The psychotropic effects of Psilocybe 'magic' mushrooms are caused by the alkaloid psilocybin, but their broader secondary metabolome is poorly understood. Analysis of four Psilocybe species identified harmane, harmine, and other tryptophan-derived β-carbolines as natural products, confirmed by NMR spectroscopy and stable-isotope labeling. MALDI-MS imaging showed β-carbolines accumulate toward hyphal apices. As potent monoamine oxidase inhibitors, these β-carbolines are neuroactive and interfere with psilocybin degradation, representing an unprecedented scenario where different natural product pathways from the same building block contribute directly or indirectly to the same pharmacological effects.
Psilocybin, the main psychoactive alkaloid in 'magic mushrooms,' is being investigated as a potential treatment for depression and anxiety. This work describes an improved method for producing psilocybin enzymatically by adding the mushroom enzyme tryptophan synthase (TrpB) to the reaction. The new route uses cheaper starting materials—4-hydroxyindole and L-serine—to form psilocybin. The same approach also produced two other compounds: a non-natural alkaloid called isonorbaeocystin and the neurotransmitter serotonin. This enzymatic method offers a more cost-effective way to synthesize psilocybin and related molecules for research and potential pharmaceutical use.