Identifying the long-term impact of drugs is crucial to understanding drug abuse and addiction. Chronic use of drugs by adults may have effects that last long after drug use has stopped. In children, exposure to drugs may impair development or contribute to behavioral disorders. But understanding these long-term effects requires well-designed research projects that may last decades. Three recent MERIT Award recipients are carrying out investigations that will provide answers to important questions about the long-term impact of drug use.

Studying the Long-term Consequences of Prenatal Exposure to Marijuana and Cigarettes

Dr. Peter A. Fried

For more than 15 years, Dr. Peter A. Fried, professor of psychology at Carleton University in Ottawa, Canada, has studied mother-child pairs to determine whether prenatal exposure to marijuana, cigarettes, or both affects the development and behavior of children and adolescents. Dr. Fried's MERIT Award will allow him to continue to follow the mother-child pairs as the children develop through their teenage years.

"Dr. Fried's research represents an immense opportunity to obtain previously unattainable information on the long-term consequences of prenatal exposure to marijuana and cigarettes," says Dr. Vincent Smeriglio of NIDA's Center for AIDS and Other Medical Consequences of Drug Abuse. "His research already has made a significant contribution not only to documenting infancy and childhood consequences, but also to exploring possible mechanisms for those consequences."

Dr. Fried's research involves more than 150 children born in the Ottawa area who were exposed before birth to cigarettes, marijuana, or both. Dr. Fried and his colleagues evaluated the children several hours after birth and at 4 days, 7 days, 9 days, 30 days, 6 months, and 1 year. The researchers have evaluated the children annually since their first year to look for developmental and behavioral problems that might be related to prenatal exposure to marijuana or cigarettes. The researchers' findings suggest that marijuana exposure is associated with impaired executive functioning - the ability to make decisions and plan for the future - in the children at 9 to 12 years of age. "The major finding in this study about regular marijuana use during pregnancy is that marijuana can have an impact that may prevent a child from achieving his or her full potential," Dr. Fried says.

Children born to women who smoked cigarettes during pregnancy showed, from infancy through early adolescence, a reduction in auditory-based abilities. From ages 9 to 12, children who were exposed prenatally to tobacco smoke showed a reduction in language scores and poorer performance in tests involving the auditory aspects of reading compared with children born to nonsmokers, with the most heavily exposed children performing worse than those exposed to smaller amounts. "The continuity, over approximately 12 years, of the relationship between auditory and language variables and prenatal exposure to cigarette smoke suggests that these important aspects of behavior are directly affected by maternal smoking," Dr. Fried says.

The MERIT Award will simplify the continuation of this research through a crucial period of the children's development, Dr. Fried notes. "Testing the children at midadolescence is particularly critical. Subtle learning difficulties are most likely to manifest themselves at this stage of development, which involves complex behaviors requiring focused attention and cognitive skills," he says.

Investigating the Effects of Chronic Heavy Marijuana Use

Research has shown that heavy and long-term marijuana users suffer impaired cognitive function during and immediately following periods of marijuana use. But does this impairment last, and for how long, if marijuana use is discontinued?

Dr. Harrison Pope, Jr.

Answers to these questions may come from NIDA-supported research under way at the McLean Hospital Biological Psychiatry Laboratory in Belmont, Massachusetts.

The research is part of the work being done by Dr. Harrison Pope, Jr., who recently received a NIDA MERIT Award to continue his investigations.

Dr. Pope's research focuses on 30- to 54-year-old individuals - including both men and women and representing a range of ethnic and socioeconomic groups - who have smoked marijuana at least 5,000 times. This rate of use is equivalent to having smoked marijuana at least once daily for more than 13 years. The study participants will be given a series of neuropsychological tests during a 28-day period of abstinence - monitored by analysis of observed daily urine collections - from marijuana and other drugs.

Using similar neuropsychological tests, Dr. Pope demonstrated that college-age heavy marijuana users performed more poorly than light users on memory, learning, and attention tests following a 24-hour period of supervised abstinence. "Testing after a longer abstinence period in our new study will allow us to distinguish between prolonged impairment that results from marijuana neurotoxicity and temporary impairment that might simply be the result of marijuana residues or withdrawal effects," Dr. Pope says.

"This unique research will allow us to get a much clearer understanding of the residual effects of chronic heavy marijuana use on brain function," says Dr. Jag Khalsa of NIDA's Clinical Medicine Branch. "Equally important is the MERIT Award's potential for expanding the current research using this rich database."

Looking for Links Between Substance Dependence and Adolescent Conduct Disorder

Many adolescents who suffer from conduct disorder are also substance dependent, and the two disorders together represent a major health problem for adolescents. Research being conducted by MERIT Award recipient Dr. Thomas Crowley will help clarify the critical relationship between conduct disorders and substance dependence.

Dr. Thomas Crowley

Dr. Crowley, at the University of Colorado School of Medicine's Addiction Research and Treatment Service in Denver, has spent more than 20 years treating adolescents referred by criminal justice agencies. "Among the patients diagnosed with conduct disorder, 80 percent are also dependent on marijuana, and more than half are dependent on nicotine," Dr. Crowley says. He found that conduct disorders preceded substance dependence in the majority of the adolescents referred to his program with both conditions. Although many of the patients began their substance use - usually with marijuana or alcohol - as early as age 12, in 75 percent of the patients conduct disorders began even earlier.

"Conduct disorder is a major contributor to substance dependence in these patients, and our work suggests that conduct disorders will coexist with most substance dependence that begins early in adolescence," Dr. Crowley says.

Dr. Crowley says his MERIT-supported research will allow him to investigate more fully the relationship between conduct disorder, attention deficit/hyperactivity disorder, and substance dependence. In addition, Dr. Crowley and his colleagues will examine the possible role of genetic and familial factors in patients suffering from both conditions.

"Antisocial drug dependence - that is, substance dependence combined with conduct disorder or antisocial personality disorder - may be due in part to genetic influences and may need special treatment," Dr. Crowley says. He and other researchers will use behavioral studies and brain imaging to investigate the action of tetrahydrocannabinol, the principal psychoactive component in marijuana, in the brains of adolescents with coexisting conduct disorder and marijuana dependence. "We will identify and quantify the characteristic of comorbidity in these patients and use that information to investigate the underlying behavioral genetics," Dr. Crowley says.

"Dr. Crowley and his research team are one of the very few groups in the country who are addressing this clinical population. Their MERIT-supported studies will be of crucial importance in understanding the psychopathology of conduct disorder, attention deficit/ hyperactivity disorder, and antisocial behavior in young adolescents with substance dependence disorder," says NIDA's Dr. Khalsa.

Sources

Crowley, T.J., et al. Substance dependent, conduct-disordered adolescent males: Severity of diagnosis predicts 2-year outcome. Drug and Alcohol Dependence 49:225-237, 1998.

Crowley, T.J.; Macdonald, M.J.; Whitmore, E.A.; and Mikulich, S.K. Cannabis dependence, withdrawal, and reinforcing among adolescents with conduct symptoms and substance use disorder. Drug and Alcohol Dependence 50:27-37, 1998.

Fried, P.A. Cigarette smoke exposure and hearing loss. Journal of the American Medical Association 280(11):963, 1998.

Fried, P.A. Prenatal exposure to marihuana and tobacco during infancy, early and middle childhood: Effects and an attempt at synthesis. Archives of Toxicology (Suppl)17:233-236, 1995.

Fried, P.A.; Watkinson, B.; and Siegel, L.S. Reading and language in 9- to 12-year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicology and Teratology 19(3):171-183, 1997.

Fried, P.A.; Watkinson, B.; and Gray, B. Differential effects on cognitive functioning in 9- to 12-year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicology and Teratology 20(3):293-306, 1998.

Gruber, A.J.; Pope, H.G., Jr.; and Oliva, P. Very long-term users of marijuana in the United States: A pilot study. Substance Use and Misuse 32(3):249-264, 1997.

Pope, H.G., Jr., and Yergulen-Todd, D. The residual cognitive effects of heavy marijuana use in college students. Journal of the American Medical Association 275(7):521-527, 1996.