Cannabinoids and treatment of horses with chronic arthritis

When I first saw this abstract I was thinking that “significant improvement” described was likely to be small but I went and read the paper anyway. It was an eyeopener with most (all?) of the horses showing large improvements in pain scores over the two weeks of the experiment. After the abstract I have included the discussion and conclusion from the article. There is relevant information there that should be considered before use of these products in horses.
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Role of cannabidiolic acid or the combination of cannabigerol/cannabidiol in pain modulation and welfare improvement in horses with chronic osteoarthritis

Front Vet Sci. 2024 Dec 10:11:1496473. doi: 10.3389/fvets.2024.1496473. eCollection 2024.
Authors
Francesca Aragona 1 , Marco Tabbì 1 , Enrico Gugliandolo 1 , Claudia Giannetto 1 , Fabiola D’Angelo 2 , Francesco Fazio 1 , Claudia Interlandi 1
Affiliations

1 Department of Veterinary Sciences, University of Messina, Messina, Italy.
2 Independent Practitioner, Varese, Italy.

PMID: 39720409
PMCID: PMC11668182
DOI: 10.3389/fvets.2024.1496473

Abstract

Cannabidiol (CBD) is a non-psychotropic cannabinoid obtained from hemp (Cannabis sativa L.) used for pain management in companion animals including horses. The present study aimed to evaluate the efficacy of cannabidiolic acid (CBDA) and cannabigerol/cannabidiol oil (CBG/CBD) oral administration in alleviating pain in adult horses affected by chronic osteoarthritis (OA). Twenty-four horses (10 geldings and 14 mares), aged between 11 and 18 years old, were equally divided into two groups. One group received CBDA 15% oil and the other group received CBG/CBD oil (CBG20%-CBD10%) for 14 consecutive days. A standard dose of 0.07 mg/kg was chosen based on the mean body weight of 450 ± 28 kg. Horse Chronic Pain Scale (HCPS) and physiological parameters monitoring heart rate (HR), respiratory rate (RR), arterial blood pressure (systolic arterial pressure- SAP, diastolic arterial pressure- DAP) were assessed before (T0) and every day for the entire administration (T1-T14). Blood samples were collected for the evaluation of complete hemogram, Leukocyte subpopulation identification and counting and leukocyte differentiation antigens CD4 and CD8 at the day before the administration (T0) and every 7 days (T7 and T14). A reduction of HCPS pain scale scores and the number of WBC, monocytes and neutrophils and CD8 was observed with both CBDA and CBG/CBD treatment. No statistical differences were found in the physiological parameters. No subject required rescue analgesia or showed any adverse effects. The results of this study showed that oral administration of both CBDA and CBG/CBD oil may promote pain reduction in adult horses affected by chronic OA.

Keywords: cannabidiol; cannabidiolic acid; cannabigerol; horses; osteoarthritis; pain.

Copyright © 2024 Aragona, Tabbì, Gugliandolo, Giannetto, D’Angelo, Fazio and Interlandi.
Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

4 Discussion
The results of this study showed that the use of CBDA and the combination of CBG/CBD oil at the dosage administered did not influence physiological and hematological parameters in horses with chronic OA. This contrasts with results obtained in previous studies on horses with acute OA treated with CBD oil, where the same parameters, such as HR and RR, were influenced by pain and decreased significantly after treatment (25). In this study, however, these parameters remained constant throughout the experimental period in both groups. The methods used to establish a direct relationship between changes in physiological parameters and the presence or severity of pain were validated by previous studies (25, 46, 47).

Over a 14-day treatment period, the administration of CBDA and the CBG/CBD combination resulted in stabilized HR, RR, and blood pressure, accompanied by a significant reduction in pain scores. This reduction in pain led to an overall improvement in the clinical condition in both treatment groups. Notably, pain reduction was observed earlier in the CBDA group at T3, compared to the CBG/CBD group, where significant pain relief was evident only from T7 onward. This suggests a potentially quicker onset of action for CBDA, probably thanks to the acid form of CBDA that is available faster than the others.

Our findings align with previous studies that demonstrated the anti-inflammatory and anxiolytic effects of cannabinoids in animal models. For example, CBDA has been shown to exert these effects when administered systemically or orally in rodent studies, both before and after carrageenan-induced inflammation (32). Previous studies have used a mix of CBD and CBDA in dogs with chronic OA administered as a dietary supplement from 4 to 8 weeks and indeed found a reduction in pain (47). Furthermore, Cabrera et al. used a CBD and CBG combination similarly to the present study, demonstrating clear anti-inflammatory effects in the lungs of humans (48). In horses, previous studies have shown a positive effect against stress and anxiety, assessed according to different scales of scores and values, as in our case, considering the effect on HR, which tends to be reduced (49, 50). The use of CBD has shown a reduction in anxiety and stress by monitoring HR also in rodents (51) and humans (52).

In this study, the use of CBDA and CBG/CBD at 0.07 mg/kg led to significant changes in inflammatory markers over time. Specifically, there was a reduction in the number of leukocytes and their subpopulations, including a decrease in CD8+ T cells, neutrophils (in the CBG/CBD group), and monocytes (in the CBDA group). The reduction in the leukocyte population suggests a possible overall reduction in the inflammatory process following treatment with CBDA and CBG/CBD.

These findings are particularly relevant considering the role of immune cells in OA pathogenesis (53). The innate immune system is essential in the host’s defense against microbial invasion and the modulation of various types of tissue injury and repair (54). Immune responses within the joint cavity have regulatory roles in driving cartilage injury toward repair or destruction. Restoration and healing, if they occur, are accompanied by the secretion of anti-inflammatory factors from immune cells and chondrogenesis. However, once damaged, the affected cartilage cannot regenerate itself. In this pathological condition, augmented inflammatory responses develop cartilage injury to OA (55). Macrophages, T cells, natural killer cells, dendritic cells (DCs), and neutrophils are among the immune cells primarily involved in cartilage injury and repair in OA pathophysiology (55). More specifically, T cells and B cells in the synovial fluid of OA patients are regulated by neutrophils, leading to cartilage breakdown and bone remodeling (53). Neutrophils, the most abundant circulating leukocytes, play a crucial role in both joint repair and chronic inflammation. They contribute to tissue repair by phagocytizing necrotic cells, releasing anti-inflammatory factors, and activating protective genes, but they also drive chronic inflammation through enzyme release and immune cell activation (56). The observed reduction in CD8+ T cells at T3 in both treatment groups may indicate a decrease in tissue destruction, as these cells are known for their cytotoxic capabilities, which contribute to tissue damage in various pathophysiological conditions (57).

In addition to the reduction in pain observed in the subjects undergoing treatment, we also noted a reduction in the number of leukocytes and their subpopulations, suggesting a possible overall reduction in the inflammatory process with both CBDA and CBG/CBD treatment (58, 59). The most interesting result, obtained using a dose of 0.07 mg/kg (CBDA 15% or CBG 10%/CBD 20%), is the variation and, in particular, the reduction over time of certain inflammatory markers compared at point T1, such as the number of WBCs in both groups, a reduction of CD8+ cells, a reduction of neutrophils in the CBG group, and a reduction of monocytes in the CBDA group. These responses involving leukocyte populations and subpopulations could be associated with a reduction in the ongoing inflammatory process due to the action of the products administered in both groups.

Despite our results are promising, this study has some limitations, including the small number of animals, the measurement of serum biochemical parameters (liver transaminases) and urine examination. The lack of a control group receiving conventional analgesics to compare with the groups receiving cannabinoids is another limitation of the study. Furthermore, considering other biomarkers of inflammation such as serum pro-inflammatory and anti-inflammatory cytokines should be advisable, as well as exploring the effects of higher cannabinoid doses, depending on the pathophysiological state of the animals. Based on the data collected in this study, the addition of CBDA 15% or CBG10%/CBD 20% in horses with chronic OA resulted in stable HR and RR, reduced pain scale scores, and a decrease in hematological markers of inflammation. These findings appear to be correlated with a reduction of the inflammatory process and an improvement in the quality of life of treated subjects.

5 Conclusion
Oral transmucosal administration of 15% CBDA oil and CBG/CBD oil (CBG20%-CBD10%) for 14 consecutive days at a dose of 0.07 mg/kg reduced HCPS scores, and decreased leukocyte, monocyte and neutrophil populations and CD8 markers. The physiological parameters monitored (HR, RR, SAP and DAP) showed no changes throughout the study period. None of the animals required rescue analgesia or experienced any adverse effects. The results support the efficacy of CBDA and CBG/CBD oils in providing optimal pain management and an overall more satisfactory quality of life in adult horses with chronic OA. Further research is required to fully understand the pharmacodynamics and pharmacokinetics of cannabinoids, to establish an optimal dosage range and to determine potential applications in this species.