psychiatry, 2002.

Percentages indicate a probability estimate of the presence of psychiatric disorders.

b Latimer et al., Experimental and Clinical Psychopharmacology, 2002.

c Data not available.

Among substance-abusing youths referred for outpatient substance abuse treatment, Hispanics reported 

higher rates of externalizing disorders than did African Americans, while African Americans reported 

higher rates of the internalizing disorder agoraphobia. In a separate study of adolescent substance 

abusers, boys were more likely to be diagnosed with externalizing disorders, while young women were 

more likely to be diagnosed with depression, an internalizing disorder.
the equally important finding that high rates of these disorders are also present among substance-abusing females.”

The researchers recruited 135 adolescents (ages 12 to 

19) who met the Diagnostic and Statistical Manual of

Mental Disorders criteria for one or more psychoactive substance use disorders (PSUD), including alcohol 

abuse or dependence, marijuana abuse or dependence, 

and abuse or dependence on drugs other than alcohol 

and marijuana. Adolescents and their parents completed 

the Diagnostic Interview of 

Children and Adolescents, 

which provided information 

about PSUDs and symptoms 

of ADHD, ODD, CD, and

mood disorders. Adolescents 

also completed the Personal 

Experience Inventory, which 

provided information about 

3-month, 12-month, and lifetime alcohol and other drug 

use frequencies and related 

consequences. Adolescents’ 

reports of substance abuse were verified by urine tests.

About 68 percent of the girls and 75 percent of the boys

were diagnosed with alcohol abuse or dependence, while 

about 85 percent of the girls and 93 percent of the boys

were diagnosed with marijuana use disorders. More than 

17 percent of the girls and 21 percent of the boys were

diagnosed with abuse or dependence on some other drug 

or drugs. The patterns of single-substance versus polysubstance use also varied with gender. Girls were more likely 

to be diagnosed with abuse or dependence on only one 

drug, while boys were more likely to be diagnosed with 

simultaneous abuse or dependence on more than 

one drug.

The researchers found that nearly twice the percentage of 

teenage male substance abusers had co-occurring ADHD 

or CD compared with female teen abusers, whereas 

roughly three times the percentage of females had a 

co-occurring major depressive disorder. However, both 

genders had similar rates of mild depression (dysthymia), 

double depression (chronic depression with episodes of 

major depression), and bipolar disorders.

“Drug abuse and psychiatric disorders co-occur at 

extremely high rates in adolescents,” says Dr. Latimer. 

“Therefore, drug treatment programs may be more 

effective if strategies that address multiple patterns of 

simultaneously occurring disorders are included. Those 

geared toward adolescent boys may benefit by incorporating strategies that address psychiatric problems related to 

behavioral dysfunctions, while those intended for adolescent girls may need to include therapies that address major 

depression.” Further examination of how simultaneously 

occurring psychiatric and 

substance abuse disorders 

interact is needed, he notes.

“When a group of patients 

shares a characteristic, 

such as age or gender, it 

seems reasonable to expect 

that they might require a 

treatment sensitive to that 

characteristic,” says Dr. 

Melissa Racioppo of NIDA’s 

Behavioral Treatment 

Development Branch. “But it is also possible that a characteristic may be irrelevant to treatment outcome. Drs. 

Robbins’ and Latimer’s studies help identify characteristics 

of groups of substance abusers, which lays the groundwork 

for testing the relevance of these characteristics to treatment interventions. In the future, we may have effective 

behavioral treatments that appropriately attend to gender 

and racial/ethnic differences among adolescent substance 

abusers.”

Sources

•	 Latimer, W.W., et al. Gender differences in psychiatric

comorbidity among adolescents with substance use 

disorders. Experimental and Clinical Psychopharmacology

10(3):310–315, 2002.

•	 Robbins, M.S., et al. Ethnic differences in comorbidity among substance-abusing adolescents referred to 

outpatient therapy. Journal of the American Academy 

of Child and Adolescent Psychiatry 41(4):394–401,

2002.

44

Girls were more likely to be diagnosed 

with abuse or dependence on only 

one drug, while boys were more likely 

to be diagnosed with simultaneous 

abuse or dependence on more than 

one drug. 
Animal Studies Show Sex Differences in Impact of Efforts To 

Reduce Drug Seeking

By Jill Schlabig Williams, NIDA NOTES Contributing Writer 

Research Findings

Volume 17, Number 6 (March 2003)

In recent studies, Dr. Marilyn Carroll and her colleagues 

at the University of Minnesota looked at the impact of 

two interventions on self-administration of heroin and 

cocaine by rats and found that, in each case, the intervention produced a greater effect on the female rats studied 

than on the male rats. These findings and the results of 

other studies looking at sex differences suggest that the 

most effective drug abuse treatments for men and women 

may be quite different.

In one study, Dr. Carroll found that administering 

baclofen, a muscle relaxer, suppressed the establishment 

of cocaine use significantly more in female rats than in 

males. The other study looked at the effect of offering 

wheel-running as an alternative to drug-seeking behavior;

again, the result was that only female rats significantly 

decreased their levels of drug self-administration—in this 

case, cocaine.

“These studies highlight the importance of paying attention to sex differences in the development of pharmacotherapies and in other drug abuse research,” says 

Dr. Cora Lee Wetherington, NIDA’s women and gender 

research coordinator. “For example, some smoking cessation medications seem to work better for men; others

work better for women. As new medications are developed for other forms of drug abuse, the story may be 

similar. Treatment effects may not be the same in males 

and females.” 

“We are increasingly finding that sex and hormonal status 

are important determinants of drug abuse at all phases of 

addiction—acquisition, maintenance, escalation/dysregulation, and reinstatement,” says Dr. Carroll, whose previous animal research has consistently found that females 

tend to use more drugs, more quickly. Recent epidemiological data indicate that in humans, females also tend 

to progress to dependence at a 

faster rate than males. 

In the first study, Dr. Carroll 

and her colleagues examined the 

effects of baclofen on 44 rats 

that had never been exposed to 

cocaine. Previous animal studies 

have demonstrated the promise 

of baclofen, which modulates 

several neurotransmitter systems, 

as a potential treatment medication. Each rat participated in 

30 daily sessions. During the

first six hours of each session, 

the rats were given repeated, 

random infusions of baclofen at 

a relatively low dose of 0.2 mg/

kg. For each infusion, a lever 

extended into the cage where 

it stayed for 15 seconds, after 

which the cocaine was administered and the lever retracted. 

If the animal touched the lever 

during the 15-second latency 

period, cocaine was administered 

immediately. In this manner, the 

rats learned within a few days 

to associate the lever with drug 

45

Pretreatment with baclofen has been shown to slow the establishment of cocaine use in rats. 

Among rats pretreated with baclofen, only 15.4 percent of females self-administered an average 

of 100 cocaine infusions for 5 consecutive days during a 30-day trial, compared to 77.7 percent 

of males. Under saline pretreatment, all of the animals tested reached this injection frequency and 

consistency within 30 days.

Baclofen Slows Establishment of Cocaine Use in Females More Than Males
infusions and to push the lever to self-administer cocaine. 

A second 6-hour component each day allowed the rats to 

freely self-administer cocaine; the lever remained extended

into the cage and a dose of cocaine was delivered each 

time the lever was pressed.

To test the effects of baclofen on the rate of acquisition 

of a habit of regular drug-taking, investigators divided the 

rats into four groups. One male and one female group

were injected with baclofen prior to each session; another

male and another female group were pretreated with 

saline. Researchers measured the number of infusions each 

rat received during the self-administration session until 

it reached the acquisition criterion or level at which it 

was considered to have developed a habit of cocaine use, 

defined as an average of 100 infusions per day for 5 days.

All of the female rats pretreated with saline reached the 

acquisition criterion by day 14. All males pretreated with 

saline met the criterion by day 19. In the group of female

rats pretreated with baclofen, only 15.4 percent met the 

acquisition criterion within the 30-day limit. In contrast,

77.7 percent of males pretreated with baclofen met the

criterion within the 30-day limit. When baclofen treatment was discontinued, all of the females who initially did 

not meet the acquisition criterion did so within 11 days.

“Pretreatment with baclofen slowed the rate at which the 

rats reached the specified level of cocaine self-administration and reduced the percentage of rats reaching that 

level to a greater extent in females than in males,” says Dr. 

Carroll. “The propensity of the female rats to use cocaine 

at the specified levels was no different than that of the 

males, because they all acquired a habit of cocaine use 

without baclofen. It was just that the baclofen had a 

different effect on the females.”

The next study looked at sex differences identified as a 

result of a behavioral intervention to reducing drug use. 

“Enriching the environment is a promising approach to 

reducing the initiation, maintenance, and reinstatement 

of drug abuse,” says Dr. Carroll. (See also, “Social 

Environment Appears Linked to Biological Changes in 

Dopamine System, May Influence Vulnerabilility to 

Cocaine Addiction,” NIDA NOTES, Vol. 17, No. 5.)

In this study, rats were offered access to a running 

wheel as an alternative to self-administering cocaine. 

Wheel-running is an activity rats enjoy, and research 

has shown that when given a choice between food and 

running wheels, rats often chose running over eating. 

Seventeen rats were initially given access to a running 

wheel alone until their average daily number of wheel 

rotations stabilized. Next, rats were trained to self-administer cocaine (0.2 mg/kg) until they reached an average of

100 infusions a day for 5 consecutive days. The rats were

then given concurrent access to cocaine and the running 

wheel. Researchers calculated the mean number of wheel 

rotations and mean number of cocaine infusions during 

the last five sessions of each phase. 

Under cocaine-only conditions, both males and females 

averaged 30 infusions per hour. Females saw a reduction

of 70.6 percent in infusions to fewer than 10 per hour

when there was concurrent access to the running wheel. In 

males, while infusions decreased slightly (21.9 percent) to

an average of 25 infusions per hour, the reduction was not 

statistically significant.

“Taken together, these studies suggest that females rats are 

more responsive than males to treatments for drug abuse,” 

says Dr. Carroll. Although few data exist on sex differences regarding treatment of drug abuse in humans, research 

is beginning to point to hormones as one cause 

of sex differences in drug abuse. “A growing body of 

research indicates that ovarian hormones, such as estrogen, may account for many of the sex differences in drug 

abuse, increasing the subjective effects of drugs and their 

reinforcing potential.” More studies are needed, both in 

animals and humans, to better understand these sex 

differences and to use this knowledge to improve treatment options.

Sources

•	 Campbell, U.C.; Morgan, A.D.; and Carroll, M.E.

Sex differences in the effects of baclofen on the acquisition of intravenous cocaine self-administration in 

rats. Drug and Alcohol Dependence 66:61–69, 2002.

•	 Cosgrove, K.P.; Hunter, R.G.; and Carroll, M.E.

Wheel-running attenuates intravenous cocaine selfadministration in rats: Sex differences. Pharmacology 

Biochemistry and Behavior 73:663–671, 2002.

46

Having access to a running wheel as an alternative to drug-seeking 

behavior caused a 70-percent reduction in cocaine self-administration among females. The difference for males was not statistically 

significant. In succession, the rats studied were given access to (1) 

cocaine only; (2) cocaine and the wheel; and (3) cocaine only.
Study Finds Significant Mental Deficits in Toddlers Exposed to 

Cocaine Before Birth

By Robert Mathias, NIDA NOTES Staff Writer 

Research Findings

Volume 17, Number 5 (January 2003)

Since the mid-1980s, up to 1 million children born in

the United States are estimated to have been exposed to 

cocaine in the womb. Determining cocaine’s impact on 

these children’s development has been difficult because 

there often are other possible explanations for physical 

and mental problems the children may have, such as the 

mother’s use of other substances during pregnancy and 

poor prenatal care. Now, a NIDA-supported study that 

was able to separate the effects of cocaine from those of 

many other such factors has found that children born to 

poor, urban women who used cocaine throughout pregnancy were nearly twice as likely as children with similar 

backgrounds but no prenatal cocaine exposure to have significant cognitive deficits during their first 2 years of life.

The study, led by Dr. Lynn Singer of Case Western 

Reserve University in Cleveland, Ohio, is the first to show

a clear association between prenatal cocaine exposure and 

cognitive impairment in 2-year-olds. “Since cognitive 

performance at this age is indicative of later performance, 

these children may continue to have learning difficulties 

that need to be addressed when they reach school age,” 

Dr. Singer says. 

“The findings of this well-controlled study make an 

important contribution to a growing body of knowledge 

about the effects of prenatal cocaine exposure that may 

help us to identify those exposed children who are at 

increased risk of developmental harm,” says Dr. Vince 

Smeriglio of NIDA’s Center on AIDS and Other Medical

Consequences of Drug Abuse. Previous findings from 

other NIDA-supported studies that have been following 

cocaine-exposed children from birth have produced conflicting results about cocaine’s impact on developmental 

outcomes at this age, he notes. “Comparing and contrasting the circumstances in this study with those found in 

other studies of cocaine-exposed children may enable us to 

identify specific biological and environmental factors that 

increase or reduce the developmental risk from cocaine 

exposure,” Dr. Smeriglio says.

The study followed a group of 415 infants born at a large 

urban teaching hospital from 1994 through 1996 to

mothers from low socioeconomic backgrounds who had 

been identified by the hospital staff as being at high risk 

of drug abuse. Women who participated in the study were 

given urine tests for drug use immediately before or after 

delivery and interviewed shortly after they gave birth to 

produce estimates of the type, frequency, and amounts of 

drugs they had used during pregnancy. Each baby’s first 

stool, known as meconium, also was analyzed for the presence of cocaine and its metabolites to help establish the 

level of drug exposure. Of the 415 babies in the study,

218 had been exposed to cocaine and 197 had not. Both

groups of infants also had been exposed to tobacco, 

alcohol, and marijuana during pregnancy.

47

Mental Development Scores For Prenatally CocaineExposed and Unexposed High-Risk Children

Tests of mental development at 6.5, 12, and 24 months showed 

average scores of cocaine-exposed and unexposed children from 

comparable backgrounds were below the normative score of 100 

for children in the general population. At age 2, cocaine-exposed 

children did significantly poorer in mental development than 

children in the comparison group.
Researchers measured the children’s developmental progress at 6.5, 12, and 24 months of age with the Bayley 

Scales of Infant Mental and Motor Development. Motor 

tests assessed the infants’ ability to control and coordinate 

their movements. Mental tests assessed language, memory, 

and ability to solve problems at 12 and 24 months. For 

example, children were asked to describe objects in pictures, remember where an object had been hidden, and 

put shaped objects into the correct spaces cut out on 

form boards.

To isolate cocaine’s effect, researchers adjusted test results 

for the effect of other risk factors, such as other drugs used 

during pregnancy; characteristics of biological mothers

and alternative caregivers; the infants’ head size, weight,

length, and gestational age at birth; and the quality of

their postnatal home environments. The analysis showed 

that while prenatal cocaine exposure had not affected 

the infants’ motor development, it was clearly linked to 

significant deficits in their cognitive performance at age 

2. Cocaine-exposed children scored 6 points lower on 

the Mental Development Index (MDI), averaging 82.7

percent compared to 88.7 percent for unexposed children

and an average general population score of 100. Other

findings include the following:

•	 From 6.5 to 24 months, MDI scores declined for

both groups, but cocaine-exposed children had a 

greater decline—14 points compared to a 9-point

decline for unexposed children.

•	 Almost 14 percent (13.7 percent) of cocaine-exposed

children had scores in the mental retardation range, 

below 70 on the MDI, nearly twice the 7.1-percent

rate found in the unexposed children and almost five 

times the rate (about 2.8 percent) expected in the

general population.

•	 Nearly 38 percent (37.8 percent) of cocaine-exposed

children had developmental delays requiring remedial 

intervention, nearly double the 20.9 percent rate for

unexposed children. 

The study found that other influences, including the 

mother’s intelligence scores and educational level, exposure to other substances, and the quality of the postnatal 

home environment, also played significant roles in poor 

outcomes for cocaine-exposed children. “However, after 

controlling for these factors in our analysis, we found 

that cocaine still has a harmful effect on cognitive 

performance,” Dr. Singer says. Additional support for this 

conclusion comes from mothers’ self-reports and biological data from mothers and infants that established a direct 

link between cocaine dose and toddlers’ cognitive performance. These data showed that children of mothers who 

used more cocaine and used it more frequently during 

pregnancy performed worse on the MDI than children of 

mothers who used less of the drug.

“The only risk factor we couldn’t completely control for 

is the effect of other drugs used during pregnancy,” Dr. 

Singer says, “because it is nearly impossible to find children who have been exposed only to cocaine.” The study 

partially adjusted for this influence by including children 

who had been heavily exposed to alcohol, tobacco, and 

marijuana in both groups. “Animal studies suggest there 

are possible synergistic effects of these drugs in combination, and the study may not have been large enough to 

control for these effects,” she notes. 

“We believe that cocaine exposure is a neurologic risk 

factor that may take a poor child who has a lower IQ 

potential because of maternal and other risk factors and 

push him or her over the edge to mental retardation,” 

Dr. Singer says. For example, average IQ scores for both 

cocaine-exposed and unexposed toddlers in the study were 

well below the average score for the general population. 

“In effect, cocaine lowered the range of IQ scores and that 

means more children may require early stimulation and 

educational programs,” she says.

“While many children in this study may require special educational services when they enter school, it is 

important not to assume that the findings from a single 

study, with its unique characteristics, necessarily apply 

to all cocaine-exposed children,” cautions NIDA’s Dr. 

Smeriglio. Ultimately, NIDA’s extensive portfolio of 

research on groups of cocaine-exposed children being 

raised in a variety of settings should provide detailed 

information about mother, child, environment, and druguse characteristics that can be used to develop interventions 

that reduce risk of harm and guide clinical care for cocaineexposed children.

Source

•	 Singer, L.T., et al. Cognitive and motor outcomes of

cocaine-exposed infants. JAMA 287(15):1952–1960,

2002.

48
NIDA-funded researchers are studying gender differences 

in smoking behavior and working to develop treatment 

plans that will help more women end their nicotine addiction. Three recent studies headed by Dr. Kenneth Perkins 

of the University of Pittsburgh add to this knowledge and 

test new treatment approaches for women.

In one set of studies, Dr. 

Perkins has found that the 

smell and taste of cigarettes 

play a greater role in women’s 

smoking behavior than in 

that of men. Another study 

found that cognitive-behavioral 

therapy aimed at changing attitudes about weight promotes 

smoking cessation by women. 

Additionally, Dr. Perkins found 

that menstrual cycle phase has 

an effect on both mood and 

tobacco withdrawal symptoms 

for women trying to quit smoking—a finding that suggests 

that women could improve 

their success rate simply by 

starting their quit attempt during certain days of their cycle.

Sensory Factors in Smoking

Dr. Perkins and his colleagues 

used a set of laboratory studies 

to examine the effects of sensory cues—seeing a lit cigarette and smelling and tasting smoke—on smoking behavior of women versus men. In one of the studies, researchers recruited 51 young smokers (21 men, 30 women)

from the nearby community for what subjects were told 

was a test of different kinds of cigarettes. The smokers 

wore opaque goggles or swimmers’ noseclips while smoking to test the roles that visual and olfactory cues—that 

is, cues related to seeing and smelling—play in smoking 

pleasure and reinforcement. Researchers measured smoking reinforcement—the number of puffs taken in different 

situations—and pleasure—using subjective measures such 

as the Rose Sensory Questionnaire—to assess the extent 

that sensory cues reinforce smoking.

They found that blocking olfactory stimuli made a 

greater difference to women than to men. While pleasure 

in smoking was reduced for both women and men when 

visual and olfactory cues were blocked, women found 

significantly less pleasure in smoking and also smoked 

less than men under the blockade conditions. This study 

shows that sensory cues play 

a larger role in smoking for 

women than for men and 

further demonstrates that the 

olfactory cues, not the visual, 

were the cause of the difference.

Dr. Perkins has recently tested 

the effects of nicotine “dose” 

in cigarettes on smoking pleasure and reinforcement in 30

men and women smokers. 

The smokers sampled, rated, 

and then smoked their regular 

brand of cigarette or an ultralow-nicotine cigarette, both 

of which were presented with 

brand markings concealed. 

The nicotine dose of cigarettes 

had less effect on self-reported 

pleasure and reinforcement in 

women compared to men, consistent with the notion that nicotine may be a less important 

influence on smoking behavior 

in women than in men. 

“Because women pay more attention to cues related to 

smell than do men,” says Dr. Perkins, “they could benefit 

from counseling to avoid those cues and could learn cognitive coping strategies to reduce the urge to smoke.” Such 

behavioral counseling is not now used widely or effectively, he says. He suggests that future research could focus on 

other conditioned reinforcers of smoking, such as brand 

markings, “hand-mouth” activity, environmental contexts, 

and consumption of other drugs (such as caffeine or 

alcohol), with the goal of finding ways to extinguish 

the reinforcing effects of these stimuli or finding 

sensory substitutes.

Women and Smoking: Sensory Factors, Attitudes About Weight, 

Phase of Menstrual Cycle All Key To Quitting

By Jill S. Williams, NIDA NOTES Contributing Writer 

Research Findings

Volume 17, Number 4 (November 2002)

49

Weight Control Methods Impact 

Smoking Abstinence

Women who participated in cognitive-behavioral therapy, 

learning to accept a modest weight gain while trying to quit 

smoking, achieved greater abstinence levels than those in the 

weight control group, who were given daily calorie goals, or 

the social support group, who received counseling that did not 

focus on weight issues.
Dr. Cora Lee Wetherington, NIDA’s Women and Gender 

Research Coordinator, points out that this study is consistent with other research showing that women may benefit 

less from the nicotine patch or gum but more from the 

nicotine inhaler than do men. “Women lose both the 

sensory cues and the nicotine when they quit smoking,” 

she says. “Therefore, replacing those cues—something 

the inhaler can do, but not the patch or gum—and learning ways to avoid or cope with those cues may help more 

women succeed in quitting.”

Attitudes About Weight Gain

Previous smoking cessation trials have found that more 

than half of women smokers have a hard time quitting, 

at least partly because of concerns about weight gain. 

The average postquit weight gain of 10 pounds sabotages

many attempts to quit smoking early on and causes some 

women to resist even trying to quit, to drop out of treatment, or to relapse after quitting. Research has found that 

dieting to prevent this weight gain is ineffective and may 

actually interfere with quit efforts. Now, a new study has 

shown that cognitive-behavioral therapy (CBT) aimed at 

reducing dietary restraint and changing attitudes about 

weight proved more successful at both controlling weight 

gain and promoting smoking cessation. 

Dr. Perkins and his colleagues studied 219 women

between the ages of 18 and 65 who wanted to quit smoking but were significantly concerned about gaining weight, 

as determined by telephone interviews during subject 

recruitment. The women, divided into three treatment 

groups, all received standard smoking cessation counseling. Each group also received either behavioral weightcontrol counseling, CBT to reduce weight concerns, or 

social support not focused on weight issues.

Members of the weight-control group were given daily 

calorie goals and instructed to track food intake in a diary, 

with the goal of reducing between-meal snacking (the primary source of excess calorie intake after quitting smoking). These women successfully prevented any weight gain 

in the month after quitting, as expected.

The CBT group received therapy to help them accept 

a modest weight gain in light of the benefits of quitting smoking. In putting together a CBT approach for 

smokers, Dr. Perkins turned to his colleague Dr. Marsha 

Marcus, who is an expert on eating disorders. “We wanted 

to help women accept the likelihood that they may gain 5 

to 10 pounds, and we used CBT to modify their attitude

toward that weight gain,” she says. “We identified unrealistic thoughts or beliefs about weight gain and smoking, 

and we developed cognitive approaches to counteract 

those thoughts. Our key message was, ‘adopt moderation

in eating, reduce stress levels, and exercise more during an 

attempt to quit smoking.’”

At 1-year followup, 21 percent of the CBT group had successfully quit smoking, compared with 13 percent of the 

weight-control group and 9 percent of the social support

group. Weight gain for those continuously abstinent at 1 

year averaged 6 pounds for the CBT group, 12 pounds 

for the weight-control group, and 17 pounds for the social

support group.

“Health care providers and smokers should be aware 

that the CBT approach has more promise than the diet 

approach,” says Dr. Perkins. He suggests that future 

research can distill the key elements of the CBT 

intervention so it can be delivered concisely and test 

a combination of CBT with medication to further 

improve outcomes.

Today, researchers are paying more attention to the possibility of sex differences and analyzing those differences 

in their own data. “Both women and health care providers 

should recognize the obstacles women face and consider 

how to approach them to maximize their chances of success at quitting smoking,” says Dr. Perkins.

Dr. Wetherington sees great value in this type of research: 

“Because of the gender-based approach Dr. Perkins has 

taken, we are beginning to see that what works best for 

males may not work best for females, and vice versa. We 

are beginning to develop better treatment strategies.”

Sources

•	 Perkins, K., et al. Sex differences in the subjective and

reinforcing effects of visual and olfactory cigarette 

smoke stimuli. Nicotine & Tobacco Research 3(2):141–

150, 2001.

•	 Perkins, K.A.; Jacobs, L.; Sanders, M.; and Caggiula,

A.R. Sex differences in the subjective and reinforcing 

effects of cigarette nicotine dose. Psychopharmocology

163(2):194–201, 2002.

•	 Perkins, K.A., et al. Cognitive-behavioral therapy

to reduce weight concerns improves smoking cessation outcome in weight-concerned women. Journal 

of Consulting and Clinical Psychology 69(4):604–613,

2001.

•	 Perkins, K.A.; Levine, M.; and Marcus, M. Tobacco

withdrawal in women and menstrual cycle phase. 

Journal of Consulting and Clinical Psychology

68(1):176–180, 2000.

•	 Perkins, K.A. Smoking cessation in women: Special

considerations. CNS Drugs 15(5):391–411, 2001.

50
Timing Quit Date May Help Women Smokers

Research Findings

Volume 17, Number 4 (November 2002)

Women trying to quit smoking may be able to improve 

their success rate by starting their quit attempt on certain 

days of their cycle. In the course of the larger smoking 

cessation trial focused on weight issues, Dr. Perkins also 

examined tobacco withdrawal and mood measures for 78

premenopausal women who maintained smoking abstinence for 1 week after quitting. Half of the women quit 

during the follicular phase of their menstrual cycle (days 1 

through 14) and half quit during the luteal phase (day 15 

or later). He found that women quitting during the luteal 

phase reported significantly more tobacco withdrawal 

symptoms and depression than those who quit during the 

follicular phase. 

“This research suggests a clear behavioral prescription for 

increasing the odds of success in quitting,” says Dr. 

Perkins. “Women should set a quit date early in the follicular phase. Withdrawal symptoms and depression may be 

less intense. If withdrawal is blunted, quitting should be 

easier. And this simple strategy for timing the quit day 

costs nothing.” 

51

Tobacco Withdrawal Symptoms, Luteal Versus 

Follicular Phase

Withdrawal symptoms for luteal-phase women 1 week after quitting smoking were significantly higher than those of follicular-phase 

women. Symptoms of irritability, anxiety, difficulty concentrating, 

restlessness, impatience, hunger, and depression were rated by 

participants on a scale ranging from 0 (none) to 100 (extremely 

intense). The graph illustrates mean values for all symptoms combined.
Prenatal Exposure to Ecstasy May Impair Memory and Cognition

By Jill S. Williams, NIDA NOTES Contributing Writer 

Research Findings

Volume 17, Number 3 (October 2002)

Dr. Harry Broening, Dr. Charles Vorhees, and colleagues 

at the Cincinnati Children’s Research Foundation and 

the University of Cincinnati have demonstrated that rats 

exposed to MDMA—ecstasy—during the developmental 

period corresponding to the third trimester of human 

pregnancy suffer memory and learning deficiencies that 

persist into adulthood.

Scientific studies have already established that ecstasy 

users are at risk for dehydration, hypertension, hyperthermia, and heart or kidney failure. The drug also has been 

shown to damage nerves in the brain’s serotonin system 

and appears to produce long-term deficits in memory and 

cognition. The new study suggests that unborn children 

of ecstasy users may suffer deleterious effects that last into 

adulthood. “The possibility that these findings in rats 

may also apply to humans raises a concern because this 

drug, which is incorrectly perceived as safe by many of its 

proponents, is sometimes being used by young women 

who are pregnant,” says Dr. Jerry Frankenheim of NIDA’s

Division of Neuroscience and Behavioral Research.

Timing and Vulnerability

In designing the current study, the researchers drew on 

previous studies by Dr. Vorhees on the effects of methamphetamine exposure on rodent brain development. 

These studies identified specific periods late in rodent 

brain development—days 11 to 20 after birth, which are

analogous to late third-trimester human fetal brain development—in which the brain is quite vulnerable to methamphetamine-induced impairments of spatial learning and 

memory. The question became, can related drugs, such 

as MDMA and other synthetic stimulants, also cause 

such impairments?

Dr. Vorhees and his colleagues decided to test the effects 

of MDMA administered to rats at this same crucial 11 to 

20 days postnatal developmental period and to a comparison group of rats on days 1 to 10 after birth (comparable

to early third trimester of human pregnancy). According 

to Dr. Vorhees, the dosages given to rats in the study are 

equivalent to a 110-lb woman taking 25 mg, a common

dose for MDMA users, up to 250 mg, an amount sometimes reached or exceeded by chronic abusers.

Testing for Learning, Memory

When the rats reached young adulthood, the researchers 

put them through a series of maze and swimming trials 

to assess the effects of MDMA exposure on learning and 

memory. An initial test revealed no significant differences 

between the MDMA-exposed rats and the controls in 

terms of swimming performance or motivation to escape 

from the water. Next, animals were evaluated in a test 

of sequential learning called the multiple-T (Cincinnati) 

water maze. The rats had to search through nine decision points to find their way through the maze and out of 

the water. The researchers found that the rats exposed to 

MDMA on days 11 to 20 after birth made significantly

more errors and took significantly longer to escape the 

maze than did either the MDMA-unexposed animals or 

those exposed to MDMA on days 1 to 10 after birth.

“The animals exposed to MDMA during the critical 11 to 

20 days postnatal brain development period cannot seem

to eliminate errors the way normal animals do,” says Dr. 

Vorhees. “The difference is the rate at which they learn. 

52

Adult rats that had been exposed to MDMA doses of 10 or 20 

mg/kg body weight (comparable to doses used by human MDMA 

abusers) on days 11 to 20 after birth (a period comparable to 

late in the third trimester of human pregnancy) took significantly 

longer to escape the multiple-T water maze than did animals 

exposed to saline solution. No statistically significant increase in 

escape times was observed among rats exposed on days 1 to 10 

after birth.

Animals Exposed to MDMA Take Longer To Escape 

Multiple-T Water Maze
All of the animals eventually learned how to navigate the 

maze, but it took the MDMA-exposed animals significantly longer to do so.”

The Morris hidden platform maze was used to further 

evaluate the animals’ spatial memory and cognitive abilities. A 6-foot diameter swimming pool was constructed 

and a small clear acrylic platform was placed so that the 

animals could escape if they found it. In increasingly difficult phases the rats had to find the platform when it 

was above the water, below the water, moved to a new 

location, or below the water and reduced in size. Memory 

trials were also performed with the platform removed. 

Animals exposed to MDMA on days 1 to 10 after birth

performed as well as unexposed animals on the trials. 

However, the animals exposed to MDMA on days 11 to 

20 after birth showed significant impairment of memory

and spatial learning when the platform was submerged and 

on memory trials when the platform was removed, but no 

differences when the platform was above the water.

“These later trials test the animals’ ability to remember 

something in space,” explains Dr. Vorhees. “We found 

that as we made the task harder, MDMA-exposed animals 

had a disproportionately harder time finding the platform. 

The harder the task was, the more their learning disability 

was revealed.”

Comparing Infant Versus Adult Exposure

Upon completion of the trials, the rats were sacrificed and 

their brains were preserved for later analysis. The researchers wanted to know if animals exposed to MDMA during 

early brain development would show the same pattern of 

damage to neurotransmitters that has been shown in adult 

animals exposed to MDMA. They did not. “This was a 

surprise because we didn’t find the same damage to neurotransmitters as was found in previous studies of animals 

exposed to MDMA as adults,” says Dr. Vorhees. “Yet, the 

animals in the current study still show cognitive impairment, as demonstrated by their performance on the learning and memory trials.” He hypothesizes that a different 

mechanism is at work in animals exposed to MDMA during brain development that later affects their memory and 

learning ability. Future research will focus on identifying 

this mechanism.

Dr. Frankenheim points out that this research is a warning that what is happening in animals may also happen 

with people. “The work of determining what drugs of 

abuse do to fetuses when the mother takes them is very 

difficult. It is not yet known whether human fetuses 

exposed to MDMA will develop persistent memory and 

learning problems. However, these findings in rats raise 

the concern that MDMA may pose a previously unrecognized risk to the developing human brain,” he says.

Future research will involve determining whether there 

are effects of MDMA exposure at earlier points in fetal 

development, such as during the period corresponding to 

the first trimester in humans, when drug exposure is more 

likely for women who may not yet be aware that they are 

pregnant. The first trimester is also the developmental 

period when humans are most sensitive to neurotoxins.

Source

•	 Broening, H.W.; Morford, L.L.; Inman-Wood, S.L.;

Fukumura, M.; and Vorhees, C.V. 3,4-methylenedioxymethamphetamine (ecstasy)-induced learning 

and memory impairments depend on the age of exposure during early development. Journal of Neuroscience

21(9):3228–3235, 2001.

53
In Drug Abuse, Gender Matters

By NIDA Acting Director Glen R. Hanson, Ph.D., D.D.S. 

Research Findings

Volume 17, Number 2 (May 2002)

Recent decades have seen a marked increase in awareness 

of the importance of gender in medical treatment and 

research. In the complex field of drug abuse research, scientists have helped us understand that there are genetic, 

physiological, psychosocial, and environmental dimensions 

to drug abuse and addiction. Male and 

female differences in any of these dimensions can give rise to gender differences 

in the causes, effects, and consequences 

of drug abuse. Researchers and clinicians 

have developed a repertoire of effective 

treatment and prevention principles that 

can now be enhanced through their adaptation for the differing needs of men and 

women and boys and girls.

NIDA’s National Drug Abuse Treatment 

Clinical Trials Network adheres to the 

overall National Institutes of Health 

requirement for analysis of data by gender and supports genderspecific protocol development. NIDA recently issued 

a Program Announcement 

for support of dissertation 

research in five areas, one 

of which is women and 

gender. A new Program 

Announcement on Women 

and Gender Differences 

will be issued soon to fund 

research specifically in the 

areas of epidemiology, prevention, and treatment. 

These efforts will build on NIDA-sponsored research 

that has established that important gender effects exist in 

biological and behavioral responses to drugs, risk for drug 

abuse, and treatment response.

Response to drugs: The neurobiological basis of drug 

abuse and addiction is essentially the same, regardless of 

the drug taken or the person taking it. Still, males and 

females may differ in their biological and behavioral 

responses to drugs. Laboratory studies have revealed 

sex-related differences in the ways that male and female 

animals metabolize drugs, the amount of drug they will 

self-administer, how soon after their first exposure they 

begin to administer drugs, and their vulnerability to 

relapse after abstinence. Preliminary results from studies of 

human drug abusers appear to be consistent with the findings from animal studies of gender differences in the patterns and the biological impact of drug use. For example, 

women typically progress from first use of cocaine, heroin, 

or marijuana to dependence more quickly 

than men. Additionally, cocaine-induced 

cognitive impairments and risk for stroke 

have been found to be more severe in men 

than in women.

Risk for drug abuse: While risk factors 

related to drug abuse vulnerability in males 

and females largely overlap, a variety of differences exist. Depression is much more common among women than men in the general 

public. This gender difference is much less 

pronounced among drug abusers. Possible 

explanations are that depression is a more 

potent risk factor for drug abuse among men 

than among women, or that drug 

abuse itself is more likely to cause 

depression among men than 

among women. Other risk factors that appear to be stronger for 

one gender than the other include 

conduct disorders, which correlate 

more with drug abuse by adolescent females, and aggression, which 

correlates with drug abuse by 

adolescent males.

Along with these differences, studies of gender and risk have revealed 

an unexpected and important 

similarity between males and females. Most experts long 

assumed that females were less attracted to or more wary 

of drug abuse than were males. That seemed a straightforward conclusion based on the fact that the percentage of 

women who abuse drugs is lower than the percentage of 

men who abuse drugs. However, the conclusion turns out 

to be not true. A recent study found that the lower rate of 

drug abuse for females is largely a matter of opportunity. 

(See “Gender Differences in Prevalence of Drug Abuse 

Traced to Opportunities to Use.”) During the youthful

ages when most drug abuse initiation occurs, more boys 

than girls receive offers of drugs. When drug offers are 

made, both genders are equally likely to accept. Once hav54

Researchers and clinicians have 

developed a repertoire of effective 

treatment and prevention principles 

that can now be enhanced through 

their adaptation for the differing 

needs of men and women 

and boys and girls. 
ing accepted, males and females generally are equally likely 

to become dependent. This underscores the importance of 

drug refusal skills in prevention efforts with 

both genders.

Response to treatment: Success in drug treatment is 

directly associated with the length of time spent in treatment: The more time in treatment, the better the outcome. Science-based drug treatments are equally effective 

for men and women, but women often spend less time 

than men in treatment. In part, this could reflect differences in social and economic circumstances. Women 

entering treatment are more likely than men to be custodial parents and to have fewer economic resources; they

are less likely than men to have graduated from high 

school, to be employed, or to have sufficient supportive social networks. Studies also indicate that males and 

females tend to relapse to drug use for different reasons. 

For example, among men relapse is more likely to be 

associated with anxiety and positive feelings, while among 

women depression and negative feelings appear to be more 

common triggers. All these differences suggest that it may 

be possible to enhance the effectiveness of treatment by 

tailoring it for the patient’s gender.

The area of nicotine addiction is one in which our understanding of gender effects is relatively advanced, although 

still far from complete. Research has shown that different 

aspects of smoking more strongly influence addiction to 

nicotine in men and women. For men, the compulsion to 

smoke is driven more strongly by nicotine’s pharmacological effects on the brain, while women’s addiction owes 

more to the visual, tactile, taste, and olfactory sensations 

involved in smoking. Because of these differences, men 

tend to get more relief overall from nicotine replacement 

therapy, and women who use nicotine replacement do 

better with nicotine inhalers than the nicotine patch. 

Recent NIDA research also suggests that women can 

increase their chances for quitting by timing their attempt 

to coincide with the first half of their menstrual cycles, 

since nicotine craving and withdrawal symptoms are generally more severe during the second half of their cycles.

Although the focus on gender is relatively new in drug 

abuse science, we already know that gender’s impact is far 

reaching and complex. A comprehensive and detailed picture of gender-related effects can lead to improvements in 

treatment and prevention efforts that bring us closer to 

the goal of individualized interventions that best meet the 

distinct needs of each patient. When it comes to reducing 

the tremendous burden of drug abuse and addiction, gender most certainly matters. 

55

Although the focus on gender is relatively new in drug abuse science, we 

already know that gender’s impact is 

far reaching and complex. 
Prenatal Exposure to Methamphetamine Increases Vulnerability to 

the Drug’s Neurotoxic Effects in Adult Male Mice

By Kimberly R. Martin, NIDA NOTES Contributing Writer 

Research Findings

Volume 17, Number 2 (May 2002)

A NIDA-funded study has shown that exposure to methamphetamine before birth results in more severe neurotoxic effects in male mice given the drug as adults than 

in females. These findings raise concerns regarding the 

long-term health consequences of methamphetamine 

use, particularly for men who were exposed to the drug 

in utero.

Methamphetamine is known to be a neurotoxic agent that 

damages the endings of brain cells containing dopamine, a 

brain chemical that regulates movement, emotion, motivation, and feelings of pleasure. Previous research in animals 

has indicated that methamphetamine causes damage to 

cells in the striatal and cortical regions of the brain. In 

humans, these regions are associated with memory, cognitive function, and movement.

“Many young people using club drugs such as methamphetamine are cavalier about its dangers. They mistakenly 

believe that they can use these drugs with no consequences,” says Dr. Jerry Frankenheim of NIDA’s Division

of Neuroscience and Behavioral Research. “Although this 

study was conducted in mice, these findings suggest that 

the children, especially sons, of pregnant women who 

abuse methamphetamine may suffer the consequences of 

their mothers’ actions later in life.”

To investigate the effects of methamphetamine exposure in utero, Drs. Alfred Heller and Lisa Won at the 

University of Chicago injected pregnant female mice with 

neurotoxic doses of methamphetamine or saline twice 

daily from gestational days 7 through 18. At 11 weeks

of age (equivalent to young adulthood), the offspring 

received two injections of either saline or methamphetamine in a range of doses. Rectal temperatures were measured hourly from just before the first injection to at least 

4 hours after the second injection. Seven days later, the 

mouse brains were analyzed for dopamine and its metabolites in the striatum, ventral and dorsal brainstem, cortex, 

and cerebellum.

Fetal exposure to methamphetamine alone did not affect 

dopamine or its metabolite levels, but after methamphetamine exposure of the adults, considerable differences 

were observed between the adult male and female offspring. Adult males had lower levels of dopamine and its 

metabolites in the striatum and cortex than did females. 

In addition, the prenatally methamphetamine-exposed 

males had greater reductions than any other group. A 20

mg/kg dose of the drug in an adult produced a 70-percent

reduction of striatal dopamine in prenatally methamphetamine-exposed males, compared to a 55-percent reduction 

in unexposed males. Females showed a 14- to 25-percent 

reduction in striatal dopamine. In the brainstem, only the 

prenatally methamphetamine-exposed males suffered a 

reduction of dopamine from exposure to the drug as an 

adult. Effects of methamphetamine on cortical dopamine 

were not enhanced by prenatal exposure to the drug.

“The increased dopamine losses observed in prenatally 

exposed males in response to adult exposure to the drug 

occurred in the regions of the brain that are affected by 

neurological disorders such as Parkinson’s disease,” says 

Dr. Heller. “If similar neurological effects are occurring 

56

Adult mice were given two doses of methamphetamine 2 hours 

apart. One week after the drug injections, their brains were analyzed for dopamine. Males that had been prenatally exposed to 

methamphetamine had a greater reduction in striatal dopamine 

levels compared with females and unexposed males. 

Effect of Prenatal Exposure to 

Methamphetamine on Striatal Dopamine

Levels of Male and Female Adult Mice
in humans, males whose mothers used methamphetamine 

during pregnancy may be at a greater risk for developing 

these ailments.”

Previous research has indicated that the neurotoxic effects 

of methamphetamine are associated, in part, with its ability to raise body temperature. Hyperthermia, however, did 

not account for the increased susceptibility of prenatally 

methamphetamine-exposed males compared to other 

males. Adult males exhibited the same rise in body temperature whether or not they had been exposed to methamphetamine in utero.

The hyperthermic effects of methamphetamine were a 

contributing factor to the differences in neurotoxicity 

observed between males and females. Adult females did 

not exhibit a change in body temperature in response to 

methamphetamine exposure, while adult males did exhibit 

a rise in body temperature.

“The finding that the female mice in this study did not 

experience the same degree of neurotoxicity or hyperthermic effects when given methamphetamine as adults does 

not mean that female offspring are safe from harm,” cautioned Dr. Heller. “Other research indicates that the age

of adult exposure to methamphetamine may play a role 

in susceptibility to the drug’s effects. This study was conducted in animals that were equivalent to young adults. 

The same findings may not hold true for younger or more 

mature female mice.”

Source

•	 Heller, A.; Bubula, N.; Lew, R.; Heller, B.; and Won,

L. Gender-dependent enhanced adult neurotoxic 

response to methamphetamine following fetal exposure to the drug. Journal of Pharmacology and 

Experimental Therapeutics 298:769–779, 2001.

57
High-Risk Sex Is Main Factor in HIV Infection for Men and Women 

Who Inject Drugs

By Robert Mathias, NIDA NOTES Staff Writer

Research Findings

Volume 17, Number 2 (May 2002)

A 10-year study has found that the biggest predictor of

HIV infection for both male and female injecting drug 

users (IDUs) is high-risk sexual behavior, not sharing 

needles used to inject drugs. High-risk homosexual activity was the most important factor in HIV transmission for 

men; high-risk heterosexual activity was most significant

for women. Risky drug-use behaviors also were strong 

predictors of HIV transmission for men but were less 

significant for women, the study found.

“In the past, we assumed that IDUs who were HIVpositive had been infected with the virus through 

needle-sharing,” says Dr. Steffanie Strathdee of the Johns

Hopkins University Bloomberg School of Public Health 

in Baltimore, who conducted the NIDA-funded study. 

“Our analysis indicates that sexual behaviors, which we

thought were less important among IDUs, really carry a 

heavy weight in terms of risks for HIV seroconversion 

for both men and women.” 

In the study, Dr. Strathdee led a team of researchers who 

analyzed data collected every 6 months from 1,800 IDUs

in Baltimore from 1988 to 1998. Participants had to be at

least 18 years of age when they entered the study, have a

history of injection drug use within the previous 10 years,

and not have HIV infection or AIDS. More than 90 percent of the participants said they had injected drugs in the 

6 months prior to enrolling in the study. In their semiannual interviews, study participants reported their recent 

drug use and sexual behavior and submitted blood samples 

to determine if they had become HIV-positive since their 

last visit.

Researchers analyzed the role of homosexual activity in 

HIV seroconversions among male IDUs in the study, after 

taking into account other factors that increased their risk 

of acquiring HIV, such as their drug injection practices. 

This analysis revealed that the incidence of HIV infection among male IDUs who had engaged in homosexual 

activity within the previous 6 months was 10.44 percent a

year, compared to 3.01 percent among men who did not

report having homosexual sex.

Visiting “shooting galleries,” where drug abusers gather 

to obtain and inject drugs, sharing needles used to inject 

drugs with multiple partners, and injecting drugs daily 

also were independently linked to significantly higher rates 

of HIV infection among men in the study. Men who said 

they had used shooting galleries had an HIV incidence 

rate of 6.28 percent per year, and men who shared needles

with more than one partner had a rate of 5.52 percent per 

year. These infection rates were more than double those 

found among men who had not engaged in these behaviors. Men who injected drugs at least once a day had HIV 

infection rates of 4.68 percent, more than one and onehalf times the rate among men who had injected less than 

once a day.

Sharing needles also increased risk of HIV infection 

among women IDUs. However, high-risk heterosexual 

activity was a much more important risk factor for these 

women, the study found. In fact, other than being younger than 30 years—which independently predicted HIV

infection for both sexes—high-risk heterosexual activity 

was the main predictor of HIV seroconversion among 

women. Women who reported having a recent 

sexually transmitted disease (STD), an indicator of 

58

High-risk sexual behavior played the biggest role in HIV 

infection for both male and female injection drug users (IDUs) 

in this study of 1,800 IDUs. Significant risk factors for men 

were high-risk homosexual activity, using shooting galleries, and 

sharing needles used to inject drugs with multiple partners. For 

women, high-risk heterosexual activity, as indicated by reporting 

a recent sexually transmitted disease (STD), was the most 

significant cause of HIV infection.

High-Risk Sexual Behavior Leading

Cause of HIV Infection Among Injection

Drug Users in 10-Year Study
unprotected sex, had more than 2.5 times the rate of HIV 

infection of women who did not have an STD.

“Both homosexual men and heterosexual women IDUs 

appear to be at dual risk for becoming infected with 

HIV,” Dr. Strathdee says. “In previous studies by our 

group, being a gay male IDU was closely linked to visiting shooting galleries and sharing needles. Heterosexual 

women IDUs tend to have more of an overlap in their 

sexual partners and their drug use than men do. This puts 

them at increased HIV risk because they are sharing 

needles and having unprotected sex with a partner who 

is more likely to be infected with the virus.

“HIV prevention programs have done a good job in 

reducing needle-sharing and other drug-use behaviors 

that spread the virus among IDUs,” Dr. Strathdee says. 

“However, our study indicates that HIV prevention programs can achieve better results by also addressing sexual 

risk behaviors among IDUs. A multifaceted approach is 

needed that screens both men and women IDUs for STDs 

at places where they go, such as needle-exchange programs 

and methadone treatment programs, and provides comprehensive treatment at those sites. 

“HIV prevention efforts also should be gender-specific, 

targeting the important differences we have found in 

sexual and drug-use behaviors among men and women 

that increase their risk of acquiring and transmitting 

HIV,” Dr. Strathdee says. “For example, women IDUs 

in stable relationships could be shown how to negotiate condom use with their partners and offered couple 

counseling to educate both partners about HIV risks 

associated with their drug use and sexual behaviors. We 

need more research to identify and evaluate HIV prevention approaches for male IDUs who have sex with men to 

determine what kinds of interventions might work.”

Source

•	 Strathdee, S.A., et al. Sex differences in risk factors for

HIV seroconversion among injection drug users. 

Archives of Internal Medicine 161:1281–1288, 2001.

59
Cocaine’s Effects on Cerebral Blood Flow Differ Between Men 

and Women

By Jill S. Williams, NIDA NOTES Contributing Writer 

Research Findings

Volume 17, Number 2 (May 2002)

Researchers studying the effects of cocaine on the brain 

have found that men and women with comparable drug 

use histories do not exhibit comparable damage. One

study showed that women suffered less neuronal injury 

than men; another, that cocaine-dependent women have

fewer abnormalities in blood flow to the brain than do 

cocaine-dependent men. Now, a recent NIDA-funded 

study has taken an important step toward explaining 

these differences between the sexes.

Cocaine constricts blood vessels, temporarily narrowing 

arteries and reducing blood flow to the brain, heart, and 

other areas of the body. Repeated exposure to cocaine can 

lead to blood-flow deficits in the brain that persist long 

after cocaine use has ended, causing permanent damage.

Dr. Marc J. Kaufman and colleagues at McLean Hospital,

Harvard Medical School, in Belmont, Massachusetts, 

found that cerebral blood flow during the follicular phase 

of women’s menstrual cycles (days 1 through 14, prior 

to ovulation) is not affected by exposure to cocaine. In 

women during their luteal phase (after ovulation, typically 

days 15 through 28) and in men, cocaine restricts cerebral

blood flow.

“We hypothesized that the differences in blood flow 

might be caused by sex hormones,” says Dr. Kaufman. 

“We decided to investigate whether women with high levels of estrogen, which improves blood-vessel elasticity, are 

more resistant to the vasoconstrictive effects of cocaine.”

Dr. Kaufman and his colleagues used dynamic susceptibility contrast magnetic resonance imaging (DSC MRI) to 

study cocaine-induced changes in cerebral blood volume 

in 13 healthy young women (average age 28) with histories of occasional cocaine use. The women’s self-reported 

lifetime cocaine use averaged 13 exposures (ranging from 

1 to 40).

Each woman was given a dose of cocaine and underwent 

a DSC MRI scan of cerebral blood volume during both 

phases of her menstrual cycle. During the first part of the 

menstrual cycle, estrogen levels are high and progesterone 

levels are low; during the second part, progesterone levels

rise. In each imaging session, two brain images were collected: one as a baseline measure of cerebral blood volume 

and the second 10 minutes after cocaine administration.

The study found no significant changes in cerebral blood 

volume after cocaine administration during the women’s 

follicular phase. During the luteal phase, when progesterone levels are highest, the women’s cerebral blood flow 

fell approximately 10 percent after cocaine administration.

These data compare to Dr. Kaufman’s findings in a 

similar 1998 study, that men experience, on average, a

20-percent reduction in cerebral blood volume after

cocaine administration.

“We found what we were expecting,” says Dr. Kaufman. 

“There was a minimal change in follicular cerebral blood 

volume, attributable, we believe, to the protective effects 

60

Magnetic resonance (MR) image intensity was measured to compare the hemodynamic effects of cocaine during two phases of a 

woman’s menstrual cycle. Following cocaine administration during 

the follicular phase, image intensity was relatively high, reflecting 

cerebral blood flow at 97 percent of its pre-cocaine baseline. When 

the drug was given during the luteal phase, lower image intensity 

reflected a fall in blood flow to 82 percent of baseline. The MR 

technique is illustrated on the next page.

Cocaine’s Effect on Cerebral

Blood Volume Varies Throughout 

Menstrual Cycle
of estrogen. The greater vasoconstrictive effect of cocaine 

in luteal-phase women may be attributable to the progesterone, which has been shown to increase cocaine’s vascular toxicity.”

Dr. Kaufman’s next step will be to administer estrogen or 

progesterone to men and luteal-phase women and measure 

the effects on cerebral blood volume after cocaine administration. The ultimate goal will be to develop a hormonelike medication to counteract the vascular effects of cocaine. 

“Beyond confirming that cocaine does have a damaging 

effect on the brain and is not safe to use, this research 

contributes to our understanding of the drug’s deleterious 

effects,” says Dr. Steven Grant, of NIDA’s Division of 

Treatment Research and Development. “Additionally, the 

research points out that we’ve got to stop thinking of both 

sexes as the same when it comes to the effects of drugs. 

Dr. Kaufman has shown that cocaine affects men and 

women differently.” 

Sources

•	 Kaufman, M., et al. Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual 

cycle phase. Biological Psychiatry 49(9):774–781,

2001.

•	 Kaufman, M., et al. Cocaine decreases relative cerebral

blood volume in humans: A dynamic susceptibility 

contrast magnetic resonance imaging study. 

Psychopharmacology 138:76–81, 1998.

61

A sequence of magnetic resonance images taken at 1-second intervals after a woman received an intravenous blood marker progresses from 

light to dark to light as her cerebral blood flow carries the marker into her brain and washes it back out again. The total marker present in 

all the images, measured as their intensity (darkness), reflects total cerebral blood volume. To study the hemodynamic effects of cocaine, investigators compared two such sequences, obtained before and after administration of the drug, during each menstrual period.

Using Magnetic Resonance Imaging (MRI) To Track Cerebral Blood Volume

Seconds After Contrast Injection
Childhood Sex Abuse Increases Risk for Drug Dependence 

in Adult Women

By Patrick Zickler, NIDA NOTES Staff Writer 

Research Findings

Volume 17, Number 1 (April 2002)

Women who are sexually abused during childhood are 

at increased risk for drug abuse as adults, according to 

NIDA-supported research conducted at the Medical 

College of Virginia Commonwealth University in 

Richmond. Using data gathered from interviews of 1,411 

adult twins, Dr. Kenneth Kendler and his colleagues 

assessed the association between three levels of childhood 

sex abuse (nongenital, genital, and intercourse) and six 

adult disorders—major depression, generalized anxiety 

disorder, panic disorder, bulimia nervosa, alcohol dependence, and drug dependence. Women who experienced 

any type of sexual abuse in childhood were roughly three 

times more likely than unabused girls to report drug 

dependence as adults.

“Overall, childhood sexual abuse was more strongly associated with drug or alcohol dependence than with any of 

the psychiatric disorders,” Dr. Kendler says. “Only drug

and alcohol dependence were significantly associated with 

all levels of abuse.”

In this study, 1,411 women born between 1934 and 1974

responded to written questionnaires that asked them if, 

before they reached age 16, any adult or person older than 

they had ever (“never,” “once,” or “more than once”):

•	 involved them in an incident that included an invitation or request to do something sexual;

•	 kissed or hugged them in a sexual way;

•	 subjected them to genital display or exposure;

•	 touched or fondled them in a sexual way;

•	 made them touch the older person or adult in a sexual

way; or

•	 attempted intercourse.

In addition, the researchers conducted written interviews 

with 90 percent of the twins’ parents to assess family

environment and parental psychopathology. The parental 

interviews did not mention possible sexual abuse of the 

children, but did provide data on family financial status;

parents’ disciplinary practices, including spanking, slapping, or hitting; church attendance; and measures of harmony, discord, authoritarianism, and protectiveness.

62

Among more than 1,400 adult females, childhood sexual abuse was associated with increased likelihood of drug dependence, alcohol dependence, and psychiatric disorders. The associations are expressed as odds ratios: for example, women who experienced nongenital sexual abuse 

in childhood were 2.93 times more likely to suffer drug dependence as adults than were women who were not abused.

Association of Childhood Sex Abuse With Drug Dependence And Psychiatric Disorders in Adult Women
“Controlling for family factors and parental psychopathology produced a small change in some of the associations, 

but the increased odds of reporting drug or alcohol dependence in adulthood after suffering sexual abuse as a child 

can’t be explained by these background factors,” 

Dr. Kendler says.

The women who participated in the research are part of 

an ongoing research investigation of female twins included 

in the Virginia Twin Registry, which represents a large 

cross-section of the population and includes data on a 

broad range of research topics, including psychiatric and 

substance abuse disorders.

“This study has particular significance because it is based 

on data from women in the general population,” says 

Dr. Cora Lee Wetherington of NIDA’s Division of 

Neuroscience and Behavioral Research. “Numerous 

clinical studies have documented high rates of childhood 

sexual abuse among women in treatment. This study, the 

first to document it in a nonclinical population, is particularly important in addressing questions concerning the 

relationship between sexual abuse and patterns of drug 

abuse and addiction.”

Source

•	 Kendler, K.S., et al. Childhood sexual abuse and adult

psychiatric and substance use disorders in women: An 

epidemiological and co-twin control analysis. Archives 

of General Psychiatry 57(10):953–959, 2000. 

63
Biochemical Brain Abnormality Found in School-Age Children 

Prenatally Exposed to Cocaine

By Robert Mathias, NIDA NOTES Staff Writer

Research Findings

Volume 16, Number 4 (October 2001)

Exposure to cocaine before birth may affect the way a 

child’s brain functions many years later, according to a 

recent NIDA-funded study. The brain-imaging study 

found a chemical abnormality in the brains of 8-year-old

children that may reflect alterations in metabolic processes 

that enable brain cells to use energy and function properly, the researchers say.

“These children were exposed to cocaine only during 

gestation and their brains have had 8 years to recover

from that exposure,” says Dr. Joseph Frascella of NIDA’s

Division of Treatment Research and Development. “It is 

surprising that they are still showing these deficits so many 

years later.” The new finding suggests that early exposure 

to drugs has more long-lasting effects on the brain than 

previously thought, he notes.

The nature and extent of possible developmental damage 

to infants and children from prenatal exposure to cocaine 

has been the subject of much apprehension and scientific 

study. In the 1980s, anecdotal reports of abnormalities

among cocaine-exposed children contributed to fears 

that these children were irreparably damaged and would 

never be able to function in society. Subsequent scientific 

research has dispelled such exaggerated concerns for the 

vast majority of prenatally exposed children. 

NIDA-funded studies that have been tracking 

the development of groups of cocaine-exposed 

babies through adolescence now indicate that 

most seem to function normally, but some 

may have subtle impairments in their ability to control emotions and focus attention 

that could put them at risk of behavioral and 

learning difficulties.

Previous brain-imaging studies of children 

prenatally exposed to cocaine have yielded 

conflicting information about the drug’s 

effects on the developing central nervous 

system. Some studies have found abnormalities in brain structure, while others have not. 

Studies in abstinent adult cocaine abusers, 

using an imaging technique called magnetic 

resonance spectroscopy (MRS), have suggested that chronic cocaine use may cause persistent damage to neurons in the frontal lobes 

of males and that brain metabolic abnormalities also could exist despite a normal-appearing brain 

structure. Dr. Lynne Smith of the Harbor-UCLA Medical 

Center in Torrance, California, and Dr. Linda Chang of 

Brookhaven National Laboratory, in Upton, New York, 

used this MRS technique to see if similar biochemical 

abnormalities might be present in the brains of children 

who had been prenatally exposed to cocaine, even if they 

appeared to have no structural damage.

The researchers used magnetic resonance imaging (MRI) 

to assess brain structure and MRS to examine brain 

biochemistry in 14 8-year-old children who had been

exposed to cocaine in the womb. They administered the 

same brain scans to a control group of 12 age-matched, 

nonexposed children. The MRS scans measured levels of 

various chemicals in different brain regions. Increased or 

reduced concentrations of these chemicals can indicate 

either damage to nerve cells or alterations in brain cell 

function in these regions. The researchers assessed a frontal area of the brain, made up of “white matter,” which 

consists mainly of nerve fibers and specialized support 

cells. They also looked at an area deep in the brain called 

the basal ganglia, which contains clusters of nerve cell 

bodies, or “gray matter.”

64

Creatine Level Alterations in Frontal White Matter of 

Cocaine-Exposed Children

MRS scans suggest cocaine-exposed children did not have significant nerve damage or 

loss in the brain regions that were examined. However, cocaine-exposed children had 

significantly higher levels of the brain metabolite creatine than nonexposed children 

in a frontal area of the brain made up of “white matter,” which consists mainly of 

nerve fibers and specialized support cells. The abnormality may reflect alterations in 

metabolic processes that enable brain cells to use energy and function properly.
The study found no difference between the exposed 

and nonexposed children in concentrations of N-acetylaspartate (NAA), a nerve cell metabolite, in either the frontal area or the basal ganglia. Because NAA levels are markers for the density and integrity of nerve cells, the normal 

NAA found in children prenatally exposed to cocaine suggests they did not have significant nerve damage or loss in 

the two brain regions that were examined. The MRI 

evaluations also showed no brain structure abnormalities in 

children in either group. However, cocaine-exposed 

children had significantly higher levels of creatine in 

the white matter of the frontal lobes than nonexposed 

children. Elevated creatine levels indicate that the brain 

cells of cocaine-exposed children use energy differently 

in this region.

“All brain cells require creatine for all functions,” says Dr. 

Chang. “The altered creatine levels we found could affect 

how both nerve cells and support cells are functioning in 

the brain. We also have found the same abnormal creatine 

levels in frontal white matter in adult cocaine abusers 

more than a year after they have stopped using cocaine. 

The drug seems to have a particularly long-lasting effect 

on energy metabolism in this brain area that merits further investigation.”

“The frontal area of the brain is involved in our ability to 

control impulses and sustain attention on a task,” notes 

Dr. Frascella. Thus, it is possible that the altered brain 

function found in this area could be a biological basis for 

findings from other research that some cocaine-exposed 

children are more impulsive and easily distracted than 

their peers. However, additional research is needed to 

make this determination, he says.

Sources

•	 Chang, L.; Ernst, T.; Strickland, T.; and Mehringer,

C.M. Gender effects on persistent cerebral metabolic 

changes in the frontal lobes of abstinent cocaine users. 

American Journal of Psychiatry 156(5):716–722, 1999.

• Chang, L., et al. Neurochemical alterations in asymptomatic abstinent cocaine users: A proton magnetic 

resonance spectroscopy study. Biological Psychiatry

42(12):1105–1114, 1997.

• Smith, L.M.; Chang, L.; et al. Brain proton magnetic

resonance spectroscopy and imaging in children 

exposed to cocaine in utero. Pediatrics 107(2):227–

231, 2001.

65

Similar Long-Term Effects Seen From 

Prenatal Methamphetamine Exposure

Dr. Linda Chang of Brookhaven National Laboratory 

in Upton, New York, and her colleagues at UCLAHarbor Medical Center in Torrance, California, have 

followed up their brain-imaging study of cocaineexposed children with a preliminary study of schoolage children who were prenatally exposed to methamphetamine. The researchers assessed the same chemical 

metabolites that they had assessed in the brains of 

cocaine-exposed children.

“The findings in methamphetamine-exposed children 

were very similar to what we saw with cocaine-exposed 

children,” Dr. Chang says. “We found the same abnormalities in creatine levels in the frontal white matter, 

which indicate altered energy metabolism. Unlike the 

cocaine-exposed children, methamphetamine-exposed 

children also showed abnormalities of N-acetylaspartate (NAA), a marker of nerve cell integrity, similar to those seen in adult methamphetamine and male 

cocaine abusers,” she says. In the adult studies, the 

researchers were able to conclude that such NAA levels 

suggested methamphetamine abuse and cocaine abuse 

by males could result in damaged or destroyed nerve 

cells. In the prenatal methamphetamine study, too few 

children were assessed for the researchers to determine 

whether the differences in NAA levels between methamphetamine-exposed and nonexposed children were 

statistically significant.

Source

•	 Smith, L.M.; Chang, L.; Yonekura, M.L.; Grob,

C.; Osborn, D.; and Ernst, T. Brain proton magnetic resonance spectroscopy in children exposed 

to methamphetamine in utero. Neurology

57(2):255–260, 2001.
Research Findings

66

Volume 16, Number 2 (May 2001)

Adolescents, Women, and Whites More Vulnerable Than Others to 

Becoming Nicotine Dependent

By Patrick Zickler, NIDA NOTES Staff Writer 

Rates of drug dependence—the percentage of users who 

experience symptoms that reinforce their drug use and 

have trouble quitting—are higher for nicotine than for 

marijuana, cocaine, or alcohol. Rates of dependence also 

vary among different groups of smokers, according to 

NIDA-supported research. A new study suggests that 

differences in sensitivity to nicotine make some smokers 

more likely than others to develop nicotine dependence. 

Age, sex, and race all appear to make a difference.

Dr. Denise Kandel and Dr. Kevin Chen of Columbia 

University in New York City analyzed data collected 

between 1991 and 1993 as part of the National Household

Survey of Drug Abuse, which surveys a representative 

sample of the U.S. population 12 years and older. In 

examining data from 22,292 respondents who had smoked

cigarettes during the preceding month, Dr. Kandel and 

her colleagues determined rates of nicotine dependence 

symptoms based on respondents’ reports of tolerance 

(needing to smoke more to feel the effects), withdrawal 

symptoms, smoking more than intended, failed efforts to 

cut down, negative social and job-related consequences, 

and persistent health problems.

The researchers found that among persons who smoke 

one-half pack of cigarettes each day, nicotine dependence 

rates are higher among females than males (31.6 percent 

compared with 27.4 percent) and higher among whites

(31.3 percent) than among blacks (25 percent) and 

Hispanics (27.6 percent). Adolescents smoke fewer

cigarettes than adults but experience significantly higher 

rates of dependence than adults at the same level of use. 

Dependence rates are lowest among adults older than 50.

Overall, the researchers say, dependence rates increase

sharply as consumption moves up to 10 cigarettes per day.

The rates level off with higher consumption, although 

dependent smokers need to smoke more to feel the 

physical effects of nicotine.

“Understanding the differences among groups in their 

vulnerability to developing nicotine dependence will be 

valuable in developing targeted strategies for prevention,” 

Dr. Kandel says. “The higher rates at which adolescent, 

women, and white smokers develop symptoms of nicotine 

dependence given the same quantity smoked daily seem 

to reflect differences in sensitivity to nicotine. Increased 

sensitivity may also account for the fact that adolescents 

develop symptoms of dependence at lower doses of 

nicotine than adults.”

Adolescents appear to be particularly vulnerable to becoming nicotine dependent, especially at low levels of cigarette 

consumption and when they continue to smoke on a regular daily basis, according to the researchers. Adolescents’ 

nicotine dependence rates were associated with the length 

of time that they had been daily smokers, in contrast with 

adults, in whom dependence rates were associated with 

the amount of tobacco smoked. “Once regular smoking has been established, quantity smoked may become a 

more important determinant of dependence than duration 

of daily smoking,” Dr. Kandel says. “This possible 

connection suggests that with adolescents we should focus 

not only on preventing the uptake of smoking but on 

shortening smoking careers as soon as possible.”

Source

•	 Kandel, D.B., and Chen, K. Extent of smoking and

nicotine dependence in the United States: 1991–1993.

Nicotine and Tobacco Research 2(3):263–274, 2000.

Data from the National Household Survey on Drug Abuse show 

that the rate of nicotine dependence is higher in people younger 

than 25 than in other age groups and that the dependence develops 

with less exposure to nicotine.

Rates of Nicotine Dependence Are Greater 

for Young Smokers
Research Findings

67

Maternal Smoking During Pregnancy Associated With Negative 

Toddler Behavior and Early Smoking Experimentation

By Josephine Thomas, NIDA NOTES Contributing Writer 

Volume 16, Number 1 (March 2001)

NIDA-funded researchers have added to the accumulating 

scientific evidence that women’s smoking during pregnancy adversely affects their children’s health and development. Two new studies have linked prenatal tobacco 

exposure to negative behavior in toddlers and smoking 

experimentation by pre-adolescents. 

In a study conducted by Dr. Judith

Brook, Dr. David Brook, and Dr. Martin 

Whiteman of the Mount Sinai School 

of Medicine in New York City, mothers 

who smoked during pregnancy indicated 

that their toddlers exhibited more negative 

behaviors—impulsiveness, risk-taking, and 

rebelliousness—than mothers who did not 

smoke during pregnancy reported among 

their children.

A study conducted by NIDA-funded 

researchers Dr. Marie Cornelius and 

Dr. Nancy Day demonstrates that, even 

more than growing up in a home where 

the mother smokes, prenatal exposure to 

smoke may predispose children to early 

smoking experimentation. Dr. Cornelius, 

Dr. Day, and their colleagues at the 

University of Pittsburgh School of 

Medicine found that not only does such 

exposure to maternal smoking predict early 

experimentation, it also appears linked to 

child anxiety, depression, and behaviors 

such as hitting and biting others.

Previous studies have supported a link between prenatal 

smoking exposure and behavioral problems in later childhood and adolescence. Combined with earlier results, the 

new studies suggest that prenatal smoking contributes to 

a train of developmental difficulties and health risks that 

begin at an early age.

Toddler Negativity

The Mount Sinai study included 99 mothers who smoked

and their 2-year-old children. The mothers are participants 

in a large community study that Dr. Judith Brook has

been conducting with Dr. Patricia Cohen of Columbia 

University in New York City for the past 25 years. In the 

new study, the mothers answered a questionnaire that elicited information about their children’s behaviors 

and their own smoking histories, alcohol and drug use, 

personalities and attitudes, styles of child-rearing, and 

socioeconomic characteristics.

Fifty-two of the women reported that they had smoked 

while pregnant, and 47 said they either stopped smoking during pregnancy or did not 

begin to smoke until after they 

had given birth. The mothers 

who smoked during pregnancy 

scored their children higher on the 

questions that measured toddler 

negativity. 

The mother’s disciplinary style 

also was strongly linked to a toddler’s negative behavior. However, 

when the researchers adjusted for 

this factor in the analysis, they 

determined that a mother’s smoking during pregnancy independently increased the estimated risk 

of negativity at age 2 by fourfold.

“We found three major maternal risk factors related to toddler 

negativity,” says Dr. Brook. “They 

are maternal smoking during 

pregnancy, conflicts between 

the mother and child, and the 

mother’s use of power-assertive 

discipline, such as hitting the child. We can speculate that 

maternal smoking during pregnancy causes disturbances 

in the neurophysiological functioning of the fetus,” says 

Dr. Brook. “This, in turn, could precipitate the toddler’s 

negative behavior.”

The potential implications of these findings reach beyond 

early childhood. Previous studies have demonstrated that 

toddlers who display negative behaviors are more likely to 

use drugs, exhibit delinquent behaviors, and achieve less as 

adolescents and to develop severe mental health problems 

later in life.

Early Experimentation With Tobacco

Although the effects of maternal smoking on childhood 

behaviors have been studied, few studies have investigated 

the connection between maternal smoking and childhood 
68

experimentation with tobacco. The connection is important because the earlier a person starts smoking, the more 

likely he or she is to become a regular smoker, become 

addicted, and suffer the long-term adverse health effects 

of smoking.

Dr. Cornelius and her colleagues interviewed 589

10-year-olds. Six percent of the children said they had

tried cigarettes, smokeless tobacco, or both. Most of 

the reported tobacco use was experimental; only a few

children had used tobacco more than a few times.

In this prospective study, begun by Dr. Day in 1982, the

children’s mothers have been providing researchers with 

information about themselves, and they reported on their 

smoking at the time they were pregnant with the children 

who are now 10. Putting data from the children together

with those reports, the researchers estimated that maternal 

smoking of at least a half-pack of cigarettes per day during 

pregnancy increased by fivefold the likelihood that a child 

would have tried tobacco by age 10. The only factor that

produced a greater risk of early experimentation was 

exposure to smoking within the child’s peer group.

It is not yet clear exactly why these factors are related 

to early experimentation. “Perhaps the nervous system damage caused by maternal smoking may later be 

expressed as impulsivity, inattention, aggression, depression, and/or anxiety and may create a vulnerability in the 

child that could contribute to poorer adjustment and an 

increased likelihood of early initiation of tobacco use,” 

Dr. Cornelius says.

Dr. Cornelius notes that in her study, the 10-year-olds

who were exposed prenatally to tobacco were more likely 

to have experimented than those whose mothers were 

current smokers. This finding reinforces the hypothesis 

that a physiological effect of prenatal exposure to smoking, rather than a genetic vulnerability affecting both 

mother and child, may be an important link between 

mothers’ smoking during pregnancy and early childhood 

experimentation.

Sources

•	 Brook, J.S.; Brook, D.W.; and Whiteman, M. The

influence of maternal smoking during pregnancy 

on the toddler’s negativity. Archives of Pediatric and 

Adolescent Medicine 154(4):381–385, 2000.

•	 Cornelius, M.D.; Leech, S.L.; Goldschmidt, L.; and

Day, N.L. Prenatal tobacco exposure: Is it a risk factor for early tobacco experimentation? Nicotine & 

Tobacco Research 2:45–52, 2000.
Research Findings

69

Volume 16, Number 1 (March 2001)

Women and Smokeless Tobacco Use

Although more than 90 percent of smokeless tobacco

users in the United States are male, a substantial number 

of women also use smokeless tobacco products. In 1998,

0.5 percent of females over the age of 12, about 573,000,

were current users of smokeless tobacco products, according to the National Household Survey on Drug Abuse.

The comparatively small percentage of women who 

use smokeless tobacco accounts in part for the lack of 

research on the patterns of smokeless tobacco use among 

women, says Dr. Dorothy Hatsukami of the University of 

Minnesota School of Medicine. In addition, “women rarely respond to our advertisements to participate in smokeless tobacco treatment studies,” she says. For example, Dr. 

Hatsukami recently reported that 99.8 percent

of 402 people who responded to advertisements for

participation in a smokeless tobacco treatment study with 

the nicotine patch were male. 

“Women may be embarrassed about admitting smokeless 

tobacco use because the general perception is that smokeless tobacco use is socially undesirable, and women don’t 

use it,” Dr. Hatsukami speculates. Among the unattractive features of smokeless tobacco use is the need to spit 

tobacco juice from time to time and dislodge particles of 

loose tobacco that get trapped between the teeth. This 

disadvantage of smokeless tobacco use was the one most 

frequently cited by women who participated in a study of 

female smokeless tobacco users who weren’t seeking treatment, conducted by Dr. Hatsukami and her colleagues.

In the study, 20 female smokeless tobacco users from

the upper Midwest completed a questionnaire and brief 

interview. The study revealed some similarities between 

females’ smokeless tobacco use and what research has 

shown about males’ smokeless tobacco use. For example, 

on average, both sexes began using smokeless tobacco 

between 16 and 18, and friends played a major role in

their initiating use. About 25 percent of men and women 

also indicated they used smokeless tobacco to help them 

stop smoking.

The study also revealed some differences in patterns of 

smokeless tobacco use by females and the patterns of 

use reported in a previous study that assessed features of 

smokeless tobacco use among males who weren’t seeking 

treatment. For example, on average, the women said they 

used 3.6 dips of moist snuff daily, compared to the 6.3 

dips reported by males, and women held the tobacco 

in their mouths about 22.5 minutes, compared to 39.9

minutes for men. A tin of snuff lasted women anywhere 

from 2 days to 3 months with a median duration of 6 

days per tin. In contrast, men used approximately 2.8

tins per week.

The women in this study may have used less smokeless tobacco than men because they had used smokeless 

tobacco for less than 4 years, Dr. Hatsukami says. This 

contrasts with the men, who averaged more than 5 years 

of smokeless tobacco use. Perceived social disapproval of 

women using smokeless tobacco also may contribute to 

lower patterns of use in women. In fact, 38 percent of

the women in Dr. Hatsukami’s study said they could not 

use smokeless tobacco in the presence of certain people, 

and another 25 percent cited social disapproval as a drawback to smokeless tobacco use. These social concerns may 

reduce opportunities for women to use smokeless tobacco 

and lead to lower levels of use, Dr. Hatsukami says. 

In spite of these drawbacks, a significant percentage of 

women in the study said the relaxing and calming effects 

and pleasure they associate with smokeless tobacco use are 

advantages of using these products.

Identifying factors associated with smokeless tobacco use 

by women and their current patterns of use could generate 

ways to prevent and treat smokeless tobacco use among 

women, Dr. Hatsukami says. “The data from this research 

could help target some of the educational and prevention 

messages that we should be giving to women,” she says. 

“However, first we have to make women smokeless tobacco users aware that other women use smokeless tobacco 

products and that they are not abnormal, so they are 

willing to seek help,” she says.

Sources

•	 Boyle, R.G.; Gerend, M.A.; Peterson, C.B.; and

Hatsukami, D.K. Use of smokeless tobacco by young 

adult females. Journal of Substance Abuse 10:19–25,

1998.

•	 Hatsukami, D.K.; Keenan, R.M.; and Anton, D.J.

Topographical features of smokeless tobacco use. 

Psychopharmacology 96:428–429, 1988.
Research Findings

70

Drug Abuse and Conduct Disorder Linked to Maternal Smoking 

During Pregnancy

By Raymond Varisco, NIDA NOTES Contributing Writer 

Volume 15, Number 5 (October 2000)

Researchers at Columbia University in New York City 

have found new evidence that children whose mothers 

smoke during pregnancy are at much greater risk than 

other children for drug abuse and conduct disorder. The 

findings reinforce those of other studies spanning more 

than 25 years that have shown similar problems associated 

with prenatal exposure to smoke in children ranging from 

toddlers through teens. The study also revealed marked 

gender differences, with girls at significantly increased risk 

for drug abuse and boys at significantly increased risk for 

conduct disorder.

The investigators interviewed 147 mother-child pairs 3

times over 10 years, with the children ranging from ages 6

to 23 at the start of the study. Both mothers and children 

were interviewed on entry into the study, again 2 years 

after the initial interview, and, finally, about 10 years after

the initial interview. Because the researchers followed the 

children through either adolescence or young adulthood—

something few studies have done before-they were able to 

collect data about whether and when the children began 

to abuse drugs, says Dr. Myrna Weissman, the study’s 

principal investigator.

Data were gathered on psychiatric and substance abuse 

disorders of parents; family environmental factors, such as

divorce and family discord; and maternal factors, such as

alcohol and coffee consumption and postnatal smoking, to 

rule out other explanations for the presence of drug abuse 

and conduct disorder.

The researchers found that maternal smoking during 

pregnancy has long-term effects on children’s behavior 

and health that cannot be explained by any other factor 

included in the study. Risk for adolescent drug abuse in 

girls was more than 5-fold higher if their mothers smoked 

more than 10 cigarettes a day during pregnancy. Among

boys whose mothers smoked more than 10 cigarettes a

day, risk for the onset of conduct disorder was greater 

than 4-fold that of boys whose mothers did not smoke, 

with the increase appearing in boys younger than 13. The 

drug most frequently abused by both boys and girls was 

marijuana, and the most frequent combination of drugs 

abused was marijuana and cocaine. Of the females who

abused drugs, 70 percent abused more than one.

Why boys exposed to smoking before birth should be at 

risk for conduct disorder and girls at risk for drug abuse 

remains to be understood, Dr. Weissman says. She 

speculates that the differences may be related to sex 

differences in prenatal brain development.

Many of the findings of this study are consistent with 

those of related studies, she notes. Researchers at the 

University of Chicago also have found a link between 

maternal smoking during pregnancy and conduct disorder 

in boys, she says. Likewise, a 1994 study conducted by

Dr. Weissman’s coinvestigator Dr. Denise Kandel found 

that maternal smoking during pregnancy increases risk 

for adolescent-onset smoking in girls. Studies also have 

found other behavioral problems in children exposed prenatally to smoke. For example, scientists at Massachusetts 

General Hospital found an association between prenatal 

exposure to smoke and attention deficit hyperactivity disorder. Similarly, a recent study by Dr. Judith Brook and

her colleagues at Mount Sinai School of Medicine in New 

York City has found negative behavior in 2-year-olds of 

mothers who smoked during pregnancy.

Sources

•	 Brook, J.S.; Brook, D.W.; and Whiteman, M. The

influence of maternal smoking during pregnancy on 

the toddler’s negativity. Archives of Pediatrics and 

Adolescent Medicine 154:381–385, 2000.

•	 Kandel, D.B.; Wu, P.; and Davies, M. Maternal

smoking during pregnancy and smoking by adolescent daughters. American Journal of Public Health

84:1407–1413, 1994.

•	 Wakschlag, L.S; Lahey, B.B.; Loeber, R.; Green,

S.M.; Gordon, R.A.; and Leventhal, B.L. Maternal

smoking during pregnancy and the risk of conduct disorder in boys. Archives of General Psychiatry

54:670–676, 1997.

•	 Weissman, M.M.; Warner, V.; Wickramaratne, P.J.;

and Kandel, D.B. Maternal smoking during pregnancy 

and psychopathology in offspring followed to adulthood. Journal of the American Academy of Child and 

Adolescent Psychiatry 38:7, 1999.
Research Findings

71

Boys and Girls Encounter Different Drug Offers, Use Different 

Refusal Strategies

Volume 15, Number 4 (September 2000)

NIDA-funded researchers at the Arizona State University 

in Phoenix found that among 12-year-olds who have 

been offered drugs, boys are most likely to have received 

those offers from other males or their parents. Girls are 

most likely to have been offered drugs by a female friend 

or family member. Although the most common strategy 

for rejecting these offers is a simple refusal, boys are more 

likely than girls to explain their refusal.

Dr. Dreama Moon (now at California State University, 

San Marcos) and Dr. Michael Hecht (now at Pennsylvania 

State University) interviewed 2,622 7th-graders in the

metropolitan Phoenix area to determine patterns of exposure to and use of illicit drugs-alcohol, tobacco, marijuana, 

or “hard drugs” (described in the interviews as hallucinogens, cocaine, or crack cocaine), and inhalants.

“Boys are more at risk than girls for offers at a younger 

age, and more likely to be offered alcohol, marijuana, and 

‘hard’ drugs by their parents or by other males—relatives, 

acquaintances, and strangers,” Dr. Moon says. “On the

other hand, girls tend to be at risk for offers from other 

girls-acquaintances or family members of roughly the 

same age-or, to a lesser extent, from older boyfriends.”

The social settings and nature of drug offers also differ by 

gender, the researchers say. Boys are more likely to receive 

offers in a public setting, such as on the street or in a 

park, and the offers to males typically emphasize the 

“benefits”—improved status or self-image—of drug use. 

Girls are more likely to receive a straightforward “do you 

want some?” offer or one that minimizes the risks of drug 

use. For girls, these offers are usually made in a private 

setting such as a friend’s home.

The strategies used to resist drug offers appear to have 

gender-based influences, Dr. Moon notes. “Boys are often 

socialized in a way that makes a simple ‘no’ unacceptable. 

They are more likely to explain their refusal,” she says. 

Girls, on the other hand, are less likely to use an “explain” 

strategy because it leads to a counter explanation. “If this 

continues through two or three cycles of explain-andcounter, girls may be susceptible to use,” according to Dr. 

Moon. “Understanding the different ways in which boys 

and girls experience and refuse offers of drugs is crucial 

to the design of more effective intervention or prevention 

programs,” she says.

Source

•	 Moon, D.G.; Hecht, M.L.; Jackson, K.M.; and

Spellers, R.E. Ethnic and gender differences and similarities in adolescent drug use and refusals of drug 

offers. Substance Use & Misuse 34(8):1059–1083,

1999.
Research Findings

72

Volume 15, Number 4 (September 2000)

Gender Differences in Drug Abuse Risks and Treatment

By Patrick Zickler, NIDA NOTES Staff Writer

Over the past few years NIDA has made a major research

commitment to identifying and understanding differences 

in the ways that women and men—or girls and boys— 

are first exposed to drugs, in their risks of abuse and 

addiction, and in the effectiveness of drug treatment. 

Understanding these differences, and incorporating that 

understanding into drug abuse prevention and treatment, 

can reduce the dangers and improve outcomes. NIDAsupported research has shown that gender differences play 

a role from the very earliest opportunity to use drugs, that 

women and men tend to abuse different drugs, that the 

effects of drugs are different for women and men, and 

that some approaches to treatment are more successful 

for women than for men.

Are Women Less Likely Than Men to Abuse Drugs?

Men are more likely than women to have opportunities to 

use drugs, but men and women given an opportunity to 

use drugs for the first time are equally likely to do so and 

to progress from initial use to addiction. However, women 

and men appear to differ in their vulnerability to some 

drugs. Both are equally likely to become addicted to or 

dependent on cocaine, heroin, hallucinogens, tobacco, and 

inhalants. Women are more likely than men to become 

addicted to or dependent on sedatives and drugs designed 

to treat anxiety or sleeplessness, and less likely than men 

to abuse alcohol and marijuana. There are also differences between men and women who seek treatment for 

drug abuse. Women in treatment programs are less likely 

than men to have graduated from high school and to be 

employed and are more likely than men to have other 

health problems, to have sought previous drug treatment, 

to have attempted suicide, and to have suffered sexual 

abuse or other physical abuse.

Are There Gender Differences In the Biological Effects 

of Drugs?

Animal research and human studies have revealed that 

males and females may differ in their biological responses 

to drugs. In studies of animals given the opportunity to 

self-administer intravenous doses of cocaine or heroin, 

females began self-administration sooner than males and 

administered larger amounts of the drugs. Women may 

be more sensitive than men to the cardiovascular effects 

of cocaine. In human studies, women and men given 

equal doses of cocaine experienced the same cardiovascular response despite the fact that blood concentrations 

of cocaine did not rise as high in women as in men. In 

studies involving long-term cocaine users, women and 

men showed similar impairment in tests of concentration, 

memory, and academic achievement following sustained 

abstinence, even though women in the study had substantially greater exposure to cocaine. Women cocaine users 

also were less likely than men to exhibit abnormalities 

of blood flow in the brain’s frontal lobes. These findings 

suggest a sex-related mechanism that may protect women 

from some of the damage cocaine inflicts on the brain.

Does Gender Play a Role in Nicotine Addiction?

Women and men are equally likely to become addicted 

to nicotine, yet women typically smoke cigarettes with 

lower nicotine content than those smoked by men, smoke 

fewer cigarettes per day, and inhale less deeply than men. 

Overall, however, women are less successful than men

in quitting smoking and have higher relapse rates after 

they do quit. Treatment involving nicotine replacement 

therapy-nicotine gum or patch-works better for men 

than for women.

What Are Women’s Risks for HIV/AIDS?

Research suggests that there are sex-related differences 

in some fundamental aspects of the HIV/AIDS disease 

process. For example, an HIV-infected woman with half 

the amount of virus circulating in the bloodstream as an 

infected man will progress to a diagnosis of AIDS in about 

the same time. And, according to the Centers for Disease 

Control and Prevention, among cases that progress to a 

diagnosis of AIDS, drug abuse accounts for a greater percentage of cases among women than among men. Nearly 

half (47 percent) of all women diagnosed with AIDS are

injecting drug users (IDUs), whereas among men, IDUs 

account for 32 percent of AIDS cases. An additional 19

percent of women, compared with 2 percent of men, with 

AIDS report having sex with users who inject drugs. In 

all, drug abuse is nearly twice as likely to be directly or 

indirectly associated with AIDS in women (66 percent) as 

in men (34 percent).

For More Information

•	 NIDA’s gender-related research is discussed in Drug

Addiction Research and the Health of Women, 

available on NIDA’s home page on the World Wide 

Web: www.drugabuse.gov.
Research Findings

73

Volume 15, Number 3 (July 2000)

NIDA Initiative Targets Increasing Teen Use of Anabolic Steroids

By Patrick Zickler, NIDA NOTES Staff Writer

To reverse the rising use of anabolic steroids by high 

school-age children, NIDA and seven national partners 

have launched an initiative designed to alert the public 

about the risks associated with anabolic steroid use.

“The most recent data from our Monitoring the Future 

survey tell us that the trends in use of these drugs and 

in teenagers’ attitudes about 

them are going in the wrong 

direction,” said NIDA Director 

Dr. Alan I. Leshner at a 

Washington, DC, press conference to announce the 

initiative. “More than a half 

million 8th- and 10th-grade

students are now using these 

dangerous drugs, and increasing 

numbers of high school seniors 

say they don’t believe the drugs 

are risky.”

Anabolic steroids are synthetic 

compounds that mimic the 

action of the male sex hormone 

testosterone. The drugs have 

some medical uses, but they 

also are abused by some athletes and sports enthusiasts 

who want to increase muscle mass and improve performance. Some teens use them because of concern about 

body image.

In adolescents, anabolic steroid abuse can halt bone 

growth and has been associated with damage to the heart, 

kidneys, and liver. In males, steroid abuse can lead to 

impotence, shrunken testicles, and breast enlargement. 

In females, the drugs’ effects include menstrual irregularities, growth of body hair and loss of scalp hair, a deepened 

voice, and reduction in breast size. Some of these biological effects are irreversible. Use of anabolic steroids also 

has been linked to increased and unpredictable levels of 

aggression in human and animal studies.

NIDA’s initiative includes a new Web site—www.steroid 

abuse.org—that provides science-based information about 

the risks and prevention of steroid abuse. NIDA has also 

released an updated Research Report on anabolic steroids 

as part of the nationwide multimedia initiative. NIDA 

and its partners will distribute 250,000 copies of a special

Community Drug Alert Bulletin on anabolic steroid 

abuse and will place 500,000 “art cards”—colorful postcards with messages about the harmful effects of steroid 

abuse—in gyms, bookstores, restaurants, and clubs in 

Washington, DC, Los Angeles, Miami, Baltimore, Seattle, 

and Indianapolis.

The Institute’s partners in the initiative include the 

National Collegiate Athletic 

Association, the American Academy 

of Pediatrics, the American College 

of Sports Medicine, the National 

Association of School Nurses, 

the National Federation of High 

Schools, International Students in 

Action, and Dr. Drew Pinsky, a physician who hosts discussions about 

relationships and sexual behavior on 

MTV’s “Loveline” and the Web site 

www.drDrew.com.

The press conference announcing the 

initiative was followed by a scientific 

session at which NIDA-supported 

scientists presented summaries of 

research on anabolic steroids. Dr. 

Charles Yesalis of Pennsylvania 

As part of NIDA’s anabolic steroids initiative, the Institute 

has distributed more than 500,000 “art” cards—colorful 

postcards with messages about the harmful effects of steroid 

abuse—in gyms, restaurants, bookstores, and clubs. 

Dr. Linn Goldberg (left) of Oregon Health 

Sciences University, explains the Adolescent 

Training and Learning to Avoid Steroids 

(ATLAS) program to reporters at a science session 

following the NIDA press conference.
74

State University discussed the history and social context 

of steroid use and abuse. Dr. Linn Goldberg and Dr. 

Diane Elliot of the Oregon Health Sciences University in

Portland described the Adolescent Training and Learning 

to Avoid Steroids (ATLAS) program, a science-based 

prevention program that uses a team-centered approach 

to educate young male athletes about the risk and protective factors associated with steroid use. The researchers 

are currently developing a similar program—Athletes 

Targeting Healthy Exercise and Nutrition Alternatives 

(ATHENA)—to prevent eating disorders and abuse of steroids and other body-shaping drugs by young women on 

school-sponsored athletic, dance and drill, and rally teams. 

Dr. Harrison Pope of the McLean Hospital in Belmont, 

Massachusetts, discussed results of a study designed to 

examine the effects of steroids on mood and increased 

aggression, a phenomenon referred to as “roid rage.” The 

research, which involved 56 men who regularly work out 

at gyms and health clubs, revealed increased aggressive 

behavior in some participants who received testosterone 

in dosages smaller than those typically used by athletes 

or body-builders. Dr. Marilyn McGinnis of Mount Sinai 

School of Medicine in New York City provided additional 

evidence that steroid use can result in aggressive behavior. 

She described recently-completed laboratory studies in 

which rats with elevated levels of steroids exhibited 

unprovoked aggression toward passive, nonthreatening rats 

as well as intensely aggressive responses to provocation.

For More Information

•	 The report and other information about anabolic

steroids can be found at the special NIDA Web site: 

www.steroidabuse.org.

“Art” cards like this and the one on the previous page help spread 

the word about the harmful effects of steroids.

“More than a half million 8thand 10th-grade students are now 

using these dangerous drugs, and 

increasing numbers of high school 

seniors say they don’t believe 

the drugs are risky.” 
Research Findings

75

Volume 15, Number 1 (March 2000)

Marijuana-Like Compound in Womb May Influence Early Pregnancy

By Steven Stocker, NIDA NOTES Contributing Writer 

Ever since scientists began discovering in the early 1990s

that marijuana-like compounds are normally produced in 

various parts of the body, they have been investigating the 

function of these compounds. Research has suggested that 

in the brain, the compounds, called endocannabinoids, 

inhibit pain perception and help to regulate movement. In 

the spleen and blood, endocannabinoids seem to be partly 

involved in suppressing inflammation and other responses 

of the immune system. Now NIDA-funded researchers 

have discovered that in the female mouse reproductive 

tract, one of these endocannabinoids, called anandamide, 

appears to help regulate the early stages of pregnancy.

Dr. Sudhansu K. Dey and his colleagues at the University 

of Kansas Medical Center in Kansas City, Kansas, have 

found that the mouse uterus contains the highest anandamide levels yet discovered in any mammalian tissue. At 

times, parts of the uterus contain anandamide levels that 

are more than 100 times higher than those in the brain.

The researchers have also found that mouse embryos contain cannabinoid receptors—proteins on the cell surfaces 

that latch on to endocannabinoids in the vicinity—again, 

at levels that exceed those of the brain.

To find out why the uterus contains anandamide and 

the embryo contains cannabinoid receptors, the scientists first examined the effects of anandamide on embryo 

development. When they placed embryos from mice in 

cell culture, about 90 percent proceeded to the next stage

of embryonic development, the blastocyst, which normally implants into the wall of the uterus and eventually 

becomes a fetus. With the addition of anandamide, only 

36 percent proceeded to the blastocyst stage. However, 

if these embryos were then placed in cell culture without 

anandamide, most started developing again.

In addition to inhibiting the growth of embryos prior to 

implantation, anandamide probably also inhibits implantation itself, the researchers found. They determined that 

administering compounds similar to anandamide prevented 

blastocysts from implanting in the uterine wall.

Functions of Anandamide

Anandamide may be serving at least three functions before 

and during implantation, suggests Dr. Dey. First, the compound may be involved in synchronizing the development 

of the embryo with the preparation of the uterus for receiving it. For example, anandamide secreted into the fluid of 

the uterus is ready to receive the implanting blastocyst and 

to sustain it once it has implanted.

Second, anandamide may be involved in embryo selection. “In the mouse, about 15 percent of embryos never 

implant, and in humans, as many as 60 percent either

don’t implant or don’t survive after implantation,” says 

Dr. Dey. “Perhaps these rejected embryos are inferior 

in some way, and high anandamide levels in the uterine 

wall may prevent them from implanting or surviving after 

implantation.” 

Finally, Dr. Dey suggests, anandamide may prevent a 

second blastocyst from implanting nearby one that has 

already implanted. After the first one implants, the anandamide level in the surrounding area increases again, which 

prevents other blastocysts from implanting at the same site.

Understanding how anandamide acts in the female 

reproductive tract may lead to an explanation for some 

cases of infertility in women, if anandamide is found to 

exist in the human uterus, suggests Dr. Dey. In these infertile women, excessive uterine levels of anandamide may 

be disrupting embryo development and implantation, 

says Dr. Dey.

This research may also lead to the development of new 

contraceptives that can inhibit embryo development 

and implantation in the same manner as anandamide. 

Conversely, it could also lead to the development of 

fertility agents that act in ways opposite to those of 

anandamide.

Sources

•	 Paria, B.C.; Das, S.K.; and Dey, S.K. The preimplantation mouse embryo is a target for cannabinoid 

ligand-receptor signaling. Proceedings of the National 

Academy of Sciences 92:9460–9464, 1995.

•	 Paria, B.C.; et al. Fatty-acid amide hydrolase is

expressed in the mouse uterus and embryo during 

the periimplantation period. Biology of Reproduction

60:1151–1157, 1999.

•	 Schmid, P.C.; et al. Changes in anandamide levels in

mouse uterus are associated with uterine receptivity 

for embryo implantation. Proceedings of the National 

Academy of Sciences 94:4188–4192, 1997.

•	 Yang, Z-M; Paria, B.C.; and Dey, S.K. Activation of

brain-type cannabinoid receptors interferes with preimplantation mouse embryo development. Biology of 

Reproduction 55:756–761, 1996.
Research Findings

Volume 14, Number 6 (March 2000)

76

Female Rats Progress Quickly to Drug Abuse

In a study conducted by Dr. Wendy Lynch and Dr. 

Marilyn Carroll of the University of Minnesota in 

Minneapolis, female rats gave themselves more cocaine 

and heroin sooner than male rats, a finding consistent 

with human studies suggesting that women progress faster 

than men to drug addiction.

The experiment consisted of a series of 6-hour sessions in 

which rats could administer the drugs to themselves freely 

by pushing a lever. Seventy percent of the females, but only 

30 percent of the males, progressed to a predetermined level

of cocaine use. For heroin, 90 percent of the females and

91.7 percent of the males reached that level.

The female rats reached the predetermined level of cocaine 

use in a mean of 7.57 sessions compared to 16.67 sessions

for males. They reached the level for heroin use in a mean 

of 8.7 sessions compared to 13 sessions for males. Among

the rats that reached that level of use, both cocaine and 

heroin use were higher in females than in males, and 

cocaine use was significantly higher. 

UCLA Study Looks at Women in Treatment

Women in women-only drug abuse treatment programs 

were more than twice as likely to complete treatment as 

women in mixed-gender programs, according to a NIDAfunded study conducted by Dr. Christine E. Grella of 

the University of California, Los Angeles. The study also 

found that, on average, pregnant women had used their 

primary drug for less time than nonpregnant women; and

pregnant women in women-only drug abuse treatment 

programs averaged more days in treatment than did those 

in mixed-gender programs, 87.4 days vs. 74 days. Overall,

pregnant women spent about 15 percent less time in treatment than nonpregnant women.

Dr. Grella’s study compared the characteristics of 4,117

women through data reported from 1987 to 1994 by all

publicly funded drug abuse treatment programs in Los 

Angeles County. The statistical analyses of the treatment 

program data by pregnancy status and gender composition 

support the premise that women in drug abuse treatment 

programs have different needs than men in treatment, and 

a successful program for women often depends on meeting those different needs, Dr. Grella says. 
Research Findings

77

Support Group Improves Outcomes for Pregnant Drug Users 

Volume 14, Number 4 (November 1999)

Participation in a support group while pregnant can 

improve maternal and infant outcomes among drugdependent women, according to a NIDA-supported study. 

Researchers from The Johns Hopkins University School

of Medicine in Baltimore, the University of Maryland 

in Baltimore, Emory University in Atlanta, and the 

University of Kansas in Lawrence found that women who 

participated in a drug abuse support group had more 

prenatal care visits than drug-abusing women who did not 

attend the support group, and their infants had higher 

birthweights. The study also found that support group 

participation resulted in lower medical care costs for 

mothers and their infants.

The researchers studied 121 drug-dependent pregnant 

women registered for prenatal care during a 16-month 

period at a high-risk obstetric clinic in a poor urban 

neighborhood. A total of 54 women attended the weekly 

support group meetings held at the clinic, and 67 did not

attend. The groups were led by a drug abuse counselor 

and discussed how drugs affect the developing fetus, how 

to avoid drug-related situations, and the benefits of staying 

in touch with each other outside of the weekly meetings. 

Average maternal medical care costs were almost $1,000

less for support group attenders than nonattenders. Costs 

were derived from review of Medicaid claims data and calculated from 1 week before delivery through 3 weeks after. 

For infants of support group attenders, average medical 

costs were about $1,500 less in their first 3 weeks than for

those whose mothers did not attend.

The researchers believe that locating the support group at 

the prenatal clinic provides a cost-effective way to deliver 

drug abuse treatment. They conclude that this type of 

“low-intensity intervention” may be an effective way for 

some women to reduce or eliminate their drug use 

during pregnancy. For other women, the support group 

may lead to more intensive drug abuse treatment, the 

researchers suggest. 
Research Findings

78

Volume 14, Number 4 (November 1999)

Twin Studies Help Define the Role of Genes in 

Vulnerability to Drug Abuse 

By Patrick Zickler, NIDA NOTES Staff Writer 

Some individuals who use drugs become drug abusers— they continue taking drugs even though doing so 

causes serious problems in their lives. Others avoid abuse

or addiction. By studying patterns of drug use in pairs of 

twins, NIDA-supported researchers are beginning to 

clarify the role that genes play in predisposing individuals 

to drug abuse.

“Twin studies explore the roles and interrelationship of 

genetic and environmental risk factors in the development 

of drug use, abuse, and dependence,” says Dr. Naimah 

Weinberg of NIDA’s Division of Epidemiology, Services, 

and Prevention Research.

In twin studies, researchers interview both members of 

identical (monozygotic) and fraternal (dizygotic) twin 

pairs, who typically are exposed to common environmental influences. If genes influence their risk for drug abuse, 

identical twin pairs, who share the same genes, will tend 

to be concordant-that is, both will abuse drugs or not 

abuse drugs. Fraternal twin pairs, on the other hand, are 

no more similar genetically than non-twin siblings, and so 

will be less concordant—there will be more pairs in which 

one twin abuses drugs and the other does not. By comparing the degree of concordance 

in identical and fraternal twins, 

researchers can estimate the extent 

to which genes influence vulnerability to drug abuse.

Marijuana and Cocaine Abuse 

Among Female Twins

NIDA-supported researchers Dr. 

Kenneth Kendler and Dr. Carol 

Prescott at the Medical College of 

Virginia in Richmond have examined the patterns of marijuana and 

cocaine use by female twins and 

found that genetic factors play a 

major role in the progression from 

drug use to abuse and dependence. 

The researchers interviewed 1,934

twins, ranging in age from 22 to 

62, recruited from the Virginia 

Twin Registry, a database compiled from Commonwealth birth 

records.

In the study, drug “use” involved at least one nonprescribed use of a drug; “abuse” was based on the definition provided in the Diagnostic and Statistical Manual 

of Mental Disorders, Fourth Edition (DSM-IV), which 

includes symptoms such as recurrent use in situations 

where it presents a physical danger, failure to meet obligations at work or school, or recurrent social or interpersonal problems caused by effects of 

the drug; and “dependence” was

based on the DSM-IV definition 

and included characteristics such 

as physical symptoms of tolerance or withdrawal, taking larger 

amounts of the drug or using it 

over a longer period than intended, or spending large amounts 

of time seeking, obtaining, and 

recovering from the effects of 

the drug.

“Our research supports other

studies that indicate family and 

social environmental factors 

are influential in determining 

whether an individual begins 

using these drugs,” Dr. Kendler 

says. “But our findings suggest 

that the progression from the use 

of cocaine or marijuana to abuse 

or dependence was due largely to 

genetic factors.”

If genes influence the risk for drug abuse, identical twin pairs, 

who share the same genes, will tend to be concordant—that 

is, both will abuse drugs or both will not abuse drugs. 

Percentages of pairs in which both twins used, abused, 

or were dependent on marijuana or cocaine were 

higher in identical twins than in fraternal twins. 

Illustration © 1998 by Richard Lillash
79

In addition, Dr. Kendler says, the study found that 

concordance rates—both twins using, abusing, or being 

dependent on drugs—were higher for identical than fraternal twins (see chart). For cocaine use, concordance was 

54 percent in identical twins and 42 percent in fraternal 

twins; for abuse, 47 percent in identical twins and 8 percent in fraternal

twins; and for dependence, 35 percent in identical twins and zero for 

fraternal twins.

“Abuse and dependence are highly 

heritable,” Dr. Kendler says. “For 

both cocaine and marijuana, genetic 

factors are responsible for roughly 60

to 80 percent of the differences in

abuse and dependence between 

fraternal and identical twin pairs.”

Genetic Risk Factors Differ Among Drugs and 

Between Males and Females

Dr. Ming Tsuang, a NIDA-supported researcher at 

Harvard University in Cambridge, Massachusetts, has 

found that, in males, genetic influences are stronger for 

abuse of some drugs than for others. Dr. Tsuang and his 

colleagues studied drug use in 1,874 identical male twin

pairs and 1,498 fraternal male twin pairs recruited from

the Vietnam Era Twin Registry, a database compiled 

from Department of Defense records. The average age 

of participants was 45.

The researchers found evidence to suggest that genetic 

influences contribute to a common vulnerability for abusing marijuana, sedatives, stimulants, heroin or opiates, and 

psychedelics. “There is some characteristic of the individual that imparts vulnerability to the abuse of all categories 

of drugs. Abusing any category of drugs was associated 

with a marked increase in the probability of abusing every 

other category of drugs,” Dr. Tsuang says. In addition to 

this shared vulnerability, the researchers found different 

vulnerabilities for different drugs. “Each category of drugs 

we looked at, except psychedelics, had unique genetic 

influences,” Dr. Tsuang says. “The genetic influence for 

abuse was greater for heroin than for any other drug.”

NIDA-supported studies involving male and female twins 

suggest that genetic factors for drug abuse are stronger in 

males than in females. Dr. Marianne van den Bree and 

Dr. Roy Pickens of NIDA’s Intramural Research Program 

and their colleagues studied 188 twin pairs in which at

least 1 twin was recruited through a drug treatment program. The sample included 56 identical male pairs, 66 

fraternal male pairs, 38 identical female pairs, and 28 fraternal female pairs. Participants were interviewed to determine drug use (five times or more) and clinical diagnosis 

(according to DSM criteria) of drug abuse, dependence, 

or both for sedatives, stimulants, opiates, marijuana, 

or cocaine. For most drugs, clinical diagnosis of abuse, 

dependence, or both was more strongly influenced by 

genetic factors than was drug use. In addition, for most 

drugs, genetic influences for 

abuse or dependence were greater 

for males than for females.

“For females, genetic influences 

accounted for 47 percent of the

differences between identical and 

fraternal twins in abuse, dependence, or both for any drug, 

compared with 79 percent for

males,” Dr. van den Bree says. 

The impact of genetic factors also seems to differ for specific drugs, she notes. The researchers found no evidence 

for genetic influence for opiate or sedative abuse, dependence, or both in females, but in males genetic influences 

were generally larger than environmental influences.

“The results we see from these twin studies are making 

important advances in our understanding of the role of 

genetic influences in drug abuse,” observes NIDA’s Dr. 

Weinberg. “Although the studies can’t tell us anything 

about the risk for a particular individual, they are of 

enormous value in helping define the variations in drug 

abuse vulnerability in the population.”

Sources

•	 American Psychiatric Association, Diagnostic and 

Statistical Manual of Mental Disorders (4th Edition) 

Washington, DC: American Psychiatric Association, 

1994.

•	 Kendler, K., and Prescott, C. Cannabis use, abuse,

and dependence in a population-based sample 

of female twins. American Journal of Psychiatry

155(8):1016–1022, 1998.

•	 Kendler, K., and Prescott, C. Cocaine use, abuse, and

dependence in a population-based sample of female 

twins. British Journal of Psychiatry 173:345–350,

1998.

•	 Tsuang, M., et al. Co-occurrence of abuse of different

drugs in men. Archives of General Psychiatry 55:967–

972, 1998.

•	 Van den Bree, M.; Johnson, E.; Neale, M.; and

Pickens, R. Genetic and environmental influences on 

drug use and abuse/dependence in male and female 

twins. Drug and Alcohol Dependence 52(3):231–241,

1998.

“The progression from the 

use of cocaine or marijuana to 

abuse or dependence was due 

largely to genetic factors.”
Research Findings

80

Volume 14, Number 3 (September 1999)

Gender Differences in Progression to AIDS

NIDA-funded research on injecting drug users (IDUs) 

conducted by Dr. Homayoon Farzadegan and his colleagues at The Johns Hopkins University School of

Hygiene and Public Health in Baltimore has shown that 

the course of HIV infection differs in women and men, so 

that gender-specific treatment may be needed. This study 

of 2,960 adult IDUs, begun in 1988 with followup in

1992 and 1997, revealed that although women progressed

to AIDS as rapidly as men, they had approximately half 

the viral load in their bloodstreams when they developed 

AIDS. Initiation of AIDS treatment is based on HIV viral 

load, and current treatment guidelines are derived mainly 

from studies with men. 

The researchers speculate that physiological factors such as 

hormones may account, in part, for their findings. Dr. 

Farzadegan and the research team believe that these gender differences must be explored further, and the possibility that women are being under-treated based on current 

guidelines warrants considering a change in when women 

start therapy. The study was published in Lancet in 

1998.
Research Findings

81

Study Shows How Genes Can Help Protect From Addiction

By Robert Mathias, NIDA NOTES Staff Writer 

Volume 13, Number 6 (March 1999)

A recent NIDA-funded study illustrates how genetic differences can contribute to or help protect individuals from 

drug addiction. The study shows that people with a gene 

variant in a particular enzyme metabolize or break down 

nicotine in the body more slowly and are significantly less 

likely to become addicted to nicotine than people without 

the variant. In addition, people with the genetic variant who 

do become tobacco-dependent smoke fewer cigarettes than 

individuals without the variant, the study indicates. 

“This study shows the importance of looking at the role of 

genetics in drug addiction and treatment,” says Dr. Jonathan

Pollock of NIDA’s Division of Basic Research. Ultimately, 

increased knowledge about underlying genetic vulnerability 

might lead to more effective treatments for nicotine 

addiction that are tailored to particular types of smokers, 

Dr. Pollock says. 

In the study, Dr. Edward Sellers and coinvestigator Dr. 

Rachel Tyndale of the University of Toronto examined the 

role that a gene for an enzyme called CYP2A6 plays in nicotine dependence and smoking behavior. CYP2A6 metabolizes 

nicotine, the addictive substance in tobacco products. Three 

different gene types, or alleles, for CYP2A6 have been identified by previous research—one fully functional allele and two 

inactive or defective alleles. Each person has a paternal and 

maternal copy of the gene. Therefore, a person can have two 

active forms of the gene and normal nicotine metabolism; one

active and one inactive copy and impaired nicotine metabolism; or two inactive copies, which would further impair

nicotine metabolism. 

The study found that people in a group who had tried smoking but had never become addicted to tobacco were much 

more likely than tobacco-dependent individuals in the study 

to carry one or two defective copies of the gene and have 

impaired nicotine metabolism. The researchers theorize that 

the unpleasant effects experienced by people learning to 

smoke, such as nausea and dizziness, last longer in people 

whose bodies break down nicotine more slowly. These longer 

lasting aversive effects would make it more difficult for new 

smokers to persist in smoking, thus protecting them from 

becoming addicted to nicotine. 

“We have proven that the risk of becoming a smoker significantly decreases if you have one of the inactive alleles for this 

enzyme,” Dr. Sellers says. Individuals who have two defective 

copies of the gene would have an even lower risk of becoming 

a smoker, he predicts. Although only 1 to 2 percent of the 

general population may carry two defective alleles, individuals 

with at least one defective allele constitute about 16 to 25 

percent of the general population, Dr. Sellers says. “We’ve 

calculated that the frequency of defective alleles that we’ve 

found would be protecting about 7 million North Americans

from becoming smokers,” he says. 

The study also found that individuals with impaired nicotine 

metabolism who do go on to become addicted to nicotine are 

afforded a measure of protection from the harmful effects of 

nicotine addiction. The study shows that smokers with at least 

one inactive allele smoked significantly fewer cigarettes daily 

and weekly than smokers with two active copies of the allele. 

Generally, smokers with slower nicotine metabolism do not 

need to smoke as many cigarettes to maintain constant blood 

and brain concentrations of nicotine, the researchers explain. 

However, this slower nicotine metabolism had a greater 

impact on reducing smoking among men than women in 

the study. This is probably because women’s smoking is 

controlled less by nicotine dependence than is men’s, the 

researchers suggest. 

In addition to illustrating the role genetics can play in vulnerability to addiction, identification of the effect of the defective 

gene on smoking has prevention and treatment implications, 

Dr. Sellers says. “If you could find a chemical or some other 

way of causing the same effect, such as blocking the enzyme, 

you might be able to prevent people from becoming smokers,” he says. “If you did the same kind of thing in people 

who were already smokers, they would be likely to smoke less, 

which could lead to smoking cessation,” Dr. Sellers concludes. 

Source 

•	 Pianezza, M.L.; Sellers, E.M.; and Tyndale, R.F.

Nicotine metabolism defect reduces smoking. Nature

393(6687):750, 1998.

Nonsmokers in a study at the University of Toronto were more 

likely than smokers to carry a copy of the CYP2A6 gene variant, 

which slows nicotine metabolism. 

Percentages of Smokers and Nonsmokers With 

Gene Variant That Slows Nicotine Metabolism 
82

Research Findings

Men and Women in Drug Abuse Treatment Relapse at Different 

Rates and for Different Reasons

By Steven Stocker, NIDA NOTES Contributing Writer 

Volume 13, Number 4 (November 1998) 

Recent NIDA-funded studies have found that women in 

drug abuse treatment relapse less frequently than men do, 

at least partly because women are more likely to engage 

in group counseling. Other NIDA-supported researchers

have found that cocaine-addicted women and men differ 

in the factors that cause them to relapse, indicating that 

males and females might benefit from different relapse 

prevention strategies. 

Likelihood of Relapse 

In a study conducted at the University of California, Los 

Angeles, Dr. Robert Fiorentine and his colleagues have 

found that women drug abusers are less likely than men 

drug abusers to relapse after entering treatment because 

women participate more frequently in group counseling 

and that this more intensive level of treatment engagement 

helps them to remain drug-free. 

The researchers followed 182 women and 148 men in 26

public outpatient drug abuse treatment programs in Los 

Angeles County. The programs provided group, individual, and family counseling; educational activities; and

referrals to other health and social services. The treatment 

lasted 6 months. 

About half the patients regularly used just one drug— 

primarily crack cocaine, marijuana, or powder cocaine, 

and about half used more than one drug. Regular use 

was defined as three or more times per week. The patients 

were interviewed while in treatment and approximately 

6 months after the first interview. 

The scientists found that the women in their sample were 

less likely than the men to relapse: only 22 percent of the 

women compared to 32 percent of the men relapsed 

to drug use in the 6 months between interviews. The 

researchers considered several theories to account for 

this finding. 

One possibility was that the women used drugs less than

the men, so abstaining from drug use was easier for them. 

However, the study findings showed otherwise. In the 

year preceding treatment, more women had used crack 

cocaine than men, and about the same percentages of 

women and men had used powder cocaine, marijuana, 

and other drugs. In addition, women used all drugs as 

frequently as men, except for crack and heroin, which 

women used more frequently. Finally, about the same percentage of women and men used two or more drugs. 

Another possibility the researchers considered was that the 

women received more social support than the men from a 

variety of sources, such as families, friends, and coworkers. 

The investigators found that, although the women were 

more likely than the men to maintain a social network, 

they were no more likely than men to receive emotional 

support for their problems and encouragement to stop 

using drugs. 

What did appear to explain the difference in relapse 

was the fact that the women were more likely to engage 

in treatment, particularly group counseling, says Dr. 

Fiorentine. In his study, the women engaged in an average 

of 10.9 sessions of group counseling per month compared

to 7.9 sessions a month for the men. Research has shown

that more intense participation in treatment is associated 

with lower rates of relapse. 

The women did not seem to be attending group counseling sessions more often than men because the sessions 

were somehow oriented more toward women. The sessions dealt with the problems of both genders more or 

less equally and were usually attended by both men and 

women, Dr. Fiorentine says. 

The reason that women attended group counseling sessions more than men may stem from women’s greater 

willingness to seek professional help for their health problems, speculates Dr. Fiorentine. “Women appear to be 

more willing to seek help for their problems, including 

their substance abuse problems,” he says. “Men, on the 

other hand, are more likely to say, I’m OK. I don’t need

help. I can take care of this. It’s just a little problem.’” He 

recommends that treatment providers discuss with male 

drug abusers the possibility that their reluctance to seek 

help may be hampering their recovery. 

Even though the women attended more group counseling 

sessions than men, they did not attend more individual 

counseling or family counseling sessions than men did. 

If women are more likely to use services in general, why 

did they not engage more often in these other types of 

therapies? The explanation seems to be that these other 

therapies are not offered as frequently as group counseling 

in Los Angeles County, primarily because of the county’s 

budget constraints, Dr. Fiorentine suggests. “Individual 

counseling, for example, is expensive and there are only 

so many counselors to go around, so treatment programs 

ration individual counseling,” he says. 
83

“Both women and men already may be attending the 

maximum number of individual counseling sessions they 

can attend. If patients could attend as many of these sessions as they desired, you might see more women than 

men in these sessions, just as you see more women than 

men in group counseling sessions.” 

In a related study, Dr. Roger Weiss and his colleagues at 

McLean Hospital in Belmont, Massachusetts, also found 

less likelihood of relapse for women than for men among 

patients who were hospitalized for cocaine addiction. 

When 74 patients were interviewed 6 months after the

hospitalization, 51 percent of the women had remained 

abstinent compared to 25 percent of the men. 

Like Dr. Fiorentine, Dr. Weiss theorizes that the women 

in his sample were more motivated for therapy than the 

men were. “Studies have identified barriers to entering 

drug abuse treatment programs that exist for women but 

not for men,” says Dr. Weiss. “These include childcare 

difficulties and the predominance of male patients and 

staff. There is also more social stigma for women in being 

labeled an addict. Women who come to these treatment 

facilities must be willing to overcome these barriers, which 

could lead to a higher percentage of women who are motivated to change.” 

Reasons for Relapse 

In addition to identifying gender differences in the likelihood that drug abusers relapse, scientists also have identified gender differences in drug abusers’ experiences before 

and during relapse. Dr. James McKay and his colleagues

at the University of Pennsylvania in Philadelphia found that 

women in treatment for cocaine addiction were more likely 

than men to report negative emotions and interpersonal 

problems before they relapsed. The men, on the other 

hand, were more likely to report positive experiences 

prior to relapsing and were more likely to engage in 

self-justification and rationalizing afterward. They reported, for example, that they felt entitled to use cocaine or 

that they believed they could control their cocaine use. 

The women also were much more likely to be impulsive in their return to cocaine use. Fifty-six percent of 

the women, compared with only 17 percent of the men,

reported that they relapsed immediately after the thought 

of using cocaine occurred to them. 

These gender differences in relapse factors suggest that 

different relapse prevention strategies might be emphasized for women and men, says Dr. McKay. For example, 

women might benefit more from techniques that enable 

them to deal more effectively with unpleasant emotions 

and interpersonal problems. “One strategy is to take

action quickly as your mood starts to deteriorate rather 

than waiting until you are in a really bad mood and then 

trying to do something about it,” he says. “If it’s a small 

problem, planning an enjoyable activity might be all that 

is needed. If, however, it’s a serious depression, medication or psychotherapy might be necessary.” 

In contrast, men might benefit more from strategies that 

counter their tendency to let down their guard when 

feeling good, Dr. McKay says. “These strategies are 

derived from concepts taught in 12-step programs, such 

as not getting too cocky or confident when your mood 

improves,” he says. “Patients are told to be on the lookout for warning signs that might be present when they’re 

feeling good, such as thinking to themselves, ‘I’m feeling 

great today. I don’t need to go to that meeting. I can go 

hang out with this friend of mine. I know he uses, but I’m 

feeling good today, and I’m not vulnerable to using.’” 

More Research 

Gender differences in drug abuse are of intense interest to 

NIDA, says Carol Cowell of NIDA’s Division of Clinical 

and Services Research. “Researchers are finding gender 

differences across the broad spectrum of drug abuse 

research —from basic research to studies such as these on 

treatment and services—and we would like to encourage 

more study of these differences,” she says. She occasionally 

suggests that NIDA-funded researchers analyze their data 

in terms of gender differences. “This sometimes results in 

a study that increases our knowledge of the role of gender 

in treatment outcomes,” she says. 

“Performing gender analyses is simply a matter of doing 

good science,” says Dr. Cora Lee Wetherington, NIDA’s 

women’s health coordinator. When gender differences exist 

but investigators fail to test for them, flawed conclusions 

may be drawn, either for males or females or both, she says. 

Sources 

•	 Fiorentine, R.; Anglin, M.D.; Gil-Rivas, V.; and

Taylor, E. Drug treatment: Explaining the gender 

paradox. Substance Use and Misuse 32(6):653–678,

1997.

•	 Fiorentine, R.; Nakashima, J.; and Anglin, M.D.

Client engagement in drug treatment. Journal of 

Substance Abuse Treatment 17(3):199–206, 1999.

•	 McKay, J.R.; Rutherford, M.J.; Cacciola, J.S.;

Kabasakalian-McKay, R.; and Alterman, A.I. Gender

differences in the relapse experiences of cocaine 

patients. The Journal of Nervous and Mental Disease

184(10):616–622, 1996.

•	 Weiss, R.D.; Martinez-Raga, J.; Griffin, M.L.;

Greenfield, S.F.; and Hufford, C. Gender differences

in cocaine dependent patients: A 6 month follow-up 

study. Drug and Alcohol Dependence 44(1):35–40,

1997.
Research Findings

84

Volume 13, Number 4 (November 1998) 

Men who abuse drugs are more likely to reduce their sexual risks of HIV infection if they are given risk-reduction 

information on the street, while women drug abusers 

respond better if they are given 

this information in an office 

with counseling. This is one of 

the findings of a NIDA-funded 

study on the effectiveness of 

HIV risk-reduction programs 

tested in two towns in Arizona. 

Dr. Robert Trotter and his colleagues at Northern Arizona 

University in Flagstaff developed 

two enhanced programs for 

reducing drug-related and sexual 

risks for HIV transmission and 

added the programs to a standard program developed by the 

Centers for Disease Control and 

Prevention and modified by 

NIDA. The standard program 

recruits drug abusers on the 

street and then provides HIV 

risk-reduction information at the project office. In the 

office, counselors provide information on proper condom 

use and bleach disinfection of drug injection equipment. 

Drug abusers also are offered testing for HIV infection. 

One of the enhanced programs developed by the researchers, called the active outreach intervention, 

provides the HIV risk-reduction information on the street 

rather than in the office. Later, the entire network of people who use drugs together and share drug use equipment 

is invited into the office for a group discussion of HIV 

transmission risks. 

The other enhanced intervention, called the office-based 

intervention, involves the same recruitment procedure 

as the standard intervention, but additional counseling 

techniques are used when the drug abuser visits the office. 

In the office, the person is first asked to identify at least 

one HIV risk in his or her life. The person is then asked 

how this risk might be reduced and is encouraged to do 

so. Like the active outreach intervention, the office-based 

intervention also involves a subsequent group session with 

the network of drug abusers. 

All three interventions, both the 

standard and the two enhanced, 

reduced HIV risk behaviors; however, for reducing sexual risks, the 

researchers found that the active 

outreach intervention worked 

better for men, and the officebased intervention worked better 

for women. The men seemed to 

respond well to being taught about 

HIV risk-reduction on the street 

because that was the environment 

in which HIV risks often occurred, 

Dr. Trotter speculates. “Some 

pretty solid social science theory 

states that, for certain kinds of 

behavior, providing the behavior 

reduction intervention in the context in which the behavior occurs 

is more effective,” he says. 

However, this theory did not apply to the women in the 

study. The women told the researchers that they felt safe 

discussing sensitive matters in the office, where they were 

not under pressure from family and other drug abusers. “If 

we had conducted the interventions with these women on 

the street or in their homes, people would be around who 

might hear what they were saying, and the women were 

afraid of the repercussions. In the office, the women felt 

emotionally and physically protected,” Dr. Trotter says.

Source 

•	 Trotter, R.T.; Bowen, A.M.; Baldwin, J.A.; and Price,

L.J. The efficacy of network-based HIV/AIDS riskreduction programs in midsized towns in the United 

States. Journal of Drug Issues 26(3):591–605, 1996.

Researchers Find Gender Differences In How Drug Abusers 

Respond To HIV Prevention Strategies

By Steven Stocker, NIDA NOTES Contributing Writer 

Dr. Robert Trotter of Northern Arizona University discusses with his staff possible strategies for reducing HIV 

transmission risks among drug abusers who use drugs 

together and share drug injection equipment.
Research Findings

85

Volume 12, Number 4 (July/August 1997)

Gender Affects Relationships Between Drug Abuse and 

Psychiatric Disorders

By Neil Swan, NIDA NOTES Staff Writer

In the general population, women are more than twice as 

likely as men to suffer depression. But among cocaine and 

alcohol abusers, men are as likely to be diagnosed with 

depression as women, a NIDA-funded study indicates. 

Why? Is cocaine more likely to trigger depression among 

men than among women? Perhaps. 

Researchers have long been aware that many drug abusers also have serious mental disorders, a status referred 

to as dual diagnosis or comorbidity. Does the psychiatric 

disorder precede and perhaps contribute to the onset of 

drug abuse? Or, conversely, do drug abuse and addiction

develop first, perhaps contributing to the development of 

the mental disorder? 

A study conducted by Dr. Kathleen T. Brady and her 

colleagues at the Medical University of South Carolina 

provides insights into these questions. The researchers 

examined gender differences in psychiatric disorders 

among 100 treatment-seeking cocaine and alcohol abusers.

Among these substance abusers, comorbidity with mental 

disorders was substantive. Some 48 percent of the men

and 70 percent of the women had a comorbid affective or

anxiety disorder. In addition, a substantial number were 

also dually diagnosed with other mental disorders including passive-aggressive, obsessive-compulsive, and antisocial 

personality disorders. Some 56 percent of the men and 68

percent of the women abusers had one or more of these 

additional disorders, either alone or with an affective or 

anxiety disorder. 

The study’s preliminary findings suggest that both onset 

scenarios—drug abuse first or mental disorder first—

sometimes may occur. It is possible that the sex of 

the drug abuser may be a factor in determining which 

comes first, depending on the comorbid psychiatric 

disorder involved. 

In the case of depressive episodes, Dr. Brady’s study suggests that for women, depression comes first more often;

for men, drug abuse appears to come first more often. 

Because cocaine has such powerful effects on the brain, it 

may be that in many people cocaine use activates depressive 

episodes that linger after the period of euphoria and withdrawal, she says. “Perhaps men are at greater risk for this 

response to cocaine, which would help explain the lack 

of gender differences in depression rates among cocaine 

abusers we studied compared to rates in the general population,” explains Dr. Brady. Also, men typically consume 

more alcohol and use more cocaine, which would increase 

the damaging effects of these substances, which, in turn, 

might lead to depression, she adds. 

The study shows that women more 

often than men were diagnosed with 

not just depression but with other 

psychiatric disorders as well before 

they began using drugs (see table on 

following page). For example, as with 

depression, women are significantly 

more likely than are men to have a 

diagnosis of panic disorder before the 

onset of drug abuse, says Dr. Brady, 

a psychiatrist. Panic disorder is 

manifested in sudden attacks of 

acute anxiety or terror that may 

be uncontrollable.

The most dramatic gender difference in prevalence rates found by the 

South Carolina researchers was in the 

diagnosis of posttraumatic stress 

disorder (PTSD)—emotional shock 

ignited by the threat of death or actual 

or threatened injury resulting in 

Percentage of 100 Cocaine and Alcohol Abusers 

Who Were Ever Diagnosed With Comorbid Psychiatric Disorders 

Individuals may have been diagnosed with more than one psychiatric disorder 

during their lifetimes.

Men (50) Women (50)

Any affective or anxiety disorder 48%	 70%

Major depressive episode 36%	 40%

Bipolar disorder (severe mood swings) 6%	 4%

Panic disorder 10%	 18%

Social phobia 14%	 10%

Posttraumatic stress disorder (PTSD) 24%	 46%
86

severe fear, feelings of helplessness or horror, and recurrent memories. Of the 50 men and 50 women whom Dr.

Brady studied, some 46 percent of women were diagnosed 

with lifetime PTSD, compared to only 24 percent of the 

men (see table on previous page). 

Social phobia—extreme shyness and fear of embarrassment and humiliation or performance anxiety such 

as stage fright—was found in 12 percent of the study 

group compared to only 2.8 percent of the population

at large, which other studies have shown. The onset of 

social phobia predated drug abuse in 100 percent of both

women and men diagnosed with the disorder in this 

study. This suggests that patients may use drugs to selfmedicate their social phobia, says Dr. Brady. 

Other epidemiologic studies have shown that social

phobia is 1.5 times more common in women than men. 

“But we found little gender difference in the prevalence of 

social phobia in the group of substance abusers,” she says. 

“This means that while social phobia is a risk factor for 

substance abuse in both sexes, it appears that it may be a 

greater risk factor for men. Perhaps cultural expectations 

for men to be more socially aggressive prompt men more 

to use drugs or alcohol to overcome shyness and other 

aspects of social phobia.” 

The study found no gender differences in the study group 

in prevalence of other psychiatric disorders such as antisocial personality disorder, paranoid or schizoid personality 

disorders, or obsessive-compulsive disorder. In general, the 

study demonstrates important gender differences in some 

psychiatric disorders, but not in others, among the substance abusers and compared to the population at large. 

Dr. Brady’s data on these disorders show similar rates 

of prevalence for these diagnoses in men and women. 

Particularly for antisocial personality disorder, these similar rates are in contrast to several earlier studies, she notes. 

In the general population, as well as in alcoholics and opiate abusers, a higher prevalence of antisocial personality 

disorder in men than in women has been reported. But in 

one earlier study of psychopathology in cocaine abusers, 

no significant gender differences in antisocial personality 

disorder rates were noted. The majority of the women in 

her study were cocaine-dependent, which may partially 

explain the discrepancy between her data and some of the 

other studies, Dr. Brady says. 

Her study results imply that different psychiatric factors 

may have differing roles prior to—or in response to—

drug abuse in women compared to men, says Dr. Brady. 

These preliminary findings are important indicators 

for designing research to develop and implement 

improved gender-specific drug abuse treatment strategies, 

says Dr. Cora Lee Wetherington, NIDA’s Women’s 

Health Coordinator. 

In another study, Dr. Brady examined cocaine-abusing 

men and women who also were diagnosed with PTSD, 

dividing them by order of onset of diagnosis—cocaine 

first or PTSD first. In the cocaine-first group, the PTSDcausing trauma was generally related to the dangers 

involved in procuring and using cocaine and was more 

common among men. In the PTSD-first group, the 

trauma was generally childhood abuse and was more common among women, the study found. For women, PTSD 

preceded cocaine dependence in 77 percent of the cases;

for men, this figure was 38 percent.

“Because much of the PTSD in substance-abusing women 

appears to be closely related to the sexual and physical victimization of women, my colleagues and I are now investigating this relationship in hopes of finding new treatments 

for PTSD and drug abuse that would address important 

gender differences,” Dr. Brady says. 

Sources 

•	 Brady, K.T.; Dansky, B.; Saladin, M.; and Sonne, S.

PTSD and cocaine dependence: The effect of order of 

onset. Presentation at annual meeting of the College 

on Problems of Drug Dependency. San Juan, P.R.,

1996.

•	 Brady, K.T.; Grice, D.E.; Dustan, L.; and Randall, C.

Gender differences in substance use disorders. 

American Journal of Psychiatry 150(11):1707–11,

1993.

Men (50) Women (50)

Total with No. with Total with No. with 

Disorder Disorder First Disorder Disorder First

Major depressive episode 18 4 20 10

Bipolar disorder (severe mood swings) 3 1 5 2

Panic disorder 5 1 9 8

Social phobia 7 7 5 5

Posttraumatic stress disorder (PTSD) 11 8 23 18

Cocaine and Alcohol Abusers Who Had Psychiatric Disorders Before the Onset of Substance Dependence
Research Findings

87

A number of studies have 

shown that women find it 

more difficult than do men to 

quit smoking cigarettes. This 

is especially evident in studies 

of nicotine replacement therapies that use nicotine patches 

or nicotine gum. Now two 

separate NIDA-funded studies 

examining gender differences 

related to smoking suggest 

that something in addition to 

nicotine is involved in women’s dependence on smoking 

tobacco.

“It appears that, compared to 

men, women may smoke less 

for nicotine and more for nonnicotine effects of smoking,” 

says Dr. Kenneth A. Perkins, a 

psychologist at the University 

of Pittsburgh Medical Center. 

These nonnicotine influences might include nondruginduced sensory effects like 

seeing and smelling tobacco 

smoke, conditioned responses 

to these smoke stimuli, or 

social pleasures involved in 

smoking rituals, he suggests.

For example, one observer 

has noted that smokers may 

exhibit gender differences in the way they gather outside 

buildings to smoke, Dr. Perkins says. Male smokers tend 

to be loners; females tend to gather in social groups. These

behaviors may indicate 

critical gender-based differences relating to tobacco 

smoking that may have little to do with nicotine, observers theorize. Dr. Perkins calls these nonnicotine influences 

“external stimuli.”

If further research supports this view of gender differences 

in external and behavioral influences related to smoking, 

says Dr. Perkins, it will be important to revise smoking 

cessation treatments for women trying to quit. This would 

mean tailoring therapy for women to increase behavioral 

support and rely less on nicotine replacement.

Dr. Perkins reviewed scores 

of studies of smoking and 

its addictive properties and 

smoking cessation programs. 

He found that these epidemiological and clinical studies 

consistently show that while 

smoking is declining among 

Americans, it is not decreasing 

as rapidly among women as 

among men. If present trends 

continue, women smokers will 

outnumber men by the next 

decade, says Dr. Perkins. The 

research suggests that this is 

at least partly because of the 

greater difficulty women have 

in quitting. Women in the 

studies tend to be less successful in smoking cessation trials, 

especially those using nicotine 

replacement therapy.

Lower cessation rates for 

women could be expected 

if women smoked more cigarettes or inhaled more nicotine 

than did men. Both are indicative of nicotine dependence, 

and smokers who are more 

strongly nicotine-dependent 

often have greater difficulty quitting. But just the opposite appears to be the case, says Dr. Perkins. Women tend 

to smoke fewer cigarettes per day, to smoke brands with 

lower nicotine yields, and to be less likely to inhale deeply, 

compared to men, according to his research review. Thus, 

evidence indicates women smokers are less, not more, 

nicotine-dependent than are men.

Further support for the notion of additional, nonnicotine 

addiction factors comes from a study of gender differences 

in the effects of different doses of nicotine gum on tobacco 

withdrawal symptoms. Dr. Dorothy Hatsukami, a psychiatry professor at the University of Minnesota, found 

that nicotine gum did not work as well to ease withdrawal 

Women’s Dependence on Smoking Affected By Something in 

Addition to Nicotine

By Neil Swan, NIDA NOTES Staff Writer

Volume 12, Number 3 (May/June 1997)

Women using nicotine gum therapy to quit smoking reported 

greater withdrawal symptoms than men did. The withdrawal 

Symptom Score was calculated from self reports of the degree to 

which study participants experienced symptoms such as craving 

for a cigarette, irritability, anxiety and tenseness, and excessive 

hunger. A high score represented greater symptoms. Source: 

D. Hatsukami in Experimental and Clinical Psychopharmacology, 

1995, American Psychological Association. Reprinted by

permission of the author.

Withdrawal Is Different for Women—Appetite, 

Craving Greater Than Men’s
88

symptoms for women trying to quit smoking as it did for 

men trying to quit. As in Dr. Perkins’ review, her results 

seemed contrary to expectations. If women are more 

sensitive to or dependent on the effects of nicotine than are 

men, as their lower smoking cessation rates would suggest, 

then women should be more responsive than are men to 

nicotine replacement, she reasoned. But this was not shown 

in her data, which paralleled Dr. Perkins’ findings. Women 

were less sensitive to the effects of nicotine, she says.

The lower cessation success with 

nicotine replacements in women 

compared to men may in part be 

attributed to this reduced effectiveness of the replacement therapy 

in relieving nicotine withdrawal 

symptoms. It also may indicate 

that something else is involved 

besides nicotine dependence, says 

Dr. Hatsukami. Like Dr. Perkins, 

she concluded that women may be more affected by other 

aspects of smoking.

What is the “something else?” In his review, Dr. Perkins 

examines alternative possibilities such as gender variations 

related to body weight or physiological effects of the 4,000

compounds found in cigarettes in addition to nicotine. He 

finds no strong evidence to support these or other alternative 

explanations for gender differences in responses to smoking 

or attempts to quit smoking, leading to his speculation on 

the role of nondrug, or external, factors.

One answer might lie in psychophysiology studies that

compare men’s and women’s abilities to detect changes 

within their bodies, such as heart-beat rate fluctuations, 

explains Dr. Perkins. Women are consistently less able 

than are men to detect changes in heart rate when no 

external clues are provided, according to a research review 

published in 1995 by Southern Methodist University

scientists. But this gender difference narrows significantly 

when subjects are provided with an external context, 

or clue, for the internal changes, such as viewing a 

horror film.

Thus, external stimuli appear to be more important 

to women than to men. It can be theorized, then, that 

women may be less responsive to internal stimuli such as 

nicotine and more responsive to external stimuli such as 

the sight and smell of tobacco and its smoke, he says.

Dr. Perkins emphasizes that it is wrong to conclude that 

nicotine is not important in reinforcing tobacco smoking 

among women. Women clearly experience nicotine withdrawal symptoms, he says. “The point is that there may 

be relatively subtle—but very important—differences in 

the sources of reinforcement [reward] that tobacco smoking provides to women relative to 

men,” he says.

Some observers have speculated 

on the role of external influences 

in gender differences related to 

the use of other abused drugs. 

Research with users of cocaine, 

heroin, and other drugs points up 

the significance of external drugcraving “cues” such as persons, 

activities, or locations associated with prior drug use. Are 

there critical gender differences in responses to these powerful craving cues?

More research is essential, says Dr. Perkins. For tobacco, 

more study is called for because studies of nonnicotine 

reinforcement may help develop more effective smoking 

cessation therapies for women, he says.

Sources

•	 Hatsukami, D.; Skoog, K.; Allen, S.; and Bliss, R.

Gender and the effects of different doses of nicotine 

gum on tobacco withdrawal symptoms. Experimental 

and Clinical Psychopharmacology 3(2):163–173, 1995.

•	 Perkins, K.A. Sex differences in nicotine versus

nonnicotine reinforcement as determinants of tobacco 

smoking. Experimental and Clinical Psychopharmacology

4(2):166–177, 1996.

•	 Pennebaker, J.W., and Roberts, T.A. Toward a his

and hers theory of emotion: Gender differences in visceral perception. Journal of Social and Clinical 

Psychology 11:199–212, 1992.

Compared to men, women 

may smoke less for nicotine 

and more for nonnicotine 

effects of smoking.
Research Findings

89

Cocaine Affects Men and Women Differently, NIDA Study Shows

By John A. Bowersox, NIDA NOTES Contributing Writer 

Volume 11, Number 1 (January/February 1996)

A recent NIDA-funded study suggests that gender differences will become an increasingly important consideration in drug abuse treatment strategies. The study by 

researchers affiliated with Harvard Medical School found 

that cocaine affects men and women differently and that 

hormonal fluctuations play an important role in women’s 

responses to the drug.

In the study, Dr. Scott E. Lukas and his colleagues at the 

Alcohol and Drug Abuse Research Center in Belmont, 

Massachusetts, measured a variety of responses to cocaine 

in six male and six female volunteers. On separate days,

the volunteers snorted single doses of cocaine and placebo 

powder in equal amounts relative to their body weights. 

The men were tested once, but the women were tested 

at two different times during their menstrual cycle: once 

during their follicular phase and again during their luteal 

phase. The follicular and luteal phases, respectively, correspond to the times before and after ovulation. The 

researchers calculated the phases of each woman’s cycle 

from the onset of menstruation:

•	 Dose 1 (midfollicular phase) was given 5 to 9 days

after the onset of menstruation;

•	 Dose 2 (midluteal phase) was given 18 to 22 days

after onset of menstruation. 

The researchers found that at both points in the menstrual 

cycle the women were much less sensitive to the drug than 

the men were. The men in the study had significantly more 

episodes of euphoria, or good feelings, and dysphoria, or 

bad feelings. When asked to rate the severity of their 

dysphoria, the men judged the bad feelings to be more 

unpleasant than the women did. The men also experienced greater heart rate and blood pressure increases and 

detected cocaine’s effects sooner than the women did. 

Although the men and women received equivalent doses 

of cocaine, women had lower levels of the drug in their 

blood than the men; their cocaine blood levels were even

lower when they took the drug during the luteal phase of 

their menstrual cycle.

Dr. Lukas says that differences in the speed with which 

cocaine is metabolized may account for the drug’s different effects in men and women. In the body, cocaine is 

broken down into inactive metabolites by enzymes known 

as cholinesterases. Although men have higher levels of 

these enzymes in their blood plasma, women have higher 

levels of a type of cholinesterase enzyme found in red 

blood cells, Dr. Lukas explains. The red blood cell enzyme 

metabolizes cocaine much more actively than the plasma 

enzyme does.

Physical changes that occur during the menstrual cycle 

also may contribute to women’s decreased sensitivity to 

intranasal cocaine, says Dr. Lukas. The increase in certain 

hormone levels during the luteal phase causes women’s 

mucous membranes, including those that line the nasal 

passages, to secrete more mucus. Dr. Lukas says that the 

increased mucus may act as a barrier to the absorption 

of cocaine when women snort the drug during the luteal 

phase of their menstrual cycle.

“We believe that the gender differences in cocaine’s effects 

that we observed are due to a combination of metabolic 

differences and the greater physical barrier to cocaine 

absorption created by the increase in mucosity,” says Dr. 

Lukas. He adds that other as yet unknown factors could 

also help produce cocaine’s differing effects.

Dr. Lukas says the findings, which he presented at the 

1994 meeting of the College on Problems of Drug

Dependence, might help explain, at least from a physiological perspective, why the prevalence of cocaine use 

among women has traditionally been much lower than 

it has been among men. According to the National 

Household Survey on Drug Abuse, approximately 3.1 

million men and 1.4 million women used cocaine at least 

once during 1993. Women also appear to take cocaine less

frequently than men do. The 1993 survey, which was

conducted by the Substance Abuse and Mental Health 

Services Administration, estimates that about 365,000

men compared with 111,000 women used cocaine at least

once a week.

Many women have reported that they did not get high 

when they first tried cocaine, says Dr. Lukas, adding that 

women’s low sensitivity to the drug combined with its 

high price create a strong disincentive to its continued use. 

On the other hand, he says, some women may become

heavy users because they need to take more cocaine to get 

the same effect as men.

If further studies substantiate Dr. Lukas’ findings, they could 

have important implications for the treatment of cocaine 
90

abusers, says Dr. Elizabeth Rahdert, a research psychologist 

in NIDA’s Division of Clinical and Services Research.

“Therapists would have to realize that for women, the 

response to cocaine will be different at different times 

of the month and not a steady state as it is for men,” 

she says.

Presumably, she adds, patterns of craving and response to 

withdrawal could also fluctuate with a woman’s menstrual 

cycle, and treatment professionals would have to recognize 

that women could be more vulnerable to relapse at different points in their cycle. Furthermore, treatment strategies 

designed to address male usage patterns would have to be 

modified in accordance with women’s usage patterns.

Dr. Lukas’ work reflects NIDA’s increased interest in 

examining the gender-specific effects of drug abuse. Basic 

research findings such as the discovery that sex hormones 

can interact with neurotransmitters during normal brain 

functioning have fueled this interest.

“Previously, drug abuse research on women focused 

mainly on issues related to pregnancy and the effects of 

drug abuse on the developing fetus,” says Dr. Cora Lee 

Wetherington, a psychologist in NIDA’s Division of 

Basic Research.

“More recently, we’ve seen a shift with the realization 

that the treatment needs of women may be different from 

those of men. Although issues related to childbearing 

and child-rearing are still important areas of drug abuse 

research, researchers are questioning whether treatment 

strategies that were developed through research conducted 

largely on male subjects are appropriate for women,” says 

Dr. Wetherington.

Source

•	 Lukas, S.E.; Sholar, M.B.; Lundahl, L.H.; et al. Sex

differences in plasma cocaine levels and subjective 

effects after acute cocaine administration in human 

volunteers. Psychopharmacology 125(4):346–354,

1996.
Research Findings

91

Volume 10, Number 5 (September/October 1995)

Daughters of Mothers Who Smoked During Pregnancy are More 

Likely to Smoke, Study Says

By Robert Mathias, NIDA NOTES Staff Writer 

Researchers have long wondered about the impact of 

prenatal exposure to drugs on a child’s vulnerability to 

drug abuse. Now, NIDA-funded studies have documented 

a relationship between prenatal exposure to nicotine 

and adolescents’ use of tobacco. Dr. Denise Kandel of 

Columbia University found that daughters of women who 

smoked cigarettes while they were pregnant are four times 

more likely to begin smoking during adolescence and to 

continue smoking than daughters of women who did not 

smoke during pregnancy. 

“The clearest message from the study is that mothers 

should not smoke during 

pregnancy,” says Dr. Kandel. 

The study suggests that 

nicotine, which crosses the 

placental barrier, may affect 

the female fetus during an 

important period of development so as to predispose the 

brain to the addictive influence of nicotine more than a 

decade later, she says. 

Prenatal smoking by these 

mothers did not have a 

strong effect on their sons’ 

smoking, but it is not clear 

why, says Dr. Kandel. Male 

hormones or structural differences of male and female 

brains may protect the developing male fetus from the 

nicotine entering the brain, 

she says, but notes, “That is 

all very speculative.”

Prenatal exposure to smoking 

has previously been linked 

with impairments in memory, learning, cognition, and 

perception in the growing child, says Dr. Jagjitsing Khalsa

of NIDA’s Division of Clinical and Services Research. 

The results of Dr. Kandel’s study suggest that smoking 

during pregnancy may create a risk of early and continued 

smoking among these women’s children, he says. Noting 

that other NIDA researchers are looking at the possible 

intergenerational transmission of a tendency to use marijuana through prenatal exposure, Dr. Khalsa says, “We 

need to let women know that if they take drugs during 

pregnancy they may put their offspring at risk for future 

drug use.” 

In previous research, Dr. Kandel had examined the intergenerational effects of drug use by following a cohort of 

New York State adolescents who were periodically reinterviewed over the course of 19 years. That research indicated that a mother’s cigarette smoking had a greater effect 

than a father’s on smoking among both sons and daughters. When analyses of different social influences could not 

identify the reason for this 

maternal effect, Dr. Kandel 

focused on one factor that 

differentiated mothers from 

fathers—a mother’s smoking 

during pregnancy. 

In her most recent study, 

Dr. Kandel analyzed followup interview data on 192

mothers and their first-born 

adolescents from the New 

York State study. The children’s mean age was 12 1/2. 

The analysis revealed that 

26.4 percent of girls whose 

mothers smoked while pregnant had smoked in the last 

year. By comparison, only 

4.3 percent of girls who were 

not prenatally exposed to 

nicotine had smoked in the 

last year. While more prenatally exposed boys had also 

smoked in the last year 

compared with boys whose 

mothers had not smoked 

during pregnancy, the difference was not statistically significant. 

Subsequently, Dr. Kandel replicated her New York State 

analysis with pre- and postnatal smoking data on 797

mothers and their children drawn from the National 

Longitudinal Survey of the Work Experience of Youth 

Cohort, a Bureau of Labor Statistics survey that has been 

conducted annually since 1979. The second analysis

Source: NIDA’s Monitoring the Future Studies, 1991-94

According to NIDA’s Monitoring the Future Study, the percent of adolescent girls who smoke cigarettes has increased in 

the last 4 years. Although smoking among adolescent girls has 

been linked to many different factors, Dr. Kandel’s study is the 

first to document a possible link between prenatal exposure to 

nicotine and an adolescent girl’s tendency to smoke cigarettes.

Trends in Adolescent Girls’ Current Use of Cigarettes
92

confirmed the findings from the New York State survey, 

says Dr. Kandel. The combined data from both surveys 

indicated a fourfold greater risk of smoking for girls whose 

mothers smoked during pregnancy. 

To ensure that it was a mother’s prenatal smoking and not 

her postnatal smoking that affected her daughter’s smoking, the researchers analyzed the impact of those mothers’ 

smoking both during and after pregnancy. They found 

that, regardless of the amount or duration of current or 

past maternal smoking, the strongest correlation between 

maternal smoking and a daughter’s smoking occurred 

when the mother smoked during pregnancy. 

Smoking activates several brain neurotransmitter systems 

including the dopamine system, which is involved in the 

reinforcing effects of addictive drugs in general, points 

out Dr. Kandel. Since this study raises the possibility that 

nicotine may modify the developing fetus’s dopamine system, 

making it more susceptible to the effects of nicotine at a 

later time in life, “The children whose mothers smoked 

during pregnancy are not only going to be more likely to 

smoke, but also may be more likely to use and become 

dependent on other drugs,” she predicts. Dr. Kandel hopes 

to research this issue by following the adolescents in her 

study for another 6 years. 

Source 

•	 Kandel, D.B.; Wu, P.; and Davies, M. Maternal

smoking during pregnancy and smoking by adolescent daughters. American Journal of Public Health

84(9):1407–1413, 1994.
Research Findings

93

Volume 10, Number 1 (January/February 1995)

Early Childhood Behavior and Temperament Predict Later 

Substance Use

By Neil Swan, NIDA NOTES Contributing Writer

By the first grade, or earlier, children show temperament 

and behavior traits that are powerful indicators of their 

inclination to use and abuse drugs in their teenage and 

adult years. Researchers have identified not only common 

childhood risk factors and behaviors that 

predict drug abuse potential but also 

protective factors that shield some children from influences to use drugs. 

A number of long-range NIDA-funded 

studies have traced at-risk children into 

adulthood and parenthood, trying to 

determine why some children are able 

to resist persistent influences to use 

substances of abuse. Studies have zeroed 

in on several important factors in predicting a first-grader’s subsequent use 

of substances: shyness, aggressiveness, 

rebelliousness, and gender. External risk 

factors include substance use among 

peers, drug use by parents, and troubles 

with the police. Protective factors 

include achievement in school or after-school activities 

and close family ties. The researchers are now designing 

drug abuse prevention and intervention strategies based 

on these findings made over 20 or more years.

Some of the earliest studies, by Dr. Margaret E. 

Ensminger and Dr. Sheppard G. Kellam and colleagues 

of The Johns Hopkins University, started in the 1960s

with first-graders and their families in Woodlawn, a poor, 

urban African-American community on the South Side 

of Chicago.

Today the researchers are following about 1,000 of the

1,242 original first-graders to continue to identify and 

monitor early childhood factors affecting later drug use 

and symptoms of psychiatric problems. These first-graders 

are now 32 or 33 years old.

Interviews in 1993 show that key risk factors such as

aggressive behavior and shy-aggressive behavior identified 

26 years ago continue to hold and are valid predictors of 

the subjects’ current levels of cocaine use as adults.

During their studies, Dr. Ensminger and her colleagues 

rated each first-grader’s mental health using two criteria: 

social adaptation and psychological health. To measure 

pupils’ social adaptation to school, researchers used teachers’ ratings of children’s classroom social performance 

and intelligence as well as the results of standardized tests. 

Psychological health was determined by a number of 

criteria, including psychological symptoms, abnormal 

behavior, and level of self-esteem.

Two important risk factors identified 

as predictors of later drug use are shy 

behavior—described by the teachers as 

sitting alone, having few friends, and 

not speaking up in class—and aggression—described as fighting with others 

or breaking rules. Shyness and aggression are types of poor social adaptation 

distinct from symptoms of anxiety or 

depression, which are internal feelings, 

noted the researchers.

While shyness and aggressiveness are 

key predictors of drug use, a complex 

relationship exists between the two 

factors. Among boys, aggressive behavior 

in the first grade leads to increased 

teenage substance abuse, while first-grade shyness alone 

without aggressiveness leads to lower levels of substance 

abuse as teenagers. However, the combination of shyness 

and aggressiveness leads to even higher levels of adolescent 

substance use among boys than aggressiveness without 

shyness does, the studies found.

Boys whose teachers said they had problems concentrating 

in class had higher levels of later substance abuse because 

concentration problems appear to be closely related to 

aggressiveness, the studies reported. By contrast, neither 

aggressiveness, nor shyness, nor concentration problems 

in the first grade were associated with later substance use 

among girls.

Understanding Gender Differences

Shyness and aggressiveness may be less important 

predictors of substance use among females than among 

males because girls’ peer groups are smaller and less 

important to them, she adds. These gender-based considerations are now being studied in drug abuse prevention 

programs, says Dr. Ensminger, who was among the first 

researchers to urge colleagues to stop dismissing gender 

as a possible key consideration in predicting children’s 

subsequent drug use.

For both sexes, higher 

scores on first-grade 

IQ and readiness-forschool tests were associated with higher levels 

of beer or wine, hard 

liquor, and marijuana 

use 10 years later. 
94

When the first-graders reached 

age 16 or 17, girls used smaller

amounts of beer, wine, liquor, 

and marijuana and other illicit 

drugs but not cigarettes than 

boys did. For both sexes, higher 

scores on first-grade IQ and 

readiness-for-school tests were 

associated with higher levels of 

beer or wine, hard liquor, and 

marijuana use 10 years later, the

researchers found. “This tells us 

that the children who are most 

ready for school are also those 

most ready to experiment with 

drugs,” says Dr. Ensminger.

Psychological well-being and 

family relationships in the first 

grade seemed more important 

to girls than to boys in terms of influencing psychiatric 

symptoms 10 years later. Mothers had an important effect

on the psychological status of their daughters but not of 

their sons. Mothers’ expectations of how far daughters 

would go in school and mothers’ own psychological health 

were positive factors in their daughters’ psychological wellbeing 10 years later, the study found. Girls with strong

family bonds tend to use drugs less than other girls do, 

but the same family influence is not so apparent with 

boys, said Dr. Ensminger.

Results from the Woodlawn study served as the basis for 

prevention programs started in Baltimore in the 1980s by

Dr. Kellam and colleagues. That prevention effort focused 

on aggressive behavior because of its relationship to 

later drug use and on underachievement because of its 

relationship to depressed feelings.

Recent data gathered on the Woodlawn study subjects 

show that early childhood aggression is still a valid predictor of drug abuse when measured against the now-adult 

subjects’ levels of use of cocaine, Dr. Ensminger reports. 

Those data are now being prepared for publication.

Examining Protective Factors

Another long-term study of drug-use predictors focuses on 

children in Northeastern States. For 20 years, Dr. Judith

S. Brook of Mt. Sinai School of Medicine has studied risk 

factors identified in early childhood and in adolescence 

that are related to drug use during adolescence. She is 

conducting a study of 1,000 children and their mothers

that began in 1975 in two communities representative of

the population of the Northeastern United States. In the 

continuing research, Dr. Brook is examining not only risk 

factors but also protective factors that help shield children 

and adolescents from these risk factors. Dr. Brook and 

her colleagues have identified 

a number of risk factors for 

subsequent drug use such as 

childhood aggression, which 

includes anger, aggression 

toward siblings, noncompliance, temper, and nonconforming behavior. Other risk factors

are unconventionality—an 

attitude of deviance, rebelliousness, and evasion of responsibility—the extent of drug 

use among peers, and parental 

sociopathy, that is, parents’ 

problems with drinking, drugs, 

or the police.

Dr. Brook’s group examined 

the risk factors and their 

implications during childhood, 

ages 5 to 10; middle adolescence, ages 13 to 18; and late

adolescence, ages 15 to 20. They found that childhood

aggression and parental sociopathy predicted increased levels of drug use in late adolescence. They also determined 

that unconventionality during the early years of adolescence had an “important and pervasive impact on all 

aspects of middle and late adolescent functioning,” including increased drug use.

The research team is now observing the original subjects’ 

children, beginning at age 2, and interviewing both parents of these children to collect data on the new generation. “So we’re now studying the third generation—the 

grandchildren of the mothers [of the original subjects] 

initially studied in 1975,” says Dr. Brook. “And we’re

finding a great deal of consistency down through the 

generations in regards to personality and family characteristics,” including traits that are drug-use risk factors.

The researchers also have studied interactions among risk 

factors and their implications for subsequent drug use as 

the children grow older. In addition to childhood aggression, they found three additional factors that influence 

late-adolescent drug use—unconventionality and drug 

use in middle adolescence and parental sociopathy during childhood. They found that little or no drug use in 

middle adolescence when combined with conventionality 

during the same age span resulted in the least amount of 

subsequent drug use.

As expected, parental sociopathy is related to late-teen 

drug use. Parents who drink or use drugs or both may be 

the most strict with their children, telling them, “Do as I 

say, not as I do,” according to Dr. Brook’s study. These 

admonitions might be effective in middle adolescence, 

when children are more likely to be influenced by parental 

demands, but not in later adolescence, when the family 

A number of long range NIDA-funded studies have traced atrisk children into adolescence and beyond trying to determine 

why some of them are able to resist influences to use substances 

of abuse.
95

has less control and the parents’ own display of negative 

behaviors becomes a drug-use risk factor, she says.

Dr. Brook agrees with other researchers that there are 

childhood protective factors that can be very powerful 

shields to safeguard children and adolescents from the 

recognized risk factors. These protective factors include 

achievement, religious commitment, strong family bonds, 

and a solid attachment to and emulation of a wholesome 

role model, she says.

“Some of these children are remarkably resilient,” says Dr. 

Brook. Among those who become successful, she found 

evidence of protective factors such as church attendance, 

childhood achievement in school or in extracurricular 

activities, or close ties to brothers and sisters.

“Many of these kids go on to lead successful, productive 

lives, yet we tend to focus on the ones that don’t,” says 

Dr. Brook. “I want to learn more about what makes those 

that do well do so.”

Family Relationships Critical

Still another continuing study of predictive factors for 

drug use focuses on a different population segment—

at-risk children of white families living in small and 

medium-sized communities in Oregon. The study by

Dr. Hyman Hops and colleagues of the Oregon Research

Institute examines family and peer-group influences on 

adolescent substance use and is now in its 10th year.

About 500 subjects were ages 11 through 15 at their first

assessment in 1984 and will be 21 through 25 at their last

assessment this year.

Among those studied, 90 percent of subjects who progressed from one substance of abuse to another did so in 

the following sequence—abstinence, alcohol, cigarettes, 

marijuana, and hard drugs. The most dramatic increase in 

drug use occurred between the ages of 13 and 14, when 

adolescents are going from middle to high school.

Parents’ use of substances, including cigarettes, is an 

important predictive factor influencing their children’s 

drug use. Within two-parent families, Dr. Hops found 

that fathers’ drinking appears to have a greater impact 

than mothers’ drinking on both girls and boys, while 

mothers’ drinking has an effect only on adolescents under 

14, before they enter high school. Parents who use 

cigarettes and alcohol may influence not only their 

children’s use of the same substances but illicit substances 

as well, he says.

Family conflict and strife are strongly associated with 

increased substance abuse, based on the researchers’ direct 

observations of problem-solving scenarios between parents 

and adolescents. Their findings suggest that families with 

substance-abusing children typically are unable to easily 

resolve problems and that the resulting confrontations 

negatively affect drug use.

In examining peer influences, the Oregon researchers

balanced each study subject’s self-reports of levels of substance use against reports of his or her substance use level 

from the child’s best friend. The scientists reported that 

the amount of both family cohesion and peer encouragement to use drugs was predictive of initial levels of 

substance abuse. A good family relationship may play a 

powerful role as a protective factor in middle and late 

adolescence, they say. On the other hand, peer encouragement to use substances plays a stronger role across the 

age range and also suggests that early peer influences may 

encourage higher levels of drug use at later ages.

“These findings underscore the importance of family 

influences on substance abuse throughout adolescence and 

suggest greater attention to the family, as well as the peer 

group, in designing prevention strategies,” says Dr. Hops. 

“You’ve got to have a healthy family relationship to counter the very powerful peer influences that kids face today.”

Sources

•	 Andrews, J.A.; Hops, H.; Ary, D.; Tildesley, E.; and

Harris, J. Parental influence on early adolescent substance use: Specific and nonspecific effects. Journal of 

Early Adolescence 13:285–310, 1993.

•	 Brook, J.S.; Whiteman, M.; Cohen, P.; and Tanaka,

J.S. Childhood precursors of adolescent drug use:

A longitudinal analysis. Genetic, Social, and General 

Psychology Monographs 118(2):195–213, 1991.

•	 Brook, J.S.; Whiteman, M.; Gordon, A.S.; and

Brook, D.W. The psychosocial etiology of adolescent drug use: A family interactional approach. 

Genetic, Social, and General Psychology Monographs

116(2):113–267, 1990.

•	 Brook, J.S.; Whiteman, M.; Hamburg, B.A.; and

Balka, E.B. African-American and Puerto Rican drug 

use: Personality, familial, and other environmental 

risk factors. Genetic, Social, and General Psychology 

Monographs 118(4):417–438, 1992.

•	 Ensminger, M.E. Sexual activity and problem

behaviors among black, urban adolescents. Child 

Development 61:2032–2046, 1990.

•	 Ensminger, M.E.; Brown, C.H.; and Kellam, S.G.

Sex differences in antecedents of substance use among 

adolescents. Journal of Social Issues 38(2):25–42,

1982.
96

•	 Hops, H.; Tildesley, E.; Lichtenstein, E.; Ary, D.; and

Sherman, L. Parent-adolescent problem-solving interactions and drug use. American Journal of Drug and 

Alcohol Abuse 16:239–258, 1990.

•	 Kellam, S.G.; Brown, C.H.; Rubin, B.R.; and

Ensminger, M.E. Paths leading to teenage psychiatric 

symptoms and substance use: Developmental epidemiological studies in Woodlawn. In: Guze, S.B.;

Earls, F.J.; and Barrett, J.E., eds. Childhood 

Psychopathology and Development. New York: Raven, 

pp. 17–51, 1983.
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