This prospective pilot study provides valuable insights into the potential benefits and safety of CBD as adjunctive therapy in the context of canine refractory epilepsy. Our findings indicate that the co-administration of CBD with conventional AEDs significantly reduced seizure frequency and cluster events in the entire cohort, albeit with notable inter-individual variability. These results are consistent with emerging evidence supporting the anticonvulsant properties of CBD and underscore critical safety considerations for clinical translation.

Potential Efficacy in Refractory Epilepsy

The observed ≥50% seizure reduction in this pilot study generally aligns with findings from previous veterinary investigations of CBD’s anticonvulsant effects. While a double-blind crossover study reported a 24.1% reduction in seizure days at a higher CBD dose (9 mg/kg/day) [15], other studies have yielded mixed results. For instance, a 2019 randomized controlled trial using a lower dose (2.5 mg/kg twice daily) reported a 33% median reduction in seizure frequency. Still, it did not demonstrate a significant difference in the proportion of dogs achieving ≥50% seizure reduction compared with placebo [13]. More recently, a study exploring a combination of CBD and CBDA (2 mg/kg twice daily) observed a mean seizure frequency reduction from 8.0 to 5.0, with 43% of dogs achieving ≥50% seizure reduction, a higher proportion than that reported in a 2019 trial [14].

These findings suggest that CBD may counteract pharmacoresistance through multiple mechanisms [13,20]. The antagonistic effects of CBD on G-protein-coupled orphan receptors (GPR18 and GPR55), and on vanilloid receptors (TRPA1 and TRPV1-4) are noteworthy [20,21]. Additional pharmacological targets, including partial agonism at 5-HT1A receptors and reduced production of pro-inflammatory cytokines through its agonistic effect on peroxisome proliferator-activated receptor-gamma (PPARγ), may further contribute to its efficacy in refractory epilepsy, as supported by ex vivo and clinical observations in treatment-resistant patients [11,21,22].

The response patterns in our study varied, with some dogs exhibiting rapid improvement and others showing gradual or fluctuating reductions—notably, a bimodal response, with some dogs becoming nearly seizure-free. In contrast, others derived minimal benefit, mirroring findings in human trials of CBD for treatment-resistant epilepsy [8], implying its potential efficacy in a distinct subpopulation. This heterogeneity may stem from genetic differences in cannabinoid receptor expression or epilepsy etiology, warranting further pharmacogenomic studies. Additionally, the weak correlation between pre- and post-treatment outcomes underscores substantial inter-individual variability, consistent with the bimodal response. Longitudinal assessments collectively suggest that while CBD holds promise for refractory epilepsy, its efficacy varies significantly across individuals.

The evidence of a differential response indicated that the temporal patterns of seizure reduction were non-uniform, with specific time points demonstrating greater efficacy than others. This variability emphasizes the critical role of longitudinal monitoring in evaluating the response to CBD treatment, as some animals require extended periods to exhibit therapeutic benefits. In contrast, others experience either no improvement or only immediate improvement. These divergent response trajectories suggest the potential presence of distinct pathophysiological subtypes of refractory canine epilepsy, which may necessitate tailored therapeutic approaches.

The pronounced reduction in seizure clusters represents a clinically significant outcome, as clusters are associated with poor prognosis and therapeutic challenges [5]. CBD’s potential interruption of ictogenesis via GABAergic enhancement and glutamate modulation may explain this effect, offering a promising strategy for cluster management where conventional therapies often fail [23].

Safety, Tolerability Profile, and Quality of Life

The analysis confirmed that the majority of hematological parameters did not show statistically significant changes over the 12-week intervention period. Similarly, most biochemical parameters remained stable. Hematological and renal parameters remained stable throughout the study, consistent with CBD’s established safety profile in dogs [13,14,18,24]. This indicated a general absence of widespread adverse effects on erythropoiesis, coagulation, or renal function attributable to CBD co-treatment during the observation period. Notably, a large proportion of the cohort (12 of 13 dogs) exhibited elevated eosinophil levels at baseline, a condition that CBD co-administration did not statistically exacerbate. Eosinophilia is a rare adverse effect of phenobarbital administration in dogs. This condition may be present as part of a broader syndrome, such as Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), or as a more localized reaction [25]. Additionally, certain dogs may exhibit hypersensitivity to AEDs, resulting in adverse reactions, specifically Anticonvulsant Hypersensitivity Syndrome (AHS) [26].

However, the statistically significant elevation in ALP levels across all post-treatment intervals raises concerns about hepatic stress. This aligns with previous studies conducted on dogs [13,14,15]. Furthermore, this is corroborated by human research in which CBD-induced ALP elevation (without concurrent bilirubin increase) was attributed to enzyme induction rather than hepatocellular damage [27,28].

Although the observed abnormal baseline and elevated ALT levels in certain dogs, particularly during the initial four weeks, did not reach statistical significance, they may suggest hepatotoxic interactions between CBD and conventional AEDs. CBD is known to inhibit cytochrome P450 enzymes, notably CYP3A4 and CYP2C19 [29,30], thereby potentially impairing phenobarbital metabolism. This issue is further complicated by polypharmacy in this group, with 2–6 AEDs administered simultaneously. Each dog was treated with phenobarbital, a CYP450 enzyme inducer, in addition to other AEDs. This regimen may increase metabolic stress caused by CBD, paralleling the interaction between CBD and valproate observed in human studies. Mechanisms such as mitochondrial dysfunction, enzyme inhibition, and transporter effects are plausible across species, as documented by Beers et al. [31].

In this context, the patterns observed in our study likely indicate sustained hepatic stress, potentially reflecting pre-existing AED-induced enzyme induction, which CBD did not ameliorate. Concurrent ALT elevations noted in several dogs suggest a degree of hepatocellular injury, thus warranting vigilant monitoring of potential hepatotoxicity. Nonetheless, these findings align with those of earlier studies, which also reported variations in hepatic enzyme markers in dogs following CBD administration [32,33].

Collectively, these findings showed that CBD co-treatment did not cause broad hematological or renal disruption. However, this may be associated with sustained elevation of hepatic enzymes in most dogs, consistent with AED-related metabolic stress. These warrant the monitoring of liver function in at-risk patients. The significant inter-individual variability in the pharmacokinetic pattern of plasma CBD underscores the need for individualized monitoring and rigorous evaluation of CBD safety in epileptic canines [18]. Subsequent analyses should prioritize longitudinal assessment of hepatobiliary markers, trends in eosinophilia, and correlations with CBD/AED dosing.

The use of CBD products in dogs is typically well tolerated, with none to moderate adverse effects [10,24,34]. Reported side effects include reduced appetite, vomiting, and variations in stool consistency, such as soft stools or diarrhea [14,15]. More serious concerns involve potential elevations in liver enzyme levels, particularly when CBD oil is used concomitantly with other anti-seizure medications, or in patients at increased risk [28].

Pet owner surveys consistently show a positive perception of CBD use in animals [35,36]. Our survey reinforced this, with all participants expressing a favorable view of giving CBD to their pets. Similarly, earlier publications related to cannabis product use in pets indicated high owner satisfaction, whether for therapeutic reasons or as a supplement [36,37].

Interestingly, our findings suggest that owners perceive a greater drop in seizure frequency with CBD than in earlier studies [14]. Although episodes of loss of balance were reported in some instances in our research, owners consistently documented that their dogs remained alert and vital, with increased appetite. The participating owners also reported other adverse events, including lethargy, urination, and thirst. These observations corroborate those reported in previous studies [14,32]. In this regard, variable systemic drug exposure, driven by factors such as dosage, treatment duration, formulation, and interactions with concurrent medications, can significantly influence adverse event profiles observed with CBD [13,17].

Nonetheless, owners of the participating dogs expressed a positive to very positive attitude regarding the improved quality of life experienced by both their pets and them after CBD co-treatment. Given this favorable context, owners showed moderate to high acceptance of the increased costs associated with CBD use. This finding aligns with previous reports indicating that owners seek affordable pricing [36].

However, it is worth noting that direct comparisons of owner perception and canine QoL in dogs with idiopathic epilepsy are challenging. Each study’s unique design for evaluating these aspects makes cross-investigation comparisons difficult [4]. Our findings are consistent with those of Bride [38], who reported that geographic, cultural, and socioeconomic factors may influence the diagnosis and treatment of epilepsy. These disparities may ultimately impact both QoL measures and owner perspectives.

Clinical Implications and Limitations

It is essential to acknowledge the limitations inherent in the design, execution, and clinical implications of this study. This single-arm, quasi-experimental pretest–post-test design was a pragmatic choice for a pilot investigation in a real-world setting, particularly for a refractory, inherently difficult-to-study population. Although practical, this study has inherent limitations that affect the strength of its conclusions. The relatively small cohort size, comparable to that of prior canine CBD trials [13,14], reduces statistical power to detect subgroup differences. This reflects the challenges of recruiting refractory epilepsy cases within a constrained timeframe, as many owners declined participation due to financial constraints or prior treatment fatigue.

Our pragmatic “start-low, go-slow” titration strategy (0.5 → 2.5 mg/kg BID) was designed to minimize severe adverse events while maintaining efficacy—a key consideration given owner concerns regarding CBD-related side effects. These findings challenge the one-dose-fits-all paradigm, which advocates personalized titration of CBD in veterinary neurology. This aligns with Bradley [24], who noted that customizing CBD dosages for each dog could lead to more comparable plasma concentrations, potentially improving effectiveness. However, the cautious dosing approach used in our study, which capped the maximum dose at 2.5 mg/kg, may have inadvertently restricted the potential therapeutic benefits if higher doses were required to achieve optimal seizure control. Consequently, the observed outcomes may reflect sub-therapeutic dosing in some cases, highlighting the balance between tolerability and efficacy.

Although numerous studies on canine epilepsy and the use of CBD for this specific disease have been conducted in Europe and North America [10,38], to our knowledge, this study represents the first scientific report originating from Asia to investigate cannabidiol as a potential adjunctive therapeutic intervention for this neurological disorder in dogs with epilepsy.