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Research: Cannabis Entourage Effect 3.0

Introductions and image by @SuperFunker.

1) Namdar et al (2019): In this examination, two types of Cannabis phytochemical synergies are defined. The intra-entourage effect refers to synergies between cannabinoids, whereas the inter-entourage effect is a reference to enhanced biological activity resulting from interaction between cannabinoids and terpenoids. It’s this combination – between cannabinoids and terpenoids – that were examined.

The cytotoxic activity of various cannabinoid and terpene combinations were used to treat MDA-MB-231 (breast cancer cells) and HCT-116 (colon cancer cells):

  • THC alone demonstrated limited cytotoxicity when applied to the MDA-MB-231 cell line (~10% cell death).
  • THCa-related terpenoids exhibited no cytotoxicity when applied to the MDA-MB-231 cell line.
  • THC combined with THCa-related terpenoids resulted in significant cytotoxicity when applied to the MDA-MB-231 cell line (~40% cell death).

  • CBD alone demonstrated nominal cytotoxicity when applied to the MDA-MB-231 cell line (~7% cell death).
  • CBDa-related terpenoids exhibited no cytotoxicity when applied to the MDA-MB-231 cell line.
  • CBD combined with CBDa-related terpenoids resulted in significant cytotoxicity when applied to the MDA-MB-231 cell line (~70% cell death).

  • THC alone demonstrated zero cytotoxicity when applied to the HCT-116 cell line.
  • THCa-related terpenoids exhibited no cytotoxicity when applied to the HCT-116 cell line.
  • THC combined with THCa-related terpenoids resulted in moderate cytotoxicity when applied to the HCT-116 cell line (~15% cell death).

  • CBD alone demonstrated moderate cytotoxicity when applied to the HCT-116 cell line (~30% cell death).
  • CBDa-related terpenoids exhibited moderate cytotoxicity when applied to the HCT-116 cell line (~10 to 36% cell death).
  • CBD combined with CBDa-related terpenoids resulted in significant cytotoxicity when applied to the HCT-116 cell line (~55% cell death).

Although Cannabis contains relatively small amounts of terpenoids, when combined with THC or CBD at naturally occurring levels, the cytotoxic activity of THC or CBD alone, is greatly enhanced.

Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity.

Abstract
Mixtures of different Cannabis sativa phytocannabinoids are more active biologically than single phytocannabinoids. However, cannabis terpenoids as potential instigators of phytocannabinoid activity have not yet been explored in detail. Terpenoid groups were statistically co-related to certain cannabis strains rich in Δ9-tetrahydrocannabinolic acid (THCA) or cannabidiolic acid (CBDA), and their ability to enhance the activity of decarboxylase phytocannabinoids (i.e., THC or CBD) was determined. Analytical HPLC and GC/MS were used to identify and quantify the secondary metabolites in 17 strains of C. sativa, and correlations between cannabinoids and terpenoids in each strain were determined. Column separation was used to separate and collect the compounds, and cell viability assay was used to assess biological activity. We found that in “high THC” or “high CBD” strains, phytocannabinoids are produced alongside certain sets of terpenoids. Only co-related terpenoids enhanced the cytotoxic activity of phytocannabinoids on MDA-MB-231 and HCT-116 cell lines. This was found to be most effective in natural ratios found in extracts of cannabis inflorescence. The correlation in a particular strain between THCA or CBDA and a certain set of terpenoids, and the partial specificity in interaction may have influenced the cultivation of cannabis and may have implications for therapeutic treatments.

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2) Pamplona et al (2018) reviewed research in an effort to understand the differences between purified CBD and CBD-rich whole-plant formulas. Although both CBD isolate and CBD-rich extracts improved the epileptic condition/symptoms among patients, CBD-rich full-spectrum formulas appeared to demonstrate greater utility. The synergy of CBD within a whole-plant mixture resulted in an Entourage Effect that was more potent (required a lower dose to induce the desired medicinal benefit) and produced fewer side-effects (appetite alteration, sleepiness, gastrointestinal disturbances, weight changes, fatigue).

Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis.

Abstract
This meta-analysis paper describes the analysis of observational clinical studies on the treatment of refractory epilepsy with cannabidiol (CBD)-based products. Beyond attempting to establish the safety and efficacy of such products, we also investigated if there is enough evidence to assume any difference in efficacy between CBD-rich extracts compared to purified CBD products. The systematic search took place in February/2017 and updated in December/2017 using the keywords “epilepsy” or “Dravet” or “Lennox-Gastaut” or “CDKL5” combined with “Cannabis,” “cannabinoid,” “cannabidiol,” or “CBD” resulting in 199 papers. The qualitative assessment resulted in 11 valid references, with an average impact factor of 8.1 (ranging from 1.4 to 47.8). The categorical data of a total of 670 patients were analyzed by Fischer test. The average daily dose ranged between 1 and 50 mg/kg, with treatment length from 3 to 12 months (mean 6.2 months). Two thirds of patients reported improvement in the frequency of seizures (399/622, 64%). There were more reports of improvement from patients treated with CBD-rich extracts (318/447, 71%) than patients treated with purified CBD (81/175, 46%), with statistical significance (p < 0.0001). Nevertheless, when the standard clinical threshold of a “50% reduction or more in the frequency of seizures” was applied, only 39% of the individuals were considered “responders,” and there was no difference (p = 0.52) between treatments with CBD-rich extracts (122/330, 37%) and purified CBD (94/223, 42%). Patients treated with CBD-rich extracts reported lower average dose (6.0 mg/kg/day) than those using purified CBD (25.3 mg/kg/day). The reports of mild (158/216, 76% vs. 148/447, 33%, p < 0.001) and severe (41/155, 26% vs. 23/328, 7%, p < 0.0001) adverse effects were more frequent in products containing purified CBD than in CBD-rich extracts. CBD-rich extracts seem to present a better therapeutic profile than purified CBD, at least in this population of patients with refractory epilepsy. The roots of this difference is likely due to synergistic effects of CBD with other phytocompounds (aka Entourage effect), but this remains to be confirmed in controlled clinical studies.

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3) Russo (2011) conducted a review of research in an effort to rationalize the exploration of the Entourage Effect. It had been well known that the combination of THC and CBD produced tangible medical outcomes, but at this date – 2011 – relatively few resources had been devoted to exploring a broader Entourage Effect associated with full-spectrum synergies. This analysis speculated that additional potential may be realized in the treatment of acne, MRSA (Methicillin-resistant Staphylococcus aureus), depression, anxiety, insomnia, dementia and addiction. Now, well beyond 2011, we know the medicinal possibilities associated with Cannabis therapies are much more reaching.

Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.

Abstract
Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL−1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant.

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