The Challenges of the MDMA Research Studies: Annie and Michael Mithoefer Part Two

Husband and wife team, Michael Mithoefer, MD, a clinical psychiatrist, and Annie Mithoefer, BSN, a registered nurse, are Clinical Investigators for MDMA and PTSD studies at the Multidisciplinary Association for Psychedelics Studies (MAPS). They specialize in treating PTSD with experimental psychotherapy through clinical research and outpatient clinical practice. Between 2004 and 2018, Michael and Annie completed two of the six MAPS-sponsored Phase II clinical trials testing MDMA-assisted psychotherapy for PTSD. Together, they have over 25 years of experience treating trauma patients.

Here’s a glimpse of what you’ll learn:

[1:02] The methodological differences between drug and psychotherapy outcome research
[9:57] Michael and Annie Mithoefer discuss the biases they faced conducting psychotherapy outcome research
[12:55] Navigating ethical concerns surrounding psychotherapy and drug research
[20:23] A deep dive into the criticisms and methodologies of the psychedelic therapeutic method
[29:02] How FDA approval will impact future drug therapy research and integration
[32:28] Advice for conducting MDMA training sessions

In this episode…

Although MDMA-assisted psychotherapy has been hailed as a groundbreaking treatment for PTSD, its path to legitimacy has been thwarted by methodological and ethical challenges. How can researchers balance the demands of rigorous scientific inquiry with the relational complexities of psychotherapy to advance this innovative approach?

Drug therapy researchers Michael and Annie Mithoefer faced significant criticisms of their methods as they worked to integrate MDMA into trauma therapy. Conventional drug trial models, which rely on strict double-blind methodologies, clashed with the participatory nature of psychotherapy. To address bias and ethical concerns, the Mithoefers designed studies with independent, remote reviewers trained to evaluate outcomes objectively. They also adjusted their protocols to prioritize participant safety after initial low-doses of MDMA increased anxiety rather than offered therapeutic benefits. Despite these challenges, the Mithoefers collaborate with the FDA continuously to create rigorous protocols that balance scientific standards with real-world therapeutic applications.

In this part-two episode of Living Medicine, Dr. Sandy Newes continues her discussion with Michael and Annie Mithoefer about the barriers they face in their MDMA research studies. Together, they discuss the unique challenges of drug research in psychotherapy, the ethical dilemmas they face, and how their work aims to transform mental health care.

Resources mentioned in this episode:

Quotable Moments:

“Participants are the primary actors in their own healing with support.”
“It’s about figuring out how to discover what’s actually going on, not just sticking to one method.”
“We need to shift the whole system toward supporting people’s inner healing capacity.”
“We’ve learned it’s easier to train an experienced trauma therapist on MDMA than someone with no trauma background.”
“We need a community where therapists can get training, ongoing supervision, and mentorship.”

Action Steps:

Embrace adaptability in research approaches: Understand research methodologies by acknowledging the need for flexibility and adaptation in research design. This allows for a more accurate reflection of psychotherapy’s complexity, addressing the challenge of rigid scientific methodologies that may not fully capture therapeutic outcomes.
Foster collaborative patient relationships: Adopt a participatory model in therapy where patients are active participants in their healing process. By shifting the focus from a passive to an active role for patients, this approach addresses the opportunity to strengthen therapeutic relationships and improve outcomes.
Enhance therapist training and supervision: Invest in thorough training and ongoing supervision for therapists involved in psychedelic-assisted therapy. This is crucial for maintaining high ethical and professional standards, ensuring patient safety, and addressing the challenge of therapist bias or unpreparedness.
Prioritize integration and follow-up: Ensure that therapy includes robust integration and follow-up sessions post-psychotherapy to maximize the benefits of the treatment. This addresses the challenge of patients feeling abandoned or unfinished in their therapy process.
Promote community and support networks: Develop community support systems and integration circles for both therapists and patients to facilitate ongoing learning and experience sharing. This creates a supportive environment that enhances the therapeutic process and mitigates risks associated with the therapy’s novelty.

Sponsor for this episode…

This episode is brought to you by the Living Medicine Institute.

LMI is a training, resource, and membership program educating providers about the legal and safe use of psychedelic-assisted psychotherapy.

To learn more or participate, visit https://livingmedicineinstitute.com.

Episode Transcript

Intro 00:03

Welcome to the Living Medicine podcast, where we talk about ethical medical use of psychedelic psychotherapy teaching skills, examining the issues and interviewing interesting people. Now let’s start today’s show.

Dr. Signi Goldman 0:19

Hi, this is Dr. Signi Goldman, your host for Living Medicine, where we interview clinical and medical professionals in the evolving ketamine and psychedelic assisted psychotherapy space. Recent interviews we’ve done are with Ron Siegel from Harvard on mindfulness and psychedelics, and Dick Schwartz, the founder of Internal Family Systems, on non-ordinary, or potential spiritual content in psychedelic Sessions. So please check those out. Today we have part two of Sandy’s recent interview with Michael and Annie Mithoefer. If you haven’t heard the first half of that interview, please check that out in our prior episode. Enjoy.

Dr. Sandy Newes 01:02

Let’s kind of talk about the piece about this piece about drug research versus psychotherapy outcome research. And I’m going to just pull out a couple pieces in particular, and then we can see where it goes. But but what I got in my readings and my watching was one of the big things was the functional blending piece. Like, you know, that in drug research that it is that, you know, ideally the patients, the participants, they don’t know which they got, they don’t know if they got a placebo or the medicine and they can’t tell. And in the MDMA study, you did these wonderful equivalent placebo groups, and they got exactly the same therapeutic process with exactly the same therapist. But within some point they’re going to know that they got the medicine and there’s no real way. Well, usually it’s interesting. Not everybody did. Not everybody. Interesting. Yeah, that’s an interesting thing to ponder, but but that and then and then that. The review panel was said that that was a bad thing, which is a very classic, like holding to the drug research methodology. But the thing is, is that in psychotherapy outcome research, you know, if you’re going to do either waitlist control, which is you know, what you do if you don’t have equivalent placebo equivalent control group, but even and then, I mean, if we’re going to just like chat, you know, and somebody else is getting CBT and then we’re just chatting, even if it’s an hour at a time, people are pretty quickly going to know, right? Yeah. You know that they’re not getting that. They’re not getting the therapy. Right. And then related to that.

Michael Mithoefer 02:38

Participant in it. So they can’t not know it’s going on. Right. That’s the whole model of this. It’s a participatory thing. It’s a relationship in which the person is an active an actor and the primary actor in their own healing with support. Not that they’re just like Irrelevant.

Annie Mithoefer 02:59

Yeah. Right? Right. Yeah. Yeah. Right.

Dr. Sandy Newes 03:03

So they’re in the MDMA session. And so so, you know, in psychotherapy outcome research, that’s just an assumption that the participant is going to know. And then another assumption that’s kind of related to it. And then I’ll stop and turn it over to you is expectancy effects that, you know, if somebody enters a psychotherapy outcome research trial, they’re going to have some hope that it’s going to work or they wouldn’t do it.

Michael Mithoefer 03:28

Why would they sign up?

Dr. Sandy Newes 03:29

Why would they sign up?

Annie Mithoefer 03:30

Right. It’s a thing. Yeah. Right.

Dr. Sandy Newes 03:31

Like somebody’s monitoring you. They’re checking why they’re there to answer a million questions. Like people are. You know, you’re going through a whole big thing. There’s video. I mean, you wouldn’t do it if you didn’t have some hope that it might. Sure.

Annie Mithoefer 03:43

Sure.

Dr. Sandy Newes 03:43

And so again, that’s just endemic in psychotherapy outcome research or research. And yet this panel brought those forth as like huge methodological concerns. So what are your thoughts about that? Yeah.

Michael Mithoefer 03:56

Well, you know, when Prozac came along. Everybody knew this was an exciting new drug being studied for depression. If they sign up to the trials, they’re going to know that. And if they can’t have an orgasm the next week, they’re probably going to notice that too. So the blinding in many drug studies is is a challenge. But, you know, science is about figuring out how to discover what’s actually going on and figuring out a method to discover that. It’s not about figuring out this is how we discover things. And so we’re only going to look at anything that doesn’t fit in this way of discovering things we can’t research. Yeah, that’s basically what it would amount to. It would mean, oh, you can’t do any meaningful research with psychotherapy because you can’t. So it just it just doesn’t make sense. It presents new challenges. There are many things that you can didn’t learn with a double blind, controlled trial. But there are other things you can’t learn with a double blind, controlled trial. And that’s what we’re coming up against. And, you know, we had so many discussions with FDA about this, trying to solve it first. We tried to do a dose response. Well, the.

Annie Mithoefer 05:16

First study was just a placebo. Inactive placebo. Right.

Dr. Sandy Newes 05:20

Like you’d just be hanging out. Yeah.

Annie Mithoefer 05:22

Yeah. You wouldn’t know, but you’d be doing therapy. But they would not get anything.

Michael Mithoefer 05:27

But the placebo was not because it was inactive.

Annie Mithoefer 05:30

The placebo was inactive in the first phase two study.

Michael Mithoefer 05:34

Yeah. So we’ve done.

Annie Mithoefer 05:35

And then the second one was the dose response.

Michael Mithoefer 05:38

Rick Doblin thesis at Harvard was about how to do this was about thinking you’d solve the blinding problem with dose escalation. So starting with a Lower dose dose, progressively higher doses, you find out, oh, the more the medicine you take, the better they do. Right. That shows even if they’re unblinded in all cases. The trouble is, that didn’t work for two reasons. I mean, we studied zero, 25, 30, 40, 50, 75, 101, 5125. So what we found was that it didn’t work for two reasons. There’s a threshold effect. If when you get to a certain dose people, it becomes useful, it becomes helpful. And you can tell people are having an MDMA experience below that dose. It’s not useful. And you can tell that they’re not having MDMA experience most of the time. There are some notable exceptions, right. And then so that was one factor. The other factor was low doses of we used low doses of MDMA because they’re documented confounds with other things. Ritalin, niacin. People have talked about all those. They’ve all got confounds and they don’t work that well for blinding. Yeah, the MDMA improved, low dose MDMA improved the binding somewhat, but it made people more anxious and they did worse.

Annie Mithoefer 07:00

They dropped out.

Michael Mithoefer 07:04

Out. We had to change in the the study with veterans where we did three different doses, 3075 and 125. We had to amend the protocol partway through because the people had to go through three of whatever they were randomized to. So it was months and three MDMA sessions, and we found after two people had had the 30mg, it was just too difficult. One of them dropped out and then across. So we changed it to only two sessions with the first dose, which was okay scientifically because we’re our outcome measure was. But we saw at the end of that study same two therapists with the low dose MDMA. We had only people improve with therapy plus low dose, but they only improve half as much as they did with therapy plus inactive placebo.

Dr. Sandy Newes 07:57

Oh, interesting.

Michael Mithoefer 07:58

So they told us it made them more anxious. They complained, they dropped out and we saw the people who didn’t drop out. It interfered with the therapy. So when we had the discussions with FDA, we discussed that we could use low dose MDMA. But we’re advantage our our product.

Dr. Sandy Newes 08:15

Well so in that is drug research methodology right. Right. Like you’re looking at different dose and you know tracking the patients and adjusting the protocol accordingly. Keeping above and beyond all else do no harm. And the fact that you start to seeing these adverse effects and stop immediately like to me that once again, it’s that’s following the most strict of drug protocols, is it not. Yeah.

Michael Mithoefer 08:38

Yeah, yeah. And we concluded with FDA, this was an in-person meeting where we hash this out for, among others, we decided there is no solution beyond very well, blinding the adherence. The Raiders.

Annie Mithoefer 08:54

Yeah not the Raiders but the outcome Raiders.

Michael Mithoefer 08:57

So the people doing the caps PTSD scores were all very well trained remote. All was done remotely and they never saw the same participant twice. So the Raiders didn’t know where the Raiders were.

Dr. Sandy Newes 09:12

Not the therapists. The Raiders.

Annie Mithoefer 09:14

Were they were not.

Dr. Sandy Newes 09:15

Even with them. They were the participants.

Annie Mithoefer 09:16

And hundreds or thousands.

Michael Mithoefer 09:18

Of miles.

Annie Mithoefer 09:18

Away. Okay. And they did.

Michael Mithoefer 09:20

Not know the whole protocol. We kept parts of it hidden.

Annie Mithoefer 09:23

And they didn’t know where the people were in the protocol, except that if the first the first session. Yeah, they had.

Michael Mithoefer 09:30

To know if it was a baseline caps, but after that, they had no idea of how many sessions they’d had or what they’d had. People were instructed and reminded three times during the adherence. During the outcome ratings don’t say anything that would reveal to your Raider whether you’ve had a session, what it was like. Don’t say anything about that. Just talk about the symptoms of the Raider wants you to.

Annie Mithoefer 09:56

So when that seems to.

Dr. Sandy Newes 09:58

Really speak to either one of the critiques, which is, you know, that the therapist and the research team was so incredibly biased that they were looking they were overlooking adverse effects. And I mean, that is a really significant effort to, like, keep these raters blinded. They don’t know anything about it. Right? I mean, right, like, I don’t know what else.

Annie Mithoefer 10:19

Well, you couldn’t do something. Yeah, right.

Michael Mithoefer 10:21

The FDA couldn’t figure out anything else for us to do. We couldn’t figure.

Dr. Sandy Newes 10:24

So you did what they said and we did.

Michael Mithoefer 10:26

And we had a special protocol session, which is an extra step. We spent months hashing out all these details, and we have a written agreement that this protocol design is adequate for approval if we get statistically significant results and no new safety problems. So that one that wasn’t really on the table for FDA. Yeah. The adcom was not apparently aware of how much time we’d we spent working this out as best we could with FDA.

Annie Mithoefer 10:56

I think that’s one frustration.

Dr. Sandy Newes 10:58

Sure I bet. I mean, you’re like, wait a minute, we did how much?

Annie Mithoefer 11:00

How much we did to work out some of these things that the committee didn’t seem to be aware of. Well, and I think.

Dr. Sandy Newes 11:08

One of the things to me that has always struck me and I remember hearing about it was like a radio, an NPR interview. It was probably after the stage one or maybe stage two. It was a long time ago where it was this like panel of researchers who were like dissecting the data. And, you know, one of them was for it, and the other three were like, we honestly came to this panel expecting, like, we really want to hate this. Like we do not want to give people drugs to feel better. And because we are methodologists, we cannot like this methodology is so rock solid that we really can’t poke holes in it. And I would imagine that you designed it knowing that it was going to be under the most incredible scrutiny ever.

Annie Mithoefer 11:49

We did.

Dr. Sandy Newes 11:50

We did. So you’re not going to leave a rock unturned. Yeah.

Michael Mithoefer 11:52

And from the beginning, Rick Doblin. I mean, we’ve all known that. But Rick has specifically said often, we got to do this better than anybody else. We got to be more rigorous. Right, exactly. And and we also got to work for the harms, too. He bought primates for George Riccardi to do the toxicity studies with MDMA. When George Riccardi was hell bent on proving MDMA was dangerous. And Rick supported. He funded some of that maps, funded some of those Riccardi safety studies. So it’s he knew we can’t we got to be extra squeaky clean. And we’ve got to look at all the risks as carefully as we can. And that’s what I mean. We’ve been doing for 25 years. And Rick was doing it before that, right, with funding those other studies.

Dr. Sandy Newes 12:43

So safety concerns have really been addressed at every step because you would know, like the FDA.

Annie Mithoefer 12:49

Well, there are some that they’re.

Dr. Sandy Newes 12:50

Educating you about it, you’re going to be doing everything because that’s obviously going to be a big criticism.

Annie Mithoefer 12:55

Right? Yeah. Well, the last the there were some criticisms about the labs that weren’t done and the positive adverse events that that was misunderstood, I think, by some of the sites in phase three. But those are those seem like things that can be addressed. Sure. Maybe in later studies.

Dr. Sandy Newes 13:14

Right. Or like, you know, just like tracking it really, really, really carefully in a highly controlled rollout. Right? Because the concern there, right, is that people have so many positive effects that it opens up addiction potential.

Annie Mithoefer 13:26

Right, right, right.

Michael Mithoefer 13:27

That’s what we you know, what they’re saying is we underreported the positive effects because we didn’t call them adverse events, which I mean, we we discussed. Discussed this. We discussed it in detail. And obviously it was a mistake not to record it differently now in retrospect. But we discussed this about.

Annie Mithoefer 13:49

Well, we we did record those in some one of the phase two studies, I think. We did record some of the positive things.

Michael Mithoefer 13:58

But not as adverse events.

Annie Mithoefer 13:59

Not as adverse events.

Michael Mithoefer 14:00

Yeah, they were expected features and we’d know we’d take note. We had a checklist actually in the beginning about, you know, if they were feeling positive mood too. But we did not report them as adverse events because we didn’t think of them as adverse events.

Dr. Sandy Newes 14:14

Well, and it’s super interesting because I’m developing a theory and that’s a whole separate conversation about what psychedelics really one of the big change agents may very well be positive affect tolerance, like increasing.

Annie Mithoefer 14:27

People’s capacity to Feel safe. Feel good. Feeling good. Yes yes yes.

Dr. Sandy Newes 14:32

And and so I suspect that that is a direction the field is going to go in. And like, you know Rick Hansen growing the good. Like that’s.

Annie Mithoefer 14:40

Yeah. And it takes so it’s not.

Dr. Sandy Newes 14:42

Really an adverse effect. It’s an expected.

Annie Mithoefer 14:46

It’s something you’re hoping for.

Michael Mithoefer 14:48

Right. It’s another mismatch in why this is confusing people. Yeah, because, you know, we use the Suds, the subjective units of distress scale every 90 minutes during the session. We did that because the IRB required us to do it because they were afraid people were going to be getting upset during the sessions. Yeah, ironically. So we said, okay, fine, we’ll track it. Yeah. Ironically, if people had never gotten upset, we would have thought that, you know, the.

Annie Mithoefer 15:16

IRB was concerned.

Michael Mithoefer 15:17

It’ll be bad if they get upset. The reality is in this model, if they never got upset and they never dealt with anything difficult, it probably would be a problem.

Dr. Sandy Newes 15:29

Well, I mean, right.

Annie Mithoefer 15:30

Like if you’re going.

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