Ligands of the CB2 cannabinoid receptors augment activity of the conventional antidepressant drugs in the behavioural tests in mice.

Behavioural Brain Research“Although a lot of information can be found on the specific dual role of the endocannabinoid system in the emotional-related responses, little is known whether stimulation or inhibition of the CB receptors may affect the activity of the frequently prescribed antidepressant drugs.

Our interests have been particularly focused on the potential influence of the CB2 receptors, as the ones whose central effects are relatively poorly documented when compared to the central effects of the CB1 receptors. Therefore, we evaluated the potential interaction between the CB2 receptor ligands (i.e., JWH133 – CB2 receptor agonist and AM630 – CB2 receptor inverse agonist) and several common antidepressant drugs that influence the monoaminergic system (i.e., imipramine, escitalopram, reboxetine).

Summarizing, the results of the present study revealed that both activation and inhibition of the CB2 receptor function have a potential to strengthen the antidepressant activity of drugs targeting the monoaminergic system. Most probably, the described interaction has a pharmacodynamic background.”

https://www.ncbi.nlm.nih.gov/pubmed/31626848

“Interplay between CB2 receptor ligands and antidepressants is pharmacodynamic in nature.”

https://www.sciencedirect.com/science/article/pii/S0166432819311891?via%3Dihub

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Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders.

 “Substance use disorder (SUD) is a major public health crisis worldwide, and effective treatment options are limited.

During the past 2 decades, researchers have investigated the impact of a variety of pharmacological approaches to treat SUD, one of which is the use of medical cannabis or cannabinoids.

Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. However, serious adverse effects such as depression and suicidality led to the withdrawal of rimonabant (and almost all other CB1R antagonists/inverse agonists) from clinical trials worldwide in 2008.

Since then, much research interest has shifted to other cannabinoid-based strategies, such as peripheral CB1R antagonists/inverse agonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, fatty acid binding protein (FABP) inhibitors, or nonaddictive phytocannabinoids with CB1R or CB2R-binding profiles, as new therapeutics for SUDs.

In this article, we first review recent progress in research regarding the endocannabinoid systems, cannabis reward versus aversion, and the underlying receptor mechanisms. We then review recent progress in cannabinoid-based medication development for the treatment of SUDs.

As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆9-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals.

Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.”

https://www.ncbi.nlm.nih.gov/pubmed/31549358

https://link.springer.com/article/10.1007%2Fs40263-019-00664-w

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Cannabinoids in Gynecological Diseases

Related image“The endocannabinoid system (ECS) is a multifunctional homeostatic system involved in many physiological and pathological conditions. The ligands of the ECS are the endo­cannabinoids, whose actions are mimicked by exogenous cannabinoids, such as phytocannabinoids and synthetic cannabinoids. Responses to the ligands of the ECS are mediated by numerous receptors like the classical cannabinoid receptors (CB1 and CB2) as well as ECS-related receptors, e.g., G protein-coupled receptors 18 and 55 (GPR18 and GPR55), transient receptor potential ion channels, and nuclear peroxisome proliferator-activated receptors. The ECS regulates almost all levels of female reproduction, starting with oocyte production through to parturition. Dysregulation of the ECS is associated with the development of gynecological disorders from fertility disorders to cancer. Cannabinoids that act at the ECS as specific agonists or antagonists may potentially influence dysregulation and, therefore, represent new therapeutic options for the therapy of gynecological disorders.”

https://www.karger.com/Article/FullText/499164

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The cannabinoid receptor 1 is involved in renal fibrosis during chronic allograft dysfunction: Proof of concept.

Publication cover image“Chronic allograft dysfunction (CAD), defined as the replacement of functional renal tissue by extracellular matrix proteins, remains the first cause of graft loss.

The aim of our study was to explore the potential role of the cannabinoid receptor 1 (CB1) during CAD.

Overall, our study strongly suggests an involvement of the cannabinoid system in the progression of fibrosis during CAD and indicates the therapeutic potential of CB1 antagonists in this pathology.”

https://www.ncbi.nlm.nih.gov/pubmed/31469511

https://onlinelibrary.wiley.com/doi/full/10.1111/jcmm.14570

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Cannabis-based treatments as an alternative remedy for epilepsy

Integrative Medicine Research“Much of the initial reports for cannabis use in seizure control centered on the compound 9-Δ-tetrahydrocannabinol (THC). However, due to the psychoactive properties of THC potential utility was somewhat limited and recent research has focused on non-psychoactive compounds such as cannabidiol (CBD).

The anti-seizure effects of CBD may come from mechanisms such as functional agonism or antagonism at several 7-transmembrane receptors, ion channels, and neurotransmitter transporters.

Recently, another compound that also is without psychoactive effects known as CBDV has also shown anti-seizure properties both in vivo and in vitro.

Many reports exist on illicit cannabis use through the smoking of marijuana by patients as a self-treatment.

Cannabis and cannabis-based treatments offer promising alternatives to traditional antiepileptic drugs (AEDs).

Due to the unfortunate fact that many patients suffer from Drug-resistant epilepsy (DRE), cannabis-based treatments have great value.

Cannabis-based treatments offer some patients with DRE a great remedy for their condition with limited side effects.

This option may prevent some patients with DRE from needing to consider more invasive options such as surgical interventions. In case studies, open label studies, and RCTs, one can see drastic improvements in the frequency of seizures in patients with certain forms of epilepsy.

It is imperative to continue research into cannabis as a potential primary treatment for epilepsy, particularly those with DRE, to help improve quality of life for millions of people suffering from epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/31463193

https://www.sciencedirect.com/science/article/pii/S221342201930157X?via%3Dihub

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Δ8 -Tetrahydrocannabivarin has potent anti-nicotine effects in multiple rodent models of nicotine dependence.

British Journal of Pharmacology banner“Both types of cannabinoid receptors – CB1 and CB2 – regulate brain functions relating to addictive drug-induced reward and relapse. CB1 receptor antagonists and CB2 receptor agonists have anti-addiction efficacy, in animal models, against a broad range of addictive drugs.

Δ9 -Tetrahydrocannabivarin (Δ9 -THCV) – a cannabis constituent – acts as a CB1 antagonist and a CB2 agonist. Δ8 -Tetrahydrocannabivarin (Δ8 -THCV) is a Δ9 -THCV analogue with similar combined CB1 antagonist/CB2agonist properties.

KEY RESULTS:

Δ8 -THCV significantly attenuated intravenous nicotine self-administration, and both cue-induced and nicotine-induced relapse to nicotine-seeking behavior in rats. Δ8 -THCV also significantly attenuated nicotine-induced conditioned place preference and nicotine withdrawal in mice.

CONCLUSIONS AND IMPLICATIONS:

We conclude that Δ8 -THCV may have therapeutic potential for the treatment of nicotine dependence. We also suggest that tetrahydrocannabivarins should be tested for possible anti-addiction efficacy in a broader range of preclinical animal models, against other addictive drugs, and eventually in humans.”

https://www.ncbi.nlm.nih.gov/pubmed/31454413

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14844

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Dual Inhibition of Cannabinoid-1 Receptor and iNOS Attenuates Obesity-induced Chronic Kidney Disease.

British Journal of Pharmacology banner“Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signaling pathways: the endocannabinoid/CB1 R system, whose activation in obesity promotes renal inflammation, fibrosis, and injury; and the inducible nitric oxide synthase (iNOS), which generates reactive oxygen species resulting in oxidative stress. Hence, a combined peripheral inhibitory molecule that targets both CB1 R and iNOS may serve as an efficacious therapeutic agent against obesity-induced CKD.

KEY RESULTS:

Enhanced expression of CB1 R and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB1 R. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signaling.

CONCLUSIONS AND IMPLICATIONS:

Collectively, our results highlight the therapeutic relevance of blocking CB1 R and iNOS in ameliorating obesity-induced CKD.”

https://www.ncbi.nlm.nih.gov/pubmed/31454063

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14849

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Myrcene and terpene regulation of TRPV1.

Publication Cover“Nociceptive Transient Receptor Potential channels such as TRPV1 are targets for treating pain. Both antagonism and agonism of TRP channels can promote analgesia, through inactivation and chronic desensitization.

Since plant-derived mixtures of cannabinoids and the Cannabis component myrcene have been suggested as pain therapeutics, we screened terpenes found in Cannabis for activity at TRPV1.

These data establish TRPV1 as a target of Myrcene and suggest the therapeutic potential of analgesic formulations containing Myrcene.”

https://www.ncbi.nlm.nih.gov/pubmed/31446830

https://www.tandfonline.com/doi/full/10.1080/19336950.2019.1654347

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The therapeutic role of cannabinoid receptors and its agonists or antagonists in Parkinson’s disease.

Progress in Neuro-Psychopharmacology and Biological Psychiatry“Parkinson’s disease (PD) is a neurodegenerative disease and its characteristic is the progressive degeneration of dopaminergic neurons within the substantia nigra (SN) of the midbrain. There is hardly any clinically proven efficient therapeutics for its cure in several recent preclinical advances proposed to treat PD.

Recent studies have found that the endocannabinoid signaling system in particular the comprised two receptors, CB1 and CB2 receptors, has a significant regulatory function in basal ganglia and is involved in the pathogenesis of PD. Therefore, adding new insights into the biochemical interactions between cannabinoids and other signaling pathways may help develop new pharmacological strategies.

Factors of the endocannabinoid system (ECS) are abundantly expressed in the neural circuits of basal ganglia, where they interact interactively with glutamatergic, γ-aminobutyric acid-ergic (GABAergic), and dopaminergic signaling systems. Although preclinical studies on PD are promising, the use of cannabinoids at the clinical level has not been thoroughly studied.

In this review, we evaluated the available evidence and reviewed the involvement of ECS in etiologies, symptoms and treatments related to PD. Since CB1 and CB2 receptors are the two main receptors of endocannabinoids, we primarily put the focus on the therapeutic role of CB1 and CB2 receptors in PD. We will try to determine future research clues that will help understand the potential therapeutic benefits of the ECS in the treatment of PD, aiming to open up new strategies and ideas for the treatment of PD.”

https://www.ncbi.nlm.nih.gov/pubmed/31442553

https://www.sciencedirect.com/science/article/pii/S0278584619302210?via%3Dihub

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Prediction and Experimental Confirmation of Novel Peripheral Cannabinoid-1 Receptor Antagonists.

Go to Volume 0, Issue ja “Small molecules targeting peripheral CB1 receptors have therapeutic potential in a variety of disorders including obesity-related, hormonal and metabolic abnormalities, while avoiding the psychoactive effects in the CNS.

We applied our in house algorithm, Iterative Stochastic Elimination, to produce a ligand-based model that distinguishes between CB1R antagonists and random molecules, by physico-chemical properties only. We screened ~2 million commercially available molecules, and found that about 500 of them are potential candidates to antagonize CB1R. We applied a few criteria for peripheral activity and narrowed that set down to 30 molecules, out of which 15 could be purchased. Ten out of those 15 showed good affinity to CB1R and two of them with nanomolar affinities (Ki of ~400 nM). The eight molecules with top affinities were tested for activity: two compounds are pure antagonists, and five others are inverse agonists.

These molecules are now being examined in vivo for their peripheral vs. central distribution, and subsequently will be tested for their effects on obesity in small animals.”

https://www.ncbi.nlm.nih.gov/pubmed/31433190

https://pubs.acs.org/doi/10.1021/acs.jcim.9b00577

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