In a dose-finding phase 2 trial, adults with treatment-resistant major depression responded to 25-mg doses of synthetic, pharmaceutical-grade psilocybin but not to 10-mg doses, researchers report. Responses were sustained over 12 weeks in the multicenter, international study.
The randomized, double-blind trial included a 1-mg dose as a control. After a run-in period of 3 to 6 weeks during which antidepressants were tapered and discontinued, participants received a single psilocybin dose in a nonclinical, calming administration room while listening to a specially designed music playlist and wearing eyeshades to help direct attention internally. Participants remained in the room until at least 6 hours after dose administration and psychedelic effects had fully dissipated. Scores on the Montgomery–Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression) served as a primary endpoint.
“A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group,” the authors report. “The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were −12.0 for 25 mg, −7.9 for 10 mg, and −5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was −6.6 (95% confidence interval [CI], −10.2 to −2.9; P <0.001) and between the 10-mg group and 1-mg group was −2.5 (95% CI, −6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups.”
Editorial: “There are broad social implications of medicalizing hallucinogenic agents,” writes an editorialist. “The momentum to medicalize hallucinogens is reflected by the fact that more than 180 clinical trials of psilocybin, MDMA (3,4-methylenedioxymethamphetamine), or LSD to treat depression, other neuropsychiatric disorders, substance use disorders, demoralization (hopelessness, inability to cope, and allied feelings of inadequacy), and enhancement of spirituality are currently listed on ClinicalTrials.gov. The momentum to also legalize hallucinogens shares strategies in common with movements that were calculated to increase legal access to prescription opioids and marijuana in the United States. One such strategy is to minimize potential adverse consequences and dismiss evidence-based safety concerns for general use. In an online survey of psilocybin mushroom users, 39% rated it as among the most challenging experiences of their lifetimes, putting themselves or others at risk of physical harm or manifesting physically aggressive or violent behavior, receiving medical help, and seeking treatment for enduring psychological symptoms. Yet, most endorsed the experience. Other such strategies are to recruit mainstream media to enthusiastically endorse a class of drugs and shape restricted access as a political ‘war on drugs’ (rather than acknowledge the need to exercise caution), develop industry-led campaigns to increase demand, and advocate legalization as a source of tax revenue. If legalization and commercialization are allied with the medical movement, psychedelic shops and ‘clinics’ could proliferate even for vulnerable populations, and rigorously designed medical protocols will be compromised.”