Posts Tagged ‘ psilocybin

Biosynthesis of 4-Substituted Tryptamine Derivatives

Biological organisms are wondrous little molecular factories, their enzyme catalyzed reactions often accomplishing in a single step what would confound a chemist in a well-stocked laboratory. Researchers have attempted to harness these biosynthetic pathways to create complex molecules not easily synthesized by conventional methods.

Psilocybin is produced via a biosynthetic grid where enzymes act on various closely related intermediate compounds in turn. The enzymes do not appear to be particularly picky about the compounds they modify. For instance, dimethyltryptamine (DMT) is hydroxylated to 4-HO-DMT naturally in psilocybin mushrooms. Other precursor compounds like tryptamine and methyltryptamine are also hydroxlyated to 4-hydroxy-tryptamine and 4-hydroxy-methyltryptamine respectively.

If an entirely new synthetic tryptamine of similar structure was introduced to these mushrooms, would the same enzymes act on it? This could produce a new and unique psychedelic compound where some of the heavy lifting of synthesis is accomplished by the biological expertise of the mushroom itself and not by conventional laboratory chemistry.

Jochen Gartz decided to attempt this by adding diethyltryptamine (DET, a close relative of DMT) to the fruiting body of psilocybe cubensis. He hoped that it would be hydroxylated to 4-HO-DET, or possibly phosphorylated even further to 4-PO-DET. He first colonized a mixture of cow dung and rice grain with psilocybe cubensis, and then injected it with a solution of DET. Within four weeks mushrooms were produced, and five total flushes of mushrooms were obtained.

First Second Third Fourth Fifth
4-HO-DET 2.5% 0.2% 3.1% 3.3% 2.1%
4-PO-DET - 0.8% 0.01% - 0.02%

all values % by weight of dry mushroom

The project was a success, with significant amounts of 4-HO-DET produced. No DET was found in the dried mushrooms. A mass balance was not conducted to determine the efficiency of the conversion and possible losses in the fruiting body itself. The demonstrated non-selectivity of the enzymes in psilocybe cubensis toward other tryptamine derivatives opened to the door to the possibility of producing truly exotic and difficult to synthesize compounds such as 4-HO-5-MeO-DMT.

Despite this little additional data is available on the tryptamine derivatives that are able to be substituted in the fruiting body and the repeatability of the experiment. Some have found little success, noting only a decrease in the size of the mushrooms produced. Other attempts have discovered perhaps a qualitative difference in potency and character of the psychedelic experience, but this has not been substantiated by quantitative measurement.


Biotransformation of tryptamine derivatives in mycelial cultures of Psilocybe
. Gartz, J. Journal of Basic Microbiology, Volume 29, Issue 6, Pages 347-352 (1989).

Grid Biosynthesis of Psilocybin

The biosynthesis of psilocybin in psychedelic mushrooms is a multi-step process, and the precise mechanism is debated by many authors. The essential amino acid l-tryptophan undergoes several modifying reactions (decarboxylation, N-methylation, 4-hydroxylation, and O-phosphorylation) but the specific order is unclear. A series of steps similar to the following is generally accepted.

Experiments with radiolabled precursors have shown that this is likely the primary path to psilocybin, however, labelled 4-hydroxytryptamine was also shown to be incorporated into the produced psilocybin indicating the possibility of an additional biosynthetic pathway. Other alkaloids present in psilocybin mushrooms such as baeocystin or norbaeocystin are not explained by this single pathway as well.

An elegant alternative has been proposed. What if instead of a single path and a set order of modifying reactions, there were multiple paths to psilocybin – with branching edges that led to baeocystin and norbaeocystin? The enzymes would compete and feed back among each other in a biosynthetic grid that preferred to produce psilocybin and psilocin but also produced small amounts of baeocystin and norbaeocystin as typically seen in nature.

There is no longer a preferred order to the modifying reactions, except for the obvious that 4-hydroxylation must precede O-phosphorylation. There are three paths to psilocin and psilocybin (the predominant alkaloids in psychedelic mushrooms), two paths to baeocystin (found in lesser concentrations than the two signature alkaloids), and one path to norbaeocystin (found in the lowest concentrations, if it is detectable at all). The number of paths does not indicate the absolute likelihood of producing a certain alkaloid, but it can be seen as a measure of resiliency. The precise weighting of each connection in the network is not clear at this point, or even if a steady state model would be an appropriate approximation.

Biosynthesis of Psilocybin. Part II: Introduction of Labelled Tryptamine Derivatives. S. Agurell and J. Lars G. Nilsson. Acta Chemica Scandinavica 22 (1968), 1210-1218.

Baeocystin and Norbaeocystin: New Analogs of Psilocybin from Psilocybe baeocystis. A.Y. Leung and A.G. Paul. Journal of Pharmaceutical Sciences, Vol. 57, No. 10, October 1968, 1667-1671.

Tryptamines as Ligands and Modulators of the Serotonin 5-HT2A Receptor and the
Isolation of Aeruginascin from the Hallucinogenic Mushroom Inocybe aeruginascens
. Niels Jensen, Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultäten der Georg-August-Universität zu Göttingen, 2004.

Psychedelics in the Public Consciousness

Google Ngram is a very interesting project which measures the frequency of the occurrence of words in a large body of books published over the last several hundred years. This can be considered somewhat as a measure of public awareness of a certain term, so let’s use it to see how various prominent psychedelic compounds (mescaline, LSD, psilocybin, and MDMA) have risen and fallen in the public consciousness from 1900 to 2000.

The first thing we see is that psychedelic compounds as a whole are a very new concept, entering popular usage only in the middle of the 20th century with knowledge becoming more widespread in the 1960s. The word LSD has an almost overwhelming frequency of use, reflecting the intimate association of the drug with the popular concept of the psychedelic experience. Switching this out for “lysergic acid diethylamide” should allow us to compare relative trends with other psychedelic compounds due to decreased frequency while still maintaining a sensible relation to the original term.

This normalizes the dataset somewhat.

Mescaline had been used for thousands of years until it was first isolated and identified in 1897. It slowly grew in the public consciousness until Aldous Huxley’s 1954 work The Doors of Perception thrust the compound into the mainstream.  
LSD (lysergic acid diethylamide) was first consumed by Albert Hofmann in 1943, initially introduced to the market as a psychiatic drug in 1947, and its potential became more clear with corporate and government experiments during the 1950s including the infamous Project MKULTRA. High potency and its positive character led to efficient distribution and widespread use in the 1960s.  
Psilocybin is another ancient compound with sacramental use spanning thousands of years. Vice President of J.P. Morgan and amateur mycologist R. Gordon Wasson travelled to a remote village of Mexico on a rumor that their religion included ingestion of mushrooms. In 1957, he published an article in Life magazine entitled Seeking the Magic Mushroom that did for psilocybin what Huxley did for mescaline.  
MDMA was first synthesized in 1912, but it languished in obscurity until the mid-1970s when Alexander Shulgin, then at University of California, heard from his students about unusual effects of the amphetamine derivative. In 1978 he and David Nichols published the first report on the drug’s psychotropic effect in humans and its use spread among the psychiatric community as an adjunct to therapy. MDMA used in a recreational context was first reported in gay nightclubs in the Dallas area in the early 1980s with usage peaking during the 1990s rave scene.  

Other trends become apparent when we separate our observations geographically. While the opportunity to do this is necessarily limited due to language restrictions, we can compare American English usage with British English usage quite easily from 1950 to 2000.

We can see that MDMA citations peaked in the mid 1990s in American English as the British rave scene made noise in North America, but the trend faded in the US while use continued to climb in British English.