The entourage effect explained – well-founded, understandable and deeply rooted in the world of Heimat.
What exactly is meant by the "entourage effect" when it comes to the effects of natural cannabis products? The term was first introduced in 1998 in a joint publication by Israeli researchers Shimon Ben-Shabat (first author) and Raphael Mechoulam (the group's lead researcher), along with other authors, in a preclinical study showing that certain endogenous cannabinoids —substances produced by our bodies—can enhance the effects of the endocannabinoid in the body when combined with other endogenous substances.
The term was not coined to describe the effect of herbal cannabis on us, but rather to describe an effect that affects our body's own cannabinoids and their synergies with other substances in the body.
The Entourage Effect of Herbal Cannabis
Only later did this lead to the hypothesis that, even in the medical use of cannabis, the totality of its plant substances can, when combined, have a stronger or different effect than isolated individual substances.
With growing understanding of the endocannabinoid system and the discovery of additional plant compounds, the entourage effect has since been discussed as a possible reason for the often reported superior effects of full-spectrum cannabis products compared to single substances.
In recent years, the concept has become established in the scientific literature and is understood as a synergistic phenomenon in which multiple components of the cannabis plant jointly modulate the therapeutic effect. While numerous preclinical and some clinical studies provide evidence of such synergistic effects, the evidence for stable and predictable clinical efficacy is limited and remains the subject of ongoing research.
Cannabis strains contain a multitude of different chemical compounds, and different strains of cannabis develop their own unique, characteristic substance profiles. Countless cannabis users and patients have repeatedly reported that different strains affect them very differently, and therefore they use certain strains specifically for specific effects.
The usual suspects: cannabinoids, terpenes, flavonoids
When describing the entourage effect, many information sources today cite the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), but often neglect the other cannabinoids that are among the "usual suspects" for synergistic effects. In addition to the cannabinoid "superstars" THC and CBD, cannabis also contains over 120 different cannabinoids, such as cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), and tetrahydrocannabivarin (THCV), all of which have distinct efficacy profiles and could potentially lead to very different effects in the body, especially in conjunction with THC or CBD.
Cannabis plants also contain approximately 200 terpenes and over 30 flavonoids. The amount and quantity of these substances varies depending on the cannabis strain. Terpenes such as limonene, myrcene, and linalool, which are responsible for the smell and taste of cannabis, among other things, are a diverse group of natural, mostly aromatic compounds. They are the main components of essential oils in many plants and are also present in high concentrations in cannabis.
Terpenes exhibit a wide range of biological effects and can act through various receptors, including cannabinoid receptors (CB1, CB2), adenosine receptors, and other signaling pathways in the nervous system. Documented effects include anti-inflammatory, pain relief, neuroprotection, antioxidant effects, antimicrobial and antitumor effects, and psychoactive effects. They can modulate mood and also influence cognitive functions and behavior.
Other prominent candidates for potential synergistic effects are flavonoids, another large group of secondary plant compounds. They are responsible for the red, blue, yellow, and purple coloring of many fruits and vegetables and play an important role in plant metabolism, for example, as protection against UV radiation and oxidative stress. They are important in human nutrition and medicine because they possess antioxidant, anti-inflammatory, and potentially cancer-preventive properties, and they support the immune system and vascular health.
Endocannabinoid-like compounds, alkaloids, phenolic compounds
In addition to cannabinoids, terpenes, and flavonoids, the cannabis plant also contains other bioactive substances that can potentially contribute to the entourage effect. These include:
1. Endocannabinoid-like compounds such as certain fatty acid esters (e.g. palmitoylethanolamide, oleoylethanolamide), which can enhance the effects of the body's own endocannabinoids
2. Alkaloids such as cannabisativine, which occur in small amounts in cannabis and can be pharmacologically active
3. Phenolic compounds that have antioxidant properties
Currently, the role of these other suspects in the entourage effect remains speculative. While terpenes and flavonoids are already considered key components, clinical or preclinical evidence for alkaloids is still lacking. Research such as that by Sexton et al. (2023) emphasizes that the complex chemistry of cannabis still includes many unexplored compounds that may contribute to the overall effect.
Disinformation, Marketing, Evidence
In recent decades, there have been extensive disinformation campaigns about cannabis, which unfortunately were also carried out by governments . I also presented an analysis of this in my book "Elevated: Cannabis as a Tool for Mind Enhancement " (2023).
In recent years, we've seen a significant increase in scientific work on cannabis and the endocannabinoid system; the PubMed scientific database alone contains over 30,000 articles. However, with the emerging cannabis market, we're also seeing a transition from the era of government-driven disinformation directly into one of marketing-driven disinformation.
The following must be said:
1. Evidence from studies on the effects of natural terpenes or other plant substances that may play a role in the entourage effect is still very limited.
2. Even if the study situation for the effects of these substances were better, it is still questionable whether they actually mediate this effect in a certain concentration in a certain type of cannabis in interaction with other substances.
3. There are various types of synergistic effects between different substances; some substances can interact to increase blood-brain barrier permeability, others can mitigate the cognitive effects of THC or enhance the possible anxiolytic effects of CBD. We still don't know enough about the dynamics of these diverse synergies.
Conclusion
The entourage effect plays a major role in both the medical and non-medicinal use of cannabis. There is clear evidence from pharmacology and thousands of reports that the effects of THC and CBD are modulated by various naturally occurring substances—however, it is still unclear exactly how these synergistic effects work. It's likely that not hundreds of substances play a role here—many of the cannabinoids and other substances occur only in very small amounts in cannabis strains—so ultimately, only a few dozen of them in a strain are likely to produce a specific effect profile.
Patients and consumers should generally be cautious of certain premature marketing claims. Regarding specific claims about the effects of individual substances, they should rely more on careful experimentation in strain selection than on wildly speculative sales claims, such as that some terpenes might trigger a "creative" or "mood-enhancing" effect.
Sources
1. Ben-Shabat, S., Fride, E., Sheskin, T., Tamiri, T., Rhee, MH, Vogel, Z., ... & Mechoulam, R. (1998). An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. European Journal of Pharmacology, 353(1), 23-31. https://doi.org/10.1016/S0014-2999(98)00392-6
2. Eyal, A., & Raz, N. (2024). Synergistic Effects of Terpenes and THC in Medical Cannabis. Bazelet White Paper.
3. Frontiers in Pharmacology. (2021). Therapeutic Applications of Terpenes on Inflammatory Diseases. Frontiers in Pharmacology, 12, Article 704197. https://doi.org/10.3389/fphar.2021.704197
4. Li, X., Wang, H., Yang, Y., & Li, X. (2017). Terpenes from forests and human health. Environmental Health and Preventive Medicine, 22, Article 70. https://doi.org/10.1186/s12199-017-0679-9
5. Marincolo, S. (2023). Elevated: Cannabis as a Tool for Mind Enhancement. Hilaritas Press
6. Namdar, D., Voet, H., Ajjampura, V., et al. (2021). Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity. Scientific Reports, 11, Article 87740. https://doi.org/10.1038/s41598-021-87740-8
7. Pellati, F., Borgonetti, V., Brighenti, V., Biagi, M., Benvenuti, S., & Corsi, L. (2018). Cannabis sativa L. and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer. BioMed Research International, 2018, Article ID 1691428. https://doi.org/10.1155/2018/1691428
8. Russo, E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology, 163(7), 1344-1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x
9. Russo, E.B., & Marcu, J. (2017). Cannabis pharmacology: The usual suspects and a few promising leads. Advances in Pharmacology, 80, 67-134. https://doi.org/10.1016/bs.apha.2017.03.0044 .
10. Russo, E. B., & McPartland, J. M. (2019). The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No "Strain," No Gain. Frontiers in Plant Science, 9, 1969. https://doi.org/10.3389/fpls.2018.01969
11. Sexton, M., Shelton, K., Haley, P., & West, M. (2023). Decoding the Postulated Entourage Effect of Medicinal Cannabis. Pharmaceuticals, 16(8), 1057. https://doi.org/10.3390/ph16081057
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