NN0031

Research

on Tobacco 

addiction
Research

on Tobacco

Addiction

NN0031
ii

Introduction

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 and social determinants of vulnerability and response to drugs;

• short- and long-term effects of drugs on the brain, including 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 evaluation of effective messages to deter young people, in particular, from abusing drugs.

Included in this document are selections of topic-specific articles reprinted from NIDA’s research newsletter, 

NIDA NOTES. 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 like the current one are intended 

to remind regular NIDA NOTES readers and inform other readers of important research discoveries during the periods 

they cover.

We hope the information contained here answers your needs and interests. To subscribe to NIDA NOTES and for 

further information on NIDA’s drug abuse and addiction research, please visit our Web site at www.drugabuse.gov.
iii

Table of Contents

Damage to Brain Area May Immediately Halt 

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

Prenatal Nicotine Exposure May Damage Receptors That 

Influence Auditory Processing (V22-3; April 2009)........ 3

New Tracer for Nicotinic Receptors Promises 

Improved Specificity (V22-3; April 2009)..................... 5

Adolescent Rats Self-Administer More Nicotine 

Than Adults (V22-3; April 2009) ................................. 5

Imaging Studies Elucidate Neurobiology of Cigarette 

Craving (V22-2; December 2008) ................................ 6

Nicotine Dependence Is Linked With Mental Disorders 

in Pregnant Women (V22-2; December 2008)............. 9

Behavioral Problems Related to Maternal Smoking 

During Pregnancy Manifest Early in Childhood 

(V21-6; June 2008)..................................................... 10

Endorphin Derivative Inhibits Reward From Morphine 

and Nicotine in Rats (V21-4; October 2007) ............. 13

Genes and Smoking 

(V21-3; April 2007).................................................... 15

Standard Treatments Help Depressed Smokers Quit 

(V21-3; April 2007).................................................... 16

Vaccine May Reduce Fetal Exposure to Nicotine 

(V21-3; April 2007).................................................... 18

Nicotine Alters the Developing Rat Brain 

(V21-2; February 2007).............................................. 20

Sensory Aspects May Drive Addiction in Obese 

Smokers (V20-6; July 2006) ....................................... 22

Bupropion Helps People With Schizophrenia Quit 

Smoking (V20-5; April 2006)..................................... 24

Genetic Predisposition and Depression Both Influence 

Teen Smoking (V20-4; March 2006).......................... 25

Study Points to Acetaldehyde-Nicotine Combination 

in Adolescent Addiction (V20-3; October 2005)........ 27

NIDA Research Illuminates Associations 

Between Psychiatric Disorders and Smoking 

(V20-2; August 2005)................................................. 29

Site on Brain Cells Appears Crucial To Nicotine 

Addiction (V20-2; August 2005) ............................... 31

Nicotine Withdrawal Linked to Disrupted Glutamate 

Signaling (V19-6; May 2005) ..................................... 33

Smoking Exposure In Utero Increases Risk of

Later Addiction (V19-4; December 2004) .................. 35

Early Nicotine Initiation Increases Severity of

Addiction, Vulnerability to Some Effects of Cocaine

(V19-2; July 2004)...................................................... 37

Smoking Decreases Key Enzyme Throughout

Body (V19-1; April 2004)........................................... 40

The Neurobehavioral Legacy of Prenatal

Tobacco Exposure (V18-6; February 2004)................ 41

Hard-to-Treat Smokers May Benefit From Medication 

That Acts on Dopamine (V18-5; December 2003)..... 44

Discovering, Developing, and Delivering

Smoking Cessation Medications Is Focus of

NIDA Symposium (V18-3; October 2003) ................ 46

Genetic Variation May Increase Nicotine Craving

and Smoking Relapse (V18-3; October 2003) ............ 48

Alternative Cigarettes May Deliver More Nicotine Than 

Conventional Cigarettes (V18-2; August 2003).......... 50

Manipulating Dopamine Levels Changes

Smoking Behavior (V18-1; June 2003)....................... 53

Nicotine’s Multiple Effects on the Brain’s Reward

System Drive Addiction (V17-6; March 2003)........... 55

NIDA’s Continued Commitment To

Nicotine Research (V17-6; March 2003).................... 57

Youths’ Opportunities To Experiment Influence

Later Use of Illegal Drugs (V17-5; January 2003)....... 59

Women and Smoking: Sensory Factors, Attitudes

About Weight, Phase of Menstrual Cycle All Key

To Quitting (V17-4; November 2002)....................... 62

Depression, PTSD, Substance Abuse Increase in Wake

of September 11 Attacks (V17-4; November 2002)...... 64

Genetic Variation in Serotonin System May Play

Role in Smoking Initiation (V17-2; May 2002).......... 67

Nicotine Disrupts Brain Development in Rats 

(V16-3; August 2001)................................................. 69

Adolescents, Women, and Whites More Vulnerable 

Than Others to Becoming Nicotine Dependent 

(V16-2; May 2001)..................................................... 70

Maternal Smoking During Pregnancy Associated

With Negative Toddler Behavior and Early Smoking 

Experimentation (V16-1; March 2001) ...................... 72
Smoking May Lead to Anxiety Disorders in 

Adolescents and Young Adults

(V16-1; March 2001).................................................. 74

Nicotine Patch Helps Smokeless Tobacco Users Quit, 

But Maintaining Abstinence May Require Additional 

Treatment (V16-1; March 2001)................................ 75

Women and Smokeless Tobacco Use 

(V16-1; March 2001).................................................. 77

Nicotine Vaccine Moves Toward Clinical Trials 

(V15-5; October 2000)............................................... 78

NIDA’s Nicotine Research Provides Scientific 

Approaches To Combat a Deadly Addiction 

(V15-5; October 2000)............................................... 79

Drug Abuse and Conduct Disorder Linked to 

Maternal Smoking During Pregnancy 

(V15-5; October 2000)............................................... 81

NIDA-Funded Researchers Identify Compound 

That Inhibits Nicotine Metabolism, Decreases 

Urge to Smoke (V15-5; October 2000) ...................... 82

Gender Differences in Drug Abuse Risks and 

Treatment (V15-4; September 2000).......................... 84

Evidence Builds That Genes Influence Cigarette 

Smoking (V15-2; August 2000).................................. 86

NIDA Joins NCI, Robert Wood Johnson 

Foundation To Launch Tobacco Research Centers 

(V15-1; March 2000).................................................. 88

New NIDA Clinic Tests Therapies to Help Teens 

Quit Smoking (V14-4; November 1999).................... 90

New Tracers Will Help Researchers Track 

Nicotine in the Brain (V14-2; August 1999) .............. 92

Nicotine Conference Highlights Research 

Accomplishments And Challenges 

(V13-5; February 1999).............................................. 93

Like Other Drugs of Abuse, Nicotine Disrupts 

the Brain’s Pleasure Circuit (V13-3; July 1998).......... 95

iv
Research Findings

Volume #, Number (Month Year)

1

Damage to Brain Area May Immediately Halt Cigarette Addiction

Patients with injury to the insula lost the urge to smoke.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 22, Number 3 (April 2009)

“My body forgot the urge to smoke.” 

That’s how one patient with damage to the insula, an area of the brain 

within the cerebral cortex, described 

the aftereffects of his stroke on his 

smoking habit. He is not alone. 

NIDA-funded investigators repeatedly heard of similar experiences while 

interviewing people who had sustained 

brain injuries.

Many people who have suffered a 

stroke or other brain injury try to 

quit smoking out of concern for their 

health, says Dr. Antoine Bechara of 

the University of Southern California 

and the University of Iowa. Most 

have difficulty. “In some brain injury 

patients, however, the urge to smoke 

seemed to be switched off, while other 

desires, such as for food, were not disrupted,” says Dr. Bechara. He and his colleagues found 

that the experience of quitting cigarettes immediately, easily, and without relapse was much more common among 

people with damage to the insula than those with injuries 

elsewhere in the brain. If Dr. Bechara’s preliminary findings are validated, the insula is likely to become an important target for future addiction research.

Different Experiences of Smoking Cessation 

Scientists suspect that in chronic abusers, drugs or drugassociated cues produce bodily sensations that the insula 

relays to other brain areas as urgent needs. To explore 

the insula’s role in addictive behavior, Dr. Bechara’s team 

contacted men and women who had suffered brain damage and were listed in the Patient Registry of the Division 

of Behavioral Neurology and Cognitive Neuroscience at 

the University of Iowa.

Before suffering brain damage, mostly from stroke, all the 

participants had been long-term, heavy cigarette smokers; 

on average, they had smoked a pack and a half a day for 

27 years.

The patients’ brains had been injured 8 years before the 

study, on average, and 32 of the 69 patients had quit 

smoking immediately following their injury or some time 

thereafter. The researchers used brain imaging to verify 

injury locations: 19 patients had insula lesions, and 50 

showed damage to other regions. Patients with damage in 

the insula and those with damage to other regions were 

matched for the number of cigarettes smoked and duration of smoking before the injury.

Patients with insula and noninsula damage were equally 

likely to have quit smoking cigarettes after their brain 

injury. To identify those whose smoking addiction had 

ceased suddenly, the researchers settled on four criteria: 

quitting cigarettes less than a day after lesion damage; 

reporting no relapse after quitting; rating the difficulty of 

quitting as less than 3 on a scale of 1 (very easy) to 7 (very 

difficult); and reporting no urges to smoke since quitting.

Of the 32 patients who quit smoking, 16 met all four 

criteria and were designated as having “disrupted smoking addiction.” They included 12 of the 13 patients with 

lesions in the insula who quit smoking, but just 4 of the 

19 quitters with lesions only in other areas. “The much 

higher likelihood of disrupted smoking among patients 

with insula damage was striking and suggests that the 

area is a prime candidate in drug-taking urges,” notes 

Dr. Bechara.

1
2

“For patients with insula damage, it seems that smoking quit them—they lost the desire to smoke—which is 

a provocative and unexpected finding,” says Dr. Steven 

Grant of NIDA’s Division of Clinical Neuroscience and 

Behavioral Research. “Dr. Bechara’s results have cast a 

searchlight onto a relatively new area of interest among 

addiction researchers.”

New Focus for Drug Abuse Research

Current interest in the role of the insula in drug abuse was 

sparked a few years ago by research that linked activity 

in that brain area with abstinence in methamphetamine 

abusers (“Brain Activity Patterns Signal Risk of Relapse 

to Methamphetamine,” NIDA Notes, Vol. 20, No. 5). 

Recent studies have also tied insula activation to cravings and drug administration among substance abusers. 

According to Dr. Bechara, his team’s next step is to examine urges for and abuse of substances—cigarettes, alcohol, 

and illicit drugs—in a larger number of patients who have 

recently suffered damage to the insula and other parts of 

the brain.

“Our findings so far suggest that the insula may be a 

structure to target in the development of new smoking 

cessation medications,” Dr. Bechara says. “Obviously, 

damaging the insula is not a therapeutic option.” But 

scientists could determine the types of receptors present 

in the insula, for example, and then test whether blocking 

them blunts nicotine reward.

Drs. Bechara and Grant agree that with animal protocols 

that mimic different aspects of addiction—reward, craving, and relapse—scientists may learn what specific role 

the insula plays in drug abuse.

Source

• Naqvi, N.H., et al. Damage to the insula disrupts 

addiction to cigarette smoking. Science

315(5811):531-534, 2007. 

2
Research Findings

Volume #, Number (Month Year)

3

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 nicotineexposed 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 stronger auditory cortex response to nicotine at 2 to 3 months 

3
4

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. 

4
Research Findings

Volume #, Number (Month Year)

5

New Tracer for Nicotinic Receptors Promises Improved Specificity

Volume 22, Number 3 (April 2009)

Researchers at NIDA’s Intramural Research Program have developed a radiolabeled compound for animal studies of 

nicotinic acetylcholine receptors in the brain. Tests in monkeys indicate that the new tracer readily enters the animals’ 

brains and binds primarily to the nicotinic receptor subtype called a4

b2*. These receptors play a role in nicotine addiction and have been implicated in other neurological conditions, including dementia, epilepsy, depression, and anxiety. 

In brain regions containing these receptors, the new radiotracer’s accumulation is greater than that of 2FA, the tracer 

currently used in human imaging studies. As a result, the new tracer produces sharper and more detailed positron emission tomography images and may be especially useful for studying a4

b2* nicotinic receptors in brain areas where they are 

sparsely distributed. The specificity of the new radiotracer accumulation for the regions with these receptors is three- to 

four-fold that of 2FA, and tests in mice indicate that the new compound is equally safe, says Dr. Alexey G. Mukhin, now 

at Duke University in Durham, North Carolina. 

If further animal and human imaging research confirms these results, the tracer could advance the study of the relationships between a4

b2* receptors and specific aspects of nicotine addiction and promote the development of medications for 

a wide variety of disorders. The chemical name for the new tracer is 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-fluoropyridin-4-yl)pyridine ([18F]NIDA522131).

Source

• Journal of Neurochemistry 104(2):306-315, 2008. 

5

Adolescent Rats Self-Administer More Nicotine Than Adults

Studies comparing adolescent and adult rats have added to the evidence that the adolescent brain is particularly vulnerable to nicotine addiction. Dr. Edward D. Levin and colleagues at the Duke University Medical Center allowed male rats 

not previously exposed to nicotine to self-administer the drug for 4 weeks. During the first 2 weeks, the 13 adolescent 

rats took more than three times as much nicotine as the 13 adults. Nicotine consumption decreased as the adolescents 

matured, and it reached adultlike levels by the end of week 4.

In a prior study with female rats, the researchers found that adolescents self-administered twice as much nicotine as 

adults. Unlike the male rats in the current study, however, as the adolescent female rats matured, they continued to selfadminister more nicotine than adults. Taken together, the team’s results suggest that adolescent male rats may initially be 

more sensitive than females to nicotine, but females may experience a more persistent vulnerability.

Source

• Neurotoxicology and Teratology 29(4):458-465, 2007. 
Imaging Studies Elucidate Neurobiology of Cigarette Craving

Researchers observe brain circuit activation, rapid receptor occupation.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 22, Number 2 (December 2008)

One difference between a smoker and an ex-smoker is that 

the latter has successfully overcome cravings for tobacco. To 

learn how people achieve this feat, NIDA-funded researcher 

Dr. Arthur Brody has been looking inside the brains of 

would-be quitters. His findings, based on three separate 

imaging studies, indicate that when smokers actively resist 

cravings, they engage brain areas that focus attention and 

regulate emotion; that heavy smokers can stave off craving 

only by keeping virtually all nicotinic receptors in the brain 

filled; and that nicotine is the only component of cigarette 

smoke that occupies these receptors.

Patterns of Resistance 

In one study, Dr. Brody and his colleagues at the 

University of California, Los Angeles charted the changes 

in cerebral activity that accompanied willful resistance 

to videotaped smoking cues. One of the changes, intensification of activity in a specific brain area, parallels the 

effects of bupropion, suggesting that the anti-smoking 

medication may reinforce cognitive strategies that people 

naturally implement when they try to quit. Other specific 

brain activity changes identified in the study may provide 

leads for developing new medications and behavioral treatments for smokers.

Dr. Brody enlisted 42 men and women from the community at the Greater Los Angeles Veterans Affairs 

Healthcare System. On the morning of the study, each 

participant smoked a final cigarette and, 25 minutes later, 

put on a pair of special goggles to watch short video clips 

during brain scanning. The clips introduced the viewer 

to everyday situations—driving, writing a letter, standing 

outside a building. Two of every three clips also featured 

images that commonly incite nicotine craving, such as a 

view of someone taking out a lighter, preparing to light a 

cigarette, or actually smoking a cigarette. The researchers 

asked the participant to record the intensity of his or her 

craving, while either passively experiencing it or actively 

resisting it. The participants said that they usually resisted 

smoking cues by trying to distract themselves or ignore 

thoughts of smoking.

In the absence of smoking cues, the participants reported 

an average craving intensity of 2.4 out of a possible 5. The 

intensity rose to 3.0 when they saw a smoking cue. The 

intensity of the craving was similar whether or not the 

participants resisted the urge to smoke.

The researchers collected functional magnetic resonance 

images (fMRI) of the participants’ brains while they were 

watching the videos. During efforts to resist smoking, 

activity increased in the dorsal anterior cingulate cortex 

(DACC) region, which participates in focusing attention 

and controlling emotions, as well as decisionmaking and 

planning, conflict avoidance, and error detection. Dr. 

Brody suggests that this DACC activation may reflect the 

participants’ struggles to direct their attention away from 

cigarettes. Other researchers have noted intensified DACC 

activity when individuals employ specific trains of thought 

to try to control their emotional responses to anxietyprovoking stimuli. Engaging this area repeatedly may 

strengthen the neural circuit and bolster smokers’ ability 

to resist cigarettes.

Dr. Brody and colleagues were intrigued by other changes 

in brain activity that occurred when their study participants resisted smoking cues. Among these were increased 

activity in the posterior cingulate cortex (PCC), which 

processes emotions and related sensory information, and 

in the precuneus, which has been related to consciousness 

of self.

Simultaneously, the team observed decreased activity in 

the lateral occipital and right postcentral gyri (LOG and 

RPG); the LOG deals with visual input and the RPG 

modulates movement. Changes in these areas had not 

been previously observed in the context of smoking ces6
sation and so may provide new clues to the cognitive and 

emotional dynamics that accompany that effort.

Taken together, these findings suggest that actively resisting the urge to smoke involves a redistribution of neural 

activity from sensory and motor areas of the brain to those 

that mediate rewards and emotions.

Smoking’s Dramatic Effects on Receptors

In another study that underscores the challenge of quitting, Dr. Brody’s team charted relationships between 

smoking, craving, and nicotinic receptors. They found 

that heavy smokers crave nicotine whenever the drug 

occupies less than 95 percent of the most common nicotinic receptors, the a4

b2*-nACh subset, in the brain. 

Smoking just a few puffs goes a long way toward saturating these receptors, which are the primary sites where nicotine attaches to brain neurons and exerts its psychoactive 

and physiological effects.

Although scientists have known that stimulation of these 

receptors underlies nicotine addiction, newly developed 

radiotracers have helped them measure receptor occupancy 

much more accurately and connect it to craving and other 

symptoms of withdrawal.

The 11 volunteers who took part in this study had 

smoked for 18 years, on average, and were currently 

smoking a pack a day. On the day of the study, following 2 days of abstinence, the participants smoked and 

reported their intensity of craving as the researchers used 

positron emission tomography (PET) imaging to observe 

a4

b2*-nACh receptors.

The images revealed that smoking occupied a4

b2*-nACh 

receptors throughout the brain with striking completeness, 

and for several hours. After the first puff, nicotine occupied one-third of the receptors; after the third puff, 75 

percent; and after a full cigarette, 88 percent. As receptor 

occupancy increased, the participants’ craving decreased, 

until—generally after 2.5 to 3 cigarettes—they achieved 

complete relief at about 95 percent occupancy.

“Our findings show how many receptors are taken up 

by nicotine,” says Dr. Brody. “My colleagues and I were 

surprised that just one puff started to fill the receptors so 

substantially.”

The team’s findings suggest that some of the behaviors 

that characterize nicotine addiction may be explained by 

smokers’ need to maintain receptor saturation. “Many 

smokers say they must have a cigarette to get their day 

going, which makes sense because receptor occupancy 

would be quite low after waking,” says Dr. Brody.

Although near saturation of nicotinic receptors relieves 

craving, nicotine dependent people smoke beyond this 

point. Moreover, Dr. Brody notes that “blood levels of 

nicotine that accompany replacement therapies, such as 

the patch or gum, would likely saturate the receptors, 

yet only 20 to 25 percent of smokers on this treatment 

stay abstinent for a year.” These observations suggest that 

other factors also drive smoking.

Evidence of Other Factors

To separate the impact of nicotine from other aspects 

of smoking—including the more than 4,000 chemicals 

other than nicotine in cigarette smoke—Dr. Brody and 

colleagues conducted a third study. The investigators followed a procedure that paralleled the one they had used 

to track the impact of smoking on a4

b2*-nACh receptors. 

Again, they charted the relationships between smoking, 

craving, and nicotinic receptors—this time in response to 

cigarettes with only a trace amount of nicotine.

The 15 volunteers who took part in this study had 

smoked for 14 years and were currently smoking 19 cigarettes a day, on average. In two sessions, each after 2 days 

of abstinence and separated by at least a week, they participated in PET imaging scans and reported their intensity 

of craving. On one study day, the participants smoked a 

denicotinized cigarette. On the other study day, seven participants did not smoke, and eight smoked a low-nicotine 

cigarette.

The images revealed that smoking a denicotinized cigarette, which contains only about 4 percent of the nicotine 

in a regular cigarette, resulted in a 26 percent occupancy 

of nicotinic receptors, compared with 79 percent after a 

low-nicotine cigarette (half the nicotine content of a regular cigarette), and no occupancy among those not given 

any cigarette. The 26 percent occupancy by smoking a 

denicotinized cigarette was predicted based on the amount 

of nicotine present.

This study demonstrates that of all the chemicals found 

in cigarette smoke, nicotine is responsible for virtually all 

a4

b2*-nACh receptor occupation, the researchers note. 

These findings also demonstrate that smoking a cigarette 

with only a trace amount of nicotine leads to substantial 

receptor occupancy in the brain.

Although smoking a denicotinized cigarette had a smaller 

impact on nicotinic receptors compared with the effects 

of a low-nicotine or regular cigarette, it did lessen craving. 

Before they smoked, the participants reported an average 

craving intensity of about 5 (on a scale of 0 to 6); these 

reports fell to 3.6 and 2.4 for those smoking a denicotinized and low-nicotine cigarette, respectively. This accords 

well with findings of prior studies indicating that denicotinized cigarettes reduce the urge to smoke. The taste, 

smell, and feel of cigarette smoke in the mouth contribute 

to smoking’s appeal, Dr. Brody says, and denicotinized 

cigarettes do provide these sensory experiences. Additional 

7
factors, such as stress and the perceived pleasure of smoking, also may play a role.

These findings elucidate why it is so difficult to give up 

cigarettes, according to Dr. Brody. “The many effects of 

smoking, including elevated mood and alleviation of anxiety, suggest that a long-term smoker may face considerable 

biochemical, cognitive, and emotional readjustments when 

he or she quits,” says Dr. Brody.

Dr. Ro Nemeth of NIDA’s Division of Clinical 

Neuroscience and Behavioral Research adds that inhalation is the fastest way for any drug to reach the brain. 

“The connection between a puff on a cigarette and the 

positive feelings it quickly generates helps maintain smoking, even when people know its negative consequences 

and want to quit,” Dr. Nemeth says.

Sources

• Brody, A.L., et al. Brain nicotinic acetylcholine receptor occupancy: Effect of smoking a 

denicotinized cigarette. International Journal of 

Neuropsychopharmacology, published online 2008. 

• Brody A.L., et al. Neural substrates of resisting craving during cigarette cue exposure. Biological Psychiatry

62(6):642-651, 2007. 

• Brody, A.L., et al. Cigarette smoking saturates 

brain alpha 4 beta 2 nicotinic acetylcholine receptors. 

Archives of General Psychiatry 63(8):907-915, 2006. 

8
Research Findings

Volume 22, Number 2 (December 2008)

9

Nicotine Dependence Is Linked With Mental Disorders in 

Pregnant Women
Research Findings

Volume #, Number (Month Year)

10

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 

10
11

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 

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 

11
12

new technique incorporates the unique information from 

both of these methods to provide a more precise estimate 

of prenatal exposure to cigarettes.”

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. 

12
Endorphin Derivative Inhibits Reward From Morphine and Nicotine 

in Rats

Recent studies suggest therapeutic potential for glycyl-glutamine in opiate and nicotine addiction.

By Sarah Teagle, NIDA Notes Contributing Writer

Research Findings

Volume 21, Number 4 (October 2007)

A naturally occurring brain chemical has shown early promise as a 

treatment for addiction. NIDAfunded researcher Dr. William 

Millington and colleagues at 

Albany College of Pharmacy demonstrated that glycyl-glutamine 

(Gly-Gln), a product of the 

conversion of one form of beta 

endorphin to another, reduces the 

rewarding effects of morphine and 

nicotine and the severity of withdrawal from these drugs in rats.

The researchers utilized an animal 

model called conditioned place 

preference (CPP; for more on 

CPP, see “Animal Experiments in 

Addiction Science,” NIDA Notes, 

Vol. 20, No. 5). When pretreated 

with Gly-Gln, rats stopped preferring a cage in which they received 

morphine infusions over another 

in which they received a physiologically inert substance. The 

investigators concluded that GlyGln completely blocked the brainrewarding effects of morphine. 

They used the same experimental 

technique to demonstrate that 

Gly-Gln pretreatment also blocks 

the rewarding effects of nicotine 

in rats.

Some chemicals that block the rewarding effects of drugs 

of abuse also take away subjects’ pleasure in normal 

healthy activities. Again using CPP, Dr. Millington’s team 

demonstrated that Gly-Gln does not have this drawback, 

at least in regard to one food—a sweetened cereal—that 

rats enjoy.

Subsequently, Dr. Millington and his coinvestigators 

examined Gly-Gln’s effect on withdrawal from morphine. 

They induced morphine dependence in the rats, injected 

some with Gly-Gln 72 hours later, and then administered the opioid antagonist naloxone to 

induce withdrawal. Across all measures, 

the Gly-Gln pretreated rats exhibited 

significantly fewer behavioral and physiological signs of withdrawal than the 

others. The researchers observed a 

similar effect when they induced withdrawal from nicotine with the agent 

mecamylamine.

Safe Analgesia, Too?

In separate studies, Dr. Millington and 

colleagues found evidence that Gly-Gln 

has potential for improving pain treatment by slowing the development of 

morphine tolerance. The investigators 

treated rats with morphine twice daily 

for 7 days and, each day, measured 

the rats’ reaction to pain with tailflick latency tests. They observed that 

the pain-relieving effects of morphine 

declined 20 percent by the second day, 

an indication that tolerance had developed rapidly. However, rats pretreated 

with Gly-Gln did not begin showing 

evidence of morphine tolerance until 

the fourth day of treatment. Their level 

of pain relief had dropped to 75 percent 

of the maximum by day 4, compared 

with 39 percent for rats that were 

not pretreated. 

These findings offer new hope for making pain treatment more effective, but without adding to the problems 

of painkiller abuse and prescription drug diversion. Dr. 

David Thomas of NIDA’s Division of Basic Neuroscience 

and Behavioral Research explains, “It is like a tug-of-war; 

we want better pain treatment, but we do not want more 

addiction. If we can find a medication that improves the 

management of chronic pain without causing addiction 

or the negative physical side effects, then it really is a winwin situation. Gly-Gln may give us that.”

13
“We need to learn much more about Gly-Gln’s pharmacology before we can develop it into a drug that is useful 

clinically,” says Dr. Thomas. “The profile of its effects 

brought out by Dr. Millington’s work is striking. It makes 

a strong argument for taking the research to the next step: 

understanding its mechanism of action in the brain. In 

our world of preclinical animal research, we really could 

not ask for better findings. So far, everything we know 

about Gly-Gln is promising.”

Sources

• Cavun, S.; Goktalay, G.; and Millington, W.R. 

Glycyl-glutamine, an endogenous beta-endorphinderived peptide, inhibits morphine-induced conditioned place preference, tolerance, dependence, and 

withdrawal. Journal of Pharmacology and Experimental 

Therapeutics 315(2):949-958, 2005.

• Goktalay, G., et al. Glycyl-glutamine inhibits nicotine 

conditioned place preference and withdrawal. 

European Journal of Pharmacology 530(1-2):95-102, 

2005. 

14
Genes and Smoking

By NIDA Director Nora D. Volkow, M.D.

Research Findings

Volume 21, Number 3 (April 2007)

Most of the 44.5 million American adults 

who smoke cigarettes would prefer not to. 

Why do so many would-be quitters fail, even 

with the help of stop-smoking interventions 

like nicotine replacement? Why, for that 

matter, do people become addicted to smoking in the first place? The answers lie partly 

in our genes.

NIDA researchers in collaboration with 

Perlegen Sciences, Inc., a private company, 

recently completed a search of the entire 

human genome for differences between individuals who 

are nicotine-dependent and those who smoked but never 

became dependent. Their target: single nucleotide polymorphisms (SNPs), locations on the genome where individuals differ by just one chemical unit in the makeup of 

their DNA. From 2.2 million known SNPs, researchers 

have identified roughly 40 to 80 that are highly correlated 

with nicotine addiction.

Once researchers link an SNP statistically to drug abuse, 

the question becomes: Does the gene do anything that 

might explain why people with one of its forms are more 

vulnerable to drugs than people with another? Some of 

the genes researchers have implicated in addiction affect 

the dopamine reward circuit. Others involve neurotransmitter systems and neural pathways not previously known 

to figure in smoking’s effects. Researchers will use techniques such as brain imaging to correlate genetic differences with differences in brain structure or function and 

psychological tests to match them to behavior. Findings 

from the genome exploration may ultimately 

yield novel, more effective interventions.

Genetic variations can only partly explain 

why people become addicted to nicotine: 

A person’s genetic makeup, experiences, 

and surroundings all combine to determine 

whether he or she will smoke and, if so, 

how difficult quitting will be. NIDA-funded 

epidemiologists and behavioral scientists 

are conducting a large longitudinal study 

to elucidate these interactions. They have 

been following pairs of twins, now 17 years old, collecting 

information about participants’ smoking and environmental factors like stressors and peer relationships that can 

increase the risk of substance abuse or protect against it. 

The next step will be to analyze these data, together with 

information on the twins’ genetic and biological traits.

NIDA-supported researchers are also working to discover 

why interventions like nicotine replacement therapy 

(NRT) work for some people and not others. By comparing smokers who have successfully used pharmacotherapy 

with those whose efforts to quit have failed, the researchers hope to identify groups of genes that predict who will 

do well with NRT, with bupropion, or with varenicline, 

the newest smoking cessation drug. The ultimate goal is to 

tailor the treatment to the smoker. Ultimately, we hope 

genetic studies will lead to strategies that protect vulnerable young people from addiction. 

15
Standard Treatments Help Depressed Smokers Quit

As smoking rates fall in the United States, mentally ill individuals comprise a larger percentage of people 

who continue to light up.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 21, Number 3 (April 2007)

Smoking cessation interventions that are effective in the 

general population also help for depressed smokers, suggests a study of outpatients at four mental health clinics. Dr. Sharon Hall and colleagues at the University of 

California, San Francisco; the University of Rhode Island; 

and Kaiser Permanente Northern California found that 

depressed smokers who were treated with a combination 

of motivational counseling, nicotine patches, and behavioral therapy were more likely than their counterparts who 

did not receive the interventions to be smoke-free at 12- 

and 18-month assessments.

“Patients in our study mirrored the general population 

of smokers in their readiness to quit, acceptance of treatment, and cessation outcomes—findings that surprised me 

and my colleagues,” says Dr. Hall, lead investigator of the 

study. Further, patients with severe symptoms of depression both accepted the interventions and benefited from 

them. “Our findings suggest that clinicians should offer 

depressed outpatients nicotine addiction treatment and 

should start with available smoking cessation interventions. They need not be overly concerned about patients’ 

levels of depression,” says Dr. Hall.

The investigators recruited 322 men and women from a 

university-based clinic and three sites of a health maintenance organization who were being treated for depression 

and smoked daily. Most of the volunteers (79 percent) 

were taking psychiatric medication for moderate depression. On average, they had smoked for 24 years, smoked 

15 cigarettes a day, and had tried to quit six times.

At the start of the study, the participants provided information on their depression severity and treatment, smoking behavior (confirmed by expired air carbon monoxide 

measurements), nicotine dependence level, readiness to 

quit smoking, previous quit attempts, and commitment to 

abstinence. They repeated these self-reports 3, 6, 12, and 

18 months later.

The active intervention in the study was Staged Care 

Intervention (SCI). At the outset and months 3, 6, and 

12, participants assigned to SCI answered a computerized questionnaire about smoking, its advantages and 

disadvantages, triggers for smoking-related thoughts and 

behaviors, and ways to change these thoughts and behaviors. The computer provided an individualized feedback 

report that the patients and counselors reviewed together 

in a 15-minute session. The report classified each patient’s 

readiness to quit based on the Stages of Change model, 

compared his or her responses with those of others in the 

program, showed changes from earlier reports, and identified triggers for smoking and strategies to move to the 

next stage. If the patient expressed a desire to quit, he or 

she began an 8-week cessation treatment. Each participant 

in the control group received a self-help guide to smoking 

cessation and a list of programs in the area, but no therapeutic contact or advice about smoking cessation.

Opportunity to Engage

About one-third (34 percent) of SCI participants entered 

cessation treatment. They received nicotine patches (7, 

14, or 21 mg, depending on level of smoking and week of 

study) and six 30-minute counseling sessions. The focus 

of counseling was immediate and complete cessation at an 

agreed-upon date. During sessions, patients developed a 

commitment to abstinence, established a quit plan, identified reasons for smoking, reviewed the benefits of quitting, and received information on nutrition and exercise. 

16
Patients who did not attain abstinence with nicotine patches were 

prescribed bupropion if their mental 

health care provider deemed it medically appropriate.

The researchers included all SCI 

participants, including those who 

did not enter cessation treatment, in 

their data analysis. At the 12-month 

assessment, 20 percent of participants 

in the SCI group and 13 percent in 

the control group had verified 7-day 

tobacco abstinence. The SCI group’s 

advantage persisted at the 18-month 

assessment (25 percent versus 19 

percent). More SCI (44 percent) 

than control group participants (34 

percent) endorsed permanent abstinence—an attitude the researchers 

say predicts success in changing 

behavior. The intervention was particularly effective for heavy smokers: 

Among participants who smoked 

more than a pack of cigarettes a day, 

those assigned to SCI were about 

twice as likely as controls to report a 

quit attempt during the study. 

“The findings of Dr. Hall and her colleagues suggest that, 

even among severely depressed smokers who are not motivated to quit, the SCI increases abstinence rates compared 

with a standard control,” says Ms. Debra Grossman of 

NIDA’s Division of Clinical Neuroscience and Behavioral 

Research. The finding adds to the justification for 

American Psychiatric Association and Agency for Health 

Care Research and Quality recommendations to offer 

smoking cessation therapy to people with mental disorders.

“The high prevalence of smoking in mental health clinics 

presents an opportunity to engage people with depression in smoking cessation,” says Dr. Hall. She adds that 

one advantage to doing so is the supportive environment 

of such settings: if cessation worsens depression, then 

patients can obtain additional help. Dr. Hall notes that 

the treatment benefits seen among the study population 

of mostly employed patients enrolled in a health maintenance organization might not apply to depressed people 

who are disadvantaged or in treatment at publicly 

funded hospitals. Dr. Hall’s team plans to conduct a 

cost-effectiveness analysis of the intervention to help 

clinic directors decide on resource allocation.

Source

• Hall, S.M., et al. Treatment for cigarette smoking 

among depressed mental health outpatients: A randomized clinical trial. American Journal of Public 

Health 96(10):1808-1814, 2006. 

17
Vaccine May Reduce Fetal Exposure to Nicotine

Antibodies that block nicotine’s path across the blood brain barrier may also inhibit placental absorption.

By Carl Sherman, NIDA Notes Contributing Writer

Research Findings

Volume 21, Number 3 (April 2007)

Vaccine-induced antibodies that facilitate smoking cessation by blocking nicotine penetration into the brain 

also markedly reduce the drug’s passage across the ex vivo

human placenta, a NIDA-funded study has demonstrated. 

The finding suggests that maternal immunization during 

pregnancy may be safe and may to some extent protect the 

fetus from exposure to nicotine.

The adverse effects of maternal smoking during pregnancy 

include increased rates of miscarriage, premature delivery, 

low birth weight, neonatal mortality, and sudden infant 

death syndrome (SIDS). Increasingly, research has linked 

prenatal smoking exposure to children’s neurobehavioral 

problems, such as attention deficit-hyperactivity disorder. 

The role of nicotine in causing this damage is not entirely 

clear, but animal studies suggest the drug may compromise fetal development directly or through its effects on 

the placenta. “We desperately need medications that can 

help women quit smoking during pregnancy, medications 

that are both effective and do not themselves harm the 

fetus. This study supports the potential use of immunization,” says Dr. Paul Pentel of the University of Minnesota 

Medical School, one of the investigators.

The Experimental Procedure

NicVAX, a vaccine being developed by Florida-based 

Nabi Biopharmaceuticals with NIDA support, joins the 

nicotine molecule to a protein. The resulting molecule 

provokes the production of antibodies that combine with 

circulating nicotine to create a complex molecule that 

is too large to cross the blood-brain barrier. When the 

amount of nicotine reaching the brain drops far enough, 

the concept goes, “the smoker will no longer get a rewarding effect and will quit,” says Dr. Scott Winston, a Nabi 

researcher. A recent small-scale clinical study found doserelated improvements in 30-day quit rates among 68 

immunized smokers (“Nicotine and Cocaine Vaccines 

Move Forward,” NIDA Notes, Vol. 20, No. 5).

The two antibodies used in the placenta transfer study, 

nicotine immune globulin (Nic-IgG) and a monoclonal 

antibody (Nic311) were taken, respectively, from rabbits 

and mice that produced them in response to immunization with NicVAX. The research team, headed by Dr. 

Mahmoud Ahmed of the University of Texas Medical 

Branch, Galveston, tested the antibodies’ effects on placental tissue and cross-placental nicotine transfer using a 

method developed in the mid-1980s: An intact lobule was 

dissected from placentas taken immediately after delivery 

and placed in phosphate-buffered saline. The researchers 

inserted catheters into blood vessels on the maternal and 

fetal side of the placental lobule and perfused each with 

tissue culture medium from a separate reservoir, creating 

distinct maternal and fetal circuits. They monitored placental function and viability for 2 hours, and then added 

nicotine to the fluid in the maternal reservoir. “We used 

a concentration (40 ng/mL) that has been reported in 

the circulation of mothers who smoke,” Dr. Ahmed says. 

Either Nic311 or Nic-IgG along with nicotine was added 

to the maternal reservoir. Following these infusions, the 

researchers continued to monitor placental tissue health 

and tracked nicotine and antibody concentrations in both 

maternal and fetal circuits for 4 more hours.

18
Safety Reassurance

“Our primary interest in these studies was vaccine safety: 

Would it be safe to vaccinate women who may become 

pregnant, or during pregnancy? Antibodies might protect 

the fetus, but we also worried that they might escort 

nicotine across the placenta or sequester it in the fetus, 

increasing exposure,” says Dr. Pentel. “The studies 

look reassuring.”

When nicotine alone was added to the maternal circuit, 

it readily crossed the placenta; its concentration in the 

fetal circuit increased rapidly over the first 30 minutes. It 

did not change in the next 210 minutes. The addition of 

either antibody markedly reduced the rate at which nicotine crossed the placenta. With Nic311, nicotine reached 

a concentration of 1.8 ± 0.8 ng/mL in the fetal circuit 

in the first 5 minutes—about one-fourth of the transfer 

in the absence of the antibody. There was no significant 

increase in fetal circuit nicotine after the first 30 minutes. 

Nic-IgG had an even more pronounced effect: The concentration of nicotine in the fetal circuit was about onehalf what it had been with Nic311 after the first 5 minutes (1.0 ± 0.04 ng/mL); it, too, rose little after that. Both 

antibodies also reduced the amount of nicotine retained in 

placental tissue.

“There was no effect of nicotine or either antibody on placental function or viability,” Dr. Ahmed says. No appreciable amount (less than 1 percent) of either antibody 

appeared in the fetal circuits at any point in the experiment, suggesting that placental transfer was negligible.

Whether vaccination would protect the fetus from nicotine if a mother continued smoking is not yet clear. “I’m 

not sure that the effect would be large enough,” Dr. 

Pentel says. Previous animal studies in which he was 

involved found that while antibodies sharply slow the rate 

at which a single dose of nicotine reaches the brain, they 

do not stop the process altogether. “When nicotine is 

administered chronically in a way that approximates daily 

smoking, its long-term accumulation in the fetal brain 

looks the same in vaccinated and unvaccinated animals.” 

Vaccination of pregnant rats reduced nicotine transfer to 

the fetal circulation and brain for 25 minutes after a single 

dose, but did not change accumulation in the fetal brain 

when nicotine was administered chronically. In another 

study, maternal vaccination did not prevent nicotineinduced upregulation of nicotinic cholinergic receptors or 

changes in gene expression (c-fos) in the fetal rat brain, Dr. 

Pentel observes. The ex vivo system used in the current 

study is not intended to model the effects of continual 

daily smoking, he says, but rather provides insight into 

the shorter term effects of antibodies on nicotine transfer 

across the placenta, as well as placental viability.

Dr. Amrat Patel, of NIDA’s Chemistry and Pharmaceutics 

Branch, says the current study represents an important advance beyond animal research in suggesting that 

nicotine-specific antibodies can reduce placental transfer 

of nicotine in humans as well, but more work is needed 

to know whether the effect will be sufficient to prevent 

neurotoxicity. “We need to determine how much nicotine 

is necessary to cause fetal damage, and how to make sure 

nicotine does not approach that level.” Antibodies with 

higher affinity for nicotine may make a difference, 

he says; as vaccine research continues, “we’ll probably 

progress to develop antibodies that are even better able 

to sponge up nicotine.”

Source

• Nekhayeva, I.A., et al. Effects of nicotine-specific 

antibodies, Nic311 and Nic-IgG, on the transfer of 

nicotine across the human placenta. Biochemical 

Pharmacology 70(11):1664-1672, 2005. 

19
Nicotine Alters the Developing Rat Brain

Exposure to the drug during gestation or adolescence may cause lasting alterations in reward and 

motivation circuits.

By Carl Sherman, NIDA Notes Contributing Writer

Research Findings

Volume 21, Number 2 (February 2007)

Most people who become chronic smokers start in adolescence, and the risk of addiction at this time is even 

greater among those whose mothers smoked while pregnant. NIDA-funded animal studies recently identified 

two neurobiological effects of nicotine that could underlie 

these vulnerabilities. Investigators at the University of 

Tennessee, led by Dr. Burt Sharp, found that prenatal 

nicotine exposure reduces the availability during adolescence of a receptor that mediates the drug’s impact on 

cells in the brain’s reward system. At the University of 

Wisconsin, Dr. Charles Landry and his research team 

found that nicotine stimulates a set of genes involved in 

synapse formation to a higher level of activity in adolescent than in adult rats.

Nicotine’s Impact on Receptors

The University of Tennessee researchers pursued a clue 

from previous work in which they examined the effects

of prenatal nicotine exposure on the mesolimbic reward 

pathway. Nicotine and other drugs of abuse stimulate 

neurons in the brain area where this pathway originates, 

the ventral tegmental area (VTA), to release the neurotransmitter dopamine in the nucleus accumbens (NAc) 

and prefrontal cortex (PFC). The dopamine influx into 

the NAc produces the feelings of reward and pleasure that 

are primary motivators of continued drug-taking. Dr. 

Sharp and colleagues found, however, that exposing rats 

prenatally to nicotine reduced the amount of dopamine 

released in the NAc when the animals were given the drug 

again as adolescents.

“We asked ourselves, ‘What causes this?’” Dr. Sharp says. 

“We decided to look at nicotine’s impact on the expression of nicotinic cholinergic receptors—the principal sites 

where nicotine molecules interact with brain cells to exert 

their stimulating effects.” The researchers hypothesized 

that exposure to nicotine during gestation would reduce 

the number of such receptors present on dopamineproducing cells in the VTA in adolescence.

They gave nicotine to pregnant rats via an implanted 

pump at the rate of 2 mg/kg/day (the equivalent of a 

human smoking a pack a day) throughout gestation. At 

birth they increased the nicotine infusions to 6 mg/kg/

day and continued them for 2 more weeks, while the rat 

pups nursed. Because rat pups are born at an earlier stage 

of development than humans, the weeks of continued 

exposure were necessary to give them cumulative nicotine 

exposure equivalent to a smoking mother’s baby at fullterm. A control group of rats received the nicotine delivery solution without the drug.

The researchers took brain sections from the rat pups 

when they were 35 days old, developmentally equivalent 

to mid-adolescence in humans, and assayed them for 

nicotinic cholinergic receptors. In confirmation of their 

hypothesis, the results showed significantly fewer receptors 

in the VTA, NAc, and PFC of the adolescent rats that 

had been exposed to nicotine in utero. Messenger RNA 

(mRNA) for the receptors declined only in the VTA, suggesting that gestational nicotine had primarily affected 

dopaminergic neurons that originate in that area. The 

total number of VTA neurons also dropped in the brains 

of nicotine-exposed rats.

These findings “show how gestational exposure to nicotine may alter maturation, literally changing the brain,” 

Dr. Sharp says. Although it is not clear how such changes 

could enhance the likelihood of dependence, “one hypothesis might be that prenatally exposed adolescents, having 

fewer nicotinic receptors, must take more puffs to release 

20
a rewarding amount of dopamine into the NAc, and this 

leads to stronger conditioning,” he says.

Dr. Allison Chausmer of NIDA’s Division of Basic 

Neuroscience and Behavioral Research says, “The findings 

confirm the long-term effect of smoking during pregnancy 

and underscore the importance of smoking cessation at 

this time.”

Nicotine Affects Synapse Development

The University of Wisconsin team studied the impact 

of nicotine on genes that contribute to neural plasticity. 

This process—the formation of new synaptic connections 

between neurons and pruning of old ones—wires the 

brain during development and reaches a crescendo during 

adolescence. The researchers specifically focused on the 

genes—including arc, c-fos, and NGFI-B—that produce a 

set of neurochemicals involved in building synapses. Using 

rats as subjects, they compared the expression—roughly, 

the production rate—of these genes following exposure to 

nicotine in adolescents (average age 30 days) and adults 

(average age 70 days).

The investigators injected the rats with nicotine at a dose 

large enough (0.4 mg/kg) to cause a behavioral response—

increased motor activity—or with saline. An hour later, 

they examined slices of the rats’ brains, with particular 

attention to areas that play central roles in learning and 

motivation: the medial PFC, ventral and lateral orbital 

cortex (VLO), cingulate cortex, somatosensory cortex, 

ventral striatum, and dorsal striatum. They assessed the 

expression of plasticity-related genes by measuring the 

amount of their corresponding mRNA.

Throughout the brain, they found higher amounts of 

mRNA for arc and c-fos in the adolescent than the adult 

brains, an indication of more synaptic plasticity overall, 

Dr. Terri Schochet suggests. In both age groups, arc and 

c-fos mRNA jumped after injection of nicotine, compared 

with saline, indicating that the drug “switched on” these 

genes. In certain prefrontal regions, the nicotine-evoked 

increase in arc mRNA was significantly greater in adolescent animals. In the VLO, for example, arc expression 

increased by 182 percent in adolescents after nicotine 

injection, compared with 98 percent in adults.

“These findings show that at the basic biochemical level, 

the adolescent brain responds differently to a single dose 

of nicotine,” says Dr. Landry, principal investigator 

for this study. “The enhanced expression of arc, a gene 

involved in dendrite formation, in adolescent forebrains 

following acute nicotine reflects a very dynamic synaptic 

milieu. It’s difficult to speculate further, but my suspicion 

is that the adolescent brain responds to the drug with a 

greater increase in synaptogenesis and pruning.”

“The adolescents’ greater changes in molecular systems 

involved in learning may indicate that this age group is 

more susceptible to developing the nicotine habit,” Dr. 

Schochet suggests. The striking effect of a single dose of 

nicotine could have implications for treatment, she adds: 

“It’s really important to intervene as early as possible to prevent adolescents from trying nicotine in the first place.”

Research that explores and compares adult and adolescent behavior and neurobiology is a particular interest 

of NIDA’s, says Dr. Susan Volman of the Institute’s 

Division of Basic Neuroscience and Behavioral Research. 

This study was valuable because it “looks at both what’s 

different in general between the maturing and adult brain 

and how that difference interacts with nicotine.”

Dr. Volman notes that the adult/adolescent disparity in 

response to nicotine was greatest in the ventrolateral PFC. 

“Neural adaptations here could have to do with altering 

motivation and the value placed on particular rewards,” 

she says. Smoking might be equally pleasurable to adults 

and adolescents, that is, but the experience would be more 

highly valued by the adolescent—a difference with potential implications for tailoring behavioral treatments to this 

age group.

Sources

• Chen, H., et al. Gestational nicotine exposure reduces 

nicotinic cholinergic receptor (nAChR) expression in 

dopaminergic brain regions of adolescent rats. European 

Journal of Neuroscience 22(2):380-388, 2005.

• Schochet, T.L., Kelley, A.E., and Landry, C.F. 

Differential expression of arc mRNA and other plasticity-related genes induced by nicotine in adolescent rat 

forebrain. Neuroscience 135(1):285-297, 2005. 

21
Sensory Aspects May Drive Addiction in Obese Smokers

Obesity appears to reduce nicotine’s rewarding effect in mice and humans.

By Patrick Zickler, NIDA Notes Contributing Writer

Research Findings

Volume 20, Number 6 (July 2006)

For obese smokers, the taste and smell of a lit cigarette 

may play as powerful a part in addiction as does the 

nicotine buzz. For these smokers, nicotine replacement 

therapies that also replace some of the sensory aspects of 

smoking—lozenges, gum, or nasal spray—may be more 

effective than a patch, according to researchers at the 

University of Pennsylvania’s Transdisciplinary Tobacco 

Use Research Center (TTURC).

Lead investigator Dr. Caryn Lerman and TTURC colleagues asked 37 smokers to describe the experiences of 

smoking two “brands” of cigarettes; although the smokers 

did not know it, one brand contained nicotine and the 

other did not. Obese smokers rated the two nearly equal, 

while nonobese smokers gave higher marks to the conventional cigarettes. When allowed to choose freely, nonobese 

smokers preferred conventional cigarettes, while obese 

smokers were equally likely to choose either type.

To validate these observations and investigate their 

physiological basis, Dr. Julie Blendy and colleagues tested 

nicotine’s rewarding effect in mice. Given access to two 

chambers, nonobese mice gravitated to the one in which 

researchers had dosed them with nicotine, whereas mice 

made obese by a high-fat diet showed no preference. 

These results suggest that the nicotine provided the nonobese mice, but not the obese mice, with an experience 

they wanted to repeat. When the researchers examined the 

brains of the mice, they found that the obese 

animals, compared with those fed a normal diet, had 

reduced levels of opioid receptors, which have been 

implicated in nicotine addiction.

“For obese smokers, sensory cues such as sights and smells 

and taste may be at least as rewarding as the pharmacological reward of nicotine,” says Dr. Lerman. “The mouse 

experiment suggests a possible biological mechanism for 

the observation in human smokers. Diet may influence 

nicotine reward through effects on the opioid system,” 

Dr. Blendy adds.

Obesity and Human Response to Nicotine

The research team recruited 17 obese and 20 nonobese 

men and women who were regular smokers. The obese 

and nonobese study participants’ average body mass 

indexes were 39.1 (range, 31.0 to 59.4) and 23.0 (range, 

18.3 to 26.3), respectively. In the first part of the study, 

the participants smoked one cigarette from each of two 

color-coded sets, one that contained nicotine and one 

that was nicotine-free, without being informed about the 

difference. Participants rated the two smokes on a scale 

ranging from 0 (none) to 7 (complete)—for “satisfaction,” “liking,” and “psychological relief.” On average, 

obese smokers gave the conventional and nicotine-free 

cigarettes almost identical ratings for satisfaction (3.0 for 

nicotine versus 2.9 for nicotine-free), liking (2.9 versus 

2.8), and psychological relief (1.4 versus 1.2). Nonobese 

smokers gave the conventional cigarettes higher ratings for 

satisfaction (3.4 versus 2.1) and liking (3.7 versus 2.3) and 

showed no significant preference in psychological relief 

(1.7 versus 1.5).

Next, the smokers were allowed to smoke cigarettes from 

either color-coded set in four sessions, spaced 30 minutes 

apart, but limited to four puffs per session. On average, 

obese smokers took as many puffs on the conventional 

(48 percent) as the nicotine-free (52 percent) cigarettes. 

Nonobese smokers took 70 percent of their puffs from the 

conventional cigarettes.

“Tobacco addiction involves an interplay of physiological 

influences, such as the effects of nicotine or other components of tobacco, with sensory influences associated with 

taste or aroma, the physical manipulation of cigarettes 

and lighters, or the sight of smoke,” Dr. Lerman says. “It 

appears that for obese smokers, non-nicotine factors play 

22
a considerable part in maintaining addiction and therefore need to be considered in developing a treatment to 

help obese smokers quit. Obesity and 

smoking are both serious health risks, 

and some research suggests they act 

synergistically to create an even greater risk. If so, helping obese smokers 

to quit may have a greater impact on 

public health than an equivalent cessation among nonobese smokers.”

Obese Mice and Nicotine

In the animal component of their 

investigation, the researchers simulated human obesity in mice by feeding them a high-fat diet (45 percent 

fat, 35 percent carbohydrates, 20 percent protein) for 15 weeks. A control 

group of mice received a normal laboratory diet (12 percent fat, 60 percent 

carbohydrates, 28 percent protein). 

The researchers injected each animal 

with nicotine while confining it to 

one compartment of a two-compartment test chamber daily for 8 days. 

Subsequently, they placed each mouse 

in the test chamber and allowed it 

free access to either compartment for 

15 minutes. Nonobese mice spent most of this time in 

the compartment where they received the drug, indicating 

that the nicotine injections had given them pleasure they 

would like to repeat. However, obese mice showed no 

preference for the side associated with the drug.

The investigators next examined the brains of the mice 

and found evidence that the animals maintained on a 

high-fat diet had less precursor associated with structures 

called mu-opioid receptors on cells in the ventral tegmental area (VTA) of the brain. The VTA is where nicotine 

acts to increase the availability of dopamine, a chemical 

that causes the pleasurable sensations 

associated with many drugs of abuse. 

Other animal research has implicated 

mu-opioid receptors in neurochemical processes that lead to nicotine 

addiction, and the finding that fewer 

of these receptors are activated in the 

brains of the high-fat-diet mice could 

in part explain their blunted response 

to nicotine’s rewarding effect.

“In this mouse study, the animals 

could not control their diet. But 

humans choose what and when to 

eat,” says Dr. Allison Chausmer of 

NIDA’s Division of Basic Neuroscience and Behavioral Research. 

“The observations made in these mice 

suggest a fascinating chain of events 

leading from a behavior, selecting 

what to eat, to a measurable biochemical change in the brain and altered 

response to an addictive drug. They 

illustrate the complexity of factors that 

contribute to the powerful addictive 

grip of tobacco and—conversely—can 

potentially be manipulated to improve 

the effectiveness of treatments that help 

smokers quit.”

Source

• Blendy, J.A., et al. Reduced nicotine reward in 

obesity: Cross-comparison in human and mouse. 

Psychopharmacology 180(2):306–315, 2005. 

23
Bupropion Helps People With Schizophrenia Quit Smoking

Data address physicians’ concerns about prescribing the medication for smokers with schizophrenia.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 20, Number 5 (April 2006)

The smoking cessation aid bupropion is safe and effective 

for people with schizophrenia, researchers at Massachusetts 

General Hospital and Harvard Medical School have found. 

In a NIDA-funded study of smokers with schizophrenia, 

those who took sustained-release bupropion were more likely 

to stop smoking by their quit date and to achieve continuous 

abstinence for a month than those who received placebo, and 

they also remained abstinent longer. The researchers did not 

observe any adverse interactions with the patients’ antipsychotic medications or exacerbation of psychiatric symptoms.

The U.S. Food and Drug Administration (FDA) approved 

sustained-release bupropion as a treatment for depression in 

1996 and as a smoking-cessation aid in 1997, but physicians 

have been reluctant to prescribe the medication for patients 

with schizophrenia. “Although 75 to 85 percent of people 

with schizophrenia smoke, we have lacked data on treatments for nicotine addiction in this population, resulting in 

many not receiving advice to quit,” says Dr. A. Eden Evins, 

lead investigator of the study.

Dr. Evins and her colleagues treated 53 patients, aged 24 

to 66, for nicotine dependence. When they began treatment, the patients smoked 30 cigarettes a day, on average, 

and typically had made two previous quit attempts. During 

the 12-week study, each participated in weekly sessions of 

group cognitive-behavioral therapy (CBT) and received 

either 300 milligrams a day of sustained-release bupropion 

or placebo. The CBT program was adapted for patients with 

schizophrenia from standard smoking-cessation therapy. 

Each patient visited the clinic once a week for evaluations 

of smoking (self-report confirmed by expired air carbon 

monoxide measurements), changes in psychiatric symptoms, 

medication compliance, and side effects.

Therapists encouraged all patients to set a quit date before 

the 4th week of treatment, and 36 percent of those taking 

bupropion—compared with 7 percent of those on placebo—achieved this goal, demonstrating abstinence at the 

4-week assessment. Sixteen percent of patients in the bupropion group, but none taking placebo, achieved abstinence 

throughout the last month of treatment. Among patients 

who were not abstinent at the end of the study, those in the 

bupropion group reduced the average number of cigarettes 

smoked daily from 34 to 9, compared with a drop from 25 

to 15 in the placebo group.

Bupropion was generally well tolerated and did not exacerbate the symptoms of schizophrenia. Depression and 

flat affect, as well as cognitive function, tended to improve 

among patients taking the medication. Common side effects 

experienced by people taking antipsychotic medications, 

such as muscle stiffness and shuffling gait, were not worsened by nicotine abstinence or bupropion. About 80 percent 

of patients in both the medication and placebo groups kept 

to their regimens throughout the study.

The findings confirm promising results from several smaller 

studies. Dr. Evins points out that the relapse rate was high 

after treatment discontinuation—75 percent of those who 

were abstinent at week 12 had relapsed to smoking at the 

3-month followup. Only about 4 percent of patients in 

either group were abstinent in the week before the 3-month 

followup. Other studies of bupropion in the general population have shown that about half of patients tend to relapse 

after treatment discontinuation. “Patients with schizophrenia 

may need a longer course of bupropion with CBT or a combination of bupropion and nicotine replacement therapy to 

avoid relapse,” says Dr. Evins.

Source

•	 Evins, A.E., et al. A double-blind placebo-controlled 

trial of bupropion sustained-release for smoking 

cessation in schizophrenia. Journal of Clinical 

Psychopharmacology 25(3):218-225, 2005. 

24
25

Genetic Predisposition and Depression Both Influence 

Teen Smoking

By Patrick Zickler, NIDA NOTES Staff Writer

Research Findings

Volume 20, Number 4 (March 2006)

NIDA-supported scientists have found that a gene, called 

DRD2, partly determines whether an adolescent who takes 

a first puff on a cigarette will progress to regular smoking. 

Adolescents who carry one of the two known forms of the 

gene (A1) are more likely than those with the other variant (A2) to become daily smokers. If the teen also suffers 

from depression, the genetic effect is amplified, further 

increasing the likelihood of smoking escalation, according to Dr. Janet Audrain-McGovern and colleagues at the 

University of Pennsylvania Transdisciplinary Tobacco Use 

Research Center (TTURC).

The new findings result from a large-scale study that Dr. 

Audrain-McGovern and her research group undertook to 

clarify outstanding issues surrounding DRD2 and smoking. Scientists have suspected for some time that variations 

in DRD2 might influence people’s responses to tobacco, 

based on the gene’s function: It helps guide construction 

of sites where the neurotransmitter dopamine—which 

plays a key role in producing the pleasurable effects of 

nicotine—attaches to brain cells. Some previous studies 

have found that, indeed, men and women who smoked or 

were nicotine-dependent were more likely to have the A1

DRD2 variant than the A2. However, other studies did 

not confirm the link.

DRD2 Variants and Smoking Progression

Dr. Audrain-McGovern’s team recruited 615 adolescents 

(322 girls, 293 boys) to participate in their study. Because 

genetic diversity would increase the difficulty of interpreting results, all the youths were of European ancestry. 

Analysis of DNA obtained from cheek swabs showed 

that the frequencies of the alternative DRD2 forms, or 

alleles, were roughly the same among the participants as 

have been seen in general population samples of people 

of European stock: Two-thirds (67 percent) had inherited 

the A2 allele from both parents, 30 percent had one A1

and one A2, and 3 percent had two copies of the A1.

The researchers interviewed the teens in ninth grade, asking questions used in the Youth Risk Behavior Survey, 

including, “Have you ever tried or experimented with 

cigarette smoking, even a few puffs?” “Have you smoked 

at least one whole cigarette?” “How many cigarettes have 

you smoked in the last 30 days?” and “How many cigarettes have you smoked in your lifetime?” Based on their 

responses, the teens were categorized as never smokers, 

puffers (a few puffs, but never a whole cigarette), experimenters (at least one but fewer than 100 lifetime cigarettes), and current smokers (smoked in the past 30 days 

and 100 or more lifetime cigarettes).

The teens answered the same questions again in the fall 

and spring of their 10th-grade year and in the spring of 

their 11th-grade year. Analyzing the teens’ sequential 

responses together with their genetic data, the researchers found no association between variation in DRD2

alleles and the likelihood that participants who had 

never smoked would start, Dr. Audrain-McGovern says. 

“However, among adolescents who had taken at least a 

single puff, we found a clear association between the 

A1 allele and progressing up the ladder of smoking frequency—for example, moving from puffer to experimenter, or experimenter to current smoker. Each additional 

copy of the A1 allele nearly doubled the odds of progression,” she says. Among teens who had at least puffed once, 

those with a single A1 allele were 1.8 times as likely, and 

teens who had inherited A1 alleles from both parents were 

3.4 times as likely as those with two A2 alleles to progress 

to heavier smoking before they finished 11th grade.

“These results clearly illustrate the important interplay 

between a gene and the environment,” Dr. AudrainMcGovern says. “The DRD2 variant appears to play no 
role in whether or not these teens took that first puff. Its 

effect isn’t seen until there is some biological exposure. 

Then, we see a markedly different response to nicotine, 

perhaps because the A1 allele is associated with reduced 

density of dopamine receptors. If individuals with this 

allele have lower baseline levels of dopamine activity, they 

might experience greater reward when nicotine triggers an 

enhanced dopamine release.” 

DRD2 and Depression

During the ninth-grade interviews, the researchers administered the Center for Epidemiological Studies Depression 

Scale (CES-D Scale) to the study participants. Each teen 

rated how frequently he or she had experienced each of 20 

depression symptoms during the past week. One hundred 

teens (16 percent) scored 23 or higher on this scale, which 

indicates clinically significant depression. Of the 100, 52 

had at least one A1 allele. Teens without an A1 allele had 

an average CES-D score of 12.3; those with one A1 and 

one A2 had an average score of 15.1; and those with two 

copies of the A1 allele averaged 16.7. There also was a significant association between the CES-D score and smoking status at the initial interview: The average score was 

12.5 for never smokers, 14.6 for puffers, 13.7 for experimenters, and 20.8 for current smokers.

Teens with high depression scale scores and the A1 allele 

were at the highest risk of smoking progression. Among 

teens with at least one A1 allele, 33 percent of depressed 

teens, compared with 25 percent of nondepressed teens, 

reported smoking progression within 2 years. 

The interaction of the DRD2 allele and depression on 

smoking progression highlights the intricate interplay 

of genetic, psychological, and social factors that influence adolescents’ smoking behavior, observes Dr. Allison 

Chausmer of NIDA’s Division of Basic Neurosciences and 

Behavior Research. “This research group has previously 

shown that adolescents who have depression are more 

receptive than nondepressed teens to the messages contained in tobacco advertising. This is not a trivial number 

of potential smokers. Roughly one in five high school 

students has symptoms that represent clinically significant 

depression. Those who succumb to the appeal of tobacco 

manufacturers’ advertising and have this particular genetic 

makeup may be more likely to progress to higher levels 

of smoking and ultimately experience consequences of 

reduced health and longevity.”

Source

• Audrain-McGovern, J., et al. Interacting effects of 

genetic predisposition and depression on adolescent 

smoking progression. American Journal of Psychiatry

161(7):1224-1230, 2004. 

26
27

Study Points to Acetaldehyde-Nicotine Combination in 

Adolescent Addiction

By Patrick Zickler, NIDA NOTES Staff Writer

Research Findings

Volume 20, Number 3 (October 2005)

The teen years are when most smokers first light up, and 

adolescents become addicted to tobacco faster than adults. 

Research has suggested that young people are particularly 

vulnerable to smoking addiction in part because their 

brains are more sensitive to nicotine, but that other factors 

also contribute. Now, NIDA-funded investigators have 

produced evidence pointing to another chemical constituent of tobacco smoke, acetaldehyde, as one of those 

factors. A recent study demonstrated that in adolescent 

but not adult laboratory rats, acetaldehyde and nicotine 

together produce a much stronger pleasure-producing, or 

reinforcing, effect than either chemical alone.

Dr. James Belluzzi and colleagues at the Transdisciplinary 

Tobacco Use Research Center at the University of 

California at Irvine hypothesized that acetaldehyde might 

play a role in smoking addiction for several reasons. 

Among them:

• Smokers exhibit more drive to take another puff on 

a cigarette than laboratory animals do to push a lever 

for another nicotine infusion, a difference that might 

be explained if smoke contains an additional reinforcing constituent besides nicotine;

• Smokers are abundantly exposed to acetaldehyde, 

which occurs naturally in tobacco leaves and also is 

formed as a combustion product of sugars added to 

tobacco during cigarette manufacture; 

• Research has suggested that acetaldehyde, which also 

is produced during alcohol metabolism, contributes 

to alcohol reinforcement and withdrawal symptoms, 

raising the possibility that it might play a similar role 

in tobacco dependence. 

To test their hypothesis that acetaldehyde contributes to 

tobacco addiction, particularly in adolescents, Dr. Belluzzi’s 

research team conducted an animal self-administration 

study with early-adolescent (27-day-old), adolescent 

(37-day-old), and adult (90-day-old) rats. The researchers 

placed the animals in cages where they could poke their 

noses through holes in the cage wall to obtain injections 

of nicotine (30 mg/kg) plus acetaldehyde (16 mg/kg), nicotine or acetaldehyde alone, or saline. In such studies, the 

Adolescent Rats, but Not Adults, Increase Intake of Nicotine When it Is Combined With 

Acetaldehyde, a Component of Tobacco Smoke

(A) Adolescent rats self-administered nicotine combined with acetaldehyde—but not nicotine alone, acetaldehyde alone, or saline—with 

increasing frequency over 5 days. (B) Adult rats did not demonstrate any preference for nicotine, acetaldehyde, or the combination over 

saline. (C) Total 5-day intake of nicotine plus acetaldehyde was greatest for the youngest group of animals, suggesting that vulnerability to 

tobacco addiction decreases with age.
frequency and persistence with which animals nose-poke 

for a particular substance is a measure of how rewarding it 

is for them, which in turn may correspond to how addictive it is for people. Over the course of five daily 3-hour 

sessions, the youngest rats worked up to poking their 

noses for nicotine plus acetaldehyde roughly three times 

as frequently than for either chemical alone or saline. The 

older adolescent rats also demonstrated a preference for 

the two-drug combination, but a less-marked one than the 

27-day old animals. The adult rats responded no differently to the drugs, alone or in combination, than they did 

to the saline solution.

“Our results show that acetaldehyde, at the same relative concentration found in cigarette smoke, dramatically 

increases the reinforcing properties of nicotine,” says 

Dr. Belluzzi. “Furthermore, the effect is age-related, with 

adolescent animals far more sensitive than adults.”

To buttress their interpretation of their results, the 

researchers tested a potential alternative explanation for 

the rats’ behavior: The animals might not be seeking 

pleasure when they poked their noses into the holes for 

nicotine and acetaldehyde, but simply exhibiting random 

activity due to chemically induced locomotor stimulation. 

To evaluate this possibility, the researchers put a control 

group of rats into the test cages and gave them injections 

of nicotine plus acetaldehyde at the test dosage. They 

predicted that these rats should nose-poke less than the 

original animals if pleasure-seeking was a main motivation 

for the behavior (because they were getting the chemicals’ 

reinforcing effects automatically without having to work 

for them), or nose-poke the same amount if locomotor stimulation was the primary cause (because the test 

animals and control animals received similar doses of the 

chemicals). The data showed that the control rats nosepoked less than the original animals.

“This research underscores the point that nicotine alone 

may not cause the intensity of dependence seen in smokers, and nicotine replacement does not, by itself, eliminate 

withdrawal or craving for people trying to quit. Other 

factors clearly are at play,” says Dr. Allison Chausmer of 

NIDA’s Division of Basic Neurosciences and Behavioral 

Research. “Dr. Belluzzi’s experiment strongly suggests that 

acetaldehyde is one of those factors, and it offers a potential explanation for age-related differences that we observe 

in epidemiological studies of the impact of tobacco.” 

Source

• Belluzzi, J.D.; Wang, R.; and Leslie, F.M. 

Acetaldehyde enhances acquisition of nicotine selfadministration in adolescent rats. 

Neuropsychopharmacology 30(4):705–712, 2005. 

28
NIDA Research Illuminates Associations Between Psychiatric 

Disorders and Smoking

By Patrick Zickler, NIDA NOTES Staff Writer

Research Findings

Volume 20, Number 2 (August 2005)

Nearly half of all cigarettes sold in 

the United States are sold to people 

with mental illness, and men and 

women with mental disorders are 

twice as likely as the general population to smoke. A recent NIDAsupported epidemiological analysis 

reveals relationships between psychiatric disorders and smoking that 

have important implications for 

public health. The findings suggest 

that treating psychiatric illness can 

contribute to reductions in smoking 

intensity and nicotine addiction, 

and that addressing smoking during 

substance abuse treatment is vital 

to counter an increased risk for 

nicotine addiction that may accompany recovery.

Dr. Naomi Breslau, at Michigan 

State University in East Lansing, 

used data from the Tobacco 

Supplement to the National 

Comorbidity Survey (NCS) to 

study the relationships between the 

temporal onset of psychiatric disorders, psychiatric symptoms, and 

smoking. The NCS, mandated by 

Congress to assess the prevalence of 

psychiatric disorders in the United 

States, surveyed a representative 

sample of the national population 

between 1990 and 1992, eliciting information about the 

onset of psychiatric disorders—as defined by the American 

Psychiatric Association’s Diagnostic and Statistical Manual 

of Mental Disorders, 3rd Edition Revised (DSM-III-R)—

and the time course of their symptoms. Disorders included in the NCS are major depression, dysthymia (similar 

to clinical depression, but with longer-lasting and milder 

symptoms), agoraphobia, generalized anxiety disorder, 

simple and social phobias, panic disorder, posttraumatic 

stress disorder, and alcohol or drug abuse or addiction. 

The NCS Tobacco Supplement asked respondents whether they smoked, when they began smoking daily, at what 

age they experienced symptoms matching DSM criteria 

for nicotine dependence, and whether they had stopped 

smoking regularly a year or more before they took part in 

the survey.

Analyzing the responses from 4,414 survey participants, 

Dr. Breslau found that:

• Men and women with histories of substance abuse, 

major depression, and most anxiety disorders reported 

increased rates of transition to daily smoking, but 

only during periods when they were experiencing 

symptoms. When their illnesses had been asymptomatic for a year or more, they became daily smokers at 

rates no higher than respondents who never experienced psychiatric illness;

29

Researchers found that active psychiatric disorders, with the exception of agoraphobia and 

panic disorder, were associated with increased risk of transition to daily smoking. In contrast, 

past disorders (those that had been inactive for a year or more) generally did not predict transition to daily smoking. Researchers also found an increased risk of transition to nicotine addiction associated with a wide range of active disorders, but only four past disorders. Risks are 

presented as odds ratios; a relative risk of 2.0 indicates twice the likelihood.
• Substance abuse and major depression predicted 

transitions from voluntary smoking to nicotine addiction when actively symptomatic (the association was 

borderline for drug, as opposed to alcohol, abuse). In 

the case of substance abuse, this relationship became 

markedly stronger when the problems had remitted 

for at least a year;

• Most anxiety disorders increased risk for nicotine 

addiction when symptomatic. For individuals with 

simple phobia or panic disorder, these risks multiplied 

during periods of remission. For those with posttraumatic stress disorder, the risk reverted to baseline 

when symptoms had been absent for a year; and

• None of the psychiatric disorders studied affected 

respondents’ chances of successfully quitting smoking, 

either when active or when remitted.

“We found that the majority of the psychiatric disorders, 

when active, predicted the onset of daily smoking,” Dr. 

Breslau says. “Respondents with one active disorder were 

1.3 times as likely, and those with four or more active 

disorders were 2.2 times as likely to begin daily smoking 

as those with no active disorders. This suggests that early 

treatment may be able to prevent patients who are not 

currently daily smokers from progressing to that status.”

“Similarly,” Dr. Breslau says, “most disorders—when 

active—predicted that smokers would progress from daily 

smoking to nicotine addiction. In this transition from one 

stage of smoking to another, daily smokers with one active 

disorder were on average 1.8 times as likely as those with 

no active disorder to develop addiction, and the odds of 

developing nicotine addiction increased with the number 

of active disorders. This suggests that successful control 

of psychiatric symptoms before smokers become addicted 

can prevent them from making that transition.” 

Substance abuse, however, is an important exception to 

this general observation. Respondents with past but not 

active alcohol and drug abuse disorders had risk ratios 

two to three times as high as respondents with current 

active disorders involving these substances. “This association suggests that cessation of substance abuse may induce 

greater smoking intensity. In treatment for substance 

use disorders it is important to be conscious of smoking 

behavior, to guard against the possibility that a person in 

treatment for one damaging condition might increase the 

danger posed by another. Treatment should assist patients 

who are abusing alcohol or drugs and who smoke to quit 

both,” Dr. Breslau says.

When Dr. Breslau looked for a relationship between mental disorders and quitting smoking, she found that neither 

active nor remitted disorders made respondents more or 

less likely to quit smoking successfully during the year 

preceding the survey. 

“The relationship between tobacco use and comorbid 

psychiatric disorders is complex,” says Dr. Kevin Conway 

of NIDA’s Division of Epidemiology, Services and 

Prevention Research. “While we see variations across the 

range of disorders included in the comorbidity survey, the 

consistent pattern in this study emphasizes the importance 

of active expression of psychiatric disorders—not simply a 

history of the disorder—in relation to smoking stages.” 

Source

• Breslau, N.; Novak, S.P.; and Kessler, R.C. 

Psychiatric disorders and stages of smoking. Biological 

Psychiatry 55(1):69-76, 2004. 

30
Site on Brain Cells Appears Crucial To Nicotine Addiction

By Patrick Zickler, NIDA NOTES Staff Writer

Research Findings

Volume 20, Number 2 (August 2005)

Using genetic engineering, 

NIDA-supported scientists have 

produced a strain of mice with 

special characteristics that can 

help researchers identify and 

study key steps in the development of nicotine addiction. By 

altering a single amino acid in 

just one of a mouse’s 30,000 

genes, the scientists produced 

mice that are exceptionally sensitive to the effects of nicotine. 

The modified mice show behaviors associated with addiction 

when exposed to nicotine doses 

far too small to cause similar 

effects in other mice. Their dramatically increased sensitivity 

suggests that the brain cell site 

affected by the modified gene is 

crucial to development of nicotine addiction. 

Dr. Andrew Tapper and colleagues at the California 

Institute of Technology in 

Pasadena and at the University 

of Colorado in Boulder built on 

work by other scientists which 

indicated that a site on some 

brain cells—the a4 subunit of nicotine receptors—plays a 

key role in the brain’s response to nicotine. The previous 

work involved “knock-out” mice, in which scientists had 

disabled a gene that directs development of the a4 site. 

When exposed to nicotine, the a4 knock-out mice did 

not respond with increased release of the pleasure-causing 

brain chemical dopamine, a reaction thought to be a key 

factor in the development of nicotine addiction.

The results with knock-out mice suggested that a4 sites 

on brain cells are necessary for development of nicotine 

addiction, but didn’t address the question of whether the 

sites are sufficient by themselves to initiate the behaviors associated with addiction. To answer that question, says Dr. Henry Lester of the California Institute of 

Technology, “We decided to create animals with hypersensitive a4 receptors. That way, instead of eliminating 

the response to nicotine, we could emphasize it and study 

the processes that lead to nicotine addiction. So we developed the a4 ‘knock-in’ mouse.”

The scientists compared the behavioral effects that are 

in part characteristic of nicotine addiction—reward, tolerance, and sensitization—in their knock-in mice and 

unmodified mice. According to Dr. Lester, the results 

indicate that activation of the a4 site by nicotine is sufficient to initiate the effects.

Reward: The researchers measured nicotine reward in 

their mice with a technique called “conditioned place 

preference,” which is based on the assumption that if 

animals like an experience, such as receiving nicotine, 

they will gravitate to the place where they have had that 

experience rather than another where they haven’t. In the 

experiment, mice with unmodified a4 receptors exhibited a preference for a compartment associated with a 

nicotine dose of 0.5 mg/kg of body weight—a typical 

31

Brain Pathway to Nicotine Addiction

Nicotine attaches to nerve cells in the brain at receptors on the cell membrane. The receptors comprise five subunits that fit together like sections of an orange. When a nicotine molecule binds to 

one of these subunits, the segments pull away from each other, creating an open channel through 

the cell membrane. This initiates a series of electrical and chemical signals that trigger release of 

dopamine by other brain cells. One type of subunit, designated a4, appears to play a central role in 

development of nicotine addiction; mice engineered to have especially sensitive a4 subunits exhibit 

behaviors characteristic of nicotine addiction when exposed to a dose of nicotine just one-fiftieth of 

that normally needed to elicit these behaviors.
dose ingested by a human smoker. The investigators then 

tested the rewarding effect of one-fiftieth of that amount, 

10 mg/kg, on the unmodified and the a4 knock-in mice. 

When allowed to move freely between the chambers 

for 20 minutes following nicotine administration, the 

unmodified mice showed no preference for the nicotineassociated compartment; they spent slightly less time in 

that chamber than they had before. In contrast, modified 

mice showed a marked preference for the compartment 

associated with nicotine, spending an average of 2 minutes 

more in that chamber following nicotine administration.

Tolerance and sensitization: To test tolerance to nicotine, 

the investigators subjected the unmodified and knock-in 

mice to repeated doses of nicotine, 15 mg/kg daily over 9 

days, and then compared the changes in nicotine-induced 

hypothermia. The unmodified mice showed no change 

in body temperature, but the knock-in mice exhibited a 

decrease of 3°C on the first and second days, and smaller 

decreases each successive day, suggesting they had developed tolerance to the nicotine-induced hypothermia. In 

tests for sensitization, only the genetically engineered 

mice increased activity levels (measured by counting the 

number of times the animals cross a beam of light in the 

60 minutes following injection) in response to daily injections of 15 mg/kg over 9 days.

“This work represents a significant step forward in understanding how nicotine hijacks the brain’s normal signaling 

process,” says Dr. Joni Rutter of NIDA’s Division of Basic 

Neurosciences and Behavior Research. “And the research 

approach—moving from manipulation of a single protein 

to an animal’s behavioral response to nicotine—also holds 

great promise. If the a4 site is also found to play a large 

role in human nicotine addiction,” Dr. Rutter adds, “it is 

a promising focus for research into medications that might 

block nicotine’s effects.” 

Source

• Tapper, A.R., et al. Nicotine activation of a4 receptors: Sufficient for reward, tolerance, and sensitization. Science 306(5698):1029-1032, 2004. 

32

Genetic Engineering Reveals Proteins’ Key Role in Sensitivity to Cocaine 

Genetic engineering strategies like those used at the California Institute of Technology to study nicotine addiction have helped other investigators identify a pair of proteins that seem to influence cocaine addiction. 

Dr. Peter Kalivas and his colleagues at the Medical University of South Carolina in Charleston developed a strain of mice lacking two 

genes, called Homer1 and Homer2, that direct production of proteins linked to cocaine’s effects in the brain. The researchers found that the 

Homer “knock-out” mice were more sensitive than unmodified mice to the behavioral effects of cocaine. 

Compared with unmodified mice, animals missing either Homer1 or Homer2 developed stronger place conditioning—when allowed to 

move freely, they would spend more time in a compartment where they had received cocaine than in a compartment with no drug association. The knock-out mice also were more sensitive to cocaine’s stimulatory effect; when placed in a chamber equipped with photoelectric 

beams that could measure activity, the knock-outs were approximately 50 percent more active than unmodified mice following cocaine 

injections. To verify the role of the Homer genes in increased sensitivity to cocaine, the researchers restored Homer genes in the brains of the 

knock-outs, eliminating the previously seen differences in stimulation and place conditioning.

“The fact that Homer deletions result in these augmented responses to cocaine suggests that disruption of Homer protein-regulated 

signaling in the brain is a central step in development of cocaine addiction,” Dr. Kalivas says. Additional evidence of this role is seen in 

changes that Homer deletion causes in levels of the brain messenger chemical glutamate, he adds. Homer knock-out mice that had never 

been exposed to cocaine had nucleus accumbens (NAc) glutamate concentrations about 50 percent lower than mice with the genes—an 

effect similar to that seen in mice after cocaine withdrawal. This effect, too, was reversed when the scientists injected Homer genes into the 

NAc. 

The association between Homer activity and the conditions of cocaine withdrawal is particularly intriguing, according to Dr. Kalivas, 

because other researchers have shown that Homer protein levels rise and fall in response to environmental cues and changing levels of 

stress. “Homer may be a window to study the molecular basis of the important link between environmental stress and cocaine addiction.”

Source: Szumlinski, K.K., et al. Homer proteins regulate sensitivity to cocaine. Neuron 43(3):401-413, 2004. 
Nicotine Withdrawal Linked to Disrupted Glutamate Signaling

By Patrick Zickler, NIDA NOTES Staff Writer

Research Findings

Volume 19, Number 6 (May 2005)

More than a third of America’s 46 

million adult smokers try to stop 

each year, but fewer than 10 percent succeed. Some relapse because 

they cannot tolerate the discomfort 

and craving associated with nicotine withdrawal. In recent animal 

studies, NIDA-supported scientists 

identified sites on some brain cells 

that appear to be key promoters 

of the negative psychological symptoms of nicotine withdrawal. The 

sites, called glutamate receptors, 

are part of the communication 

network that uses the neurotransmitter glutamate as a chemical 

messenger. 

Neurobiologists have previously 

shown that glutamate helps produce the good feelings smoking 

causes. When nicotine attaches to 

receptors on cells in the brain’s 

ventral tegmental area (VTA), the 

cells release glutamate, which in 

turn triggers other VTA cells to 

release dopamine, a neurotransmitter that produces pleasure. Dr. 

Athina Markou of The Scripps 

Research Institute (TSRI) in La 

Jolla, California, and colleagues 

reasoned that just as glutamate 

surges caused by nicotine give rise 

to smoking pleasure, glutamate 

depletion related to nicotine abstinence might underlie the displeasure of withdrawal. The researchers 

speculated that when nicotine is 

withdrawn after chronic use, the 

feedback system that restores glutamate to normal levels following 

surges could overshoot its mark, 

resulting in a glutamate dearth—

and symptoms of depression and 

irritability.

To test this idea, Dr. Markou and 

Dr. Paul Kenny at TSRI, along 

with Dr. Fabrizio Gasparini of 

Novartis Institutes for Biomedical 

Research in Basel, Switzerland, 

focused on a specific group of glutamate receptors called group II 

metabotropic glutamate (mGluII) 

receptors. These inhibitory receptors 

are key components of the glutamate 

feedback system: They detect high 

glutamate levels and signal glutamateproducing cells to reduce their activity to bring the levels back down. 

Inactivating the mGluII receptors 

interrupts this process, leaving glutamate levels high. The researchers 

hypothesized that if they inactivated 

rats’ mGluII receptors while subjecting the animals to nicotine withdrawal, the plunge in glutamate levels 

may be avoided, and the animals’ 

withdrawal symptoms attenuated.

The scientists implanted tiny pumps 

under the skin on the backs of adult 

male rats. The pumps dispensed a 

nicotine solution that maintained 

high nicotine levels equivalent to 

those produced in a human who 

smokes 30 cigarettes per day. After 

the rats had been exposed to nicotine 

for 7 days, the investigators removed 

the pumps, depriving the animals of 

nicotine and thus leading to nicotine 

withdrawal. Then, after 18 hours of 

withdrawal, half the rats were injected 

with a chemical that blocks the action 

of mGluII receptors, in effect switching off the inhibitory feedback signals 

to the glutamate-producing cells. 

Over the next 72 hours the scientists 

evaluated the rats at regular intervals 

using a technique, called intracranial 

self-stimulation (see “Asking a Rat, 

‘How Do You Feel?’”), that measures 

withdrawal-like depression in laboratory animals. As the scientists had 

predicted, the rats with active mGluII 

receptors exhibited significant discomfort; the withdrawal discomfort rapidly 

33

Dr. Athina Markou and her colleagues used this 

experimental technique, known as intracranial 

self-stimulation, to assess animals’ discomfort 

from nicotine withdrawal and evaluate the role 

of mGluII receptors in withdrawal.
dissipated in those in which mGluII receptors were 

turned off.

To help confirm the association between mGluII receptors and withdrawal-like symptoms, Dr. Markou’s team 

treated nicotine-dependent rats with a compound that 

stimulates the same receptors. In these animals, activation of the inhibitory glutamate loop triggered discomfort 

comparable with that in nicotine withdrawal. 

“Other research has shown how nicotine changes regulation of excitatory glutamate signaling,” Dr. Markou says. 

“Our study helps explain how nicotine also commandeers 

inhibitory glutamate circuits. The altered function of 

the mGluII receptors appears to mediate, at least partly, 

the depression-like aspects of nicotine withdrawal.” The 

effect, she explains, is a carrot-and-stick influence strong 

enough to thwart the most sincere attempts to quit smoking. “Nicotine provides a positive effect through the excitatory circuits, making smoking a rewarding and reinforcing experience. Now we see that nicotine has a similarly 

powerful aversive effect through the inhibitory circuits, 

making withdrawal an unpleasant experience.” 

The role of mGluII receptors in withdrawal suggests that 

these receptors might also offer a target for therapeutic 

intervention, Dr. Markou adds. “Easing the depressionlike aspects of withdrawal would significantly decrease 

discomfort and make it easier for people to maintain 

abstinence and resist the temptation to relapse to smoking.” 

Source:

• Kenny P.J.; Fabrizio, G.; and Markou, A. Group II 

metabotropic and alpha-amino-3-hydroxy-5-methyl4-isoxazole propionate (AMPA)/kainate glutamate 

receptors regulate the deficit in brain reward function 

associated with nicotine withdrawal in rats. Journal of 

Pharmacology and Experimental Therapeutics

306(3):1068-1076, 2003. 

34

Rats that had been exposed to nicotine for 7 days showed 

discomfort 12 hours after withdrawal from nicotine. Rats 

that were injected, at 18 hours into withdrawal, with a 

compound that blocked mGluII receptors showed no increase 

in withdrawal-associated discomfort. (Discomfort measurement technique is described in “Asking a Rat, ‘How Do You 

Feel?’” on the previous page). Untreated rats experienced 

increasing discomfort through 24 hours of withdrawal.
35

Smoking Exposure In Utero Increases Risk of Later Addiction

By Arnold Mann, NIDA NOTES Contributing Writer

Research Findings

Volume 19, Number 4, (December 2004)

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.
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.

36

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.
Early Nicotine Initiation Increases Severity of Addiction, 

Vulnerability to Some Effects of Cocaine

By Patrick Zickler, NIDA NOTES Staff Writer

Research Findings

Volume 19, Number 2 (July 2004)

Most tobacco use begins during adolescence, 

and people who start in their teens are more 

likely to become life-long smokers than are 

those who first light up as adults. Adolescent 

smokers are more likely than adult smokers to become dependent on nicotine. And 

when compared with nonsmoking peers, 

young smokers are more likely to be abusers 

of other drugs: In 2002, the National Survey 

on Drug Use and Health reported that 

roughly half (48.1 percent) of youths aged 

12 to 17 who smoked cigarettes in the past 

month also used an illicit drug, whereas only 

6.2 percent of nonsmoking youths reported 

using an illicit drug in the past month.

These observations suggest that teen smokers 

are especially vulnerable to the physiological effects of nicotine. Two recent NIDAsupported animal studies lend support to this 

interpretation of the epidemiological data. 

The results indicate that smoking may be 

more addictive if it is initiated during adolescence and that early exposure to nicotine may heighten 

response to other addictive drugs. An additional finding 

was that males and females may differ in their susceptibility to these effects.

Early Initiation to Nicotine

Dr. Edward Levin and colleagues at Duke University 

in Durham, North Carolina, investigated whether the 

developmental period during which rats are first exposed 

to nicotine makes a difference in their subsequent drive 

to obtain the drug. One experiment looked at short-term 

effects, the other at long-term effects.

In the first experiment, the researchers showed that adolescent initiation to nicotine produced a greater intensity 

of nicotine taking in the days immediately following exposure than was seen in rats initiated to nicotine in adulthood. The researchers trained eight female adolescent rats 

and seven female adult rats to press a lever to obtain an 

intravenous injection of nicotine. Following this 2-week 

training, the researchers gave the rats, now 54 to 62 days 

old (adolescents) and 84 to 90 days old (adults), free 

access to the lever daily for 1 hour. The nicotine dosage 

delivered with each lever push changed each day, in different order for each rat, but over the 8 days of the study 

every animal had one day each with dosages of 0.01, 0.02, 

0.03, 0.04, 0.05, 0.06, 0.07, or 0.08 mg/kg of its body 

weight. Regardless of dose, the adolescent animals administered more injections each day (average 10.4) than the 

adults (average 7.5).

Dr. Levin and colleagues next demonstrated that this 

greater propensity of adolescent-initiated female rats to 

self-administer nicotine persists into their adulthood.

The researchers trained 13 adolescent and 7 adult rats to 

self-administer nicotine, then tracked their nicotine selfadministration for 4 weeks, during which time the adolescents matured into adulthood. Throughout this period, 

the rats exposed as adolescents pressed the lever for nicotine (at a dose of 0.03 mg/kg) more often than the rats 

initially exposed as adults (10.1 times per session versus 

5.1 times per session).

“At the end of this 4-week period, the adolescent-onset 

rats were at least 82 days old and were themselves adult,” 

says Dr. Levin. “This finding suggests that those who 

begin smoking during adolescence are at greater risk for 

increased smoking over the long term.”

37

Nicotine Infusions

per Session

0

2

4

6

8

10

12

Adult 

Exposure

Adolescent 

Exposure

0.0

0.1

0.2

0.3

0.4

Adult

Exposure

Adolescent

Exposure

Nicotine Amounts Infused

per Session

Number of Infusions 

 mg/kg

Rats Exposed to Nicotine in Adolescence

Self-Administer More Nicotine Than Rats

First Exposed as Adults

Female rats first exposed to nicotine as adolescents self-administered nicotine more 

often and in higher total doses per session than rats first exposed as adults.
These findings are likely to be meaningful for humans 

as well as lab animals, Dr. Levin observes, since human 

brains as well as rat brains continue to develop during 

adolescence. “Self-administration of nicotine during teenage years, when the brain is still developing, may cause 

some of the developmental processes to proceed inappropriately, in effect sculpting the brains of these adolescents 

in ways that facilitate the addiction process.”

Animal self-administration studies have become a standard 

tool in nicotine research, but investigation into a possible 

link between adolescent exposure and severity of addiction 

has been limited and most work has involved male animals, Dr. Levin points out. In humans, there are notable 

differences between adult men and women smokers. Men 

tend to be heavier smokers than women, for example, and 

women report more severe withdrawal symptoms than 

men. It is possible that sex differences also occur in adolescent smoking, Dr. Levin observes. “An animal study that 

uses female rats will more closely model adolescent-onset 

smoking in teenage girls, a group that is showing a rise in 

smoking rates,” he says.

Smoking may be more addictive if it

is initiated during adolescence,

and early exposure to nicotine may 

heighten response to other addictive 

drugs. Males and females may differ 

in their susceptibility to these effects.

“Epidemiological data show that adolescent girls exhibit 

signs of nicotine dependence sooner than adolescent boys. 

Animal studies show that adult females exhibit greater 

motivation to self-administer nicotine than do males,” 

points out Dr. Cora Lee Wetherington, NIDA’s women 

and gender research coordinator. “The growing body 

of evidence on sex differences in response to nicotine 

emphasizes the importance of including females in animal 

models of adolescent nicotine use. Dr. Levin’s plan to follow up these intriguing findings with a parallel study with 

males is particularly important,” she adds.

Sensitization Differs in Males, Females

Repeated exposure to the same dose of an addictive 

drug may result in increasingly more intense behavioral 

response. A dose of cocaine, for example, may elicit more 

activity on the second day of exposure than did the same 

dose a day before. This phenomenon, called sensitization, 

involves drug-induced brain changes that may underlie 

addiction and can be used to identify differences in susceptibility to the effects of drugs.

Dr. Sari Izenwasser and Dr. Stephanie Collins at the 

University of Miami found that female adolescent rats 

show more rapid and pronounced sensitization to behavioral effects of nicotine than adolescent males or adult rats 

of either sex. In addition, when the researchers administered cocaine to adolescent and adult rats previously 

exposed to nicotine, adolescent males, but not adolescent 

females or adults of either sex, exhibited sensitization to 

some effects of cocaine.

The researchers administered nicotine (0.4 mg/kg of body 

weight) daily for 7 days to 20 rats, 5 adolescents and 5 

adults of each sex. After each injection, the animals were 

placed in activity monitors—chambers equipped with 

infrared light beams aimed at detectors on the opposite 

wall—for 60 minutes while the researchers monitored two 

aspects of their behavior. Horizontal locomotion was measured by counting the number of times an animal broke 

light beams. Stereotypy, which involves repetitive actions 

such as head bobbing, was measured by counting repeated 

breaks of the same beam. Adolescent females showed 

increased stereotypy and locomotion in response to nicotine on their second exposure, signifying sensitization, 

which persisted over the 7 days of repeated administration. Adolescent males, in contrast, showed no locomotor 

sensitization to nicotine and no stereotypy sensitization 

until the fourth day of repeated exposures. Adult male and 

female rats showed sensitization (stereotypy and locomotion) after the fifth day of repeated exposures.

On the eighth day of the study, the researchers investigated the extent to which nicotine exposure affected 

sensitization to cocaine. They administered cocaine to all 

the rats in three sequential injections (1, 2, and 7 mg/kg) 

and monitored the animals’ activities for 10 minutes after 

each injection. For females, previous exposure to nicotine 

was associated with cocaine sensitization as evidenced 

by cocaine-induced stereotypy—but not by horizontal 

movement. Adult males that received nicotine exhibited 

sensitization to cocaine’s effect on horizontal movement 

but not stereotypy. Adolescent males exposed to nicotine 

also exhibited greater sensitization than did adult males 

to cocaine’s effect on horizontal movement and were the 

only group to exhibit sensitization in both stereotypy and 

horizontal movement.

“Overall, it appears that sensitization to cocaine is more 

pronounced in adolescent than in adult rats after treatment with nicotine. This suggests that early nicotine use 

may create an increased risk for young people who subsequently use cocaine, and that adolescent males who smoke 

may be particularly vulnerable to the risk of cocaine 

abuse,” Dr. Izenwasser says.

“Animal studies such as these are an important addition 

to a research base that suggests that adolescents show a 

very different responsiveness to nicotine—upon both 

38
acute and chronic or repeated administration—than do adults. The rapid sensitization of adolescent females to nicotine’s 

behavioral effects highlights the need to 

be aware of gender differences in addictive 

processes during adolescence,” observes 

Dr. Minda Lynch of NIDA’s Division of 

Neuroscience and Behavioral Research. 

“Studies such as these also raise important 

questions about vulnerability to nicotine 

addiction and on nicotine’s potential for 

cross-sensitization to other drugs of abuse 

in adulthood or adolescence. And they 

illustrate the importance of studying drug 

effects, and the neurological changes they 

trigger, in the context of the dynamic processes that characterize adolescent 

brain development.”

Sources

• Collins, S.L., and Izenwasser, S. 

Chronic nicotine differentially alters 

cocaine-induced locomotor activity in 

adolescent vs. adult male and female 

rats. Neuropharmacology 46(3):349-

362, 2004.

• Levin, E.D., et al. Adolescent-onset 

nicotine self-administration modeled 

in female rats. Psychopharmacology

169(2):141-149, 2003. 

39

Rats exposed to nicotine in adolescence and then exposed to cocaine were more sensitive 

to cocaine’s locomotor stimulating effects than rats first exposed to nicotine as adults. 

Nicotine-induced presensitization to cocaine was greatest in young male rats.

Dose of Cocaine (mg/kg)

Activity (counts/10 min)*

0

500

1,000

1,500

2,000

2,500

3,000

Saline pretreatment

Nicotine pretreatment

0 1 3 10

Dose of Cocaine (mg/kg)

Activity (counts/10 min)*

Adult Male Rats

0

500

1,000

1,500

2,000

2,500

3,000

Saline pretreatment

Nicotine pretreatment

0 1 3 10

Dose of Cocaine (mg/kg)

Activity (counts/10 min)*

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

Saline pretreatment

Nicotine pretreatment

0 1 3 10

Adolescent Male Rats

Adolescent Female Rats

Dose of Cocaine (mg/kg)

Activity (counts/10 min)*

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

Saline pretreatment

Nicotine pretreatment

0 1 3 10

Adult Female Rats

*Activity level after cocaine administration was measured by counting the number of times in 10 minutes each 

 rat crossed light beams projected in a grid across its cage.

Rats First Exposed to Nicotine in Adolescence

Show Greater Sensitization to Cocaine Than

Rats First Exposed as Adults
Smoking Decreases Key Enzyme Throughout Body

By Patrick Zickler, NIDA NOTES Staff Writer 

Research Findings

Volume 19, Number 1 (April 2004)

Nicotine addiction and tobacco use wreak enormous 

worldwide health consequences, including more than 

400,000 deaths in the United States each year from

tobacco-related diseases. Most of this health toll involves 

disease related to the effects of inhaled smoke on the lungs 

and respiratory system and on the heart and circulatory 

system. However, recent NIDA-supported research has 

demonstrated that a compound found in cigarette smoke 

reduces levels of an important enzyme throughout the 

body—in the spleen, kidneys, and brain as well as the 

lungs. The enzyme, monoamine oxidase B (MAO-B), 

plays a critical role in breaking down neurotransmitters 

and helping to regulate blood pressure. Too much or too 

little of the enzyme can affect mental or physical health.

Dr. Joanna Fowler and colleagues at the Brookhaven 

National Laboratory in Upton, New York, and the State 

University of New York at Stony Brook used positron 

emission tomography (PET) imaging to show reduced 

levels of MAO-B in the kidneys, heart, lungs, and spleen 

of smokers. “When we think about smoking and smoking toxicity, we usually think of the lungs,” Dr. Fowler 

observes. “But here we see a very marked effect of smoking on one of the major enzymes in the body, and we see 

that this effect extends far beyond the lungs.”

In earlier research, the Brookhaven scientists—whose 

research also is supported in part by the Department 

of Energy and the National Institute of Biomedical 

Imaging and Bioengineering—had found decreased levels 

of MAO-B in the brains of smokers. “Because smoking 

exposes the entire body to the tobacco compounds that 

inhibit MAO-B, we believed it had the potential to limit 

MAO-B activity elsewhere in the body,” Dr. Fowler says.

The study involved 10 men and 2 women (average age 41 

years) who had been smoking for an average of 21 years. 

Each participant underwent PET scanning of his or her 

torso after receiving injections of radioactive MAO-B 

tracers. When the researchers compared these scans with 

scans previously performed on nonsmokers, they found 

that MAO-B distribution in the heart, lungs, kidneys, and 

spleen of smokers was 33 to 46 percent lower than levels 

seen in nonsmokers.

The reduction in MAO-B levels is not due to nicotine, 

but to an unidentified component of tobacco smoke—one 

of roughly 4,000 chemicals to which smokers are exposed 

with each puff. “With the whole body exposed to the 

thousands of compounds in tobacco smoke, we need to

be aware that these may contribute to the physiological 

effects of smoking,” Dr. Fowler adds.

“Nicotine establishes the addiction, and continuous smoking maintains levels of all these compounds throughout 

the body,” Dr. Fowler says. “The health consequences of 

reduced MAO-B levels in the organs are unclear. There 

may be adverse effects that are indirect and associated with 

the dietary substances or environmental compounds normally broken down by the enzyme. At the very least, however, it is clear that enzyme levels in smokers’ peripheral 

organs are significantly affected by their tobacco use.”

Source

• Fowler, J.S., et al. Low monoamine oxidase B in 

peripheral organs of smokers. Proceedings of the 

National Academy of Sciences 100(20):11600-11605, 

2003. 

40

Smoking Decreases Enzyme in 

Peripheral Organs of Smokers

PET scans compare the distribution of the enzyme 

MAO-B in a nonsmoker and smoker. Circled areas 

indicate the highest MAO-B concentrations, areas captured in squares show intermediate levels, and areas 

with the lowest concentrations are unmarked. The 

smoker has lower MAO-B concentrations in peripheral 

organs than the nonsmoker.
The Neurobehavioral Legacy of Prenatal Tobacco Exposure

By Jill Schlabig Williams, NIDA NOTES Contributing Writer 

Research Findings

Volume 18, Number 6 (February 2004)

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 

41

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.

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
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 

42

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 dose-related: 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.
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 neurobehavioral 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. 

43
Hard-to-Treat Smokers May Benefit From Medication

That Acts on Dopamine

By Patrick Zickler, NIDA NOTES Staff Writer 

Research Findings

Volume 18, Number 5 (December 2003)

Nearly 23 percent of Americans 18 and older smoke

cigarettes. Although this figure represents a substantial 

decrease since smoking rates were at their highest in

1965, most current smokers say they would like to 

quit. According to the Centers for Disease Control and 

Prevention, 71 percent of smokers interviewed in 2000 

said they wanted to quit smoking, with 41 percent having 

tried to quit in the preceding year.

Many of those who still smoke are the hardest to treat, 

having failed to stop despite numerous attempts. Their 

efforts to quit are frustrated by nicotine’s addictive effects, 

which result in large part from the drug’s ability to trigger 

and sustain release of the pleasure-producing neurotransmitter dopamine in the brain. At Yale University in New 

Haven, Connecticut, NIDA-supported researchers have 

found that selegiline, a medication currently used by physicians primarily to delay the progression of symptoms in 

Parkinson’s disease, can help smokers who want to quit 

but have been unsuccessful with other treatments.

“Our research group focused on difficult-to-treat smokers, 

who aren’t responsive to nicotine replacement therapy or 

to bupropion,” says Dr. Tony George of Yale University 

School of Medicine. “Many smokers who attempt to quit 

fail because of the powerful withdrawal symptoms smokers experience when they stop smoking. There is strong 

evidence that the symptoms of nicotine withdrawal are 

associated with sharp declines in dopamine levels, so we 

thought a medication that acts to boost dopamine levels might be of benefit.” In Parkinson’s disease, which 

involves massive loss of dopamine-producing cells, treatment with selegiline helps the brain retain its stores of 

dopamine longer by inhibiting the activity of monoamine 

oxidase-B, an enzyme that breaks down dopamine.

To evaluate the effect of selegiline in smoking cessation treatment, the researchers recruited 40 smokers (75 

percent Caucasian, 15 men, 25 women, average age 49) 

who had unsuccessfully tried (at least 3 times and some 

as many as 20) to stop smoking and described themselves 

as highly motivated to quit. Over 8 weeks, all participants 

received weekly smoking cessation counseling that included motivational enhancement for the first 3 weeks of the 

study and work on relapse prevention strategies for the 

last 5 weeks. They took pills containing either placebo or 

5 mg selegiline once a day for the first week and twice a 

day for the remaining 7 weeks. Twenty participants (8 

men, 12 women) received selegiline and 20 (7 men, 13 

women) received placebo. All participants were allowed to 

smoke during the first 2 weeks of the study, and a “quit 

date”was set for the first day of the third week.

At the end of the eighth week, 45 percent of the participants who received selegiline reported they had not 

smoked during the preceding week, compared with 15 

percent of those receiving placebo. Measurement of carbon monoxide levels in the participants’ exhaled breath 

verified their self-reports. The difference between the two 

treatment groups was even more pronounced when reports of 4-week abstinence were considered: Compared 

with 5 percent of the placebo group, 30 percent of those 

who received selegiline reported they had not smoked 

in the last 4 weeks of the study. Six weeks after the 

study ended, 20 percent of the selegiline group were 

still not smoking, compared with 5 percent of those 

who received placebo.

“In this study, selegiline appeared to substantially improve 

outcomes for smokers who have had a difficult time 

stopping,” says Dr. Ivan Montoya of NIDA’s Division 

of Treatment Research and Development. “The results, 

44

Selegiline Helps Smokers Quit, 

Remain Abstinent Longer 

Smoking Abstinence Rate

45

0

10

20

30

40

50%

Placebo

Selegiline

6-Month 

Followup

End of 

Study

Last 4 Weeks

 of Study

Period When Abstinence Reported

15

30

5

15

5

Smokers who received selegiline plus counseling

were more likely to stop smoking and remain 

abstinent than smokers who received placebo

and counseling.
which are better than those typically achieved by smokers using nicotine replacement therapy to help them quit, 

offer strong confirmation that controlling the dopamine 

system could be an important approach to successful 

treatment of nicotine addiction, particularly for smokers 

with a history of unsuccessful quit attempts. Our next 

step is to confirm this in a much larger trial with several 

hundred smokers.”

Source 

• George, T.P., et al. A preliminary placebo-controlled 

trial of selegiline hydrochloride for smoking cessation. 

Biological Psychiatry 53(2):136-143, 2003. 

45
Research Findings

46

Discovering, Developing, and Delivering Smoking Cessation 

Medications Is Focus of NIDA Symposium

By Patrick Zickler, NIDA NOTES Staff Writer

Volume 18, Number 3 (October 2003)

NIDA, joined by the 

National Cancer Institute 

(NCI) and the National 

Institute on Alcohol Abuse 

and Alcoholism (NIAAA), 

sponsored a symposium 

on drug discovery, development, and delivery as 

part of the 2003 Annual 

Meeting of the Society for 

Research on Nicotine and 

Tobacco. More than 300 

researchers, treatment providers, and policymakers 

attended the 1-day meeting on February 9 in New 

Orleans. The symposium 

featured discussions of 

current efforts to discover 

new targets for potential medications, the development 

of medications based on existing knowledge of nicotine’s 

effects in the brain, and factors that might speed the delivery of new treatments to smokers who want to quit.

During the discovery section of the program, speakers discussed recent findings in nicotine receptor biology and the 

role of neurotransmitters, such as gamma-aminobutyric 

acid (GABA) and glutamate, in nicotine’s effects on the 

brain. The presentations on medication development 

provided a background on the drug development process; emerging medications, such as antidepressants and 

nicotine vaccines; and an overview of medications now 

in development. The delivery portion of the symposium 

focused on strategies to create widespread medication 

access and use by individual smokers and within the 

health care system.

Discovery. Dr. William Corrigall, director of NIDA’s 

Nicotine and Tobacco Addiction Program and symposium moderator, described the neurobiological targets of 

current research: genes and gene products that play a role 

in the structure and response of nicotinic receptors and 

in brain signaling pathways that involve the neurotransmitters dopamine, GABA, serotonin, and glutamate. 

Dr. Caryn Lerman, of the University of Pennsylvania in 

Philadelphia, further explored the genetic factor in nicotine research, describing studies on the effect of genetic 

variations on the activity 

of enzymes that metabolize nicotine (see “Genetic 

Variation May Increase 

Nicotine Craving and 

Smoking Relapse.”)

Dr. Marina Picciotto, of 

Yale University in New 

Haven, Connecticut, discussed research that has 

expanded our understanding of the role of nicotine 

receptors—the sites at 

which nicotine attaches 

to brain cells. This portion of the program also 

featured discussions of the 

possibility that neurotransmitters other than dopamine might represent new avenues for pharmacotherapy. 

For example, Dr. Julie Staley, also of Yale University, 

described current investigations into the treatment possibilities represented by medications known to act on the 

serotonin system. The GABA neurotransmitter system, 

which normally acts to limit dopamine’s effect in the 

brain’s pleasure center, might also help in smoking cessation treatment, according to Dr. George McGehee of 

the University of Chicago. He discussed the mechanism 

by which nicotine simultaneously stimulates dopamine 

release and depresses the effect of GABA. 

Development. Dr. Frank Vocci, director of NIDA’s 

Division of Treatment Research and Development, 

described the steps involved in the development of new 

medications and their approval by the Food and Drug 

Administration (FDA)—a process that may require a 

decade of research and testing, at a cost as high as $500 

million per medication. Accelerating the process at 

any stage, from basic research to human clinical trials, 

will speed the availability of new treatments. Dr. John 

Hughes, of the University of Vermont in Burlington, 

suggested that psychiatric medications already approved 

for treating neurochemical imbalances in the brain might 

hold clues for developing medications to treat the neurochemical effects of smoking.

Nicotiana tobacum—

Tobacco 

Growing Area:

North, Central, and South America

Active Component: Nicotine

Annual U.S. Deaths From SmokingRelated Causes: Nearly 450,000

Annual U.S. Health-Related Economic 

Costs: More Than $150 Billion*

*CDC, Morbidity and Mortality Weekly Report, 2002.
47

Dr. Charles Grudzinskas, of 

Georgetown University Medical 

Center in Washington, D.C., summarized potential medications now 

in FDA Phase I, II, or III trials. 

These medications include additional nicotine replacement therapies and nicotine vaccines. Dr. Paul 

Pentel of the Hennepin County 

Medical Center in Minneapolis, 

Minnesota, described progress in 

the development of one type of 

nicotine vaccine—antibodies that 

bind to nicotine in the blood, preventing it from crossing the bloodbrain barrier and reaching the areas 

of the brain that underlie addiction. 

Vaccines may be particularly effective as relapse-prevention medications for smokers who are trying to 

remain abstinent.

Delivery. Dr. Scott Leischow, chief 

of NCI’s Tobacco Control Research 

Branch, discussed barriers to 

delivery and utilization of current 

tobacco cessation treatments. These 

include the high relapse rate associated with current treatments and 

the cost and “hassle” factor that deter patients from using 

nicotine replacement therapy, which they contrast to the 

simplicity of nicotine delivery by cigarettes. To address 

barriers to use, Dr. Saul Shiffman of the University of 

Pittsburgh discussed strategies that might increase utilization of existing treatments, including regulatory changes 

that make cigarettes more expensive and increased advertising and education to encourage more smokers to try 

to quit.

Providers and insurers also need to address barriers within 

their control, noted several speakers. Dr. Richard Hurt,

of the Mayo Clinic’s Nicotine Dependence Center in 

Minneapolis, Minnesota, discussed the limitations of 

current clinical treatment. He noted that relatively few 

medications are available, clinicians are not familiar 

with them, and patients are reluctant to begin treatment 

because of embarrassment, inadequate relief from withdrawal, and the difficulty of complying with instructions 

for use of gum, inhalers, or nasal sprays. Dr. Susan Curry 

of the University of Illinois at Chicago suggested steps 

that insurers and health care organizations could take to 

improve the delivery, utilization, and effectiveness of treatment. For example, she said, health care systems should 

adopt a chronic disease model to treat smoking, and insurers should include the cost of medications in coverage that 

provides comprehensive pharmacological and behavioral 

treatment.

In concluding remarks, Dr. Corrigall noted that the 

enthusiastic response to the day-long discussion illustrates 

broad support for steps that will increase and accelerate 

available treatment options for smokers. “Clinicians and 

patients need better treatment options, and this symposium represents a significant first step in a collaboration 

that can help speed the process of getting new and more 

effective medications to smokers who want to quit.”

Chronic Care Model

Informed,

Activated

Patient

Productive

Interactions

Prepared,

Proactive

Practice Team

Functional and Clinical Outcomes

Delivery

System

Design

Decision

 Support

Clinical

Information

Systems

SelfManagement

Support

Health System

Resources and

 Policies

Community Health Care Organization

At the 2003 meeting of the Society for Research on Nicotine and Tobacco, Dr. Susan Curry

discussed use of a chronic care model to improve the delivery, utilization, and effectiveness 

of tobacco cessation treatment. This approach draws on the community—of which the 

health system is a part—to help patients and their practitioners effectively work toward 

desired health goals.
Research Findings

48

Genetic Variation May Increase Nicotine Craving and

Smoking Relapse

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 18, Number 3 (October 2003)

Smokers who want to quit can get 

help with a variety of treatments, 

including counseling, nicotine 

replacement therapy (patches, 

gum, lozenges, or inhalers), and 

medications. Some smokers use 

these treatments and succeed; for 

many, however, the discomfort of 

withdrawal and craving for nicotine 

lead to relapse. Recent NIDAfunded research suggests that 

our genes may partly explain this 

variable success.

The research evaluated the effect 

of an enzyme, designated CYP2B6, 

on craving and relapse. This 

enzyme breaks down nicotine in 

the brain. Some people’s genes 

produce a more active form of the 

enzyme, while others have a less 

active form. Dr. Caryn Lerman at 

the NIDA- and NCI-supported 

Transdisciplinary Tobacco Use 

Research Center (TTURC) at the 

University of Pennsylvania found 

that among smokers enrolled in a 

smoking cessation program, those with the genetic variant 

that decreases activity of CYP2B6 reported greater craving 

than did those with the more active form of the enzyme. 

Moreover, those with the less active enzyme were 1.5 

times more likely to resume smoking during treatment.

The same enzyme helps break down bupropion, an antidepressant medication that acts on the brain’s dopamine 

system—where nicotine exerts much of its addictive influence—and helps some smokers quit. Dr. Lerman, along 

with colleagues at Georgetown University in Washington, 

D.C., the State University of New York at Buffalo, and 

Brown University in Providence, Rhode Island, also investigated the relationship of CYP2B6 activity with bupropion treatment. They found that bupropion nearly tripled 

the success rate for women with the less active enzyme.

“These findings provide initial evidence that smokers who 

have decreased CYP2B6 activity experience greater craving 

for nicotine than those with the more active form of this 

enzyme,” Dr. Lerman says. “Perhaps of greater interest is 

the preliminary evidence that, among women, bupropion 

may overcome the effect this genetic predisposition has 

on relapse.”

Genes, Treatment, and Abstinence

Most people—about 70 percent of the U.S. population—

inherit two copies of the “C” variant of the gene that 

influences CYP2B6 activity. The rest of the population 

inherits from one or both parents the less common form 

of the gene—the “T” variant associated with decreased 

CYP2B6 activity. Among the 426 participants (232 men, 

194 women) in the TTURC study, 128 (29.6 percent) 

had one or two copies of the T form of the gene. All 

participants received counseling to quit smoking; 229 

received bupropion (300 mg/day) and 197 received placebo throughout the 10-week study. The participants 

provided weekly reports on craving and smoking rates. 

Abstinence (7 consecutive days without smoking) was 

Genetically Determined Enzyme Level Affects 

Treatment Response

0

10

20

30

40

50

60

70% Men Women

Abstinence Rates

Counseling 

+ placebo Counseling 

+ bupropion

Counseling 

+ placebo

38 42

19

56 54

64

38

50

Smokers with less active enzyme Smokers with more active enzyme

Counseling 

+ bupropion

In a study of 426 smokers in a 10-week smoking cessation program, those with a gene form 

that decreases activity of an enzyme that metabolizes nicotine reported greater craving and were 

less likely to achieve abstinence during treatment than were participants with the gene form 

that increases the enzyme’s activity. Supplementing counseling with bupropion helped women 

with the less active enzyme nearly triple their abstinence rate to 54 percent—roughly equal that 

of women with the more active enzyme.
49

verified with blood tests. At the end of treatment, participants who received counseling and bupropion had 

higher abstinence rates than those who received counseling and placebo. With one exception, participants with 

the less active enzyme had lower abstinence rates than 

those with the more active enzyme. Women with the less 

active enzyme who received bupropion showed the largest treatment effect, with 54 percent achieving abstinence, 

up from a 19-percent rate among women in the placebo 

group, notes Dr. Lerman.

This study suggests that properly 

selected treatment matched to a 

patient’s characteristics can improve 

a smoker’s chance of quitting.

Theories To Explain Outcomes

The higher abstinence rate with bupropion for women 

with the lower activity enzyme may be due, in part, to 

reduced susceptibility to low moods that accompany nicotine withdrawal; overall, women reported more negative 

feelings than did men when asked to rate their mood during withdrawal. “This rate may reflect better management 

of the negative moods and craving that abstinence can

create. But more study is needed to clarify the mechanisms by which bupropion influences smokers’ success

in quitting,” Dr. Lerman says.

Researchers theorize that the association between the less 

active enzyme and increased craving could be the result of 

nicotine’s remaining longer in the brains of smokers with 

the less active enzyme. When nicotine lingers in the brains 

of these smokers, it may change their brain cells more

profoundly than those of smokers with the more active 

enzyme. If so, the changes might produce more severe 

addiction marked by more intense craving during abstinence and increased risk of relapse.

“This study offers additional evidence of the important 

role genes play in smoking and treatment,” says Dr.

Joni Rutter of NIDA’s Division of Neuroscience and 

Behavioral Research. “While illustrating the increased 

craving and vulnerability to relapse that may be associated 

with inherited traits, it also suggests that properly selected 

treatment matched to a patient’s characteristics—in this 

case, bupropion for some women—can improve a smoker’s 

chance of quitting.”

Source

• Lerman, C., et al. Pharmacogenetic investigation of 

smoking cessation treatment. Pharmacogenetics

12(8):627-634, 2002. 
Research Findings

50

Alternative Cigarettes May Deliver More Nicotine Than 

Conventional Cigarettes

By Susan Farrer, NIDA NOTES Contributing Writer 

Volume 18, Number 2 (August 2003)

Clove cigarettes, bidis, 

and additive-free cigarettes deliver at least 

as much nicotine as 

conventional cigarettes, 

suggests recent research 

conducted by NIDA 

Intramural Research 

Program (IRP) investigators in Baltimore. 

Smokers who choose 

these cigarettes are 

as likely to become 

addicted to nicotine as 

are other smokers and 

are exposing themselves 

to the increased risk of 

cancers, respiratory

disease, and heart 

disease associated 

with smoking.

Dr. Wallace Pickworth 

and his IRP colleagues 

conducted two studies 

comparing the effects of smoking clove cigarettes, bidis, 

and additive-free cigarettes with the effects of smoking 

conventional filtered cigarettes as part of an ongoing IRP 

program that examines nicotine delivery of alternative cigarettes. Their findings refute some consumers’ belief that 

alternative tobacco products—sold on the Internet and at 

health food stores, ethnic groceries, and drug paraphernalia shops—are safer than conventional cigarettes.

Effects of Smoking Clove Cigarettes

In the clove cigarette study, the IRP investigators analyzed 

the physical composition of a particular clove cigarette 

brand and conventional cigarettes and measured the nicotine, tar, and carbon monoxide (CO) delivery of the clove 

cigarette. They also conducted a small-sample clinical 

study comparing the nicotine delivery and physiologic

and subjective effects of smoking clove cigarettes and

conventional cigarettes.

In the nonclinical portion of the study, the investigators removed, weighed, and chemically analyzed the 

contents of 10 clove cigarettes and 10 each of 4 popular 

conventional cigarette 

brands. To measure 

how much nicotine, 

tar, and CO the clove 

cigarette delivered, they 

used machine-smoking 

methods based on

those developed by

the Federal Trade 

Commission. Analysis 

showed that the clove 

cigarette contained less 

nicotine and tobacco, 

but the smokingmachine analysis 

revealed that the clove 

product delivered more 

nicotine, tar, and CO 

than did the conventional cigarettes. The 

researchers attribute the 

clove cigarette’s higher 

delivery of toxins to the 

lower porosity of its 

paper wrapper and its 

lack of filter ventilation holes, which are found on most 

ordinary cigarettes and dilute the smoke inhaled with 

each puff.

In the clinical part of the study, 10 volunteers (7 men 

and 3 women) were asked to smoke a clove cigarette and 

a filtered conventional cigarette of their usual brand. The 

volunteers, whose mean age was 30.3 years, smoked an 

average of 21.3 cigarettes a day and had been smoking for 

an average of 13.4 years. Four of the volunteers had previously smoked clove cigarettes and all had smoked bidis in 

the past.

After the volunteers smoked the clove or conventional 

cigarette, the researchers measured their plasma nicotine 

levels, exhaled CO levels, blood pressure, and heart rates. 

They also recorded the time and number of puffs taken to 

smoke each cigarette, and the volunteers rated their satisfaction with smoking each cigarette and its sensory effects.

The researchers found comparable increases in the volunteers’ plasma nicotine levels, exhaled CO levels, heart 

rates, and systolic blood pressure after smoking the clove 

Bidi makers rolling tobacco into tendu leaves, a wrapping that has less porosity than that of conventional cigarettes and that lacks the filter ventilation 

holes seen in filtered brands. Despite having less nicotine, bidis deliver as 

much—or more—nicotine as conventional cigarettes. 
51

and conventional cigarettes. However, the volunteers took 

longer and more frequent puffs of the clove cigarette than 

of their own cigarette brands (mean of 549 seconds and 

15.1 puffs for the clove cigarette versus 314 seconds and 

9.4 puffs for their own brands). This change in smoking 

behavior increases the amount of nicotine extracted from 

each cigarette, making it possible for smokers to achieve 

comparable blood concentrations of nicotine, even though 

clove cigarettes contain less of the drug per cigarette than 

do conventional brands.

Effects of Smoking Bidis and Additive-Free Cigarettes

In a related study, Dr. Pickworth and his colleagues compared the clinical effects of smoking bidis, additive-free 

cigarettes, and conventional cigarettes. As in the clove 

cigarette study, this research involved 10 volunteers (9 

men and 1 woman), all of whom had a history of smoking 

bidis. However, the volunteers’ average age was younger 

(24.5 years) and they smoked more per day (25 cigarettes) 

than participants in the clove cigarette study, although 

they had smoked for fewer years (8.7 years).

In each of four separate sessions, each volunteer smoked

a single cigarette: an unfiltered, additive-free cigarette; 

a strawberry-flavored bidi; an unflavored bidi; and one 

of the subject’s usual, filtered cigarettes. The researchers 

made the same analytical and physiological measurements 

and gathered the same behavioral information as they did 

in the clove cigarette study.

The analysis showed that 2 minutes after smoking, plasma 

nicotine levels increased the most for participants who 

had smoked the additive-free brand, followed by levels for 

smokers of the strawberry bidi, the unflavored bidi, and 

the conventional cigarette. The volunteers’ average heart 

rate also increased significantly for all of the cigarettes, 

with the greatest difference (8.5 beats per minute) seen 

after smoking the additive-free brand and the least difference (2.5 beats per minute) after smoking their own 

brand. The volunteers spent more time smoking the additive-free cigarette and unflavored bidi (mean of 453 seconds, and 354 seconds, respectively) than the strawberry 

bidi or their own brands (322 seconds and 297 seconds, 

respectively). They also took more puffs to smoke any of 

the bidis and additive-free cigarettes (approximately 14 

puffs each) than to smoke their own brand (10 puffs).

Like clove cigarettes, the additive-free cigarette and bidis 

delivered more nicotine than did conventional cigarettes. 

Although both the flavored and unflavored bidis are 

smaller and contain less tobacco than conventional cigarettes, the bidis raised plasma nicotine to levels equal to or 

greater than the volunteers’ own brands. The researchers 

theorize that like the thicker clove cigarette wrappers, the 

bidis’ nonporous wrappers limit air dilution.

Not Safe Products

The NIDA scientists conclude that clove cigarettes, bidis, 

and additive-free cigarettes are not safe products and may 

be as harmful as conventional cigarettes. “Even though 

the bidis and the clove cigarettes have less nicotine in the 

cigarette rod—in the case of the bidis about one-third and 

in the case of the clove cigarettes about one-half or less—

people are still able to extract about the same or even 

more nicotine than they would from a conventional

cigarette,” says Dr. Pickworth. “When individuals smoke 

Alternative Cigarettes and Young 

Smokers

Clove cigarettes, made in Indonesia and exported 

worldwide, are composed of 60 to 80 percent tobacco 

and 20 to 40 percent ground clove buds. They are 

usually machine rolled, are available with or without 

filters, and usually are sold in brightly colored packages. 

Clove cigarettes are sometimes referred to as “trainer 

cigarettes” and may serve as “gateway” products that 

introduce young people to smoking. The Monitoring 

the Future (MTF) survey, conducted by the University 

of Michigan’s Institute for Social Research and funded 

by NIDA, tracks 8th-, 10th-, and 12th-graders’ drug use, 

including use of tobacco products. In 2002, prevalence 

of clove cigarette smoking in the past year was 2.6 percent for 8th-graders, 4.9 percent for 10th-graders, and 

8.4 percent for 12th-graders. 

Bidis are small, brown, hand-rolled cigarettes that are 

made primarily in India and other South Asian countries. They are available in many flavors, such as chocolate, raspberry, and strawberry, making them appealing 

to adolescent smokers. The 2002 MTF survey reported 

that 2.7 percent of 8th-graders had smoked bidis in 

the past year; figures for 10th- and 12th-graders were 

3.1 percent and 5.9 percent, respectively. In some 

geographic areas, rates are even higher. For example, 

a 1999 study by the Massachusetts Tobacco Control 

Program found that 16 percent of students in grades 7 

through 12 in one large metropolitan area had smoked 

bidis in the 30 days prior to the study.

Additive-free cigarettes are made with whole-leaf 

tobacco and contain no chemical additives, preservatives, or reconstituted tobacco. IRP researchers report 

that many adolescents—and adults— believe that 

additive-free cigarettes are less harmful or less addictive 

than ordinary cigarettes, although scientific evidence 

contradicts that belief. 
52

these novel cigarettes, they adjust their cigarette smoking behavior to achieve plasma levels of nicotine comparable to those attained by smoking their own brands 

of cigarette. By that standard, they are at least equally 

dependence-producing. As a consequence, smokers will 

increase their smoking as dependence increases, exposing 

themselves to ever-greater smoking-related health risks.”

Sources

• Malson, J.L.; Lee, E.M.; Moolchan, E.T.; and 

Pickworth, W.B. Nicotine delivery from smoking 

bidis and an additive-free cigarette. Nicotine and 

Tobacco Research 4(4):485-490, 2002.

• Malson, J.L.; Lee, E.M.; Murty, R.; Moolchan, 

E.T.; and Pickworth, W.B. Clove cigarette smoking: 

Biochemical, physiological, and subjective effects. 

Pharmacology Biochemistry and Behavior 74(3):739-

745, 2003.

• Malson, J.L.; Sims, K.; Murty, R.; and Pickworth, 

W.B. Comparison of the nicotine content of tobacco 

used in bidis and conventional cigarettes. Tobacco 

Control 10(2):181-183, 2001.
Research Findings

53

Manipulating Dopamine Levels Changes Smoking Behavior

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 18, Number 1 (June 2003)

NIDA-supported researchers have 

demonstrated that lowering and 

raising the concentration of dopamine in the brain changes smoking 

behavior and nicotine intake in 

smokers. After taking a chemical 

compound that blocks release of 

dopamine to the brain’s pleasure 

center, smokers lit up sooner and 

smoked more cigarettes than 

they did after taking a compound 

that stimulates dopamine release.

Nicotine triggers the release of 

dopamine in the brain, and the 

pleasurable sensations that result

are thought to be a driving force

in establishing addiction. Animal 

studies, in which brain cells can 

be carefully analyzed after nicotine 

administration, confirm the link 

between dopamine and addictive 

behavior. This study demonstrates 

that in humans, an individual’s smoking behavior can be 

manipulated by stimulating or blocking dopamine release.

Dr. Nicholas Caskey and his colleagues at the University of 

California at Los Angeles (UCLA) and the Veterans Affairs 

West Los Angeles Healthcare Center monitored

the smoking behavior of heavy smokers who received

oral doses of either haloperidol or bromocriptine.

“Our study was designed to use these compounds to 

decrease or increase availability of dopamine in a single 

group of otherwise healthy smokers and evaluate the

effect on smoking behavior,” explains Dr. Caskey.

Haloperidol is used to treat some psychiatric disorders, 

and earlier studies found that patients with schizophrenia 

smoked more during treatment with haloperidol than when 

they were not taking the antipsychotic medication. Other 

studies have shown decreased smoking and craving for 

nicotine among smokers who received bromocriptine 

(used to treat Parkinson’s disease and disorders of the 

pituitary gland).

Participants in the study (14 men, 6 women, average age 30 

years) smoked 15 or more cigarettes per day for at least 2 

years. On average, they had been smoking more than

12 years and smoked 20 cigarettes per day at the time of 

the study. All participants received both haloperidol and 

bromocriptine over the course of the study, which consisted 

of two 5-hour sessions spaced roughly a week apart. In their 

first session, the participants received an oral dose of either 

2.0 mg haloperidol or 2.5 mg bromocriptine; in their second session, the participants received the other drug. Over 

the next 5 hours, the participants were allowed to smoke 

their preferred brand of cigarettes at will, using a cigarette 

holder linked to a device that measured characteristics of 

each puff. They also answered questions about craving and 

discomfort.

With haloperidol, participants smoked more cigarettes (in 

total, three cigarettes) per session and smoked them faster 

(44.8 total puffs, or roughly 15 puffs per cigarette) than 

they did with bromocriptine (2.3 cigarettes, with 13.5 puffs 

per cigarette). Participants also reported greater craving with 

haloperidol (4.5 on a 1-7 scale) than with bromocriptine 

(3.8). “These results show that smoking behavior can be 

manipulated within the same subjects by alternately blocking and stimulating dopamine and indicates the importance 

of dopamine in smoking,” Dr. Caskey says.

Smoking Behavior Changes With Decrease or 

Increase of Dopamine

Smokers who received haloperidol, a dopamine antagonist, smoked more cigarettes during a

5-hour period and took more puffs per cigarette than did smokers who received bromocriptine, 

which enhances dopamine’s effects.

Haloperidol Bromocriptine

(inhibits dopamine) (enhances dopamine)

Total number of 

cigarettes smoked 3.0 2.3

Total puffing time

(seconds) 77.6 52.0

Number of puffs taken 44.8 31.1

Time between 

cigarettes (minutes) 32.1 41.2
54

There currently are no human trials investigating the 

effectiveness of bromocriptine treatment as part of smoking cessation therapy, but NIDA-supported investigations 

of selegiline, another medication that acts on the dopamine system, are under way. “There are very few studies 

that look at the effect of dopamine on smoking in subjects 

who don’t also suffer psychiatric disorders,” observes Dr. 

Allison Chausmer of NIDA’s Division of Neuroscience 

and Behavioral Research. “The findings in this study, 

particularly the results seen for bromocriptine, offer additional support for investigating potential medications that 

help control smoking by acting on the dopamine system.”

Source

• Caskey, N.H., et al. Modulating tobacco smoking 

rates by dopaminergic stimulation and blockade. 

Nicotine & Tobacco Research 4(3):259-266, 2002. 
Research Findings

55

Nicotine’s Multiple Effects on the Brain’s Reward System

Drive Addiction

By Patrick Zickler, NIDA NOTES Staff Writer

Volume 17, Number 6 (March 2003)

NIDA researchers have 

added another piece to 

the puzzle of what makes 

nicotine so addictive. 

Dr. Daniel McGehee 

and colleagues at the 

University of Chicago 

have shown that along 

with directly stimulating 

the brain’s reward system, 

nicotine also stimulates it 

indirectly by altering the 

balance of inputs from 

two types of neurons that 

help regulate its activity level. This additional 

stimulation intensifies the 

pleasure from smoking 

and makes it last longer.

Scientists have long 

known that nicotine, like 

other addictive drugs, 

attaches to the core 

neurons of the brain’s 

reward system, where 

beneficial behaviors (such 

as drinking water when 

thirsty) are rewarded and 

reinforced. Situated in a 

region of the brain called 

the ventral tegmental area 

(VTA), these rewardsystem neurons, called 

dopaminergic neurons, 

trigger release of the neurotransmitter dopamine 

(DA) in a nearby brain 

region called the nucleus accumbens (NAc). When nicotine attaches to these neurons they increase their activity, flooding the NAc with dopamine, which produces 

pleasure and a disposition to repeat the behaviors that led 

to it. That pleasure and disposition drive the process of 

addiction.

In the new research, Dr. McGehee’s team followed up 

on a clue that nicotine attachment to the DA neurons in 

the VTA accounts for 

only part of the drug’s 

pleasure-producing and 

ultimately addictive 

effect: Nicotine attachment stimulates the DA 

neurons for only a few 

minutes at most, yet 

dopamine levels in the 

NAc remain elevated for 

much longer.

To explain this discrepancy, the researchers studied nicotine’s 

impact on two other 

types of neurons that 

affect dopamine levels. 

These neurons produce 

neurotransmitters, called 

glutamate and GABA, 

that act as fundamental 

pacemakers throughout 

the brain. Once released 

by its producing neuron, 

glutamate attaches to 

other neurons, including the DA neurons in 

the VTA, and stimulates 

them to speed up their 

activities. GABA has the 

opposite effect: It slows 

neurons down.

The researchers hypothesized that nicotine might 

act on these pacemaker 

neurons so as to increase 

the ratio of glutamate to GABA in the VTA. If the amount 

of glutamate acting on DA cells were to increase while the 

amount of GABA remained the same or decreased, the 

result would favor high levels of dopamine in the NAc.

If the glutamate-GABA imbalance were long-lasting, it 

would explain why dopamine levels in the NAc remain

elevated even after nicotine stops directly affecting the 

dopamine-producing neurons.

Nicotine’s Double Effect on

Dopamine Release

Relative Activity

(unstimulated condition=100%) DA

GABA

Glu

To NAc

GABA

400% Glu

300

200

100

0

-2 0 2 4 6 8 10

DA

GABA

Glu

To NAc

Time (minutes)

Nic

Nic

Nicotine (Nic) directly stimulates (+) 

neurons in the ventral tegmental 

area (VTA) to release dopamine (DA)

in the nucleus accumbens (NAc). 

Nic also stimulates release of 

glutamate (Glu), triggering additional 

DA release. VTA cells stimulate release 

of GABA to moderate DA’s effect. 

Minutes later, Glu cells continue to 

stimulate DA release (++), but release 

of GABA becomes inhibited (-), 

resulting in sustained high dopamine 

levels in the NAc. 

The increase in the VTA's glutamate-to-GABA ratio lasts for more than 

1 hour after a single exposure to nicotine, prolonging and intensifying 

the drug’s pleasurable effects. 

Exposure to nicotine has direct and indirect effects on dopamine release 

in the brain’s reward center, the nucleus accumbens. 
56

To test their hypothesis, Dr. 

McGehee and his colleagues 

exposed rat VTA cells to nicotine for 10 minutes—roughly 

the time it takes a person to 

smoke a single cigarette. By 

measuring electrical properties 

of the brain tissue, they found 

that nicotine affected both 

pacemaker neurons. In glutamate-producing cells, the brief 

nicotine application induced 

a condition known as long-term potentiation, which 

promotes high-level activity for an extended time. When 

they evaluated the effect on GABA-producing cells, the 

researchers found that after an initial increase in GABA 

transmission lasting only a few minutes, GABA transmission decreased and did not recover fully for more than an 

hour after nicotine exposure ended. Overall, the result was 

what the researchers hypothesized: a sustained increase in 

the VTA’s glutamate-to-GABA ratio.

“A brief application of nicotine can induce a lasting effect 

on excitatory [glutamate] signals to the brain’s reward 

system,” summarizes Dr. McGehee. “This suggests that 

in humans a relatively short nicotine exposure, even for 

someone who has never smoked before, can cause longlasting changes in excitatory neurotransmission. It may 

be an important early step in the process that results in 

addiction.”

“The combination of effects—

increasing dopamine release 

and decreasing the inhibitory 

[GABA] response—results in 

an amplification of the rewarding properties of nicotine,” 

explains Dr. McGehee. “It 

would be difficult to design 

a better drug to promote 

addiction.”

“Understanding these mechanisms is an important step in 

explaining how a brief exposure to nicotine results in the 

long-term excitation of the brain’s reward areas,” says

Dr. William Corrigall, director of NIDA’s Nicotine and 

Tobacco Addiction Program. “It gives us a clearer picture 

of how smoking can lead so quickly to dependence and 

addiction, and it also suggests a possible new avenue of 

investigation for pharmacological treatment.”

Sources

• Mansvelder, H.D., and McGehee, D.S. Long-term 

potentiation of excitatory inputs to brain reward

areas by nicotine. Neuron 27(2):349-357, 2000.

• Mansvelder, H.D.; Keath, J.R.; and McGehee, D.S. 

Synaptic mechanisms underlie nicotine-induced 

excitability of brain reward areas. Neuron 33(6):

905-919, 2002.

The combination of effects—

increasing dopamine release 

and decreasing the inhibitory 

[GABA] response—results in an 

amplification of the rewarding 

properties of nicotine.
Research Findings

57

NIDA’s Continued Commitment To Nicotine Research

By Glen R. Hanson, Ph.D., D.D.S., NIDA Acting Director 

Volume 17, Number 6 (March 2003)

Tobacco use is the Nation’s most profound public health problem. Each year, 

tobacco use accounts for an estimated $50 

billion in health care costs, and the human 

cost is even more staggering. More than 

400,000 Americans die annually from 

tobacco-related diseases. Of course, most 

smokers want to reduce their risks of heart 

and lung diseases, cancers, and strokes, 

but once addicted, smokers and other 

tobacco users find it very difficult to stop.

NIDA’s contribution to the Nation’s 

efforts to reduce tobacco use has been 

critically important. NIDA-supported 

research has led the way to development 

of smoking-cessation medications and 

has illuminated the causes of addiction. 

Recent studies have shown how the social and environmental influences that lead people to begin using tobacco 

conspire with powerful biological effects to quickly produce addiction to nicotine.

NIDA-funded investigations have made major advances

in understanding, preventing, and treating tobacco use, 

but a complete understanding of the complex mechanisms 

of smoking initiation and nicotine addiction requires a 

comprehensive and coordinated research effort. NIDA

has long recognized the need for an interdisciplinary 

approach to nicotine research and has forged partnerships 

with other research institutions in collaborative efforts to 

reduce nicotine addiction.

In 1998, NIDA cosponsored a groundbreaking conference 

that brought together leading investigators from throughout the Nation. At this conference, the researchers identified research hypotheses and approaches that have 

great potential to yield information that will significantly improve our ability to reduce tobacco use and 

nicotine addiction.

Following up on ideas generated at the conference, NIDA 

joined with the National Cancer Institute and the Robert 

Wood Johnson Foundation to establish the Transdisciplinary Tobacco Use Research Centers (TTURCs). These 

research coalitions have improved our understanding of 

nicotine addiction at levels from the cellular to the societal, from the role of individual genes to the effects of 

gender. For example, TTURC researchers 

have found that genetic influences may 

help explain why some young people 

begin smoking while others do not (see 

“Genetic Variation in Serotonin System 

May Play Role in Smoking Initiation,” 

NIDA NOTES, Vol. 17, No. 2). Other 

TTURC investigators have helped identify factors that may improve women 

smokers’ chances of successfully quitting 

(see “Women and Smoking: Sensory 

Factors, Attitudes About Weight, Phase 

of Menstrual Cycle All Keys to Quitting,” 

NIDA NOTES, Vol. 17, No. 4).

NIDA-supported research has shown 

how the social and environmental 

influences that lead people to begin 

using tobacco conspire with powerful 

biological effects to quickly produce 

nicotine addiction.

To amplify the success of these research partnerships, 

NIDA plans continued support for TTURC researchers 

and an expanded scope of collaborative efforts. We are 

joining with the National Institute of Mental Health in a 

research partnership (RFA MH-03-008) to identify and 

develop pharmacological compounds that can be used to 

investigate the roles of specific neurochemical receptors 

in mood disorders and nicotine addiction. These receptors are important: They are the sites on brain cells where 

nicotine initiates the cascade of neurochemical activities that contribute to development of dependence and 

addiction (see “Nicotine’s Multiple Effects on the Brain’s 

Reward System Drive Addiction”). This collaboration 

with NIMH—the National Cooperative Drug Discovery 

Group Program—will encourage academic and pharmaceutical industry researchers to develop compounds that 

bind to specific subtypes of nicotine receptors. This will,

in turn, make possible the development of specifically
58

targeted medications for treating nicotine addiction.

Another NIDA initiative—

Translating Tobacco Addiction 

Research to Treatment (RFA 

DA-03-010)—supports the 

development of new treatment 

and prevention options. The 

initiative encourages researchers from diverse disciplines 

in their efforts to move beyond animal studies and basic 

science to clinical applications. Specifically, it will support the use of phase I-style clinical studies or laboratory 

studies with human volunteers to investigate approaches 

built upon what we now know about the biological and 

behavioral mechanisms of nicotine addiction and tobacco 

use. Behavioral research, for example, demonstrates the 

important role of environmental cues in drug craving; 

neurochemical research has identified some of the brain 

pathways involved in cue-induced craving. Under this new 

initiative, researchers could investigate the effectiveness of 

medications that target the neurochemical processes that 

underlie craving.

NIDA’s achievements in nicotine and tobacco research are 

impressive. NIDA-supported 

research identified nicotine as 

the addictive component of 

tobacco smoke, and NIDAfunded research laid the foundation for the most effective 

medication now available to 

treat nicotine addiction—

skin patches, gum, and inhalers used to deliver nicotine 

replacement therapy. But the research, and the results, 

must continue.

Each day, 3,000 adolescents start smoking; each year more 

than 30 million smokers try to quit, but most are unsuccessful. NIDA’s commitment to new initiatives, as well as 

continued basic and clinical research, will speed the development of new programs that prevent young people from 

becoming smokers and will make available new treatments 

for the millions of Americans who smoke and want to 

quit. 

A complete understanding of the 

complex mechanisms of smoking 

initiation and nicotine addiction 

requires a comprehensive and 

coordinated research effort.
Research Findings

59

Youths’ Opportunities To Experiment Influence Later Use of

Illegal Drugs

By Kimberly R. Martin, NIDA NOTES Contributing Writer 

Volume 17, Number 5 (January 2003)

NIDA-supported researchers have reported new epidemiological evidence about the associations linking earlier 

alcohol or tobacco use with later use of marijuana, and 

the link from earlier marijuana use to later use of other 

illegal drugs such as cocaine and hallucinogens. This study 

builds on the many prior NIDA-supported studies of the 

“gateway” theory of youthful drug involvement: Once use 

of tobacco or alcohol begins, there is greater likelihood 

of marijuana use, and once marijuana use begins, there is 

greater likelihood of other illegal drug use.

“This research increases our understanding of the complex relationship between the different stages of drug 

use and raises concerns about factors that promote the 

transition from opportunities to initiate drug use to patterned use,” says Dr. Kathleen Etz of NIDA’s Division 

of Epidemiology, Services and 

Prevention Research. “We 

know that earlier drug use is 

associated with later, more 

advanced use; however, this 

research identifies a previously 

overlooked aspect of this transition, opportunities to use.”

Using annual data from the 

1991 through 1994 National 

Household Survey on Drug 

Abuse (NHSDA), the research 

team, led by Dr. James C. 

Anthony from Johns Hopkins 

University Bloomberg School of Public Health in 

Baltimore, analyzed the responses of 26,015 individuals 

aged 12 to 18 who answered questions regarding marijuana use and the responses of 44,624 individuals aged 12

to 25 who answered questions regarding cocaine use.

The research focused on a concept called “drug exposure 

opportunities.” This concept takes into account that some 

young people actively seek out opportunities to try marijuana or cocaine, whereas others are more passive recipients of drug exposure opportunities.

The researchers found that alcohol and tobacco users were 

more likely than nonusers to have an opportunity to try 

marijuana and were also more likely to try the drug when 

the opportunity arose. About 75 percent of alcohol or 

tobacco users reported an opportunity to try marijuana by 

age 18, and more than 85 percent of them made the transition to marijuana use. Only about 25 percent of nonsmokers and nondrinkers were given an opportunity to 

try marijuana by the same age. Of these, fewer than 25 

percent began smoking marijuana within 6 years after 

they were first given the opportunity. Overall, alcohol or 

tobacco users were seven times more likely to start using 

marijuana than individuals who had used neither alcohol 

nor tobacco. 

Prior marijuana use was closely associated with the 

opportunity to try cocaine and the likelihood of young 

people’s starting to use cocaine once given the opportunity. Among the young people who were given the chance 

to try cocaine, those who were already using marijuana 

were 15 times more likely to use cocaine than those who 

did not use marijuana. About 

50 percent of marijuana users 

used cocaine within 2 years of 

their first opportunity to do so. 

However, among young people 

who never used marijuana, 

fewer than 10 percent initiated 

cocaine use.

In a separate but related study, 

the researchers analyzed data 

from 41,271 young people

who participated in the 1991 

through 1994 NHSDA, 

investigating the relationship 

between the use of marijuana and use of hallucinogens. 

The results showed that marijuana users are more likely 

than nonusers to be offered an opportunity to use LSD, 

mescaline, mixed stimulant-hallucinogens, and PCP and 

more likely than nonusers to try these hallucinogenic 

drugs when they’re offered. By age 21, nearly one-half of 

the teenagers who had smoked marijuana were presented 

with the opportunity to try hallucinogens, compared to 

only one-sixteenth of those who had not used marijuana. 

Once given the opportunity to use hallucinogens, marijuana smokers were about 12 times more likely to use hallucinogens than those who did not use marijuana.

“These studies are the first to support the idea of two 

separate mechanisms linking the use of alcohol, tobacco, 

marijuana, cocaine, and hallucinogens—one mechanism 

Prior marijuana use was

closely associated with the 

opportunity to try cocaine and 

the likelihood of young people’s 

starting to use cocaine once 

given the opportunity.
60

Drug Use Associated With More Opportunities To Use,

Higher Rates of Acceptance

Age

0

10

20

30

40

50

60

70

80

90

100%

Alcohol/tobacco use started

No alcohol/tobacco use

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Years since first marijuana opportunity

Estimated probability of 

starting to use

Estimated probability of 

drug being offered

0

10

20

30

40

50

60

70

80

90

100%

Alcohol/tobacco use and marijuana use started

No alcohol/tobacco use but marijuana 

use started

Alcohol/tobacco use but no marijuana use

No alcohol/tobacco use and no marijuana use

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Age

Estimated probability of 

drug being offered

0

10

20

30

40

50

60

70

80

90

100%

Marijuana use started, adjusted for alcohol/tobacco use

No marijuana use, adjusted for alcohol/tobacco use

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Estimated probability of 

starting to use

Years since first cocaine opportunity

0

10

20

30

40

50

60

70

80

90

100%

Marijuana users

Nonusers of marijuana

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Age

Estimated probability of 

drug being offered

0

10

20

30

40

50

60

70

80

90

100%

Marijuana users

Nonusers of marijuana

1 2 3 4 5 6 7 8 9 10

Years since first hallucinogen opportunity

Estimated probability of

starting to use 

 Exposure to Cocaine Probability of Cocaine Use

Exposure to Hallucinogens Probability of Hallucinogen Use

Exposure to Marijuana Probability of Marijuana Use

Sources: Wagner and Anthony,American Journal of Epidemiology, 2001; Wilcox et al.,Drug and Alcohol Dependence,2002.

The likelihood that a nonsmoking, nondrinking 14-year old will be exposed 

to marijuana is only 14 percent, but the odds jump to 47 percent for a user of 

alcohol or tobacco.

Among nonsmoking, nondrinking youth, 11 percent will be marijuana users 

1 year after their first exposure to marijuana, compared to 40 percent of 

alcohol/tobacco users. Over time, the likelihood of marijuana use for the 

alcohol/tobacco users climbs to greater than 95 percent.

A 14-year-old user of tobacco or alcohol and marijuana is 10 times more likely 

to be exposed to cocaine than a nonsmoking nondrinker. 

Having been exposed to cocaine, fewer than 1 in 10 nonusers of marijuana will 

use cocaine, compared to 50 to 75 percent for marijuana users.

Although fewer that 5 percent of nonusers of marijuana are exposed to 

hallucinogens, the likelihood jumps to nearly 50 percent for marijuana users 

over time.

Fewer than one in five nonusers of marijuana who are exposed to hallucinogens will 

use hallucinogens, but 70 to 90 percent of marijuana users will try hallucinogens. 

0

10

20

30

40

50

60

70

80

90

100%

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Alcohol/tobacco use started

No alcohol/tobacco use
61

involving increased drug exposure opportunity, and a 

separate mechanism involving increased likelihood to use 

once the opportunity occurs,” says Dr. Anthony. “Even if 

there is an underlying common vulnerability or predisposition that accounts for the observed sequencing of drug 

exposure opportunities and actual drug use, these observations may have implications for the design and evaluation 

of drug prevention activities. Drug users often are members of social circles where drug use and experimentation 

are more common and friends are likely to share drugs. 

In addition to trying to persuade young people not to use 

drugs, it may be worthwhile for us to persuade users not to 

share their drugs with friends.” Previous research has also 

shown that although males are more likely than females to 

have opportunities to use drugs, both are equally likely to 

make a transition into drug use once an opportunity to try 

a drug has occurred. Dr. Anthony and his colleague, Dr. 

Fernando Wagner, also from Johns Hopkins University 

Bloomberg School of Public Health, have made similar 

observations in ongoing research studies.

Dr. Anthony believes that his research carries a strong 

message for parents and pediatricians, who often neglect 

the opportunity to ask children and adolescents about 

whether they have had chances to try illegal drugs. As Dr. 

Anthony notes, “Kids will talk to us about their chances 

to try illegal drugs even when they are unwilling to talk 

about actual drug use. Once the chance to try marijuana 

or cocaine occurs, it is a red flag, and we need to be paying close attention to what happens next.”

“Future research in this area will be a great asset to the 

development of effective drug prevention programs,” says 

Dr. Etz. “It will assist us in understanding the process 

through which the use of one drug is related to use of 

another and help us to target prevention programs to individuals more likely to progress to advanced substance use.”

Sources

• Wagner, F.A., and Anthony, J.C. Into the world 

of illegal drug use: Exposure opportunity and other 

mechanisms linking the use of alcohol, tobacco, marijuana, and cocaine. American Journal of Epidemiology

155(10):918-925, 2001.

• Wilcox, H.C.; Wagner, F.A.; and Anthony, J.C. 

Exposure opportunity as a mechanism linking youth 

marijuana use to hallucinogen use. Drug and Alcohol 

Dependence 66(2):127-135, 2002. 
Research Findings

62

Women and Smoking: Sensory Factors, Attitudes About Weight, 

Phase of Menstrual Cycle All Key To Quitting

By Jill S. Williams, NIDA NOTES Contributing Writer 

Volume 17, Number 4 (November 2002)

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 ultra-low-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 

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.

0

10

20

30

40

50

60

Social Support Group

Weight Control Group

Cognitive-Behavioral Therapy Group

Month 1 Month 3 Month 6 Month 12

Percentage Abstinent

Months After Quitting
63

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.

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.A.; Jacobs, L.; Sanders, M.; and Caggiula, 

A.R. Sex differences in the subjective and reinforcing 

effects of cigarette nicotine dose. Psychopharmacology 

163(2):194-201, 2002.

• Perkins, K.A., et al. Sex differences in the influence of nicotine dose instructions on the reinforcing and self-reported rewarding effects of smoking. 

Psychopharmacology 184(3-4):600-607, 2006. 

• 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. 
64

Research Findings

Depression, PTSD, Substance Abuse Increase in Wake of 

September 11 Attacks

By Jill S. Williams, NIDA NOTES Contributing Writer 

Volume 17, Number 4 (November 2002)

A survey of New York City

residents in the wake of the 

September 11, 2001, terrorist 

attacks found high levels of both 

depression and posttraumatic 

stress disorder (PTSD) among 

respondents and documented an 

increase in substance abuse. The 

survey, conducted by NIDAfunded researchers Dr. David 

Vlahov and his colleagues at the 

New York Academy of Medicine 

5 to 8 weeks after the terrorist 

attacks, quantifies the relationships among stress, depression, 

and substance abuse. The results 

provide insight into public health 

service delivery needs as well as 

clues to effective treatment strategies to help individuals cope with 

traumatic events.

Stress has long been recognized 

as one of the most powerful 

triggers for drug craving and 

relapse to drug abuse. Research 

has shown that survivors of 

disasters are prone to stress-related problems such as PTSD and 

depression. People who experience major trauma and those 

with PTSD or depression may self-medicate with drugs

or alcohol to relax, cope with stress, or relieve symptoms. 

“This study is one of the first to capture data on the 

effects of traumatic events on substance abuse patterns,” 

says Dr. Jacques Normand of NIDA’s Center on AIDS 

and Other Medical Consequences of Drug Abuse. “The 

increase in substance abuse found here was of significant 

magnitude. This study reminds counselors and treatment 

providers to be alert to increased use of alcohol, tobacco, 

and marijuana in the wake of such events.”

Survey respondents reported post-attack rates of depression and PTSD that were approximately twice the baseline levels previously documented in a 1999 benchmark 

national study. Some 9.7 percent had symptoms of

depression, and 7.5 percent qualified for a diagnosis of 

PTSD compared to baseline 

levels of 4.9 percent for depression and 3.6 percent for PTSD.

In looking at rates of new substance use among respondents, 

the researchers found that, of 

respondents who did not use 

these substances during the 

week before September 11, 

3.3 percent started smoking 

cigarettes after September 11; 

19.3 percent started drinking 

alcohol; and 2.5 percent began 

using marijuana. Overall, the 

percentages of respondents who 

smoked, consumed alcohol, 

and used marijuana increased 

9.7 percent, 24.6 percent, and 

3.2 percent, respectively, after 

the attacks.

Almost 29 percent of respondents reported that they were 

smoking more cigarettes and/

or marijuana and/or drinking 

more alcohol. Among those 

who were already using these 

substances before September 

11, 41.2 percent smoked more 

cigarettes and 41.7 percent 

drank more alcohol after the 

attacks. Among smokers, 8.2 percent smoked at least 

one additional pack of cigarettes a week; 20.8 percent of 

drinkers had at least one additional drink a day.

“The survey results are significant for the sheer numbers 

of people revealed to be affected by the disaster, the scope 

of the problem on a citywide scale, and challenges to the 

delivery of services,” says Dr. Vlahov. He estimates that 

of the approximately 911,000 people in the area of New 

York under study, 67,000 had PTSD and approximately 

87,000 had depression at the time of the study. Likewise, 

he estimates that 265,000 people increased their use of 

any of the substances in question: 89,000 smoked more 

cigarettes, 226,000 consumed more alcohol, and 29,000 

used more marijuana. “This survey demonstrated that 

Manhattan residents living closest to the World Trade 

Center, south of Canal Street, were three times more 

likely than residents from Canal to 110th Street to suffer 

symptoms of posttraumatic stress disorder.

Map of Study Area Relative 

to World Trade Center
65

whole populations are affected by 

such disasters,” says Dr. Vlahov. 

“The increases in use of cigarettes, 

alcohol, and marijuana across the 

population are large, making this a 

broad public health issue.”

While the initial survey goal was to 

perform a public health assessment 

to document the scope of the problems and to help authorities apply 

for appropriate aid, Dr. Vlahov says 

that other questions also drove the 

research. “From a scientific perspective, we knew that attention typically focuses on victims, rescue 

workers, and their families. But here 

was an event that affected everyone 

in a major way. We asked, how 

do people cope with the stress of a 

disaster? Do they turn to cigarettes, 

alcohol, or marijuana? What are 

the implications for public health 

planning and delivery?”

Survey Methodology

Researchers randomly selected 1,008 

adults living south of 110th Street 

in Manhattan, the area closest to the 

World Trade Center, to take part 

in the telephone survey. A 35-minute questionnaire was 

used to assess respondents’ exposure to the September 11 

events, psychological symptoms after the attacks, changes in 

substance abuse patterns, and other factors such as demographics, levels of social support, and previous life stressors. 

Surveyors referred respondents for counseling services as 

appropriate. The overall cooperation rate for the survey was 

64.3 percent; 52 percent of respondents were women, and 

71.6 percent were white. The mean age of respondents was 

42 years.

Surveyors used a series of questions based on accepted psychological tests to diagnose both depression and PTSD. To 

determine levels of pre- and post-September 11 substance 

abuse, surveyors asked respondents to estimate how many 

times they had used cigarettes, alcohol, and marijuana during the week before September 11, and then asked about 

the number of times they had used each substance during 

the week before the survey was conducted.

Analyses revealed that those who were most directly 

exposed to events were more likely to suffer PTSD;

those who experienced loss—of jobs, possessions, friends or 

family members—were more likely to suffer from depression. Dr. Vlahov says that the key demographic, event 

experience, and other characteristics most closely related to 

diagnosis of either PTSD or depression provide important 

clues to immediate crisis intervention: “Clinicians can 

learn that getting a history of an individual’s exposure to 

events can help focus or target issues and clarify how he or 

she may be reacting.”

The survey data revealed associations between specific psychological diagnoses and drug use patterns. Survey respondents diagnosed with PTSD were approximately five times 

Association Between Respondents’ 9/11 Experiences and 

Current Posttraumatic Stress Disorder and Depression

PTSDa Depressiona

Number of Odds Ratio Odds Ratio

Characteristics Respondents (95% C.I.) (95% C.I.)

Had symptoms of a 124 7.6 (4.2-13.7) 2.6 (1.3-4.9) 

panic attack during or 

soon after the events of 

9/11/01

Lost possessions 36 5.6 (2.5-12.4) NSb

Lost job because of 64 NSb 2.8 (1.2-6.3)

the attacks

Friend or relative killed 108 NSb 2.3 (1.1-4.6)

Two or more life stressors 183 5.5 (2.6-11.6) 3.4 (1.8-6.6)

in the previous 12 months

Low social support in 358 NSb 2.4 (1.2-4.8)

previous 6 months

Residence south of 50 2.9 (1.3-6.8) NSb

Canal Street

Hispanic ethnicity 114 2.6 (1.3-5.5) 3.2 (1.7-6.3)

Certain characteristics of survey respondents were found to significantly elevate the odds that 

they would report symptoms consistent with a diagnosis of PTSD or depression. For example, 

respondents who reported symptoms of a panic attack during or soon after the terrorist attacks 

were 7.6 times more likely to suffer from PTSD and 2.6 times more likely to suffer depression 

than respondents who did not report panic attack symptoms.

a Current PTSD and depression defined as symptoms consistent with the diagnosis within 30 days before the interview.

b

 Not a significant association.

For More Information

Help for those struggling with stress and substance 

abuse issues is available in two recent NIDA

publications:

• “Stress and Substance Abuse: A Special Report” 

is a research summary that can be downloaded 

from NIDA’s Web site. Go to www.drugabuse.

gov/stressanddrugabuse.html.

• Community Drug Alert Bulletin: Stress and 

Substance Abuse is available from NIDA.

Order publication #PHD914 by phone 

(877-643-2644; 240-645-0228 for the deaf) 

or at the NIDA Web site, www.drugabuse.gov.
66

as likely as other respondents to increase their use of cigarettes or marijuana. Survey respondents who were diagnosed with depression were much more likely to increase 

use of all three substances than were those who were not 

depressed. Again, Dr. Vlahov suggests that these data may 

be important to clinicians. “Increased use of cigarettes, 

alcohol, and marijuana may be an indicator of underlying psychological response issues. Clinicians should look 

for links between PTSD, depression, and increased use of 

cigarettes, alcohol, or marijuana.” 

Followup studies will assess outcomes at 4 months, 6 to 8 

months, and 12 months after the attacks. “We need a better understanding of the extent to which substance abuse 

complicates psychological problems,” says Dr. Vlahov. 

“Longitudinal studies will help us determine whether 

increased use of substances leads to dependence, and to 

identify predictors of drug dependence that will help us 

guide intervention planning.”

Sources

• Galea, S.; Ahern, J.; Resnick, H.; Kilpatrick, 

D.; Bucuvalas, M.; Gold, J.; and Vlahov, D. 

Psychological sequelae of the September 11 terrorist 

attacks in New York City. New England Journal of 

Medicine 346(13):982-987, 2002.

• Vlahov, D., et al. Increased use of cigarettes, alcohol, 

and marijuana among Manhattan, New York, residents after the September 11th terrorist attacks. 

American Journal of Epidemiology 155(11):988-996, 

2002. 
67

Research Findings

Genetic Variation in Serotonin System May Play Role in

Smoking Initiation

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 17, Number 2 (May 2002)

Each day more than 3,000 young people 

smoke their first cigarette, and the likelihood of becoming addicted to nicotine is 

higher for these young smokers than for 

those who begin later in life. A number of 

biological, social, and environmental factors 

combine to influence smoking initiation, 

and NIDA-supported research suggests that 

genetic factors play a role in determining 

a smoker’s susceptibility to nicotine addiction. (See “Evidence Builds That Genes 

Influence Cigarette Smoking,” NIDA 

Notes, Vol. 15, No. 2.) Now, researchers at the University of Pennsylvania in 

Philadelphia and Virginia Commonwealth 

University in Richmond have found an 

association between smoking initiation and 

variations in a gene related to the brain’s 

serotonin system, which is involved in 

mood v and behavior.

At the NIDA-supported Transdisciplinary Tobacco Use 

Research Center at the University of Pennsylvania, Dr. 

Caryn Lerman and her colleagues investigated the possible relationship between smoking behavior and different 

forms (alleles)—designated 779A and 779C—of a gene 

that regulates tryptophan hydroxylase (TPH), an enzyme 

involved in the synthesis of serotonin. “There is evidence 

from previous studies linking the less common 779A 

allele with behaviors related to poor impulse control,” 

Dr. Lerman says. “Because of the association of tobacco 

and other substance use with poor impulse control, we 

speculated that the TPH gene may play a role in smoking 

initiation as well.”

To investigate this possibility, the researchers recruited 

249 smokers (smoked at least 5 cigarettes per day for 

the past year) and 202 nonsmokers (smoked fewer than 

100 cigarettes in their lifetime). All the participants were 

white; their average age was 44 years, and slightly more 

than half (56 percent) were women. All participants 

completed written questionnaires that provided information on their age, education, marital status, and certain 

psychological traits. Smokers provided smoking histories, 

including the age when they started smoking at least one 

cigarette per day.

The researchers tested samples of the participants’ blood 

to determine whether they had the 779A or 779C alleles 

for the TPH gene. The overall allele frequency was 42 

percent for the THP 779A allele and 58 percent for the 

779C allele. There was no significant association of the 

presence or absence of the 779A allele with becoming a 

regular smoker, Dr. Lerman says. But among participants 

who did become smokers, the 779A allele was associated 

with the age at which they began smoking. Those who 

inherited copies of 779A from both parents started smoking at age 15.6 years, those with one A and one C allele 

began smoking at 17.1, and those with two copies of 

779C began smoking at 17.3 years.

“In light of other findings that 779A is associated with 

poor impulse control, one interpretation of this study is 

that individuals with that allele may be prone to engage

in risky behavior such as smoking initiation at an earlier 

age,” Dr. Lerman says.

Dr. Lerman discussed her research results with Dr. Patrick 

Sullivan at Virginia Commonwealth University. Dr. 

Sullivan and his colleagues then developed a study to look 

for possible associations between the TPH 779A allele and 

smoking initiation in a group of 740 participants who had 

previously been enrolled in research dealing with genetic 

influences on a range of behaviors, including drug abuse 

and addiction. As part of the earlier study, the participants 

Variation in Gene May Affect

Likelihood of Smoking at Early Age

Distribution

among smokers

Age at smoking

initiation (yr)

A/A A/C C/C

18% 51% 31%

15.6 17.1 17.5

Allele Combination

Researchers at the University of Pennsylvania have found that women and men who 

inherit the “A” form (allele) of the tryptophan hydroxylase gene from both parents and 

who become smokers are likely to begin smoking at an earlier age than women and 

men who inherit the “C” allele.
68

had completed extensive questionnaires that included 

information about smoking, including age at which smoking began, age at which smokers first became dependent 

on nicotine (suffered withdrawal if they tried to quit), and 

the severity of their dependence—measured by a standard tool called the Fagerstrom Tolerance Questionnaire 

(FTQ). For the TPH study, the participants were divided 

into three categories: those who had never smoked, regular 

smokers who had a low degree of dependence (scores of 

0 to 3 on the 11-point FTQ), and regular smokers with a 

high degree of dependence (FTQ scores of 7 or higher). 

Dr. Sullivan and his colleagues analyzed the participants’ 

TPH genes and found that the 779A allele was strongly 

associated with whether participants initiated smoking, 

but, unlike the University of Pennsylvania study, not 

strongly associated with an early age of smoking initiation.

“The fact that there is not complete agreement is not surprising,” Dr. Sullivan says. “The two studies used different 

populations of subjects and were not designed to test the 

same hypothesis. Nonetheless, the two studies appear to 

have captured a similar influence that plays a role in the 

web of factors that underlies smoking initiation.”

“It is rare to find confirmation of a candidate gene related 

to addiction, and these studies make a good case for an 

association between the TPH gene variant and smoking 

initiation,” says Dr. Rebekah Rasooly of NIDA’s Division 

of Neuroscience and Behavioral Research. “This kind of 

association helps us to better understand the factors that 

influence young potential smokers. They are the most 

vulnerable to becoming regular smokers and need to 

clearly understand all the risks associated with smoking 

that first cigarette.”

Sources

• Lerman, C., et al. Tryptophan hydroxylase gene 

variant and smoking behavior. American Journal of 

Medical Genetics 105(6):518-520, 2001.

• Sullivan, P.F., et al. Association of the tryptophan 

hydroxylase gene with smoking initiation but not

progression to nicotine dependence. American Journal 

of Medical Genetics 105(5):479-484, 2001. 
69

Nicotine Disrupts Brain Development in Rats

By Patrick Zickler, NIDA NOTES Staff Writer 

Research Findings

Volume 16, Number 3 (August 2001)

Exposure to nicotine during a brief but crucial stage of 

brain development in rats appears to cause long-lasting 

disruption of some brain functions. NIDA-supported 

researchers Dr. Frances Leslie, Dr. Raju Metherate, and 

colleagues at the University of California, Irvine, found 

that nicotine injected into rats throughout the second 

postnatal week affected development of an area of the 

brain that is concerned with the interpretation of sounds, 

and that the effects persisted for at least 10 days after 

nicotine injections were discontinued.

“There are critical periods during which nicotine exposure 

can produce profound changes in brain function,” Dr. 

Leslie says. “Our study suggests that the nicotine content 

of tobacco triggers responses in developing brains that are 

strikingly different from those in an adult brain.” 

In rats, there is a dramatic increase during the second 

postnatal week in the number of nicotinic acetylcholine 

receptors—brain cell structures that are sensitive to nicotine and help regulate the action of the chemical messenger acetylcholine. Developments in the rat brain during this period correspond to changes that take place in 

human fetuses during the last weeks of gestation.

To evaluate the effect of nicotine during this period of 

brain development, the researchers injected rat pups twice 

each day with saline or with nicotine (1 or 2 mg per kilogram of body weight-levels typically used by researchers to 

simulate exposure levels thought to occur in human fetuses due to maternal smoking) for 1 week (postnatal days 8 

through 14). Two other groups of rats received injections 

(2 mg/kg) on postnatal days 1 through 8 and on postnatal 

days 20 through 25, respectively. The researchers then 

measured electrical properties of brain cells in the auditory 

cortex to determine the cells’ ability to properly process 

electrical signals involved in hearing. They found that 

cells from animals exposed to nicotine—at doses of 1 or 

2 mg/kg—during the second postnatal week had significant impairment while those exposed to the higher dose 

earlier or later did not.

“Together, these findings indicate that chronic nicotine 

exposure during week 2, but not before or after, alters 

development in the auditory cortex of rats,” Dr. Leslie 

says. The resulting defects do not impair the animals’ ability to distinguish sounds—they are not hard of hearing—

but the defects make the rats less able to associate sounds, 

such as the yips of littermates, with specific activities such 

as feeding, according to the researchers. “In humans, 

maternal smoking has been associated with cognitive 

deficits in infants, and particularly with auditory-related 

cognitive impairments such as reduced ability to orient 

toward clearly heard sounds. This animal study suggests a 

mechanism that might underlie these impairments,” Dr. 

Leslie says.

Source

• Aramakis, V.B.; Hsieh, C.Y.; Leslie, F.M; and 

Metherate, R. A critical period for nicotine-induced 

disruption of synaptic development in rat auditory 

cortex. Journal of Neuroscience 20(16):6106-6116, 

2000. 

To determine the effect 

of nicotine on developing 

brains in the auditory 

cortex (the part of the 

brain where sounds are 

associated with meanings), researchers measured 

an electrical property 

(excitatory postsynaptic 

potential or EPSP) that 

influences the transmission 

of signals from one nerve 

cell to another. In animals 

not exposed to nicotine 

(top), neurons exhibited 

smooth short-duration 

EPSPs. Nerve cells from 

animals exposed daily to 

nicotine at doses of 1 mg/

kg (middle) and 2 mg/

kg (bottom) during the 

second week after birth 

exhibited longer duration 

EPSPs marked by frequent 

spikes, which interfere 

with effective transmission.
Research Findings

70

Adolescents, Women, and Whites More Vulnerable Than Others to 

Becoming Nicotine Dependent

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 16, Number 2 (May 2001)

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 

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.

Number of cigarettes smoked per day
71

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. 
Research Findings

72

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, risktaking, 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 (see “Drug Abuse and 

Conduct Disorder Linked to Maternal Smoking During 

Pregnancy,” NIDA NOTES, Vol. 15, No. 5). 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 

experimentation with tobacco. The connection is important because the earlier a person starts smoking, the more 
73

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-yearolds. 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

74

Smoking May Lead to Anxiety Disorders in Adolescents 

and Young Adults

Volume 16, Number 1 (March 2001)

Using a wealth of data obtained through a 25-year 

longitudinal study, NIDA-funded researcher Dr. Judith 

Brook of the Mount Sinai School of Medicine in New 

York, Dr. Patricia Cohen of Columbia University in 

New York, and their colleagues have documented adverse 

effects of smoking in several critical areas of functioning 

during young adulthood. Most recently, the team has 

reported a connection between tobacco use by adolescents 

and young adults and the likelihood that they will develop 

agoraphobia (fear of leaving home or of the outdoors), 

generalized anxiety disorder, or panic disorder. Analyzing 

data from their Children in the Community study, funded by NIDA and the National Institute of Mental Health, 

the researchers were able to separate the effects of smoking 

from the effects of age, gender, childhood temperament, 

alcohol and other drug abuse, and depression among the 

adolescents, as well as parents’ smoking, education, and 

behavioral and/or mental health problems.

The researchers interviewed 688 youths and their mothers in 1983, between 1985 and 1986, and again between 

1991 and 1993. A total of 69 of the youths smoked 

heavily—at least 20 cigarettes every day—and experienced 

an anxiety disorder during adolescence, early adulthood, 

or both. Of these 69 youths, 29 (42 percent) began smoking before they were diagnosed with an anxiety disorder. 

The remaining 40 youths were split between those who 

were diagnosed with anxiety disorders before they reported heavy smoking (13, or 19 percent) and those who 

reported smoking and were diagnosed with anxiety disorders at the same interview session (27, or 39 percent).

Adolescents who smoked heavily were 6.8 times more 

likely to develop agoraphobia, 5.5 times more likely to 

develop generalized anxiety disorder, and 15.6 times more 

likely to develop a panic disorder as young adults than 

were their counterparts who smoked fewer than 20 cigarettes a day or not at all. The investigators speculate that 

impaired respiration and the potentially damaging effects 

of nicotine on blood vessels to the brain may help explain 

why the adolescents who smoked heavily were at increased 

risk of developing anxiety disorders.

The long-held notion that depression causes some adolescents to smoke may be true. But Dr. Brook’s study 

suggests the opposite may also be true—that smoking 

increases the risk of depression in this population. Dr. 

Brook and her team recommend that future research 

examine further the possible relationships between various 

anxiety disorders and smoking.

Source

• Johnson, J.G.; Cohen, P.; Pine, D.S.; Klein, D.F.; 

Kasen, S.; and Brook, J.S. The association between 

cigarette smoking and anxiety disorders during adolescence and early adulthood. Journal of the American 

Medical Association 284(18):2348-2351, 2000. 
Research Findings

75

Nicotine Patch Helps Smokeless Tobacco Users Quit, But 

Maintaining Abstinence May Require Additional Treatment

By Robert Mathias, NIDA NOTES Staff Writer 

Volume 16, Number 1 (March 2001)

An estimated 9.6 million 

people in the United States 

used smokeless tobacco products—moist snuff and chewing 

tobacco—during 1998, according to the National Household 

Survey on Drug Abuse. More 

than 70 percent of these individuals had used smokeless 

tobacco during the month 

before they were surveyed.

People who are trying to quit 

using smokeless tobacco may 

benefit from a transdermal nicotine patch during the first critical months after stopping use, a 

NIDA-supported study suggests. 

Study participants treated with 

the nicotine patch experienced less 

severe withdrawal symptoms and 

lower levels of craving for nicotine and 

were significantly more likely to maintain short-term abstinence than users in 

a control group who were treated with 

an inactive patch. Treatment with 

nicotine-free mint snuff also reduced 

withdrawal symptoms and craving but 

had no effect on abstinence rates.

“These findings suggest that the nicotine 

patch can reduce the discomfort that 

people experience when quitting smokeless tobacco,” says 

Dr. Dorothy Hatsukami of the University of Minnesota 

School of Medicine, who conducted the study. “Knowing 

that withdrawal symptoms can be minimized may encourage more people to try to quit,” she says. While the study 

suggests that the nicotine patch may help patients achieve 

initial abstinence from smokeless tobacco, it remains 

unclear how the patch and other treatments should be 

used to sustain abstinence over the long term, she says.

Most tobacco-related research has focused on cigarette 

smoking with its more extensive range of harmful consequences, Dr. Hatsukami says. “However, we also need 

to study smokeless tobacco use because it is not an insignificant problem by any means,” she says. Regular use of 

smokeless tobacco products may cause 

such problems as receding gums, tooth 

decay, mouth sores, precancerous lesions, 

and cancers of the mouth and throat. 

Smokeless tobacco users also may be at 

increased risk of heart disease and smoking cigarettes. Undesirable social consequences include bad breath, tobaccostained teeth, and the need to spit 

tobacco juice.

Many individuals use smokeless 

tobacco despite its obvious drawbacks 

because they are hooked on nicotine, 

a highly addictive drug. As with cigarettes, smokeless tobacco products 

deliver substantial doses of nicotine 

along with powerful cancer-causing 

chemicals. Users of moist snuff—

which consists of finely ground 

tobacco—place a pinch, or 

dip, of snuff between their 

cheek and gum and hold 

it there. Users of chewing 

tobacco—which comes in leaf 

and plug forms—place a wad, 

or chew, in their cheek pouch 

and chew it. Because nicotine 

from smokeless tobacco is 

absorbed through the mouth, 

the drug takes longer to produce its rewarding effect in the brain than it does when it 

is absorbed through the lungs during cigarette smoking. 

The amount of nicotine obtained from smokeless tobacco 

is comparable to that of cigarettes, and once smokeless 

tobacco users become addicted they find it just as difficult 

as cigarette smokers do to quit, Dr. Hatsukami says. She 

notes that more than 90 percent of the smokeless tobacco 

users in her study had tried unsuccessfully to quit on 

their own at least once. Nearly 25 percent of the study’s 

participants had made more than 6 unsuccessful quit 

attempts, and nearly 10 percent had tried to quit more 

than 10 times.

In her study, Dr. Hatsukami randomly assigned a total 

of 402 smokeless tobacco users to one of 4 treatments: 

active nicotine patch, inactive patch, a combination of 
76

active patch and a non-nicotine 

mint snuff, or a combination 

of inactive patch and mint 

snuff. All participants received 

initial counseling on smokeless 

tobacco cessation methods and 

a self-help manual to take home 

prior to beginning treatment. 

On their quit date, patients 

began using their assigned treatments and continued for 10 weeks. During treatment, 

participants met weekly with counselors for brief support sessions. Results were assessed 15, 25, 36, and 62 

weeks after participants stopped using smokeless tobacco. 

The study found that both the active patch and mint 

snuff reduced craving and withdrawal symptoms, such 

as irritability, frustration, anger, anxiety, and depressed 

mood. Withdrawal symptoms generally peaked during the first week after use was stopped. Only the active 

patch improved rates of continuous abstinence at 10 and 

15 weeks following cessation. By the 23rd week, the differences in abstinence rates among all treatments had 

become marginal, although active patch users were still 

slightly more likely to be abstinent. At 62 weeks following cessation, no significant differences in abstinence were 

observed for any of the treatment conditions.

“A number of studies have shown that the nicotine patch 

is more effective than a placebo patch in sustaining longterm abstinence from cigarette smoking, but the patch 

appeared to be effective with smokeless tobacco users only 

during the period of actual patch use and shortly thereafter,” notes Dr. Hatsukami. “We don’t know if this means 

we need to use the patch for longer periods of time with smokeless 

tobacco users or if sensory or behavioral aspects of smokeless tobacco 

use, such as putting something in 

one’s mouth, may be as important as 

the nicotine in sustaining use,” she 

says. The fact that a nicotine-free 

mint snuff also reduced withdrawal 

symptoms illustrates the potential 

importance of the sensory aspects of smokeless tobacco in 

sustaining its use, she says. Previous research does suggest 

that intensive, multicomponent, behavioral treatment may 

help smokeless tobacco users to sustain abstinence over 

the longer term, she says.

“Many questions about smokeless tobacco use and its 

treatment remain unanswered,” Dr. Hatsukami says. 

“We really need to learn more about all the dimensions 

of smokeless tobacco use to develop effective treatments 

that are better tailored to this underserved population,” 

she says.

Sources

• Hatsukami, D.K., et al. Treatment of spit tobacco 

users with transdermal nicotine system and mint 

snuff. Journal of Consulting and Clinical Psychology

68(2):241-249, 2000.

• Hatsukami, D.K., and Severson, H. Oral spit 

tobacco: addiction, prevention and treatment. 

Nicotine and Tobacco Research 1(1):21-44, 1999. 

Many individuals use 

smokeless tobacco despite its 

obvious drawbacks because 

they are hooked on nicotine, 

a highly addictive drug.
Research Findings

77

Women and Smokeless Tobacco Use

Volume 16, Number 1 (March 2001)

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. (See “Nicotine Patch Helps Smokeless 

Tobacco Users Quit, But Maintaining Abstinence May 

Require Additional Treatment.”)

“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

78

Nicotine Vaccine Moves Toward Clinical Trials

By Barbara Shine, NIDA NOTES Staff Writer 

Volume 15, Number 5 (October 2000)

A new vaccine that prevents nicotine from reaching the brains of 

rats may offer hope for smokers 

trying to break their addiction. 

The compound, called NicVAX, 

may even prove useful as an inoculation against nicotine addiction, 

much like those that protect children from tetanus, measles, 

and polio.

“Some form of vaccination against 

nicotine would be highly useful 

because vaccinated individuals 

would not be able to get a ‘kick’ 

from the nicotine in tobacco 

smoke or chewing tobacco,” 

says NIDA Director Dr. Alan 

I. Leshner. “If people found tobacco less rewarding, they 

would be less likely to continue using it. Ultimately, however, our best treatment for nicotine addiction is prevention.”

NicVAX is manufactured by Nabi, a Florida-based 

pharmaceutical company that has NIDA grant support 

to conduct preclinical studies to determine whether the 

vaccine is toxic to animals and, then, if the compound is 

proven safe, clinical trials to evaluate its safety and efficacy in humans. The 4-year project begins this fall, and 

clinical trials are planned for 2002. Primary coinvestigators include Dr. Ali Fattom and other Nabi scientists in 

Rockville, Maryland, as well as the Minnesota- and Texasbased researchers who conducted the early animal studies.

Paul Pentel and his colleagues at the Minneapolis 

Research Foundation and Hennepin County Research 

Center in Minneapolis and Dr. David Malin at the 

University of Houston at Clear Lake tested NicVAX with 

rats. Injection of NicVAX stimulated antibodies to neutralize nicotine in the blood, reducing by 65 percent the 

amount of nicotine that reached the animals’ brains. The 

nicotine-specific antibodies produced by NicVAX also 

reduced the effects of nicotine on blood pressure and 

the heart.

Now NicVAX is proposed as a therapy that can enhance 

current treatments for nicotine addiction by helping quitting smokers resist the urge to light up. The hypothesis is 

that the vaccine may inhibit nicotine’s “priming effect”—

the phenomenon in which a formerly addicted individual 

experiences an increased desire 

to use a drug after a single 

exposure, which contributes to 

relapse. A treatment program 

built around NicVAX might also 

include supportive counseling 

and a medication such as bupropion (Zyban) to reduce withdrawal symptoms.

The animal studies suggest the 

vaccine’s potential for preventing 

addiction in new tobacco users 

as well. When rats were injected 

simultaneously with a nicotine 

solution and the vaccine, the 

antibodies that reduced nicotine levels in the rat brains also 

reduced nicotine dependence. When the nicotine dosing 

was stopped, the control group, rats injected with nicotine and a placebo solution, showed significantly greater 

levels of dependence—measured by abstinence signs such 

as teeth chattering and tremors—than did the rats treated 

with NicVAX. Rats were exposed to nicotine at levels 

comparable to 10 packs of cigarettes daily for a week.

Continuing doses of nicotine do not interfere with the 

vaccine’s ability to induce antibodies in the rats. Animals 

immunized with NicVAX while they were being injected 

with nicotine still produced nicotine-specific antibodies. 

Thus it may be possible to vaccinate a smoker while he or 

she is still using tobacco so that adequate antibodies will 

be in place at smoking cessation. The vaccine will continue 

to work during any relapse, inhibiting the pleasurable 

response that nicotine would otherwise cause. Further, the 

vaccine never enters the brain and is therefore unlikely to 

produce neurological side effects.

Sources

• Pentel, P.R.; Malin, D.H.; Ennifar, S.; et al. A nicotine conjugate vaccine reduces nicotine distribution to 

brain and attenuates its behavioral and cardiovascular 

effects in rats. Pharmacology Biochemistry and Behavior

65(1):191-198, 1999.

• Hieda, Y.; Keyler, D.E.; VanDeVoort, J.T.; et al. 

Immunization of rats reduces nicotine distribution to 

brain. Psychopharmacology 143(2):150-157, 1999. 

Dr. Ali Fattom (left) and Dr. Sham Shirali of Nabi 

examine a flask of the nicotine preparation used to 

produce NicVAX. Photo by Jane Barrett, Nabi, 

Rockville, Maryland.
Research Findings

79

NIDA’s Nicotine Research Provides Scientific Approaches To 

Combat a Deadly Addiction

By NIDA Director Dr. Alan I. Leshner 

Volume 15, Number 5 (October 2000)

Nicotine addiction takes a terrible toll on 

American health. More than 430,000 people 

die in this country each year from smokingrelated causes, and the annual cost of these 

preventable illnesses—in health care expenditures and lost productivity—is more than $97 

billion. Despite growing public awareness of 

the deadly dangers of tobacco, nearly 3,000 

people younger than 18 become smokers 

every day and, once addicted, find it very difficult to stop.

Over the past decade, NIDA’s nicotine-related 

research has provided crucial insights into 

the neurobiological and behavioral 

aspects of nicotine addiction, and 

this research has led the way to 

important advances in treating 

nicotine addiction. For example, 

NIDA-supported basic science 

research and clinical pharmacological studies played a major role 

in the development of nicotine 

replacement therapy—a skin patch 

or chewing gum that reduces the 

physical discomfort of nicotine 

withdrawal. Our behavioral science 

research has contributed to the 

development, testing, and validation of new behavioral therapies to 

help smokers resist the craving that 

often defeats the most determined efforts to stop smoking.

Many of the accomplishments of NIDA’s nicotine 

research effort have been incorporated into a new set of 

recommendations for primary care practitioners, “Treating 

Tobacco Use and Dependence: A Clinical Practice 

Guideline.” The recommendations, which were released 

by U.S. Surgeon General Dr. David Satcher in June, are 

based on an evaluation of nearly 6,000 peer-reviewed 

research studies. They endorse pharmacotherapies—

sustained release bupropion or nicotine replacement 

therapy by patch, gum, inhaler, or nasal spray—as well 

as behavioral therapy, counseling, and support programs 

to help patients overcome their addiction to nicotine. 

NIDA—along with the National Cancer Institute; the 

National Heart, Lung, and Blood Institute; the Centers 

for Disease Control and Prevention; the 

Agency for Healthcare Research and 

Quality; The Robert Wood Johnson 

Foundation; and the University of 

Wisconsin Medical School’s Center for 

Tobacco Research and Intervention—

sponsored development of the guidelines.

The dividends from NIDA’s ongoing 

investment in nicotine research are increasing. For example, investigators at the 

Minneapolis Medical Research Foundation 

have developed a vaccine that, in rats, 

produces nicotine-specific antibodies that 

reduce by as much as 65 percent the amount of nicotine 

that passes from the blood to 

the brain. The vaccine also prevents some of nicotine’s cardiovascular effects and reduces the 

development of nicotine dependence. This research is a promising first step toward development of a medication that 

could limit the movement of 

nicotine from the blood to the 

brain, reducing the “rush” that 

addicted smokers experience 

when they light up and making it easier for them to quit 

(for more detailed information 

on this research, see “Nicotine Vaccine Moves Toward 

Clinical Trials”). Other NIDA-supported researchers have 

demonstrated important connections between addictions 

to nicotine and other addictive drugs. This knowledge can 

help us develop better therapies for patients with multiple 

addictions (see “Nicotine Craving and Heavy Smoking 

May Contribute to Increased Use of Cocaine and Heroin,” 

NIDA Notes, Vol. 15, No. 5). NIDA’s program of 

research into genetic factors that influence nicotine addiction has identified a genetically determined variation in 

liver metabolism that significantly decreases the rate at 

which the body breaks down and eliminates nicotine from 

the blood. Individuals with this genetic trait are less likely 

to become addicted to nicotine and more likely to be able 

to quit if they do become addicted. NIDA-supported 

Over the past decade, NIDA’s 

nicotine-related research has 

provided crucial insights into the 

neurobiological and behavioral 

aspects of nicotine addiction, 

and this research has led the 

way to important advances in 

treating nicotine addiction. 
80

researchers have found a medication—methoxsalen—

that inhibits nicotine metabolism in the same way as the 

genetic variation. Their studies of the effects of methoxsalen in humans suggest the possibility of developing an entirely 

new approach to pharmacological 

treatment of nicotine addiction 

(see “NIDA-Funded Researchers 

Identify Compound That Inhibits 

Nicotine Metabolism, Decreases 

Urge to Smoke”).

Earlier this year, NIDA 

announced a new research program designed to expand our 

understanding of the basic science 

that influences neurobiological 

and behavioral effects of nicotine 

and other tobacco chemicals. This 

program will support investigations that further explain the connections between nicotine and 

regional brain metabolism, the 

roles of nicotinic receptors and 

endocrine regulation, genetic contributions to variations in susceptibility to nicotine addiction, and 

the neurobiological and behavioral 

components of nicotine craving.

NIDA’s scientific inquiries have 

provided critical insights into 

numerous discrete features of nicotine addiction. But tobacco use 

and nicotine addiction are 

complex subjects that can only be 

truly understood as a dynamic interaction of genetic, environmental, neurophysiological, and behavioral effects. To 

give us the broad perspective we need to fully understand 

this interaction, last year NIDA 

joined with the National Cancer 

Institute and The Robert Wood 

Johnson Foundation to create seven 

Transdisciplinary Tobacco Use 

Research Centers (TTURCs) devoted 

to investigating new ways to combat 

tobacco use and nicotine addiction. 

The TTURCs represent an important new approach to research. They 

bring together collaborators who will 

have the freedom to investigate broad 

aspects of nicotine addiction, from 

factors that influence smoking initiation to the function of specific neurochemicals, and to study the issues 

at levels ranging from molecular 

genetics to peer interactions.

The deadly effects of nicotine reach 

from the individual cell to our 

national health. NIDA is committed 

to continuing and expanding a program of scientific research that provides comprehensive and detailed 

knowledge that can be transformed 

into effective tools to prevent and 

treat the chronic and catastrophic 

effects of nicotine addiction. 

An important part of NIDA’s mission is dissemination of the knowledge gained through 

research. NIDA’s newest “art card” describes 

the similarity between nicotine’s addictive 

properties and those of other addictive drugs. 

The colorful postcards are distributed at restaurants, bookstores, and coffee shops.
Research Findings

81

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

82

NIDA-Funded Researchers Identify Compound That Inhibits 

Nicotine Metabolism, Decreases Urge to Smoke

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 15, Number 5 (October 2000)

In 1998, NIDA-supported investigators identified a 

genetic variation that makes some individuals less liable to 

become addicted to nicotine and, if addicted, more likely 

to smoke fewer cigarettes and have an easier time quitting than do individuals without the variation. Now the 

researchers have found that methoxsalen, a medication 

that mimics the effect of the genetic variation by partially 

blocking the body’s ability to break down nicotine, significantly improves the effectiveness of oral nicotine replacement in reducing a smoker’s urge for nicotine. And, 

according to Dr. Edward Sellers and his colleagues at the 

University of Toronto, when smokers who receive methoxsalen do light a cigarette, they take fewer and shorter 

puffs, thereby reducing their exposure to tobacco smoke’s 

carcinogenic components.

“These results suggest that methoxsalen, or other medications that act at the primary site of nicotine metabolism, 

may represent part of a potent new treatment for nicotine 

addiction,” Dr. Sellers says. “Methoxsalen therapy could 

reduce smokers’ exposure to the harmful constituents of 

tobacco smoke while serving as part of a step-by-step program of smoking reduction leading to cessation.”

Addicted smokers maintain the nicotine in their blood at 

a concentration that prevents the physical discomfort of 

withdrawal. They light up a cigarette when that concentration falls. Many smokers who are trying to quit rely 

on nicotine replacement by transdermal patch or nicotine 

chewing gum to maintain nicotine levels without smoking. Regardless of the nicotine’s source, the drug’s blood 

level falls as it is metabolized by an enzyme produced in 

the liver, cytochrome P450 2A6 (or CYP2A6).

Dr. Sellers and his colleagues tested more than 200 

medications to find compounds that decreased CYP2A6 

activity. They found that methoxsalen, which currently is 

used in treatment regimens for severe psoriasis, reduces the 

activity of CYP2A6 and makes more nicotine—whether 

from a cigarette or nicotine replacement—available in the 

blood for longer. “We found that methoxsalen is a potent 

CYP2A6 inhibitor,” Dr. Sellers says.

The researchers conducted two studies of methoxsalen’s 

effect on nicotine metabolism and craving for nicotine in 

smokers with normal CYP2A6 metabolism who were 

not trying to quit smoking. In one study, 17 smokers 

(8 men and 9 women) received methoxsalen or placebo 

in combination with oral nicotine replacement. Blood 

levels of nicotine were measured in samples taken at 

30-minute intervals for 3 hours. Participants who received 

either 10 or 30 milligrams of methoxsalen had mean nicotine levels roughly twice as high as those given placebo. 

The participants also were asked at hourly intervals to 

rate their urge to smoke. Those who received methoxsalen 

reported far less desire to smoke.

In a second study, 11 participants (5 men and 6 women, 

all of whom had participated in the first study) received 

either methoxsalen or placebo in combination with nicotine or placebo. Following a 60-minute abstinence, the 

participants were allowed to smoke at will for 90 minutes. 

Methoxsalen inhibits the normal liver metabolism of 

nicotine, and the resulting higher concentration of nicotine 

in the blood reduces a smoker’s desire to smoke. Horizontal 

bars indicate average blood nicotine concentrations measured 

5 times during 3 hours following the administration of oral 

nicotine combined with placebo or methoxsalen. Cigarettes 

indicate the participants’ desire to smoke, rated from 0 

(none) to 100 (strongest).
83

Smokers who had received methoxsalen plus nicotine 

smoked fewer cigarettes, had longer intervals between 

cigarettes, and took fewer puffs on each cigarette.

The doses of methoxsalen used in the studies are lower 

than the dose approved for human use in treating 

psoriasis, Dr. Sellers says, but the medication has not been 

proven safe for long-term use in humans. “We need to 

establish methoxsalen’s safety and efficacy in chronic use 

before it could be used as part of any smoking cessation 

treatment,” he says. 

Methoxsalen offers several advantages as a part of treatment for smoking cessation, Dr. Sellers says. For example, 

it would make possible the use of a pill, rather than a 

patch or gum, for nicotine replacement. “Most patients 

prefer taking an oral medication, and there are places 

where gum is not appropriate,” he says. And, because 

methoxsalen eliminates almost completely the activity of 

CYP2A6, which varies from person to person, its use with 

a nicotine pill could result in more predictable response to 

nicotine replacement than is possible with either patch or 

gum, Dr. Sellers says.

Source

• Sellers, E.M.; Kaplan, H.L.; Tyndale, R.F. Inhibition 

of cytochrome P450 2A6 increases nicotine’s bioavailability and decreases smoking. Clinical Pharmacology 

and Therapeutics 68(1):35-43, 2000. 

Participants were allowed to smoke at will for 90 minutes 

following the administration of combinations of placebo, oral 

nicotine, and 30 milligrams of methoxsalen. Participants 

who received methoxsalen and nicotine had significant 

reductions in the number of cigarettes smoked and carbon 

monoxide—one of tobacco smoke’s most harmful components—measured in breath.
Research Findings

84

Gender Differences in Drug Abuse Risks and Treatment

By Patrick Zickler, NIDA NOTES Staff Writer

Volume 15, Number 4 (September 2000)

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).
85

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 or from the DrugPubs Research 

Dissemination Center, by phone: 877-643-2644 (TTY/

TDD: 240-645-0228), or e-mail: drugpubs@nida.nih.gov.
Research Findings

86

Evidence Builds That Genes Influence Cigarette Smoking

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 15, Number 2 (August 2000)

More than one in four 

Americans older than 17 

regularly smokes cigarettes 

despite increasing public awareness of tobacco’s 

severe health risks. Some 

start younger than others 

and, among those who try 

to quit, some are more successful than others. NIDAsupported scientists are 

finding increasing evidence 

that these differences may be 

due in part to an inherited 

vulnerability to nicotine 

addiction.

At the St. Louis University 

Health Sciences Center, 

Dr. William True and Dr. 

Hong Xian interviewed male 

twin pairs to assess genetic 

influences on smoking. 

In twin studies, researchers compare patterns of 

tobacco use in fraternal and 

identical twin pairs, who 

typically are exposed to common environmental influences. If genes play a role 

in determining tobacco use, 

identical twins—who share the same genes—will be more 

similar in their use of tobacco than fraternal twins, who 

share roughly half of their genes. The St. Louis University 

researchers found that among the 3,356 twin pairs studied, genetic factors make a stronger contribution to nicotine dependence (61 percent) than do environmental factors (39 percent) and also play a more prominent role (55 

percent) than environmental factors (45 percent) in alcohol dependence. In another study, Dr. Kenneth Kendler 

and his colleagues at the Medical College of Virginia in 

Richmond interviewed 949 female twin pairs and found 

that genetic factors play a more important role (78 percent) than do environmental factors (22 percent) in smoking initiation and in nicotine dependence (72 percent vs. 

28 percent).

“These studies emphasize 

the importance of understanding the role of genetic 

influences in smoking,” says 

Dr. Jaylan Turkkan, chief of 

NIDA’s Behavioral Sciences 

Research Branch. “The more 

we understand about vulnerabilities, risks, and possible 

protective factors, the better 

able we will be to tailor 

treatments that help people 

stop smoking.”

Other NIDA-supported 

scientists are studying genes 

that are polymorphic—that 

is, in different individuals the 

same gene has slight variations called alleles—and have 

found that individuals with 

one type of allele are more 

likely to begin smoking or 

to have greater success quitting than are individuals with 

another type. For example, 

researchers at the University 

of Toronto have found that 

different alleles in a gene 

that helps regulate nicotine 

metabolism may protect 

some smokers from becoming dependent on nicotine 

(see “Study Shows How Genes Can Help Protect from 

Addiction,” NIDA NOTES, V13-6, 1998).

Dr. Caryn Lerman, principal investigator of the NIDAsupported Transdisciplinary Tobacco Use Research Center 

at Georgetown University in Washington, D.C., and her 

colleagues studied two genes, designated SLC6A3 and 

DRD2, that may influence smoking behavior by affecting the action of the brain chemical dopamine. In a study 

involving 289 smokers and 233 nonsmokers (42 percent 

male, 58 percent female, average age 43), the researchers 

found that smokers were less likely to have an allele designated SLC6A3-9 (46.7 percent) than were nonsmokers 

(55.8 percent). The likelihood of smoking was even lower 

if the individual had both the SLC6A3-9 allele and the 

A Medical College of Virginia study involving 949 female twin 

pairs found genetic factors to be more influential than environmental factors in smoking initiation and nicotine dependence. 

Likewise, a St. Louis University study of 3,356 male twin pairs 

found genetic factors to be more influential for dependence on nicotine and alcohol. 
87

DRD2-A2 allele. In addition, Dr. Lerman observed 

that smokers with the 

SLC6A3-9 allele were more 

likely to have started smoking later and to have had 

longer periods of smoking 

cessation than those without 

the allele. These findings 

imply that the allele may 

impart a protective effect. Therefore, Dr. Lerman suggests, 

smokers without the SLC6A3-9 allele may be better able 

to quit smoking if their treatment incorporates a medication such as bupropion that acts on the brain’s dopamine 

pathway. This hypothesis is currently being tested in a 

randomized trial.

Dr. Lerman and her colleagues also studied a polymorphism in a gene, designated 5-HTTLPR, that helps 

regulate the brain chemical serotonin to determine the 

gene’s possible role in smoking. The polymorphism has 

two alleles, one designated the short, or S, allele, the other 

the long, or L allele. In previous studies the S allele has 

been linked to neuroticism—an anxiety-related personality 

trait. Dr. Lerman and her colleagues studied 185 smokers 

(46 percent male, 54 percent female, and average age 45) 

to investigate the possible relationship between genetically influenced neuroticism and smoking behavior. They 

found that neuroticism was associated with increased 

nicotine dependence, smoking for stimulation, and smoking to relieve negative mood in the group of smokers who 

had the S allele. Among smokers with the L allele, neuroticism was not associated with these smoking patterns. 

“Anxious persons tend to smoke more and have more 

difficulty quitting,” Dr. Lerman says. The new findings 

suggest that among smokers with neuroticism, determining the 5-HTTLPR genotype 

may help identify who will be 

more responsive to a particular 

type of treatment. “Once validated, these results may lead to 

targeted pharmacotherapy for 

smoking cessation,” says Dr. 

Lerman.

“This area of research represents our first small steps along a very complicated 

path to understanding the role that genes play in drug 

abuse,” notes Dr. Harold Gordon of NIDA’s Clinical 

Neurobiology Branch. “Many genes interact with each 

other and with other biological and environmental factors. 

Defining these interactions and understanding their influence on nicotine addiction will be crucial to development 

of treatments for smoking and for other addictions.”

Sources

• Kendler, K., et al. A population-based twin study in 

women of smoking initiation and nicotine dependence. Psychological Medicine 29(2):299-308, 1999.

• Lerman, C., et al. Evidence suggesting the role of 

specific genetic factors in cigarette smoking. Health 

Psychology 18(1):14-20, 1999.

• Lerman, C., et al. Interacting effects of the serotonin 

transporter gene and the neuroticism in smoking 

practices and nicotine dependence. Molecular 

Psychiatry 5(2):189-192, 2000.

• True, W.R., et al. Common genetic vulnerability for 

nicotine and alcohol dependence in men. Archives of 

General Psychiatry 56(7):655-661, 1999. 

“The more we understand about 

vulnerabilities, risks, and protective 

factors, the better able we will be to 

help people stop smoking.”
Research Findings

88

NIDA Joins NCI, Robert Wood Johnson Foundation To Launch 

Tobacco Research Centers 

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 15, Number 1 (March 2000)

NIDA, the National 

Cancer Institute (NCI), 

and The Robert Wood 

Johnson Foundation 

(RWJF) have awarded 

grants to seven academic 

research institutions to 

establish Transdisciplinary 

Tobacco Use Research 

Centers (TTURCs) devoted to investigating new 

ways to combat tobacco 

use and nicotine addiction. The institutions will 

receive $70 million from 

NIDA and NCI for the 

project. RWJF will provide 

an additional $14 million 

over 5 years to support 

improved communications 

and policy development at 

the TTURCs.

In the past, research grants 

typically have focused 

on single components of 

tobacco use and nicotine 

addiction, treatment, or 

prevention, notes Dr. 

Jaylan Turkkan, chief of NIDA’s Behavioral Sciences 

Research Branch and coordinator of NIDA’s TTURC 

efforts. “The transdisciplinary approach will bring together 

collaborators who will have the freedom to investigate wider 

aspects of nicotine addiction, such as factors that influence 

smoking initiation, and to study the issues at levels ranging 

from genetics to peer interactions,” Dr. Turkkan says.

“The transdisciplinary centers represent an important new 

approach to research,” says NIDA Director Dr. Alan I. 

Leshner. “Tobacco use and nicotine addiction are incredibly complex subjects, and transdisciplinary investigation 

can give us the broad perspective we need to understand 

the etiology of this addiction. This approach will lead 

to the development of new interventions that will help 

prevent tobacco use, particularly among teens and younger 

children.”

The TTURC concept 

evolved from informal 

conversations among 

researchers and policymakers at a July 1998 

conference—“Addicted 

to Nicotine”—cosponsored by NIDA, RWJF, 

NCI, and the Centers 

for Disease Control 

and Prevention. Several 

months later, NCI’s 

Tobacco Research Implementation Group recommended transdisciplinary 

centers as its highest 

tobacco use research

priority. Within a year, 

NIDA and NCI jointly 

issued a Request for 

Applications from academic centers interested 

in developing such centers. The first TTURC 

awards were announced 

in October 1999. The 

centers, principal investigators, and research areas are: 

• Brown University Center for Behavioral and 

Preventive Medicine at the Miriam Hospital, 

Providence, Rhode Island; Principal Investigator Dr. 

David Abrams; Research Area Identification of early 

childhood and lifetime psychiatric factors that determine smoking initiation, dependence, use patterns, 

cessation, and response to cessation treatment. 

• University of California, Irvine; Principal Investigator

Dr. Frances Leslie; Research Area Identification of 

predictors of nicotine addiction in animals and 

tobacco susceptibility and use in humans; 

• University of Southern California, Los Angeles; 

Principal Investigator Dr. C. Anderson Johnson; 

Research Area Preventing tobacco use among youth of 

diverse cultures. 

Although the prevalence of adult cigarette smokers is high, the 

numbers reflect only one piece of the problem. NIDA’s new research 

centers will seek ways to combat all types of tobacco use among all 

population segments, adults and children alike. Statistics from 

Centers for Disease Control and Prevention in Atlanta. 

Percentages of Adults*

Who Smoke Cigarettes
89

• Georgetown University, Washington, D.C.; Principal 

Investigator Dr. Caryn Lerman; Research Area

Identification of biobehavioral basis of smoking initiation, smoking treatment, and harm from tobacco 

exposure. 

• University of Minnesota, Minneapolis; Principal 

Investigator Dr. Dorothy Hatsukami; Research Area

Treating smokers who have been resistant to conventional methods of intervention or who have not been 

previously targeted. 

• University of Wisconsin Medical School, Madison; 

Principal Investigator Dr. Michael Fiore; Research Area

Relapse to tobacco use. 

• Yale University, New Haven, Connecticut; Principal 

Investigator; Dr. Stephanie O’Malley; Research Area

Treatment of tobacco addiction. 
Research Findings

90

New NIDA Clinic Tests Therapies to Help Teens Quit Smoking 

By Steven Stocker, NIDA NOTES Contributing Writer 

Volume 14, Number 4 (November 1999)

NIDA’s Intramural Research 

Program (IRP) recently opened 

a new Teen Tobacco Addiction 

Treatment Research Clinic at 

the Bayview Medical Center 

in Baltimore. At the clinic, 

researchers will evaluate promising therapies for adolescent 

nicotine addiction.

One of the clinic’s first research 

projects will be a pilot study 

of smoking cessation treatments for 13- to 17-year-old 

cigarette smokers. “More than 

one-third of 17-year-olds who 

smoke say they are interested in 

some form of treatment to help 

them quit,” says IRP’s Dr. Eric 

Moolchan, director of the new 

clinic and leader of the smoking 

cessation study.

The research project will test 

the combination of nicotine 

replacement therapy (NRT) and group counseling for 

treating nicotine addiction in adolescents. NRT helps 

smokers learn to abstain from smoking by replacing the 

nicotine that they previously obtained from cigarettes, 

thereby preventing withdrawal symptoms and craving for 

nicotine. NRT forms currently available include the nicotine patch and gum.

Dr. Moolchan says that many health care providers are 

reluctant to prescribe nicotine patches or gum for adolescents because of a lack of studies showing that these products are safe and effective in this age group. The IRP pilot 

study will help determine whether adolescents can use the 

nicotine patch and gum safely, whether they can tolerate 

the same nicotine doses in the patch and gum as adults, 

and whether they will follow the instructions on how to 

use these products. Later studies will focus more on the 

effectiveness of the patch and gum in helping adolescents 

quit smoking.

“It’s important that we develop effective treatments 

for young people to try to get them to quit smoking as 

early as possible,” says IRP Director Dr. Barry Hoffer. 

“Research shows that 90 percent of people who die 

prematurely of a cigaretterelated disease started 

smoking when they were 

adolescents. If we can help 

adolescents quit smoking, 

we should be able to prevent many of these premature deaths.”

The IRP study will have 3 

groups, each with 18 adolescents. The first group 

will receive active patches 

containing nicotine and 

placebo gum without nicotine, the second group will 

receive placebo patches 

and active gum, and the 

third group will receive 

placebo patches and placebo gum. Participants will 

not be told whether the 

products they receive are 

active or placebo.

All three groups will also participate in group counseling 

sessions because studies with adult smokers have indicated 

that smoking cessation programs that combine behavioral 

therapy with medications produce the highest abstinence 

rates. In the counseling sessions, a mental health professional and Dr. Moolchan, who is a pediatrician, will discuss various topics involving smoking and health and will 

teach the adolescents how to modify their behavior to deal 

with situations that might cause them to smoke.

Even though smoking is the primary focus of the sessions, 

other topics—such as peer relations, school, and dating—

will be discussed. “Addressing these other issues is important because adolescent smokers often think that smoking 

helps them in their social relations,” says Dr. Moolchan. 

“Furthermore, problems concerning social relations can 

negatively affect mood, and smokers often regulate their 

mood with nicotine.”

The IRP project also will examine other aspects of adolescent smoking. One study will analyze how adolescents 

smoke cigarettes—for example, how deeply they inhale 

or how many puffs they take per cigarette. IRP researchers will also study whether nicotine withdrawal causes 

Cutting the ribbon to dedicate NIDA’s new Teen Tobacco 

Addiction Treatment Research Clinic (TTATRC) in Baltimore 

are, from left, Dr. Jean Lud Cadet, clinical director, NIDA’s 

Intramural Research Program (IRP); NIDA Director 

Dr. Alan I. Leshner; Dr. Barry Hoffer, director of NIDA’s 

IRP; Dr. Eric Moolchan, director of TTATRC; and 

Dr. Monique Ernst, IRP researcher. 
91

adolescents to experience problems with concentration and 

short-term memory and whether 

nicotine-replacement treatments 

can reverse these deficits. Another 

project will measure chemical evidence of cigarette consumption 

in saliva to determine whether 

adolescents metabolize the components of cigarette smoke in the 

same way that adults do.

The researchers will recruit adolescents 

from the Baltimore area through referrals from healthcare providers, schools, 

churches, and youth centers. Dr. 

Moolchan hopes that this study will 

establish contacts in the community that 

can be used to recruit adolescents for 

future studies. 

“More than one-third of 

17-year-olds who smoke 

say they are interested in 

some form of treatment 

to help them quit.”
Research Findings

92

New Tracers Will Help Researchers Track Nicotine in the Brain

Volume 14, Number 2 (August 1999)

Dr. Edythe D. London and her colleagues at the Brain 

Imaging Center of NIDA’s Intramural Research Program 

in Baltimore have developed a new class of radio-labeled 

chemicals capable of binding tightly to nicotinic acetylcholine receptors, the molecules in the brain where 

nicotine acts. These probes will enable scientists to monitor nicotinic pathways in the brain by external imaging. 

Because these radiotracers attach themselves with more 

selectivity and less toxicity than currently available nicotinic radiotracers, researchers believe they may be ideal 

for both positron emission tomography (PET) and single 

photon emission computed tomography (SPECT), two 

common brain imaging technologies. 

Testing in primates has led scientists to conclude that this 

new class of radiotracers will be practical for studying the 

underlying mechanisms of nicotine dependence in 

humans and will be useful for developing and testing therapies for nicotine addiction. These radiotracers may also 

benefit the study of Alzheimer’s disease, Parkinson’s disease, and Tourette’s syndrome, which scientists believe are 

conditions characterized at least in part by abnormalities 

in nicotinic receptors. The Brain Imaging Center is now 

seeking FDA approval to use the new radiotracers in 

studies with human volunteers. 
Research Findings

93

Nicotine Conference Highlights Research Accomplishments 

And Challenges

By Barbara Cire, NIDA NOTES Associate Editor 

Volume 13, Number 5 (February 1999)

Provocative new research findings about the nicotine 

addiction process, how nicotine addiction drives tobacco 

use, and nicotine addiction treatment were the focus of 

“Addicted to Nicotine: A National Research Forum,” 

held in Bethesda, Maryland in July. The meeting was 

sponsored by NIDA and The Robert Wood Johnson 

Foundation and cosponsored by the National Cancer 

Institute and the Office on Smoking and Health of the 

Centers for Disease Control and Prevention. NIDA 

Associate Director Dr. Timothy P. Condon and Dr. 

Jaylan Turkkan, Chief of NIDA’s Behavioral Sciences 

Research Branch, served as cochairs of the conference 

planning committee. 

Keynote speaker Vice President Al Gore noted that the 

conference had drawn some of the world’s best researchers “to reinforce that nicotine is a drug—a dangerous, 

highly addictive drug, and we should treat it as a drug.” 

He cited recent research findings indicating that while the 

overall incidence of smoking has decreased, the number of 

adolescents starting to smoke has increased. “If children 

don’t start smoking by age 19, they are unlikely to start,” 

he said. “But, if they do start, it’s hard to stop. Seventy 

percent of current smokers say they want to stop smoking, but can’t. That’s because nicotine is a highly addictive 

drug—as addictive as heroin or cocaine.” 

“We are here to apply the power of science to this problem,” said NIDA Director Dr. Alan I. Leshner. He challenged the approximately 600 participants to highlight 

what is known about nicotine addiction and tobacco 

use and to “tell us what else we need to know to set the 

research agenda for the next decade.” More than 40 scientists from the United States, Canada, and Sweden presented research results in four topic areas: the pharmacology of nicotine; individual and environmental risk factors 

for smoking initiation and nicotine intake; the biology of 

nicotine addiction; and treatment of nicotine addiction. 

Dr. Jack Henningfield of The Johns Hopkins University 

School of Medicine in Baltimore said that, since the 

beginning of the 20th century, scientists have known that 

nicotine is a potent substance that affects the nervous system and stimulates heart rate and muscular activity, that 

nicotine’s effects depend on the amount administered, and 

that responsiveness to nicotine diminishes with repeated 

use. NIDA-supported research has demonstrated conclusively that nicotine meets all the criteria of an addictive 

drug, he stressed. 

Nicotine is now understood to affect the structure and 

function of the nervous system, Dr. Henningfield said. 

Chronic nicotine exposure and withdrawal produce 

changes in brain function, including cerebral metabolism 

and hormone levels, he added. 

Dr. Rachel Tyndale of the University of Toronto presented information about a gene variant for an enzyme 

called CYP2A6 that may protect some individuals 

from becoming addicted to nicotine. In humans, 60 to 

80 percent of nicotine is metabolized by the CYP2A6 

enzyme. Individuals with a defective version of the gene 

for CYP2A6 metabolize nicotine slowly and inefficiently. 

When people start to smoke, they often experience dizziness or nausea; when nicotine metabolism is slowed, these 

unpleasant effects may last longer, Dr. Tyndale explained. 

Thus, people with a defective version of this gene are less 

likely to continue smoking and, if they do smoke, are 

more likely to smoke less than people with a fully functioning version of this gene. 

“This genetic defect protects approximately 7 million 

North Americans from smoking,” said Dr. Tyndale. 

“Inhibiting the CYP2A6 enzyme may provide new 

therapeutic approaches to the prevention and treatment 

In his keynote address at NIDA’s nicotine conference, Vice President 

Al Gore tells participants that 3,000 young people start smoking each 

day, ultimately resulting in death for one-third of them. 
94

of smoking. The manipulation of CYP2A6 must be 

explored.” 

Dr. Marina Picciotto of Yale Medical School in New 

Haven, Connecticut, discussed a particular protein that 

she and her colleagues in France, Sweden, and Switzerland 

have identified as essential to the nicotine addiction 

process. Using sophisticated bioengineering tools, the 

researchers produced a strain of mice that lack this protein. They found that the genetically altered mice did not 

experience the normal rewarding and reinforcing aspects 

of nicotine that typically lead to addiction. 

“The majority of smokers try to quit on their own without seeking help. The quit rate for this group is 5 percent 

or less,” said Dr. Maxine Stitzer of The Johns Hopkins 

University School of Medicine, summarizing treatment 

research that compared the effectiveness of nicotine 

replacement therapy and behavioral therapy separately 

and combined. Because these treatments operate by different mechanisms, complementary and potentially additive 

effects may be expected when they are used in combination, she said. 

“Typical long-term abstinence rates of 6 to 12 months 

for one type of therapy alone are about 20 percent,” Dr. 

Stitzer said. “Combining therapies can produce long-term 

abstinence rates as high as 35 to 40 percent. We need to 

know how to improve access, affordability, and acceptability of both pharmacologic and behavioral therapies to 

take better advantage of existing treatments such as overthe-counter nicotine-replacement products. We must also 

learn how to strengthen the linkage between the two 

therapy types.” 

For More Information 

Additional information about nicotine and its addictive 

properties can be obtained by calling NIDA Infofax at 

1-888-NIH-NIDA (644-6432) or by accessing NIDA’s 

home page on the World Wide Web at www.nida.nih.gov 

and going to the “Addicted to Nicotine” conference

information. 

Dr. Marina Picciotto 

of Yale Medical School 

discusses a recently 

identified protein that 

is involved in the 

reinforcing and 

rewarding aspects of 

nicotine addiction. 
Research Findings

95

Like Other Drugs of Abuse, Nicotine Disrupts the Brain’s 

Pleasure Circuit

By Neil Swan, NIDA NOTES Staff Writer

Volume 13, Number 3 (July 1998)

All drugs of abuse disrupt the normal flow of the neurotransmitter dopamine, stimulating its release and 

increasing its brain levels. This action is believed to be significantly involved in producing drug-induced feelings of 

pleasure and reward and, over time, addiction and vulnerability to withdrawal symptoms. Drugs of abuse begin this 

action by chemically binding to specific molecular sites 

called receptors, some of which are found on dopamine 

nerve cells.

Recent findings from several NIDA-funded researchers 

confirm not only that nicotine is highly addictive but 

that it affects the same brain mechanism as other drugs 

of abuse and increases brain levels of dopamine. The 

findings also suggest how nicotine abstinence and withdrawal activate the body’s stress systems. Two research 

teams have spotlighted how nicotine, just like heroin or 

cocaine, activates dopamine-containing nerve cells in the 

brain’s mesolimbic system, which is involved in emotion 

and behavior. Another group has shown that some brain 

changes during withdrawal from chronic nicotine use are 

similar to those that occur during withdrawal from other 

drugs of abuse.

Dr. John A. Dani of Baylor College of Medicine in 

Houston and his colleagues have shown that nicotine 

binds at multiple receptors on dopamine nerve cells, or 

neurons, to activate the neurons. Theoretically, this activation of dopamine neurons by nicotine begins the response 

that leads to feelings of pleasure and reward, and then 

addiction. The researchers examined dopamine nerve cells 

from the brains of rats that had been exposed to nicotine 

for prolonged periods. They found that nicotine at levels 

comparable to those found in human smokers first activates or sensitizes these neurons but then quickly desensitizes them.

The researchers believe nicotine-induced desensitization of 

dopamine cells may explain why smokers report that they 

rapidly become tolerant to the effects of smoking during 

the day. The tolerance fades overnight so that by the next 

morning the dopamine cells are resensitized to nicotine, 

the researchers theorize.

“This finding suggests a cellular explanation for smokers’ reports that their first cigarette of the day is the most 

pleasurable,” while the pleasurable effect of cigarettes 

smoked later in the day is greatly reduced, says Dr. Dani. 

“It’s a biophysical extrapolation to explain how the cellular response to nicotine ultimately affects behavior,” he 

explains. The results further support the theory that nicotine acts through the same cellular mechanism as other 

addictive drugs and that this mechanism—dopamine 

activity in the mesolimbic system—is implicated in various ways in the cellular and behavioral effects of addictive 

drugs, he says.

Dr. Marina Picciotto of Yale Medical School in New 

Haven, Connecticut, and her colleagues in France, 

Sweden, and Switzerland have gone a step further 

and have pinpointed the specific protein to which 

nicotine binds on a particular nicotinic receptor on a 

dopamine cell.

The researchers used a strain of mouse developed by 

Dr. Picciotto in which the gene that encodes this protein 

is eliminated or “knocked out.” The researchers found 

that these knockout mice did not self-administer nicotine as their normal sisters did. The finding suggests that 

the mice without the protein, called the beta 2 subunit, 

did not experience the normal reinforcing, or rewarding, effects of nicotine. But the mice did self-administer 

cocaine, an indication that knocking out the beta 2 

subunit affected only their response to nicotine, not to 

other drugs.

The experiment tested the behavioral response of the 

mice. But what about their physiological response? If the 

knockout mice were injected with nicotine, would the nicotine increase dopamine levels? No. In a followup experiment, nicotine injections did not boost dopamine levels in 

the brains of knockout mice. This finding provided further evidence of the influential role of the beta 2 subunit 

in the nicotine addiction process. The study findings are 

consistent with the theory that the dopamine brain circuit 

is the reward pathway used by all drugs of addiction but 

that different drugs activate this pathway through different molecular gateways.

“In our altered mice, we’ve shown that if you take away 

one subunit of the nicotinic receptor, you take away the 

ability of nicotine to stimulate dopamine release,” explains 

Dr. Picciotto.

“To actually pinpoint a particular protein shown to be 

critical to nicotine addiction is a major discovery,” says 
96

NIDA Director Dr. Alan I. Leshner. Future medications 

for nicotine addiction might target that specific protein, 

he says.

Dr. Picciotto is now studying how this nicotinic receptor 

and its subunits affect the rewarding properties of other 

drugs such as morphine, cocaine, and alcohol. “People 

who abuse other drugs are also likely to be smokers, and 

we would like to know more about interactions between 

the different systems that mediate the rewarding effects of 

these different drugs,” she says.

Another NIDA-funded study shows that the severity of 

changes that occur in the brain’s pleasure circuits during 

withdrawal from chronic nicotine use rivals that experienced during withdrawal from other abused drugs such as 

cocaine, amphetamine, morphine, and alcohol.

The study found dramatically decreased sensitivity to 

pleasurable electrical stimulation in the brains of rats 

after nicotine administration was stopped. The decreased 

sensitivity, which lasted several days, may correspond to 

the depression experienced by humans who quit smoking 

“cold turkey.”

“Understanding these decreases in the brain’s sensitivity to 

pleasurable stimulation during nicotine abstinence helps 

explain why it’s so hard for people to stop smoking and 

may help develop better treatments for nicotine withdrawal 

symptoms such as depression, anxiety, irritability, and 

craving for a cigarette,” says Dr. Leshner. “The brainchange similarities to other drugs of abuse emphasize that 

there are common characteristics to withdrawal from all 

addictive substances, one of which is decreased sensitivity 

to pleasure,” he says.

Dr. Athina Markou and her colleagues at The Scripps 

Research Institute in La Jolla, California, measured the 

effects of nicotine abstinence on the brain’s sensitivity 

to pleasure-inducing electric pulses. They taught rats to 

self-administer brief electrical pulses in the lateral hypothalamus, part of the brain’s reward circuitry, and then 

monitored the level of pleasure, or reward, experienced 

by the animals.

Reward sensitivity measures were taken during and after 

administration of nicotine. For a week the rats were 

infused with a steady dose of nicotine to produce nicotine 

blood levels equivalent to those of a human smoking 30 

cigarettes a day.

While nicotine was administered, the animals’ sensitivity to brain reward remained stable, as shown by the fact 

that they self-administered pleasure-inducing pulses at the 

same level as before nicotine was introduced. When the 

rats’ nicotine was cut off, however, the scientists had to 

increase the intensity of electrical current by more than 40 

percent before the rats showed through their behavior that 

electrical pulses to the brain were again pleasurable.

“These results are comparable to the altered brain reward 

sensitivity found during withdrawal from many other 

addictive drugs,” says Dr. Markou. The experiment 

provides a valid animal model for studying the function 

of brain reward circuits involved in nicotine withdrawal 

and to help develop treatments for nicotine addiction, 

she adds.

Sources

• Epping-Jordan, M.P.; Watkins, S.S.; Koob, G.F.; 

and Markou, A. Dramatic decreases in brain reward 

function during nicotine withdrawal. Nature 393:76, 

1998.

• Picciotto, M.R., et al. Acetylcholine receptors containing the b2 subunit are involved in the reinforcing 

properties of nicotine. Nature 391:173-177, 1998. 

• Pidoplichko, V.I.; DeBiasi, M.; Williams, J.T.; and 

Dani, J.A. Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390:401-404, 

1997. 
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