Article

Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

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Abstract

(−)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5′ pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2 – 3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive. (+)-5′-DMH-CBD and (+)-7-hydroxy-5′-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (−)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM). CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (−)-7-hydroxy-CBD (IC50=34 μM), but not the other analogues (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis. Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (−)-5′-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent. British Journal of Pharmacology (2001) 134, 845–852; doi:10.1038/sj.bjp.0704327

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... CBD acts as a TRPV1 agonist. Indeed, the pharmacological action of CBD is similar to some natural and synthetic TRPV1 agonists, as it first binds vanilloid receptor type 1 and then induces its desensitization (Bisogno et al., 2001). Interestingly, the administration of a TRPV1 antagonist blocks some of CBD's effects (Long et al., 2006). ...
... The simplest explanation, as suggested by Galaj, is the desensitization of TRPV1 receptors following CBD's binding. CBD, similarly to both natural and synthetic TRPV1 agonists, induces TRPV1 receptor desensitization (Bisogno et al., 2001). Another possibility is that CBD increases levels of anandamide via inhibition of fatty acid amide hydrolase (FAAH) or fatty acid-binding proteins actions (Bisogno et al., 2001), which subsequently suppresses cocaine-taking and seeking behavior (Adamczyk et al., 2012) by activation of both CB1Rs and TRPV1 channels (Fenwick et al., 2017). ...
... CBD, similarly to both natural and synthetic TRPV1 agonists, induces TRPV1 receptor desensitization (Bisogno et al., 2001). Another possibility is that CBD increases levels of anandamide via inhibition of fatty acid amide hydrolase (FAAH) or fatty acid-binding proteins actions (Bisogno et al., 2001), which subsequently suppresses cocaine-taking and seeking behavior (Adamczyk et al., 2012) by activation of both CB1Rs and TRPV1 channels (Fenwick et al., 2017). As extensively reported by Scherma and co-authors (Scherma et al., 2019), increasing AEA levels via FAAH-blockade (e.g., URB597 or AM404) leads to a reduction in nicotine-induced CPP and SA. ...
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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.
... Cannabidiol is also reported to affect the degradation of endocannabinoids. CBD was shown to block the activity of FAAH (Bisogno et al., 2001) and increase the serum concentration of AEA as well as those of two additional FAAH substrates, palmitoylethanolamide and oleoylethanolamide, in human subjects (200 mg to 800 mg of CBD/day) (Leweke et al., 2012). Furthermore, injection of CBD (3 nmol) into the periaqueductal gray of rats increased the concentration of 2-AG in lipid extracts at the injection site to levels 2.6-fold higher than that of rats with vehicle injection (Maione et al., 2011). ...
... This effect might underlie the anticonvulsive effect of CBD (Kaplan et al., 2017). Also, CBD is reported to bind to and activate TRPV1 (Bisogno et al., 2001), which induces rapid desensitization of TRPV1 (Bisogno et al., 2001;De Petrocellis et al., 2011). Therefore, CBD might act as a blocker of TRPV1, although CBD-mediated increase in AEA may activate TRPV1. ...
... This effect might underlie the anticonvulsive effect of CBD (Kaplan et al., 2017). Also, CBD is reported to bind to and activate TRPV1 (Bisogno et al., 2001), which induces rapid desensitization of TRPV1 (Bisogno et al., 2001;De Petrocellis et al., 2011). Therefore, CBD might act as a blocker of TRPV1, although CBD-mediated increase in AEA may activate TRPV1. ...
Article
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Research on endocannabinoid signaling has greatly advanced our understanding of how the excitability of neural circuits is controlled in health and disease. In general, endocannabinoid signaling at excitatory synapses suppresses excitability by inhibiting glutamate release, while that at inhibitory synapses promotes excitability by inhibiting GABA release, although there are some exceptions in genetically epileptic animal models. In the epileptic brain, the physiological distributions of endocannabinoid signaling molecules are disrupted during epileptogenesis, contributing to the occurrence of spontaneous seizures. However, it is still unknown how endocannabinoid signaling changes during seizures and how the redistribution of endocannabinoid signaling molecules proceeds during epileptogenesis. Recent development of cannabinoid sensors has enabled us to investigate endocannabinoid signaling in much greater spatial and temporal details than before. Application of cannabinoid sensors to epilepsy research has elucidated activity-dependent changes in endocannabinoid signaling during seizures. Furthermore, recent endocannabinoid research has paved the way for the clinical use of cannabidiol for the treatment of refractory epilepsy, such as Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Cannabidiol significantly reduces seizures and is considered to have comparable tolerability to conventional antiepileptic drugs. In this article, we introduce recent advances in research on the roles of endocannabinoid signaling in epileptic seizures and discuss future directions.
... This could provide a plausible explanation for CBD counteracting some of the negative side effects of THC, such as intoxication, sedation, and tachycardia (for a review, see [43]). The extended endocannabinoid system likewise includes other receptors modulated by cannabinoids, such as transient receptor potential vanilloid 1 (TRPV1), which is activated by AEA [44] and CBD [45]. In these experiments, the latter compound was found to be inactive in affinity binding experiments to CB 1 and CB 2 receptors [45]. ...
... The extended endocannabinoid system likewise includes other receptors modulated by cannabinoids, such as transient receptor potential vanilloid 1 (TRPV1), which is activated by AEA [44] and CBD [45]. In these experiments, the latter compound was found to be inactive in affinity binding experiments to CB 1 and CB 2 receptors [45]. Moreover, NADA has been shown to increase intracellular calcium concentration via binding to TRPV1 [46]. ...
Article
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Drugs targeting the endocannabinoid system are of interest as potential systemic chemotherapeutic treatments and for palliative care in cancer. In this context, cannabinoid compounds have been successfully tested as a systemic therapeutic option in preclinical models over the past decades. Recent findings have suggested an essential function of the endocannabinoid system in the homeostasis of various skin functions and indicated that cannabinoids could also be considered for the treatment and prophylaxis of tumour diseases of the skin. Cannabinoids have been shown to exert their anticarcinogenic effects at different levels of skin cancer progression, such as inhibition of tumour growth, proliferation, invasion and angiogenesis, as well as inducing apoptosis and autophagy. This review provides an insight into the current literature on cannabinoid compounds as potential pharmaceuticals for the treatment of melanoma and squamous cell carcinoma.
... In addition to its action on cannabinoid receptors, CBD was found to inhibit the activity of fatty acid amide hydrolase (FAAH) (Bisogno et al., 2001), a major enzyme involved in anandamide (AEA) hydrolysis. As AEA is the main endogenous CB1 receptor agonist, this suggests an indirect effect of CBD on cannabinoid receptors due to increase in endogenous AEA concentration. ...
... Another proposed molecular target for CBD is the transient receptor potential vanilloid 1 (TRPV1) receptor (also known as VR1 receptor), which is involved in pain perception and regulation of various physiological functions, such as the release of inflammatory mediators in the body, gastrointestinal motility function and temperature regulation (Du et al., 2019). A study by Bisogno and colleagues (Bisogno et al., 2001) showed that CBD can displace capsaicin from the TRPV1 receptor and increase intracellular Ca 2+ levels to the same extent as the full agonist capsaicin in heterologous cells overexpressing TRVR1, suggesting that it functions as an agonist of this receptor. The interaction of CBD with TRPV1 receptors has been confirmed by in vivo studies (Turner et al., 2017). ...
Article
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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.
... CB2 receptors, responsible for the anti-inflammatory effect of cannabinoids, are located majorly in immune cells [1,6], but also within astrocytes and microglia, where they are involved in the modulation of the immune response, cell migration and cytokine release [5]. What is more, cannabinoids interact with some non-cannabinoid receptors, including vanilloid receptor 1 (TRPV1) [7], transient receptor potential ankyrin 1 (TRPA1) [8], G55 proteincoupled receptor (GPR55) [9] and peroxisome proliferator-activated receptors (PPARα, PPARγ) [4,10]. The diversity of cannabinoids' mechanisms of action might partially explain their pharmacological effects in very different clinical situations. ...
... Despite their reputation in the society, apart from THC, phytocannabinoids present minimal psychoactive activity. Effects of CBD mostly depend on the stimulation of neurotransmission mediated by the serotonin 1A receptor (5-HT 1A ) [12,13] and on decrease in metabolism and reuptake of anandamide [7], one of the two main endocannabinoids. CBD seems to be a non-intoxicating substance which shows anxiolytic, antipsychotic, anti-inflammatory, anti-oxidative, anti-convulsant and neuroprotective effects [14,15]. ...
Article
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Cannabinoids can be successfully used in the treatment of many symptoms and diseases; however, most often they are not the drugs of first choice. They can be added to the primary therapy, which can improve its effectiveness, or be introduced as the basic treatment when the conventional methods have failed. Small clinical trials and case reports prove the benefits of applying medicinal cannabis in various indications; however, clinical trials in larger groups of patients are scarce and often controversial. Due to limited scientific evidence, it is essential to conduct further experimental trials. Understanding the role of endocannabinoids, as well as the composition of cannabis containing both phytocannabinoids and terpenes plays an important role in their clinical use. The clinical effects of cannabinoids depend, among other things, on the activity of the endocannabinoid system, the proportion of phytocannabinoids, such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and the dosage used. The article discusses the role of phytocannabinoids and the potential of using them in different clinical cases in patients suffering from chronic pain, opioid dependence, depression and migraine, who did not respond to the conventional therapeutic methods. In each of the presented cases, the implementation of cannabinoids altered the course of the disease and resulted in symptom relief. Every decision to introduce cannabinoids to the treatment should be made individually with careful attention paid to details. Additionally, it is worth taking care of good clinical communication and education so that the implemented therapy is safe, effective and properly perceived by the patient.
... One possibility is the influence of the 'entourage effect' in the plant-extracted preparations, reflecting any one of 150 cannabinoids or terpenes and secondary metabolites, any one of which might be biologically active (Ferber et al. 2020). Indeed, their potential interactions with other receptor families including the vanilloid receptor (TRVP1) (Bisogno et al. 2001) (implicated in pain pathways; (Caterina and Julius 2001)) and monoaminergic receptors, such as the 5-HT1A and 5-HT2 receptors, the β-adrenergic and α-adrenergic receptors, and dopamine receptors (Bisogno et al. 2001;Seeman 2016;Marchese et al. 2003), could contribute to outcomes in measures of BPSD and motor phenotypes. Interestingly, THC does not appear to exert any effect on dopamine D2 receptors (Marchese et al. 2003), explaining why the purer forms of THC, e.g., nabilone and dronabinol, were less likely to be associated with improvement in motor deficits in the current systematic review. ...
... One possibility is the influence of the 'entourage effect' in the plant-extracted preparations, reflecting any one of 150 cannabinoids or terpenes and secondary metabolites, any one of which might be biologically active (Ferber et al. 2020). Indeed, their potential interactions with other receptor families including the vanilloid receptor (TRVP1) (Bisogno et al. 2001) (implicated in pain pathways; (Caterina and Julius 2001)) and monoaminergic receptors, such as the 5-HT1A and 5-HT2 receptors, the β-adrenergic and α-adrenergic receptors, and dopamine receptors (Bisogno et al. 2001;Seeman 2016;Marchese et al. 2003), could contribute to outcomes in measures of BPSD and motor phenotypes. Interestingly, THC does not appear to exert any effect on dopamine D2 receptors (Marchese et al. 2003), explaining why the purer forms of THC, e.g., nabilone and dronabinol, were less likely to be associated with improvement in motor deficits in the current systematic review. ...
Article
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Aim We undertook this systematic review to determine the efficacy and safety of cannabis-based medicine as a treatment for behavioral, psychological, and motor symptoms associated with neurocognitive disorders. Methods We conducted a PRISMA-guided systematic review to identify studies using cannabis-based medicine to treat behavioral, psychological, and motor symptoms among individuals with Alzheimer's disease (AD) dementia, Parkinson’s disease (PD), and Huntington’s disease (HD). We considered English-language articles providing original data on three or more participants, regardless of design. Findings We identified 25 studies spanning 1991 to 2021 comprised of 14 controlled trials, 5 pilot studies, 5 observational studies, and 1 case series. In most cases, the cannabinoids tested were dronabinol, whole cannabis, and cannabidiol, and the diagnoses included AD ( n = 11), PD ( n = 11), and HD ( n = 3). Primary outcomes were motor symptoms (e.g., dyskinesia), sleep disturbance, cognition, balance, body weight, and the occurrence of treatment-emergent adverse events. Conclusions A narrative summary of the findings from the limited number of studies in the area highlights an apparent association between cannabidiol-based products and relief from motor symptoms in HD and PD and an apparent association between synthetic cannabinoids and relief from behavioral and psychological symptoms of dementia across AD, PD, and HD. These preliminary conclusions could guide using plant-based versus synthetic cannabinoids as safe, alternative treatments for managing neuropsychiatric symptoms in neurocognitive vulnerable patient populations.
... Unlike THC, in vitro assay results indicated CBD has a low affinity or can even function as an antagonist or inverse agonist of CB1 receptors (Thomas et al. 2007;Laprairie et al. 2015). However, CBD can also block the metabolism and/or uptake of anandamide (Bisogno et al. 2001;Schubart et al. 2014). This last action is the primary effect of CBD on the CB1-or CB2mediated neurotransmission complex. ...
... Regarding the endocannabinoidome, CBD presents pharmacological targets that may be relevant to ASD. CBD can activate TRPV1 receptors (Bisogno et al. 2001), facilitating glutamate release (Musella et al. 2010;Ho et al. 2012). This compound can facilitate 5-HT1A-mediated neurotransmission causing anxiolytic, antidepressant, and pro-cognitive effects. ...
Article
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Rationale Autism spectrum disorder (ASD) is defined as a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction, restricted and repetitive patterns of behavior, and varying levels of intellectual disability. ASD is observed in early childhood and is one of the most severe chronic childhood disorders in prevalence, morbidity, and impact on society. It is usually accompanied by attention deficit hyperactivity disorder, anxiety, depression, sleep disorders, and epilepsy. The treatment of ASD has low efficacy, possibly because it has a heterogeneous nature, and its neurobiological basis is not clearly understood. Drugs such as risperidone and aripiprazole are the only two drugs available that are recognized by the Food and Drug Administration, primarily for treating the behavioral symptoms of this disorder. These drugs have limited efficacy and a high potential for inducing undesirable effects, compromising treatment adherence. Therefore, there is great interest in exploring the endocannabinoid system, which modulates the activity of other neurotransmitters, has actions in social behavior and seems to be altered in patients with ASD. Thus, cannabidiol (CBD) emerges as a possible strategy for treating ASD symptoms since it has relevant pharmacological actions on the endocannabinoid system and shows promising results in studies related to disorders in the central nervous system. Objectives Review the preclinical and clinical data supporting CBD’s potential as a treatment for the symptoms and comorbidities associated with ASD, as well as discuss and provide information with the purpose of not trivializing the use of this drug.
... Similarly, monophenols, plant cannabinoids, monophenolic ethers (like THC), or resorcinols (as CBD) are strong antioxidants. In a study, Hampson et al. (64) observed that CBD is a non-psychoactive ingredient of marijuana; also, it has a stronger effect than either α-tocopherol, which contains vitamin E, and is a dietary antioxidant, or ascorbate, which contains vitamin C, could prevent ROS-caused cell death and glutamate neurotoxicity. In a newer study (15), Hamelink et al. discovered that CBD safeguarded rats as opposed to hippocampalentorhinal-cortical neurodegeneration while they were administered simultaneously with ethanol exposure. ...
... It is suggested that CBD via TRPV1 may modify GABA release and brain glutamate, which leads to decreased cocaine reward. (64). Previous research showed that pretreatment with an antagonist of TRPV1(capsazepine) was in a position to stop CBD-induced reduction in the cocaine selfadministration (65), proposing that activation of TRPV1 might as well come to the aid of the therapeutic effects from CBD. ...
Article
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As a strong and addictive psychostimulant, methamphetamine (METH) is often misused worldwide. Although relapse is the greatest challenge to the effective treatment of drug dependency, now, for METH addiction, there is not available accepted pharmacotherapy. To characterize a probable new target in this indication, a biological system comprised of endocannabinoids, known as the endocannabinoid system (ECS), has been advised. As a non-psychotomimetic Phytocannabinoid in Cannabis sativa, cannabidiol (CBD) has been used in preclinical and clinical studies for treating neuropsychiatric disorders. In this review article, we focus on the effects of CBD in the treatment of addiction in a preclinical investigation concerning the pharmaceutic effectiveness and the underlying mechanisms of action on drug abuse specially METH. Growing evidence shows that CBD is a potential therapeutic agent in reducing drug reward, as evaluated in conditioned place preference (CPP), brain-stimulation reward paradigms, and self- administration. Furthermore, CBD plays an effective role in decreasing relapse in animal research. Through multiple-mechanisms, there is a belief that CBD modulates brain dopamine responding to METH, resulting in a reduction of METH-seeking behaviors. As our studies indicate, CBD can decrease METH addiction-associated problems, for example, symptoms of withdrawal and craving. It is needed for conducting more preclinical investigations and upcoming clinical trials to entirely assess the CBD capability as interference for METH addiction.
... There is a growing body of evidence that the endocannabinoid system is implicated in the pathophysiology of psychosis (Bossong et al., 2014;Zamberletti et al., 2012), thus CBD has been proposed as a candidate pharmacotherapy (Davies and Bhattacharyya, 2019). Preclinical work indicates that CBD inhibits the degradation of anandamide (Bisogno et al., 2001), an endocannabinoid which plays a major role in mood regulation, cognition, and behavior (Di Marzo and Petrosino, 2007). Indeed, increased levels of anandamide has been associated with reduced psychotic symptoms in humans after CBD administration (more details on this study below) (Leweke et al., 2012), which provides clinical support for this mechanisms of action. ...
... 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.
... Several studies have been centered on elucidating cannabidiol's actions on improving stress-related alterations, involving multiple targets (reviewed by Silote et al., 2019;García-Gutiérrez et al., 2020), such as a multimodal pharmacologic profile over the endocannabinoid system (Bisogno et al., 2001;Thomas et al., 2007;Pertwee, 2008;Campos et al., 2012;Laprairie et al., 2015;Martínez-Pinilla et al., 2017;Tham et al., 2019), an agonistic potential over TRPV1 receptors (Bisogno et al., 2001), as well as the regulation of other neurotransmitter systems [i.e., serotoninergic, opioidergic, and dopaminergic; reviewed in Silote et al. (2019)] or neuroprotective targets (i.e., hippocampal neurogenesis; Marchalant et al., 2009;Fogaça et al., 2018;Luján et al., 2018Luján et al., , 2020. For that reason, and since hippocampal function is altered with aging (Rosenzweig and Barnes, 2003), the current study evaluated the potential regulation of CB1 and CB2 receptors, as well as that of an early stage of neurogenesis (i.e., cell proliferation) following cannabidiol's treatment in the hippocampus of aged rats. ...
... Several studies have been centered on elucidating cannabidiol's actions on improving stress-related alterations, involving multiple targets (reviewed by Silote et al., 2019;García-Gutiérrez et al., 2020), such as a multimodal pharmacologic profile over the endocannabinoid system (Bisogno et al., 2001;Thomas et al., 2007;Pertwee, 2008;Campos et al., 2012;Laprairie et al., 2015;Martínez-Pinilla et al., 2017;Tham et al., 2019), an agonistic potential over TRPV1 receptors (Bisogno et al., 2001), as well as the regulation of other neurotransmitter systems [i.e., serotoninergic, opioidergic, and dopaminergic; reviewed in Silote et al. (2019)] or neuroprotective targets (i.e., hippocampal neurogenesis; Marchalant et al., 2009;Fogaça et al., 2018;Luján et al., 2018Luján et al., , 2020. For that reason, and since hippocampal function is altered with aging (Rosenzweig and Barnes, 2003), the current study evaluated the potential regulation of CB1 and CB2 receptors, as well as that of an early stage of neurogenesis (i.e., cell proliferation) following cannabidiol's treatment in the hippocampus of aged rats. ...
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Aging predisposes to late-life depression and since antidepressants are known to change their efficacy with age, novel treatment options are needed for our increased aged population. In this context, the goal of the present study was to evaluate the potential antidepressant-like effect of cannabidiol in aged rats. For this purpose, 19–21-month-old Sprague–Dawley rats were treated for 7 days with cannabidiol (dose range: 3–30 mg/kg) and scored under the stress of the forced-swim test. Hippocampal cannabinoid receptors and cell proliferation were evaluated as potential molecular markers underlying cannabidiol’s actions. The main results of the present study demonstrated that cannabidiol exerted a dose-dependent antidepressant-like effect in aged rats (U-shaped, effective at the intermediate dose of 10 mg/kg as compared to the other doses tested), without affecting body weight. None of the molecular markers analyzed in the hippocampus were altered by cannabidiol’s treatment. Overall, this study demonstrated a dose-dependent antidepressant-like response for cannabidiol at this age-window (aged rats up to 21 months old) and in line with other studies suggesting a beneficial role for this drug in age-related behavioral deficits.
... CBD has a very low affinity for CB1 and CB2 receptors (Pertwee, 1997), and there is evidence for allosteric modulation of these receptors (Laprairie et al., 2015). CBD can also produce effects mediated by the activation of cannabinoid receptors due to increased anandamide levels through the inhibition of FAAH (Bisogno et al., 2001). In addition, a variety of other targets has been implicated in the CBD effects, such as TRPV1, PPAR , and serotonin 1A (5-HT1A) receptors . ...
Chapter
Schizophrenia is a complex and heterogeneous neurodevelopmental psychiatric disorder characterized by a variety of symptoms classically grouped into three main domains: positive (hallucinations, delusions, and thought disorder) and negative symptoms (social withdrawal, lack of affect) and cognitive dysfunction (attention, working and episodic memory functions, and processing speed). This disorder places an immense emotional and economic pressure on the individual and society-at-large. Although the etiology of schizophrenia is not completely known, it is proposed to involve abnormalities in neurodevelopmental processes and dysregulation in the signaling mediated by several neurotransmitters, such as dopamine, glutamate, and GABA. Preclinical research using animal models are essential in our understanding of disease development and pathology as well as the discovery and advance of novel treatment choices. Here we describe rodent models for studying schizophrenia, including those based on the effects of drugs (pharmacological models), neurodevelopmental disruption, demyelination, and genetic alterations. The advantages and limitations of such models are highlighted. We also discussed the great potential of proteomic technologies in unraveling the molecular mechanism of schizophrenia through animal models.
... The antiseizure mechanism of action of CBD is unresolved but likely independent of its action on the endocannabinoid system [24,25]. Several antiseizure mechanisms have been hypothesized, with few identified as most relevant [26][27][28][29][30][31]. (Table 2) Specifically for antiseizure action in TSC, facilitation of gamma-aminobutyric acid (GABA)ergic neurotransmission and activation of mTOR intracellular protein pathway may be most suitable for further investigation. ...
Article
Cannabidiol (CBD) has recently been approved as an add-on therapy by various regulatory agencies for tuberous sclerosis complex (TSC)-associated seizures based on its short-term efficacy and safety in a pivotal randomized controlled trial. However, critical information about which patients with TSC and seizure types respond best to CBD (clinical, electrophysiological, and genetic predictors of responsiveness), when to use CBD in the treatment algorithm, and how CBD can be combined with other antiseizure medications (ASMs) in the form of a rational polypharmacy therapy is still lacking. In general, there is a limited in-depth critical review of CBD for the treatment of TSC to facilitate its optimal use in a clinical context. Here, we utilized a scoping review approach to report the current evidence of efficacy and safety of pharmaceutical-grade CBD in patients with TSC, including relevant mechanism of action and drug–drug interactions with other ASMs. We also discussed emerging information about CBD’s long-term efficacy and safety data in patients with TSC. Finally, we discussed some critical unanswered questions in several domains related to effective clinical management of TSC using CBD, including barriers to early and aggressive treatment in infants, difficulty with universal access to CBD, a lack of studies to understand CBD’s impact on seizure severity and specific seizure types, insufficient exploration of CBD in TSC-related cognitive and behavioral issues, and the need for more research into CBD’s effects on various biomarkers.
... Specifically, the interaction of CBD with these receptors causes a reduction in the level of pro-inflammatory cytokine levels and an increase in anti-inflammatory cytokine levels (Campos et al., 2016;Costa et al., 2007;Weiss et al., 2008). In addition to these, the molecule exhibits antioxidant effects (Atalay et al., 2019;García-Arencibia et al., 2007) and also inhibits keratinocyte proliferation, which is beneficial in conditions such as psoriasis (Bisogno et al., 2001;Bodó et al., 2005;Maccarrone et al., 2003;Ross, 2003). These pharmacological properties present CBD as a valuable treatment for many inflammatory skin disorders including psoriasis as justified above and atopic dermatitis. ...
Article
Cannabidiol, a non-psychoactive constituent of cannabis, has garnered much attention after United States Food and Drug Administration approved Epidiolex® for oral use. Although therapeutic effect of cannabidiol after systemic absorption has been investigated extensively, its therapeutic potential in treating skin disorders after local delivery still needs further exploration. Our study has investigated the effect of cannabidiol concentration, chemical enhancers, and essential oils on percutaneous absorption of cannabidiol. In vitro permeation tests were conducted on human skin. The 24 h study results suggest no significant difference in amount of drug absorbed into skin, between 5% (242.41±12.17 µg/cm²) and 10% (232.79±20.82 cm²) cannabidiol solutions. However, 1% delivered (23.02±4.74 µg/cm²) significantly lower amount of drug into skin than 5% and 10%. Transcutol and isopropyl myristate did not enhance delivery of cannabidiol. However, oleic acid was found to be useful as chemical enhancer. Oleic acid (43.07±10.11 µg/cm²) had significantly higher cannabidiol delivery into skin than the group without oleic acid (10.98±3.40 µg/cm²) after a 4 h in vitro permeation study. Essential oils at concentrations tested had lower total cannabidiol delivery when compared to control. This study's findings will help guide future research on the pharmacological effect of percutaneously delivered cannabidiol on inflammatory skin disorders.
... CBD has a very low affinity for CB1 and CB2 receptors (Pertwee, 1997), and there is evidence for allosteric modulation of these receptors (Laprairie et al., 2015). CBD can also produce effects mediated by the activation of cannabinoid receptors due to increased anandamide levels through the inhibition of FAAH (Bisogno et al., 2001). In addition, a variety of other targets has been implicated in the CBD effects, such as TRPV1, PPAR , and serotonin 1A (5-HT1A) receptors . ...
Chapter
Schizophrenia is a psychiatric disorder of neurodevelopmental origin that is thought to result from the combination of genetic and socioenvironmental factors. Several studies have linked the endocannabinoid system with the pathophysiology of schizophrenia. Here, we provide a brief overview of the role of the endocannabinoid system (ECS) in the context of biological processes relevant to schizophrenia, such as neurodevelopment, synaptic plasticity, and brain energy metabolism. We also discuss alterations related to the ECS in schizophrenia and current efforts in both in vivo and in vitro studies that have provided a better understanding of the functioning of this system in the context of the disorder. Finally, we highlighted the modulation of the ECS as a potential for discovering novel therapeutic targets, suggesting new avenues for future research in the field.
... FAAH inhibition by CBD may reduce PTSD symptoms by increasing the amount of the endogenous endocannabinoid and suppressing amygdala hyperactivity. Thus, this cannabinoid can inhibit anandamide uptake and metabolism, enhancing endocannabinoid tonus (Bisogno et al., 2001). Moreover, CBD can also increase adult neurogenesis, and this effect appears to be dependent on the CB1 receptors (Wolf et al. 2010). ...
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Studies with cannabidiol (CBD) suggest that this compound has anxiolytic properties and may mediate the reconsolidation and extinction of aversive memories. The objective of this study was to test whether the administration of CBD 300 mg before the recall of traumatic events attenuated symptoms usually induced by recall in subjects diagnosed with posttraumatic stress disorder (PTSD) and if its potential effects interfere with the reconsolidation of aversive memories. The double-blind trial included 33 participants of both sexes, aged between 18 and 60 years, diagnosed with PTSD according to the SCID-5 and randomly allocated to two groups treated with CBD (n = 17) and placebo (n = 16). In the first experimental section, participants were matched by sex, age, body mass index (BMI), and PTSD symptoms as assessed with the Posttraumatic Stress Disorder Checklist (PCL-5). On the same day, participants prepared the behavior test, recording accounts of their traumas in digital audio for a minute and a half and then imagining the trauma for 30 s. After 7 days, participants received CBD (300 mg) or placebo and performed the behavioral test, listening to the trauma account and imagining themselves in that situation. Before and after the behavioral test, subjective changes in mood and anxiety were recorded (Visual and Analogical Mood Scale — VAMS and STAI-state), along with physiological correlates of anxiety blood pressure (BP), heart rate (HR), and salivary cortisol (SC). Seven days later, participants underwent the same procedures as the previous session, but without the pharmacological intervention, to assess the effect on reconsolidation of traumatic memories. We found that CBD significantly attenuated the increase in the VAMS scale cognitive impairment factor scores, under the CBD’s effect, with this effect remaining 1 week after drug administration. No significant differences between the effects of CBD and placebo on anxiety, alertness, and discomfort induced by the recall of the traumatic event during the pharmacological intervention and in the subsequent week, in the absence of it. There were no significant differences between the CBD and placebo groups regarding physiological data (BP, HR, and SC). The attenuation of cognitive impairments during trauma recall under the effect of CBD may have interfered with the reconsolidation of traumatic memories concerning its association with cognitive impairments.
... Lastly, CBD has physiologic properties that are not yet clearly related to a specific mechanism, such as antioxidant, anticonvulsant, analgesic, and immunomodulatory functions [16]. CBD is also an agonist of PPAR-γ, and of TRPV1 and TRPV2 [18]. CBD is highly lipophilic, has a poor oral bioavailability and accumulates in body fat. ...
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Medical case reports suggest that cannabinoids extracted from Cannabis sativa have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of its major component, Δ9-tetrahydrocannabinol (THC). The new scientific discoveries related to the endocannabinoid system, including new receptors, ligands, and mediators, allowed the development of new therapeutic targets for the treatment of several pathological disorders minimizing the undesirable psychotropic effects of some constituents of this plant. Today, FDA-approved drugs, such as nabiximols (a mixture of THC and non-psychoactive cannabidiol (CBD)), are employed in alleviating pain and spasticity in multiple sclerosis. Dronabinol and nabilone are used for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Dronabinol was approved for the treatment of anorexia in patients with AIDS (acquired immune deficiency syndrome). In this review, we highlighted the potential therapeutic efficacy of natural and synthetic cannabinoids and their clinical relevance in cancer, neurodegenerative and dermatological diseases, and viral infections.
... FAAH breaks down anandamide, an endocannabinoid and CB1 receptor agonist [23]. CBD subsequently increases the concentration of anandamide at synapses, resulting in similar clinical effects to CB1 agonists [24]. This mechanism, in tandem with agonism of the serotonin 1A receptor and transient receptor potential vanilloid type 1, is thought to play a role in CBD's proposed anxiolytic effects [12,25]. ...
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Objectives Anxiety disorders are one of the most common reasons for seeking treatment with cannabis-based medicinal products (CBMPs). Current pharmacological treatments are variable in efficacy and the endocannabinoid system has been identified as a potential therapeutic target. This study aims to detail the changes in health-related quality-of-life (HRQoL) and clinical safety following CBMP therapy for generalised anxiety disorder. Methods A case series of the UK Medical Cannabis Registry was performed. Primary outcomes included change from baseline in patient-reported outcome measures (the General Anxiety Disorder Scale (GAD-7), EQ-5D-5L (a measure of health-related quality of life), and Sleep Quality Scale (SQS)) at 1, 3 and 6 months. Statistical significance was defined as p<0.050. Results 67 patients were treated for generalised anxiety disorder. Statistically significant improvements were observed in GAD-7, EQ-5D-5L Index Value, EQ5D Visual Analogue Scale, and SQS scores at 1, 3 and 6 months (p<0.050). 25 (39.1%) patients reported adverse events during the follow-up period. Conclusion This study suggests that CBMPs may be associated with improvement in HRQoL outcomes when used as a treatment for generalised anxiety disorder. These findings must be treated with caution considering limitations of study design; however this data may help inform future clinical studies and practice.
... Of note, while these opposing effects in modulating expression and reconsolidation of the memory likely recruit distinct projections from the IL cortex (i.e., IL → lateral septum and IL → central nucleus of the amygdala; Chen et al., 2021), CBD infused into the PL cortex reduced contextual fear memory expression (Lemos et al., 2010;Fogaça et al., 2014) and impaired memory reconsolidation (Fig. 6C). Furthermore, CBD is thought to potentiate the endocannabinoid neurotransmission by inhibiting the fatty acid amide hydrolase enzyme (Bisogno et al., 2001;De Petrocellis et al., 2011), which ultimately enhances the anandamide-mediated signaling (for a review, see Lee et al., 2017). Thus, another possibility is that IL cortex anandamide levels after retrieval may be relatively low, so the indirect CB1 receptor activation induced by CBD does not necessarily impair the contextual fear memory reconsolidation as significantly as the CB1/CB2 receptor agonist CP55,940 did (Santana et al., 2016). ...
Article
Growing evidence indicates that cannabidiol (CBD), a substance present in the Cannabis sativa plant, has potential therapeutic value to regulate abnormal emotional memories associated with post-traumatic stress and drug use disorders. CBD can attenuate their valence after retrieval (i.e., during reconsolidation) or potentiate their suppression by extinction. Pharmacological research has now focused on elucidating how it acts. Systemic antagonism of cannabinoid type-1 (CB1) receptors has often prevented the abovementioned effects of CBD. However, it is unknown in which brain regions CBD stimulates CB1 receptors and how it interferes with local activity-related plasticity to produce these effects. The present study addressed these questions considering the reconsolidation of contextual fear memories in rats. We focused on the medial prefrontal cortex (mPFC), which comprises the anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) subregions, as local activity or plasticity has been associated with the process to-be-investigated. Animals that received post-retrieval systemic CBD treatment presented relatively fewer cells expressing Zif268/Egr1 protein, a proxy for synaptic plasticity related to reconsolidation, in the AC and PL. At the same time, there were no significant differences in the IL. Pretreatment with the CB1 receptor antagonist/inverse agonist AM251 into the AC, PL, or IL prevented the impairing effects of systemic CBD treatment on reconsolidation. CBD also caused reconsolidation impairments when injected directly into the AC or PL but not the IL. Together, these findings show complementary mechanisms through which CBD may hinder the reconsolidation of destabilized aversive memories along the dorsoventral axis of the mPFC.
... In parallel, it inhibits the enzymatic hydrolysis and the uptake of AEA. The increase in AEA levels induced by CBD seems to mediate part of its effects [36]. In addition, CBD differs from THC by its non-psychoactive effect [29,37,38]. ...
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Objective: The purpose of this review was to present general data of cannabinoids, its function related to orofacial pain management, and its adverse effects. Methods: The data was searched through PubMed database and Google Scholars by various keywords without time limits. Hand searching and citation mining were also applied. Unpublished, incomplete, non-English data were excluded. Results: The presence of cannabinoids receptors throughout orofacial tissues has been reported, which could be a therapeutic site of action. Only in neuropathic pain, cannabinoids have been proven to be successful over conventional treatment. More clinical approvals of its analgesic effects are extremely required for pain originating from other tissues. When prescribing cannabis, dentists should be cautious about its adverse effects in many systems. Conclusion: Currently, cannabinoids have not been officially endorsed for analgesic effects in orofacial area. It can be useful for neuropathic orofacial pain especially when the standard treatment was unsuccessful.
... reported inverse agonist or antagonist action at CB 1 and CB 2 receptors or acting as an allosteric modulator (5). Several other pharmacological mechanisms are reported for CBD as a modest agonist at the 5-hydroxytryptamine (or serotonin) 5-HT 1A receptor as a potential inhibitor of arachidonoyl-ethanolamine degradation or reuptake and as inducing the heteromerization of a cannabinoid receptor with the 5-HT 2A receptor (6)(7)(8)(9). CBD also activates the transient receptor potential cation channel 1 and is a cyclooxygenase inhibitor. Although studies supporting analgesic effects of CBD in humans are scant, high doses have anticonvulsant, sedative, anxiolytic, and antiinflammatory activity. ...
Article
Cannabis and cannabinoids are increasingly being accessed and used by patients with advanced cancer for various symptoms and general quality of life. Specific symptoms of pain, nausea and vomiting, loss of appetite and cachexia, anxiety, sleep disturbance, and medical trauma are among those that have prompted patients with cancer to use cannabis. This conference report from the National Cancer Institute’s “Cannabis, Cannabinoid and Cancer Research Symposium” on the topic of “Cancer Symptom/Treatment Side Effect Management” is an expert perspective of cannabis intervention for cancer and cancer treatment-related symptoms. The purpose of the symposium was to identify research gaps, describe the need for high-quality randomized prospective studies of medical cannabis for palliative care in patients with cancer, and evaluate the impact of medical cannabis on cancer survivors’ quality of life. Further, education of clinicians and affiliated health-care providers in guiding cancer patients in using cannabis for cancer care would benefit patients. Together, these steps will further aid in refining the use of cannabis and cannabinoids for symptom palliation and improve safety and efficacy for patients.
... CBD is the most studied phytocannabinoid in TNBC (Table 2). It has been reported that this phytocannabinoid reduces the proliferation of MDA-MB-231 cells through the direct activation of TRPV1 receptors and possibly through other yet uncharacterized CBD targets [109,110]. However, it was also proposed that CBD induces apoptosis in this cell model through the involvement of CB1, CB2 and TRPV1 receptors. ...
Article
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Although cannabinoids have been used for centuries for diverse pathological conditions, recently, their clinical interest and application have emerged due to their diverse pharmacological properties. Indeed, it is well established that cannabinoids exert important actions on multiple sclerosis, epilepsy and pain relief. Regarding cancer, cannabinoids were first introduced to manage chemotherapy-related side effects, though several studies demonstrated that they could modulate the proliferation and death of different cancer cells, as well as angiogenesis, making them attractive agents for cancer treatment. In relation to breast cancer, it has been suggested that estrogen receptor-negative (ER−) cells are more sensitive to cannabinoids than estrogen receptor-positive (ER+) cells. In fact, most of the studies regarding their effects on breast tumors have been conducted on triple-negative breast cancer (TNBC). Nonetheless, the number of studies on human epidermal growth factor receptor 2-positive (HER2+) and ER+ breast tumors has been rising in recent years. However, besides the optimistic results obtained thus far, there is still a long way to go to fully understand the role of these molecules. This review intends to help clarify the clinical potential of cannabinoids for each breast cancer subtype.
... Around the turn of the millennium, the non-selective cation channel transient receptor potential vanilloid 1 (TRPV1) was described as an additional receptor target for several cannabinoids such as AEA [16] and the non-psychoactive phytocannabinoid CBD [17]. Among the phytocannabinoids, THC exhibits the properties of an agonist at the CB 2 receptor and a partial agonist at the CB 1 receptor [18], as well as an agonist at the G protein-coupled receptor (GPR) 55 [19]. ...
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Drugs that target the endocannabinoid system are of interest as pharmacological options to combat cancer and to improve the life quality of cancer patients. From this perspective, cannabinoid compounds have been successfully tested as a systemic therapeutic option in a number of preclinical models over the past decades. As a result of these efforts, a large body of data suggests that the anticancer effects of cannabinoids are exerted at multiple levels of tumour progression via different signal transduction mechanisms. Accordingly, there is considerable evidence for cannabinoid-mediated inhibition of tumour cell proliferation, tumour invasion and metastasis, angiogenesis and chemoresistance, as well as induction of apoptosis and autophagy. Further studies showed that cannabinoids could be potential combination partners for established chemotherapeutic agents or other therapeutic interventions in cancer treatment. Research in recent years has yielded several compounds that exert promising effects on tumour cells and tissues in addition to the psychoactive Δ ⁹ -tetrahydrocannabinol, such as the non-psychoactive phytocannabinoid cannabidiol and inhibitors of endocannabinoid degradation. This review provides an up-to-date overview of the potential of cannabinoids as inhibitors of tumour growth and spread as demonstrated in preclinical studies.
... In addition, its relaxing effect could help attenuate symptoms emotionally and mentally, in a typical way of integrative medicine, meeting the exceptional demands and growing public enthusiasm for botanical medicines [24,25]. Recently, the neuroprotective effects of CBD have been reported in animal models of PD [26,27] that are either cannabinoid-receptor independent by reducing glutamate toxicity mediated by NMDA, AMPA, or kainate receptors or indirectly act on the cannabinoid system by blocking anandamide uptake and inhibiting its enzymatic hydrolysis [28][29][30]. However, the clinical relevance of CBD based therapies on PD motor symptoms has not been systematically evaluated [31]. ...
Article
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Parkinson’s disease (PD) is a common neurodegenerative disease characterized by a disorder of the dopaminergic system in the midbrain, causing classical PD motor symptoms. The therapeutic effect of cannabidiol (CBD) on PD has been a research frontier in recent years. However, the pathogenesis of PD and the therapeutic mechanism of cannabinoid remain unclear. To further study the causes of PD and the effect of CBD on PD, we exposed the PD transgenic mouse model to CBD and then estimated the motorial and postural coordination through a modified swim test. Afterwards, the mechanism was investigated via the histopathology of substantia nigra and the gut-brain metabolic analysis in the approach of UHPLC-TOF-MS. The results showed that CBD significantly improved motor deficits of PD model and protected the substantia nigra area. The metabolic function of fatty acid biosynthesis, arginine biosynthesis/metabolism, butanoate (ketone body) metabolism, β-alanine metabolism, and pantothenate/CoA biosynthesis was highlighted in the pathological and therapeutic process along the gut-brain axis. In conclusion, CBD could attenuate PD via the neuroprotective effect on the midbrain. The attenuation of the central nervous system in turn improved motor performance of PD, which might be partially induced by the metabolic interaction between the gut-brain. In view of gut-brain metabolomics, the mechanism of PD pathogenesis and the effect of CBD on PD are highly related to the biosynthesis and metabolism of energy and essential substance.
... CBD has been reported to be an antagonist of the type 1 vanilloid receptor in protein binding studies. Both CBD and 7-OH-CBD inhibit fatty acid amid hydrolase in rats [66]. CBD and 6-alpha/beta-OH-CBD and other hydroxy-lated metabolites are capable of inhibiting microsomal CYP 2C and 3A in in vivo mouse model studies [54]. ...
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Background: In the past 60 years, Cannabis sativa L. has been an object of increasing interest because of the psychotropic effects of some of its constituents. These effects mainly arise from the cannabinoid ∆ 9-tetrahydrocannabinol (∆ 9-THC). C. sativa species also synthesize and accumulate the non-psychotropic compound cannabidiol (CBD). Due to their therapeutic potential, both cannabinoids are an object of medical research and drug development. More recently, CBD has received increasing interest as an ingredient in electronic cigarette liquids (e-liquids). This trend may have been reinforced by health and disease-related claims, often based on clinical studies, which are used to advertise CBD. CBD liquids may be based on full-spectrum hemp extracts, CBD isolates, or synthetic CBD, all of which may contain some residual levels of ∆ 9-THC from either natural content (in the extracts) or from possible degradation of CBD to ∆ 9-THC, which may occur during storage. There is uncertainty about safety regarding the consumption of CBD (and ∆ 9-THC) in e-liquids. The aim of this publication was to present an approach for a toxicological risk assessment of CBD and ∆ 9-THC relevant to e-liquids by using the benchmark dose (BMD) approach. Materials and Methods: Before an analysis to estimate a reference dose (RfD) for both cannabinoids, a systematic review of dose-response data was conducted. The data obtained were analyzed using the BMD approach to derive a benchmark dose lower confidence limit (BMDL). The BMDL was used as a point of departure to estimate the RfD. Results: No adequate human data suitable for dose-response modeling were identified. Based on animal data, the RfD values for the most sensitive endpoints were selected. For CBD, an RfD for acute exposure of 1 mg/kg body weight (bw) was estimated. For ∆ 9-THC, an acute RfD was found to be 0.006 mg/kg bw. Additionally, the RfD for chronic exposure to CBD was estimated to be 4 mg/kg bw per day. The respective endpoints for CBD were a reduction in norepinephrine turnover and a reduction in uterus weight. The endpoint for ∆ 9-THC was a change in blood pressure. Conclusions: Because of the limited availability and quality of dose-response data, it cannot be excluded that the estimated RfD values might be afflicted with considerable uncertainties. Therefore, it is recommended to conduct further research on dose-response data, preferably from human studies. Keywords: cannabis; cannabidiol; ∆ 9-tetrahydrocannabinol; CBD; ∆ 9-THC; e-cigarette; e-liquid; inhalation; risk assessment; benchmark dose; toxicology
... CBD decreases glutamate concentration under in vitro hypoxia/ischemia conditions, an effect associated with activating adenosine A 1A , CB 1 , and CB 2 receptors [75]. Concerning the endocannabinoid system, studies indicate that CBD inhibits the enzymatic degradation and reuptake of anandamide [76]. Enhanced levels of anandamide can result in activation of CB 1 receptors with a subsequent decrease of glutamate release [77,78]. ...
Article
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This study aimed to determine if orally administered cannabidiol (CBD) lessens the cortical over-release of glutamate induced by a severe traumatic brain injury (TBI) and facilitates functional recovery. The short-term experiment focused on identifying the optimal oral pretreatment of CBD. Male Wistar rats were pretreated with oral administration of CBD (50, 100, or 200 mg/kg) daily for 7 days. Then, extracellular glutamate concentration was estimated by cortical microdialysis before and immediately after a severe TBI. The long-term experiment focused on evaluating the effect of the optimal treatment of CBD (pre- vs. pre- and post-TBI) 30 days after trauma. Sensorimotor function, body weight, and mortality rate were evaluated. In the short term, TBI induced a high release of glutamate (738% ± 173%; p < 0.001 vs. basal). Oral pretreatment with CBD at all doses tested reduced glutamate concentration but with higher potency at when animals received 100 mg/kg (222 ± 33%, p < 0.01 vs. TBI), an effect associated with a lower mortality rate (22%, p < 0.001 vs. TBI). In the long-term experiment, the TBI group showed a high glutamate concentration (149% p < 0.01 vs. SHAM). In contrast, animals receiving the optimal treatment of CBD (pre- and pre/post-TBI) showed glutamate concentrations like the SHAM group (p > 0.05). This effect was associated with high sensorimotor function improvement. CBD pretreatment, but not pre-/post-treatment, induced a higher body weight gain (39% ± 2.7%, p < 0.01 vs. TBI) and lower mortality rate (22%, p < 0.01 vs. TBI). These results support that orally administered CBD reduces short- and long-term TBI-induced excitotoxicity and facilitated functional recovery. Indeed, pretreatment with CBD was sufficient to lessen the adverse sequelae of TBI.
... Studies that investigated acute and chronic treatments of chronic neuropathic pain-induced rats with isolated CBD showed significantly increased mechanical and thermal threshold when compared to animals that received vehicle, evaluated by von Frey and hot plate tests (Xiong et al., 2012;Harris et al., 2016;King et al., 2017;Abraham et al., 2020;Silva-Cardoso et al., 2021). A plausible hypothesis that might explain how CBD improves the pathologic pain sensation is related to an increase in AEA levels due to FAAH inhibition and their agonist activity on TRPV1 agonist (Bisogno et al., 2001;Massi et al., 2008;Silva-Cardoso et al., 2021; Figure 2A). Silva-Cardoso et al. (2021) also demonstrated that CBD treatment decreased CB1R expression in pain matrix regions, which was up-regulated in animals submitted to chronic neuropathic pain models. ...
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Despite the importance of pain as a warning physiological system, chronic neuropathic pain is frequently caused by damage in the nervous system, followed by persistence over a long period, even in the absence of dangerous stimuli or after healing of injuries. Chronic neuropathic pain affects hundreds of millions of adults worldwide, creating a direct impact on quality of life. This pathology has been extensively characterized concerning its cellular and molecular mechanisms, and the endocannabinoid system (eCS) is widely recognized as pivotal in the development of chronic neuropathic pain. Scientific evidence has supported that phyto-, synthetic and endocannabinoids are efficient for pain management, while strong data arise from the therapeutic use of Cannabis-derived products. The use of medicinal Cannabis products is directed toward not only relieving symptoms of chronic pain, but also improving several aspects of patients’ welfare. Here, we review the involvement of eCS, along with other cellular and molecular elements, in chronic neuropathic pain pathology and how this system can be targeted for pain management.
... The main nonpsychotomimetic constituent of Cannabis sativa is cannabidiol (CBD) (Izzo et al. 2009), a multi-target compound, which interferes with G-protein-coupled receptors (Thomas et al. 2007;Laprairie et al. 2015;Russo et al. 2005;Seeman 2016;Carrier et al. 2006;Gonca and Darıcı 2015), ion channel receptors (Ali et al. 2015;Ghovanloo et al. 2018), and enzymes (Usami et al. 2008;Jiang et al. 2013;Valvassori et al. 2013;Evans et al. 1987). CBD modulates the endocannabinoid system by inhibiting the degradation of anandamide, catalyzed by the enzyme fatty acid amide hydrolase (FAAH) (Bisogno et al. 2001), and indirectly enhancing the function of cannabinoid receptors (CB1R and CB2R). Preliminary clinical trials have suggested that CBD reduces PTSD severity (García-Gutiérrez et al. 2020). ...
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Rationale and objectives Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience and disturbances in fear memory regulation, and currently lacks effective medication. Cannabidiol is a main constituent of Cannabis sativa; it has no psychotomimetic effects and has been implicated in modulating fear learning in mammals. Using a mouse PTSD model, we investigated the effects of CBD on PTSD-like behaviors and the modulation of trauma-related fear memory, a crucial process leading to core symptoms of PTSD. Methods We applied the modified pre-shock model to evaluated PTSD-like behaviors from days 3 to 26. The measures included the freezing time to the conditioned context, open field test, elevated plus maze test, and social interaction test. CBD and sertraline were administered at different stages of fear memory. Results CBD (10 mg/kg, i.p.) administration alleviated main PTSD-like symptoms in the mouse pre-shock model by attenuating trauma-related fear memory and anxiety-like behavior, and increasing social interaction behavior. The effects of CBD were apparent irrespective of whether it was administered before, during, or after re-exposure to the aversive context. However, sertraline (15 mg/kg, p.o.) was only effective when administered before the behavioral test. CBD also reduced the consolidation, retrieval, and reconsolidation of trauma-related fear memory, whereas sertraline only reduced fear-memory retrieval. Conclusion CBD produced anti-PTSD-like actions in mice and disrupted trauma-related fear memory by interfering with multiple aspects of fear memory processing. These findings indicate that CBD may be a promising candidate for treating PTSD.
Article
The legalization of cannabis in many countries, as well as the decrease in perceived risks of cannabis, have contributed to the increase in cannabis use medicinally and recreationally. Like many drugs of abuse, cannabis and cannabis-derived drugs are prone to misuse, and long-term usage can lead to drug tolerance and the development of Cannabis Use Disorder (CUD). These drugs signal through cannabinoid receptors, which are expressed in brain regions involved in the neural processing of reward, habit formation, and cognition. Despite the widespread use of cannabis and cannabinoids as therapeutic agents, little is known about the neurobiological mechanisms associated with CUD and cannabinoid drug use. In this article, we discuss the advances in research spanning animal models to humans on cannabis and synthetic cannabinoid actions on synaptic transmission, highlighting the neurobiological mechanisms following acute and chronic drug exposure. This article also highlights the need for more research elucidating the neurobiological mechanisms associated with CUD and cannabinoid drug use.
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The medical application of cannabidiol (CBD) has been gathering increasing attention in recent years. This non-psychotropic cannabis-derived compound possesses antiepileptic, antipsychotic, anti-inflammatory and anxiolytic properties. Recent studies report that it also exerts antineoplastic effects in multiple types of cancers, including melanoma. In this in vitro study we tried to reveal the anticancer properties of CBD in malignant melanoma cell lines (SK-MEL 28, A375, FM55P and FM55M2) administered alone, as well as in combination with mitoxantrone (MTX) or cisplatin (CDDP). The effects of CBD on the viability of melanoma cells were measured by the MTT assay; cytotoxicity was determined in the LDH test and proliferation in the BrdU test. Moreover, the safety of CBD was tested in human keratinocytes (HaCaT) in LDH and MTT tests. Results indicate that CBD reduces the viability and proliferation of melanoma-malignant cells and exerts additive interactions with MTX. Unfortunately, CBD produced antagonistic interaction when combined with CDDP. CBD does not cause significant cytotoxicity in HaCaT cell line. In conclusion, CBD may be considered as a part of melanoma multi-drug therapy when combined with MTX. A special attention should be paid to the combination of CBD with CDDP due to the antagonistic interaction observed in the studied malignant melanoma cell lines.
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Cannabis sativa L. is increasingly emerging for its protective role in modulating neuroinflammation, a complex process orchestrated among others by microglia, the resident immune cells of the central nervous system. Phytocannabinoids, especially cannabidiol (CBD), terpenes, and other constituents trigger several upstream and downstream microglial intracellular pathways. Here, we investigated the molecular mechanisms of a CBD‐ and terpenes‐enriched C. sativa extract (CSE) in an in vitro model of neuroinflammation. We evaluated the effect of CSE on the inflammatory response induced by exposure to lipopolysaccharide (LPS) in BV‐2 microglial cells, compared with CBD and β‐caryophyllene (CAR), CB2 receptors (CB2r) inverse and full agonist, respectively. The LPS‐induced upregulation of the pro‐inflammatory cytokines IL‐1β, IL‐6, and TNF‐α was significantly attenuated by CSE and only partially by CBD, whereas CAR was ineffective. In BV‐2 cells, these anti‐inflammatory effects exerted by CSE phytocomplex were only partially dependent on CB2r modulation and they were mediated by the regulation of enzymes responsible for the endocannabinoids metabolism, by the inhibition of reactive oxygen species release and the modulation of JNK/p38 cascade with consequent NF‐κB p65 nuclear translocation suppression. Our data suggest that C. sativa phytocomplex and its multitarget mechanism could represent a novel therapeutic strategy for neuroinflammatory‐related diseases.
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Plant-based, synthetic, and endogenous cannabinoids have been shown to control a diverse array of biological processes, including regulation of cell fate across cancers. Their promise as broad-based antitumor agents in preclinical models has led to the initiation of pilot clinical trials. Session 5 of the National Cancer Institute’s Cannabis, Cannabinoids and Cancer Research Symposium provides an overview of this research topic. Overall, the presentations highlight cannabinoid signal transduction and specific molecular mechanisms underlying cannabinoid antitumor activity. They also demonstrate the broad-based antitumor activity of the plant-based, synthetic, and endogenous cannabinoid compounds. Importantly, evidence is presented demonstrating when cannabinoids may be contraindicated as a treatment for cancer, as in the case of human papilloma virus–meditated oropharynx cancer or potentially other p38 MAPK pathway–driven cancers. Finally, it is discussed that a key to advancing cannabinoids into the clinic is to conduct well-designed, large-scale clinical trials to determine whether cannabinoids are effective antitumor agents in cancer patients.
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Cannabidiol (CBD) is a phytocannabinoid contained in the Cannabis sativa plant, devoid of psychotomimetic effects but with a broad-spectrum pharmacological activity. Because of its pharmacological profile and its ability to counteract the psychoactive Δ9-tetrahydrocannabinol (Δ9THC), CBD may be a potential treatment for several psychiatric and neurodegenerative disorders. In this study, we performed a doseresponse evaluation of CBD modulatory effects on BDNF, a neurotrophin subserving pleiotropic effects on the brain, focusing on the cortico-striatal pathway for its unique role in the brain trafficking of BDNF. Male adult rats were exposed to single and repeated CBD treatments at different dosing regimen (5, 15, and 30 mg/kg), to investigate the rapid modulation of the neurotrophin (1 h after the single treatment) as well as a potential drug-free time point (24 h after the repeated treatment). We show here, for the first time, that CBD can be found in the rat brain and, specifically, in the medial prefrontal cortex (mPFC) following single or repeated exposure. In fact, we found that CBD is present in the mPFC of rats treated either acutely or repeatedly with the phytocannabinoid, with a clear doseresponse profile. From a molecular standpoint, we found that single, but not repeated, CBD exposure upregulates BDNF in the mPFC, while the repeated exposure increased BDNF only in the striatum, with a slight decrease in the mPFC. Together, these data reveal a CBD dose-dependent and anatomically specific modulation of BDNF, which may be functionally relevant and may represent an added value for CBD as a supplement.
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Dravet syndrome (DS) is a channelopathy, neurodevelopmental, epileptic encephalopathy characterized by seizures, developmental delay, and cognitive impairment that includes susceptibility to thermally induced seizures, spontaneous seizures, ataxia, circadian rhythm and sleep disorders, autistic-like behaviors, and premature death. More than 80% of DS cases are linked to mutations in genes which encode voltage-gated sodium channel subunits, SCN1A and SCN1B, which encode the Nav1.1α subunit and Nav1.1β1 subunit, respectively. There are other gene mutations encoding potassium, calcium, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels related to DS. One-third of patients have pharmacoresistance epilepsy. DS is unresponsive to standard therapy. Cannabidiol (CBD), a non-psychoactive phytocannabinoid present in Cannabis, has been introduced for treating DS because of its anticonvulsant properties in animal models and humans, especially in pharmacoresistant patients. However, the etiological channelopathiological mechanism of DS and action mechanism of CBD on the channels are unclear. In this review, we summarize evidence of the direct and indirect action mechanism of sodium, potassium, calcium, and HCN channels in DS, especially sodium subunits. Some channels’ loss-of-function or gain-of-function in inhibitory or excitatory neurons determine the balance of excitatory and inhibitory are associated with DS. A great variety of mechanisms of CBD anticonvulsant effects are focused on modulating these channels, especially sodium, calcium, and potassium channels, which will shed light on ionic channelopathy of DS and the precise molecular treatment of DS in the future.
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Transient receptor potential (TRP) channels are critical receptors in the transduction of nociceptive stimuli. The microenvironment of diverse types of cancer releases substances, including growth factors, neurotransmitters, and inflammatory mediators, which modulate the activity of TRPs through the regulation of intracellular signaling pathways. The modulation of TRP channels is associated with the peripheral sensitization observed in patients with cancer, which results in mild noxious sensory stimuli being perceived as hyperalgesia and allodynia. Secondary metabolites derived from plant extracts can induce the activation, blocking, and desensitization of TRP channels. Thus, these compounds could act as potential therapeutic agents, as their antinociceptive properties could be beneficial in relieving cancer-derived pain. In this review, we will summarize the role of TRPV1 and TRPA1 in pain associated with cancer and discuss molecules that have been reported to modulate these channels, focusing particularly on the mechanisms of channel activation associated with molecules released in the tumor microenvironment.
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Background: The mechanisms underlying the antipsychotic potential of cannabidiol (CBD) remain unclear but growing evidence indicates that dysfunction in the insula, a key brain region involved in the processing of motivationally salient stimuli, may have a role in the pathophysiology of psychosis. Here, we investigate whether the antipsychotic mechanisms of CBD are underpinned by their effects on insular activation, known to be involved in salience processing. Methods: A within-subject, crossover, double-blind, placebo-controlled investigation of 19 healthy controls and 15 participants with early psychosis was conducted. Administration of a single dose of CBD was compared with placebo in psychosis participants while performing the monetary incentive delay task, an fMRI paradigm. Anticipation of reward and loss were used to contrast motivationally salient stimuli against a neutral control condition. Results: No group differences in brain activation between psychosis patients compared with healthy controls were observed. Attenuation of insula activation was observed following CBD, compared to placebo. Sensitivity analyses controlling for current cannabis use history did not affect the main results. Conclusion: Our findings are in accordance with existing evidence suggesting that CBD modulates brain regions involved in salience processing. Whether such effects underlie the putative antipsychotic effects of CBD remains to be investigated.
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Background The prevalence of cannabis use and cannabis use disorders (CUD) has significantly increased over time. However, there are no approved pharmacological treatments for CUD. The aim of this study was to determine the efficacy and safety of various medical cannabinoids in the treatment of CUD.Methods We conducted a systematic review of randomized controlled trials which evaluated the therapeutic potential of medical cannabinoids in individuals with CUD and summarized the main study outcomes in terms of cannabis use, abstinence, withdrawal symptoms, craving, retention in treatment and adverse events.ResultsWe identified eight trials with a total of 667 study participants. Dronabinol reduced cannabis withdrawal symptoms whereas nabiximols, cannabidiol and PF-04457845, a fatty acid amide inhibitor, also reduced cannabis use and improved abstinence, compared to placebo. Nabilone failed to demonstrate efficacy in the treatment of CUD. All medications were well-tolerated.Conclusions Cannabinoid receptor agonists, i.e., dronabinol and nabilone, showed only limited or no therapeutic potential in the treatment of CUD. In contrast, modulators of endocannabinoid activity, i.e., nabiximols, cannabidiol and PF-04457845, demonstrated broader efficacy which covered almost all aspects of CUD. Endocannabinoid modulation appears to be a promising treatment approach in CUD, but the evidence to support this strategy is still small and future research in this direction is needed.
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The general use of “medical cannabis” and “cannabis-based drugs” in the treatment of cancer patients cannot be recommended due to the currently, still insufficient amount of data available. However, taking into account the legal framework, it is possible to consider its use in selected cases. Patients must be informed in detail about treatment goals, relevant side effects to be expected, and the character of a “therapy attempt”. Further the effectiveness and safety of the treatment should be critically re-evaluated after a few weeks and, if necessary, be terminated in the event of insufficient clinical improvement or if intolerable side effects occur. Smoking cannabis should be avoided and oral or oromucosal preparations should be used. Due to the narrow therapeutic range, the lowest possible starting dose is recommended, particularly for older patients, in the case of comorbidities, or in patients taking centrally acting drugs. Little is known about the clinically relevant interaction risks of cannabis. Especially in the context of modern cancer treatment, increased attention is required.
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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.
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The latest years have witnessed a growing interest towards the relationship between neuropsychiatric disease in children with autism spectrum disorders (ASD) and severe alterations in gut microbiota composition. In parallel, an increasing literature has focused the attention towards the association between derangement of the endocannabinoids machinery and some mechanisms and symptoms identified in ASD pathophysiology, such as alteration of neural development, immune system dysfunction, defective social interaction and stereotypic behavior. In this narrative review, we put together the vast ground of endocannabinoids and their partnership with gut microbiota, pursuing the hypothesis that the crosstalk between these two complex homeostatic systems (bioactive lipid mediators, receptors, biosynthetic and hydrolytic enzymes and the entire bacterial gut ecosystem, signaling molecules, metabolites and short chain fatty acids) may disclose new ideas and functional connections for the development of synergic treatments combining “gut-therapy,” nutritional intervention and pharmacological approaches. The two separate domains of the literature have been examined looking for all the plausible (and so far known) overlapping points, describing the mutual changes induced by acting either on the endocannabinoid system or on gut bacteria population and their relevance for the understanding of ASD pathophysiology. Both human pathology and symptoms relief in ASD subjects, as well as multiple ASD-like animal models, have been taken into consideration in order to provide evidence of the relevance of the endocannabinoids-microbiota crosstalk in this major neurodevelopmental disorder.
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The endocannabinoid system (ECS) is composed of the endocannabinoid ligands anandamide (AEA) and 2-arachidonoylgycerol (2-AG), their target cannabinoid receptors (CB1 and CB2) and the enzymes involved in their synthesis and metabolism (N-acyltransferase and fatty acid amide hydrolase (FAAH) in the case of AEA and diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) in the case of 2-AG). The origins of ECS dysfunction in major neuropsychiatric disorders remain to be determined, and this paper explores the possibility that they may be associated with chronically increased nitro-oxidative stress and activated immune-inflammatory pathways, and it examines the mechanisms which might be involved. Inflammation and nitro-oxidative stress are associated with both increased CB1 expression, via increased activity of the NADPH oxidases NOX4 and NOX1, and increased CNR1 expression and DNA methylation; and CB2 upregulation via increased pro-inflammatory cytokine levels, binding of the transcription factor Nrf2 to an antioxidant response element in the CNR2 promoter region and the action of miR-139. CB1 and CB2 have antagonistic effects on redox signalling, which may result from a miRNA-enabled negative feedback loop. The effects of inflammation and oxidative stress are detailed in respect of AEA and 2-AG levels, via effects on calcium homeostasis and phospholipase A2 activity; on FAAH activity, via nitrosylation/nitration of functional cysteine and/or tyrosine residues; and on 2-AG activity via effects on MGLL expression and MAGL. Finally, based on these detailed molecular neurobiological mechanisms, it is suggested that cannabidiol and dimethyl fumarate may have therapeutic potential for major depressive disorder, bipolar disorder and schizophrenia.
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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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Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid- and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (β = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (β = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens.
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Rationale Cannabidiol (CBD) and cannabidiolic acid (CBDA) are non-psychoactive components of the cannabis plant. CBD has been well characterised to have anxiolytic and anticonvulsant activity, whereas the behavioural effects of CBDA are less clear. Preclinical and clinical data suggests that CBD has antipsychotic properties and reduces methamphetamine self-administration in rats. An animal model that is commonly used to mimic the neurochemical changes underlying psychosis and drug dependence is methamphetamine (METH) sensitisation, where repeated administration of the psychostimulant progressively increases the locomotor effects of METH. Objective The aim of this study was to determine whether CBD or CBDA attenuate METH-induced sensitisation of locomotor hyperactivity in rats. Methods Eighty-six male Sprague Dawley rats underwent METH sensitisation protocol where they were subjected to daily METH (1 mg/kg on days 2 and 8, 5 mg/kg on days 3–7; i.p.) injections for 7 days. After 21 days of withdrawal, rats were given a prior injection of CBD (0, 40 and 80 mg/kg; i.p.) or CBDA (0, 0.1, 10 and 1000 µg/kg; i.p.) and challenged with acute METH (1 mg/kg; i.p.). Locomotor activity was then measured for 60 min. Results Rats displayed robust METH sensitisation as evidenced by increased locomotor activity to METH challenge in METH-pretreated versus SAL-pretreated rats. CBD (40 and 80 mg/kg) reduced METH-induced sensitisation. There was no effect of any CBDA doses on METH sensitisation or acute METH-induced hyperactivity. Conclusion These results demonstrate that CBD, but not CBDA, reduces METH sensitisation of locomotor activity in rats at pharmacologically effective doses, thus reinforcing evidence that CBD has anti-addiction and antipsychotic properties.
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Cannabidiol (CBD) may represent a promising therapeutic tool for treating opioid use disorder (OUD). This study was aimed to evaluate the effects of CBD on the behavioural and gene expression alterations induced by spontaneous heroin withdrawal. Thirty hours after cessation of 8‐day heroin treatment (5, 10, 20 and 40 mg·kg−1/12 h; s.c.), spontaneous heroin withdrawal was evaluated in CD1 male mice. The effects of CBD (5, 10 and 20 mg·kg−1; i.p.) on withdrawal‐related behaviour were evaluated by measuring anxiety‐like behaviour, motor activity and somatic signs. Furthermore, gene expression changes of mu‐opioid receptor (Oprm1), proopiomelanocortin (Pomc), cannabinoid CB1 (Cnr1) and CB2 (Cnr2) receptors in the nucleus accumbens (NAcc) and tyrosine hydroxylase (TH) and Pomc in the ventral tegmental area (VTA) were also evaluated by real‐time PCR. Anxiety‐like behaviour, motor activity and withdrawal‐related somatic signs were significantly increased in heroin‐treated mice compared to the control group. Interestingly, CBD treatment significantly reduced these behavioural impairments and normalized gene expression of Cnr1 and Pomc in the NAcc and TH in the VTA of mice exposed to spontaneous heroin withdrawal. Also, CBD induced an up‐regulation of Cnr2, whereas it did not change the increased gene expression of Oprm1 in the NAcc of abstinent animals. The results suggest that CBD alleviates spontaneous heroin withdrawal and normalizes the associated gene expression changes. Future studies are needed to determine the relevance of CBD as a potential therapeutic tool for the treatment of heroin withdrawal. CBD alleviates spontaneous heroin withdrawal and normalizes the associated gene expression changes in CD1 male mice.
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The endocannabinoid system is widely studied due to its interactions with cannabis and its role in modulating physiological responses. While most research has focused on the effects of cannabis on adult endocannabinoid systems, recent studies have begun to investigate the role of the endocannabinoid system in developing organisms. However, little is known about the spatial or temporal expression of these receptors during early development. This study combines reverse-transcriptase PCR with in situ hybridizations to compile a timeline of the developmental expression of six key cannabinoid receptors; cb1, cb2, trpv1, trpa1a, trpa1b, and gpr55 in zebrafish embryos, starting from as early as 6 hours post fertilization (hpf) until 3 days post fertilization. This time frame is roughly equivalent to two to ten weeks in human embryonic development. All six genes were confirmed to be expressed within this time range and share similarities with human and rodent expression. Cb1 expression was first detected between 12 and 24 hpf in the retina and CNS, and its expression increased thereafter and was more evident in the olfactory bulb, tegmentum, hypothalamus and gut. Cb2 expression was relatively high at the 6 and 24 hpf timepoints, as determined by RT-PCR, but was undetectable at other times. Trpv1 was first detected at 1 dpf in the trigeminal ganglia, Rohon-Beard neurons and lateral line, and its expression increased in the first 3 days post fertilization (dpf). Expression of trpa1a was first detected as late as 3 dpf in vagal neurons, whereas trpa1b was first detected at 1 dpf associated with trigeminal, glossopharyngeal and vagal ganglia. Expression of gpr55 was diffuse and widespread throughout the brain and head region but was undetectable elsewhere in the embryo. Thus, receptor expression was found to be enriched in the central nervous system and within sensory neurons. This work aims to serve as a foundation for further investigation on the role of cannabinoid and cannabinoid-interacting receptors in early embryonic development.
Chapter
The global demand for innovative consumer products containing cannabis- and hemp-derived constituents has placed safety at the forefront of consumers, retailers, and regulatory agencies. Safety studies have not kept pace with the diverse number of consumer “health” products, containing the main constituents of cannabis and hemp (e.g., Δ⁹-tetrahydrocannabinol (THC), cannabidiol, (CBD), and terpenes), entering the marketplace. In particular, the reproductive and developmental effects of cannabis, hemp, and their isolated constituents on vulnerable populations including pregnant women, newborns, and youth remain to be fully understood. Discrepancies in existing preclinical and clinical data do not project confidence in the safety concerns concluded from investigators. This chapter focuses on the potential reproductive and developmental toxicities of both cannabis- and hemp-derived constituents with a focus on the interpretation and translation of nonclinical data to humans given ethical constraints over conducting intervention-type clinical trials in sensitive populations.
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Parkinson’s disease (PD) is a neurodegenerative disease usually caused by neuroinflammation, oxidative stress and other etiologies. Recent studies have found that the cannabinoid system present in the basal ganglia has a strong influence on the progression of PD. Altering the cannabinoid receptor activation status by modulating endogenous cannabinoid (eCB) levels can exert an anti-movement disorder effect. Therefore, the development of drugs that modulate the endocannabinoid system may be a novel strategy for the treatment of PD. However, eCB regulation is complex, with diverse cannabinoid receptor functions and the presence of dopaminergic, glutamatergic, and γ-aminobutyric signals interacting with cannabinoid signaling in the basal ganglia region. Therefore, the study of eCB is challenging. Here, we have described the function of the cannabinoid system in the basal ganglia and its association with PD in three parts (eCBs, cannabinoid receptors, and factors regulating the cannabinoid metabolism) and summarized the mechanisms of action related to the cannabinoid analogs currently aimed at treating PD. The shortcomings identified from previous studies and the directions that should be explored in the future will provide insights into new approaches and ideas for the future development of cannabinoid-based drugs and the treatment of PD.
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Cannabis is now legal in many countries and while numerous studies have reported on its impact on cognition and appetite regulation, none have examined fatty acid metabolism in young cannabis users. We conducted an exploratory analysis to evaluate cannabis impact on fatty acid metabolism in cannabis users (n = 21) and non‐cannabis users (n = 16). Serum levels of some saturated and monounsaturated fatty acids, including palmitic, palmitoleic, and oleic acids were higher in cannabis users compared to nonusers. As palmitic acid can be derived from diet or lipogenesis from sugars, we evaluated lipogenesis using a de novo lipogenesis index (palmitate/linoleic acid) and carbon‐specific isotope analysis, which allows for the determination of fatty acid 13C signature. The significantly higher de novo lipogenesis index in the cannabis users group along with a more enriched 13C signature of palmitic acid suggested an increase in lipogenesis. In addition, while serum glucose concentration did not differ between groups, pyruvate and lactate were lower in the cannabis user group, with pyruvate negatively correlating with palmitic acid. Furthermore, the endocannabinoid 2‐arachidonoylglycerol was elevated in cannabis users and could contribute to lipogenesis by activating the cannabinoid receptor 1. Because palmitic acid has been suggested to increase inflammation, we measured peripheral cytokines and observed no changes in inflammatory cytokines. Finally, an anti‐inflammatory metabolite of palmitic acid, palmitoylethanolamide was elevated in cannabis users. Our results suggest that lipogenic activity is increased in cannabis users; however, future studies, including prospective studies that control dietary intake are required.
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Anandamide (arachidonoylethanolamide, AnNH) and palmitoylethanolamide (PEA) have been proposed as the physiological ligands, respectively, of central and peripheral cannabinoid receptors. Both of these receptors are expressed in immune cells, including macrophages and mast cells/basophils, where immunomodulatory and/or anti-inflammatory actions of AnNH and PEA have been recently reported. We now provide biochemical grounds to these actions by showing that the biosynthesis, uptake, and degradation of AnNH and PEA occur in leukocytes. On stimulation with ionomycin, J774 macrophages and RBL-2H3 basophils produced AnNH and PEA, probably through the hydrolysis of the corresponding N-acylphosphatidylethanolamines, also found among endogenous phospholipids. Immunological challenge of RBL-2H3 cells also caused AnNH and PEA release. The chemical structure and the amounts of AnNH and PEA produced upon ionomycin stimulation were determined by means of double radiolabeling experiments and isotope dilution gas chromatography/electron impact mass spectrometry. Both cell lines rapidly sequestered the two amides from the culture medium through temperature-dependent, saturable and chemically inactivable mechanisms. Once uptaken by basophils, AnNH and PEA compete for the same inactivating enzyme which catalyzes their hydrolysis to ethanolamine. This enzyme was found in both microsomal and 10,000 × g fractions of RBL cell homogenates, and exhibited similar inhibition and temperature/pH dependence profiles but a significantly higher affinity for PEA with respect to neuronal “anandamide amidohydrolase.” The finding of biosynthetic and inactivating mechanisms for AnNH and PEA in macrophages and basophils supports the previously proposed role as local modulators of immune/inflammatory reactions for these two long chain acylethanolamides.
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The effects of the enantiomers of 11-hydroxy-Δ8-tetrahydrocannabinol-dimethylheptyl (11-OH-Δ8-THC-DMH) on spontaneous activity, rectal temperature, tail-flick latency, and catalepsy were studied in mice and in the dog static-ataxia model to determine the relative potency of each enantiomer. The (−)-enantiomer was active in all tests between 3–100 μg/kg, while the (+)-enantiomer was inactive at 30 mg/kg in the mouse and 1 mg/kg in the dog. The (−)-enantiomer was 100–800 times more potent than Δ9-THC in the mouse. The high degree of enantioselectivity and potency are suggestive of an interaction at a specific site such as a receptor.
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Evidence for the role of the cannabimimetic fatty acid derivatives (CFADs), i.e. anandamide (arachidonoylethanolamide, AEA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PEA), in the control of inflammation and of the proliferation of tumor cells is reviewed here. The biosynthesis of AEA, PEA, or 2-AG can be induced by stimulation with either Ca2+ ionophores, lipopolysaccharide, or platelet activating factor in macrophages, and by ionomycin or antigen challenge in rat basophilic leukemia (RBL-2H3) cells (a widely used model for mast cells). These cells also inactivate CFADs through re-uptake and/or hydrolysis and/or esterification processes. AEA and PEA modulate cytokine and/or arachidonate release from macrophages in vitro, regulate serotonin secretion from RBL-2H3 cells, and are analgesic in some animal models of inflammatory pain. However, the involvement of endogenous CFADs and cannabinoid CB1 and CB2 receptors in these effects is still controversial. In human breast and prostate cancer cells, AEA and 2-AG, but not PEA, potently inhibit prolactin and/or nerve growth factor (NGF)-induced cell proliferation. Vanillyl-derivatives of anandamide, such as olvanil and arvanil, exhibit even higher anti-proliferative activity. These effects are due to suppression of the levels of the 100 kDa prolactin receptor or of the high affinity NGF receptors (trk), are mediated by CB1–like cannabinoid receptors, and are enhanced by other CFADs. Inhibition of adenylyl cyclase and activation of mitogen-activated protein kinase underlie the anti-mitogenic actions of AEA. The possibility that CFADs act as local inhibitors of the proliferation of human breast cancer is discussed here.
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Capsaicin and its analogue N-arachidonoyl-vanillyl-amine (arvanil) are agonists of vanilloid VR1 receptors, and suppress spontaneous activity in mice through an unknown mechanism. Here, we tested in rats the effect on motor behavior of: (1) capsaicin; (2) N-linoleoyl-vanillyl-amine (livanil) and N-α-linolenoyl-vanillyl-amine (linvanil), which, unlike arvanil, have very little affinity for cannabinoid CB1 receptors; and (3) the endocannabinoid anandamide (N-arachidonoyl-ethanolamine), which is a full agonist at both cannabinoid CB1 and vanilloid VR1 receptors. All compounds, administered i.p., dose-dependently (0.1–10 mg/kg) inhibited ambulation and stereotypic behavior and increased inactivity in the open field test. The rank of potency observed in vivo (livanil>capsaicin>linvanil>anandamide) bore little resemblance with the relative potencies in a functional assay for rat vanilloid VR1 receptors (livanil=linvanil>capsaicin>anandamide) and even less with the relative affinities in rat CB1 receptor binding assays (anandamide>livanil>linvanil>capsaicin). The vanilloid VR1 receptor antagonist capsazepine (10 mg/kg, i.p.) blocked the effect of capsaicin but not of livanil or anandamide, whereas the CB1 receptor antagonist (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide.HCl (SR141716A, 3 mg/kg, i.p.) antagonized the actions of the CB1 receptor agonist Δ9-tetrahydrocannabinol, but not of livanil, anandamide or capsaicin. Anandamide occluded the effects of livanil on locomotion, possibly suggestive of a common mechanism of action for the two compounds. Finally, stimulation with capsaicin of cells expressing rat vanilloid VR1 receptors led to anandamide formation. These data suggest that motor behavior can be suppressed by the activation of: (1) vanilloid receptors, possibly via the intermediacy of anandamide; or (2) capsazepine- and SR141716A-insensitive sites of action for anandamide, livanil and linvanil, possibly the same that were previously suggested to mediate arvanil hypokinetic effects in mice.
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The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
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The 1,1-dimethylheptyl (DMH) homologue of 7-hydroxy-delta 6-tetrahydrocannabinol (3) is the most potent cannabimimetic substance reported so far. Hydrogenation of 3 leads to a mixture of the epimers of 5'-(1,1-dimethylheptyl)-7-hydroxyhexahydrocannabinol or to either the equatorial (7) or to the axial epimer (8), depending on the catalysts and conditions used. Compound 7 discriminates for delta 1-THC (2) in pigeons (ED50 = 0.002 mg/kg, after 4.5 h), at the potency level of 3, and binds to the cannabinoid receptor with a KD of 45 pM, considerably lower than the Ki of 180 pM measured for compound 3 and the Ki of 2.0 nM measured for CP-55940 (1), a widely employed ligand. Tritiated 7 was used as a novel probe for the cannabinoid receptor.
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The recent preparation of the enantiomers of 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl (THC-DMH), recrystallized to absolute enantiomeric purity, has made it possible to examine the requirement for stereospecificity for the interaction of this component with the cannabinoid receptor, defined by the binding of [3H]CP-55,940 and the adenylate cyclase enzyme. The enantiomer (-)11-OH-delta 8-THC-DMH exhibited a fully efficacious and potent (IC50 = 1.8 nM) inhibition of the accumulation of cAMP in intact N18TG2 cells. The (-)enantiomer was as efficacious and potent (Kinh = 7.2 nM) as desacetyllevonantradol in inhibiting adenylate cyclase activity in membrane preparations. The (-)enantiomer was able to compete fully for the specific binding of [3H]CP-55,940 to membranes from the brain of the rat in homologous displacement studies (Ki = 234 pM). The potency ratios exhibited by the (-) to (+)enantiomers of 11-OH-delta 8-THC-DMH exceeded 1000 for each of these activities.
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The effects of the enantiomers of 11-hydroxy-delta 8-tetrahydrocannabinol-dimethylheptyl (11-OH-delta 8-THC-DMH) on spontaneous activity, rectal temperature, tail-flick latency, and catalepsy were studied in mice and in the dog static-ataxia model to determine the relative potency of each enantiomer. The (-)-enantiomer was active in all tests between 3-100 micrograms/kg, while the (+)-enantiomer was inactive at 30 mg/kg in the mouse and 1 mg/kg in the dog. The (-)-enantiomer was 100-800 times more potent than delta 9-THC in the mouse. The high degree of enantioselectivity and potency are suggestive of an interaction at a specific site such as a receptor.
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Cannabidiol (CBD) has been shown to inhibit mouse hepatic mixed-function oxidations of several drugs after acute treatment, whereas repetitive treatment resulted in the restoration of drug-metabolizing capabilities. We have found that acute CBD treatment modestly decreased cytochrome P-450 content but markedly decreased hexobarbital hydroxylase, erythromycin N-demethylase, and 6 beta-testosterone hydroxylase activities. Repetitive CBD treatment, on the other hand, resulted in the restoration of cytochrome P-450 content as well as hexobarbital hydroxylase and erythromycin N-demethylase activities. However, after such repeated treatments a fresh dose of CBD can once again inactivate erythromycin N-demethylase activity but not hexobarbital hydroxylase activity. The resistance of hexobarbital hydroxylase to re-inactivation by CBD was paralleled by stimulation of pentoxyresorufin O-dealkylase activity and the appearance of a 50 kD protein that was immunoreactive to an antibody raised against rat hepatic cytochrome P-450b. CBD metabolism in vitro by microsomes prepared from such CBD-"induced" animals, resulted in a pattern of metabolites different from that observed from comparable incubations with liver microsomes from either untreated or phenobarbital-treated animals. Thus, it appears that CBD initially inactivates at least one cytochrome P-450 isozyme, but after repetitive CBD treatment, an isozyme is induced that is resistant to further re-inactivation by CBD. This isozyme appears to be immunochemically similar to, but somewhat functionally distinct from, the isozyme induced by phenobarbital treatment in mice.
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Rats and pigeons were trained to discriminate between the presence and absence of the effects of (-)-delta 9-tetrahydrocannabinol (THC) at doses of 3 and 0.56 mg/kg, respectively; injections were i.p. and i.m., 0.5 and 1.5 hr before session onset for the two species, respectively. Tests with the 1,1 dimethylheptyl (DMH) homolog of (-)- delta 8-THC as well as its 11-hydroxylated (11-OH) derivative [(-)-11-OH-delta 8-THC-DMH], showed that both compounds were more potent than the training compound, especially so in the case of the 11-OH product (66 and 80 times more potent than delta 9-THC in rats and pigeons, respectively). The enantiomer, (+)-11-OH-delta 8-THC-DMH, was inactive as a THC-like psychotomimetic in doses even up to 10 mg/kg [ED50 of (-)-11-OH-delta 8-THC being 0.01 mg/kg and 0.002 mg/kg in rats and pigeons, respectively]. Hence, the typical THC-like effects in rats and pigeons (and by extrapolation possibly also the feeling of "high" in humans), reside exclusively in the levo [(-)]-enantiomers of THC-type cannabinoids (at least in the pair studied by us) as demonstrated clearly in this study. Both (-)-delta 8-THC-DMH and (-)-11-OH-delta 8-THC-DMH had a slow onset and a long duration of action.
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The stimulation of prostaglandin E2 synthesis by delta 1-tetrahydrocannabinol in cultured cells is rapidly diminished by successive exposures to the drug at 24-hr intervals. Cannabidiol and cannabicyclol, two other constituents of cannabis, also displayed this in vitro tolerance effect. The phenomenon could, in addition, be observed by measuring the release of arachidonic acid from these cells, suggesting that the site of action of the cannabinoids is at one or more of the lipases that are believed to control prostaglandin synthesis under most conditions. Tolerance to cannabinoid action has been reported for a variety of in vivo parameters; thus, this in vitro system exhibits similar behavior and may, therefore, be a good model for studies on the molecular mechanisms involved in tetrahydrocannabinol action.
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This review will summarize the pharmacokinetic properties of Δ1-tetrahydrocannabinol mainly in man, since only limited information is available in experimental animals. We will also review the metabolites of Δ1-THC, with particular emphasis on those metabolites which have either psychotomimetic properties similar to Δ1-THC or which are eliminated in man. Metabolic tranformations have mainly been elucidated in various in vitro systems and in experimental animals. Only recently, more extensive information on the metabolism of Δ1-THC in man has become available. The pharmacokinetics of the isomer of Δ1-THC, viz. Δ6-THC, will be dealt with very briefly, because it only represents a minute constituent of marihuana. Two other major cannabinoids, cannabinol (CBN) and cannabidiol (CBD), will also only be briefly reviewed, because available data for these compounds is somewhat limited. We will review only more significant and recent results, since an extensive survey of all published material in the area would be too voluminous. Thus, much of the early literature not directly related to pharmacokinetics and metabolisms is referred to in review articles and in proceedings of symposia. Unfortunately, two almost equally popular numbering systems are in use today. The biogenetically based monoterpene system (Δ1-THC) is used in this survey since it is applicable to both Δ1-THC, CBD, and CBN. The dibenzopyran (Δ9-THC) system which is also shown cannot be used for CBD but has lately been adopted by Chemical Abstracts. The use of these two systems has caused even more confusion when dealing with the metabolites. The chemistry of cannabinoids has been reviewed recently by Mechoulam and Harvey. Of more than 60 cannabinoids - the term cannabinoid is used for the typical C21-compounds and their transformation products - only Δ1-THC has profound psychoactive properties. CBN i.v. shows about 1/10 the potency of Δ1-THC in man, whereas CBD is devoid of psychotomimetic properties. Δ6-THC is about equipotent with Δ1-THC itself but is usually present in very small amounts compared to Δ1-THC, CBD, and CBN. The latter three compounds occur in marihuana-type cannabis preparations in concentrations usually around 1 to 2%.
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Cannabidiol (CBD) exhibits anticonvulsant activity in experimental animals and in man. As part of a structure-activity study, analogs were prepared wherein the terpene unit, the aryl unit, and/or the side chain were modified. Thus, several pinenyl and carenyl derivatives, aryl ethers and acetates, and a variety of 1",1"-dialkylhexyl and 1",1"-dialkylheptyl analogs were synthesized. The compounds were evaluated for anti-convulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rat rotorod (ROT) test. Comparisons of stereoisomers of CBD and several analogs revealed a general lack of stereoselectivity for anticonvulsant and other CNS properties of this class of compounds.
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The 1,1-dimethylheptyl homolog of (-)-(3R,4R)-7-hydroxy-delta-6- tetrahydrocannabinol (compound II) is highly psychotropic in mice, rats and pigeons. The (+)-(3S,4S) enantiomer (III) was found to be psychotropically inactive at doses up to several thousand times those of the ED50 of (II).
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Cannabidiol, one of the major components of hashish, has been shown to possess structure IIIa.