In Medicinal Chemistry


Author: Luke Khoury, Senior Scientist
Editor: Angelica Shubbie, Quality Systems Coordinator

The emergence of novel cannabinoid therapies into the healthcare space marks the early stages of a paradigm shift in modern medicine (see Epidolex).1 Although complete mechanisms for the efficacy of these formulations have yet to be realized, cutting-edge analytical techniques provide tools to discover these deeply complex biochemical processes. These methodologies are principally applied in the field of pharmacogenomics, which focuses on how genes affect an individual’s response to drugs. Today’s pharmaceutical pipelines aim to develop treatments for as many individuals as possible with a single formulation. Realistically however, this “one size fits all” approach does not address the issue that countless drugs do not work the same for the entire population. This notion partly explains variance in each person’s response to cannabis consumption, a phenomenon that has long been discussed but never fully understood.

Through an editorial published in Pharmacogenomics, author Emmanuel Onaivi describes the endocannabinoid system (ECS) and our current understanding of how it affects various health conditions.2 For example, the ECS plays a modulatory role in a diverse range of physiological systems, from pregnancy to metabolomic syndromes in the human body. The ECS operates through fundamental biochemical factors including endocannabinoids, their metabolic enzymes, G-protein coupled cannabinoid receptors CB1 and CB2, and specific genes in human chromosomes 6 and 1 which encode for cannabinoid receptors CB1 and CB2, respectively. In addition, there exists a variety of other potential sites of action for cannabinoids including opioid or muscarinic G-protein coupled receptors, ligand-gated ion channels (e.g. nicotinic, serotonin, glycine), other ion channels (e.g. calcium, potassium, sodium), and nuclear receptors (e.g. peroxisome proliferator-activated receptors).3

By utilizing advanced molecular tools, researchers examine genetic variants within the ECS and various phenotypic expressions they cause. Common strategies employ a multitude of approaches. For example, heritability studies can indicate relative contributions of genetic and environmental influences on phenotypic expression. Linkage studies can analyze pedigrees of related individuals for genetic markers of interest. Candidate gene association studies can be used to further explore gene-phenotype relationships suggested by linkage studies, as well as provide focus on genes selected for their physiological or pharmacologic relevance to the phenotype. Genome-wide association (GWA) studies look for gene-phenotype relationships by simultaneously comparing hundreds of thousands of gene variants in DNA samples taken from large numbers of individuals.4 All together, these techniques can efficiently characterize the dynamics between drug response, genetic predispositions, and epigenetic factors that modify gene expression. An example of this work has been reported by Sachse-Seeboth et al. where researchers examined the impact of the CYP2C9 gene polymorphism on the pharmacokinetics of orally-administered Δ9-THC.5 It was concluded that certain variants may influence both therapeutic and adverse effects of Δ9-THC, an important step in evolving medical application of cannabinoid therapies.

In order to resolve the bigger picture of cannabinoid-drug interactions and genetic response, clinical research is essential for distinguishing the exact properties of cannabinoid-based medical products. Although this field of research is still in its infancy, the current application in healthcare has taken great steps towards the individualization of cannabinoid-based therapeutic treatments.

1. Devinsky, O., Verducci, C., Thiele, E. A., Laux, L. C., Patel, A. D., Filloux, F., … Friedman, D. (2018). Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy & Behavior. 86:131-137.
2. Onaivi, E. S. (2010). Endocannabinoid system, pharmacogenomics and response to therapy. Pharmacogenomics. 11(7):907–910.
3. Stout, S. M., & Cimino, N. M. (2013). Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metabolism Reviews, 46(1), 86–95.
4. Mroziewicz M., Tyndale R.F. (2010). Pharmacogenetics: A tool for identifying genetic factors in drug dependence and response to treatment. Addict. Sci. Clin. Pract. 5:17–29.
5. Sachse-Seeboth, C., Pfeil, J., Sehrt, D., Meineke, I., Tzvetkov, M., Bruns, E., … Brockmöller, J. (2008). Interindividual Variation in the Pharmacokinetics of Δ9-Tetrahydrocannabinol as Related to Genetic Polymorphisms in CYP2C9. Clinical Pharmacology & Therapeutics, 85(3), 273–276.

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