Anika Begay
But psychedelic compounds are difficult to test this way because their psychedelic effects are so recognizable to those taking them. In the Lykos studies, about 90 percent of participants were able to correctly guess whether they had received MDMA or a placebo, effectively “debunking” the study.
If participants had known that 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 that they had not, they might have been predisposed to think that the psychotherapy they had received was less effective. Both scenarios could have affected how they reported their PTSD symptoms after MDMA sessions.
“Once you have an unblinded clinical trial, you potentially have all sorts of questions about efficacy,” says David Rind, medical director of the nonprofit Boston-based Institute for Clinical and Economic Review, which published a report in May raising concerns about the validity of the Lykos study data.
Blinded placebo-controlled clinical trials 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 participants an inert placebo, Lykos could administer a safe but active drug that is known to produce some physiological effects. That would at least leave patients in doubt about what they were getting, Rind says.
Another issue Lykos will face is the therapy portion 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 trials. Rind says that because Lykos was testing its psychotherapy protocol in both drug and placebo groups, rather than an established trauma-focused therapy, it’s difficult to know how effective the therapy component was.
One way to address this issue might be to study an established trauma therapy in combination with MDMA, or to test different psychotherapeutic approaches against each other.
Sandhya Prashad, president of the American Society of Ketamine Physicians, Psychotherapists, and Practitioners, says the therapeutic component likely complicated Lykos’s case in the eyes of the FDA. “I don’t think the FDA knew what to do with it,” she says.
He thinks the psychedelic field can learn from Spravato’s 2019 approval. Johnson & Johnson asked the FDA to approve the drug alone, rather than the drug along with psychotherapy.
Because Spravato can induce dissociation and hallucinogenic effects, the FDA has special requirements for how it is prescribed. It must be administered in a certified physician’s office where a healthcare provider can monitor the patient. A patient does not receive therapy during the session.
Still, Prashad says he understands why Lykos sought 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 treatment for depression. Giving ketamine off-label isn’t subject to the same FDA requirements. It’s not regulated as a treatment for depression, Prashad says. “You see a lot of poor quality of care. I think Lykos was trying to prevent that and distribute it responsibly.”
Other companies are pursuing psychedelics solely as medications rather than combining them 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 the session, and provides follow-up support afterward. Sessions can last six to eight hours. The company notes that this type of counseling is not psychotherapy.
Similarly, Beckley Psytech is studying an intranasally administered DMT derivative, as well as an IV version of psilocybin, as potential treatments for depression. Both are designed to have short-lived effects, with the peak experience lasting only 10 to 15 minutes. In the Lykos studies, MDMA sessions lasted eight hours.
“What we offer in the therapy session is support, not psychotherapy,” says Rob Conley, chief scientific and medical officer of Beckley Psytech. “From a safety standpoint, we think brief is a good thing.”
It remains to be seen whether Lykos will stick with its plans to pursue MDMA-assisted therapy, or whether it will seek approval or MDMA alone. Either way, the company said it remains “deeply committed” to bringing MDMA to PTSD sufferers.
