Magic is in the air, at least in the medical community. Psilocybin - the psychedelic component in magic mushrooms - has entered a renaissance as a therapeutic approach to mental health disorders. This article will discuss what psilocybin is, its history, and how it’s opening up a different space in medicine.
Psilocybin is a psychoactive substance that alters perception, mood, and cognitive processes. How does it work? When consumed, psilocybin, a prodrug, is metabolized via dephosphorylation into psilocin19. Without a phosphate group, psilocin is more lipid-soluble than psilocybin and is therefore more metabolically available, having the ability to cross the blood-brain barrier. Due to their similar metabolic patterns, psilocybin and psilocin are often discussed together19. Both components are structurally similar to “feel-good” neurotransmitters serotonin and norepinephrine, and these molecules therefore have an affinity towards these same receptors and over-stimulates them20. Other derivatives include norpsilocin, baeocystin, norbaeocystin, and aeruginascin, which vary in amounts depending on the species. Psilocybin’s effects usually surface within 30-40 minutes post-digestion, but can take as long as an hour.
Psilocybin has been used for centuries by various populations, including the Aztecs of Mexico, who used magic mushrooms - teonanácatl, meaning “God’s flesh” - in sacramental healings and rites. Along with other psychotropics, magic mushrooms were used to induce a trance and communicate with the goods. In the 1950s, psilocybin and LSD were studied as being comparable to alcoholism. During this same decade, mushroom enthusiast Gordon Wasson had come back from his Mexican vacation with psychoactive drugs. He brought the magic mushrooms to Albert Hofmann, the chemist who had discovered LSD; under his lab at Sandoz Pharmaceuticals, Hofmann then isolated psilocybin and produced 2 mg pills for research purposes6. Hofmann’s synthesis of psilocybin opened the door for future clinical researchers driving the current medicinal “shroom boom”. When the 1960s rolled in with a wave of counterculture, psilocybin also gained a notorious reputation in the sensationalized media as causing suicide and accidental death. In 1970, Congress passed the Controlled Substances Act (CSA), which classified psilocybin, along with other drugs, as having a high risk of “drug abuse and drug dependence” and no accepted medical use3. By virtue of this act, psilocybin and psilocin are categorized as Schedule 1 drugs, illegalizing the cultivation or possession psilocybin-producing mushrooms for either personal consumption or distribution; scientific research under tightly-controlled conditions, however, was and is allowed. While medical research on this psychedelic was legal and suggested potential for psychotherapeutic effectiveness, psilocybin’s negative media coverage, coupled with a lack of modern medical methodological rigor, essentially ceased its continuation11. In 1992, the National Institute on Drug Abuse worked with a Food and Drug Administration advisory committee that ultimately allowed for the resumption of research of psychedelic agents17. Recently, in 2019, Johns Hopkins established its $17 million-funded Center for Psychedelic and Consciousness Research, where researchers aim to evaluate psilocybin as a therapy for ailments ranging from post-traumatic stress disorder to opioid addiction.
Psilocybin therapy is offering some hope for certain conditions that seemed to reach dead-ends. For a drug that was painted to cause suicide, recent results from epidemiological studies point otherwise: there are lower rates of mental health disorders and suicide among people who have used psychedelics like psilocybin11. Psilocybin has shown to improve inner peace, patience, good-natured humor/playfulness, interpersonal regard, anger, and compassion8, and may facilitate processing of prior trauma by enhancing recall of autobiographical memories4. Several studies support psilocybin as a legitimate and promising way to treat issues. In 2016, Johns Hopkins Medicine researchers reported that a psilocybin treatment under psychologically supported conditions significantly relieved existential anxiety and depression in people with a life-threatening cancer diagnosis14. So far, psilocybin has been shown to improve mood among people with anxiety disorders9, decrease alcohol dependency1, and cease tobacco addiction12.
More recently, another Johns Hopkins study found that psilocybin can be applied to a wider net of people. The study accounted for 24 participants, in which 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 no longer qualified as being depressed. “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, Ph.D., adjunct assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine14. Though several types of major depressive disorders were included in the study, most participants found the psilocybin treatment to be effective. In neurobiological terms, many neurological issues - from major depression to addiction - are associated with an increased 5-HT2A receptor density in the prefrontal cortex. Psychedelics down-regulate this receptor, which may reduce limbic - parts of the brain related to emotion and motivation - hyperactivity6. While psilocybin certainly appears to have some efficacy as an alternative agent to managing mental health conditions, it is worth noting that these studies are often done with a small group and in tightly controlled environments due to its CSA Schedule I classification. Future research on psilocybin should move towards more robust studies to determine its true clinical utility and application.
At this point, some may wonder what the difference would be between taking a traditional pharmaceutical drug and psilocybin. Aside from psilocybin being more effective in treating depression as per the Johns Hopkins study, psilocybin can lead to enduring meaning and belief changes after experiencing it. According to Johns Hopkins neuropharmacologist Roland Griffiths, “it’s almost like reprogramming the operating system of a computer”5.
Part of this “reprogramming” takes the form of ego death, or a distortion of the sense of self in response to psychedelics. A hallmark study by Griffiths et. al found that when psilocybin was “administered under a comfortable, structured, interpersonally supported conditions to volunteers who reported regular participation in religious or spiritual activities, occasioned experiences which had marked similarities to classic mystical experiences and which were rated by volunteers as having substantial personal meaning and spiritual significance” 8. The volunteers who felt this mystical experience also sustained positive changes in attitudes and behavior that were consistent with changes rated by friends and family. Some people react positively to the experience, as if being more connected to the world. For others, it’s anxiety provoking due to a sense of losing control. One study examined the role of glutamate, the principal excitatory neurotransmitter in the central nervous system, in the acute action of psilocybin on brain and behavior; a glutamate increase in the medial prefrontal cortex predicted a negative ego dissolution experience, while a glutamate decrease in the hippocampus predicted a positive experience13. The hippocampus is where autobiographical information is stored, so less glutamate in this area could mean that people lose access to this part of it during a mushroom trip. This study demonstrates the complexity of psilocybin, and how the response of the brain might be different depending on the person.
So, how about safety? Psilocybin mushrooms are also considered to be one of the least toxic drugs known, with the risks from psilocybin being more dependent on set and setting15. Common reactions include dilated pupils, elevated blood pressure, and increased heart rate, though this depends often from person to person. Long-term physical effects attributed to the pharmacology of psilocybin are rare, though Hallucinogen Persisting Perception Disorder (HPPD) - recurrences of certain drug experiences - is possible. Contrary to popular thought, psilocybin is not considered to be addictive, and no overdose deaths have occurred after ingestion of typical doses of psilocybin10,16.
This marks an exciting time in management of mental health conditions, as psilocybin’s potential is being investigated. Since 2015, Netherlands ablizes psilocybin retreats, which often cater to affluent tourists2. This style retreat was recently reflected in the American television show, Tranquillium, which featured psilocybin as a way of interacting and making peace with those who have died. Even Gwyneth Paltrow's Netflix show, The Goop Lab, featured a psilocybin retreat in Jamaica. In the United States, certain areas - like Oakland, Denver, Ann Arbor and Washington, D.C. - have loosened their restrictions in an attempt to decriminalize psilocybin for legal therapeutic usages. Recently, Oregon passed the Psilocybin Therapy Ballot Measure by more than 1.2 million votes (55.7 percent). “Our goal was to move psilocybin out of the medical framework [to also include counseling therapists, not just doctors] so we could provide access to anyone who might safely benefit,” therapist Tom Eckert, co-author of the bill, told Scientific American. Now, pharmaceutical and health companies are looking into ways to make psilocybin. One of the main advantages of synthetic, pharmaceutical psilocybin is its precision and reproducibility in dosing. Since mushrooms generally grow in meadows and even manure, pharmaceutical-made psilocybin can provide more consistency, both in production volume and potency7. Recently, Optimi Health Corp. has discovered a novel, high yielding extraction technique that is in the patent process18. Other companies like Cybin, a Canadian life sciences startup focused on developing psychedelic pharmaceutical products to treat mental disorders, raised $34-million to fund clinical trials21. These recent measures indicate that psilocybin will soon occupy a greater space in our conversations and actions around addressing mental health.
Works Cited
[1] Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa P, Strassman RJ. (2015). Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. Journal of Psychopharmacology. 29(3), 289- 99. DOI: 10.1177/0269881114565144.
[2] Berlinger, M. (2021, August 15). All-Inclusive Magic Mushroom Retreats Are the New Luxury ‘Trips.’ Bloomberg. https://www.bloomberg.com/news/articles/2021-08-19/all-inclusive-magic-mushroom-ayahuasca-retreats-are-new-luxury-trips
[3] Bureau of Narcotics and Dangerous Drugs, Controlled substances inventory list: Subject to the controlled substances act of 1970 (public law 91-513) (1970). Washington.
[4] Carhart-Harris RL, Leech R, Williams TM, et al. (2012). Implications
for psychedelic-assisted psychotherapy: Functional magnetic resonance imaging study with psilocybin. British Journal of Psychiatry, 200, 238–244.
[5] Cormier, Z. (2020, December 1). Psilocybin Treatment for Mental Health Gets Legal Framework. Scientific American. https://www.scientificamerican.com/article/psilocybin-treatment-for-mental-health-gets-legal-framework/
[6] Drug Policy Alliance. (2017, January). Psilocybin Mushrooms Fact Sheet. https://drugpolicy.org/sites/default/files/Psilocybin_Mushrooms_Fact_Sheet.pdf
[7] Dubey, G. (2021, August 6). Pharmaceutical Psilocybin: What Is It & How is it Impacting the Industry. Microdose. https://microdose.buzz/news/pharmaceutical-psilocybin-what-is-it-how-is-it-impacting-the-industry/
[8] Griffiths RR, Richards WA, McCann U, et al. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology 187, 268–283.
[9] Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, et al. (2011). Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 68(1), 71- 8. DOI: 10.1001/archgenpsychiatry.2010.116.
[10] Hallucinogens DrugFacts. (2021, June 30). National Institute on Drug Abuse. https://www.drugabuse.gov/publications/drugfacts/hallucinogens
[11] Hendricks, Peter & Thorne, Christopher & Clark, Charles & Coombs, David & Johnson, Matthew. (2015). Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population. Journal of psychopharmacology (Oxford, England). 29. 10.1177/0269881114565653.
[12] Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR. (2014). Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol. 28 11: 983- 92. DOI: 10.1177/0269881114548296.
[13] Mason, N.L., Kuypers, K.P.C., Müller, F. et al. (2020). Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin. Neuropsychopharmacol. 45, 2003–2011. https://doi.org/10.1038/s41386-020-0718-8
[14] McMain, V. (2020, October 29). Psychedelic Treatment with Psilocybin Shown to Relieve Major Depression. Johns Hopkins Medicine. https://www.hopkinsmedicine.org/news/articles/psychedelic-treatment-with-psilocybin-shown-to-relieve-major-depression
[15] Nichols, David E. "Hallucinogens." (February 2004). Pharmacology & Therapeutics 101(2), 131-81. doi: 10.1016/j.pharmthera.2003.11.002.
[16] Nichols D. E. (2016). Psychedelics. Pharmacological reviews, 68(2), 264–355. https://doi.org/10.1124/pr.115.011478
[17] Nichols D. E. (2014). The Heffter Research Institute: past and hopeful future. Journal of psychoactive drugs, 46(1), 20–26. https://doi.org/10.1080/02791072.2014.873688
[18] Optimi Health Corp. (2021, October 5). Optimi Health Natural Psilocybin Extraction Breakthrough Submitted for Provisional Patent Application. GlobeNewswire News Room. https://www.globenewswire.com/news-release/2021/10/05/2308824/0/en/Optimi-Health-Natural-Psilocybin-Extraction-Breakthrough-Submitted-for-Provisional-Patent-Application.html
[19] Psilocybin. (2021, September 21). Psychedelic Science Review.
https://psychedelicreview.com/compound/psilocybin/
[20] University of Bristol, School of Chemistry. (n.d.). Psilocybin - Molecule of the Month. Retrieved October 13, 2021, from http://www.chm.bris.ac.uk/motm/psilocybin/psilocybinv.htm
[21] Yakowicz, W. (2020, October 25). Pharmaceutical Startup Developing Sublingual Psilocybin Raises $34 Million To Fund Clinical Trials. Forbes. https://www.forbes.com/sites/willyakowicz/2020/10/22/pharmaceutical-startup-developing-sublingual-psilocybin-raises-34-million-to-fund-clinical-trials/amp/