Mushrooms for Depression

Having fallen out of favor over 50 years ago, scientific research investigating the therapeutic potential of psychedelic drugs is in the midst of a captivating second wave.

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“The psychedelic renaissance” has seen an explosion of research in recent years after a frustrating decades-long pause, and psychedelic compounds like psilocybin, the active ingredient in so-called “magic mushrooms,” LSD, and DMT are once again being treated with a level of respect that is justified by their healing potential. 

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One is tempted to bemoan the introduction of the Controlled Substances Act of 1970 which placed all classic psychedelics in schedule 1, putting an abrupt halt to psychedelic research and placing a stubborn barrier in the way of further scientific exploration.

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Described as the “worst censorship of scientific research in history” by esteemed neuropsychopharmacologist and Imperial College London researcher Dr. David Nutt, the prolonged impact of prohibition has undoubtedly created a gap in our understanding of the therapeutic potential of psychedelic drugs.

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Thankfully, a new generation of skilled psychedelic researchers are providing many reasons to be optimistic. Scientists at research institutions around the world have taken the reins with a keen eye to resurrecting the psychedelic science of the ‘50s and ‘60s. 

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Specifically, researchers are investigating the potential of psychedelic medicines to treat a variety of health conditions including end-of-life anxiety, depression, post-traumatic stress disorder, substance use disorders, and chronic pain. 

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This renewed interest in psychedelic medicine comes at a rather convenient time as traditional antidepressants, despite being helpful for some, continue to insufficiently address skyrocketing rates of anxiety, depression, and addiction, and the crushing despair that so often accompanies such afflictions. 

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How Psilocybin Sparked the Psychedelic Renaissance

A 2006 publication on the safety and enduring positive effects of a single dose of psilocybin is widely considered a watershed moment that catalyzed the revival of psychedelic research. 

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In this study, 67% of healthy participants rated their psilocybin experience to be either the single most meaningful experience of their entire lives or among the top five.

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Johns Hopkins recently launched their very own first-of-its-kind Center for Psychedelic and Consciousness Research that focuses on the effects of psychedelics on brain functioning and mood in both healthy individuals and those affected by psychiatric disorders.

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Psilocybin, which has been shown to reliably induce “mystical-type experiences” commonly characterized by profound alterations of consciousness and a profound sense of the unity or interconnectedness of living things, has since demonstrated therapeutic efficacy for the treatment of depression.

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Psilocybin’s active metabolite psilocin binds to 5-HT2A serotonin receptors widely expressed in brain areas involved in learning and cognition that have been implicated in several psychiatric illnesses. Psilocin’s activation of this receptor elicits a psychedelic experience that appears to correlate with the disruption of self-defeating, ruminative thought patterns and firmly held, futile beliefs associated with depression. 

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Psilocybin for Depression: What Does the Research Say? 

Since the publication of their landmark 2006 paper, Johns Hopkins scientists have continued to publish encouraging research, including a 2016 study demonstrating the efficacy of psilocybin-assisted psychotherapy to significantly reduce symptoms of depressed mood and anxiety and to enhance the quality of life in patients with a life-threatening cancer diagnosis. 

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This study extended earlier psilocybin research in which psilocybin was also shown to reduce symptoms of depression and anxiety related to end-stage cancer patients. 

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Also in 2016, psychedelic researchers across the pond at Imperial College London were investigating the feasibility of psilocybin-assisted therapy to treat a cohort of patients with treatment-resistant depression who, on average, had been depressed for 17.8 years. Their study reported reductions in depression that remained significant at 6 month follow-up, and, in so doing, provided preliminary support for the efficacy of psilocybin for treatment-resistant depression. 

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Imperial launched their own Psychedelic Research Center in 2019, and have since conducted landmark studies that could lay the foundations for a paradigm shift in mental health treatment.

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Psilocybin vs. Escitalopram 

In addition to reporting positive effects of psilocybin on depression and well-being in individuals diagnosed with an eating disorder, Imperial researchers conducted the first-ever double-blind, randomized, controlled trial comparing the therapeutic effects of psilocybin and escitalopram (Cipralex/Lexapro), an established antidepressant medication. 

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Although psilocybin outperformed escitalopram on the primary outcome measure, the QIDS-SR-16 depression scale, the difference between the two interventions was not statistically significant. However, psilocybin convincingly outperformed escitalopram in all secondary outcomes which included three alternative depression inventories, an emotional breakthrough inventory, and wellbeing scores, as well as reductions in suicidal ideation, anxiety, anhedonia, and sexual dysfunction. 

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Recent Results: Strong Reductions in Depressive Symptoms 

The research team at Johns Hopkins have also continued to inspire hope in people with depression. A randomized trial published last year investigating psilocybin’s efficacy for the treatment of Major Depressive Disorder (MDD) reported substantial and fast-acting antidepressant effects that were durable for at least 12 months — producing a therapeutic effect approximately four times larger than that typically seen with traditional antidepressants. 

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Most recently, biotech company Compass Pathways published positive results from their phase 2b trial investigating the efficacy of their proprietary psilocybin formulation — COMP360 — for treatment-resistant depression in the New England Journal of Medicine.

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In what is the largest peer-reviewed psilocybin therapy clinical trial published to date, 25 mg of psilocybin, administered in conjunction with psychological support, produced statistically significant reductions in depression compared to placebo (1 mg psilocybin). 3 weeks after the psilocybin session, 37% of participants were observed to have responded to treatment and 29% were in remission. 

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Though expected considering the nature of both the intervention and the treatment population, findings were somewhat marred by the high occurrence of adverse serious events among participants — the direct cause of which is likely to be determined by future research. For now, Compass Pathways plans to advance with their Phase 3 program consisting of two concurrent randomized, placebo-controlled clinical trials involving over 900 participants across 14 countries. 

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Most recently, researchers at the University of Zurich, Switzerland showed that a single, moderate dose of psilocybin significantly reduces depressive symptoms compared to a placebo condition for at least two weeks. 54% of participants that received psilocybin were observed to be in remission at the end of treatment according to the criteria of the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS). 

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The Therapeutic Context of Psychedelic-assisted Psychotherapy

The critical importance of the environment in which psychedelic-assisted psychotherapy takes place cannot be understated. The healing power of psilocybin is optimized when it is used as an adjunct to psychotherapy in a controlled therapeutic context following carefully designed safety protocols. 

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Of course, there may be instances where uncontrolled recreational use spontaneously initiates profound healing effects, but uncontrolled use outside of a therapeutic environment could do more harm than good, particularly for inexperienced users.  

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Perhaps one of the greatest obstacles facing the progression of psychedelic medicine is attributing its healing effects to the drug alone. It is important to highlight the controlled therapeutic context as a core element of psychedelic-assisted psychotherapy that is foundational to positive outcomes. 

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For instance, hours of preparatory therapy sessions take place in the lead-up to the psilocybin experience allowing patients to develop a rapport with their therapist that is based on mutual trust, openness, and understanding. 

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True healing can only take place when patients feel safe enough to surrender to the experience and voluntarily confront unconscious memories and arising sensations that may be unpleasant or uncomfortable, and embrace awesome realizations of interconnectedness and belonging. 

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During psilocybin sessions, participants lay on a couch wearing eye shades and headphones playing a carefully curated music playlist that is geared towards easing tension and promoting healing. This takes place in the presence of a co-therapy team that is trained to identify the most appropriate time for offering words of reassurance and encouragement. 

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In the weeks after psilocybin sessions, patients are invited back to the therapist's office for integrative therapy sessions. This helps patients to consolidate meaningful insights and supports the integration of fresh perspectives into their lives. 

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Integrative therapy sessions also help patients to make sense of any confusing or frightening phenomena that may have surfaced during their psychedelic experience. 

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Is Psilocybin-assisted Psychotherapy on the Horizon? 

Due to growing evidence indicating that psilocybin may demonstrate improvement over other available depression treatments, the US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to psilocybin for both Major Depressive Disorder and Treatment-Resistant Depression. Breakthrough therapy status is intended to accelerate the study and development of drugs that are intended to treat serious illnesses. 

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Clinical trials (which can be found here) exploring psilocybin’s antidepressant potential — currently the only setting in which psilocybin-assisted therapy can be legally administered in the United States — are ongoing all over the world. Should clinical trials continue to produce consistently positive outcomes, psilocybin-assisted therapy may soon become an FDA-approved treatment for depression.

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Notably, the states of Oregon and Colorado recently legalized the “supported adult use” of psilocybin for people 21 and over, allowing adults to access supervised psilocybin sessions without a mental health diagnosis. Interestingly, professional training in medicine, mental health, or related fields is not required of guides and facilitators at these state-licensed psilocybin service centers. 

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In the meantime, researchers need to emphasize the equal importance of the therapeutic process and the drug, not only in psilocybin treatments, but psychedelic-assisted psychotherapy across the board. Psilocybin is a powerful tool that, used responsibly, in a therapeutic context, can catalyze life-changing healing journeys.

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