Can Psychedelics Work Without Being ‘Psychedelic’?

With two phase 3 clinical trials going on this year and others being proposed, the introduction of psychedelics into psychiatric practice is just a question of time. Nonetheless, there are still many unknowns that need to be researched. At a session on Monday, Adrian Jacques Ambrose, M.D., M.P.H., and Michael Avissar, M.D., Ph.D., both assistant professors of psychiatry at Columbia University, discussed some of these pertinent issues.

Perhaps most relevant from a treatment perspective is this question: Is ego dissolution the solution? That is, do patients need to feel that sensation of transcendence of having an out-of-body experience to get a therapeutic benefit?

The idea that psychedelic substances are a tool that alters the mind in a way to facilitate a therapeutic experience in the proper setting is one of the bedrocks of the field. Many human studies have validated this association, finding that participants who report more acute mystical experiences (such as a sense of being beyond time and space or having complete tranquility) tend to have better clinical responses, such as lowered depression or reduced drug cravings.

As Avissar pointed out, all current evidence is correlational. Causality requires evidence that having these acute experiences is both necessary and sufficient to result in successful treatment. In addition, current measures of psychedelic experience are highly subjective, raising questions about whether people are overestimating their experience because they feel better.

Ambrose noted that the requirement of reaching a state of ego dissolution is pertinent since current models of psychedelic-assisted psychotherapy involve two therapists per patient and treatment sessions up to eight hours. Being able to only treat one patient a day is a significant barrier to access.

Basic and translational studies have suggested that having a mystical experience is not essential. Studies in rodents have firmly demonstrated that psychedelics can reduce fear in the animals even when the serotonin 2A receptor (believed to be primary site of action for classic psychedelics) is being blocked by another compound. Other investigators have demonstrated that nonhallucinogenic analogs of psychedelic substances also exert beneficial effects in rodents.

But just as correlation is not causation, so too mice are not little humans, Avissar said. A head-to-head study in humans comparing an active psychedelic with an analog would seem ideal, but because of the pronounced effects of tripping, such a study cannot be blinded, and since subjects might have high expectations of receiving a psychedelic, the analog group could have skewed results. It might be possible to conduct separate experiments in which patients know the substance they are taking, and objective biomarkers could be used to compare the results. Avissar noted that EEG readings might be a possible biomarker since they are an affordable measure, are reproducible in individuals, and are direct reflections of brain activity.

Even if a mystical experience is needed to achieve a therapeutic effect, it might be possible to do so with shorter therapy sessions, Ambrose noted, and that could be another area for future research. “But we should find out what are the core aspects of a psychedelic substance that must be preserved so it remains therapeutic but also scalable so many patients can benefit.” ■