The Endocannabinoid System: Beyond Cannabinoid Receptors
Endocannabinoids (endogenous cannabinoids [ECs]), endocannabinoid receptors, several other receptors activated by ECs, and the enzymes that synthesize and degrade ECs constitute the endocannabinoid system (ECS).1 The ECS is an integral neuromodulatory system that is involved in neuronal development, synaptic plasticity, and homeostasis regarding immunity as well as brain and other physiological functions.1 Endocannabinoids primarily refer to 2-arachidonoyl glycerol and arachidonoyl ethanolamide (anandamide), both of which have been well studied.1 In the CNS, ECs are secreted through the postsynaptic membrane of neurons and act on presynaptic receptors—endocannabinoid receptors 1 and 2 (CB1 and CB2 receptors)—causing hyperpolarization following increasing K+ cell influx.2 This leads to inhibitory neurotransmitter modulation that can facilitate diverse biological and physiological processes such as anxiety, pain, metabolic regulation, immunity, and bone growth.3 In addition, ECs have different affinities to CB receptors, and their half-life is short due to the rapid metabolism by enzymes (fatty acid amide hydrolase and monoacylglycerol lipase).4
CB1 receptors are expressed primarily on cells in the CNS.5 CB2 receptors are identified mainly on leukocytes but also on neurons and, to a small degree, glial cells, especially during pathological conditions such as degeneration, inflammation, and anxiety, although its level of expression on neurons in the brain is lower than that of CB1 receptors.6,7 CB2 receptors have been shown to play an essential role in the anti-inflammatory and immunomodulatory properties of cannabinoids and can contribute to induction of apoptosis, which contributes to the immunosuppression effects of cannabinoids.7–9 Interaction between ECS and cannabinoids will be discussed in more detail in each clinical application section below.
Plant-derived Cannabinoids
As described, the ECS has tremendous implications in neurological homeostasis, and Cannabis sativa– or Cannabis indica–derived cannabinoids have the potential for profound interplay within this system as enzymatic inhibitors or receptor-mediated interactions that can influence many different pathologies. The basic understanding of the Cannabis-derived cannabinoids is necessary to fully appreciate the cannabinoids of interest. Cannabis species can produce over 400 different flavonoids, cannabinoids, and terpenes, many of which can have biological implications. The biosynthesis of cannabinoids in plants is high due to extensive breeding and duplications in synthase genes in the plant, leading to rhizome production in the flowering portion.10
The cannabinoid synthesis in a typical Cannabis plant comes from the precursors olivetolic acid and geranyl diphosphate and highly expressed cannabinoid synthase activity that produces the backbone molecule to all cannabinoids called cannabigerolic acid (CBGA; Figure 1). Depending on the specific strain of Cannabis, the biosynthesis of other cannabinoids can vary; however, many of the Cannabis strains used recreationally produce tetrahydrocannabinolic acid. This molecule, when decarboxylated, results in Δ9-tetrahydrocannabinol (THC), which leads to psychotropic effects primarily through actions at the CB1 receptor mentioned in the previous section. Due to the increased interest in cannabidiol (CBD), hemp-derived cultivars, which produce less than 0.3% THC, have become much more popular recently. The hemp-derived cannabinoid made in the plant is primarily cannabidiolic acid (CBDA) rather than tetrahydrocannabinolic acid (THCA). Another lesser known and studied cannabinoid can be made through synthase activity to make cannabichromenic acid (CBCA), and fewer varietals have been developed that make this specific cannabinoid but can still be found in many hemp-based products on the veterinary market.11
Depiction of major cannabinoid production in typical Cannabis cultivars showing the formation of cannabigerolic acid (CBGA) from geranyl diphosphate (GPP) and olivetolic acid (OA). Based on synthase activity, CBGA will become either cannabidiolic acid (CBDA), tetrahydrocannabinolic acid (THCA), or cannabichromenic acid (CBCA) as native cannabinoids to the plant. When heated, extracted, or exposed to UV light, decarboxylation occurs to form neutral cannabinoids cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC), or cannabichromene (CBC).
Citation: Journal of the American Veterinary Medical Association 261, 5; 10.2460/javma.23.02.0064
The natural acidic forms of these major cannabinoids are not found in many products. This has been reportedly due to the lack of stability of these acids, whereby rapid decarboxylation can occur under high temperatures or chemically harsh extraction practices, typically producing the neutral cannabinoids, namely CBD and THC.12 This being said, there are now data from pharmacokinetic studies in veterinary species suggesting that these acidic cannabinoids are quite stable in products and may have pharmacologic properties themselves.13–16
The focus in human and veterinary medicine has been around CBD, which is the major cannabinoid marketed as the most well studied of the nonpsychotropic cannabinoids. CBD and CBDA are both found in marketed hemp products in the veterinary arena with other trace cannabinoids found in many products.11 Due to the higher concentrations of CBD/CBDA in products, it is thought that the biological effects, which will be discussed in subsequent sections, are primarily from CBD/CBDA. However, it cannot be ruled out that the other cannabinoids and terpenes in the product are not facilitating absorption and metabolism changes called the “entourage effect.”17 This “entourage effect” comes from sparse data, suggesting that use of a whole hemp plant extract can sometimes elicit the same response as does pure isolates of CBD, yet at lower doses.18,19
The Endocannabinoid System: Potential Targets
As described in the previous section, cannabinoids are a family of naturally occurring compounds that are extracted and isolated from plants,20 the most abundant of which are THC, CBD, and cannabigerol (CBG), which is the precursor of both CBD and cannabichromene (CBC). Many studies have shown that cannabinoids may have anticancer properties and antiangiogenic, anti-inflammatory, and antiseizure effects using in vitro and in vivo models.21–27
Cannabinoid mechanisms of action are not yet fully understood. Binding of THC, CBD, or other plant constituents to receptors are considered to elicit a great number of pathways, including the mitogen-activated protein kinase–driven apoptosis and autophagy pathways, endoplasmic reticulum stress-related pathways, and inflammasome-mediated signaling pathways.28–30 Cannabinoids can bind to a superfamily of G coupled protein receptors, such as CB1 and CB2 receptors. Activation of these receptors leads to various intracellular signaling processes involved in cellular functions, but those interactions are diverse due to different affinities of each cannabinoid with relevant receptors.31 For instance, THC has much higher affinities for CB1 and CB2 receptors than other components and exhibits a direct interaction.4,31 On the other hand, CBD is a minimal agonist for both receptors and acts via an indirect negative allosteric modulation of CB1 receptors.4 Therefore, bioavailability, pharmacological effects, and tolerability vary among different cannabinoids. Importantly CBD, CBG, and possibly other components lack the psychoactive effect that THC possesses. This may be explained by their low affinity for the CB1 and CB2 receptors.32
Clinical applications for seizure management
CBD’s anticonvulsant properties have been demonstrated in open-label and placebo-controlled randomized clinical trials in humans with genetic syndromes causing refractory seizures in the past decade.25–27 Based on the evidence, the FDA, European Medicines Agency, and National Institute for Health and Care Excellence have approved highly purified CBD (Epidiolex), which is also stipulated by the European Medicines Agency and National Institute for Health and Care Excellence to be used as adjunctive medication with clobazam for treatment of Dravet syndrome (a genetic epileptic encephalopathy known as a severe myoclonic epilepsy of infancy that exhibits focal or generalized convulsive seizures) and Lennox-Gastaut syndrome (a severe form of epileptic encephalopathy with several different types of seizures such as atonic, tonic, and absence seizures that typically occurs during infancy or early childhood).33
Thus far, the mechanism of CBD’s antiseizure properties has not yet been fully elucidated in humans or veterinary medicine; however, CB1 and CB2 endocannabinoid receptors are considered to play a role. Several possible mechanisms have drawn attention based on experimental research: modulation of sodium and calcium influx, decrease in intracellular calcium concentration, and inhibition of adenosine reuptake.34
First, transient receptor potential vanilloid-1 (TRPV1) is a nonselective cation channel with a preference for calcium and activated by noxious stimuli, heat, and noxious natural product (eg, capsaicin).35 It modulates sodium and calcium influx, resulting in increased synaptic activity, and is considered to be involved in CBD’s antiseizure effects. TRPV1 is expressed in several brain regions such as the cerebral cortices, limbic system, and hypothalamus.35,36 CBD acts as an agonist on TRPV1, diminishing the activity of TRPV1-driven signaling pathways by desensitization, limitation, and downregulation.37,38 However, involvement of TRPV1 in the mechanism of CBD’s anticonvulsant effect is still controversial due to the results of a recent experimental study39 in a genetic mouse model of Dravet syndrome.
Second, an increase in intracellular calcium concentration in presynaptic vesicles leads to release of neurotransmitters, resulting in modulation of neuroexcitability that causes either excitatory or inhibitory activity. CBD can act as an antagonist on orphan G protein–coupled receptor-55 (GPR55), which is responsible for increasing intracellular calcium concentrations, as well as increasing the production of proinflammatory cytokines by activated monocytes (IL-12 and TNF-α). GPR55 receptors represent a potential pharmacological target to manage seizures. It is thought that CBD may be successful in modulating the function of GPR55 and potentially changing the patterns of gene expression.40–42
Third, adenosine is a well-known endogenous antiseizure substance and agonist of A1 and A2 receptors, which terminate seizure activity. Therefore, low levels of extracellular adenosine may lead to proconvulsant activity; in other words, increasing its concentration could have anticonvulsant effects.37,43 Experimental evidence has been identified supporting that CBD may be effective in increasing extracellular adenosine levels by inhibiting purine cellular intake.37
In addition to the aforementioned possible targets, GABAergic modulation, endocannabinoid signaling pathways via CB1 receptors, mitochondrial CB1 receptors, large conductance calcium-activated potassium channels, mechanistic target of rapamycin signaling pathways, and voltage-gated sodium channels have also been considered potential targets for CBD, although the evidence is still scarce.34,44–46 Overall, CBD’s antiseizure effects may be attributable to the interplay of multiple mechanisms that are derived from targets discussed earlier or those still unknown.46
The antiseizure effects of CBD has been well demonstrated in human clinical trials, as well as rodent studies, which revealed antiseizure effect on treatment-resistant epilepsy and developmental and epileptic encephalopathies, including Dravet syndrome and Lennox-Gastaut syndrome.47,48 In addition, experimental studies with rodents have shown CBD’s effect on focal and generalized seizures, including nonconvulsive seizures in acute and chronic seizure mouse models49 and genetic absence epilepsy rats.50
Likewise, canine clinical trials have also been conducted in dogs with idiopathic epilepsy. In 1 randomized blinded crossover clinical trial, idiopathic epileptic dogs with tier I or II confidence level51 were allocated into 2 groups: CBD/CBDA-rich hemp extract in a sesame oil preparation (2 mg/kg, q 12 h) or placebo and were crossed over after 3 months.52 Seizure frequency and the number of seizure days significantly decreased during the CBD/CBDA treatment period compared to placebo. In the treatment phase, 43% (6/14) of dogs achieved ≥ 50% reduction in seizure frequency and were regarded as responders, while there were no responders in the placebo phase.52
In another randomized blinded controlled clinical trial,53 idiopathic drug-refractory epileptic dogs with tier II confidence level were randomly allocated to receive CBD-infused oil or placebo in addition to traditional antiseizure medication. The CBD-infused oil was administered every 12 hours at a dose of 2.5 mg/kg. The result revealed a 33% reduction in mean monthly seizure frequency in the CBD group; on the other hand, no change was noted in the placebo group. Interestingly, a negative correlation was identified between CBD plasma concentrations and the percent decrease in seizure frequency.53 Despite those 2 studies,52,53 further randomized clinical trials with larger populations are required to better understand CBD’s efficacy in controlling seizures in veterinary medicine and whether it fits into current treatment protocols.
It is noteworthy that the therapeutic effect of THC on epileptic seizure control is not supported reliably and consistently by experimental and clinical human studies.54 Due to discrepancy of these results, currently clinical use of THC is not recommended for epileptic human patients. Furthermore, worsening of epileptic seizures, ataxia, and behavioral alterations were identified in pediatric patients who received highly concentrated CBD with 3% to 4% THC.55 Likewise, ingestion of excessive THC by dogs commonly results in intoxication, manifesting as behavioral alterations, lethargy, tremors, ataxia, gastrointestinal signs (vomiting and diarrhea), and autonomic signs (hypothermia and bradycardia).56,57
Clinical applications for anxiety
Experimental rodent studies have revealed CBD’s potential antianxiety and antidepressant effects, as well as its effect on clinical signs associated with cognitive dysfunction.58–60 CBD’s antianxiety effects have been identified when doses ranging from 2.5 to 10 mg/kg were given to rats and 20 mg/kg to mice.60,61 However, a different study62 revealed an IP injection of CBD at 10 mg/kg led to anxiogenic effect. This discrepancy of experimental study results could be explained by a biphasic effect of CBD (antianxiety at lower doses and proanxiety at higher doses).61 Further, the duration of CBD administration (acute vs chronic) may contribute to the discrepancy. An acute anxiolytic effect of CBD has been reported in both rodents and humans63,64; on the other hand, chronic administration for 14 days did not reveal that effect and instead showed anxiogenic effects in rats.62
In people, CBD monotherapy of dosages between 400 and 600 mg significantly diminished anxiety of patients with generalized social anxiety disorder,63,65 although the chronic effect of CBD on anxiety symptoms has not yet been thoroughly studied.66 However, controlled clinical trials in people with social anxiety and panic disorders revealed no significant effect of CBD as an adjunctive medication.67 A recently published meta-analysis68 revealed that cannabinoids may have a potent anxiolytic effect; however, the study conclusions may be skewed by publication bias, small sample populations, and inconsistent results.
In veterinary medicine, although scientific evidence supporting CBD’s anxiolytic effect is still limited, according to a questionnaire, approximately half of pet owners giving CBD to their dogs noticed a reduction of their dogs’ fear or anxiety with various doses of CBD.69 In addition, shelter dogs receiving approximately 3.75 mg of CBD/kg for 45 days manifested reduction of aggressiveness against humans but without improvement of other stress-related behaviors.70 Another study71 failed to demonstrate CBD as an anxiolytic in dogs using a fireworks model of noise-induced fear. In this study, dogs were given 1.4 mg of CBD/kg/d for 7 days, with no improvement of heart rate or fearful behavior triggered by loud noise compared to the control group.71
With respect to the mechanism of CBD’s antianxiety effect, it has been proposed that CBD can modulate various receptors that regulate fear- and/or anxiety-driven behaviors; however, the mechanism has not yet been fully elucidated. As previously discussed, CBD interacts with CB1 receptors as an indirect antagonist, which may contribute to amelioration of fear and decrease in chronic stress by mobilizing negative feedback of the neuroendocrine stress response.66 One mouse study2 demonstrated that 5-HT1A-mediated (ie, serotonin 1A receptor) neurotransmission may be integral to CBD’s antianxiety effect by interrupting intracellular signaling pathways and/or allosteric interaction with the 5-HT1A receptor binding site. A study72 on gene sequencing of the 5-HT1A receptor revealed that its amino acid composition in dogs is comparable to that in humans (92% homology) and mice (89% homology), with several areas showing 100% homology. This may indicate CBD’s effect on the 5-HT1A receptor in dogs would have analogous effects as mice and humans.72
Moreover, as discussed before, CBD’s antianxiety properties may exhibit a bell-shaped dose response. This may be explained, at least in part, by activation of TRPV1 receptors in the brain. TRPV1 receptors are located in several brain regions associated with control of stress and defensive responses (hippocampus, prefrontal cortex, dorsolateral periaqueductal gray [dLPAG], etc).36 Some studies have indicated that activation of TRPV1 receptors may facilitate glutamate release,73 which is the primary excitatory neurotransmitter in the CNS. Antagonism of its receptors in the dLPAG has revealed antianxiety responses.74 Therefore, it is speculated that high doses of CBD or endocannabinoids could activate TRPV1 receptors in the dLPAG, leading to glutamate neurotransmission and resulting in increased anxiety.35
Clinical applications for osteoarthritis
As elucidated in the prior sections, the receptor biology outlined in the ECS is likely at play for transmission of the pain response and may play a role in chronic pain as well. In humans, the use of CBD-rich hemp for osteoarthritis is currently not particularly well established due to the variety of products and isolates used as well as limited absorption of CBD in human trials.75 A dose of 2 mg/kg leads to over 100 ng/mL serum concentrations as a maximum serum concentration in dogs, while humans using similar dosing only achieve approximately 10 ng/mL, meaning that very high oral dosing is required in humans, as evidenced by the current dosing recommendations for the human CBD isolate, Epidiolex.75–77 Rodent models suggest that CBD and CBDA have utility in mitigating the pain response; however, a majority of these studies deliver cannabinoids through IP injections at high doses, bypassing hepatic metabolism, which is not feasible in human or veterinary patients.78 In humans, osteoarthritis literature for the use of CBD for mitigation of pain is sparse, while more literature surrounding neuropathic pain associated with muscular sclerosis shows some efficacy. In human arthritis, the dosing based on pharmacokinetics appears to have not been optimized particularly, as most studies have been observational in nature.79–81
In dogs, there are 4 randomized placebo blinded control studies examining the effects of oral CBD-rich products. The first study82 used a CBD/CBDA-rich hemp product, which was an equal mix of CBD and CBDA, provided to dogs in a crossover placebo blinded study over 4 weeks for each arm of the study. It showed clinical benefits based on validated subjective measurements using the Canine Brief Pain Inventory (CBPI).82 Owners were provided these surveys at 2 and 4 weeks of treatment, with an average 20-point drop in the CBPI survey as well as a nearly 20-point increase when utilizing the Hudson Activity scale as a measure of activity. The mean differences from baseline in the treatment group were significant at 2 and 4 weeks. The dose utilized in this study was 2 mg/kg every 12 hours in an olive oil base, which was the oil also used in the placebo group.
A second study83 utilized a smaller cohort of dogs using a CBD-rich hemp product. There were 4 groups of 5 dogs in each cohort receiving a placebo as medium chain triglyceride (MCT) oil, 20 or 50 mg/d of CBD-rich isolate in MCT base or a 20-mg dose of a microsomal encapsulated CBD-rich hemp product. The trial was for 30 days, utilizing the Helsinki Pain Index, which showed a significant drop in the pain index in the groups treated with the 50-mg/d dose of CBD-rich hemp in MCT oil and 20-mg dose of microsomal encapsulated formulation.
A third randomized placebo-controlled study84 examined dogs with clinical arthritis that were being managed on firocoxib or low-dose prednisone as well as amitriptyline and gabapentin as concomitant therapeutics during a 12-week trial. The CBD-rich hemp product was delivered in an MCT base at 2 mg/kg every 12 hours through a transmucosal application into the buccal pouch in 9 dogs and MCT oil only to 12 dogs in the control group. This should be cautiously interpreted as dogs naturally swallow applied products. The dogs were assessed using the CBPI evaluation at 0, 1, 2, 4, and 12 weeks of treatment. Significant decreases in CPBI scoring were observed between the control and treatment groups at 1, 2, 4, but not 12 weeks, and significant differences in pain scoring from baseline were observed over time in the treatment group that were not observed in the control group.
The fourth study85 was a randomized placebo controlled crossover study in which 23 dogs were administered placebo of only hempseed oil or treatment using 2.5 mg/kg of a CBD-rich hemp in hempseed oil for a 6-week trial of each. The outcome measures at 3, 6, 9, and 12 weeks were compared to initial screening, which included subjective CBPI, the Liverpool Osteoarthritis in Dogs questionnaire, assessments of total weight-bearing, and percentage of weight-bearing. For nearly all subjective and objective observations, there were improvements during the CBD-rich isolate treatment. However, there were also improvements in portions of the CBPI and the Liverpool Osteoarthritis in Dogs assessment in the placebo phase, and a treatment X time effect was not found to be significantly different between groups. Although negative overall, it should be pointed out that there was THC detected in the blood of dogs on the placebo, and the omega 3 fatty acid differences between hempseed oil and other oil bases may have influenced these results.
Regarding pain management, osteoarthritis pain is often deemed to arise from mechanisms that are different from those of acute surgical pain, and the use of CBD-rich hemp has been limited in this regard.86 A recent study87 investigated the use of 2 mg of CBD/CBDA/kg every 12 hours for the first month postoperative tibial plateau leveling osteotomy utilizing veterinary pain and mobility assessments and owner CBPI surveys 2 and 4 weeks postoperatively. This study showed no improvements in veterinary/owner assessments using CBD/CBDA, with both placebo and treatment groups exhibiting similar improvements over time. Interestingly, the use of trazodone to limit activity was required less in the treatment group than the placebo at the 2-week interval postoperatively.87 However, a recent abstract88 demonstrated pain management in postsurgical intervertebral disc disease with the same product at a higher dose of 5 mg of CBD/CBDA/kg. It suggested lower postsurgical pain scoring based on blinded veterinary assessment compared to placebo. Whether CBD/CBDA can be utilized and how much dose is necessary for postsurgical pain are still undetermined.
Clinical applications for atopic dermatitis
Although in its infancy, the ideation that cannabinoids may influence allergic skin disease stems from the neurological perception of pruritus, as outlined in prior sections, which are similar to neurotransmission interference through similar pain and seizure pathways, as well as the anti-inflammatory capabilities surrounding CBD and CBDA. They activate peroxisomal proliferation activation receptors in inflammatory cells to mitigate cytokine production upregulated in the skin of dogs with atopic dermatitis and other cannabinoid targets.89–91 A recent placebo blinded study92 was performed utilizing a dose of 2 mg of CBD/CBDA-rich hemp/kg every 12 hours in 17 dogs with 12 receiving placebo sesame oil for 4 weeks. Subjective veterinary measurements of inflammation using the Canine Atopic Dermatitis Scoring Index and vertical analog pruritus assessments by owners were performed, suggesting that dogs in the CBD/CBDA-rich treatment group had significant decreases in pruritus, with an average 2-point reduction and approximately 30% achieving resolution of pruritus. This was significantly different from the placebo group at 2 and 4 weeks. Interestingly, neither the Canine Atopic Dermatitis Scoring Index nor cytokine profiles (interleukin-31, interleukin-34, or monocyte chemotactic protein-1) changed between the week 0 and 4 assessments of treatment, implying that cannabinoid treatment likely altered neurological perception rather than dampening the inflammatory response. Surprisingly, a study93 examining normal healthy activity in dogs at similar dosing with accelerometry data showed that only meaningfully significant alteration in activity in kenneled dogs was “itching” behaviors, suggesting alteration in pruritus activity. In concert with the lack of immunological alteration in the study by Loewinger et al,92 a study by Morris et al,94 who examined similar dosing (2.5 mg/kg, q 12 h) and followed generalized humoral responses to keyhole limpet antigen, showed that CBD did not negatively or positively influence humoral immunity.
Adverse events across studies
Adverse events are not commonly reported with the use of CBD products, with occasional reports of somnolence and behavioral issues in general, and are often not severe enough across canine studies to preclude continued treatment with CBD products.52,53,82–85,92,95,96 Many canine clinical studies have followed CBC and serum biochemistry. Three- and 6-month safety studies of chronic administration of CBD-rich product at 2 and 4 mg/kg/d showed safe administration with no alterations in CBC and occasional rises in serum ALP as the primary observation in some dogs.97,98 This elevation suggests potential differences in hepatic cannabinoid metabolism and potential upregulation of cytochrome p450 metabolism, which is addressed in the companion Currents in One Health by Schwark and Wakshlag, AJVR, May 2023, for further in-depth reading. Clinically, rises in ALP concurrently with CBD use is not accompanied by rises in other liver-associated parameters such as GGT and bilirubin. Therefore, an ALP rise of this nature is often innocuous; however, it should be monitored with routine blood work, particularly to differentiate a drug effect or endocrine effect/disease such as hyperadrenocorticism.
Conclusions
Although the use of cannabinoids, particularly CBD products, is in its infancy in veterinary medicine, there appears to be cautious optimism regarding its utilization concurrently with other therapeutics for a range of disorders including epileptic seizure control, pain associated with osteoarthritis, and atopic dermatitis. There is currently no appreciable evidence that CBD products have utility in the treatment of situational or chronic anxiety in dogs. Drug interactions have been poorly elucidated across veterinary species with emerging evidence that many of the current antiepileptic drugs do not seem to be a major concern in dogs. It must also be highlighted that all of these clinical studies are canine trials and there are currently no clinical studies of cats, horses, or other companion veterinary species to show any clinical benefits at the time of writing this review.
Acknowledgments
Dr. Wakshlag is a consultant for Ellevet Sciences, and Dr. McGrath is on the Scientific Advisory Board for Panacea Life Sciences. The authors declare that there were no conflicts of interest.
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