Amphetamines: A Critique

by | Jun 16, 2023 | Education

The views presented here are described with citations to primary data in our review, downloadable below (1).

Amphetamines, including all versions of methylphenidate, are antidepressants, and thus share all of the risks described elsewhere with those agents in bipolar illness.  In the largest study of amphetamines in adults with bipolar disorder, we found a 40% manic switch rate, even with mood stabilizers.  These are highly mood destabilizing agents.   I also will comment that their use for purported adult ADHD is often, in my view, incorrect, because the manic symptom of distractibility or the depressive symptom of poor concentration is then being mistakenly converted into its own diagnosis.  Indeed in the largest epidemiological study of adult ADHD, the National Comorbidity study, about 80% of those persons who meet adult ADHD criteria also meet bipolar or MDD criteria, which either means that such persons are highly unlucky, and every time they have one disease they get two, or it means that the adult ADHD definition really overlaps almost completely with mood disorder definitions.  Since mood disorders are accepted as primary and higher on the hierarchy than ADHD (even adult ADHD proponents accept this view), one should not diagnosed adult ADHD in the context of active mood symptoms, nor even if diagnosed when patients are euthymic, should it be treated extensively, especially with amphetamines, in my view, given these mood destabilization data.    

Amphetamines improve attention short-term, in everyone, not just patients with ADHD, which is why they are addictive drugs.  Thus, symptomatic improvement with them is not at all diagnostic.  There are risks that need to be weighed against this short term benefit.  (All the following discussion about amphetamines includes methylphenidate, and all its derivatives).

It is important to also note that amphetamine stimulants are far from benign.  A number of animal studies have shown that amphetamine stimulants are harmful to the developing brain in rats:  they lead to decreased hippocampal size (2) decreased dopaminergic activity (3) and increased corticosteroid response to stress (4).  All these effects, it should be noted, are the opposite of the neurobiological effects of antidepressants and lithium, which appear to be neuroprotective, leading to larger hippocampal size and decreased corticosteroid activity (5).  In other words, amphetamine stimulants, neurobiologically, appear harmful to the brain, like drugs of abuse (6), and unlike most prescribed psychotropic medications. Further amphetamine use in adolescent animals has been associated with higher amounts of depressive and anxiety behavior in adulthood (4, 7),  perhaps due to this hippocampal atrophy (8, 9).

Obviously these animal findings may not translate into humans, but we cannot assume that they will not, and these results, so at odds with most medications that are beneficial for mental illness, should give us pause, at least in terms of long-term treatment for years.

Further, amphetamines cause mania, or worsen mania, and like antidepressants, likely cause mood destabilization in persons with bipolar disorder.  These risks would also be present in this case since he has a neurological susceptibility to manic-like symptoms.  Studies in children indicate that the frequency of amphetamine induced mania ranges from 10-50%, less when given with a mood stabilizer, and especially if given after mood symptoms are initially stabilized with a mood stabilizer in the absence of antidepressants.  However, in general, when amphetamines are used chronically, mood stabilizers appear to be ineffective, in my view, only because they are given with mood destabilizers– the amphetamines.  It is not a therapeutic trial, in my view, of the mood stabilizer unless the amphetamines are stopped first, and then, in my experience, the attentional symptoms usually improve along with the mood symptoms.  Sometimes they may not; and in those cases low doses of stimulants can be carefully added after the mood has been stabilized with other agents. 

Also, the longest term randomized study of children with amphetamines, the MTA study, found that after one year, functional outcomes were equal with intensive behavior therapy versus amphetamines.  The medications are not more effective than psychosocial interventions for functional outcomes (meaning school, academic, and interpersonal function).  The question is what kind of psychosocial interventions to institute. These can range from individual psychotherapies including behavior modification and social skills training aimed at helping with attentional impairment and impulsivity, and programs for parents and teachers aimed at increasing the kind of structure that helps such children. One such program is called The Incredible Years, and it found that 2/3 of children with ADHD had completely improved within one year of follow up in a randomized trial. 

The main peer-reviewed scientific paper where we provide the citations to original data to support this summary can be downloaded here.


1.            Vergne DE WE, Barroilhet S, Fradkin Y, Ghaemi SN: Adult ADHD and amphetamines: a new paradigm. Neuropsychiatry 2011; 1(6):591-598

 2.           Lagace DC, Yee JK, Bolanos CA, Eisch AJ: Juvenile administration of methylphenidate attenuates adult hippocampal neurogenesis. Biol Psychiatry 2006; 60(10):1121-30

3.             Brandon CL, Marinelli M, White FJ: Adolescent exposure to methylphenidate alters the activity of rat midbrain dopamine neurons. Biol Psychiatry 2003; 54(12):1338-44

4.             Bolanos CA, Barrot M, Berton O, Wallace-Black D, Nestler EJ: Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood. Biol Psychiatry 2003; 54(12):1317-29

5.             Duman RS, Malberg J, Nakagawa S: Regulation of adult neurogenesis by psychotropic drugs and stress. J Pharmacol Exp Ther 2001; 299(2):401-7

6.             Brandon CL, Steiner H: Repeated methylphenidate treatment in adolescent rats alters gene regulation in the striatum. Eur J Neurosci 2003; 18(6):1584-92

7.             Carlezon WA, Jr., Mague SD, Andersen SL: Enduring behavioral effects of early exposure to methylphenidate in rats. Biol Psychiatry 2003; 54(12):1330-7

8.          Lagace DC, Noonan MA, Eisch AJ: Hippocampal neurogenesis: a matter of survival. Am J Psychiatry 2007; 164(2):205

9.          Duman RS: Depression: a case of neuronal life and death? Biol Psychiatry 2004; 56(3):140-5