Species‐specific susceptibility to cannabis‐induced convulsions

Abstract

BACKGROUND AND PURPOSENumerous claims are made for cannabis' therapeutic utility upon human seizures, but concerns persist about risks. A potential confounder is the presence of both Δ 9 -tetrahydrocannabinol (THC), variously reported to be pro-and anticonvulsant, and cannabidiol (CBD), widely confirmed as anticonvulsant. Therefore, we investigated effects of prolonged exposure to different THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling. EXPERIMENTAL APPROACHCannabis extract effects on in vivo neurological and behavioural responses, and on bioanalyte levels, were measured in rats and dogs. Extract effects on seizure activity were measured using electroencephalography telemetry in rats. eCB signalling was also investigated using radioligand binding in cannabis extract-treated rats and treatment-naïve rat, mouse, chicken, dog and human tissue. KEY RESULTSProlonged exposure to cannabis extracts caused spontaneous, generalized seizures, subserved by epileptiform discharges in rats, but not dogs, and produced higher THC, but lower 11-hydroxy-THC (11-OH-THC) and CBD, plasma concentrations in rats versus dogs. In the same rats, prolonged exposure to cannabis also impaired cannabinoid type 1 receptor (CB 1 receptor)-mediated signalling. Profiling CB 1 receptor expression, basal activity, extent of activation and sensitivity to THC suggested interspecies differences in eCB signalling, being more pronounced in a species that exhibited cannabis extract-induced seizures (rat) than one that did not (dog). CONCLUSIONS AND IMPLICATIONSSustained cannabis extract treatment caused differential seizure, behavioural and bioanalyte levels between rats and dogs. Supporting radioligand binding data suggest species differences in eCB signalling. Interspecies variations may have important implications for predicting cannabis-induced convulsions from animal models. AbbreviationsCBD, cannabidiol; EEG, electrocorticography; eCB, endocannabinoid; PCA, principal component analysis; PSD, power spectrum density; THC, Δ 9 -tetrahydrocannabinol British Journal of

Pharmacokinetics of Sativex® in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders

“…Pharmacokinetic and pharmacodynamic properties of Sativex have been extensively investigated in humans and laboratory species (e.g., rodents) [34][35][36], but not in other species, such as dogs. The only study conducted with the 1.08:1 ratio of ∆ 9 -THC and CBD extracts in dogs has been recently published [31], but it used an oral administration instead sublingual delivery, and, as has been mentioned above, rather than being a pharmacokinetic study, was aimed more at investigating the proconvulsant activity of different doses of the 1.08:1 ratio of ∆ 9 -THC and CBD extracts in dogs in comparison to other animal species [31]. Given the interest to evaluate whether this phytocannabinoid-based medicine has beneficial effects on different central and peripheral canine disorders, the pharmacokinetic profile of Sativex, when administered via sublingual delivery to naïve dogs, has been determined.…”

“…Such development should be initiated by conducting pharmacokinetic studies, which are currently lacking in dogs. There is only a recent study carried out in dogs with different doses of 1.08:1 ratio of ∆ 9 -THC and CBD extracts, but they were administered orally [31] not via sublingual delivery. In addition, the study was not specifically aimed at investigating in depth the pharmacokinetic properties of a Sativex treatment in dogs but its possible adverse effects by analyzing its proconvulsant activity in these dogs in comparison to other animal species [31].…”

“…There is only a recent study carried out in dogs with different doses of 1.08:1 ratio of ∆ 9 -THC and CBD extracts, but they were administered orally [31] not via sublingual delivery. In addition, the study was not specifically aimed at investigating in depth the pharmacokinetic properties of a Sativex treatment in dogs but its possible adverse effects by analyzing its proconvulsant activity in these dogs in comparison to other animal species [31]. Therefore, with the purpose of determining the best dosage and timing for using Sativex in dogs affected by different pathologies, we designed the present study to investigate the pharmacokinetics of Sativex when administered using single or multiple administrations to naïve, healthy dogs via sublingual delivery, which is the classic route used for this medicine in humans.…”

A practical guide for transparent reporting of research on natural products in the British Journal of Pharmacology: Reproducibility of natural product research

“…i BJP will consider studies on chemically characterized herbal extracts with applications that are potentially clinically interesting. For instance, Whalley et al (2019) (Castro, Hogan, Benson, Shehata, & Landauer, 1995;Jacob & Herschler, 1986;Parisi et al, 2010).…”

Cannabinoids and their actions: An update

“…The rest of the research papers look at cannabinoids in animal models with diverse elements of a CNS focus. Thus, one paper focusses on prefrontal cortex regulation of pain (Rea, McGowan, Corcoran, Roche, & Finn, 2019), while another looks at species differences in cannabinoid-induced convulsions (Whalley et al, 2019), and a third investigates endocannabinoid regulation of feeding (Sticht et al, 2019). Two papers look at features of reward and dependency: One looks at the roles of CB 1 and CB 2 receptors on behavioural responses to cocaine (Gobira et al, 2019).…”