MDMA Failed to Receive FDA Approval: What Happens Next?

Federal health regulators recently declined to approve the use of the psychedelic drug midomafetamine (3,4-methylenedioxymethamphetamine or MDMA) as a treatment for post-traumatic stress disorder (PTSD), disappointing many advocates who were hopeful for the next breakthrough in the psychedelic therapy movement. Drug company Lykos Therapeutics, which had filed the new drug application for MDMA therapy, was informed by the US Food and Drug Administration (FDA) that the data submitted was insufficient to receive approval, requesting that the company conduct an additional Phase 3 trial to further test the safety and efficacy of the drug. Unfortunately, such large-scale clinical studies typically take years and cost millions of dollars to perform. Lykos has expressed plans to request that the regulatory agency reconsider the decision and meet for a productive discussion, but no one has announced any new developments in this effort yet. 

PTSD is a mental health disability that affects approximately 5% of US adults in a given year, with an estimated 13 million cases reported nationally in 2020. Veterans, members of the LGBTQIA community, and women are disproportionately impacted due to their positions of vulnerability to traumatic events, such as life-threatening violence or sexual assault. 

With first-line recommended mental health interventions for PTSD treatment failing to eliminate symptoms in an average of 40% of patients in clinical studies, finding alternative effective and accessible treatments for PTSD is an urgent task from both an economic and public health standpoint. PTSD in the US population is estimated to produce an economic burden of about $232 billion annually, costing more economic excess per person affected than coronary heart disease (CHD), anxiety, or major depressive disorder (MDD), both of which are considered to be relatively costly health conditions. Alongside these economic concerns, the illness also poses significant risks and detriments to public health, as people experiencing PTSD are at higher risk of developing a substance use disorder and dying by suicide. 

MDMA, also known as ‘molly’ or ‘ecstasy’ in the recreational drug scene, is a synthetic compound that produces euphoric, prosocial, empathetic, stimulant, and psychedelic effects. Although the US Drug Enforcement Agency (DEA) strictly regulates the drug as a dangerous Schedule I controlled substance with no recognized medical use, MDMA has attracted increased attention over the past decade as a growing body of research reveals promising evidence that MDMA can be used in the treatment of PTSD to produce significant, lasting benefits for individuals unable to relieve their symptoms with other available treatment approaches. Presently, Australia is the only country in the world to legalize the medical application of MDMA to treat PTSD and depression. 

A Disappointing Outcome for Decades of Research and Advocacy 

For nearly four decades, advocates of psychedelic medicine have been striving to legalize the use of MDMA therapy to treat severe mental health conditions. Before the Controlled Substances Act (CSA) legally banned MDMA in 1985, therapists in the 1970s and 1980s reportedly used legal MDMA to enhance patients’ emotional openness and communication, which proved especially helpful in couples therapy practices.

In 1986, the nonprofit research and educational organization known as the Multidisciplinary Association for Psychedelic Studies (MAPS) was founded in response to the federal decision to classify MDMA as a Schedule I drug. Since its formation, MAPS has led campaigns and research projects to advance medical research on psychedelic substances, conducted clinical trials on MDMA-assisted therapy, and raised over $140 million in donations for education and research. Psychedelics researchers at Lykos Therapeutics—created in 2014 as MAPS’ drug-development arm—had high hopes that the company would successfully guide MDMA-assisted therapy through the FDA approval process.

Lykos developed a distinct treatment regimen where MDMA is integrated into a structured series of psychotherapy sessions, rather than used as a standalone drug. According to this procedure, patients attend multiple preparatory therapy sessions before receiving MDMA in three supervised sessions with a two-person therapist team. Therapists intend the drug to facilitate deeper engagement with self-reflection and openness, helping patients process traumatic experiences they might otherwise find too difficult to confront.

Lykos’ application to the FDA cited two late-stage clinical trials (MAPP1, 2021, and MAPP2, 2023) published in Nature Medicine in which approximately 200 participants diagnosed with PTSD were randomly assigned to receive either MDMA or a placebo. The results were promising: MAPS reported that over 80% of participants who received MDMA experienced significant improvements in their symptoms. The first study reported that more than two-thirds of participants no longer met diagnostic criteria for PTSD, and the second study cited 71.2%. 

In comparison, 32 to 48 percent of participants who received a placebo paired with talk therapy no longer had sufficient symptoms for a PTSD diagnosis. Moreover, follow-up assessments between six months and two years after treatment showed that MDMA patients experienced long-lasting symptom improvements.

Despite these findings, the FDA rejected Lykos’ application, stating that the data provided was insufficient, and believe the harms didn’t outweigh the benefits. The regulatory board also required Lykos to conduct an additional late-stage clinical trial to further test the safety and efficacy of MDMA therapy. Conducting such a study would require substantial funding and would likely take years to complete, making the decision a critical disappointment for many clinicians and patients interested in the potential benefits offered by psychiatric MDMA treatments. 

READ: Nasal Spray as First and Only Standalone Therapy for Treatment-Resistant Depression

Reasons for the FDA’s Rejection Decision

The FDA’s rejection of Lykos Therapeutics’ application for MDMA-assisted therapy was based on certain concerns regarding the rigor and reliability of the data presented. Scientists on the independent FDA committee raised multiple issues related to the methodology, participant selection, efficacy, potential harms, and ethical oversight of the trials, leading to the decision to require further research before potential approval.

Methodological Concerns with Blinding

A particular concern raised by the FDA is the lack of effective blinding in the clinical trials. Namely, the majority of patients and therapists were able to correctly guess whether the patient received the MDMA or the placebo dose. According to FDA internal staffers, such obvious differences in effect make it “nearly impossible” for MDMA researchers to maintain the blinding that medical research requires.

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Additionally, many participants took other drug treatments—including psychedelic drugs—between the trial and the follow-up period, which made it difficult to determine whether their sustained improvements resulted from the trial MDMA-assisted therapy sessions alone.”

Participant Bias and Variability

Another issue raised by the advisory committee was the potential for pre-existing biases among participants. Because over 40% of the participants had experience with illicit MDMA before the trial, FDA scientists were concerned that these individuals’ prior experiences with the drug might have influenced their reactions to the experiment. 

Additionally, many participants took other drug treatments—including more MDMA and psychedelics—between the trial and the follow-up period, making it difficult to determine if the trial’s MDMA-assisted therapy sessions alone led to their sustained improvements.

Psychotherapy Inconsistencies

Reviewers criticized Lykos for allowing psychotherapists too much discretion in how they chose to treat clients, highlighting the variability in the psychotherapy component of the treatment as a point of contention. Some committee members worried that the quality and nature of therapy could have varied depending on whether a participant had received MDMA or a placebo. 

Critics argue that a skilled therapist could make an ineffective drug appear successful, making it difficult to distinguish the drug’s effects from those of psychotherapy. This issue became more complicated because the FDA regulates drug administration, not psychotherapy, limiting its authority to oversee the therapy component of the treatment regimen. 

Ethical Violations and Retractions

Ethical controversies associated with the Lykos experiments also played a role in the FDA’s decision. One particularly infamous incident involved a therapist who engaged in a sexual relationship with a trial participant after the conclusion of a mid-stage (Phase 2) clinical trial in Canada. This raised concerns about the oversight and ethical safeguards within Lykos’s research program.

Further scrutiny was raised toward the project, considering the retraction notices issued by the journal Psychopharmacology for three papers analyzing the Phase 2 trial, citing “protocol violations amounting to unethical conduct.” However, it is important to note that the data under review in the most recent FDA decision came from Phase 3 studies, not the retracted Phase 2 studies. Nevertheless, these scandals stir suspicion surrounding the methodological care taken and oversight performed in these experiments.

Critical Responses to the FDA’s Decision

The FDA’s reasoning for the rejection has received criticism from other researchers with expertise in psychedelic-assisted therapy. Michael Mithoefer, a clinical psychiatry faculty member at the Medical University of South Carolina who has worked on MDMA trials since 2001, expressed frustration: “I expected a delay, but I didn’t expect this—this is extreme.”

Opponents to the decision argue that the advisory committee failed to understand the therapy model by not adequately recognizing that psychotherapy is an essential component of MDMA treatment. Instead, the committee interpreted variations in psychotherapy as a weakness of the methodology. 

Critics also point out that some of the FDA’s points of concern, such as difficulties in blinding, are inherent challenges to studying the effects of psychoactive drugs. Moreover, other psychiatric medications have been approved in the past despite similar limitations. 

Additionally, Lykos maintains that excluding data from the studies where ethical violations occurred did not significantly alter the overall findings from the Phase 2 trials. Furthermore, these studies were not even the ones under review in the FDA application.

Moving Forward 

The FDA’s decision to reject Lykos’s application demonstrates the agency’s quality standards for rigorous clinical science, but the movement has also ignited debate about whether those standards can be appropriately applied in the context of psychedelic-assisted therapy. While the committee raised significant concerns about blinding, participant bias, psychotherapy variability, and ethical oversight, many researchers believe the advisory committee failed to adequately consider the unique nature of MDMA-assisted therapy. Moreover, critics have argued that the agency’s decision shows its lack of preparation to implement the broader regulatory changes that the approval of MDMA-assisted therapy would require.

Currently, the only FDA-approved medications for PTSD are antidepressants, which have limited effectiveness and are associated with significant side effects in certain individuals. With the economic and public health burdens generated by PTSD in the US, the demand for more effective treatments is particularly urgent, especially among veterans, survivors of sexual or other physical trauma, and other high-risk groups.

For now, the FDA’s rejection delays the possibility of MDMA-assisted therapy becoming an approved treatment for PTSD, but efforts to improve current research and secure approval for MDMA treatment continue. If Lykos secures the resources to conduct the additional research and successfully appeals the decision, MDMA could still become the first entactogen drug to receive federal approval and further pave the way for broader acceptance and expanded research of hallucinogenic drugs in psychiatric treatment. However, with potentially years of further study and administrative approval processes required, the timeline for this long-awaited breakthrough remains uncertain.