Psilocybin and other psychedelic compounds are being studied for therapeutic use, but little is known about norbaeocystin, a pathway intermediate, due to difficulties obtaining it. Researchers developed a new E. coli platform to produce gram-scale amounts of norbaeocystin, finding that even minor genetic changes required reoptimization of production. In vivo tests on Long-Evans rats showed a dose response to psilocybin, but norbaeocystin did not elicit any pharmacological response, suggesting it and its metabolites may not strongly bind to the serotonin 2A receptor. This work enables future studies of norbaeocystin in animal models and supports the safety of using cell broth as a drug delivery vehicle.
A two-step bacterial pathway converting L-tryptophan to the psychoactive alkaloid N,N-dimethyltryptamine (DMT) was reconstructed in Escherichia coli. The pathway combined a tryptophan decarboxylase from Ruminococcus gnavus and a methyltransferase from the cane toad Rhinella marina. Methionine supplementation increased DMT levels 2.8-fold, indicating that methylation capacity is a key constraint. In shake-flask cultures, a co-expression strain produced 103 mg/L DMT after 48 hours in complex medium. Using a tryptophan-enriched supernatant from Corynebacterium glutamicum enabled de novo DMT formation at 16 mg/L in defined medium. The findings identify methyltransferase capacity as a target for yield improvements.