Tag Archives: THC

Neuromodulatory role of the endocannabinoid signaling system in alcoholism: an overview.

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Abstract

“The current review evaluates the evidence that some of the pharmacological and behavioral effects of ethanol (EtOH), including EtOH-preferring behavior, may be mediated through the endocannabinoid signaling system. The recent advances in the understanding of the neurobiological basis of alcoholism suggest that the pharmacological and behavioral effects of EtOH are mediated through its action on neuronal signal transduction pathways and ligand-gated ion channels, receptor systems, and receptors that are coupled to G-proteins. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB1 receptor) that was activated by Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. To date, two fatty acid derivatives identified to be arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) have been isolated from both nervous and peripheral tissues. Both these compounds have been shown to mimic the pharmacological and behavioral effects of Delta(9)-THC. The involvement of the endocannabinoid signaling system in the development of tolerance to the drugs of abuse including EtOH has not been known until recently. Recent studies from our laboratory have demonstrated for the first time the down-regulation of CB1 receptor function and its signal transduction by chronic EtOH. The observed down-regulation of CB1 receptor binding and its signal transduction results from the persistent stimulation of the receptors by the endogenous CB1 receptor agonists, AEA and 2-AG, the synthesis of which has been found to be increased by chronic EtOH treatment. This enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid EtOH intake, have significantly reduced brain-CB1-receptor function consistent with other studies, where the CB1 receptor antagonist SR141716A has been shown to block voluntary EtOH intake in rodents. Similarly, activation of the CB1 receptor system promoted alcohol craving, suggesting a role for the CB1 receptor gene in excessive EtOH drinking behavior and development of alcoholism. Ongoing investigations may lead to the development of potential therapeutic strategies for the treatment of alcoholism.”

http://www.ncbi.nlm.nih.gov/pubmed/12052043

ROLE OF THE ENDOCANNABINOID SYSTEM IN THE DEVELOPMENT OF TOLERANCE TO ALCOHOL

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“Alcohol dependence is a leading cause of morbidity and various medical and socio-economic problems. It is defined by compulsive, excessive use of alcohol despite negative consequences. Alcohol dependence is usually accompanied by tolerance to the intoxicating effects of alcohol and by withdrawal symptoms including tremors and confusion when consumption of alcohol ceases. Although important advances have been made in recent years in understanding the mechanisms underlying the development of tolerance to and dependence on alcohol, the exact mechanisms are still elusive. The present article reviews the role played by the endocannabinoid system in the molecular mechanism involved in the development of alcohol tolerance, which possibly influences alcohol-drinking behaviour.”

“The present review evaluates the evidence that the endocannabinoid system plays in the development of tolerance to alcohol. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB1 receptor), which was activated by Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. Until now, four fatty acid derivatives identified to be arachidonylethanolamide (AEA), 2-arachidonylglycerol (2-AG), 2-arachidonylglycerol ether (noladin ether) and virodhamine have been isolated from both nervous and peripheral tissues. Both AEA and 2-AG have been shown to mimic the pharmacological and behavioural effects of Δ9-THC. The role of the endocannabinoid system in the development of tolerance to alcohol was not known until recently. Recent studies from our laboratory have implicated for the first time a role for the endocannabinoid system in development of tolerance to alcohol. Chronic alcohol treatment has been shown to down-regulate CB1 receptors and its signal transduction. The observed downregulation of CB1 receptor function results from the persistent stimulation of the receptors by AEA and 2-AG, the synthesis of which has been shown to be increased by chronic alcohol treatment. The enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid alcohol intake, have significantly reduced CB1 receptor function in the brain, consistent with other studies in which the CB1 receptor antagonist SR 141716A has been shown to block voluntary alcohol intake in rodents. Similarly, activation of the CB1 receptor system promoted alcohol craving, suggesting a role for the CB1 receptor gene in excessive alcohol drinking behaviour and development of alcoholism. Ongoing investigations may lead to a better understanding of the mechanisms underlying the development of tolerance to alcohol and to develop therapeutic strategies to treat alcoholism.”

“CONCLUSION

Over the past seven years, remarkable advances have been made towards our understanding of the role played by the endocannabinoid system in the development of alcohol tolerance and alcohol-drinking behaviour. These studies have provided strong evidence that CB1 receptors and the endocannabinoid system serve as an attractive therapeutic target for the treatment of alcohol tolerance and alcohol-related disorders. The data reviewed here provide convincing evidence that alcohol tolerance involves the downregulation of the CB1 receptor and its function. The observed neuro-adaptation may be due to increased accumulation of the endocannabinoids AEA and 2-AG. Treatment with the CB1 receptor antagonist SR 141716A led to reduced consumption of alcohol in rodents and activation of the same endogenous cannabinoid systems by the CB1 receptor agonist promoted alcohol craving, which may be related to the change in the levels of dopamine in the NAc. Further, reduced alcohol intake by the CB1 receptor knockout mice is consistent with our previous observation that significantly lower levels of functional CB1 receptors are found in the alcohol-avoiding DBA/2 mouse strain compared with the alcohol-preferring C57BL/6 mouse strain. These observations suggest the involvement of the CB1 receptors in controlling voluntary alcohol consumption and the involvement of the endocannabinoid system in the development of alcohol tolerance. However, further studies are necessary to unfold the exact mechanism by which alcohol exerts its pharmacological and behavioural effects through the endocannabinoid system. The investigation of the detailed signalling cascade for the actions of both endocannabinoids and CB1 receptors will be of great value in understanding their physiological and functional role in several neurological disorders, voluntary alcohol intake and alcohol craving, including the behavioural neuroadaptation to alcohol. Such studies may also lead to the development of endocannabinoid signalling-targeted drugs, which may help to reduce both alcohol intake and alcohol craving. These results suggest that the cannabinoid antagonist, SR 141716A, may be useful as a potential therapeutic agent in alcohol dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/15550443

http://alcalc.oxfordjournals.org/content/40/1/15.long

Addiction and the pharmacology of cannabis: implications for medicine and the law.

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Abstract

“The topic of drug addiction or misuse of drugs has numerous far-reaching ramifications into areas such as neuroscience, medicine and therapeutics, toxicology, epidemiology, national and international economics and politics, and the law. The general principles of drug addiction are first summarised. A recurring and intrinsic problem is lack of adequate characterisation of the independent variable, namely the drug taken. Secondly, it is not feasible to allocate subjects randomly to treatments. Thirdly, the heterogeneity of different forms of addiction precludes facile generalisations. “A problem drug user is anyone who experiences social, psychological, physical, or legal problems related to intoxication, and/or regular excessive consumption, and/or dependence as a consequence of their use of drugs” (UK Advisory Council on Misuse of Drugs, 1982). Cannabis is a genus of flowering plants whose products are used as recreational drugs. Claims have been made for a range of therapeutic properties. Its two main active principles are delta9 – tetrahydrocannabinol (THC) and cannabidiol (CBD). These compounds have contrasting pharmacological properties. THC is suspected of causing psychotic phenomena, but CBD seems more sedative and may even be antipsychotic. The past use of cannabis, particularly the concentrations of THC and CBD, can be monitored with hair analysis. Recent studies involving the administration of THC and CBD to human subjects are reviewed. Suggestions are made for further research into the pharmacology and toxicology of CBD. Such data may also point to a more rational evidence-based approach to the legal control of cannabis preparations.”

http://www.ncbi.nlm.nih.gov/pubmed/19306615

Endocannabinoid system involvement in brain reward processes related to drug abuse.

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“Cannabis is the most commonly abused illegal drug in the world and its main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), produces rewarding effects in humans and non-human primates. Over the last several decades, an endogenous system comprised of cannabinoid receptors, endogenous ligands for these receptors and enzymes responsible for the synthesis and degradation of these endogenous cannabinoid ligands has been discovered and partly characterized. Experimental findings strongly suggest a major involvement of the endocannabinoid system in general brain reward functions and drug abuse. First, natural and synthetic cannabinoids and endocannabinoids can produce rewarding effects in humans and laboratory animals. Second, activation or blockade of the endogenous cannabinoid system has been shown to modulate the rewarding effects of non-cannabinoid psychoactive drugs. Third, most abused drugs alter brain levels of endocannabinoids in the brain. In addition to reward functions, the endocannabinoid cannabinoid system appears to be involved in the ability of drugs and drug-related cues to reinstate drug-seeking behavior in animal models of relapse. Altogether, evidence points to the endocannadinoid system as a promising target for the development of medications for the treatment of drug abuse.”

“The endogenous cannabinoid is a recently discovered system that appears to play an important and pervasive role in many types of drug abuse and dependence. Endogenous cannabinoids are neuromodulators that are involved in the signalling of rewarding events and can produce reinforcing and rewarding effects in experimental animals, as they do in humans. Endogenous cannabinoids can also activate other brain systems involved in reward signalling, can modulate the reinforcing and rewarding effects of other non-cannabinoid abused drugs, and are released by drugs of abuse in brain areas involved in reward and reinforcement processes. Accumulating evidence points to the endocannabinoid system as a major target for the development of new pharmacological agents for the treatment of many different types of drug abuse and dependence.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189556/

The endocannabinoid system: emotion, learning and addiction.

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Abstract

“The identification of the cannabinoid receptor type 1 (CB1 receptor) was the milestone discovery in the elucidation of the behavioural and emotional responses induced by the Cannabis sativa constituent Delta(9)-tetrahydrocannabinol. The subsequent years have established the existence of the endocannabinoid system. The early view relating this system to emotional responses is reflected by the fact that N-arachidonoyl ethanolamine, the pioneer endocannabinoid, was named anandamide after the Sanskrit word ‘ananda’, meaning ‘bliss’. However, the emotional responses to cannabinoids are not always pleasant and delightful. Rather, anxiety and panic may also occur after activation of CB1 receptors. The present review discusses three properties of the endocannabinoid system as an attempt to understand these diverse effects. First, this system typically functions ‘on-demand’, depending on environmental stimuli and on the emotional state of the organism. Second, it has a wide neuro-anatomical distribution, modulating brain regions with different functions in responses to aversive stimuli. Third, endocannabinoids regulate the release of other neurotransmitters that may have even opposing functions, such as GABA and glutamate. Further understanding of the temporal, spatial and functional characteristics of this system is necessary to clarify its role in emotional responses and will promote advances in its therapeutic exploitation.”

http://www.ncbi.nlm.nih.gov/pubmed/18422832

A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation.

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Abstract

“Δ 9-tetrahydrocannabinol (Δ 9-THC) is the main compound of the Cannabis Sativa responsible for most of the effects of the plant. Another major constituent is cannabidiol (CBD), formerly regarded to be devoid of pharmacological activity. However, laboratory rodents and human studies have shown that this cannabinoid is able to prevent psychotic-like symptoms induced by high doses of Δ 9- THC. Subsequent studies have demonstrated that CBD has antipsychotic effects as observed using animal models and in healthy volunteers. Thus, this article provides a critical review of the research evaluating antipsychotic potential of this cannabinoid. CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of Δ 9-THC involve the striatum and temporal cortex that have been traditionally associated with psychosis. Although the mechanisms of the antipsychotic properties are still not fully understood, we propose a hypothesis that could have a heuristic value to inspire new studies. These results support the idea that CBD may be a future therapeutic option in psychosis, in general and in schizophrenia, in particular.”

http://www.ncbi.nlm.nih.gov/pubmed/22716160

Potential antipsychotic properties of central cannabinoid (CB1) receptor antagonists.

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Abstract

“Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the principal psychoactive constituent of the Cannabis sativa plant, and other agonists at the central cannabinoid (CB(1)) receptor may induce characteristic psychomotor effects, psychotic reactions and cognitive impairment resembling schizophrenia. These effects of Delta(9)-THC can be reduced in animal and human models of psychopathology by two exogenous cannabinoids, cannabidiol (CBD) and SR141716. CBD is the second most abundant constituent of Cannabis sativa that has weak partial antagonistic properties at the CB(1) receptor. CBD inhibits the reuptake and hydrolysis of anandamide, the most important endogenous CB(1) receptor agonist, and exhibits neuroprotective antioxidant activity. SR141716 is a potent and selective CB(1) receptor antagonist. Since both CBD and SR141716 can reverse many of the biochemical, physiological and behavioural effects of CB(1) receptor agonists, it has been proposed that both CBD and SR141716 have antipsychotic properties. Various experimental studies in animals, healthy human volunteers, and schizophrenic patients support this notion. Moreover, recent studies suggest that cannabinoids such as CBD and SR141716 have a pharmacological profile similar to that of atypical antipsychotic drugs. In this review, both preclinical and clinical studies investigating the potential antipsychotic effects of both CBD and SR141716 are presented together with the possible underlying mechanisms of action.”

http://www.ncbi.nlm.nih.gov/pubmed/20218784

Opposite Effects of Δ-9-Tetrahydrocannabinol and Cannabidiol on Human Brain Function and Psychopathology

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 “Pretreatment with CBD prevented the acute induction of psychotic symptoms by Δ-9-tetrahydrocannabinol. Δ-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD’s ability to block the psychotogenic effects of Δ-9-THC”

“In healthy individuals, Δ-9-tetrahydrocannabinol (Δ-9-THC), the main psychoactive ingredient of the Cannabis sativa plant, can induce psychotic symptoms and anxiety, and can impair memory and psychomotor control. In patients with schizophrenia, Δ-9-THC may exacerbate existing psychotic symptoms, anxiety and memory impairments, and Δ-9-THC is thought to be the ingredient responsible for the increased risk of developing schizophrenia following regular cannabis use. In contrast, Cannabidiol (CBD), the other major psychoactive constituent of C. sativa, has anxiolytic and possibly antipsychotic properties, does not impair memory or other cognitive functions. Although CBD has been shown to have neuroprotective effects, Δ-9-THC may have neurotoxic as well as neuroprotective effects. Moreover, when co-administered with Δ-9-THC, CBD may be able to reduce some of the symptomatic effects of Δ-9-THC like anxiety and paranoia. CBD may thus have therapeutic potential as a treatment for cannabis-induced psychopathology, and as an anxiolytic and an antipsychotic.”

 “Our data are consistent with a potential therapeutic role for CBD in ameliorating the psychiatric consequences of cannabis use in the general population, and in patients with existing psychiatric disorders, particularly as conventional antipsychotic medication is relatively ineffective for such conditions. It might also have a role in the treatment of psychotic and anxiety disorders independent of cannabis use. From a public health point of view, one worrying implication of our results is that cannabis users may be at an increased risk of acute adverse psychological reactions following cannabis use, in light of the increasingly potent forms of cannabis with decreasing CBD content available on the street.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055598/

Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment.

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“Community-based studies suggest that cannabis products that are high in Δ(9)-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ(2)=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6±18.9%) compared with the CBD group (-0.4%±9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.”

http://www.ncbi.nlm.nih.gov/pubmed/23042808

Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study

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“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.”

“We have recently found evidence to suggest that use of strains richer in cannabidiol may protect cannabis users from the chronic psychotic-like effects of THC. Given the opposing neuropharmacological actions of THC and cannabidiol – the former is a partial agonist whereas the latter is an antagonist at CB1 and CB2 receptors – we hypothesised that cannabidiol may also protect users against other harmful effects of the drug such as cognitive impairment and psychosis-like effects. The current study set out to test these hypotheses by employing a novel methodology that enabled analysis of cannabinoids in the cannabis actually smoked by each individual user.”

“The constituents of street cannabis have changed over the past 20 years with high THC, low-cannabidiol strains now dominating the market. Our findings suggest that this increases the cognitive harms to cannabis users. The research reported here also contributes to the growing body that suggests a range of potential therapeutic uses of cannabidiol, including the ability to modulate the acute amnestic effects of THC. Given the widespread use of cannabis across the globe, there are clear public health implications of this study. 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.”

Conclusions

“The antagonistic effects of cannabidiol at the CB1 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.”

http://bjp.rcpsych.org/content/197/4/285.long