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Entourage effect

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The entourage effect is a proposed mechanism by which cannabis compounds other than tetrahydrocannabinol (THC) act synergistically with it to modulate the overall psychoactive effects of the plant.[1][2] Cannabidiol (CBD) is under preliminary research for its potential to modify the effects of THC, possibly mitigating some of the negative[3], psychosis-like effects of THC. 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.[4][5][6]

Background

The phrase entourage effect was introduced in 1999.[7][8] 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.[9] 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”.[4] Other cannabinoids, terpenoids, and flavonoids may be part of an entourage effect.[8] The entourage effect is considered a possible cannabinoid system modulator and is achieved in pain management.[1][8][10]

Pharmacology

Endogenous 2-acyl-glycerols can increase 2-arachidonoylglycerol biological activity, which alone shows no significant activity. This entourage effect may represent a novel endogenous cannabinoid activity molecular regulation route.[7] Cannabinoid system modulators like N-palmitoylethanolamine may exhibit the entourage effect, increasing receptor affinity to enhance endogenous anandamide activity and/or reducing enzymatic anandamide degradation.[11]

Criticism

One study found that none of the six most common terpenoids in Cannabis directly activated CB1 or CB2, or modulated the signalling of the phytocannabinoid agonist Δ9-THC. The study focused on whether the terpenes had activity at the CB receptor but did not identify other receptors ( non CB-receptors) whose function may be altered by the terpenes, causing indirect modulation of the CB-receptors.[12]

A 2020 review of the entourage effect discusses multiple studies comparing the effects of pure THC with whole plant or full spectrum (WP/FS) cannabis extracts. Many of the included studies found no entourage effect at play, while several others discovered the WP/FS extracts to produce worse outcomes, including mitigated benefit, worsening of the condition being treated, or an increase in incidence or severity of adverse events.[13] The author concludes that while the concept of an entourage effect is commonly framed as the mitigation of THC adverse effects by other plant components, it can with equal justification be invoked to explain the observation that presence of THC in the entourage of other plant components (e.g. CBD) reliably increases the incidence of adverse events associated with those other components. For instance, whole plant cannabis exposure is known to have a variety of side effects relative to pure CBD. In such cases, the entourage effect can be considered a net liability.

References

  1. ^ a b Grof, Christopher P. L. (24 May 2018). "Cannabis, from plant to pill". British Journal of Clinical Pharmacology. 84 (11): 2463–2467. doi:10.1111/bcp.13618. ISSN 0306-5251. 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. ^ "Cannabis study reveals how CBD offsets the psychiatric side-effects of THC". ScienceDaily. Retrieved 2020-01-22.
  4. ^ a b Chen, Angus (20 April 2017). "Some of the Parts: Is Marijuana's "Entourage Effect" Scientifically Valid?". Scientific American. Retrieved 2017-12-31. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  5. ^ 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.
  6. ^ Russo, Ethan B (2011). "Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects". British Journal of Pharmacology. 163 (7): 1344–1364. doi:10.1111/j.1476-5381.2011.01238.x. PMC 3165946. PMID 21749363.
  7. ^ a b Ben-Shabat, Shimon; Fride, Ester; Sheskin, Tzviel; Tamiri, Tsippy; Rhee, Man-Hee; Vogel, Zvi; Bisogno, Tiziana; De Petrocellis, Luciano; Di Marzo, Vincenzo; Mechoulam, Raphael (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.
  8. ^ a b c Gupta, Sanjay (11 March 2014). "Medical marijuana and 'the entourage effect'". CNN. Retrieved 31 December 2017. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  9. ^ Russo, Ethan B. (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. ISSN 1664-462X. PMC 6334252. PMID 30687364.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ Jerome, Bouaziz (April 1, 2017). "The Clinical Significance of Endocannabinoids in Endometriosis Pain Management". Cannabis and Cannabinoid Research. 2 (1): 72–80. doi:10.1089/can.2016.0035. PMC 5436335. PMID 28861506.
  11. ^ Bouaziz, Jerome; Bar On, Alexandra; Seidman, Daniel S.; Soriano, David (January 2017). "The Clinical Significance of Endocannabinoids in Endometriosis Pain Management". Cannabis and Cannabinoid Research. 2 (1): 72–80. doi:10.1089/can.2016.0035. PMC 5436335. PMID 28861506.
  12. ^ Santiago, Marina; Sachdev, Shivani; Arnold, Jonathon C.; McGregor, Iain S.; Connor, Mark (6 March 2019). "Absence of entourage: Terpenoids commonly found in Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1and CB2 receptors". bioRxiv: 569079. doi:10.1101/569079.
  13. ^ Cogan (2 March 2020). "The 'entourage effect' or 'hodge-podge hashish': the questionable rebranding, marketing, and expectations of cannabis polypharmacy". Expert Review of Clinical Pharmacology: online. doi:10.1080/17512433.2020.1721281.
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