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Cannabidiol inhibits the reward-facilitating effect of morphine: Involvement of 5-HT1A receptors in the dorsal raphe nucleus

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Abstract

Cannabidiol is a non-psychotomimetic constituent of Cannabis sativa, which induces central effects in rodents. It has been shown that cannabidiol attenuates cue-induced reinstatement of heroin seeking. However, to the best of our knowledge, its effects on brain stimulation reward and the reward-facilitating effects of drugs of abuse have not yet been examined. Therefore, we investigated the effects of cannabidiol on brain reward function and on the reward-facilitating effect of morphine and cocaine using the intracranial self-stimulation (ICSS) paradigm. Rats were prepared with a stimulating electrode into the medial forebrain bundle (MFB), and a guide cannula into the dorsal raphe (microinjection experiments), and were trained to respond for electrical brain stimulation. A low dose of cannabidiol did not affect the reinforcing efficacy of brain stimulation, whereas higher doses significantly elevated the threshold frequency required for MFB ICSS. Both cocaine and morphine lowered ICSS thresholds. Cannabidiol inhibited the reward-facilitating effect of morphine, but not cocaine. This effect was reversed by pre-treatment with an intra-dorsal raphe injection of the selective 5-HT(1A) receptor antagonist WAY-100635. The present findings indicate that cannabidiol does not exhibit reinforcing properties in the ICSS paradigm at any of the doses tested, while it decreases the reward-facilitating effects of morphine. These effects were mediated by activation of 5-HT(1A) receptors in the dorsal raphe. Our results suggest that cannabidiol interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids, thus indicating that cannabidiol may be clinically useful in attenuating the rewarding effects of opioids.

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... Capitalizing on the intracranial self-stimulation paradigm (ICSS), Katsidoni et al. (2013) showed that acute injection of CBD (5 mg/kg) in the dorsal raphe of young adult male rats did not inhibit the decrease in the ICSS threshold frequency observed following cocaine consumption. ...
... In another study, Ren et al. (2009) found that CBD (one dose of 5 mg/ kg or once daily for 3 days) attenuated heroin-seeking behaviors and that this effect lasted at least for 2 weeks in young adult rats. Katsidoni et al. (2013) reported that acute administration of CBD reduced brain reward function and increased the ICSS threshold of morphine in young adult rats. Moreover, in this study, the administration of a 5-HT1A receptor antagonist altered CBD's influence on the reward-facilitating effect of morphine. ...
... No major adverse effect was reported in the few weeks after administration, but no studies to date have explored its long-term potential adverse effects. Studies have also shown that CBD lacks hedonic properties, unlike THC (Katsidoni et al., 2013). Moreover, in animal and humans studies, CBD did not show any abuse potential, as reported in a World Health Organization review of CBD (World Health Organization, 2018). ...
Article
Introduction Cannabidiol (CBD) is a phytocannabinoid found in the Cannabis plant. CBD has received significant medical attention in relation to its anticonvulsant, anxiolytic, and antipsychotic characteristics. An increasing number of studies focusing on the anti-addictive properties of CBD have recently been published. In this systematic review, we aim to offer a comprehensive overview of animal and human studies regarding the impact of CBD on substance use disorders (SUDs). Methods A systematic search was performed on the PubMed database in February 2021. We included all articles assessing the effects of CBD on substance use disorders. Results The current systematic review suggests that CBD might offer promising therapeutic potential for the treatment of SUD, based on available animal and human studies. Animal studies showed a positive impact of CBD in the context of alcohol, opioids, and methamphetamine use (e.g., diminishing of drug-seeking behaviors). The results for cocaine use were mixed among reviewed studies, and CBD was not found to have an effect in animal studies on cannabis use, No animal study was identified that focused on the impact of CBD on nicotine use. Human studies showed a positive impact of CBD in the context of nicotine, cannabis, and opioid use (e.g., frequency and quantity of consumption). In contrast, CBD was not found to have an effect in human studies on cocaine or alcohol use. No human study was identified that investigated the impact of CBD on methamphetamine use. Conclusions CBD might offer promising therapeutic potential for the treatment of SUD, especially for nicotine, cannabis, and opioid use disorders, based on available human studies. The available research evidence is, however, sparse and more research on humans is needed.
... Furthermore, the endocannabinoid system (ECBS) has an effect on the attainment and preservation of drug-seeking behaviors due to its function in reward and brain plasticity. According to the preliminary evidence, cannabidiol (CBD) can have healing outcomes for treating disorders of drug abuse (7)(8)(9). This review is intended to refine our present understanding of how CBD affects drug abuse such as METH and to discuss the existing data pointing to the possible effectiveness of CBDbased treatments for addiction treatment. ...
... CBD is considered a non-intoxicating constituent in the company of more than 80 different cannabinoids that are present only in the cannabis plant (8,9). THC is the cannabinoid most closely associated with euphoria, dependence, and mental health side effects associated with cannabis consumption (10)(11)(12). ...
... CBD blocks the brain's reward system. Recent evidence demonstrated that high doses of CBD (10 and 20 mg/kg) significantly increased Intracranial Self-Stimulation (ICSS) threshold frequency in the medial forebrain bundle (9). This possibly will denote the anti-reward effect of CBD; nevertheless, in the mentioned study, a 5 mg/kg dosage CBD, although efficient to reduce the morphine effects, did not adjust the acute strengthening properties of cocaine (8); it is also consistent with a previous report suggesting that CBD does not induce conditioned place preference (CPP) and therefore lacks hedonic properties (18). ...
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.
... Taking this all into consideration, new molecules should be discovered for treating drug abuse. Preliminary studies suggest that CBD may have therapeutic impacts helpful in treating drug use disorders (Crippa et al., 2013;Katsidoni et al., 2013). Several studies suggest that CBD, a phytocannabinoid devoid of the psychoactive effects associated with THC, may have therapeutic effects for treating drug use disorders (Crippa et al., 2013;Katsidoni et al., 2013). ...
... Preliminary studies suggest that CBD may have therapeutic impacts helpful in treating drug use disorders (Crippa et al., 2013;Katsidoni et al., 2013). Several studies suggest that CBD, a phytocannabinoid devoid of the psychoactive effects associated with THC, may have therapeutic effects for treating drug use disorders (Crippa et al., 2013;Katsidoni et al., 2013). CBD is not associated with adverse cognitive effects, presents good safety and tolerability profiles in humans, and has a broad pharmacological spectrum of action (Zhornitsky and Potvin, 2012;niesink & van laar, 2013). ...
... Many of these serotonergic neurons express 5-HT1A auto-receptors localized at the somatodendritic compartment, functioning to regulate neuronal excitability (Müller et al., 2007). Katsidoni et al. demonstrated that CBD suppresses the rewarding properties of morphine, an effect which was reversed by intra-dorsal raphe pretreatment with the selective 5HT1A receptor antagonist, WAY-100635 (Katsidoni et al., 2013), thus suggesting 5HT1A receptors as a CBD molecular target. Although the precise mechanism of action has not been elucidated, the authors posit that activating 5-HT1A receptors by CBD might decrease extracellular serotonin concentrations, leading to reduced mesolimbic activity. ...
Article
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.
... However, there is some evidence suggesting CBD attenuates opiate reward. Co-administration of CBD with morphine dosedependently increases the intracranial self-stimulation (ICSS) threshold in the medial forebrain bundle in rats, indicating a reduction in brain reward threshold [91]. CBD's reduction in morphine-induced ICSS was reversed by pretreatment with the serotonergic (5-HT) 1A receptor antagonist and potent dopamine D4 receptor (D4R) agonist, WAY-100635, indicating CBD mediates morphine reward via stimulation of 5-HT1A or inhibition of D4R [91]. ...
... Co-administration of CBD with morphine dosedependently increases the intracranial self-stimulation (ICSS) threshold in the medial forebrain bundle in rats, indicating a reduction in brain reward threshold [91]. CBD's reduction in morphine-induced ICSS was reversed by pretreatment with the serotonergic (5-HT) 1A receptor antagonist and potent dopamine D4 receptor (D4R) agonist, WAY-100635, indicating CBD mediates morphine reward via stimulation of 5-HT1A or inhibition of D4R [91]. CBD alone also dose-dependently reduces brain reward thresholds [91]. ...
... CBD's reduction in morphine-induced ICSS was reversed by pretreatment with the serotonergic (5-HT) 1A receptor antagonist and potent dopamine D4 receptor (D4R) agonist, WAY-100635, indicating CBD mediates morphine reward via stimulation of 5-HT1A or inhibition of D4R [91]. CBD alone also dose-dependently reduces brain reward thresholds [91]. While infusions of CBD alone into the ventral hippocampus do not affect subthreshold morphine CPP, infusions of CBD in the ventral hippocampus reverse THC's enhancement of subthreshold morphine reward, and these effects are mediated by modulation of extracellular signal-regulated kinase (ERK) phosphorylation [57]. ...
Article
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Opioid abuse is a growing global problem. Current therapies for opioid abuse target withdrawal symptoms and have several adverse side effects. There are no treatments to address opioid-induced neural adaptations associated with abuse and addiction. Preclinical research demonstrates interactions between the endogenous opioid and cannabinoid systems, suggesting that cannabinoids may be used to treat opioid addiction and dependence. The aim of this review is to assess how cannabinoids affect behavioural and molecular measures of opioid dependence and addiction-like behaviour in animal models. It appears that cannabidiol and cannabinoid receptor 1 (CB1R) antagonists have potential for treating drug-craving and drug-seeking behaviour, based on evidence from preclinical animal models. Ligands which inhibit the action of cannabinoid degradation enzymes also show promise in reducing opioid withdrawal symptoms and opioid self-administration in rodents. Agonists of CB1R could be useful for treating symptoms of opioid withdrawal; however, the clinical utility of these drugs is limited by side effects, the potential for cannabinoid addiction and an increase in opiate tolerance induced by cannabinoid consumption. The mechanisms by which cannabinoids reduce opioid addiction-relevant behaviours include modulation of cannabinoid, serotonin, and dopamine receptors, as well as signalling cascades involving ERK-CREB-BDNF and peroxisome proliferator-activated receptor-α. Identifying the receptors involved and their mechanism of action remains a critical area of future research.
... Importantly, CBD lacks addictive potential in contrast to THC. Several studies in animals and humans demonstrated the absence of rewarding properties (Parker et al., 2004;Katsidoni et al., 2013;Babalonis et al., 2017;Schoedel et al., 2018). Indeed, recent studies carried out in mice in our laboratory further demonstrate that CBD is not an addictive substance. ...
... Indeed, authors showed that CBD inhibited the reward-facilitating effect of morphine employing the intracranial self-stimulation (ICSS) paradigm. Interestingly, pre-treatment with an intra-dorsal raphe injection of the selective 5HT1a receptor antagonist WAY-100635 reversed the effects of CBD, suggesting the involvement of these receptors in the CBD-mediated inhibition of morphine-induced reward (Katsidoni et al., 2013). Also, the efficacy of CBD to regulate morphine-induced CPP was investigated by two independent studies. ...
... On the contrary to the positive findings supporting the therapeutic potential of CBD in the regulation of the reinforcing and motivational actions of cocaine, one study found that CBD (5 mg/kg, i.p.) did not modify the rewardfacilitating effect of cocaine in the ICSS paradigm (Katsidoni et al., 2013). Also, another publication showed that CBD (5 and 10 mg/kg, i.p.) did not attenuate the motivation to self-administer cocaine (breaking point) nor the cue-induced cocaine seeking in rats after a withdrawal period (Mahmud et al., 2017). ...
Article
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Drug treatments available for the management of substance use disorders (SUD) present multiple limitations in efficacy, lack of approved treatments or alarming relapse rates. These facts hamper the clinical outcome and the quality of life of the patients supporting the importance to develop new pharmacological agents. Lately, several reports suggest that cannabidiol (CBD) presents beneficial effects relevant for the management of neurological disorders such as epilepsy, multiple sclerosis, Parkinson’s, or Alzheimer’s diseases. Furthermore, there is a large body of evidence pointing out that CBD improves cognition, neurogenesis and presents anxiolytic, antidepressant, antipsychotic, and neuroprotective effects suggesting potential usefulness for the treatment of neuropsychiatric diseases and SUD. Here we review preclinical and clinical reports regarding the effects of CBD on the regulation of the reinforcing, motivational and withdrawal-related effects of different drugs of abuse such as alcohol, opioids (morphine, heroin), cannabinoids, nicotine, and psychostimulants (cocaine, amphetamine). Furthermore, a special section of the review is focused on the neurobiological mechanisms that might be underlying the ‘anti-addictive’ action of CBD through the regulation of dopaminergic, opioidergic, serotonergic, and endocannabinoid systems as well as hippocampal neurogenesis. The multimodal pharmacological profile described for CBD and the specific regulation of addictive behavior-related targets explains, at least in part, its therapeutic effects on the regulation of the reinforcing and motivational properties of different drugs of abuse. Moreover, the remarkable safety profile of CBD, its lack of reinforcing properties and the existence of approved medications containing this compound (Sativex®, Epidiolex®) increased the number of studies suggesting the potential of CBD as a therapeutic intervention for SUD. The rising number of publications with substantial results on the valuable therapeutic innovation of CBD for treating SUD, the undeniable need of new therapeutic agents to improve the clinical outcome of patients with SUD, and the upcoming clinical trials involving CBD endorse the relevance of this review.
... It is well-documented that the prefrontal cortex, HIP, NAc, VTA, and dorsal raphé nucleus contribute to rewarding and rewarding impacts of drugs are affected by CBD administration [13,[17][18][19]. It is confirmed that CBD has a low affinity to cannabinoid receptors CB1 and CB2 [20]; while there is a wide range of non-cannabinoid receptors including 5-HT1A, α7-nicotinic, TRPV, adenosine-2A, and D2-dopamine receptors that are functionally modulated by CBD [18,[21][22][23][24]. ...
... It is well-documented that the prefrontal cortex, HIP, NAc, VTA, and dorsal raphé nucleus contribute to rewarding and rewarding impacts of drugs are affected by CBD administration [13,[17][18][19]. It is confirmed that CBD has a low affinity to cannabinoid receptors CB1 and CB2 [20]; while there is a wide range of non-cannabinoid receptors including 5-HT1A, α7-nicotinic, TRPV, adenosine-2A, and D2-dopamine receptors that are functionally modulated by CBD [18,[21][22][23][24]. ...
... As described above, CBD can effectively alleviate the rewarding characteristics of psychostimulants [14,16,25] that are induced by different types of non-cannabinoid receptors [18,[21][22][23][24]. Besides, some brain areas in the reward system, including HIP, are involved in CBD's inhibitory impact on drug-induced CPP [14,17,19] CPP. ...
Article
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Cannabidiol (CBD) is a non-psychotomimetic compound with strong potential to decrease the psychostimulant’s rewarding effect with unclear receptors. Furthermore, as a part of the reward circuit, the hippocampus plays a crucial role in regulating the reward properties of drugs as determined by conditioned place preference (CPP). In the current research, CPP was used to evaluate the role of intra-CA1 microinjection of D1-like dopamine receptor antagonists in CBD's inhibitory effect on the acquisition and expression phases of methamphetamine (METH). Animals were treated by METH (1 mg/kg; sc) in a five-day schedule to induce CPP. To find out the impact of D1-like dopamine receptor antagonist, SCH23390, in the CA1 on the inhibitory influence of CBD on the acquisition of METH, the rats received intra-CA1 administration of SCH23390 (0.25, 1, and 4 µg/0.5 µl) following ICV treatment of CBD (10 µg/5 µl) over conditioning phase of METH. Furthermore, animals were given SCH23390 in the CA1 ensuing ICV microinjection of CBD (50 µg/5 µl) in the expression phase of METH to rule out the influence of SCH23390 on the suppressive effect of CBD on the expression of METH CPP. Intra-CA1 microinjection of SCH23390 abolished CBD's suppressive impact on both METH-induced CPP phases without any side effect on the locomotion. The current research disclosed that CBD inhibited the rewarding characteristic of METH via D1-like dopamine receptors in the CA1 region of the hippocampus.
... Currently, cocaine dependence is an important social and health problem for which no pharmacological treatment has been proven to be safe and effective (Kampman, 2019). Some preclinical studies have indicated that cannabidiol (CBD), a component of the Cannabis sativa plant (Izzo et al., 2009;Pertwee, 2008) devoid of rewarding effects (Babalonis et al., 2017;Katsidoni et al., 2013;Luján et al., 2018;Parker et al., 2004;Viudez-Martínez et al., 2019), could be useful for the treatment of cannabinoid, alcohol and opiate dependence (Hurd, 2017;Navarrete et al., 2018;Turna et al., 2019;Viudez-Martínez et al., 2018a, 2018b. However, evidence for its usefulness in cocaine use disorders is more limited and controversial (Calpe-López et al., 2019). ...
... The effects of CBD on cocaine reward have been studied in the main animal models of addictive disorders with inconsistent results. CBD did not modify the reward-facilitating effect of cocaine in the intracranial self-stimulation (ICSS) paradigm (Katsidoni et al., 2013), did not affect progressive ratio cocaine self-administration (Mahmud et al., 2017) and did not prevent reinstatement of cocaine seeking induced by drug-paired cues (Mahmud et al., 2017) or exposure to an injection of the drug (cocaine priming) (Luján et al., 2018). In contrast to these negative findings, other studies have demonstrated that CBD attenuated the cocaine-induced enhancement of brain-stimulation reward (Galaj et al., 2020), reduced self-administration of cocaine (Galaj et al., 2020;Luján et al., 2018Luján et al., , 2020 and the breaking point in a progressive ratio (Galaj et al., 2020) and attenuated the reinstatement of cocaine self-administration induced by a compound contextual stimulus (consisting of an olfactory and an auditory component) associated with cocaine availability and the reinstatement of cocaine self-administration induced by exposure to the pharmacological stressor yohimbine (Gonzalez-Cuevas et al., 2018). ...
... After a careful examination of the literature, we have identified three relevant conditions that can explain the different findings. The first factor is the dose of CBD employed, since doses below 10 mg/kg are always ineffective to prevent cocaine effects in the brain stimulation reward, self-administration and CPP paradigms (for example, see Galaj et al., 2020;Katsidoni et al., 2013;Luján et al., 2018;Mahmud et al., 2017), with the exception of extinction of cocaine CPP, which is prevented by 5 mg/kg of CBD (Parker et al., 2004). Doses of 20 mg/kg of CBD reduced the effects of cocaine on brain stimulation reward (Galaj et al., 2020), impaired acquisition (Luján et al., 2018) and maintenance (Galaj et al., 2020) of cocaine self-administration and impaired acquisition of cocaine CPP (Luján et al., 2018). ...
Article
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Background Cocaine dependence is an important problem without any effective pharmacological treatment. Some preclinical studies have suggested that cannabidiol (CBD), a component of the Cannabis sativa plant, could be useful for the treatment of cocaine use disorders. Aims This work aims to evaluate the ability of CBD to reduce priming- and stress-induced reinstatement of the conditioned place preference (CPP) induced by cocaine. Methods Young adult CD-1 male mice were allocated to 10 groups ( n = 12/group), conditioned with cocaine (10 mg/kg) and exposed to extinction of CPP (two sessions per week). When extinction was achieved, each group received the corresponding treatment before the reinstatement test. In experiment 1, six groups were used: vehicle+saline (Veh+Sal), 5 mg/kg cocaine alone (Veh+Coc) or with CBD 30 or 60 mg/kg (CBD30+Coc, CBD60+Coc) and CBD alone (CBD30+Sal, CBD60+Sal). In experiment 2, four groups were used: exploration (Veh+Expl), social defeat (Veh+SD) and social defeat with CBD (CBD30+SD and CBD60+SD). Furthermore, the relative gene expression of the dopamine transporter (DAT) in the ventral tegmental area was measured. Results All mice acquired cocaine CPP and extinguished it after three or four weeks. Only the groups treated with cocaine priming (Veh+Coc) or exposed to social defeat (Veh+SD) showed reinstatement of CPP. Interestingly, CBD itself did not induce reinstatement and blocked the reinstating effects of cocaine priming and social defeat. Furthermore, cocaine priming increased DAT gene expression in the ventral tegmental area and CBD completely reversed this effect. Conclusion These results suggest that CBD could reduce reinstatement to cocaine seeking after a period of abstinence.
... Interestingly, there is some evidence that CBD modulates various neural circuits and behavioral outcomes involved in drug addiction (Calpe-López et al., 2019). For example, CBD raises the threshold for the activation of the brain reward mechanisms mediated by the increase of mesocorticolimbic dopamine (DA) release after drug administration (Katsidoni et al., 2013;Mijangos-Moreno et al., 2014;Murillo-Rodríguez et al., 2011). Intra-accumbal infusion of CBD reverses the increase in the firing frequency of DA in the ventral tegmental area (VTA), psychomotor sensitization effects, and deficits in pre-pulse inhibition after an amphetamine challenge in rats (Pedrazzi et al., 2015;Renard et al., 2016). ...
... Although, to date, no medication has yet been approved for the treatment of CUD, some of the most promising pharmacotherapeutic agents include dopamine agonists. Ideally, the use of partial agonists for the receptor of the same neurotransmitter activated by drugs of abuse (e. g., dopamine D2 receptors in the case of cocaine), are considered to be the most effective treatments against diverse addictive disorders such as CUD (Kampman, 2019). Interestingly, CBD has been shown to be a partial agonist of D2 receptors (Seeman, 2016). ...
Article
Cocaine dependence is a highly prevalent disease in modern society and lacks an effective treatment. Cannabidiol (CBD), a major non-psychoactive constituent of Cannabis sativa, has been shown to be a promising tool in the management of some neuropsychiatric disorders, including cocaine abuse. However, its therapeutic effects on the behavioral outcomes related to cocaine addiction remain unclear. The present research evaluates the effects of CBD (30, 60 and 120 mg/kg; injected intraperitoneally) on the acquisition, expression, extinction and reinstatement of cocaine (10 mg/kg)-induced conditioned place preference (CPP; Study 1); cocaine (25 mg/kg)-induced locomotor stimulation (Study 2); and cocaine withdrawal symptoms (Study 3) in male C57BL/6 J mice. The results show that CBD does not possess motivational properties in itself and does not modify the acquisition, expression or extinction of cocaine-induced CPP. Interestingly, when administered during the extinction phase of the cocaine-induced CPP, CBD (30 and 60 mg/kg) prevented priming-induced reinstatement of CPP. Moreover, CBD abolished cocaine-induced hyperactivity without altering the spontaneous locomotion of the animals. Furthermore, CBD (120 mg/kg) reduced the memory deficits induced by cocaine withdrawal in the object recognition test, though it did not reverse depressive-like symptoms measured in the tail suspension test. Overall, our data suggest that CBD can prevent the development of cocaine addiction, and, when administered during cocaine abstinence, may be of help in avoiding relapse to drug-seeking and in ameliorating the memory disturbances provoked by chronic consumption of cocaine.
... dollars by 2022 [1], due in part to reports of their positive effects on psychological phenotypes. In rodent studies, exposure to CBD in adulthood has been shown to reduce immobility and increase swimming time in the forced swim test, a measure of depression [2,3], increase time spent in the open arm of the elevated plus maze, a measure of anxiety [4][5][6][7], and reduce responsiveness to drugs of addiction such as morphine and cocaine [4,8]. In human trials, CBD additionally reduces psychotic symptoms in schizophrenia [9,10] and lowers subjective measures of anxiety [11,12]. ...
... Twenty-two six-to ten-week-old, sexually mature nulliparous wild-type a/a females were randomized into two groups and received either 20 mg/ kg Epidiolex ™ (GW Pharmaceuticals, Cambridge, UK) emulsified in honey or vehicle only daily via oral administration using the tip of a 14-gauge gavage needle for 14 days prior to mating. This dose was chosen based on previous CBD studies and approximates casual human use (~ 1.5 mg/kg) due to scaling factors for body surface area [3,4,8,65,66]. On day 14, F0 females were harem-mated with A vy /a males (8-12 weeks of age) and daily dosing continued through gestation, lactation, and behavior testing for a total exposure time of approximately 9 weeks. ...
Article
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Background Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow ( A vy ) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 A vy /a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively. Results F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in A vy /a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms. Conclusions These findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.
... CBD has therapeutic potential in a variety of psychiatric disorders (Freeman et al., 2019;Khan et al., 2020). Preclinical research has demonstrated that CBD administration can affect reward-related behaviours, particularly reducing drug-seeking behaviour (Hay et al., 2018;Katsidoni et al., 2013;Parker et al., 2004;Ren et al., 2009;Schier et al., 2014;Viudez-Martínez et al., 2018). Speculatively, CBD could ameliorate addictive behaviour by enhancing the sensitivity of the reward system to natural rewards, such that pharmacological rewards are less desired. ...
... The present results leave open the intriguing possibility that CBD may only exert an effect on reward networks that have already been perturbed, for example in people with a drug addiction. CBD administration has been shown to modulate rewardrelated behaviours in animals when addiction is being modelled (Katsidoni et al., 2013;Parker et al., 2004;Ren et al., 2009;Schier et al., 2014;Viudez-Martínez et al., 2018). Moreover, behavioural evidence from human studies suggests that CBD can reduce the salience of drug-related cues in those with cannabis (Morgan et al., 2010) and nicotine (Hindocha et al., 2018) dependencies, and reduce drug cue-induced cravings in those addicted to heroin (Hurd et al., 2019). ...
Article
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Background Cannabidiol has potential therapeutic benefits for people with psychiatric disorders characterised by reward function impairment. There is existing evidence that cannabidiol may influence some aspects of reward processing. However, it is unknown whether cannabidiol acutely affects brain function underpinning reward anticipation and feedback. Hypotheses We predicted that cannabidiol would augment brain activity associated with reward anticipation and feedback. Methods We administered a single 600 mg oral dose of cannabidiol and matched placebo to 23 healthy participants in a double-blind, placebo-controlled, repeated-measures design. We employed the monetary incentive delay task during functional magnetic resonance imaging to assay the neural correlates of reward anticipation and feedback. We conducted whole brain analyses and region-of-interest analyses in pre-specified reward-related brain regions. Results The monetary incentive delay task elicited expected brain activity during reward anticipation and feedback, including in the insula, caudate, nucleus accumbens, anterior cingulate and orbitofrontal cortex. However, across the whole brain, we did not find any evidence that cannabidiol altered reward-related brain activity. Moreover, our Bayesian analyses showed that activity in our regions-of-interest was similar following cannabidiol and placebo. Additionally, our behavioural measures of motivation for reward did not show a significant difference between cannabidiol and placebo. Discussion Cannabidiol did not acutely affect the neural correlates of reward anticipation and feedback in healthy participants. Future research should explore the effects of cannabidiol on different components of reward processing, employ different doses and administration regimens, and test its reward-related effects in people with psychiatric disorders.
... Doses of 20 mg/kg of CBD were observed to reduce the cocaine-induced rewarding effects in mice [53], while 10 mg/kg of CBD effectively blocked the memory reconstruction induced by cocaine [54] and attenuated cocaineand METH-induced CPP [13]. CBD at 5 and 10 mg/kg significantly reduced the rewarding effects and drug-seeking behaviors induced by heroin [12,55]. Further, CBD at 10 mg/kg has been shown to inhibit morphine-induced CPP in mice [56]. ...
... The present research demonstrates that CBD has potential therapeutic use for mitigating the rewarding effects induced by METH. However, the CBD dosage levels identified as effective in previous studies differ from those in the present study [12,55]. This discrepancy could be explained by the choices of drugs across the studies, the varying pharmacological effects of CBD on those drugs, the use of different animal models for experimentation, and the varied drug delivery methods and experimental protocols used [38,[41][42][43]. ...
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Methamphetamine (METH) is a highly addictive psychostimulant. Cannabidiol (CBD) is an exogenous cannabinoid without psychostimulating activity, which has potential therapeutic effects on opioid addiction. However, it is unclear whether CBD has therapeutic effects on METH-induced motivational effects. The present study examines whether CBD has a protective effect on METH-induced conditioned place preference (CPP) in rats by regulating the Sigma1R and AKT-GSK3β-CREB signaling pathway. Seventy rats were equally and randomly divided into seven groups. The rat CPP model was established via the intraperitoneal injection (IP) of 2 mg/kg of METH. Next, the intraperitoneal injection of 10, 20, 40, and 80 mg/kg CBD was performed 1 h prior to the injection of saline or METH. The protein expression levels of Sigma1R, AKT, p-AKT, GSK-3β, p-GSK-3β, CREB, and p-CREB in the rats' prefrontal cortex, nucleus accumbens, and hippocampus and ventral tegmental were detected using western blot analysis. CBD was found to inhibit METH-induced CPP in a dose-dependent fashion. The expression levels of Sigma1R, p-AKT, p-GSK3β, and p-CREB increased significantly in the METH-induced CPP model. Treatment involving different doses of CBD caused differential inhibitory responses in the cellular protein abundance of Sigma1R, p-AKT, p-GSK3β, and p-CREB across various brain regions. The present study found that METH can induce CPP in rats. When a pretreatment of CBD is applied, the CBD can weaken CPP in METH-induced rats by regulating the SigmaR1/AKT/GSK-3β/CREB signaling pathway. The results of this study indicate that CBD has a potential therapeutic effect on METH-induced rewarding effects.
... CBD also attenuated the rewarding effects of cocaine in a BSR paradigm via multiple receptor mechanisms, including CB2Rs [253]. An earlier study indicated that CBD had no effect on cocaine-enhanced BSR but attenuated morphineenhanced BSR via stimulation of 5-HT 1A receptors [258]. In a CPP paradigm, CBD disrupted the development of cocaine CPP [252] and blocked the expression of CPP induced by cocaine [252] or morphine [259] but not by amphetamine [260] (Table 7). ...
... CBD appears to have low reinforcing properties with limited abuse potential as it does not induce CPP on its own [260], nor does it affect BSR in rodents [258]. An additional CBD effect of therapeutic interest might be protective against acute cocaine toxicity, particularly liver damage and seizures [265]. ...
Article
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Substance use disorder (SUD) is a major public health crisis worldwide, and effective treatment options are limited. During the past 2 decades, researchers have investigated the impact of a variety of pharmacological approaches to treat SUD, one of which is the use of medical cannabis or cannabinoids. Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. However, serious adverse effects such as depression and suicidality led to the withdrawal of rimonabant (and almost all other CB1R antagonists/inverse agonists) from clinical trials worldwide in 2008. Since then, much research interest has shifted to other cannabinoid-based strategies, such as peripheral CB1R antagonists/inverse agonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, fatty acid binding protein (FABP) inhibitors, or nonaddictive phytocannabinoids with CB1R or CB2R-binding profiles, as new therapeutics for SUDs. In this article, we first review recent progress in research regarding the endocannabinoid systems, cannabis reward versus aversion, and the underlying receptor mechanisms. We then review recent progress in cannabinoid-based medication development for the treatment of SUDs. As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆9-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals. Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.
... While the United States holds a patent on a unique form of cannabidiol purported not to affect brain chemistry, research is progressing on existing cannabidiol compounds that activate the 5-H1A (serotonin) and TRPV-1 receptors and inverse-agonize the CB1 receptors, thereby contributing to the treatment of opiate addiction, cocaine addiction, nicotine addiction, heroin addiction, Ecstasy addiction, THC addiction, and methamphetamine addiction [45,46,47,48]. ...
Article
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This disquisition provides historical context illustrating the psychosocial, political, and bureaucratic barriers to applying a biomolecular approach to substance use disorders, focusing on what are arguably the most stigmatized molecules in America. It provides a biomolecular treatment strategy designed to mitigate multiple types of addiction by influencing the dopamine and serotonin neurotransmitters' activity through phytocannabinoid supplementation of the endocannabinoid system and proposes a strategy for circumventing the bureaucratic obstacles.
... Additionally, chronic administration of psychoactive substances such as morphine, ethanol, and cocaine have been found to reduce the basal levels of extracellular serotonin within the brain, potentially resulting in increased sensitivity (Pelloux et al., 2012;Müller & Homberg, 2015). Preclinical research focused on 5-HT1A receptor modulation in the context of drug reward and addictive behaviors found CBD decreased morphine-induced reward facilitation in an operant behavioral paradigm within rats that was mediated through 5-HT1A receptor activation in the dorsal raphe nucleus (Katsidoni et al., 2013). Though further studies are required, current research has provided proof of concept regarding the treatment of drug dependency and use disorders with cannabinoids, suggesting their use as an alternative or coadjuvant therapeutic. ...
Article
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Cannabinoids, including those found in cannabis, have shown promise as potential therapeutics for numerous health issues, including pathological pain and diseases that produce an impact on neurological processing and function. Thus, cannabis use for medicinal purposes has become accepted by a growing majority. However, clinical trials yielding satisfactory endpoints and unequivocal proof that medicinal cannabis should be considered a frontline therapeutic for most examined central nervous system indications remains largely elusive. Although cannabis contains over 100 + compounds, most preclinical and clinical research with well-controlled dosing and delivery methods utilize the various formulations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two most abundant compounds in cannabis. These controlled dosing and delivery methods are in stark contrast to most clinical studies using whole plant cannabis products, as few clinical studies using whole plant cannabis profile the exact composition, including percentages of all compounds present within the studied product. This review will examine both preclinical and clinical evidence that supports or refutes the therapeutic utility of medicinal cannabis for the treatment of pathological pain, neurodegeneration, substance use disorders, as well as anxiety-related disorders. We will predominately focus on purified THC and CBD, as well as other compounds isolated from cannabis for the aforementioned reasons but will also include discussion over those studies where whole plant cannabis has been used. In this review we also consider the current challenges associated with the advancement of medicinal cannabis and its derived potential therapeutics into clinical applications.
... Whereas pre-clinical studies suggest that cannabis may play a role in ameliorating the impact of opioid use disorder (Katsidoni et al. 2013;Markos et al. 2018), evidence in man is still limited and mixed. Ecological studies in states that allow medical cannabis have reported a lower use of opioids and a slower rate of increase in opioid overdose deaths compared to states without such laws (Shah et al. 2019), supporting isolated observations on a reduced opioid consumption for severe chronic pain (Meng et al. 2016). ...
Article
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Currently, there is a renewed interest in treatments with medical cannabis and cannabinoids. Based on an increasing number of publications over the last decades that permitted new insights into mechanisms, efficacy and safety of cannabinoids, the use of cannabinergic medications is authorised in an increasing number of European and non-European countries. The alleviation of chronic, painful conditions is, since thousands of years, one of the primary reasons for the use of cannabis. Depending on the country, a wide range of medicinal cannabis preparations are available:ranging from defined cultivars of medical cannabis, mainly varying in their THC:CBD ratio, that are inhaled or taken as whole plant extracts,to highly purified single cannabinoids, such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD),or mixtures of two enriched extracts, standardised to a 1:1 ratio of THC:CBD (nabiximols). Although conflicting opinions continue to exist, the majority of reviews in the past concluded that medical cannabis and cannabinoids play a significant role in the management of pain. Surprisingly, systematic studies to date do not support an “entourage effect” of the other plant constituents of cannabis (mainly terpenoids) in treatment of chronic pain. An emerging cannabinoid is CBD which is the only cannabinergic medication available at present that does not cause the typical “cannabis high”; it is not a “controlled substance”. However, despite years of research, there is either no study or no well-conducted, head-to-head, comparison available between different cannabis cultivars, between pure cannabinoids, and between pure cannabinoids and extracts. It remains unanswered which is the optimal treatment approach. Graphical abstract
... This effect is opposite to that of drugs of abuse such as cocaine, methamphetamine and opioids which lower the threshold. [55] Increased dopamine release in cells of the mesolimbic ventral tegmental areanucleus accumbens pathway is a common effect characteristic of almost all drugs of abuse. While THC has been shown to increase the firing rate of these cells, cannabidiol had no effect. ...
Experiment Findings
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This report has been drafted under the responsibility of the WHO Secretariat, Department of Essential Medicines and Health Products,Team of Innovation, Access and Use.The report is an update and extension of the pre-review on cannabidiol, that was prepared by Prof Jason White, Adelaide, Australia, for the 39thECDD meeting in November 2017. The WHO Secretariat would like to thank the following people for their contribution in producing this review report: Dr Sharon Walsh and Dr Susanna Babalonis, Kentucky USA (update and extension search, review and drafting), and J. Rehm et al, Toronto, Canada(analysis on WHO questionnaire for the Review of Psychoactive Substances for the 40thECDD: evaluation of Cannabidiol, and report drafting).
... = 0.53, p = 0.59), nor on cocaine-seeking and cue-induced cocaine-reinstatement after 14 withdrawal days (F[2,7] = 2.31, p = 0.17; F[2,14] = 0.59, p = 0.57) ( Mahmud et al., 2017 ). Single CBD (5 mg/kg, i.p.) administration after intracranial self-stimulation learning and 20 minutes before cocaine (5 mg/kg, i.p.) administration had no impact on the reward-facilitating effects of cocaine (p > 0.05) ( Katsidoni et al., 2013 ). CBD (20 mg/kg, i.p.) administration daily for ten days, immediately before cocaine self-administration acquisition learning sessions reduced cocaine self-administration acquisition (x2 = 18.1, p < 0.001), intake (F[1,36] = 13.74, ...
Article
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Cocaine use entails severe health-and social-related harms globally. Treatment options for cocaine dependence are highly limited. Benefits of cannabinoids for addiction have been documented , making it opportune to examine existing data on the possible outcomes associated with cannabinoids and cocaine co-use. We conducted a systematic scoping review following the PRISMA guidelines of peer-reviewed, English-language studies published from 2000 to 2021 in four databases (Medline, Web-of-Science, CINAHL Plus, and PsycInfo), assessing the co-exposure of cannabis/cannabinoids with cocaine on behavioural, biological or health outcomes. Both quantitative and qualitative, as well as humans and pre-clinical animals' studies (n = 46) were included. Pre-clinical studies (n = 19) showed mostly protective effects of cannabidiol (CBD) administration on animal models of addiction (e.g., cocaine-craving,-relapse, and-withdrawal) and cocaine-toxicity. Tetrahydrocannabinol (THC) had more inconsistent results, with both protective and counter-protective effects. Human studies (n = 27) were more heterogeneous and assessed natural ongoing cannabis and cocaine use or dependence. Quantitative-based studies showed mostly enhanced harms in several outcomes (e.g., cocaine use, mental health); two available clinical trials found no effect upon CBD administration on cocaine-related treatment outcomes. Qualitative data-based studies reported cannabis use as a substitute for or to alleviate harms of crack-cocaine use. While pre-clinical studies suggest a potential of cannabinoids, especially CBD, to treat cocaine addiction, the few trials conducted in humans found no benefits. Cannabis co-use by cocaine users commonly presents a risk factor , entailing enhanced harms for users. More rigorous, controlled trials are still necessary to investigate cannabinoids' potential considering pre-clinical findings and reported benefits from specific drug users.
... Driven by findings of epidemiological studies, authors focused on the adverse and beneficial effects of medical cannabinoids on opioid sensitivity during the last 10 years. Cannabidiol has especially raised interest, since an associated reduction of the reward-facilitating effect of morphine [91] and cue-induced heroin-seeking behavior has been affirmed [92]. The non-rewarding cannabinoid has shown to provoke diminished cue-induced cravings and a reduction of anxiety in individuals who are abstinent from heroin use in clinical pilot studies [93]. ...
Article
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Purpose of Review This article aims to provide an overview of standard and adjunctive treatment options in opioid dependence in consideration of therapy-refractory courses. The relevance of oral opioid substitution treatment (OST) and measures of harm reduction as well as heroin-assisted therapies are discussed alongside non-pharmacological approaches. Recent Findings Currently, recommendation can be given for OST with methadone, buprenorphine, slow-release oral morphine (SROM), and levomethadone. Heroin-assisted treatment using diamorphine shall be considered as a cost-effective alternative for individuals not responding to the afore-mentioned opioid agonists in order to increase retention and reduce illicit opioid use. The modalities of application and the additional benefits of long-acting formulations of buprenorphine should be sufficiently transferred to clinicians and the eligible patients; simultaneously methods to improve planning of actions and self- management need to be refined. Regarding common primary outcomes in research on opioid treatment, evidence of the effectiveness of adjunctive psychological interventions is scarce. Summary Maintaining a harm reduction approach in the treatment of opioid addiction, a larger range of formulations is available for the prescribers. Embedding the pharmacological, ideally individualized treatment into a holistic, structure-giving concept also requires a reduction of fragmentation of ancillary services available, drug policies, and treatment philosophies on a global scale.
... While the United States holds a patent on a unique form of cannabidiol purported not to affect brain chemistry, research is progressing on existing cannabidiol compounds that activate the 5-H1A (serotonin) and TRPV-1 receptors and inverse-agonize the CB1 receptors, thereby contributing to the treatment of opiate addiction, cocaine addiction, nicotine addiction, heroin addiction, Ecstasy addiction, THC addiction, and methamphetamine addiction [45,46,47,48]. ...
Article
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Dysfunction of the dopamine system has been proposed to explain clinical manifestations of ADHD. ADHD patients have been demonstrated to lack appropriate dopamine levels. The neurotransmitter dopamine is commonly associated with the brain’s pleasure system, providing a feeling of enjoyment and motivation to perform specific tasks. The endocannabinoid system has been implicated in various dopamine-deficiency-related disorders, including ADHD. A complex interaction between the endocannabinoid system and dopamine production has been experimentally demonstrated. The endocannabinoid primarily responsible for the release of dopamine is anandamide and increasing the concentrations of this molecule has demonstrated therapeutic value in treating ADHD. In this review article, synthetic and natural exogenous and endogenous methods for increasing anandamide concentrations are described.
... This compound does not bind to the orthosteric site of any known cannabinoid receptor. Instead and as previously described in this chapter, it is a multi-target compound, and among other receptors, it acts as a CB1R negative allosteric modulator (Laprairie et al., 2015) and as a 5-HT1AR agonist (Katsidoni et al., 2013;Russo et al., 2005). Acute CBD decreases the firing rate of 5-HT neurons in the dorsal raphe nucleus while repeated CBD treatment increases their firing activity (De Gregorio et al., 2019). ...
Chapter
Accumulating evidence has proven that both exogenous cannabinoids as well as imbalances in the endocannabinoid system are involved in the onset and development of mental disorders such as anxiety, depression, or schizophrenia. Extensive recent research in this topic has mainly focused on the molecular mechanisms by which cannabinoid agonists may contribute to the pathophysiology of these disorders. Initially, serotonin neurotransmitter garnered most attention due to its relationship to mood disorders and mental diseases, with little attention to specific receptors. To date, the focus has redirected toward the understanding of different serotonin receptors, through a demonstration of its versatile pharmacology and synergy with different modulators. Serotonin 2A receptors are a good example of this phenomenon, and the complex signaling that they trigger appears of high relevance in the context of mental disorders, especially in schizophrenia. This chapter will analyze most relevant attributes of serotonin 2A receptors and the endocannabinoid system, and will highlight the evidence toward the functional bidirectional interaction between these elements in the brain as well as the impact of the endocannabinoid system dysregulation on serotonin 2A receptors functionality.
... CBD as a potential tool for the treatment of Opioid Use Disorder (OUD) pointing out that CBD is not rewarding54 and as such has limited misuse potential. Moreover CBD has remarkable positive effects on the treatment of anxiety 55 and sleep disorders, 56 major behavioral features of drug addiction, as well as a neuroprotective effect 57 making it safe to be used at high doses for the treatment of a variety of conditions.58 ...
Article
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Cannabidiol (CBD) is the second most abundant component of the Cannabis plant and is known to have effects distinct from Δ9 -tetrahydrocannabinol (THC). Many studies that examined the behavioral effects of CBD concluded that it lacks the psychotomimetic effects attributed to THC. However, CBD was shown to have a broad spectrum of effects on several conditions such as anxiety, inflammation, neuropathic pain, and epilepsy. It is currently thought that CBD engages different targets and hence CBD's effects are thought to be due to multiple molecular mechanisms of action. A well-accepted set of targets include GPCRs and ion channels, with the serotonin 5-HT1A receptor and the transient receptor potential cation channel TRPV1 channel being the two main targets. CBD has also been thought to target G protein-coupled receptors (GPCRs) such as cannabinoid and opioid receptors. Other studies have suggested a role for additional GPCRs and ion channels as targets of CBD. Currently, the clinical efficacy of CBD is not completely understood. Evidence derived from randomized clinical trials, in vitro and in vivo models and real-world observations support the use of CBD as a drug treatment option for anxiety, neuropathy, and many other conditions. Hence an understanding of the current status of the field as it relates to the targets for CBD is of great interest so, in this review, we include findings from recent studies that highlight these main targets.
... 8 Cannabinoids have a lower risk for dependence compared with opioids and the predicted median lethal dose for THC is >1000 fold higher than the effective dose. 7,9,10 Previous studies have found that cannabinoids can improve pain-related outcomes, quality of life and, importantly, have an opioid-sparing effect. 8,[11][12][13][14][15][16][17][18] In addition, it has been reported that patients commonly use medical cannabis as a substitute for opioid medication. ...
Article
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Aims Opioid misuse and overuse has contributed to a widespread overdose crisis and many patients and physicians are considering medical cannabis to support opioid tapering and chronic pain control. Using a five‐step modified Delphi process, we aimed to develop consensus‐based recommendations on: 1) when and how to safely initiate and titrate cannabinoids in the presence of opioids, 2) when and how to safely taper opioids in the presence of cannabinoids, and 3) how to monitor patients and evaluate outcomes when treating with opioids and cannabinoids. Results In patients with chronic pain taking opioids not reaching treatment goals, there was consensus that cannabinoids may be considered for patients experiencing or displaying opioid‐related complications, despite psychological or physical interventions. There was consensus observed to initiate with a cannabidiol (CBD)‐predominant oral extract in the daytime and consider adding tetrahydrocannabinol (THC). When adding THC, start with 0.5–3 mg, and increase by 1–2 mg once or twice weekly up to 30–40 mg/day. Initiate opioid tapering when the patient reports a minor/major improvement in function, seeks less as‐needed medication to control pain, and/or the cannabis dose has been optimized. The opioid tapering schedule may be 5%–10% of the morphine equivalent dose (MED) every 1 to 4 weeks. Clinical success could be defined by an improvement in function/quality of life, a ≥ 30% reduction in pain intensity, a ≥ 25% reduction in opioid dose, a reduction in opioid dose to < 90 mg MED, and/or reduction in opioid‐related adverse events. Conclusions This five‐stage modified Delphi process led to the development of consensus‐based recommendations surrounding the safe introduction and titration of cannabinoids in concert with tapering opioids.
... This is probably because of its anxiolytic, antidepressant, antipsychotic, and neuroprotective actions [35] and the lack of risk for becoming a drug of abuse [18]. Indeed, CBD effectively modulates the reinforcing and motivational properties of different drugs of abuse such as alcohol, cannabis, or opiates [20,21,[36][37][38], along with context-and stress-induced cocaine seeking in rats [23], and cocaine self-administration [25]. In this study, the administration of CBD normalized the increase in motor activity induced by spontaneous cocaine withdrawal. ...
Article
The aim of this study was to evaluate the effects of cannabidiol (CBD) on the behavioural and gene expression changes in a new animal model of spontaneous cocaine withdrawal. For this purpose, male CD-1 mice were exposed to progressive increasing doses of cocaine for 12 days (15 to 60 mg/kg/day, i.p.), evaluating spontaneous cocaine withdrawal 6 h after the last cocaine administration. The effects of CBD (10, 20, and 40 mg/kg, i.p.) were evaluated on cocaine withdrawal–induced alterations in motor activity, somatic signs, and anxiety-like behaviour. Furthermore, gene expression changes in dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the ventral tegmental area, and in cannabinoid receptors 1 (CNR1) and 2 (CNR2) in the nucleus accumbens, were analysed by real-time PCR. The results obtained in the study showed that mice exposed to the spontaneous cocaine withdrawal model presented increased motor activity, somatic withdrawal signs, and high anxiety-like behaviour. Interestingly, the administration of CBD normalized motor and somatic signs disturbances and induced an anxiolytic effect. Moreover, the administration of CBD blocked the increase of DAT and TH gene expression in mice exposed to the cocaine withdrawal, regulated the decrease of CNR1 and induced an additional upregulation of CNR2 gene expression. Thus, this model of spontaneous cocaine withdrawal induces clear behavioural and gene expression changes in mice. Interestingly, CBD alleviates these behavioural and gene expression alterations suggesting its potential for the management of cocaine withdrawal.
... This is probably because of its anxiolytic, antidepressant, antipsychotic, and neuroprotective actions [35] and the lack of risk for becoming a drug of abuse [18]. Indeed, CBD effectively modulates the reinforcing and motivational properties of different drugs of abuse such as alcohol, cannabis, or opiates [20,21,[36][37][38], along with context-and stress-induced cocaine seeking in rats [23], and cocaine self-administration [25]. In this study, the administration of CBD normalized the increase in motor activity induced by spontaneous cocaine withdrawal. ...
... Unlike THC, studies have shown that CBD lacks any rewarding effects of its own given that it fails to induce conditioned place preference or enhance the reinforcing effects of electrical brain self-stimulation. [72][73][74] CBD is already being evaluated as a potential treatment during the active coronavirus disease phase, and we suggest that the pre-clinical and clinical evidence base supports the hypothesis that CBD could be a novel pharmacological option for treating COVID-related anxiety disorders that merits testing through well-designed clinical trials. CBD could be more preferable compared with some of the medicines currently available with respect to its safety and side effect profile, although prescribers need to be aware of potential drug interactions with concomitant medication because of the effect of CBD on liver enzymes. ...
Article
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Coronavirus disease-19 (COVID-19)-related anxiety and post-traumatic stress symptoms (PTSS) or post-traumatic stress disorder (PTSD) are likely to be a significant long-term issue emerging from the current pandemic. We hypothesize that cannabidiol (CBD), a chemical isolated from Cannabis sativa with reported anxiolytic properties, could be a therapeutic option for the treatment of COVID-19-related anxiety disorders. In the global over-the counter CBD market, anxiety, stress, depression, and sleep disorders are consistently the top reasons people use CBD. In small randomized controlled clinical trials, CBD (300–800 mg) reduces anxiety in healthy volunteers, patients with social anxiety disorder, those at clinical high risk of psychosis, in patients with Parkinson’s disease, and in individuals with heroin use disorder. Observational studies and case reports support these findings, extending to patients with anxiety and sleep disorders, Crohn’s disease, depression, and in PTSD. Larger ongoing trials in this area continue to add to this evidence base with relevant patient cohorts, sample sizes, and clinical end-points. Pre-clinical studies reveal the molecular targets of CBD in these indications as the cannabinoid receptor type 1 and cannabinoid receptor type 2 (mainly in fear memory processing), serotonin 1A receptor (mainly in anxiolysis) and peroxisome proliferator-activated receptor gamma (mainly in the underpinning antiinflammatory/antioxidant effects). Observational and pre-clinical data also support CBD’s therapeutic value in improving sleep (increased sleep duration/quality and reduction in nightmares) and depression, which are often comorbid with anxiety. Together these features of CBD make it an attractive novel therapeutic option in COVID-related PTSS that merits investigation and testing through appropriately designed randomized controlled trials.
... proteins (reviewed data of Katsidoni et al. 2013;Bih et al. 2015;Pyszniak et al. 2016). According to analysis of Bih et al. (2015) receptor targets of CBD account for only 15% of the known different molecular targets of cannabinoids described in the literature. ...
Article
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Chemotherapy is one of the therapeutic approaches for cancer treatment and has demonstrated great success with the introduction of selectively acting molecules against specific biomarkers of some types of tumors. Despite this success there is a large unmet need for novel therapies that provide effective control on the progression of advanced or drug-resistant cancer diseases. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, as possible agents for cancer therapy. We analyzed the anticancer properties and mechanism of action of cannabidiol (CBD), the main non-psychoactive cannabinoid received from hemp of Cannabis plant. Despite of data for pleiotropic effects of CBD, we here present the results for the efficacy of CBD in the modulation of different stages of cancer development. The analysis of the anticancer properties of CBD is made in relation to the proposed or newly discovered molecular targets of action. Thereafter, we consider the specific effects of CBD on primary tumors, their invasiveness and metastases, whether the influence on identified tumor markers in different types of tumors reflect the therapeutic potential of CBD. The studies reviewed herein indicate that CBD elicit activity through the cannabinoid receptor dependent and independent pathways. The processes such as ceramide production, ER-stress, autophagy and apoptosis, angiogenesis and matrix remodeling also appear to regulate the anticancer activity of CBD. So, the pharmacological basis for therapeutic application of CBD is constructed on the scientific data for its antitumor activity, extensively provided studies in vitro and in vivo in animal tumor models, and available data on the safety profile of clinically approved CBD products. We also try to reduce the deficits of our understanding in relation of pharmacological synergistic interactions of CBD with cytostatic drugs, where data remains limited. It is recognized that more studies for defining the specific molecular and signaling mechanisms of anticancer action of cannabinoids, particularly CBD, requires further evaluation. We believe that the therapeutic advantages of CBD are associated not only with its non-psychoactive behavior, but also are related to its influence on the important biochemical pathways and signal molecules, defining the genome instability and specific changes of the malignant tumor cells.
... According to several studies, CBD in marijuana has limited misuse and diversion potential. It has a low lethality rate, which reduces overdose risk [38]. Furthermore, when marijuana in its entirety is combined with a strong opioid agonist, it remains safe and does not induce severe adverse effects, with evidence from many in vitro, in vivo, and human studies across a broad dosage range -up to 50 mg/kg/daily in humans [30]. ...
Article
Introduction The opioid epidemic has resulted in the deaths of millions of Americans and was declared a public health emergency in 2017. In response, many states have enacted policies and analyzed various interventions for harm reduction and overdose prevention, which have embraced limited success. With more states legalizing medical marijuana, another intervention of interest in pain management, much research has since focused on the potential for medical marijuana laws (MMLs) to curb the opioid epidemic. Nonetheless, marijuana legalization and its use for medical purposes has been a polarizing debate from ethical, social, and clinical perspectives. Areas covered We examine evidence on the merits of medical marijuana to address its potential as a diversion from prescription painkillers. Additionally, we review the impact of MMLs on opioid-related outcomes. Furthermore, we provide multi-layered recommendations for future directions in the evaluation of medical marijuana and MMLs as potential mitigators of the opioid epidemic. Expert opinion Despite limited and mixed evidence of efficacy, medical marijuana may still play an important role in addressing the opioid epidemic in the United States. Furthermore, we believe coordinated responses among the federal government, states, researchers, and patients are crucial in producing more robust evaluations of medical marijuana and MMLs.
... With such a pool of targets, numerous hypotheses have tried to explain CBD's therapeutic mechanisms in each of the psychiatric models addressed. The modulation of neuronal network dynamics in the mesolimbic system via 5-HT 1A activation (Norris et al., 2016) is positioned as the best approximation to CBD's anti-craving actions (Katsidoni et al., 2013;Bi et al., 2019;Galaj et al., 2020). On the other hand, the presumed motivational consequences of in vivo CBD's CB1 effects remain unclear. ...
Article
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During the last decades, researchers have investigated the functional relevance of adult hippocampal neurogenesis in normal brain function as well as in the pathogenesis of diverse psychiatric conditions. Although the underlying mechanisms of newborn neuron differentiation and circuit integration have yet to be fully elucidated, considerable evidence suggests that the endocannabinoid system plays a pivotal role throughout the processes of adult neurogenesis. Thus, synthetic, and natural cannabinoid compounds targeting the endocannabinoid system have been utilized to modulate the proliferation and survival of neural progenitor cells and immature neurons. Cannabidiol (CBD), a constituent of the Cannabis Sativa plant, interacts with the endocannabinoid system by inhibiting fatty acid amide hydrolase (FAAH) activity (the rate-limiting enzyme for anandamide hydrolysis), allosterically modulating CB1 and CB2 receptors, and activating components of the “extended endocannabinoid system.” Congruently, CBD has shown prominent pro-neurogenic effects, and, unlike Δ9-tetrahydrocannabinol, it has the advantage of being devoid of psychotomimetic effects. Here, we first review pre-clinical studies supporting the facilitating effects of CBD on adult hippocampal neurogenesis and available data disclosing cannabinoid mechanisms by which CBD can induce neural proliferation and differentiation. We then review the respective implications for its neuroprotective, anxiolytic, anti-depressant, and anti-reward actions. In conclusion, accumulating evidence reveals that, in rodents, adult neurogenesis is key to understand the behavioral manifestation of symptomatology related to different mental disorders. Hence, understanding how CBD promotes adult neurogenesis in rodents could shed light upon translational therapeutic strategies aimed to ameliorate psychiatric symptomatology dependent on hippocampal function in humans.
... In animal studies, CBD has been shown to reduce the rewarding effects of opioids and it also reduces the heroinseeking behaviors. CBD acts on the same receptors that heroin does and antagonizes the heroin's effect on CB1 and glutamate receptors [91]. ...
Article
Full-text available
Cannabidiol (CBD) is a substance chemically derived from Cannabis sativa and discussed to be non-psychoactive. According to the FDA, marijuana is classified as a schedule I substance; however, hemp which is defined as extracts from marijuana including cannabinoids containing less than 0.3% tetrahydrocannabinol (THC), is excluded from that controlled substance act and available at local convenience stores in the US as it is seen as an herbal supplement. CBD is purported to be used for various medical and psychiatric conditions: depression, anxiety, post-traumatic stress disorder, Alzheimer's or other cognitive illnesses as well as pain. There is also a new trend to use CBD for the treatment of opioid use disorder. The one CBD product on the market that is FDA approved for the treatment of childhood epilepsy forms Dravet and Lennox-Gastaut syndromes is available under the name Epidiolex. There is a significant difference between this medication and the over-the-counter CBD products that contain very inconsistent strengths of CBD, if they contain it at all, and vary in percentage even from sample to sample. Frequently the so-called CBD products are not containing any CBD at all, but mostly containing THC. This article is a systematic review of literature reviewing the available clinical data on CBD, for use in various medical and psychiatric conditions with focus on a review of the pharmacology and toxicity. Resources used were ORVID, PubMed, MEDLINE, PsychINFO, EMBASE with keywords CBD, cannabidiol, hemp and cannabinoids.
... 8 Cannabinoids have a lower risk for dependence compared with opioids and the predicted median lethal dose for THC is >1000 fold higher than the effective dose. 7,9,10 Previous studies have found that cannabinoids can improve pain-related outcomes, quality of life and, importantly, have an opioid-sparing effect. 8,[11][12][13][14][15][16][17][18] In addition, it has been reported that patients commonly use medical cannabis as a substitute for opioid medication. ...
... We have previously shown that primming-induced reinstatement of cocaine seeking behavior was not affected in mice treated with CBD (20 mg/kg, 10 days) during the acquisition phase of selfadministration behavior (Luján et al., 2018). In a different paradigm, acute CBD (5 mg/kg) did not prevent the reward-facilitating effects of cocaine in an intra-cranial selfstimulation study (Katsidoni et al., 2013). Also, Ren et al. (2009) found that CBD (10, 20 mg/kg, 5 days) was unable to reduce drug-induced reinstatement of heroin seeking behavior. ...
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Cocaine addiction is a brain disorder characterized by the consumption of the drug despite harmful consequences, the loss of control over drug intake and increased risk of relapse. Albeit prolonged research efforts, there is no available medication approved for the treatment of cocaine addiction. In the last decade, cannabinoid-based compounds have drawn increased interest for its potential therapeutic applications in various psychiatric conditions. Cannabidiol, a non-psychotomimetic constituent of the C. sativa plant, shows promising results in rodent models of anxiety, schizophrenia, depression and drug addiction. However, the specific effects and mechanisms of action of cannabidiol in a rodent model of extinction-based abstinence and drug seeking relapse remain unclear. Here, we administered cannabidiol (20 mg/kg) to male CD-1 mice trained to self-administer cocaine (0.75 mg/kg/inf) during extinction training (8-12 days). Then, we evaluated the reinstatement of cocaine seeking induced by cues, stress and drug priming. To ascertain the participation of CB1 receptors in these behavioral responses, we systemically administered the neutral cannabinoid antagonist AM4113 (5 mg/kg) before each reinstatement session. The results document that cannabidiol (20 mg/kg) does not modulate extinction training but attenuates extinction bursting behavior after one cannabidiol injection. Furthermore, cannabidiol specifically blocked the reinstatement of cocaine seeking triggered by a cue presentation, an effect prevented by AM4113 (5 mg/kg). Unexpectedly, cannabidiol facilitated stress-induced reinstatement of cocaine seeking behavior, also by a CB1-dependent mechanism. Finally, cannabidiol did not affect cocaine-primed (10 mg/kg) precipitation of cocaine seeking. Our results reveal a series of complex changes induced by cannabidiol treatment with opposite implications for the reinstatement of cocaine seeking behavior that may limit therapeutic opportunities. The activity of CB1 receptors seems to play a crucial role in the expression of cannabidiol-induced neuroplasticity underlying both the desirable and undesirable reinstatement effects here detailed.
... Most studies on the effect of CBD on opioid use disorders are animal studies. In the recent research, CBD has been shown to block the reward-facilitating effect of morphine (18). CBD was also found to have some efficacy in heroin studies in rats. ...
Article
Cannabidiol (CBD) is the second-most common phytocannabinoid found in cannabis plants after tetrahydrocannabinol (THC). Unlike THC, no psychoactive effect has been demonstrated for CBD. Due to its effect on various neurotransmitter systems, it has been tried for the treatment of many physical and psychiatric diseases, considering its neuroprotective and anti-inflammatory properties. In this Editorial, the characteristics of CBD and its place in various psychiatric disorders will be briefly discussed. © 2019 Yerkure Tanitim ve Yayincilik Hizmetleri A.S. All rights reserved.
... In order to provide a causal link between the rewarding effects of acute opioid exposure and the cerebellum, some animal experiments could be highly valuable. For this purpose, the effects of cerebellar manipulations could be assessed in responses like the locomotion-stimulating effects (Steidl et al., 2017a) or the lowering of intracranial self-stimulation thresholds (Katsidoni et al., 2013) induced by a single exposure to these drugs. Unlike traditional conditioned preference or self-administration paradigms, these readouts allow measuring rewarding effects of a single drug administration, and do not rely on drugreinforced learning processes (and associated brain modifications) to measure such effects. ...
Article
Opioid addiction has reached the epidemic status in the United States in recent years. A multitude of factors have contributed to an alarming increase in misuse and health issues related to these drugs. Although medications exist to treat some aspects of opioid addiction since long ago, relapse and fatality rates remain very high despite their long-term availability. Therefore, more research devoted to better understanding its neural substrates is needed to aid developing new treatment options. Interestingly, a number of studies show the cerebellum to be involved in the effects of opioids and addiction-related processes, though it is not usually regarded as part of the opioid addiction-related brain circuitry. This review provides a summary of cerebellar anatomy and synaptic organization, followed by discussing the studies reporting cerebellar involvement in opioid effects in animals and humans, and their possible role in opioid addiction. Additionally, future experimental approaches will be proposed. We hope this work will contribute considering the cerebellum as an integral part of the circuitry underlying opioid-related disorders.
... In order to provide a causal link between the rewarding effects of acute opioid exposure and the cerebellum, some animal experiments could be highly valuable. For this purpose, the effects of cerebellar manipulations could be assessed in responses like the locomotionstimulating effects (Steidl et al., 2017a) or the lowering of intracranial self-stimulation thresholds (Katsidoni et al., 2013) induced by a single exposure to these drugs. Unlike traditional conditioned preference or self-administration paradigms, these readouts allow measuring rewarding effects of a single drug administration, and do not rely on drugreinforced learning processes (and associated brain modifications) to measure such effects. ...
Preprint
Full-text available
Opioid addiction has reached the epidemic status in the United States in recent years. A multitude of factors have contributed to an alarming increase in misuse and health issues related to these drugs. Although medications exist to treat some aspects of opioid addiction since long ago, relapse and fatality rates remain very high despite their long-term availability. Therefore, more research devoted to better understanding its neural substrates is needed to aid developing new treatment options. Interestingly, a number of studies show the cerebellum to be involved in the effects of opioids and addiction-related processes, though it is not usually regarded as part of the opioid addiction-related brain circuitry. This review provides a summary of cerebellar anatomy and synaptic organization, followed by discussing the studies reporting cerebellar involvement in opioid effects in animals and humans, and their possible role in opioid addiction. Additionally, future experimental approaches will be proposed. We hope this work will contribute considering the cerebellum as an integral part of the circuitry underlying opioid-related disorders.
Chapter
Drug abuse and dependency liability assessments are important components of the discovery, development, and evaluation of novel drug entities and are often included in comprehensive drug safety evaluation programs. Many abuse-related effects of drugs have been modeled in laboratory animals using well-established and validated procedures both to study the underlying neurobiological and behavioral phenomena associated with drug abuse and to assess whether new chemical entities have a likelihood of abuse in humans. Although studies in laboratory animals do not fully capture the complexity of drug abuse and substance use disorders in humans, they have proven to be highly predictive of effects in humans. Preclinical abuse and dependence liability studies typically comprise the following approaches and procedures: physical dependence, tolerance, drug discrimination, self-administration, conditioned place preference, and intracranial self-stimulation. This chapter outlines approaches commonly employed in studies of abuse and dependence liability assessments and highlights recent trends and advances in the utilization of each approach over the last decade.
Article
Chronic pain patients report analgesic effects when using cannabidiol (CBD), a phytocannabinoid found in whole-plant cannabis extract (WPE). Several studies suggest that cannabis-derived products may serve as an analgesic adjunct or alternative to opioids, and importantly, CBD may also attenuate the abuse potential of opioids. Vaping is a popular route of administration among people who use cannabis, however both the therapeutic and hazardous effects of vaping are poorly characterized. Despite the fact that chronic pain is more prevalent in women, the ability of inhaled high-CBD WPE to relieve pain and reduce opioid reward has not been studied in females. Here, we present a comprehensive analysis of high-CBD WPE vapor inhalation in female rats. We found that WPE was modestly efficacious in reversing neuropathy-induced cold allodynia in rats with spared nerve injury (SNI). Chronic exposure to WPE did not affect lung cytoarchitecture or estrous cycle, and it did not induce cognitive impairment, social withdrawal or anxiolytic effects. WPE inhalation prevented morphine-induced conditioned place preference and reinstatement. Similarly, WPE exposure reduced fentanyl self-administration in rats with and without neuropathic pain. We also found that WPE vapor lacks of reinforcing effects compared to the standard excipient used in most vapor administration research. Combined, these results suggest that although high-CBD vapor has modest analgesic effects, it has a robust safety profile, no abuse potential, and it significantly reduces opioid reward in females. Clinical studies examining high-CBD WPE as an adjunct treatment during opioid use disorder are highly warranted.
Article
In psychostimulant drug addiction, relapse is the most concerning outcome to be managed, considering there is no approved treatment for this neuropsychiatric condition. Here, we investigated the effects of the CBD treatment on the relapse behavior triggered by stress, after being submitted to the amphetamine (AMPH)-induced conditioned place preference (CPP) in rats. To elucidate the mechanisms of action underlying the CBD treatment, we evaluated the neuroadaptations on dopaminergic and endocannabinoid targets in the ventral striatum (VS) and ventral tegmental area (VTA) of the brain. Animals received d,l-AMPH (4 mg/kg, i.p.) or vehicle in the CPP paradigm for 8 days. Following the first CPP test, animals were treated with CBD (10 mg/kg, i.p.) or its vehicle for 5 days and subsequently submitted to forced swim stress protocol to induce AMPH-CPP relapse. Behavioral findings showed that CBD treatment prevented AMPH-reinstatement, also exerting anxiolytic activity. At the molecular level, in the VTA, CBD restored the CB1R levels decreased by AMPH-exposure, increased NAPE-PLD, and decreased FAAH levels. In the VS, the increase of D1R and D2R, as well as the decrease of DAT levels induced by AMPH were restored by CBD treatment. The current outcomes evidence a substantial preventive action of the CBD on the AMPH-reinstatement evoked by stress, also involving neuroadaptations in both dopaminergic and endocannabinoid systems in brain areas closely involved in the addiction. Although further studies are needed, these findings support the therapeutic potential of CBD in AMPH-relapse prevention.
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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.
Article
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.
Article
Background and Purpose: This study sought to determine whether cannabidiol (CBD) or a CBD derivative, CBD monovalinate monohemisuccinate (CBD-val-HS), could attenuate the development of oxycodone reward while retaining its analgesic effects. Experimental Approach: To determine the effect on oxycodone reward, animals were enrolled in the conditioned place preference paradigm and received either saline or oxycodone (3.0 mg/kg) in combination with either CBD or CBD-val-HS utilizing three sets of drug-/no drug-conditioning trials. To determine if the doses of CBD or CBD-val-HS that blocked opioid reward would affect nociceptive processes, animals were enrolled in the hot plate and abdominal writhing assays when administered alone or in combination with a subanalgesic (1.0 mg/kg) or analgesic (3.0 mg/kg) dose of oxycodone. Key Results: Results from condition place preference demonstrated CBD was not able attenuate oxycodone place preference while CBD-val-HS attenuated these rewarding effects at 8.0 mg/kg and was void of rewarding or aversive properties. In contrast to CBD, CBD-val-HS alone produced analgesic effects in both nociceptive assays but was most effective compared with oxycodone against thermal nociception. Of interest, there was a differential interaction of CBD and CBD-val-HS×oxycodone across the two nociceptive assays producing subadditive responses on the hot plate assay, whereas additive responses were observed in the abdominal writhing assay. Conclusion: These findings suggest CBD-val-HS alone, a nonrewarding analgesic compound, could be useful in pain management and addiction treatment settings.
Chapter
Adolescence is a crucial developmental period where neural circuits are refined and the brain is especially vulnerable to external insults. The endocannabinoid (eCB) system undergoes changes during adolescence which affect the way in which it modulates the development of other systems, in particular dopamine circuits, which show protracted development into adolescence. Given the rise of cannabis use by adolescents and young people, as well as variants containing increasingly higher concentrations of THC, it is now crucial to understand the unique effects of adolescent exposure to cannabis on the developing brain and it might shape future adult vulnerabilities to conditions such as psychosis, schizophrenia, addiction and more. Here we discuss the development of the eCB system across the lifespan, how CB1 receptors modulate dopamine release and potential neurobiological and behavioral effects of adolescent THC exposure on the developing brain such as alterations in excitatory/inhibitory balance during this developmental period.
Article
Cannabidiol, as component of cannabis, can potentially hinder the rewarding impact of drug abuse; however, its mechanism is ambiguous. Moreover, the nucleus accumbens (NAc), as a key area in the reward circuit, extensively receives dopaminergic projections from the ventral tegmentum area. To elucidate the role of accumbal D1 and D2 dopamine receptor families in Cannabidiol's inhibitory impact on the acquisition and expression phases of methamphetamine (MET), the conditioned place preference (CPP) procedure as a common method to assay reward characteristics of drugs was carried out. Six groups of rats were treated by various doses of SCH23390 or Sulpiride (0.25, 1, and 4 μg/0.5 μL) in the NAc as D1 or D2 dopamine receptor family antagonists, respectively, prior to infusion of Cannabidiol (10 μg/5 μL) in the lateral ventricle (LV) over conditioning phase in the acquisition experiments. In the second step of the study, animals received SCH23390 or Sulpiride in the NAc before Cannabidiol (50 μg/5 μL) infusion into the LV in the expression phase of MET to illuminate the influence of SCH23390 or Sulpiride on the inhibitory impact of Cannabidiol on the expression of MET-induced CPP. Intra-NAc administration of either SCH23390 or Sulpiride impaired Cannabidiol's suppressive impact on the expression phase, while just Sulpiride could suppress the Cannabidiol's impact on the acquisition phase of the MET-induced CPP. Also, the inhibitory impact of Sulpiride was stranger in both phases of MET reward. It seems that Cannabidiol prevents the expression and acquisition phases of MET-induced CPP partly through the dopaminergic system in the NAc.
Article
Methamphetamine (MET) is one of the most prevalently abused psychostimulants in the world with drastic repercussions. Several studies emphasized the inhibitory effect of Cannabidiol (CBD) on the reward properties of psychostimulants. The current investigation utilized conditioned place preference (CPP) to assay CBD's impact on MET's reward characteristic, including acquisition and expression phases of MET-induced CPP. Like our prior researches, animals received MET (1 mg/kg; sc) in a five-day schedule to induce CPP. The rats were given intracerebroventricular (ICV) microinjection of CBD (2, 10, and 50 µg/5 µl DMSO) during the 5-day conditioning phase in the CPP paradigm to highlight the CBD's impact on the development (acquisition) of MET-induced place preference. Furthermore, animals were treated with CBD (2, 10 and 50 µg/5 µl) in the lateral ventricle on the post-conditioning day to elucidate the effect of ICV injection of CBD on the expression of MET-induced CPP. It was revealed that CBD (10 and 50 µg/5 µl) microinjection profoundly inhibited both phases of MET-induced CPP without any side effect on the locomotion in animals were treated by MET injection over conditioning phase. Also, CBD's inhibitory impact was more potent in the acquisition phase than the expression phase of MET-induced CPP. Ultimately, the current research reported that CBD could be a beneficial compound to treat drug abuse however more investigations are needed.
Chapter
Most of our current understanding of the neuromolecular mechanisms of Cannabis action focusses on two plant cannabinoids, THC and CBD. THC acts primarily through presynaptic CB cannabinoid receptors to regulate neurotransmitter release in the brain, spinal cord and peripheral nerves. CBD action, on the other hand, is probably mediated through multiple molecular targets.
Article
Methylphenidate (MPH) is a mild CNS stimulant that has been used in hyperactive children, and patients with neurodegenerative and major depressive disorders. Exposure to MPH-associated cues enhances craving and arousal in drug users. On the other hand, cannabidiol (CBD) has antipsychotic potential that might be useful in alleviating symptoms of drug addiction. The aim of this study was to investigate the effect of CBD administration on extinction and reinstatement of MPH-induced conditioning place preference (CPP) in rats. Male rats received MPH (1, 2.5 or 5 mg/kg, i.p) or morphine (5 or 10 mg/kg, s.c.) during the conditioning phase. Following the establishment of CPP, during extinction training, 60 min prior to every CPP session, animals were given daily ICV CBD (10 or 50 μg/5 μL), vehicle alone (DMSO) 10 % or were treatment-naïve. On the reinstatement day animals after receiving the initial dose of MPH, 0.5 mg/kg, and were placed into the CPP box to evaluate the CPP scoring for 10-min. Our findings indicated that morphine (5 and 10 mg/kg; s.c.) and MPH (1 and 2.5 mg/kg; i.p.) induced a CPP. The ICV administration of both doses of CBD (10 and 50 μg/5 μL) prevented the reinstatement of MPH-induced CPP, which displayed shorter extinction latency compared to treatment-naïve or DMSO 10 % groups. Therefore, CBD’s site of action is a potential target for reducing the risk of MPH relapse; however, more investigation is required.
Article
Physical exercise could be a protective factor against the development of substance use disorders; however, a number of preclinical studies report reward-enhancing effects of exercise for various drugs of abuse. We examined the effects of chronic wheel-running on brain reward sensitivity, reaction to novelty, reward-facilitating and locomotor-stimulating effects of morphine, using the intracranial self-stimulation (ICSS) and the open field test (OFT). Male Sprague-Dawley rats were randomly assigned to a sedentary or exercised group. For the ICSS procedure, rats were implanted with electrodes and trained to respond for electrical stimulation. Several indices were recorded in the training phase to estimate brain reward sensitivity. Once responding was stable, the animals of both groups received systemic injections of morphine and their ICSS thresholds were measured with the curve-shift paradigm. Employing the OFT, basal and morphine-induced locomotor activity was measured. Finally, basal and morphine-evoked tissue levels of dopamine and its metabolites were determined in the striatum using gas chromatography/mass spectrometry. Chronic wheel-running decreased brain reward sensitivity and subsequently increased the reward-facilitating effect of morphine. Exercised animals demonstrated a decreased reaction to novelty and reduced morphine-induced locomotion. Lastly, dopaminergic activity was decreased in the striatum of exercised animals under basal conditions, whereas morphine administration led to an increase in dopamine turnover. These findings indicate that chronic voluntary exercise exerts divergent effects on reward function, psychomotor activity and the reward-facilitating and locomotor-activating effects of opioids during adulthood. Our results provide insights into the increased non-medical use of opioids among young athletes reported in the literature.
Article
Background Cannabinoids may have an important therapeutic potential for the treatment of dependence on crack cocaine. Cannabidiol (CBD), in particular, has anxiolytic, antipsychotic and anticonvulsant properties and plays a role in regulating motivation circuitry and controlling sleep disorders. Several studies were performed evaluating CBD in experimental models for cocaine. This systematic review aims evaluate the potential use of CBD in the treatment of cocaine use disorder. Method Five databases (Scielo; Medline/PubMed; PsycINFO; Cochrane Library; Virtual Health Library-VHL) were searched up to January 2020. Full-text reports published in English were included if they were experimental studies that administered CBD to human and/or adult animals in use or with a history of crack/cocaine administration. The risk of bias of each study selected was appraised by two independent reviewers following the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) protocol. Major findings Fifty-one studies were analyzed, and 14 were selected. No studies conducted with humans were found; only one clinical trial was ongoing. The results were grouped into the following categories: cocaine self-administration, brain-stimulation reward, conditioned place preference, neuronal proliferation, anxiety, hepatic protection, anticonvulsant effect and locomotor sensitization response Only four studies had a low risk of bias. CBD promotes reduction on cocaine self-administration. Also, it interferes in cocaine induce brain reward stimulation and dopamine release. CBD promotes alteration in contextual memory associated with cocaine and in the neuroadaptations, hepatotoxicity and seizures induced by cocaine. Conclusion The evidence indicates that CBD is a promising adjunct therapy for the treatment of cocaine dependence due to its effect on: cocaine reward effects, cocaine consumption, behavioral responses, anxiety, neuronal proliferation, hepatic protection and safety. Moreover, clinical trials are strongly required to determine whether the findings in animal models occur in humans diagnosed for cocaine or crack cocaine use disorder.
Article
Neuropsychiatric disorders, such as addiction, are associated with cognitive impairment, including learning and memory deficits. Previous research has demonstrated that the chronic use of methamphetamine (METH) induces long-term cognitive impairment and cannabidiol (CBD), as a neuroprotectant, can reverse spatial memory deficits induced by drug abuse. The study aimed to evaluate the effect of CBD on METH-induced memory impairment in rats chronically exposed to METH (CEM). For the induction of CEM, animals received METH (2 mg/kg, twice/day) for 10 days. Thereafter, the effect of intracerebroventricular (ICV) administration of CBD (32 and 160 nmol) during the (10 days) abstinence period on spatial memory was evaluated using the Y-Maze test, while recognition memory was examined using the novel object recognition (NOR) test. The results revealed a significant increase in the motor activity of METH-treated animals compared with the control group and, after the 10-day abstinence period, motor activity returned to baseline. Notably, the chronic administration of METH had impairing effects on spontaneous alternation performance and recognition memory, which was clearly observed in the NOR test. Additionally, although the ICV administration of CBD (160 nmol) could reverse long-term memory, a lower dose (32 nmol) did not result in any significant increase in exploring the novel object during short-term memory testing. These novel findings suggest that the chronic administration of METH induces memory impairment and presents interesting implications for the potential use of CBD in treating impairment deficits after chronic exposure to psychostimulant drugs such as METH.
Article
Background: Cannabis was used for cancer patients as early as about 2500 years ago. Experimental studies demonstrated tumor-inhibiting activities of various cannabinoids more than 40 years ago. In view of the status of tetrahydrocannabinol (THC) as a regulated substance, non-psychotomimetic cannabidiol (CBD) is of particular importance. Objectives: Efficacy of pure CBD in various animal models as well as initial results (case reports) from patients. Methods: Review of the literature on animal experiments and observations in humans. Results: Preclinical studies, particularly recent ones, including numerous animal models of tumors, unanimously suggest the therapeutic efficacy of CBD. In isolated combination studies, synergistic effects were generally observed. In addition, CBD may potentially play a role in the palliative care of patients, especially concerning symptoms such as pain, insomnia, anxiety, and depression. Further human studies are warranted.
Chapter
Cannabis sativa (cannabis) is one of the oldest plants cultivated by men. Cannabidiol (CBD) is the major non-psychomimetic compound derived from cannabis. It has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders. In this narrative review, we have summarized a selected number of pre-clinical and clinical studies, examining the effects of CBD in neuropsychiatric disorders. In some pre-clinical studies, CBD was demonstrated to potentially exhibit anti-epileptic, anti-oxidant, anti-inflammatory anti-psychotic, anxiolytic and anti-depressant properties. Moreover, CBD was shown to reduce addictive effects of some drugs of abuse. In clinical studies, CBD was shown to be safe, well-tolerated and efficacious in mitigating the symptoms associated with several types of seizure disorders and childhood epilepsies. Given that treatment with CBD alone was insufficient at managing choreic movements in patients with Huntington's disease, other cannabis-derived treatments are currently being investigated. Patients with Parkinson's disease (PD) have reported improvements in sleep and better quality of life with CBD; however, to fully elucidate the therapeutic potential of CBD on the symptoms of PD-associated movement disorders, larger scale, randomized, placebo-controlled studies still need to be conducted in the future. Currently, there are no human studies that investigated the effects of CBD in either Alzheimer's disease or unipolar depression, warranting further investigation in this area, considering that CBD was shown to have effects in pre-clinical studies. Although, anxiolytic properties of CBD were reported in the Social Anxiety Disorder, antipsychotic effects in schizophrenia and anti-addictive qualities in alcohol and drug addictions, here too, larger, randomized, placebo-controlled trials are needed to evaluate the therapeutic potential of CBD.
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There is ample evidence that blockade of CB 1 receptors reduces reward seeking. However, the reported effects of CB 1 blockade on performance for rewarding electrical brain stimulation stand out as an exception. By applying a novel method for conceptualizing and measuring reward seeking, we show that AM-251, a CB 1 receptor antagonist, does indeed decrease performance for rewarding electrical stimulation of the medial forebrain bundle in rats. Reward seeking depends on multiple sets of variables, including the intensity of the reward, its cost, and the value of competing rewards. In turn, reward intensity depends both on the sensitivity and gain of brain reward circuitry. We show that drug-induced changes in sensitivity cannot account for the suppressive effect of AM-251 on reward seeking. Therefore, the role of CB 1 receptors must be sought among the remaining determinants of performance. Our analysis provides an explanation of the inconsistencies between prior reports, which likely arose from the following: (1) the averaging of data across subjects showing heterogeneous effects and (2) the use of methods that cannot distinguish between the different determinants of reward pursuit. By means of microdialysis, we demonstrate that blockade of CB 1 receptors attenuates nucleus accumbens dopamine release in response to rewarding medial forebrain bundle stimulation, and we propose that this action is responsible for the ability of the drug to decrease performance for the electrical reward.
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During past years the 5-HT1A C(-1019)G polymorphism has been associated with vulnerability to depression, anxiety-disorder and personality traits related to negative emotionality (e.g. neuroticism). Many of these studies focused on case-control comparisons or associations between genetic markers and personality traits assessed by the use of questionnaires. In contrast, overt behaviour and physiological measures in experimental paradigms, although very promising, have seldom been the focus of studies investigating the role of the 5-HT1A polymorphism for behaviour and psychopathology. To fill this gap, we examined the relationship between the 5-HT1A C(-1019)G polymorphism and reaction times (in a reward/punishment paradigm) as well as electrodermal activity, as a marker of autonomic arousal, in 123 healthy subjects. This paradigm seems very promising, as sensitivity to punishment in particular, is strongly associated to traits related to negative emotionality. Carriers of the GG genotype, which is related to increased expression of 5-HT1A autoreceptors, exhibited increased reaction times when they were able to win money (reward condition). In direct contrast to the reward condition, these subjects show faster reaction times in the punishment condition (losing money). Moreover, GG carriers are characterized by an enhanced electrodermal activity in all experimental conditions (win, lose and verbal feedback). Finally, the reaction-time pattern mentioned was related to higher scores on negative emotionality as revealed by self-reports. These findings demonstrate for the first time that the 5-HT1A polymorphism is related to personality on the level of a triadic approach including behaviour, physiology and self-reports.
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Pharmacological activation of group II metabotropic glutamate (mGlu2 and mGlu3) receptors inhibits reward-seeking behavior and/or rewarding efficacy induced by drugs (cocaine, nicotine) or natural rewards (food, sucrose). In the present study, we investigated whether elevation of brain N-acetylaspartylglutamate (NAAG), an endogenous group II mGlu receptor agonist, by the NAAG peptidase inhibitor 2-PMPA attenuates cocaine's rewarding effects, as assessed by intravenous cocaine self-administration and intracranial electrical brain-stimulation reward (BSR) in rats. Systemic administration of 2-PMPA (10, 30, 100 mg/kg, i.p.) or intranasal administration of NAAG (100, 300 μg/10 μl/nostril) significantly inhibited intravenous cocaine self-administration under progressive-ratio (PR), but not under fixed-ratio 2 (FR2), reinforcement conditions. In addition, 2-PMPA (1, 10, 30 mg/kg, i.p) or NAAG (50, 100 μg/10 μl/nostril) significantly inhibited cocaine-enhanced BSR, but not basal BSR. Pretreatment with LY341495 (1 mg/kg, i.p.), a selective mGlu2/3 receptor antagonist, prevented the inhibitory effects produced by 2-PMPA or NAAG in both the self-administration and BSR paradigms. In vivo microdialysis demonstrated that 2-PMPA (10, 30, 100 mg/kg) dose-dependently attenuated cocaine-enhanced extracellular dopamine (DA) in the nucleus accumbens (NAc). 2-PMPA alone inhibited basal NAc DA release, an effect that was prevented by LY341495. These findings suggest that systemic administration of 2-PMPA or intranasal administration of NAAG inhibits cocaine's rewarding efficacy and cocaine-enhanced NAc DA – likely by activation of presynaptic mGlu2/3 receptors in the NAc. These data suggest a potential utility for 2-PMPA or NAAG in the treatment of cocaine addiction.
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The presence and function of cannabinoid CB(2) receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB(2) receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB(1) receptor knockout (CB(1)(-/-), also known as Cnr1(-/-)) mice, but not in CB(2)(-/-) (Cnr2(-/-)) mice. This inhibition was mimicked by GW405833, another CB(2) receptor agonist with a different chemical structure, and was blocked by AM630, a selective CB(2) receptor antagonist. Intra-accumbens administration of JWH133 alone dose-dependently decreased, whereas intra-accumbens administration of AM630 elevated, extracellular dopamine and locomotion in wild-type and CB(1)(-/-) mice, but not in CB(2)(-/-) mice. Intra-accumbens administration of AM630 also blocked the reduction in cocaine self-administration and extracellular dopamine produced by systemic administration of JWH133. These findings suggest that brain CB(2) receptors modulate cocaine's rewarding and locomotor-stimulating effects, likely by a dopamine-dependent mechanism.
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There is ample evidence that blockade of CB(1) receptors reduces reward seeking. However, the reported effects of CB(1) blockade on performance for rewarding electrical brain stimulation stand out as an exception. By applying a novel method for conceptualizing and measuring reward seeking, we show that AM-251, a CB(1) receptor antagonist, does indeed decrease performance for rewarding electrical stimulation of the medial forebrain bundle in rats. Reward seeking depends on multiple sets of variables, including the intensity of the reward, its cost, and the value of competing rewards. In turn, reward intensity depends both on the sensitivity and gain of brain reward circuitry. We show that drug-induced changes in sensitivity cannot account for the suppressive effect of AM-251 on reward seeking. Therefore, the role of CB(1) receptors must be sought among the remaining determinants of performance. Our analysis provides an explanation of the inconsistencies between prior reports, which likely arose from the following: (1) the averaging of data across subjects showing heterogeneous effects and (2) the use of methods that cannot distinguish between the different determinants of reward pursuit. By means of microdialysis, we demonstrate that blockade of CB(1) receptors attenuates nucleus accumbens dopamine release in response to rewarding medial forebrain bundle stimulation, and we propose that this action is responsible for the ability of the drug to decrease performance for the electrical reward.
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Chapter
Intracranial self-stimulation (ICSS) is an operant behavioral paradigm in which experimental animals learn to deliver brief electrical pulses into specific regions of their own brains that are considered to be part of the brain's reward pathways mediating both natural and ICSS reward. Several brain sites support ICSS, with the lateral hypothalamus, medial forebrain (MFB) bundle, and ventral tegmental area (VTA) among the sites that produce the most vigorous ICSS responding. Various ICSS procedures have been designed and used during the last decades since the discovery of ICSS. Two of the most commonly used ICSS procedures, which have been experimentally validated and have shown to be reward-selective, are the rate-frequency curve-shift procedure and the discrete-trial current-intensity threshold procedure. In all ICSS procedures, lowering of ICSS thresholds indicates a facilitation of brain stimulation reward, whereas elevations in ICSS thresholds reflect the diminished reward value of the stimulation and thus an anhedonic state. Acute administration of most drugs of abuse, including cocaine, amphetamine, nicotine, morphine, and heroin, lower ICSS thresholds in experimental animals. By contrast, withdrawal from chronic administration of these compounds induces elevations in ICSS thresholds, indicating an anhedonic state that resembles the negative affective state of the drug withdrawal syndrome experienced by humans. However, certain drugs of abuse, such as ethanol and cannabinoids, have shown inconsistent effects in ICSS procedures, primarily because of the minimal effects induced by these drugs in the ICSS procedure. In summary, the ICSS procedure provides unique ways to investigate the anatomical basis of reward and motivation and is an important tool for the assessment of the reward-facilitating and anhe-donic effects of various drugs of abuse with addictive properties.
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Based on previous observations that cannabidiol (CBD) blocks some effects of Δ9-tetrahydrocannabinol (Δ9-THC) in laboratory animals, the present work was carried out to study possible interaction between CBD and Δ9-THC in human beings. In a double blind procedure, 40 healthy male volunteers were assigned to 1 of 8 experimental groups, receiving per oral route, placebe, 30 mg Δ9-THC, 15 30 or 60 mg of CBD, and mixtures of 30 mg of Δ9-THC plus either 15, 30 or 60 mg of CBD respectively. Pulse rate, time production tasks and psychological logical reactions were measured at several time intervals after drug ingestion. 30 mg Δ9-THC alone increased pulse rate, disturbed time tasks and induced strong psychological reactions in the subjects. 15–60 mg of CBD alone provoked no effects. On the other hand, CBD was efficient in blocking most of the effects of Δ9-THC when both drugs were given together. CBD also decreased the anxiety component of Δ9-THC effects, in such a way that the subjects reported more pleasurable effects.
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Increasing evidence indicates that brain kappa-opioid receptors (KORs) are involved in regulation of mood states. In animal models often used to study psychiatric illness, KOR agonists produce depressive-like effects (e.g., anhedonia), whereas KOR antagonists produce antidepressant- and anxiolytic-like effects. The ability of KOR agonists to produce anhedonia-like signs in laboratory animals raises the possibility that this class of drugs might be useful to ameliorate states characterized by excess reward or motivation, such as mania or stimulant intoxication. We examined how the selective KOR agonist U69,593 affects cocaine-induced facilitation of intracranial self-stimulation (ICSS), a model of the abnormally increased reward function that characterizes mania and stimulant intoxication. Rats with stimulating electrodes implanted in the medial forebrain bundle (MFB) were tested with intraperitoneal injections of U69,593 (.063-.5 mg/kg) alone, cocaine (1.25-10 mg/kg) alone, and combinations of the drugs. Cocaine dose-dependently decreased ICSS thresholds, indicating that it enhanced the rewarding impact of MFB stimulation. In contrast, U69,593 dose-dependently increased ICSS thresholds, indicating that it decreased the rewarding impact of the stimulation. Pretreatment with U69,593 blocked cocaine-induced decreases in ICSS thresholds at doses that had negligible effects on their own. Activation of KORs reduces the reward-related effects of cocaine. Inasmuch as cocaine-induced behavioral stimulation in rodents may model key aspects of enhanced mood in humans, these findings raise the possibility that KOR agonists might ameliorate symptoms of conditions characterized by increased motivation and hyperfunction of brain reward systems, such as mania and stimulant intoxication.