Category Archives: Endocannabinoid System

The Cannabinoid Receptor Agonist THC Attenuates Weight Loss in a Rodent Model of Activity-Based Anorexia

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“Anorexia nervosa (AN) is characterized by anhedonia whereby patients experience little pleasure or reward in many aspects of their lives. Reward pathways and the endocannabionid system have been implicated in the mediation of food intake. The potential to exploit these systems to reverse weight loss is investigated in a rodent model of activity-based anorexia (ABA).

Given the powerful role of the endocannabionid system in stimulating reward processes and the apparent poor development of these processes in AN, it is important to test the hypothesis that exogenous administration of cannabinoid type 1 (CB1) receptor agonists can reverse the anorexia displayed in a rodent ABA model…

Importantly, the data presented here show for the first time the efficacy of THC  in retarding the progression of ABA…

In conclusion, these data establish for the first time the effectiveness of THC in rescuing animals from profound body weight loss associated with the development of ABA, independent of physical activity, which is enhanced if allowed access to highly palatable foods.

These results from the animal-based model of AN highlight the potential of cannabinoids and of the endocannabinoid system in the treatment of human anorexia.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096804/

Cannabis and Δ9-tetrahydrocannabinol (THC) for weight loss?

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“Obesity is one of the highest preventable causes of morbidity and mortality in the developed world. It has been well known for a long time that exposure to cannabis produces an increase of appetite (a phenomenon referred to as the ‘munchies’). This phenomenon led to an exploration of the role of the endocannabinoid system in the regulation of obesity and associated metabolic syndrome.

This effort subsequently led to the development of a successful therapeutic approach for obesity that consisted of blocking the cannabinoid CB1 receptors using ligands such as Rimonabant in order to produce weight loss and improve metabolic profile. Despite being efficacious, Rimonabant was associated with increased rates of depression and anxiety and therefore removed from the market.

We recently discovered that the prevalence of obesity is paradoxically much lower in cannabis users as compared to non-users and that this difference is not accounted for by tobacco smoking status and is still present after adjusting for variables such as sex and age.

Here, we propose that this effect is directly related to exposure to the Δ(9)-tetrahydrocannabinol (THC) present in cannabis smoke.

We therefore propose the seemingly paradoxical hypothesis that THC or a THC/cannabidiol combination drug may produce weight loss and may be a useful therapeutic for the treatment of obesity and its complications.”

http://www.ncbi.nlm.nih.gov/pubmed/23410498

Cannabinoid receptor subtypes 1 and 2 mediate long-lasting neuroprotection and improve motor behavior deficits after transient focal cerebral ischemia.

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“The endocannabinoid system is crucially involved in the regulation of brain activity and inflammation… we show that the endocannabinoid system assembles a comprehensive machinery to defend the brain against the devastating consequences of cerebral ischemia.

 In summary, this study underlines the therapeutic potential of CB1 and/or CB2 receptor agonists against neurodegenerative diseases or injuries involving acute or chronic imbalances of cerebral blood flow and energy consumption.”

http://www.ncbi.nlm.nih.gov/pubmed/23069763

Alcohol and cannabis use and mortality in people with schizophrenia and related psychotic disorders.

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“The impact of co-morbid substance use on mortality is not well studied in psychotic disorders. The objective of this study was to examine the impact of substance use on mortality in people with psychotic disorders and alcohol and/or drug use.

…In a Cox model, predicted mortality risk was higher in age group 35-55 compared to <35 years and in males, but reduced in cannabis users. Overall five- (3.1% vs 7.5%) and ten-year mortality risk (5.5% vs. 13.6%) was lower in cannabis users than in non-users with psychotic disorders (p = 0.005) in a survival model.

 We observed a lower mortality risk in cannabis-using psychotic disorder patients compared to cannabis non-users despite subjects having similar symptoms and treatments.

 Future research is warranted to replicate these findings and to shed light on the anti-inflammatory properties of the endocannabinoid system and its role in decreased mortality in people with psychotic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/22595870

Cannabinoids and Schizophrenia: Therapeutic Prospects.

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“Approximately one third of patients diagnosed with schizophrenia do not achieve adequate symptom control with standard antipsychotic drugs (APs).

The endocannabinoid system (ECS) in the brain plays an important role in maintaining normal mental health.

ECS modulates emotion, reward processing, sleep regulation, aversive memory extinction and HPA axis regulation…

The cannabis plant synthesises a large number of pharmacologically active compounds unique to it known as phytocannabinoids. In contrast to the euphoric and pro-psychotic effects of delta-9-tetrahydrocannabinol (THC), certain non-intoxicating phytocannabinoids have emerged in pre-clinical and clinical models as potential APs.

Since the likely mechanism of action does not rely upon dopamine D2 receptor antagonism, synergistic combinations with existing APs are plausible.

The anti-inflammatory and immunomodulatory effects of the non-intoxicating phytocannabinoid cannabidiol (CBD) are well established and are summarised below.

Preliminary data reviewed in this paper suggest that CBD in combination with a CB1 receptor neutral antagonist could not only augment the effects of standard APs but also target the metabolic, inflammatory and stress-related components of the schizophrenia phenotype.”

http://www.ncbi.nlm.nih.gov/pubmed/23829368

“6”-Azidohex-2″-yne-cannabidiol: a potential neutral, competitive cannabinoid CB1 receptor antagonist… 6″-azidohex-2″-yne-cannabidiol was as potent as cannabidiol in producing surmountable antagonism… it is a competitive cannabinoid CB(1) receptor antagonist…it may be a neutral cannabinoid CB(1) receptor antagonist.”  http://www.ncbi.nlm.nih.gov/pubmed/15033394

 

WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway.

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“Cannabinoids have been shown to exert neuroprotective effects in a plethora of neurodegenerative conditions.

Over the past decade, some studies demonstrate that cannabinoids can interact with nuclear peroxisome proliferator-activated receptors (PPARs).We investigated protective properties of WIN55212-2 (WIN, a non-selective cannabinoid receptor agonist) in beta-amyloid (Aβ)-induced neurodegeneration in rat hippocampus and possible involvement of PPAR-gamma (PPAR-γ). Aβ (1-42) was injected into the hippocampus of male rats. Animals were administered by intracerebroventricular rout the following treatments on days 1, 3, 5, 7: vehicle, WIN, GW9662 (selective PPAR-γ antagonist) plus WIN, AM251 (selective CB₁ receptor antagonist) plus WIN, SR144528 (selective CB₂ receptor antagonist) plus WIN, each of antagonists alone. Injection of Aβ-induced spatial memory impairment and a dramatic rise in hippocampal TNF-α, active caspase 3, nuclear NF-kB levels and TUNEL-positive neurons. WIN administration significantly improved memory function and diminished the elevated levels of these markers, while antagonizing either CB₁ or CB₂ receptor subtype partially attenuated the protective effects. Intriguingly, WIN significantly increased PPAR-γ level and transcriptional activity, the latter being partially inhibited with AM251 but not with SR144528. The enhancing effect on PPAR-γ pathway was crucial to WIN-induced neuroprotection since GW9662 partially reversed the beneficial actions of WIN. Co-administration of the three antagonists led to the complete abrogation of WIN effects.

Our findings indicate that WIN exerts neuroprotective and anti-inflammatory actions against Aβ damage through both CB₁ and CB₂ receptors. Of great note, both direct and CB₁-mediated increase in PPAR-γ signaling also contributes to WIN-induced neuroprotection.”

http://www.ncbi.nlm.nih.gov/pubmed/22634229

Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions.

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“Previous studies have shown that modulation of the receptor-mediated cannabinoid system during neuroinflammation can produce potent neuroprotective and anti-inflammatory effects

…Together, these results suggest that pharmacological CB2R ligands offer a new strategy for BBB protection during neuroinflammation.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325902/

Marijuana and its receptor protein in brain control epilepsy

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“VCU study is first to test anticonvulsant potential of marijuana and brain recurrent seizures. 

Ingredients in marijuana and the cannabinoid receptor protein produced naturally in the body to regulate the central nervous system and other bodily functions play a critical role in controlling spontaneous seizures in epilepsy, according to a new study by researchers at Virginia Commonwealth University.

The study, the first to look at marijuana and the brain’s cannabinoid system in live animals with spontaneous, recurrent seizures, suggests new avenues that researchers can explore in their search for more-effective drugs to treat epileptic patients who don’t respond to today’s anticonvulsant medications or surgery.

The results appear in the Oct. 1 issue of the Journal of Pharmacology and Experimental Therapeutics.

“Although marijuana is illegal in the United States, individuals both here and abroad report that marijuana has been therapeutic for them in the treatment of a variety of ailments, including epilepsy,” says Dr. Robert J. DeLorenzo, professor of neurology in the VCU School of Medicine.

 “If we can understand how marijuana works to end seizures, we may be able to develop novel drugs that might do a better job of treating epileptic seizures.” 

Epilepsy is one of the most common neurological conditions, characterized by spontaneously recurrent seizures. Approximately 1 percent of Americans have epilepsy, and 30 percent of those patients are resistant to conventional anticonvulsant drug treatments.

Cannabinoids have been used as a natural remedy for seizures for thousands of years, and studies since at least 1974 have found that the primary psychoactive compound in marijuana displays anticonvulsant properties.” 

More:http://www.news.vcu.edu/news/Marijuana_and_its_receptor_protein_in_brain_control_epilepsy

Study: Cannabinoids Offer Likely Therapeutic Option For Patients With Post-Traumatic Stress

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“Future research targeting cannabinoids and their receptors may lead to evidence-based treatments for patients diagnosed with post-traumatic stress disorder (PTSD), according to clinical trial data published in May in the journal Molecular Psychiatry.

Investigators at the New York University School of Medicine reported that subjects diagnosed with PTSD typically possess elevated quantities of endogenous cannabinoid receptors in regions of the brain associated with fear and anxiety. Investigators also determined that many of these subjects experience a decrease in their natural production of anandamide, an endogenous cannabinoid neurotransmitter, resulting in an imbalanced endocannibinoid regulatory system.

Researchers speculated that an increase in the body’s production of cannabinoids would likely restore subjects’ natural brain chemistry and psychological balance. They affirmed, “[Our] findings substantiate, at least in part, emerging evidence that … plant-derived cannabinoids such as marijuana may possess some benefits in individuals with PTSD by helping relieve haunting nightmares and other symptoms of PTSD.”

Authors concluded: “The data reported herein are the first of which we are aware of to demonstrate the critical role of CB1 (cannabinoid) receptors and endocannabinoids in the etiology of PTSD in humans. As such, they provide a foundation upon which to develop and validate informative biomarkers of PTSD vulnerability, as well as to guide the rational development of the next generation of evidence-based treatments for PTSD.”

More: http://norml.org/news/2013/05/30/study-cannabinoids-offer-likely-therapeutic-option-for-patients-with-post-traumatic-trauma

Transient changes in the endocannabinoid system after acute and chronic ethanol exposure and abstinence in the rat: a combined PET and microdialysis study.

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“Recent biochemical and post-mortem evidence suggests involvement of the endocannabinoid system in alcohol drinking behaviour and dependence…

CONCLUSION:

This study provides in vivo evidence that acute ethanol consumption is associated with enhanced endocannabinoid signalling in the NAcc, indicated by an increased CB1R binding and AEA content. In addition, chronic ethanol exposure leads to regional dysfunctions in CB1R levels, involving the hippocampus and caudate-putamen that are reversible within 2 weeks in this animal model.”

http://www.ncbi.nlm.nih.gov/pubmed/23740372