The entourage effect explained: well-founded, easy to follow 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 preclinical study by the Israeli researchers Shimon Ben-Shabat (first author) and Raphael Mechoulam (head of the research group) and other authors. It showed that certain endogenous cannabinoids (substances produced by our own body) can enhance the effect of the endocannabinoid in the body together with other endogenous substances.
So the term was not coined to describe the effect of plant cannabis on us, but to describe an effect involving our body's own cannabinoids and their synergies with other substances produced by the body.
The entourage effect of plant cannabis
Only later did this lead to the hypothesis that in the medical use of cannabis, too, the plant's substances as a whole might, by working together, have a stronger or different effect than isolated single compounds.
With a growing understanding of the endocannabinoid system and the discovery of more plant compounds, the entourage effect has since been discussed as a possible reason why full-spectrum cannabis products are often reported to work better than single substances.
In recent years the concept has become established in the scientific literature and is understood as a synergistic phenomenon in which several components of the cannabis plant together modulate the therapeutic effect. While numerous preclinical and some clinical studies point to such synergies, the evidence for stable and predictable clinical efficacy is still limited and the subject of ongoing research.
Cannabis plants produce a large number of different chemical compounds, and each variety develops its own characteristic profile. Countless cannabis users and patients have reported again and again that different strains affect them very differently, which is why they choose certain strains for certain effects.
The usual suspects: cannabinoids, terpenes, flavonoids
When it comes to describing the entourage effect, many sources today name the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), but often overlook the other cannabinoids that are among the "usual suspects" for synergistic effects. Besides the cannabinoid "superstars" THC and CBD, cannabis contains more than 120 other cannabinoids such as cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN) and tetrahydrocannabivarin (THCV), each with its own profile, which, especially in combination with THC or CBD, could potentially lead to very different effects in the body.
Cannabis plants also contain around 200 terpenes and more than 30 flavonoids. The amount and composition of these substances varies from strain to strain. Terpenes such as limonene, myrcene or linalool, which are partly responsible for the smell and taste of cannabis, are a diverse group of natural, mostly aromatic compounds. They are the main components of many plants' essential oils and are also present in cannabis in high concentrations.
Terpenes show a wide range of biological effects and can act via different receptors, including the cannabinoid receptors (CB1, CB2), adenosine receptors and other signalling pathways in the nervous system. Studies, mostly preclinical, have looked at inflammation-related, pain-related, neuroprotective, antioxidant, antimicrobial and antitumour properties as well as psychoactive effects; possible influences on mood, cognitive function and behaviour are also being researched.
Other prominent candidates for possible synergistic effects are flavonoids, another large group of secondary plant compounds. They give many fruits and vegetables their red, blue, yellow and purple colours and play an important role in plant metabolism, for example as protection against UV radiation and oxidative stress. They are widely studied in nutrition and medical research, among other things for antioxidant and inflammation-related properties and for possible links with the immune system and vascular health.
Endocannabinoid-like compounds, alkaloids, phenolic compounds
Beyond cannabinoids, terpenes and flavonoids, the cannabis plant also contains other bioactive substances that could potentially contribute to the entourage effect. These include:
1. Endocannabinoid-like compounds such as certain fatty acid amides (e.g. palmitoylethanolamide, oleoylethanolamide), which can enhance the effect of the body's own endocannabinoids
2. Alkaloids such as cannabisativine, which occur in cannabis in small amounts and may be pharmacologically active
3. Phenolic compounds with antioxidant properties
For now, 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) stresses that the complex chemistry of cannabis includes many compounds yet to be studied that may contribute to the overall effect.
Disinformation, marketing, evidence
In recent decades there have been extensive disinformation campaigns about cannabis, some of them, sadly, run by governments. I presented an analysis of this in my book Elevated. Cannabis as a Tool for Mind Enhancement (2023).
In recent years we have seen a big increase in scientific work on cannabis and the endocannabinoid system; the scientific database PubMed alone lists more than 30,000 articles. With the emerging cannabis market, however, we are also seeing a shift straight from the age of government-driven disinformation into an age of marketing-driven disinformation.
A few things need to be said here:
1. The evidence from studies on the effects of natural terpenes or other plant compounds that might play a role in the entourage effect is still very limited.
2. Even if the research on these substances were better, it is still questionable whether they actually produce this effect at a given concentration in a given cannabis strain in combination with other substances.
3. There are different kinds of synergy between substances: some can, in combination, increase permeability at the blood-brain barrier, others might soften cognitive effects of THC or change effects of CBD. We still know too little about the dynamics of these many synergies.
Conclusion
The entourage effect plays a major role both in the medical use of cannabis and in its use for other purposes. Pharmacology and thousands of personal reports give clear indications that the effect of THC and CBD is modulated by various naturally occurring substances. How exactly these synergies work, however, is not yet clear. It is probably not hundreds of substances that matter, since many cannabinoids and other substances occur in strains only in very small amounts. In the end, it is likely just a few dozen of them that give a strain its particular profile.
Patients and consumers should generally be wary of hasty marketing claims. When it comes to specific claims about the effects of individual substances, they should rely on mindful experimenting when choosing strains rather than on wildly speculative sales promises, for example that certain terpenes might have a "creative" or "mood-lifting" effect.
Sources
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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.
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