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, obsessive compulsive disorder, and psychosis. 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. 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.

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.

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.

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.

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. Psilocybin research in the United States ended in 1970 when the use and possession of psilocybin mushrooms became illegal.

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.

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

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.

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. This preparation often involves medical and psychological evaluation, as well as 6–8 hours of psychotherapy provided by a licensed clinician.

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.

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.

Research has also been conducted on psilocybin therapy for the treatment of migraines and cluster headaches.

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). 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. 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.

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.

Legal status
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.

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

In Australia, authorised psychiatrists can prescribe psilocybin for treatment-resistant depression.

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). 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.