Two recent studies present clinical evidence that the use of stimulants to treat boys with attention deficit hyperactivity disorder (ADHD) does not increase their risk of later substance use disorders. This evidence provides clinicians and families with much needed reassurance.
“It is very important for families to know that treatment does not increase the risk of substance abuse in late adolescence and early adulthood; this information should be a key source of comfort to them,” said Joseph Biederman, MD, professor of psychiatry at Harvard Medical School and chief of pediatric psychopharmacology at Massachusetts General Hospital, both in Boston, and lead author of a naturalistic 10-year follow-up study on ADHD.1
ADHD affects between 5% and 10% of children and adolescents. One of the great debates in childhood psychiatry has been whether widespread use of stimulants to treat ADHD might lead to later substance use disorder. The idea is theoretically plausible, according to researchers, because both stimulant medications and drugs of abuse increase concentrations of dopamine(Drug information on dopamine) in the nucleus accumbens—the neural mechanism considered crucial for their reinforcing effects.2 Also, some studies have suggested a causal link between stimulant treatment in childhood and later substance use disorder.3
That was not the case, however, in a 17-year prospective follow-up study conducted by Salvatore Mannuzza, PhD, and colleagues.4 Coauthor Francisco Castellanos, MD, professor of child and adolescent psychiatry at New York University and director of research for its Child Study Center, said that the study is one of the “most methodologically sound” of those that cumulatively suggest that medication treatment does not increase the long-term risk of substance abuse problems.
Results of the Mannuzza study might influence clinical practice, Castellanos told Psychiatric Times. He explained that he and many other clinicians have adhered to a conservative approach and waited as long as possible before prescribing stimulants for a child with ADHD, “based on the general principle that the longer we can wait, the more brain development can occur unaffected by any medication. . . . Now, I would say we shouldn’t try to hold out to the very last minute; there may really be a cost to doing that.
“The study looks at ADHD from childhood through the late 20s,” Castellanos said. “We found no evidence that treatment with stimulants at younger ages had a deleterious effect. In fact, . . . having medication treatment at earlier ages may have had a beneficial effect.”
The team conducted a prospective longitudinal study of 176 white, middle-class boys (aged 6 to 12) who were treated for ADHD with methylphenidate(Drug information on methylphenidate) (Ritalin, Concerta, Metadate, Methylin). At baseline, none of the youngsters displayed conduct disorder, which is regarded as a precursor of antisocial personality disorder and a risk factor for substance abuse. The participants were followed through late adolescence and into adulthood. For comparison, the researchers also tracked 178 boys without ADHD.
Boys with ADHD who started stimulant treatment early (at age 6 or 7) faced a lower risk of later drug abuse than those who began taking the medication later (at ages 8 through 12), the team reported.
Among participants who were treated early, 27% abused drugs by their mid-20s—a percentage close to that of comparison participants without ADHD (29%). In contrast, substance use disorders developed in 44% of the boys who were treated later.
Researchers used 9 predictor variables, including the child’s age at initiation of methylphenidate treatment, treatment duration, dosage, severity of hyperactivity, socioeconomic status, and lifetime parental psychopathology. None of the predictor variables accounted for the association between age at treatment initiation and non- alcohol(Drug information on alcohol) substance use disorder.
“Unexpectedly, the development of antisocial personality disorder accounted for the association between age at first treatment with methylphenidate and substance abuse,” the researchers said. They added that “it is unclear why age at initiation of . . . treatment and . . . later development of substance use and antisocial personality disorder appear to be related.”
Currently, the team is conducting an adult follow-up study on the participants, now in their 30s and 40s. MRI scans are being used.
“We will be able to see whether there are any measurable structural differences in their brains that might be related to their . . . diagnosis; how that diagnosis developed over time; whether they were affected by when they started treatment and how long they were in treatment; and whether any of that was related to how their lives turned out,” Castellanos said.
Massachusetts team
The team led by Biederman assessed 112 young men 10 years after ADHD had been diagnosed. They ranged in age from 16 to 27 years at the time of their reassessment; 82 (73%) had been treated with stimulants at some time and 25 (22%) were currently receiving stimulant treatment.
“This was a naturalistic study and not a clinical trial,” Biederman said, “so the children were using the medication as prescribed by their treating physicians for varied periods of time.”
The mean age at stimulant treatment onset was 8.8 years. Half of the patients began treatment between 6 and 10 years of age. The mean duration of treatment was 6 years; 50% of patients underwent stimulant treatment for 2 to 10 years.
Study participants were interviewed using standard tools for assessment of psychiatric disorders. Additional questions were asked about their use of nicotine(Drug information on nicotine), alcohol, and various psychoactive drugs (such as cocaine, amphetamines, sedatives, opiates, and nonprescription sleeping or diet pills).
The follow-up study, which controlled for the presence of conduct disorder in the original diagnosis, found no evidence that “prior treatment with stimulants was associated with subsequent increased or decreased risk for alcohol, drug, or nicotine use disorders.”
“Our work also documents that the use of stimulants does not hasten or increase the risk of substance abuse in those children who use [them] for a long time,” Biederman said.
In addition, no significant association was detected between the age at onset of stimulant treatment and subsequent substance use disorders. Those results differed from an earlier study by Biederman and colleagues. That 1999 report was a 4-year follow-up of adolescents in the same sample that detected a protective effect of stimulant treatment.5
“There may be some protective effect by adolescence, but it is not maintained into adult life,” Biederman said.
“We do not know why the protective effect of stimulants is not evident in adulthood,” said Biederman and colleagues. “It is possible that because of parental monitoring, treatment compliance—and hence—efficacy—is greater for youths than adults. Another possibility is that because adolescents have not fully passed through the age of risk [for] substance use disorders, stimulants may delay rather than stop subsequent substance use disorders.”
Noting limitations with their 10-year follow-up study, Biederman and colleagues warned that their results may not be the same in children with ADHD in the general population, especially in females and in those of other racial or ethnic backgrounds. However, information on females is forthcoming. Biederman told Psychiatric Times that his team has just completed a study on females with ADHD and submitted it for publication.
“We found results similar to those in boys,” he said.
ADHD and substance use disorder
While the studies by Biederman and colleagues and Mannuzza and associates showed that stimulant treatment for ADHD does not increase the risk of substance abuse in adulthood, both research teams acknowledged that childhood ADHD itself is significantly associated with adolescent and adult substance use disorders.
In an editorial in the May 2008 issue of the American Journal of Psychiatry, Nora Volkow, MD, director of the National Institute on Drug Abuse, and James Swanson, PhD, the University of California at Irvine, said that the studies “highlight the need to develop a better understanding of the natural history of ADHD over time,” and also the “need for the development of integrated treatments that target both ADHD and substance abuse in order to go beyond standard treatment and find a way to reduce or prevent substance abuse and provide better treatments if these disabling outcomes emerge.”
Substance abuse prevention is an important and very challenging area, Castellanos said. “We know that nicotine is usually the gateway drug, and kids are starting to use nicotine in middle school. Often it is the impulsive, hyperactive kids who are among the leaders in that process, so . . . having parents know what is going on, talking to each other, and being extremely firm about [avoiding] nicotine in all of its forms—that’s a battle . . . parents want to be fighting.”
