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Process Chemistry

‘Magic mushroom’ enzyme mystery solved

Researchers unravel the biosynthesis of the psychoactive drug psilocybin, making large-scale production a possibility

by Stephen K. Ritter
August 14, 2017

Credit: Dirk Hoffmeister (mushrooms)
Researchers deciphered the biosynthetic route in Psilocybe cyanescens “magic mushrooms” (shown) that makes the psychoactive natural product psilocybin and then used the key enzymes in a one-pot enzymatic synthesis starting from 4-hydroxy-L-tryptophan.

The euphoria and hallucinations induced from eating Psilocybe “magic mushrooms” have earned the fungi a cult following. Sandoz chemist Albert Hofmann isolated and determined the structure of psilocybin, the main ingredient in mushrooms that leads to the psychedelic effects, nearly 60 years ago. That discovery and subsequent mind-altering experiments by Harvard University psychologist Timothy F. Leary have left scientists longing to develop a large-scale synthesis of the compound for medical uses, which include treating anxiety and depression in people with terminal cancer and treating nicotine addiction. Yet no one has been able to unravel the enzymatic pathway the mushrooms use to make psilocybin, until now.

Janis Fricke, Felix Blei, and Dirk Hoffmeister of Friedrich Schiller University Jena have identified and characterized to the greatest extent so far the four enzymes that the mushrooms use to make psilocybin. The team then developed the first enzymatic synthesis of the compound, setting the stage for its possible commercial production (Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201705489).

During their study, Hoffmeister and coworkers sequenced the genomes of two mushroom species to identify the genes that govern fungal enzymatic production of psilocybin. They further used engineered bacteria and fungi to confirm the gene activity and exact order of synthetic steps. This process includes a newly discovered enzyme that decarboxylates tryptophan, an enzyme that adds a hydroxyl group, an enzyme that catalyzes phosphorylation, and an enzyme that mediates two sequential amine methylation steps. With that knowledge in hand, the team designed a one-pot reaction using three of the enzymes to prepare psilocybin from 4-hydroxy-L-tryptophan.

Medicinal chemist Courtney Aldrich of the University of Minnesota, Twin Cities, praises Hoffmeister and his coworkers for their painstaking efforts to elucidate the biosynthesis of psilocybin. “Our knowledge of the biosynthesis of fungal natural products has lagged behind our understanding of the corresponding bacterial biosynthetic pathways owing to a number of unique challenges,” Aldrich says. For instance, the genomes of fungi are more complex than bacteria, many fungi are still not amenable to genetic manipulation, and cultivating fungi to produce sufficient amounts of desired metabolites is not always straightforward. “The new work lays the foundation for developing a fermentation process for production of this powerful psychedelic fungal drug, which has a fascinating history and pharmacology,” Aldrich adds.

“The publication by Hoffmeister and colleagues highlights a terrific example of genomics-based biocatalyst-pathway discovery,” adds natural products researcher Jon S. Thorson of the University of Kentucky. “While psilocybin biosynthesis derives from a series of fairly simple chemical transformations, this new study identifies the contributing genes and biocatalysts for the first time and, importantly, provides strong evidence to support a revision of the order of the key steps proposed more than five decades ago. This work clearly sets the stage for bioengineered psilocybin production and/or for analogs that may serve as compelling alternatives to existing synthetic strategies.”

This article has been translated into Spanish by and can be found here.



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Nero (August 14, 2017 8:47 PM)
I was wondering what benefits by discovering the biosynthesis of psilocybin would bring to the table of humanity or was it for nothing an only for sake of curiosity?
mohawk mick (August 15, 2017 12:51 PM)
they have found healing benifits for curing depresion with no need to continue medication, ptsd, and close to death individuals to deal with end of days
John Miller (August 16, 2017 6:26 PM)
They even have a movie about that on Netflix.
Beatrice (August 19, 2017 5:51 PM)
I'd love to know the name of the movie, I'm really interested in this subject. Thank you. :-)
Belle (November 14, 2017 4:01 PM)
Would it have been better to genetically alter a yeast to synthesize psilocybin; or is it that bacteria are just more efficient for culturing? Also, shouldn't we try to see if there are any other molecules that work along with psilocybin to get the best effects? No organisms in nature work in isolation.
Steve Ritter (November 17, 2017 3:32 PM)
I think these are all good points and ones that the researchers described in this article and others will be pursuing, to find out which strategy works best.
Bob (August 15, 2017 1:00 PM)
Its basically a cure for cluster-headaches.
Daniel (August 15, 2017 1:03 PM)
Recent research has shown promise as am effective antidepressant

"High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety."
Steve Ritter (August 15, 2017 1:21 PM)
Part of it, like most of science, is the curiosity.The goal here is to develop a way to produce larger amounts of the active compounds (more than the mushrooms produce) so they might be used as prescription drugs, for example to treat anxiety, depression, and pain. One would not have to grow and consume the mushrooms. This is parallel to medical marijuana use; if one had synthetic cannabinoid compounds, you would not need to smoke or eat marijuana.
Dab Sonic (August 15, 2017 11:39 PM)
Isn't synthetic cannabis called Marinol? I've heard it's pretty terrible stuff.
(August 16, 2017 11:35 AM)
Synthetic cannabis doesn't make sense. Cannabis is a genus of flowering plants that includes three different species: sativa, indica, and ruderalis. Marinol is a brand name for just THC, Tetrahydrocannabinol (DRONABINOL).
Anon (December 22, 2017 4:07 PM)
Adding to that, the number of cannabinoids working together to provide the effects of consuming cannabis is in the hundreds (as far as we have been able to identify) so synthetic production of a single cannabinoid doesn't provide the same treatment. In mushrooms, as far as I know there are 3-4 known active compounds (baeocystin, norbaeocystin, psilocybin, psilocin) and the prior two are precursors to the latter. This makes it a much simpler target for synthesis.
Jennifer Schaafsma (August 15, 2017 2:15 PM)
to develop a large-scale synthesis of the compound for medical uses, which include treating anxiety and depression in terminal cancer patients and treating nicotine addiction. first paragraph
William (August 15, 2017 4:22 PM)
It has long been suspected as a beneficial compond, and is theorized to have played a role in the development of Humanity.

Underground, non-scientific, non-peer-reviewed, empirical "research" suggests a wealth of discovery to be made through predictable and controllable study.
Halbax (August 15, 2017 7:25 PM)
Psilocybin is currently undergoing clinical trials for depression, as well as for anxiety in patients facing a terminal illness. The results to date are compelling. That means that one day in the future psilocybin may become an FDA approved medication. To support such use, methods need to be developed to synthesize large amounts of psilocybin. Unfortunately, the current methods used to synthesize psilocybin are not economical, not are they easy to scale-up to the extent necessary to meet the anticipated demand. Producing psilocybin by fermentation in bioreactors would be a great solution to these problems.
Rachel (August 16, 2017 8:45 AM)
Look up psilocybin and cluster headache research :)
R (August 14, 2017 9:44 PM)
Those are not Psilocybin Mushrooms in the picture. Do not eat anything you find that looks like that picture.
Steve Ritter (August 15, 2017 1:09 PM)
Thanks for your concern R, it is well-founded. The photo shows Psilocybe cyanescens, one species of potent "magic mushrooms" and one of the actual samples the researchers used in part of their experiments. These Psilocybe may not look like the mushrooms you might be familiar with. Typical "homegrown" mushrooms, usually P. cubensis, look different; the researchers worked with those as well. Hoffmeister does agree with you (because mushrooms are hard to identify safely): "Do not eat any little brown shrooms and do not eat any hallucinogenic fungi (it is illegal to do so in most countries anyway)." Hoffmeister has a certification from the German government to work with these controlled substances.
B (August 15, 2017 1:35 PM)
Yes they are, they're Psilocybe Cyanescens, Google has plenty of examples.
Andre (August 15, 2017 9:03 PM)
These are indeed typical lignocolus Psilocybe fungi. The key to differentiating these from the deadly Gallerina lookalikes is in the spore print color: Psilocybe species have dark purple/brown spore prints, while Gallerina have a rusty-brown spore print. It is in fact often possible to see the spore color from spores that have stuck to the remnants of the cortinate partial view on the stem. However, caution is to be observed in all cases as Gallerina can grow in the very midst of a patch of P cyanaescens or similar species. Please refer to Paul Stamets' Psilocybin Mushrooms of the World for further detail.
Tony v (August 18, 2017 8:40 PM)
It's a classic beautiful example of psilocybe cyanescens
Riley (August 15, 2017 1:21 PM)
"That discovery and subsequent mind-altering experiments by Harvard University psychologist Timothy F. Leary have left scientists longing to develop a large-scale synthesis of the compound for medical uses..."

I understand the need to deliver a medical and cultural history of psilocybin in the space of a couple sentences, but this summary still strikes me as factually misleading.

The shenanigans at Harvard, if anything, directed scientific attention AWAY from this compound for about three decades. It took an entire generation and a new cohort of reseachers, taking a much more conservative approach, to finally get back to work on these compounds as therapeutic agents.
Ajosin (January 21, 2018 10:49 PM)
Please don't blame a particular ex Harvard professor for our situation and history. Science stalling for decades in this important field of research is due the combination of the US government's illogical approach to these natural substances coupled with passive complicit silence from the larger scientific community. I'm very grateful to the handful of scientists that put their careers and reputation on the line to go against the 'norm' and perform this kind of research. Unfortunately, there is still a lot of work left to do before we can outgrow bad old habits such as: (1) the human endocannabinoid system not being generally taught in med school, and (2) these natural therapeutic substances still being scheduled I in the US.

Thank you.
Shaggy (August 15, 2017 2:26 PM)
Please add cluster headaches (no, not migraines) for conditions that Psilocybin works for. I could see how a specific dose pharmaceutical would be helpful to have instead of collecting the wild ones.
James Hoffman (August 15, 2017 3:52 PM)
Interesting work. But, if large-scale production is a goal, why not use conventional chemical synthesis? Won't extraction and purification become the challenge in biological production?
Hein Wijma (August 17, 2017 2:45 AM)
If you have to produce it from the mushrooms itself the answer is probably yes. If on the other hand you can isolate it from the enzyme mix, then the extraction and purification could even be easier than with conventional synthesis. Enzymes often give fewer side reactions, so less contaminants.
Jim Hunter (August 15, 2017 5:15 PM)
The good thing is the purity of a known product. But as a cynic, I'd expect Big Pharma to get a patent on production and market an expensive, highly controlled pill. And the FDA/DEA to continue the ban on the real thing. Same thing happened with red yeast rice and statin drugs. It's about $$$.
mr m j fletcher (August 16, 2017 12:59 PM)
Very true, sadly.
Felix Domestica (August 15, 2017 8:22 PM)
Mushroom experts will tell you that LBMs -- little brown mushrooms that look like the common supermarket varieties -- account for a large percentage of mushroom poisonings. They tend to be hard even for experts to identify reliably, and not many of them are edible. If you really want to go hunting for wild food, it's a lot safer to look for more distinctive edible varieties. And even then you should check spores to be sure, and eat carefully since even if identified correctly there is always some risk of allergic reaction to a novel food.

Double or treble those warnings, at least, if you insist on hunting for something which has strong medicinal effects. Remember the actual meaning of "intoxication".
(August 16, 2017 12:39 AM)
Like marijuana, big pharma will always find a way to put natural cures into pills and mass reproduce them. Gotta make money, you know. Question is in isolating the compounds, are the effects still akin to gorging a natural shroom or will there be unintended consequences?
richard franck (August 16, 2017 4:42 PM)
in Germany, many town health boards employ a mushroom expert who determines edibility/safety-usually on Monday morning. This is when the weekender mushroom gatherers come in to Town Hall to get the OK for their harvest. I wish we had the same here in the U.S.
SURESH MISHRA (August 17, 2017 12:05 AM)
William (August 17, 2017 10:50 AM)
The addition to the 4-position of indoles is pretty tricky, so even if for no other reason than that, access to the synthesis of exclusively 4-modification is important. (Ninenetscu synthesis does not give 4-modified indoles, Fischer synthesis may do so, but is much usually lower in yield than other positions). Moreover, hydroxylation there is probably a redox active modification upon exposure to light (cf. Saito pathway), i.e. electron transfer upon uv excitation possibly leads to indole ring oxidation (whence the relative instability of psilocin - and maybe even the purple turning of P. cyanescens upon exposure to light) - hence the need to phosphorylate ASAP.
Hoping for a day (August 23, 2017 3:32 PM)
An old article in Journal of the Chemical Society indicated that oxidation in Ascorbate buffered H2O2 (?) of N,N-DimethylTryptamine gives the 4-OH (Psilocin) derivative which is the active metabolite of Psilocybin. Perhaps worth resurrection for improvement if scale-up for developmental studies will be done if DEA becomes enlightened ?
William (August 24, 2017 12:48 PM)
I wonder if light was required for the reaction (i.e. or if they checked for that)?
In any case, an enzymatic reaction is more promising, for selectivity and also for modifiability -- if by some sequence modification one could make the enzyme e.g. halogenate instead, or do other tricks, possibly by using nonaqueous or other unusual reaction conditions.
Bill (August 17, 2017 2:00 PM)
Just what the world needs, more dope. This won't end well.
Fun Guy (August 17, 2017 7:30 PM)
Relax, Bill. And maybe read a book or something. This is a positive development, possibly even for you. You should look into it.
Albert Y Leung (August 18, 2017 12:06 PM)
My name is Albert Y. Leung. My Ph.D. thesis was on production of psilocybin and its analogs (baeocystin & norbaeocystin) from submerged culture of Psilocybe baeocystis at Dept of Pharmacognosy in Ann Arbor in the 1960s. I isolated enough analogs to elucidate the structures of 2 from the mycelium pellets. Not too many Psilocybe spp. could grow in liquid cultures but P. baeocystis happened to be one and if the culture media are right, it produces psilocybin and several analogs. With advanced technics nowadays, production of psilocybin from Psilocybe spp in fermentation vessels should be feasible. In carboys, the highest yield of psilocybin, psilocin, and analogs was in 2 weeks, then it rapidly declined. Several papers re these findings were published in J. Pharm. Sci. and Lloydia in the late 1960s.

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