Enlarge / President of Multidisciplinary Association for Psychedelic Studies (MAPS) Rick Doblin speaks onstage during the 2023 Concordia Annual Summit at Sheraton New York on September 18, 2023, in New York City. (credit: Getty | John Lamparski)

There's more bad news for the company behind an experimental MDMA therapy for post-traumatic stress disorder, which the Food and Drug Administration roundly rejected earlier this month.

According to a report from The Wall Street Journal, the FDA is now expanding an investigation into clinical trials behind the experimental psychedelic therapy—even though the agency has already rejected it. Agency investigators reportedly interviewed four additional people last week, asking questions regarding whether the trials underreported side effects.

People involved in the trial have previously alleged, among other things, that ill effects, such as suicidal thoughts, went undocumented, and trial participants were discouraged from reporting them to bolster the chances of FDA approval. Overall, the MDMA trials faced crushing criticism amid the FDA's review, with outside experts and agency advisers calling out allegations of sexual misconduct at one trial site, as well as flaws in overall trial designs, multiple sources of biases, and claims that the company behind the therapy, Lykos, fostered a cult-like belief in psychedelics.

Enlarge (credit: Getty | RJ Sangosti)

After an MDMA therapy for post-traumatic stress disorder dramatically failed to impress Food and Drug Administration advisers earlier this month, researchers are moving forward with another psychedelic—a slow-release oral dose of the hallucinogenic drug ketamine—as a therapy for treatment-resistant depression.

In a mid-stage, randomized, placebo-controlled clinical trial, researchers tested slow-release ketamine pills, taken twice weekly. The trial, sponsored by New Zealand-based Douglas Pharmaceuticals, found ketamine to be safe compared with placebo. At the trial's highest dose, the treatment showed some efficacy against depression in patients who had previously tried an average of nearly five antidepressants without success, according to the results published Monday in Nature Medicine.

But the Phase II trial, which started with 231 participants, indicated that the pool of patients who may benefit from the treatment could be quite limited. The researchers behind the trial chose an unusual "enrichment" design to test the depression treatment. This was intended to thwart the high failure rates generally seen in trials for depression treatments, even in patients without treatment-resistant cases. But even after selecting patients who initially responded to ketamine, 59.5 percent of the enriched participants still dropped out of the trial before its completion, largely due to a lack of efficacy.

Enlarge / MDMA pills up close. (credit: Getty | Universal History Archive)

After a remarkably sensational regulatory drug review, advisers for the Food and Drug Administration on Tuesday voted overwhelmingly against approving midomafetamine (MDMA, aka ecstasy or molly) as part of therapy for post-traumatic stress disorder.

In a response to the question, "Do the available data show that the drug is effective in patients with posttraumatic stress disorder?" advisers voted 9 "no" to 2 "yes" against MDMA.

The votes come after a full-day meeting in which the independent expert advisers heard detailed reviews of clinical trial data from the company that proposed the therapy—Lykos, formerly MAPS—as well as internal FDA reviews.

Enlarge / MDMA is now in the FDA's hands. (credit: Getty | PYMCA/Avalon)

The safety and efficacy data on the use of MDMA (aka ecstasy) for post-traumatic stress disorder therapy is "challenging to interpret," the Food and Drug Administration said in a briefing document posted Friday. The agency noted significant flaws in the design of the underlying clinical trials as well as safety concerns for the drug, particularly cardiovascular harms.

On Tuesday, June 4, the FDA will convene an advisory committee that will review the evidence and vote on MDMA's efficacy and whether its benefits outweigh its risks. The FDA does not have to follow the committee's recommendations, but it often does. If the FDA subsequently approves MDMA as part of treatment for PTSD, it would mark a significant shift in the federal government's stance on MDMA, as well as psychedelics, generally. Currently, the US Drug Enforcement Administration considers MDMA a Schedule I drug, defined as one with "no currently accepted medical use and a high potential for abuse." It would also offer a new treatment option for patients with PTSD, a disabling psychiatric condition with few treatment options currently.

As Ars has reported previously, the submission of MDMA for approval is based on two clinical trials. The first trial, published in Nature Medicine in 2021, involved 90 participants with moderate PTSD and found that MDMA-assisted psychotherapy significantly improved Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) scores compared with participants who were given psychotherapy along with a placebo. In the second study, published in September in Nature Medicine, the finding held up among 104 participants with moderate or severe PTSD (73 percent had severe PTSD).