Second Thoughts on 3,4-Methylenedioxymethamphetamine (MDMA) Neurotoxicity

by Charles Grob et al., from Arch. Gen. Psychiatry 1990; 47: 288-289.

by CHARLES GROB, MD, GARY BRAVO, MD, ROGER WALSH, MD, PHD, University of California, Irvine Medical Center, Department of Psychiatry and Human Behavior, 101 City Dr S Rte 88, Orange, CA 92668

To the Editor. -- Recent attention has been drawn to the purported neurotoxic dangers associated with 3,4-methylenedioxymethamphetamine ( MDMA) . Price et al [n1] have attempted to assess possible serotonergic neurotransmitter damage by contrasting serum prolactin response to the challenge with intravenous L-tryptophan in subjects with a history of MDMA use vs control subjects. Their primary finding was a blunted rise in the expected serum prolactin level in MDMA users, but not to a statistically significant degree. The importance of this finding appears to be questionable and perhaps misleading. Even if the data had yielded a statistically significant result, would such a correlation necessarily imply causation?

A methodological limitation to the study would appear to be that subjects were not adequately screened on selection to exclude those who were using other psychotropic drugs. There is no mention that toxicology screens were ever performed. In fact, three subjects (33%) admitted to marijuana use during the 3-week supposed drug-free interval prior to the testing. As marijuana is known to affect dopaminergic function (and, consequently, prolactin secretion), [n2] the implications for MDMA effect on serotonergic function are further questioned. One additional point regarding this study is that even if one could demonstrate that MDMA users had diminished serotonergic function compared with control subjects, what does this imply? Without data as to baseline serotonergic functioning prior to the first ingestion of MDMA, such findings are of limited significance.

Numerous animal studies have been performed over the past several years that were designed to evaluate the neurotoxic potential of MDMA. Until recently, most have examined short-term degeneration of serotonin neurons in animal brain following repeated systemic administration of MDMA. Battaglia et al [n3] have examined the brains of rats treated with massive subcutaneous dosages of MDMA (cumulatively up to 100 times the usual human oral dose) over time, and have noted complete regeneration 1 year after administration of the drug. This, together with the fact that there have yet to be documented clinical cases of MDMA -induced serotonergic neurotoxicity (ie, there have been no reports of sleep, mood, appetite, aggressive, or sexual dysregulation), may indicate that concerns over long-term neuropsychiatric damage have been overstated.

The related controversy over fenfluramine hydrochloride has some relevance here. During the last 25 years, approximately 50 million people have been clinically treated with fenfluramine. [n4] Fenfluramine has been utilized primarily as a weight-reducing agent and has also been used in clinical trials for the treatment of infantile autism and childhood attention-deficit disorder with hyperactivity. However, animal studies have demonstrated that fenfluramine has a serotonergic neurotoxic capability three times that of MDMA. [n5] Yet despite such findings, fenfluramine has accepted clinical indications, has a history of widespread use, and is without the known induction of neurological side effects.

Claims have been made that MDMA enhances the processes of psychotherapy by facilitating empathy, heightening introspection, and lowering defensive anxiety. [n6] Because of concerns of possible neurotoxicity, however, rigorous clinical trials designed to validate these claims have not been performed. The data reviewed suggest that fears of MDMA neurotoxicity may have been exaggerated and it may well be significantly less toxic than a very widely used medication, fenfluramine. In view of its purported unique psychoactive properties, it may be appropriate to pursue clinical trials of MDMA. Alternatively, the search for a nontoxic analogue should be encouraged.

References

1. Price LH, Ricaurte GA, Krystal JH, Henninger GR. Neuroendocrine and mood responses to intravenous L-tryptophan in 3,4-methylenedioxymethamphetamine ( MDMA) users. Arch Gen Psychiatry. 1989;46:20-22.
2. Markianos M, Stefonis C. Effects of acute cannabis use and short-term deprivation on plasma prolactin and dopamine-beta-hydroxylase in long-term users. Drug Alcohol Depend. 1982;9:251-255.
3. Battaglia G, Yeh SY, DeSouza EB. MDMA -induced neurotoxicity: parameters of degeneration and recovery of brain serotonin neurons. Pharmacol Biochem Behav. 1987;29:269-274.
4. Derome-Tremblay M, Nathan C. Fenfluramine studies. Science. 1989;243:991.
5. Barnes DM. Neurotoxicity creates regulatory dilemma. Science. 1989;243:29-30.
6. Grinspoon L, Bakalar JB. Can drugs be used to enhance the psychotherapeutic process? Am J Psychother. 1986;40:393-404.

In Reply. -- Grob et al raise some valid points regarding the methodological limitations of our findings, which we ourselves had attempted to acknowledge, both in the "Comment" section and in our characterization of our results as "preliminary observations." There are, however, several other issues raised by Grob et al on which we offer the following comments:

1. Urine toxicology by enzyme immunoassay (EMIT) was obtained on all subjects on the morning of the intravenous L-tryptophan test, immediately prior to beginning the test. Although inadvertently omitted from the final draft of the article, these screens revealed no evidence of recent use of psychoactive drugs. However, most of our subjects did have a past history of use of illicit psychoactive drugs; as Grob et al imply, we cannot state with certainty that use of these other drugs did not account for or contribute to the altered responses to L-tryptophan. The fact is, however, that extensive preclinical evidence demonstrates considerable effects of MDMA on serotonergic function, and our subjects were primarily heavy users of MDMA. We disagree with the assertion that the demonstration of altered serotonergic function in MDMA users would be of limited significance "Without data as to baseline serotonergic functioning prior to the first ingestion of MDMA. " Altered serotonergic function in MDMA users would suggest, but not confirm, effects of MDMA on serotonergic functioning in such individuals. Even though inconclusive, we believe such a suggestion would be of very real significance. As Grob et al well know, the classification of MDMA as a schedule I drug currently makes it virtually impossible to conduct the kind of study that we and they agree would be "conclusive."

2. As Grob et al note, the clinical implications of serotonergic neurotoxicity are controversial and currently undefined. Their reference to the current debate surrounding fenfluramine is entirely appropriate. However, their citation of the Barnes [n1] report is somewhat disingenuous. In that article, it is noted that "Fenfluramine has demonstrated clinical usefulness, whereas MDMA does not. MDMA is also classified as a substance that people abuse, but fenfluramine is not." We would further point out that the general tone of the Barnes article is not exculpatory, but cautionary; although fenfluramine has not been known frequently to cause clinically significant neurotoxic effects, the possibility that it may do so is now under intensive scrutiny.

3. Claims that MDMA may be a useful pharmacological adjunct to psychotherapy are of great theoretical and practical interest. Of course, such claims have been made for numerous other compounds over the years, and none have borne fruit. We agree that rigorous clinical trials are necessary to validate such claims, but we do not feel that "concerns of possible neurotoxicity" are irrelevant to the initiation or conduct of such trials. It may be that Grob et al are correct in suggesting that fears of MDMA neurotoxicity have been exaggerated; we trust that further research can and will clarify this point. Until such clarification is made, we believe it would be premature to pursue clinical trials of MDMA in conditions that are not life-threatening.

LAWRENCE H. PRICE, MD
JOHN H. KRYSTAL, MD
GEORGE R. HENINGER, MD
Department of Psychiatry
Yale University School of Medicine and the Connecticut Mental Health Center
Clinical Neuroscience Research Unit
Ribicoff Research Facilities
34 Park St
New Haven, CT 06508

GEORGE A. RICAURTE, MD, PHD
Department of Neurology
The Johns Hopkins University School of Medicine
4940 Eastern Ave
Baltimore, MD 21224