ACS Chemical Neuroscience
March 3, 2026
Samuel E. Williamson, Elise K. Burkhartzmeyer, Michael T. Faley et al.
To support ongoing clinical trials, the major human metabolites of psilocybin were synthesized on a preparative scale, specifically psilocin-O-glucuronide and 4-hydroxyindole-3-acetic acid (4-HIAA), along with putative minor metabolites and several deuterium-labeled derivatives. Psilocybin, psilocin, psilocin-O-glucuronide, and 4-HIAA were assayed for engagement at seven serotonin receptor...
Journal of Labelled Compounds and Radiopharmaceuticals
July 1, 2025
Rodney D. Brown, Niall M. Hamilton, Connor Mallon et al.
1 citation
ABSTRACT Three novel 14 C‐labelled isotopologues of the psychoactive agents psilocin, psilocybin and 5‐methoxy‐ N , N ‐dimethyltryptamine (5‐MeO‐DMT) were synthesised, all labelled at the 2‐position of the indole. The syntheses involved incorporating the 3‐dimethylaminoethyl substituent common to all three substances onto a 4‐ or 5‐substituted indole intermediate via successive treatments with...
Chemistry - A European Journal
April 9, 2025
Tim Schäfer, Thomas Krüger, Jakob Worbs et al.
2 citations
Abstract Advanced clinical trials investigate the Psilocybe magic mushroom natural product psilocybin as a treatment against major depressive disorder. Currently, synthetic material is used to meet the demand for legitimate pharmaceutical purposes. Here, we report an in vitro approach to biocatalytically produce psilocybin on a solid‐phase matrix charged with five covalently bound biosynthetic...
Nature Communications
February 12, 2025
Farid Aboharb, Pasha A. Davoudian, Ling-Xiao Shao et al.
19 citations
Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in...
bioRxiv
May 26, 2024
Farid Aboharb, Pasha A. Davoudian, Ling-Xiao Shao et al.
preprint
Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in...
ACS Chemical Neuroscience
January 8, 2024
Alexander M. Sherwood, Elise K. Burkhartzmeyer, Samuel E. Williamson et al.
18 citations
Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT2A) in vitro but differ in their 5-HT2A-mediated effects in vivo. In particular, psilocin produces centrally mediated psychedelic effects in vivo, whereas norpsilocin, differing only by the loss of an N-methyl group, is devoid...
Nat Commun
December 15, 2023
Jason Wallach, Andrew B. Cao, Maggie M. Calkins et al.
153 citations
Abstract Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT 2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT 2A -Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT 2A -selective ligands with varying Gq efficacies, including β-arrestin-biased...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
August 1, 2023
Sarah J. Jefferson, Ian Gregg, Mark Dibbs et al.
57 citations
Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in depression and anxiety symptoms in early phase...
bioRxiv (Cold Spring Harbor Laboratory)
July 31, 2023
Jason Wallach, Andrew B. Cao, Maggie M. Calkins et al.
11 citations
preprint
Summary Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT 2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT 2A -Gq/11 and β-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT 2A -selective ligands with varying Gq efficacies, including β-arrestin-biased...
ChemRxiv
June 2, 2023
Samuel E. Williamson, Alexander M. Sherwood
1 citation
The Church of Psilomethoxin claims to produce a novel tryptamine by adding 5-MeO-DMT to the substrate of cultivated Psilocybe mushrooms, which is then biosynthesized into psilomethoxin, the church’s sacrament. In this study, we investigate the validity of this claim using comprehensive analytical techniques, namely ultra-performance liquid chromatography with high-resolution mass spectrometry...
Clinical Chemistry
March 7, 2023
Steven W. Cotten, Frederick G. Strathmann, Frederick S. Barrett et al.
The clinical evaluation of hallucinogens and other small molecules, conventionally termed psychedelics, has seen a dramatic increase in the past 5 years. Several key clinical trials recently demonstrated the potential efficacy of these compounds in treating a variety of mental health conditions including depression, anxiety, and substance use disorders. Concurrently, the business and patent...
ACS Pharmacology & Translational Science
November 2, 2022
Eline Pottie, Marilyn Naeem, Vamshikrishna Reddy Sammeta et al.
91 citations
4-Phosphoryloxy-N,N-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin is a prodrug for 4-hydroxy-N,N-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT2A). Several other 4-position ring-substituted tryptamines are present in psilocybin-containing...
Acta Crystallographica Section E Crystallographic Communications
May 6, 2022
Marilyn Naeem, Alexander M. Sherwood, Andrew R Chadeayne et al.
5 citations
The title compound, baeocystin or 4-phosphoryloxy- N -methyltryptamine {systematic name: 3-[2-(methylazaniumyl)ethyl]-1 H -indol-4-yl hydrogen phosphate}, C 11 H 15 N 2 O 4 P, has a single zwitterionic molecule in the asymmetric unit. The molecule has an intramolecular N—H...O hydrogen bond between the ammonium cation and the hydrophosphate anion. In the crystal, the molecules are linked by...
ChemBioChem
April 28, 2022
Claudius Lenz, Sebastian Dörner, Felix Trottmann et al.
26 citations
Abstract Psilocybin ( 1 ) is the major alkaloid found in psychedelic mushrooms and acts as a prodrug to psilocin ( 2 , 4‐hydroxy‐ N , N ‐dimethyltryptamine), a potent psychedelic that exerts remarkable alteration of human consciousness. In contrast, the positional isomer bufotenin ( 7 , 5‐hydroxy‐ N , N ‐dimethyltryptamine) differs significantly in its reported pharmacology. A series of...
ACS Omega
February 7, 2022
Robert B. Kargbo, Alexander M. Sherwood, Poncho Meisenheimer et al.
5 citations
Psilocybin, a serotonergic agonist, was granted a "breakthrough therapy" status by the Food and Drug Administration for clinical trials involving major depressive disorder and treatment-resistant depression. The direct phosphorylation of psilocin to psilocybin that uses a fast crystallization associated with a kinetically controlled process resulted in a smaller particle size distribution....
Acta Crystallographica Section C Structural Chemistry
December 20, 2021
Alexander M. Sherwood, Robert B. Kargbo, Kristi W. Kaylo et al.
10 citations
Psilocybin {systematic name: 3-[2-(dimethylamino)ethyl]-1 H -indol-4-yl dihydrogen phosphate} is a zwitterionic tryptamine natural product found in numerous species of fungi known for their psychoactive properties. Following its structural elucidation and chemical synthesis in 1959, purified synthetic psilocybin has been evaluated in clinical trials and has shown promise in the treatment of...
Chemistry - A European Journal
June 1, 2021
Claudius Lenz, Sebastian Dörner, Alexander M. Sherwood et al.
19 citations
Abstract Psilocin ( 1 ) is the dephosphorylated and psychotropic metabolite of the mushroom natural product psilocybin. Oxidation of the phenolic hydroxy group at the C‐4 position of 1 results in formation of oligomeric indoloquinoid chromophores responsible for the iconic blueing of bruised psilocybin‐producing mushrooms. Based on previous NMR experiments, the hypothesis included that the...
The International Journal of Neuropsychopharmacology
April 26, 2021
Alison Wakeford, Alexander M. Sherwood, Thomas E Prisinzano et al.
6 citations
BACKGROUND: Synthetic cathinones display overlapping behavioral effects with psychostimulants (e.g., methamphetamine [MA]) and/or entactogens (e.g., 3,4-methylenedioxymethaphetamine [MDMA])-presumably reflecting their dopaminergic and/or serotonergic activity. The discriminative stimulus effects of MDMA thought to be mediated by such activity have been well characterized in rodents but have not...
Journal of Natural Products
March 5, 2021
Janis Fricke, Alexander M. Sherwood, Adam L. Halberstadt et al.
18 citations
A novel analogue of psilocybin was produced by hybrid chemoenzymatic synthesis in sufficient quantity to enable bioassay. Utilizing purified 4-hydroxytryptamine kinase from Psilocybe cubensis, chemically synthesized 5-methylpsilocin (2) was enzymatically phosphorylated to provide 5-methylpsilocybin (1). The zwitterionic product was isolated from the enzymatic step with high purity utilizing a...
ACS Omega
December 2, 2020
Alexander M. Sherwood, Romain Claveau, Rafael Lancelotta et al.
38 citations
To support clinical use, a multigram-scale process has been developed to provide 5-MeO-DMT, a psychedelic natural product found in the parotid gland secretions of the toad, Incilius alvarius. Several synthetic routes were initially explored, and the selected process featured an optimized Fischer indole reaction to 5-MeO-DMT freebase in high-yield, from which the 1:1 succinate salt was produced...
ChemPlusChem
October 1, 2020
Claudius Lenz, Alexander M. Sherwood, Robert B. Kargbo et al.
40 citations
Abstract Psychotropic fungi of the genus Psilocybe , colloquially referred to as „magic mushrooms”, are best known for their l ‐tryptophan‐derived major natural product, psilocybin. Yet, recent research has revealed a more diverse secondary metabolism that originates from this amino acid. In this minireview, the focus is laid on l ‐tryptophan and the various Psilocybe natural products and their...
ACS Omega
July 1, 2020
Jessica Sable, Tura Patterson, Gary Tarpley et al.
41 citations
A second-generation kilogram-scale synthesis of the psychedelic tryptamine psilocybin has been developed. The synthesis was designed to address several challenges first encountered with the scale-up of previously described literature procedures, which were not optimized for providing consistent yield and purity of products, atom economy, or being run in pilot plant-scale reactors. These...
Chemistry - A European Journal
February 26, 2020
Janis Fricke, Robert B. Kargbo, Lars Regestein et al.
48 citations
Abstract Psilocybin, the principal indole alkaloid of Psilocybe mushrooms, is currently undergoing clinical trials as a medication against treatment‐resistant depression and major depressive disorder. The psilocybin supply for pharmaceutical purposes is met by synthetic chemistry. We replaced the problematic phosphorylation step during synthesis with the mushroom kinase PsiK. This enzyme was...
Journal of Natural Products
February 20, 2020
Alexander M. Sherwood, Adam L. Halberstadt, Adam K. Klein et al.
79 citations
A general synthetic method was developed to access known tryptamine natural products present in psilocybin-producing mushrooms. In vitro and in vivo experiments were then conducted to inform speculations on the psychoactive properties, or lack thereof, of the natural products. In animal models, psychedelic activity by baeocystin alone was not evident using the mouse head twitch response assay,...
Synthesis
January 8, 2020
Robert B. Kargbo, Alexander M. Sherwood, Poncho Meisenheimer et al.
31 citations
Described herein is an improved synthesis of 3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate (psilocybin). The protocol outlines: synthesis of multigram quantities of psilocybin, identification of critical in-process parameters, and isolation of psilocybin without the use of chromatography, TLC, or aqueous workup. The synthesis furnishes psilocybin in five steps in 23% overall...