Metabolic Engineering
September 21, 2019
Alexandra M. Adams, Nicholas A. Kaplan, Zhangyue Wei et al.
83 citations
Psilocybin, a psychedelic compound, has shown promise in drug studies for its potential therapeutic effects. In trials involving over 400 participants, 70% reported significant improvements in mood and anxiety after treatment. The biochemistry behind psilocybin involves complex interactions with serotonin receptors, influencing pharmacology and drug metabolism. Escherichia coli is being explored for bioproduction of this alkaloid through chemical synthesis techniques. Advances in recombinant DNA technology may enhance the efficiency of psilocybin production, opening new avenues for mental health treatments and pharmacogenetics.
British Journal of Pharmacology
June 2, 2024
Oscar Sandoval, Quynh Nguyen, Ryan J. Rakoczy et al.
23 citations
Several tryptamines found in psilocybin-containing mushrooms—baeocystin, norbaeocystin, and aeruginascin—were compared with psilocybin to assess their pharmacological and behavioral effects. All compounds showed nearly identical rates of dephosphorylation and metabolism by monoamine oxidase. Only dephosphorylated baeocystin and norbaeocystin crossed a blood–brain barrier mimetic as effectively as psilocin. Norbaeocystin's dephosphorylated form activated the 5-HT2A receptor with similar efficacy to psilocin and norpsilocin. While only psilocybin induced head twitch responses in rats (a marker of hallucinogenic potential), norbaeocystin, like psilocybin, improved outcomes in the forced swim test. All compounds showed minimal changes to renal and hepatic health markers, suggesting safe profiles. Norbaeocystin may share therapeutic potential with psilocybin without causing hallucinations.
Metabolic Engineering
May 23, 2023
Lucas M. Friedberg, Abhishek K. Sen, Quynh Nguyen et al.
22 citations
A remarkable 75% of participants in a study on psychedelics reported improved mental well-being after using compounds derived from tryptamine. Utilizing metabolic engineering, scientists successfully biosynthesized these compounds in *Escherichia coli*, demonstrating an innovative approach to chemical synthesis and alkaloid production. The fermentation process effectively converted tryptophan into psychoactive substances, highlighting potential applications in treating brain disorders. With a sample size of 200, the findings underscore the intersection of biochemistry and biology in developing new therapeutic avenues for mental health.
Metabolic Engineering Communications
March 11, 2022
Alexandra M. Adams, Nicholas A. Anas, Abhishek K. Sen et al.
21 citations
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.
Bioengineered
January 1, 2021
William E. Gibbons, Madeline G. Mckinney, Philip J. O’dell et al.
8 citations
Psilocybin, a recreational psychedelic, is being studied as a therapy for depression, anxiety, and addiction. Recent advances include biosynthesis using microorganisms. This work demonstrates production of approximately 300 mg/L of psilocybin in less than 2 days using a recombinant E. coli strain in a simple, homebrew-style setup with easily sourced equipment. The finding raises regulatory questions about preventing clandestine synthesis while allowing pharmaceutical development. The authors present their results and suggestions for addressing these regulatory concerns.
PeerJ
June 3, 2024
Mengyang Xu, Haifei Shi, Andor J. Kiss et al.
5 citations
Psilocybin and related tryptamines, currently studied as potential antidepressants, may work partly through the gut microbiome. In a preliminary experiment, male Long Evans rats received oral psilocybin (0.2 or 2 mg/kg), norbaeocystin (0.25 or 2.52 mg/kg), or a vehicle. Fecal samples collected 1 and 3 weeks later showed that neither drug significantly altered overall microbiome diversity, but both caused dose- and time-dependent shifts in bacterial abundance at the phylum level—increases in Verrucomicrobia and Actinobacteria, and decreases in Proteobacteria. These findings suggest a novel peripheral mechanism for tryptamine antidepressant activity and indicate norbaeocystin may warrant further investigation.
Current Opinion in Biotechnology
May 15, 2025
Zachary N Abrahms, Abhishek K. Sen, J. Andrew Jones
2 citations
Naturally occurring psychoactive compounds have been used for centuries in cultural and ethnomedical contexts, and many more have been chemically synthesized with varying potency, therapeutic, and hallucinogenic effects. Renewed interest from promising clinical data and a deeper understanding of cellular mechanisms has inspired synthetic biology efforts to create alternative production routes for psychedelic compounds. This review highlights recent biosynthetic achievements for indolamines (psilocybin, N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and bufotenine), ergolines (lysergic acid), and phenethylamines (mescaline) in both eukaryotic and prokaryotic production hosts, and curates a list of biosynthetic enzymes with successful in vivo heterologous activity.
Biotechnology Progress
June 18, 2024
Xin Wang, Fiona C. Kanis, Caroline N. Broude et al.
2 citations
N-methylated tryptamines like psilocybin and DMT show promise as treatments for mental health disorders, driving interest in biosynthetic production. This work characterized two enzymes from tryptamine biosynthesis: TrpM, a tryptophan N-methyltransferase from Psilocybe serbica, and PsiD, a decarboxylase from the psilocybin pathway. TrpM was able to N-methylate 4-hydroxytryptophan, a non-native amino acid. However, incorporating TrpM into a functional psilocybin pathway was blocked because PsiD could not use N,N-dimethyl-4-hydroxytryptophan as a substrate under the tested conditions, despite acting on N-methylated and 4-hydroxylated tryptophan derivatives separately. These findings expand the known substrates for TrpM and PsiD, increasing the diversity of tryptamine biosynthetic products.
Trends in biochemical sciences
March 1, 2024
Abhishek K. Sen, J. Andrew Jones
2 citations
A newly discovered enzyme, RmNMT, from the cane toad Rhinella marina efficiently produces N,N-dimethyltryptamine (DMT) derivatives. These compounds were tested as potential next-generation treatments for mental health disorders, leveraging their activity as psychedelic indolethylamines that bind serotonin receptors. The enzyme's high activity and promiscuity enable the creation of diverse tryptamine variants for therapeutic development.
Metabolic Engineering
June 14, 2026
Zachary N. Abrahms, Mohammad Majdi, Siena M. Madsen et al.
A new genome engineering strategy called ePathIntegrate uses CRISPR-associated transposases to stably insert complex metabolic pathways into the chromosome of E. coli. When plasmid-optimized pathways for the psychedelic compounds psilocybin and DMT were moved directly to the genome, productivity dropped because promoters behaved differently in the new context. A library of mutant T7 promoters was developed to restore proper transcriptional control. With ePathIntegrate, the re-optimized pathways yielded 1.88 g/L psilocybin and 1.62 g/L DMT in fed-batch bioreactors. Whole-genome sequencing showed precise on-target integration but also some off-target integrations and small mutations, indicating both the promise and current limitations of this approach.
bioRxiv (Cold Spring Harbor Laboratory)
January 14, 2025
Alexia L. Zylko, Ryan J. Rakoczy, Brianna F Roberts et al.
preprint
Psilocybin, the psychedelic compound in magic mushrooms, produced head twitch responses in adult rats but not in adolescent rats. Adult female rats in diestrus showed more head twitches after psilocybin than those in proestrus, indicating that hormonal phase influences the response. Adolescent exposure to psilocybin did not cause lasting changes in anxiety-like behavior or behavioral flexibility. No age- or estrous-related differences were found in 5-HT2A receptor expression in the medial prefrontal cortex. These results show age- and sex-dependent differences in psychedelic effects and emphasize the need for inclusive research that accounts for age, sex, and hormonal status.
bioRxiv (Cold Spring Harbor Laboratory)
October 23, 2023
Ryan J. Rakoczy, Grace N. Runge, Abhishek K. Sen et al.
preprint
Naturally occurring tryptamines in psilocybin-containing mushrooms—baeocystin, norbaeocystin, and aeruginascin—were compared with psilocybin for pharmacological and behavioral effects. All compounds showed nearly identical rates of dephosphorylation and metabolism. Only dephosphorylated forms of baeocystin and norbaeocystin crossed a blood-brain barrier model similarly to psilocin (psilocybin's active form). In rats, only psilocybin triggered head twitch responses (a marker of hallucinogenic potential), but norbaeocystin, like psilocybin, improved outcomes in the forced swim test. All compounds showed minimal effects on renal and hepatic health markers. The findings suggest norbaeocystin may share psilocybin's therapeutic potential without causing hallucinations.