But psychedelic compounds are difficult to test this way because their psychedelic effects are so recognizable to those taking them. In the Lykos trials, about 90 percent of participants were able to correctly guess whether they received MDMA or a placebo, effectively “unravelling” the study.
If participants had known they had received MDMA, they might have been more receptive to psychotherapy and felt more positive about the trial experience. And if they had known they had not, 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 do an open-label trial, all sorts of questions about efficacy can arise,” says David Rind, medical director of the Institute for Clinical and Economic Review, a Boston-based nonprofit that published a report in May raising concerns about the validity of the Lykos trial data.
Blind 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 example, instead of giving control group participants 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 with no doubt about what they received, Rind says.
Another issue that Lykos will have to address is the therapeutic part of its treatment. The company says that its treatment manual allows for a “personalized experience,” but FDA advisers had concerns about the variability of psychotherapy offered in the trials. Rind says that because Lykos was testing its own psychotherapy protocol in both the drug and placebo groups, rather than an established trauma-focused therapy, it’s difficult to know how effective the therapeutic component was.
One way to address this would be to study an established trauma therapy in combination with MDMA, or to test different psychotherapy approaches head-to-head.
Sandhya Prashad, president of the American Society of Ketamine Physicians, Psychotherapists and Practitioners, says the therapeutic component likely complicated Lykos’ case with the FDA. “I don’t think the FDA knew what to do with it,” she says.
She believes the psychedelic field can learn from the Spravato approved in 2019Johnson & Johnson asked the FDA to approve the drug alone, rather than in conjunction with psychotherapy.
Because Spravato can induce dissociation and hallucinogenic effects, the FDA has special requirements regarding how it is prescribed. It must be administered in a certified medical office where a healthcare provider can monitor the patient. The patient does not receive therapy during the session.
But Prashad says he understands why Lykos was seeking approval for combining MDMA with psychotherapy. Contrast Spravato with generic ketamine, which was approved as an anesthetic in 1970 and is often administered off-label as a treatment for depression. Off-label ketamine doesn’t carry the same FDA requirements. It’s not regulated as a treatment for depression, Prashad says. “You see a lot of substandard care. I think Lykos was trying to avoid that and implement this responsibly.”
Other companies are using psychedelics solely as a drug rather than combining them with psychotherapy. The 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 the session, and provides follow-up support afterward. Sessions can last six to eight hours. The company notes that this type of psychological support is not psychotherapy.
Similarly, Beckley Psytech is studying an intranasally administered DMT derivative, as well as an intravenous version of psilocybin, as potential treatments for depression. Both are designed to have short-acting effects, with the peak experience lasting only 10 to 15 minutes. In the Lykos trials, MDMA sessions lasted eight hours.
“What we offer during the therapy session is support, not talk therapy,” says Rob Conley, chief scientific and medical officer at Beckley Psytech. “From a safety standpoint, we think a short session is good.”
It remains to be seen whether Lykos will stick to its plans to move forward with MDMA-assisted therapy, whether it will seek approval or just MDMA. Either way, the company said it remains “deeply committed” to bringing MDMA to those suffering from PTSD.