For a while, it looked like the psychedelic drug MDMA was poised to become an approved treatment for post-traumatic stress disorder. Now, after being rejected by the US Food and Drug Administration, MDMA faces an uphill battle to becoming legalized as medicine.
In 2017, the FDA granted MDMA “breakthrough therapy” status, a designation that recognizes a new drug’s potential benefits and expedites its review. Then came promising data from two clinical trials showing that MDMA reduced PTSD symptoms in people when it was used alongside talk therapy. The approach won over military veterans and dozens of members of Congress.
But after a disastrous meeting with advisers in June, the FDA last week declined to approve MDMA for treating PTSD based on current evidence. In a further blow, the journal Psychopharmacology retracted three papers authored by Lykos Therapeutics, the company behind the treatment, due to “protocol violations amounting to unethical conduct.” On Thursday, as part of the fallout, Lykos announced that it was cutting its staff by 75 percent, and that its founder Rick Doblin would leave the company.
The FDA decision underscores the difficulty of getting regulatory approval for a psychedelic-based treatment. Not only was the FDA evaluating an illegal psychedelic for the first time, it was also reviewing the drug in combination with a type of psychotherapy developed by Lykos. Advisers struggled with disentangling the drug’s effects from the psychotherapy—a realm the FDA doesn’t regulate.
Now, Lykos may be headed in a new direction after the company announced the appointment of David Hough, a former executive at Johnson & Johnson, as chief medical adviser. At Johnson & Johnson, Hough led the development of Spravato, a form of ketamine approved in 2019 for treatment-resistant depression.
"As we prepare to address the FDA decision, we need to focus on delivering the FDA the robust clinical data necessary to support the approval of this potential new treatment," Lykos CEO Amy Emerson said in a statement. To do that, the company said it will need to run an additional Phase 3 trial, which means it could be years before MDMA-assisted therapy becomes a legal, established treatment for PTSD.
Meanwhile, other companies are advancing psychedelic compounds without the therapy component—a path that might be a clearer shot to regulatory approval.
“You’ve got to acknowledge that, universally, this area is really difficult from a trial-design perspective,” says Fran Brown, senior vice president of Certara, a firm that designs software to speed drug development.
It’s thought that MDMA may enhance psychotherapy by helping patients open up more so that they can better process and communicate traumatic experiences. To test this, Lykos ran what’s known as a double-blind placebo-controlled trial, in which neither the participants nor the researchers are supposed to know who received the experimental treatment or the placebo. Blinded trials are meant to avoid bias that could occur when someone thinks they got the real drug and think they feel better as a result.
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GearBut psychedelic compounds are tricky to test in this way because their psychedelic effects are so recognizable to those who take them. In the Lykos trials, around 90 percent of the participants were able to correctly guess whether they received MDMA or a placebo, effectively “unblinding” the study.
If participants knew they received MDMA, they could have been more receptive to the psychotherapy and felt more positive about the trial experience. And if they knew they hadn’t, they might have been predisposed to think that the psychotherapy they received was less effective. Both scenarios could have influenced how they reported their PTSD symptoms after the MDMA sessions.
“Once you have an unblinded trial, you potentially have all kinds of questions about efficacy,” says David Rind, chief medical officer of the Boston-based nonprofit Institute for Clinical and Economic Review, which published a report in May raising concerns about the validity of the Lykos trial data.
Blinded trials with a placebo group are often considered the gold standard in medical research, but Rind says there are other ways to ensure reliable results. For instance, instead of giving participants in the control arm an inert placebo, Lykos could administer a safe but active drug that is known to produce some physiological effects. This would at least leave patients in doubt about what they received, Rind says.
Another issue Lykos will have to address is the therapy part of its treatment. The company says its treatment manual allows for a “personalized experience,” but FDA advisers had concerns about the variability of psychotherapy offered in the trials. Rind says because Lykos was testing its own psychotherapy protocol in both the drug and placebo groups, rather than an established trauma-focused therapy, it’s hard to know how effective the therapy component was.
One way to address this would be to study an established trauma therapy in combination with MDMA, or test different psychotherapy approaches head-to-head.
Sandhya Prashad, president of the American Society of Ketamine Physicians, Psychotherapists, and Practitioners, says the therapy component likely complicated Lykos’ case to the FDA. “I don’t think the FDA knew what to do with that,” she says.
She thinks the psychedelics field can learn from the 2019 approval of Spravato. Johnson & Johnson asked the FDA to approve just the drug, rather than the drug alongside psychotherapy.
Because Spravato can induce disassociation and hallucinogenic effects, the FDA has special requirements around how it is prescribed. It must be administered in a certified medical office where a health care provider can monitor the patient. A patient doesn’t get therapy during the session.
However, Prashad says she understands why Lykos was seeking approval for MDMA combined with psychotherapy. Compare Spravato to generic ketamine, which was approved as an anesthetic in 1970 and is often given off-label as a depression treatment. Giving ketamine off-label doesn’t come with the same FDA requirements. It’s unregulated as a depression treatment, says Prashad. “You see a lot of subpar quality of care. I think Lykos was trying to prevent that and roll this out in a responsible way.”
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GearOther companies are pursuing psychedelics solely as a drug rather than combining it with psychotherapy. Biotech company Compass Pathways is testing psilocybin, the active compound in magic mushrooms, in Phase 3 trials for treatment-resistant depression. A licensed medical professional prepares participants for the psilocybin session, observes and is present with them during their session, and provides follow-up support after. Sessions can last six to eight hours. The company notes that this type of psychological support is not psychotherapy.
Similarly, Beckley Psytech is studying a compound related to DMT given intranasally, as well as an IV version of psilocybin, as potential treatments for depression. Both are designed to have short-acting effects, with the peak experience lasting just 10 to 15 minutes. In the Lykos trials, MDMA sessions lasted eight hours.
“What we offer during the therapeutic session is support, there’s no psychotherapy,” says Rob Conley, Beckley Psytech’s chief scientific and medical officer. “From a safety standpoint, we think short is good.”
Whether Lykos will stick with its plans to pursue MDMA-assisted therapy, or pursue approval or just MDMA, remains to be seen. Either way, the company said it remains “deeply dedicated” to bringing MDMA to those suffering from PTSD.
Updated 8-19-2024 8:00 pm BST: The description of Beckley Psytech’s intranasal compound was corrected. It is related to, not derived from, DMT.