Cannabis is an Asian herb of the family Cannabaceae
—the hemp family, that has tough fibre and is often separated into a tall loosely branched species (Cannabis sativa
) and a low-growing densely branched species (C. indica
]. Unfortunately, the term is used interchangeably in popular culture with marijuana although strains of cannabis can be either marijuana or hemp depending on their concentration of THC (delta-9-trans tetrahydrocannabinol).
Hemp (Cannabis sativa
) is legally defined in the United States (US) [6
] and European Union (EU) as any part of the cannabis plant that contains less than or equal to 0.3% THC on a dry weight basis. Hemp has traditionally been farmed for industrial uses (e.g., textiles, paper, biodiesel, constructions materials), as well as for food (hemp seeds and hemp seed oil). Typically, hemp contains relatively high amounts of non-psychoactive cannabinoids. In the US, hemp is not legally recognized as a dietary supplement for either people or animals, nor as a feed supplement for animals, so products labelled as such are illegally marketed [7
]. Certain varieties of the hemp plant are legally grown in EU under license. The varieties of hemp permitted to be grown are those listed in the EU’s “Common Catalogue of Varieties of Agricultural Plant Species” [8
]. The term used to describe these varieties is “Industrial Hemp”.
Marijuana refers to a mixture of cut, dried, and ground flowers, leaves and stems of leafy green cannabis plant. The term “Marijuana” is typically used for the psychoactive dried resinous flower buds and leaves of the cannabis plant (C. sativa
or C. indica
), but can refer to any part of the cannabis plant that contains greater than 0.3% of THC [9
]. Marijuana may be smoked, vaped, or ingested (e.g., baked goods) in some countries especially for its intoxicating effect [10
]. In some countries, home-made hash oil (also called honey oil or butane hash oil) is also popular. This potent oil is obtained by the extraction of cannabis using an organic solvent, often butane or n-butane [11
]. Marijuana is typically classified as a Schedule 1 drug in EU countries and in the US, based on the UN Treaties on Psychoactive Substances of 1961 (revised 1971) [12
]. In informal discussions, “marijuana” and “cannabis” are both terms used to describe the dried leaves and flowering heads of the cannabis plant. Subdivisions of the terms are Medical Marijuana or Medical Cannabis and Recreational Marijuana or Recreational Cannabis, despite the fact that cannabis may be marijuana or hemp depending on its THC concentration (measured on a dry weight basis). In some countries, like Canada, the term Cannabis is now used to reference all types of Cannabis to remove the stigma of the term Marijuana [13
Cannabinoids are any of the various naturally occurring, biologically active, chemical constituents of the cannabis plants that bind to cannabinoid receptors (See Section 9
“Pharmacokinetics”). Over 480 cannabinoids and other substances have been isolated [14
]. The amount of each substance contained in a sample of cannabis depends on the subspecies, the age of the plant, the time of year the leaves were harvested, the way they have been dried, and other factors [15
]. During the growth of the plant, they are present in the acid forms THCa and CBDa, which through “decarboxylation” by heating transform in THC and CBD [16
]. While most research has been done on the medical qualities of CBD and THC, further research is starting to look at other components of the hemp plants, such as THCa, CBDa and cannabigerol (CBG) oil [17
Delta-9-trans-tetrahydrocannabinol (Δ9-THC, more commonly called tetrahydrocannabinol (THC), is the principal psychoactive constituent of marijuana [19
]. THC is a lipid, assumed to be involved in the plant’s self-defence against insect predation [20
], ultraviolet light [21
], and environmental stress [23
]. The concentration of THC found in plants depends on environmental conditions, including amounts of light, moisture, soil type, pH, nutrients, and trace minerals [24
THC is the psychoactive chemical that gives marijuana performance as a recreational drug. Different components of the cannabis plant yield between 5 and 20% THC, the highest concentration produced largely by plant hairs (trichomes) and the female flower [25
]. Traditionally, marijuana varietals of Cannabis sativa
plants have up to 10% THC [26
Cannabidiol (CBD) is generally made from the Cannabis sativa
L. plant [17
]. The plant contains hundreds of different active compounds and of these, more than 100 are cannabinoids which, depending on the compound, have either psychoactive or non-psychoactive effects. CBD is a non-psychoactive lipid cannabinoid [19
]. CBD has been used in human medicine to mitigate anxiety [28
], improve appetite [29
], relieve nausea [30
], control seizures of certain types [31
], and assist in the management of sleep disorders [32
]. Assorted CBD products are available throughout Europe for human use both online and through dispensaries [33
]. A similar scenario exists in the US where CBD products are also widely available and often marketed for therapeutic purposes. To legally market such products, claims of safety and efficacy must be substantiated through the federal government approval process. If such CBD products are not granted such approval, they cannot be legally marketed and, with one exception, all products in the US that have such a therapeutic claim have not been approved [7
] (See also Section 5
“The Industry of Cannabis in North America” and Section 6
“Regulatory Framework in the EU and North America”).
Resin comes from the dried leaves (‘marijuana’), the more potent female flowering heads of the plant (‘sinsemilla’), or the sticky cannabis resin that can be smoked or consumed in a variety of foodstuffs. Several cannabinoids are present in the plant resin, but THC is considered the most active and main psychoactive agent. Hashish is the resin extracted from the top of the flowering plant and is higher in THC concentration than marijuana.
Pharmacokinetics/toxicokinetic parameters are important to consider when evaluating the potential for efficacy/toxicity with varying dose regime (doses, interval, and duration of administration). CBD is a small molecule with a molecular weight of 314.2 g/mol. CBD is highly lipophilic, which raises concerns over potential long-term tissue build-up and toxicity. After a dose of 45 mg of CBD was administered intravenously [79
], it was rapidly distributed followed by a terminal plasma half-life (T1/2β
) of 9 h and a total body clearance (CL) of 0.017 L/h/kg. This study also gave six dogs orally 180 mg of CBD resulting in no analytical detection of CBD in the plasma in three dogs, and an oral bioavailability ranging from 13% to 19% in the other three dogs. The low bioavailability of CBD is due to an extensive first pass or presystemic metabolism in the liver in which CBD and its metabolites are mostly excreted via the kidneys [80
]. The presystemic metabolism restrains the systemic exposure (i.e., CBD is greatly reduced before it reaches the systemic circulation).
Another dog study [82
] administered a cannabis oil extract Bedrocan®
(Bedrocan, Veendam, the Netherlands) (20% delta-9-tetrahydrocannabinol (THC) and 0.5% cannabidiol (CBD)) in fasting and fed dogs at 1.5 and 0.037 mg/kg THC and CBD. Blood samples (1 mL) were withdrawn at 5, 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 10, 24, 36, 48, 72 and 96 h after administration of Bedrocan®
. No analytical detectable concentrations of CDB were found at any collection time. THC was quantifiable from 0.5 to 10 h, although there was large inter-subject variability. Fed dogs showed a longer absorption phase (Tmax 5 versus 1.25 h) and lower maximal blood concentration (7.1 versus 24 ng/mL) compared with the fasted group. THC is a lipophilic compound and should have increased bioavailability in the fed condition (bioavailability: 48.22%; fasted no reported) [82
In humans, a study on the food effect on the pharmacokinetics of cannabidiol oral capsules administered with and without food in adults with refractory epilepsy, showed that the fat content of a meal can lead to significant increases in the peak serum concentration (Cmax) (14 times higher in the fed state compared to fasting) and area under the plasma concentration-time curve (AUC0-u
) (4 times higher in the fed state compared to fasting), Tmax was found to be highly variable within states with the fasting state Tmax ranging from 2 to 5 h and 1 to 6 h for the fed state and therefore can account for variability in bioavailability. Blood samples were collected from an indwelling catheter or venipuncture. During both fed and fasting states, blood samples were collected at predose and at 0.5, 1, 2, 2.5, 3.5, 4, 5, 6, 24, 48, and 72 h. CB doses were 200 mg for one subject and 300 mg for all others during the fed and fasting sessions. Steady state concentrations post 300 mg once daily dose ranged from 4.73 to 40 ng/mL with an average of 21.33 ng/mL [83
In another pharmacokinetics study, each dog was injected intravenously (cephalic vein) with CBD (90 mg in 2 mL of 70% ethanol). After dosing, the urine volumes were continuously collected for 30 h at intervals of 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 22, 26, and 30 h. The apparent terminal plasma half-life (T1/2β
) of CBD from the urine data was significantly shorter than the elimination half-life (T1/2
) of CBD calculated from the plasma data (7–9 h). The T1/2
of all the metabolites was similar to that of CBD indicating that the excretion of these urinary metabolites was formation-rate limited [84
In dogs, the onset of clinical signs in cases of marijuana toxicosis typically occurs within 30–90 min of exposure and can last up to 96 h [85
]. After oral ingestion, THC is almost completely absorbed. THC goes through a substantial first-pass or presystemic metabolism. It is metabolized by liver microsomal hydroxylation and non-microsomal oxidation. THC is highly lipophilic and readily distributes to the brain and other fatty tissues following absorption. Its high lipid solubility contributes to its large volume of distribution (Vd) and long elimination half-life (T1/2
). One pharmacokinetic study investigated the use of a phytocannabinoid-based medicine—Sativex®
(GW Pharma Ltd., Sovereign House, Vision Park, Histon, Cambridge, UK) in dogs which is currently marketed for the treatment of spasticity and pain of multiple sclerosis in humans. It was shown that single or multiple doses administered sublingually to dogs resulted in maximum plasma concentrations of phytocannabinoids at 1–2 h and suggested progressive accumulation after the multiple dose treatment [86
]. Another study carried out in dogs found non-proportional increases in plasma cannabinoid concentrations with increasing oral doses, this as well as potential differences in Cannabis herbal extract product composition and dose regimen consistency, which may all lead to adverse effects [87
]. One study showed adverse events associated with CBD administration including elevation in liver enzymes (n
= 14) and vomiting (n
= 2) [88
Finally, it was stated that most pharmaceuticals follow a familiar pharmacokinetics pattern by demonstrating a linear dose–response curve and thus displaying a direct linear relationship between the increasing dose and increased efficacy until a maximum level of efficacy is reached. The dosing of cannabis above this maximal effect may lead to an increase in adverse effects with little to no increase in therapeutic value [18
6.1. Mechanism of Action
A major advance in our understanding of how cannabis works has been the discovery of specific receptor proteins in the brain that recognize cannabinoids including THC.
Among several that have been identified, the two primary types of cannabinoid receptors are CB1 and CB2, both coupled to G-proteins [19
]. CB1 and CB2 receptors have been identified in rats, guinea pigs, dogs, monkeys, pigs, and humans [89
]. CB1 receptors are widely distributed in the brain (central nervous system—CNS) and correlate with cannabinoid effects on cognition, appetite, emotions, memory, perception and control of movement. An interspecies variation in the anatomical location of the CB1 receptors is seen in dogs. Dogs in particular have a higher density of CB1 receptors in their cerebellum compared to any other species studied [90
]. The existence of endogenous cannabinoid receptor agonists has also been demonstrated. These discoveries have led to the development of selective cannabinoid CB1 and CB2 receptor ligands.
CB1 receptors are located within lipid membranes of presynaptic neurons. They inhibit cAMP and stimulate mitogen-activated protein kinases to modulate the control of ion channels, particularly voltage-activated calcium ion channels and potassium channels. The result is the inhibition of the neurotransmitter release, both excitatory and inhibitory. CB1 receptors also activate phospholipase C and PI-3-kinase. The endogenous ligand for cannabinoid receptors, known as endocannabinoids, are derived from arachidonic acids and are closely related to prostaglandins.
CB2 receptors are less frequently found in the CNS but are highly concentrated in the peripheral nervous system and immune system where they play a part in inflammation and pain regulation [91
]. CB2 receptors regulate ceramide biosynthesis. The endogenous cannabinoids bind to these receptors as part of the modulation of signalling pathways and in association with several pathophysiological conditions (e.g., neurological disorders).
CBD is believed to act on unique receptors in the brain that are selective for cannabinoids and responsible for the CNS effects. Cannabinoids can enhance the formation of norepinephrine, dopamine, and serotonin. Toxic effects are an extension of the pharmacological and clinical effects. The oral LD50
values of pure THC in rats and mice are 666 and 482 mg/kg body weight, respectively [56
]. The minimum lethal oral dose in the dog for THC is greater than 3 g of plant material per kg body weight [92
8. Concerns Regarding Illegal Product Claims and Unknown Composition
CBD oil products may be marketed that do not conform to regulations, both animal and human. In the US, the FDA has also had to cite multiple companies illegally selling CBD products because the companies claimed they could prevent, diagnose, treat, or cure disease with some of these companies marketing products targeted toward animals [106
The marketing of illegitimate products occurs, particularly when the regulatory framework is not well known and during periods of the rapid expansion of any particular sector. In the EU, all labelling information for CBD feed additives is controlled by EFSA for animal feed and human food, under the Regulation (EU) No 1169/2011 [107
], (EC) No 178/2002 [55
], and Regulation (EC) No 1924/2006 [63
]. The principles behind the legislation are the 100% accuracy of labelling and claims based on scientific evidence. Veterinarians may be the most likely professional group to observe abnormal reactions, for example, psychoactive responses in animals that may have received a defective product (see Section 9
). Veterinarians may also be approached to stock CBD products in their clinics.
In all regions, the inaccurate labelling of the identity and strength of active ingredients is of particular concern, making administration according to a dosage regimen very difficult to impossible [108
]. In Europe, only the composition of medical cannabis is known and controlled [30
]. In the US, the composition of FDA-approved therapeutic products for humans is known and controlled, but less consistency in quality assurance exists around cannabis sold for medicinal purposes by dispensaries regulated at the state and local levels [109
]. Only a few US states have extensive product tracing programs where specific testing methods to confirm the label accuracy of the intended chemical components as well as unintended contaminants are established. Much variation exists in which intended and unintended chemical constituents are analysed, as well as in methods of analysis [110
]. Therefore, the label accuracy of cannabinoid constituents and potential contaminants for non-FDA-approved cannabis products may vary considerably within and among US states. Few studies have been done on the safety and tolerability of these products in animals [111
]. Several studies have shown quality and safety issues related to the use of products, often illegal, labelled for animal use [113
], some of which have been associated with toxicoses.
9. Cannabis Toxicosis in Veterinary Medicine
Veterinary cases of cannabis toxicosis in dogs stem most commonly from exposure to edibles. In these cases, there may be additional toxic ingredients involved—such as chocolate, raisins, or xylitol—which result in a poorer prognosis. Cats may also directly consume the plant material.
The likelihood of pets becoming exposed is increasing as cannabis and cannabis products become more widely available and recreational drug use more commonplace. A US study in 2012 reported increased rates of toxicosis seen in dogs living in Colorado, a state in which cannabis had been recently legalized for human medicinal use; in fact, a four-fold increase in toxicoses was reported between 2005 and 2010 [115
]. In 2019, the US ASPCA’s Animal Poison Control Center noted a large jump in calls about marijuana ingestion by animals; a 765% increase in the first few months over the same period the previous year. An increase was seen even in US states where cannabis has not yet been legalized [116
]. This pattern may be a result of the general shift towards cultural acceptance of marijuana use, and the growing availability and use of marijuana edibles, the leading cause of intoxication in dogs.
There is currently little research performed on thresholds for toxicosis. Although the available data suggest that CBD may be well tolerated by animals and produces few side effects, the lack of industry-wide quality control can result in an animal’s exposure to hemp or CBD products contaminated with THC or toxins, such as heavy metals or pesticides, that may cause harm. In the US, animal poison control organizations indicate that up to 50% of pets exposed to products labelled as CBD or hemp may develop clinical signs severe enough to require veterinary intervention, indicating that such products may not be pure CBD [117
]. Several deaths were reported to have been related to cannabis toxicoses, and these appear to be the result of associated complications, such as aspiration.
In dogs, excessive THC intake can easily result in clinical signs of toxicosis. Synthetic cannabinoids can have a higher potency than THC. Clinical signs of anxiety, hallucinations, seizures, psychosis, and tachycardia are reported in patients but most recover within several hours [118
]. Smaller dogs are particularly susceptible due to the smaller amount required to produce clinical signs. Cats are not immune to toxic side effects but are much more selective in their food intake and do not appear to consume cannabis edibles as often as dogs. Cats, as a species, generally avoid eating garbage and scavenging cigarette butts, or table, or counter surfing in comparison to dogs. They also seem to be less attracted to products with a high concentration of sugars, so we do not see them take in baked good “pot” products like dogs typically do. One experimental study of cannabis exposure in cats showed that, cannabinoids caused bradycardia, hypotension and respiratory depression, which depending on the chemical composition of the product and the exposure amount, may be expected in the case of intoxication [101
9.1. Clinical Signs
A wide range of clinical signs have been associated with cannabis toxicosis. A classic presentation is a depressed or ataxic dog that is dribbling urine. Further clinical signs are listed in Table 3
. Most of them are neurological signs.
Cannabis toxicosis can look similar to intoxication with numerous other sedatives, with the most common and serious of those being anti-freeze poisoning (i.e., ethylene glycol) or ivermectin toxicosis. In most cases, the diagnosis can be made based on the history of exposure, anamnesis and clinical signs. Cannabinoids are difficult to detect in body fluids, particularly because of their high lipid solubility and low concentrations found in urine and plasma. Urine testing can be performed but can give false negatives. The confirmation of positive screening tests requires the use of chromatographic analytical techniques (GLC, HPLC, TLC, GC–MS) that are capable of separating and detecting the major metabolites. GC–MS is the most reliable confirmatory method, especially when used with electron impact (EI) and chemical ionization (CI) detector modes. Common adulterants that mask a positive test for marijuana metabolites include detergents, salt, use of diuretics, and vinegar [92
9.3. Treatment and Prognosis
Because no antidote has been described to date, the treatment of cannabis toxicosis consists of supportive care [116
]. Because of the wide margin of safety of most known cannabinoids, toxicosis is rarely fatal. Steps that should be taken include:
If less than 30 min have passed since consumption, the animal should be decontaminated by inducing emesis and administering activated charcoal and cathartic. Repeated dosing with activated charcoal and cathartic may reduce the elimination half-life of THC by interrupting enterohepatic recirculation.
If clinical signs have started, inducing emesis might be difficult (due to the psychoactive properties of THC) and could be dangerous if the patient is heavily sedated, as vomit could be inhaled and lead to aspiration pneumonia.
Fluid support and keeping the patient warm may also be needed due to hypothermia. The patient should be rotated frequently to prevent dependent oedema or decubital ulceration.
Diazepam can be given for sedation or to control seizures.
Administer oxygen to assist respiration or relieve respiratory depression, if needed.
Treat central nervous system depression, if needed.
IV lipid emulsion therapy may be helpful in the treatment of severe cases [122
If the patient has lost consciousness, intense observation and support are needed. The chance of fatality is statistically small but possible.
Recovery may take 24 to 72 h, or longer (up to 5 days), depending on the ingested dose.
10. Conclusions and Recommendations
Further research is recommended to improve our understanding of the safety and effectiveness of the use of cannabis-derived products in veterinary medicine. Current research is limited, mostly done on small samples and at times with conflicting outcomes. This suggests that cannabinoid products may potentially be beneficial in certain cases to reduce pain, particularly osteoarthritis pain, and as an adjunctive treatment of canine epilepsy. Currently, no cannabis-derived veterinary medicinal products are authorised in the EU or North America. The off-label use of human medicinal products might be allowed to be used in animals in certain EU countries or in the US, only when using EU or USFDA-approved products, respectively. It is the responsibility of the veterinarian to understand their legal obligations.
For the future we recommend the following initiatives:
Well-controlled clinical trials (double-blinded, placebo controlled) and pursuit of EU/North American approval or approval at the national level by manufacturers of cannabis-derived products should be conducted, so that high-quality products of known safety and efficacy can be made available for veterinarians and their patients.
Clinical trial studies should be encouraged to investigate the potential therapeutic value and safety of hemp-derived products for companion animals.
Harmonize the analytical procedure of the determination of the THC level in serum and oral fluids and set up harmonised tolerable limits of cannabinoids in different products.
Use of hemp-derived products for animals should require a veterinary prescription.
Prohibition on producing pet food with cannabis-derived products without known safety and efficacy and without the knowledge of the intended purpose of the included cannabis-derived products as specified by the pet food manufacturers.
The prohibition on producing feed supplements or beddings for food producing animals with CBD/Cannabis without known safety and efficacy and without knowledge of the intended purpose of the included cannabis-derived products as specified by manufacturers, and data on any residue in the food derived from these animals.
We encourage veterinarians to act cautiously, as there may be risks associated with having such products in their possession if the product(s) were subsequently shown to contain illegal levels of THC. Any suspected breaches should be reported to Competent Authorities in the EU Member State where the event occurred.
Greater international cooperation is needed to help define standards, promote safety, education, research, and policy.