Psilocybin therapy

Psilocybin therapy is the use of psilocybin (the psychoactive ingredient in psilocybin mushrooms) in treating a range of mental health conditions, such as depression, anxiety, addictions,^[1] obsessive compulsive disorder, and psychosis.^[2] It is one of several forms of psychedelic therapy under study. Psilocybin was popularized as a psychedelic recreational drug in the 1970s and was classified as a Schedule I drug by the DEA. Research on psilocybin as a medical treatment was restricted until the 1990s because of the sociocultural fear of dependence on this drug. As of 2022, psilocybin is the most commonly researched psychedelic due to its safety and low potential for abuse and dependence.^[2] Clinical trials are being conducted at universities and there is evidence confirming the use of psilocybin in the treatment of depression, PTSD and end of life anxiety.^[3]

Psilocybin-containing mushrooms

History

The first historical record of psilocybin use dates back to Mesoamerica. A Codex known as the "Yuta Tnoho" that belonged to the Mixtec culture in the 1500s BCE depicted religious ritual ingestion of psilocybin-containing mushrooms.^[1]

Ritualistic consumption of psilocybe mushrooms continues into modern spiritual and medicinal practice. The hallucinations produced by the psilocybin induces a trance-like state that is believed to allow the soul to disconnect from the body, resulting in healing and spiritual enlightenment.^[1]

In 1959, Albert Hofmann, a Swiss chemist, was the first person to extract pure psilocybin from the mushroom Psilocybe mexicana. Sandoz, the company that employed Hofmann, then began to sell the active compound to clinicians as an aid in psychedelic psychotherapy.^[4]

Albert Hofmann's discovery of psilocybin played a pivotal role in catalyzing the Psychedelic Era, a cultural phenomenon that unfolded during the 1960s and 1970s. This era witnessed significant societal, musical, and artistic transformations, many of which were heavily influenced by the use of psychedelic substances, including psilocybin. At this time though, there was very little known about psychedelics and their long-term effects

In August 1960, Timothy Leary conducted a self-experiment using psilocybin mushrooms. After trying pure, extracted psilocybin, he and Dr. Richard Alpert tested whether it could help reduce recidivism rate and constitute an effective psychotherapy aid. In 1963, Leary and Alpert were suspended from their jobs at Harvard University, due to irresponsible and dangerous experimentation with psilocybin mushrooms.^[5] Psilocybin research in the United States ended in 1970 when the use and possession of psilocybin mushrooms became illegal.^[6][4]

In 2018–19, the United States Food and Drug Administration (FDA) granted breakthrough therapy designation to facilitate further research for psilocybin in the possible treatment of depressive disorders.^[7]

Neuroscience and Pharmacology

Psilocybin is the main psychoactive compound in the mushroom genus Psilocybe. Psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine) and its active metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine) are part of a group of tryptamine/indolamine hallucinogens that are related to serotonin. In the GI tract psilocybin is converted to psilocin. Psilocyn is a selective agonist of the 5HT receptors, specifically 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C.^[8] Nausea, vomiting, muscle weakness, and lack of coordination are some of the physical side effects. Hallucinations and an inability to distinguish fiction from reality are among the psychological effects of psilocybin use. Panic attacks and psychotic-like episodes are also possible, especially if a high amount is consumed.^[9] Given that most studies on psilocybin therapy are in early phases, little is understood about the highly complicated mechanisms that support the efficacy of psilocybin therapy. Psilocybin is a prodrug for psilocin, meaning that psilocybin is dephosphorylated to psilocin in the body so it can cross the blood-brain barrier. Psilocin primarily bonds to the 5-HT1A and 5-HT1B serotonin receptors. Although to a lesser extent, psilocin also bonds to dopamine-3 receptors, which may aid in treating substance use disorders.^[2]

 

Chemical compound of psilocybin

Further, psilocin has some effect on the amygdala and hypothalamus that aids in circadian rhythm regulation.^[2]

Research

Research conducted using psilocybin spans a diverse range of fields and disciplines, reflecting the compound's complex effects on the human mind. Primarily, psilocybin research is prominent in the realms of psychology and psychiatry, where its potential therapeutic applications for mental health conditions such as depression, anxiety, and post-traumatic stress disorder (PTSD) are being explored.^[10]

Research has shown the importance of preparing individuals before undergoing psilocybin therapy and controlling the setting in order to maximize the therapeutic effect and minimize risk.^[1] This preparation often involves medical and psychological evaluation, as well as 6–8 hours of psychotherapy provided by a licensed clinician.^[11]

As of 2022, there are over 60 clinical trials researching the therapeutic effects of psilocybin by the United States National Institute of Health (NIH). While short-term effects have been acknowledged, the long-term efficacy and safety of psilocybin therapy is yet to be determine due to most trials being ongoing. However, preliminary results indicate that psilocybin therapy is efficacious in treating depression, smoking cessation, alcohol use disorder, and obsessive-compulsive disorder.^[1]

Studies investigating the effectiveness in psilocybin therapy in treating major depressive disorder (MDD) have found that psilocybin had comparable efficacy to selective serotonin reuptake inhibitors (SSRIs). Further, meaningful clinical change was observed in the treatment of obsessive-compulsive disorder.^[1]

Research has also been conducted on psilocybin therapy for the treatment of migraines^[12][13] and cluster headaches.^[14]

Safety

In the United States, psilocybin and other psychedelic drugs have been heavily criminalized since the 1960s, classified as a Schedule I substance under the federal Controlled Substances Act (Schedule I is defined as a substance having substantial potential for abuse, absence of adequate safety evidence, and no currently accepted clinical uses for therapy).^[15] Prior to the 1960s, psychedelics were not considered "hard drugs," and were studied extensively for their immense medicinal potential for treating psychiatric disorders; the criminalization of psychedelics via their classification as Schedule I substances is inconsistent with over 70 years of scientific and medical research and was contrary to all available evidence at the time.^[16] According to the largest controlled clinical study of psilocybin to date at King's College London, volunteers who received doses of psilocybin experienced no serious adverse side effects, experiencing some changes in mood and perception but no negative effects on cognitive or emotional functioning.^[17]

An important area of concern is identifying appropriate candidates for psilocybin therapy. In patients with depression, it will be important to consider psychological, social, and biological factors. These factors may predispose them to negative reactions to the substance and result in adverse events. Individuals who present with acute suicidality would not be good candidates for psilocybin therapy because such experiences can be extremely psychologically tolling and destabilizing.^[18]

Legal status

See also: Legality of psilocybin mushrooms

According to the Controlled Substances Act, psilocybin is classified as a Schedule I drug. Heroin and LSD are examples of Schedule I substances, which have a high potential for misuse and have no accepted medical use in the US.^[19]

While the use and possession of psilocybin in the United States is still illegal under federal law,^[20] several U.S. cities have decriminalized its use.

In Australia, authorised psychiatrists can prescribe psilocybin for treatment-resistant depression.^[21]

They are currently petitions being made advocating for general considerations to sponsors developing psychedelic drugs for treatment of medical conditions (e.g., psychiatric disorders, substance use disorders).^[22] For psychedelic drugs that are Schedule I controlled substances, activities associated with IND (Investigational New Drug) must comply with the applicable Drug Enforcement  Administration (DEA) regulations for research, manufacturing, importation/exportation, handling, and storage.^[22]

References

1. Van Court, R.C.; Wiseman, M.S.; Meyer, K.W.; Ballhorn, D.J.; Amses, K.R.; Slot, J.C.; Dentinger, B.T.M.; Garibay-Orijel, R.; Uehling, J.K. (April 2022). "Diversity, biology, and history of psilocybin-containing fungi: Suggestions for research and technological development". Fungal Biology. 126 (4): 308–319. doi:10.1016/j.funbio.2022.01.003. PMID 35314062.
2. Geiger, Haden A.; Wurst, Madeline G.; Daniels, R. Nathan (2018-10-17). "DARK Classics in Chemical Neuroscience: Psilocybin". ACS Chemical Neuroscience. 9 (10): 2438–2447. doi:10.1021/acschemneuro.8b00186. ISSN 1948-7193. PMID 29956917. S2CID 49591766.
3. Marks, Mason; Cohen, Glen (October 4, 2021). "Psychedelic therapy: A roadmap for wider acceptance and utilization". Nature Medicine. 27 (10): 1669–1671. doi:10.1038/s41591-021-01530-3. PMID 34608331. S2CID 238355863.
4. Daniel, Jeremy; Haberman, Margaret (2018-03-23). "Clinical potential of psilocybin as a treatment for mental health conditions". The Mental Health Clinician. 7 (1): 24–28. doi:10.9740/mhc.2017.01.024. ISSN 2168-9709. PMC 6007659. PMID 29955494.
5. "When Did Psilocybin Mushrooms First Appear In Human Culture?". The Third Wave. 2016-07-27. Retrieved 2018-05-15.
6. "Psilocybin" (PDF). Drug Enforcement Agency, US Department of Justice. 1 April 2020. Retrieved 24 March 2021.
7. "FDA grants Breakthrough Therapy Designation to Usona Institute's psilocybin program for major depressive disorder". www.businesswire.com. 2019-11-22. Retrieved 2019-11-25.
8. Jann, Michael W (March 9, 2021). "Psilocybin Revisited: The Science Behind the Drug and Its Surprising Therapeutic Potential". Psychiatric Times. 38 (3).
9. "Psilocybin - Alcohol and Drug Foundation". adf.org.au. Retrieved 2023-12-06.
10. Ziff, Shawn; Stern, Benjamin; Lewis, Gregory; Majeed, Maliha; Gorantla, Vasavi Rakesh (2022). "Analysis of Psilocybin-Assisted Therapy in Medicine: A Narrative Review". Cureus. 14 (2): e21944. doi:10.7759/cureus.21944. ISSN 2168-8184. PMC 8901083. PMID 35273885.
11. Gukasyan, Natalie; Davis, Alan K; Barrett, Frederick S; Cosimano, Mary P; Sepeda, Nathan D; Johnson, Matthew W; Griffiths, Roland R (February 2022). "Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up". Journal of Psychopharmacology. 36 (2): 151–158. doi:10.1177/02698811211073759. PMC 8864328. PMID 35166158.
12. Schindler, EAD; Sewell, RA; Gottschalk, CH; Luddy, C; Flynn, LT; Lindsey, H; Pittman, BP; Cozzi, NV; D'Souza, DC (12 November 2020). "Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin". Neurotherapeutics. 18 (1): 534–543. doi:10.1007/s13311-020-00962-y. PMC 8116458. PMID 33184743.
13. Dolan, Eric W. (2021-05-18). "A single dose of psilocybin has a lasting therapeutic effect on migraine headache, according to a new placebo-controlled study". PsyPost. Retrieved 2022-09-30.
14. Sewell, RA; Halpern, JH; Pope HG, Jr (27 June 2006). "Response of cluster headache to psilocybin and LSD". Neurology. 66 (12): 1920–2. doi:10.1212/01.wnl.0000219761.05466.43. PMID 16801660. S2CID 31220680.
15. "Psilocybin (magic mushrooms)". Drugs.com. 2021. Retrieved 24 March 2021.
16. Sproul, Conrad (2021). ""Don't Kill My Buzz, Man!" - Explaining the Criminalization of Psychedelic Drugs". Oregon Undergraduate Research Journal. 19 (1): 1–53. doi:10.5399/uo/ourj.19.1.2. S2CID 237845545.
17. "Magic mushroom compound psilocybin found safe for consumption in largest ever controlled study". The Independent. 2019-12-18. Retrieved 2022-08-24.
18. Agin-Liebes, Gabrielle; Davis, Alan K. (2022). "Psilocybin for the Treatment of Depression: A Promising New Pharmacotherapy Approach". Current Topics in Behavioral Neurosciences. 56: 125–140. doi:10.1007/7854_2021_282. ISBN 978-3-031-12183-8. ISSN 1866-3370. PMC 10072288. PMID 34811715.
19. "Psilocybin Fast Facts". www.justice.gov. Retrieved 2023-12-06.
20. "Psilocybin Fast Facts". www.justice.gov.
21. Shepherd, Tory (2023-02-03). "Australia to allow prescription of MDMA and psilocybin for treatment-resistant mental illnesses". The Guardian. ISSN 0261-3077. Retrieved 2023-10-26.
22. Research, Center for Drug Evaluation and (2023-06-26). "Psychedelic Drugs: Considerations for Clinical Investigations". www.fda.gov. Retrieved 2023-12-06.