Entourage effect

The entourage effect is a hypothesis that cannabis compounds other than tetrahydrocannabinol (THC) act synergistically with it to modulate the overall psychoactive effects of the plant.[1][2]

Compounds

CBD

Vaped or smoked Cannabidiol (CBD), primarily between 250 °C (482 °F) to 300 °C (572 °F), may be converted into THC.[3] However, CBD oil can be delivered via other routes of administration if this effect is not desired. For example, CBD is under preliminary research for its potential to modify the effects of THC, possibly mitigating some of the negative,[4][5] psychosis-like effects of THC.

Cannabis strains with relatively high CBD:THC ratios have been proposed to be less likely to induce anxiety than vice versa, though this assertion has been challenged on account of contradictory findings in the literature.[6][7] As an example, a 2022 cross-over study based on 47 participants exposed to pure THC as well as 1:1, 2:1, and 3:1 ratios of CBD:THC concluded that CBD did not mitigate any of the studied effects of THC at any ratio tested.[8]

This may be due to CBD's antagonistic effects at the cannabinoid receptors, compared to THC's partial agonist effect.[9] CBD is also a 5-HT1A receptor (serotonin) agonist, which may also contribute to an anxiolytic-content effect.[10]

Terpenes

There are numerous terpenes present in the cannabis plant and variation between strains. Some of the different terpenes have known pharmacological effects and have been studied.[11][12][2]

One hypothesis is that myrcene is a prominent sedative terpenoid in cannabis, and combined with THC, may produce the "couch-lock" phenomenon.[2]

Hypothetical differences between C. indica and C. sativa

The effects of sativa are well known for its cerebral high, while indica is well known for its sedative effects, which some prefer for nighttime use.[10] Both types are used as medical cannabis.

  • Cannabinoid ratios: On average, Cannabis indica has higher levels of THC compared to CBD, whereas Cannabis sativa has lower levels of THC to CBD.[13] However, huge variability exists within either species. A 2015 study shows the average THC content of the most popular herbal cannabis products in the Netherlands has decreased slightly since 2005.[14]
  • Terpene ratios: Sativa ancestry is associated with farnesene and bergamotene, while Indica ancestry is associated with myrcene, elemene, and sesquiterpene alcohols.[15]

Criticism

In 2022, studies found that plants identified as "indica" or "sativa" based on common methods of differentiation (e.g. plant height or leaf shape) are not, in fact, chemically distinguishable, with many identified as "sativa" having cannabinoid ratios predicted of "indica" plants and vice versa. The authors have concluded that the chemical makeup of cannabis plants cannot be reliably determined by simple inspection of the plants' physical characteristics and that the "indica" and "sativa" labels are not informative as to the cannabinoids (or other chemical components) delivered.[16][17]

Background

The phrase entourage effect was introduced in 1999.[18][19] While originally identified as a novel method of endocannabinoid regulation by which multiple endogenous chemical species display a cooperative effect in eliciting a cellular response, the term has evolved to describe the polypharmacy effects of combined cannabis phytochemicals or whole plant extracts.[20] The phrase now commonly refers to the compounds present in cannabis supposedly working in concert to create "the sum of all the parts that leads to the magic or power of cannabis".[11] Other cannabinoids, terpenoids, and flavonoids may be part of an entourage effect.[19]

Criticism

A 2020 review of research found no entourage effect in most studies, while other reports claimed mixed results, including the possibility of increased adverse effects.[6] The review concluded that the term, "entourage effect", is unfounded and used mainly for marketing.[6] The author also notes that there is no reason to expect that entourage synergism should result in a net benefit. That is to say, one might just as well expect cannabinoid/cannabinoid or cannabinoid/terpene interactions to amplify/augment the adverse effects or mitigate/diminish any beneficial effects of both cannabinoids and terpenes.[6]

References
  1. Grof CP (November 2018). "Cannabis, from plant to pill". British Journal of Clinical Pharmacology. 84 (11): 2463–2467. doi:10.1111/bcp.13618. PMC 6177712. PMID 29701252.
  2. Russo EB (August 2011). "Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects". British Journal of Pharmacology. 163 (7): 1344–64. doi:10.1111/j.1476-5381.2011.01238.x. PMC 3165946. PMID 21749363.
  3. Czégény, Z; Nagy, G; Babinszki, B; Bajtel, Á; Sebestyén, Z; Kiss, T; Csupor-Löffler, B; Tóth, B; Csupor, D (26 April 2021). "CBD, a precursor of THC in e-cigarettes". Scientific Reports. 11 (1): 8951. Bibcode:2021NatSR..11.8951C. doi:10.1038/s41598-021-88389-z. PMC 8076212. PMID 33903673.
  4. Hudson R, Renard J, Norris C, Rushlow WJ, Laviolette SR (October 2019). "Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus through Bidirectional Control of ERK1-2 Phosphorylation". The Journal of Neuroscience. 39 (44): 8762–8777. doi:10.1523/JNEUROSCI.0708-19.2019. PMC 6820200. PMID 31570536.
  5. https://www.scielo.br/j/bjmbr/a/5sGSHxqFkYHxCYhRZh6fWKH/?format=pdf&lang=en. {{cite web}}: Missing or empty |title= (help)
  6. Cogan PS (August 2020). "The "entourage effect" or "hodge-podge hashish": the questionable rebranding, marketing, and expectations of cannabis polypharmacy". Expert Review of Clinical Pharmacology. 13 (8): 835–845. doi:10.1080/17512433.2020.1721281. PMID 32116073. S2CID 211726166.
  7. Russo EB, Tyler VM (22 December 2015). Handbook of Psychotropic Herbs: A Scientific Analysis of Herbal Remedies for Psychiatric Conditions. Routledge. pp. 233–. ISBN 978-1-136-38607-7.
  8. Englund, A., Oliver, D., Chesney, E., Chester, L., Wilson, J., Sovi, S., De Micheli, A., Hodsoll, J., Fusar-Poli, P., Strang, J., Murray, R. M., Freeman, T. P., McGuire, P. (16 November 2022). "Does cannabidiol make cannabis safer? A randomised, double-blind, cross-over trial of cannabis with four different CBD:THC ratios". Neuropsychopharmacology: 1–8. doi:10.1038/s41386-022-01478-z. ISSN 1740-634X. PMID 36380220. S2CID 253551601. Retrieved 25 November 2022.
  9. "Marijuana Chemicals Cannabinoids, Terpenes, Flavonoids (THC and CBD)". Howtogrowmarijuana.com. 2015.
  10. Joy JE, Watson Jr SJ, Benson Jr JA (1999). Marijuana and Medicine: Assessing The Science Base. Washington D.C: National Academy of Sciences Press. ISBN 978-0-585-05800-9.
  11. Chen A (20 April 2017). "Some of the Parts: Is Marijuana's "Entourage Effect" Scientifically Valid?". Scientific American. Retrieved 2017-12-31.
  12. Fine PG, Rosenfeld MJ (2013-10-29). "The endocannabinoid system, cannabinoids, and pain". Rambam Maimonides Medical Journal. 4 (4): e0022. doi:10.5041/RMMJ.10129. PMC 3820295. PMID 24228165.
  13. Karl W. Hillig; Paul G. Mahlberg (2004). "A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae)". American Journal of Botany. 91 (6): 966–975. doi:10.3732/ajb.91.6.966. PMID 21653452.
  14. Niesink RJ, Rigter S, Koeter MW, Brunt TM (2015). "Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005-15". Addiction. 110 (12): 1941–50. doi:10.1111/add.13082. PMID 26234170.
  15. "Programm of the 28th Annual Symposium of the International Cannainoid Research Society" (PDF). 2018-06-03. Retrieved 2021-07-12.
  16. Smith, Christiana J.; Vergara, Daniela; Keegan, Brian; Jikomes, Nick (2022). "The phytochemical diversity of commercial Cannabis in the United States". PLOS ONE. 17 (5): –0267498. Bibcode:2022PLoSO..1767498S. doi:10.1371/journal.pone.0267498. ISSN 1932-6203. PMC 9119530. PMID 35588111.
  17. Murovec, Jana; Eržen, Jan Jurij; Flajšman, Marko; Vodnik, Dominik (2022). "Analysis of Morphological Traits, Cannabinoid Profiles, THCAS Gene Sequences, and Photosynthesis in Wide and Narrow Leaflet High-Cannabidiol Breeding Populations of Medical Cannabis". Frontiers in Plant Science. 13: 786161. doi:10.3389/fpls.2022.786161. ISSN 1664-462X. PMC 8907982. PMID 35283868.
  18. Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee MH, Vogel Z, et al. (July 1998). "An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity". European Journal of Pharmacology. 353 (1): 23–31. doi:10.1016/s0014-2999(98)00392-6. PMID 9721036.
  19. Gupta S (11 March 2014). "Medical marijuana and "the entourage effect"". CNN. Retrieved 31 December 2017.
  20. Russo EB (2019-01-09). "The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No "Strain," No Gain". Frontiers in Plant Science. 9: 1969. doi:10.3389/fpls.2018.01969. PMC 6334252. PMID 30687364.
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