'Ecstasy' : A Human Neurotoxin?

Letter by Stephen J. Peroutka, from Arch. Gen. Psychiatry, 1989.

Arch Gen Psychiatry 1989; 46: 191.

STEPHEN J. PEROUTKA, MD, PHD, Department of Neurology, C-338, Stanford University Medical Center, Stanford, CA 94305

To the Editor. -- 3,4-Methylenedioxymethamphetamine ( MDMA; "ecstasy" ) is a ring-substituted amphetamine derivative that is chemically related to both hallucinogens and stimulants. The drug appears to have unique psychoactive properties and has been advocated by certain therapists as an adjunct to psychotherapy. [n1] However, due to findings in laboratory animals [n2] of neurotoxicity caused by MDMA and related compounds, the drug was placed on Schedule I by the Food and Drug Administration in July 1985. Significant controversy exists concerning the legal status of MDMA, its potential clinical efficacy, and, most importantly, the possibility that it may cause irreversible neurotoxicity in human users. [n3]

In addition, undocumented reports have suggested that the recreational use of MDMA has been increasing at university campuses in the United States during the past few years. Although no formal epidemiological studies have been performed, a recent informal survey found that a significant number of students on an undergraduate campus reported taking at least one recreational dose of MDMA. [n4] The median amount of MDMA usage was four doses, while the mean number of doses taken was 5.4. The amount of drug taken in a single dose ranged from 60 to 250 mg (approximately 1 to 4 mg/kg). Similar dosage patterns have been reported to be neurotoxic in primates, [n3] and at least five deaths in humans have been attributed to recreational use of MDMA and related compounds. [n5]

Presently, there are no data to indicate that recreational doses of MDMA permanently damage the human brain. However, it should also be stressed that no scientific studies have addressed this problem. Nonetheless, based on informal discussions with approximately 100 recreational users of MDMA, a number of personal observations suggest that MDMA is much different from other recreational drugs, as described below.

1. Recreational users of MDMA frequently state that they usually wait at least two to three weeks between doses of the drug. The reason given for this unusual pattern of recreational drug use is that the "good" effects of the drug appear to diminish while the "negative" side effects of the drug appear to increase if the drug is taken too frequently. For example, taking a double dose of MDMA does not double the supposed good effects of the drug but simply increases the negative effects of the drug.
2. The majority of people who have taken more than five individual doses of MDMA state that the good effects of the drug change with successive doses. As stated by one college student, "Freshmen love it; sophomores like it; juniors are ambivalent, and seniors are afraid of it." These observations are of concern, since no other drugs are known that, when taken at very infrequent intervals (ie, every month or so), cause different effects with successive doses.
3. MDMA is not "addictive." It is extremely rare to find individuals who have taken large quantities of this drug. Again, this is quite different from many recreational drugs, which tend to be either psychologically or physically addictive. To my knowledge, there are simply no reports of individuals who take frequent and large amounts of MDMA for an extended period.

In summary, these completely informal anecdotal observations are consistent with the belief that there is a long-term, and potentially irreversible, effect of MDMA on the human brain. Obviously, a definitive assessment of the human neurotoxic potential of MDMA must await the completion of formal clinical [n6] and epidemiological studies. However, a reasonable and informed conclusion would be that recreational use of MDMA should be avoided.

References:

1. Greer G, Tolbert R: Subjective reports of the effects of MDMA in a clinical setting. J Psychoactive Drugs 1986;18:319-328.
2. Schmidt CJ: Neurotoxicity of the psychedelic amphetamine, MDMA. J Pharmacol Exp Ther 1987;240:1-7.
3. Barnes DM: New data intensify the agony over ecstasy. Science 1988;239:864-866.
4. Peroutka SJ: Incidence of recreational use of 3,4-methylenedioxymethamphetamine ( MDMA, 'Ecstasy' ) on an undergraduate campus. N Engl J Med 1987;317:1542-1543.
5. Dowling GP, McDonough ET, Bost RO: 'Eve' and ' ecstasy' : A report of five deaths associated with the use of MDEA and MDMA. JAMA 1987;257:1615-1617.
6. Price LH, Ricaurte GA, Krystal JH, Heninger GR: Neuroendocrine and mood responses to intravenous L-tryptophanin 3,4-methylenedioxymethamphetamine ( MDMA) users: Preliminary observations. Arch Gen Psychiatry 1989;46:20-22.