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.

Terpenes/Terpenoids in <b><i>Cannabis</i></b>: Are They Important?

“…Current evidence of medicinal properties of terpenes was given by Baron [103] and Nuutinen [104] in their reviews. Entourage effect of terpenes/terpenoids and cannabinoids and their pharmacological activity were also studied by Namdar et al [105] and Ferber et al [106]. Blasco-Benito et al [46] extracted fresh cannabis flowers in ethanol, after evaporation, followed by magnetic stirring on hot plate, which achieved cannabinoid decarboxylation.…”

Chronological Review and Rational and Future Prospects of Cannabis-Based Drug Development

“…We suggested that the “entourage effect” was one of the main motivations and considerations in the domestication of cannabis [ 31 ]. Synergy in cannabis was recently demonstrated between phytocannabinoids [ 32 , 33 ] and further between phytocannabinoids and terpenes [ 34 ]. Moreover, insight into the synergy between cannabis compounds was provided at the levels of both chemical composition and respective biological activity [ 33 , 35 ].…”

“…Natural ratios of phytocannabinoids have been used as the basis for drug development. Several ratios found in plants display higher activity than others [ 34 ]. When these phytocannabinoid ratios are altered, there is no enhancement of activity [ 44 ].…”

“…As for the future, we appreciate the aspects involved in cannabis-based drug development, such as complex entourage effects and terpene considerations [ 33 , 34 , 35 , 36 , 37 ]. We also acknowledge the current difficulties of the pharma industry to include natural preparations, as discussed above.…”

Medical Cannabis in Children

“…While 99% pure cannabinoids are more reproducible and standardized than whole-plant extract and thus preferred as a study drug, several studies suggest a synergistic effect for the numerous cannabis compounds in the whole-plant extract. 4,[14][15][16][17][18][19] This so-called "entourage effect" remains controversial. 20 Future studies should directly assess the effects of pure cannabinoids versus whole-plant extracts in various disorders among different target populations.…”