Psilocybin therapy

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Psilocybin-containing mushrooms

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]

Contents

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 Psilocybn.svg
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]

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]

Related Research Articles

<span class="mw-page-title-main">Psilocybin</span> Chemical compound found in some species of mushrooms

Psilocybin is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. The most potent are members of genus Psilocybe, such as P. azurescens, P. semilanceata, and P. cyanescens, but psilocybin has also been isolated from about a dozen other genera. Psilocybin is itself biologically inactive but is quickly converted by the body to psilocin, which has mind-altering effects similar, in some aspects, to those of lysergic acid diethylamide (LSD), mescaline, and dimethyltryptamine (DMT). In general, the effects include euphoria, visual and mental hallucinations, changes in perception, distorted sense of time, and perceived spiritual experiences. It can also cause adverse reactions such as nausea and panic attacks.

<span class="mw-page-title-main">Psychedelic drug</span> Hallucinogenic class of psychoactive drug

Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states and an expansion of consciousness. Also referred to as classic hallucinogens or serotonergic hallucinogens, the term psychedelic is sometimes used more broadly to include various types of hallucinogens, such as those which are atypical or adjacent to psychedelia like salvia and MDMA, respectively.

<i>Psilocybe cubensis</i> Species of fungus

Psilocybe cubensis, commonly known as the magic mushroom, shroom, golden halo, cube, or gold cap, is a species of psilocybin mushroom of moderate potency whose principal active compounds are psilocybin and psilocin. It belongs to the fungus family Hymenogastraceae and was previously known as Stropharia cubensis. It is the best-known psilocybin mushroom due to its wide distribution and ease of cultivation. This mushroom being optimal for home cultivation specifically, as was suggested in the 1970s, is primarily what led to P. cubensis being the psilocybin mushroom species most common on the black market as a street drug.

<span class="mw-page-title-main">Psilocybin mushroom</span> Mushrooms containing psychoactive indole alkaloids

Psilocybin mushrooms, commonly known as magic mushrooms or shrooms, are a polyphyletic informal group of fungi that contain psilocybin, which turns into psilocin upon ingestion. Biological genera containing psilocybin mushrooms include Psilocybe, Panaeolus, Inocybe, Pluteus, Gymnopilus, and Pholiotina.

<i>Psilocybe</i> Genus of fungi

Psilocybe is a genus of gilled mushrooms, growing worldwide, in the family Hymenogastraceae. Many species contain the psychedelic compounds psilocybin and psilocin.

Psychedelic therapy refers to the proposed use of psychedelic drugs, such as psilocybin, MDMA, LSD, and ayahuasca, to treat mental disorders. As of 2021, psychedelic drugs are controlled substances in most countries and psychedelic therapy is not legally available outside clinical trials, with some exceptions.

<span class="mw-page-title-main">Psilocin</span> Chemical compound

Psilocin is a substituted tryptamine alkaloid and a serotonergic psychedelic substance. It is present in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin. Psilocin is a Schedule I drug under the Convention on Psychotropic Substances. Acting on the 5-HT2A receptors, psilocin modulates the production and reuptake of serotonin. The mind-altering effects of psilocin are highly variable and subjective and resemble those of LSD and DMT.

The Multidisciplinary Association for Psychedelic Studies (MAPS) is an American nonprofit organization working to raise awareness and understanding of psychedelic substances. MAPS was founded in 1986 by Rick Doblin and is now based in San Jose, California.

Treatment-resistant depression (TRD) is a term used in psychiatry to describe people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Definitions of treatment-resistant depression vary, and they do not include a resistance to psychotherapy. Inadequate response has most commonly been defined as less than 50% reduction in depressive symptoms following treatment with at least one antidepressant medication, although definitions vary widely. Some other factors that may contribute to inadequate treatment are: a history of repeated or severe adverse childhood experiences, early discontinuation of treatment, insufficient dosage of medication, patient noncompliance, misdiagnosis, cognitive impairment, low income and other socio-economic variables, and concurrent medical conditions, including comorbid psychiatric disorders. Cases of treatment-resistant depression may also be referred to by which medications people with treatment-resistant depression are resistant to. In treatment-resistant depression adding further treatments such as psychotherapy, lithium, or aripiprazole is weakly supported as of 2019.

<i>O</i>-Acetylpsilocin Chemical compound

O-Acetylpsilocin is a semi-synthetic psychoactive drug that has been suggested by David Nichols to be a potentially useful alternative to psilocybin for pharmacological studies, as they are both believed to be prodrugs of psilocin. However, some users report that O-acetylpsilocin's subjective effects differ from those of psilocybin and psilocin. Additionally, some users prefer 4-AcO-DMT to natural psilocybin mushrooms due to feeling fewer adverse side effects such as nausea and heavy body load, which are more frequently reported in experiences involving natural mushrooms. It is the acetylated form of the psilocybin mushroom alkaloid psilocin and is a lower homolog of 4-AcO-MET, 4-AcO-DET, 4-AcO-MiPT and 4-AcO-DiPT.

<span class="mw-page-title-main">Ethocybin</span> Chemical compound

Ethocybin is a homologue of the mushroom alkaloid psilocybin, and a semi-synthetic psychedelic alkaloid of the tryptamine family. Effects of ethocybin are comparable to those of a shorter LSD or psilocybin trip, although intensity and duration vary depending on dosage, individual physiology, and set and setting.

<span class="mw-page-title-main">Esketamine</span> Medication

Esketamine, sold under the brand names Spravato and Ketanest among others, is the S(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. Esketamine is the active enantiomer of ketamine in terms of NMDA receptor antagonism and is more potent than racemic ketamine.

<span class="mw-page-title-main">Drug policy of California</span> Overview of the drug policy of the U.S. state of California

Drug policy of California refers to the policy on various classes and kinds of drugs in the U.S. state of California. Cannabis possession has been legalized with the Adult Use of Marijuana Act, passed in November 2016, with recreational sales starting January of the next year. With respect to many controlled substances, terms such as illegal and prohibited do not include their authorized possession or sale as laid out by applicable laws.

The legal status of unauthorised actions with psilocybin mushrooms varies worldwide. Psilocybin and psilocin are listed as Schedule I drugs under the United Nations 1971 Convention on Psychotropic Substances. Schedule I drugs are defined as drugs with a high potential for abuse or drugs that have no recognized medical uses. However, psilocybin mushrooms have had numerous medicinal and religious uses in dozens of cultures throughout history and have a significantly lower potential for abuse than other Schedule I drugs.

Psychedelic microdosing involves consuming sub-threshold doses (microdoses) of serotonergic psychedelic drugs like LSD and psilocybin to potentially enhance creativity, energy, emotional balance, problem-solving abilities, and to address anxiety, depression, and addiction. This practice has gained popularity in the 21st century.

<span class="mw-page-title-main">Magic truffle</span> Hallucinogenic mushroom preparation

Magic truffles are the sclerotia of psilocybin mushrooms that are not technically the same as "mushrooms". They are masses of mycelium that contain the fruiting body which contains the hallucinogenic chemicals psilocybin and psilocin.

MDMA-assisted psychotherapy is the use of prescribed doses of MDMA as an adjunct to psychotherapy sessions. Research suggests that MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), including Complex PTSD, might improve treatment effectiveness. In 2017, a Phase II clinical trial led to "breakthrough therapy" designation by the US Food and Drug Administration (FDA) for potential use as a treatment for PTSD.

<span class="mw-page-title-main">MindMed</span> Psychedelic medicine biotech company

Mind Medicine Inc., also known as MindMed, is a New York-based psychedelic medicine biotech company that develops psychedelic-inspired medicines known as psychoplastogens and therapies to address addiction and mental illness.

Psychoplastogens are a group of small molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single administration. Several existing psychoplastogens have been identified and their therapeutic effects demonstrated; several are presently at various stages of development as medications including ketamine, MDMA, scopolamine, and the serotonergic psychedelics, including LSD, psilocin, DMT, and 5-MeO-DMT. Compounds of this sort are being explored as therapeutics for a variety of brain disorders including depression, addiction, and PTSD. The ability to rapidly promote neuronal changes via mechanisms of neuroplasticity was recently discovered as the common therapeutic activity and mechanism of action.

Psychedelic treatments for trauma-related disorders are the use of psychedelic substances, either alone or used in conjunction with psychotherapy, to treat trauma-related disorders. Trauma-related disorders, such as post-traumatic stress disorder (PTSD), have a lifetime prevalence of around 8% in the US population. However, even though trauma-related disorders can hinder the everyday life of individuals with them, less than 50% of patients who meet criteria for PTSD diagnosis receive proper treatment. Psychotherapy is an effective treatment for trauma-related disorders. A meta-analysis of treatment outcomes has shown that 67% of patients who completed treatment for PTSD no longer met diagnostic criteria for PTSD. For those seeking evidence-based psychotherapy treatment, it is estimated that 22-24% will drop out of their treatment. In addition to psychotherapy, pharmacotherapy (medication) is an option for treating PTSD; however, research has found that pharmacotherapy is only effective for about 59% of patients. Although both forms of treatment are effective for many patients, high dropout rates of psychotherapy and treatment-resistant forms of PTSD have led to increased research in other possible forms of treatment. One such form is the use of psychedelics.

References

  1. 1 2 3 4 5 6 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. Bibcode:2022FunB..126..308V. doi: 10.1016/j.funbio.2022.01.003 . PMID   35314062.
  2. 1 2 3 4 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.
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  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.
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  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. 1 2 Research, Center for Drug Evaluation and (2023-06-26). "Psychedelic Drugs: Considerations for Clinical Investigations". www.fda.gov. Retrieved 2023-12-06.
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