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