Psilocybin has gained popularity as of late as a wonder drug of sorts. It has been used therapeutically, ritualistically and recreationally for millennia, and for good reason. Psilocybin may be useful for the treatment of a multitude of psychological conditions and chronic pain. Recent studies by researchers at Johns Hopkins Medicine have confirmed that psilocybin is effective at treating depression for not only one month as previously reported, but up to one year. Oregon legalized “magic mushrooms” in 2020 by the passage of Measure 109. This measure allows the use of psilocybin at licensed treatment facilities under the supervision of a care professional. Denver, CO and Oakland, CA have individually decriminalized magic mushrooms and offer similar treatment options.
In other words, the use of psilocybin as a therapeutic no longer seems to be disputed as legalization starts to take hold. So lets do as nerds do and talk about how this amazing neurotransmitter, psilocybin, is actually synthesized in magic mushrooms. Fun fact, it all starts with the amino acid tryptophan!
Who Are the Magic Mushrooms
The “magic” mushrooms are considered psychedelic because they synthesize various neurotransmitters that light up the brain. There is actually quite a lengthy list of compounds identified as “psychedelic”. The Psilocybin specific magical mushrooms are generally categorized as Psilocybe carpophores. The synthesis of psilocybin by enzymes in species P. cubensis was the primary focus of a recent study published in Angewandte Chemie, where the following enzymatic pathways were revealed.

The Magic of Enzymatic Synthesis
It’s as if nature just decides to place little puzzle pieces together. The wonders of how enzymes catalyze organic chemistry reactions have baffled us simple benchtop chemists for centuries. Below I’ll describe, briefly, the stepwise biosynthetic pathway of psilocybin in P. cubensis as proposed by Fricke et. al.
Tryptophan Decarboxylase PsiD
This enzyme comes in and does what we here at Decarbitation do best: it decarboxylates our starting material, tryptophan, to form tryptamine. Apparently this enzyme was particularly interesting, as it was identified as a new class of fungal L-tryptophan decarboxylases.

P450 Monooxygenase PsiH
Then this crazy enzyme comes in and just like that, tacks on a hydroxyl -OH group, generating 4-hydroxytryptamine.

Kinase PsiK
Then kinase comes along and assists with the phosphorylation step. During this process, ATP (adenosine tri-phosphate, our primary source of energy!) is broken down into ADP (adenosine di-phosphate) and the intermediate norbaeocystin is formed. This step causes chemists in the lab a great headache, as phosphorylation agents are generally quite reactive and dangerous. All the more reason to keep the plants doing their thing!

Methyl transferase PsiM
The final step in this biosynthesis also seems to pose a challenge for benchtop synthetic chemists attempting to recreate this in the lab: selective methylation of the amine group, twice.

What Lies Ahead
It’s still very difficult to synthesize psilocybin at a large scale. Interestingly enough, psilocybin is not actually itself responsible for the ‘high’ experienced with ingesting psilocybin, but rather it is psilocin, the topic for another day. It will be interesting to see how the laboratory synthesis progresses, now that we better understand the biosynthetic pathways of psilocybin.
Very interesting!