Demystifying Psychedelic Treatments in Psychiatry: Is Ego Dissolution the Solution?

For thousands of years, psychedelics have been used for religious, ceremonial, or medicinal purposes. In 1896, Arthur Heffter successfully synthesized a classic psychedelic—mescaline (naturally occurring in peyote), which was subsequently studied in Emil Kraepelin’s clinic as a psychotomimetic agent. In 1936, Swiss chemist Albert Hoffman synthesized LSD, which galvanized researchers to investigate therapeutic uses ranging from treatment of alcoholism to depression. As psychedelics spread outside of scientific circles in the 1960s, a cultural backlash led to increased regulation; the subsequent federal Controlled Substances Act passed in 1970 halted clinical research for decades. Renewed interest in the 1990s led to a new wave with more rigorous methodologies investigating multiple indications—treatment-resistant depression, existential distress in terminal illness, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder, body dysmorphic disorder, eating disorders, alcohol use disorder, smoking cessation, autism spectrum disorder, and cluster/migraine headaches.

Most psychedelic studies are currently funded by small pharmaceuticals or foundations. The National Institute of Mental Health held its first psychedelics workshop in January. The studies typically include intensive psychotherapy protocols with preparatory sessions, supportive therapy during dosing, and integrative sessions.

While there is no FDA-approved classic psychedelic, psilocybin and MDMA have received “breakthrough therapy” FDA designations for depression and PTSD, respectively. A phase 3 trial of MDMA-assisted therapy for PTSD in 90 participants published May 10, 2021, in Nature Medicine yielded a large effect size of 0.91 on the primary outcome (CAPS-5 score), which was a considerably larger effect size than the standard pharmacological treatments. In a phase 2b trial of psilocybin-assisted therapy in 233 participants with treatment-resistant depression, Compass Pathways reported significant reduction in depressive symptomatology (MADRS score) in the highest dose group (25 mg) compared with the control low-dose group (1 mg) even at 12-week follow-up. Compass plans to begin a phase 3 trial this year.

Current limitations of psychedelic research include concerns of representativeness and generalizability, as most participants are self-selected prior users and predominantly consist of White, educated, high socioeconomic status populations. Furthermore, participants with comorbidities or vulnerability to psychosis are often excluded. High expectancy, nocebo effects, and poor blinding may also limit interpretability of findings.

Surprisingly, there is no definitive proof that the ego dissolution (for example, conscious hallucinogenic experience) is necessary or sufficient for therapeutic effects. In rodents, studies using 5HT2A blockers or pharmaceutically designed nonhallucinogenic analogs demonstrate antidepressant effects despite reductions in psychedelic-induced head-twitch responses. The analogous study has not been done in humans, but similar findings in humans could have profound implications on treatment protocols: If therapeutic effects are independent of “tripping,” many existing safety and study design barriers could be circumvented. As larger trials attempt to establish efficacy, a pressing question with implications for assisted-therapy protocols, safety, and accessibility of treatment remains unanswered: Is ego dissolution the solution? ■