Psilocybin biosynthesis enhancement through gene source optimization.
Madeleine R Keller, Madeline G. Mckinney, Abhishek K. Sen, Felicia G Guagliardo, Elle B. Hellwarth, Khondokar Nowshin Islam, Nicholas A. Kaplan, William J Gibbons, Grace E Kemmerly, Chance Meers, Xin Wang, J Andrew Jones
Metabolic Engineering April 16, 2025 DOI: 10.1016/j.ymben.2025.04.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with comparative gene analysis and proteomics Peer reviewed |
|---|---|
| Population | Escherichia coli strains engineered with psilocybin biosynthesis genes from Psilocybe cubensis, Psilocybe cyanescens, Panaeolus cyanescens, and Gymnopilus dilepis |
| Interventions | psiK Psilocybe cyanescens Panaeolus cyanescens and Gymnopilus dilepis |
| Topics | Psilocybin |
| Keywords | Gene source optimization Gymnopilus dilepis Norbaeocystin methyltransferase Promoter library Psim Psilocybe cubensis Genetic engineering Psychedelic medicine Mushroom biotechnology Psilocybin biosynthesis Pharmaceutical production |
| Citations | 8 |
| Key findings | The strain Gymdi30, containing psiM from Gymnopilus dilepis, achieved a psilocybin titer of 1.46 ± 0.13 g/L, the highest reported to date. |
Abstract
Psilocybin, the prodrug to the psychoactive compound in 'magic' mushrooms, is currently being studied in clinical trials as a treatment for severe mental health conditions, such as depression and anxiety. Previous reports of psilocybin biosynthesis as reconstituted in E. coli reported maximum titers of 1.16 g/L, exclusively using genes from the most common recreationally used mushroom, Psilocybe cubensis. This study explores the effect of gene species variation on psilocybin and baeocystin production using various exogenous genes sourced from psilocybin-producing mushrooms Psilocybe cubensis, Psilocybe cyanescens, Panaeolus cyanescens, and Gymnopilus dilepis. The psiD and psiK genes sourced from P. cubensis demonstrated unequivocally superior performance, while psiM showed varied production levels of psilocybin and the pathway intermediate baeocystin with changes in gene source. Strains containing a psiM gene sourced from Psilocybe cyanescens demonstrated a higher degree of baeocystin selectivity as compared to other psiM genes, demonstrating a key difference between species. Most notably, the strain Gymdi30, containing psiM sourced from G. dilepis, achieved a psilocybin titer of 1.46 ± 0.13 g/L, the highest reported to date. Comparative proteomic analysis of Gymdi30 during periods of high and low productivity was also performed to investigate bottlenecks in cellular metabolism, which could be limiting strain performance. This work represents a significant improvement in psilocybin biosynthesis, a key step towards the development of a biosynthetic manufacturing route for psilocybin.
Comparable studies
Other experimental studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin Participants in controlled laboratory experiments receiving a moderate to high oral... | 2015 | Validation study using pooled data from five laboratory experiments | n = 184 |
| Broadband Cortical Desynchronization Underlies the Human Psychedelic State Healthy human participants | 2013 | Experimental study | |
| Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer Participants with cancer-related psychiatric distress who completed a parent randomized... | 2020 | Long-term within-subjects follow-up analysis | n = 15 |
| Enzymatic Synthesis of Psilocybin | 2017 | Laboratory study |
Citations in the library
Cited by 7
- Engineering artificial biosynthetic pathways for efficient microbial production of psilocybin and psilocin Metabolic Engineering November 5, 2025
- Complete biosynthesis of psychedelic tryptamines from three kingdoms in plants Science Advances April 1, 2026
- Psilocybin Production With Genetically Modified Aspergillus nidulans Under Pressurized Conditions Biotechnology and Bioengineering December 30, 2025
- Psilocybin, From Ancestral Use to Therapeutic Potential: A Multidimensional Review of Its Pharmacological Basis and Current Perspectives Human Psychopharmacology: Clinical and Experimental September 1, 2026
- 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 2 more in the library
Cites 17
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer Archives of General Psychiatry September 7, 2010
- Psilocybin-Occasioned Mystical Experiences in the Treatment of Tobacco Addiction Current Drug Abuse Reviews January 9, 2015
- Enzymatic Synthesis of Psilocybin Angewandte Chemie International Edition August 1, 2017
- Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives Metabolic Engineering March 26, 2020
and 12 more in the library