What went wrong with the plan to legalise therapeutic MDMA?

In August this year, the US Food and Drug Administration (FDA) rejected a long-planned application that would legalise the therapeutic use of MDMA.

The rejection was seen as a huge setback by many in the psychedelic community. The new drug application (NDA), made by Lykos Therapeutics, would have enabled the use of  MDMA-assisted psychotherapy (also called talk therapy) for posttraumatic stress disorder (PTSD). To the dismay of many, the FDA insisted that Lykos conduct additional trials to further study the safety and efficacy of MDMA.

Lykos has been working with its parent organisation Multidisciplinary Association for Psychedelic Studies (MAPS) on trial design for psychedelic therapy for around 20 years. This was the first time anyone had sought FDA approval for MDMA-assisted therapy for PTSD in adults.

Rick Doblin, the founder of MAPS, has been pushing for the legitimisation of psychedelic-assisted therapy since he founded the non-profit medical research organisation in 1986. Their efforts led to the first FDA-approved, double-blind, placebo-controlled phase 1 study of MDMA in 1996, published in collaboration with Charles Grob, M.D. Long before the FDA green-lit the Phase 3 clinical trials for PTSD treatment in 2016, MAPS had already spent 2 decades supporting research that investigates how MDMA can treat various mental illnesses. 

MDMA, commonly known as ecstasy or molly, is currently listed as a Schedule 1 controlled substance in the US, sharing company with other drugs such as heroin and cannabis. Schedule 1 controlled substances in the US are regarded as having no accepted medical use and a high potential for abuse. Besides being the first new proposed treatment for PTSD in over 20 years, this was the first time the FDA advisory committee ever reviewed a psychedelic – and yet, using MDMA therapeutically, in a clinical setting, is not a novel idea: 

In the 1970s and early 1980s, mental health providers used MDMA in conjunction with talk therapy to support patients in processing and communicating difficult emotions and experiences. MDMA is different from other psychoactive compounds such as psilocybin or LSD – while it shares some characteristics with other psychedelics sometimes used in therapy, such as its ability to increase neuroplasticity, where your brain is particularly malleable and primed to learn new things, MDMA is classified as an entactogen: a class of psychedelic drugs that promote emotional openness, interpersonal trust and empathy. Evidence suggests that MDMA could be particularly useful in treating PTSD as it decreases the brain’s fear response, supporting a patient in accessing and processing painful memories.

Last year, Australia was the first country to recognise MDMA and psilocybin as medicines. Besides using these for treatment-resistant depression, MDMA is also permitted to be used in tablet form for PTSD. Earlier this year in the Netherlands, the Dutch State Commission on MDMA also urged the government to allow clinical use of the drug to treat PTSD, submitting a report that states the positive effects of MDMA justify its transfer from a Schedule I substance to a Schedule II substance, supporting MDMA-assisted therapy for PTSD as they believe it’s “not only effective, but also relatively safe” in a controlled, clinical setting. 

In Lykos’ second phase 3 trial, about 71.2% of participants who received MDMA and talk therapy no longer met the criteria for PTSD. Despite promising results, the FDA’s review concluded that it could not approve the study based on data submitted to date. While the FDA’s complete response letter (CRL) to Lykos’ trial is not available to the public in full detail, concerns around the trial have been discussed in a number of statements, with campaigners and experts weighing in with their speculations as to why the study was rejected. Here we seek to outline the most common objections to Lykos’ phase 3 trial: 

Lack of data

Lykos’ research was predominantly based on two phase 3 trials (MAPP1 and MAPP2). Both included placebo-controlled, randomised studies trialling MDMA-assisted therapy in conjunction with therapy over the span of several months. The MAPP2 trial screened 324 research participants, 121 of which were enrolled. 17 of those didn’t achieve enrolment confirmation after initiation of preparation therapy, meaning 104 were confirmed for randomisation, with 53 assigned to the group that was administered MDMA and 51 receiving a placebo. Following 9 dropouts, 94 participants with mild to severe PTSD ended up completing the full study.

The FDA’s review concluded that it could not approve the study based on data submitted to date. This came as a surprise to Lykos: The FDA’s draft guidance for industry on psychedelic drugs says that endpoint data should be collected at 12 weeks. Lykos’ Phase 3 studies collected endpoint data at 18 weeks, with additional exploratory endpoints collected six months or more later. It’s also worth noting that the drop-out rate for the trial was low compared to other studies: rates for phase 3 clinical trials are often substantial and can sometimes be as high as 30% or more. 

Lykos claims that any of the concerns raised by the FDA could be addressed with existing data, post-approval requirements and reference to the scientific literature. Considering the novelty of psychedelic-assisted therapy for PTSD, some have speculated that the FDA decided to err on the side of caution and that it was heavily influenced by concerns raised by their Advisory Committee, while others have described it as “sacrificing the good for perfect”, claiming that the FDA is holding the trial to unattainable standards. Lykos stated in a press release that they seek to address the FDA’s concerns and to “take advantage of agency processes to resolve scientific disagreements”, hoping for the possibility of resubmission.

Risk of harm: heart function, suicide risk and MDMA abuse

Some members of the Advisory Committee, who consulted the FDA ahead of the decision, raised concerns with a lack of data collected on electrocardiograms and liver function, and participant feelings of euphoria. The Phase 3 trial itself reported that Treatment-Emergent Adverse Event (TEAEs) – defined as an undesirable event that occurs during or shortly after treatment – were “similar to previous studies and consistent with expected effects of MDMA”: in their study, cardiac TEAEs were low and increases in heart rate were mild. MDMA also did not appear to increase the risk of suicidal ideation and no suicidal behaviours were observed in either group, although they did observe suicidal ideation in both the MDMA and placebo group. 

There are also concerns around the long-term safety of MDMA-assisted treatment for PTSD. The potency and psychoactive nature of psychedelics naturally comes with risks, including negative psychological reactions such as anxiety and even psychosis, as well as risk of substance abuse, although more research is needed to establish a definitive risk. Lykos’ study also pointed out that “long-term data is needed to assess the risk of MDMA abuse or misuse after study participation.”

Concerns over functional unblinding

There were several concerns around the trial methodology, particularly the issue of functional unblinding, which can influence data outcomes. Blinding methods are used in scientific research to maintain objectivity in trials. While in double-blind studies, all parties are unaware of which participants have received the drug they’re testing versus the placebo, functional unblinding is an unintentional breakdown of blinding that can occur even if the study is designed to be technically blinded. In Lykos’ second Phase 3 trial, more than 90% of people in the MDMA group and 75% in the placebo group correctly guessed whether they had received the placebo or not. 

This is a common challenge in the psychedelic space, considering the potent effects of psychedelics. To avoid compromising the integrity of the trial results, the FDA had recommended using an active placebo which mimics some of the effects of MDMA without its therapeutic benefits. This was not sufficiently addressed by Lykos, although they said in their response letter that they took steps to minimise the risk of functional blinding and that “the weight of evidence suggests a very low likelihood that the observed MDMA effect can be adequately explained by functional unblinding”. 

In a response to the critical draft report, published by clinical investigators, clinicians, supervisors, trainers and medical monitors who worked on the Phase 3 clinical trials, they argued that:

“Though frequently discussed in psychedelic research, functional unblinding is also a concern in conventional clinical research. For example, pharmaceutical interventions are frequently unblinded due to medication side effects, and neither the patient nor the clinician is blinded to treatment in a comparative-efficacy psychotherapy trial (e.g., EMDR vs. CPT). The fact of functional unblinding therefore cannot undermine efforts to approve new treatments for PTSD.”

Bias and prior use of MDMA

Another issue brought up by critics of the trial, also related to the trial design, is the risk of bias amongst the participants. About 40% had a prior, good experience with MDMA, with most having taken the drug two to four times in the past 10 years. To minimise bias, Lykos had followed the FDA’s Special Protocol Assessment in 2017 on bias minimisation measures in the study design. In Lykos’ Phase 2 studies, nearly 30% of participants had used MDMA before, which they shared with the FDA before finalising the criteria of who would be allowed to participate in the Phase 3 trial design. Prior MDMA use amongst participants had not been seen as detrimental. The studies also reported no statistical differences between participants who had tried MDMA before and those who didn’t. 

Scepticism around the use of psychotherapy

The FDA does not have a framework to regulate psychotherapy, as therapists are regulated by licensing boards and individual state licensure laws and regulations. However, Advisory Committee panellists questioned the efficacy and requirement of psychotherapy, with some raising concerns about the lack of standardisation of talk therapy across clinical trial sites. 

Many researchers emphasise the importance of using a psychotherapy setting when administering MDMA to treat PTSD, as this is what allows therapists and patients to take advantage of “critical periods” – limited moments of neuroplasticity – which enable therapists to retrieve traumatic memories for modification. Lykos and other stakeholders were concerned that the limited number of subject matter experts on the Advisory Committee panel meant that they may have misunderstood aspects of the treatment and could therefore not provide sufficient advice to the FDA. Just one member of the panel had expertise in psychedelics. The FDA has since acknowledged this and is seeking to improve the Advisory Committee process.

What happens next?

Following the FDA’s CRL, Lykos announced they planned to request a meeting with the regulator to reconsider their decision. 

“The FDA request for another study is deeply disappointing, not just for all those who dedicated their lives to this pioneering effort, but principally for the millions of Americans with PTSD, along with their loved ones, who have not seen any new treatment options in over two decades,” said Amy Emerson, Chief Executive Officer of Lykos Therapeutics, who has since stepped down as CEO. The company’s founder, Rick Doblin, has also left the board.

We were all very excited about the potential decision, so it took the wind out of our sails… it will ultimately sharpen our future attempts to permit the clinical use of psychedelics

Prospective patients for PTSD might also be looking for alternative treatment, such as ketamine-assisted treatment for PTSD, and other psychedelic options like those signposted to by VETS, an advocacy organisation seeking to end veteran suicide through providing resources and access to psychedelic-assisted therapy, supporting scientific research and driving public advocacy for legislative change.

“It’s disappointing, but I would have to admit that I was personally not as fully educated as I could have been,” Craig Cates, VETS’ non-profit Director of Strategic Partnerships, tells us. Following 27 years of service and 9 deployments in the US Navy, Craig has undergone the organisation’s Foundational Healing Grants programme, successfully treating his symptoms related to mild traumatic brain injury through ibogaine and 5-MeO-DMT therapy abroad.

According to the National Centre for PTSD, 5% of the US population suffers from PTSD, with the percentage being even higher amongst veterans. In 2020, as many as 13 million Americans suffered from PTSD. In the UK, 4 in 100 people are expected to have PTSD (excluding C-PTSD), equating to 2.6 million people, with a Channel 4 documentary revealing last year that about 311,000 16-24 year olds in England and Wales have PTSD, predominantly linked to personal assault and violence. 

“We were all very excited about the potential decision, so it took the wind out of our sails a little bit. But upon further review and reflection, I think that it’s healthy overall to have some back and forth, and it will ultimately sharpen our future attempts to permit the clinical use of psychedelics. It is a setback temporarily, but it’s not the end of the story.”

VETS’ published response to the FDA decision was that they “respect [the regular’s] commitment to safety, but implore them to consider the cost of inaction.” 

“We’re losing about 20 veterans a day to suicide and we think that psychedelic-assisted therapy is going to be one of the primary keys for ending the epidemic of veteran suicide that we have today. Taking care of veteran suicide is an urgent matter. When we have setbacks like the FDA decision, there are real-world consequences, so we absolutely want to see this move forward and taken back up as quickly as possible.”

Conducting another Phase 3 study will take several years. Since the FDA decision, Lykos has decided to lay off about 100 employees. The remaining staff will be led by David Hough, former vice president for research and development at Johnson & Johnson, who has been brought in to oversee the clinical development and FDA engagement regarding the resubmission of MDMA. 

In the meantime, we might also see other companies such as Compass Pathways and MindMed conduct research in this field, with some speculation that they may be distancing themselves from Lykos’ trial designs, particularly their approaches to therapy used in conjunction with psychedelics, some potentially even excluding intensive psychotherapy altogether. Despite the FDA decision being regarded as a major setback for the psychedelic movement, some trial participants remain optimistic about the treatment’s potential to help millions of people experiencing PTSD as research in the field expands.