Psilocybin: from ancient magic to modern medicine

This paper (2020) reviews the history of psilocybin from its use by indigenous cultures in South America to the modern clinical studies of today.

Abstract

“Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is an indole-based secondary metabolite produced by numerous species of mushrooms. South American Aztec Indians referred to them as teonanacatl, meaning “god’s flesh,” and they were used in religious and healing rituals. Spanish missionaries in the 1500s attempted to destroy all records and evidence of the use of these mushrooms. Nevertheless, a 16th century Spanish Franciscan friar and historian mentioned teonanacatl in his extensive writings, intriguing 20th century ethnopharmacologists and leading to a decades-long search for the identity of teonanacatl. Their search ultimately led to a 1957 photo-essay in a popular magazine, describing for the Western world the use of these mushrooms. Specimens were ultimately obtained, and their active principle identified and chemically synthesized. In the past 10-15 years several FDA-approved clinical studies have indicated potential medical value for psilocybin-assisted psychotherapy in treating depression, anxiety, and certain addictions. At present, assuming that the early clinical studies can be validated by larger studies, psilocybin is poised to make a significant impact on treatments available to psychiatric medicine.”

Author: David E. Nichols

Summary

Psilocybin, an indole-based secondary metabolite produced by numerous species of mushrooms, was used by South American Aztec Indians in religious and healing rituals. It was later discovered and chemically synthesized, and has shown potential medical value in treating depression, anxiety, and certain addictions.

Introduction

Secondary metabolites from plants, fungi, and bacteria have been recognized and exploited for their anti-infective and anticancer properties.

Psilocybin, a secondary metabolite of psilocybin mushrooms, has recently received increasing attention for its potential ability to treat a host of CNS disorders, including depression, anxiety, and various addictions.

History and discovery of psilocybin

The story of psilocybin begins with Spanish Franciscan friar Bernardino de Sahagn who journeyed to Mexico (“New Spain”) in 1529 and carried out ethnographic research studies. He eventually compiled the Historia general de las cosas de la Nueva Espaa, which contains references to teonanacatl, “God’s Flesh,” the sacred mushrooms of Mesoamerica.

In 1952, banker and amateur mycologist R. Gordon Wasson made several trips to Mexico in search of mushrooms, and in 1955, he was allowed to participate in a mushroom ritual with Mazatec curandera Maria Sabina. A follow-up expedition by French mycologist Roger Heim identified several mushrooms as species of Psilocybe. Albert Hofmann, the natural products chemist at Sandoz Pharmaceuticals who had discovered the effects of LSD in 1943, ingested 2.4 g of the dried mushrooms to convince himself that the mushrooms were indeed active.

Hofmann identified the active component in the mushroom extract, psilocybin, and isolated a sufficient amount of material for chemical characterization. Psilocin is not water soluble and slowly decomposes at room temperature.

Bioactive dose and molecular target

HPLC analysis of 20 species from seven genera of Pacific Northwest mushrooms found psilocybin in seven species from three genera. Psilocybin has an average potency of 4-8 mg/g.

Psilocybin is rapidly dephosphorylated to psilocin after ingestion, and psilocin is the actual active species in vivo. Psilocin is an agonist at cortical serotonin 5-HT2A receptors, and this receptor mediates the effect of psilocybin and other psychedelics.

Chemical synthesis of psilocin and psilocybin

Kargbo et al. developed an efficient synthesis of psilocybin utilizing a direct phosphorylation of psilocin with phosphorous oxychloride. This method affords high yields of relatively pure psilocybin.

Biosynthesis of psilocybin

A biosynthetic pathway for psilocybin was reconstructed in vitro using heterologously produced enzymes and 4-hydroxy-L-tryptophan as the substrate. The pathway was led by a new class of fungal L-tryptophan decarboxylases and involved iterative N-methyl transfer as the terminal biosynthetic step.

Adams et al. developed a modular biosynthetic production platform in Escherichia coli and achieved a psilocybin titer of 1.16 g/L, the highest psilocybin titer achieved to date from a recombinant organism.

Fricke et al. [22] described the first combined chemical/biocatalytic synthesis of psilocybin, which involved treatment of chemically synthesized psilocin with heterologously produced P. cubensis PsiK.

Clinical studies with psilocybin

Sandoz Pharmaceuticals began distributing tablets containing 2 mg of psilocybin in 1960 and proposed it to be useful as a drug adjuvant to psychotherapy. Since 1980, however, there have been more than 200 published reports focused on various aspects of psilocybin pharmacology, chemistry, and biochemistry as well as careful studies in humans.

Nine subjects with OCD were given psilocybin, and several reported reductions in symptoms. A larger study is currently underway at Yale University.

Griffiths et al. administered psilocybin to 30 healthy hallucinogen-naive volunteers and found that they had increased measures of mystical experience, increased esthetic appreciation, imagination, and creativity, and had sustained positive changes in attitudes and behavior.

Grob et al. administered moderate doses of psilocybin to 12 adults with advanced-stage cancer and anxiety and found that the trait anxiety subscale decreased significantly at 1 and 3 months after treatment.

The next therapeutic trial was conducted by Johnson et al. , who administered psilocybin to 15 psychiatrically healthy nicotine-dependent smokers. 12 of 15 participants (80%) showed 7-day point prevalence abstinence at 6-month follow-up.

A controlled trial using psilocybin in combination with Motivational Enhancement Therapy was conducted on ten volunteers with DSM-IV alcohol dependence. The results showed that abstinence increased significantly following psilocybin administration and was largely maintained at 36-week follow-up.

In December 2016 Griffiths et al. reported the effects of psilocybin-assisted psychotherapy on 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. The high-dose psilocybin produced large and significant decreases in clinician- and self-rated measures of depressed mood and anxiety.

In a double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression received treatment with single-dose psilocybin or niacin, both in conjunction with psychotherapy. Psilocybin produced rapid, robust, and enduring anxiolytic and antidepressant effects in patients with cancer-related psychological distress.

The FDA gave breakthrough therapy status to psilocybin treatments for treatment-resistant depression and major depressive disorder in late 2018.

Mechanism of action

Psilocybin activates the serotonin 5-HT2A receptor, which is densely expressed on apical dendrites of cortical pyramidal cells. This results in a hyperfrontal metabolic pattern that parallels comparable metabolic findings associated with acute psychotic episodes in chronic schizophrenics.

Psilocybin increased MRGlu in distinct right hemispheric frontotemporal cortical regions and decreased MRGlu in the thalmus in a double-blind, placebo-controlled human FDG-positron emission tomographic PET study.

Modern imaging methods have identified several brain hubs that are crucial for efficient neuronal signaling and communication. These hubs participate in a range of cognitive and affective tasks.

Imaging studies have shown that psilocybin causes marked alterations in brain network connectivity during the time of drug action. These results indicate that the subjective effects of psilocybin are caused by decreased activity and connectivity in the brain’s key connector hubs.

Although psilocybin PET research suggested increased glucose metabolism in frontal cortex (hyperfrontality), a more recent study using pseudo-continuous ASL to measure perfusion changes after two doses of oral psilocybin showed decreased perfusion in left hemispheric parietal and temporal cortices and left subcortical regions.

Muthukumaraswamy et al. [35] found that psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices and from 8 to 100 Hz in frontal association cortices, and that this effect was mediated by 5-HT2A receptor-mediated excitation of deep pyramidal cells.

A subset of deep pyramidal cells in layer V of the prefrontal cortex is directly depolarized by 5-HT2A receptor activation, and subsequently recruits other select cell types to produce distinct and regional responses.

Psychedelics cause a decrease in connectivity within a key brain network, and a synchronization of sensory functional networks and disintegration of associative networks. This leads to a brain state where there is a greater repertoire of connectivity motifs that form and fragment over time.

Psilocybin may cause long-term changes in brain functioning, such as decreases in negative affect and increases in positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally conflicting stimuli.

Conclusions

Psilocybin has been studied for its potential to treat end of life distress, depression, anxiety, and certain addictions. It has recently been given a Breakthrough Therapy Designation by the FDA.