Psilocybin — “magic mushrooms” — failed to improve symptoms of depression over a selective serotonin reuptake inhibitor (SSRI) in a 59-patient phase II trial, though the study’s leaders are not ready to give up on the hallucinogen.
At 6 weeks, psilocybin did not have a significantly greater effect on symptoms of moderate-to-severe major depressive disorder compared with the SSRI escitalopram (Lexapro), as measured by mean change from baseline on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16) score, with a between-group difference of 2 points (95% CI -5.0 to 0.9, P=0.17), reported Robin Carhart-Harris, PhD, of Imperial College London, and colleagues.
However, secondary outcomes show psilocybin’s potential for the future of depression treatment, they noted in the New England Journal of Medicine.
The psilocybin group received two 25-mg doses of the drug in capsule form 3 weeks apart plus daily placebo for 6 weeks. Those assigned to the escitalopram group were given two doses of 1-mg psilocybin 3 weeks apart, which researchers presumed to have a negligible effect, plus 10-mg doses of the SSRI daily, increasing the dosage to 20 mg by the end of the trial. In order to standardize expectations, all participants were told that they would be receiving psilocybin, without knowing the amount they were given.
Mean age of participants was 41, 34% were women, and almost all were white.
At baseline, the mean scores on the QIDS-SR-16 were 14.5 for the psilocybin group and 16.4 for the escitalopram group. The change from baseline to week 6 was -8.0 ± 1.0 in the psilocybin group, and was -6.0 ± 1.0 for the escitalopram group.
Sixteen secondary outcomes were measured, including QIDS-SR-16 response, defined as a reduction in score of >50%, and QIDS-SR-16 remission, defined as a score of ≤5 at the final week of the trial. Researchers found that a QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group compared with 48% of those in the escitalopram group, with a between-group difference of 22 points (95% CI -3 to 48). QIDS-SR-16 remission occurred in 57% of patients in the psilocybin group and 28% in the escitalopram group, for a between-group difference of 28 points (95% CI 2-54).
Carhart-Harris and team noted that other secondary outcomes “generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons.” But for Carhart-Harris, this is an understatement, to say the least.
“The paper takes a very conservative approach to the data,” he told MedPage Today, pointing to NEJM paper’s supplemental appendix to get a fuller picture of psilocybin’s positive outcomes in comparison with escitalopram.
Ten out of 11 secondary outcomes related to efficacy favored psilocybin with a level of confidence exceeding 95%, Carhart-Harris emphasized, including well-being, flourishing, work and social functioning, anxiety, three of four depression rating scales, avoidance, feeling pleasure, and suicidality.
“That’s not spin, that’s stats,” he said. As for the trial’s negative primary outcome, Carhart-Harris believes that this may be due to the rigidity and tight scoring range of the QIDS-SR-16.
Roland Griffiths, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins Medicine in Baltimore, had similar frustrations.
“I think the problem they came upon is that they provided a minimalist description of their outcome measures,” Griffiths told MedPage Today. “And they didn’t describe how they would go about analyzing multiple measures — and they could’ve done that, but they didn’t.”
Both Carhart-Harris and Griffiths acknowledged the trial’s most notable limitations, including its brief run period — particularly limiting when measuring the effects of SSRIs — and its lack of a placebo group. They also underlined one of the major challenges when studying psilocybin in blind trials: the fact that it becomes fairly obvious to the participants in the psilocybin group what treatment they’re receiving, based on the psychedelic nature of the drug.
“Notably, they didn’t ask people whether they could guess which condition they were in,” Griffiths said. “It’s almost impossible to think that the conditions wouldn’t be immediately discriminable to people.”
The authors also pointed out that, although they made efforts to recruit participants through referrals, many volunteered themselves and expressed a preference for psilocybin over escitalopram.
“I’m not saying that [psilocybin] should replace SSRIs or that this trial signals the death of SSRIs,” Carhart-Harris said. “It’s more, can we add this to the toolkit for treating depression?”
This study was supported by a private donation from the Alexander Mosley Charitable Trust and by Imperial College London’s Centre for Psychedelic Research.
Carhart-Harris disclosed receiving consulting fees from COMPASS Pathways, Entheon Biomedical, Mydecine, Synthesis Institute, Tryp Therapeutics, and Usona Institute.
Co-authors reported receiving fees from Small Pharma, Usona Institute, Synthesis Institute, Field Trip, Mydecine, Awakn, H. Lundbeck, Psyched Wellness, COMPASS Pathways, and Takeda Medical Research Foundation.
One co-author disclosed owning stock in Alcarelle.
One co-author is employed by the Synthesis Institute.
Griffiths reported no conflicts of interest.