Molecular Targets of Cannabidiol in Neurological Disorders.

Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells. It is not an agonist of the classical CB1/CB2 cannabinoid receptors and the mechanism by which it functions is unknown. Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells. Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death. Density gradient fractionation analysis by mass spectrometry and western blotting showed colocalization of CBD with protein markers of mitochondria. Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance. Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD. Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD. The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.

Clearing the haze around medicinal cannabis

Cannabidiol is an ultra potent sensitizer for 2-APB responses in rTRPV2 and mTRPV3 channels but not in rTRPV1 through a mechanism that engages channel regions further from the cannabidiol binding site and the pore.

The cannabis conundrum: Thinking outside the THC box.

Background: Social cognition abilities such as empathy and the Theory of Mind (ToM) have been shown to be impaired in neuropsychiatric conditions such as psychotic, autistic, and bipolar disorders. The endocannabinoid system (ECS) seems to play a role in social behavior and emotional processing while it also seems to play a role in those neuropsychiatric conditions showing social cognition impairments. Main plant cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) modulate the ECS and, due to their opposite effects, have been proposed as both cause and treatment for neuropsychiatric-related disorders such as schizophrenia, anxiety, or post-traumatic stress disorder (PTSD). The aim of this study was to test the effects of THC and CBD on social cognition abilities in chronic cannabis users. Method: Eighteen members from a cannabis social club were tested for social cognition effects under the effects of different full spectrum cannabis extracts containing either THC, CBD, THC+CBD, or placebo in a naturalistic randomized double-blind crossover placebo-controlled study. Results: Results showed that participants under the effects of THC showed lower cognitive empathy when compared with the effects of CBD but not when those were compared with THC+CBD or placebo. Also, participants showed higher cognitive ToM under the effects of CBD when compared with the effects of placebo, but not when those were compared with THC or THC+CBD. However, we did not find differences on the emotional scales for empathy or ToM. Conclusions: This study provides evidence for the interaction between the effects of THC and CBD and social cognition abilities in a naturalistic environment, which can be of special interest for the clinical practice of medical cannabis on neuropsychiatric disorders. We show for the first time that CBD can improve ToM abilities in chronic cannabis users. Our results might help to understand the role of the ECS in social cognition, and their association with psychiatric and neurodevelopmental disorders such as schizophrenia or autism. Finally, we demonstrate how reliable methodologies can be implemented in naturalistic environments to collect valid ecological evidence outside classic laboratory settings.

Δ-Tetrahydrocannabinol Increases Dopamine D1-D2 Receptor Heteromer and Elicits Phenotypic Reprogramming in Adult Primate Striatal Neurons.

Voltage-gated sodium (NaV) channel blockade by plant cannabinoids does not confer anticonvulsant effects per se

Introduction: Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States) has demonstrated efficacy with an acceptable safety profile in patients with Lennox–Gastaut or Dravet syndrome in four randomized controlled trials. CBD possesses affinity for many target classes with functional effects relevant to the pathophysiology of many disease types, including epilepsy. Although the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, transient receptor potential vanilloid 1 (TRPV1) represents a plausible target because (1) CBD activates and then desensitizes TRPV1, (2) TRPV1 is overexpressed in models of temporal lobe epilepsy and patients with epilepsy, (3) and TRPV1 modulates neuronal excitability.Methods: To investigate a potential role of TRPV1 in the anticonvulsive effects of CBD, the effect of CBD on seizure threshold was assessed using a mouse maximal electroshock threshold model of generalized seizure in TRPV1 knockout and wildtype mice. The dose dependence of the CBD effect was determined and compared with that of the positive comparator diazepam and vehicle.Results: At 50 and 100 mg/kg, CBD significantly (p<0.0001) increased seizure threshold in wildtype mice compared with TRPV1 knockout and vehicle controls. This effect was observed only at 100 mg/kg in TRPV1 knockout mice compared with knockout vehicle mice, in which gene deletion partially attenuated the CBD-increased seizure threshold. The effect of high-dose CBD in wildtype mice was nevertheless significantly different from vehicle-treated TRPV1 knockout mice (p<0.0001). Bioanalysis confirmed that genotype-specific differential brain exposure to CBD was not responsible for the observed effect on seizure threshold.Conclusion: These data strongly implicate TRPV1 in the potential mechanisms of action for the anticonvulsive effects of CBD. The partial inhibition of the anticonvulsive effect of high-dose CBD in TRPV1 knockout mice may indicate the involvement of targets other than TRPV1. Further characterization of TRPV1 in the anticonvulsive effect of CBD in validated models of seizure is warranted, as is pharmacological investigation of the molecular interaction between CBD and TRPV1.

PURPOSE: The consumption of cannabidiol (CBD) to support recovery has become popular among athletes. Potential anti-inflammatory and anti-oxidative properties of CBD are supposed to result in pro-regenerative effects after strength training. Therefore three studies were conducted to investigate the effects of CBD treatment on performance and muscle recovery after resistance training. METHODS: Three independent randomized, double-blind, placebo-controlled trials were conducted in cross-over designs. The effect of a single CBD (60 mg) application was investigated in 1. advanced (n = 16) and 2. highly advanced resistance-trained athletes (n = 8) after intensive strength training on back squat (BS) and muscle damage proxies (MDP). Furthermore, 3. a repeated application (60 mg each day for one week) during an intensive training week was examined in advanced (n = 10) and highly advanced (n = 8) resistance-trained athletes. In addition to BS and MDP, bench press performance, anti-inflammatory, and anti-oxidative effects were investigated. RESULTS: In highly advanced athletes a single CBD application reduced creatine kinase concentrations (CK) 24 h after the training bout (CBD: +87.9 ± 100.9 U/L; PL: +290.0 ± 309.4 U/L). This was not confirmed for less advanced athletes. A small but significant effect of CBD was observed on CK (p < 0.05; ES = 0.24) and myoglobin (MYO)(p < 0.05; ES = 0.21) concentrations after 72 h (CK: CBD: +50.7 ± 44.7 U/L; PL: 3069.7 ± 2106.6 U/L); MYO: CBD:6.3 ± 8.3 ng/ml; PL: 6.8 ± 15.8 ng/ml). These results are in line with previous interventions, which detected a small effect on muscle soreness via visual analog scale. Only advanced athletes showed small effect of CBD on squat performance after 72 h (CBD: +1,3 ± 0.9 kg; PL: -2.0 ± 1.6 kg; p < 0.05; ES = 0.37). For the third intervention, analysis is currently performed. Initial trends indicate differential effects on MDP and performance depending on the level of performance. CONCLUSIONS: The results indicate small but significant effects of a single CBD application after strength training on MDP. Interestingly the effects varied depending on the performance level. First trends suggest similar effects after short-term repeated treatment. On performance, the results are currently inconsistent. Therefore, further human studies are needed.

P.3.006 Effects of cannabidiol (CBD) on regional cerebral blood flow

Probing the endocannabinoid system in healthy volunteers: Cannabidiol alters fronto-striatal resting-state connectivity

Reprint of “Caffeine protects against memory loss induced by high and non-anxiolytic dose of cannabidiol in adult zebrafish (Danio rerio)”

Caffeine protects against memory loss induced by high and non-anxiolytic dose of cannabidiol in adult zebrafish (Danio rerio)

To evaluate the hypothesis that activation of somatodendritic 5-HT(1A) autoreceptors in the dorsal raphe nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non-psychoactive cannabinoid found in cannabis. The potential of systemic and intra-DRN administration of 5-HT(1A) receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT(1A) receptors and to modify the ability of the 5-HT(1A) agonist, 8-OH-DPAT, to stimulate [(35) S]GTPγS binding in rat brainstem membranes. CBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg·kg(-1) , but not 40 mg·kg(-1) )-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [(35) S]GTPγS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping. These results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT(1A) autoreceptors in the DRN. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Rodents acquire food information from their conspecifics and display a preference for the conspecifics' consumed food. This social learning of food information from others promotes the survival of a species, and it is introduced as the socially transmitted food preference (STFP) task. The cholinergic system in the basal forebrain plays a role in the acquisition of STFP. Cannabidiol (CBD), one of the most abundant phytocannabinoids, exerts its therapeutic potential for cognitive deficits through versatile mechanisms of action, including its interaction with the cholinergic system. We hypothesize a positive relationship between CBD and STFP because acetylcholine (ACh) is involved in STFP, and CBD increases the ACh levels in the basal forebrain. Male C57BL/6J mice were trained to acquire the STFP task. We examined whether CBD affects STFP memory by administering CBD (20mg/kg, i.p.) before the STFP social training. The involvement of cholinergic system in CBD's effect on STFP was examined by knockdown of brain acetylcholinesterase (AChE), applying a nonselective muscarinic antagonist SCO (3mg/kg, i.p.) before CBD treatment, and measuring the basal forebrain ACh levels in the CBD-treated mice. We first showed that CBD enhanced STFP memory. Knockdown of brain AChE also enhanced STFP memory, which mimicked CBD's effect on STFP. SCO blocked CBD's memory-enhancing effect on STFP. Our most significant finding is that the basal forebrain ACh levels in the CBD-treated mice, but not their control counterparts, were positively correlated with mice's STFP memory performance. This study indicates that CBD enhances STFP memory in mice. Specifically, those which respond to CBD by increasing the muscarinic-mediated ACh signaling perform better in their STFP memory.