Role of cannabinoids in alcohol-induced neuroinflammation

 Progress in Neuro-Psychopharmacology and Biological Psychiatry“Alcohol is a psychoactive substance highly used worldwide, whose harmful use might cause a broad range of mental and behavioural disorders. Underlying brain impact, the neuroinflammatory response induced by alcohol is recognised as a key contributing factor in the progression of other neuropathological processes, such as neurodegeneration. These sequels are determined by multiple factors, including age of exposure.

Strikingly, it seems that the endocannabinoid system modulation could regulate the alcohol-induced neuroinflammation. Although direct CB1 activation can worsen alcohol consequences, targeting other components of the expanded endocannabinoid system may counterbalance the pro-inflammatory response.

Indeed, specific modulations of the expanded endocannabinoid system have been proved to exert anti-inflammatory effects, primarily through the CB2 and PPARγ signalling. Among them, some endo- and exogeneous cannabinoids can block certain pro-inflammatory mediators, such as NF-κB, thereby neutralizing the neuroinflammatory intracellular cascades.

Furthermore, a number of cannabinoids are able to activate complementary anti-inflammatory pathways, which are necessary for the transition from chronically overactivated microglia to a regenerative microglial phenotype. Thus, cannabinoid modulation provides cooperative anti-inflammatory mechanisms that may be advantageous to resolve a pathological neuroinflammation in an alcohol-dependent context.”

https://pubmed.ncbi.nlm.nih.gov/32758518/

“Cannabinoid modulation represents an extremely interesting therapeutic target in alcohol-induced chronic neuroinflammation.”

https://www.sciencedirect.com/science/article/pii/S0278584620303705?via%3Dihub

Fig. 1

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Pharmacological activation of CB2 receptor protects against ethanol-induced myocardial injury related to RIP1/RIP3/MLKL-mediated necroptosis

 Molecular and Cellular Biochemistry | Home“Chronic ethanol abuse can lead to harmful consequences for the heart, resulting in systolic dysfunction, variability in the heart rate, arrhythmia, and cardiac remodelling. However, the precise molecular mechanism responsible for ethanol-induced cardiomyopathy is poorly understood. In this regard, the present study aimed to describe the RIP1/RIP3/MLKL-mediated necroptotic cell death that may be involved in ethanol-induced cardiomyopathy and characterize CBR-mediated effects on the signalling pathway and myocardial injury.

We performed an ethanol vapour administration experiment to analyse the effects of ethanol on cardiac structure and function in male C57BL/6J mice. Ethanol induced a significant decline in the cardiac structure and function, as evidenced by a decline in ejection fraction and fractional shortening, and an increase in serum Creatine Kinase levels, myocardial collagen content, and inflammatory reaction. Furthermore, ethanol also upregulated the expression levels of necroptosis-related markers such as p-RIP1, p-RIP3, and p-MLKL in the myocardium. Nec-1 treatment exerted significant cardioprotective effects by salvaging the heart tissue, improving the cardiac function, and mitigating inflammation and necroptosis.

In addition, ethanol abuse caused an imbalance in the endocannabinoid system and regulated two cannabinoid receptors (CB1R and CB2R) in the myocardium. Treatment with selective CB2R agonists, JWH-133 or AM1241, markedly improved the cardiac dysfunction and reduced the ethanol-induced necroptosis in the myocardium.

Altogether, our data provide evidence that ethanol abuse-induced cardiotoxicity can possibly be attributed to the RIP1/RIP3/MLKL-mediated necroptosis. Moreover, pharmacological activation of CB2R may represent a new cardioprotective strategy against ethanol-induced cardiotoxicity.”

https://pubmed.ncbi.nlm.nih.gov/32681290/

https://link.springer.com/article/10.1007%2Fs11010-020-03828-1

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Cannabidiol attenuates methamphetamine-induced conditioned place preference via the Sigma1R/AKT/GSK-3β/CREB signaling pathway in rats

 Issue Cover“Methamphetamine (METH) is a highly addictive psychostimulant.

Cannabidiol (CBD) is an exogenous cannabinoid without psychostimulating activity, which has potential therapeutic effects on opioid addiction. However, it is unclear whether CBD has therapeutic effects on METH-induced motivational effects.

The present study examines whether CBD has a protective effect on METH-induced conditioned place preference (CPP) in rats by regulating the Sigma1R and AKT-GSK3β-CREB signaling pathway.

The present study found that METH can induce CPP in rats. When a pretreatment of CBD is applied, the CBD can weaken CPP in METH-induced rats by regulating the SigmaR1/AKT/GSK-3β/CREB signaling pathway.

The results of this study indicate that CBD has a potential therapeutic effect on METH-induced rewarding effects.”

https://pubmed.ncbi.nlm.nih.gov/32670551/

https://academic.oup.com/toxres/article-abstract/9/3/202/5831937?redirectedFrom=fulltext

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Association between marijuana use and electrocardiographic abnormalities by middle age The Coronary Artery Risk Development in Young Adults (CARDIA) Study

 Addiction

“Aims

To evaluate the prevalence of electrocardiogram (ECG) abnormalities in marijuana users as an indirect measure of subclinical cardiovascular disease (CVD).

Findings

Among the 2,585 participants with an ECG at Year 20, mean age was 46, 57% were women, 45% were black. 83% had past exposure to marijuana and 11% were using marijuana currently. One hundred and seventy‐three participants (7%) had major abnormalities and 944 (37%) had minor abnormalities. Comparing current with never use in multivariable‐adjusted models, the OR for major ECG abnormalities was 0.60 (95% CI: 0.32 to 1.15) and for minor ECG abnormalities 1.21 (95% CI: 0.87 to 1.68). Results did not change after stratifying by sex and race.

Cumulative marijuana use was not associated with ECG abnormalities.

Conclusion

In a middle‐aged US population, lifetime cumulative and occasional current marijuana use were not associated with increases in electrocardiogram abnormalities. This adds to the growing body of evidence that occasional marijuana use and cardiovascular disease events and markers of subclinical atherosclerosis are not associated.”

https://onlinelibrary.wiley.com/doi/abs/10.1111/add.15188?af=R

“Using cannabis not associated with heart abnormalities at middle age: study”  https://leaderpost.com/wellness/using-cannabis-not-associated-with-heart-abnormalities-at-middle-age-study/wcm/a43cafba-42b3-4b74-9ea7-50a2cf0d62e3/

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Evaluation of the Potential Use of Cannabidiol in the Treatment of Cocaine Use Disorder: A Systematic Review

 Pharmacology Biochemistry and BehaviorCannabinoids may have an important therapeutic potential for the treatment of dependence on crack cocaine.

Cannabidiol (CBD), in particular, has anxiolytic, antipsychotic and anticonvulsant properties and plays a role in regulating motivation circuitry and controlling sleep disorders. Several studies were performed evaluating CBD in experimental models for cocaine.

This systematic review aims evaluate the potential use of CBD in the treatment of cocaine use disorder.

Major findings: Fifty-one studies were analyzed, and 14 were selected. No studies conducted with humans were found; only one clinical trial was ongoing. The results were grouped into the following categories: cocaine self-administration, brain-stimulation reward, conditioned place preference, neuronal proliferation, anxiety, hepatic protection, anticonvulsant effect and locomotor sensitization response Only four studies had a low risk of bias. CBD promotes reduction on cocaine self-administration. Also, it interferes in cocaine induce brain reward stimulation and dopamine release. CBD promotes alteration in contextual memory associated with cocaine and in the neuroadaptations, hepatotoxicity and seizures induced by cocaine.

Conclusion: The evidence indicates that CBD is a promising adjunct therapy for the treatment of cocaine dependence due to its effect on: cocaine reward effects, cocaine consumption, behavioral responses, anxiety, neuronal proliferation, hepatic protection and safety. Moreover, clinical trials are strongly required to determine whether the findings in animal models occur in humans diagnosed for cocaine or crack cocaine use disorder.”

https://pubmed.ncbi.nlm.nih.gov/32645315/

“CBD is a promising adjunct therapy for the treatment of cocaine dependence. CBD promotes reduction on cocaine self-administration.”

https://www.sciencedirect.com/science/article/pii/S0091305720300307?via%3Dihub

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Cannabinoid 1 Receptor (CB1R) Antagonists Play a Neuroprotective Role in Chronic Alcoholic Hippocampal Injury Related to Pyroptosis Pathway

 Alcoholism: Clinical and Experimental Research“Alcohol use disorders affect millions of people worldwide and there is growing evidence that excessive alcohol intake causes severe damage to the brain of both humans and animals.

Numerous studies on chronic alcohol exposure in animal models have identified that many functional impairments are associated with the hippocampus, which is a structure exhibiting substantial vulnerability to alcohol exposure. However, the precise mechanisms that lead to structural and functional impairments of the hippocampus are poorly understood.

Herein, we report a novel cell death type, namely pyroptosis, which accounts for alcohol neurotoxicity in mice.

Conclusions: Alcohol induces hippocampal pyroptosis, which leads to neurotoxicity thereby indicating that pyroptosis may be an essential pathway involved in chronic alcohol-induced hippocampal neurotoxicity. Further, cannabinoid receptors are regulated during this process, which suggests promising therapeutic strategies against alcohol-induced neurotoxicity through pharmacologic inhibition of CB1R.”

https://pubmed.ncbi.nlm.nih.gov/32524615/

https://onlinelibrary.wiley.com/doi/abs/10.1111/acer.14391

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Cannabidiol Prevents the Expression of the Locomotor Sensitization and the Metabolic Changes in the Nucleus Accumbens and Prefrontal Cortex Elicited by the Combined Administration of Cocaine and Caffeine in Rats

 SpringerLink“In the last years, clinical and preclinical researchers have increased their interest in non-psychotomimetic cannabinoids, like cannabidiol (CBD), as a strategy for treating psychostimulant use disorders. However, there are discrepancies in the pharmacological effects and brain targets of CBD.

We evaluated if CBD was able to prevent the locomotor sensitization elicited by cocaine and caffeine co-administration. The effect of CBD on putative alterations in the metabolic activity of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), and its respective subregions (cingulated, prelimbic, and infralimbic cortices, and NAc core and shell) associated to the behavioral response, was also investigated.

Rats were intraperitoneally and repeatedly treated with CBD (20 mg/kg) or its vehicle, followed by the combination of cocaine and caffeine (Coc+Caf; 5 mg/kg and 2.5 mg/kg, respectively) or saline for 3 days. After 5 days of withdrawal, all animals were challenged with Coc+Caf (day 9). Locomotor activity was automatically recorded and analyzed by a video-tracking software.

The metabolic activity was determined by measuring cytochrome oxidase-I (CO-I) staining. Locomotion was significantly and similarly increased both in Veh-Coc+Caf- and CBD-Coc+Caf-treated animals during the pretreatment period (3 days); however, on day 9, the expression of the sensitization was blunted in CBD-treated animals. A hypoactive metabolic response and a hyperactive metabolic response in mPFC and NAc subregions respectively were observed after the behavioral sensitization.

CBD prevented almost all these changes.

Our findings substantially contribute to the understanding of the functional changes associated with cocaine- and caffeine-induced sensitization and the effect of CBD on this process.”

https://pubmed.ncbi.nlm.nih.gov/32415526/

https://link.springer.com/article/10.1007%2Fs12640-020-00218-9

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State Medical Cannabis Laws Associated With Reduction in Opioid Prescriptions by Orthopaedic Surgeons in Medicare Part D Cohort.

Current Issue Cover Image“Opioid prescriptions and abuse remain a significant national concern.

Cannabinoids offer a potentially attractive nonopioid analgesic option for orthopaedic patients, and 32 US states have passed medical cannabis laws (MCLs), legalizing patient access to cannabinoids.

We examine the association between implementation of state cannabis laws and prescribing patterns for opioids by orthopaedic surgeons in Medicare Part D patients between 2013 and 2017.

RESULTS:

State MCLs were associated with a statistically significant reduction in aggregate opioid prescribing of 144,000 daily doses (19.7% reduction) annually (95% confidence interval [CI], -0.535 to -0.024 million; P < 0.01). States with MCLs allowing access to in-state dispensaries had a statistically significant reduction in total opioid prescriptions of 96,000 daily doses (13.1%) annually (95% CI, -0.165 to -0.026 million; P < 0.01). Specifically, MCLs were associated with a statistically significant reduction of 72,000 daily doses of hydrocodone annually (95% CI, -0.164 to -0.019 million; P < 0.01). No significant association between recreational marijuana legalization and opioid prescribing was found.

CONCLUSION:

Orthopaedic surgeons are among the highest prescribers of opioids, highlighting the importance of providing nonopioid analgesic alternatives in efforts to reduce opioid use in the patient cohort. This study is the first to examine the association between implementation of state cannabis laws and prescribing patterns for opioids by orthopaedic surgeons in Medicare Part D patients.”

https://www.ncbi.nlm.nih.gov/pubmed/32404683

https://journals.lww.com/jaaos/Abstract/9000/State_Medical_Cannabis_Laws_Associated_With.99112.aspx

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Cross-Generational THC Exposure Alters Heroin Reinforcement in Adult Male Offspring.

Drug and Alcohol Dependence“An emerging area of preclinical research has investigated whether drug use in parents prior to conception influences drug responsivity in their offspring.

The present work sought to further characterize such effects with cannabis by examining whether a parental THC history modified locomotor sensitization to morphine and self-administration of heroin in adult progeny.

RESULTS:

Germline THC exposure had no effect on morphine locomotor sensitization. However, F1-THC males displayed a reduced motivation to self-administer heroin relative to F1-Veh males.

CONCLUSIONS:

The present data indicate that parental THC exposure alters the reinforcing properties of heroin in a sex-specific manner. As such, mild to moderate cannabis use during adolescence may alter heroin abuse liability for males in the subsequent generation, but have limited effects on females.”

https://www.ncbi.nlm.nih.gov/pubmed/32386920

https://www.sciencedirect.com/science/article/abs/pii/S0376871620301502?via%3Dihub

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The impact of naturalistic cannabis use on self-reported opioid withdrawal.

A Case of Mutism Subsequent to Cocaine Abuse - Journal of ...“Four states have legalized medical cannabis for the purpose of treating opioid use disorder. It is unclear whether cannabinoids improve or exacerbate opioid withdrawal. A more thorough examination of cannabis and its impact on specific symptoms of opioid withdrawal is warranted.

METHOD:

Two hundred individuals recruited through Amazon Mechanical Turk with past month opioid and cannabis use and experience of opioid withdrawal completed the survey. Participants indicated which opioid withdrawal symptoms improved or worsened with cannabis use and indicated the severity of their opioid withdrawal on days with and without cannabis.

RESULTS:

62.5% (n = 125) of 200 participants had used cannabis to treat withdrawal. Participants most frequently indicated that cannabis improved: anxiety, tremors, and trouble sleeping. A minority of participants (6.0%, n = 12) indicated cannabis worsened opioid withdrawal, specifically symptoms of yawning, teary eyes, and runny nose. Across all symptoms, more participants indicated that symptoms improved with cannabis compared to those that indicated symptoms worsened with cannabis. Women reported greater relief from withdrawal with cannabis use than men.

DISCUSSION:

These results show that cannabis may improve opioid withdrawal symptoms and that the size of the effect is clinically meaningful. It is important to note that symptoms are exacerbated with cannabis in only a minority of individuals. Prospectively designed studies examining the impact of cannabis and cannabinoids on opioid withdrawal are warranted.”

https://www.ncbi.nlm.nih.gov/pubmed/32359667

“Cannabis alleviates self-reported opioid withdrawal symptoms.”

https://www.journalofsubstanceabusetreatment.com/article/S0740-5472(19)30564-1/pdf

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