Is Kratom a Psychedelic Drug?

Technically the answer is no, but subjective experiences may vary.

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Kratom is a plant with the scientific name Mitragynia speciosa that grows in Southeast Asia and Africa.1 Over 40 compounds have been isolated from the leaves of kratom. Some are biologically active, some are not, and the actions of many are unknown.

What is a Psychedelic Drug?

The term psychedelic was created by English psychologist and researcher Humphry Osmond. He derived it from the Greek words for mind or soul (psyche) and show (deloun) to describe the effect LSD had on the mind. Osmond first used the word in a presentation he gave at the New York Academy of Sciences in 1957.2

Basically, there are two ways to figure out if a drug is a psychedelic. The first is based on its receptor binding. The second is to compare the effects of the drug to what are considered psychedelic effects. If a compound passes the test for either or both, then it is psychedelic.

In terms of receptors, scientists classify a drug as psychedelic if it binds to serotonin 5-HT2A receptors (5-HT2AR) as an agonist or partial agonist (these are typically tryptamine compounds which are chemically similar to serotonin).3–5 The hallucinogenic effects of agonist binding are mediated via the 5-HT2AR receptor-coupled signaling pathway.4,5 This pathway is not entirely understood, but researchers theorize that it involves activation of the enzyme phospholipase C leading to the formation of inositol phosphates and diglycerol (signaling molecules), which causes the release of calcium ions from the endoplasmic reticulum in the cell. The possibility also exists that other serotonin receptors may be involved in the overall psychedelic experience of a user.

From a medical standpoint, it is now understood by researchers that having a mystical experience results in a dramatic improvement for patients using psychedelic-assisted therapy.6–9 However, the mystical phenomenon can occur when using almost any dose of a psychedelic as long as the set and setting have been optimized to promote an altered state of consciousness.3

Kratom is a Cocktail of Compounds

Kratom is an excellent example of the chemical diversity of natural compounds. The leaves of kratom contain several biologically active compounds, including mitragynine, 7-hydroxymitragynine (7-OH), and paynantheine.1,10 Studies indicate that mitragynine and 7-OH have analgesic effects.11–14 Whole-plant extracts from kratom may also have analgesic effects at higher doses.10

Researchers have not evaluated the effects of many of the compounds in kratom. Further, it is unknown if and how these compounds may interact with each other and various receptors in the body. These mysteries make dosing to achieve the desired effects difficult.

The Pharmacodynamics of Kratom

Research thus far indicates that opioid receptors are the primary site of action of several kratom compounds. This is in contrast to many psychedelics that elicit their effects via the 5-HT2A.3,15 Some kratom compounds are active at other serotonin receptor types, however(see below).

For example, both mitragynine and 7-OH are partial agonists at the human mu opioid receptor (hMOR).16,17 The data indicate that 7-OH has a higher potency than mitragynine. The binding affinity for mitragynine was 233 nM and 47 nM for 7-OH (to help with understanding binding affinities, see the PSR article Binding of Psilocin and Psilocybin to Serotonin Receptors). Also, mitragynine and 7-OH are competitive antagonists at the human kappa (hKOR) and delta (hDOR) receptors.

Mitragynine also binds to several other receptor types, including dopamine D2 and the serotonin 5-HT2C and 5-HT7 receptors.18 This bioactivity may prove to be relevant to the overall effects of whole kratom extracts, individual compounds, or both.

Therefore, receptor-wise, kratom compounds do not fit the definition of a psychedelic. This could change with continuing research on the individual compounds.

Comparing the Effects of Kratom and Known Psychedelics

Another way to evaluate if kratom is a psychedelic drug is to compare its effects to those of known psychedelics. Some people share their experiences with kratom on websites like Bluelight and Reddit. Reading over the experience reports reveals that the reviews are mixed about kratom having psychedelic effects, both for experienced psychonauts as well as new users.

The psychedelic website Erowid does not have the terms psychedelic or hallucinogenic listed in their section on the effects of kratom. And, the site PsychonautWiki has kratom listed under opioids, not psychedelics.

From this brief survey, one could conclude two things: 1) The jury is still out as to whether kratom is a psychedelic drug based on the subjective effects of users, and 2) Two of the more well-known websites devoted to the subject don’t classify kratom as a psychedelic drug.

What Do the Experts Say (And Not Say)?

In 2016, psychedelics expert and researcher Dr. David Nichols published a comprehensive paper in Pharmacological Reviews titled simply Psychedelics.3 He does not mention kratom or any of the main compounds it contains. Dr. Nichols does say that,

Mechanistically, psychedelics have agonist or partial agonist activity at brain serotonin 5-HT2A receptors.

A January 2020 review paper in the journal Pain and Therapy says that kratom has “distinctive psychotropic properties.” 19 The authors say,

Given the diversity of alkaloids present in kratom extracts and the unique potential pharmacodynamic properties of each, the net physiological effect of the substance is complex, intermixing stimulant and opiate-like properties in a dose-dependent manner (primarily stimulant-like at low amounts, with opioid effects predominating at higher doses).

So, given the above, it appears that expert researchers do not consider kratom a psychedelic drug.

Summary

The compounds in kratom that have been studied are not psychedelic in terms of activity at what is currently accepted as the main psychedelic receptor, 5-HT2A. However, the activity of mitragynine at other serotonin receptors like 5-HT2C and 5-HT7 is intriguing. A better understanding of this and other receptor activity is essential for getting a complete picture of the pharmacology of mitragynine and other kratom compounds.

In terms of the effects of kratom, some users report psychedelic effects from ingesting whole-plant extracts. However, it must be remembered that there is a great deal of subjectivity built into what is captured in experience reports. Further research may find that individual experiences are highly variable due to the cocktail of compounds in kratom.

Continuing research is needed to understand these kratom compounds. Then, researchers can harness that knowledge by creating formulations with precise amounts of selected compounds.

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    References
  1. Tohar N. Volatile compounds and alkaloids from the aqueous extract of Mitragyna speciosa and their in vitro and in vivo anti-inflammatory studies. Doctoral thesis. University of Malaya, Kuala Lumpur. 2016. https://pdfs.semanticscholar.org/6279/b3f059c3225e71b6f0bb36cb1fa3ff0bc810.pdf.
  2. Osmond H. A Review of the Clinical Effects of Psychotomimetic Agents. Annals of the New York Academy of Sciences. 1957;66(3):418-434. doi:10.1111/j.1749-6632.1957.tb40738.x
  3. Nichols DE. Psychedelics. Pharmacological Reviews. 2016;68(2):264-355. doi:10.1124/pr.115.011478
  4. Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38(8):1083-1152. doi:10.1016/S0028-3908(99)00010-6
  5. Nichols DE, Nichols CD. Serotonin Receptors. Chem Rev. 2008;108(5):1614-1641. doi:10.1021/cr078224o
  6. Garcia-Romeu A, R. Griffiths R, W. Johnson M. Psilocybin-Occasioned Mystical Experiences in the Treatment of Tobacco Addiction. Current Drug Abuse Reviews. 2014;7(3):157-164. https://www.ingentaconnect.com/content/ben/cdar/2014/00000007/00000003/art00005.
  7. Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology. 2006;187(3):268-283. doi:10.1007/s00213-006-0457-5
  8. Griffiths R, Richards W, Johnson M, McCann U, Jesse R. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J Psychopharmacol. 2008;22(6):621-632. doi:10.1177/0269881108094300
  9. Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R. Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology. 2011;218(4):649-665. doi:10.1007/s00213-011-2358-5
  10. Kruegel AC, Grundmann O. The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. Neuropharmacology. 2018;134:108-120. doi:10.1016/j.neuropharm.2017.08.026
  11. Matsumoto K, Horie S, Ishikawa H, et al. Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa. Life Sciences. 2004;74(17):2143-2155. doi:10.1016/j.lfs.2003.09.054
  12. Matsumoto K. Pharmacological Studies on 7-Hydroxymitragynine, Isolated from the Thai Herbal Medicine Mitragyna speciosa: Discovery of an Orally Active Opioid Analgesic. Doctoral Thesis. Chiba University, Chiba, Japan. 2006.
  13. Carpenter JM, Criddle CA, Craig HK, et al. Comparative effects of Mitragyna speciosa extract, mitragynine, and opioid agonists on thermal nociception in rats. Fitoterapia. 2016;109:87-90. doi:10.1016/j.fitote.2015.12.001
  14. Sabetghadam A, Navaratnam V, Mansor SM. Dose-Response Relationship, Acute Toxicity, and Therapeutic Index between the Alkaloid Extract of Mitragyna speciosa and Its Main Active Compound Mitragynine in Mice: Mitragynine Efficacy and Safety. Drug Development Research. 2013;74(1):23-30. doi:10.1002/ddr.21052
  15. Madsen MK, Fisher PM, Burmester D, et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology. January 2019:1. doi:10.1038/s41386-019-0324-9
  16. Kruegel AC, Gassaway MM, Kapoor A, et al. Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. J Am Chem Soc. 2016;138(21):6754-6764. doi:10.1021/jacs.6b00360
  17. Yamamoto LT, Horie S, Takayama H, et al. Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa. General Pharmacology: The Vascular System. 1999;33(1):73-81. doi:10.1016/S0306-3623(98)00265-1
  18. Boyer EW, Babu KM, Adkins JE, McCurdy CR, Halpern JH. Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa korth). Addiction. 2008;103(6):1048-1050. doi:10.1111/j.1360-0443.2008.02209.x
  19. Eastlack SC, Cornett EM, Kaye AD. Kratom—Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review. Pain Ther. January 2020. doi:10.1007/s40122-020-00151-x