Anti-Obesity Effect of the CB2 Receptor Agonist JWH-015 in Diet-Induced Obese Mice.

“The cannabinoid receptor 2 (CB2) is well known for its immune modulatory role. However, recent localisation of CB2 receptors in metabolically active tissue suggests that the CB2 receptor plays a significant role in energy homeostasis.

This study was designed to investigate the impact of chronic CB2 receptor stimulation on food intake, body weight and mood.

These results demonstrate a role for CB2 receptors in modulating energy homeostasis and obesity associated metabolic pathologies in the absence of any adverse impact on mood.”

http://www.ncbi.nlm.nih.gov/pubmed/26588700

New insights on the role of the endocannabinoid system in the regulation of energy balance.

“Within the last 15 years, the endocannabinoid system (ECS) has emerged as a lipid signaling system critically involved in the regulation of energy balance, since it exerts a regulatory control on every aspect related to the search, the intake, the metabolism and the storage of calories.

An overactive endocannabinoid-cannabinoid type 1 (CB1) receptor signaling promotes the development of obesity, insulin resistance and dyslipidemia, representing a valuable pharmacotherapeutic target for obesity and metabolic disorders.

However, due to psychiatric side effects, the first generation of brain-penetrant CB1 receptor blockers developed as anti-obesity treatment was removed from the European market in late 2008.

Since then, recent studies have identified new mechanisms of action of the ECS in energy balance and metabolism, as well as novel ways of targeting the system that may be efficacious for the treatment of obesity and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26374449

Pro-inflammatory obesity in aged cannabinoid-2 receptor deficient mice.

“Cannabinoid-1 receptor signaling increases the rewarding effects of food intake and promotes the growth of adipocytes, whereas CB2 possibly opposes these pro-obesity effects by silencing the activated immune cells that are key drivers of the metabolic syndrome.

Pro- and anti-orexigenic cannabimimetic signaling may become unbalanced with age because of alterations of the immune and endocannabinoid system…

CB2 agonists may fortify CB2-mediated anti-obesity signaling without the risk of anti-CB1 mediated depression that caused the failure of rimonabant.”

http://www.ncbi.nlm.nih.gov/pubmed/26303348

Chronic administration with AM251 improves albuminuria and renal tubular structure in obese rats.

“Modulation of the endocannabinoid system as an anti-obesity therapeutic is well established, however the direct effects of CB1 antagonism on renal function and structure in a model of diet-induced obesity (DIO) are unknown. The aim of this study was to characterise the renal effects of the CB1 antagonist AM251 in a model of DIO.

Antagonism of CB1 with AM251 significantly reduced weight gain, systolic blood pressure, plasma leptin, and reduced albuminuria and plasma creatinine levels in obese rats.

Importantly, there was a significant reduction in tubular cross-section diameter in the obese rats treated with AM251. An improvement in albuminuria was likely due to the reduction in tubular size, reduced leptinemia and maintenance of megalin expression levels. In obese rats, AM251 did not alter diastolic blood pressure, sodium excretion, creatinine clearance or expression of the fibrotic proteins VEGF, TGFb1 and collagen IV in the kidney.

This study demonstrates that treatment with CB1 antagonist AM251 improves renal outcomes in obese rats.”

http://www.ncbi.nlm.nih.gov/pubmed/25804605

Alexandros Makriyannis is a professor in the Department of Medicinal Chemistry at Northeastern University, where his research group has synthesized many new compounds with cannabinoid activity… AM-251 — an inverse agonist at the CB1 cannabinoid receptor that is structurally related to SR141716A (rimonabant), but has a higher binding affinity with a Ki value of 7.5nM.”  http://en.wikipedia.org/wiki/List_of_AM_cannabinoids

Neural Effects of Cannabinoid CB1 Neutral Antagonist Tetrahydrocannabivarin (THCv) on Food Reward and Aversion in Healthy Volunteers.

“Disturbances in the regulation of reward and aversion in the brain may underlie disorders such as obesity and eating disorders.

We previously showed that the cannabis receptor (CB1) inverse agonist rimonabant, an anti-obesity drug withdrawn due to depressogenic side effects, diminished neural reward responses yet increased aversive responses. Unlike rimonabant, tetrahydrocannabivarin (THCv) is a neutral CB1 receptor antagonist and may therefore produce different modulations of the neural reward system…

Conclusions: Our findings are the first to show that treatment with the CB1 neutral antagonist THCv increases neural responding to rewarding and aversive stimuli.

This effect profile suggests therapeutic activity in obesity, perhaps with a lowered risk of depressive side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/25542687

http://www.thctotalhealthcare.com/category/obesity-2/

Synthetic and Patented Cannabinoids

“Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam.

Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids.

Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.

Medications containing natural or synthetic cannabinoids or cannabinoid analogs:

  • Dronabinol (Marinol), is Δ9-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic, and analgesic
  • Nabilone (Cesamet), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol, which is Schedule III
  • Sativex, a cannabinoid extract oral spray containing THC, CBD, and other cannabinoids used for neuropathic pain and spasticity in Canada and Spain. Sativex develops whole-plant cannabinoid medicines
  • Rimonabant (SR141716), a selective cannabinoid (CB1) receptor antagonist used as an anti-obesity drug under the proprietary name Acomplia. It is also used for smoking cessation

Other notable synthetic cannabinoids include:

  • CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC
  • Dimethylheptylpyran
  • HU-210, about 100 times as potent as THC
  • HU-331 a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase II.
  • SR144528, a CB2 receptor antagonists
  • WIN 55, a potent cannabinoid receptor agonist
  • JWH-133, a potent selective CB2 receptor agonist
  • Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine”

http://www.news-medical.net/health/Synthetic-and-Patented-Cannabinoids.aspx

Obesity, the Endocannabinoid System, and Bias Arising from Pharmaceutical Sponsorship

“Previous research has shown that academic physicians conflicted by funding from the pharmaceutical industry have corrupted evidence based medicine and helped enlarge the market for drugs. Physicians made pharmaceutical-friendly statements, engaged in disease mongering, and signed biased review articles ghost-authored by corporate employees.

 This paper tested the hypothesis that bias affects review articles regarding rimonabant, an anti-obesity drug that blocks the central cannabinoid receptor.

CONCLUSIONS:

The findings are characteristic of bias that arises from financial conflicts of interest, and suggestive of ghostwriting by a common author. Resolutions for this scenario are proposed.

In summary, financial conflicts permeate the system and are by no means limited to corporations referenced in this article, such as Merck, Parke-Davis, Pfizer, Sanofi-Aventis, and Wyeth-Ayerst. On balance, pharmaceutical corporations do good work and aid in humanitarian efforts. For example Sanofi-Aventis provides artemisinin at cost to malaria-endemic countries. Nevertheless, ghost authorship and the corrupting effects of covert financial support must cease. Only three of eight rimonabant review articles disclosed corporate sponsorship; two authors specifically denied conflicts. Lack of disclosure prevents readers from judging the credibility of an author. Medical journals should require stronger author disclosure procedures, and universities should discipline academics who sign ghostwritten articles. This behavior should be regarded as unethical misconduct. More broadly, researchers with conflicts of interest should not be allowed to sit on guideline committees and regulatory boards. Corporate funding of CME programs and review articles should be abolished.

While this paper was under review, Merck halted taranabant RCTs, and Sanofi-Aventis removed rimonabant from the European market. The FDA rejected rimonabant after data submitted by Sanofi-Aventis revealed adverse effects in RIO trials that went unreported in RIO publications [86], including one death in a rimonabant-treated subject (ruled a suicide by the FDA, [86]) that did not appear in the pertinent publication [7]. Although the risk-benefit ratio of cannabinoid receptor blockade may preclude its use for chronic conditions such as obesity and drug or alcohol dependence, cannabinoid receptor blockade could serve in the treatment of acute endocannabinoid dysregulation, such as hepatic cirrhosis, hemorrhagic or endotoxic shock, cardiac reperfusion injury, and doxorubicin-induced cardiotoxicity.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659447/

 

Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity.

Abstract

“Obesity is a global problem with often strong neurobiological underpinnings. The cannabinoid 1 receptor (CB1R) was put forward as a promising drug target for antiobesity medication. However, the first marketed CB1R antagonist/inverse agonist rimonabant was discontinued, as its use was occasionally associated with negative affect and suicidality. In artificial cell systems, CB1Rs can become constitutively active in the absence of ligands. Here, we show that such constitutive CB1R activity also regulates GABAergic and glutamatergic neurotransmission in the ventral tegmental area and basolateral amygdala, regions which regulate motivation and emotions. We show that CB1R inverse agonists like rimonabant suppress the constitutive CB1R activity in such regions, and cause anxiety and reduced motivation for reward. The neutral CB1R antagonist NESS0327 does not suppress constitutive activity and lacks these negative effects. Importantly, however, both rimonabant and NESS0327 equally reduce weight gain and food intake. Together, these findings suggest that neutral CB1R antagonists can treat obesity efficiently and more safely than inverse agonists.”

http://www.ncbi.nlm.nih.gov/pubmed/23070073

The Central Cannabinoid CB1 Receptor Is Required for Diet-Induced Obesity and Rimonabant’s Antiobesity Effects in Mice

Abstract

“Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably in the peripheral tissues responsible for energy metabolism. It is unclear if the antiobesity effects of rimonabant, a CB1 antagonist, are mediated through the central or the peripheral CB1 receptors. To address this question, we generated transgenic mice with central nervous system (CNS)-specific knockdown (KD) of CB1, by expressing an artificial microRNA (AMIR) under the control of the neuronal Thy1.2 promoter. In the mutant mice, CB1 expression was reduced in the brain and spinal cord, whereas no change was observed in the superior cervical ganglia (SCG), sympathetic trunk, enteric nervous system, and pancreatic ganglia. In contrast to the neuronal tissues, CB1 was undetectable in the brown adipose tissue (BAT) or the liver. Consistent with the selective loss of central CB1, agonist-induced hypothermia was attenuated in the mutant mice, but the agonist-induced delay of gastrointestinal transit (GIT), a primarily peripheral nervous system-mediated effect, was not. Compared to wild-type (WT) littermates, the mutant mice displayed reduced body weight (BW), adiposity, and feeding efficiency, and when fed a high-fat diet (HFD), showed decreased plasma insulin, leptin, cholesterol, and triglyceride levels, and elevated adiponectin levels. Furthermore, the therapeutic effects of rimonabant on food intake (FI), BW, and serum parameters were markedly reduced and correlated with the degree of CB1 KD. Thus, KD of CB1 in the CNS recapitulates the metabolic phenotype of CB1 knockout (KO) mice and diminishes rimonabant’s efficacy, indicating that blockade of central CB1 is required for rimonabant’s antiobesity actions.”

http://www.nature.com/oby/journal/v19/n10/full/oby2011250a.html

Anti-Obesity diet drug from cannabis works!

“For those whose New Year’s resolution was to yet again try to lose those extra kilos help may be at hand in the form of a new wonder drug derived from cannabis.

At first glance cannabis appears an unlikely candidate in the search for a weight-loss miracle drug, but the very same compound which switches off the same brain circuits that make people hungry when they smoke cannabis, could may well be the first blockbuster anti-obesity drug ever.”

http://www.news-medical.net/news/2006/01/17/15421.aspx