In the current study, daily exposure to CBD, CBD + CBG and CBD + CBDA at 5 mg/kg bw of total cannabinoids for 90 consecutive days was well tolerated. The significant changes seen in some clinical pathology parameters were transient, within reference ranges, of low magnitude, present in a small number of animals or sporadic in nature and all were considered not to be clinically relevant. Biological variability is discussed in Flatland et al. where the authors concluded that a single clinical value needs to be interpreted within three aspects of variation – individual, group, and analytical method (21). In the current study, review for clinical relevance was determined using a reference range set by the baseline values of the animals in the study as previously described. If a parameter for any individual on any post-administration day fell outside this reference range, the CFB for the treatment group was compared to the CFB for the control group, and the CFB within the treatment group was checked for significance. If all the above were statistically significant, further clinical review was completed. Following this method, individual and group variation is accounted for via reference range determination and by placing emphasis on the CFB as indicative of a treatment-related change but only if the treatment group CFB was different from the control group CFB for any parameter. Analytical variation is not applicable in this study as all measurements were made under the same conditions as part of a research study, and not in a clinical setting where variation between equipment, staff, etc. could be notable.

The results from this study correlate with other studies conducted with CBD in healthy dogs which have concluded that CBD, CBG, and CBD with CBDA is well tolerated. Bradley et al. (22) conducted a randomized, placebo-controlled, blinded study with broad-spectrum CBD in healthy dogs. The CBD treated dogs received 4 mg/kg bw/day for 6 months without any adverse effects on health and wellbeing. A transient elevation in ALP was reported in approximately half of the CBD treated dogs which returned to baseline at the end of the 4-week recovery period. Bone ALP was evaluated to determine the tissue source of the ALP and was significantly elevated as compared to controls at the end of 26 weeks of treatment with a significant and strong positive correlation between ALP and bone ALP. Based on these and other results, the authors concluded that the increased ALP was not a clinically relevant biomarker of impaired liver health in healthy dogs following CBD treatment (22). Vaughn et al. (23) also evaluated the safety of CBD in healthy dogs in a 28-day repeat dose trial. In the randomized, blinded, placebo-controlled study, the healthy dogs received either a placebo or 1, 2, 4 or 12 mg CBD/kg bw/day which was well tolerated. All reported AE were mild and self-limiting and occurred in all groups, including the placebo group. Increased serum ALP above the upper reference limit was reported in the 2, 4 and 12 mg/kg bw/day groups which began to decrease after 2 weeks of dosing, but these animals did not have any concomitant increases in other hepatic markers. As with the current study, hypersalivation was seen with greater frequency in the CBD treated groups but this was not considered to be a SAE in either study (23). Deabold et al. (8) evaluated the safety and adverse effects of a CBD containing hemp product in healthy dogs over a 12-week dosing period. The dogs were given 2 mg CBD/kg bw/day and serum chemistry and hematology evaluations showed no clinically relevant changes during the study (8).

In a study by Amstutz et al. (14), CBG and CBGA was trialed in fed and fasted dogs (n = 6 intact male beagles) at 2 mg/kg bw twice daily for 2 weeks. The fasted state was tested initially for two-weeks, followed by a two-week washout and then treatment was given in the fed state for two-weeks. On the first day of treatment in both states, a 24-h pharmacokinetic analysis of serum cannabinoids was completed. The authors reported that there were no statistically significant differences in pharmacokinetic parameters between fed and fasted states, however, they note that the serum concentration of CBG tended to be higher in the fasted state. Serum ALP decreased in both fed and fasted states by week 2, which is contrary to other studies of cannabinoids. The authors suspect this may be related to differences in the effect of CBG and CBD on cytochrome P450 although no further evidence is discussed. The only AE reported was vomiting from one dog during the fasting phase with no other clinical symptoms. The authors concluded that CBG and CBGA at 2 mg/kg bw twice daily was well tolerated in fed and fasted healthy beagle dogs (14). In the current study, the test item contained CBD + CBG in a 1:2 ratio. Although not clinically relevant, the CBD and CBD/CBDA treatment groups each showed at least one measurement that was statistically different from the control group for ALP, whereas the CBD/CBG group did not differ from the control group.

Two studies evaluated CBD/CBDA mixed cannabinoid products. Tittle et al. (13) evaluated the pharmacokinetics of a CBD/CBDA extract that also included a low level of THC/THCA when dosed in oil verses a gel capsule. Beagles (7 male and one female) were dosed at 2 mg/kg bw twice daily with food. The initial treatment was the cannabinoid product in a capsule. Pharmacokinetic parameters were measured over 24 h on the first day of dosing and over a subsequent 7 days, followed by a 2-week washout period before the next treatment (cannabinoids in oil) and pharmacokinetic measurements for 7 days. No safety end points were assessed, however, AE noted were mild and included vomiting, diarrhea, licking, and head shaking. Vomiting and diarrhea was observed in three dogs during the washout period as well (13). Wakshlag et al. (11) evaluated a CBD/CBDA product that contained a small amount of THC and THCA, as well as measurable CBGA and cannabichromene. The intent of this study was to evaluate two different oil vehicles and a soft chew format with 2-week treatments followed by 3-week washout periods, resulting in a 12-week trial. Six intact female beagles were dosed at 2 mg/kg bw (oil) or 2.0–2.3 mg/kg bw (soft chew) of CBD/CBDA twice daily. Safety end points measured included ALP, AST, and ALT, albumin, total bilirubin, cholesterol, and glucose. No changes were observed in these parameter during treatment or between successive treatments, and no abnormalities in behavior or health were reported during the trial (11). A key difference in the test item for these studies compared to the current study was the presence of THC at a low level, however, like the current study, no AE related to administration of CBD/CBDA were reported.

Several studies evaluated the clinical efficacy of CBD and other cannabinoids in disease and behavioral conditions. The endpoints evaluated in these studies may not be specifically targeted towards safety, but they can provide some valuable tolerability information regardless. For example, studies have been conducted to evaluate the analgesic effect of CBD in dogs with spontaneous osteoarthritis at varying dose levels and durations, as well as in dogs who recently underwent orthopedic surgery. The dogs received up to 5 mg/kg bw orally for 4 weeks following surgery, which was shown to be well tolerated (12, 24–27). Treatment with CBD-CBDA was evaluated for efficacy on refractory epileptic seizures, intractable idiopathic epilepsy, atopic dermatitis, and immune response (28–31). The effect of CBD on behavioral conditions such as aggression towards animal shelter staff, separation anxiety and car travel, noise-induced fear, and voluntary activity was also evaluated (32–35). In all studies, few minor or zero AE were reported and no SAE that could be attributable to treatment were reported.

In the United States, “pet supplements,” also called Dosage Form Animal Health Products, are unapproved animal drugs and available to consumers either through State-level regulations or enforcement discretion by the FDA (3). Products containing CBD are sold in substantial numbers and post-market surveillance data supports the safety of cannabinoids given orally. In 2022, there were 274,129,622 administrations, in dogs, of hemp and hemp derivative products sold, as determined by the National Animal Supplement Council (NASC). The NASC is a 501(c) (6) non-profit trade association that represents most of the industry selling products containing hemp, hemp derived compounds as well as cannabinoids in the US. The NASC requires all member companies marketing products to enter product information, upload product labels and to report AE monthly through its Adverse Event Reporting System (NAERS™) which is a powerful tool for post-market surveillance. Individual companies are also required to record, report, and evaluate AE monthly. Both serious and non-serious AE are reported in the NAERS™ system. Each AE is evaluated and given a risk score using the NASC Adverse Event reporting form, which is also maintained in the NAERS™ system.

In the NAERS™ system, AE and SAE are defined as follows:

• Adverse Event: “An Adverse Event is a type of Complaint where a patient has suffered any negative physical effect or health problem that MAY be connected to or associate with use of the product.”
• Serious Adverse Event: “An Adverse Event with a transient incapacitating effect (i.e., rendering the animal unable to function normally for even a short period of time, such as with a seizure) or non-transient (i.e., permanent) health effect. Transient vomiting or diarrhea do not constitute Serious Adverse Events. A purported Serious Adverse Event requires follow-up with a veterinarian. A layperson diagnosis does not constitute a Serious Adverse Event.”

Data from each company is aggregated, statistically processed, and compiled into an Ingredient Risk Report which provides information relating the ingredient(s) to reported AE, both serious and non-serious. The event rates are reported based on the number of administrations in each container sold and unit data is updated quarterly.

Data from NASC Members’ products was also used in determining the dosing level used in the current study, 5 mg/kg bw of dogs, which is based on actual products currently in the marketplace. Based on the information from the Ingredient Risk Report, the straight mean and weighted mean doses for all hemp and hemp derivative products were determined to be 6.97 and 9.91 mg/kg bw. Comparatively, the straight mean and weighted mean doses for all CBD products were 0.83 mg/kg and 0.67 mg/kg (maximum 2.10 mg/kg). This provides important information that is difficult to ascertain from consumer surveys. Alvarenga et al. (1) reported that when asked about dose, survey respondents gave empiric answers of volume without concentration or missing a measuring unit, making analysis and reporting unfeasible (1).

The use of CBD in Dosage Form Animal Health Products has been growing; however, the safety of longer-term use has been questioned and deemed to be lacking (8, 22). A recent review of the current literature available for CBD use in dogs documented 19 tolerability studies, 10 pharmacokinetic studies with oral CBD products, seven clinical trials for efficacy in pain control, three for epilepsy, three for behavioral disorders, and three for skin diseases (20) The limitations of this body of evidence are that the number of types of extracts, the study population, and the duration of use are constrained by necessity. Post-market surveillance of AE and SAE in the NAERS™ database assists in the safety evaluation of CBD through real-world use data and supports the conclusion of the aforementioned studies that CBD products are well tolerated.

The information collected from the NAERS™ system report for all products containing hemp and hemp derived compounds shows that the overall report rate per million administrations sold from 2010 to 2023 (as of November 20th, 2023) for AE and SAE in dogs is 2.19 and 0.01, respectively, from over one billion administrations (Table 3). When limited to products specifying CBD, the total administrations in dogs for 2015–2023 (as of November 18, 2023) were 86,081,473, with AE and SAE rates of 1.61 and 0.02 per million administrations, respectively.

For interpretation of these results, it is important to note that regulatory restrictions on label statements affect the classification of dosage form animal health products in the NAERS™ system as the input classification is determined by the producer’s or retailer’s label. A product containing CBD may be labelled only as hemp or may include a qualifier such as broad-spectrum or full-spectrum, and not all products labelled as hemp contain CBD. NASC provides guidance to their membership that a broad-spectrum hemp extract contains “some or all of the compounds found naturally occurring in the plant, where THC has been processed to levels less than 0.3%” and a full-spectrum extract contains “all compounds found naturally occurring in the plant including, but not limited to, terpenes, cannabinoids and THC, where the cultivar’s THC level are grown or diluted to be less than 0.3%.” Administrations reported for broad-spectrum hemp products for dogs were 84,306,219 and for full-spectrum hemp products for dogs were 287,828,119. The hemp and hemp derivatives report is inclusive of AE for broad-spectrum and full spectrum hemp products, but the AE and SAE rates when calculated separately from the larger category are similar. Broad-spectrum hemp products had an AE and SAE rate of 2.40 and 0.02 per million administrations, respectively, and full-spectrum products had an AE and SAE rate of 2.83 and 0.03 per million administrations, respectively. Effectively, total administrations calculated for hemp and hemp-derivatives overestimates the post-market exposure of dogs to CBD products, and CBD total administrations underestimates the post-market exposure. Based on this information, it is reasonable to surmise that the rate of AE is between 1.6 and 2.8 per million administrations.

It is also important to separate animal health product AE from acute toxicosis due to marijuana (Cannabis sativa L. with a THC content higher than 0.3% by dried weight; defined in 21 CFR 1308.11) products intended for human consumption. Howard-Azzeh et al. analyzed factors influencing cannabis poisoning of dogs in the United States between 2009 and 2014 (4). The authors reported that an average of 1.12% of all calls to the Animal Poison Control Center were due to cannabis consumption and concluded that as cannabis products became more available for human consumption, the rate of poisoning in dogs increased.

The low AE rate reported in the NAERS™ system is supported by consumer survey data (1). Of respondents who had given their pet CBD, 45.3% indicated that they observed no side effects. The remaining side effect options included lethargy and sleepiness as the most common (24.2%, n = 116 each, participants could choose more than one answer). Other side effects were each indicated by <2% of respondents. In 2016, a similar survey of pet owners in the US via a link on a pet hemp product company website reported that 58.8% of survey respondents (n = 631) were currently using a hemp product for their dog. In this survey, pet owners reported sedation as the most common significant effect (53/278 respondents reporting sedation as “significant effect” vs. 4/278 reporting as “no effect,” however 190/278 reported this effect as “NA or do not know”). Although other side effects were reported, the authors reported that expense and ineffectiveness were the most common reasons for discontinuation of a product (36).

Variation in hemp product composition and quality could be responsible for differences in efficacy and safety. Botanical extracts prepared from hemp contain a number of phytochemicals including cannabinoids and terpenes, the levels of which can vary between extracts and can have a number of potential bioactivities (37). Extracts are susceptible to issues with product quality such as failure to follow good manufacturing practices, poor quality control, failure to screen for heavy metals, contamination from other plant products, etc. In a recent analysis of pet-specific cannabinoid products, CBD concentrations ranged from 0 to 66 mg/mL (including only oil delivery forms), which represented 0–154% of the label claim concentration. In addition, CBDA was found at high levels in two products (38). While quality control issues are outside the intent of this study, the lack of standardized products is a major hurdle for evaluating the safety of CBD products and supports the necessity of post-market surveillance.

Post market surveillance data and systems that provide continued vigilance are critical to monitor the risk of cannabinoid product use in animals. Even the most well defined and carefully conducted clinical studies cannot duplicate all possible scenarios or potential negative occurrences due to the use of products in the broader marketplace. The current study utilizes clinically relevant doses in a tolerability study to provide supportive baseline data for the evaluation of cannabinoids in domestic dogs. A limitation of this study is that only a single dose level is used for each product, although the dose level was chosen to be representative of real-world use of cannabinoid supplements in dogs. For clinicians and pet owners, information on the tolerability of different cannabinoids combinations can support informed use of these products. This study contributes to a data set demonstrating the safety of cannabinoids, which can be used to support future research in client-owned animals.

The results of the current study indicate that CBD, CBD + CBG and CBD + CBDA at the ratios and doses utilized were well tolerated when healthy male and female beagles were dosed for 90 consecutive days. These clinically determined conclusions are also supported by data from NAERS™ which is the most advanced system in the world for these types of products given to companion animals (specifically animals not intended for use in the human food chain).

Based on the data available it would be the conclusion of the authors that the substances do not pose significant risk to dogs in long-term use.