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Cannabidiol inhibits the reward-facilitating effect of morphine: Involvement of 5-HT1A receptors in the dorsal raphe nucleus
Addiction Biology
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.
... 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). ...
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). ...
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. ...
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]. ...
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). ...
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. ...
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). ...
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.
... Although humans readily self-administer various ratios of CBD:THC, using an operant vapor self-administration approach we found that WPE is not rewarding in female rats, which is consistent with previous reports describing the inability of CBD to produce reinforcing effects in males across various paradigms [59,99,100]. Historically in preclinical research, the self-administration of THC has been particularly difficult to establish compared to other drugs of abuse (e.g. ...
... Because WPE did not disrupt cognitive function as measured by the NOR test, it is likely that the reward-modulating effects of WPE were genuine (that is, rats were able to successfully establish morphine context associations). The morphine-reward modulating effects of WPE may be at least partially mediated by CBD's activation of 5-HT1A receptors in the dorsal raphe [100]. In i.v. ...
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.
... 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). ...
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. ...
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.
... Moreover, selective lesions of basal forebrain cholinergic neurons with 192 IgG-saporin impaired the acquisition of STFP memory in rats (Berger-Sweeney et al. 2000;Vale-Martinez et al. 2002). Hence, we examined Katsidoni et al. 2013;Parker et al. 2004;Vann et al. 2008). Prior research indicates that CBD has multi-therapeutic potential through versatile mechanisms of action, such as being a negative allosteric modulator for cannabinoid CB 1 receptors and a complex agonist/antagonist/inverse agonist for CB 2 receptors (Galaj and Xi 2021;Ibeas Bih et al. 2015;Laprairie et al. 2015;McPartland et al. 2015). ...
Rationale and objective
Rodents acquire food information from their conspecifics and display a preference for the conspecifics’ consumed food. This social learning of food information from others promotes the survival of a species, and it is introduced as the socially transmitted food preference (STFP) task. The cholinergic system in the basal forebrain plays a role in the acquisition of STFP. Cannabidiol (CBD), one of the most abundant phytocannabinoids, exerts its therapeutic potential for cognitive deficits through versatile mechanisms of action, including its interaction with the cholinergic system. We hypothesize a positive relationship between CBD and STFP because acetylcholine (ACh) is involved in STFP, and CBD increases the ACh levels in the basal forebrain.
Materials and methods
Male C57BL/6J mice were trained to acquire the STFP task. We examined whether CBD affects STFP memory by administering CBD (20 mg/kg, i.p.) before the STFP social training. The involvement of cholinergic system in CBD’s effect on STFP was examined by knockdown of brain acetylcholinesterase (AChE), applying a nonselective muscarinic antagonist SCO (3 mg/kg, i.p.) before CBD treatment, and measuring the basal forebrain ACh levels in the CBD-treated mice.
Results
We first showed that CBD enhanced STFP memory. Knockdown of brain AChE also enhanced STFP memory, which mimicked CBD’s effect on STFP. SCO blocked CBD’s memory-enhancing effect on STFP. Our most significant finding is that the basal forebrain ACh levels in the CBD-treated mice, but not their control counterparts, were positively correlated with mice’s STFP memory performance.
Conclusion
This study indicates that CBD enhances STFP memory in mice. Specifically, those which respond to CBD by increasing the muscarinic-mediated ACh signaling perform better in their STFP memory.
... Cannabidiol Cannabidiol (CBD) has a theoretical role in mediating addiction and has been shown to have therapeutic properties relevant to opioid withdrawal, including anxiolysis, analgesia and reduced cue-induced opioid cravings due to actions at the CB1R, CB2R, lopioid receptor, 5-HT1A receptor and TRPV1 [29,34,35,[63][64][65]. Results from animal studies suggest that CBD can decrease opioid reward effects and opioid-seeking behaviours and a recent systematic review of existing evidence found that CBD might have therapeutic benefit in substance use disorders, including OUD [56,[66][67][68]. However, there remains a scarcity of human studies evaluating the effects of CBD use in opioid-dependent individuals [28,66]. ...
This narrative review explores current insights into the potential use of medicinal cannabis-related products as an emerging therapy for opioid use disorder in the landscape of increasing knowledge about medicinal cannabis-based products, commercialisation and global legalisation. Preclinical studies have provided preliminary insight into the putative neurobiological mechanisms that underpin the potential for medicinal cannabis to be considered a therapeutic in opioid use disorder and addiction. With the progressive legalisation of cannabis in many jurisdictions worldwide, contemporary research has highlighted further evidence that medicinal cannabis may have efficacy in reducing cravings and withdrawal effects, and therefore may be considered as an adjunct or standalone to current medications for opioid use disorder. Despite this potential, the landscape of research in this space draws from a large number of observational studies, with a paucity of rigorous randomised controlled trials to ascertain a true understanding of effect size and safety profile. With current challenges in implementation that arise from political and legal qualms about adopting medicinal cannabis on the background of associated social stigma, significant hurdles remain to be addressed by government, policy-makers, healthcare providers and researchers before medical cannabis can be introduced globally for the treatment of opioid use disorder.
... Similarly, dronabinol (synthetic THC) improved withdrawal symptoms in people with cannabis use disorder (Levin et al., 2011). In contrast, in rats with the chronic use of cocaine and morphine, a reduction in the "reward-facilitating effect" was only found for morphine (Katsidoni et al., 2013). Other studies found no effect of CBD regarding the reduction of craving among individuals with cocaine/CUD compared to placebo (Meneses-Gaya et al., 2020;Mongeau-Pérusse et al., 2021). ...
Cannabidiol (CBD) has been studied for substance use disorders treatment due to its anxiolytic effects, for sleep, appetite, reduction of craving, and maintenance of abstinence. The study aims to assess CBD’s feasibility, safety/tolerability, and preliminary efficacy compared to pharmacological treatment as usual for reducing crack use in people with crack use disorder (CUD) and investigate other parameters: adverse events, physical health symptoms, and craving. A double-blind, randomized clinical trial (RCT) with two treatment arms (CBD and control group) was conducted. Ninety participants were randomized and 73 were allocated: 37 control group and 36 CBD group for a 10-week treatment, comparing CBD (600 mg) with three drugs (fluoxetine, valproic acid, and clonazepam). The per-protocol analysis of participants who did not deviate from the study protocol compared the control and CBD treatment groups. Thirty-four completed at least half of the study and 25 finished. Participants attended weekly meetings for the study procedures (e.g., to receive the medication and provide urine for toxicological tests). Inter-group differences were performed with the Mann–Whitney test, the Wilcoxon test for differences intra-group, and Pearson’s Chi-square test or Fisher’s exact test to compare inter-group demographic data. The significance level was 5%. A “veracity index” (VI) was created as counterevidence (questionnaire data vs. the toxicological test result). Medications were considered safe/tolerable. The CBD group presented significantly fewer adverse events compared to the control group [e.g., dizziness (p = 0.001), memory impairment (p = 0.043)], which performed better in the reduction of clinical and psychiatric complaints (p = 0.008). In the intra-group analyses, the CBD group performed better in more parameters than the control group [e.g., reducing crack use (p = 0.016; T0 to T1)]. Data questionnaires were reliable regarding the use/non-use of crack (VI = 0.787). CBD is a safe/tolerable product. The CBD group manifested fewer adverse events than the control group, which had better clinical and psychiatric complaints results. There are some advantages for the CBD group in the intra-group analysis. Drug use self-report methodologies can be reliable. Trial registration details: This study is registered with Universal Trial Number (UTN) code: U1111-1234-0806. Available at https://ensaiosclinicos.gov.br/rg/RBR-4stgs8 (Effect of cannabidiol in the treatment of crack dependents)
... However, those that demonstrate impaired learning, often find greater deficits in relation to greater chronicity (Delibaş et al., 2017;Hermann et al., 2009) frequency (Bolla et al., 2005;Verdejo-Garcia et al., 2007), higher THC potency (Shannon et al., 2010) and dependence (Gonzalez et al., 2012). Similarly, animal studies show that cannabis administration, particularly high THC doses, results in failure to develop reward associations in a conditioned place preference paradigm, or even led to place aversion (Han et al., 2017;Sañudo-Peña et al., 1997;Vann et al., 2008) and attenuates electrical self-stimulation (Anagnostou & Panagis, 2013;Wiebelhaus et al., 2015). Together, the evidence suggests a potential dose-dependent relationship, where greater reward learning impairment is associated with indications of more severe cannabis use. ...
Cannabis use has been linked to deficient reward processing; however, little is known about its relation to the specific construct of reward learning, in which behavior is modified through associating novel stimuli with a positive outcome. The probabilistic reward task was used to objectively evaluate reward learning in 38 individuals who use recreational cannabis and 34 control comparison participants from the community. Reward learning was evidenced by the development of a response bias, which indicates the propensity to modulate behavior as a function of prior reinforcement. Both cannabis and control groups demonstrated reward learning, with no group differences in response bias development. Among cannabis participants, trending significant relationships between greater chronicity, r(36) = −.30, p = .077, self-reported potency, r(19) = −.33, p = .052, and poorer reward learning were found. Nonsignificant relationships were found between reward learning and frequency, age of initiation, weekly quantity or Cannabis Use Disorder Identification Test–Revised (CUDIT-R) scores (all p > .05). The ability to form noncannabis reward associations is promising for the success of therapeutic interventions for problematic cannabis use; however, indications of severity of use in relation to poorer reward learning suggests a need for a better pharmacological and pharmacokinetic understanding of cannabis.
... Repeated administration of the exogenous cannabinoid cannabidiol (CBD) can increase endogenous AEA levels in humans (Leweke et al. 2012). CBD is a phytocannabinoid without hedonic properties (Katsidoni et al. 2012;Parker et al. 2004) and with a favorable safety profile, although effects and side effects of chronic administration are still understudied (Bergamaschi et al. 2011;Iffland and Grotenhermen 2017;Kwee et al. 2022a). A recent meta-analysis demonstrated beneficial effects of systemic (mostly single) CBD administration on fear extinction and fear memory expression in rodents and experimentally induced anxiety in humans, although the quality of the evidence was low (Kwee et al. 2023). ...
Preclinical research suggests that pharmacologically elevating cannabinoid levels may attenuate fear memory expression and enhance fear extinction.
We studied the effects of cannabidiol (CBD) on fear memory expression and fear re-extinction in 69 patients with panic disorder with agoraphobia or with social anxiety disorder. Moderation by sex, diagnosis, and serotonergic antidepressant (AD) use was explored.
A cued fear conditioning paradigm was applied before the first treatment session with 300 mg CBD/placebo augmented exposure therapy. Study medication was administered orally preceding 8 weekly sessions. Fear acquisition and suboptimal extinction took place prior to the first medication ingestion (T0). After the first medication ingestion (T1), we investigated effects on fear memory expression at retention and fear re-extinction. Subjective fear, shock expectancy, skin conductance, and startle responses to conditioned (CS+) and safety stimulus (CS−) were measured.
Across the sample, CBD reduced shock expectancy at retention under low and ambiguous threat of shock, but fear re-extinction at T1 was unaffected by CBD. However, in AD users, re-extinction of subjective fear was impaired in the CBD condition compared to placebo. In female AD users, CBD interfered with safety learning measured with fear-potentiated startle.
The current findings provide no evidence for enhanced fear re-extinction by CBD. However, CBD acutely decreased threat expectation at retention, without affecting other indices of fear. More studies are needed to elucidate possible interactions with AD use and sex, as well as potential effects of CBD on threat expectancies.
... Endocannabinoids also have powerful roles in eating behavior [62,63], reward [64], and anxiety [65], indicating these neurotransmitters may play a role in reducing hyperphagia and metabolic abnormalities that are present early in the course of psychotic illness [66,67] and associated with antipsychotic administration. CB1 antagonists have been shown to markedly reduce food intake, significantly reduce weight gain, and regulate serum glucose in mouse models [68]. ...
Background
Psychotic disorders are a leading cause of disability in young adults. Antipsychotics have been the primary intervention for psychosis for over 60 years, and yet, we have made little progress in treating negative symptoms, neurocognition, and functional disability. There is growing evidence that cannabidiol (CBD) is effective in treating positive psychotic symptoms, possibly also negative and neurocognitive symptoms, and moreover is well tolerated compared to other psychotropic medications. Anecdotally, patients participating in the Cognitive Assessment and Risk Evaluation (CARE) Early Psychosis Treatment Program at the University of California, San Diego, are self-administering CBD and report subjective improvement in stress, anxiety, and ability to cope with symptoms. The overarching aim of the trial is to explore the effectiveness of CBD augmentation on symptoms and neurocognition in early psychosis while also exploring the mechanism of action of CBD and predictors of response to treatment. The mechanism by which cannabidiol has a therapeutic effect on psychosis is poorly understood. Recent evidence has suggested that CBD may reduce stress and pro-inflammatory biomarker levels. Endocannabinoids also have powerful roles in eating behavior, reward, and mood, indicating these neurotransmitters may play a role in reducing hyperphagia and metabolic abnormalities that are present early in the course of psychotic illness and exacerbated by antipsychotic medication. The neurophysiological effects of CBD have been studied in animal models of psychosis that show improvements in information processing in response to CBD, but there are no studies in individuals with early psychosis.
Method
A total of 120 individuals in the early stages of psychosis will be randomized to 1000 mg of CBD versus placebo as an adjunct to existing treatment in a 8-week, double-blind superiority randomized control trial. The primary outcome measures are symptoms and neurocognition.
Discussion
We hypothesized that CBD will improve symptoms and neurocognition as well as secondary outcome measures of neurohormones, inflammation, eating behaviors, and information processing. Importantly, predictors, moderators, and mediators of the CBD effects will be examined. A better understanding of which individuals are likely to respond to CBD can inform treatment planning and personalize treatment.
Trial registration
ClinicalTrials.gov NCT04411225. Registered on June 2, 2020.
... Prior studies reviewed elsewhere 23 have highlighted links between cannabis and cocaine including similar neuropharmacological actions of cannabinoids and cocaine, and endocannabinoid system involvement in cocaine addiction. In contrast, cannabidiol has been shown to inhibit the reward-facilitating effect of opioids and other substances that were part of the second cluster in the present study 24,25 . Beyond differences in brain reward effects, the separate clustering of cocaine and cannabis from the other SUDs investigated here documents immunogenetic differences between the two clusters of SUDs. ...
Substance use disorders (SUDs) are common and costly conditions that are partially attributable to genetic factors. In light of immune system influences on neural and behavioral aspects of addiction, the present study evaluated the influence of genes involved in the human immune response, human leukocyte antigen (HLA), on SUDs. We used an immunogenetic epidemiological approach to evaluate associations between the population frequencies of 127 HLA alleles and the population prevalences of six SUDs (alcohol, amphetamine, cannabis, cocaine, opioid, and “other” dependence) in 14 countries of Continental Western Europe to identify immunogenetic profiles of each SUD and evaluate their associations. The findings revealed two primary groupings of SUDs based on their immunogenetic profiles: one group comprised cannabis and cocaine, whereas the other group comprised alcohol, amphetamines, opioids, and “other” dependence. Since each individual possesses 12 HLA alleles, the population HLA-SUD scores were subsequently used to estimate individual risk for each SUD. Overall, the findings highlight similarities and differences in immunogenetic profiles of SUDs that may influence the prevalence and co-occurrence of problematic SUDs and may contribute to assessment of SUD risk of an individual on the basis of their HLA genetic makeup.
... In addition to the effects of CBD on attenuating the negative affective states produced by naloxone-precipitated opioid withdrawal, CBD also inhibits the reward-facilitating effects of morphine in the conditioned place preference [25,26] and on intracranial self-stimulation in rodents [27]. The intra-dorsal raphe nucleus administration of the 5-HT1A receptor antagonist WAY100635 blocked this latter effect. ...
The misuse of and addiction to opioids are serious public health problems in some countries, such as the USA. Drug addiction is a chronic and relapsing medical condition that involves motivational and memory-related processes due to the strong associations between drugs and consuming-related stimuli. These stimuli usually trigger continuous and compulsive use and are associated with relapses after periods of withdrawal. Several factors contribute to relapse, including withdrawal-induced mood changes. Therefore, drugs attenuating withdrawal-induced affective alterations could be useful alternative treatments for relapse prevention. Cannabidiol (CBD), a non-psychotomimetic component from the Cannabis sativa plant, has anti-anxiety and anti-stress properties and has been investigated as an alternative for the treatment of several mental disorders, including drug addiction. Here, we evaluated if CBD administered 30min prior to test for a conditioned place aversion (CPA) would attenuate the aversion induced by morphine withdrawal precipitated by the opioid receptor antagonist naloxone in male C57BL/6 mice. We also investigated if this effect involves the activation of 5-HT1A receptors, a mechanism previously associated with CBD anti-aversive effects. As expected, morphine-treated mice spent less time exploring the compartment paired with the naloxone-induced withdrawal, indicating a CPA induced by naloxone-precipitated morphine withdrawal. This effect was not observed in animals treated with CBD, at 30 and 60mg/kg, prior to the CPA test, indicating that CBD attenuated the expression of CPA induced by naloxone-precipitated morphine withdrawal. Pretreatment with the 5-HT1A receptor antagonist WAY100635 (0.3mg/kg) blocked CBD effects. Our findings suggest that CBD may reduce the expression of a previously established conditioned aversion induced by morphine withdrawal by a mechanism involving the activation of 5-HT1A receptors. Thus, CBD may be a therapeutic alternative for preventing relapse to opioid addiction by decreasing withdrawal-induced negative affective changes.
... Konopie posiadają w swoim składzie kannabidiol (CBD), drugi najpowszechniej występujący pod względem ilości kannabinoidów składnik tych roślin, który, jak wykazano w licznych badaniach przedklinicznych, moduluje różne obwody neuronalne zaangażowane w uzależnienie od substancji narkotycznych, opioidów, kokainy i środków psychostymulujących [21]. Udowodniono, że CBD posiada działanie przeciwlękowe, przeciwpsychotyczne, przeciwdepresyjne i neuroprotekcyjne [22,23]. ...
1 Katedra i Zakład Fizjologii, Uniwersytet Medyczny im. K. Marcinkowskiego w Poznaniu 2 Toplanta Sp. z o. o. Streszczenie Konopie (Canabis sativa L.) posiadają szereg składników biologicznie czynnych o działaniu prozdrowot-nym. Z uwagi na psychoaktywne działanie THC (delta-9-tetrahydrakannabinol) uznawane są za potencjalnie uzależniające, jednak tylko te odmiany, w których ilość THC znacznie przewyższa ilości innych kannabinoidów. Paradoksalnie te same rośliny przeciwdziałają i leczą uzależnienia nie tylko od THC, ale również od innych sub-stancji o działaniu uzależniającym i psychoaktywnym. Abstract Hemp (Canabis sativa L.) has a number of biologically active ingredients that promote health. Due to the psychoactive effects of THC (delta-9-tetrahydrocannabinol), they are considered potentially addictive, but only those types where the amount of THC significantly exceeds the amount of other cannabinoids. Paradoxically, the same plants counteract and heal addiction not only to THC, but also to other substances with addictive and psychoactive effects.
... However, from a pharmacological approach, the involvement of the 5-HT 1A R in the effects of CBD on drug-induced reward is the only one that has been demonstrated. The intra-dorsal raphe injection of a 5-HT 1A R antagonist abolished the CBD-mediated inhibition of the reward-facilitating effect of morphine measured in the intracranial self-stimulation (ICSS) paradigm [171], blocked the effects on ethanol self-administration, in combination with naltrexone, [206] and attenuated CBD-mediated reduction of cocaine self-administration [208]. ...
Cannabidiol (CBD) is a major phytocannabinoid present in Cannabis sativa (Linneo, 1753). This naturally occurring secondary metabolite does not induce intoxication or exhibit the characteristic profile of drugs of abuse from cannabis like Δ⁹-tetrahydrocannabinol (∆⁹-THC) does. In contrast to ∆⁹-THC, our knowledge of the neuro-molecular mechanisms of CBD is limited, and its pharmacology, which appears to be complex, has not yet been fully elucidated. The study of the pharmacological effects of CBD has grown exponentially in recent years, making it necessary to generate frequently updated reports on this important metabolite. In this article, a rationalized integration of the mechanisms of action of CBD on molecular targets and pharmacological implications in animal models and human diseases, such as epilepsy, pain, neuropsychiatric disorders, Alzheimer’s disease, and inflammatory diseases, are presented. We identify around 56 different molecular targets for CBD, including enzymes and ion channels/metabotropic receptors involved in neurologic conditions. Herein, we compiled the knowledge found in the scientific literature on the multiple mechanisms of actions of CBD. The in vitro and in vivo findings are essential for fully understanding the polypharmacological nature of this natural product.
... Some of the major differences between THC and CBD are their highly divergent central effects. Indeed, through different preclinical experimental approaches (i.e., conditioned place preference and electrical brain stimulation), it has been demonstrated that CBD, unlike THC, does not show any rewarding effects [87][88][89] or psychoactive properties [90][91][92]; this may be due, in part, to its inability to alter extracellular dopamine (DA) levels in the ventral striatum [83]. Moreover, whereas THC exposure is able to induce dysregulation of mesolimbic DA transmission and affect salience stimuli evaluation [93][94][95][96], CBD is able to normalize/restore aberrant DA signaling and salience processing [93][94][95][96]. ...
Cannabis is the most used drug of abuse worldwide. It is well established that the most abundant phytocannabinoids in this plant are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These two compounds have remarkably similar chemical structures yet vastly different effects in the brain. By binding to the same receptors, THC is psychoactive, while CBD has anxiolytic and antipsychotic properties. Lately, a variety of hemp-based products, including CBD and THC, have become widely available in the food and health industry, and medical and recreational use of cannabis has been legalized in many states/countries. As a result, people, including youths, are consuming CBD because it is considered “safe”. An extensive literature exists evaluating the harmful effects of THC in both adults and adolescents, but little is known about the long-term effects of CBD exposure, especially in adolescence. The aim of this review is to collect preclinical and clinical evidence about the effects of cannabidiol.
... Pre-clinical studies investigating the CBD use on animal models of addiction showed possibilities to reduce the behavioral and molecular manifestations of maladaptive neuroplasticity underlying drug addiction. For instance, CBD reduced the consumption and relapse to ethanol (Viudez-Martinez et al., 2017), craving and relapse to heroin (Ren et al., 2009) as well as reward and withdrawal symptoms to morphine (Bhargava, 1976;Katsidoni et al., 2013). In addition, CBD administration reduced the intake (Weiss and Gonzalez-Cuevas, 2019) and prevented reinstatement of cocaine-seeking (Gonzalez-Cuevas et al., 2018). ...
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.
... 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]. ...
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. ...
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.
... 17 Several reports suggest that CBD modulates the reinforcing and motivational effects and withdrawal-related actions of alcohol, 18,19 cannabis, 20,21 cocaine, 22,23 amphetamine, 24,25 nicotine, 26,27 and opioids. 28 In a small pilot study, CBD reduced cue-induced and general craving in opioid-dependent individuals. 29 Interestingly, a recent double-blind, randomized placebo-controlled clinical trial showed that CBD significantly reduced both craving and anxiety in drug-abstinent patients with heroin use disorder. ...
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.
... 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). ...
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. ...
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, ...
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]. ...
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]. ...
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). ...
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.
Opioid use disorder is a public health problem that includes symptoms such as withdrawal syndrome and opioid-induced hyperalgesia. Currently, drugs to treat side effects of opioids also have undesirable effects, which lead to limitations. This study investigated the effect of a treatment with cannabidiol in morphine-induced hyperalgesia and withdrawal behavior in morphine-dependent rats. Male and female rats were submitted to a morphine-induced physical dependence protocol consisting of a twice daily treatment with morphine (filtered solution, dose of 7.89 mg/kg, 1 ml/kg, s.c.) for 10 days. Nociception was measured using the hot plate test and morphine-induced thermal hyperalgesia was equally achieved following 7–10 days of morphine administration in male and female rats. Repeated treatment with cannabidiol (30 mg/kg) was sufficient to prevent thermal hyperalgesia in male and female rats. Subsequently, rats received an acute administration of naloxone (2 mg/kg. s.c.), 90 min after the morphine treatment on day 11, the number of withdrawal behaviors was scored. Rats that received treatment exclusively with morphine presented significant withdrawal behaviors compared to control (Water). Morphine-dependent female rats showed a prevalent stereotyped behavior of rearing, whereas male rats had teeth chattering behavior as the most preeminent. Treatment with cannabidiol on day 11 partially attenuated withdrawal behavior in morphine-dependent male rats, with mild effects in female rats (high withdrawal responders only). Altogether, our data provide evidence of an anti-hyperalgesic effect of cannabidiol in rats. Male and female rats treated chronically with morphine exhibited withdrawal behaviors in different ratios, and cannabidiol treatment attenuated withdrawal behavior in a sex-dependent manner.
Despite evidence of the beneficial effects of cannabidiol (CBD) in animal models of cocaine use disorder (CUD), CBD neuronal mechanisms remain poorly understood. This study investigated the effects of CBD treatment on brain glucose metabolism, in a CUD animal model, using [ ¹⁸ F]FDG positron emission tomography (PET). Male C57Bl/6 mice were injected with cocaine (20 mg/kg, i.p.) every other day for 9 days, followed by 8 days of CBD administration (30 mg/kg, i.p.). After 48 h, animals were challenged with cocaine. Control animals received saline/vehicle. [ ¹⁸ F]FDG PET was performed at four time points: baseline, last day of sensitization, last day of withdrawal/CBD treatment, and challenge. Subsequently, the animals were euthanized and immunohistochemistry was performed on the hippocampus and amygdala to assess the CB1 receptors, neuronal nuclear protein, microglia (Iba1), and astrocytes (GFAP). Results showed that cocaine administration increased [ ¹⁸ F]FDG uptake following sensitization. CBD treatment also increased [ ¹⁸ F]FDG uptake in both saline and cocaine groups. However, animals that were sensitized and challenged with cocaine, and those receiving only an acute cocaine injection during the challenge phase, did not exhibit increased [ ¹⁸ F]FDG uptake when treated with CBD. Furthermore, CBD induced modifications in the integrated density of NeuN, Iba, GFAP, and CB1R in the hippocampus and amygdala. This is the first study addressing the impact of CBD on brain glucose metabolism in a preclinical model of CUD using PET. Our findings suggest that CBD disrupts cocaine‐induced changes in brain energy consumption and activity, which might be correlated with alterations in neuronal and glial function.
Opioid addiction is a chronically relapsing disorder that causes critical public health problems. Currently, there is a lack of effective drug treatment. Herein, one cannabidiol derivative, CIAC001, was discovered as an effective agent for treating morphine-induced addiction. In vitro, CIAC001 exhibited significantly improved anti-neuroinflammatory activity with lower toxicity. In vivo, CIAC001 ameliorated the morphine-induced withdrawal reaction, behavioral sensitization, and conditional position preference by inhibiting morphine-induced microglia activation and neuroinflammation. Target fishing for CIAC001 by activity-based protein profiling led to the identification of pyruvate kinase M2 (PKM2) as the target protein. CIAC001 bound to the protein-protein interface of the PKM2 dimer and promoted the tetramerization of PKM2. Moreover, CIAC001 exhibited an anti-neuroinflammatory effect by reversing the decrease of the PKM2 tetramer and inhibiting the nuclear translocation of PKM2. In summary, this study identified CIAC001 as a lead compound in targeting PKM2 to treat morphine-induced addiction.
Introduction
Cocaine is a highly addictive drug that is abused due to its excitatory effect on the central nervous system. It is critical to reveal the mechanisms of cocaine addiction and identify key genes that play an important role in addiction.
Methods
In this study, we proposed a centrality algorithm integration strategy to identify key genes in a protein–protein interaction (PPI) network constructed by deferential genes from cocaine addiction-related datasets. In order to investigate potential therapeutic drugs for cocaine addiction, a network of targeted relationships between nervous system drugs and key genes was established.
Results
Four key genes (JUN, FOS, EGR1, and IL6) were identified and well validated using CTD database correlation analysis, text mining, independent dataset analysis, and enrichment analysis methods, and they might serve as biomarkers of cocaine addiction. A total of seventeen drugs have been identified from the network of targeted relationships between nervous system drugs and key genes, of which five (disulfiram, cannabidiol, dextroamphetamine, diazepam, and melatonin) have been shown in the literature to play a role in the treatment of cocaine addiction.
Discussion
This study identified key genes and potential therapeutic drugs for cocaine addiction, which provided new ideas for the research of the mechanism of cocaine addiction.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Epidemiological studies have shown that adolescent smoking is associated with health risk behaviors, including high-risk sexual activity and illicit drug use. Using rat as an animal model, we evaluated the behavioral and biochemical effects of a 4-day, low-dose nicotine pretreatment (60 μg/kg; intravenous) during adolescence and adulthood. Nicotine pretreatment significantly increased initial acquisition of cocaine self-administration, quinpirole-induced locomotor activity, and penile erection in adolescent rats, aged postnatal day (P)32. These effects were long lasting, remaining evident 10 days after the last nicotine treatment, and were observed when nicotine pretreatment was administered during early adolescence (P28-31), but not late adolescence (P38-41) or adulthood (P86-89). Neurochemical analyses of c-fos mRNA expression, and of monoamine transmitter and transporter levels, showed that forebrain limbic systems are continuing to develop during early adolescence, and that this maturation is critically altered by brief nicotine exposure. Nicotine selectively increased c-fos mRNA expression in the nucleus accumbens shell and basolateral amygdala in adolescent, but not adult animals, and altered serotonin markers in these regions as well as the prefrontal cortex. Nicotine enhancement of cocaine self-administration and quinpirole-induced locomotor activity was blocked by co-administration of WAY 100 635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide), a selective serotonin 1A (5-HT1A) receptor antagonist. Early adolescent pretreatment with the mixed autoreceptor/heteroceptor 5-HT1A receptor agonist, 8-OH-DPAT, but not the autoreceptor-selective agonist, S-15535, also enhanced quinpirole-induced locomotor activation. Nicotine enhancement of quinpirole-induced penile erection was not blocked by WAY 100 635 nor mimicked by 8-OH-DPAT. These findings indicate that early adolescent nicotine exposure uniquely alters limbic function by both 5-HT1A and non-5-HT1A receptor mechanisms.
The two main constituents of cannabis, cannabidiol and Δ(9)-tetrahydrocannabinol (THC), have opposing effects both pharmacologically and behaviourally when administered in the laboratory. Street cannabis is known to contain varying levels of each cannabinoid.
To study how the varying levels of cannabidiol and THC have an impact on the acute effects of the drug in naturalistic settings.
Cannabis users (n = 134) were tested 7 days apart on measures of memory and psychotomimetic symptoms, once while they were drug free and once while acutely intoxicated by their own chosen smoked cannabis. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analysed for levels of cannabinoids. On the basis of highest and lowest cannabidiol content of cannabis, two groups of individuals were directly compared.
Groups did not differ in the THC content of the cannabis they smoked. Unlike the marked impairment in prose recall of individuals who smoked cannabis low in cannabidiol, participants smoking cannabis high in cannabidiol showed no memory impairment. Cannabidiol content did not affect psychotomimetic symptoms, which were elevated in both groups when intoxicated.
The antagonistic effects of cannabidiol at the CB(1) receptor are probably responsible for its profile in smoked cannabis, attenuating the memory-impairing effects of THC. In terms of harm reduction, users should be made aware of the higher risk of memory impairment associated with smoking low-cannabidiol strains of cannabis like 'skunk' and encouraged to use strains containing higher levels of cannabidiol.
The serotonin 5-HT(2A) and 5-HT(2C) receptors, which are found in abundance in the mesolimbocortical dopaminergic system, appear to modulate the behavioral effects of cocaine.
The present series of studies set out to investigate the role of 5-HT(2A) and 5-HT(2C) receptors on brain reward and on the reward-facilitating effect of cocaine and localize the neural substrates within the mesolimbocortical dopaminergic system that are responsible for these effects.
Male Sprague-Dawley rats were implanted with stimulating electrodes and bilateral cannulae for the experiments involving microinjections and were trained to respond to electrical stimulation. In the first study, we examined the effects of systemic administration of selective 5-HT(2A) and 5-HT(2C) receptor agonists (TCB-2 and WAY-161503) and antagonists (R-96544 and SB-242084) on intracranial self-stimulation (ICSS). In the second study, we examined the effectiveness of TCB-2, WAY-161503, R-96544, and SB-242084 in blocking the reward-facilitating effect of cocaine. In the third study, we examined the effects of intra-medial prefrontal cortex (mPFC), intra-nucleus accumbens (NAC), and intra-ventral tegmental area (VTA) injection of WAY-161503 on the reward-facilitating effect of cocaine.
Acute systemic administration of TCB-2 and WAY-161503 increased ICSS threshold. Systemic WAY-161503 attenuated the reward-facilitating effect of cocaine. This effect was reversed by pretreatment with SB-242084. Intracranial microinjections of WAY-161503 into the mPFC and the NAC shell/core, but not the VTA, attenuated the reward-facilitating effect of cocaine.
These data indicate that 5-HT(2C) receptors within the mPFC and the NAC modulate the reinforcing effects of cocaine and provide evidence that 5-HT(2C) receptor agonists could be a possible drug discovery target for the treatment of psychostimulant addiction.
Worldwide cannabis dependence is increasing, as is the concentration of Delta(9)-tetrahydrocannabinol (THC) in street cannabis. At the same time, the concentration of the second most abundant cannabinoid in street cannabis, cannabidiol (CBD), is decreasing. These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory. No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans. A total of 94 cannabis users were tested 7 days apart, once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analyzed for levels of cannabinoids. On the basis of CBD : THC ratios in the cannabis, individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs, explicit liking, and implicit attentional bias to drug stimuli. When intoxicated, smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC. Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days. Our findings suggest that CBD has potential as a treatment for cannabis dependence. The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders.
There remains debate regarding the impact of cannabis on neuropsychiatric disorders. Here, we examined the effects of cannabidiol (CBD), a nonpsychoactive constituent of cannabis, on heroin self-administration and drug-seeking behavior using an experimental rat model. CBD (5-20 mg/kg) did not alter stable intake of heroin self-administration, extinction behavior, or drug seeking induced by a heroin prime injection. Instead, it specifically attenuated heroin-seeking behavior reinstated by exposure to a conditioned stimulus cue. CBD had a protracted effect with significance evident after 24 h and even 2 weeks after administration. The behavioral effects were paralleled by neurobiological alterations in the glutamatergic and endocannabinoid systems. Discrete disturbances of AMPA GluR1 and cannabinoid type-1 receptor expression observed in the nucleus accumbens associated with stimulus cue-induced heroin seeking were normalized by CBD treatment. The findings highlight the unique contributions of distinct cannabis constituents to addiction vulnerability and suggest that CBD may be a potential treatment for heroin craving and relapse.
Cannabis contains over 70 unique compounds and its abuse is linked to an increased risk of developing schizophrenia. The behavioural profiles of the psychotropic cannabis constituent Delta9-tetrahydrocannabinol (Delta9-THC) and the non-psychotomimetic constituent cannabidiol (CBD) were investigated with a battery of behavioural tests relevant to anxiety and positive, negative and cognitive symptoms of schizophrenia. Male adult C57BL/6JArc mice were given 21 daily intraperitoneal injections of vehicle, Delta9-THC (0.3, 1, 3 or 10 mg/kg) or CBD (1, 5, 10 or 50 mg/kg). Delta9-THC produced the classic cannabinoid CB1 receptor-mediated tetrad of hypolocomotion, analgesia, catalepsy and hypothermia while CBD had modest hyperthermic effects. While sedative at this dose, Delta9-THC (10 mg/kg) produced locomotor-independent anxiogenic effects in the open-field and light-dark tests. Chronic CBD produced moderate anxiolytic-like effects in the open-field test at 50 mg/kg and in the light-dark test at a low dose (1 mg/kg). Acute and chronic Delta9-THC (10 mg/kg) decreased the startle response while CBD had no effect. Prepulse inhibition was increased by acute treatment with Delta9-THC (0.3, 3 and 10 mg/kg) or CBD (1, 5 and 50 mg/kg) and by chronic CBD (1 mg/kg). Chronic CBD (50 mg/kg) attenuated dexamphetamine (5 mg/kg)-induced hyperlocomotion, suggesting an antipsychotic-like action for this cannabinoid. Chronic Delta9-THC decreased locomotor activity before and after dexamphetamine administration suggesting functional antagonism of the locomotor stimulant effect. These data provide the first evidence of anxiolytic- and antipsychotic-like effects of chronic but not acute CBD in C57BL/6JArc mice, extending findings from acute studies in other inbred mouse strains and rats.
Cannabis preparations as recreational drugs are the most widely used illicit drugs in the world. Although cannabis derivatives produce clear subjective motivational responses in humans leading to drug-seeking behavior and in a specific proportion in repeated drug use, the reinforcing/rewarding attributes of these subjective effects are difficult to define in experimental animals. This led to the notion of cannabinoids being considered as "atypical" or "anomalous" drugs of abuse. To this end, our knowledge and understanding of the way cannabis and its main psychoactive constituent, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), act in the central nervous system to exert their reinforcing/rewarding effects is far from complete. The aim of the present article is to review from a preclinical perspective the current status of what is known about the behavioral pharmacology of cannabinoids including the recently identified cannabinoid neurotransmission modifiers with a particular emphasis on their motivational/reinforcing and dependence-producing properties. We conclude that cannabinoids exhibit reinforcing/rewarding properties in experimental animals mostly under particular experimental conditions, which is not the case for other drugs of abuse, such as opiates, psychostimulants, alcohol and nicotine. The paper will discuss these findings critically and also point to open questions that should be addressed in the future in order to improve our understanding of these specific actions of cannabinoids that will also impact drug discovery and development efforts of related compounds as therapeutics in the clinic.
While Delta(9)-tetrahydrocannabinol (THC) is the main psychoactive constituent of the cannabis plant, a non-psychoactive constituent is cannabidiol (CBD). CBD has been implicated as a potential treatment of a number of disorders including schizophrenia and epilepsy and has been included with THC in a 1:1 combination for the treatment of conditions such as neuropathic pain. This study investigated the effect of THC and CBD, alone or in combination, on some objective behaviours of rats in the open field. Pairs of rats were injected with CBD or vehicle followed by THC or vehicle and behaviour in the open field was assessed for 10 min. In vehicle pretreated rats THC (1 mg/kg) significantly reduced social interaction between rat pairs. Treatment with CBD had no significant effect alone, but pretreatment with CBD (20 mg/kg) reversed the THC-induced decreases in social interaction. A higher dose of THC (10 mg/kg) produced no significant effect on social interaction. However, the combination of high dose CBD and high dose THC significantly reduced social interaction between rat pairs, as well as producing a significant decrease in locomotor activity. This data suggests that CBD can reverse social withdrawal induced by low dose THC, but the combination of high dose THC and CBD impairs social interaction, possibly by decreasing locomotor activity.
In order to assess the presence of anxiolytic properties in cannabidiol (CBD) the drug was tested in an elevated plus-maze model of anxiety, in rats. Doses of 2.5, 5.0 and 10.0 mg/kg significantly increased the entry ratio (open/total number of entries), an anxiolytic-like effect. CBD at a dose of 20.0 mg/kg was no longer effective. None of the doses of CBD used changed total number of entries, a measure of total exploratory activity. Diazepam (2.0 mg/kg) also caused an anxiolytic-like effect in this model. These results indicate that CBD causes a selective anxiolytic effect in the elevated plus-maze, within a limited range of doses.
Until now, the problem of fitting self-stimulation rate-frequency functions has been dealt with by using linear models applied to the linear portion of the empirical curve. In this article, an alternative procedure is presented, together with three sigmoid growth models that seem to accurately fit rate-frequency data. From any of these models, it is possible to compute the two indices of stimulation efficacy in use in the parametric study of brain stimulation reward (M50 and theta 0), in addition to the inflection point of the curve, which can be used as an alternative to M50. Important relations allowing initial estimation of each parameter are provided, allowing use of computer programs derived from the Gauss-Newton algorithm for nonlinear regression. The considerations relevant to the choice of a nonlinear model are discussed in terms of each efficacy index.
Defines the reward summation function as the empirical function relating running speed in a runway and waiting-box paradigm to the number of electrical pulses a rat receives for running. 5 experiments with male white rats are described in which repeated determination of this function was made, with other performance variables-priming, task difficulty, degree of training, health, and pharmacological state of the rat-varied between determinations. Results show that these other performance factors affected the height (asymptotic speed) of the function but not the location of the sharp rise in the function. It is concluded that since manipulation of stimulation parameters that affect the amount of reward excitation substantially alters the location of the sharp rise, the reward summation function provides a suitable basis for a neuropharmacological investigation of the reward effect in self-stimulation.
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by delta 9-THC in normal volunteers, and whether this effect occurs by a general block of the action of delta 9-THC or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg delta 9-THC, 1 mg/kg CBD, a mixture containing 0.5 mg/kg delta 9-THC and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by delta 9-THC, however this effect also extended to marihuana-like effects and to other subjective alterations induced by delta 9-THC. This antagonism does not appear to be caused by a general block of delta 9-THC effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of delta 9-THC. These results suggest that the effects of CBD, as opposed to those of delta 9-THC, might be involved in the antagonism of effects between the two cannabinoids.
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by ?9-TCH in normal volunteers, and whether this effect occurs by a general block of the action of ?9-TCH or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg ?9-TCH, 1 mg/kg CBD, a mixture containing 0.5 mg/kg ?9-TCH and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by ?9-TCH, however this effect also extended to marihuanalike effects and to other subjective alterations induced by ?9-TCH. This antagonism does not appear to be caused by a general block of ?9-TCH effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of ?9-TCH.
(−)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA).
CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5′ pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase.
Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2 – 3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive.
(+)-5′-DMH-CBD and (+)-7-hydroxy-5′-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (−)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM).
CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (−)-7-hydroxy-CBD (IC50=34 μM), but not the other analogues (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis.
Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors.
These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (−)-5′-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.
British Journal of Pharmacology (2001) 134, 845–852; doi:10.1038/sj.bjp.0704327
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.
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.
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.
Cannabis is associated with psychotic outcomes in numerous studies, an effect that is commonly attributed to Δ (9)-tetrahydrocannabinol (Δ 9-THC). An increasing number of authors identify cannabidiol, another component of the cannabis plant, as an antipsychotic agent. The objective of the current study is to investigate the role of cannabidiol content in the association between cannabis use and psychiatric symptoms in a large non-clinical population of cannabis users.
In a web-based cross-sectional study we obtained detailed information about cannabis use and subclinical psychiatric experiences using the Community Assessment of Psychic Experiences (CAPE). Different types of cannabis (i.e. marijuana, hashish etc.) have distinctive proportions of Δ 9-THC and cannabidiol. Since average concentrations of Δ 9-THC and cannabidiol in the most popular types of cannabis sold on the Dutch market are annually measured, we were able to estimate exposure to Δ 9-THC and cannabidiol.
We included 1877 subjects (mean age 23, SD 6.0) who used the same type of cannabis in the majority of the occasions (in >60% of occasions). We found a significant inverse relationship (F(1,1877): 14.577, p<0.001) between cannabidiol content and self-reported positive symptoms, but not with negative symptoms or depression. The estimated effect size of cannabidiol content was small.
Although the observed effects are subtle, using high cannabidiol content cannabis was associated with significantly lower degrees of psychotic symptoms providing further support for the antipsychotic potential of cannabidiol.
The major non-psychoactive component of Cannabis sativa, cannabidiol (CBD), displays a plethora of actions including wakefulness. In the present study, we addressed whether perfusing CBD via microdialysis into lateral hypothalamus (LH) during the lights-on period would modify the sleep-wake cycle of rats as well as the contents of dopamine (DA) collected from nucleus accumbens (AcbC). Additionally, we tested whether perfusion of CBD into LH would block the sleep rebound after a sleep deprivation period.
Electroencephalogram and electromyogram electrodes were implanted in rats as well as a guide-cannula aimed to LH or AcbC. CBD perfusion was carried out via cannulae placed into LH whereas contents of DA were collected from AcbC and analyzed using HPLC means.
We found that microdialysis perfusion of CBD (30, 60, or 90 nM) into LH of rat enhances alertness and suppresses sleep. This effect was accompanied with an increase in DA extracellular levels collected from the AcbC. Furthermore, perfusion of CBD into LH after total sleep deprivation prevented the sleep rebound.
These findings enhance the investigation about the neurobiological properties of CBD on sleep modulation.
Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic-like effects in rodents and humans after systemic administration. Previous results from our group showed that CBD injection into the bed nucleus of the stria terminalis (BNST) attenuates conditioned aversive responses. The aim of this study was to further investigate the role of this region on the anxiolytic effects of the CBD. Moreover, considering that CBD can activate 5-HT1A receptors, we also verified a possible involvement of these receptors in those effects.
Male Wistar rats received injections of CBD (15, 30, or 60 nmol) into the BNST and were exposed to the elevated plus-maze (EPM) or to the Vogel conflict test (VCT), two widely used animal models of anxiety.
CBD increased open arms exploration in the EPM as well as the number of punished licks in the VCT, suggesting an anxiolytic-like effect. The drug did not change the number of entries into the enclosed arms of the EPM nor interfered with water consumption or nociceptive threshold, discarding potential confounding factors in the two tests. Moreover, pretreatment with the 5-HT1A receptor antagonist WAY100635 (0.37 nmol) blocked the effects of CBD in both models.
These results give further support to the proposal that BNST is involved in the anxiolytic-like effects of CBD observed after systemic administration, probably by facilitating local 5-HT1A receptor-mediated neurotransmission.
Cannabidiol (CBD) is a major non-psychotomimetic component of Cannabis sativa that has been shown to have an anxiolytic effect in human and animal models. Earlier studies suggest that these effects involve facilitation of serotonin, a neurotransmitter that has also been related to obsessive-compulsive disorder. On the basis of this evidence, this study investigated the effects of CBD in C57BL/6J mice submitted to the marble-burying test (MBT), an animal model proposed to reflect compulsive behaviour. CBD (15, 30 and 60 mg/kg) induced a significant decrease in the number of buried marbles compared with controls (34, 41 and 48%, respectively). A similar, although larger, decrease was also found after the serotonin selective reuptake inhibitor paroxetine (10 mg/kg, 77% decrease) and the benzodiazepine diazepam (2.5 mg/kg, 84% decrease). The effect of CBD (30 mg/kg) was still significant after 7 days of daily repeated administration, whereas the effect of diazepam disappeared. Pretreatment with WAY100635 (3 mg/kg), a 5HT1A receptor antagonist, prevented the effects of paroxetine but failed to alter those of CBD. These latter effects, however, were prevented by pretreatment with the CB1 receptor antagonist AM251 (1 mg/kg). These results indicated that CBD and paroxetine decrease the number of buried marbles in the MBT through distinct pharmacological mechanisms. They also suggest a potential role of drugs acting on the cannabinoid system in modulating compulsive behaviour.
Metabotropic glutamate receptor 2/3 (mGluR2/3) agonists were shown previously to nonselectively decrease both cocaine- and food-maintained responding in rats. mGluR2 positive allosteric modulators (PAMs) may represent improved therapeutic compounds because of their modulatory properties and higher selectivity for mGluR2. We analyzed the effects of the selective, brain penetrant, and systemically active mGluR2 PAM potassium 3'-([(2-cyclopentyl-6-7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl)biphenyl l-4-carboxylate (BINA) and the mGluR2/3 agonist LY379268 on intravenous cocaine self-administration and cocaine-seeking behavior in rats that had short (1 h, ShA) or long (6 h, LgA) access to cocaine. The effects of BINA on food responding and food-seeking behavior were also analyzed. Finally, we examined the effects of BINA on brain reward function and cocaine-induced reward enhancement using the intracranial self-stimulation procedure. BINA decreased cocaine self-administration in both ShA and LgA rats, with no effect on food self-administration. Alternatively, LY379268 nonselectively decreased both cocaine and food self-administration. BINA decreased cue-induced reinstatement of cocaine seeking with no effect on food seeking. The cocaine-induced enhancement of brain reward function was blocked by BINA, although the highest doses of BINA decreased brain reward function when administered alone, suggesting additive, rather than interactive, effects of BINA and cocaine. In conclusion, BINA attenuated the reinforcing and counteracted the reward-enhancing effects of cocaine and decreased cue-induced cocaine-seeking behavior, without affecting behaviors motivated by food reinforcement. The higher selectivity of BINA compared with an mGluR2/3 agonist for drug- vs food-motivated behaviors suggests a therapeutic role for mGluR2 PAMs for the treatment of cocaine addiction and possibly other drugs of abuse.
Intracranial self-stimulation (ICSS) is a sophisticated paradigm that can be used to assess the rewarding properties of drugs of abuse such as cocaine and amphetamine. Initial studies using this method to assess brain stimulation reward (BSR) examined the enhancement of response rates after drug administration. In the mid to late 1980s several groups began implementing paradigms to assess the direct rewarding effects of drugs of abuse that, for the most part, are independent of rate (i.e., progressive-ratio, auto-titration, rate-frequency curve), providing a representative assessment of a drugs rewarding effects. However, some drugs such as morphine and ethanol, which are known to have abuse potential, have sedative effects that may impede the ability to accurately quantify rewarding effects, even in these rate-independent paradigms. Few studies to date report effects of morphine in the ICSS paradigm and those that do appear to be inconsistent, lack robustness, have not been reproducible by other groups, or require inconvenient experimental designs. Here, we demonstrate a reliable and robust method to assess the rewarding effects of morphine using the rate-frequency curve paradigm.
Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic- and antipsychotic-like effects in animal models. Effects of CBD may be mediated by the activation of 5-HT(1A) receptors. As 5-HT(1A) receptor activation may induce antidepressant-like effects, the aim of this work was to test the hypothesis that CBD would have antidepressant-like activity in mice as assessed by the forced swimming test. We also investigated if these responses depended on the activation of 5-HT(1A) receptors and on hippocampal expression of brain-derived neurotrophic factor (BDNF).
Male Swiss mice were given (i.p.) CBD (3, 10, 30, 100 mg*kg(-1)), imipramine (30 mg*kg(-1)) or vehicle and were submitted to the forced swimming test or to an open field arena, 30 min later. An additional group received WAY100635 (0.1 mg*kg(-1), i.p.), a 5-HT(1A) receptor antagonist, before CBD (30 mg*kg(-1)) and assessment by the forced swimming test. BDNF protein levels were measured in the hippocampus of another group of mice treated with CBD (30 mg*kg(-1)) and submitted to the forced swimming test.
CBD (30 mg*kg(-1)) treatment reduced immobility time in the forced swimming test, as did the prototype antidepressant imipramine, without changing exploratory behaviour in the open field arena. WAY100635 pretreatment blocked CBD-induced effect in the forced swimming test. CBD (30 mg*kg(-1)) treatment did not change hippocampal BDNF levels.
CBD induces antidepressant-like effects comparable to those of imipramine. These effects of CBD were probably mediated by activation of 5-HT(1A) receptors.
Quetiapine is an effective atypical antipsychotic medication that was reported to reduce substance use and craving in patients with schizophrenia. This clinical effect of quetiapine is hypothesized to be due to its low affinity for dopamine receptors and its weak attenuation of central reward functions. The present study was designed to determine the magnitude of the reward attenuation induced by different doses of quetiapine and its effectiveness at reducing the effect of cocaine. Experiments were performed on male Sprague-Dawley rats that were trained to produce operant responses to receive rewarding stimulations to the medial forebrain bundle. In a first study, we tested the effects of three doses of quetiapine (5, 10, 20 mg/kg) on brain stimulation reward using a within-subject design and the curve-shift method. In a second study, we tested the effectiveness of a low and high dose of quetiapine (5 and 20 mg/kg) at blocking the reward enhancing effect of cocaine (4 mg/kg) in different groups of animals. Quetiapine produced a weak (20%) but significant attenuation of reward. Cocaine enhanced reward by 20% and the combination of cocaine with the high dose of quetiapine lead to cancellation of each drug effect. The low dose of quetiapine did not alter baseline reward but completely blocked the effect of cocaine. The magnitude of the reward attenuation induced by quetiapine is consistent with its low affinity for dopamine receptors. Its actions on dopamine and non-dopamine neurotransmission are likely to account for its effectiveness at blocking the enhancement of reward by cocaine.
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
The actions of cannabidiol (CBD), one of the cannabis constituents, were assessed on the sleep-wakefulness cycle of male Wistar rats.
During acute experiments, single doses of 20 mg/kg CBD decreased slow-wave sleep (SWS) latency. After 40 mg/kg SWS time was significantly increased while wakefulness was decreased. REM sleep was not significantly modified. Following the once-daily injections of 40 mg/kg CBD for a period of 15 days, tolerance developed to all the above-mentioned effects.
Opening of the pyran ring of delta 9-tetrahydrocannabinol (THC) produces cannabidiol, a bicyclic cannabinoid devoid of many pharmacological properties produced by delta 8-THC or delta 9-THC. Interestingly, the bicyclic compound CP-47,497 (VI) has been described as producing many of the pharmacological effects produced by delta 9-THC, and another related bicyclic analog CP-55,940 (XIV) has been used to successfully define a cannabinoid binding site. A series of 16 bicyclic analogs of VI and XIV were evaluated and compared with the pharmacological profile of cannabidiol, delta 8-THC and delta 9-THC. The goals of the studies described herein were to determine whether these bicyclic analogs possess similar pharmacological properties of delta 9-THC, to compare pharmacological activity after s.c. and i.v. administration, and to evaluate the structure-activity relationship of this series of analogs for further insight into cannabinoid mechanism of action. Each analog was evaluated for its ability to produce hypoactivity, hypothermia, antinociception and catalepsy in mice. The ED50 values generated from these assays were averaged to provide an index of activity. The ED50 values for delta 9-THC varied from 1.0 to 1.5 mg/kg, giving an overall index of activity of 1.3. The index for delta 8-THC was 6.0, making this isomer 4-fold less potent. Although several bicyclic analogs (V, VI, VII, VIII, XI, XII, XIV and XVI) proved to be truly cannabimimetic, three (IV, IX and X) were sufficiently unique to be classified as noncannabimimetic. The index of activity of cannabimimetic bicyclic analogs varied from 0.2 to 2.2, although some minor differences between the bicyclics and delta 9-THC exist.(ABSTRACT TRUNCATED AT 250 WORDS)
While the evidence is strong that dopamine plays some fundamental and special role in the rewarding effects of brain stimulation, psychomotor stimulants, opiates, and food, the exact nature of that role is not clear. One thing is clear: Dopamine is not the only reward transmitter, and dopaminergic neurons are not the final common path for all rewards. Dopamine antagonists and lesions of the dopamine systems appear to spare the rewarding effects of nucleus accumbens and frontal cortex brain stimulation (Simon et al 1979) and certainly spare the rewarding effects of apomorphine (Roberts & Vickers 1988). It is clear that reward circuitry is multisynaptic, and since dopamine cells do not send axons to each other or receive axons from each other, dopamine can at best serve as but a single link in this circuitry. If dopamine is not a final common path for all rewards, could it be an intermediate common path for most rewards? Some workers have argued against such a view, but at present they must do so on incomplete evidence. For example, Phillips (1984) has argued that there must be multiple reward systems, functionally independent and organized in parallel with one another. His primary evidence, however, is the fact that brain stimulation is rewarding at different levels of the nervous system. As we have seen in the case of midline mesencephalic stimulation, the location of the electrode tip in relation to the dopamine cells and fibers tells us little about the role of dopamine in brain stimulation reward. It seems clear that the ventral tegmental dopamine system plays a critical role in midline mesencephalic reward, despite the distance from the electrode tip to the dopamine cells where morphine causes its dopamine-dependent facilitory effects or to the dopamine terminals where low-dose neuroleptics presumably cause theirs. Until pharmacological challenge has been extended to the cases discussed by Phillips, we can only speculate as to the role of dopamine in each of those cases. In the cases where pharmacological challenge has been examined, only nucleus accumbens and frontal cortex have been found to have dopamine-independent reward sites. It is not consistent with the dopamine hypothesis that dopamine-independent reward sites should exist in these areas, since any reward signals carried to nucleus accumbens or frontal cortex by dopamine fibers would-unless we are to believe that reward "happens" at these sites-have to be carried to the next stage of the circuit by nondopaminergic fibers (there are no dopaminergic cell bodies in any of the dopamine terminal areas).(ABSTRACT TRUNCATED AT 400 WORDS)
Monopolar moveable stimulation electrodes were implanted in male adult rats in order to map the reward substrate in the pontine tegmentum. Electrodes were implanted 6 mm below the surface of the skull and subsequently lowered by steps of 0.16 or 0.32 mm. Each bar press in a Skinner box delivered a train (0.4 s in duration) of cathodal rectangular pulses of fixed intensity (200 microA) and width (0.1 ms). Self-stimulation was recorded from zero to maximum performance by varying the number of pulses per train. The rewarding effectiveness of the stimulation at each positive site was inferred by determining the frequency threshold. Out of 476 sites that were sampled, 137 supported self-stimulation. Eighty-one percent of the positive sites (111 out of 137) were located within 1 mm of the midline. Of the 181 sites that were sampled in the region posterior to the caudal end of the dorsal raphe, only 9 sites (less than 5%) supported self-stimulation. These results suggest that the majority of neurons that constitute the brainstem reward substrate either originate from and/or terminate in the rostral pons.
Abstract— Tetrahydrocannabinol (THC) induced catalepsy in mice, whereas a cannabis oil (6.68% w/w THC), four cannabinoids and a synthetic mixture did not. Cannabinol (CBN) and olivetol inhibited THC-induced catalepsy in the mornings and the evenings, but cannabidiol (CBD) exhibited this effect only in the evenings. A combination of CBN and CBD inhibited THC-induced catalepsy equal to that of CBN alone in the mornings, but this inhibition was greater than that produced by CBN alone in the evenings.
Eleven rats were trained to press a lever in an operant chamber in order to earn rewarding trains of cathodal rectangular pulses of fixed intensity and variable frequency. The rate-frequency functions were examined under administration of two neuroleptics (pimozide and chlorpromazine) and three manipulations that interfered with bar pressing (muscular relaxation with methocarbamol, increased lever weight, and limitation of maximum response rates by an F1 reinforcement schedule). Chlorpromazine, and pimozide at low dosages produced a near parallel shift of the rate-frequency functions on the logarithmic axis of pulses, suggesting that these drugs decreased the reinforcing efficacy of the stimulation. The three conditions that interfered with bar-pressing decreased the asymptotic rates and produced small or moderate lateral shifts. Changes in the reinforcing efficacy of the stimulation following the above manipulations were inferred from the shift in the number of pulses required at zero and half-maximal performance (theta 0 and M50 indices, respectively). In the cases of the manipulations that interfered with bar-pressing, M50 indicated a larger artifactual change in the efficacy of the stimulation, compared to theta 0. This phenomenon was mainly due to the fact that the asymptote of the altered functions was shifted towards higher pulse numbers.
The effect of morphine was studied on self-stimulation (SS) behavior in rats implanted with bipolar electrodes in the posterior hypothalamus. A single dose (10 mg/kg) of morphine decreased SS responding within 10-20 min, reaching a minimum level between 20-40 min after which the responding gradually returned to normal. The SS responding then increased above the control level at 120-180 min postdrug, then slowly returned to normal, thus showing a rebound effect. The combination treatment with morphine (10 mg/kg) and chloramphenicol (50 mg/kg) on SS behavior produced an accentuation of the initial decrease in responding, which was prolonged before gradually returning to the control levels without showing any rebound effect. The data suggest that alterations in protein synthesis may underlie the suppressed excitatory effect of a high dose of morphine on SS behavior.
Determination of the function relating rate of pressing to the number of pulses in a train of fixed duration (the rate-frequency function) yields a physiologically interpretable measure of changes in the rewarding efficacy of the stimulation, because the number of action potentials in the reward-relevant first stage axons is directly proportional to the number of pulses in the train. We describe a system, based on a low cost microcomputer, which permits determination of 16-data-point rate-frequency functions in 4-6 animals simultaneously in less than 10 minutes. We give an empirical and theoretical justification for using the curve-shift measurement procedure in drug and lesion work, where the experimental treatments must be presumed to have substantial effects on performance factors.
Single or twin, moveable monopolar stimulating electrodes were implanted in male adult rats in order to map the medial pons and mesencephalon for self-stimulation behaviour. The electrodes were implanted 6 mm below the surface of the skull and subsequently moved down by steps of 0.13 or 0.16 mm. Each bar press in a Skinner box delivered a train (0.4 s in duration) of cathodal rectangular pulses of fixed intensity (200 microA) and width (0.1 ms). Self-stimulation was recorded from zero to the maximum performance by varying the number of pulses per stimulating train. The rewarding efficacy of the stimulation at each electrode location was inferred from determination of the pulse period corresponding to the threshold and half-maximal performance. Out of 361 mesencephalic and pontine sites sampled, 289 supported self-stimulation. Within the metencephalon, the study revealed a continuous band of positive sites, extending over a dorso-ventral distance of 4 mm, between the floor of the aqueduct and the pontine nuclei. Hence, all electrode locations in the central grey, dorsal raphe and median raphe supported self-stimulation. Within the mesencephalon, the positive band was restricted between the floor of the central grey and the middle part of the interpeduncular nucleus. At the rostral mesencephalon, it shifted laterally towards the substantia nigra. The overlap between the self-stimulation sites and some of the best known ascending and descending pathways is discussed.
The objective of this investigation was to study the influence of the dose ratio between cannabidiol (CBD) and delta 9-tetrahydrocannabinol (delta 9-THC) on the effects of mixtures of the two cannabinoids on variable-interval (VI) schedule performance in rats. The effect on VI performance of a control solution, 10 mg/kg CBD, delta 9-THC (0.125, 0.5, 2 and 8 mg/kg) and a mixture of 10 mg/kg CBD + delta 9-THC (0.125, 0.5, 2 and 8 mg/kg) was investigated in 10 rats, with a different sequence of treatments for each animal. The results were expressed in terms of rate-dependency. The control solution, 10 mg/kg CBD, 0.125 mg/kg delta 9-THC, or 10 mg/kg CBD + delta 9-THC (0.125 mg/kg) did not cause rate-dependent effects. Delta 9-THC (0.5 and 2 mg/kg) produced rate-dependent effects. The dose of 8 mg/kg delta 9-THC almost suppressed responding. The combination of 10 mg/kg CBD + 0.5 mg/kg delta 9-THC did not cause rate-dependent effects but produced a response pattern similar to that obtained with 0.125 mg/kg delta 9-THC. At these doses CBD antagonized delta 9-THC. The combination of 10 mg/kg CBD + 2 mg/kg delta 9-THC caused rate-dependent effects. The rate-dependent regression line determined by this mixture was parallel to that produced by 2 mg/kg delta 9-THC. However, the lower intercept of the mixture with the y axis suggested potentiation of the depressant effects of delta 9-THC by CBD.(ABSTRACT TRUNCATED AT 250 WORDS)
Direct electrical or chemical stimulation of specific brain regions can establish response habits similar to those established by natural rewards such as food or sexual contact. Cocaine, mu and delta opiates, nicotine, phencyclidine, and cannabis each have actions that summate with rewarding electrical stimulation of the medial forebrain bundle (MFB). The reward-potentiating effects of amphetamine and opiates are associated with central sites of action where these drugs also have their direct rewarding effects, suggesting common mechanisms for drug reward per se and for drug potentiation of brain stimulation reward. The central sites at which these and perhaps other drugs of abuse potentiate brain stimulation reward and are rewarding in their own right are consistent with the hypothesis that the laboratory reward of brain stimulation and the pharmacological rewards of addictive drugs are habit forming because they act in the brain circuits that subserve more natural and biologically significant rewards.
Background
Cannabis is commonly regarded as an innocuous drug and the prevalence of lifetime and regular use has increased in most developed countries. However, accumulative evidence highlights the risks of dependence and other adverse effects, particularly among people with pre-existing psychiatric disorders.
Aims
To re-evaluate the adverse effects of cannabis in the general population and among vulnerable individuals, including those with serious psychiatric disorders.
Method
A wide-ranging review of the topics related to these issues.
Results and conclusions
An appreciable proportion of cannabis users report short-lived adverse effects, including psychotic states following heavy consumption, and regular users are at risk of dependence. People with major mental illnesses such as schizophrenia are especially vulnerable in that cannabis generally provokes relapse and aggravates existing symptoms. Health workers need to recognise, and respond to, the adverse effects of cannabis on mental health.
A discrete-trial current-threshold self-stimulation procedure was used to assess the effects of increased and decreased serotonergic neurotransmission, and 5-HT(1A) receptor activation on brain stimulation reward. Systemic administration of the 5-HT(1A) receptor agonist 8-OH-DPAT had a biphasic effect on brain reward thresholds, without affecting the latency to respond, a measure of performance. The low dose of 8-OH-DPAT (0.03 mg/kg) lowered reward thresholds, whereas higher doses (0.1 and 0.3 mg/kg) elevated thresholds. The 5-HT(1A) receptor antagonist p-MPPI had no effect on brain stimulation behavior, but reversed both the 8-OH-DPAT-induced lowering and elevation of thresholds, indicating that both of these effects of 8-OH-DPAT are mediated through the 5-HT(1A) receptor. Injections of 8-OH-DPAT into the median raphé nucleus also lowered brain reward thresholds, without affecting measures of performance, whereas injections of 8-OH-DPAT into the dorsal raphé nucleus had no effect. A high dose of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) elevated reward thresholds and responses latencies, whereas lower doses (2.5 and 5.0 mg/kg) increased response latencies without affecting thresholds. Furthermore, the coadministration of a 5-HT(1A) antagonist, p-MPPI, and a previously ineffective dose of fluoxetine, a drug combination that increases serotonin levels, significantly elevated thresholds. Thus, it is suggested here that the reward-potentiating effects of systemically administered low doses of 8-OH-DPAT may be the result of reduced serotonergic neurotransmission, mediated by activation of 5-HT(1A) somatodendritic autoreceptors in the median, but not the dorsal, raphé nucleus. In conclusion, the present data support the hypothesis that serotonin exerts an inhibitory influence on reward processes.
Over the past few years, considerable attention has focused on cannabidiol (CBD), a major nonpsychotropic constituent of cannabis. The authors present a review on the chemistry of CBD and discuss the anticonvulsive, antianxiety, antipsychotic, antinausea, and antirheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors, and its mechanism of action is yet unknown. It is possible that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its antioxidative effect.