Comments by:

Rick Doblin   Julie Holland   Lamont Granquist  Correlation analysis by R.Doblin  

MDMA Neurotoxicity Study on Erowid
(Includes Press Release and article from The Lancet, Interview with Ricaurte from Ecstasy.org, San Jose Mercury News article, Associated Press article, Times article, additional commentary)

For further commentary see also:

MAPS Neurotoxicity FAQ (highly recommended)
MDMA Neurotoxicity: New Data, New Risk Analysis by Rick Doblin (highly recommended)
Criticism of Methods in McCann et al. 1998 by Kish (2002) by Ilsa Jerome
MDMA Neurotoxicity : Commentary on Article by Ricaurte et al by James O'Callaghan, Ph.D.
MDMA Neurotoxicity Overview Fall 1990
The Swiss Neurotoxicity Collaborative Research Project Summer 1989
MAPS MDMA Analysis Project
Diary of an MDMA Research Subject
MDMA research: more than I bargained for...

Date: Fri, 30 Oct 1998 21:00:52 EST
From: RickMAPS@aol.com
To: maps-forum@maps.org
Subject: MAPS: MDMA Neurotoxicity Research

You may have seen publicity about a new study of MDMA users that just came out in the Lancet. The study is by George Ricaurte, M.D. I spoke with him several days ago about the results and feel it is important to keep several points in mind.

First, the MDMA subjects in the study feel fine.
Second, it is difficult to make sure that matched controls are really matched on all dimensions. The best way to study MDMA-related serotonin changes is to test people before and after the administration of MDMA. This has yet to be done.
Third, even if the serotonin transporter changes are due to MDMA, they make be entirely without significance. Brain cells can up and down regulate to function in enviroments of greater or lesser amounts of neurotransmitters.
Fourth, the serotonin system does not seem to substantially decline with age. Therefore, the idea that reduced serotonin system changes that are asymptomatic will become a problem over time is not supported by the evidence about the serotonin system, or by the observation of problems of MDMA users age 60 or older, of which there are many.
Fifth, there is no evidence at all that a few doses of MDMA given in a therapeutic context, or any context, would have a significant impact on serotonin levels, much less produce functional or behavioral consequences related to serotonin deficits. Thus, this research does not provide evidence sufficient to justify refusal to permit MDMA psychotherapy research.

The Novartis Foundation is sponsoring a conference on the risks of MDMA, to take place in London on December 4. Dr. Ricaurte will be presenting his findings there, as will other researchers who have looked at the risk side of the equation. MAPS is paying for Dr. Charles Grob to attend the conference, and also Dr. Moshe Kotler and Dr. Adam Darnell, the MDMA researchers from Israel who are working to obtain permission to study the use of MDMA in the treatment of PTSD in a MAPS-funded study. As always, MAPS is interested in all the scientific information about MDMA, both risks and benefits.

Unfortunately, ever since MDMA was criminalized in 1985, no research in the US has yet been permitted into the beneficial uses of MDMA, while probably in excess of $10 million has been spent seeking evidence of harmful effects. MAPS has been supporting Dr. Grob's efforts to initiate a study of the use of MDMA in cancer patients for many years. The FDA has taken three months to review the third draft of the protocol, with some response expected soon.

To the editor:

Regarding "Nerve Damage to Brain Linked To Heavy Use of Ecstasy Drug," by Erica Goode (10/30/98), it is important to distinguish drug abuse from therapeutic use. Many potent medicines have toxic doses--even Tylenol can be fatal, for example, as can lithium. But that does not exclude them as therapeutic agents. MDMA, an extraordinarily valuable drug when used as an adjunct to psychotherapy, should be considered in this context.

Ricaurte's research subjects averaged more than two hundred doses of "ecstasy" within four to five years, at 386 milligrams per dose. This does not represent the dosage and frequency of MDMA as it was safely used in psychotherapy for many years, which is 125 mg in a single oral dose, perhaps repeated once several months after the initial session. Dr. Ricaurte himself gave monkeys single oral doses of MDMA every two weeks, and failed to produce any adverse effects.

Further, equating a loss in the number of serotonin reuptake sites with "brain damage" is presumptive. There are many psychiatric medications, such as Prozac and Zoloft, which essentially decrease the number of these receptors by their blockade. This is the mechanism of action in antidepressant therapy. In general, the brain responds to repeated doses of chemicals by changing the number of receptors it creates, so this could be interpreted as an adaptive respose as opposed to a toxic or "damaged" response.

Julie Holland, MD
Bellevue Hospital, NYC

It seems on a preliminary examination of Ricaurte's study (in other words i skimmed it pretty fast) that Figure 3 and Figure 4 are where the "meat" of this study is, and they're not terribly impressive. It has already been reported that subchronic (less than a month) administration of 5-HT transporter ligands like antidepressants (SSRIs, TCAs and tianeptine) reduce 5-HT transporter mRNA and radioligand binding to 5-HT transporter[1,2,3]. These results call into question the interpretation of reduced [11C]McN-5652 binding in human brain as "neurotoxicity." To reach this conclusion Ricaurte would really need to show decreases in binding to the 5-HT transporter in excess of a 25% reduction -- I would accept that as valid evidence since there is no known non-neurotoxic 5-HTT ligand which "down-regulates" the 5-HTT by this amount, while the neurotoxic doses of MDMA (5mg/kg x 2/day x 4 days in non-human primates, 20mg/kg x 2 x 4 in rats) do produce more substantial reductions. However, eyeballing Figure 3, I don't see such a clear and substantial reduction. Furthermore in Ricaurte's Figure 4 barring one outlying point in a user of appx 150 MDMA doses, none of the MDMA users range lower than the low end of the control subjects, and the reduction (if i understand this plot correctly) is of the order of 25% and therefore not significant.

And, of course, there are other issues with the study -- such as the possible exposure to other neurotoxins like methamphetamine, and possible selection effects (perhaps MDMA users with low initial 5-HTT counts tend to be the ones that wind up using it 300 times). Ultimately, I think these matched retrospective studies are probably worthless in general unless there are very strong correlations, which I just don't see. The more I look at this study the more I think there's even less to worry about here than there was in the CSF 5-HIAA studies of human users...

[1] Watanabe, Y, Sakai, RR, McEwen, BS, Mendelson, S. Stress and Antidepressant effects on hippocampal and cortical 5-HT1A and 5-HT2 receptors and transport sites for serotonin. Brain Research. Vol 615. P 87-94. 1993.

[2] Kuroda, Y, Watanabe, Y, McEwen, BS. Tianeptine Decreases Both Serotonin Transporter mRNA and Binding Sites in Rat Brain. European Journal of Pharmacology. Vol 268. P R3-R5. 1994.

[3] Lesch, PK, Aulakh, CS, Wolozin, BL, Tolliver, TJ, Hill, JL, Murphy, DL. "Regional Brain Expression of Serotonin Transporter mRNA and its Regulation by Reuptake Inhibiting Antidepressants." Molecular Brain Research. Vol 17. P 31-35. 1993.

--
Lamont Granquist (206)616-1469 fax:(206)543-5380 Human Interface Technology Lab. University of Washington. Seattle, WA PGP pubkey: finger -l lamontg@hitl.washington.edu | pgp -fka

As you know, there has been some concern expressed about George Ricaurte's data analysis reporting a correlation between the amount of MDMA used and reductions in serotonin transporter sites. This concern centered around the inclusion of both the control group and the MDMA group in the analysis, along with the claim that the analysis should have been conducted with just the MDMA group alone.

I roughly estimated the data points for the 14 members of the MDMA group and did the correlation analysis myself between amounts of MDMA and serotonin transporter sites, omitting the control group. I still found a -0.33 correlation (George and Una reported a -0.5 correlation with the controls included). However, when just one data point in the MDMA group was omitted, that of the MDMA subject who happened to have both the fewest exposures to MDMA and the highest serotonin transporter site levels, the correlation disappeared. With this information in hand, I called George Ricaurte and talked it over with him.

First, he said that the correlation was still significant when the controls were omitted, meaning that he had already looked at the data this way. When I noted that just the exclusion of one data point would eliminate the correlation, he said that the low number of subjects made the correlation not all that dependable anyway and that it wasn't the central part of the paper. He said the lower overall average of the MDMA group as compared to the control group was what mattered most, and that the average was still significantly lower regardless of whether outliers were omitted from the analysis. He also said that if there was no correlation, that could imply that the reductions were caused by the initial doses and that further administrations of MDMA caused no additional reductions. He then made the leap of saying that this could mean that even a single dose of MDMA caused all the initial reductions. This latter point is a key issue in whether the administration of one or several doses of MDMA to patients in research might be considered too risky to permit. At the present time, it is still an open question as to how this latest study will impact regulatory decisions regarding MDMA research. I remain convinced that a reasonable risk/benefit analysis would result in approval of the expansion of MDMA research.

Rick Doblin

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