Psilocybin Delivers 'Remarkable' Relief in Severe Depression

Batya Swift Yasgur, MA, LSW

November 05, 2020

Psilocybin, the psychedelic compound in "magic mushrooms," rapidly improves symptoms and produces remission in as little as two sessions for patients with major depression, new research suggests.

Results of a small randomized trial showed that treatment with psilocybin was associated with a greater than 50% reduction in depressive symptoms in 67% of study participants. In addition, 71% showed improvement at 4-week follow-up, with more than 50% achieving remission.

"The finding that the majority of people whom we treated showed efficacy was quite a remarkable and gratifying finding and really sets the stage for psilocybin as a treatment for major depression," senior investigator Roland Griffiths, PhD, Oliver Lee McCabe III Professor in the Neuropsychopharmacology of Consciousness, Johns Hopkins University School of Medicine, Baltimore, Maryland, said in a statement.

"Perhaps the most exciting aspect of this as a new therapy is that psilocybin works as a therapeutic intervention with a single session or a few sessions, and then the effects are enduring. In contrast, most conventional treatments for depression...are given chronically and also have chronic side effects," Griffiths, who is also director of the Johns Hopkins Center for Psychedelic and Consciousness Research, added.

The study was published online November 4 in JAMA Psychiatry.

Growing Evidence Base

As previously reported, psilocybin improves depressive symptoms for patients with cancer. However, these patients might be regarded as having a "reactive depression" to their life-threatening illness, said Griffiths.

"This study built on that previous research by asking the question, is psilocybin effective in patients who have major depressive disorder, [which is] a much larger population?" he said.

In addition, prior studies of psilocybin-assisted therapy had no control group, lead author Alan Davis, PhD, adjunct assistant professor in the Psychedelic Research Unit, Johns Hopkins University, told Medscape Medical News.

The researchers created a control condition by randomly assigning 24 individuals (mean age, 39.8 years[SD, 12.2 years]; 67% women) who were currently experiencing a moderate or severe major depressive episode to receive either immediate treatment (IT) (n = 13) or delayed treatment (DT) (n = 11).

Participants had long-standing depression, with a mean of 22.4 months in the current depressive episode. They were required to avoid using other antidepressants for 4 weeks prior to screening and up to 4 months following enrollment.

Patients were also required to be medically stable; have no personal/family history of psychotic or bipolar disorders; no past-year alcohol, substance, or nicotine use disorder; and no substantial lifetime or recent use of ketamine or classic hallucinogens.

Depression was measured using the Structured Clinical Interview for DSM-5 and the GRID-Hamilton Depression Rating Scale (GRID-HAMD). A baseline score of ≥17 was required for enrollment.

Participants received eight preparatory meetings with two session facilitators before the first psilocybin session and then 2 to 3 hours of follow-up meetings after the psilocybin sessions. In addition, they received 13 sessions of psychotherapy.

After completing these preparatory sessions, they underwent two psilocybin sessions, administered a mean of 1.6 weeks apart.

Participants in the DT group were assessed for depressive symptoms weekly for 8 weeks prior to entering the treatment protocol.

"Surprising" Findings

Participants in the IT group exhibited significantly lower depression scores on the GRID-HAMD at 1 and 4 weeks after the second psilocybin session in comparison with patients in the DT group during the corresponding weeks.

Group Baseline mean (SD) Week 5 mean (SD) Week 8 mean (SD)
IT 22.9 (3.6) 8.0 (7.1) 8.5 (5.7)
DT 22.5 (4.4) 23.8 (5.4) 23.5 (6.0)

Moreover, the effect sizes at weeks 5 and 8 were "large" (d = 2.2; 95% CI, 1.4 – 3.0; and d = 2.6; 95% CI, 1.7 – 3.6, respectively).

An analysis of outcomes showed that for all 24 participants, at 1 and at 4 weeks following the psilocybin intervention, 67% and 71% of participants, respectively, had a "clinically significant response" in depressive symptoms; 60% and 56%, respectively, met criteria for remission.

Within-subject t-tests likewise revealed significant decreases in depression scores from baseline to 1- and 4-week follow-ups (P < .001; d=3.6; 95% CI, 2.2 – 5.0; and P < .001; d = 3.6 95% CI, 2.2 – 4.9, respectively).

Importantly, participants experienced no serious adverse effects.

Griffiths said he was "surprised" by the findings. "We knew that psilocybin would be effective in reactive depression of the type associated with illness, but we did not know that this would be the case in the large number of individuals who qualify for having MDD [major depressive disorder]," he said.

Davis said the finding "represents a large effect of this treatment among people with major depressive disorder — an approximately 4 times larger effect compared to studies of antidepressant drugs."

Davis noted that psychotherapy was an "essential" component of the study protocol. "It is likely that the combination of psychotherapy and psilocybin is what makes this treatment efficacious and that this treatment will always have a psychotherapy component and will not be FDA-approved as a stand-alone medication."

Tipping Point

Commenting on the study for Medscape Medical News, Collin Reiff, MD, clinical assistant professor, Department of Psychiatry, New York University Grossman School of Medicine, New York City, noted that because psychedelics are "still stigmatized," the publication of this study in "one of the highest-impact journals in all of psychiatry suggests that research into psychedelics is now in the mainstream and that the academic psychiatry research community is paying close attention to what is happening." He described this as a "tipping point."

Reiff, who was not involved with the study, noted that research had been conducted on psychedelic compounds until the 1960s, "when they left the research lab and went mainstream, leading to the shutting down and subsequent dormancy of the research for the next 30 to 40 years."

Psychedelic research is "undergoing a renaissance and no longer regarded with as much skepticism, but it is important to take our time doing this research so we do not repeat what happened in the 1960s," said Reiff.

In an accompanying editorial, Charles F. Reynolds III, MD, endowed professor in geriatric psychiatry at the University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, questioned "for whom psychedelic-assisted psychotherapy is appropriate (or not), particularly in patients with depression who are suicidal of have a history of suicide attempt."

Reynolds, who is also director of the Aging Institute of UPMC, who was not involved with the study, wrote, "personalizing the management of depression has to entail an understanding of the multiple contexts in which depression occurs, including genetic, developmental, psychosocial, cultural, medical, neurocognitive, and spiritual."

The study was supported by a crowdsourcing campaign organized by Tim Ferris, as well as by grants from the Riverstyx Foundation. The Center for Psychedelic and Consciousness Research is funded by the Steven and Alexandra Cohen Foundation and receives support from Tim Ferriss, Matt Mullenweg, Craig Nerenberg, and Blake Mycoskie. It is also supported by grants from the National Institute on Drug Abuse. Davis received support from the National Institute on Drug Abuse. Griffiths was partially supported by a NIDA grant. Disclosures for the other authors are listed in the original article. Reiff reports owning stock in Compass Pathways. Reynolds reports no relevant financial relationships.

JAMA Psychiatry. Published online November 4, 2020. Full text, Editorial

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