Clinical MDMA Brief (25 Feb 2008)
February 25, 2008
As a brief update on my posts on the clinical use of MDMA (Part 1, Part 2) I’ll note that the MAPS folks are trumpeting the initiation of yet another clinical trial with extra oomph because it is at dear auld Haavahd.
One of my agents passed along a message MAPS honcho Rick Doblin sent out to one of his mailing lists (I can’t find it duplicated on the MAPS site, but the info will be there eventually you can bet):
On Saturday, February 23, 2008, after more than a decade of hard work, Dr. John Halpern conducted the first experimental session in his study of MDMA-assisted psychotherapy in twelve subjects with treatment-resistant anxiety associated with advanced-stage cancer (or PDF). Dr. Halpern is also conducting a major five-year NIDA-funded study into the neurocognitive risks of heavy use of Ecstasy, enhancing his ability to balance the risks and benefits of MDMA. This historic start of the MDMA/cancer anxiety study would not have been possible without the contributions of many people, including his co-investigators, the members of Institutional Review Boards (IRBs) at both the Lahey Clinic Medical Center and McLean Hospital, both institutions’ administrators and staff, and federal regulatory officials at FDA and even DEA. The study’s $250,000 budget is funded by Mr. Peter Lewis through a direct grant to McLean Hospital. MAPS assisted Dr. Halpern in the protocol design and approval process.
The funny thing is that this reminded me of a curious article forwarded by the PP a while back. It was an update of a rather old bust of a ring of LSD suppliers. The reason this case was in the news is because the feds caught the money guy, Stefan Wathne, who had apparently been running around the globe evading arrest in the case. Mired deep in the story we find:
Wathne was introduced to Pickard through Dr. John Halpern, a leading psychedelic researcher from Harvard’s prestigious McLean Hospital.
Halpern, records show, was paid $319,000 by Pickard from 1996 to 1999 – the same years Wathne is charged with laundering money for Pickard.
Testimony at Pickard’s drug trial suggested that Halpern was paid for the Wathne introduction.
Wathne’s alleged role in the LSD ring was to take drug money, cycle it through Russia and then send it back to Pickard, partly in the form of a “donation” to his UCLA research program, according to testimony at Pickard’s trial.
After the silo bust, Halpern made a deal with the feds and ratted out his friends.
Interesting story here, no doubt. Especially given Halpern’s LSD study and NIDA-funded MDMA study.
Writedit has been known to get a little het up about legal drug pushers (the tobacco industry) supporting scientific research projects. Aunt Janet also isn’t too keen on tobacco company funding for academic research. How should we view cases in which illicit drug pusher money ends up back supporting research projects?
DrugMonkey 
February 26, 2008 at 2:48 am
Read your own post you moron: “The study’s $250,000 budget is funded by Mr. Peter Lewis through a direct grant to McLean Hospital.” So… NO drug pusher money ended up back supporting research projects. With lack of intelligence so on display, NO WONDER you claim you are NIH funded. Bet you wouldn’t if you were open with your name. But the honest researchers who have their lives picked over by the vultures… somehow do. I wonder who is leading the ring through your dick?
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February 26, 2008 at 3:33 am
It was actually the $319,000 from Pickard that I was referring to in that part. You raise a decent point, however. I am so used to the people who want to criticize NIH/NSF grantholders insinuating that the total grant award (direct and indirect costs) is going into the PI’s personal bank account, and the $ amount seemed high for conventional “consulting”, that I suppose I assumed this was somehow a research award.
My bad. It could easily have been straight payola. If so, however, this raises even more analogies with BigPharma or tobacco company funding and consulting. Situations in which researchers who consult (to the tune of much less than $319,00!) may be questioned on their “bias” for the entire rest of their research program.
And this brings us back to the Lewis funding. The guy’s a huge supporter of all that MAPS is doing to Trojan up legalization for psychedelics and cannabis. Halpern’s accepted research funding from this chap outside of any pretense of the sort of investigator independence that is the hallmark of the NIH system. outside of competition or peer review, apparently. Is this really much different from taking research funds from a BigTobacco or BigPharma company? At least with the BigTobacco situations they usually have some degree of distancing from the funding foundation and a competitive peer review process for selection. If we are going to question the independence, agenda and motivations of researchers who take such funding, how should we view someone who takes money from an advocacy philanthropist? Can we really assume that Halpern’s NIH funded MDMA project is uncontaminated by the MDMA legalization agenda of his sponsors for the psychotherapy work?
If we assume so, than do we extend this right to investigators taking grant awards and/or consulting money from Pharma or Tobacco?
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February 27, 2008 at 6:04 pm
Well, at least DrugMonkey is a friendly chap. Let’s support this work. I assume you posted it because you do, no? There are tons of foundations that offer grants without extra NIH review also. And regarding investigator independence: the study was already approved prior to $$ from the billionaire. I read that MAPS was the sponsor and then had to leave the project. Are you saying that MAPS is not a legitimate funder of research? Also, isn’t the peer-review process essential at time of publication? Also, isn’t it important to note that NONE of these people are part of Big Tobacco? Finally, wouldn’t we assume that all the people that work with Halpern additional proof that it is unlikely that an NIH Neuroscience study can be impacted by a small study of cancer patients? Uncle Fester says your logic is warped but I’ll be polite from now on.
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February 27, 2008 at 6:55 pm
I assume you posted it because you do, no?
My position on the clinical trials is probably best laid out in the post linked to “part 1” above. with PTSD particularly, there is decent enough reason to start some trials. cancer anxiety, I don’t really have a position. with that said, I have a big problem with the way advocates deny much of the body of MDMA-related research and this is really the reason I post on MDMA. I also think the science denial blinds the advocates to the real risks and the things that we do not know yet that are potential risks. It is my firmest belief that they are going to lose someone in these trials once they get up to sample sizes in the few hundreds. N.b., I would be delighted to be wrong on this.
There are tons of foundations that offer grants without extra NIH review also. … Are you saying that MAPS is not a legitimate funder of research?
Most mainstream foundations have a peer review process of some sort. They rely on scientists active in the fields of interest to evaluate the potential of the proposal. I am not aware that MAPS had such a process in place to select Halpern, Mithoefer, etc. This is common to BigPharma, btw, which often contracts with specific labs to do some study or other because they lab has a model, assay or expertise they need. It is “legitimate” in some ways, it is just not peer reviewed independently-proposed research. My point is that all the ethical and “bias” aspersions that are cast for BigPharma (and BigTobacco) funded projects should be extended to this situation as well.
If one believes, as Aunt Janet and writedit seem to believe, that accepting research funding from BigTobacco means that one is irretrievably compromised, this logic should be applied to Halpern. It will not escape your notice, btw, that MAPS types assert the exact same inevitable bias thing about NIDA funding! If we line all these situations up, it should be clear that the one that is most lacking in overt procedures to avoid funder bias is in fact the MAPS funding of MDMA clinical trials.
Also, isn’t the peer-review process essential at time of publication?
Peer-review of grant applications and of scientific manuscripts serve different purposes. There is no obligation that a clinical trial be published, for example.
wouldn’t we assume that all the people that work with Halpern additional proof that it is unlikely that an NIH Neuroscience study can be impacted by a small study of cancer patients?
Again, what I am trying to do here is draw the parallel with BigPharma and BigTobaccofoundation funding of research. There is a certain theme critical of scientists that tries to question their autonomy and independence based on the sources of their research funding. My understanding of the way scientists behave, their sources of motivation and reward and their training makes me think these are bullshit charges when applied generally. As the MDMA advocates and tobacco critics are wont to do.
I therefore assume that scientists are not specifically biased by these sorts of funding concerns unless there is specific reason to do so.
Now bias having to do with one’s underlying interests, gut feeling, etc? ‘nother issue.
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March 2, 2008 at 3:21 pm
“It is my firmest belief that they are going to lose someone in these trials once they get up to sample sizes in the few hundreds.”
Sigh. Once again though, as you had already made abundantly clear to me drugmonkey, is that no one really knows what the lower levels of toxicity are for orally administered MDMA (see comments of part 2). As you said yourself, there are only two studies that come close to addressing this question in animal models. Both are by Ricaurte and one was retracted, leaving just the one study which has never been independently verified. Please correct me if this assessment isn’t accurate.
Are you really willing to base your “firmest belief” on this one study? Or am I missing something yet again? Personally I reserve my “firmest beliefs” on verified studies or studies I have conducted myself repeatedly.
Most of the the other MAPS studies I skimmed (via your links) all seemed to be using high dose intravenous injection of MDMA. I have to admit that setting up studies in this way seems profoundly stupid to me unless you are trying to see a damaging effect, as opposed to trying to find a lower threshold of safety, which among the MDMA research crowd does not appear to be a priority. Does this sound fair?
So, ya “high dose, short course” injected MDMA administration always seems to cause damage, but isn’t this also true of many drugs which when used properly are taken orally and with lower doses? Any of the opiates I think are decent examples of my point. I suspect (and do correct me if I am wrong, again) that toxicity thresholds for injected “high dose, short course” oxycontin for instance, are far lower than what has been found for MDMA. If not, I’m sure you won’t have to look very hard to find another drug that illustrates the point I’m trying to make a little better (alprolazam perhaps?).
Did they “lose anyone” when they were doing the phase I trials for oxycontin? Based on the pre-clinical data, would you have “firmly believed” that they would? What is the biggest difference about the body of pre-clinical work for oxycontin vs that of MDMA? That is, how were the pre-clinical questions asked? What was the focus and how were they different between the two drugs?
Moving on, doesn’t it seem obvious that damage will happen if you inject mice and monkeys with megadoses of drugs that are intended to be taken in small oral doses? “gee, I wonder if I will get permanent liver damage if I mainline a 5-10 mg/kg dose of naproxen/benzedrine/alprazolam?” derrrr. Funding 2 or 3 studies asking these kinds of questions is good, 10 is better, but funding 80+ studies along these lines sounds like an agenda.
There, I said it.
I wonder if the federal government might have an agenda surrounding MDMA? I wonder how many federally funded scientists with “dogs in the hunt” as you say, stay federally funded if they don’t align well with this putative agenda, all while ostensibly maintaining an air of impartiality? How well do politics and science mix, really? How much “firm belief” can be created when lots of jobs and money are at stake?
I know you’ve answered it all before, but if you are going to be casting aspersions at the potential for the clinical benefits of MDMA, I think perhaps this all bears repeating.
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March 2, 2008 at 3:43 pm
Just to wrap up I wanted to more specifically address this comment –
“There is a certain theme critical of scientists that tries to question their autonomy and independence based on the sources of their research funding. My understanding of the way scientists behave, their sources of motivation and reward and their training makes me think these are bullshit charges when applied generally. As the MDMA advocates and tobacco critics are wont to do.”
As I was trying to illustrate above in my tirade, the mechanism at play here is not a lack of autonomy and independence of the scientists themselves. Every scientist I know has the highest principles, but the fact is they all have to eat, and that means they have to do research for which the market has an interest in funding. General market forces dictate what gets studied and what questions get asked. It doesn’t matter how good the science is if the only question you can get funding to ask is, “how toxic can MDMA be?” (or to use your anaolgies, “how healthy are cigarettes?”)
In my opinion the only scientists that can address questions truly disentangled from politics or commerce are the ones that can support themselves. There are gradients between the tobacco company researchers and NIDA scientists and the independently wealthy scientists of course, and these are the people who really represent the bulk of what the public view as impartial scientists. You unfortunately do not fit into this category. So while I’m sure the science you do is excellent, you can’t realistically pretend that the broad questions you get to ask aren’t at least somewhat pre-determined. Everyone has to “get with the program” one way or another except for the people who own “the program” and guess what chief, that isn’t you or I.
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March 3, 2008 at 6:18 pm
Casey levels a fair number of charges in the comments above:
just the one study AFAIK. The 2002 science paper used s.c. and i.m. administration. For the record, I think the fact that the field has spent minimal specific effort on the threshold issue is idiotic.
The place where I differ is in assigning the above sad state of affairs to an anti-drug “agenda” over the natural way that science is biased for positive, repeatable results. You view the “80+ studies along these lines” as all being part of an agenda to show that MDMA causes harm. I view it as the tendency to work-over the mechanisms underlying a well-defined and reliable effect. This latter is how much of science operates, for good or bad. It does so in many different areas and drug abuse is not unique in this.
Even though the so called neurotox studies are not focused on threshold, some information does result and it is published, not hidden. The NCTR group (Slikker as senior author) did some studies with full-range dosing back in the day. There are many negative results reported. The three nonhuman primate studies dedicated to examining the behavioral outcome of the defined “neurotox” exposure were all negative and they all chose to publish (check the Winsauer, Paule and Gold studies). In the human ex-user studies, there are a whole host of negative findings, not to mention demonstrations that cognitive failure just might not accrue to MDMA (but rather cannabis; you can appreciate the bind this puts on the MAPS types who want to deny MDMA and cannabis research!). So it is absolute nonsense to suggest that the only research that is publishable or fundable is that which shows MDMA to be toxic. Now admittedly, in order for the advocates to recognize this they would also have to credit the apparently positive findings. They seem to find it easier to pooh-pooh all of the data.
The notion that there are “independently wealthy” scientists doing any substantial amount of work in any area relevant to modern bioscience is absurd. I’m sure there may be one or two examples in the world but c’mon. At best we have people partially funded on a lab-basis (as opposed to the project-basis of NIH fame) by independent philanthropy or HHMI. But they are also tied into the rewards/inducements of the publication system as well as in many cases additional funding from NIH/NSF/DOD, etc.
Admittedly I’ve laid this out elsewhere and didn’t repeat it here. In short my view is based on the following. First, the blood levels of MDMA in the case reports. The take-away for me is the rather low blood levels in many (not all, many) cases in which medical emergency or death resulted from MDMA ingestion. Levels consistent with one or two tablets consumed. There are many caveats, yes and you are welcome to your own reading of the data. The second point has to do with relatively recent reports from the animal literature in which doses where are way under the apparent 95%CI for MDMA (Hardman et al 1973) and which have apparently been perfectly safe in the wealth of “neurotox” studies from the 80s and 90s seem to be resulting in the odd death. Rodents as well as monkeys. You have to read the papers fairly closely because nobody highlights this. Third, and admittedly you have to be in the biz to some extent, conference presentation and chats with some of the relevant scientists underlines the impression which sneaks out in the papers. Namely that in some small percent of cases weird stuff happens; rare, but frequent enough to suggest that this is going to be relevant once you get up into the hundreds of clinical trial cases.
As a few final thoughts, there is nothing about MDMA metabolism or PK that suggests that oral dosing is going to provide some categorical protection. A quantitative protection, probably. So that argument boils down, yet again, to discussing dose.
With respect to the idea of animal models being “massive overdose”, this is a red herring. First, you will go broke in short order asserting what the entire population of human drug users will or will not do. No matter what crazy dose or regimen you come up with, you can find someone. usually with an online trip report! seriously though, since we are in the realm of idiosyncratic responses, it is silly to argue about what “average” or “typical” users do. More useful to discuss what the full range of doses might do to the full range of likely users. the more one wants to broaden the pool of likely users (via legalization, “debunking” of the science “agenda”, clinical trials, etc) the more important this becomes.
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March 5, 2008 at 4:18 pm
1. No MAPS studies use INJECTED MDMA: all are oral administration.
2. What matters most is peer-reviewed publication. Peer-review and distributed co-authorship and clear statements in the acknowledgments of funding and potential conflicts of interest addresses all of the more silly concerns expressed by Drug Monkey about research funding. I recommend reading Halpern’s published works: that is more significant than the hypotheticals in this posting and apparently in a newspaper rag. Are you saying his peer-reviewed publications stink? Did peer-review fail to catch a crappy set of data published because you don’t like that he has funding from NIDA or from MAPS or from whomever? I just don’t get your point still. There are many many foundations and wealthy types out there who donate to research all the time, every day, and the key is doing good research -at least that is what I like to read.
Oh 3. Serious adverse events, even a death, does not shut down the development of any drug necessarily. Halpern’s MDMA study is with dying cancer patients.
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March 5, 2008 at 5:00 pm
No MAPS studies use INJECTED MDMA: all are oral administration.
So what? This is the classic diversionary tactic. There is nothing that I can see about the pharmacokinetics or metabolism of MDMA that suggests any qualitative difference. All we are talking about is, in essence, dose. And we know we are dealing with idiosyncratic responses which makes arguments about absolute dose thresholds for “safety” naive at best. If you know something about toxic endpoints that require a rapid jump in brain levels that absolutely cannot be produced with an oral dose, throw down. Otherwise, stop tossing out “it’s oral, it’s oral” as if this were an argument instead of MAPS-type spin.
I recommend reading Halpern’s published works: that is more significant than the hypotheticals in this posting and apparently in a newspaper rag. Are you saying his peer-reviewed publications stink? … I just don’t get your point still.
My point on this topic is that if one is going to question the validity of the science and the independence of the scientists on the basis of NIDA funding (as do the MAPS folks, repeatedly and in spades) then one must question the validity of the science and independence of the scientists who are funded by such well-confirmed legalization advocates as MAPS, Lewis, etc.
OTOH, if one really believes that Halpern’s work should not be questioned just because he happens to have a colorful history with drug dealers involving mysterious payments and existing “research” funding from sources which make no bones about their pre-existing biases…well one should then extend such courtesy to BigPharma/BigTobacco/NIDA-funded scientists as well.
Halpern’s MDMA study is with dying cancer patients.
So what? The PTSD trials are not with the dying and these trials involve more patients at present. With respect to “serious adverse events” not shutting down drug development, true enough. So what? All I’m saying is that I think the existing state of knowledge supports a prediction. I further think that the advocates are in denial about this, although I could be wrong. Certainly I have not been able to find anything in the MAPS writings on this that anticipates any deaths.
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March 12, 2008 at 5:10 pm
A good reply to my comments drugmonkey. The only thing i want to follow up is a clarification of one of my comments.
“The notion that there are “independently wealthy” scientists doing any substantial amount of work in any area relevant to modern bioscience is absurd.”
Yes, by “independently wealthy” scientists I was not alluding to some Bruce Wayne figure in a batcave somewhere, filled to the brim with Raman spectroscopes, 454 Sequencers, and Patch-clamp machines. I was alluding more to the likes of Craig Venter and Steve Wozniak. Yes, they too have to respond to market forces, but are freer from them than most other researchers I can think of (I would hold up the whole Sargasso Sea sequencing project as a good example of this freedom).
“The place where I differ is in assigning the above sad state of affairs to an anti-drug “agenda” over the natural way that science is biased for positive, repeatable results. You view the “80+ studies along these lines” as all being part of an agenda to show that MDMA causes harm. I view it as the tendency to work-over the mechanisms underlying a well-defined and reliable effect.”
In my opinion it is actually both mechanisms in operation. No time to elaborate at the moment tho, maybe later.
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March 12, 2008 at 11:42 pm
OK I’m back with some more time, lucky you I’ve got some insomnia again. Where was I? Oh ya, “The place where I differ is in assigning the above sad state of affairs to an anti-drug “agenda” over the natural way that science is biased for positive, repeatable results.”
Again, I think both things are happening. The point may not be illustrated by the MDMA example as it is with marijuana. There are several examples of the government pulling funding from research illustrating that marijuana is safer than legal recreational drugs for instance. Of course, this is the first time I’ve brought up recreation in this thread, whcih brings me to my last and final point.
“With respect to the idea of animal models being “massive overdose”, this is a red herring. First, you will go broke in short order asserting what the entire population of human drug users will or will not do.”
I’m sorry but admit it, this was totally unfair on your part. The conversation up to this point had been all about the studies being done to find a clinically useful application of MDMA. If such a benefit is found, presumably the drug would be administered in controlled doses by strict prescription. As I understand it, the patient wouldn’t even be adminstered the drug outside of a monitored setting, as the potential application is currently being imagined. So why on Earth are you suddenly talking about crack-head ravers taking 20 pills a night?
So again, I’m sticking to my guns on this one. My point about the “massive overdoses” given to animal models is a very relevant one to our discussion as I understood it, and not a red herring at all.
I don’t think we disagree on the point that it is shameful that better “low threshold” investigations haven’t been done. I also don’t disagree with you that much of the reason for this neglect may be attributed to the fact that researchers like to build on what has been done before. However I strongly disagree with what seems to be your view that none of the blame for this lack of low threshold research can be assigned to the politics of government grant funding. I’m not calling it a conspiracy or anything quite so sinister, in fact, I think the political battles between the ONDCP and DEA vs the NIDA and NIH are very out in the open and well documented. Sometimes the ONDCP wins some of these battles and it does affect public health research funding. That’s a fact.
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March 13, 2008 at 12:04 am
I should also note that I agree with you on this statement you made in response to another commenter.
“My point on this topic is that if one is going to question the validity of the science and the independence of the scientists on the basis of NIDA funding (as do the MAPS folks, repeatedly and in spades) then one must question the validity of the science and independence of the scientists who are funded by such well-confirmed legalization advocates as MAPS, Lewis, etc.”
However, the blade cuts both ways. The ultimate purpose of those funding research into potential medical benefits of MDMA may indeed be to use any new clinical status as a stepping stone to decriminalization of the drug for recreational purposes. However, if the research being done towards that path (ie demonstration of medical benefit) happens to be excellent and stands up to peer review, shouldn’t it also get the same level of respect and inform the debate just as strongly as any NIDA-funded research of similar caliber? As you pointed out yourself, the source of the funding doesn’t impact the data itself. Science will say what what science learns. But to my point, what proposals do get funded or not is determined by those with the purse strings. So while I think it is healthy to think about the motivations behind what questions are selected for answering, it is not fair to question the results, author’s interpretation, or the caliber of any given study on anything more than the merits of the work itself. Can we agree on that?
It seems obvious enough to me that the current data does not at all support a rationale for the use of uncontrolled recreational use of MDMA, that would be profoundly stupid and hopefully will never happen. But the question of medical benefit is still wide open from my perspective, and your slant about “losing someone” in one these studies if they get big enough, does indeed smack of speculative bias. Like you however, I care far less about who the people funding the research are as long as the research will stand up to peer review. I may wish that different research was being done, but that’s another thing.
Cheers.
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January 14, 2012 at 7:44 am
Hey, I sent an email (re: the last topic). Does the “website” e-mail work?
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