Weeding out the truth: Cannabinoid Pharmacology, Risks and Benefits

Open Access
- Author:
- Nachnani, Rahul
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- December 12, 2023
- Committee Members:
- Lisa Shantz, Program Head/Chair
Andras Hajnal, Outside Unit Member
Erika F H Saunders, Outside Field Member
Kirsteen Browning, Major Field Member
Kent Vrana, Chair & Dissertation Advisor
Patricia Grigson Kennedy, Major Field Member - Keywords:
- THC
CBD
CBG
delta-9-tetrahydrocannabinol
cannabinoid
cannabis
clinical pharmacology
chronic use
physiology
pharmacokinetics
pharmacodynamics
drug-drug interactions
cisplatin-induced neuropathy
analgesia
cannabinoid hyperemesis syndrome
CHS
hypophosphatemia
cannabigerol
cannabidiol
delta-8-tetrahydrocannabinol - Abstract:
- Cannabinoid pharmacology is a rapidly expanding field that is highly relevant to a significant portion of the population. In the Western world, Cannabis and cannabinoids are the most widely used illicit drug, and much of the population either uses, has used, or knows someone who uses cannabinoid products. In the United States, recreational and medical access to Cannabis and cannabinoid products expands every year, with the majority of states and territories allowing medical cannabis (38 states, 3 territories, and the District of Columbia (D.C.)) and a near half of the states allowing recreational use (24 states and D.C.). Furthermore, healthcare providers, clinicians, and researchers have the daunting task of trying to perform, publish, and communicate evidence-based knowledge of cannabinoids against the competing interests of commercial forces and public opinion. Therefore, it is important now, more than ever, to provide rigorous understanding of the benefits and harms of the compounds from the Cannabis plant which are readily available in the current market. The increasing accessibility of cannabinoids other than Δ9-tetrahydrocannabinol (THC) requires further research into uncommon and “minor” cannabinoids, many of which have rarely been studied outside of comparisons to “major” cannabinoids like THC and cannabidiol (CBD). These minor cannabinoids, such as cannabigerol (CBG), have largely uncharacterized pharmacological profiles and are rapidly being studied for novel therapeutic and harmful effects. A review of the pharmacological profile of CBG is provided in Chapter 2. The profile revealed it to be modestly similar to THC and CBD at cannabinoid related receptors (CB1R, CB2R, GPR55). However, a distinct profile at key central nervous system receptors and channels (α2 adrenergic, 5HT1A, TRPV1) provided theoretical potential of CBG as an analgesic. Other minor cannabinoids, such as Δ8-tetrahydrocannabinol (“delta-8”), have overlapping, but still misunderstood pharmacological profiles and are under legal scrutiny in the U.S.. The risk profile of delta-8 is reviewed in Chapter 6. We tested the ability of CBG to provide long-lasting pain relief in a translatable model of cisplatin-induced neuropathy (Chapter 3). CBG administered to neuropathic male and female mice at 10mg/kg and 15mg/kg, respectively, provided acute relief of neuropathic pain. Then, 24 hours after their most recent injection after seven daily injections and fourteen daily injections, the same mice experienced pain relief to 60-80% of their baseline pain tolerances. These effects were resistant to sex differences and drug tolerance. Additionally, no estrous cycle variations were found to be implicated in the level of pain relief in female mice. Finally, the gene expression of the dorsal root ganglia in mice that received CBG versus vehicle did not reveal clinically significant changes due to treatment. These reproducible results provide strong evidence for CBG as an acute and chronic neuropathic pain therapeutic and allow for further study into the mechanism of its long-lasting relief in this model. While minor cannabinoids are seeing an increase in public access and interest, there has been no slowing in use patterns and interest in major cannabinoids (THC and CBD). In fact, clinical adverse events and syndromes are growing in the clinical literature. For example, we present a case series of three adolescents who chronically used cannabinoid products (largely THC-based), had a diagnosis of cannabinoid hyperemesis syndrome (CHS), and developed severe hypophosphatemia during their hospital stays (Chapter 4). These adolescents not only were experiencing intractable and uncomfortable vomiting due to CHS, a syndrome with very little pathophysiology and treatment knowledge available, but also were under acute observation due to these metabolic abnormalities. This side effect of the syndrome is slowly being addressed and studied, because transient hypophosphatemia is rarely investigated in the absence of clinical suspicion. This case series provides further evidence that the syndrome may include pathophysiology that has been previously undiscovered. Continuing the dive into clinical manifestations of cannabis use, we note that many patients in “medical marijuana” programs concurrently use prescription medications along with cannabinoid products. The medical marijuana sites do not routinely communicate with medical health records or medical providers and so the healthcare field is largely in the dark about medical and recreational use unless a patient is forthcoming with the information. Due to social, legal, and political stigma, patients may be hesitant to be honest with their providers about cannabis use and providers may not be fully aware about how this use affects the patients’ care. To address this, our team conducted a systematic review of drug-drug interactions with Cannabis and cannabinoids (Chapter 5), focusing on the pharmacometabolic profile of cannabinoids and prescription drugs and their metabolism in the liver and gut. Chapter 5 uses several databases and a list of narrow therapeutic index (NTI) drugs which are metabolized by cytochrome P450 and UDP-glucuronosyltransferases (UGTs) enzymes in common with THC and CBD. This search focused on adverse events or published records of clinicians needing to adjust prescription medications to prevent or react to harmful adverse events discovered in clinic. We reported 31 reports of these incidents, and describe the quality, pharmacological information, and potential takeaway from each report. In summary, prescription medications like warfarin, tacrolimus, tricyclic antidepressants, and valproic acid are susceptible to interference with cannabinoids and potential interactions should be noted by patients and caregivers alike. This dissertation addresses several gaps in the literature and provides bench to bedside research and reviews of cannabinoid pharmacology as it affects human health. Chronic use, clinical pharmacology, and physiology of cannabinoids and human health are each explored in Chapters 2-6. The cannabinoid use patterns of the public are dynamic and sway with political and legal shifts worldwide, and the work published in this dissertation provides two edges of a scientific blade: support for the unique potential for some cannabinoids to aid in human disease and simultaneous warnings for chronic or unregulated use interfering with quality of life and appropriate medical care.