The basic science of Cannabinoids Part 2
Myron Yaster MD and Elliot J. Krane MD FAAP
The January issue of Anesthesia and Analgesia has several articles devoted to the medicinal use of cannabinoids. Over the next 2-4 weeks, the PAAD will be reviewing several of them, continuing with today’s editorial1 and basic science review.2 Because of the complexity of the receptor pharmacology of the cannabinoid system, today’s PAAD was divided into 2 parts. Yesterday we discussed the basics. In today’s PAAD we will dive more deeply into the endocannabinoid system, pain modulation, regulation of nausea and vomiting, and perioperative use of drugs that aren’t cannabinoids but may be achieving their effects through this system. Myron Yaster MD
Editorial
Shah S, Narouze S. Cannabis as a Therapeutic or Snake Oil? A Desperate Call for Critical Appraisal of the Literature. Anesth Analg. 2024 Jan 1;138(1):2-4. doi: 10.1213/ANE.0000000000006592. Epub 2023 Dec 15. PMID: 38100796.
Original article
Sideris A, Lauzadis J, Kaczocha M. The Basic Science of Cannabinoids. Anesth Analg. 2024 Jan 1;138(1):42-53. doi: 10.1213/ANE.0000000000006472. Epub 2023 Dec 15. PMID: 38100799.
As discussed in yesterday’s PAAD, the cannabinoids inhibit adenylate cyclase by binding to G-protein-coupled receptors, named cannabinoid receptor type 1 (CB1) and type 2 (CB2). These receptors are widely distributed in the brain and periphery. “While cannabinoid receptor density, localization, and functional state can help explain the myriad roles of the endocannabinoid (eCB) system, cannabinoids themselves are not alike. Ligand binding affinities vary substantially and influence the duration and type of physiological effect. Phyto-, endo- and synthetic cannabinoids exhibit distinct and oftentimes dose-dependent pharmacological effects at cannabinoid and non-CB1/CB2 receptors, such as members of the transient receptor potential (TRP) family, gamma–aminobutyric acid (GABA) receptors, and serotonin receptors. Cannabinoids can act as partial, full, neutral, and inverse agonists, and antagonists (Figure 4 from article, below). When comparing the 2 main endogenous cannabinoids (eCBs), Arachidonoyl Ethanol Amide, or anandamide (AEA), has a high-binding affinity to the CB1 receptor but is a partial agonist and thus does not elicit strong intracellular responses. In contrast, 2-arachidonoylglycerol (2-AG) has a lower binding affinity but elicits robust intracellular signaling because it is a full agonist at CB1. Consequently, it is thought that 2-AG is more involved in activity-depending regulation of synaptic transmission, whereas AEA is involved in more tonic regulation of neuronal activity.”2
Before diving deeper into how the cannabinoid system modulates pain, it is important to underline that human studies using cannabinoids in acute and chronic pain have been inconsistent because marijuana as an FDA class I drug has been notoriously difficult to study. Indeed, “there is a lack of uniform quality control of cannabis products and a paucity of high-quality research to adequately inform the practitioner and patient on dosing.”2-8 Further, as Shah and Narouze point out in their accompanying editorial “one will quickly appreciate that while the basic science of cannabis is rich, it does not often and reliably translate to important clinical outcomes in humans, and understanding how cannabis data are presented is often key to this misalignment.”1 Put more succinctly, many of the beneficial effects of cannabinoids in the lay and medical literature are anecdotal, confusing, contradictory, and not supported by much human research. “The unfortunate consequences are patients using cannabis and providers guiding patients with limited science.”2,6
On the other hand, in animal models “using inflammatory and neuropathic paradigms, CB1 and CB2 receptor agonists, including THC, consistently decreased pain behaviors in inflammatory and nerve-injury models, while CBD and inhibitors of fatty acid amide hydrolase (FAAH) reduced nerve-injury-induced pain behaviors.9,2
Although CB1 receptors are widely distributed in the nervous system in areas involved with pain transmission, they are also expressed in neurons projecting to the area postrema that contribute are involved in nausea and vomiting.10,11 CB2 receptors have also been identified in the brainstem structures and contribute to antiemetic effects.12 “To date, 3 cannabis-based medications received FDA approval for the treatment of chemotherapy-induced nausea and vomiting (CINV): 2 forms of dronabinol, which is a synthetic version of THC (Marinol [capsule]and Syndros [oral solution] ) and a synthetic cannabinoid nabilone (Cesamet).”2 Unfortunately, there isn’t much data to support the use of cannabinoids in the prevention or treatment of postoperative nausea and vomiting (PONV). We believe that this would be an ideal opportunity for research in (pediatric) anesthesia. Indeed, I (MY) have long speculated about the use of inhaled marijuana in (pediatric) anesthesia. Why not build a vaporizer to use cannabinoids intraoperatively? It would almost certainly reduce MAC AND would probably work as effectively as any of our other commonly used antiemetics perioperatively. Would it delay emergence? Cause post operative confusion? Almost certainly, but that may be a small price to pay if they also reduced the amount of opioids needed for postoperative pain control. But I (EK) think this idea is completely nuts.
Finally, several drugs that we routinely use in our anesthetic practice may produce some of their analgesic effects through the endocannabinoid system. These include ketamine, propofol and acetaminophen. Acetaminiophen? Yes, as discussed yesterday, the endogenous cannabinoids are derived from arachidonic acids, and inhibition of arachidonic synthesis pathways affects how many NSAIDs and acetaminophen work. Thus, it is very possible that many of the analgesic effects of acetaminophen are through modulation of eCB signalling. Who knew?
What do you think? Send your thoughts and comments to Myron who will post in a Friday reader response. And keep your eyes posted to the PAAD, we will be reviewing several more articles from this issue in the weeks to come.
References
1. Shah S, Narouze S. Cannabis as a Therapeutic or Snake Oil? A Desperate Call for Critical Appraisal of the Literature. Anesthesia and analgesia 2024;138(1):2-4. (In eng). DOI: 10.1213/ane.0000000000006592.
2. Sideris A, Lauzadis J, Kaczocha M. The Basic Science of Cannabinoids. Anesthesia and analgesia 2024;138(1):42-53. (In eng). DOI: 10.1213/ane.0000000000006472.
3. Anand U, Pacchetti B, Anand P, Sodergren MH. Cannabis-based medicines and pain: a review of potential synergistic and entourage effects. Pain management 2021;11(4):395-403. (In eng). DOI: 10.2217/pmt-2020-0110.
4. Moore RA, Fisher E, Finn DP, et al. Cannabinoids, cannabis, and cannabis-based medicines for pain management: an overview of systematic reviews. Pain 2021;162(Suppl 1):S67-s79. (In eng). DOI: 10.1097/j.pain.0000000000001941.
5. Haroutounian S, Gilron I, Belton J, et al. Societal issues and policy implications related to the use of cannabinoids, cannabis, and cannabis-based medicines for pain management. Pain 2021;162(Suppl 1):S110-s116. (In eng). DOI: 10.1097/j.pain.0000000000002001.
6. Haroutounian S, Arendt-Nielsen L, Belton J, et al. International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia: research agenda on the use of cannabinoids, cannabis, and cannabis-based medicines for pain management. Pain 2021;162(Suppl 1):S117-s124. (In eng). DOI: 10.1097/j.pain.0000000000002266.
7. Fisher E, Moore RA, Fogarty AE, et al. Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials. Pain 2021;162(Suppl 1):S45-s66. (In eng). DOI: 10.1097/j.pain.0000000000001929.
8. Campbell FA, Tramèr MR, Carroll D, Reynolds DJ, Moore RA, McQuay HJ. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ (Clinical research ed) 2001;323(7303):13-6. (In eng). DOI: 10.1136/bmj.323.7303.13.
9. Soliman N, Haroutounian S, Hohmann AG, et al. Systematic review and meta-analysis of cannabinoids, cannabis-based medicines, and endocannabinoid system modulators tested for antinociceptive effects in animal models of injury-related or pathological persistent pain. Pain 2021;162(Suppl 1):S26-s44. (In eng). DOI: 10.1097/j.pain.0000000000002269.
10. Van Sickle MD, Oland LD, Mackie K, Davison JS, Sharkey KA. Delta9-tetrahydrocannabinol selectively acts on CB1 receptors in specific regions of dorsal vagal complex to inhibit emesis in ferrets. Am J Physiol Gastrointest Liver Physiol 2003;285(3):G566-76. (In eng). DOI: 10.1152/ajpgi.00113.2003.
11. Sharkey KA, Darmani NA, Parker LA. Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. Eur J Pharmacol 2014;722:134-46. (In eng). DOI: 10.1016/j.ejphar.2013.09.068.
12. Van Sickle MD, Duncan M, Kingsley PJ, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 2005;310(5746):329-32. (In eng). DOI: 10.1126/science.1115740.