Inside the battle for FDA approval of MDMA therapy

If not for a busted bike chain, I would never have met Rick Doblin. In 2021, I was heading back to the INSIGHT Psychedelic Research Conference in Berlin trying to catch Johns Hopkins scientist Matthew Johnson’s talk. Fated with a twisted chain, I was late. Moments after staff ushered me upstairs to the balcony, Doblin sat beside me and started munching on a sandwich. We chatted about my book, which I’d just sent to be considered for publication. He leaned forward, eyes glimmering, and said, “What do you think’s gonna happen?” 

Now, three years later, I get to turn the question back on him.    

In August, the FDA rejected Lykos Therapeutics’ application to legalize MDMA-assisted therapy for PTSD. Lykos is the for-profit arm of MAPS (the Multidisciplinary Association for Psychedelic Studies), a non-profit founded by Doblin.

The rejection was a crushing blow to the organization and the field itself. MAPS has spent nearly two decades conducting clinical trials on MDMA-assisted therapy for PTSD and was slated to receive FDA approval after a successful Phase 3 study. However, the FDA rejected the application based on several factors outlined in an official statement, citing insufficient scientific evidence and flawed study design. 

Those concerns and others were raised in June when an independent FDA advisory panel voted against the treatment. The panel noted that Lykos failed to report data on “positive adverse effects,” like feelings of euphoria — information that’s relevant in assessing MDMA’s potential for abuse. It also considered a case of misconduct and the possibility that biases on the part of investigators, therapists, and patients might have swayed the reporting of harms and benefits, as described in May by a report from the Institute for Clinical and Economic Review.

“I absolutely agree that we need new and better treatments for PTSD,” said Paul Holtzheimer, a panelist on the advisory board and deputy director for research at the National Center for PTSD, who voted that the benefits of the MDMA therapy do not outweigh the risks. “However, I also note that premature introduction of a treatment can actually stifle development, stifle implementation and lead to premature adoption of treatments that are either not completely known to be safe, not fully effective or not being used at their optimal efficacy.”

In August, Doblin resigned from the board of Lykos, weeks after the company laid off 75% of its staff. As Lykos continues to work with the FDA on a path forward, the future of MDMA therapy for PTSD remains unclear, as does the question of whether it’s the drug, the therapy, or both in combination that may someday prove to be a safe and effective way to treat PTSD.

What is clear is that the FDA’s decision marks a major turning point for both Lykos and MAPS — and in determining which aspects of psychedelic treatment will be prioritized by stakeholders going forward. 

To blind or not to blind

To understand the FDA’s industry-rattling decision, it’s worth untangling a few threads in the story. The first is that MAPS applied not to legalize a drug but to get approval for its drug-assisted therapy — which involves patients taking MDMA and receiving Lykos’ particular brand of psychotherapy in an eight-hour session. 

“The way it’s been framed is that the FDA is against psychotherapy and that they don’t regulate psychotherapy; they just want to be about drugs,” Doblin tells Big Think. “That’s not the case. The FDA doesn’t regulate psychotherapy — that’s very true — but they understand that it’s not just about giving a drug.”

In a letter issued to Lykos, rejecting approval at the time, the FDA suggested they move forward by combining MDMA with what they called “evidence-based psychotherapy.” 

“Our therapy, I believe, is evidence-based,” Doblin says. “We’ve been studying it for twenty years. It’s produced great outcomes. We’ve studied it in research settings. Many of the companies are jumping on this idea of, ‘Oh yeah, let’s not do psychotherapy, let’s do psychological support.’ That’s not what’s in the best interest of the patients, but that might be what the pharma companies think will make them the most money.” 

But even if the therapy itself is sufficiently evidence-based, it’s less clear how to combine a drug like MDMA with it in a way that enhances, rather than diminishes, its effectiveness. Which leads to the other point of contention in this story: The FDA made a series of decisions over the course of the research process that may have prioritized patient safety at the cost of scientific rigor.  

When designing a clinical trial, the gold standard is to conduct a double-blind, randomized control trial where researchers try to reduce bias by ensuring that some trial participants don’t know they’re getting the drug in question. In many drug trials, that problem is addressed with an inactive placebo like a sugar pill, but seeing as psychedelics have such noticeable effects, psychedelic scientists often turn to active placebos instead. In other words: all participants receive an active drug, and can feel they’ve taken an active drug; they just don’t know which one it is. This approach, which allows researchers to study the effects of psychedelics with a higher degree of empiricism, is called “functional blinding.” By contrast, when that same group of trial participants simply receives an inactive placebo instead of an active drug, researchers run the risk of ”functional unblinding,” which occurs when participants can guess which treatment they received. Doblin says the FDA chose to take this risk, in a move that helped ensure participant safety but threatened the integrity of the trial design itself. 

“The FDA chose therapy with inactive placebo, and that kind of got lost. They betrayed their agreement with us by saying, ‘Oh, now we don’t believe these results because of the functional unblinding.’ We negotiated eight months in a special protocol assessment process with the FDA to come up with the design. The media has missed this whole real point that we understand functional unblinding. We discussed functional unblinding with the FDA at length, and that’s why they chose the inactive placebo.” 

Doblin, who wrote his dissertation on the blinding problem, says his solution was therapy with low-dose MDMA versus therapy with full-dose MDMA. “That is the best way to do a double-blind with psychedelics.” 

In sixteen years of phase-two pilot studies, MAPS compared inactive placebo with a wide range of doses: 25 milligrams, 30 milligrams, 40 milligrams, 50 milligrams, 75, 100, 125, and 150. 

“The challenge is to find the dose that’s high enough to cause some confusion with the full dose. A microdose doesn’t work, because you don’t really know you’ve got it, but not so high that you get so much therapeutic potential that then there’s no difference between the two groups, or it’s really hard to find a difference.” 

What they discovered was that the lower doses — 25, 30, 40, 50 milligrams — could produce some confusion over whether people are getting the full dose or not. But here’s the real kicker: they had an “anti-therapeutic” effect. 

“People who got therapy with low doses of MDMA still got better, but when you compare it to therapy with inactive placebo, people got better with the inactive placebo than with low doses of MDMA,” Doblin explains. “The reason is that the MDMA activated them, but it didn’t have enough of the fear reduction. These are the worst memories of people’s lives, and when they confront them in therapy, if you’re activated in a therapeutic setting, it can be very difficult.” 

That’s why, he says, with standard therapies — prolonged exposure and cognitive processing therapies, the two main therapies used in the VA for PTSD — there’s a dropout rate of roughly 50%. “Half the people can’t stand the therapy because the therapy says, ‘Talk about your trauma over and over and over’ and it’s difficult for people to do.” 

What they discovered during the research process, to their surprise, is that while the lower doses activated people and made them uncomfortable, the dose that was therapeutic was lower than they thought: 75 milligrams. For functional blinding purposes, that made it virtually impossible to find a sweet spot in dosage between a dose that causes confusion but doesn’t hurt the therapy and a dose that suddenly helps the therapy.  

“So we went to the FDA and we said, ‘We will give you blinding if you want blinding, but you’re going to make our job easier to find the difference between the two groups.’” 

In their official rejection statement, Doblin says, functional unblinding was cited as one factor influencing their decision.  

Somewhat ironically, the baseline recovery rates in the control group — without MDMA — were remarkable: 47.6% of chronic PTSD patients no longer met the criteria for the disorder at the two-month follow-up (compared to 71.2% who received MDMA and psychotherapy). These rates generally aligned with the first phase-three study, where one-third of patients with severe PTSD no longer met the criteria for the disorder after receiving psychotherapy but no MDMA.

“We had very minimal dropout rates. The [process involves] eight-hour therapy sessions […] When you have a one-hour therapy meeting once a week for, let’s say, a whole year, and the first 10 minutes you settle in. The next 20 minutes, you’re kind of getting deeper. Thirty minutes and then you’re starting to think, “Oh, my time’s almost up. Now I gotta collect myself and get ready to walk out the door, and I gotta focus on my traumas.” But when you have an eight-hour session with music, with two people to help you go inward, that can be incredibly effective, because people can choose when they’re ready to do the work with trauma, when they’re talking about other memories, when they’re talking about other issues. The essence of our therapeutic method is to support what’s emerging. It’s non-directive and inner-directed.” 

Had the FDA approved Lykos’ application, some might conclude there’s something special about the drug that is enhanced by the therapy. Others might think it’s the therapy that gets enhanced by the drug. In the aftermath of rejection, however, we’re left with another thread in a slowly unspooling truth about what makes psychedelics so hard to study. 

Inner-healer-assisted therapy

When I ask Doblin about mechanisms of action — how MDMA-assisted therapy works — his initial response is pragmatic.

“When you try to work with the FDA, you have to prove safety and efficacy, but you don’t have to prove any mechanism of action. Consequently, we have left the physiological mechanism of action to other scientists.” 

With a wry smile, he adds: “You hear about translational neuroscience. What I would say is that nothing is translated from neuroscience to help the clinician.”

In recent years, researchers have found that MDMA reduces activity in the amygdala, increases activity in the frontal cortex, and increases connectivity between the amygdala and the hippocampus, where memories are put into long-term storage. Oxytocin and serotonin work together synergistically to enhance neuroplasticity. 

“Those are good explanations, but none of that is really filtered down to how you do the therapy differently,” Doblin says, noting the thousands of years of psychedelic healing ceremonies preceding brain scans.   

Doing the therapy differently, however, is the exact platform on which MAPS has sold itself. 

“The main thing we’ve learned is that there’s this inner wisdom, this inner kind of logic to what’s emerging. It could be they’re moving into terror, they’re moving into shaking and just reenacting, reliving in their mind the trauma experience, or they’re talking about something in childhood, or they’re talking about happy memories. Whatever it is, the therapists don’t have an agenda. They support what’s emerging. We’ve called this the ‘inner healing intelligence.’ We know our body has this, that it heals itself in this quest to wholeness below our level of conscious awareness.” 

“Inner healing intelligence” — which MAPS’ treatment manual defines as “a person’s innate capacity to heal the wounds of trauma” — seems intuitive enough. After all, cuts and scrapes heal on their own without direct intervention from the mind, so couldn’t your mind “get out of its own way,” through ego dissolution or some similar mechanism, to help facilitate emotional healing?

MAPS’ treatment strategy is based on the assumption that it can. 

“Therapists should trust that any fear, memories, etc. that keep coming up are doing so to be healed, to be more fully understood, and that the participant’s psyche/inner healer knows when the best time is for this to occur,” states MAPS’ treatment manual. “This very process of surrendering ego/directed functions to self/inner healer may be the method of therapeutic action that is so hard to come by without the help of MDMA.”

Scientists have not empirically corroborated the existence of an “inner healer” or a “self” that seeks “wholeness” in the way MAPS describes it. Some also question the efficacy and safety of the non-directive therapeutic approach. Neşe Devenot, a senior lecturer at Johns Hopkins who specializes in psychedelic bioethics and submitted a citizen petition to the FDA arguing against Lykos, wrote that assuming there’s an “inner healer” guiding the processing of trauma may prime “both clients and therapists to associate distress with healing, even in situations where actual harm is occurring,” and that it risks encouraging study participants to “interpret any outcome as successful.”

Doblin is aware of such criticisms within the science community.

“‘Oh, this inner healing intelligence. It’s woo, woo. It’s not scientific. It’s, you know, it’s terrible, it’s scary. You’re smuggling religion into this and stuff like that.’” 

“I was just with a scientist from Johns Hopkins, and he said I should stop using the word ‘inner healing intelligence’ because people don’t know what we mean. None of that is true. All it is is just to say that we support what’s emerging, whatever it is: If it’s terrifying, if it’s pleasant, if it’s just neutral, whatever it happens to be. We let people come around to the trauma at their own pace, and people will always eventually get to it — because that’s what their problem is. But they might not get to it in a straight line, and that’s why the cognitive processing therapy and the prolonged exposure are so re-traumatizing. You say, ‘We’ve got an hour meeting. Tell me about your trauma.’ It’s just a different kind of approach.” 

The idea of an inner healer phenomenon has caught the interest of certain figures within the psychedelic science community. In a post last year on X, the neuroscientist Robin Carhart-Harris wrote: “Can someone quote me something from a book or in academic literature referring to the inner healing mechanisms of psychedelic therapy?” Several months later, he posted: “A small step on a brave journey to consider & examine the validity of the ‘inner healer’ phenomenon in context of psychedelics,” sharing his new paper on the topic, titled, “Psychedelics and the inner healer: myth or mechanism?” Carhart-Harris wrote that he “does not see it as a mystical/supernatural phenomenon at all.”

Doblin notes that proponents of the inner healing approach argue that it “helps people feel that they can trust what’s happening, even if it’s leading them into fear and terror,” adding that it’s a gentle salve for moments during a trip when someone might be thinking, “I’m going to lose control, I’m going to be crazy.” 

“Difficult is not the same as bad in terms of psychedelic experiences,” Doblin tells me. “What turns something difficult into something bad is resistance. So I think, again, part of the mechanism of action is that you open up to it and you descend into it. If you are fully open to it–life is constant change–something will change.” 

The future of psychedelic therapy

In October, Lykos issued a press release after a meeting with the FDA about the path forward. 

“They have to do another Phase 3 study, review the videotapes, do various things,” Doblin says. “What we are now currently thinking is probably three years from now, they’ll come to an agreement and FDA approval will be very likely.” 

When I ask Doblin how Lykos and MAPS will navigate forward from here, he expresses a few concerns. 

“The switch I worry about [is moving away] from maximizing therapeutic outcomes — which I believe has been essential for changing the whole culture, changing the ecosystem, getting people enthused about psychedelics, getting MDMA research throughout the VA — to now the pharma company way forward. And this is true for other psychedelic pharma companies too — just looking at what’s the minimal viable product, what’s the lowest cost.” 

Questions remain: What type of psychotherapy, if any, might be paired with MDMA if the FDA does approve MDMA therapy? Does psychedelic therapy even need therapists? Or will trained sitters without a therapy background suffice?

“Lykos, in particular, is all about the FDA. Lykos will eventually succeed, I believe.”  

MAPS the nonprofit has plans of its own. Doblin tells me he just got off a two-hour call with a woman from Rwanda who wants to bring MDMA to Rwanda. MAPS’ itinerary of global humanitarian projects so far includes work in Somaliland, Denmark, Bosnia, and an upcoming training in Ukraine in the first quarter of 2025. 

“The pharma company is going where the suffering is and where there’s money, and MAPS the nonprofit is going where there’s suffering but where there’s no money.” 

The organization also plans to start focusing on group therapy, both to reduce costs and to see whether “those groups can be supportive of each other in the integration process, and maybe they’ll get results comparable to the outstanding results that we get from working with individuals.”

In October, Lykos published a statement saying it had a “productive” meeting with the FDA regarding the next steps for gaining approval for its treatment, and that the company “will continue to work with the FDA on finalizing a plan.”