CBD for Pets: Only Mild Side-effects Even with the Highest Doses

CBD is safe for pets. The newest research shows excellent tolerability of CBD oil formulations in cats and dogs, with carrier oil probably responsible for gastrointestinal adverse effects.

Online surveys show that there is a growing interest in the potential therapeutic uses of cannabinoids in pets. In the most developed markets, such are the U.S. and Canada, when pet owners purchase cannabis products, they mostly purchase them for the management of pain, inflammation, and anxiety in their animal companions.

The existing data suggest that there are differences in the metabolism of cannabinoids across different species. For example, rodents, dogs, monkeys, and humans have different CBD and THC metabolic profiles. The differences in the behavioral and physiological effects of cannabinoids across species have also been reported.

‘Start low and go slow’

Following these notions, a study published in Frontiers in Veterinary Science in February 2020 looked into determining the safety and tolerability of escalating doses of three cannabis oil formulations, containing predominantly CBD, THC, or CBD and THC. A hallmark dosing strategy for cannabis initiation is said to be “start low and go slow”, to avoid adverse effects associated with THC. Slow upward dose titration was used in this study, meaning the dose was increased very gradually. A secondary objective was to determine blood levels of CBD, THC, and their metabolites at higher dose levels of CBD (>50 mg/kg) and THC (>30 mg/kg).

The dose levels in this study went up to 640.5 mg of CBD. Previously, there was evidence that even lower doses than 20 mg per kg cause side effects, with gastrointestinal upset as the most common clinical sign.

In this randomized, placebo-controlled, and blinded study, 20 healthy adult purpose-bred Beagle dogs, aged three to 7.8 years, weighing 10 to 14 kilos, were randomized to one of five treatment groups with four dogs per group (two males, two females). The subjects of the trial were placed into steel boxes with a sufficient water supply and fed once a day with standard commercial feed.

The study observes that the dogs tolerated dose escalation of the CBD oil well. CBD for pets seems to be completely safe. Even with this high dosage, they were experiencing only mild adverse effects. The conclusion of this study is that the CBD-predominant oil formulations are safer and more tolerated in dogs than oil formulations containing higher concentrations of THC.

Also, CBD oil had the least effect on the food intake and physical activity of the dogs. Food intake decreased on dosing days as compared to non-dosing days by 4.6%. Nonetheless, their body weight remained stable throughout the study, as with other dogs included.

Risk of ataxia with THC

While CBD for pets proved to be safe, there should be some concern with THC. The most striking side-effect happened to one of four dogs in the THC oil group. The subject experienced severe ataxia at the 7th dose and was discontinued from further dosing. Two of four dogs in the CBD/THC oil group experienced severe ataxia and/or lethargy at the fourth or fifth doses (one dog at the fourth dose and a second dog at the fifth dose) and thus further dosing ceased for all dogs in this group. Again, with CBD oil or placebo group, no dogs were discontinued as a result of adverse effects.

Side-effects in high dosage

All in all, the adverse effects were reported in all 20 dogs across the five groups. Of the total number of adverse effects observed across the entire study (n = 505), 104 of them occurred in the placebo groups, and 401 occurred across the three cannabinoid groups: 80 with CBD oil (10 doses), 206 with THC oil (10 doses), and 115 with CBD/THC oil (five doses).

Compared to dogs receiving CBD oil, dogs receiving THC oil experienced more than double side effects. Those effects were 7-fold more neurological and constitutional, 5-fold more dermatological, and 3-fold more ocular and respiratory. The greatest difference between the CBD oil and THC oil groups seems to be the first dose given. Altogether, there was a 7-fold difference in the average number of adverse effects experienced per dog.

When intaking the remaining nine doses, dogs receiving the THC oil experienced between a 2- and 3-fold greater number of adverse effects per dose vs. dogs receiving the CBD oil. While CBD for pets can be used without concerns of serious side-effects when it comes to the CBD/THC oil group, there was a steep increase in the average number of adverse effects per dog at the fifth dose; each of the three dogs experienced 10 adverse effects at this dose vs. the other two cannabinoid oil groups wherein an average of 4.8 adverse effects (THC oil group) and 1.5 adverse effects (CBD oil group) were experienced per dog. The scientists find it noteworthy that the total number of adverse effects and the adverse effect profile in the CBD oil group were comparable to the MCT placebo oil group. Moreover, across the cannabinoid oil groups, at each escalating dose, dogs in the CBD oil group experienced a lower average number of adverse effects as compared to the THC oil group and the CBD/THC oil group.

Mild adverse effects accounted for 479 of the 505 in the total study (94.9%). The mild adverse effects occurred in all dogs and mainly manifested as gastrointestinal (nausea, emesis, diarrhea), constitutional (lethargy, hyperesthesia), or neurological (muscle tremor, ataxia) symptoms.

No moderate adverse effects with CBD oil

Moderate adverse effects accounted for 22 of the total 505 (4.4%) and occurred in 40% (8 of 20 dogs) across three groups: MCT oil (two dogs at the tenth dose), THC oil (two dogs at the third or seventh doses), or CBD/THC oil (four dogs across the five doses tested). They manifested as constitutional (lethargy, hypothermia) or neurological (ataxia) symptoms. The most common moderate adverse effect was hypothermia (rectal temperature <36.0°C), which accounted for 14 of the 22 moderate adverse effects (64%). The majority of hypothermia occurrences (13 of 14) occurred in the CBD/THC oil group, wherein all 4 dogs experienced hypothermia at four of the five doses tested (excluding the first dose). The lowest dose of CBD/THC oil at which hypothermia occurred was at the second dose (35.2/24.2 mg CBD/THC = ~3 mg/kg CBD and ~2 mg/kg THC). The remaining hypothermia event occurred in the THC oil group at the third dose (82.2 mg THC = ~7 mg/kg THC). As compared to the other cannabinoid and placebo oils, a greater decline in the rectal temperature of dogs occurred following the intake of the CBD/THC oil. Moderate adverse effects were transient and resolved in 3–24 h. Most importantly, there were no moderate adverse effects, including hypothermia, in the CBD oil group at any of the doses tested.

There were no severe adverse effects in the CBD oil group at any of the doses tested. Severe adverse effects accounted for 4 of the 505 total study (0.8%) and occurred in three of 20 dogs (15%) across two groups: THC oil (one dog at the seventh dose) and CBD/THC oil (one dog at the fourth dose and a second dog at the fifth dose). They manifested as severe ataxia and/or lethargy and were transient, resolving in 9–28 h.

CBD can potentiate the effects of THC

In blood, there was at least a 2-fold increase in total bilirubin or plasma levels of liver enzymes. The enzyme mostly affected by the highest doses of CBD was alkaline phosphatase (ALP). After the final dose, the levels exceeded the upper limit of normal. The altered liver functions were observed only in CBD and CBD/THC groups, while plasma levels of liver enzymes and total bilirubin were stable in the THC oil group. All abnormalities resolved seven days following the final dose.

Considering that the CBD/THC group was the only group with recorded severe side effects, the scientist concluded that CBD is not always a functional antagonist of THC. In fact, CBD can potentiate, rather than antagonize, the psychoactive and physiological effects of THC. The interaction depends on the dosage and the sequence of administration – whether CBD is administered before THC (pharmacokinetic interaction more likely) or concurrently with THC. In very high doses, CBD for pets could be most safely used as an isolate.

CBD for pets: The first feline safety study

There are no published studies on the efficacy of cannabinoids in cats but a brand new study on the safety and tolerability of escalating cannabinoid doses in healthy cats, published in the Journal of Feline Medicine and Surgery in March 2021, shows that cats can tolerate maximum doses of 30.5 mg/kg CBD (CBD oil), 41.5 mg/kg THC (THC oil) or 13.0:8.4 mg/kg CBD:THC (CBD/THC oil).

Although CBD for pets is gaining in popularity, this was the first feline study to explore the safety and tolerability of CBD and THC, alone and in combination, in a controlled research setting. In a placebo-controlled, blinded study, 20 healthy adult cats were randomized to one of five treatment groups and given up to 11 escalating doses.

All observed adverse events were mild, transient, and resolved without medical intervention. Gastrointestinal adverse effects were more common with formulations containing medium-chain triglyceride oil (MCT). Again, the constitutional (lethargy, hypothermia), neurologic (ataxia), and ocular (protrusion membrana nictitans) adverse effects were more common with oils containing THC (CBD/THC and THC oils).

Previously, a 2019 study showed that 2 mg per kg twice daily was well tolerated in both, cats and dogs. In this study, the doses went up to 30.5 mg per kg of CBD and 41.5 mg per kg of THC. For the combination of CBD and THC, the maximum dose used was 13.0/8.4 mg/kg. The subjects were fasted, kept in steel boxes with sufficient water supply, and exercised together daily for at least one hour, except on dosing days or when an adverse event was being monitored.

All adverse effects were mild

This study investigated 11 escalating volumes/doses of placebo or test formulations with at least three days separating doses. The total study duration was 71 days.

The study included 20 randomized subjects, aged 1.0–1.2 years, weighing over four kilograms. Interestingly, body weight increase over the treatment phase was significant for the CBD group compared with the MCT oil placebo. The CBD/THC oil group showed a small but significant decrease in body weight relative to the sunflower (SF) oil placebo group, as well as the THC oil group and the CBD oil group, whereas the CBD group exhibited a small increase in body weight relative to the THC oil group. Following the completion of the last dose, the CBD/THC oil group exhibited a gain in weight relative to the SF placebo oil group.

Most importantly, all the adverse effects in the study were rated as mild. Adverse effects that occurred within 24 h of dose administration across 11 escalating doses were classified as gastrointestinal (27.6%), respiratory (15.4%), neurologic (14.6%) or ocular (8.3%), or as constitutional signs (29.9%; non-specific clinical signs that can affect multiple body systems and have several potential causes). Cardiovascular adverse effects (pale mucous membranes, bradycardia, tachycardia) and respiratory adverse effects (primarily tachypnoea), occurred with uniform frequency across all treatment groups.

Intolerability to MCT carrier oil?

The occurrence of gastrointestinal adverse effects significantly differed between the two placebo groups – their occurrence was greater with MCT oil (n = 43) than SF oil (n = 1). Moreover, 99% of emesis and diarrhea occurrences (n = 89/90) were with MCT oil formulations (placebo, CBD oil, THC oil). The occurrence of the two most frequently observed gastrointestinal adverse effects – hypersalivation and emesis – did not significantly differ between CBD or THC vs MCT oil. Emesis was not observed in the CBD/THC or SF oil treatment groups but was more frequently observed with CBD than THC oil. Hypersalivation did not significantly differ between CBD, THC, or CBD/THC treatment groups.

Neurologic adverse effects in cats occurred more frequently with THC oil and CBD/THC oil than with CBD oil but did not differ between THC and CBD/THC groups. Again, ataxia occurred predominantly following the administration of THC-containing oils, with eight-fold and 11-fold greater frequency than with CBD oil, but did not differ between THC and CBD/THC treatment groups. In the CBD oil group, ataxia did not occur until the ninth (24.9 mg/kg CBD + 0.94 mg/kg THC) or tenth dose (27.7 mg/kg CBD + 1 mg/kg THC).

Liver markers remained within the normal reference intervals at all measured time points. The exception was one cat that received the MCT placebo and had elevated alanine aminotransferase (ALT) that resolved in one week. Furthermore, the comparison of gastrointestinal adverse effects between the two placebo oils suggests that SF oil is better tolerated by healthy cats than MCT oil. Therefore, emesis and diarrhea secondary to CBD or THC oil administration may be explained by intolerability to the MCT carrier oil rather than the cannabinoids themselves.

These findings support continuing research on the potential therapeutic uses of orally delivered CBD in cats, and for its consideration as a safe treatment option in veterinary medicine. CBD for pets will most probably continue to grow in popularity.

Reviewed by Sasha Bajilo, founder of ILESOL Pharmaceuticals, an industrial scale producer of CBD products and formulations. Expert on Hemp/Cannabis policy, member of the Croatian Ministry of Health regulatory commission for medical cannabis.