The biosynthetic pathway of the hallucinogen mescaline and its heterologous reconstruction
Paula Berman, Luis Alejandro de Haro, Ana-Rita Cavaco, Sayantan Panda, Younghui Dong, Nikolay Kuzmich, Gabriel Lichtenstein, Yoav Peleg, Hila Harat, Adam Jóźwiak, Jianghua Cai, Uwe Heinig, Sagit Meir, Ilana Rogachev, Asaph Aharoni
Molecular Plant June 3, 2024 DOI: 10.1016/j.molp.2024.05.012 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Lophophora williamsii (Peyote) plants, Nicotiana benthamiana plants, and yeast cells |
| Topics | Mescaline |
| Keywords | Heterologous Computational biology Hallucinogen Biotechnology |
| Citations | 15 |
| Key findings | Four groups of enzymes catalyze the six steps of mescaline biosynthesis in peyote, and an N-methyltransferase modulates mescaline levels. |
Abstract
Mescaline, among the earliest identified natural hallucinogens, holds great potential in psychotherapy treatment. Nonetheless, despite the existence of a postulated biosynthetic pathway for more than half a century, the specific enzymes involved in this process are yet to be identified. In this study, we investigated the cactus Lophophora williamsii (Peyote), the largest known natural producer of the phenethylamine mescaline. We employed a multi-faceted approach, combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling, enzymatic assays, molecular modeling, and pathway engineering for pathway elucidation. We identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway, and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates, likely modulating mescaline levels in Peyote. Finally, we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells, providing novel insights into several challenges hindering complete heterologous mescaline production. Taken together, our study opens up avenues for exploration of sustainable production approaches and responsible utilization of mescaline, safeguarding this valuable natural resource for future generations.
Comparable studies
Other experimental studies on mescaline, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Enzymatic Formation of Psychotomimetic Metabolites from Normally Occurring Compounds Rabbit lung | 1961 | Experimental study | |
| PSYCHOTOMIMETICS, CLINICAL AND THEORETICAL CONSIDERATIONS: HARMINE, WIN-2299 AND NALLINE Schizophrenic patients | 1957 | Experimental study | |
| Phencyclidine, Lysergic Acid Diethylamide, and Mescaline: Cerebral Artery Spasms and Hallucinogenic Activity Isolated basilar and middle cerebral arteries | 1981 | Experimental study | |
| Acquired and Crossed Tolerance to Mescaline, LSD-25, and BOL-148 | 1959 | Experimental study | |
| Effects of Hallucinogenic and Tranquilizing Drugs on Serotonin Evoked Uterine Contractions. Uterus of spayed rat | 1956 | Experimental study |
Citations in the library
Cited by 6
- New frontiers in the biosynthesis of psychoactive specialized metabolites Current Opinion in Plant Biology September 16, 2024
- Pathway engineering for the biosynthesis of psychedelics Current Opinion in Biotechnology May 15, 2025
- Complete biosynthesis of psychedelic tryptamines from three kingdoms in plants Science Advances April 1, 2026
- Plant drugs: Transcending the mescaline biosynthesis. Current Biology August 19, 2024
- Chemical ecology and convergent evolution of natural hallucinogens: From ecological defense to conserved neural targets Proceedings of the National Academy of Sciences June 24, 2026
and 1 more in the library
Cites 7
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- The neural basis of psychedelic action. Nature Neuroscience October 24, 2022
- The promises and perils of psychedelic pharmacology for psychiatry. Nature Reviews Drug Discovery June 1, 2022
- Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants. Neuropsychopharmacology October 1, 2023
- Dark Classics in Chemical Neuroscience: Mescaline ACS Chemical Neuroscience May 30, 2018
and 2 more in the library