Direct Phosphorylation of Psilocin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin

This paper (2020) describes and makes available the method for producing psilocybin on a large (1kg) scale.


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 challenges were addressed and circumvented with the design of the second-generation route, which featured an optimized cGMP large-scale Speeter–Anthony tryptamine synthesis to the intermediate psilocin with improved in-process control and impurity removal over the three steps. Psilocin was subsequently phosphorylated directly with phosphorous oxychloride for the first time, avoiding a tedious and poor atom economy benzyl-protecting group strategy common to all previously described methods for producing psilocybin. In this report, the challenges encountered in a 100 g scale first-generation literature-based synthesis are highlighted, followed by a detailed description of the newly developed second-generation synthesis to provide over one kilogram of high-purity psilocybin under cGMP.

Authors: Robert B. Kargbo, Alexander Sherwood, Andrew Walker, Nicholas V. Cozzi, Raymond E. Dagger, Jessica Sable, Kelsey O’Hern, Kristi Kaylo, Tura Patterson, Gary Tarpley & Poncho Meisenheimer


This paper is included in our ‘Top 10 Articles on Psychedelics in the Year 2020

This open-access paper describes how one could make psilocybin on a large scale. This work is made available by the non-profit Usona Institute, and (partially) prevents for-profit companies from taking out patents on a/this method for making psilocybin at scale.

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