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  • Writer's pictureDr. Dan Jin

The Entourage Effect - Botanical vs. Single Molecule Cannabinoid Drug Development Strategies

Cannabis is made up of a number of compounds, including cannabinoids, terpenoids, and flavonoids, that are believed to act together to create something called the “entourage effect” or “synergistic effect” [1–3]. Studies have shown that extracts with full spectrum of metabolites have better medicinal effects than pure CBD or THC alone [2, 4]. In one study, whole cannabis extract was more effective in inducing cancer cell death than pure THC [4]. In another study, extracts from different cannabis varieties with similar CBD concentrations had different anticonvulsant properties in mice [5]. These studies suggest that there may exist therapeutic-enhancing interactions or synergistic effects amongst cannabinoids as well as between cannabinoids and other secondary metabolites [1–3]. The mechanisms of the therapeutic-enhancing interactions are still under investigation [6].


The merits of botanical drug development are that it offers the promise of synergy amongst the diverse chemical characteristics of the cannabis plant [7]. Meanwhile, there are also substantial challenges in determining the optimal constituents in formulation development for treating a certain condition, ensuring the consistency of the chemical profile in raw materials as well as in the final products, and evaluating the underline science and mechanisms of the therapeutic effects. In contrast, the single molecule approach is the most widely adopted with clear guidelines for drug discovery, evaluation of pharmacology and toxicology, quality control, and clinical studies [7].


Although there are challenges and difficulties to develop a botanical form of cannabis drug, it is not impossible. Currently, a botanical drug Sativex® developed by GW Pharmaceuticals based in the UK, contains the combination of extracts of two different but standardized strains of cannabis with equal amounts of THC and CBD and a range of other metabolites in the final product. Sativex® has been regulatory approved in many countries, including Canada, UK, Germany, Denmark, Sweden, Spain, and Czech Republic, for the treatment of multiple sclerosis spasticity. A review of the cultivation and processing of cannabis for production of Sativex® showed that the company was able to produce consistent chemical profile in the biomass by managing the genetics of the plant, the growing and storage conditions, the state of maturity at harvest, and the methods used to process and formulate the material [8, 9].

Reference

  1. Russo EB (2011) Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British journal of pharmacology 163:1344–1364

  2. Blasco-Benito S, Seijo-Vila M, Caro-Villalobos M, et al (2018) Appraising the “entourage effect”: Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer. Biochem Pharmacol 157:285–293

  3. McPartland JM, Russo EB (2001) Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts? Journal of Cannabis Therapeutics 1:103–132

  4. Baram L, Peled E, Berman P, Yellin B, Besser E, Benami M, Louria-Hayon I, Lewitus GM, Meiri D (2019) The heterogeneity and complexity of Cannabis extracts as antitumor agents. Oncotarget 10:4091–4106

  5. Berman P, Futoran K, Lewitus GM, Mukha D, Benami M, Shlomi T, Meiri D (2018) A new ESI-LC/MS approach for comprehensive metabolic profiling of phytocannabinoids in Cannabis. Sci Rep 8:1–15

  6. Santiago M, Sachdev S, Arnold JC, McGregor IS, Connor M (2019) Absence of Entourage: Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Functional Activity of Δ9-THC at Human CB1 and CB2 Receptors. Cannabis Cannabinoid Res 4:165–176

  7. Bonn-Miller MO, ElSohly MA, Loflin MJE, Chandra S, Vandrey R (2018) Cannabis and cannabinoid drug development: evaluating botanical versus single molecule approaches. Int Rev Psychiatry 30:277–284

  8. Potter DJ (2014) A review of the cultivation and processing of cannabis (Cannabis sativa L.) for production of prescription medicines in the UK. Drug testing and analysis 6:31–38

  9. Potter DJ (2009) The propagation, characterisation and optimisation of Cannabis sativa L. as a phytopharmaceutical. PhD Thesis, King’s College

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