Single and Synergistic Effects of Cannabidiol and Δ-9-Tetrahydrocannabinol on Zebrafish Models of Neuro-Hyperactivity

Abstract

In this study, we aimed to investigate the effect of the two main active cannabinoids extracted from cannabis: Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on two distinct behavioral models of induced neuro-hyperactivity. We have taken advantage of two previously developed zebrafish models of neuro-hyperactivity: a chemically induced pentylenetetrazole model and a genetic model caused by loss-of-function mutations in the GABA receptor subunit alpha 1 (GABRA1−/−). Both CBD and THC have a significant effect on the behavioral changes induced by both models. Importantly, we have also shown that when applied together at different ratios of THC to CBD (1:1, 1:5, and 1:10), there was a synergistic effect at a ratio of 1:1. This was particularly important for the genetically induced neuro-hyperactivity as it brought the concentrations of THC and CBD required to oppose the induced behavioral changes to levels that had much less of an effect on baseline larval behavior. The results of this study help to validate the ability of THC and CBD to oppose neuro-hyperactivity linked to seizure modalities. Additionally, it appears that individually, each cannabinoid may be more effective against the chemically induced model than against the GABRA1−/− transgenic model. However, when applied together, the concentration of each compound required to oppose the GABRA1−/− light-induced activity was lowered. This is of particular interest since the use of cannabinoids as therapeutics can be dampened by their side-effect profile. Reducing the level of each cannabinoid required may help to prevent off target effects that lead to side effects. Additionally, this study provides a validation of the complimentary nature of the two zebrafish models and sets a platform for future work with cannabinoids, particularly in the context of neuro-hyperactivity disorders such as epilepsy.

Interactions between cannabidiol and Δ9‐tetrahydrocannabinol in modulating seizure susceptibility and survival in a mouse model of Dravet syndrome

“…This result is consistent with studies reporting synergistic effects of acute CBD and Δ 9 ‐THC co‐treatment in other animal models of disease including neuropathic pain and epilepsy (Casey et al, 2017; Samarut et al, 2019). Notably, Varvel et al (2006) showed that CBD potentiated the antinociceptive effects of a low 0.3 mg·kg −1 Δ 9 ‐THC dose in mice (Varvel et al, 2006).…”

“…We, therefore, examined acute CBD and Δ 9 -THC co-treatment effects on hyperthermiainduced seizures in Scn1a +/− mice and discovered that a subthreshold dose of CBD (12 mgÁkg −1 ) combined with 0.1 mgÁkg −1 THC resulted in a greater anticonvulsant effect than either phytocannabinoid alone. This result is consistent with studies reporting synergistic effects of acute CBD and Δ 9 -THC co-treatment in other animal models of disease including neuropathic pain and epilepsy (Casey et al, 2017;Samarut et al, 2019). Notably, Varvel et al (2006) showed that CBD potentiated the antinociceptive effects of a low 0.3 mgÁkg −1 Δ 9 -THC dose in mice (Varvel et al, 2006).…”

“…Pharmacological interactions between CBD and Δ 9 ‐THC are well documented and many medicinal cannabis products contain both phytocannabinoids (Boggs, Nguyen, Morgenson, Taffe, & Ranganathan, 2018; Boggs, Peckham, Boggs, & Ranganathan, 2016; Silveira et al, 2017). CBD and Δ 9 ‐THC can interact synergistically to improve therapeutic outcomes in some animal models of disease (Casey, Atwal, & Vaughan, 2017; Samarut, Nixon, Kundap, Drapeau, & Ellis, 2019) and CBD has sometimes been found to reduce sedative, anxiogenic, and other adverse side effects of Δ 9 ‐THC (Freeman et al, 2019; Todd & Arnold, 2016; Vann et al, 2008). In contrast, in some human (Arkell et al, 2019) and animal studies (Klein et al, 2011) CBD has been found to potentiate THC‐induced adverse effects.…”

Phenotype-based screening of synthetic cannabinoids in a Dravet Syndrome zebrafish model

“…These properties combined with the ease of large-scale pharmacological screening make larval zebrafish a good model system for investigating drug targets. A recent study 31 , limited only to locomotion assay read-outs in larval zebrafish, reported a synergistic effect of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on hyperactive behaviors. Unfortunately, these studies failed to include electrophysiology measures of efficacy and were limited to only these two compounds.…”

Phenotype-Based Screening of Synthetic Cannabinoids in a Dravet Syndrome Zebrafish Model

“…investigating drug targets. A recent study (Samarut et al, 2019), limited only to locomotion assay read-outs in larval zebrafish, reported a synergistic effect of D-9-tetrahydrocannabinol (THC) and CBD on hyperactive behaviors. Unfortunately, these studies failed to include electrophysiology measures and were restricted to these two compounds.…”