Psilocybin as an antidepressant clears early-phase trial

A single dose of psilocybin paired with psychological support helps alleviate depressive symptoms and improve functional disability, with sustained effects and no serious adverse events, according to data from a phase II trial.

“Improvements in depression were apparent within 8 days of psilocybin dosing, consistent with a rapid onset of action, and were maintained across the 6-week follow-up period, without attenuation of the effect, and with higher point prevalence rates of Montgomery-Asberg Depression Rating Scale (MADRS)-defined response and remission than has been observed in recent psilocybin studies of treatment-resistant depression,” the investigators said. [Psychopharmacology 2018;235:399-408; N Engl J Med 2022;387:1637-1648]

In a cohort of 104 participants (mean age 41.1 years, 50 percent women) with major depressive disorder (MDD), those who received a single 25-mg dose of psilocybin (n=51) than a 100-mg dose of niacin (n=53) showed significantly lower MADRS scores—the primary outcome—at day 8 (mean difference, −12.0, 95 percent confidence interval [CI], −16.6 to −7.4; p<0.001) and at day 43 (mean difference,−12.3, 95 percent CI, −17.5 to −7.2; p<0.001). [JAMA  2023;doi:10.1001/jama.2023.14530]

Psilocybin treatment was associated with significantly greater rates of sustained depressive symptom response (42 percent vs 11 percent; odds ratio [OR], 5.6, 95 percent CI, 1.9–16.7; p=0.002). Remission rates were also better with psilocybin than with niacin (25 percent vs 9.1 percent), but their difference was not significant (OR, 3.4, 95 percent CI, 1.0–11.5; p=0.05).

In parallel, functioning in participants’ work/school, social, and family/home responsibilities improved, with a significant drop in Sheehan Disability Scale scores from baseline to day 43 observed in the psilocybin vs the niacin arm (mean difference, −2.31, 95 percent CI, 3.50–1.11; p<0.001).

“Psilocybin was generally well-tolerated, with most adverse events (AEs) being of mild or moderate severity and generally limited to the acute dosing period,” the investigators noted.

The rates of drug-related, treatment-emergent (TE)AE at day 9 were 82 percent in the psilocybin arm and 44 percent in the niacin arm (relative incidence [RI], 1.8, 95 percent CI, 1.3–1.8). From day 10 through day 43, the rates of drug-related TEAEs were 4 percent and 2 percent, respectively.

Solicited AEs were documented in 76 percent of participants in the psilocybin arm and in 30 percent of those in the niacin arm (RI, 2.6, 95 percent CI, 1.7–4.0). The most common solicited AEs were headache (66 percent vs 24 percent) and nausea (48 percent vs 6 percent).

Rethinking mental healthcare delivery

Around the world, researchers have been looking into the therapeutic potential of psychedelics, such as psilocybin. Their work is spurred by, first, increasing awareness of the limitations of currently approved pharmacological treatments for MDD and, second, mounting evidence of psilocybin possessing a rapid antidepressant response that lasts long after the substance exits the body. [Psychol Med 2022;52:419-432; PLoS One 2022;17:e026592; JAMA Psychiatry 2021;78:481-489; J Psychopharmacol 2022;36:151-158; N Engl J Med 2022;387(18):1637-1648]

A naturally occurring compound, psilocybin belongs to a class of compounds known as hallucinogens, similar to lysergic acid diethylamide (LSD) and mescaline (peyote). [https://www.msdmanuals.com/professional/special-subjects/illicit-drugs-and-intoxicants/hallucinogens]

A team of experts who are not included in the study stressed that understanding psilocybin’s therapeutic efficacy requires an appreciation of the context in which the drug is used, pointing out that the psychedelic approach is “radically different” from traditional approaches that seek to suppress depressive symptoms in that psychedelics target presumptive underlying pathophysiology or biological dysregulation. 

“When a psychedelic is taken with the proper preparation, intention, facilitation, and therapeutic environment, the patient can use the experience to gain new insights that can catalyze healing and recovery,” wrote Drs Rachel Yehuda and Amy Lehrner of Icahn School of Medicine at Mount Sinai, New York, New York, US, in an editorial piece. [JAMA  2023;doi:10.1001/jama.2023.12900]

“The psychedelic allows feelings such as self-compassion, forgiveness, understanding, and self-acceptance to surface that can be powerful antidotes to shame, guilt, anger, isolation, disconnection, or other negative emotions that patients find difficult to discuss in therapy and that do not seem to be mitigated by traditional antidepressants. Furthermore, a sense of boundlessness or ego dissolution may be felt as a mystical or spiritual experience, helping people find meaning, perspective, and connection with others and the world,” Yehuda and Lehrner explained. [Nat Rev Neurosci 2020;21:611-624; Psychopharmacology 2006;187:268-283]

Such experiences have been associated with symptom reduction and may represent an important mechanism of action, they continued.

In contrast, “the benefits of psychopharmacotherapy and psychotherapy are often small and incremental, and true remission is generally not obtained for months or years… [On top of that], psychotropic medications require chronic use, and when discontinued, symptoms can reappear even in stabilized patients,” Yehuda and Lehrner noted.  [PLoS Med 2008;5:e45; J Consult Clin Psychol 2008;76:909-922]

“Psychedelic therapies necessitate a rethinking of mental healthcare delivery in which medication is integrally paired with psychotherapy and delivered in a novel setting and framework… If psychedelic therapies do prove to have enduring effects after just a single or a few administrations in the context of a few sessions for preparation and integration, they have the potential to offer not just a new approach to mental healthcare, but an entirely new paradigm of care,” they said.