Species-specific susceptibility to cannabis-induced convulsions
Benjamin J Whalley, Hong Lin, Lynne Bell, Thomas Hill, Amesha Patel, Roy A Gray, C Elizabeth Roberts, Orrin Devinsky, Michael Bazelot, Claire M Williams and Gary J Stephens
British Journal of Pharmacology, 2018, 1-18.
Doi : 10.1111/bph.14165
BACKGROUND AND PURPOSE
Numerous claims are made for cannabis’ therapeutic utility upon human seizures, but concerns persist about risks. A potential confounder is the presence of both Δ9-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.
Cannabis 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.
Prolonged 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 (CB1 receptor)-mediated signalling. Profiling CB1 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 IMPLICATIONS
Sustained 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.
Abbreviations : CBD, cannabidiol; EEG, electrocorticography; eCB, endocannabinoid; PCA, principal component analysis; PSD, power spectrum density; THC, Δ9-tetrahydrocannabinol
Recent legal and regulatory change in the USA and elsewhere has increased awareness, and use of, cannabis (marijuana) for recreational and potential medicinal purposes, including treatment-resistant paediatric epilepsies (Devinsky et al., 2014; 2015). Such cannabis preparations typically contain significant amounts of Δ9-tetrahydrocannabinol (THC), a high potency, low intrinsic efficacy, CB1 receptor partial agonist; however, there is little evidence of THC efficacy or safety in epilepsy (Press et al., 2015). Moreover, reports are tempered by psychiatric complications of cannabis in adolescents (Volkow et al., 2014) and medical and psychiatric emergencies, including seizures and mortality, among recreational users of novel synthetic CB1 receptor high intrinsic efficacy agonists (Castaneto et al., 2014; Gurney et al., 2014). Short term exposure to CB1 receptor partial or full agonists typically exerts anticonvulsant effects in animal models of seizure and epilepsy (Rosenberg et al., 2015). By contrast, sustained THC administration is reported to cause convulsions in rats and mice (Chan et al., 1996; NTP, 1996) and, anecdotally, chickens. The othermost common cannabinoid, cannabidiol (CBD), is not psychoactive, is widely confirmed as anticonvulsant in animalmodels of seizure and epilepsy and lacks reported proconvulsant effects (Rosenberg et al., 2015). CBD reduces convulsive seizures in children and young adults with Dravet syndrome and with Lennox–Gastaut syndrome (Devinsky et al., 2016; 2017). A meta-analysis found that CBD behavioural pharmacology is unrelated to direct effects at CB1 receptors (McPartland et al., 2015), although indirect CBD effects on the endocannabinoid (eCB) system, as well as negative allosteric modulation of CB1 receptors in vitro (Laprairie et al., 2015) have been reported; rather, CBD has several potential non-CB1 receptor-mediated actions (Hill et al., 2012).
Despite this knowledge, it remains unknown whether sustained cannabis-induced convulsions are spontaneous and/or epileptiform in nature, with reports of both depressed and enhanced epileptogenesis in animal models (Rosenberg et al., 2017). Moreover, no relationship between convulsion incidence and other aberrant behaviours has been established. The extent to which changes in eCB signalling that may be involved in cannabis-induced convulsions in rodents are recapitulated in other species also remains to be elucidated. With these points in mind, we examined the effects of standardized extracts containing different doses of THC and CBD on in vivo behaviour and seizure activity in rats and dogs, species reportedly prone and resistant to cannabis-induced seizure respectively. We demonstrate for the first time that prolonged exposure to cannabis extracts produces dose-related motor convulsions subserved by epileptiform activity and associated seizurerelated behaviours in rats. By contrast, cannabis extracts never caused seizures in dogs, which exhibited reduced THC but higher 11-OH-THC and CBD plasma concentrations than rats. Across several species, the eCB system signalling profile was highest in the rat but lowest in the dog. These data clarify several apparent inconsistencies in the field and suggest that choice of model species has important implications in the study of cannabis induced convulsions.