by Carmen H. Li

Graphic design by Geneviève Groulx

In 2022, the Centre for Addiction and Mental Health (CAMH) received Canada’s first federal grant to study psilocybin, the active “magic mushrooms” component, for its therapeutic effect on treatment-resistant depression. The phase two trial titled “Does Psilocybin Require Psychedelic Effects to Treat Depression? (PSI-RIS)” investigates whether experiencing psilocybin’s psychedelic effects is necessary to have an antidepressant effect.¹ Though preliminary results are not yet available; investigators are confident that their study will inform future clinical trials with psilocybin. Also, given the psychedelic effects of psilocybin, investigating whether a psychedelic effect is necessary may increase treatment accessibility to patients with a history of psychosis and individuals who may be cautious of a negative psychedelic experience. 

Why is this remarkable? Several prior trials have reported that psilocybin has an antidepressant effect, particularly when delivered in combination with psychotherapy. ² 

Other recently published trials suggest that psilocybin can be as effective as other antidepressants. For example, the Psilodep-RCT study published in the New England Journal of Medicine in 2021, compared psilocybin to escitalopram for the treatment of moderate-to-severe major depressive disorder over a 6-week period. The study found that there was no significant difference in antidepressant effect between psilocybin and escitalopram in these patients.³ If psilocybin is still effective without causing a psychedelic state, it would make the therapeutic more accessible and remove the time and resource-intensive psychotherapeutic support during treatment administration. 

To backtrack, what exactly is psilocybin and how did it go from being popularized as recreational “magic mushrooms”, to being banned in the 60’s, to now being investigated as a therapeutic? 

To understand psilocybin’s effects, it’s helpful to understand how it interacts biochemically with the brain. The feature of interest is psilocybin’s ability to increase brain plasticity.² Psilocybin is a compound in fungi, commonly found in species of the genus Psilocybe. In the body, it is converted into psilocin which activates the 5 HT_2A serotonin receptors in the brain for its psychedelic effect. Notably, when the 5 HT_2A receptors are blocked pharmacologically such as with Buspirone, which is a 5 HT_2A  receptor agonist, there is an attenuation of psilocybin’s effects.² However, much of psilocybin’s effects on the brain are still not fully understood. As psilocybin is being researched, its mechanisms, dosages, and delivery with and without psychotherapies are being assessed for treating various mental health conditions.

If psilocybin is so impactful, why hasn’t it been investigated earlier? Humans have taken advantage of psychedelic compounds for spiritual and mental wellbeing since early civilization. For example, a 1000 CE dated ritual bundle belonging to a shaman of the pre-Inca Tiwanaku civilization in southwestern Bolivia held traces of cocaine metabolites, psilocin, and components of the psychedelic tea known as ayahuasca.⁴ Ancient Greeks and Romans conducted seasonal rites with a drink called kykeon, which contained fungi with LSD-like psychedelic alkaloids.⁵ In modern society, understanding the therapeutic potential of psilocybin and other psychedelic compounds has been a process of re-discovery. Psilocybin emerged in mainstream culture after amateur ethnomycologist R. Gordon Wasson and his partner Valentina P. Wasson, a physician, witnessed a Mazatec ritual use of psychoactive mushrooms in the Mexican village Huautla de Jimenez.⁶ 

Albert Hofmann, a Swiss chemist, was the first to isolate psilocybin from the mushroom Psilocybe mexicana in 1959, and the compound was later used in experimental research to investigate its psychotherapeutic use.⁷ However, restrictive drug laws in the 1960s and the ban on psychedelics by the United Nations Convention in 1971 halted research in this direction.⁷ Research interest re-emerged in the early 2000s, as clinical trials showed success for treatment-resistant depression and other mental health disorders, including alcoholism, substance use disorder, and obsessive compulsive disorder.^2,10 In 2023, Australia became the first country to legalize MDMA and psilocybin for post-traumatic stress disorder and treatment-resistant depression.⁹ In Canada, psilocybin is still only accessible through clinical trials, but there is a growing interest in wider accessibility. 

What lies in store for the future of psilocybin in medicine? Interestingly, psilocybin has also been investigated as a therapeutic for end-of-life anxiety and depression. In a double-blind, placebo-controlled pilot study, psilocybin was tested in 12 patients with various forms of advanced-stage cancer to reduce the psychological burden of a terminal diagnosis. Patients had a clinical diagnosis of acute stress disorder, generalized anxiety disorders, anxiety disorder due to cancer, or adjustment disorder with anxiety. In the study, psilocybin led to a significant decrease in survey-reported depression symptoms compared to placebo by the six-month follow-up visit.¹¹ Psychedelics including psilocybin, are also being investigated as potential treatments for neurodegenerative disorders, which highlights the exciting and unexplored potential of these therapeutics for neurological conditions and the subtle aspects of well-being, such as the end-of-life care.¹⁰

Of course, while this news is exciting, there are still many barriers ahead in developing psilocybin and other psychedelics into appropriate therapies. How will public perception and stigma affect future access to these therapeutics? Further research into the long-term effects of psilocybin therapy and risk factors for individuals with a history of psychotic disorders or comorbidities is still needed. Access barriers to mental health services may also undermine the development of new, more effective interventions. Despite these uncertainties, the resurgence of research and interest in psilocybin still proves to be a step in a hopeful direction to navigate our present-day mental health crisis.

References

1. Husain MI, Blumberger DM, Castle DJ, et al. Psilocybin for treatment-resistant depression without psychedelic effects: study protocol for a 4-week, double-blind, proof-of-concept randomised controlled trial. BJPsych Open. 2023 Jul;9(4):e134. 

2. Sarparast A, Thomas K, Malcolm B, et al. Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review. Psychopharmacology. 2022 Jun;239(6):1945-76.

3. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine. 2021 Apr 15;384(15):1402-11.

4. Miller MJ, Albarracin-Jordan J, Moore C, et al. Chemical evidence for the use of multiple psychotropic plants in a 1,000-year-old ritual bundle from South America. Proceedings of the National Academy of Sciences. 2019 Jun 4;116(23):11207-12.

5. Samorini G. The oldest archeological data evidencing the relationship of Homo sapiens with psychoactive plants: A worldwide overview. Journal of Psychedelic Studies. 2019 Jun;3(2):63-80.

6. Wasson RG. The hallucinogenic fungi of Mexico: an inquiry into the origins of the religious idea among primitive peoples. Botanical Museum Leaflets, Harvard University. 1961 Feb 17;19(7):137-62.

7. Hofmann A, Heim R, Brack A, et al. Psilocybin und Psilocin, zwei psychotrope Wirkstoffe aus mexikanischen Rauschpilzen. Helvetica Chimica Acta. 1959;42(5):1557-72.

8. Nutt D, Carhart-Harris R. The current status of psychedelics in psychiatry. JAMA psychiatry. 2021 Feb 1;78(2):121-2.

9. Ritchie OD, Donley CN, Ritchie GD. From prohibited to prescribed: The rescheduling of MDMA and psilocybin in Australia. Drug Science, Policy and Law. 2023 Sep;9:20503245231198472.

10. Kozlowska U, Nichols C, Wiatr K, et al. From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders. Journal of Neurochemistry. 2022 Jul;162(1):89-108.

11. Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of general psychiatry. 2011 Jan 3;68(1):71-8.