Michael Mithoefer, MD is a psychiatrist with a history in emergency and internal medicine practicing in Charleston, South Carolina. Along with his wife, Annie Mithoefer, who is a psychiatric nurse, he has been the principal investigator for FDA-approved clinical trials of MDMA for the treatment of severe post-traumatic stress disorder (PTSD). (As a street drug, MDMA is known as Ecstasy or Molly; however, those products also may contain adulterants.)
Phase II clinical trials have been completed, and the Mithoefers are currently conducting a second trial with U.S. military veterans. Dr. Mithoefer is the medical monitor for other MDMA trials being held around the world. He spoke with CATALYST recently about his work, the history of MDMA as a therapeutic drug, and the future of MDMA therapy.
CATALYST: What brought you to begin research with MDMA? Did you work with it before it was made illegal in the 1980s?
Mithoefer: I never did use MDMA with patients before starting the research, though I did have several sessions myself with a therapist before it became illegal. What led me to begin research was that the focus of my psychiatric practice was PTSD and I knew we needed a wider array of effective treatments for the large percentage of patients who did not respond adequately to existing treatments. Seeing that need, and knowing
about the published reports from therapists who used it clinically prior to 1985, convinced me that rigorous controlled trials were important to do.
The MDMA sessions you experienced—what were they like?
A number of therapists were using it as a catalyst for self-exploration. It was used for individuals and couples therapy quite a lot. Couples therapy was a promising area because MDMA helps people communicate without being defensive or blaming.
When was this taking place?
It was definitely a late-’70s and early-’80s phenomenon.
So MDMA was made illegal in 1986, I understand, over the objection of many of these therapists who had been successfully using it [see sidebar]. What happened then?
Rick Doblin at that time founded MAPS (the Multidisciplinary Association for Psychedelic Studies) when he realized that the only way to have a chance of MDMA being used again was to support rigorous research. The first study that MAPS supported was by [Dr.] Charlie Grob of UCLA, which was a Phase I clinical trial. Rick and MAPS also supported some of the work done at Johns Hopkins by Dr. George Ricaurte on the toxicity of MDMA. Rick realized the importance of taking an even-handed approach and looking at both the risks and the benefits of the drug.
How safe is MDMA in therapeutic doses, then, compared to other drugs used for PTSD?
Like any drug we use in the practice of medicine, MDMA is not without risks, but MDMA has now been administered to over 800 people in clinical trials worldwide (both Phase I and Phase II trials), and it appears to have a favorable risk/benefit ratio when used in moderate doses of pure MDMA in controlled clinical settings in carefully screened subjects. In our clinical trials we have not had any unexpected drug-related serious adverse events. We have seen expected side effects but they have been self-limiting.
Have the recent “molly deaths” affected your research, or the public reception of your research? Is the proliferation of “alternative psychedelics” and molly knockoffs affecting your research?
It has not affected our research because the regulatory agencies understand the differences you point out in your article [“The Molly Misnomer,” CATALYST, October 2013]. They’re focused on the science, and we have a good track record of safety, scientific rigor and regulatory compliance. I don’t know about the public perception, but I haven’t heard any blowback so far.
I’ve read that a 2002 study concluding MDMA causes irreversible brain damage was flawed, and that the substance used in the lab rats was methamphetamine, not MDMA.
You’re referring to a study by George Ricaurte at Johns Hopkins claiming that MDMA caused dopamine toxicity and in some cases death in baboons and squirrel monkeys. It was published in the journal Science accompanied by a press release and quite a lot of media attention. We wrote a letter in response, which was published, saying that something didn’t add up. Then a year later, the study was retracted because they found they had administered methamphetamine (which is, incidentally, a legal prescription medication), not MDMA. This set our research back by more than a year.
Did this flawed study have anything to do with the ads we would see on TV, the ones about having holes poked in your brain?
Those ads were done before [the study]. Ricaurte had already done quite a few animal studies showing that high doses did change serotonin neurons in the brain, but those visuals showing “holes in the brain” were extremely misleading. They were showing blood flow patterns in the brain, and then turning the gain all the way up (so the contrast between levels of activity in different areas of the brain looks really extreme) and then talking about the dark areas as if they were actually anatomical holes. It was all a really misleading campaign.
Back before MDMA was made illegal, were therapists using it for PTSD? Was there such a thing as a PTSD diagnosis?
By the late 1970s PTSD was understood as a diagnosis [it was added to the DSM-III in 1980]. MDMA wasn’t formally studied with PTSD back then, but it was reported as helpful in some case reports, particularly one by [Dr. Joseph] Downing. He wrote about Kathy Tamm, a patient of his who had been raped in 1985 [and who received MDMA therapy]. Her husband was a judge. Later, they went on TV talking about her experience. The judge said that although when his wife had done MDMA therapy it had been legal, now knowing what he knew about how the treatment saved his wife’s life, if he had to, he’d break the law to get this treatment for her. That was strong language coming from a judge; these are pretty mainstream people. I once met Kathy at a meeting and she was really happy to hear we were finally doing research.
What is the prevalence of PTSD among the general population?
The lifetime prevalence of PTSD in the US is about 8%. In veterans returning from Iraq and Afghanistan it is much higher.
How is the US Veterans study going?
We’re about halfway through and the results are very encouraging. We had a mutually respectful interaction with the DEA agents and the count of MDMA in our safe was correct and jived with our records.
We did have a long delay getting DEA permission for the first study—longer than two years. But even then our interactions were cordial, and we have developed a good working relationship with FDA, DEA and our Institutional Review Board. We’re not encountering the same kind of delays anymore.
So the veterans study is looking at PTSD in military vets coming home from Iraq and Afghanistan. Have you also enrolled any subjects from the Vietnam era?
We screened some Vietnam vets but none of them decided to be in the study, so we haven’t got any. We’ve studied people who were in Gulf War 1 and Bosnia as well as Iraq and Afghanistan, but most of our subjects are from the current or more recent conflicts and wars. We are hoping to include some Vietnam vets in future studies, though.
It’s been up to them to decide to be part of the study and they’ve declined?
The few Vietnam vets we have talked to have decided not to do it. I think it’s more of a challenge for them because they’ve adapted to the trauma in some way even if they’re still suffering from it. They are concerned that this might stir things up and they could lose the equilibrium they’ve worked so hard to develop. Even if it’s a constricted kind of living, they haven’t been able to take that leap, which I can totally understand. We don’t try to persuade anybody.
In the studies, what is a therapeutic dose?
We’ve been using 125 milligrams as a full dose in the first study and the current study, but in the current study we’ve also been using 75 mg and 30 mg doses as well. We’ve had very good results with the 75 mg dose. We’re changing the protocol to try out 100 mg doses as well, and tweaking it to find out the best design for the larger trials. That’s going to change according to what we see as we go along.
We consider a full dose to be either 100 mg or 125 mg. The medium dose is 75 mg, and so far that’s working as well as the 100 mg or 125 mg doses. The 30 mg dose is not working as well. These are just preliminary results and we’re not drawing any conclusions, but that’s what we are seeing so far.
So right now you are in small trials, building a protocol for much larger trials—what will those look like?
They will probably be between 200 and 300 people, in maybe eight to 10 locations around the country. It’s hard to recruit that many people in one location, so we’re looking at multiple centers. It’s also good to have many different teams doing the work, so you don’t have questions as to whether one set of results can be replicated by another team. We’ll have to do two of those larger studies, two Phase III trials, in order to ask the FDA to consider making MDMA a prescription medicine. As long as we submit the protocols to the FDA ahead of time, the data will be admissible to the FDA for this purpose.
Ideally, where would you like us to be in 10 years, with regard to MDMA and other psychedelics research?
We hope to have finished Phase III clinical trials within seven or eight years, and, if they show results similar to what we’ve seen in Phase II trials so far, we hope MDMA will be approved for clinical use in specialized clinics within 10 years.
Can you tell me what it’s like to take part in one of your trial sessions?
In addition to spending time with the subject and going over informed consent, we have three 90-minute prep sessions spread out over several weeks. During that time they have to taper off any psychiatric medications. We spend those sessions preparing them, helping them understand our approach to therapy, and giving them a chance to get to know us beforehand. That’s very important.
On the morning of the session, they will come in at 9:30. We will talk to them a little, do a urine drug screen so we know they don’t have any drugs in their system that they’re not supposed to be taking, and also a pregnancy test if they are a female. We give them the MDMA around 10 a.m.
The test is double-blind, meaning that the patients don’t know what dose they are getting (30 mg, 75 mg, or 125 mg), and we don’t know either. Not long after that we encourage them to sit back or lie down. They’re on a futon, so they can sit with pillows against the wall, or lie down fully. Most people choose to lie down, and then to focus inward, often using eyeshades, and headphones to listen to music if they’re comfortable with that. Then we just see what happens next. We encourage the subjects to have an open mind about what’s going to happen without having an agenda about what it should look like.
We have an agreement that at some point we will talk about their trauma, and that we can bring it up if it doesn’t come up, but we have never had to do that in over 100 sessions. The trauma doesn’t always come up right away, but sometimes it does, in which case we will help process that. Sometimes other things come up first, sometimes more affirming experiences, and then they’ll go into their trauma. They’ll go back and forth, so it’s quite non-directed that way.
We then encourage them to alternate periods of talking with periods of focusing inward quietly. I think it’s very important that we don’t have a set schedule for that. Each person develops their own rhythm. Sometimes if we’ve been talking for a while, we’ll say this might be a good time to go back inside and see what comes. Sometimes they will say to us, ‘I think it’s time to go back inside now.’ They often have the experience that, if they just stay with whatever’s happening, it does what it needs to do and they have whatever sense of relief and shift in awareness, or change in their thinking about things, or their expression of emotion. A lot of it tends to happen spontaneously.
How long are these sessions?
The sessions are eight hours. We are with them for at least eight hours. There will be both male and female co-therapists at a session the whole time. Occasionally one of the therapists will go to get tea or lunch or a bathroom break, but one therapist is with the subject the entire time, and both are usually there.
That sounds pretty intense.
It is, yeah. Often the sessions are very intense.
What kind of support do you provide afterward?
They spend the night in the clinic. An attendant comes in at 5:30 p.m. and the therapists leave. If people are still in the middle of processing something, we’ll stay longer. The subjects will spend the night so they don’t have to deal with the outside world right away. We encourage them to have a quiet night and a relaxing evening, and to just let the experience unfold as it is. The next morning we have an hour and a half meeting with them before they go home.
We encourage them to eat dinner and have a good breakfast. We talk to them on the phone every day for a week, and meet with them two more times over the next several weeks before the next sessions.
The MDMA sessions are a month apart, and there are three full-dose sessions for everybody. A month after the second session we break the blind. Depending upon the randomization, if they got a medium (75 mg) or low (30 mg) dose, they will get three full-dose sessions, or if they got full-dose sessions for the first two (125 mg) we will do only one more full-dose session. Everyone gets three full-dose sessions in total, spaced one month apart, and that’s all the MDMA they get.
The followup sessions are really important for integration. It’s not just that they experience the MDMA and then everything’s fine…the experience continues to unfold, and sometimes it stirs things up and there can be challenging emotions afterwards. We prep people for that. It can be part of their healing, as long as they have proper support and help in processing what comes up afterwards.
What do you love about what you do?
It’s gratifying to be able to support people doing deep inner work, though it can be challenging at times. Really processing trauma, even with MDMA as a catalyst, can be difficult for people. They need good support to integrate the experiences. And, of course, when people say they feel this treatment has saved their life, which we hear quite often, we’re especially gratified.
The History of MDMA
December 24, 1912: German pharmaceutical company Merck files a patent on 3,4-methylenedioxy-N-methylamphetamine, better known as MDMA.
1927: Max Oberlin studies MDMA’s pharmaceutical effects on blood sugar and smooth muscle, and finds them to be similar to those of ephedrine.
1953, 1954: The U.S. Army orders tests of MDMA toxicity in animals.
1950s: MDMA is studied as part of Project MKUltra, a U.S. Government covert human research operation in mind control, overseen by the CIA.
1965: Chemist Alexander Shulgin synthesizes some MDMA. He puts it on a shelf and forgets about it for a couple of years.
1967: Shulgin tries MDMA and becomes fascinated by its psychological effects.
1972: First record of street MDMA by the Chicago P.D.
1977: Leo Zeff, a psychologist, tries some of Shulgin’s MDMA and immediately realizes its therapeutic potential. Zeff christens the drug “Adam.”
1981: Researchers Myron and Jean Stolaroff interview Zeff: “A single MDMA-assisted therapy session could accomplish as much as six or more months of traditional therapy.”
1983: Ralph Metzner suggests the term “empathogen” (empathy promoter) as a descriptor for the effects of MDMA.
1984: Catholic seminary student Michael Clegg believes that he has seen the mind of God while taking MDMA. Now a priest, he begins openly selling MDMA in Texas, under the name of “Ecstasy,” and soon becomes a millionaire. The police and the DEA take notice.
July 27, 1984: The DEA announces its intention to make MDMA illegal.
April 25, 1985: The Donahue show on TV features MDMA, discussing both its therapeutic benefits and the troubling rise in street use.
May 31, 1985: Despite Judge Francis Young’s hearing recommendation that it be placed under Schedule III (has currently accepted medical treatment use), MDMA is placed by the DEA under Schedule I (high risk for abuse, no accepted medical use). All legal therapeutic use of MDMA is halted.
1986: Rick Doblin founds the Multidisciplinary Association for Psychedelic Studies (MAPS).
Late 1980s to early 1990s: The “Madchester” rave music scene develops in around Manchester, England. Illegal MDMA fuels the culture.
1992: A Phase I safety study of MDMA by Dr. Charles Grob is approved by the FDA. The study is concluded in 1995.
March, 2001: The U.S. government increases penalties for possession and distribution of MDMA, making it 10 times more severely punished than heroin, in spite of opposition by prominent scientists and the former head of the National Institute on Drug Abuse.
November 2, 2001: First FDA approval for human testing of MDMA as a therapy for post-traumatic stress disorder (PTSD).
2002: The journal Science prints purported MDMA study in primates that claims dopamine toxicity. Receives widespread news coverage. Then author announces the study was flawed; methamphetamines had been used, not MDMA. No party involved takes responsibility for the substitution.
September 2003: The flawed primate study is withdrawn. MDMA research can proceed.
April 1, 2004: ABC News airs investigative reporter Peter Jennings’ TV documentary on the history of MDMA. Presents strong arguments against government claims of serious danger.
2004: Phase II trials of MDMA for PTSD are initiated. They are concluded in 2008 with “remarkably promising results.”
2011: In a federal court hearing, the ACLU successfully argued that the sentencing guideline for MDMA is based on outdated science, leading to excessive prison sentences.
Current: MDMA PTSD studies sponsored by MAPS are ongoing in U.S. veterans, and another study is being initiated in Colorado. Overseas, studies are under way in Canada and Israel and under development in Australia. MDMA has also been studied for anxiety in end-stage cancer patients, and a study looking at its potential to benefit social anxiety in autistic adults is also being assembled.