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Fuad Ziai, MD, a doctor in suburban Chicago, has helped some obese children in his practice shed pounds with amphetamine-dextroamphetamine (Adderall/Adderall XR, Shire), a medication currently approved for use in children and adolescents with attention deficit hyperactivity disorder (ADHD).
But while some applaud this application of amphetamines to combat the problem of an increasingly overweight pediatric population, others believe it raises ethical questions about off-label use and possibly poses legal risks as well. The use of amphetamines for weight loss also reignites debate over their benefits as appetite suppressants versus their risks for abuse and dependence.
Meanwhile, the youth overweight epidemic is an ever more pressing concern: Prevalence of overweight among children and adolescents has increased significantly—during the years 1999–2004, it rose from 13.8% to 16% among girls and from 14% to 18.2% among boys, according to the National Health and Nutrition Examination Surveys (NHANES).1 During the same period, prevalence of type 2 diabetes in children grew right along with their waist sizes.2
Clinicians have met with varying degrees of success using a range of behavioral and medical modalities to avert or lessen obesity (DOC News, August 2006, page 9)—and for some, like Ziai, Adderall is another welcome tool in their arsenal.
AMPHETAMINE SALTS SHOW WEIGHT LOSS
Physicians more or less stumbled on Adderall's weight-loss capabilities.
"One of my colleagues treating an overweight child with ADHD noticed significant weight loss after prescribing Adderall XR," says Ziai, director of the division of pediatric endocrinology at Advocate Hope Children's Hospital in Oak Lawn, Ill. "Amphetamines as a class have been used as appetite suppressants for the past half century or so, and this looked like it might be an interesting use for this medication."
To test his theory, Ziai and colleagues studied 63 patients ages 5–19 who came to his practice over a 2-year period with a body mass index (BMI) above the 95th percentile and no endogenous explanations for their obesity. The researchers obtained baseline blood chemistries as well as fasting and 2-hour postprandial glucose and insulin levels.
Participants were stratified into hyperinsulinemic or normoinsulinemic groups based on age-adjusted fasting and postprandial insulin results. Finally, a comprehensive family and personal health history was obtained.
After completing the initial work-up, patients in the hyperinsulinemic group began taking mixed amphetamine salts (the ingredient in Adderall XR) and metformin (Glucophage, Bristol-Myers Squibb). Patients in the normoinsulinemic group received only the amphetamine salts.
"What we noticed clinically during the first 12 to 18 months of treatment was that 90% of those in both groups responded to therapy, with significant BMI reductions being seen in both [hyperinsulinemic]—12.7%—and [normoinsulinemic]—13.3%," Ziai says. "There was a significant and dramatic decrease in insulin levels by 37.4% at fasting and 55.8% postprandial. The improvement in the BMI score of the [normoinsulinemic] group with amphetamine salts alone suggests the primary role of this compound in inducing weight reduction and improvement in BMI."
The investigators presented the results of this retrospective study as a poster at The Endocrine Society meeting in June 2005.3
TREATMENT RAISES CONCERNS
Although Ziai views treatment of obesity with amphetamine salts as safe and effective, others are not convinced.
"As with any medication decision, we are talking about risk versus benefit," says Mohab Hanna, MD, a child and adolescent psychiatrist in Lutherville, Md., and author of the book Making the Connection: A Parent's Guide to Medication in ADHD.
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"Mixed amphetamine salts can potentially increase irritability, moodiness, anxiety, and perseveration, and can potentially increase heart rate and blood pressure," Hanna says. "The latter can result in sudden death in those with underlying structural heart problems, which led the Food and Drug Administration to add a black box warning to the label recently."4
Ziai acknowledges those concerns and addresses them by including a cardiac component to the history and physical. If indicated, he will order an electrocardiogram and chest X-ray with referral to the appropriate specialties for follow-up as needed.
"There has been a fear about amphetamines and their potential for addiction, changes in personality, making you a zombie, or things like that," Ziai says. "Very much to our pleasant surprise, we have found none of these concerns surface in our group. Even when we see things like irritability or emotionalism, they are transient and disappear very quickly. We have never had a parent call us and ask about withdrawal symptoms."
Another concern is that Ziai's protocol does not include referral for lifestyle and dietary changes—widely viewed as an important part of enduring success in any weight-loss therapy.
"While this medication results in weight loss, it does not affect lifestyle and behavior that are crucial to long-term success of obesity treatment," says Seema Kumar, MD, assistant professor of pediatrics at the Mayo Clinic in Rochester, Minn. "There is lack of data on the optimal duration of treatment with this class of drugs and on weight trends after discontinuation of the medication."
Although Ziai has made no official referrals to dietitians or other support professionals, he says anecdotally he has seen many patients begin dietary and other lifestyle-intervention programs on their own in response to their weight loss.
"What we have noticed is that once they begin to lose weight, following failure after failure, suddenly there is an increase in self-esteem and confidence," Ziai says. "As a result of this positive development, they begin to do things on their own about exercise and diet. This establishes a virtuous cycle in the place of the vicious cycle they were in before."
Another major concern for some is potential legal and ethical troubles triggered by off-label use of amphetamine salts for weight loss in children.
"Physicians need to carefully consider the liability issue in the off-label use of a controlled substance for treating someone without much data to support its potential benefit for this condition," Hanna says.
Both Hanna and Kumar say they would not recommend the use of amphetamine salts to young obese patients in their practices.
"At this time, because of the potential for drug dependence and lack of randomized, placebo-controlled trials, I would not recommend this medication in treatment of childhood obesity," Kumar says. "I would favor lifestyle modifications and only those medications that have been shown to be safe and effective in this age group."
For his part, Ziai remains convinced. "Although this approach is new
and we don't have all the information we need yet, the response we have seen
clinically suggests that the response to this medication for around 90% of our
patients is as good as gastric bypass without the surgical scars or metabolic
disorders," he says. 
References
2. Rowell HA, Evans BJ, Quarry-Horn JL, et al.: Type 2 diabetes mellitus in adolescents. Adolesc Med 13: 1–12, 2002.[Medline]
3. Ziai F, Sahhar HS, Blais A: Pharmacological treatment of obesity in children with and without hyperinsulinemia. Poster presented at the 65th Scientific Sessions of the Endocrine Society,June 4–7, 2005, San Diego. Poster 18-LB.
4. Food and Drug Administration: Public Health Advisory for Adderall and Adderall XR. February 9, 2005. Available online at www.fda.gov/cder/drug/advisory/adderall.htm. Accessed June 12, 2007.
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