Psilocybin Shows Promising and Sustained Antidepressant Effects in Patients With Major Depressive Disorder

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One 25-mg dose of psilocybin administered with psychological support is enough to cause a “large, rapid, powerful drop” in depressive symptoms among patients with major depressive disorder.

BERLIN—One 25-mg dose of psilocybin administered with psychological support is enough to cause a “large, rapid, powerful drop” in depressive symptoms among patients with major depressive disorder (MDD)—demonstrating tangible benefits for this psychedelic agent found in more than 200 species of mushrooms.

That’s the conclusion of a phase 2 trial published on August 31, 2023, in JAMA and announced the next day by Charles L. Raison, MD, at the INSIGHT 2023 conference in Berlin, Germany.1 Dr. Raison is Director of Clinical and Translational Research at Usona Institute and Professor of Human Ecology and Psychiatry at the University of Wisconsin–Madison. Usona Institute is a medical research nonprofit organization founded in 2014 to further the scientific understanding and the therapeutic application of consciousness-expanding medicines.

Charles L. Raison, MD, presents findings from his latest study at at the INSIGHT 2023 conference in Berlin, Germany.
Credit: Larry Luxner

“We at Usona have a profound interest in [MDD]. It’s a larger population than treatment-resistant depression, and so there’s a huge unmet medical need not just in people who have failed traditional antidepressants, but in all patients struggling with depression,” Dr. Raison said. “A lot of people who are depressed have more and more episodes, and they become more resistant to treatments. You begin to dig a hole that is very hard to get out of or to feel good about. Many of these people have issues that would depress you, too. A psychedelic like psilocybin may, in the future, offer new hope for preventing this type of worsening disease pattern.”

A Worldwide Need

Dr. Raison spoke to conference attendees in Berlin on September 1, 2023, in a presentation titled “Latest Developments in Clinical Studies for Depression.”

“Depression is not a little bitty condition, but something that afflicts millions around the world—and that by all measures appears to be worsening,” Dr. Raison said.

“I’ve become increasingly concerned that our standard antidepressants can change how the brain functions over time,” he said. “Long-term use of antidepressants appears to make people dependent on them, partly because the brain changes. So, if you stop it, you’re at much greater risk of relapse.”

He cited a 2016 study on the use of psilocybin to treat anxiety and depression in patients with life-threatening cancer.2 In the study, Dr. Raison noted that of 29 patients treated with a single dose of psilocybin, 19 were no longer clinically depressed 6 months after that single dose. Significantly, 16 of the 29 were still alive 4.5 years later.

“I think there’s increasing evidence to suggest that some conditions are going to be more amenable to a sustained response to psychedelics than others,” he said. “In this case, these cancer patients did not have depression before their [cancer] diagnosis.”

Promising Results With Sustained Effects

Dr. Raison conducted his latest study, “Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial,” between December 2019 and June 2022. The study involved 11 sites across 10 states and included a total of 104 patients.1 Participants—all of whom had been diagnosed with moderate or severe MDD on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition index—were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support.

“We took people with MDD, gave them 6 to 8 hours of therapy preparation, and then gave them either a 25-mg dose of psilocybin or 100 mg of niacin. We had 51 people in the psilocybin group and 53 in the niacin group, evenly divided between men and women, and overwhelmingly white,” he said. “Only 13% had treatment-resistant depression.”

What he found was “significantly reduced scores” on the Montgomery-Asberg Depression Rating Scale among patients taking psilocybin compared with patients taking niacin from baseline to day 43. No serious treatment-emergent adverse effects were reported, although psilocybin did lead to a higher rate of severe adverse effects than niacin.

“We don’t know what would have happened after 6 weeks, but the effect [of psilocybin] was larger at 6 weeks than at 1 week,” Dr. Raison said. “People were less anxious and had better quality of life, with generally mild adverse effects—mainly headache and nausea. Everybody benefited from this.”

Looking Forward

Asked what’s next, Dr. Raison described the pending inauguration of the Usona Institute campus on a 17-acre wooded landscape in Fitchburg, Wisconsin. The building is scheduled to open in late 2023. It is described on the Usona website as the world’s first facility designed specifically for the scientific study of the therapeutic effects of psychedelic drugs.

“This will be a place of convening, treatment, and research, a unique resource for the world,” he said. “Every time I go in it, my depression score drops significantly.”


  1. Raison CL, Sanacora G, Woolley J, et al. Single-dose psilocybin treatment for major depressive disorder: a randomized clinical trial. JAMA. 2023;330(9):843-853. doi:10.1001/jama.2023.14530
  2. Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30(12):1165-1180. doi:10.1177/0269881116675512