PROBLEM SOLVED: Why no DMT in Magic Mushrooms?

Why No DMT in Magic Mushrooms?

For decades, scientists have wondered why DMT (N,N-Dimethyltryptamine or N,N-DMT) is not found in any of the over 200 species of mushrooms that produce psilocybin.  Recent studies regarding the biosynthesis of psilocybin provide an answer to this age-old question.

Longstanding Questions about DMT

In 1997, Alexander and Ann Shulgin published their groundbreaking research on the group of psychoactive drugs known as tryptamines in a book titled TiHKAL.In TiHKAL, Dr. Shulgin studied about 50 tryptamine derivatives, including many psilocybin derivatives.  Through these studies, he published the first syntheses for many previously unknown tryptamine molecules. He also (bravely) published anecdotal reports on the effects of these molecules had on him. Shulgin laid the groundwork for elucidating the structure-activity relationship within this class of molecules.

Despite Shulgin’s pioneering work in this area, he was never able to understand why DMT was never found in magic mushrooms:

“All of these [mushrooms] contain 4-hydroxy-DMT compounds in various guises, but not one of them contains DMT, which I find totally amazing.”

Until recently, this was a curious problem because tryptamine molecules are abundant in nature — yet two important and structurally similar analogs could never be found in the same place at the same time.

The Answer to Shulgin’s DMT Puzzle

Recently, a team of scientists characterized four psilocybin biosynthesis enzymes, which are responsible for converting tryptophan (a naturally occurring amino acid) into psilocybin and its derivatives.Aside from making several other contributions to the field, the paper shows the most plausible biosynthetic pathway for making psilocybin:

  1. Decarboxylation of tryptophan to tryptamine
  2. 4-hydroxylation of tryptamine
  3. Phosphorylation of 4-hydroxytryptamine to norbaeocystin
  4. Methylation of norbaeocystin to baeocystin
  5. Methylation of baeocystin to psilocybin
  6. Methylation of psilocybin to aeruginascin.

The previously accepted biosynthetic pathway stated tryptamine (from step #1 above) was first methylated before hydroxylation and phosphorylation. The molecular sites of the reactions are shown below in Figure 1.

DMT
Figure 1: A DMT molecule showing two different sites that are modified to make psilocybin.

This change in understanding regarding the biosynthetic pathway of psilocybin explains why DMT is never found in mushrooms:

  • Making DMT would require methylating tryptamine before further the other biosynthetic steps.
  • But, new research shows that tryptamine gets “used up” before any methylation takes place.

Opportunities for Future Research in DMT Synthesis

The new information about the biosynthetic pathway of psilocybin explains why DMT is not found in magic mushrooms.  This information also raises questions as to whether we could cultivate mushrooms that do make DMT.  At a high level, making DMT could be accomplished by finding methyltransferase enzymes that accept tryptamine as a substrate and/or slowing down the monooxygenase enzyme that converts tryptamine into 4-hydroxytryptamine.

** As always, we would appreciate your feedback (or suggested changes) on any information presented here.  Our only goal is getting it right.  Your help is welcomed and appreciated.

References

1. TiHKAL. In: Wikipedia. 2018. https://en.wikipedia.org/w/index.php?title=TiHKAL&oldid=823540789. Accessed September 30, 2018.
1. Fricke J, Blei F, Hoffmeister D. Enzymatic Synthesis of Psilocybin. Angewandte Chemie International Edition. 2017;56(40):12352-12355. doi:10.1002/anie.201705489