鈥淭he future is psychedelic,鈥� declared , founder of Lykos Therapeutics, at a conference on psychedelic drugs last year. Several studies, many of them funded by Lykos, had provided tantalising signs that pairing MDMA with talk therapy could dramatically reduce symptoms of post-traumatic stress disorder (PTSD). As a result, Doblin was one of many advocates touting the drug as key to revolutionising mental healthcare.
But just a year later, the US Food and Drug Administration (FDA) decided not to approve MDMA-assisted therapy, and questions have arisen about the methods, and potential ethical misconduct, in Lykos鈥檚 clinical trials.
Some of the concerns about MDMA therapy come down to the trials鈥� methodology, which an FDA advisory committee considered to have undermined the reliability of results and raised alarms about the therapy鈥檚 safety and efficacy. The drug and associated therapy have been approved for use in some countries. Still, psychedelics are inherently difficult to study 鈥� leaving some to wonder whether we can ever build robust enough clinical trials to see them widely approved for use.
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The road from rave drug to psychedelic therapy
So how did a party drug become the top contender for treating PTSD? Decades before the 1980s rave scene popularised the recreational use of MDMA, also known as ecstasy or Molly, psychologists had already begun experimenting with the then legal drug as a tool to enhance treatments. In fact, it was known by another name for a short time: .
Unlike other psychedelic substances, such as LSD and psilocybin, MDMA rarely produces vivid hallucinations. Instead, it fosters feelings of euphoria, openness and connection.
鈥淢DMA produces a kind of change in consciousness and an increase in emotionality and sense of connectedness to other people, which makes it an adjunctive treatment for psychotherapy,鈥� says at Compass Pathways, a UK biotechnology company. 鈥淭he interaction with the therapist is, if anything, increased under the influence of MDMA.鈥�
The idea behind MDMA鈥檚 potential therapeutic use was that it could help people more readily and effectively process emotions in talk therapy, and the early evidence was promising. In a , 16 therapists using MDMA-assisted therapy said most of their patients improved with the drug, especially those with depression, phobias and PTSD. But the US government outlawed the substance a year later, citing concerns over its potential to be abused, which .
It wasn鈥檛 until 2004 that the FDA approved the . The study, which only included 20 participants, found that of those treated with MDMA no longer met the criteria for PTSD two months later compared with 25 per cent of those given a placebo.
Additional trials showed similar results, prompting the FDA to grant Lykos Therapeutics 鈥� a spin-off company of the Multidisciplinary Association for Psychedelic Studies (MAPS) 鈥� breakthrough designation for MDMA-assisted therapy in 2017. This meant the agency believed MDMA had significant potential for treating PTSD, a condition for which only two FDA-approved medications are available, both of which lead to remission in just 20 to 30 per cent of cases.
What went wrong in the MDMA trials?
At first, the trials run by Lykos showed real promise. Results published from one trial in 2021 found that MDMA in combination with talk therapy led to remission of PTSD symptoms for . Another phase III trial released last year showed the same for (see 鈥淐linical trial phases鈥�, below).
The seemingly remarkable results left many psychedelic proponents feeling all but certain that the FDA would greenlight MDMA-assisted therapy, especially after became the first country to legally allow its use in July 2023. Roughly a year later, urged swift approval of MDMA-assisted therapy for people with PTSD. However, in August hopes of a similar outcome for the US were dashed. Before the decision, an FDA advisory panel voted 9 to 2 that the research had not proven MDMA鈥檚 effectiveness.
While the FDA declined to comment on the rationale behind the decision, a briefing document reviewed by the panel sheds light on the agency鈥檚 apprehensions.
One of the primary concerns was related to the issue of blinding, a technique that prevents doctors and participants from knowing whether someone received a treatment or a placebo. Blinding is crucial for minimising bias. If a participant believes they received a treatment, they can anticipate their symptoms lessening, and this expectation often leads to improvement 鈥� even if the intervention was ineffective. This phenomenon is called the placebo effect.
In clinical trials of MDMA-assisted therapy, roughly of those assigned to the drug and 75 per cent of those receiving just talk therapy could accurately guess which treatment group they were in. As such, those who believed they received MDMA may have expected 鈥� and thus experienced 鈥� improved symptoms, whereas those who presumed they got a placebo fared worse due to potential disappointment in not receiving MDMA.
鈥淚t is really important to conduct blinded studies, but it鈥檚 difficult 鈥� and some say even impossible 鈥� to completely effectively blind psychedelic studies,鈥� says at Johns Hopkins University in Maryland.
This is due to the drugs鈥� psychoactive effects. MDMA profoundly alters mood, perception and consciousness, making it easy for participants and their doctors to accurately guess whether or not they received the drug.
鈥淲hile there is no perfect solution to functional unblinding, we took many steps to minimise its potential impact, including the use of independent, blinded third-party clinician raters to assess outcomes,鈥� said Lykos in a in June.
鈥淭he ideal, which we haven鈥檛 really found, is something that works by different mechanisms, produces very similar subjective effects and wouldn鈥檛 be expected to have any therapeutic benefit,鈥� says at Columbia University in New York.
Clinical trial phases
Pharmaceutical companies must show that a drug is safe and effective in order to seek its authorisation. They do so by testing the drug in several phases of clinical trials.
Phase I trials involve between 20 and 100 people with the condition being treated. Their purpose is to test the safety of a medication and to identify the proper dose.
Phase II trials usually include several hundred people, making them large enough to begin assessing a drug鈥檚 efficacy. They also provide additional data on any side effects.
Phase III trials are usually the final step before a drug is submitted for regulatory review. They can include several thousand people and they demonstrate whether a treatment works. Their size also makes it possible to identify rare side effects or long-term risks that may have gone undetected in smaller trials.
What other drugs could be used as a placebo in psychedelic trials?
Researchers haven鈥檛 identified a placebo that meets every necessary criterion for blinding. But that doesn鈥檛 mean psychedelic therapies are doomed. For one, the FDA has approved treatments, without effective blinding.
Researchers could also use other, albeit imperfect, placebos, says Yaden. These could include already approved PTSD treatments, or psychoactive substances like THC, that aren鈥檛 expected to have therapeutic effects. Another option would be to use a low dose of the same substance.
That is the approach Compass Pathways is taking. In its phase III trials investigating high-dose psilocybin for treatment-resistant depression, the company is using a lower dose of the psychedelic as a placebo, says Goodwin. The hope is this will improve blinding and reduce bias, as all of the participants know they are receiving the drug, he says.
Confusion over the role of therapy vs MDMA
Another central reason the FDA rejected MDMA-assisted therapy was based on concerns about the talk therapy component. During the advisory committee meeting in June, some panel members struggled to disentangle the extent to which talk therapy contributed to outcomes, and whether MDMA could suffice on its own.
Yet Lykos is ardent that talk therapy and MDMA go hand in hand. The company says the drug helps participants to address trauma in therapy. In other words, MDMA may act as a catalyst for therapeutic processing by helping participants engage with traumatic experiences without being overwhelmed by painful emotions.
But evidence for this mechanism is scant. Because all of the trials included talk therapy and didn鈥檛 investigate the standalone effect of MDMA, the FDA 鈥� which doesn鈥檛 regulate talk therapy 鈥� struggled to characterise MDMA鈥檚 contribution to treatment.
To complicate matters even further, the FDA鈥檚 states that Lykos doesn鈥檛 provide rigorous guidance for how therapists should conduct talk therapy in concert with MDMA treatment. 鈥淚t was so free-form that their manual could be interpreted in almost any way you chose,鈥� says Goodwin.
For instance, Lykos suggests therapists build on their own background in various psychotherapy models. The approach intends to provide 鈥渃reative latitude for individual therapist teams to apply their own intuition and training鈥�, states the company鈥檚 , which also encourages therapists to use, at their own discretion, a broad range of interventions such as bodywork, breathing techniques and nurturing touch. As a result, therapeutic interventions almost certainly differed between participants, further muddying trial results.
However, Lykos disagrees: 鈥淪ignificant steps were taken to ensure standardisation and consistency in the psychological intervention across therapists, sites and treatment groups, and thus allowed for valid comparison between [MDMA] and placebo groups,鈥� it said in a statement.
Still, Lykos could have an MDMA-only group in future trials or implement a standardised model of talk therapy to assuage the FDA鈥檚 concerns.
Credibility and safety concerns of the MDMA trials
The FDA鈥檚 other major worries with MDMA-assisted therapy were related to the drug鈥檚 safety. Past research has suggested MDMA can raise the risk of heart conditions and impair liver function. Yet, , Lykos submitted incomplete data on cardiac safety in its application for approval and didn鈥檛 monitor participants鈥� liver function despite acknowledging liver toxicity was a potential concern. The company also didn鈥檛 collect data on the potential for participants to abuse MDMA, even though the FDA advised it to do so.
There have been allegations of research misconduct as well. One phase III trial participant, Sarah McNamee, in a submission to the FDA that three people in the study experienced worsening suicidal ideation in the weeks after taking the drug. These adverse effects weren鈥檛 published in study results, however a Lykos spokesperson told 快猫短视频 that these were 鈥渦nsubstantiated claims鈥�.
In a June , Lykos asserted that 鈥淎ll adverse events and serious adverse events were reported to the FDA.鈥� McNamee also raised concerns about people becoming more vulnerable and impressionable on the drug, saying she felt pressured to cuddle with therapists while under MDMA鈥檚 influence.
Another participant from Lykos鈥檚 phase II trial alleges she was by her therapist during the study. The company didn鈥檛 include phase II trial results in its FDA application, and the scientific journal where they were published has them due to unethical conduct.
鈥淭his was a terrible and harmful instance of malpractice that caused profound suffering to a participant,鈥� said Lykos in a statement, noting it reported the violation to appropriate regulatory agencies and has . 鈥淪ince then, we carefully developed and implemented new policies and practices aimed to prevent, detect, investigate, encourage reporting of, and thoroughly respond to potential instances of misconduct or unethical behaviour.鈥�
In addition, almost 40 per cent of participants in the phase III trials reported previously using MDMA recreationally. This could potentially obscure safety data: if people with previous use are open to using a drug again, that suggests they may not have previously experienced negative side effects and may be less likely to experience them again, says Gukasyan. The FDA also found that some participants used other therapeutic interventions during the follow-up period six months to two years after treatment, obscuring data that otherwise suggested MDMA-assisted therapy had lasting effects on PTSD symptoms.
All of these flaws undermined the credibility of these trial results and made it challenging for the FDA to understand the extent to which MDMA may be able to treat PTSD.
鈥淲e are engaging with the FDA to determine a pathway to address [its] concerns and questions,鈥� said a Lykos spokesperson. 鈥淲e maintain that many of the requests that had been previously discussed with the FDA and raised at the advisory committee meeting can be addressed with existing data, post-approval requirements or through reference to the scientific literature.鈥�
The FDA has requested Lykos to conduct an additional phase III trial, though this will take several years to complete, the spokesperson said. If the agency had better evidence for the effectiveness of the drug, we may have seen a very different decision. But instead, a potentially groundbreaking treatment has been put on the back burner.
