But 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.”
Other 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 derivative of 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.