Cannabidiol (CBD) is a nonintoxicating phytocannabinoid of the cannabis plant.
The Agriculture Improvement Act of 2018, also known as the 2018 Farm Bill, removed hemp-derived cannabis from the federal definition of marijuana. It is now considered legal on a federal level; however, its status varies by state.
Hemp-derived cannabis contains no more than 0.3% delta-9-tetrahydrocannabinol (THC) on a dry matter basis per US standards and typically contains 0.3–4.2% cannabidiol (CBD). Selective breeding can lead to higher CBD concentration in plants, especially in those grown for medicinal purposes (1). By contrast, the average CBD content can be as little as 0.15% in plants bred for higher THC concentrations (2).
The first FDA-approved cannabidiol product, developed to aid in the management of drug-resistant seizures in children over 1 year old, was approved in 2018, with expanded approval in 2020. This remains the only FDA-approved CBD product (3). No over-the-counter CBD products are approved by the FDA.
In part because of a lack of regulatory oversight, there can be great variability in CBD product quality. Poorly manufactured products might display inaccurate CBD content in label claims and can inadvertently contain THC or contaminants such as synthetic cannabinoids and heavy metals (4, 5).
Most research on the use of CBD in veterinary patients has been either for pharmacokinetic purposes or for investigating CBD's therapeutic use in osteoarthritis and epilepsy patients. Cannabinoids have been therapeutically considered in companion animal diseases ranging from dermatological to neurological, ocular, endocrine, and respiratory (6).
Etiology and Pathogenesis of CBD Toxicosis in Dogs and Cats
Cannabidiol in part interacts with the body's endocannabinoid system (ECS), which is present in most animals. The ECS plays a role in managing homeostasis and physiological balance, with widespread receptor distribution that includes the CNS, inflammatory pathways, and immune cells or systems. The ECS is comprised of innate endocannabinoids that bind and interact with endocannabinoid receptors, the endocannabinoid receptors CB1 and CB2, and the enzymes that produce and remove these endocannabinoids (7).
Endocannabinoids act as neurotransmitters in retrograde fashion on the presynaptic neuron, preventing neurotransmitter release. Some degree of nonretrograde signaling can occur as well (8). The primary targets for endocannabinoids and some phytocannabinoids are cannabinoid types 1 and 2 (CB1 and CB2) receptors (9).
CB1 receptors are concentrated in the CNS (with a lower concentration in the peripheral nervous system) and are involved in cognitive function, emotion, motion and motor control, hunger, neuroprotection, posttraumatic events, and degenerative diseases. CB1 receptors in the sensory and autonomic nervous systems influence pain perception and cardiovascular, GI, and respiratory function (10).
CB2 receptors are more concentrated in the peripheral nervous system than in the CNS (6, 10). Phytocannabinoid interaction with CB2 receptors imparts nonintoxicating effects. Endocannabinoid interaction with these receptors helps to moderate inflammation and chronic pain (10).
The ECS can cross-react with or influence many other receptor systems. Endocannabinoid or endocannabinoid-like molecules might not directly interact with CB1 and CB2 but rather might potentiate the effects of endocannabinoids, resulting in the “entourage effect.” Some phytocannabinoids, including CBD, and phytochemicals, including terpenes and flavonoids, mechanistically participate and impart their effects in this manner (7).
CBD has a low affinity for CB1 and CB2 receptors. It acts as a negative allosteric modulator of CB1, especially when THC is also present, and can help mitigate some of the effects of THC (11, 12). CBD also acts as an inverse agonist at the CB2 receptor, decreasing active receptor levels and actions (9).
CBD interacts more notably with other receptor systems that cross-interact with the ECS. Overall, CBD has more than 76 molecular targets of action, some of which manage inflammatory and nociceptive systems (6). Some of these targets include influences on transient receptor potential vanilloid I receptors, adenosine uptake, and levels of anandamide (a natural endocannabinoid) (13). CBD can also influence 5-hydroxytryptamine, cyclooxygenase, multidrug resistance gene (MDR1), dopamine, and opiate receptor systems (14, 15).
Centrally, CBD can act with antipsychotic, anxiolytic, anticonvulsant, neuroprotective, and antinausea influence; peripherally, it can impart anti-inflammatory and ocular effects (1, 16).
Toxicity and Pharmacokinetics of CBD in Dogs and Cats
Note: Pharmacokinetic data pertain to dogs unless otherwise indicated.
CBD is rapidly absorbed when consumed orally, with time to maximum concentration (Tmax) reached within 1.2–6.2 hours in dogs (15,17, 18, 19, 20) and 2–3 hours in cats (21, 22). The maximum concentration (Cmax) in cats is much lower than that in dogs (18).
Oral bioavailability ranges from 6% to 20% (23). CBD is highly lipophilic and rapidly distributed to tissues. It undergoes extensive first-pass hepatic metabolism. CBD is metabolized by hydroxylation, oxidation, carboxylation, and glucuronidation (18, 20, 24, 25).
CBD metabolism is heavily reliant on cytochrome P450 (CYP) enzymes, and metabolites vary substantially by species (23). The elimination half-life of oral CBD in dogs ranged from 0.5 to 5.8 hours across studies using CBD oil, gel capsules, and soft chew formulations. Elimination is primarily via feces, and secondarily through urine (15, 17, 18, 19, 20, 22). The elimination half-life of oral CBD in cats ranged from 6.7 to 13.2 hours (21).
CBD is well tolerated in chronic therapeutic use and overdose exposures in dogs and cats. The therapeutic use of CBD is beyond the scope of this chapter.
Acute oral overdose up to 62 mg/kg caused diarrhea in dogs (26). Chronic doses of CBD in dogs in some studies led to ALP elevations that were suspected to be secondary to CYP induction and were transient (3). In cats, acute oral overdoses up to 80 mg/kg have been well tolerated, with no CBD-related clinical signs documented. Carrier-related transient salivation was noted in some cats (21).
Elevated ALT was documented in a single cat in one CBD dosing study, and the elevation abated after discontinuing the product (18). Liver profile monitoring with chronic therapeutic use might be indicated until further studies can be completed.
Clinical Signs of CBD Toxicosis in Dogs and Cats
Given its mechanism of action, nonintoxicating nature, pharmacokinetics, and published studies in dogs and cats, CBD could lead, at most, to GI distress when ingested in overdoses, even large ones.
From January 2018 through February 2023, approximately 45% of CBD cases documented at Pet Poison Helpline, a US-based 24/7 animal poison control center, remained clinically normal (see ). An additional 15% of cases had clinical signs of vomiting, 5% were hypersalivating, and 3% had diarrhea.
An unexpected 30% of CBD cases exhibited clinical signs of lethargy, 21% were ataxic, and 6–7% had hyperesthesia, trembling, or urinary incontinence; this set of clinical signs is likely attributable either to ingestion of a large volume of hemp-derived product that contains less than 0.3% delta-9-THC or to poor product quality and contamination with unlabeled quantities of THC, synthetic cannabinoids (SCBs), or other chemicals or compounds. These uncommon cases might continue to occur in the veterinary field with overdose exposures to CBD products until better and more effective regulatory oversight is established.
Courtesy of Pet Poison Helpline & SafetyCall International, LLC.
Diagnosis and Treatment of CBD Toxicosis in Dogs and Cats
Diagnostic testing for cannabidiol intoxication is rarely indicated with acute overdose. Chronic therapeutic use or chronic overdose might benefit from hepatic profile monitoring.
Clinically normal CBD overdose patients can often be monitored at home. Veterinary care may be pursued if clinical signs are noted.
Massive CBD-containing product ingestions can be decontaminated by inducing emesis with apomorphine (dogs: 0.03 mg/kg, IV, or 0.04 mg/kg, IM) or ropinirole (dogs: 3.75 mg/m2, with dose range of 2.7–5.4 mg/m2, ocular application); neither apomorphine nor ropinirole should be administered to cats (27, 28). Activated charcoal is generally not indicated, given the safety profile of CBD in patients.
Patients showing GI signs may be treated supportively with antiemetics (maropitant 1 mg/kg, SC or IV, every 24 hours, or ondansetron 0.1–0.2 mg/kg, IV, every 8 hours), digestive diets, probiotics, gastroprotectants (omeprazole 1 mg/kg, PO, every 12–24 hours; famotidine 1 mg/kg, PO or IV, every 12 hours; sucralfate 0.25–1 g, PO, every 8 hours), and fluid support (SC fluids 30–50 mL/kg; rarely, IV fluids 75–100 mL/kg, every 24 hours) as needed (29, 30, 31, 32, 33, 34, 35, 36).
If patients exhibit clinical signs more consistent with THC intoxication, the product was likely of poor quality and contaminated with unlabeled THC, SCBs, or other compounds. In such cases, care should be supportive.
Key Points
Clinical effects of CBD intoxication are generally mild and affect the GI system; supportive care is indicated.
Lethargy, ataxia, trembling, hyperesthesia, and urinary incontinence can also occur in a subset of cases.
Signs are self-limiting and no specific diagnostics are required; however, monitoring of liver enzymes might be indicated.
For More Information
Also see pet owner content regarding poisonings from illicit and abused drugs.
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