Scalable Hybrid Synthetic/Biocatalytic Route to Psilocybin

Psilocybin, the main psychoactive alkaloid in Psilocybe mushrooms, is being tested as a treatment for depression. Pharmaceutical psilocybin is currently made by synthetic chemistry. Replacing a difficult chemical phosphorylation step with the mushroom enzyme PsiK allowed production of one gram of psilocybin from psilocin in 20 minutes. A pilot-scale protocol also yielded 150 mg of active, soluble PsiK enzyme. This combination of tryptamine chemistry and enzymatic catalysis may provide access to psilocybin at potentially lower cost.

Study at a glance

Abstract

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 biochemically characterized and used to produce one gram of psilocybin from psilocin within 20 minutes. We also describe a pilot‐scale protocol for recombinant PsiK that yielded 150 mg enzyme in active and soluble form. Our work consolidates the simplicity of tryptamine chemistry with the specificity and selectivity of enzymatic catalysis and helps provide access to an important drug at potentially reasonable cost.