Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis.

Cell Metabolism

“Endocannabinoids acting on the cannabinoid-1 receptor (CB1R) or ghrelin acting on its receptor (GHS-R1A) both promote alcohol-seeking behavior, but an interaction between the two signaling systems has not been explored. Here, we report that the peripheral CB1R inverse agonist JD5037 reduces ethanol drinking in wild-type mice but not in mice lacking CB1R, ghrelin peptide or GHS-R1A. JD5037 treatment of alcohol-drinking mice inhibits the formation of biologically active octanoyl-ghrelin without affecting its inactive precursor desacyl-ghrelin. In ghrelin-producing stomach cells, JD5037 reduced the level of the substrate octanoyl-carnitine generated from palmitoyl-carnitine by increasing fatty acid β-oxidation. Blocking gastric vagal afferents abrogated the ability of either CB1R or GHS-R1A blockade to reduce ethanol drinking. We conclude that blocking CB1R in ghrelin-producing cells reduces alcohol drinking by inhibiting the formation of active ghrelin and its signaling via gastric vagal afferents. Thus, peripheral CB1R blockade may have therapeutic potential in the treatment of alcoholism.”

https://www.ncbi.nlm.nih.gov/pubmed/31105045

https://www.sciencedirect.com/science/article/pii/S1550413119301962?via%3Dihub

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Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial

Image result for american journal of psychiatry“Despite the staggering consequences of the opioid epidemic, limited nonopioid medication options have been developed to treat this medical and public health crisis.

This study investigated the potential of cannabidiol (CBD), a nonintoxicating phytocannabinoid, to reduce cue-induced craving and anxiety, two critical features of addiction that often contribute to relapse and continued drug use, in drug-abstinent individuals with heroin use disorder.

Acute CBD administration, in contrast to placebo, significantly reduced both craving and anxiety induced by the presentation of salient drug cues compared with neutral cues. CBD also showed significant protracted effects on these measures 7 days after the final short-term (3-day) CBD exposure. In addition, CBD reduced the drug cue–induced physiological measures of heart rate and salivary cortisol levels. There were no significant effects on cognition, and there were no serious adverse effects.

 Conclusions:

CBD’s potential to reduce cue-induced craving and anxiety provides a strong basis for further investigation of this phytocannabinoid as a treatment option for opioid use disorder.”

https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2019.18101191

“Study finds CBD effective in treating heroin addiction”  https://www.cnn.com/2019/05/21/health/heroin-opioid-addiction-cbd-study/index.html

“CBD oil may help limit cravings and anxiety in heroin users, study finds”  https://www.nbcnews.com/health/health-news/cbd-oil-may-help-limit-cravings-anxiety-heroin-users-study-n1007856

“Cannabis Compound Eases Anxiety and Cravings of Heroin Addiction”  https://www.scientificamerican.com/article/cannabis-compound-eases-anxiety-and-cravings-of-heroin-addiction/?redirect=1

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Effect of cannabidiol on muscarinic neurotransmission in the pre-frontal cortex and hippocampus of the poly I:C rat model of schizophrenia.

Progress in Neuro-Psychopharmacology and Biological Psychiatry

“Cognitive impairment is a core symptom of schizophrenia; however, current antipsychotic drugs have limited efficacy to treat these symptoms and can cause serious side-effects, highlighting a need for novel therapeutics.

Cannabidiol (CBD) is a non-intoxicating phytocannabinoid that has demonstrated pro-cognitive effects in multiple disease states, including a maternal immune activation (poly I:C) model of schizophrenia, but the mechanisms underlying the efficacy of CBD require investigation.

We examined alterations in markers of muscarinic neurotransmission in the pre-frontal cortex (PFC) and hippocampus (HPC) following CBD treatment.

These findings demonstrate that CBD can normalise muscarinic neurotransmission imbalances in male poly I:C offspring in regions of the brain implicated in cognition.”

https://www.ncbi.nlm.nih.gov/pubmed/31108177

https://www.sciencedirect.com/science/article/pii/S0278584618308121?via%3Dihub

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Cannabis use as a risk factor for causing motor vehicle crashes: a prospective study.

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“We conducted a responsibility analysis to determine whether drivers injured in motor vehicle collisions who test positive for Δ-9-tetrahydrocannabinol (THC) or other drugs are more likely to have contributed to the crash than those who test negative.

There was no increased risk of crash responsibility in drivers with THC<2ng/mL or 2≤THC<5ng/mL.

In this sample of non-fatally injured motor vehicle drivers in British Columbia, Canada, there was no evidence of increased crash risk in drivers with THC<5ng/mL and a statistically non-significant increased risk of crash responsibility (OR=1.74) in drivers with THC≥5ng/mL.”

https://www.ncbi.nlm.nih.gov/pubmed/31106494

https://onlinelibrary.wiley.com/doi/abs/10.1111/add.14663

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Supplementation of Cannabis sativa L. leaf powder accelerates functional recovery and ameliorates haemoglobin level following an induced injury to sciatic nerve in mouse model.

Image result for Pak J Pharm Sci.

“Peripheral nerve injury is a common condition with a multitude of signs and symptoms. The major consequence of injury is limited physical activity. Presently, we are lacking effective therapies for PNI and it is need of the hour is to explore potential remedies for the recovery of functional loss.

Here, we have investigated the role of crude Cannabis sativa L. leaf powder in promoting functions recovery, in mouse model subjected to a traumatic sciatic nerve injury.

A dose of 200mg/kg of the body weight per day was administered orally from the day of nerve crush till the end of the experiment. The motor functions were evaluated by measuring sciatic functional index, muscle grip strength and muscle mass; whereas the sensory functions were assessed by hotplate test. The haematology and serum analyses were carried out to estimate the effect of treatment on the systemic index and oxidative stress.

The gain of motor functions was significantly improved and was early noticed in the treated mice. Restoration of muscle mass and elevated haemoglobin level were statistically significant in the treatment group.

This study indicates that Cannabis sativa L. supplementation accelerates the motor functions recovery after nerve compression injury.”

https://www.ncbi.nlm.nih.gov/pubmed/31103973

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Role of the endocannabinoid and endovanilloid systems in an animal model of schizophrenia-related emotional processing/cognitive deficit.

Neuropharmacology

“Studies suggest that the endocannabinoid and endovanilloid systems are implicated in the pathophysiology of schizophrenia.

The Spontaneously Hypertensive Rats (SHR) strain displays impaired contextual fear conditioning (CFC) attenuated by antipsychotic drugs and worsened by pro-psychotic manipulations. Therefore, SHR strain is used to study emotional processing/associative learning impairments associated with schizophrenia and effects of potential antipsychotic drugs.

Here, we evaluated the expression of CB1 and TRPV1 receptors in some brain regions related to the pathophysiology of schizophrenia. We also assessed the effects of drugs that act on the endocannabinoid/endovanilloid systems on the CFC task in SHRs and control animals (Wistar rats – WRs).

These results reinforce the involvement of the endocannabinoid/endovanilloid systems in the SHRs CFC deficit and point to these systems as targets to treat the emotional processing/cognitive symptoms of schizophrenia.”

https://www.ncbi.nlm.nih.gov/pubmed/31103618

https://www.sciencedirect.com/science/article/pii/S0028390819301649?via%3Dihub

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Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer’s Disease.

“Finding a therapy for Alzheimer’s disease (AD) is perhaps the greatest challenge for modern medicine. The chemical scaffolds of many drugs in the clinic today are based upon natural products from plants, yet Cannabis has not been extensively examined as a source of potential AD drug candidates.

Here, we determine if a number of non-psychoactive cannabinoids are neuroprotective in a novel pre-clinical AD and neurodegeneration drug-screening platform that is based upon toxicities associated with the aging brain.

This drug discovery paradigm has yielded several compounds in or approaching clinical trials for AD. Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuroprotective effects that were greater than additive.

Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support. Structure-activity relationship (SAR) data show that functional antioxidant groups such as aromatic hydroxyls are necessary but not sufficient for neuroprotection. Therefore, there is a need to focus upon CB1 agonists that have these functionalities if neuroprotection is the goal.

Pairwise combinations of THC and CBN lead to a synergistic neuroprotective interaction.

Together, these results significantly extend the published data by showing that non-psychoactive cannabinoids are potential lead drug candidates for AD and other neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/31104297

https://link.springer.com/article/10.1007%2Fs12035-019-1637-8

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Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome.

toxins-logo “In this review, we discuss the role of the endocannabinoid (eCB) system in regulating energy and metabolic homeostasis. Endocannabinoids, via activating the cannabinoid type-1 receptor (CB1R), are commonly known as mediators of the thrifty phenotype hypothesis due to their activity in the central nervous system, which in turn regulates food intake and underlies the development of metabolic syndrome. Indeed, these findings led to the clinical testing of globally acting CB1R blockers for obesity and various metabolic complications. However, their therapeutic potential was halted due to centrally mediated adverse effects. Recent observations that highlighted the key role of the peripheral eCB system in metabolic regulation led to the preclinical development of various novel compounds that block CB1R only in peripheral organs with very limited brain penetration and without causing behavioral side effects. These unique molecules, which effectively ameliorate obesity, type II diabetes, fatty liver, insulin resistance, and chronic kidney disease in several animal models, are likely to be further developed in the clinic and may revive the therapeutic potential of blocking CB1R once again.”

https://www.ncbi.nlm.nih.gov/pubmed/31096702

https://www.mdpi.com/2072-6651/11/5/275

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CBD: A New Hope?

 ACS Medicinal Chemistry Letters“The nonpsychoactive phytocannabinoid, CBD, was recently approved by the Food and Drug Administration for the treatment of children with drug-resistant epilepsy. This milestone opens new avenues for cannabinoid research. In this Viewpoint, we provide an overview of recent progress in the field highlighting molecular insights into CBD’s mechanism of action, as well as its therapeutic potential.”

https://www.ncbi.nlm.nih.gov/pubmed/31097982

https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00127

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CB2 receptor deletion on myeloid cells enhanced mechanical allodynia in a mouse model of neuropathic pain.

 Scientific Reports“Neuropathic pain can develop after nerve injury, leading to a chronic condition with spontaneous pain and hyperalgesia.

Pain is typically restricted to the side of the injured nerve, but may occasionally spread to the contralateral side, a condition that is often referred to as mirror-image pain.

Mechanisms leading to mirror-image pain are not completely understood, but cannabinoid CB2 receptors have been implicated.

In this study, we use genetic mouse models to address the question if CB2 receptors on neurons or on microglia/macrophages are involved.

We conclude that CB2 receptors on microglia and macrophages, but not on neurons, modulate neuropathic pain responses.”

https://www.ncbi.nlm.nih.gov/pubmed/31097758

https://www.nature.com/articles/s41598-019-43858-4

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