The Basic Science of Cannabinoids

Abstract

The cannabis plant has been used for centuries to manage the symptoms of various ailments including pain. Hundreds of chemical compounds have been identified and isolated from the plant and elicit a variety of physiological responses by binding to specific receptors and interacting with numerous other proteins. In addition, the body makes its own cannabinoid-like compounds that are integrally involved in modulating normal and pathophysiological processes. As the legal cannabis landscape continues to evolve within the United States and throughout the world, it is important to understand the rich science behind the effects of the plant and the implications for providers and patients. This narrative review aims to provide an overview of the basic science of the cannabinoids by describing the discovery and function of the endocannabinoid system, pharmacology of cannabinoids, and areas for future research and therapeutic development as they relate to perioperative and chronic pain medicine.

DISCOVERY OF THE ENDOCANNABINOID SYSTEM

Research on the cannabis plant spurred the discovery of one of the most important neuromodulatory systems in the body. Although the effects of using the plant were well known throughout history, it was through the isolation of certain compounds in cannabis, referred to as phytocannabinoids, that opened up a field of scientific inquiry that continues to intrigue the scientific and medical communities to this day (Figure 1). The 2 most well-known phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), were characterized in the 1960s by Mechoulam et al in Israel.^1,2 These discoveries enabled the design of synthetic cannabimimetic analog compounds that served as the basis for several ground-breaking discoveries. Seminal in vitro and in vivo experiments demonstrated that cannabinoids inhibit adenylate cyclase³ and that there are specific binding sites for cannabinoids in the mammalian brain^4,5 and periphery.⁶ These G-protein-coupled receptors were named the cannabinoid receptors type 1 (CB1) and type 2 (CB2). Because it was highly unlikely that the body would expend significant resources to create and maintain specific receptors exclusively for binding phytocannabinoids or synthetic cannabinoids, the quest was on to identify compounds made within the body that targeted these same receptors. Indeed, 2 endogenous cannabinoids (endocannabinoids) were isolated and characterized: arachidonoyl ethanolamide or anandamide (AEA)⁷ and 2-arachidon-oylglycerol (2-AG)^8,9 are the main endocannabinoids (eCBs) that bind to the cannabinoid receptors with varying selectivity. Emerging research has identified a novel putative cannabinoid receptor G protein-coupled receptor-55 (GPR55),¹⁰ as well as additional putative eCBs. Collectively, the receptors, endogenous cannabinoids, and the enzymes that catalyze their synthesis and degradation and facilitate their transport form the eCB system.¹¹

Figure 1.

Examples of phytocannabinoids, synthetic cannabinoids, and endocannabinoids. THC and CBD are the most studied phytocannabinoids though there are currently >100 that have been identified to date. Figure created with mindthegraph.com.

The CB1 receptor is the most abundant G protein-coupled receptor in the mammalian nervous system, suggestive of its critical role in numerous functions.^12,13 Its brain distribution pattern accounts for the well-known psychotropic effects of THC. In cortical areas of the primate brain, higher expression is found in association areas rather than primary somatosensory or cortical areas. In subcortical areas, CB1 is highly expressed in the amygdala and basal ganglia, and there is very little expression in the white matter and thalamus.¹⁴

Importantly, CB1 is located on neuronal circuits along the pain pathway, including peripheral and spinal loci (Figure 2). In the peripheral nervous system, rodent studies have identified CB1 expression on the neuronal somata of dorsal root ganglia, which contain primary sensory neurons, and their terminals synapsing in the dorsal horn of the spinal cord.^15–17 Within the spinal cord, CB1 is localized on dorsal horn interneurons, motor neurons, astrocytes, and ependymal cells of the central canal.^16,18,19

Figure 2.

Cannabinoid 1 (CB1) and 2 receptors (CB2) are located in key areas responsible for the generation and propagation of nociceptive signals, and inflammation, respectively. Figure created with mindthegraph.com.

CB1 is also expressed in neurons projecting to the area postrema that contribute to its antiemetic effects,²⁰ neurogenic niches of the brain such as the hippocampus²¹ implicating its essential role in memory formation and consolidation, the cerebellum, striatum, and amygdala.¹³ Although highly enriched in neuronal synapses, CB1 has been identified on neuronal bodies and dendrites, on mitochondria within neurons,^22,23 on astrocytes,²⁴ as well as peripheral organs involved in energy metabolism: muscle, liver, endocrine pancreas, and adipose tissue.²⁵ The receptors are also expressed on rodent and human cardiac tissues,^26,27 rodent small intestine and kidney,²⁸ and rodent alveolar class type II cells.²⁹

In contrast to the widespread expression of CB1 in the nervous system, under normal physiological conditions, CB2 expression has been identified in specific subpopulations of neurons within the rodent brainstem and hippocampus.^30–32 After injury or inflammation, however, CB2 is highly induced in microglia,^33,34 the resident immune cells in the central nervous system. CB2 is also expressed on peripheral immune cells such as macrophages,³⁴ osteoclasts,^35,36 and osteoblasts^36,37 as well as other organs involved in the inflammatory response,³⁴ including the spleen and thymus gland as confirmed by studies in humans.^37,38 Activation of CB2 on immune cells largely produces anti-inflammatory effects.^34,39

It should be noted that the cannabinoid receptors and other components of the eCB system are temporally expressed in a coordinated manner throughout neurodevelopment as documented in animal and human studies.^40–43 Rodent studies suggest that perturbation of this system through perinatal or adolescent exposure to exogenous cannabinoids such as THC may have enduring consequences on neuronal development, pain sensitivity, and the endogenous opioid system.^44–50

ENDOCANNABINOID SIGNALING IN THE NERVOUS SYSTEM

In the neuronal synapse, the eCB system acts in a negative feedback capacity to regulate the magnitude of neurotransmitter release. Neurotransmitters synthesized in the presynaptic neuron are stored in vesicles, which release their contents into the synaptic cleft in a calcium-dependent manner upon the arrival of action potentials at the terminal boutons. Neurotransmitters released into the synaptic cleft bind to receptors located on the postsynaptic neuron to help propagate or diminish electrical impulses. In contrast to this anterograde information transfer, eCBs are synthesized “on demand” in a rapid enzymatic process within the postsynaptic neuron by activity-dependent cleavage of phospholipid precursors. The synthesized eCBs then travel retrogradely where they bind to CB1 receptors located in the presynaptic terminal.⁵¹ Through G_i/o-protein-coupled signaling mechanisms, CB1 receptor activation decreases the probability of neurotransmitter release through inhibition of voltage-gated calcium channels or activation of inwardly rectifying potassium channels (Figure 3). CB1 receptors can be found on GABAergic, glutamatergic, serotonergic, and dopaminergic neurons.^52,53 Thus, neuronal eCB signaling is an elegant and tightly coordinated neuromodulatory system, effectively functioning as a “circuit breaker.”⁵³

Figure 3.

Endocannabinoid system components at the neuronal synapse and control of neurotransmitter release. Endocannabinoids are synthesized in the postsynaptic neuron in an activity-dependent manner from lipid precursors by enzymes and bind to presynaptically localized CB1 receptors to inhibit the probability of neurotransmitter release; 2-AG is inactivated by MAGL and AEA is inactivated by FAAH. 2-AG indicates 2-arachidonoylglycerol; AEA, anandamide; CB1, cannabinoid 1 receptor; DAGL, diacylglycerol lipase α; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; NAPE-PLD, N-acyl-phosphatidylethanolamine-specific phospholipase D; NAT, N-acyltransferase; PLC, phospholipase C. Figure created using mindthegraph.com.

Receptor expression and density in normal and pathological states suggest function and can predict therapeutic potential of receptor engagement or potential side effects.⁵⁴ Depending on the neuroanatomical site,⁵⁵ subcellular localization, neuronal circuit, and functional state, CB1 receptors can activate or sequester different G-proteins,⁵⁶ form heterodimers with other GPCRs like opioid⁵⁷ or serotonin receptors,⁵⁸ or interact with other proteins that affect CB1 signaling.^59–61 These dynamic signaling mechanisms may underlie the oftentimes paradoxical effects of cannabinoids, including the noted dose-dependent biphasic effects on pain, anxiety, and vascular tone.^62–65 Though most neuronal signaling through cannabinoid receptors engages pathways associated with G_i/o resulting in inhibition of adenylate cyclase activity or activation of mitogen-activated protein kinase activity, the receptors can also engage G-protein-independent signaling pathways through arrestins.^66,67 It is interesting that activation of CB1 receptors on astrocytes increases intracellular calcium, likely through Gq coupling, and stimulates release of gliotransmitters to act on neighboring or distant neurons.^68–70

COMPLEX PHARMACOLOGY OF CANNABINOIDS

While cannabinoid receptor density, localization, and functional state can help explain the myriad roles of the 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). When comparing the 2 main eCBs, 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-AG has a lower binding affinity but elicits robust intracellular signaling because it is a full agonist at CB1.^25,71 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. Synthetic cannabinoid receptor agonists (SCRAs) referred to as “K2” or “spice” that made their way into the mainstream as new psychoactive substances are examples of highly potent, full agonists at the CB1 receptor.⁷² This property partly explains the significant toxicity or death that can result from SCRA use compared to THC, which is relatively innocuous as a partial agonist at the CB1 receptor.^73–76 Moreover, cannabinoids can function as positive or negative allosteric modulators (PAMs or NAMs, respectively). An allosteric modulator binds to a receptor and affects its response to an orthostatic ligand by either enhancing (PAM) or diminishing (NAM) its effect. CBD can act as an NAM at the CB1 receptor to decrease the efficacy and potency of the phytocannabinoid THC and the eCB 2-AG,⁷⁷ but is also an inverse agonist/antagonist at the CB2 receptor (Figure 4).^78,79

Figure 4.

Cannabinoid receptor pharmacology. Phyto-, synthetic, and endocannabinoids can act as full, partial, neutral, and inverse agonists and well as positive or negative allosteric modulators (PAM or NAM). NAM indicates negative allosteric modulator; PAM, positive allosteric modulator. Figure created using mindthegraph.com.

Because of the complex pharmacology of “cannabinoids,” caution must be exercised against making broad statements about their therapeutic efficacy and side-effect profile. Each individual cannabinoid has numerous targets that elicit a myriad of responses (Table 1).⁸⁰ The pharmacological complexity is compounded when considering crude cannabis preparations. There are 3 main species of the plant, C. sativa, C. indica, and C. ruderalis, though this taxonomy remains controversial.⁸¹ Depending on the plant cultivar and formulation, ratios of cannabinoids vary considerably within the plant.^82,83 The chemical heterogeneity of the cannabis plant constituents extends to terpenes and flavonoids, which have their own distinct pharmacological profiles and mechanisms of action that engage noncannabinoid receptor pathways.^84–87 It has been proposed that there may be synergy among the various constituents of the plant in what is broadly referred to as an “entourage” effect.^88–90 The entourage concept has been exploited medicinally in the development of a pharmaceutical drug, nabiximols, which has equal ratios of THC and CBD. Though not FDA approved, it has received approval in Europe and Canada for spasticity associated with multiple sclerosis (MS). It also received authorization under the notice of compliance with conditions (NOC/c) policy in Canada for 2 additional uses: cancer pain as well as MS-related neuropathic pain. These indications have since been removed, as the clinical studies did not support a therapeutic benefit.⁹¹ An entourage effect rationale also underlies recently published cannabis dosing and titration guidelines that recommend balanced versus enriched preparations depending on patient tolerance, symptoms, and desired effects.^92,93 Outside of the FDA or health agency-approved cannabinoid medications, 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. Any recommendations for a specific cannabis strain or phytochemical ratio to ameliorate symptoms such as pain are based on suboptimal evidence at best. More research in preclinical and clinical contexts is warranted to identify optimal combinations of these chemicals, routes, and doses of cannabis constituents for specific indications.⁹⁰

Table 1.

Major Phytocannabinoids and Their Functions at Cannabinoid and Noncannabinoid Receptors and Targets

Phytocannabinoid	Targeta	Function at target
Δ9–THC	CB1	Partial agonist
	CB2	Partial agonist
	5-HT3A	Antagonist
	GPR18	Agonist
	GPR55	Agonist
		LPI inhibitor
		No response
CBD (cannabidiol)	CB1	NAM
	CB2	Antagonist
	AEA uptake	Inhibitor
	5-HT1A	Agonist
	5-HT2A	Partial agonist
	5-HT3A	Antagonist
	A1A	Agonist
	μ and δ opioid receptors	Allosteric modulator
	PPARγ	Agonist
	GlyR α1 and α3	PAM
	GABA A	PAM
	TRPA1, V1, V2, V3	Agonist
CBC (cannabichromene)	CB1	Agonist
	CB2	Agonist
	AEA uptake	Inhibitor
	TRPA1, V3, V4	Agonist
	TRPM8	Antagonist
CBG (cannabigerol)	CB1	Partial agonist
	CB2	Partial agonist
	5-HT1A	Antagonist
	GPR55	LPI inhibitor
	α2-AR	Agonist
	TRPA1, V1, V2	Agonist
	TRPM8	Antagonist

Adapted from the work by Morales et al.⁸⁰

Abbreviations: 2-AR, 2-arachidonoylglycerol; 5-HT, 5-hydroxytryptamine; AEA, anandamide; CB1, cannabinoid 1 receptor; CB2, cannabinoid 2 receptor; GABA, gamma–aminobutyric acid; GlyR, glycine receptor; GPR18, G protein-coupled receptor 18; LPI, lysophosphatidylinositol; PAM, positive allosteric modulator; PPARγ, peroxisome proliferator-activated receptor gamma; TRPA1, transient receptor potential cation channel, subfamily A, member 1; TRPM8, transient receptor potential cation channel subfamily M (melastatin) or menthol receptor.

^aThis is not an exclusive list of all targets or functions at those targets.

ENDOCANNABINOID SYSTEM AND PAIN MODULATION

The elucidation of the eCB system in pain modulation has been facilitated by animal models of injury and disease that employ a variety of sophisticated methodologies, including genetic knockout techniques, pharmacology, and histology. Although there is the caveat that genetic manipulations may lead to compensatory changes, these techniques have nevertheless provided insights into the roles of specific neuronal or cellular subtype functions of eCB components in painful conditions. The earliest studies describing the importance of the eCB system in the modulation of pain behaviors came from global deletion of the CB1 receptor,⁹⁴ which revealed receptor modulation of thermal and tactile sensitivity, and reinforcing properties of opioids.^94–97 Pharmacological studies using brain-impenetrant or site-specific injections of drugs and conditional knock out mouse studies have revealed that peripheral, spinal, and supraspinal sites are involved in cannabinoid-mediated analgesia.^98–103

In a recent systematic review and meta-analysis of animal studies 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.¹⁰⁴ There are significant limitations with these animal studies; the risk of bias was unclear, most (>80%) utilized males even though there is documented sexual dimorphism in cannabinoid pharmacokinetics and behavioral effects,^105–108 and the potential influence of side effects, such as motor impairment, catalepsy, or anxiolysis, on the measured outcomes (ie, evoked paw withdrawal to a stimulus) was not accounted for. Importantly, animal models cannot recapitulate multidimensional clinical pain, and there is indeed discordance between the apparent robust effect of cannabinoids in animal models compared to mixed evidence from human studies of cannabis.¹⁰⁹ Many published studies on cannabis’ effect on clinical pain are primarily either retrospective in nature, not adequately controlled, or of a small sample size. Unless the cannabis was procured from a source that performs quality control on its plants and products to ensure phytocannabinoid content, dosing in clinical populations is unknown. Given the complexity of the plant, lack of product quality control, and the numerous routes and modes of administration, conclusive statements about cannabis’ or individual cannabinoids’ analgesic benefits in clinical populations cannot be made at this time.

A better understanding of the role of cannabinoid receptors after surgery¹¹⁰ or during painful pathological states, such as osteoarthritis,¹¹¹ is also needed. Although eCB levels and CB receptor expression are generally upregulated in local tissues in response to disease or injuries and these are understood to contribute to analgesia,^54,112 emerging studies paint a more nuanced regulation of the various eCB components throughout peripheral and central nervous symptom sites.^112,113 The functional roles of these dynamic changes to the “endocannabinoidome” are not yet clear. It is plausible that these changes are protective, contributory to pathology and symptoms, or epiphenomena.

In clinical studies, total knee arthroplasty patients who developed higher postoperative pain (NRS ≥ 5) had significantly elevated preoperative levels of the eCB 2-AG in their cerebral spinal fluid and synovial fluid compared to those who reported lower pain levels; higher synovial fluid 2-AG levels were also correlated with postoperative opioid use in this cohort at 12 hours and 24 hours postoperatively.¹¹⁰ 2-AG is a precursor to proinflammatory eicosanoids,¹¹⁴ and elevated levels of 2-AG in this patient cohort at baseline may suggest an increased inflammatory burden manifesting as higher pain levels. Fibromyalgia patients have increased levels of circulating eCBs, but their biological roles are also uncertain.^115,116 In patients with orofacial pain and headache syndromes, significantly lower levels of salivary 2-AG were observed in patients with trigeminal neuralgia and tension-type headache, while patients with burning mouth syndrome had significantly elevated AEA levels compared to pain-free controls.¹¹⁷

Genetic polymorphisms can influence the state of the eCB system and have been associated with pain intensity, opioid-related side effects, and adverse outcomes.^105–110 In a rare yet extreme case, a female patient who inherited a microdeletion of a FAAH pseudogene in dorsal root ganglia and brain tissues and a single-nucleotide polymorphism (SNP) in FAAH had reduced expression of this enzyme with consequent elevated levels of circulating AEA and other eCBs. The behavioral consequence was pain insensitivity and no analgesic requirements even after a painful orthopedic surgery.¹¹⁸ More common FAAH SNPs have been associated with cold sensitivity in human experimental models and oxycodone consumption in patients undergoing surgery for breast cancer.¹¹⁹ In a study of low back pain patients, a FAAH SNP was significantly associated with mechanical and cold pain sensitivity.¹²⁰

REGULATION OF NAUSEA AND EMESIS BY THE ENDOCANNABINOID SYSTEM

As reviewed previously, CB1 receptors are widely distributed in the nervous system and can be found in central and peripheral structures involved in nausea and vomiting.¹²¹ In animal models, cannabinoids inhibit acute and delayed emesis, primarily through a CB1 receptor mechanism in the dorsal vagal complex of the brain stem.¹²¹ CB2 receptors have also been identified in the brainstem structures and contribute to antiemetic effects of the eCB 2-AG in the ferret, but the mechanisms are not clear and clinical studies are needed to further elucidate therapeutic potential.¹²²

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). In a double-blind placebo-controlled study, tolerability, and efficacy of dronabinol, ondansetron (a 5-HT3 antagonist), and combination treatment were evaluated over 5 days in patients who experienced delayed CINV. Of the 61 patients analyzed for efficacy, dronabinol or ondansetron was similarly effective, and combination treatment was not more effective than either medication alone.¹²³ Nabilone was compared to D2-receptor antagonists for their antiemetic/antinausea effects in patients receiving chemotherapy; nabilone treatment resulted in fewer vomiting episodes and nausea severity when patients received moderately toxic chemotherapeutic agents, but the drug was equally effective as a D2 receptor antagonist in reducing vomiting when given cisplatin, a more toxic agent, was administered.¹²¹

There is a paucity of literature regarding cannabinoid efficacy for managing clinical postoperative nausea and vomiting, either as a prophylactic or rescue treatment. In a study examining prophylactic IV THC or placebo in 40 high-risk patients, the relative risk reduction of PONV in the treatment group was 12% (compared to 25% demonstrated by other medications); the study was terminated after 40 patients because the antiemetic effects were unclear, and the side effects of sedation and confusion were clinically unacceptable.¹²⁴ In a pragmatic study comparing oral nabilone versus placebo in high-risk patients scheduled for surgery with general anesthesia, there was no difference in the incidence of PONV between the groups (20.9% vs 21.4%, respectively). Patients were also given any combination of typical prophylactic antiemetics such as dexamethasone and metoclopramide, but addition of nabilone did not confer any benefit.¹²⁵ In a case study, a patient who developed severe, intractable nausea after Rou-en-y gastric bypass surgery was treated with dronabinol and experienced significant improvement after 1 day, having previously suffered with persistent symptoms for 4 weeks after her surgery.¹²⁶ As with treatment of CINV, therapeutic efficacy of CB1 receptor agonists for PONV may be limited by side effects, including euphoria, sedation, or hallucinations.

COMMON MEDICATIONS USED IN THE PERIOPERATIVE PERIOD ENGAGE THE ENDOCANNABINOID SYSTEM

Evidence suggests that several medications commonly used perioperatively directly interact with the eCB system. From animal and in vitro studies, the general anesthetic and sedative propofol increased whole brain levels of AEA presumably by inhibiting its degrading enzyme FAAH,¹²⁷ but findings from patients are contradictory.^128,129 Animal models also suggest that the antinociceptive effects of propofol injected in the hind paw are mediated locally, in part, by CB1 and CB2 receptors,¹³⁰ and propofol-mediated retrograde memory consolidation and anterograde amnesia are dependent on CB1.^131–133

Antinociception by ketamine involves central and peripheral CB1 receptors. Intracerebroventricular injection of a CB1 antagonist completely reversed ketamine’s antinociceptive effect in mice, while drugs that enhanced AEA levels significantly augmented ketamine’s effect.¹³⁴ Involvement of peripheral antinociceptive action was demonstrated by ketamine’s selective elevation of AEA in an inflammatory pain model, leading to increased mechanical thresholds of rat hind paws in a CB1-dependent manner.¹³⁵

A purported mechanism of acetaminophen (paracetamol) analgesic activity is the formation of the metabolite N-arachidonoylphenolamin (AM404) in a FAAH-dependent manner.¹³⁶ AM404 is a potent TRPV1 agonist¹³⁶ and eCB reuptake inhibitor that increases levels of AEA.¹³⁷ Further support of eCB involvement is that acetaminophen’s analgesic effects are abolished in the presence of CB1 selective antagonists, CB1 knockout mice, FAAH knock-out mice, and FAAH inhibitors.^138–141 A recent study in mice implicates the importance of CB1 receptors in the rostral ventromedial medulla, a supraspinal site, in acetaminophen analgesia.¹⁴²

FUTURE RESEARCH AND POTENTIAL THERAPEUTIC DEVELOPMENT

The eCB system is an intricate and essential neuromodulatory system. Characterizing cannabinoid receptor expression, eCB levels in relevant anatomical areas, and determining associations with pain intensity and function are important for predicting the effectiveness of a particular cannabinoid, informing dosing, and spurring the development of precision cannabinoid therapeutics that avoid untoward side effects. Further research is warranted to understand how endogenous cannabinoids can be exploited for analgesic benefit. Given the importance of eCB signaling through CB1 in the brain, development of eCB modulators that are peripherally restricted and agonists that primarily bind to CB2 receptors are promising drug strategies that may decrease pain and inflammation, while avoiding undesirable central effects. In addition, studies using diverse, well-characterized cannabis preparations with defined cannabinoid and noncannabinoid content are urgently needed. Preclinical studies on mechanisms of action of crude cannabis extracts and single cannabinoids continue, but translation into the clinic is hindered by research barriers.¹⁴³ The unfortunate consequences are patients using cannabis and providers guiding patients with limited science. The future of quality cannabinoid research is bright, but depends on continued concerted efforts among government, academia, and industry partners.

GLOSSARY

2-AG

2-arachidonoylglycerol

5-HT

5-hydroxytryptamine or serotonin receptor

A1A

adenosine A1 receptor

AEA

anandamide

CB1

cannabinoid 1 receptor

CB2

cannabinoid 2 receptor

CBD

cannabidiol

CINV

chemotherapy-induced cause and vomiting

eCB

endocannabinoid

FAAH

fatty acid amid hydrolase

FDA

US Food and Drug Administration

GABA

gamma–aminobutyric acid

Gly α1 and α2

glycine alpha receptor

GPR18

G protein-coupled receptor 18

GPR55

G protein-coupled receptor-55

MAGL

monoacylglycerol lipase

MS

multiple sclerosis

NAM

negative allosteric modulator

NOC/c

notice of compliance with conditions

NRS

numerical rating scale

PAM

positive allosteric modulator

PONV

postoperative nausea and vomiting

PPAR γ

peroxisome proliferator-activated receptor gamma

SCRA

synthetic cannabinoid receptor agonist

SNP

single-nucleotide polymorphism

THC

delta-9-tetrahydrocannabinol

TRPA1

transient receptor potential cation channel, subfamily A, member 1

TRPM8

transient receptor potential cation channel subfamily M (melastatin) or menthol receptor