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 (OCD), 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, post-traumatic stress disorder (PTSD) and end of life anxiety.^[3]

The first historical record of psilocybin use dates back to Mesoamerica. A Codex known as the "Yuta Tnoho" or "Vindobonensis Mexicanus I" that belonged to the Mixtec culture in the 1500s BCE depicted religious and medicinal ritual ingestion of psilocybin-containing mushrooms.^[4][5] Fungi were a prominent feature in Mixtec cultures, with over 5,000 different names of common edible mushrooms known across Mexican languages.^[5]

Despite colonists efforts to eradicate these ceremonies, ritualistic consumption of psilocybe mushrooms continues into modern spiritual and medicinal practice.^[6] 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.^[4]

Traditional psilocybin use was typically achieved through the consumption of dried or fresh psilocybin containing mushrooms.^[6] However, in 1959, Albert Hofmann, a Swiss chemist, became 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.^[7]

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.^[8] Psilocybin research in the United States ended in 1970 when the use and possession of psilocybin mushrooms became illegal.^[9][10]

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.^[11]

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.

Psilocybin is a prodrug for psilocin, meaning that psilocybin is de-phosphorylated in the GI tract of the body into psilocin so it can cross the blood-brain barrier. Psilocyn is a selective agonist of the 5HT receptors, specifically 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT2C.^[12] Although to a lesser extent, psilocin also bonds to dopamine-3 receptors, which may aid in treating substance use disorders.^[2]

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.^[13]

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

Use of psilocybin for treating depression is under preliminary research.^[14]

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. Research into the effects of psilocybin on those experiencing suicidality varies. While some research found that psilocybin therapy could be destabilizing and upsetting to these patients, other studies found psilocybin treatment resulted in reduced suicidal behavior and thoughts.^[14]

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.^[18]

While the use and possession of psilocybin in the United States is still illegal under federal law,^[19] several U.S. cities and a few states have decriminalized its use.

In Australia, authorized psychiatrists can prescribe psilocybin for treatment-resistant depression.^[20]

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).^[21] 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.^[21]