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MDMA Neurotoxicity DiscussionCompiled by MAPS -- Autumn 1998 There are several issues related to MDMA neurotoxicity: 1. Do persistent reductions in serotonin levels in humans result from taking MDMA? If so, from what doses and frequency? 2. If there are persistent reductions, are they temporary or permanent? 3. If there are persistent reductions in serotonin levels in humans under any circumstances, do these reductions have any functional or behavioral consequences? In other words, does MDMA cause lowered serotonin levels and, if so, does it matter? The answer to the first question is that there is some suggestive evidence that there are serotonin reductions in a group of people who have taken MDMA an average of 90 or more times [1,2,3]. However, this evidence is not conclusive, since MDMA users were compared to matched control groups, which may or may not be matched on all factors that impact on serotonin levels. The most persuasive evidence would come from studies in which MDMA-naive subjects were tested, then given multiple exposures to MDMA, then tested again. Unfortunately, no studies of this sort have been conducted. It is also as yet unknown whether the reductions in serotonin as suggested in some MDMA human studies are linked to damage or to down-regulation, in which neurons adapt to lower levels of serotonin, or to some other factor unrelated to MDMA [4]. There is no evidence that there are serotonin reductions in groups of people who have taken MDMA fewer than 90 times. No subjects meeting these criteria have been evaluated since it makes more sense to see if there are any reductions at higher doses before spending money on testing people where the reductions, if any, are likely to be smaller and more difficult to detect than in heavy users. The extent of MDMA-related "damage" would depend - among other factors - on the frequency of use and the doses used. The present state of knowledge does not allow us to tell at which frequency and dosage to draw the line between non- neurotoxic and neurotoxic use in humans. The line would certainly have to be individually drawn at different dosages and frequencies in different users, due to individual variability. Of course, the best way to avoid the risk of MDMA- related neurotoxicity is to avoid MDMA. The balancing of risk and benfit is a decision that each individual must make for themselves. An unpublished MAPS-funded study by Ricaurte, in which oral 2.5 mg/kg MDMA was administered to non-human primates once every two weeks for four months (8 administrations) showed no effect in levels of serotonin. This is at or above the normal therapeutic or recreational dose level. However, the relative sensitivity to MDMA's effects on serotonin of non-human primates as compared to human beings is unknown. In animal studies, there is evidence that an SSRI taken acutely (once) even a few hours after MDMA will provide "neuroprotection" against the possibility of toxicity to serotonin neurons. This suggests that a person who ingests MDMA could take a Prozac for neuroprotection within six hours after ingestion. It is obviously not clear if this hold true for humans, not only because a prospective study has not been done, but also because it is still controversial whether MDMA induces structural changes which can be considered "neurotoxic." [5] As to the second question, whether reductions are temporary or permanent, there is clear evidence of regeneration of serotonin neurons. However, this regeneration pattern does not restore the pattern exactly to the original state. [6] The answer to the third question is that there is a lot of circumstantial evidence, and no convincing evidence to the contrary, that serotonin reductions, if there are any, make no difference.
One should certainly note from the analyses of "Ecstasy" tabs
conducted by Nicholas Saunders that most MDMA tablets are
not pure and can easily contain harmful drugs taken acutely
or on a chronic basis (e.g. atropine, ephedrine -- see
Finally, Fenfluramine, a drug with actions identical to those of
MDMA with respect to effects on serotonergic neurons, does
not appear to have toxic effects on these neurons in humans
taking the drug twice daily for several years, nor is there
evidence of functional or behavioral problems in fenfluramine
users. However, no thorough studies have been conducted
searching for such effects. Nevertheless, the absence of
reported neurotoxic effects from fenfluramine suggests that
such effects, if any exist, are likely to be subtle. For example,
the dramatic neurotoxic effects of MPTP, the synthetic heroin
that caused Parkinson's-like symptoms and for which the
term "designer drug" was originally used, were noticed after
only a handful of people had taken the drug. In contrast,
MDMA has been used for about two decades and millions of
people have taken it, some excessively so. Some people have
had problematic psychological reactions but there is still no
clear evidence of any functional or behavioral consequences
linked to MDMA neurotoxicity. While subtle changes can still be
important, perhaps crucially so to what it means to be fully
human, no such changes have yet been demonstrated from
the yet unproven mechanism of MDMA neurotoxicity. At the
same time, many people report long-term benefits from their
use of MDMA. As a result of these reports of long-term
benefits, MAPS focuses on the development of clinical studies
designed to scientifically investigate the therapeutic
applications of MDMA.
References:
[1] McCann U, Hatzidimitriou G, Shaham Y, and Ricaurte G.
Serotonin neurotoxicity after 3,4-
methylenedioxymethamphetamine (MDMA, "Ecstasy"): a
controlled study in humans. Neuropsychopharmacology
10:129-138, 1994.
[2] Ricaurte, GA, Finnegan, KT, Irwin, I and Langston, JW:
Aminergic metabolites in cerebrospinal fluid of humans
previously exposed to MDMA: Preliminary observations. Ann
NY Acad Sci 600:699-710, 1990.
[3] Peroutka, SJ, Pascoe, N and Faull, KS: Monoamine
metabolites in the cerebrospinal fluid of recreational users of
MDMA. Res Comm Substance Abuse 8:125-138, 1987. [This
study found no serotonin reductions.]
(MAPS played a major role in recruiting volunteers for
the first two of the studies referenced above and in
covering travel expenses involved in bringing many of
the volunteers to be tested in the study referenced as
#2.)
[4] O'Callaghan JP, Miller DB, Jensen KF and Schmidt CJ:
Serotonin depletions are not predictive of neurotoxicity:
evidence from increases in glial fibrillary acidic protein
induced by methylenedioxymethamphetamine (MDMA) and
5,7-dihydroxytryptamine
(5,7-DHT) [abstract] Society for Neurosciences Abstracts, 16
(part 1):256,1990.
[5] Schmidt CJ; Abbate GM; Black CK; Taylor VL. Selective 5-
hydroxytryptamine receptor antagonists protect against the
neurotoxicity of methylenedioxymethamphetamine in rats.
J Pharmacol Exp Ther 255 (2): 478-83, 1990.
[6] Fischer C, Hatzidimitriou G, Wios J, Katz J, Ricaurte G.
Reorganization of Ascending 5-HT Axon Projections in
Animals Previously Exposed to the Recreational Drug (±)
3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"). J
of Neuroscience 15 (8):5476-5485, 1995.
For further commentary on these issues see also:
November 1998 Neurotoxicity Commentary (highly recommended)
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