The Next Generation of Cannabis Based Drugs
Only a few cannabis-based pharmaceutical grade medicines have been developed and marketed. To date, most of the cannabis-based products are dried flowers (inflorescence) or oils that contain inflorescence extracts, which sometimes suffer from unknown, undefined and/or non-standardized content.
Cannabis produces a multitude of phytomolecules, including approximately 150 different phytocannabinoids and hundreds of other compounds as terpenes and flavonoids. Nevertheless, registered or common cannabis-based products usually follow the common, rather dated, dichotomous chemo-variation approach to Cannabis sativa. In this approach, only the relative contents of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are considered.
Taking Advantage of the ‘Entourage Effect’
The ‘entourage effect’ is considered as the enhanced activity of combinations of phytocannabinoids. It was first recognized by Mechoulam and Ben-Shabat . The ‘entourage effect’ may derive from synergy between phytocannabinoids and further between phytocannabinoids and terpenes . As synergistic effects activate new biological pathways not activated by each of the components alone, they may lead to enhanced biological and medical activity (Figure 1).
Avoiding the ‘Parasitage Effect’
While the richness of compounds in cannabis can enhance activity, they can also depress activity. In some cases, whole extracts contain compounds that do not contribute to the desired biological or clinical effect. Moreover, some compounds may even have negative effects and suppress activity. Evidently, in some of the cases activity is improved by selecting the most active fractions and eliminating other parts of the whole extract. This phenomenon may be called the ‘parasitage effect’: the contra-‘entourage effect’, a phenomenon in which certain co-produced compounds interfere with each other to diminish a biological activity . The mechanism of the ‘parasitage effect’ might be, for example, blockage of receptors that are targeted by phytocannabinoids (e.g., CB1, CB2,), but this has yet to be established.
Identification of Active Plant Ingredients
To take advantage of the ‘entourage effect’ and avoid the ‘parasitage effect’, we suggest the selection of combinations of highly active plant ingredients (API) from cannabis as a plausible approach for cannabis-based drug development (Figure 1; ). Identification of API should be specific to medical or health condition, and be based on scientific evidences.
The Challenge Ahead
Once the APIs and their specific compositions are identified within a cannabis extract, the challenge ahead is the development of the medical product. Several avenues of operation can be envisioned.
One, extracts of several cannabis strains could be blended to achieve API composition that was scientifically shown to have high activity for a specific medical condition. Two, an extract could be fractionated and fractions with the desired composition could be taken for product preparation. Three, and the most demanding route (regulatory-wise), is the usage of isolated or synthesized molecules for the development of pharmaceutical drugs inspired by – or based on – cannabis API composition.
In all the three routes, beneficial compositions of compounds for a certain medical condition might be used, the product might be targeted to specific mechanisms involved with various diseases and importantly, the product might be better standardized and dosed.
by Professor Hinanit Koltai, Volcani Institute
- Mechoulam R., Ben-Shabat S. From gan-zi-gun-nu to anandamide and 2-arachidonoylglycerol: the ongoing story of cannabis. Nat Prod Rep, 16, 131-143.
- Namdar D., Anis O., Poulin P. and Koltai H. Chronological Review and Rational and Future Prospects of Cannabis-Based Drug Development. Molecules, 25, 4821.
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