FDA Declines Approval of MDMA-Assisted Therapy for PTSD

The US Food and Drug Administration (FDA) has declined to approve a treatment that combines the psychedelic drug midomafetamine with assisted therapy (MDMA-AT) for the treatment of posttraumatic stress disorder (PTSD). 

In a statement, drug manufacturer Lykos Therapeutics said the agency had issued a complete response letter, determining that the therapy “could not be approved based on data submitted to date” and requesting additional study. 

“The FDA has requested that Lykos conduct an additional Phase 3 trial to further study the safety and efficacy of midomafetamine. Lykos plans to request a meeting with the FDA to ask for reconsideration of the decision and to further discuss the agency’s recommendations for a resubmission seeking regulatory approval for midomafetamine capsules,” the statement said. 

The decision comes after an FDA advisory panel voted overwhelming against approval, citing insufficient evidence of efficacy and finding that the benefits of the therapy did not outweigh its risks. 

MDMA-AT would have been the first psychedelic-based therapeutic cleared by the FDA for any condition in the United States and the first PTSD medication to receive approval in 24 years.

The rejection is a blow to drug manufacturer Lykos Therapeutics, which sought approval of the therapy based on two pivotal trials that were plagued with criticisms of potential unblinding and investigator bias. 

In recent weeks, a campaign by veteran’s groups had urged the agency to overrule the advisory panel’s recommendation and approve the therapy. And just this week, a bipartisan group of about 80 federal lawmakers sent a letter to President Joe Biden in support of the treatment. 

“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,” Amy Emerson, chief executive officer of Lykos Therapeutics, said in the statement. “While conducting another Phase 3 study would take several years, we 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.”

Approximately 13 million US adults have PTSD. About 7% of all veterans experience PTSD during their lifetime (compared with 6% of the general population), but for some service members, this proportion is reportedly as high as 29%.

Several veterans groups submitted public comments in support of the treatment prior to the June FDA advisory panel hearing and leaders in the US Department of Veterans Affairs had thrown their weight behind the promise of psychedelics in treating PTSD.

MDMA-AT was initially developed by the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS). MAPS formed a Public Benefit Corporation (MAPS PBC) subsidiary in 2014, which fully separated from MAPS in 2024 when it became Lykos. 

The FDA designated MDMA-AT as a breakthrough therapy in 2017, putting it on a fast track for approval.

As reported previously by Medscape Medical News, investigators presented and published data in 2021 from MAPP1, the company’s first clinical trial of the therapy. 

The study evaluated 90 patients with PTSD randomly assigned to receive MDMA 80 mg or 120 mg or placebo, followed by three integrative psychotherapy sessions lasting a total of 8 hours. 

Patients could receive a supplemental dose of MDMA after the first dose. The company reported that 82% of patients reported a significant improvement, with more than half saying they no longer had PTSD. 

Eleven patients (12%) experienced relapse within 12 months. Last year, Medscape Medical News reported findings from the second trial, MAPP2, which showed similar results in 104 patients.

However, in June, the FDA’s Psychopharmacologic Drugs Advisory Committee voted 11-2 that the efficacy data was unconvincing. Only one panelist agreed that the benefits outweighed the risk.

In their rejection, panelists cited potential bias due to participants’ prior use of MDMA, claims of unreported adverse events, a lack of data on whether the drug could be misused, and at least one documented case of sexual assault during a phase 2 study.

All of the panel members had concerns about “functional unblinding” in the two trials. Most patients — and it appeared to be the therapists too — were aware of who had received an active treatment, which probably biased results, they said.

As reported previously by Medscape Medical News, concerns were also raised about the trial design, a citizen petition calling on the FDA to investigate allegations of ethical misconduct, and complaints from former employees.

In a bid to respond to some of the FDA panel’s concerns, Lykos announced last week that the company would take steps to ensure additional oversight of MDMA-AT if the FDA approved the therapy. 

This would include the creation of an independent advisory board made up of external experts to inform a commercial launch. MDMA-AT would only be available at behavioral health centers that meet FDA and Drug Enforcement Agency requirements. Lykos also pledged to collaborate with other institutions on training in how to administer the therapy. 

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in publications including JAMA and Smithsonian.com. You can find her on X @aliciaault. 

Kelli Whitlock Burton is an assistant managing editor for Medscape Medical News.