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The Direct Actions of Cannabidiol and 2-Arachidonoyl Glycerol at GABAA Receptors

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Abstract

Cannabidiol (CBD) is a major non-intoxicating component of cannabis and possesses anti-epileptic, anxiolytic and anti-hyperalgesic properties. The mechanism of action of CBD in producing such effects remains unclear. Despite evidence that some endogenous and synthetic cannabinoids interact with GABAA receptors, no-one has yet investigated the effects of CBD. Here we used two-electrode voltage clamp electrophysiology to compare the actions of CBD with those of the major central endocannabinoid, 2-arachidonoyl glycerol (2-AG) on human recombinant GABAA receptors (synaptic α1-6βg2 and extrasynaptic α4β2δ) expressed on Xenopus oocytes. CBD and 2-AG were positive allosteric modulators at α1-6βγ2 receptors, with low micromolar potencies. The maximal level of enhancement seen with either CBD or 2-AG were on α2-containing GABAA receptor subtypes, with approximately a 4-fold enhancement of the GABA EC5 evoked current, more than twice the potentiation seen with other α-subunit receptor combinations. Further we observed β-subunit selectivity, whereby modulatory activity was higher at β2/β3 over β1 subunits. The β1-subunit homologous mutant β2(V436T) substantially diminished the efficacy of both drugs to a third of that obtained with wild-type β2 subunit combinations, but without changing potency. The potency of CBD increased and efficacy preserved in binary α1/α2β2 receptors indicating that their effects do not involve the classic benzodiazepine site. Exploration of extrasynaptic α4β2δ receptors revealed that both compounds enhanced GABA EC5 evoked currents at concentrations ranging from 0.01–1 μM. Taken together these results reveal a mode of action of CBD on specifically configured GABAA receptors that may be relevant to the anticonvulsant and anxiolytic effects of the compound.

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... Interestingly, in another structure, a PIP2 molecule was found in an overlapping localization . This region has been subjected to mutational studies aimed at the identification of binding sites for endo-and phytocannabinoids (Sigel et al., 2011;Xiong et al., 2011;Bakas et al., 2017), and is thus considered to be an interaction site for both endogenous and exogenous lipophilic ligands. ...
... Assessing Candidate Binding Sites for the Phytocannabinoid Δ 9 -THC For phytocannabinoids, the literature demonstrates interactions with multiple family members (Barann et al., 2002;Oz et al., 2004;Yang et al., 2008;Yang et al., 2010;Xiong et al., 2011;Bakas et al., 2017;Schmiedhofer, 2017). Effects differ depending on the protein subtype, as well as the cannabinoid molecule. ...
... We again turned to the literature to search for evidence on binding sites, and to prioritize docking for family members with known effects. For GABA A Rs, both CBD and Δ 9 -THC have been investigated in multiple subunit combinations (Bakas et al., 2017;Schmiedhofer, 2017). Both phytocannabinoids elicit similar effects in most GABA A R subunit combinations that were tested, enhancing GABA currents in most of them and reducing currents in β1containing assemblies (Schmiedhofer, 2017). ...
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Background: Human pentameric ligand-gated ion channels (pLGICs) comprise nicotinic acetylcholine receptors (nAChRs), 5-hydroxytryptamine type 3 receptors (5-HT 3 Rs), zinc-activated channels (ZAC), γ-aminobutyric acid type A receptors (GABA A Rs) and glycine receptors (GlyRs). They are recognized therapeutic targets of some of the most prescribed drugs like general anesthetics, anxiolytics, smoking cessation aids, antiemetics and many more. Currently, approximately 100 experimental structures of pLGICs with ligands bound exist in the protein data bank (PDB). These atomic-level 3D structures enable the generation of a comprehensive binding site inventory for the superfamily and the in silico prediction of binding site properties. Methods: A panel of high throughput in silico methods including pharmacophore screening, conformation analysis and descriptor calculation was applied to a selection of allosteric binding sites for which in vitro screens are lacking. Variant abundance near binding site forming regions and computational docking complement the approach. Results: The structural data reflects known and novel binding sites, some of which may be unique to individual receptors, while others are broadly conserved. The membrane spanning domain, comprising four highly conserved segments, contains ligand interaction sites for which in vitro assays suitable for high throughput screenings are critically lacking. This is also the case for structurally more variable novel sites in the extracellular domain. Our computational results suggest that the phytocannabinoid Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC) can utilize multiple pockets which are likely to exist on most superfamily members. Conclusion: With this study, we explore the potential for polypharmacology among pLGICs. Our data suggest that ligands can display two forms of promiscuity to an extent greater than what has been realized: 1) Ligands can interact with homologous sites in many members of the superfamily, which bears toxicological relevance. 2) Multiple pockets in distinct localizations of individual receptor subtypes share common ligands, which counteracts efforts to develop selective agents. Moreover, conformational states need to be considered for in silico drug screening, as certain binding sites display considerable flexibility. In total, this work contributes to a better understanding of polypharmacology across pLGICs and provides a basis for improved structure guided in silico drug development and drug derisking.
... It has already been reported that CBD exerts its antiinflammatory and neuroprotective effects also due to its ability to activate PPARγ [17,64]. Furthermore, it is a positive allosteric modulator of GABAA receptors, thereby exerting its anticonvulsant, analgesic and anxiolytic properties [65]. However, despite all this evidence, the molecular mechanisms underlying the effects of CBD remain complex. ...
... It has already been reported that CBD exerts its anti-inflammatory and neuroprotective effects also due to its ability to activate PPARγ [17,64]. Furthermore, it is a positive allosteric modulator of GABA A receptors, thereby exerting its anticonvulsant, analgesic and anxiolytic properties [65]. However, despite all this evidence, the molecular mechanisms underlying the effects of CBD remain complex. ...
... It is known that CBD interacts with many non-endocannabinoid signaling systems such as G protein coupled-receptors, TRPV1 and PPARγ [75]. Additionally, CBD therapeutic potential possibly derives from its GABAergic modulation [65]. ...
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Cannabidiol (CBD) is a non-psychoactive phytocannabinoid known for its beneficial effects including antioxidant and anti-inflammatory properties. Moreover, CBD is a compound with antidepressant, anxiolytic, anticonvulsant and antipsychotic effects. Thanks to all these properties, the interest of the scientific community for it has grown. Indeed, CBD is a great candidate for the management of neurological diseases. The purpose of our review is to summarize the in vitro and in vivo studies published in the last 15 years that describe the biochemical and molecular mechanisms underlying the effects of CBD and its therapeutic application in neurological diseases. CBD exerts its neuroprotective effects through three G protein coupled-receptors (adenosine receptor subtype 2A, serotonin receptor subtype 1A and G protein-coupled receptor 55), one ligand-gated ion channel (transient receptor potential vanilloid channel-1) and one nuclear factor (peroxisome proliferator-activated receptor γ). Moreover, the therapeutical properties of CBD are also due to GABAergic modulation. In conclusion, CBD, through multi-target mechanisms, represents a valid therapeutic tool for the management of epilepsy, Alzheimer’s disease, multiple sclerosis and Parkinson’s disease.
... In fact, several studies have shown evidence that CBD modulates the activity of GABA A receptors reducing frequency and severity of seizure [61]. For example, Bakas et alobserved that CBD acts as a positive allosteric modulator (PAM) in many subtypes of GABA A receptors, increasing currents mediated by GABA A and reducing hyperexcitability [66]. As a PAM of GABA A receptor, CBD is capable of eliciting anticonvul- Percentages of mortality indicated that 23% of the animals from the PTZ-SAL group died, whereas the PTZ-CBD group had 10% mortality (C) incidence of seizures in the PTZ-SAL group was 92% compared to 70% of animals treated with CBD (D) with no significant differences. ...
... Percentage of seizure severity was based on type 6 seizures and show 69% for PTZ-SAL compared to 30% of the PTZ-CBD group (E) (Chi square, p < 0.0001). sant effects, and although it has low affinity for the benzodiazepine site [66], CBD shows properties similar to those of PAMs with anticonvulsant activity [55,67]. Considering that CBD treatment decreased the duration and severity of seizures induced by PTZ, we hypothesize that CBD may preferentially suppress the component that prolongs seizures by modulating the hyperexcitability and consequently shortening the temporal mechanism of the seizure duration, and diminishing their severity. ...
Article
Approximately 70% of women with epilepsy experience additional challenges in seizure exacerbation due to hormonal changes, particularly during fluctuations of estrogen-progesterone levels in the menstrual cycle, which is known as catamenial epilepsy. In animal models of epilepsy, a sustained increase in seizure frequency has been observed in female rats during the proestrus-estrus transition when estrogen levels are high and progesterone levels are low resembling catamenial epilepsy. Cannabidiol (CBD) has been proposed to have anticonvulsant and anti-inflammatory effects, able to decrease seizure duration and increase seizure threshold in rats with epilepsy. However, most studies have used males to investigate the pharmacological effects of CBD on seizures, and the neuroprotective effects of CBD against seizures exacerbated by hormonal fluctuations in females are still little explored. Given this scenario, the aim of the present study was to investigate whether CBD would protect against acute seizures induced by pentylenetetrazole (PTZ) in female rats during a pro-convulsant hormonal phase. Therefore, CBD (50 mg/kg) or saline was administered during the proestrus-estrus transition phase, 1 h prior to induction of seizures with PTZ (60 mg/kg), and the following parameters were recorded: duration, latency to first seizure, as well as percentage of convulsing animals (incidence), mortality, and severity of seizures. Brains were processed for immunohistochemistry for microglial cells (Iba-1), and blood was collected for the analysis of cytokines (IL-1b, IL-6, IL-10, and TNF-a). Cannabidiol pre-treated rats showed a significant reduction in duration and severity of seizures, and IL-1b levels, although the latency, incidence of seizures , and mortality rate remained unchanged as well the quantification of microglia in the selected areas. Therefore, acute administration of CBD in a single dose prior to seizure induction showed a partial neuroprotective effect against seizure severity and inflammation, suggesting that female rats in the pro-convulsant phase of proestrus-estrus have a low seizure threshold and are more resistant to the anticon-vulsant effects of CBD. It appears that other doses or administration windows of CBD may be required to achieve a full protective effect against seizures, suggesting that CBD could be used as an adjunctive therapy during fluctuations of estrogen-progesterone levels. In this sense, considering the hormonal fluctuation as a seizure-potentiating factor, our study contributes to understand the anticonvulsant activity of CBD in females in a pro-convulsant hormonal phase, similar to catamenial seizures in humans.
... CBD is a positive allosteric modulator (PAM) of GABA A receptors, so we explored whether CBGA exhibited similar activity Bakas et al., 2017). Using Xenopus oocytes expressing concatenated human GABA A receptors (γ2-β2-α1-β2-α1), a concentration-response curve of CBGA modulation of GABAevoked currents was generated (Figure 5d). ...
... The effects of CBGA at this array of molecular targets are also observed for CBD, suggesting a possible overlap in mechanism of action between these two cannabinoids Bakas et al., 2017;Kaplan et al., 2017;Vilela et al., 2017). CBD has been suggested to exert its anticonvulsant effects via inhibition of GPR55 Kaplan et al., 2017;Vilela et al., 2017). ...
Article
Background and purpose: Cannabis has been used to treat epilepsy for millennia, with such use validated by regulatory approval of cannabidiol (CBD) for the treatment of Dravet syndrome. Unregulated artisanal cannabis-based products used to treat children with intractable epilepsies often contain relatively low doses of CBD but are enriched in other phytocannabinoids. This raises the possibility that other cannabis constituents might have anticonvulsant properties. Experimental approach: We used the Scn1a+/- mouse model of Dravet syndrome to interrogate the cannabis plant for phytocannabinoids with anticonvulsant effects against hyperthermia-induced seizures. The most promising, cannabigerolic acid (CBGA), was further examined against spontaneous seizures and survival in Scn1a+/- mice. CBGA was also examined in conventional electroshock seizure models. In addition, we surveyed the pharmacological effects of CBGA across multiple drug targets. Key results: The initial screen identified three phytocannabinoids with novel anticonvulsant properties: CBGA, cannabidivarinic acid (CBDVA) and cannabigerovarinic acid (CBGVA). CBGA was the most potent and potentiated the anticonvulsant effects of clobazam against hyperthermia-induced and spontaneous seizures, and was anticonvulsant in the MES threshold test. However, CBGA was proconvulsant in the 6-Hz threshold test and a high dose increased spontaneous seizure frequency in Scn1a+/- mice. CBGA was found to interact with numerous epilepsy-relevant targets including GPR55, TRPV1 channels and GABAA receptors. Conclusion: These results suggest CBGA, CBDVA and CBGVA may contribute to the effects of cannabis-based products in childhood epilepsy. While these phytocannabinoids have anticonvulsant potential and could be lead compounds for drug development programs, several liabilities would need to be overcome before CBD is superseded by another in this class.
... Research indicates that CBD acts in multiple ways such as N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) binding to two G-protein-coupled receptors, cannabinoid 1 (CB 1 ) and cannabinoid 2 (CB 2 ), and thus interacting with the endocannabinoid system [170]. CBD may have positive effects on behavior issues through gamma-aminobutyric acid (GABA) signaling by acting as a positive allosteric modulator and anxiolytic effects through modulation of serotonin-1A receptor (5-HT 1A ) [175][176][177]. ...
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Autism spectrum disorders (ASD) are subdivided into idiopathic (unknown) etiology and secondary, based on known etiology. There are hundreds of causes of ASD and most of them are genetic in origin or related to the interplay of genetic etiology and environmental toxicology. Approximately 30 to 50% of the etiologies can be identified when using a combination of available genetic testing. Many of these gene mutations are either core components of the Wnt signaling pathway or their modulators. The full mutation of the fragile X mental retardation 1 (FMR1) gene leads to fragile X syndrome (FXS), the most common cause of monogenic origin of ASD, accounting for ~ 2% of the cases. There is an overlap of molecular mechanisms in those with idiopathic ASD and those with FXS, an interaction between various signaling pathways is suggested during the development of the autistic brain. This review summarizes the cross talk between neurobiological pathways found in ASD and FXS. These signaling pathways are currently under evaluation to target specific treatments in search of the reversal of the molecular abnormalities found in both idiopathic ASD and FXS. © 2020, The American Society for Experimental NeuroTherapeutics, Inc.
... AEA may interact with its channel targets at their intracellular [54,87] or extracellular side [42,48,50,51,59,61], or plug the channel pore from the cytoplasmic side as an open-channel blocker [60]. AEA has been implicated in diverse physiological and pathophysiological processes, and both AEA and another endocannabinoid 2-AG have anxiolytic, analgesic and neuroprotective effects [28,104]. Considering the importance of the endocannabinoid system in human physiology and the therapeutic implications of cannabinoids and ion channels in a vast number of medical conditions, further investigation into the molecular mechanisms underlying the interactions between different types of cannabinoids and their ion channel targets is needed for future development of novel cannabinoid-based therapeutic strategies with improved specificity. ...
Article
Endocannabinoids are a group of endogenous mediators derived from membrane lipids, which are implicated in a wide variety of physiological functions such as blood pressure regulation, immunity, pain, memory, reward, perception, reproduction, and sleep. N-Arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) represent two major endocannabinoids in the human body and they exert many of their cellular and organ system effects by activating the Gi/o protein-coupled, cannabinoid type 1 (CB1) and type 2 (CB2) receptors. However, not all effects of cannabinoids are ascribable to their interaction with CB1 and CB2 receptors; indeed, macromolecules like other types of receptors, ion channels, transcription factors, enzymes, transporters, and cellular structure have been suggested to mediate the functional effects of cannabinoids. Among the proposed molecular targets of endocannabinoids, potassium channels constitute an intriguing group, because these channels not only are crucial in shaping action potentials and controlling the membrane potential and cell excitability, thereby regulating a wide array of physiological processes, but also serve as potential therapeutic targets for the treatment of cancer and metabolic, neurological and cardiovascular disorders. This review sought to survey evidence pertaining to the CB1 and CB2 receptor-independent actions of endocannabinoids on ion channels, with an emphasis on AEA and potassium channels. To better understand the functional roles as well as potential medicinal uses of cannabinoids in human health and disease, further mechanistic studies to delineate interactions between various types of cannabinoids and ion channels, including members in the potassium channel superfamily, are warranted.
... In mutant mice of neuregulin 1 (Nrg1 HET), as genetic animal model of SCZ, CBD partially reversed the PPI impairment [162], through at least a GABA-A receptor mediated mechanism. In vitro and in vivo studies suggest that CBD may directly or indirectly modulate GABAergic transmission [163]; thus further studies are necessary to assess its involvement in the CBD effect. Peres and colleagues [156] reported that repeated adolescent CBD treatment counteracted in SHR model the development of deficits both in PPI of startle and in the contextual fear conditioning paradigm (Table 1). ...
Article
The recent shift in socio-political debates and growing liberalization of Cannabis use across the globe has raised concern regarding its impact on vulnerable populations such as adolescents. Concurrent with declining perception of Cannabis harms, more adolescents are using it daily in several countries and consuming marijuana strains with high content of psychotropic delta (9)-tetrahydrocannabinol (THC). These dual, related trends seem to facilitate the development of compromised social and cognitive performance at adulthood, which are described in preclinical and human studies. Cannabis exerts its effects via altering signalling within the endocannabinoid system (ECS), which modulates the stress circuitry during the neurodevelopment. In this context early interventions appear to circumvent the emergence of adult neurodevelopmental deficits. Accordingly, Cannabis sativa second-most abundant compound, cannabidiol (CBD), emerges as a potential treatment for neuropsychiatric disorders. We first focus on human and preclinical studies on the long-term effects induced by adolescent THC exposure as “critical window” of enhanced neurophysiological vulnerability, which could be involved in the pathophysiology of schizophrenia and related primary psychotic disorders. Then, we focus on adolescence as “window of opportunity” for early pharmacological treatment, as novel risk reduction strategy for neurodevelopmental disorders. Thus, we review current preclinical and clinical evidence regarding the efficacy of CBD in terms of positive, negative and cognitive symptoms treatment, safety profile, and molecular targets.
... Although CBD activation of TRP channels is well described in the literature [9], the upregulation and sensitization of TRP channels in an animal model of osteoarthritis may explain why CBD-induced heat hyperalgesia was not observed before and also why CBD failed to meet the desired endpoint in clinical settings [17]. Of note, CBD possesses even more favorable antinociceptive molecular targets; the antinociceptive effects of 5-HTR3A antagonists have already been described [10,18,19], similar to positive allosteric modulation of the GABAA receptor [11,20]. However, these effects may be masked through the activation of various TRP channels by CBD, as shown in the present study. ...
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Systems pharmacology employs computational and mathematical methods to study the network of interactions a drug may have within complex biological pathways. These tools are well suited for research on multitarget drugs, such as natural compounds, in diseases with complex etiologies, such as osteoarthritis (OA). The present study focuses on cannabidiol (CBD), a non-psychoactive constituent of cannabis, targeting over 60 distinct molecular targets as a potential treatment for OA, a degenerative joint disease leading to chronic pain with a neuropathic component. We successfully identified molecular targets of CBD that were relevant in the context of OA treatment with both beneficial and detrimental effects. Our findings were confirmed by in vivo and molecular studies. A key role of PPARγ in mediating the therapeutic potential of CBD was revealed, whereas upregulation of multiple transient receptor potential channels demasked CBD-induced heat hyperalgesia. Our findings pave the way for novel CBD-based therapy with improved therapeutic potential but also encourage the use of bioinformatic tools to predict the mechanism of action of CBD in different conditions. We have also created an accessible web tool for analogous analysis of CBD pharmacology in the context of any disease of interest and made it publicly available.
... Furthermore, therapies that potentiate Na V 1.1 channel function abolish seizures and reduce mortality in a mouse model of DS . It remains possible that the promiscuous target activity of the cannabinoids and terpenes in NP affects other epilepsy-relevant drug targets such as GABA A receptors (Anderson et al. 2019a;Bakas et al. 2017), G-protein coupled receptor 55 (GPR55) (Kaplan et al. 2017) and TRPV1 channels ) which overshadow any deleterious effects of Na V 1.1 channel inhibition. Alternatively, the brain concentrations of the NP might be insufficient to inhibit Nav1.1 in vivo. ...
Article
Background Purified cannabidiol (CBD), a non-psychoactive phytocannabinoid, has gained regulatory approval to treat intractable childhood epilepsies. Despite this, artisanal and commercial CBD-dominant hemp-based products continue to be used by epilepsy patients. Notably, the CBD doses used in these latter products are much lower than that found to be effective in reducing seizures in clinical trials with purified CBD. This might be because these CBD-dominant hemp products contain other bioactive compounds, including phytocannabinoids and terpenes, which may exert unique effects on epilepsy-relevant drug targets. Voltage-gated sodium (Na V ) channels are vital for initiation of neuronal action potential propagation and genetic mutations in these channels result in epilepsy phenotypes. Recent studies suggest that Na V channels are inhibited by purified CBD. However, the effect of cannabis-based products on the function of Na V channels is unknown. Methods Using automated-planar patch-clamp technology, we profile a hemp-derived nutraceutical product (NP) against human Na V 1.1–Na V 1.8 expressed in mammalian cells to examine effects on the biophysical properties of channel conductance, steady-state fast inactivation and recovery from fast inactivation. Results NP modifies peak current amplitude of the Na V 1.1–Na V 1.7 subtypes and has variable effects on the biophysical properties for all channel subtypes tested. NP potently inhibits Na V channels revealing half-maximal inhibitory concentration (IC 50 ) values of between 1.6 and 4.2 μg NP/mL. Purified CBD inhibits Na V 1.1, Na V 1.2, Na V 1.6 and Na V 1.7 to reveal IC 50 values in the micromolar range. The CBD content of the product equates to IC 50 values (93–245 nM), which are at least an order of magnitude lower than purified CBD. Unlike NP, hemp seed oil vehicle alone did not inhibit Na V channels, suggesting that the inhibitory effects of NP are independent of hemp seed oil. Conclusions This CBD-dominant NP potently inhibits Na V channels. Future study of the individual elements of NP, including phytocannabinoids and terpenes, may reveal a potent individual component or that its components interact to modulate Na V channels.
... Studies have shown cannabinoids act on different targets in the peripheral and central nervous system [130,131]. Their targets include CB1/CB2 receptors, GPR55, GPR18, Narachidonoyl glycine (NAGly) receptor, nuclear receptors, ion channels, and other potential targets in the CNS [130,132]. Furthermore, cannabinoids may also act on γ-aminobutyric acid, serotonergic, adrenergic and opioid receptors that are part of the analgesic pathway [121]. ...
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In this review, a timeline starting at the willow bark and ending in the latest discoveries of analgesic and anti-inflammatory drugs will be discussed. Furthermore, the chemical features of the different small organic molecules that have been used in pain management will be studied. Then, the mechanism of different types of pain will be assessed, including neuropathic pain, inflammatory pain, and the relationship found between oxidative stress and pain. This will include obtaining insights into the cyclooxygenase action mechanism of nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen and etoricoxib and the structural difference between the two cyclooxygenase isoforms leading to a selective inhibition, the action mechanism of pregabalin and its use in chronic neuropathic pain, new theories and studies on the analgesic action mechanism of paracetamol and how changes in its structure can lead to better characteristics of this drug, and cannabinoid action mechanism in managing pain through a cannabinoid receptor mechanism. Finally, an overview of the different approaches science is taking to develop more efficient molecules for pain treatment will be presented.
... CB1 is one the most common GPCR in the human and canine brain (Zou and Kumar, 2018;Silver, 2019). CBD has low binding affinity to the cannabinoid receptors, but is capable of modifying them and exerting effects through a diverse cornucopia of other receptors including, but not limited to: TRPV1, mTOR, PPAR, GABA, and 5HT receptors (Zador and Wollemann, 2015;O'Sullivan, 2016;Bakas et al., 2017;De Gregorio et al., 2019). The TRPV1 receptor has been implicated in many of CBD's clinical effects such as analgesia (Zador and Wollemann, 2015). ...
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Cannabidiol (CBD), the major non-psychoactive compound found in cannabis, is frequently used both as a nutraceutical and therapeutic. Despite anecdotal evidence as an anticancer agent, little is known about the effect CBD has on cancer cells. Given the intractability and poor prognoses of brain cancers in human and veterinary medicine, we sought to characterize the in vitro cytotoxicity of CBD on human and canine gliomas. Glioma cells treated with CBD showed a range of cytotoxicity from 4.9 to 8.2 μg/ml; canine cells appeared to be more sensitive than human. Treatment with >5 μg/ml CBD invariably produced large cytosolic vesicles. The mode of cell death was then interrogated using pharmacologic inhibitors. Inhibition of apoptosis was sufficient to rescue CBD-mediated cytotoxicity. Inhibition of RIPK3, a classical necroptosis kinase, also rescued cells from death and prevented the formation of the large cytosolic vesicles. Next, cellular mitochondrial activity in the presence of CBD was assessed and within 2 hours of treatment CBD reduced oxygen consumption in a dose dependent manner with almost complete ablation of activity at 10 μg/ml CBD. Fluorescent imaging with a mitochondrial-specific dye revealed that the large cytosolic vesicles were, in fact, swollen mitochondria. Lastly, calcium channels were pharmacologically inhibited and the effect on cell death was determined. Inhibition of mitochondrial channel VDAC1, but not the TRPV1 channel, rescued cells from CBD-mediated cytotoxicity. These results demonstrate the cytotoxic nature of CBD in human and canine glioma cells and suggest a mechanism of action involving dysregulation of calcium homeostasis and mitochondrial activity.
... Preclinical and clinical studies have indicated that THC and CBD may have various effects on anxiety, with THC being bi-modal (anxiolytic or anxiogenic) and CBD being considered an anxiolytic (Degroot, 2008). Based on preclinical studies, CBD may impart its anxiolytic properties through indirect modulation of the CB1 receptor (Pertwee, 2008) and enhanced anandamide levels (Bisogno et al., 2001), 5-HT 1A agonism (Zanelati et al., 2010), or through effects on GABA (Bakas et al., 2017;Jones et al., 2012). For a detailed review of possible anxiogenic mechanisms from preclinical and clinical work, see review by Blessing et al. (Blessing et al., 2015). ...
Article
Cannabidiol (CBD) has become a fast-growing avenue for research in psychiatry, and clinicians are challenged with understanding the implications of CBD for treating mental health disorders. The goal of this review is to serve as a guide for mental health professionals by providing an overview of CBD and a synthesis the current evidence within major psychiatric disorders. PubMed and PsycINFO were searched for articles containing the terms “cannabidiol” in addition to major psychiatric disorders and symptoms, yielding 2,952 articles. Only randomized controlled trials or within-subject studies investigating CBD as a treatment option for psychiatric disorders (N=16) were included in the review. Studies were reviewed for psychotic disorders (n =6), anxiety disorders (n =3), substance use disorders (tobacco n= 3, cannabis n= 2, opioid n= 1), and insomnia (n= 1). There were no published studies that met inclusion criteria for alcohol or stimulant use disorder, PTSD, ADHD, autism spectrum disorder, or mood disorders. Synthesis of the CBD literature indicates it is generally safe and well tolerated. The most promising preliminary findings are related to the use of CBD in psychotic symptoms and anxiety. There is currently not enough high-quality evidence to suggest the clinical use of CBD for any psychiatric disorder.
... A comparative study of CB 1 receptor activation on GABA A -and GABA B -mediated synaptic transmission demonstrated that activation of CB 1 receptor inhibits GABA A -mediated induced pluripotent stem cells via presynaptic mechanism [209]. The study conducted by injecting recombinant DNA into Xenopus laevis oocytes demonstrated 2-AG or CBD as a positive allosteric modulator of GABA A receptors with potency in the low micromolar range but higher efficacy in α2containing receptors [210]. However, Δ 9 -THC did not act on GABA A receptors [211]. ...
Article
Novel therapeutic strategies are needed to address depression, a major neurological disorder affecting hundreds of millions of people worldwide. Cannabinoids and their synthetic derivatives have demonstrated numerous neurological activities and may potentially be developed into new treatments for depression. This review highlights cannabinoid (CB) receptors, monoamine oxidase (MAO), N-methyl-D-aspartate (NMDA) receptor, gamma-aminobutyric acid (GABA) receptor, and cholecystokinin (CCK) receptor as key molecular targets of cannabinoids that are associated with depression. The anti-depressant activity of cannabinoids and their binding modes with cannabinoid receptors are discussed, providing insights into rational design and discovery of new cannabinoids or cannabimimetic agents with improved druggable properties.
... Another potential avenue for CBD's anti-inflammatory action could be its inhibition of voltage-dependent anion selective channel protein 1 (VDAC1) conductance, leading to a decrease in neuroinflammation (192). CBD was also found to enhance the inhibitory γ-Aminobutyric acid (GABA)'s activation of its associated GABA A receptors which regulate inhibitory neurotransmission (193) and are targeted by drugs such as clobazam; indeed, co-administration of CBD with clobazam significantly increased the inhibitory effects of GABA compared to either compound alone (194). Additionally, CBD's amplifying effects on GABA receptors could compensate for the reduced GABAergic transmission observed in FXS (195). ...
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Neurodevelopmental and neuropsychiatric disorders (such as autism spectrum disorder) have broad health implications for children, with no definitive cure for the vast majority of them. However, recently medicinal cannabis has been successfully trialled as a treatment to manage many of the patients' symptoms and improve quality of life. The cannabinoid cannabidiol, in particular, has been reported to be safe and well-tolerated with a plethora of anticonvulsant, anxiolytic and anti-inflammatory properties. Lately, the current consensus is that the endocannabinoid system is a crucial factor in neural development and health; research has found evidence that there are a multitude of signalling pathways involving neurotransmitters and the endocannabinoid system by which cannabinoids could potentially exert their therapeutic effects. A better understanding of the cannabinoids' mechanisms of action should lead to improved treatments for neurodevelopmental disorders.
... Pharmacological research suggests CBD is a partial 5-HT1a receptor agonist which supports anxiolytic and stress-reducing properties (Russo et al. 2005;Resstel et al. 2009), the activation of which has been associated with anxiolytic, antidepressant, and antipsychotic effects (Zuardi et al. 1993;Bergamaschi et al. 2011;de Faria et al. 2020; Vilazodone for major depressive disorder | MDedge Psychiatry n.d.; Newman-Tancredi and Kleven 2011). CBD also modulates specifically configured GABA A receptors that may be relevant to anxiolytic effects (Bakas et al. 2017;Deshpande et al. 2011). CBD is anxiolytic under experimental conditions in animals, healthy humans and in those with generalised social anxiety disorder (de Faria et al. 2020;Elms et al. 2019;Newman-Tancredi and Kleven 2011) although large clinical trials have not been conducted. ...
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Background: Public and medical interest in cannabidiol (CBD) has been rising, and CBD is now available from various sources. Research into the effects of low-dose CBD on outcomes like stress, anxiety, and sleep problems have been scarce, so we conducted an online survey of CBD users to better understand patterns of use, dose, and self-perceived effects of CBD. Methods: The sample consisted of 387 current or past-CBD users who answered a 20-question online survey. The survey was sent out to CBD users through email databases and social media. Participants reported basic demographics, CBD use patterns, reasons for use, and effects on anxiety, sleep, and stress. Results: The sample (N = 387) consisted of 61.2% females, mostly between 25 and 54 years old (72.2%) and primarily based in the UK (77.4%). The top 4 reasons for using CBD were self-perceived anxiety (42.6%), sleep problems (42.5%), stress (37%), and general health and wellbeing (37%). Fifty-four per cent reported using less than 50 mg CBD daily, and 72.6% used CBD sublingually. Adjusted logistic models show females had lower odds than males of using CBD for general health and wellbeing [OR 0.45, 95% CI 0.30-0.72] and post-workout muscle-soreness [OR 0.46, 95%CI 0.24-0.91] but had higher odds of using CBD for self-perceived anxiety [OR 1.60, 95% CI 0.02-2.49] and insomnia [OR 1.87, 95% CI 1.13-3.11]. Older individuals had lower odds of using CBD for general health and wellbeing, stress, post-workout sore muscles, anxiety, skin conditions, focusing, and sleep but had higher odds of using CBD for pain. Respondents reported that CBD use was effective for stress, sleep problems, and anxiety in those who used the drug for those conditions. Conclusion: This survey indicated that CBD users take the drug to manage self-perceived anxiety, stress, sleep, and other symptoms, often in low doses, and these patterns vary by demographic characteristics. Further research is required to understand how low doses, representative of the general user, might impact mental health symptoms like stress, anxiety, and sleep problems.
... Moreover, 2-AG acts at this receptor isoform in a superadditive manner with neurosteroids and diazepam and it is able to modulate α1β2δ receptors, in which γ2 is replaced by δ subunit. Bakas et al. [64] identified CBD as a positive allosteric modulator of GABA A Rs regardless of α subunit compositions, albeit it exhibits higher efficacy at receptors containing the α2 subunit. The study has been also carried out in parallel on 2-AG. ...
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Cannabidiol (CBD), the major nonpsychoactive Cannabis constituent, has been proposed for the treatment of a wide panel of neurological and neuropsychiatric disorders, including anxiety, schizophrenia, epilepsy and drug addiction due to the ability of its versatile scaffold to interact with diverse molecular targets that are not restricted to the endocannabinoid system. Albeit the molecular mechanisms responsible for the therapeutic effects of CBD have yet to be fully elucidated, many efforts have been devoted in the last decades to shed light on its complex pharmacological profile. In particular, an ever-increasing number of molecular targets linked to those disorders have been identified for this phytocannabinoid, along with the modulatory effects of CBD on their cascade signaling. In this view, here we will try to provide a comprehensive and up-to-date overview of the molecular basis underlying the therapeutic effects of CBD involved in the treatment of neurological and neuropsychiatric disorders.
... With regard to brain neurochemistry in clinical trials, CBD reduction in SAD was associated with increased blood flow in the limbic and paralimbic brain areas [84]. CBD is anxiolytic through direct binding of the GABA A receptor and activating the GABAnergic pathway [85][86][87]. CBD also bind to the NGF receptor, TRKA which signals the ERK1/2 signal transduction pathway and stimulates neurite outgrowth in PC12 cells [88]. Indeed the mechanism of action of CBD is recognized to help with the neuronal plasticity through autophagy and neuritogenesis and may help not only with anxiety, but also with other psychiatric disorders [88,89]. ...
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Diet impacts anxiety in two main ways. First anxiety can be caused by deficiencies in antioxidants, neurotransmitter precursors, amino acids, cations and vitamins and other cofactors. Second, anxiety can be reduced by anxiolytic nutraceuticals which are food molecules that bind to molecular targets of the amygdala and the hypothalamus-pituitary–adrenal axis (HPA-axis). Anxiety is a feeling of fear that arises from a perceived threat and can be a beneficial coping mechanism to threats and stressors. However excessive anxiety is a disorder that interferes with healthy responses to stressors. The amygdala is responsible for assigning value to a threat or stressor and triggering the HPA-axis to support the body wide system responses to the threat. The amygdala also communicates with the neuroplastic learning and memory centers of the hippocampus to fix or set a learned value to the threat. Interestingly, many anxiolytic nutraceuticals that show benefits in human clinical trials have neurotrophic activity and increase neuronal plasticity. Moreover, anxiolytic nutraceuticals either act like the neurotrophins, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF and neurotrophin-3 (NT3) by either directly binding to or potentiating the tyrosine receptor kinase (TRK) family of receptors (TRKA, TRKB and TRKC) and activating the ERK1/2 signal transduction pathway associated with neurite outgrowth and neural plasticity. This chapter will explore the neuritogenic activity of clinically proven plant-based anxiolytic nutraceuticals and examine the commonality of TRKA-C receptors and the ERK1/2 signaling pathway in the pharmacological and nutraceutical treatment of anxiety disorders.
... Furthermore, CBD can act as an agonist of vanilloid receptor TRPV1 and therefore influences pain perception, inflammation (Costa et al., 2004). Beyond that, CBD is also known to have affinity for glycine (Ahrens et al., 2009), GABA A (Bakas et al., 2017), adenosine A1 (Gonca and Darıcı, 2015) and nuclear receptors (Scuderi et al., 2014). ...
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Major depressive disorder is a high-impact, debilitating disease and it is currently considered the most prevalent mental illness. It is associated with disability, as well as increased morbidity and mortality. Despite its significant repercussions in our society, its exact pathophysiology remains unclear and therefore, available antidepressant treatment options are limited and, in some cases, ineffective. In the past years, research has focused on the development of a multifactorial theory of depression. Simultaneously, evidence supporting the role of the endocannabinoid system in the neurobiology of neuropsychiatric diseases has emerged. Studies have shown that the endocannabinoid system strongly impacts neurotransmission, and the neuroendocrine and neuroimmune systems, which are known to be dysfunctional in depressive patients. Accordingly, common antidepressants were shown to have a direct impact on the expression of cannabinoid receptors throughout the brain. Therefore, the relationship between the endocannabinoid system and major depressive disorder is worth consideration. Nevertheless, most studies focus on smaller pieces of what is undoubtedly a larger mosaic of interdependent processes. Therefore, the present review summarizes the existing literature regarding the role of the endocannabinoid system in depression aiming to integrate this information into a holistic picture for a better understanding of the relationship between the two.
... However, olivetolic acid had modest anticonvulsant effects in Scn1a +/mice but was also ineffective at these molecular targets implying the importance of other targets with this ligand. Future studies could examine the effects of olivetolic acid at alternate epilepsy-relevant targets common to CBD and CBGA such as GABA A receptors, TRPV1 and voltage-gated sodium channels (Anderson et al. 2019a;2021;Bakas et al. 2017;Ghovanloo et al. 2018;Gray and Whalley 2020;Iannotti et al. 2014). Alternatively, the anticonvulsant efficacy could be the effect of an active metabolite. ...
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Objective: Cannabigerolic acid (CBGA), a precursor cannabinoid in Cannabis sativa, has recently been found to have anticonvulsant properties in the Scn1a+/- mouse model of Dravet syndrome. Poor brain penetration and chemical instability of CBGA limits its potential as an anticonvulsant therapy. Here, we examined whether CBGA methyl ester, a more stable analogue of CBGA, might have superior pharmacokinetic and anticonvulsant properties. In addition, we examined whether olivetolic acid, the biosynthetic precursor to CBGA with a truncated (des-geranyl) form, might possess minimum structural requirements for anticonvulsant activity. We also examined whether olivetolic acid and CBGA methyl ester retain activity at the epilepsy-relevant drug targets of CBGA: G-protein-coupled receptor 55 (GPR55) and T-type calcium channels. Methods: The brain and plasma pharmacokinetic profiles of CBGA methyl ester and olivetolic acid were examined following 10 mg/kg intraperitoneal (i.p.) administration in mice (n = 4). The anticonvulsant potential of each was examined in male and female Scn1a+/- mice (n = 17-19) against hyperthermia-induced seizures (10-100 mg/kg, i.p.). CBGA methyl ester and olivetolic acid were also screened in vitro against T-type calcium channels and GPR55 using intracellular calcium and ERK phosphorylation assays, respectively. Results: CBGA methyl ester exhibited relatively limited brain penetration (13%), although somewhat superior to that of 2% for CBGA. No anticonvulsant effects were observed against thermally induced seizures in Scn1a+/- mice. Olivetolic acid also showed poor brain penetration (1%) but had a modest anticonvulsant effect in Scn1a+/- mice increasing the thermally induced seizure temperature threshold by approximately 0.4°C at a dose of 100 mg/kg. Neither CBGA methyl ester nor olivetolic acid displayed pharmacological activity at GPR55 or T-type calcium channels. Conclusions: Olivetolic acid displayed modest anticonvulsant activity against hyperthermia-induced seizures in the Scn1a+/- mouse model of Dravet syndrome despite poor brain penetration. The effect was, however, comparable to the known anticonvulsant cannabinoid cannabidiol in this model. Future studies could explore the anticonvulsant mechanism(s) of action of olivetolic acid and examine whether its anticonvulsant effect extends to other seizure types.
... PB is a barbiturate that facilitates neuronal hyperpolarization acting as an allosteric modulator of GABA A receptor that prolongs the amount of time the chloride ion channel is open [41]. It is possible that CBD did not modify the PB effects because it induces a similar effect, i.e., this phytocannabinoid also acts as a positive allosteric modulator of GABA A receptors [42]. ...
Article
Purpose : To evaluate the effects of cannabidiol alone or in combination with antiseizure drugs in the expression of recurrent generalized seizures in a rat model. Methods : Group A: Male Wistar rats received 3-mercaptopropionic acid (MP) every 12 h for 5 days to induce recurrent generalized seizures. Thereafter, the animals were submitted to a crossover protocol to receive different treatments with cannabidiol, phenytoin and phenobarbital, alone and in combination. Group B: Rats were manipulated as group A, but they received cannabidiol during the induction of recurrent seizures. Results : Minor and major seizures were induced after each MP administration. Status epilepticus (SE) detected during the last MP administrations was considered a sign of high seizure severity. Cannabidiol did not modify the expression of the MP induced seizures but reduced the prevalence of SE in both experimental groups. Phenytoin decreased the expression of major seizures but did not modify the prevalence of SE (groups A and B). Cannabidiol combined with phenytoin did not modify these effects. Phenobarbital diminished the expression of major seizures, an effect more evident when combined with cannabidiol (groups A and B). The combination of phenobarbital and cannabidiol reduced the expression of SE of group B. The mortality rate of groups A and B at the end of the crossover protocol was 30% and 9%, respectively (p=0.2). Conclusion : CBD associated with appropriate antiseizure drugs reduces the severity and prevalence of generalized seizures. In contrast, CBD alone reduces the seizure severity, but does not avoid the expression of generalized seizures.
... (As a net effect, CBD, unlike THC, restrains rather than activates CB1 receptor signaling, and therefore does not induce the psychoactive effects of THC.) CBD also directly acts as positive allosteric modulator at various GABA A receptor subtypes. 6 Moreover, CBD exerts action on receptors that mediate pain signaling and inflammation, and one of the main CBD targets is at least one receptor for the neurotransmitter serotonin, the 5HT 1A receptor. 7 Furthermore, CBD seems to bind to an orphan GPCR called GPR55, potentially mediating its antiepileptic effects. ...
Article
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The use of cannabis as a drug has undergone a remarkable change of direction: considered as a symbol of countercultures in past decades, it is presently being hailed as a cure for any number of diseases and conditions. Thus, despite concerns about the safety of cannabis and cannabinoids, quite a few drugs that contain cannabinoids have recently been approved by several drug agencies, and the medicinal and recreational use of cannabis has been legalized in various countries and states. The promise of cannabinoids for therapeutic use, as well as potentially detrimental health risks and regulatory issues, will need to be carefully weighed. .
... Bakas and colleagues also identified CBD as a positive allosteric modulator of c-aminobutyric acid type A (GABAA) receptors (Bakas et al., 2017), which could account for its anti-seizure, anxiolytic and analgesic effects. CBD potentiates glycine currents (Ahrens et al., 2009) by acting as a positive allosteric modulator, possibly at a1 glycine receptors. ...
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The European Commission has determined that cannabidiol (CBD) can be considered as a novel food (NF), and currently, 19 applications are under assessment at EFSA. While assessing these, it has become clear that there are knowledge gaps that need to be addressed before a conclusion on the safety of CBD can be reached. Consequently, EFSA has issued this statement, summarising the state of knowledge on the safety of CBD consumption and highlighting areas where more data are needed. Literature searches for both animal and human studies have been conducted to identify safety concerns. Many human studies have been carried out with Epidyolex®, a CBD drug authorised to treat refractory epilepsies. In the context of medical conditions, adverse effects are tolerated if the benefit outweighs the adverse effect. This is, however, not acceptable when considering CBD as a NF. Furthermore, most of the human data referred to in the CBD applications investigated the efficacy of Epidyolex (or CBD) at therapeutic doses. No NOAEL could be identified from these studies. Given the complexity and importance of CBD receptors and pathways, interactions need to be taken into account when considering CBD as a NF. The effects on drug metabolism need to be clarified. Toxicokinetics in different matrices, the half-life and accumulation need to be examined. The effect of CBD on liver, gastrointestinal tract, endocrine system, nervous system and on psychological function needs to be clarified. Studies in animals show significant reproductive toxicity, and the extent to which this occurs in humans generally and in women of child-bearing age specifically needs to be assessed. Considering the significant uncertainties and data gaps, the Panel concludes that the safety of CBD as a NF cannot currently be established.
... On the other hand, stimulation of the tooth pulp and URB597 caused changes in the expression of CB2R mRNA only in the hypothalamus, where downregulation of CB2R expression in response to URB597 administration compared to the control was observed. This may be because the signaling of CB1 and CB2 receptors is pleiotropic and it is difficult to activate these receptors directly without affecting other receptors, such as TRPV1 [40][41][42], PPARy [43,44], GABA A [45][46][47], Adenosine A3 [48] and GPR55 [43,49], by binding to endocannabinoids, which can exert physiological effects. Moreover, CB receptors form both homo-and heterodimers and undergo allosteric modulation, which correlates with the receptor functionality and anatomical localization [50][51][52]. ...
Article
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Endocannabinoids act as analgesic agents in a number of headache models. However, their effectiveness varies with the route of administration and the type of pain. In this study, we assessed the role of the fatty acid amide hydrolase inhibitor URB597 in an animal model of orofacial pain based on tooth pulp stimulation. More specifically, we assessed the effects of intracerbroventricular (i.c.v.) and intraperitoneal (i.p.) administration of URB597 on the amplitude of evoked tongue jerks (ETJ) in rats. The levels of the investigated mediators anandamide (AEA), 2-arachidonyl glycerol (2-AG), Substance P (SP), calcitonin-gene-related peptide (CGRP), endomorphin-2 (EM-2) and fatty acid amide hydrolase (FAAH) inhibitor by URB597 and receptors cannabinoid type-1 receptors (CB1R), cannabinoid type-2 receptors (CB2R) and µ-opioid receptors (MOR) were determined in the mesencephalon, thalamus and hypothalamus tissues. We have shown that increasing endocannabinoid AEA levels by both central and peripheral inhibition of FAAH inhibitor by URB597 has an antinociceptive effect on the trigemino-hypoglossal reflex mediated by CB1R and influences the activation of the brain areas studied. On the other hand, URB597 had no effect on the concentration of 2-AG in the examined brain structures and caused a significant decrease in CB2R mRNA expression in the hypothalamus only. Tooth pulp stimulation caused in a significant increase in SP, CGRP and EM-2 gene expression in the midbrain, thalamus and hypothalamus. In contrast, URB597 administered peripherally one hour before stimulation decreased the mRNA level of these endogenous neuropeptides in comparison with the control and stimulation in all examined brain structures. Our results show that centrally and peripherally administered URB597 is effective at preventing orofacial pain by inhibiting AEA catabolism and reducing the level of CGRP, SP and EM-2 gene expression and that AEA and 2-AG have different species and model-specific regulatory mechanisms. The data presented in this study may represent a new promising therapeutic target in the treatment of orofacial pain.
... More recently, an electrophysiological study comparing the actions of CBD and 2-AG on human recombinant GABA(A) receptors expressed on Xenopus oocytes showed that CBD acts as a positive allosteric modulator at GABA(A) receptors containing α2 subunits. This study supported the fact that the site of action of CBD is different from the classic BZD site [90]. Altogether the results obtained suggest that the effects of CBD on GABAergic neurotransmission may be a potential target for its anxiolytic and antidepressant properties that deserve to be explored in future studies. ...
Article
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The anxiolytic and antidepressant properties of cannabidiol (CBD) have been evaluated in several studies. However, the molecular mechanisms involved in these actions remain unclear. A total of 130 male mice were used. CBD’s ability to modulate emotional disturbances (anxiety and depressive-like behaviors) was evaluated at different doses in wild-type (CD1; 10, 20 and 30 mg/kg; i.p.) and knockout (CB1KO, CB2KO; GPR55KO; 20 mg/kg) mice. Moreover, CBD effects (20 mg/kg; i.p.) were evaluated in mice previously treated with the CB1r-antagonist SR141716A (2mg/kg; i.p.). Relative gene expression analyses of Cnr1 and Cnr2, Gpr55 and GABA(A)α2 and γ2 receptor subunits were performed in the amygdala (AMY) and hippocampus (HIPP) of CD1 mice. CBD (10 and 20 mg/kg) showed anxiolytic and antidepressant actions in CD1 mice, being more effective at 20 mg/kg. Its administration did not induce anxiolytic actions in CB1KO mice, contrary to CB2KO and GPR55KO. In all of them, the lack of cannabinoid receptors did not modify the antidepressant activity of CBD. Interestingly, the administration of the CB1r antagonist SR141716A blocked the anxiolytic-like activity of CBD. Real-time PCR studies revealed a significant reduction in Cnr1 and GABA(A)α2 and γ2 gene expression in the HIPP and AMY of CD1 mice treated with CBD. Opposite changes were observed in the Cnr2. Indeed, Gpr55 was increased in the AMY and reduced in the HIPP. CB1r appears to play a relevant role in modulating the anxiolytic actions of CBD. Moreover, this study revealed that CBD also modified the gene expression of GABA(A) subunits α2 and γ2 and CB1r, CB2r and GPR55, in a dose- and brain-region-dependent manner, supporting a multimodal mechanism of action for CBD.
... In fact, some authors have proposed that CBD may act on GABAergic and glutamatergic systems indirectly, but not exclusively, through its direct action on different targets of the ECS, serotonergic or opioid systems [205]. However, recent in vitro [206] and in vivo [207] studies suggested that CBD modulates the GABAergic system by acting directly on GABA A receptors. Consequently, the effects of CBD on the GABAergic circuits may be the result of both direct and indirect modulation of this system. ...
Article
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The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD displays an interesting pharmacological profile without the potential for becoming a drug of abuse, unlike THC. In this review, we focused on the anxiolytic, antidepressant, and antipsychotic effects of CBD found in animal and human studies. In rodents, results suggest that the effects of CBD depend on the dose, the strain, the administration time course (acute vs. chronic), and the route of administration. In addition, certain key targets have been related with these CBD pharmacological actions, including cannabinoid receptors (CB1r and CB2r), 5-HT1A receptor and neurogenesis factors. Preliminary clinical trials also support the efficacy of CBD as an anxiolytic, antipsychotic, and antidepressant, and more importantly, a positive risk-benefit profile. These promising results support the development of large-scale studies to further evaluate CBD as a potential new drug for the treatment of these psychiatric disorders.
... Moreover, CBD is an antagonist for TRPM8 with an IC50 approximately 80 nM [31,32] and negative allosteric modulator for serotonin receptor 5HT3a (IC50 = 600 nM, [36]) and α7 nicotinic acetylcholine receptor (IC50 = 11,300 nM, [37]), which are also selective for positively charged ions. On the other hand, CBD is also a positive allosteric modulator in micromolar concentration ranges for anionic ligand-gated ion channels, such as GABA A [38] and glycine receptors (GlyRs) [39]. CBD also inhibits cationic currents through voltage gated calcium channels Cav3.1 and Cav3.2 with IC50 approximately 800 nM [40] and voltage-gated sodium channels and Cav3.3 with IC50 approximately 3000 nM [40,41]. ...
Article
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Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not to be responsible for psychotropic effects of cannabis. Numerous anecdotal findings testify to the therapeutic effects of CBD, which in some cases were further supported by research findings. However, data regarding CBD’s mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding molecular mechanism of CBD’s action with particular focus on its analgesic potential. Moreover, this article describes the detailed analgesic and anti-inflammatory effects of CBD in various models, including neuropathic pain, inflammatory pain, osteoarthritis and others. The dose and route of the administration-dependent effect of CBD, on the reduction in pain, hyperalgesia or allodynia, as well as the production of pro and anti-inflammatory cytokines, were described depending on the disease model. The clinical applications of CBD-containing drugs are also mentioned. The data presented herein unravel what is known about CBD’s pharmacodynamics and analgesic effects to provide the reader with current state-of-art knowledge regarding CBD’s action and future perspectives for research.
... The understanding of the pharmacological effects of CBD in CNS is still incomplete. Notwithstanding, recent scientific reports regarding the application of cannabis-derived constituents in different neurological disorders, show the important role of CBD in CNS, including the modulation of γ-aminobutyric acid type A receptors (GABA A Rs) both directly and through the activation of CB1 and CB2 [63,64]. As shown in Figure 3, CBD targets (including other cannabis-derived constituents, such as THC or CBDV) are placed both at the presynaptic and postsynaptic membranes. ...
Article
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As the major nonpsychotropic constituent of Cannabis sativa, cannabidiol (CBD) is regarded as one of the most promising therapeutic agents due to its proven effectiveness in clinical trials for many human diseases. Due to the urgent need for more efficient pharmacological treatments for several chronic diseases, in this review, we discuss the potential beneficial effects of CBD for Alzheimer’s disease, epilepsy, multiple sclerosis, and neurological cancers. Due to its wide range of pharmacological activities (e.g., antioxidant, anti-inflammatory, and neuroprotective properties), CBD is considered a multimodal drug for the treatment of a range of neurodegenerative disorders, and various cancer types, including neoplasms of the neural system. The different mechanisms of action of CBD are here disclosed, together with recent progress in the use of this cannabis-derived constituent as a new therapeutic approach.
... In earlier studies, CBD, in the concentration range of 1-30 μM, has been shown to modulate the functions of ligandgated ion channels including nicotinic α 7 (Mahgoub et al., 2013), 5-HT 3 (Yang et al., 2010), glycine (Ahrens et al., 2009), and GABA A (Bakas et al., 2017) receptors as well as voltage-gated Na + (Ghovanloo et al., 2018), L-type Ca 2+ (Ali et al., 2015), T-type Ca 2+ (Ross et al., 2008) and K + (Orvos et al., 2020) channels. Drugs interacting with such a large repertoire of ion channels can legitimately be suspected to cause cardiac safety concerns due to their arrhythmogenic potential. ...
Article
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Cannabidiol (CBD), a major non-psychotropic cannabinoid found in the Cannabis plant, has been shown to exert anti-nociceptive, anti-psychotic, and anti-convulsant effects and to also influence the cardiovascular system. In this study, the effects of CBD on major ion currents were investigated using the patch-clamp technique in rabbit ventricular myocytes. CBD inhibited voltage-gated Na ⁺ and Ca ²⁺ channels with IC 50 values of 5.4 and 4.8 µM, respectively. In addition, CBD, at lower concentrations, suppressed ion currents mediated by rapidly and slowly activated delayed rectifier K ⁺ channels with IC 50 of 2.4 and 2.1 µM, respectively. CBD, up to 10 μM, did not have any significant effect on inward rectifier I K1 and transient outward I to currents. The effects of CBD on these currents developed gradually, reaching steady-state levels within 5–8 min, and recoveries were usually slow and partial. Hill coefficients higher than unity in concentration-inhibition curves suggested multiple CBD binding sites on these channels. These findings indicate that CBD affects cardiac electrophysiology by acting on a diverse range of ion channels and suggest that caution should be exercised when CBD is administered to carriers of cardiac channelopathies or to individuals using drugs known to affect the rhythm or the contractility of the heart.
... CBD is the non-psychotropic component of marijuana, and there are numerous therapeutic effects of this drug including treatment of anxiety, pain, nausea, and motor deficits including the tremor in Parkinson's disease [116]. CBD has both neuromodulatory and neuroprotective effects through a number of mechanisms including blocking neuroinflammation and potentiating anti-inflammatory pathways, improving mitochondrial function, GABA A agonist potentiation, stimulation of 5HT 1A receptors, and enhancing levels of anandamide (AEA) [116][117][118][119]. ...
Article
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While behavioral interventions remain the mainstay of treatment of autism spectrum disorder (ASD), several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years. These are promising for the potential to, in future, become part of the mainstay treatment in addressing the core symptoms of ASD. Although it is likely that the development of future targeted treatments will be influenced by the underlying heterogeneity in etiology, associated genetic mechanisms influencing ASD are likely to be the first targets of treatments and even gene therapy in the future for ASD. In this article, we provide a review of current psychopharmacological treatment in ASD including those used to address common comorbidities of the condition and upcoming new targeted approaches in autism management. Medications including metformin, arbaclofen, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, and dietary supplements including sulforophane and N-acetylcysteine are discussed. Commonly used medications to address the comorbidities associated with ASD including atypical antipsychotics, serotoninergic agents, alpha-2 agonists, and stimulant medications are also reviewed. Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD.
... CBD has a pharmacological profile like atypical antipsychotic drugs and inhibits the FAAH enzyme increasing the levels of AEA [99,[224][225][226]. High level of AEA was linked to reduced stress, anxiety, and depression. Other mechanisms of canabidiol anxiolytic effect may be activation of metabotropic receptors for serotonin or adenosine and interaction with TRPV1, GABA A and PPAR receptors [226][227][228][229][230]. CBD has demonstrated efficacy in animal models of anxiety and stress [231][232][233][234]. Preclinical data strongly suggest that CBD has a potential as therapy for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder as well as prevention of the longterm anxiogenic effects of stress [235][236][237]. ...
Article
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Autism spectrum disorder (ASD) is a group of disabilities with impairments in physical, verbal, and behavior areas. Regardless the growing frequency of autism, no medicine has been formed for the management of the ASD primary symptoms. The most frequently prescribed drugs are off-label. Therefore, there is necessity for an advance tactic for the treatment of autism. The endocannabinoid system has a central role in ruling emotion and social behaviors. Dysfunctions of the system donate to the behavioral deficits in autism. Therefore, the endocannabinoid system represents a potential target for the development of a novel autism therapy. Cannabis and associated compounds have produced substantial research attention as a capable therapy in neurobehavioral and neurological syndromes. In this review we examine the potential benefits of medical cannabis and related compounds in the treatment of ASD and concurrent disorders
... It has been ascertained that CBD exhibits activity at some additional receptors, including the type 2 dopamine receptor (D2R; partial agonist) (Seeman, 2016), mu-and delta-opioid receptors (negative allosteric modulator) (Kathmann et al., 2006), γ-Aminobutyric acid (GABA) type A receptor (positive allosteric modulator) (Bakas et al., 2017), Glycine α3 receptors (GlyR; positive allosteric modulator) (Xiong et al., 2011), type 1 dopamine receptor (D1R) , and α7-nicotinic receptors in CA1 (Mahgoub et al., 2013). Accordingly, CBD decreases μ-opioid (Oprm1) gene expression in the NAc (Viudez-Martínez et al., 2018), underlining its potential role in treating opioid use disorder. ...
Article
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Background Cannabidiol (CBD) is one of the major constituents of Cannabis sativa L. that lacks psychotomimetic and rewarding properties and inhibits the rewarding and reinforcing effects of addictive drugs such as cocaine, methamphetamine (METH), and morphine. Additionally, CBD's safety profile and therapeutic potential are currently evaluated in several medical conditions, including pain, depression, movement disorders, epilepsy, multiple sclerosis, Alzheimer's disease, ischemia, and substance use disorder. There is no effective treatment for substance use disorders such as addiction, and this review aims to describe preclinical and clinical investigations into the effects of CBD in various models of opioid, psychostimulant, cannabis, alcohol, and nicotine abuse. Furthermore, the possible mechanisms underlying the therapeutic potential of CBD on drug abuse disorders are reviewed. Methods The current review considers and summarizes the preclinical and clinical investigations into CBD's effects in various models of drug abuse include opioids, psychostimulants, cannabis, alcohol, and nicotine. Results Several preclinical and clinical studies have proposed that CBD may be a reliable agent to inhibit the reinforcing and rewarding impact of drugs. Conclusions While the currently available evidence converges to suggest that CBD could effectively reduce the rewarding and reinforcing effects of addictive drugs, more preclinical and clinical studies are needed before CBD can be added to the therapeutic arsenal for treating addiction.
Article
The full understanding of the real therapeutic potential of cannabis preparations and of the dangers that their recreational use pose can only stem from the assessment of the chemical composition of such preparations and the knowledge of the pharmacology of their main components, the cannabinoids. Much in the same way cannabis is not just one plant, cannabinoids were not made all equal, and profound differences exist between the pharmacological properties of Δ9-tetrahydrocannabinol (Δ9-THC), the most abundant euphoric and psychotropic cannabinoid, and the other over one hundred natural products belonging to the same class of compounds. So far, only the bioactivity of Δ9-THC, the main component of marijuana, and a handful of cannabinoids, including cannabidiol (CBD), the most abundant cannabinoid in industrial varieties of cannabis, has been thoroughly investigated. While pharmacological studies on Δ9-THC led to the discovery of cannabinoid receptors, endocannabinoids (eCBs) and the endocannabinoid (eCB) system, which underlie most of the effects of this compound in mammals, the mechanisms of action of CBD and other non-euphoric cannabinoids are much more complex and are based on several molecular targets, including, but not limited to, the proteins (receptors and enzymes) of the “expanded eCB system,” or “endocannabinoidome” (eCBome), and hence on their capability of modulating the actions or tissue concentrations of eCB-related lipid mediators. In this article, we discuss to what extent the pharmacology of cannabinoids, and of Δ9-THC and CBD in particular, can be explained by the existence of the eCB system and the eCBome.
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Cannabinoid-based medications possess unique multimodal analgesic mechanisms of action, modulating diverse pain targets. Cannabinoids are classified based on their origin into three categories: endocannabinoids (present endogenously in human tissues), phytocannabinoids (plant derived) and synthetic cannabinoids (pharmaceutical). Cannabinoids exert an analgesic effect, peculiarly in hyperalgesia, neuropathic pain and inflammatory states. Endocannabinoids are released on demand from postsynaptic terminals and travels retrograde to stimulate cannabinoids receptors on presynaptic terminals, inhibiting the release of excitatory neurotransmitters. Cannabinoids (endogenous and phytocannabinoids) produce analgesia by interacting with cannabinoids receptors type 1 and 2 (CB1 and CB2), as well as putative non-CB1/CB2 receptors; G protein-coupled receptor 55, and transient receptor potential vanilloid type-1. Moreover, they modulate multiple peripheral, spinal and supraspinal nociception pathways. Cannabinoids-opioids cross-modulation and synergy contribute significantly to tolerance and antinociceptive effects of cannabinoids. This narrative review evaluates cannabinoids’ diverse mechanisms of action as it pertains to nociception modulation relevant to the practice of anesthesiologists and pain medicine physicians.
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Cannabidiol is claimed to bind to a large number of protein targets based on in vitro assays. This suggests opportunities for a wide range of therapeutic applications. On the other hand, the existence of phytochemical 'nuisance compounds' suggests some measure of caution - these compounds are capable of altering membrane biophysical properties and changing protein function without directly contacting a binding site. Like cannabidiol, cholesterol alters membrane properties, but it also binds directly to membrane proteins through abundant cholesterol recognition sites. We present the evidence that cannabidiol and cholesterol may bind to the same site on some proteins. As a starting point for further research, we also used blind docking to show that cannabidiol binds to a cholesterol binding site on the CB1 receptor. Elucidation of the mechanism(s) of action of cannabidiol will assist the prioritisation of in vitro hits across targets, improve the success rate of medicinal chemistry campaigns, and ultimately benefit patient populations by focusing resources on programs with the most translational potential.
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Cannabidiol, approved for treatment of pediatric refractory epilepsy, has anti-seizure effects in various animal seizure models. Chemical warfare nerve agents, including soman, are organophosphorus chemicals that can induce seizure and death if untreated or if treatment is delayed. Our objective was to evaluate whether cannabidiol would ameliorate soman-induced toxicity using a mouse model that similar to humans lacks plasma carboxylesterase. In the present study, adult female plasma carboxylesterase knockout (Es1-/-) mice were pre-treated with cannabidiol (20−150 mg/kg) or vehicle 1 h prior to exposure to a seizure-inducing dose of soman and evaluated for survival and seizure activity. The muscarinic antagonist atropine sulfate and the oxime HI-6 were administered at 1 min after exposure, and the benzodiazepine midazolam was administered at 30 min after seizure onset. Cannabidiol (150 mg/kg) pre-treatment led to a robust increase in survival rate and attenuated body weight loss in soman-exposed mice treated with medical countermeasures, compared to mice pre-treated with vehicle. In addition, mice pretreated with cannabidiol (150 mg/kg) had a modest reduction in seizure severity after midazolam treatment compared to vehicle-pretreated. These findings of improved outcome with cannabidiol administration in a severe seizure model of soman exposure provide additional pre-clinical support for the benefits of cannabidiol against exposure to seizure-inducing chemical agents and suggest cannabidiol may augment the anti-seizure effects of midazolam.
Article
The therapeutic potential of cannabidiol (CBD) in seizure disorders has been known for many years, but it is only in the last decade that major progress has been made in characterizing its preclinical and clinical properties as an antiseizure medication. The mechanisms responsible for protection against seizures are not fully understood, but they are likely to be multifactorial and to include, among others, antagonism of G protein-coupled receptor, desensitization of transient receptor potential vanilloid type 1 channels, potentiation of adenosine-mediated signaling, and enhancement of GABAergic transmission. CBD has a low and highly variable oral bioavailability, and can be a victim and perpetrator of many drug-drug interactions. A pharmaceutical-grade formulation of purified CBD derived from Cannabis sativa has been evaluated in several randomized placebo-controlled adjunctive-therapy trials, which resulted in its regulatory approval for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Interpretation of results of these trials, however, has been complicated by the occurrence of an interaction with clobazam, which leads to a prominent increase in the plasma concentration of the active metabolite N-desmethylclobazam in CBD-treated patients. Despite impressive advances, significant gaps in knowledge still remain. Areas that require further investigation include the mechanisms underlying the antiseizure activity of CBD in different syndromes, its pharmacokinetic profile in infants and children, potential relationships between plasma drug concentration and clinical response, interactions with other co-administered medications, potential efficacy in other epilepsy syndromes, and magnitude of antiseizure effects independent from interactions with clobazam. This article is part of the special issue on ‘Cannabinoids’.
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The non-psychoactive component of Cannabis Sativa, cannabidiol (CBD), has centered the attention of a large body of research in the last years. Recent clinical trials have led to the FDA approval of CBD for the treatment of children with drug-resistant epilepsy. Even though it is not yet in clinical phases, its use in sleep-wake pathological alterations has been widely demonstrated.Despite the outstanding current knowledge on CBD therapeutic effects in numerous in vitro and in vivo disease models, diverse questions still arise from its molecular pharmacology. CBD has been shown to modulate a wide variety of targets including the cannabinoid receptors, orphan GPCRs such as GPR55 and GPR18, serotonin, adenosine, and opioid receptors as well as ligand-gated ion channels among others. Its pharmacology is rather puzzling and needs to be further explored in the disease context.Also, the metabolism and interactions of this phytocannabinoid with other commercialized drugs need to be further considered to elucidate its clinical potential for the treatment of specific pathologies.Besides CBD, natural and synthetic derivatives of this chemotype have also been reported exhibiting diverse functional profiles and providing a deeper understanding of the potential of this scaffold.In this chapter, we analyze the knowledge gained so far on CBD and its analogs specially focusing on its molecular targets and metabolic implications. Phytogenic and synthetic CBD derivatives may provide novel approaches to improve the therapeutic prospects offered by this promising chemotype.
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The endocannabinoid system (ECS) is involved in all aspects of the pathophysiological processes of pain. The nociceptive pathway includes transduction, transmission, modulation and perception, with the ECS playing an essential role in both afferent and efferent pain stimuli. Interest in using cannabinoid products for pain is of continued research and clinical interest. Data in human, lab animals and now companion animals does show efficacy for use especially for chronic pain states. The relative therapeutic index appears favorable and the addition of these compounds at least gives veterinary practitioners another tool to consider for pain management. Careful consideration is important for product selection, not only quality but cannabinoid and terpene profiles that may best fit a patient’s pain state. The clinically relevant science of medical cannabinoids for veterinary patients is in its infancy but is very encouraging. We now have our first well conducted clinical trials with more underway. The future looks promising for medical cannabinoids, specifically CBD, for the treatment of pain conditions in our patients. Given the numerous nuances of products and the ECS dosing for pain, both acute and chronic, dosing should be done in an escalating manner. Reasonable considerations for CBD dominant or isolate products can start as low as 0.5 mg/kg by mouth twice to three times a day and increase significantly until the therapeutic benefit is appreciated.
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Cannabinoids modulate diverse pain targets and possess unique multimodal analgesic mechanisms of action. Cannabinoids produce analgesia by interacting with cannabinoid receptor types 1 and 2 (CB1 and CB2), as well as G protein-coupled receptor 55 (GPR55) and transient receptor potential vanilloid type 1 (TRPV1). Cannabinoids modulate multiple supraspinal, spinal, and peripheral nociception pathways. Endocannabinoids are released on demand from postsynaptic terminals and travel retrograde to stimulate cannabinoid receptors on presynaptic terminals, inhibiting the release of excitatory neurotransmitters. Cannabinoids are classified based on their origin into three categories: endocannabinoids (present endogenously in human tissues), phytocannabinoids (plant-derived), and synthetic cannabinoids (pharmaceutical). The phytocannabinoids THC and CBD are lipophilic substances that readily cross the blood-brain barrier and interact with receptors in both the central and peripheral nervous systems, exerting analgesic effects especially in hyperalgesia and inflammatory states. This book chapter will review cannabinoids’ mechanisms of action in nociception.
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Objective: CBD is a phytocannabinoid compound derived from the cannabis plant and has been gaining attention as a potential anxiolytic, anti-panic, and analgesic without the psychoactive effects associated with tetrahydrocannabinol; however, these beneficial therapeutic effects have not yet been explored in dogs and cats. Design: We conducted an open-label study in eight dogs and four cats with each diagnostic symptom and investigated the efficacy, tolerability, and safety of CBD products for treatment. The efficacy of CBD in dogs and cats with problematic behaviors, such as conflict-related, fear-related, repetitive or self-injury behaviors, were assessed. Methods: CBD at 0.15–1.85 mg/kg/day was administered twice daily on an empty stomach with a small piece of food. Behavioral symptoms were measured before the first application (day 0) and after 2 (day 14), 4 (day 28), or 8 weeks (day 56) of regular administration. The efficacy was assessed using a behavior index and rating the degree of overall owner satisfaction and veterinarian observational results. Result: At the end of the study, among the twelve animals that continued to receive this supplement for 8 weeks, four cases were rated as considerably decreased and six were rated as decreased. Conclusion: CBD was used at a dose of 0.3–1.7 mg/kg/day in 8 dogs and 4 cats for 8 weeks, then behavioral changes were observed in 10 subjects. No serious adverse events were observed, and there were no notable problems in safety and tolerability.
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Epilepsy is a neurological disorder with a high prevalence worldwide. Several studies carried out during the last decades indicate that the administration of cannabinoids as well as the activation of the endocannabinoid system (ECS) represent a therapeutic strategy to control epilepsy. However, there are controversial studies indicating that activation of ECS results in cell damage, inflammation and neurotoxicity, conditions that facilitate the seizure activity. The present review is focused to present findings supporting this issue. According to the current discrepancies, it is relevant to elucidate the different effects induced by the activation of ECS and determine the conditions under which it facilitates the seizure activity.
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People with kidney failure can experience a range of symptoms that lead to suffering and poor quality of life. Available therapies are limited, and evidence for new treatment options is sparse, often resulting in incomplete relief of symptoms. There is growing interest in the potential for cannabinoids, including cannabidiol and tetrahydrocannabinol, to treat symptoms across a wide range of chronic diseases. As legal prohibitions are withdrawn or minimized in many jurisdictions, patients are increasingly able to access these agents. Cannabinoid receptors, CB1 and CB2, are widely expressed in the body, including within the nervous and immune systems, and exogenous cannabinoids can have anxiolytic, anti-emetic, analgesic and anti-inflammatory effects. Considering their known physiological actions and successful studies in other patient populations, cannabinoids may be viewed as potential therapies for a variety of common symptoms affecting those with kidney failure, including pruritus, nausea, insomnia, chronic neuropathic pain, anorexia, and restless legs syndrome. In this review, we summarize the pharmacology and pharmacokinetics of cannabinoids, along with what is known about the use of cannabinoids for symptom relief in those with kidney disease, and the evidence available concerning their role in management of common symptoms. Presently, while these agents show varying efficacy with a reasonable safety profile in other patient populations, evidence-based prescribing of cannabinoids for people with symptomatic kidney failure is not possible. Given the symptom burden experienced by individuals with kidney failure, there is an urgent need to understand the tolerability and safety of these agents in this population, which must ultimately be followed by robust, randomized controlled trials to determine if they are effective for symptom relief.
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Cannabidiol (CBD) is an abundant non-psychoactive phytocannabinoid in Cannabis extracts which has high affinity on a series of receptors, including type 1 cannabinoid receptor (CB1), type 2 cannabinoid receptor (CB2), GPR55, transient receptor potential vanilloid (TRPV), and peroxisome proliferator-activated receptor gamma (PPARγ). By modulating the activities of these receptors, CBD exhibits multiple therapeutic effects, including neuroprotective, antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, analgesic and anti-cancer properties. CBD could also be applied to treat or prevent COVID-19 and its complications. Here, we provide a narrative review of CBD's applications in human diseases: from mechanism of action to clinical trials.
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Cannabidiol (CBD) is one of the most abundant components of Cannabis and has long been used in Cannabis-based preparations. Recently, CBD has become a promising pharmacological agent because of its beneficial properties in the pathophysiology of several diseases. Although CBD is a kind of cannabinoid and acts on cannabinoid receptors (CB1 and CB2), molecular targets involved in diverse therapeutic properties of CBD have not been identified because CBD also interacts with other molecular targets. Considering that CBD alters the intracellular calcium level by which calpain activity is controlled, and both CBD and calpain are associated with various diseases related to calcium signaling, including neurological disorders, this review provides an overview of calpain and calcium signaling as possible molecular targets of CBD. As calpain is known to play an important role in the pathophysiology of neurological disease, a deeper understanding of its relationship with CBD will be meaningful. To understand the role of CBD as a calpain regulator, in silico structural analysis on the binding mode of CBD with calpain was performed.
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Background and purpose: T-type Ca channels (ICa ) regulate neuronal excitability and contribute to neurotransmitter release. The phytocannabinoids Δ9 -tetrahydrocannabinol and cannabidiol effectively modulate T-type ICa , but effects of other biologically active phytocannabinoids on these channels are unknown. We thus investigated the modulation of T-type ICa by low abundance phytocannabinoids. Experimental approach: A fluorometric (FLIPR) assay was used to investigate modulation of human T-type ICa (CaV 3.1, 3.2 and 3.3) stably expressed in FlpIn-TREx HEK293 cells. The biophysical effects of some compounds were examined using whole-cell patch clamp recordings from the same cells. Key results: In the FLIPR assay, all eleven phytocannabinoids tested modulated T-type ICa , with most inhibiting CaV 3.1 and CaV 3.2 more effectively than CaV 3.3. Cannabigerolic acid was the most potent inhibitor of CaV 3.1 (pIC50 6.1 ± 0.6) and CaV 3.2 (pIC50 6.4 ± 0.4); in all cases phytocannabinoid acids were more potent than their corresponding neutral forms. In patch clamp recordings, cannabigerolic acid inhibited CaV 3.1 and 3.2 with similar potency to the FLIPR assay, the inhibition was associated with significant hyperpolarizing shift in activation and steady state inactivation of these channels. In contrast, cannabidiol, cannabidivarin and cannabigerol only affected channel inactivation. Conclusion and implications: Modulation of T-type calcium channels is a common property of phytocannabinoids, which all increase steady state inactivation at physiological membrane potentials, with some also affecting channel activation. Thus, T-type ICa may be a common site of action for phytocannabinoids, and the diverse actions of phytocannabinoids on channel gating may provide insight into structural requirement for selective T-type ICa modulators.
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Introduction: In the last two decades, our understanding of the therapeutic utility and medicinal properties of cannabis has greatly changed. This change has been accompanied by widespread cannabis use in various communities and different age groups, especially within the United States. With this increase, we should consider the potential effects of cannabis-hemp on general public health and how they could alter therapeutic outcomes. Material and methods: The present investigation examined cannabis use for recreational and therapeutic use and a review of pertinent indexed literature was performed. The focused question evaluates "how cannabis or hemp products impact health parameters and do they provide potential therapeutic value in dentistry, and how do they interact with conventional medicines (drugs)." Indexed databases (PubMed/Medline, EMBASE) were searched without any time restrictions but language was restricted to English. Results: The review highlights dental concerns of cannabis usage, the need to understand the endocannabinoid system (ECS), cannabinoid receptor system, its endogenous ligands, pharmacology, metabolism, current oral health, and medical dilemma to ascertain the detrimental or beneficial effects of using cannabis-hemp products. The pharmacological effects of pure cannabidiol (CBD) have been studied extensively while cannabis extracts can vary significantly and lack empirical studies. Several metabolic pathways are affected by cannabis use and could pose a potential drug interaction. The chronic use of cannabis is associated with health issues, but the therapeutic potential is multifold since there is a regulatory role of ECS in many pathologies. Conclusion: Current shortcomings in understanding the benefits of cannabis or hemp products are limited due to pharmacological and clinical effects not being predictable, while marketed products vary greatly in phytocompounds warrant further empirical investigation. Given the healthcare challenges to manage acute and chronic pain, this review highlights both cannabis and CBD-hemp extracts to help identify the therapeutic application for patient populations suffering from anxiety, inflammation, and dental pain.
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Editors note: The article "Update on Antiseizure Medications 2022" by Dr Abou-Khalil was first published in the February 2016 Epilepsy issue of Continuum: Lifelong Learning in Neurology as "Antiepileptic Drugs," and at the request of the Editor-in-Chief was updated by Dr Abou-Khalil for the 2019 issue and again for this issue.
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Cannabidiol (CBD), as a major phytocannabinoid of Cannabis sativa, has emerged as a promising natural compound in the treatment of diseases. Its diverse pharmacological effects with limited side effects have promoted researchers to pursue new therapeutic applications. It has little affinity for classical cannabinoid receptors (CB1 and CB2). Considering this and its diverse pharmacological effects, it is logical to set up studies for finding its putative potential targets other than CB1 and CB2. A class of ion channels, namely transient potential channels (TRP), has been identified during two recent decades. More than 30 members of this family have been studied, so far. They mediate diverse physiological functions and are associated with various pathological conditions. Some have been recognized as key targets for natural compounds such as capsaicin, menthol, and CBD. Studies show that CBD has agonistic effects for TRPV1-4 and TRPA1 channels with antagonistic effects on the TRPM8 channel. In this article, we reviewed the recent findings considering the interaction of CBD with these channels. The review indicated that TRP channels mediate, at least in part, the effects of CBD on seizure, inflammation, cancer, pain, acne, and vasorelaxation. This highlights the role of TRP channels in CBD-mediated effects, and binding to these channels may justify part of its paradoxical effects in comparison to classical phytocannabinoids.
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Changes in the legality of marijuana for medicinal use and the further legalization for recreational use have brought about renewed interest in the properties of the cannabis plant. Cannabidiol (CBD), a derivative of the cannabis plant, has emerged as a widely available panacea. The purpose of this review is to discuss the differences in the active ingredients of the cannabis plant as well as the mechanisms by which CBD may provide benefit. In addition, the evidence for pain management and anxiety are evaluated. Finally, safety, tolerability, and legal issues surrounding CBD are examined.
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Cannabidiol (CBD) is currently being investigated as a novel therapeutic for the treatment of CNS disorders like schizophrenia and epilepsy. ABC transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) mediate pharmacoresistance in these disorders. P-gp and Bcrp are expressed at the blood brain barrier (BBB) and reduce the brain uptake of substrate drugs including various antipsychotics and anticonvulsants. It is therefore important to assess whether CBD is prone to treatment resistance mediated by P-gp and Bcrp. Moreover, it has become common practice in the drug development of CNS agents to screen against ABC transporters to help isolate lead compounds with optimal pharmacokinetic properties. The current study aimed to assess whether P-gp and Bcrp impacts the brain transport of CBD by comparing CBD tissue concentrations in wild-type (WT) mice versus mice devoid of ABC transporter genes. P-gp knockout ( Abcb1a/b −∕− ), Bcrp knockout ( Abcg2 −∕− ), combined P-gp/Bcrp knockout ( Abcb1a/b −∕− Abcg2 −∕− ) and WT mice were injected with CBD, before brain and plasma samples were collected at various time-points. CBD results were compared with the positive control risperidone and 9-hydroxy risperidone, antipsychotic drugs that are established ABC transporter substrates. Brain and plasma concentrations of CBD were not greater in P-gp, Bcrp or P-gp/Bcrp knockout mice than WT mice. In comparison, the brain/plasma concentration ratios of risperidone and 9-hydroxy risperidone were profoundly higher in P-gp knockout mice than WT mice. These results suggest that CBD is not a substrate of P-gp or Bcrp and may be free from the complication of reduced brain uptake by these transporters. Such findings provide favorable evidence for the therapeutic development of CBD in the treatment of various CNS disorders.
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Agonists at the benzodiazepine-binding site of GABAA receptors (BDZs) enhance synaptic inhibition through four subtypes (α1, α2, α3 and α5) of GABAA receptors (GABAAR). When applied to the spinal cord, they alleviate pathological pain; however, insufficient efficacy after systemic administration and undesired effects preclude their use in routine pain therapy. Previous work suggested that subtype-selective drugs might allow separating desired antihyperalgesia from unwanted effects, but the lack of selective agents has hitherto prevented systematic analyses. Here we use four lines of triple GABAAR point-mutated mice, which express only one benzodiazepine-sensitive GABAAR subtype at a time, to show that targeting only α2GABAARs achieves strong antihyperalgesia and reduced side effects (that is, no sedation, motor impairment and tolerance development). Additional pharmacokinetic and pharmacodynamic analyses in these mice explain why clinically relevant antihyperalgesia cannot be achieved with nonselective BDZs. These findings should foster the development of innovative subtype-selective BDZs for novel indications such as chronic pain.
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Based on evidence that the therapeutic properties of Cannabis preparations are not solely dependent on the presence of Δ9-tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and Δ9-tetrahydrocannabivarin (THCV). Results from some of these studies have fostered the view that CBD and THCV modulate the effects of THC via direct blockade of cannabinoid type-1 (CB1) receptors, thus behaving like first generation CB1 inverse agonists, such as rimonabant. Here we review in vitro and ex vivo mechanistic studies of CBD and THCV, and synthesize data from these studies in a meta-analysis. Synthesized data regarding mechanisms are then used to interpret results from recent preclinical animal studies and clinical trials. The evidence indicates that CBD and THCV are not rimonabant-like in their action, and thus appear very unlikely to produce unwanted central nervous system effects. They exhibit markedly disparate pharmacological profiles particularly at CB1 receptors: CBD is a very low affinity CB1 ligand which can nevertheless affect CB1 activity in vivo in an indirect manner, whilst THCV is a high affinity CB1 ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 antagonism. THCV also has high affinity for CB2 and signals as a partial agonist, a departure from both CBD and rimonabant. These cannabinoids illustrate how in vitro mechanistic studies do not always predict in vivo pharmacology, and underlie the necessity of testing compounds in vivo before drawing any conclusion on their functional activity at a given target.
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Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim of the present systematic review is to examine the randomized and crossover studies that administered CBD to healthy controls and to clinical patients. A systematic search was performed in the electronic databases PubMed and EMBASE using the key word "cannabidiol". Both monotherapy and combination studies (e.g., CBD + ∆9-THC) were included. A total of 34 studies were identified: 16 of these were experimental studies, conducted in healthy subjects, and 18 were conducted in clinical populations, including multiple sclerosis (six studies), schizophrenia and bipolar mania (four studies), social anxiety disorder (two studies), neuropathic and cancer pain (two studies), cancer anorexia (one study), Huntington's disease (one study), insomnia (one study), and epilepsy (one study). Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC. Moreover, some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and/or intensify ∆9-THC-induced effects, whereas others suggest that it may inhibit ∆9-THC-induced effects. Finally, preliminary clinical trials suggest that high-dose oral CBD (150-600 mg/d) may exert a therapeutic effect for social anxiety disorder, insomnia and epilepsy, but also that it may cause mental sedation. Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed.
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Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABAA receptors (GABAARs) containing α2 subunits (α2-GABAARs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal α2-GABAARs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABAAR-mutated mice, which either lack α2-GABAARs specifically from the spinal cord, or, which express only benzodiazepine-insensitive α2-GABAARs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all α2-GABAARs were benzodiazepine insensitive. The major (α2-dependent) component of GABAAR-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal α2-GABAARs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target α2-GABAARs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions.Neuropsychopharmacology advance online publication, 18 September 2013; doi:10.1038/npp.2013.221.
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Owing to the low therapeutic index of barbiturates, benzodiazepines (BZDs) became popular in this country and worldwide many decades ago for a wide range of conditions. Because of an increased understanding of pharmacology and physiology, the mechanisms of action of many BZDs are now largely understood, and BZDs of varying potency and duration of action have been developed and marketed. Although BZDs have many therapeutic roles and BZD-mediated effects are typically well tolerated in the general population, side effects and toxicity can result in morbidity and mortality for some patients. The elderly; certain subpopulations of patients with lung, liver, or kidney dysfunction; and patients on other classes of medication are especially prone to toxicity. This review details the present knowledge about BZD mechanisms of action, drug profiles, clinical actions, and potential side effects. In addition, this review describes numerous types of BZD-mediated central nervous system effects. For any patient taking a BZD, the prescribing physician must carefully evaluate the risks and benefits, and higher-risk patients require careful considerations. Clinically appropriate use of BZDs requires prudence and the understanding of pharmacology.
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Anandamide and 2-arachidonoylglycerol (2-AG) are the two main endocannabinoids, exerting their effects by activating type 1 (CB1r) and type 2 (CB2r) cannabinoid receptors. Anandamide inhibits anxiety-like responses through the activation of CB1r in certain brain regions, including the dorsolateral periaqueductal gray (dlPAG). 2-AG also attenuates anxiety-like responses, although the neuroanatomical sites for these effects remained unclear. Here, we tested the hypothesis that enhancing 2-AG signaling in the dlPAG would induce anxiolytic-like effects. The mechanisms involved were also investigated. Male Wistar rats received intra-dlPAG injections of 2-AG, URB602 (inhibitor of the 2-AG hydrolyzing enzyme, mono-acylglycerol lipase - MGL), AM251 (CB1r antagonist) and AM630 (CB2r antagonist). The behaviour was analyzed in the elevated plus maze after the following treatments. Exp. 1: vehicle (veh) or 2-AG (5pmol, 50pmol, 500pmol). Exp. 2: veh or URB602 (30pmol, 100pmol or 300pmol). Exp. 3: veh or AM251 (100pmol) followed by veh or 2-AG (50pmol). Exp. 4: veh or AM630 (1000pmol) followed by veh or 2-AG. Exp. 5: veh or AM251 followed by veh or URB602 (100pmol). Exp. 6: veh or AM630 followed by veh or URB602. 2-AG (50pmol) and URB602 (100pmol) significantly increased the exploration of the open arms of the apparatus, indicating an anxiolytic-like effect. These behavioral responses were prevented by CB1r (AM251) or CB2r (AM630) antagonists. Our results showed that the augmentation of 2-AG levels in the dlPAG induces anxiolytic-like effects. The mechanism seems to involve both CB1r and CB2r receptors.
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Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects.
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Δ 9-tetrahydrocannabinol (Δ 9-THC) is the main compound of the Cannabis Sativa responsible for most of the effects of the plant. Another major constituent is cannabidiol (CBD), formerly regarded to be devoid of pharmacological activity. However, laboratory rodents and human studies have shown that this cannabinoid is able to prevent psychotic-like symptoms induced by high doses of Δ 9- THC. Subsequent studies have demonstrated that CBD has antipsychotic effects as observed using animal models and in healthy volunteers. Thus, this article provides a critical review of the research evaluating antipsychotic potential of this cannabinoid. CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of Δ 9-THC involve the striatum and temporal cortex that have been traditionally associated with psychosis. Although the mechanisms of the antipsychotic properties are still not fully understood, we propose a hypothesis that could have a heuristic value to inspire new studies. These results support the idea that CBD may be a future therapeutic option in psychosis, in general and in schizophrenia, in particular.
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Chapter
The 5-HT3 and glycine receptors are pentameric ion channels belonging to a Cys-loop ligand-gated ion channel superfamily. While the glycine receptors can mediate fast inhibitory synaptic transmission, the 5-HT3 receptors are involved in both excitatory and inhibitory synaptic transmission in the central and peripheral nervous system. These receptors play important roles in several physiological and pathological processes such as vomiting reflex, neuromotor activity, pain process, reward mechanism of drugs of abuse, cognition, and anxiety control. Emerging evidence has identified both receptors as primary targets for the action of nonpsychoactive cannabinoids in the brain. Psychoactive and nonpsychoactive cannabinoids alter the amplitudes of 5-hydroxytryptamine and glycine-activated currents in native neurons and in cell lines expressing recombinant 5-HT3 and glycine receptors through CB1 and CB2 receptor-independent mechanisms. However, little is known about molecular mechanisms and behavioral implications of this specific cannabinoid modulation. Results from recent studies have shed light on the molecular basis of nonpsychoactive cannabinoid modulation of glycine receptors. Evidence has also emerged to suggest that cannabinoid modulation of glycine receptors contributes to some of the cannabis-induced analgesic effect. This research direction could help develop novel therapeutic agents for the treatment of pain and other diseases. This chapter summarizes recent research progress in our knowledge about the mechanisms and in vivo consequence of cannabinoid modulation of 5-HT3 and glycine receptors.
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GABAA receptors that contain the α4 and δ subunits are thought to be located extrasynaptically, mediating tonic currents elicited by low concentrations of GABA. These α4βδ receptors are modulated by neurosteroids and certain anesthetics, identifying them as important drug targets in research. However, pharmacological studies on these receptors have often yielded variable results, possibly due to the expression of receptors in different stoichiometries or arrangements. In this study, we injected different ratios of α4, β2 and δ cRNA into Xenopus oocytes and measured the sensitivity to GABA and DS2 activation of the resulting receptor populations. By creating a matrix of RNA injection ratios from stock RNA concentrations, we were able to compare the changes in pharmacology between injection ratios where the ratio of only one subunit was altered. We identified two distinct populations of receptors, the first with an EC50 value of approximately 100 nM to GABA, a low Hill slope of approximately 0.3 and substantial direct activation by DS2. The second population had an EC50 value of approximately 1 μM to GABA, a steeper Hill slope of 1 and little direct activation, but substantial potentiation, by DS2. The second population was formed with high α4 ratios and low β2 ratios, but altering the ratio of δ subunit injected had little effect. We propose that receptors with high sensitivity to GABA and direct activation by DS2 are the result of a greater number of β2 subunits being incorporated into the receptor.
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Background: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. Methods: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Results: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0-96·0) at baseline and 15·8 (5·6-57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0-64·7). Interpretation: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. Funding: GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.
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Background and purpose: It has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ9-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 is to investigate whether CBD modulates THC-induced functional effects and c-Fos expression in a 1:1 dose ratio that approximates therapeutic strains of cannabis and nabiximols. Experimental approach: Male C57BL/6 mice were treated with vehicle, CBD, THC, or a combination of CBD and THC (10 mg.kg(-1) 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 results: CBD 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 6 of these brains regions. This effect was most pronounced in the medial preoptic nucleus and lateral PAG. CBD alone treatment diminished c-Fos expression only in the central nucleus of the amygdala compared to vehicle. Conclusions and implications: These data re-affirm that CBD modulates the pharmacological actions of THC and provide information regarding brain regions involved in the interaction between CBD and THC.
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Cannabidiol has been reported to act as an antagonist of cannabinoid agonists at type 1 cannabinoid receptors (CB1 ). We hypothesized that cannabidiol can inhibit cannabinoid agonist activity through negative allosteric modulation of CB1 . CB1 internalization, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 and in the STHdh(Q7/Q7) cell model of striatal neurons endogenously expressing CB1 . Cells were treated with 2-arachidonylglycerol or Δ(9) -tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol. Cannabidiol reduced the efficacy and potency of 2-arachidonylglycerol and Δ(9) -tetrahydrocannabinol on PLCβ3- and ERK1/2-dependent signaling in cells heterologously (HEK 293A) or endogenously (STHdh(Q7/Q7) ) expressing CB1 . By reducing arrestin2 recruitment to CB1 , cannabidiol treatment prevented CB1 internalization. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino-terminus. Cannabidiol behaved as a non-competitive negative allosteric modulator of CB1 . Allosteric modulation, in conjunction with non-CB1 effects, may explain the in vivo effects of cannabidiol. Allosteric modulators of CB1 have the potential to treat central nervous system and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of CB1 . This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article. Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored. We report elevated CLB and nCLB levels in these subjects. The mean (± standard deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [-2-91%] at 4 weeks); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90-610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction. Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.
Article
There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety. Copyright © 2015 Elsevier Inc. All rights reserved.