This study, currently in pre-print at BioRxIv, conducted by the world’s largest cannabis research group and led by the well-known Israeli cannabis researcher David “Dedi” Meiri, investigates the synergistic effects of three specific cannabinoids (331-18A, CBDV, and CBD) in targeting NOTCH1-Mutated T-Cell Lymphoblastic Acute Leukemia (T-ALL) through the Integrated Stress Response Pathway . The research paper provides an impressive and comprehensive breakdown of the molecular interactions and therapeutic potential of these combined cannabinoids using both in-vitro and in-vivo experiments. The complex pharmacology suggests that an ‘entourage effect’ fairly similar to Mechoulam’s original definition from 1998 might be at work, but with phytocannabinoids rather than endocannabinoid-like molecules at center stage.
- In Vitro Analysis: Various cell lines were used to study the effects of the cannabinoid combination on cancer cell proliferation and signaling pathways, including interactions with CB2 and TRPV1 receptors.
- In Vivo Analysis: Conducted experiments on NOD-SCID and NSG mice to evaluate the anti-tumor properties of the cannabinoids, including subcutaneous tumor models and intravenous models.
- Synergy Scoring: The *HSA model was employed to calculate synergy scores of the cannabinoid combinations, shedding light on how the cannabinoids work together.
*The HSA (Highest Single Agent) model is a mathematical approach used to evaluate the synergistic, additive, or antagonistic effects of drug combinations. It’s particularly useful in pharmacology to understand how different drugs or compounds interact when combined.
- Therapeutic Potential: The article highlights the potential of a unique phytocannabinoid combination in inhibiting cancer progression of Notch1-mutated T-ALL.
- Molecular Insights: The article offers fresh insights into the interactions of multiple cannabinoids, enhancing our understanding of their therapeutic effects.
Implications for Future Research:
- Targeted Therapy Development: The study lays a foundation for developing targeted therapies using phytocannabinoid polypharmacy.
- Further Exploration: It encourages more research to understand the broader applicability of these findings to additional cancer types.
- Very Comprehensive Analysis: 96 different phytocannabinoids were analyzed in the “extract 12”, and the paper includes both in vitro and in vivo studies.
- Novel Findings: Unveils novel ‘entourage effects’ where a combination of three specific phytocannabinoids captures the full therapeutic effects of a highly complex cannabis extract in multiple disease models for Notch1-mutated T-ALL.
- Limited Scope: The study’s focus on one specific cancer subtype means broader applicability needs to be explored in the future.
- Complexity of Cannabinoid Interactions: The intricate interactions between cannabinoids may require more detailed analysis to be fully understood. This complexity represents both a challenge and an opportunity for future research.
Editor’s Comments about The Entourage Effect
In the article’s study, the ‘entourage effect’ is explored in the context of three specific phytocannabinoids (331-18A, CBDV, and CBD) targeting NOTCH1-Mutated T-ALL.
The study’s findings, where the inclusion of CBDV enhances CBD’s effects, despite being a less effective TRPV1 agonist, align rather well with Mechoulam’s original description of ‘entourage’ pharmacology . A potential explanation, though speculative at this point, is that CBDV might interfere with the breakdown of CBD, enhancing its effects at the TRPV1 receptor.
Dr. Russo’s interpretation of the ‘entourage effect’ focuses on the potential synergistic interaction between cannabinoids and specific aromatic compounds found in the cannabis plant. He posits that terpenes and flavonoids can enhance the therapeutic properties of cannabinoids through various molecular mechanisms .
While both concepts acknowledge the potential for complex interactions among the various compounds found within the cannabis plant, they diverge somewhat in focus and application, as illustrated in the table above. Both perspectives are valuable, and the article does not favor one over the other but presents them as two complementary views.
This research marks a significant advancement in the field of molecular pharmacology, particularly in the context of the Master Homeostatic Regulatory System (MHRS), more commonly referred to as the ECS/eCBome. It also heavily impacts phytocannabinoid research and future drug development. By elucidating novel “entourage-like” effects of multiple specific phytocannabinoids, the study manages to open up new avenues for targeted cancer therapy.
The integration of in vitro and in vivo analyses strengthens the validity of the findings, positioning this work as a valuable reference for future research in molecular pharmacology and therapeutic development for T-ALL. The insights gained from this study contribute to a broader understanding of the MHRS and the complex multifaceted mechanisms of actions of phytocannabinoids.
Stefan Broselid, Ph.D.
Editor-In-Chief, Aurea Care Medical Science Journal
- Besser, Elazar, et al. “Cannabinoid Combination Targets NOTCH1-Mutated T-ALL Through the Integrated Stress Response Pathway.” bioRxiv (2023): 2023-08.
- Ben-Shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol. 1998;353(1):23-31. doi:10.1016/s0014-2999(98)00392-6
- Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364. doi:10.1111/j.1476-5381.2011.01238.x