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Understanding the evolution of Psychedelics

Neuroletter, Volume 2 Issue 1

The door to psychedelics was first opened in 1938 when the discovery of Lysergic Acid Diethylamide (LSD) came into the picture. [1] Lysergic Acid Diethylamide (LSD) was first synthesized by Albert Hoffman. [1] The psychoactive properties of LSD in 1943 gave a major boost to psychedelic research in the 20th century. The discovery of LSD is considered the discovery of the “Great Chemical '' which unfolded the mystery of psychedelics to the world. However, granting the entire credit to LSD will do an injustice to other psychedelics such as mescaline, psilocybin, DMT, and Ololiuhqui (a Mexican seed, also known as “magic” morning glory seeds). The research interest in these psychedelics either preceded or coincided with LSD. Psychedelic drugs obtained hype during the 1950s and 1960s due to their potential to treat alcoholism, depression, and anxiety. [1] However, ethical issues, pressure from political parties in power and opposition, and sensational news from the media led to the halting of the research and use of LSD and other psychedelics. [2] Fortunately, the halt was temporary and research on psychedelics again began in the year 1994. [2]

Psychedelics can be classified as classical and nonclassical, a classification first devised in 1960. Classic psychedelic compounds are so-called mainly because they interact with the serotonergic system. Most of them are derived from plants or are semi-synthetic. Classical psychedelics include LSD psilocybin, N, N-dimethyltryptamine (DMT), 5-

MeO-DMT, lysergic acid amide, mescaline, etc. Nonclassical psychedelics are synthetic compounds like MDMA, MDA, ketamine, etc.[3]

Classic psychedelics primarily act on the serotonin receptor known as 5HT2A. They are either partial agonists or agonists at these receptors. Although many people suggested the role of serotonin in the action of psychedelics, Vollenweider et al. (1998) were the first to definitively prove the role of 5HT2A receptors. They showed that the 5-HT2A receptor-selective antagonist ketanserin blocked the effects of psilocybin. [4] Visual hallucinations produced by classical psychedelics are due to the activation of postsynaptic 5HT2A receptors in layer V of the medial prefrontal cortex. [5] 5HT2A receptor is a metabotropic receptor, i.e. it is a G protein-coupled receptor. Its activation triggers a molecular cascade that activates a protein, beta-arrestin, a key molecule behind the “psychedelic experience”. [6] Other receptors are also variably involved in the action of psychedelics. These include other serotonin receptors like 5HT1A, dopamine receptors D1 and D2, and glutamate receptors.[7]

The ego dissolving effect produced by psychedelics suggested the location of these receptors in the brain. Pazos et al. (1985), found that 5HT2A receptors were present in high density in the cerebral cortex. [8] Further studies reported these receptors in the thalamus, locus coeruleus (LC), basal ganglia, primary visual cortex, and ventral tegmental area (VTA). These brain regions play a key role in sensory perception and cognition. Hemodynamic changes lead to increased blood flow in these areas, contributing to the strong experiences produced by a psychedelic. [9]

Their role in psychiatric illnesses and addiction is attributed to their action on these receptors. While most research on psychedelics had ended with the Controlled Substances Act of 1970, the renewed interest and research on these compounds since 1994 have substantiated the claims of their therapeutic benefit. [10] Most studies have found psychedelics to be relatively safe and have little to no abuse potential. [11] Researchers are studying indigenous populations who have been using psychedelics traditionally to experience moments of enhanced consciousness to explore their applications in modern society. [12] More recently, they are effective anti-inflammatory drugs. [13]

An accidental journey that began in 1943, led to these compounds being referred to as miracle drugs. Psychiatric illnesses like mood disorders and PTSD had a faster, more effective treatment. In the past 80 years, our understanding of psychedelics has vastly changed. We now know much more about the hows and whys regarding psychedelics yet we are far from solving this mystery. We need more studies regarding their efficacy, the practice of microdosing, their long-term side effects, and most feared, their abuse potential.


1. Jacob S. Aday, Emily K. Bloesch & Christopher C. Davoli (2019) Beyond LSD: A Broader Psychedelic Zeitgeist during the Early to Mid-20th Century, Journal of Psychoactive Drugs, 51:3, 210-217

2. Aday, Jacob S.; Mitzkovitz, Cayla M.; Bloesch, Emily K.; Davoli, Christopher C.; Davis, Alan K. Long-term effects of psychedelic drugs: A systematic review. Neuroscience & Biobehavioral Reviews, 2020; 179-189

3. Inserra A, De Gregorio D, Gobbi G. Psychedelics in psychiatry: neuroplastic, immunomodulatory, and neurotransmitter mechanisms. Pharmacological Reviews. 2021 Jan 1;73(1):202-77.

4. Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport. 1998 Dec 1;9(17):3897-902.

5. De Gregorio D, Enns JP, Nuñez NA, Posa L, Gobbi G. d-Lysergic acid diethylamide, psilocybin, and other classic hallucinogens: mechanism of action and potential therapeutic applications in mood disorders. Progress in brain research. 2018 Jan 1;242:69-96.

6. Schmid CL, Bohn LM. Physiological and pharmacological implications of beta-arrestin regulation. Pharmacology & therapeutics. 2009 Mar 1;121(3):285-93.

7. Ray TS. Psychedelics and the human receptorome. PloS one. 2010 Feb 2;5(2):e9019. 8. Pazos A, Hoyer D, Palacios JM. The binding of serotonergic ligands to the porcine choroid plexus: characterization of a new type of serotonin recognition site. European journal of pharmacology. 1984 Nov 27;106(3):539-46.

9. Spain A, Howarth C, Khrapitchev AA, Sharp T, Sibson NR, Martin C. Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain. Neuropharmacology. 2015 Dec 1;99:210-20.

10. Act, Controlled Substances. "Controlled Substances Act." (1970).

11. Schlag AK, Aday J, Salam I, Neill JC, Nutt DJ. Adverse effects of psychedelics: From anecdotes and misinformation to systematic science. Journal of Psychopharmacology. 2022 Mar;36(3):258-72.

12. Nichols DE. Psychedelics. Pharmacological reviews. 2016 Apr 1;68(2):264-355.13. Flanagan TW, Nichols CD. Psychedelics as anti-inflammatory agents. International Review of Psychiatry. 2018 Jul 4;30(4):363-75.

Authors: Visakha Gouda, Harsh Srivastava

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