1′,1′-Dimethylheptyl-Δ-8-tetrahydrocannabinol-11-oic Acid: A Novel, Orally Effective Cannabinoid with Analgesic and Anti-inflammatory Properties

  “1′,1′-Dimethylheptyl-Δ-8-tetrahydrocannabinol-11-oic acid (CT-3) is a novel cannabinoid that is under development by Atlantic Pharmaceuticals as an anti-inflammatory and analgesic drug. The objective of the study was to investigate the effects of CT-3 on overt symptom complex (Irwin’s test), nociception, gastrointestinal (GI) ulceration, and pharmacological availability after intragastric (i.g.) and intraperitoneal (i.p.) administration… .The evidence indicates that CT-3 exhibits a large dissociation between its anti-inflammatory/analgesic effects and its ulcerogenic actions. CT-3 warrants clinical development as a novel anti-inflammatory and analgesic drug.”

“1′,1′-Dimethylheptyl-Δ-8-tetrahydrocannabinol-11-oic acid (CT-3) is a novel cannabinoid with analgesic and anti-inflammatory activities. CT-3 is chemically similar to Δ-9-tetrahydrocannabinol (THC, dronabilone) and nabilone.”

“Analgesia is one of the most profound effects of THC in most species after its parenteral administration, and THC had shown equivalent potency to morphine in rats and mice in a variety of analgesic tests, including the tail-flick latency measurements. Several synthetic cannabinoids have also shown analgesic activities in animal models selective for detecting opiate analgesics.”

“The analgesic action of CT-3 is well confirmed in rats and in mice. Available evidence indicates that CT-3 exhibits two distinct pharmacological properties: an anti-inflammatory property occurring at a very low dose (ED50 = ∼0.1 mg/kg i.g.; and an analgesic property occurring at a higher dose (ED50 = ∼5 mg/kg i.g. and i.p.). The present results indicate that CT-3 is an orally effective analgesic drug, and acceptable pharmaceutical formulation of CT-3 would not require the adjuvant use of permeability enhancers to promote its bioavailability. CT-3 clearly warrants clinical development as an analgesic and anti-inflammatory drug.”

http://jpet.aspetjournals.org/content/291/1/31.long

Cannabinoid-like anti-inflammatory compounds from flax fiber.

Abstract

“Flax is a valuable source of fibers, linseed and oil. The compounds of the latter two products have already been widely examined and have been proven to possess many health-beneficial properties. In the course of analysis of fibers extract from previously generated transgenic plants overproducing phenylpropanoids a new terpenoid compound was discovered.The UV spectra and the retention time in UPLC analysis of this new compound reveal similarity to a cannabinoid-like compound, probably cannabidiol (CBD). This was confirmed by finding two ions at m/z 174.1 and 231.2 in mass spectra analysis. Further confirmation of the nature of the compound was based on a biological activity assay. It was found that the compound affects the expression of genes involved in inflammatory processes in mouse and human fibroblasts and likely the CBD from Cannabis sativa activates the specific peripheral cannabinoid receptor 2 (CB2) gene expression. Besides fibers, the compound was also found in all other flax tissues. It should be pointed out that the industrial process of fabric production does not affect CBD activity.The presented data suggest for the first time that flax products can be a source of biologically active cannabinoid-like compounds that are able to influence the cell immunological response. These findings might open up many new applications for medical flax products, especially for the fabric as a material for wound dressing with anti-inflammatory properties.”

http://www.ncbi.nlm.nih.gov/pubmed/22706678

Analgesic and antiinflammatory activity of constituents of Cannabis sativa L.

Abstract

“Two extracts of Cannabis sativa herb, one being cannabinoid-free (ethanol) and the other containing the cannabinoids (petroleum), were shown to inhibit PBQ-induced writhing in mouse when given orally and also to antagonize tetradecanoylphorbol acetate (TPA)-induced erythema of mouse skin when applied topically. With the exception of cannabinol (CBN) and delta 1-tetrahydrocannabinol (delta 1-THC), the cannabinoids and olivetol (their biosynthetic precursor) demonstrated activity in the PBQ test exhibiting their maximal effect at doses of about 100 micrograms/kg. delta 1-THC only became maximally effective in doses of 10 mg/kg. This higher dose corresponded to that which induced catalepsy and is indicative of a central action. CNB demonstrated little activity and even at doses in excess of 10 mg/kg could only produce a 40% inhibition of PBQ-induced writhing. Cannabinoid (CBD) was the most effective of the cannabinoids at doses of 100 micrograms/kg. Doses of cannabinoids that were effective in the analgesic test orally were used topically to antagonize TPA-induced erythema of skin. The fact that delta 1-THC and CBN were the least effective in this test suggests a structural relationship between analgesic activity and antiinflammatory activity among the cannabinoids related to their peripheral actions and separate from the central effects of delta 1-THC.”

http://www.ncbi.nlm.nih.gov/pubmed/3169967

Activation of peripheral cannabinoid CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception: a comparative analysis

“Effects of locally administered agonists and antagonists for cannabinoid CB1 and CB2 receptors on mechanical and thermal hypersensitivity were compared after the establishment of chronic inflammation.”

“Cannabinoids act locally through distinct CB1 and CB2 mechanisms to suppress mechanical hypersensitivity after the establishment of chronic inflammation, at doses that produced modest changes in thermal hyperalgesia. Additive antihyperalgesic effects were observed following prophylactic co-administration of the CB1– and CB2-selective agonists. Our results suggest that peripheral cannabinoid antihyperalgesic actions may be exploited for treatment of inflammatory pain states.”

“In summary, our results demonstrate that selective activation of CB1 or CB2 receptors in the inflamed paw is sufficient to suppress tactile allodynia and mechanical hyperalgesia. This suppression is observed under conditions in which only a partial suppression of thermal hyperalgesia was observed. Collectively, our data suggest that peripheral cannabinoid analgesic mechanisms may be exploited to suppress the tactile hypersensitivity observed in chronic inflammatory pain states.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042894/

Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study

  Journal of Neuroinflammation logo

“The phytocannabinoid cannabidiol (CBD) exhibits antioxidant and antiinflammatory properties. The present study was designed to explore its effects in a mouse model of sepsis-related encephalitis by intravenous administration of lipopolysaccharide (LPS).”.

“CBD prevented LPS-induced arteriolar and venular vasodilation as well as leukocyte margination. In addition, CBD abolished LPS-induced increases in tumor necrosis factor-alpha and cyclooxygenase-2 expression as measured by quantitative real time PCR. The expression of the inducible-nitric oxide synthase was also reduced by CBD. Finally, preservation of Blood Brain Barrier integrity was also associated to the treatment with CBD.”

“These data highlight the antiinflammatory and vascular-stabilizing effects of CBD in endotoxic shock and suggest a possible beneficial effect of this natural cannabinoid.”

“Cannabidiol (CBD] is a phytocannabinoid with well-known antiinflammatory and antioxidant properties. El-Remessy et al recently reported that CBD prevented inflammatory and oxidative damage and preserved endothelial integrity in an experimental model of diabetic retinopathy. Furthermore, CBD preserves cerebral circulation in pathological conditions such as brain ischemia. Recent data support the clinical use of CBD for the treatment of a variety of damaging conditions, including nephropathy and diabetic cardiomyopathy. In particular, the antioxidant properties of CBD seem to play a major role in the protective effects of this phytocannabinoid against the oxidative and nitrosative stress induced by chemoterapy agents and by high glucose conditions.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034694/

https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-8-5

Cannabinoid-based drugs as anti-inflammatory therapeutics.

“In the nineteenth century, marijuana was prescribed by physicians for maladies ranging from eating disorders to rabies. However, as newer, more effective drugs were discovered and as the potential for abuse of marijuana was recognized, its use as a therapeutic became restricted, and only recently has its therapeutic potential been re-evaluated.

 

 Recent studies in animal models and in humans have produced promising results for the treatment of various disorders – such as obesity, cancer, and spasticity and tremor due to neuropathology – with drugs based on marijuana-derived cannabinoids.

 

 Moreover, as I discuss here, a wealth of information also indicates that these drugs have immunosuppressive and anti-inflammatory properties; therefore, on the basis of this mode of action, the therapeutic usefulness of these drugs in chronic inflammatory diseases is now being reassessed.”

 

http://www.ncbi.nlm.nih.gov/pubmed/15864274

Cannabinoid agonist WIN-55,212-2 partially restores neurogenesis in the aged rat brain

“A decline in neurogenesis in the hippocampus may underlie age-related memory impairment in rats and humans. We now show that WIN 55,212-2 administration for 3 weeks can partially restore neurogenesis in the hippocampus of aged rats. Cannabinoid receptor stimulation therapy may thus provide clinical benefit for humans with age-associated memory impairment.”

“This report shows for the first time the potential therapeutic efficacy of endocannabinoid receptor stimulation in stimulating neurogenesis from proliferation to engraftment during normal aging in vivo. The current results, coupled with our previous observations regarding the role of endocannabinoid receptors, underscores the potential clinical benefits of cannabinoid pharmacotherapies during normal and pathological brain aging.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011092/

Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation

“Cannabinoid receptors (CBr) stimulation induces numerous central and peripheral effects. A growing interest in the beneficial properties of manipulating the endocannabinoid system has lead to the possible involvement of CBr in the control of brain inflammation… Our results emphasize the potential use of CBr agonists in the regulation of inflammatory processes within the brain; this knowledge may lead to the use of CBr agonists in the treatment of neurodegenerative diseases associated with chronic neuroinflammation, such as Alzheimer disease.”

“The current report is the first to our knowledge to demonstrate the modulatory role of cannabinoids in an animal model of chronic neuroinflammation, pointing out the effectiveness of a CBr agonist on the consequences of LPS mediated neuroinflammation at a dose (0.5 mg/kg/day i.p. of WIN-55212-2) that does not impair performance in a patial memory task. These results further advocate for the manipulation of the endocannabinoid system to diminish the consequences of neuroinflammation in progression of AD and others inflammation-related diseases.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852513/

Cannabinoid receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence: results from a placebo-controlled, double-blind trial.

Abstract

“Multiple lines of evidence suggest that the endocannabinoid system is implicated in the development of alcohol dependence. In addition, in animal models, the cannabinoid receptor 1 blocker rimonabant was found to decrease alcohol consumption, possibly by indirect modulation of dopaminergic neurotransmission. This was a 12-week double-blind, placebo-controlled, proof-of-concept study to assess the possible efficacy of the cannabinoid receptor 1 antagonist rimonabant 20 mg/d (2 x 10 mg) in the prevention of relapse to alcohol in recently detoxified alcohol-dependent patients. A total of 260 patients were included, 258 were exposed to medication, and 208 (80.6%) were men. Patients had an alcohol history of 15 years on average. More patients in the rimonabant group (94/131 [71.8%]) completed treatment compared with the placebo group (79/127 [62.2%]). Although there was a modest effect of rimonabant with respect to relapse rate, there were no statistically significant differences between treatment groups. Approximately 41.5% of the rimonabant group had relapsed to drinking at the end of the study compared with 47.7% of the placebo group (obtained from Kaplan-Meier-curve). Differences were more marked but not statistically significant in patients who relapsed to heavy drinking: 27.7% versus 35.6%, respectively. Safety and tolerance of the drug were good. Similar rates of adverse events were reported between the 2 groups; less patients experienced serious events or discontinued the treatment with rimonabant compared with placebo. Rates of depression-related events were low (3.8% with rimonabant compared with 1.6% with placebo). Patients on rimonabant lost weight (Mean, -1.7 kg) compared with baseline, whereas there was no such change in the placebo group. Weight loss was more pronounced in patients with a higher body mass index. In addition, there was a significant decrease in leptin levels in the rimonabant group compared with baseline. Lack of efficacy in this study may be explained by a very high response rate in the placebo group and a relatively short treatment duration. Taking the substantial numbers of animal studies suggesting a possible role of CB1 antagonists for the treatment of alcohol dependence into account, it seems worthwhile to further test cannabinoid blockers in the treatment of alcoholism.”

http://www.ncbi.nlm.nih.gov/pubmed/18480689

Functional interactions between endogenous cannabinoid and opioid systems: focus on alcohol, genetics and drug-addicted behaviors.

Abstract

“Although the first studies regarding the endogenous opioid system and addiction were published during the 1940s, addiction and cannabinoids were not addressed until the 1970s. Currently, the number of opioid addiction studies indexed in PubMed-Medline is 16 times greater than the number of cannabinoid addiction reports. More recently, functional interactions have been demonstrated between the endogenous cannabinoid and opioid systems. For example, the cannabinoid brain receptor type 1 (CB1) and mu opioid receptor type 1 (MOR1) co-localize in the same presynaptic nerve terminals and signal through a common receptor-mediated G-protein pathway. Here, we review a great variety of behavioral models of drug addiction and alcohol-related behaviors. We also include data providing clear evidence that activation of the cannabinoid and opioid endogenous systems via WIN 55,512-2 (0.4-10 mg/kg) and morphine (1.0-10 mg/kg), respectively, produces similar levels of relapse to alcohol in operant alcohol self-administration tasks. Finally, we discuss genetic studies that reveal significant associations between polymorphisms in MOR1 and CB1 receptors and drug addiction. For example, the SNP A118G, which changes the amino acid aspartate to asparagine in the MOR1 gene, is highly associated with altered opioid system function. The presence of a microsatellite polymorphism of an (AAT)n triplet near the CB1 gene is associated with drug addiction phenotypes. But, studies exploring haplotypes with regard to both systems, however, are lacking.”

http://www.ncbi.nlm.nih.gov/pubmed/20196742cannabinoid op