Arch Gen Psychiatry 1990; 47: 288-289
                                  March, 1990
LENGTH: 1278 words
TITLE: Second Thoughts on 3,4-Methylenedioxymethamphetamine ( MDMA)
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
   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.

[n1.] 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.
[n2.] 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.
[n3.] 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.
[n4.] Derome-Tremblay M, Nathan C. Fenfluramine studies. Science. 1989;243:991.
[n5.] Barnes DM. Neurotoxicity creates regulatory dilemma. Science.
[n6.] 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
   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
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
Department of Neurology
The Johns Hopkins University School of Medicine
4940 Eastern Ave
Baltimore, MD 21224
[n1.] Barnes DM. Neurotoxicity creates regulatory dilemma.