ACS Pharmacology & Translational Science
November 2, 2022
Eline Pottie, Marilyn Naeem, Vamshikrishna Reddy Sammeta et al.
91 citations
Psilocybin is a prodrug for psilocin, which produces psychedelic effects by activating serotonin 5-HT2A receptors. This study examined three naturally occurring compounds from psilocybin-containing mushrooms—psilocybin, baeocystin, and aeruginascin—along with their synthetic 4-acetoxy and 4-hydroxy analogues. In cell-based assays, secondary and tertiary tryptamines with 4-acetoxy or 4-hydroxy substitutions showed nanomolar affinity for several human serotonin receptor subtypes, including 5-HT2A and 5-HT1A. In mice, only the tertiary amines psilocin, psilocybin, and psilacetin induced head twitch responses (ED50 0.11–0.29 mg/kg), indicating psychedelic-like activity, which was blocked by a 5-HT2A antagonist.
Journal of Natural Products
February 20, 2020
Alexander M. Sherwood, Adam L. Halberstadt, Adam K. Klein et al.
79 citations
A new synthetic method allows access to tryptamine natural products found in psilocybin-producing mushrooms. Laboratory and animal experiments tested whether these compounds are psychoactive. In mice, the natural product baeocystin did not produce a head twitch response, a behavioral marker of psychedelic activity, even though its predicted breakdown product, norpsilocin, strongly activates the 5-HT2A receptor, which is associated with psychedelic effects. This suggests that baeocystin itself may not be psychedelic, despite its metabolite's activity.
ACS Omega
July 1, 2020
Jessica Sable, Tura Patterson, Gary Tarpley et al.
41 citations
A new chemical process produces over one kilogram of high-purity psilocybin, the active compound in psychedelic mushrooms, using a second-generation synthesis designed for large-scale manufacturing. The method improves on earlier procedures by optimizing the Speeter-Anthony tryptamine synthesis to create the intermediate psilocin with better control and impurity removal. It then directly phosphorylates psilocin with phosphorous oxychloride, avoiding a complex benzyl-protecting group strategy used in previous methods. This approach addresses challenges in yield, purity, atom economy, and suitability for pilot plant-scale reactors, providing a more efficient and consistent route for producing psilocybin under current Good Manufacturing Practices.
ACS Omega
December 2, 2020
Alexander M. Sherwood, Romain Claveau, Rafael Lancelotta et al.
38 citations
A multigram-scale process was developed to produce 5-MeO-DMT, a psychedelic natural product from the toad Incilius alvarius, for clinical use. An optimized Fischer indole reaction yielded 5-MeO-DMT freebase, which was converted to the 1:1 succinate salt, producing 136 g of crystalline active pharmaceutical ingredient with 99.86% purity by HPLC and a net yield of 49%. The report details in-process monitoring, validated analytical methods, impurity formation and removal, and solid-state characterization essential for clinical development.
Acta Crystallographica Section C Structural Chemistry
December 20, 2021
Alexander M. Sherwood, Robert B. Kargbo, Kristi W. Kaylo et al.
10 citations
Psilocybin, a natural product from psychoactive fungi, exists in three distinct crystal forms: Hydrate A, Polymorph A, and Polymorph B. This article presents newly solved crystal structures for the two anhydrate forms using X-ray diffraction and computational methods. Analysis of psilocybin samples produced between 1963 and 2021 shows that all contain one or more of these three forms, with no additional forms needed to explain their diffraction patterns. The composition correlates with process methods, sample age, and storage conditions. The authors also identify that a recently granted patent incorrectly described a mixture of about 81% Polymorph A and 19% Polymorph B as a single-phase variant, recommending revision of such characterizations.