Introduction
Psychedelics are recreational drugs that induce visual hallucinations and warp perceptions of time. Although they are predominantly used in spiritual practices, their use is considered illegal under US law. Two hallucinogens are the most well-known and stand out amongst the rest. These are LSD (lysergic acid diethylamide) and psilocybin (magic mushrooms). What is the origin and chemistry of these two mind-bending and fascinating drugs that took the world by storm in the 1960’s all the way up until today?
Firstly, there are two ways to group the vast number of hallucinogens. One of these ways is to group them based on whether they are natural or synthetic. Naturally occurring psychedelics include psilocybin (magic mushrooms) and N, N-dimethyltryptamine (DMT), while synthetic psychedelics include lysergic acid diethylamide (LSD) and ketamine. Another way (which is perhaps more interesting) is grouping them based on their chemical structures, the two groups being Tryptamines and Phenethylamines. LSD and psilocybin are both considered tryptamine psychedelics. Let's dive further into their structure.
Tryptamines
Figure 1: Chemical structure of indolealkylamines. Credit: Indolealkylamines: biotransformations and potential drug-drug interactions.
To understand the chemistry of LSD and Psilocybin, it is essential to first understand their molecular structure. Tryptamine is a monoamine alkaloid: an alkaloid that contains one amino group connected to an aromatic ring by a two-carbon chain. The tryptamine skeleton is found in the vast majority of psychedelics such as DMT. Psychedelics can also be classified as indole alkaloids, a class of plant-derived alkaloids which contain indole rings, which is the basis of their structure. Neurotransmitters such as dopamine and serotonin are very similar to psychedelics in their chemical structure, as they also possess the tryptamine skeleton and indole ring. This similarity in structure allows for psychedelics such as LSD to activate and bind to the 5HT2A receptor with high affinity.
Even more specifically, tryptamines can be divided into two subsets: simple tryptamines and ergolines. Simple tryptamines include 5-methoxy diethylamide (5-MeO DMT) and psilocybin, which are considered configurationally flexible. Ergolines such as LSD are considered to be a more rigidified tryptamine, and this rigidness helps the potency of the drug. Ergolines are complex molecules, containing a tricyclic ergoline structure. Some people, however, consider ergolines as their own group.
LSD.
Lysergic acid diethylamide, more commonly known as LSD, is a powerful hallucinogenic belonging to a class of compounds called ergolines. LSD is a semisynthetic drug derived from a substance found in the fungus called ergot, making it an ergoline alkaloid. In a typical dose of 20-80 micrograms, LSD can cause changes in mood, perception, thought and cause visual disturbances. In higher doses of 300 micrograms it can warp the user’s perception of time and space. Like most psychedelics, LSD is a partial agonist to the 5HT2A receptor, which is considered to be the way it creates its effects of euphoria and synaesthesia, though its true mechanism of action is not fully understood yet. It is colorless, odorless and its solubility in water allows it to rapidly dissolve when placed on the tongue. It is commonly taken in paper blots, where it then dissolves on the tongue. Although it is an illegal substance in the U.S, it was never made to be a recreational drug, but rather for medicinal purposes. Before the boom in its recreational usage in the 1960s, LSD was on its way to becoming a therapeutic treatment against alcoholism. However, this research was quickly halted and abandoned when Sandoz Pharmaceutical laboratory (where it was first synthesized) stopped development and when it was made illegal. In modern times, LSD, as well as other psychedelics, are making a comeback in the realm of medicine, with researchers realizing the anti-depressant effects that LSD can induce.
Returning to its chemistry, LSD is a condensation product of lysergic acid and diethylamide. Lysergic acid is composed of 6-methyl ergoline, an ergoline alkaloid derived from a hydride of ergoline. When it reacts with diethylamide, the hydroxyl group of the lysergic acid is displaced by the diethylamide functional group, resulting in LSD. At its core structure, it is a bicyclic compound, with four cyclic carbon atoms attached to a six-membered benzene ring fused with a pyrrole, known as an indole ring. It also contains a diethylamide functional group. Other functional groups that LSD contains are a carboxylic acid group, primary amine, and secondary amine group. LSD is a chiral compound with two chiral centers, meaning that four optical isomers of LSD exist: D-, L-, D- isomer, and L-isomer. D-isomer LSD is the only hallucinogenic isomer.
Synthesis of LSD
The first synthesis of LSD was conducted by Swiss chemist Albert Hoffmann, who synthesized the ergot alkaloid over 80 years ago at Sandoz Pharmaceutical Laboratories in Switzerland. Today, there are approximately 22 methods of LSD synthesis, which are performed through either biotechnological methods or through organic synthesis.
The first method for LSD synthesis was published in 1956 by Robert B. Woodward, titled “The Total Synthesis of Lysergic Acid”. Woodward was a renowned organic chemist known for his synthesis of complex organic molecules which helped him acquire a Nobel Prize in chemistry. The synthesis involves a fifteen-stage sequence. Beginning with β-carboxyethyl dihydroindole, it is then made into a tricyclic ketone 5-1-benzoyl-2,2a,3,4-tetrahydrobenzo(cd)indol-5(1H)-one. The amine is then introduced by adding an alkyl fragment at the C4 or C5 position which then closes the D ring. Finally, the racemic product (a mixture of two chiral molecules) is isolated, and LSD is obtained. However, the synthesis faced a challenge, as its hetero ring was highly reactive which could create undesirable byproducts. Woodward and his team overcame this problem by using dihydroindole compounds as the base, and then planning on turning it into the indole of LSD later in the synthesis.
Psilocybin
Psilocybin, more commonly known as “magic mushrooms” or “shrooms”, is a naturally occurring psychedelic prodrug and tryptamine alkaloid, which contains an active compound named “Psilocin”. Psilocybin can be found in over 200 species of fungi such as Psilocybe cubensis and Psilocybe semilanceata (liberty caps). Magic mushrooms are considered sacred and are extremely important to many indigenous groups around the world for their spiritual and medicinal use. The effects and duration of a trip vary from person to person and depend on how much was taken and the species of fungi taken. When ingested, psilocybin makes a person giggly, euphoric, excited yet paranoid and anxious, as well as warping the ingestor’s senses.
When psilocybin enters the body and travels through the intestines, it is absorbed by the blood, which is then filtered through the liver. In the liver, psilocybin is transformed into psilocin by dephosphorylation, caused by alkaline phosphatase (a kind of enzyme found throughout the entire body). Afterwards, the psilocin makes its way into the brain, where it interacts and binds to a serotonin receptor. Dephosphorylation is a process in which a phosphate group is removed from an organic compound via hydrolysis by enzyme phosphates. This causes the psychedelic experience to last 4-8 hours.
Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine) contains a tryptamine structure and diethylamide substitute at the amine position. It also contains a phosphate ester at the 4-position. The molecular formula for psilocybin is C12H17N2O4P with a molecular weight of 284.25 g/mol. Psilocybin is soluble in water, methane, and ethanol. It is also partially soluble in acidic solutions due to its phosphate ester. Its appearance is that of a white crystal.
The dephosphorylated model, psilocin (4-Hydroxy-N, N-dimethyltryptamine), contains a hydroxyl group at the 4-position, and 2-methyl groups attached to its amino nitrogen. The molecular formula for psilocin is C12H16N2O with a molecular weight of 204.27 g/mol. Psilocin is soluble in water, mostly soluble in methane and ethanol, but insoluble in chloroform and hexane.
Isolation and synthesis of Psilocybin
Albert Hoffman and his team were the first to isolate and synthesize both psilocybin and psilocin from the Mexican plant Psilocybe mexicana in 1959. Although there isn't much information as to how exactly the isolation was performed, his employer sold it to various doctors to be used for therapeutic purposes.
In 2017, Dirk Hoffmeister and his colleagues finally identified the biosynthesis of psilocybin after a long period of mystery. They identified that the drug can be synthesized enzymatically in four steps starting from 4-hydroxy-l-tryptophan. This discovery leads to the possibility of psilocybin becoming a biotechnological foundation used in medicine and agriculture. The four steps to this synthesis are as follows:
PsiD
In this step, the fungal enzyme PsiD decarboxylates the L-Tryptophan to form tryptamine, which as mentioned before, is the basic structure found in Psilocybin. Decarboxylation is the removal of a carboxyl group (-COOH), in return this causes the release of carbon dioxide (CO2).
PsiK
The enzyme, PsiK, catalyzes the phosphototransfer in this step. The PsiK transfers a phosphate group from a donor molecule to an acceptor molecule which would be the tryptamine. This creates 4-phosphoryloxy-tryptamine.
PsiM
Again, another transfer happens; the enzyme in this step catalyzes iterative N-methyl transfer reactions, also known as methyltransferase. PsiM adds two methyl groups to the 4-phosphoryloxy-tryptamine. This step is the most essential for producing psilocybin, as it finally creates 4-phosphoryloxy-N, N-dimethyltryptamine after the addition of the methyl groups.
PsiH
So, what is the point of the final step? PsiH is a monooxygenase enzyme meaning it catalyses the conversion of oxygen atoms into organic molecules. However, the exact role PsiH plays in the enzymatic synthesis of psilocybin is being studied, but it is likely needed for the final modifications and synthesis of the structure.
Conclusion
The chemistry of psychedelics is fascinating, from their chemical structure all the way to their methods of synthesis. Understanding the chemistry of these molecules and how they interact is essential for future drug development and possible treatment against psychiatric disorders. Psychedelics continue to influence mankind, and will likely continue to do so far into the future. In the past, these substances were prominent in Aztec culture, and later were a symbol of the counterculture movement in the 1960s. In the present they are prevalent in pop culture and used by celebrities, and in the future they may finally be used for therapeutic purposes, as originally intended, and pave new paths for drug discovery.
Acknowledgements
Thank you to Alma Altesbehji for checking the spelling and grammar and providing me with feedback.
Reference list
ChEBI (n.d.). tryptamine (CHEBI:16765). [online] www.ebi.ac.uk. Available at: https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:16765.
Clifton, J. (2020). The Science Behind LSD. [online] ReAgent. Available at: https://www.reagent.co.uk/blog/science-behind-lsd/.
DrugBank (n.d.). Indole. [online] go.drugbank.com. Available at: https://go.drugbank.com/drugs/DB04532# [Accessed 5 Jun. 2024].
Fricke, J., Blei, F. and Hoffmeister, D. (2017). Enzymatic Synthesis of Psilocybin. Angewandte Chemie (International ed. in English), [online] 56(40), pp.12352–12355. doi:https://doi.org/10.1002/anie.201705489.
Hall, C. (2014). LSD Synthesis and Discovery: What You May Not Know About It. [online] Chemistry Hall. Available at: https://chemistryhall.com/probably-not-know-discovery-synthesis-lsd/.
Horita, A. and Weber, L.J. (1961). Dephosphorylation of Psilocybin to Psilocin by Alkaline Phosphatase. Experimental Biology and Medicine, 106(1), pp.32–34. doi:https://doi.org/10.3181/00379727-106-26228.
Jastrzębski, M.K., Kaczor, A.A. and Wróbel, T.M. (2022). Methods of Lysergic Acid Synthesis—The Key Ergot Alkaloid. Molecules, 27(21), p.7322. doi:https://doi.org/10.3390/molecules27217322.
Knight, B.J., Harbit, R.C. and Smith, J.M. (2023). Six-Step Synthesis of (±)-Lysergic Acid. The Journal of Organic Chemistry, 88(4), pp.2158–2165. doi:https://doi.org/10.1021/acs.joc.2c02564.
Kornfeld, E.C., Fornefeld, E.J., Kline, G.B., Mann, M.J., Jones, R.G. and Woodward, R.B. (1954). THE TOTAL SYNTHESIS OF LYSERGIC ACID AND ENGROVINE. Journal of the American Chemical Society, 76(20), pp.5256–5257. doi:https://doi.org/10.1021/ja01649a100.
Kwan, A.C., Olson, D.E., Preller, K.H. and Roth, B.L. (2022). The neural basis of psychedelic action. Nature Neuroscience, 25(11), pp.1407–1419. doi:https://doi.org/10.1038/s41593-022-01177-4.
Liechti, M.E. (2017). Modern Clinical Research on LSD. Neuropsychopharmacology, [online] 42(11), pp.2114–2127. doi:https://doi.org/10.1038/npp.2017.86.
Ritter, S.K. (2017). ‘Magic Mushroom’ enzyme mystery solved. [online] Acs.org. Available at: https://cen.acs.org/articles/95/web/2017/08/Magic-mushroomenzyme-mystery-solved.html.
ScienceDirect (n.d.). Tryptamine - an overview | ScienceDirect Topics. [online] www.sciencedirect.com. Available at: https://www.sciencedirect.com/topics/medicine-and-dentistry/tryptamine.
Wang, S., Zhu, A., Paudel, S., Jang, C.-G., Lee, Y.S. and Kim, K.-M. (2023). Structure–Activity Relationship and Evaluation of Phenethylamine and Tryptamine Derivatives for Affinity towards 5-Hydroxytryptamine Type 2A Receptor. Biomolecules & Therapeutics, [online] 31(2), pp.176–182. doi:https://doi.org/10.4062/biomolther.2022.096.
Yu, A.-M. (2008). Indolealkylamines: Biotransformations and Potential Drug–Drug Interactions. The AAPS Journal, 10(2). doi:https://doi.org/10.1208/s12248-008-9028-5.
Comments