Evidence that stimulant medications may damage the developing brain, especially the nucleus accumbens

Stimulant medications on the market today, such as Adderall, Ritalin, Concerta, Metadate, Vyvanse, Focalin, Daytrana, are all variations on just two molecules, amphetamine and methylphenidate. Both amphetamine and methylphenidate mimic the action of dopamine in the brain. Many scholarly studies - some of which are listed below - have now demonstrated that methylphenidate and amphetamine can cause lasting changes to those areas of the developing brain where dopamine receptors are found. The disrupting effects appear to be centered on the nucleus accumbens. This is not surprising, because the nucleus accumbens has a high density of dopamine receptors.

William Carlezon at Harvard was one of the early leading investigators in this field. You might begin by reading three of his papers on this topic:

• Carlezon, Mague, and Andersen, “Enduring behavioral effects of early exposure to methylphenidate in rats,” Biological Psychiatry, 2003, 54:1330-1337.

• Carlezon and Konradi, “Understanding the neurobiological consequences of early exposure to psychotropic drugs,” Neuropharmacology, 2004, 47 Suppl 1:47-60

• Mague, Andersen, and Carlezon, “Early developmental exposure to methylphenidate reduces cocaine-induced potentiation of brain stimulation reward in rats,” Biological Psychiatry, 2005, 57:120-125.

More recently, Dr. Carlezon has written a recent review emphasizing the role of the nucleus accumbens in motivation: see his paper, “Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis,” Neuropharmacology, 2009, 56 Supp 1:122-132.

Terry Robinson and Bryan Kolb at the University of Michigan were among the first to demonstrate that low-dose amphetamine leads to damage to dendrites and dendritic spines in the nucleus accumbens. They reviewed this emerging field in their article "Structural plasticity associated with exposure to drugs of abuse,” Neuropharmacology, 2004, 47:33-46. They first documented this finding in their 1997 paper, “Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experiences with amphetamine,” Journal of Neuroscience, 17:8491-8497.

Other relevant articles include:

• S. P. Onn and A. A. Grace, “Amphetamine Withdrawal Alters Bistable States and Cellular Coupling in Rat Prefrontal Cortex and Nucleus Accumbens Neurons Recorded in Vivo”, Journal of Neuroscience, volume 20, pp. 2332–2345, 2000.

• Y. Li and J. A. Kauer, “Repeated Exposure to Amphetamine Disrupts Dopaminergic Modulation of Excitatory Synaptic Plasticity and Neurotransmission in Nucleus Accumbens,” Synapse, volume 51, pp. 1–10, 2004.

• R. Diaz-Heijtz, B. Kolb, and H. Forssberg, “Can a Therapeutic Dose of Amphetamine During Pre-adolescence Modify the Pattern of Synaptic Organization in the Brain?European Journal of Neuroscience, volume 18, pp. 3394–3399, 2003.

• Louk J. Vanderschuren, E. Donné Schmidt, T. J. De Vries, et al., “ A Single Exposure to Amphetamine is Sufficient to Induce Long-term Behavioral, Neuroendocrine, and Neurochemical Sensitization in Rats,” Journal of Neuroscience, volume 19, pp. 9579–9586, 1999.

Those are some of the “classic” studies on this topic. For more recent updates, you might begin by reading:

·         Russo et al., 2010: “The addicted synapse: mechanisms of synaptic and structural plasticity in the nucleus accumbens,” Trends in Neuroscience, 33:267 – 276.

·         Mameli & Lüscher, 2011: “Synaptic plasticity and addiction: learning mechanisms gone awry,” Neuropharmacology, 61:1052-1059.

·         Margery Pardey et al., 2012 “Long-term effects of chronic oral Ritalin administration on cognitive and neural development in adolescent Wistar Kyoto Rats”, Brain Sciences, 2:375-404.

·         Esther Gramage et al., 2013, Periadolescent amphetamine treatment causes transient cognitive disruptions and long-term changes in hippocampal LTP”, Addiction Biology, 18:19-29.


Studies like these strongly suggest that even short-term, low-dose exposure to amphetamine or to methylphenidate, particularly in the juvenile brain, may induce long-lasting changes both neurally (particularly in the nucleus accumbens and hippocampus) and behaviorally. In some studies, e.g. a 2010 report from Canada, the effects are dramatic in the juvenile or adolescent, but absent in the adult brain. Remember that in humans, longitudinal studies suggest that females do not reach full maturity in terms of brain development until about 20 to 22 years of age; males do not reach full maturity in terms of brain development until 28 to 30 years of age.

Most of the studies cited above were conducted in laboratory animals, not in humans. What is the likelihood that similar toxicity might occur in human children or teenagers? No one can say with certainty. The risks to human children and teenagers are uncertain. But "uncertain risk" does not mean "no risk." On the contrary, the risk could be very great. A prescribing physician must balance risks, including uncertain risks, against benefits. I provide my analysis of this cost/benefit trade-off in chapters 4 and 8 of my book Boys Adrift, a book which the Journal of the American Medical Association reviewed favorably, saying that Boys Adrift is ". . . is powerfully and persuasively presented. . . Excellent and informative references and information are provided." (It is unusual for JAMA to review a parenting book written for laypeople, so I was quite honored by their decision to review my book.) You can link to the full review via this link. One of the points I make in chapter 8 of Boys Adrift is that safer alternatives are available. Non-stimulant medications such as bupropion (Wellbutrin) and atomoxetine (Strattera) are effective in the treatment of ADHD, but they do not act as dopamine agonists and therefore would not be expected to cause damage to the nucleus accumbens. These medications are much slower to "kick in" compared with the stimulants, but with Wellbutrin and/or Strattera on board, the clinician often finds that she can use a much lower dose of the stimulant. Instead of Adderall 30mg every morning, the clinician may find that Strattera 40mg plus Adderall 10mg accomplishes the same behavioral outcome. Because the risk of stimulant medications appears to follow a dose-response curve, a lower dose of stimulant is preferable whenever possible. (For the record, please note that I have no affiliation, commercial or otherwise, with the manufacturers of Wellbutrin or Strattera.)

One might reasonably wonder why the leaders of child and adolescent psychiatry have not done more to bring the potential risks of stimulant medications to public attention. For example, consider Dr. Joseph Biederman, chief of pediatric psychopharmacology at Massachusetts General Hospital: far from warning about these medications, he strenuously encourages their use. Indeed, Dr. Biederman was the first to suggest the analogy between the use of stimulant medications for children with ADHD and the use of insulin for diabetics. We now know that Dr. Biederman accepted more than $1,100,000 in undisclosed payments from the drug companies. He was in fact a well-paid spokesperson for the drug companies; he just didn’t let us in on that fact. I should note that Dr. Biederman’s acceptance of these payments did not break any federal or state law. Many medical schools still do not require faculty to disclose large payments from drug companies. Most often, the medical school simply requires faculty to disclose that they have received payments, but the amount is not disclosed. If Dr. X acknowledges "financial support from Drug Company Y," we don't know whether that support was $1,000 or $1,000,000. For more on this point, please see the New York Times editorial entitled "Expert or Shill?" pointing out "appalling conflicts of interest" in the behavior of Dr. Biederman and Dr. Fred Goodwin, former chief of the National Institute of Mental Health (NIMH). Dr. Biederman remains Chief of Pediatric Psychopharmacology at Harvard Medical School, http://www.massgeneral.org/psychiatry/doctors/doctor.aspx?id=17789.

I have on several occasions spoken to psychiatrists on this topic. My presentation is usually entitled “The differential diagnosis of attention deficit.” This presentation, which is given in Grand Rounds format – i.e. beginning with a case presentation – describes the many conditions which can mimic ADHD, such as depression, anxiety, giftedness, late sequelae of child abuse, and sleep deprivation. Sleep deprivation in particular is becoming very common in the United States and Canada, as more and more boys stay up late playing video games, and more and more girls stay up late texting and/or tweaking their Facebook page or their Tumblr page. Sleep deprivation mimics ADHD almost perfectly: the child is impaired across multiple domains, has difficulty concentrating and remembering, etc. Adderall is dramatically effective for such children: it is, after all, a mixture of four different amphetamines, and compensates very well for sleep deprivation beginning with the very first dose. Parents and practitioners often misinterpret a dramatic positive response to Adderall or other stimulants as confirmation of the diagnosis of ADHD. But many of these kids don’t have ADHD, and they don’t need medication; they need their parents to turn off the video games at 9 PM rather than 2 AM. You will find a similar case presentation in my third book Girls on the Edge, in my description of a girl I call “Mariah,” on pages 43 – 52, under the heading “Better living through chemistry.”

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(c) 2012-2013 Leonard Sax MD PhD