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New Research in Animals Reveals Possible Long-Term Effects of Stimulants on Brain and Behavior

Three new studies conducted in animals, published in the December issue of the journal Biological Psychiatry, provide evidence that misuse of the stimulant methylphenidate (Ritalin) may have long-term effects on the brain and behavior. While methylphenidate and other stimulant medications are the recommended treatments for Attention Deficit Hyperactivity Disorder (ADHD), based on the more than 150 controlled studies demonstrating their safety and efficacy when used as prescribed, these three studies showed changes in the brains of young (adolescent or pre-adolescent) animals that persisted into adulthood. In both animals and humans, the brain continues to develop throughout adolescence. If the current studies are applicable to humans, they could have important implications for young people who use stimulants for recreational purposes.

In the first study, Dr. Cindy Brandon and her colleagues at the Finch University of Health Sciences/The Chicago Medical School examined how low doses of methylphenidate affect dopamine cells in the brains of adolescent rats. Dopamine is a brain chemical that has been implicated in natural rewards, such as food and sex, as well as in drug abuse and addiction. The study showed that the rats experienced brain cell changes that subsequently made them more sensitive to the rewarding effects of cocaine.

In the second study, Dr. William Carlezon, Jr., and his colleagues at Harvard Medical School and McLean Hospital in Belmont, Massachusetts, looked at how pre-adolescent exposure to methylphenidate affected certain behaviors in rats when they reached adulthood. They found that early exposure to twice-daily injections of methylphenidate actually reduced the sensitivity to cocaine reward, but increased other behaviors that could indicate depression. The timing of exposure to methylphenidate may be important — in this study the rats were exposed at an age corresponding to childhood, whereas in the study by Dr. Brandon et al., the rats were slightly older, more akin to adolescence.

In the third study, Dr. Carlos Bolaños and his colleagues at the University of Texas Southwestern Medical Center in Dallas assessed certain behaviors of adult rats given methylphenidate prior to adolescence. They found that compared to drug-naive rats, those chronically exposed to methylphenidate were less responsive to natural rewards, such as sugar and sex, and more sensitive to stressful situations. The methylphenidate-exposed animals also had increased anxiety-like behaviors, and enhanced blood levels of stress hormones.

In an editorial accompanying the Brandon, Carlezon, and Bolaños papers, Dr. Nora D. Volkow, director of the National Institute on Drug Abuse (NIDA), and Dr. Thomas Insel, director of the National Institute of Mental Health (NIMH), both components of the National Institutes of Health, articulate the important contributions of these studies as well some of the caveats that need to be considered before these results can be applied to humans. Importantly, the studies show changes in the function of brain dopamine cells and in behavior following chronic exposure to doses of methylphenidate similar to those used to treat ADHD in children.

ADHD affects an estimated 3 to 5 percent of school-age children around the world and is considered to be the most prevalent psychiatric disorder of childhood. Among the caveats noted by Drs. Volkow and Insel in their editorial, is the way in which the drug is administered to rats (by injection into the abdominal cavity) compared to the oral route (by tablet) used by humans. This could lead to differences in how much and how quickly the drug affects the brain. In addition, for these studies to be truly applicable to ADHD, they may need to be carried out in an animal model of the disorder, rather than in normal rats. Thus, the results may be more applicable to children and adolescents who do not have ADHD, but who take stimulants for non-medical purposes, or to those who are treated with stimulants as a result of misdiagnosis. This underscores the importance of proper diagnosis of this disorder.

Drs. Volkow and Insel further state that "Because the use of stimulant medications for the treatment of ADHD has increased significantly over the past 10 years, it is vitally important that we evaluate the long-term effects of these drugs in the human brain and on behavior. Such knowledge is essential for a better understanding of ADHD and its management, and will help inform those with ADHD and their relatives about the risks and benefits of stimulant medications."

The National Institute on Drug Abuse is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports more than 85 percent of the world’s research on the health aspects of drug abuse and addiction. The Institute carries out a large variety of programs to ensure the rapid dissemination of research information and its implementation in policy and practice. Fact sheets on the health effects of drugs of abuse and information on NIDA research and other activities can be found on the NIDA home page at http://www.drugabuse.gov.


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