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A Brief Review of the Pharmacology of Psilocybin Cameron Behram

Abstract: Following a decades-long hiatus in research after its classification as a Schedule I drug in the United States, psilocybin (4-phosphoryloxy-N,Ndimethyltryptamine) has become a new area of interest for those researching potential psychotherapeutic adjuncts. This article will briefly review the known pharmacology of psilocybin, as well as its pharmacokinetic and pharmacodynamic potential to both supplement therapeutic exercises inmentally illindividuals as well as help scientists better understand neurological mechanisms of sensory processing and even human consciousness as a whole due to its alteration in states of consciousness.

Introduction: Psilocin, the psychoactive metabolite of the psilocybin found in psilocybin mushrooms (colloquially known as “magic mushrooms”) is a serotonergic hallucinogen that has recently become a focal point in the research of psychotherapeutic adjuncts. The use of psilocybin-containing mushrooms datesback to the Aztec Empire in shamanic and divinatory practices,1 but it was first chemicallyisolatedbythenow-famousSwiss chemist Albert Hoffman in 1957 and synthetically manufactured in 1958, when it was sold as an experimental psychotherapeutic adjunct under the name Indocybin® Sandoz after thorough human and animal testing.2 It has since been classified as a Schedule I drug in the United States, meaning that it has “no currently accepted medical use and a high potential for abuse”3, according to the United States Drug Enforcement Agency. This classification led to a 25-year-long gapin research, until several breakthrough studies of psilocybin’s potential medical use drew attention from the scientific community, thus leading to a revival in both public and scientific interest in hallucinogens.4 The pharmacokineticsofpsilocybinisnowwelldocumented, but vast amounts of research are being conducted to further understand its potential pharmacological uses to both ameliorate mental illness and better understand the mechanisms of the human brain due to its potent effects that alter the human state of consciousness.

Pharmacokinetics of psilocin:

Pharmacokinetics generally refers to the branch of pharmacology concerning a drug’s given mechanism of action and its physiological impacts on the human body. Recently, the scientific community has gained a comparatively thorough understanding of the pharmacokinetic mechanisms of psilocybin and psilocin through the use of modern brain imaging techniques. Upon oral ingestion of psilocybin, approximately 50% of it was actually absorbed into the bloodstream (calculated through isotropic labelling of the 14th carbon in psilocybin). Following absorption into the bloodstream, the psilocybin is enzymatically converted into 4 primary metabolites through a hepatic mechanism using the alkaline phosphatase enzyme. These metabolites consist of psilocin (4-hydroxy-N,N-dimethyltryptamine), which constitutes the primary metabolic product of psilocybin, which is further metabolized into 4-hydroxyindole-3yl-acetaldehyde, then into 4-hydroxyindole3-yl-acetic-acid and 4-hydroxytryptophol, which are largely clinically insignificant.2 The only clinically significant metabolite of psilocin is psilocin-O-glucuronide, which is the main urinary metabolite of psilocin and can be used to detect the presence of the drug.5 The specific metabolic pathway for psilocybin is pictured in Figure 1.

Figure 1: Metabolic Pathway of Psilocybin5

Pharmacodynamics of psilocin:

As previously discussed, psilocin is the psychoactive metabolite of psilocybin that is actually responsible for the drug’s hallucinatory and psychoactive effects. Therefore, psilocybin is often classified as a prodrug, meaning that the molecule itself has no significant physiological impact on the body, but it gets metabolized into the actual psychoactive compound.5 The pharmacodynamic mechanism of action of psilocin in the brain has been elucidated through recent studies and imaging techniques, revealing that it acts as a 5hydroxytryptamine (5-HT2A) agonist due to its structural similarities to the neurotransmitter serotonin, which binds to these same receptors. It has a high binding affinity of Ki=6nM with 5-HT2A receptors in the brain, thus revealing that chemical interactions with this receptor is the genesis of the drug’s hallucinogenic and somatic effects. Moreover, while psilocin has not been shown to interact with D2 receptors (a part of the brain’s dopaminergic pathway), research suggests that this system is functionally altered as a result of alterations of the brain’s serotoninergic Pathways.2 Furthermore, the use of PET (positron emission tomography) scans in 2 double-blind studies have elucidated the changes in metabolic consumption in the brain, thus revealing how psilocin alters brain activity in specific regions. It was found that neural metabolism increased by 25% in both the anterior cingulate gyrus (whichregulatescomplexcognitivefunctions such as emotion and empathy) and temporal-medial cortex (which includes the hypothalamus and is responsible for the formation of explicit memories), by 24% bilaterally in the frontomedial and frontolateral cortex (which controls sensorimotor responses), by 19% in thebasal ganglia (which regulates emotion and voluntary motor movement), and by 14% in the occipital cortex (which processes visual sensory stimuli). Conversely, metabolism decreased in the thalamus, which is the region that coordinates sensory input.6 These findings have immense implications relating to the psychopharmacology of the drug, as it drastically alters high-functioning cognitive areas of the brain without a high abuse potential due to its lack of interaction with D2 receptors, as an opiate would.7

Pharmacology of psilocybin: The previously discussed pharmacokinetics and pharmacodynamics of psilocybin and psilocin contribute to their unique pharmacological identity, which manifests itself largely through psychic symptoms and largely inconsequential somatic symptoms. In a clinical setting, psilocybin’s primary objective would likely be treatment of psychological, rather than physical, ailments due to the overall lack of somatic effects,2 as pictured in Figures 2 and 3.

Figure 2: Somatic Symptoms of Psilocybin2

1Nichols,DavidE.“Psychedelics.”Pharmacological reviews vol. 68,2 (2016): 264-355. doi: 10.1124/pr.115.011478 2 Passie, Torsten, et al. "The Pharmacology of Psilocybin." Addiction Biology, digital ed., 2002, pp. 357-64. 3 "Drug Scheduling." United States Drug Enforcement Administration, DEA, www.dea.gov/drug-scheduling. Accessed 2 May 2020. 4 Carhart-Harris, Robin L., and Guy M. Goodwin. "The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future." Nature, 26 Apr. 2017. Nature, www.nature.com/articles/npp201784#cite as. Accessed 2 May 2020.

Figure3:Blood Pressureand Heart RateChangesAfter Psilocybin Ingestion2

In fact, a thorough evaluation of both the physiologicalandpsychologicalsymptomsof psilocybin and psilocin suggests that it should be classified as a Schedule IV drug due to its low potential for abuse and low toxicity.6 Its actual clinical applicability, however, remains a point of contention among researchers and is currently being thoroughly investigated in various psychological contexts.4 However, this article will not delve into this, as it mainly aims to provide a review of what is already known about psilocybin and psilocin. Conclusion: After a long period of dormancy, a recent revival in interest regarding serotonergic hallucinogens as having potential clinical uses has led both scientists and society to rethink previous assertions regarding their use. As of the publication of this article, psilocybin has not yet been approved as a clinical treatment for psychological illnesses, but this very well may change in the coming years due to vast amounts of new research being conducted.4

5 Ricardo Jorge Dinis-Oliveira (2017) Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance, Drug Metabolism Reviews, 49:1, 8491, DOI: 10.1080/03602532.2016.1278228 6 Vollenweider, F. X., M.D., et al. "Positron Emission Tomography and Fluorodeoxyglucose Studies of Metabolic Hyperfrontality and Psychopathology in the Psilocybin Model of Psychosis." Nature, vol. 17, May 1997, pp. 357-72, www.nature.com/articles/1380557.pdf. Accessed 3 May 2020. 7 Johnson, Matthew W et al. “The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act.” Neuropharmacology vol. 142 (2018): 143-166. doi:10.1016/j.neuropharm.2018.05.012