FDA Rejects Lykos’s NDA for MDMA-Assisted Therapy for PTSD

This summer, all eyes from the psychedelic community were on MDMA. On August 9, 2024, Lykos Therapeutics (formally MAPS PBC) published a news release stating they had received a complete response letter about the FDA’s decision.

“This is the epitome of bureaucratic red tape — and the result is people will keep dying.”

— Heroic Hearts Project

Lykos did not receive approval for its application for MDMA-assisted therapy for the treatment of post-traumatic stress disorder (PTSD) in adults. Read on to learn why the FDA (U.S. Food and Drug Administration) made this decision and what this means for patients and healthcare providers.

Background

The FDA accepted Lykos’ New Drug Application (NDA) for MDMA-assisted therapy on February 9, 2024. The Institute for Clinical and Economic Review (ICER), a nonprofit focused on improving the accessibility and affordability of health treatments, published a draft evidence report on MDMA therapy for PTSD in March. ICER expressed concerns about the quality of evidence Lykos provided in its NDA, citing issues related to trial design, conduct, and potential safety and ethical problems.

One significant trial design issue was that in their placebo-controlled trials, participants who received MDMA could easily tell that they’d taken the active drug rather than a placebo due to its distinct effects. This issue unblinds the trials, which can affect the reliability of the data.

On June 4, 2024, Lykos announced that the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) would review the evidence in the NDA. The review included two Phase 3 clinical trials sponsored and conducted by MAPS. The outcome of this review played a crucial role in the FDA’s decision-making process regarding MDMA-assisted therapy for PTSD. 

Decision: Not Approved, Request for Additional Phase 3 Trial

On August 9, 2024, Lykos released a statement that informed the public of the FDA’s decision regarding their NDA for midomafetamine capsules in treating PTSD.

“The FDA communicated that it had completed its review of the NDA and determined that it could not be approved based on data submitted to date. The FDA has requested that Lykos conduct an additional Phase 3 trial to further study the safety and efficacy of midomafetamine.”

Lykos said it is planning to request a meeting with the FDA to ask for reconsideration of the decision. They will also discuss resubmission seeking regulatory approval for midomafetamine capsules.

Amy Emerson, Chief Executive Officer of Lykos Therapeutics, said in the news release that conducting another Phase 3 study would take several years; however, they “still 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.”

Trial Design Issues

Lykos stated that the FDA’s decision reflected the issues found in the FDA Advisory Committee’s review conducted in June 2024, such as the concerns about whether participants were truly blinded and the impact on data reliability. 

There were concerns that Lykos’ clinical data did not demonstrate durability and efficacy due to expectancy bias since participants had previous experiences with MDMA. Lykos reaffirmed that their data was in line with the FDA’s draft guidance on psychedelic drugs and followed the FDA’s Special Protocol Assessment (“SPA”) to include various bias minimization measures in the study design.

Unclear Role of Psychotherapy

In the news release, Lykos said that the FDA Advisory Committee panelists expressed concerns about the role of psychotherapy. Some emphasized the need to understand further how much psychotherapy contributes to the treatment’s effectiveness. There were questions about whether the treatment required psychotherapy to establish the benefits. 

An article published in the Science journal wrote that the FDA struggled to assess how psychotherapy fits in treating PTSD with MDMA since it does not regulate psychotherapy. This regulatory challenge may have been the most formidable barrier for Lykos to overcome. 

Boris Heifets, an anesthesiologist at Stanford University whose lab studies psychedelics, told Science that the FDA’s decision “strongly reinforces the view that ‘drug-assisted psychotherapy’ adds cost and complexity to trials…and the confusion over ‘is this a drug or a therapy?’ did not help Lykos with the FDA either.”

The Science article added that “[s]ome companies are already using psychedelics purely as a drug therapy, rather than to assist psychotherapy, including the two aiming to treat depression with psilocybin.” 

Lykos said they recognize that MDMA-assisted therapy is an innovative combination of medication and therapy, which presents unique research challenges. The company plans to continue working closely with the FDA to address these issues and remains dedicated to advancing this integrated treatment approach.

Lykos Controversies

Nature published an article that discussed the controversies surrounding Lykos that may or may not have affected the FDA’s decision. The ICER announced they were investigating the ethical practices of Lykos therapists. Specifically, it alleges that Lykos’ employees strongly persuaded research participants to report only positive outcomes. 

The other controversy involved a sexual abuse ethical violation by an unlicensed therapist working for MAPS with a study subject who was under the drug’s influence at the MP4 Canadian study site. As a result, the journal Psychopharmacology retracted three of Lykos’ published papers, even though other journals allowed the correction of the data to remove the four participants treated at the Canadian site. These articles pooled data from six phase 2 trials, including the one participant who experienced the ethical violation.

MDMA-Assisted Therapy for PTSD

Even though the FDA requested Lykos conduct an additional phase 3 trial, there is substantial evidence from decades of research on how MDMA works in the brain and why MDMA-assisted therapy may help those with PTSD? Here are some potential mechanisms that researchers have studied:

• Reduces of Fear and Anxiety:
  MDMA reduces activity in the amygdala, the part of the brain involved in processing fear and emotional responses. This reduction allows patients to discuss traumatic memories with less fear and anxiety.
  
• Enhances Emotional Processing:
  MDMA increases the release of serotonin, dopamine, and oxytocin, which enhances feelings of trust and emotional openness. This amplification can help patients reconnect with positive emotions and process their trauma in a more balanced way.
  
• Strengthens Therapeutic Relationship:
  The effects of MDMA foster a stronger connection between the patient and therapist, enhancing trust and collaboration during therapy sessions.
  
• Facilitates Memory Reconsolidation:
  Under the influence of MDMA, patients can revisit traumatic memories with a new perspective, allowing for memory reconsolidation. This process can reduce the emotional intensity of the trauma over time.
  
• Increases Insight and Cognitive Flexibility:
  MDMA promotes cognitive flexibility, allowing patients to reframe negative beliefs about themselves and their trauma, leading to greater insight and potential healing.
  
• Temporarily Suspends Hypervigilance:
  Many people living with PTSD experience hypervigilance or a constant state of alertness. MDMA helps relax this response, allowing the brain and body to feel safe enough to engage in the therapeutic process.

These effects make MDMA-assisted therapy a promising approach for treating PTSD, particularly in cases where conventional therapies have been less effective. 

What Does This Mean for Patients and Healthcare Providers?

If the FDA had approved Lykos’ NDA, it would have been a monumental step toward providing broad access to MDMA treatment for those who have PTSD. However, the decision makes it incredibly difficult for researchers to investigate MDMA therapy, given the existing red tape. FDA approval would not mean MDMA is legal since only Lykos could administer its formulation under a specific protocol. However, Heifets expressed to Nature that “[the approval] would have been enough…[now] getting the kind of evidence that people want will continue to be inordinately painful.”

Emerson stated, “Our heart breaks for the millions of military veterans, first responders, victims of sexual and domestic abuse, and countless others suffering from PTSD who may now face more years without access to new treatment options. We intend to work tirelessly and use all available regulatory pathways to find a reasonable and expeditious path forward for patients who deserve access to midomafetamine-assisted therapy for PTSD.”

The Heroic Hearts Project, a veterans organization, told NPR that the “FDA’s decision is disgraceful…This is the epitome of bureaucratic red tape — and the result is people will keep dying.”

Rebecca Brendel Weintraub, a bioethicist at Harvard University, told Science that the FDA needs to be “very clear about what it expects of Lykos on the next go-around to establish safety and efficacy. Otherwise, people might seek psychedelic experiences on their own given enthusiasm for the potential benefits.”

A Silver Lining for Researchers

Some researchers are viewing the FDA’s decision as an opportunity to bolster the evidence that supports MDMA-assisted therapy in treating PTSD. David Yaden, a psychedelics researcher at Johns Hopkins University, told Science that he believes “the field of psychedelic research, in general, requires more large-scale, controlled, and rigorous trials…[data from another phase 3 trial] would be valuable for policymakers, regulators, and the public.”

Dr Mason Marks, a law professor and senior fellow with the Project on Psychedelics Law and Regulation at Harvard Law School’s Petrie-Flom Center, told NPR that he thinks the FDA’s decision won’t slow down the progress of psychedelic research. In fact, he predicts it “might intensify because the other companies might see an opportunity to really get in there and compete.” 

What Providers Can Do Now

Despite the decision, the Psychedelic Support team believes that there are more pressing issues than FDA’s approval. For instance, MAPS has set a goal to treat 1 million PTSD patients by 2031. Without sufficient numbers of qualified psychedelic therapists, FDA approval alone won’t be enough to make these therapies widely accessible.

Given the positive outcomes of ongoing clinical trials, we are optimistic that approval will eventually occur. The real challenge in psychedelic medicine lies in the shortage of well-trained, knowledgeable therapists.

To ensure that people can access psychedelic-assisted therapy once these treatments are approved, we need a significant increase in the number of therapists trained in both facilitation and integration. 

Now is the time to begin your journey toward becoming a psychedelic therapist. You could start by working with ketamine therapy today or even facilitate psilocybin therapy in Oregon next year. With the possibility of FDA approval for psilocybin (and eventually, MDMA) on the horizon, the field is rapidly expanding.

If you’re interested in joining the psychedelic medicine movement, Psychedelic Support offers valuable resources to support your journey, no matter where you are in the process.

References 

Feduccia, A. A., & Mithoefer, M. C. (2018). MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms? Progress in Neuro-Psychopharmacology and Biological Psychiatry, 84(84), 221–228. https://doi.org/10.1016/j.pnpbp.2018.03.003.

Kupferschmidt, K. (2024, August 12). FDA Rejected MDMA-Assisted PTSD Therapy: Other Psychedelics Firms Intend to Avoid That Fate [Dataset].Science. https://doi.org/10.1126/science.zhveq6h.

Lykos Therapeutics. (2024, August 9). Lykos Therapeutics Announces Complete Response Letter for Midomafetamine Capsules for PTSD [Press release]. Lykos Therapeutics  – News Release Archive. https://news.lykospbc.com/2024-08-09-Lykos-Therapeutics-Announces-Complete-Response-Letter-for-Midomafetamine-Capsules-for-PTSD.

Keshavan, M. (2024, August 16). Three MDMA Therapy Papers Retracted Over Ethics Violations.  STAT. www.statnews.com/2024/08/11/mdma-ptsd-lykos-maps-retractions/.

Pedersen, T., & Whitington, R. (2023, August 4). Your Guide to MDMA’s Effects on the Brain. Healthline. https://www.healthline.com/health/substance-use/mdma-effects-on-brain.

Reardon, S. (2024, August 13). FDA Rejects Ecstasy as a Therapy: What’s Next for Psychedelics? Nature. https://doi.org/10.1038/d41586-024-02597-x.

Stone, W. (2024, August 9). FDA Gives Thumbs Down to MDMA for Now, Demanding Further Research. NPR. www.npr.org/sections/shots-health-news/2024/08/09/nx-s1-5068634/mdma-therapy-fda-decision-ptsd-psychedelic-treatment.