What is the “entourage effect?”

By Josh Kaplan, Ph.D.

Cannabis’ therapeutic potential is enhanced by multiple cannabinoids in combination with terpenes. This results from synergy between a combination of chemicals that impact multiple brain and body targets, affect how cannabinoids are processed by the body, and reduce side effects.  

The entourage effect is the theory that multiple cannabinoids in combination with terpenes have stronger therapeutic effects on the brain and body than the individual cannabinoids on their own18,39. It was first termed by Israeli cannabis science pioneers, S. Ben-Shabat and Raphael Machoulam, in 1998 to describe the improved strength of 2-AG’s action in the presence of otherwise inactive molecules39. The entourage effect has since been generalized to the notion that whole-plant extracts (i.e., many cannabinoids, terpenes, and flavonoids) are more therapeutically effective than individual cannabinoids. Fittingly, a survey of medicinal cannabis users found that 98.2% preferred inhaled or infused methods of multiple cannabinoids than just THC40.

 

A brief survey of cannabinoids beyond THC and CBD

There are over 100 known cannabinoids, but many are present in such low concentrations that they’ve eluded scientific investigation. However, several cannabinoids have received more attention, and like CBD and THC, have therapeutic potential41. A brief summary of these effects are listed in the table below.

Cannabinoid (common abbreviations) Observed Effects
Tetrahydrocannabivarin (THCV) Anticonvulsant

Treatment of metabolic syndrome

Pain reduction

Cannabidivarin (CBDV) Anticonvulsant
Cannabigerol (CBG) Antidepressant

Decrease anxiety

Pain reduction

Cannabinol (CBN) Sedative

Pain reduction

Anti-inflammatory

Cannabichromene (CBC) Anti-inflammatory

Pain reduction

Antidepressant

Table adapted from 18

Some of these effects occur through action at the cannabinoid receptors, CB1 or CB2, while others are mediated by different brain and body targets. This range of targets enables their spectrum of potential therapeutic applications.

 

A brief survey of terpenes

Terpenes are not cannabinoids but give cannabis its distinctive odor. Over 200 different terpenes have been reported and often make up only 1% of cannabis extract. The most well-studied individual terpenes are presented in the table below. While terpenes are thought to alter the effects of cannabinoids on brain function, they’re also thought to alter brain function and behavior on their own. Merely inhalation of terpene odor has an effect on mouse behavior42,43. Some of these actions are thought to be mediated directly by terpene action cell membranes, neurotransmitter receptors, and enzymes44.

Terpene Observed Effects
Limonene (lemon) Increases immune system function
Alpha-Pinene (pine) Anti-inflammatory

Aids memory

Beta-Myrcene (hops) Anti-inflammatory

Pain reduction

Protects against liver cancer

Linalool (lavender) Decrease anxiety

Sedative

Pain reduction

Anti-convulsant

Beta-Caryophyllene (pepper) CB2 agonist

Anti-inflammatory

Nerolidol (orange) Sedative

 Table adapted from 18

 

Interactive synergy

As noted above, cannabinoids and terpenes can independently have a range of therapeutic benefits, but these benefits may be enhanced when consumed in combination. The type of enhancement is thought to be synergistic, in which the strength of the beneficial effect is greater than the benefit conveyed by each element, alone.

There are three basic mechanisms* of cannabis synergy that improve therapeutic benefits45:

  • Multi-target effects: Cannabis’ therapeutic benefits are elevated when multiple brain and body targets can be activated simultaneously by different cannabinoids and terpenes. This also reduces the risk of developing tolerance, thereby preventing a weakening of therapeutic benefit with long-term use.
  • Speed and duration of cannabis’ effects: Certain cannabinoids can block the enzymes that break down other chemicals in the body, including cannabinoids46. This can prolong their duration of effect on brain and body targets.
  • Reduction of side effects: Certain cannabinoids and terpenes can reduce drug action on CB1 receptors and other targets. This facilitates cannabis’ therapeutic benefits and enables the consumption of higher doses without many of the adverse side effects.

* There’s also a fourth proposed mechanism, anti-fungal and anti-bacterial effects47, which can aid in the treatment of bacterial infections like MRSA.

The entourage effect doesn’t mean that individual cannabinoids can’t be therapeutically beneficial on their own. Chemically-synthesized THC (Marinol) is FDA-approved and has known therapeutic benefits. But why not improve these effects? Scientific research is shifting from studying the effects of individual cannabinoids towards more whole-plant approaches to harness cannabis’ therapeutic potential. This is the future of medicinal cannabis.

Summary: The entourage effect describes the interactive synergy between multiple cannabinoids and their terpenes. There are numerous cannabinoids beyond CBD and THC that have therapeutic benefits on their own. Similarly, some of the aromatic terpenes in cannabis have demonstrated effects on brain function and behavior. In combination, they can achieve synergistic therapeutic benefits by activating multiple targets, altering the speed and duration that the drug is present in the body, and reduce adverse side effects. This promotes a whole-plant pharmacological approach to achieve therapeutic gains beyond what’s possible with individual elements alone.

 

References:

1          ElSohly, M. A. et al. Changes in Cannabis Potency Over the Last 2 Decades (1995-2014): Analysis of Current Data in the United States. Biol Psychiatry 79, 613-619, doi:10.1016/j.biopsych.2016.01.004 (2016).

2          Niesink, R. J. & van Laar, M. W. Does Cannabidiol Protect Against Adverse Psychological Effects of THC? Front Psychiatry 4, 130, doi:10.3389/fpsyt.2013.00130 (2013).

3          Mechoulam, R., Peters, M., Murillo-Rodriguez, E., & Hanus, L.O. . Cannabidiol – Recent Advances. Chemistry & Biodiversity 4, 1678-1692 (2007).

4          Gaoni, Y. & Mechoulam, R. Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. Journal of the American Chemical Society 86, 1646-1647

(1964).

5          Mechoulam, R. & Parker, L. A. The endocannabinoid system and the brain. Annu Rev Psychol 64, 21-47, doi:10.1146/annurev-psych-113011-143739 (2013).

6          Katona, I. & Freund, T. F. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 14, 923-930, doi:10.1038/nm.f.1869 (2008).

7          Iannotti, F. A., Di Marzo, V. & Petrosino, S. Endocannabinoids and endocannabinoid-related mediators: Targets, metabolism and role in neurological disorders. Prog Lipid Res 62, 107-128, doi:10.1016/j.plipres.2016.02.002 (2016).

8          Onaivi, E. S. et al. Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann N Y Acad Sci 1074, 514-536, doi:10.1196/annals.1369.052 (2006).

9          Onaivi, E. S. Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain. Neuropsychobiology 54, 231-246, doi:10.1159/000100778 (2006).

10        Benito, C. et al. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J Neurosci 23, 11136-11141 (2003).

11        Palazuelos, J. et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain 132, 3152-3164, doi:10.1093/brain/awp239 (2009).

12        Patel, K. D., Davison, J. S., Pittman, Q. J. & Sharkey, K. A. Cannabinoid CB(2) receptors in health and disease. Curr Med Chem 17, 1393-1410 (2010).

13        Schurman, L. D. & Lichtman, A. H. Endocannabinoids: A Promising Impact for Traumatic Brain Injury. Front Pharmacol 8, 69, doi:10.3389/fphar.2017.00069 (2017).

14        Laaris, N., Good, C. H. & Lupica, C. R. Delta9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus. Neuropharmacology 59, 121-127, doi:10.1016/j.neuropharm.2010.04.013 (2010).

15        Pertwee, R. G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153, 199-215, doi:10.1038/sj.bjp.0707442 (2008).

16        Resstel, L. B. et al. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol 156, 181-188, doi:10.1111/j.1476-5381.2008.00046.x (2009).

17        Kaplan, J. S., Stella, N., Catterall, W. A. & Westenbroek, R. E. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A 114, 11229-11234, doi:10.1073/pnas.1711351114 (2017).

18        Russo, E. B. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 163, 1344-1364, doi:10.1111/j.1476-5381.2011.01238.x (2011).

19        Nagarkatti, P., Pandey, R., Rieder, S. A., Hegde, V. L. & Nagarkatti, M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem 1, 1333-1349, doi:10.4155/fmc.09.93 (2009).

20        Russo, E. B., Guy, G. W. & Robson, P. J. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers 4, 1729-1743, doi:10.1002/cbdv.200790150 (2007).

21        Mackie, K. Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46, 101-122, doi:10.1146/annurev.pharmtox.46.120604.141254 (2006).

22        Freeman, D. et al. How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia. Schizophr Bull 41, 391-399, doi:10.1093/schbul/sbu098 (2015).

23        Zhuang, S. et al. Effects of long-term exposure to delta9-THC on expression of cannabinoid receptor (CB1) mRNA in different rat brain regions. Brain Res Mol Brain Res 62, 141-149 (1998).

24        Bolla, K. I. et al. Sleep disturbance in heavy marijuana users. Sleep 31, 901-908 (2008).

25        Nestor, L., Roberts, G., Garavan, H. & Hester, R. Deficits in learning and memory: parahippocampal hyperactivity and frontocortical hypoactivity in cannabis users. Neuroimage 40, 1328-1339, doi:10.1016/j.neuroimage.2007.12.059 (2008).

26        Crean, R. D., Crane, N. A. & Mason, B. J. An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions. J Addict Med 5, 1-8, doi:10.1097/ADM.0b013e31820c23fa (2011).

27        Jager, G., Kahn, R. S., Van Den Brink, W., Van Ree, J. M. & Ramsey, N. F. Long-term effects of frequent cannabis use on working memory and attention: an fMRI study. Psychopharmacology (Berl) 185, 358-368, doi:10.1007/s00213-005-0298-7 (2006).

28        Hanson, K. L. et al. Longitudinal study of cognition among adolescent marijuana users over three weeks of abstinence. Addict Behav 35, 970-976, doi:10.1016/j.addbeh.2010.06.012 (2010).

29        French, L. et al. Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence. JAMA Psychiatry 72, 1002-1011, doi:10.1001/jamapsychiatry.2015.1131 (2015).

30        Vaucher, J. et al. Cannabis use and risk of schizophrenia: a Mendelian randomization study. Mol Psychiatry, doi:10.1038/mp.2016.252 (2017).

31        Zuardi, A. W., Shirakawa, I., Finkelfarb, E., & Karniol, I.G. Action of cannabidiol on the anxiety and other effects produced by delta-9-THC in normal subjects. Psychopharmacology 76, 245-250 (1982).

32        Blessing, E. M., Steenkamp, M.M., Manzanares, J., & Marmar, C.R. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics 12, 825-836, doi:10.1007/s13311-015-0387-1 (2015).

33        Devinsky, O. et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55, 791-802, doi:10.1111/epi.12631 (2014).

34        Devinsky, O. et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med 376, 2011-2020, doi:10.1056/NEJMoa1611618 (2017).

35        Hurd, Y. L. Cannabidiol: Swinging the Marijuana Pendulum From ‘Weed’ to Medication to Treat the Opioid Epidemic. Trends Neurosci 40, 124-127, doi:10.1016/j.tins.2016.12.006 (2017).

36        Bergamaschi, M. M. et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology 36, 1219-1226, doi:10.1038/npp.2011.6 (2011).

37        Piñeiro, R., Maffucci, T. & Falasca, M. The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation. Oncogene 30, 142-152, doi:10.1038/onc.2010.417 (2011).

38        Kargl, J. et al. GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis. Br J Pharmacol 173, 142-154, doi:10.1111/bph.13345 (2016).

39        Ben-Shabat, S. et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol 353, 23-31 (1998).

40        Hazekamp, A., Ware, M. A., Muller-Vahl, K. R., Abrams, D. & Grotenhermen, F. The medicinal use of cannabis and cannabinoids–an international cross-sectional survey on administration forms. J Psychoactive Drugs 45, 199-210, doi:10.1080/02791072.2013.805976 (2013).

41        Izzo, A. A., Borrelli, F., Capasso, R., Di Marzo, V. & Mechoulam, R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30, 515-527, doi:10.1016/j.tips.2009.07.006 (2009).

42        Buchbauer, G., Jirovetz, L., Jäger, W., Plank, C. & Dietrich, H. Fragrance compounds and essential oils with sedative effects upon inhalation. J Pharm Sci 82, 660-664 (1993).

43        Buchbauer, G., Jirovetz, L., Jäger, W., Dietrich, H. & Plank, C. Aromatherapy: evidence for sedative effects of the essential oil of lavender after inhalation. Z Naturforsch C 46, 1067-1072 (1991).

44        Buchbauer, G. Biological activity of essential oils. 2nd edn,  235-280 (CRC Press, 2015).

45        Wagner, H. & Ulrich-Merzenich, G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine 16, 97-110, doi:10.1016/j.phymed.2008.12.018 (2009).

46        Yamaori, S. et al. Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet 27, 294-300 (2012).

47        Appendino, G. et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod 71, 1427-1430, doi:10.1021/np8002673 (2008).

48        MacCallum, C. A. & Russo, E. B. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med 49, 12-19, doi:10.1016/j.ejim.2018.01.004 (2018).

49        Russell, C., Rueda, S., Room, R., Tyndall, M. & Fischer, B. Routes of administration for cannabis use – basic prevalence and related health outcomes: A scoping review and synthesis. Int J Drug Policy 52, 87-96, doi:10.1016/j.drugpo.2017.11.008 (2018).

50        Tashkin, D. P. Effects of marijuana smoking on the lung. Ann Am Thorac Soc 10, 239-247, doi:10.1513/AnnalsATS.201212-127FR (2013).

51        Subritzky, T., Pettigrew, S. & Lenton, S. Into the void: Regulating pesticide use in Colorado’s commercial cannabis markets. Int J Drug Policy 42, 86-96, doi:10.1016/j.drugpo.2017.01.014 (2017).

52        Lemberger, L., Martz, R., Rodda, B., Forney, R. & Rowe, H. Comparative pharmacology of Delta9-tetrahydrocannabinol and its metabolite, 11-OH-Delta9-tetrahydrocannabinol. J Clin Invest 52, 2411-2417, doi:10.1172/JCI107431 (1973).

53        Barrus, D. G. et al. Tasty THC: Promises and Challenges of Cannabis Edibles. Methods Rep RTI Press 2016 (2016).