The Food and Drug Administration declined Friday to approve an application to treat post-traumatic stress disorder using the drug midomafetamine, also known as MDMA or the street drug ecstasy, citing “significant limitations” with the data submitted to the agency.

Drugmaker Lykos Therapeutics had asked the FDA to approve its MDMA capsules as part of a therapy regimen they argued could be a breakthrough for treating challenging cases of PTSD. 

Lykos said the FDA asked for another phase 3 trial to study the safety and efficacy of MDMA. 

“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, the CEO of Lykos Therapeutics, said in a release.

Emerson said that conducting another phase 3 study, as requested by the FDA, “would take several years” to be done. Phase 3 trials are typically the final and largest stages of clinical studies that drugmakers conduct before seeking approval. 

Lykos acknowledged that the concerns the FDA raised echoed those that were brought up by an advisory committee earlier this year. That panel had voted by a majority against the application over a number of concerns about the trials it had done so far.

The company says it plans to eventually seek resubmission, as it works “diligently in the coming months to address” the concerns raised by the agency.

Calls for the FDA to approve the application have mounted in recent weeks ahead of the decision, including from veterans groups and lawmakers. 

But earning the FDA’s green light hit a stumbling block at a June advisory meeting to discuss the application. While the FDA is not required to follow the advice of its outside expert panels, it usually does.

“As discussed at the Advisory Committee meeting, there are significant limitations to the data contained in the application that prevent the agency from concluding that this drug is safe and effective for the proposed indication,” an FDA spokesperson said in a statement.

The spokesperson said the FDA “generally cannot disclose” the details of why it rejected the application, but said Lykos was free to release the letter it received from the FDA.

“The agency recognizes that there is great need for additional treatment options for mental health conditions such as PTSD. We will continue to encourage research and drug development that will further innovation for psychedelic treatments and other therapies to address these medical needs,” the spokesperson said.

Why an advisory committee voted against MDMA

Lykos said the FDA’s letter echoed the issues that came up during the June advisory committee meeting. Some of the concerns shared by the panel have long plagued attempts to study MDMA and other hallucinogenic drugs like it. 

For example, unlike most studies that compare a drug to a placebo to measure its effectiveness, it is difficult to mask whether participants are actually getting MDMA or a dummy — a dilemma that researchers call “functional unblinding.”

Participants in the trial are often eager for the drug they signed up to study and could be more likely to report a benefit when they know they are getting it, compared to the general population of patients suffering from PTSD.

Concerns about the way that trials of the treatment were run also came up throughout the meeting, especially after a number of speakers during the meeting’s time for public comment raised concerns about misconduct and data meddling during the studies.

FDA officials also acknowledged some limits to their ability to regulate use of MDMA.

The FDA has authority to draw up rules around how the drug is marketed and can require some safety measures for patients, like monitoring for a certain amount of time after they are given MDMA. 

But the agency told the panel that their hands were tied when it came to regulating the actual content of the therapy that would be paired with the capsules, which the company has said is key to the success of the treatment.

Even among the FDA panelists who voted against the application in June, many also echoed hope about the potential for MDMA to treat patients with PTSD.

“I think this is a really exciting treatment. I’m really encouraged by the results to date, but I feel that both from an efficacy and a safety standpoint, it is still premature,” Dr. Paul Holtzheimer of the National Center for PTSD said at the meeting, explaining his vote against whether the benefits outweighed the risks for patients with PTSD.

Responding to concerns from the meeting

In the time since the meeting, the drugmaker has insisted it remained confident in the “rigor and thoughtfulness that the FDA will give our application” and rejected “misinformation” about its program.

In responding to the concerns raised from the panel, Lykos said the effect seen in its trials was unlikely to be explained by “functional unblinding” only. 

They said “psychotherapy is already a regulated field” with standards and oversight. And about specific concerns about misconduct during the studies, Lykos said they were continuing to cooperate with the FDA amid inspections of its clinical trial sites.

In June, the nonprofit Institute for Clinical and Economic Review also cited “substantial concerns” about bias in how the trials were conducted, like therapists encouraging patients only to report positive benefits and not harms. 

The drugmaker later criticized the group for relying on “anonymous reports” without corroborating evidence for casting “unfair doubt on the integrity” of the trials.

Lykos also announced a series of “new initiatives and measures of additional oversight” as it prepared for a potential approval, including a pledge to only make the drug commercially available at “top behavioral health facilities” treating patients under “layers of oversight.”

“Given the novelty of this approach, we are taking steps to help ensure additional oversight for this drug plus therapy modality, if FDA approved, and to help integrate into the real-world healthcare setting,” Emerson had said.