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A small study of adults with major depressive disorder (MDD) by Johns Hopkins Medicine researchers has found that two doses of a psychedelic compound found in “magic mushrooms,” can produce large reductions in depressive symptoms, when administered with supportive psychotherapy. The randomized, waiting list-controlled clinical trial involved 24 participants diagnosed with MDD, who weren’t using other antidepressant medicines during the trial. The results showed that psilocybin-assisted therapy led to improvements in most of the patients, with half of the study participants achieving remission through the four-week follow-up.

“The magnitude of the effect we saw was about four times larger than what clinical trials have shown for traditional antidepressants on the market,” said Alan Davis, PhD, adjunct assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “Because most other depression treatments take weeks or months to work and may have undesirable effects, this could be a game changer if these findings hold up in future ‘gold-standard’ placebo-controlled clinical trials.”

The researchers, reporting on their study in JAMA Psychiatry, suggest that psilocybin may be effective in the much wider population of patients who suffer from major depression than previously appreciated. Their paper is titled, “Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder. A Randomized Clinical Trial.”

Major depressive disorder (MDD) affects more than 300 million individuals worldwide, and is a “substantial public health concern,” the authors wrote. “In the United States, approximately 10% of the adult population has been diagnosed with MDD in the past 12 months, and the yearly economic burden of MDD is estimated to be $210 billion.”

Current drug treatments for depression have limited efficacy, and are associated with adverse side effects, which can lead patients to stop taking them, the researchers continued. Most of the drugs currently used—including selective serotonin reuptake inhibitors (SSRIs)—increase levels of the brain neurotransmitters serotonin and norepinephrine. More recently, increasing evidence has suggested that newer, ketamine-like drugs have therapeutic efficacy in MDD through their effects on glutamate neurotransmission. However, the team pointed out, ketamine has a high abuse liability, and its use can be associated with moderate physiological risk that needs to be monitored. Given the public health impact of MDD, much more research into drugs with rapid and sustained antidepressant effects is needed. “Novel antidepressants with rapid and sustained effects on mood and cognition could represent a breakthrough in the treatment of depression and may potentially improve or save lives.”

Psilocybin, a compound found in magic mushrooms, produces visual and auditory hallucinations and profound changes in consciousness over a few hours after ingestion. In 2016, Johns Hopkins Medicine researchers first reported that treatment with psilocybin under psychologically supported conditions significantly relieved existential anxiety and depression in people with a life-threatening cancer diagnosis. The compound demonstrates combined serotonergic and glutamatergic activity, and the early evidence of its antidepressant effects suggests the potential for psilocybin-assisted therapy as a novel approach to treating depression, the team commented. “Moreover, psilocybin has lower addiction liability and toxic effects compared with ketamine and is generally not associated with long-term perceptual, cognitive, or neurological dysfunction.”

For the new study, the team recruited 24 people with a long-term documented history of depression, most of whom experienced persisting symptoms for approximately two years before enrolling in the study. The average age of participants was 39 years; 16 participants were women. Participants had to taper off their use of any other antidepressants prior to the study, with the help of their personal physician to ensure safe exposure to this experimental treatment.

Thirteen participants received the psilocybin treatment immediately after recruitment and after preparation sessions, and 11 participants received the same preparation and treatment after an eight-week delay. Treatment consisted of two psilocybin doses given by two clinical monitors who provided guidance and reassurance. The doses were given two weeks apart between August 2017 and April 2019 at the Johns Hopkins Bayview Medical Center Behavioral Biology Research Building. Each treatment session lasted approximately five hours, with the participant lying on a couch wearing eyeshades and headphones that played music, in the presence of the monitors.

All participants were given the GRID-Hamilton Depression Rating Scale – a standard depression assessment tool—when they enrolled into the trial, and then at one week, and four weeks following completion of their treatment. On the scale, a score of 24 or more indicates severe depression, 17–23 indicates moderate depression, 8–16 mild depression, and 7 or less no depression. At enrollment, participants had an average depression scale rating of 23, but one week and four weeks after treatment, they had an average depression scale score of 8. After treatment, most participants showed a substantial decrease in their symptoms, and almost half were in remission from depression at the follow-up. Participants in the delayed group didn’t show decreases in their symptoms before receiving the psilocybin treatment.

For the entire group of 24 participants, 67% showed a more than 50% reduction in depression symptoms at the one-week follow-up and 71% at the four-week follow-up. Overall, four weeks post-treatment, 54% of participants were considered in remission—meaning they no longer qualified as being depressed.

“Because there are several types of major depressive disorders that may result in variation in how people respond to treatment, I was surprised that most of our study participants found the psilocybin treatment to be effective,” said Roland Griffiths, PhD, the Oliver Lee McCabe III Professor in the Neuropsychopharmacology of Consciousness at the Johns Hopkins University School of Medicine, and director of the Johns Hopkins Center for Psychedelic and Consciousness Research. Griffiths, whose research with psilocybin started in the early 2000s, suggested that the major depression treated in the new study may have been different when compared with the “reactive” form of depression in patients they studied in a 2016 cancer trial. He further noted that his team was encouraged by public health officials to explore psilocybin’s effects in the broader population of those with major depressive disorder because of the much larger potential public health impact.

The researchers say they will follow the participants for a year after the study to see how long the antidepressant effects of the psilocybin treatment last, and will report their findings in a later publication. “This randomized clinical trial documented the substantial rapid and enduring antidepressant effects of psilocybin-assisted therapy among patients with MDD,” the authors concluded. “The present trial showed that psilocybin administered in the context of supportive psychotherapy (approximately 11 hours) produced large, rapid, and sustained antidepressant effects … The effectiveness of psilocybin therapy after a single or only a few administrations represents another substantial advantage over commonly used antidepressants that require daily administration.”

The team acknowledged that there were some limitations to their study, including short-term follow-up, and small sample size, and say further research with larger, more diverse patient populations, longer-term follow-up, and placebo control, will be needed to better investigate the safety (including abuse potential of psilocybin, suicide risk, and emergence of psychosis) and efficacy of psilocybin therapy among patients with MDD. Nevertheless, they wrote. “These data expand the findings of previous studies involving patients with cancer and depression as well as patients with treatment-resistant depression by suggesting that psilocybin may be effective in the much larger population of MDD. Further studies are needed with active treatment or placebo controls and in larger and more diverse populations.”

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