Today's Curio(ous) highlights include:

• What is a psychedelic?
• What are the effects of different psychedelics?
• Is ketamine a psychedelic?

A Dive into Definitions

It has been a subject of discussion and debate what a “true” psychedelic is. The TL;DR version is that we are all still figuring out what to call different compounds and how to use them for reliable effects in the clinical setting.

Today, I hope to clear up some of the confusion behind the question, “Is ketamine a psychedelic?”

What is a “psychedelic?”

The term psychedelic comes from Greek. psykhe meaning "mind" and deloun meaning "make visible, reveal," from delos "visible, clear." ¹

The term was first coined by Humphry Osmond in 1956 in a letter to Aldous Huxley (yes, the author of Brave New World). Osmond was a psychiatrist who conducted pioneering research in his Canadian laboratory. Some of his work included helping cure addiction to alcohol using LSD. One of his patients was Bill W, who later co-founded Alcoholics Anonymous. ²

Notably, however, there is not an agree-upon boundary for what specifically defines a psychedelic. It is generally agreed that psychedelic states are those with meditative, psychodynamic, or transcendental alterations of the conscious state. The rest of the criteria for definition as a psychedelic differ from authority to authority, group by group. ³

Different types of chemistry

One common way to distinguish classes of psychedelics from one another are by mechanism, or families of chemical compounds. Here we’ll describe the differences as noted by their main neurotransmitter and/or receptor action. This is the easiest way to get a better sense of the overall effects of each class of psychedelic, although there are many other ways to categorize and slice and dice the dozens of psychedelic compounds existing.

Serotonin

Serotonin (AKA 5-hydroxytryptamine or 5-HT) is the neurotransmitter commonly tied to mood, sleep, appetite, temperature regulation, anxiety, digestion including nausea, and more.⁴ It is the reason by SSRIs like escitalopram (Lexapro) or fluoxetine (Prozac) have broad-reaching side-effects from weight gain to sexual disfunction. Its receptors are also the ones impacted by most of the classical psychedelics, including DMT, LSD, mescaline, and psilocybin.

Because of their cultural significance, most people call such classical psychedelics the “true” psychedelics. The effects vary from compound to compound, but subjective experiences have been reported below in research studies:

LSD: bliss, audiovisual synesthesia, altered meaning of perceptions, derealization, depersonalization, and mystical experiences. It increases feelings of closeness to others, openness, trust, and suggestibility.⁵

Psilocybin: feelings of joy, bliss, and love, embodiment, ineffability, alterations to identity, interconnectedness, transient psychological distress, appearance of loved ones as guiding spirits, and synesthesia.⁶

DMT: rapidly moving, brightly colored visuals, loss of control with a “rush,” dissociation, euphoria, anxiety, and less commonly audio hallucinations.⁷

As you can tell, while there are differences due to the different structures of each psychedelic, these serotonergic medicines tend to all have similar effects on emotion, visuals, and synesthesia. There are dozens of other psychedelics in this category, such as 5-MeO-DMT and Bufo, among may others.

Quick note - while these psychedelics work on serotonin, the same that SSRIs work on, the benefit of intermittent use of psychedelics as an intervention is that you avoid the side effects of long-term frequent use (as in SSRI treatment). More on this in future issues.

Norepinephrine

Epinephrine and norepinephrine are the neurotransmitters we refer to when we say “adrenaline rush.” They make your heart beat faster, blood pressure go up, and energy spike. Note that while I’m categorizing the following under norepinephrine, the truth is our most common psychedelics here also affect other neurotransmitters to a large extent, leading to a mixed bag of subjective experiences.

Mescaline (Peyote): euphoria, hallucinations, depersonalization, and psychoses. It also causes sympathomimetic effects, which include muscle stiffness, agitation, tachycardia (faster heartbeat), increased temperature, etc.⁸

MDMA: extreme emotion, increased energy, body temperature changes, dehydration, and nausea.⁹ Note that this is not a classic psychedelic, and does not have a 5-HT2A receptor agonist (unlike the serotonergic psychedelics mentioned above). It is instead a serotonin releasing agent (empathogen) and, in fact, results in a huge release of norepinephrine and somewhat less of dopamine as well. This is what causes the huge burst of extreme feeling people describe subjectively on MDMA.¹⁰

Glutamate

While I am categorizing the one psychedelic of note here (ketamine), the reality is that ketamine is a multi-effect drug that is complicated to categorize simply.

Ketamine: dissociative experiences such as disembodiment and ego transcendence (ego dissolution), alertness disturbances (somnolence or insomnia), and sensory disturbances including taste changes, numbness, tingling, hot, cold.^{11 12}

Notably, ketamine has a higher association with some of the most powerful psychedelic effects, including ego dissolution. This is an area in need of greater research, but practitioners note that such effects may be related to a psychedelic’s positive effects on emotional healing and growth.

What does it all mean?

I realize that this issue has been full of scientific terms which may have caused confusion as well as clarity. To help simplify, here are some concluding thoughts:

• Psychedelics have a variety of mechanisms depending on their chemical structure.
• Different psychedelics have different effects when taken.
• We are in an exciting time of blossoming research and clinical use specific to each psychedelic’s effects.
• Ketamine is indeed a psychedelic.
• We should perhaps get used to referring to psychedelics more based on their effects than their chemical compounds, which vary greatly.

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About the Author

Hillary Lin, MD is a Stanford-trained physician and Co-founder of Curio - Psychedelics for Healthcare. She is an advisor to digital health companies and published researcher in the fields of neuroscience, medical education, and oncology. Follow her @hillarylinmd on Twitter, Instagram, and TikTok.

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References

1. Psychedelic (adj.). Etymology. (n.d.). Retrieved August 30, 2022, from https://www.etymonline.com/word/psychedelic
2. Wikipedia contributors. (2022, August 16). Humphry Osmond. In Wikipedia, The Free Encyclopedia . Retrieved 19:14, August 30, 2022, from https://en.wikipedia.org/w/index.php?title=Humphry_Osmond&oldid=1104660435
3. Wikipedia contributors. (2022, August 30). Psychedelic drug. In Wikipedia, The Free Encyclopedia. Retrieved 19:18, August 30, 2022, from https://en.wikipedia.org/w/index.php?title=Psychedelic_drug&oldid=1107520434
4. MOHAMMAD-ZADEH, L.F., MOSES, L. and GWALTNEY-BRANT, S.M. (2008), Serotonin: a review. Journal of Veterinary Pharmacology and Therapeutics, 31: 187-199. https://doi.org/10.1111/j.1365-2885.2008.00944.x
5. Liechti, M. Modern Clinical Research on LSD. Neuropsychopharmacol 42, 2114–2127 (2017). https://doi.org/10.1038/npp.2017.86
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7. Strassman RJ, Qualls CR, Uhlenhuth EH, Kellner R. Dose-Response Study of N,N-Dimethyltryptamine in Humans: II. Subjective Effects and Preliminary Results of a New Rating Scale. Arch Gen Psychiatry. 1994;51(2):98–108. doi:10.1001/archpsyc.1994.03950020022002
8. Dinis-Oliveira RJ, Pereira CL, da Silva DD. Pharmacokinetic and Pharmacodynamic Aspects of Peyote and Mescaline: Clinical and Forensic Repercussions. Curr Mol Pharmacol. 2019;12(3):184-194. doi: 10.2174/1874467211666181010154139. PMID: 30318013; PMCID: PMC6864602.
9. Baylen, C.A. and Rosenberg, H. (2006), A review of the acute subjective effects of MDMA/ecstasy. Addiction, 101: 933-947. https://doi.org/10.1111/j.1360-0443.2006.01423.x
10. Mustafa NS, Bakar NHA, Mohamad N, Adnan LHM, Fauzi NFAM, Thoarlim A, Omar SHS, Hamzah MS, Yusoff Z, Jufri M, Ahmad R. MDMA and the Brain: A Short Review on the Role of Neurotransmitters in Neurotoxicity. Basic Clin Neurosci. 2020 Jul-Aug;11(4):381-388. doi: 10.32598/bcn.9.10.485. Epub 2020 Jul 1. PMID: 33613876; PMCID: PMC7878040.
11. Vlisides, P. E., Bel-Bahar, T., Nelson, A., Chilton, K., Smith, E., Janke, E., Tarnal, V., Picton, P., Harris, R. E., & Mashour, G. A. (2018). Subanaesthetic ketamine and altered states of consciousness in humans. British Journal of Anaesthesia, 121(1), 249–259. https://doi.org/10.1016/j.bja.2018.03.011
12. Enarson, M. C., Hays, H., Woodroffe, M. A., & Bscn. (1999). Clinical experience with oral ketamine. Journal of Pain and Symptom Management, 17(5), 384–386. https://doi.org/10.1016/s0885-3924(99)00011-1

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