This literature review (2018) looks back at the research that has been done with psilocybin, and the promise that it holds in current clinical trials.

Abstract

“Psilocybin is found in a family of mushrooms commonly known as “magic mushrooms” that have been used throughout history to induce hallucinations. In the late 1950s Albert Hofmann, of Sandoz Laboratories, identified and synthesized the psychoactive compounds psilocybin and psilocin which are found in psilocybe mushrooms. Psilocybin was marketed by Sandoz as Indocybin for basic psychopharmacological and therapeutic clinical research. Psilocybin saw a rapid rise in popularity during the 1960s and was classed as a Schedule I drug in 1970. This led to a significant decrease in psilocybin research. Recently, however, preliminary studies with psilocybin have shown promise as potential for the treatment of obsessive compulsive disorder, alcohol addiction, tobacco addiction, and major depressive disorder, and the treatment of depression in terminally ill cancer patients. This review describes in detail the synthesis, metabolism, pharmacology, adverse drug reactions, and importance of psilocybin to neuroscience in the past and present.”

Authors: Haden A. Geiger, Madeline G. Wurst & R. Nathan Daniels

Summary

Just Accepted

Psilocybin is found in psilocybe mushrooms, and was synthesized by Albert Hofmann of Sandoz Laboratories. It was classified as a Schedule I drug in 1970, but has shown promise in the treatment of depression in terminally ill cancer patients.

Psilocybin, a tryptamine alkaloid, is found in mushrooms of the genus Psilocybe, and was synthesized in 1959 by Albert Hofmann. It was used in experimental research for the understanding of etiopathogenesis of selective mental disorders and showed psychotherapeutic potential. Psilocybin became increasingly popular as a hallucinogenic recreational drug, but was eventually classed as a Schedule I drug in 1970. It is still used in human studies due to its relative safety and moderately long active duration.

Psilocybin, a naturally occurring psychedelic of the indolealkylamine class of hallucinogens, has six hydrogen bond acceptors, three hydrogen bond donors, and a logP of 0.03. It is thought to be unable to freely cross the blood-brain barrier.

The biosynthesis of psilocybin begins with tryptophan, which is decarboxylated to tryptamine, which is then hydroxylated to form 4-hydroxytryptamine, which is phosphorylated by PsiK and methylated by PsiM to form psilocybin.

A benzyl protected 4-hydroxyindole is treated with oxalyl chloride and dimethyl amine to give the functionalized indole, which is then reduced with lithium aluminum hydride in tetrahydrofuran to yield benzyl protected psilocin, which is then debenzylated under hydrogen gas with palladium on carbon to give psilocybin.

Once ingested, psilocybin undergoes hepatic first-pass metabolism where it is rapidly dephosphorylated into psychoactive psilocin. Psilocin enters the systemic circulation and crosses into the brain where it may exert its psychoactive effects.

IV. Manufacturing Information

Psilocybin is a Schedule-I substance in the United States and many other developed countries, except for The Netherlands, have made it illegal to use and sell psilocybin-containing mushrooms.

Psilocybin is a prodrug for psilocin, which binds to serotonin receptors and inhibits the sodium-dependent serotonin transporter. Psilocin exerts its psychoactive effects by inhibiting serotonin receptors, histamine-1 receptors, alpha-2A and -2B receptors, and dopamine-3 receptors. Psilocybin activates a broad spectrum of receptors, including 5-HT2A and 5-HT2C, and can cause hallucinations, enhanced memory and learning, bronchial and gastric smooth muscle contraction, cardiovascular and gastrointestinal anti-inflammatory effects, and increased production and release of oxytocin, prolactin, adrenocorticotropic hormone, and renin. Psilocin acts as a partial agonist at 5-HT1A receptors, which are primarily expressed in the dorsal raphe nucleus and median raphe nucleus, located near the midline of the brainstem along its entire rostro-caudal extension.

Psilocin preferentially binds to DRN presynaptic 5-HT1A receptors, and dampens DRN effects while leaving downstream cells unaffected and enhancing sympathetic activity associated with the locus coeruleus. This may explain why psilocin breaks down the usual regulation of neural communication, and allows parts of the brain that have previously never been communicative to ‘talk’. Although dopamine-2 receptors are involved in psychiatric illnesses, psilocin has been found to have little to do with its psychoactive effects. However, dopamine-3 receptors may play a significant role in psilocin’s psychoactive effects. Psilacetin is a chemically modified psilocin precursor that replaces the phosphoryloxy group found on psilocybin with an acetoxy group. It is believed to act as an identical pharmacological substitute for psilocybin, but has a faster onset of action and a more peaceful experience throughout. Animal studies suggest that psilocybin and psilocin have a therapeutic window of 0.25-10 mg/kg, which is substantially smaller than the lethal rat dose of psilocin at 293 mg/kg.

Psilocybin effects are usually dose-dependent and include physiologic, visual, auditory, cognitive effects, transpersonal, and multi-sensory effects. The physical euphoria or ‘body high’ is often described as a light, pleasurable tingling sensation that covers the body and provides a feeling of “glowing weightlessness”.

Psilocybin-containing mushrooms are associated with tachycardia, anxiety, nausea, vomiting, diarrhea, emotional lability, delusions, feelings of impending doom, and confusion. More serious adverse events include hallucinogen persisting perception disorder (HPPD), seizures, and a hypothetical risk of a type of cardiac valvulopathy. Damage to the cardiac valves is possible with frequent long-term use due to psilocin’s 5-HT2B receptor activity at the heart, and dose-independent intensity is a rare but possible side effect. Several studies have found no correlation between psychedelic use and mental illness, including attempted suicide, and a 2015 study found that psychedelic users were 36% less likely to attempt suicide. Psilocybin may interact with other drugs, including tramadol, which lowers the seizure threshold. Some drugs may also alter the course of the experience, including caffeine, opioids, ethanol, gamma-hydroxybutyric acid, selective serotonin reuptake inhibitors, and benzodiazepines.

Psilocybin has been found in over 100 species of mushrooms, and its presence is likely to have begun in Africa and Europe before the emergence of modern humans. Psilocybin-containing mushrooms can be found in the wild or grown in a controlled environment from spore prints. The danger of misidentification is ever present, and can lead to anything from mild discomfort to death.

Egyptians used magic mushrooms in their tombs and in their stories, and they were also used by Central and South American shamans. Modern study of psychedelic substances began in the late 1950s with ethnomycologist R. Gordon Wasson. Psychedelic research continued in the 1960s and early 1970s with Timothy Leary, Ralph Metzner and Ram Dass at Harvard University, Albert Hofmann at Sandoz Labs, Terrence McKenna, and Jonathan Ott. Due to psilocybin being a Schedule I drug since the 1970s, research has been limited. However, religious use by indigenous peoples is taking place, and many countries have relaxed enforcement policies. Psilocybin is less addictive than LSD, produces less anxiety, fewer panicking and affective disturbances, and milder vegetative side effects. It is also associated with seeking medical treatment to a very low extent compared to other abused drugs, and the perceived risk of harm is low according to drug experts. Researchers found rapid, notable, and lasting anti-anxiety and anti-depressive effects after treatment with psilocybin in terminal cancer patients and treatment resistant depression. No serious or unexpected adverse effects occurred. Two studies showed promising use of psilocybin to treat late-stage cancer patients with depression and anxiety. Both studies showed long-term reductions in anxiety and depression, existential distress, and improved quality of life after a single oral dose of psilocybin. In a study on the treatment of tobacco addiction with psilocybin, participants showed positive changes in behavior, attitudes, values, and increased openness in personality. Furthermore, those successful in abstaining during the 6 months scored significantly higher when measuring their mystical experience. In a proof-of-concept study, abstinence was increased significantly following administration of psilocybin, and was largely maintained at follow-up to 36 weeks. There were no abnormal adverse effects presented.

Some studies on psilocybin’s effect on alcoholism have been preliminary and do not show statistical significance. More research is needed to confirm causation and to determine the efficacy of psilocybin in treating alcoholism. Psilocybin has been shown to have its drawbacks, including short-term adverse psychological reactions, low toxicity, and low risk of addiction. Carefully controlled settings would improve psilocybin’s potential safety. A survey of 2000 participants showed that 39% reported their experiences as one of the top 5 most challenging experiences of their lifetime, and 11% reported putting themselves or others at risk of physical harm. Despite these difficulties, 84% reported having benefited from the experience. In a study on the immediate and persisting effects of psilocybin, 39% reported experiencing extreme fear, fear of insanity, or feeling trapped during the session, usually during the highest dosage. Despite these challenges, none reported feeling a decreased sense of well-being or life satisfaction. Even if psilocybin therapies prove to be effective, the obstacles that come with drug approval are intimidating. However, if future clinical trials continue to show therapeutic promise and low adversity of effects, psilocybin could be on the track for regulatory approval.

Psilocybin has shown promise in preliminary studies for the treatment of obsessive compulsive disorder, alcohol addiction, tobacco addiction, major depressive disorder, and depression in terminally ill cancer patients.