But psychedelic drugs are difficult to test this way because their hallucinogenic effects are highly visible to the person taking them: In the Lycos trial, about 90% of participants were able to correctly guess whether they had been given MDMA or a placebo, effectively unblinding the study.
If participants knew they had received MDMA, they may have been more receptive to psychotherapy and felt more positive about their study experience. Also, if they knew they had not, they may have been more likely to perceive any psychotherapy they received as less effective. Either scenario could have influenced how they reported their PTSD symptoms after the MDMA sessions.
“Doing an open-label trial can raise all kinds of questions about efficacy,” said David Lind, chief medical officer at the Boston-based nonprofit Institute for Clinical and Economic Review, which issued a report in May expressing concerns about the validity of the Lycos trial data.
While blinded trials with placebo groups are often considered the gold standard in medical research, Lind says there are other ways to ensure reliable results. For example, instead of giving control subjects an inactive placebo, Lycos could give them a safe but effective drug that’s known to have some physiological effect. This would at least make patients question the medicine they’re getting, Lind says.
Another issue Lycos must address is the therapy portion of the treatment. The company says its treatment manual allows for a “personalized experience,” but FDA advisers were concerned about variability in the psychotherapy provided in the trial. Lind says Lycos was testing its own psychotherapy protocol in both the drug and placebo groups, rather than established trauma-focused treatments, so it’s hard to know how effective the therapy component was.
One way to address this would be to study established trauma therapies in combination with MDMA, or to test different psychotherapy approaches in a head-to-head comparison.
Sandhya Prashad, president of the American Association of Ketamine Physicians, Psychotherapists and Practitioners, says the treatment element likely complicated the Lycos case for the FDA. “I don’t think the FDA knew what to do with it,” she says.
She thinks the psychedelic drug field can learn from the 2019 approval of Spravato. Johnson & Johnson urged the FDA to approve the drug alone, rather than in combination with psychotherapy.
Because Spravato can cause dissociative and hallucinogenic effects, the FDA has special requirements for prescribing it. It must be administered in a certified medical facility where a medical professional can monitor the patient. Patients are not receiving medical treatment during the session.
But Prashad says he understands why Lycos was seeking approval for MDMA combined with psychotherapy. Comparing Spravato to generic ketamine, ketamine was approved as an anesthetic in 1970 and is often prescribed off-label to treat depression. FDA requirements don’t apply to off-label ketamine use; it’s not regulated for depression, Prashad says. “We’re seeing a lot of poor quality care, and I think Lycos was trying to prevent that and roll this out in a responsible way.”
Other companies are pursuing psychedelics solely as drugs, rather than combining them with psychotherapy. Biotech company Compass Pathways is testing psilocybin, the active ingredient in magic mushrooms, in a Phase 3 trial for treatment-resistant depression. Qualified medical professionals prepare participants for the psilocybin sessions, observe and chaperone them during the sessions, and provide follow-up support after the sessions. Sessions last six to eight hours. The company points out that this type of psychological support is not psychotherapy.
Similarly, Beckley Psytech is investigating an intranasal DMT derivative and an IV version of psilocybin as potential treatments for depression. Both are short-acting, with the peak experience lasting just 10 to 15 minutes. In Lycos’ trials, MDMA sessions lasted eight hours.
“What we provide in therapy sessions is support, not psychotherapy,” says Rob Conley, chief scientific and medical officer at Beckley SciTech. “From a safety perspective, we think shorter is better.”
It remains to be seen whether Lycos sticks with its plans for MDMA-assisted therapy or pursues approval for MDMA alone. Either way, the company said it is “committed” to getting MDMA to people suffering from PTSD.
