Mescaline, one of the earliest identified natural hallucinogens, has potential for psychotherapy, but its biosynthesis in the peyote cactus (Lophophora williamsii) was not fully understood. By combining genome and transcriptome sequencing with chemical profiling, enzymatic assays, and modeling, researchers identified four groups of enzymes responsible for the six catalytic steps in mescaline production, plus an N-methyltransferase that modifies all phenethylamine intermediates and likely modulates mescaline levels. The pathway was successfully reconstructed in tobacco plants and yeast cells, revealing challenges for complete heterologous production. This work enables sustainable production approaches and responsible use of mescaline.
A biosynthetic pathway for dimethyltryptamine (DMT) was reconstructed in a plant assay, along with the full pathways of five natural psychedelics: psilocin, psilocybin, DMT, bufotenin, and 5-methoxy-DMT. Halogenated analogs of these molecules, which do not occur naturally and may have therapeutic potential for psychiatric conditions, were also engineered. By blending catalytic functions from different organisms and using rational protein design to create mutant enzymes, the production of indolethylamine components in plants became substantially more efficient. This platform enables concurrent biosynthesis and diversification of psychoactive indolethylamines.