Tag Archives: alcoholism

Medical Marijuana as Treatment for Alcoholism & Addiction

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“Medical marijuana is frequently in the news, and hopefully the growing awareness of the benefits of medical marijuana will lead to more sensible regulations and deeper research into why cannabis is so helpful in treating so many different conditions. Among the conditions that medical marijuana can treatis addiction, whether to drugs or alcohol.”

“Medical Marijuana as a Recovery Treatment”

“Marijuana as a recovery treatment is controversial, not least because there is conflicting research about whether medical marijuana is or is not addictive. However, many studies have found that medical marijuana is not addictive, or as harmful, as other drugs such as alcohol and opiates. Additionally, several studies have shown that marijuana can be an effective treatment for recovery from other substances.”

Read more: http://www.unitedpatientsgroup.com/blog/2012/07/26/medical-marijuana-as-treatment-for-alcoholism-addiction/

Involvement of the endogenous cannabinoid system in the effects of alcohol in the mesolimbic reward circuit: electrophysiological evidence in vivo.

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Abstract

“RATIONALE:

Several lines of evidence indicate that the endogenous cannabinoid system is involved in the pharmacological and behavioural effects of alcohol. The mesolimbic dopaminergic (DA) system and the nucleus accumbens (NAc) process rewarding properties of drugs of abuse, including alcohol and cannabinoids, whereas endocannabinoids in these regions modulate synaptic function and mediate short- and long-term forms of synaptic plasticity.

OBJECTIVES:

The present study was designed to investigate the contribution of the endogenous cannabinoid system in alcohol electrophysiological effects in the mesolimbic reward circuit.

METHODS:

We utilized extracellular single cell recordings from ventral tegmental area (VTA) DA and NAc neurons in anesthetized rats. DA neurons were antidromically identified as projecting to the shell of NAc, whereas NAc putative medium spiny neurons were identified by their evoked responses to basolateral amygdala (BLA) stimulation.

RESULTS:

Alcohol stimulated firing rate of VTA DA neurons and inhibited BLA-evoked NAc neuron spiking responses. The cannabinoid type-1 receptor (CB1) antagonist rimonabant (SR141716A) fully antagonized alcohol effect in both regions. In the NAc, either inhibition of the major catabolic enzyme of the endocannabinoid anandamide, the fatty-acid amyd hydrolase, with URB597 or a pretreatment with the CB1 receptor agonist WIN55212-2 significantly depressed alcohol-induced effects in the NAc.

CONCLUSIONS:

These results corroborate the notion of the involvement of endocannabinoids and their receptors in the actions of alcohol and highlight the endocannabinoid system as a valuable target in the therapy for alcoholism.”

http://www.ncbi.nlm.nih.gov/pubmed/16228194

Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans.

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Abstract

“We tested if cannabinoid type 2 receptor (CB2) in the central nervous system plays a role in alcohol abuse/dependence in animal model and then examined an association between the CB2 gene polymorphism and alcoholism in human. Mice experiencing more alcohol preference by drinking showed reduced Cb2 gene expression, whereas mice with little preference showed no changes of it in ventral midbrain. Alcohol preference in conjunction with chronic mild stress were enhanced in mice treated with CB2 agonist JWH015 when subjected to chronic stress, whereas antagonist AM630 prevented development of alcohol preference. There is an association between the Q63R polymorphism of the CB2 gene and alcoholism in a Japanese population (P=0.007; odds ratio 1.25, 95% CI, (1.06-1.47)). CB2 under such environment is associated with the physiologic effects of alcohol and CB2 antagonists may have potential as therapies for alcoholism.”

http://www.ncbi.nlm.nih.gov/pubmed/17189959

Cannabinoid receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence: results from a placebo-controlled, double-blind trial.

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Abstract

“Multiple lines of evidence suggest that the endocannabinoid system is implicated in the development of alcohol dependence. In addition, in animal models, the cannabinoid receptor 1 blocker rimonabant was found to decrease alcohol consumption, possibly by indirect modulation of dopaminergic neurotransmission. This was a 12-week double-blind, placebo-controlled, proof-of-concept study to assess the possible efficacy of the cannabinoid receptor 1 antagonist rimonabant 20 mg/d (2 x 10 mg) in the prevention of relapse to alcohol in recently detoxified alcohol-dependent patients. A total of 260 patients were included, 258 were exposed to medication, and 208 (80.6%) were men. Patients had an alcohol history of 15 years on average. More patients in the rimonabant group (94/131 [71.8%]) completed treatment compared with the placebo group (79/127 [62.2%]). Although there was a modest effect of rimonabant with respect to relapse rate, there were no statistically significant differences between treatment groups. Approximately 41.5% of the rimonabant group had relapsed to drinking at the end of the study compared with 47.7% of the placebo group (obtained from Kaplan-Meier-curve). Differences were more marked but not statistically significant in patients who relapsed to heavy drinking: 27.7% versus 35.6%, respectively. Safety and tolerance of the drug were good. Similar rates of adverse events were reported between the 2 groups; less patients experienced serious events or discontinued the treatment with rimonabant compared with placebo. Rates of depression-related events were low (3.8% with rimonabant compared with 1.6% with placebo). Patients on rimonabant lost weight (Mean, -1.7 kg) compared with baseline, whereas there was no such change in the placebo group. Weight loss was more pronounced in patients with a higher body mass index. In addition, there was a significant decrease in leptin levels in the rimonabant group compared with baseline. Lack of efficacy in this study may be explained by a very high response rate in the placebo group and a relatively short treatment duration. Taking the substantial numbers of animal studies suggesting a possible role of CB1 antagonists for the treatment of alcohol dependence into account, it seems worthwhile to further test cannabinoid blockers in the treatment of alcoholism.”

http://www.ncbi.nlm.nih.gov/pubmed/18480689

Endocannabinoid system and alcohol addiction: pharmacological studies.

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Abstract

“The present paper describes the results of recent pharmacological studies implicating the cannabinoid CB1 receptor in the neural circuitry regulating alcohol consumption and motivation to consume alcohol. Cannabinoid CB1 receptor agonists have been found to specifically stimulate alcohol intake and alcohol’s motivational properties in rats. Conversely, the cannabinoid CB1 receptor antagonist, SR 141716, has been reported to specifically suppress acquisition and maintenance of alcohol drinking behavior, relapse-like drinking and alcohol’s motivational properties in rats. More recent data indicate that opioid receptor antagonists a) blocked the stimulatory effect of cannabinoids on alcohol intake, and b) synergistically potentiated the suppressing effect of SR 141716 on alcohol intake and alcohol’s motivational properties. Consistently, SR 141716 blocked the stimulatory effect of morphine on alcohol intake. These results suggest a) the existence of a functional link between the cannabinoid and opioid receptor systems in the control of alcohol intake and motivation to consume alcohol, and b) that novel and potentially effective therapeutic strategies for alcoholism may come from the combination of cannabinoid and opioid receptor antagonists.”

http://www.ncbi.nlm.nih.gov/pubmed/15939463

Role of endocannabinoids and cannabinoid CB1 receptors in alcohol-related behaviors.

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Abstract

“This review presents the remarkable research during the past several years indicating that some of the pharmacological and behavioral effects of alcohol, including alcohol drinking and alcohol-preferring behavior, are mediated through one of the most abundant neurochemical systems in the central nervous system, the endocannabinoid signaling system. The advances, with the discovery of specific receptors and the existence of naturally occurring cannabis-like substances in the mammalian system and brain, have helped in understanding the neurobiological basis for drugs of abuse, including alcoholism. The cDNA and genomic sequences encoding G-protein-coupled cannabinoid receptors (CB1 and CB2) from several species have now been cloned. This has facilitated discoveries of endogenous ligands (endocannabinoids). To date, two fatty acid derivatives characterized to be arachidonylethanolamide and 2-arachidonylglycerol have been isolated from both nervous and peripheral tissues. Both these compounds have been shown to mimic the pharmacological and behavioral effects of Delta9-tetrahydrocannabinol, the psychoactive component of marijuana. The involvement of the endocannabinoid signaling system in tolerance development to drugs of abuse, including alcohol, were unknown until recently. Studies from our laboratory demonstrated for the first time the downregulation of CB1 receptor function and its signal transduction by chronic alcohol. The observed downregulation of CB1 receptor binding and its signal transduction results from the persistent stimulation of receptors by the endogenous CB1 receptor agonists arachidonylethanolamide and 2-arachidonylglycerol, the synthesis of which is increased by chronic alcohol treatment. The deletion of CB1 receptor has recently been shown to block voluntary alcohol intake in mice, which is consistent with our previous findings where the DBA/2 mice known to avoid alcohol intake had significantly reduced brain CB1 receptor function. These findings suggest a role for the CB1 receptor gene in excessive alcohol drinking behavior and development of alcoholism. Ongoing investigations may lead to the development of potential therapeutic agents to modulate the endocannabinoid signaling system, which will be helpful for the treatment of alcoholism.”

http://www.ncbi.nlm.nih.gov/pubmed/15542757

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

The endocannabinoid signaling system: a potential target for next-generation therapeutics for alcoholism

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“Alcoholism is a complex disorder affecting modern society in many ways, yet there are few effective treatment strategies currently available.”

“Research into the endocannabinoid signaling system has grown exponentially in recent years following the discovery of cannabinoid receptors (CB) and their endogenous ligands, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Important advances have been made in our understanding of the endocannabinoid signaling system in various aspects of alcoholism, including alcohol-seeking behavior. Alcohol increases the synthesis or impairs the degradation of endocannabinoids, leading to a locally elevated endocannabinoid tone within the brain. Elevated endocannabinoid tone might be expected to result in compensatory down-regulation of CB1 receptors or dampened signal transduction. Following release, endocannabinoids diffuse back to the presynaptic neuron where they act as short-range modulators of synaptic activity by altering neurotransmitter release and synaptic plasticity. Mice treated with the CB1 receptor antagonist SR141716A (rimonabant) or homozygous for a deletion of the CB1 receptor gene exhibit reduced voluntary alcohol intake. CB1 knockout mice also show increased alcohol sensitivity, withdrawal, and reduced conditioned place preference. Conversely, activation of CB1 receptor promotes alcohol intake. Recent studies also suggest that elevated endocannabinoid tone due to impaired degradation contributes to high alcohol preference and self-administration. These effects are reversed by local administration of rimonabant, suggesting the participation of the endocannabinoid signaling system in high alcohol preference and self-administration. These recent advances will be reviewed with an emphasis on the endocannabinoid signaling system for possible therapeutic interventions of alcoholism.”

“Overwhelmingly, recent studies suggest that cannabinoids and alcohol activate similar reward pathways. The CB1 receptors also seem to regulate the reinforcing properties of alcohol. The discovery of cannabinoid receptors and their endogenous ligands set a landmark in cannabinoid research. These discoveries impacted significantly on alcohol research, too, since there is now considerable evidence that endocannabinoid signaling plays a key role in alcohol addiction, and this has promising clinical consequences. The purpose of this article is to analyze the interaction between alcohol and endocannabinoid signaling, paying particular attention to the reward mechanism. Therapeutic aspects driving from these new insights are also discussed.”

“THERAPEUTIC OPPORTUNITY”

“Although the detailed physiology, biochemistry and pathophysiology of the endocannabinoid signaling system have not been fully investigated, there is already overwhelming evidence to indicate that pharmacological modulation of the endocannabinoid signaling system could provide new treatments for a number of disease states, including alcohol addiction. Recently it was reported that rimonabant holds an important therapeutic role in treating liver fibrosis and alcohol abuse accounts for more than half of the prevalence of liver fibrosis and cirrhosis in the western world. Therefore, it is important to examine whether alcohol-induced liver fibrosis and cirrhosis results in increased endocannabinoid levels and rimonabant reverses alcohol-induced liver fibrosis/cirrhosis. In terms of drug development, the CB1 receptor antagonist rimonabant has progressed furthest and is in late phase III trials for the treatment of obesity and as an aid for smoking cessation. An NIAAA clinical study of the effectiveness of rimonabant to reduce voluntary alcohol drinking has progressed to phase I trials. Pending results of the clinical trials, rimonabant could become an important addition to the limited arsenal of effective treatments for alcoholism. During drug abuse there are changes in endocannabinoid levels in various brain regions. Therefore, drugs which regulate the level of endocannabinoids by inhibiting their metabolism (FAAH inhibitors such as URB597) or uptake (AM404) could locally target sites while limiting effects in uninvolved cognitive areas to produce a higher therapeutic value. Cannabinoid interactions with the dopamine system have been offered as a possible mechanism for some of the therapeutic potential of cannabinoid-based drugs in alcoholism. A recent study provides evidence of the ability of CB1 receptor antagonist to mitigate alcohol-withdrawal symptoms, and block the formation of physical dependency by inhibiting alcohol intake. Recent data on the role of CB1 receptors in alcohol drinking behavior, including alcohol tolerance as discussed in the earlier sections, clearly suggest that agents such as CB1 receptor antagonists, including rimonabant, will be promising therapeutic agents for the treatment of alcoholism.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1975858/