Publikationsdatenbank

Oral cannabidiol administrations in horses:
Pharmacokinetic modelling, behavioural observations and implications for medication control (2024)

Art

Hochschulschrift

Autor

Eichler, Fabienne (WE 17)

Quelle

Berlin, 2024 — iv, 108 Seiten

Sprache

Englisch

Verweise

URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/45385

Kontakt

Pferdeklinik

Oertzenweg 19 b
14163 Berlin
+49 30 838 62299 / 62300
pferdeklinik@vetmed.fu-berlin.de

Abstract / Zusammenfassung

The use of cannabidiol (CBD) products is becoming increasingly popular among animal owners and veterinarians as an alternative treatment for stress, anxiety or pain in horses. In equestrian sports, all cannabinoids are banned due to their potentially psychotropic effects. However, there are only a few studies on the detection times of CBD concentrations in blood or urine, and the actual effectiveness in horses. The aim of this study was to determine the pharmacokinetic properties of CBD after oral administration in healthy horses and to analyse stress parameters, including behavioural observations, heart rate and cortisol levels. Study products were two pastes for oral administration, one with CBD as active ingredient and one without active ingredient. Paste administration was blinded. In the first study part (dose escalation study), the pastes were administered in escalating trials as single doses (0.2 mg CBD/kg, 1 mg CBD/kg, 3 mg CBD/kg) to a treatment and a control group. In the second part of the study (multiple dose study), both pastes were administered twice daily for 15 days (treatment group: 3 mg CBD/kg). For the pharmacokinetic analysis, blood and urine samples were taken daily during both study parts. After day 15 of the multiple dose study, additional samples were collected for two weeks to analyse the elimination phase. Concentrations of CBD, CBD metabolites and other cannabinoids were determined using gas chromatography/tandem mass spectrometry. Pharmacokinetic parameters were assessed using two approaches: Non-compartmental analysis and population pharmacokinetic analysis using a nonlinear mixed-effects model. During the elimination phase, the ratio between the steady-state concentrations of CBD in urine to serum (Rss) was calculated. In the dose escalation study, behavioural parameters were assessed using photographs to evaluate the horses' facial expressions on a specifically developed scale, which was based on existing scales (FaceSed and Horse Grimace Scale). To identify potential sedation, the horses' reactions to acoustic and visual stimuli were video recorded. The evaluation of the photos and videos was conducted in a blinded manner. In addition, the heart rate was continuously recorded via heart rate sensors throughout the study with subsequent analysis of heart rate (HR) and heart rate variability (HRV). In the multiple dose study, facial expressions and the depth of sedation were analysed daily following the same protocol as in the dose escalation study. In addition, blood and saliva samples were daily collected and analysed for cortisol levels using liquid chromatography/tandem mass spectrometry. The behavioural observations and cortisol levels were compared between the groups. A novel object test and a trailer test were performed prior to study start. Both tests were repeated on study day 13. Assessment included reactivity, movement patterns such as gait changes and behavioural characteristics. Heart rate was recorded during the tests and analysed using HR and HRV parameters. Blood and saliva samples were obtained before and after the tests for cortisol analysis. The CBD paste was well-tolerated and no side effects were observed. The non-compartmental analysis showed a maximum serum concentration of 12.2 ng/ml after single administration of CBD (3 mg/kg). The population pharmacokinetic analysis showed that a three-compartment model with zero-order absorption most accurately describes the pharmacokinetic properties of CBD. High volumes of distribution into peripheral compartments and high concentrations of the metabolite 7-carboxy-CBD were identified. In the multiple dose study, the mean maximum serum concentration was 38.4 ng/mL. The terminal half-life was 161.3 hours in serum and Rss was 4.5. In the dose escalation study, analysis of behavioural parameters, HR and HRV showed no consistently significant differences between the treatment and control group. During the multiple dose study, daily behavioural observations and cortisol levels also did not differ between treatment and control group. When analysing reactivity, movement patterns, HR, HRV and cortisol levels during the novel object test and the trailer test, no consistently significant differences were observed between groups. This study was the first to investigate pharmacokinetic parameters combined with the effect of CBD on behaviour and stress after regular oral administration of CBD in horses over two weeks. The pharmacokinetic analysis showed an extensive metabolism of CBD with a high distribution into peripheral tissues and a long elimination phase. The results of the behavioural assessments provided no reliable evidence for a stress-reducing or sedative effect of CBD in horses after regular oral administration at a dose of 3 mg/kg twice daily. The main limitation of this study is the small sample size. Further investigation of the potential stress-reducing effects of CBD in conjunction with pharmacokinetic analysis is essential to determine relevant CBD concentrations for medication control at equestrian sport events. Subsequent studies may consider administering higher CBD doses, such as 10 mg CBD/kg, and specifically explore the effect on horses known to exhibit signs of nervousness and are easily stressed.