The article overall gives the impression that it's a positive development that MDMA psychotherapy research is starting and that MAPS and I are indeed interested in looking at both risks and benefits. The article starts with the treatment of the first patient in the MDMA/PTSD study and ends with a fantastic quote, "We are at the forefront of studying risk and benefit," Doblin says. "We hope that there's enough respect for science that people will judge us on the basis of our data."

The article also contains a startlingly historic admission by Dr. Una McCann who, along with her husband Dr. George Ricaurte, have been the most prominent proponents for the neurotoxic risks of MDMA. She says that she "initially gave the study [MAPS' MDMA/PTSD protocol] her tentative backing, believing that it would be conducted in a hospital. But when she later learned that it would be run in a psychiatrist's office, she expressed misgivings." While Una can't quite come around to saying that she supports the study, her statement says that she, and presumably also her husband George Ricaurte, did not think that concerns over neurotoxicity should stop the study. This admission confirms that we have come to the end to the era of using fears over the risks of neurotoxicity to stop MDMA psychotherapy research. I discuss below how Una's concerns over the setting of the study have been addressed to the satisfaction of the FDA, the IRB and experts in emergency medicine, which is not Una's area of expertise.

Furthermore, the sidebar article presents the resumption of research with psilocybin in a positive light, saying, "While the controversy over surrounding ecstasy has been grabbing the headlines, a quiet revolution in psychedelic drug research has been underway. Over the past year, doctors have begun a handful of trials to test natural hallucinogenic drugs in psychiatric medicine."

For the above reasons and more, I think the article is a strong positive development that will help build momentum for the approval of further MDMA psychotherapy research (in subjects with advanced cancer with anxiety, at Harvard; in subjects with war and terrorism-related PTSD in Israel; and in woman survivors of sexual assault with PTSD, which we are trying to restart in Spain), and further psychedelic research in general.

That said, I have some serious critiques of the article and editorial. The article tries so hard to be balanced that it cites Ricaurte and McCann's discredited Lancet paper on their PET research into serotonin neurotoxicity as if it were the final word, ignoring the methodological critiques of that paper by Kish, Laruelle, O'Callaghan, etc., as well as the larger and better-controlled Buchert paper that failed to confirm the Lancet paper's dire findings. McCann's sleep study is presented as reporting "hints that MDMA affects processes such as sleep cycles" but no mention is made of the fact that the study shows that MDMA users have more efficient sleep patterns (Una's exact words to me) with MDMA subjects falling into deep sleep faster (fewer minutes in Stages 1 and 2 non-REM) and spending more time in restorative sleep (Stages 3 and 4 non-REM and REM). Nor has this finding been replicated. Even the parenthetical mention of George's spinal tap studies is problematic since in George and Una's letter to Science in June 2003, they defend against the criticism that they ignored their own spinal tap study which showed dopaminergic metabolite levels to be the same in MDMA users as controls by stating that spinal tap studies of dopamine metabolites are unreliable markers for brain dopamine levels (I'm not sure if serotonin metabolite levels are also unreliable markets for brain serotonin but I would assume so.)

Also problematic is that the struggle over MDMA research is presented in large part as a battle between me and George/Una. As such, it's simplifies my views and then questions the simplification, in the process giving the research of George and Una too much credence and too much importance. The three page article basically has an excellent first and third pages and gives the middle page to resurrecting Ricaurte/McCann's credibility and portraying MDMA as causing neurotoxicity, with the implication being that this occurs even in the doses administered in clinical research settings.

INITIAL EDITORIAL COMMENTS

The editorial is overall a positive statement that leaves the impression of supporting research into the therapeutic use of MDMA. Still, it also has some major flaws, due again to the desire for balance and the apparent need to call down a pox on both their houses. The most problematic part of the editorial is that statement that "The available evidence shows that MDMA can cause psychosis, hyperthermia, and even death in some people who take the drug recreationally. But there is no research to indicate whether or not this will be a problem in the controlled settings of a clinical trial, or whether such controlled administration might result in long-term brain damage."

Actually, there is lots of research that bears on the risks of administering MDMA in the controlled settings of a clinical trial. Numerous Phase I studies in the United States, England, Spain, the Netherlands and Switzerland with over 200 subjects have already been conducted and have produced evidence suggesting that MDMA in a clinical setting with prescreened subjects presents a vanishingly small risk of causing hyperthermia, psychosis or death. No serious adverse effects have occurred in any of the Phase I studies nor has any persisting emotional or neurocognitive damage been found to result from clinical research with MDMA.

The risk of hyperthermia in a clinical context is practically non- existent in the absence of vigorous exercise (dancing) and with adequate hydration, with some Phase I studies showing no statistically significant temperature increase and others showing only a minor 1 degree temporary increase at higher doses. There hasn't been any evidence to suggest a risk of psychosis in clinical research. The evidence from a large German longitudinal study (N= 2462, Lieb et al, 2002) concluded that "Care should be taken in cross sectional studies in interpreting mental disorder signs and symptoms merely as a consequence of ecstasy use, as ecstasy use might be associated with the use of multiple substances, and onset of mental disorder is more likely to precede rather than to follow use of ecstasy and related substances."

The editorial moves from its position of ignorance regarding the Phase 1 studies to the statement that, "both sides in the debate would benefit by taking a step back and re-focusing their work." While the editorial then talks only about what MDMA's detractors in particular should study, there is no step back that MDMA's proponents can take without abandoning therapeutic research. There's nowhere back to go from a small pilot study that has taken almost 20 years to get approved.

The editorial doesn't mention, nor does the article, that MAPS helped start John Halpern's study of neurocognitive effects of MDMA in a population that is the closest to an MDMA-only exposure group of any neurocognitive study ever conducted, or that the neurocognitive literature as a whole has failed to find differences between MDMA users with fewer than 50 exposure and controls, thus providing evidence that the clinical use of MDMA is not likely to cause any neurocognitive reductions.

Fortunately, the editorial ends with a sentence about "ensuring that safe treatments reach the patients who need them," which leaves the impression that the initiation of MDMA psychotherapy research is an important development. ADDITIONAL ARTICLE COMMENTS

Here are some more specific comments about the article, with some more details about some of the points above:

IRB-Related Issues

The article's discussion of the Western IRB's review, and Una's role in the revocation of approval, is quite shallow. The article focuses on the issue of Una's concern, and supposedly the Western IRB's as well, as to whether the study is conducted in a clinic or a hospital setting. What the article fails to mention is that the "clinic" setting that we have created is superior to a hospital setting in terms of risk reduction in case of a serious adverse event. We have a board certified ER doctor and registered ER nurse sitting in the next room with a crash cart on site during the first 5 hours of each experimental session. Also, Dr. Mithoefer, the PI and psychiatrist providing the treatment, was a board-certified ER doc for about 10 years before he became a board-certified psychiatrist. Thus, in the unlikely event of a serious adverse event, our "clinic" setting would provide faster, immediate care from a more highly qualified medical team than if the study were to be conducted in a hospital, where most likely a resident would be called from a distant ER and would take minutes, at least, to arrive.

The Western IRB knew of this special ER team when it initially approved the study, since this was in our FDA-approved protocol that we submitted to the Western IRB. The IRB's revocation of approval months later mostly cited neurotoxicity as the rationale and mentioned a discussion about this with Una McCann. When I spoke to George on the phone after I read the Western IRBs revocation letter, he agreed that emergency medicine was not Una's specialty. He further indicated that the Western IRB had quoted her as saying things that she clearly didn't believe, namely that MDMA was the only psychedelic with neurotoxic effects.

After MAPS had letters of support for the study written to the Western IRB from MDMA researchers around the world, including the PIs of all three FDA-approved Phase I studies, the Western IRB refused to justify or defend its decision to revoke approval on scientific grounds. Instead, the Western IRB's Executive Policy Committee made a policy decision not to provide IRB services and refunded MAPS' money.

The IRB that finally approved the protocol had moved beyond issues of neurotoxicity well before George retracted his Science article claiming that MDMA could cause Parkinson's. It was already clear, even if George had indeed administered MDMA instead of methamphetamine, that the doses given were not relevant to the doses that would be administered in clinical research. The IRB, as well as the FDA, had reviewed the human research that had already been published, but wasn't even mentioned by George in his original Science paper, that showed no effect of heavy MDMA use on dopamine. As a result, the IRB had already done its risk/benefit balancing regarding neurotoxicity and had decided to let the study proceed. At the time of Ricaurte's retraction, the IRB was focusing on emotional issues related to working with subjects with treatment-resistant PTSD. While the retraction certainly gave the IRB an added comfort level since the case for the risks to dopamine had disappeared and our challenge to Ricaurte's serotonin claims was given more credence, the retraction wasn't the key step that led to the IRB approving the study.

MDMA History

The article, in the third paragraph, says, "People who take Ecstasy recreationally generally experience a feeling of euphoria. And in the 1980s, a few patients started taking the drug as an aid to psychotherapy."

This gets the history of MDMA backwards. About half a million doses of MDMA were legally used in therapeutic contexts (not as a prescription medicine, just not illegal) from the mid-1970s until MDMA became criminalized in 1985. MDMA leaked out of the therapeutic community context around 1980, became renamed Ecstasy, became used more widely as a recreational drug, and then eventually became criminalized.

PET Research and MDMA's Effect on Serotonin

On page 2, the article says, "Using a radioactive chemical that binds to serotonin receptors, the researchers [Ricaurte and McCann] have also shown from positron emission tomography brain scans that MDMA users have fewer receptors for the neurotransmitter." The reference is to McCann and Ricaurte's discredited, unreplicated 1998 Lancet paper. Not mentioned in the article is that Buchert et. al. have published a more recent, larger (N=117 v. N=29) and better controlled study (Buchert studied current users, former users, non-drug users, drug users who hadn't tried MDMA v. Ricaurte/McCann who studied current users and controls with no use of MDMA and no info about other drug use), published in 2003 in the J. of Nuclear Medicine. Buchert et al. found virtually no reductions in current users who had used Ecstasy about 800 times (only 4-6% and in only two of the brain regions measured), with former users showing no reductions.

Here's a comment on the McCann/Ricaurte Lancet paper from a Dec. 2, 2003 New York Times article, " Dr. Nora Volkow, the new director of the national drug institute, declined to pass judgment on his whole body of work, but called his latest error "crying wolf and losing your credibility." Because of it, she said, she spent a weekend checking the agency's Web page on the dangers of Ecstasy "to make sure it was not overstated."The agency had already removed all current references to another well-known study from the site, one from 1998 by Dr. Ricaurte and his wife, Dr. Una McCann. Dr. Volkow described it as using "methodologies that were not optimal." Pictures from the study 'PET scans of the brains of Ecstasy users' were used on a famous postcard from the drug agency, "Plain Brain/Brain After Ecstasy." The postcards were distributed to thousands of teenagers and implied that Ecstasy users had shrunken brains with holes in them. The study had nothing to do with holes, but with serotonin levels, which Dr. Ricaurte found drastically depleted in 14 subjects who had taken Ecstasy 70 to 400 times. Dr. Marc Laruelle, a Columbia University PET scan specialist, called the work so technically flawed that it was "something to put under the rug." He cited a recent German study showing that serotonin decreased only modestly and returned to normal within six weeks. The Hopkins team, he said, presented its data in logarithmically compressed graphs that seemed calculated to mask the fact that it had found impossible results: its 15 "control" subjects had serotonin levels 50 times normal. Dr. Ricaurte defended the study, saying his recalculation technique was common when results from two groups varied widely, although he said he no longer used it."

The Lancet paper was also critiqued by neuroscientist Dr. Steve Kish in his 2003 editorial in Movement Disorders, and in Peter Jennings' April 1, 2004 Ecstasy documentary. It's ironic that the science behind the PET research into MDMA neurotoxicity was more accurately portrayed on network TV than in Nature.

The article mentions Dr. Franz Vollenweider's Phase I research with MDMA-naive subjects but notes only that he found that the acute administration of MDMA caused "moderate thought disorder." Vollenweider's published finding of no neurocognitive effects after the administration of two doses of MDMA in the therapeutic range was not mentioned in the Nature article. Also not mentioned was Vollenweider's prospective PET research showing no changes in serotonin transporters in MDMA-naive subjects after two doses of MDMA in the therapeutic range. This data has been presented at conferences in poster sessions with abstracts published, cited in peer-reviewed articles and letters, shared with the FDA and IRBs, and submitted to a journal for publication.

That's enough discussion for now!

Rick