In 2018, I wrote a brief summary of the evidence concerning medical cannabis in veterinary patients. At that time, there were no published veterinary clinical trials. Any conclusion about the safety and efficacy of cannabis-based medicines was necessarily extremely tentative, as it could only be based on extrapolation from preclinical lab studies and research in humans. At that point, I concluded: There is substantial evidence for only a couple of uses in humans, including pain and chemotherapy-induced nausea. There is no direct evidence for any use of cannabis in dogs and cats, though there is clear evidence for the toxicity of marijuana. All veterinary cannabis products are unregulated, and most have not been tested for safety or quality control, much less clinical benefits. Until further research is available, use of cannabis in dogs and cats is entirely experimental and based only on anecdote...1 Cannabis is a “hot topic” right now, and the combination of loosening legal restrictions and great enthusiasm among its proponents and pet owners is driving research. As such, the evidence landscape is changing rapidly. In humans, clinical trials have provided convincing evidence for efficacy of cannabidiol (CBD) as an adjunctive treatment in some kinds of refractory epilepsy, and the U.S. Food and Drug Administration (FDA) has now licensed one CBD product for this use.2 Though the evidence is still considerably weaker in veterinary patients, two clinical studies have been published since 2017. CBD for osteoarthritis A randomized, double-blinded, placebo-controlled study was published in 2018 evaluating a commercial CBD product in dogs with osteoarthritis.3 Twenty-two dogs were recruited and 16 completed the study (a 27 percent dropout rate). The subjects were given placebo or 2 mg/kg of the CBD product every 12 hours for four weeks during one condition, followed by a two-week washout period and then crossover treatment under the other condition. Subjects also could take NSAIDs (about half did) or nutraceuticals, such as fish oil or glucosamine (the authors didn’t report how many did). Subjective measures of pain and lameness included validated owner pain scales and veterinary exams. Objective measures (force-plate analysis) were attempted, but the data were not usable. Complete blood counts and chemistries also were monitored. The owner pain scales showed significant improvement during the CBD treatment phase and not during the placebo phase. Veterinarian exams suggested an improvement in pain, but did not show amelioration in lameness or weight-bearing (unlike NSAIDs, which improved all three measures). The only clinical laboratory value affected by the cannabidiol was the alkaline phosphatase (ALK), which increased during the CBD treatment phase. The authors did not report any adverse effects in the study subjects, but they also did not report whether any formal monitoring of adverse effects was conducted. Strengths This study incorporated important measures to control for bias and error, including randomization, placebo control, and blinding of owners and veterinarians (though no assessment was made to ensure the blinding was effective). Appropriate statistical methods were employed, and the assessment tools used were validated measures of clinically relevant signs. Limitations The sample size of 16 dogs is quite small, which increases the risk of random error and limits confidence in the generalizability of the results. It is also concerning that 27 percent of the subjects initially enrolled dropped out of the study, since loss to follow-up greater that 20 percent is often considered a risk for bias in such studies.4 Subjects dropped out for a variety of reasons, and none seemed obviously related to the treatment under study. Clinical trials are important steps forward in understanding the potential risks and benefits of cannabidiol (CBD) for osteoarthritis and epilepsy in dogs. There was no apparent placebo effect, which is unusual for an arthritis study using subjective measurement instruments. The authors suggest one explanation for this may be that so many owners were veterinary professionals and might be less susceptible to placebo effects. This is unlikely given other studies of arthritis treatments have shown caregiver placebo effects impact veterinarians similarly to pet owners.5 The significance of this is unclear. There also were no reported adverse effects of the CBD. Human trials evaluating CBD have consistently showed relatively high rates of minor side effects, including some limiting tolerability of the treatment.6,7 Any effective medicine is going to have some risks and undesirable effects that have to be balanced against its benefits. A study showing no adverse effects at all could be a sign the treatment is not active or the study did not properly detect side effects that may emerge once it is more widely used in the real world. Conclusions This study is encouraging and suggests further clinical trial research on the potential of CBD as a therapy for canine osteoarthritis is warranted. However, the evidence provided by a single, small trial is always weak and tentative, so confident claims of safety and efficacy are not justified. CBD for epilepsy In 2019, a randomized, blinded, placebo-controlled study was published evaluating CBD in dogs with refractory epilepsy.8 Only 26 patients (~10 percent of applicants) met the stringent inclusion requirement: idiopathic epilepsy with MRI, cerebrospinal fluid (CSF) analysis, other diagnostics to rule out other seizure etiologies, and a minimum of two seizures per month over the previous four months despite at least one conventional anti-seizure medication. Patients were randomized to receive placebo (n=14) or CBD at 2.5 mg/kg every 12 hours for 12 weeks (n=12). The two main outcomes were change in monthly seizure frequency and the proportion of dogs identified as responders (≥ 50 percent decrease in mean monthly seizure frequency). Nineteen dogs completed the trial (a dropout rate of 27 percent). The median for the group mean monthly seizure frequency decreased from 4.0 to 2.7 in the CBD group and was unchanged at 2.0 in the placebo group. However, there were two dogs classified as responders in each group, so no difference in the proportion of responders was found. As in the CBD study, an increase in ALK was seen in dogs taking cannabidiol. However, unlike the other study, two dogs (17 percent) dropped out of the treatment group as a result of ataxia. This appeared to be due to the CBD, as it resolved once the treatment was discontinued. Strengths The design of this study included standard measures for controlling bias, and the analysis appeared to be appropriate. Limitations This is, again, a very small study. While the stringent exclusion criteria were appropriate for a preliminary trial, the result is a study population unlikely to be representative of the general epileptic population in which CBD would typically be used. The dropout rate was quite high, and a relatively large proportion of the dogs in the treatment group (17 percent) had adverse events severe enough to require withdrawal from the study. The presence of such adverse events does indicate an active treatment and appropriate monitoring, but it also suggests this may be a significant risk for patients on this treatment. Conclusions This study provided some evidence that CBD might be useful in refractory epilepsy in dogs, but one of the two primary outcomes did not differ between the treatment and placebo groups, and the results are likely of limited applicability to the typical epileptic patient population. Further study is warranted, but this is insufficient evidence to justify recommending CBD for epilepsy. Bottom line These two clinical trials are important steps forward in understanding the potential risks and benefits of CBD for osteoarthritis and epilepsy in dogs. Neither, however, provides strong evidence or justifies confident claims or clinical use outside of the research context. As frustrating as it is to wait for good evidence, doing so is ultimately better for our patients than prescribing insufficiently tested treatments that we later find have adverse effects we did not anticipate or that simply don’t work (e.g. oral tramadol for dogs).9 The other issues with cannabis-based medicines, such as the legal status and the lack of appropriate regulation or product quality control, are improving; however, significant problems remain. Despite the speed at which enthusiasm is growing and research is being conducted, the use of CBD and other cannabis-based products still involves a great deal of uncertainty about efficacy and safety. Though acutely fatal reactions to such products are extremely unlikely, there is insufficient evidence to show their use in any specific condition will lead to reliable improvement for patients, and these are very much experimental remedies. References 1 McKenzie BA. Cannabis-based remedies: No reliable clinical research evidence. Vet Pract News. August 2017:38. https://bit.ly/334fSrc 2 Stockings E, Zagic D, Campbell G, et al. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry. 2018;89(7):741-753. doi:10.1136/jnnp-2017-317168 3 Gamble L-J, Boesch JM, Frye CW, et al. Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs. Front Vet Sci. 2018;5:165. doi:10.3389/fvets.2018.00165 4 Dettori JR. Loss to follow-up. Evid Based Spine Care J. 2011;2(1):7-10. doi:10.1055/s-0030-1267080 5 Conzemius MG, Evans RB. Caregiver placebo effect for dogs with lameness from osteoarthritis. J Am Vet Med Assoc. 2012;241(10):1314-1319. doi:10.2460/javma.241.10.1314 6 Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017;376(21):2011-2020. doi:10.1056/NEJMoa1611618 7 National Academies of Sciences E. The Health Effects of Cannabis and Cannabinoids : The Current State of Evidence and Recommendations for Research. 8 McGrath S, Bartner LR, Rao S, Packer RA, Gustafson DL. Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy. J Am Vet Med Assoc. 2019;254(11):1301-1308. doi:10.2460/javma.254.11.1301 9 McKenzie BA. Is tramadol an effective analgesic for dogs and cats? Vet Pract News. June 2018:32-33. https://bit.ly/2YvGqSr Brennen McKenzie, MA, MSc, VMD, cVMA, discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists’ opinions do not necessarily reflect those of Veterinary Practice News.
