The Entourage Effect: New Trends in Research

Cannabis has been used as a source of medicinal compounds for thousands of years. Cannabis is a complex plant, producing several classes of secondary metabolites  including at least 104 cannabinoids, 120 terpenoids, 26 flavonoids and 11 steroids among 545 identified compounds (Dan et al., 2020). Crude extracts of the cannabis flowers contain hundreds of molecules and compounds that have more recently been shown to elicit bio-active responses in the human body. These molecules and compounds are collectively known as phytomolecules.

As the cannabis industry has labored to produce a wider variety of strains with clearly distinct characteristics, one of the driving factors has been to enhance the “entourage effect”. That is, the combination of phytomolecules produced by the plant, taken together, is believed to increase the range of therapeutic properties and have a greater effect than when taken individually. There has been a great deal of anecdotal data and “urban legend” surrounding the entourage effect. Combinations of these phytomolecules have been recently established as superior to the use of a single phytomolecules thereby providing a better understanding of the entourage effect, how it works, and how it can be utilized to improve human health (Koltai and Namdar, 2020). Research data suggests that a wider range of bioactive phytomolecules should be included when examining the beneficial medicinal properties of cannabis preparations.

To transition from traditional medicine to an evidence-based understanding of the entourage effect, bio-active phytomolecules from the cannabis plant must be identified and their molecular mechanisms determined through preclinical and clinical studies. Early research into the entourage effect was focused on the interaction between terpenes and cannabinoids and how they interact to alleviate chronic pain, migraines, inflammation, anxiety, depression, addiction, and cancer (Russo and Gut, 2006). Additional data has provided good evidence that the combination of terpenes and the cannabinoids THC and CBD can enhance the body’s response to illness better than the cannabinoids alone (Russo, 2011). More recently, Namdar et al. (2019) introduced the concept of intra-entourage and inter-entourage effects. Intra-entourage effects would be those observed between molecules of the same biochemical type (cannabinoids, terpenes, or flavonoids). Inter-entourage effects result from the interactions of molecules from the various biochemical types interacting to produce an enhanced effect. Using cancer cell cytotoxicity assays, this research team clearly demonstrated that the greatest potential for initiating the “entourage effect” was found in the inter-entourage assembly of molecules.

A comprehensive profile of the bio-active phytomolecules and their participation in the entourage effect enables the correlation between plant composition and therapeutic effects, ultimately bridging traditional herbal medicine with modern science. The collection of current research lays the foundation for formulating specific combinations of cannabis-derived phytomolecules resulting in medical products with desired therapeutic effects and will significantly impact the research and development of cannabis-based medicines.

Dan, J., Dai, K., Xie, Z., and Chen, J. 2020. Secondary Metabolites Profiles in Cannabis Inflorescences, Leaves, Stem Barks, and Roots for Medicinal Purposes. Scientific Reports 10:3309.
Koltai, H. and Namdar, D. 2020 Cannabis Phytomolecule “Entourage”: From Domestication to Medical Use. Trends Plant Sci. May 13; S1360-1385(20)30122-9.
Russo, E., Guy, W. 2006. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 66: 234-246.
Russo, E.B. 2011. Taming THC: Potential Cannabis Synergy and Phytocannabinoid-terpenoid Entourage Effects. Br. J. Pharm., 163, 1344-1364.
Namdar, D. Voet, H., Ajjampura, V., Nadarajan, S., Mayzlish-Gati, E., Mazuz, M., Shalev, N., and Koltai, H. 2019. Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity. Molecules, 24, 3031.

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