Neural correlates of interactions between cannabidiol and Δ⁹‐tetrahydrocannabinol in mice: implications for medical cannabis

Abstract

BACKGROUND AND PURPOSEIt has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ 9 -tetrahydrocannabinol (THC) to cannabidiol (CBD), as CBD reduces the adverse psychotropic effects of THC. However, our understanding of CBD and THC interactions is limited and the brain circuitry mediating interactions between CBD and THC are unknown. The aim of this study was to investigate whether CBD modulated the functional effects and c-Fos expression induced by THC, using a 1:1 dose ratio that approximates therapeutic strains of cannabis and nabiximols. EXPERIMENTAL APPROACHMale C57BL/6 mice were treated with vehicle, CBD, THC or a combination of CBD and THC (10 mg·kg À1 i.p. for both cannabinoids) to examine effects on locomotor activity, anxiety-related behaviour, body temperature and brain c-Fos expression (a marker of neuronal activation). KEY RESULTSCBD potentiated THC-induced locomotor suppression but reduced the hypothermic and anxiogenic effects of THC. CBD alone had no effect on these measures. THC increased brain activation as measured by c-Fos expression in 11 of the 35 brain regions studied. CBD co-administration suppressed THC-induced c-Fos expression in six of these brain regions. This effect was most pronounced in the medial preoptic nucleus and lateral periaqueductal gray. Treatment with CBD alone diminished c-Fos expression only in the central nucleus of the amygdala compared with vehicle. CONCLUSIONS AND IMPLICATIONSThese data confirm that CBD modulated the pharmacological actions of THC and provide new information regarding brain regions involved in the interaction between CBD and THC. AbbreviationsBNST, bed nucleus of the stria terminalis; CBD, cannabidiol; PAG, periaqueductal gray; PVH, paraventricular hypothalamic nucleus; THC, Δ 9 -tetrahydrocannabinol BJP IntroductionCannabis is a complex mixture of approximately 100 different cannabinoids that may modulate the effects of Δ 9 -tetrahydrocannabinol (THC), the main psychoactive constituent of the plant (Elsohly and Slade, 2005;Radwan et al., 2008). A number of studies now support the view that cannabidiol (CBD) may reduce the negative psychotropic effects of THC while enhancing its positive therapeutic actions (Russo, 2011;Niesink and van Laar, 2013). In naturalistic human studies where cannabinoid content in smoked material or the user's hair is compared with the subjective effects of cannabis, it has been inferred that CBD attenuates some effects of THC, such as memory impairment, attentional bias to drug-related stimuli, appetite stimulation, anxiety and psychotic-like states (Morgan and Curran, 2008;Niesink and van Laar, 2013). Controlled human laboratory studies administering known doses of CBD and THC largely agree with the results of the naturalistic studies, with CBD decreasing the psychoactive and physiological effects of THC. Specifically, CBD was shown to reduce the effects of THC on anxiety (Zuardi et al., 1982), hippocampus-dependent episodic memory, psy...

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…On the other hand, as suggested also by epidemiological studies showing that the abuse of cannabis preparations with higher relative amounts of CBD produces less central effects (342,759,856), coadministration of CBD with ⌬ 9 -THC reduces several psychoactive and psychotic-like actions of the latter compound, thus widening its therapeutic window.…”

Cannabis use during pregnancy: Pharmacokinetics and effects on child development

“…Specific strains of cannabis may also produce high levels of a second phyto-CB, cannabidiol (CBD), often referred to as non-psychoactive. Although not associated with cannabis-induced euphoria or intoxication (Grotenhermen et al, 2017), CBD exposure is psychoactive and affects several brain functions and behaviors, including neuronal activity, seizure incidence and social interactions (Renard et al, 2017a; Todd and Arnold, 2016). Accordingly, CBD has been linked to influencing a wide range of clinical outcomes such as epilepsy and neuropsychiatric disorders.…”

Seeing through the smoke: Human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks

“…For example, CBD was shown to hinder the aversive effects of THC in rodents as measured in the conditioned place aversion paradigm and in animal models of anxiety (Todd and Arnold, 2016; Vann et al, 2008). However, there is conflicting evidence for whether CBD protects against THC-induced impairments in memory.…”

“…At a network level, clues on the brain circuitry involved in CBD’s ability to inhibit the neuropharmacological actions of THC are provided by a recent study. CBD administration robustly inhibited THC-induced c-Fos expression, a marker of neuronal activation, in the medial preoptic nucleus of the hypothalamus, the dentate gyrus of the hippocampus and periaqueductal gray (Todd and Arnold, 2016). These brains regions are implicated in the hypothermic, memory-impairing and anxiogenic actions of THC, respectively.…”