Cannabidiol, cannabinol and their combinations act as peripheral analgesics in a rat model of myofascial pain.

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Archives of Oral Biology

“This study investigated whether local intramuscular injection of non-psychoactive cannabinoids, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC) and their combinations can decrease nerve growth factor (NGF)-induced masticatory muscle sensitization in female rats.

RESULTS:

In behavioral experiments, CBD (5 mg/ml) or CBN (1 mg/ml) decreased NGF-induced mechanical sensitization. Combinations of CBD/CBN induced a longer-lasting reduction of mechanical sensitization than either compound alone. No significant change in mechanical withdrawal threshold was observed in the contralateral masseter muscles and no impairment of motor function was found with the inverted screen test after any of the treatments. Consistent with behavioral results, CBD (5 mg/ml), CBN (1 mg/ml) and the combination of CBD/CBN (1:1 mg/ml) increased the mechanical threshold of masseter muscle mechanoreceptors. However, combining CBD/CBN (5:1 mg/ml) at a higher ratio reduced the duration of this effect. This may indicate an inhibitory effect of higher concentrations of CBD on CBN.

CONCLUSIONS:

These results suggest that peripheral application of these non-psychoactive cannabinoids may provide analgesic relief for chronic muscle pain disorders such as temporomandibular disorders and fibromyalgia without central side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/31158702

https://www.sciencedirect.com/science/article/pii/S0003996919302249?via%3Dihub

Countering the Modern Metabolic Disease Rampage With Ancestral Endocannabinoid System Alignment.

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“When primitive vertebrates evolved from ancestral members of the animal kingdom and acquired complex locomotive and neurological toolsets, a constant supply of energy became necessary for their continued survival. To help fulfill this need, the endocannabinoid (eCB) system transformed drastically with the addition of the cannabinoid-1 receptor (CB1R) to its gene repertoire. This established an eCB/CB1R signaling mechanism responsible for governing the whole organism’s energy balance, with its activation triggering a shift toward energy intake and storage in the brain and the peripheral organs (i.e., liver and adipose).

Although this function was of primal importance for humans during their pre-historic existence as hunter-gatherers, it became expendable following the successive lifestyle shifts of the Agricultural and Industrial Revolutions. Modernization of the world has further increased food availability and decreased energy expenditure, thus shifting the eCB/CB1R system into a state of hyperactive deregulated signaling that contributes to the 21st century metabolic disease pandemic.

Studies from the literature supporting this perspective come from a variety of disciplines, including biochemistry, human medicine, evolutionary/comparative biology, anthropology, and developmental biology. Consideration of both biological and cultural evolution justifies the design of improved pharmacological treatments for obesity and Type 2 diabetes (T2D) that focus on peripheral CB1R antagonism. Blockade of peripheral CB1Rs, which universally promote energy conservation across the vertebrate lineage, represents an evolutionary medicine strategy for clinical management of present-day metabolic disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31156558

https://www.frontiersin.org/articles/10.3389/fendo.2019.00311/full

A selective CB2 agonist protects against the inflammatory response and joint destruction in collagen-induced arthritis mice.

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Biomedicine & Pharmacotherapy

“Rheumatoid arthritis (RA) is a chronic, inflammatory, synovitis-dominated systemic disease with unknown etiology. RA is characterized by the involvement of multiple affected joints, symmetry, and invasive arthritis of the limbs, which can lead to joint deformity, cartilage destruction, and loss of function. Cannabinoid receptor 2 (CB2) has potent immunomodulatory and anti-inflammatory effects and is predominantly expressed in non-neuronal tissues. In the current study, the role of CB2 in the process of inflammatory bone erosion in RA was examined. The selective agonist or high-affinity ligand of CB2 (4-quinolone-3-carboxamides CB2 agonist, 4Q3C CB2agonist, 4Q3C) significantly reduced the severity of arthritis, decreased histopathological findings, and markedly reduced bone erosion in collagen-induced arthritis (CIA) mice. In addition, 4Q3C prevented an increase in the nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio and inhibited the formation of osteoclasts in CIA mice. Furthermore, the expression of tumor necrosis factor-alpha, interleukin-1β, cyclooxygenase-2, and inducible nitric oxide synthase was lower in 4Q3C-treated CIA mice than in control CIA mice. Micro-computed tomography corroborated the finding that 4Q3C reduced joint destruction. These data clearly indicate that the CB2-selective agonist, 4Q3C, may have anti-inflammatory and anti-osteoclastogenesis effects in RA and may be considered to be a novel treatment for RA.”

https://www.ncbi.nlm.nih.gov/pubmed/31154267

https://www.sciencedirect.com/science/article/pii/S0753332219307528?via%3Dihub

CB2 Cannabinoid receptor agonist ameliorates novel object recognition but not spatial memory in transgenic APP/PS1 mice.

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Neuroscience Letters

“The cannabinoid receptor 2 (CB2R) has been considered as a potential therapeutic target to ameliorate the neuroinflammation and cognitive impairments of Alzheimer’s disease (AD). However, there has been little research on the diverse roles of CB2R in regulating different forms of cognitive abilities and underlying neuroinflammatory mechanisms. Thus, the focus of the present study was to investigate the effects of CB2R activation on cognitive abilities, activation and phenotype conversion of microglia, and dendrite complexity.

Results showed that CB2R activation normalized the cortex-dependent novel object recognition memory deficit in a novel object recognition test (P < 0.05) and CB2R activation was ineffective for hippocampus-dependent spatial cognitive dysfunction in the Morris water maze test (P > 0.05). Moreover, activation of CB2R did not affect the formation of plaque in either the cortex or hippocampus (P > 0.05). Interestingly, in the cortex but not in the hippocampus of APP/PS1 mice, there was decreased immunofluorescence intensity of Iba1, M1 to M2 microglial phenotype conversion, and restored dendritic complexity after a long treatment period of CB2R agonist (All P < 0.05).

Our results demonstrated that CB2R activation exerts a beneficial role in novel object recognition ability concomitant with region-specific regulation in microglia-mediated neuroinflammation and dendritic complexity in AD-model mice.”

https://www.ncbi.nlm.nih.gov/pubmed/31150731

https://www.sciencedirect.com/science/article/pii/S0304394019303581?via%3Dihub

The Endocannabinoid System: A New Treatment Target for Obsessive Compulsive Disorder?

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“Obsessive-compulsive disorder (OCD) is a disabling illness that is associated with significant functional impairment. Although evidence-based pharmacotherapies exist, currently available medications are ineffective in some patients and may cause intolerable side effects in others. There is an urgent need for new treatments.

Discussion: A growing body of basic and clinical research has showed that the endocannabinoid system (ECS) plays a role in anxiety, fear, and repetitive behaviors. At the same time, some patients with OCD who smoke cannabis anecdotally report that it relieves their symptoms and mitigates anxiety, and several case reports describe patients whose OCD symptoms improved after they were treated with cannabinoids. Taken together, these findings suggest that the ECS could be a potential target for novel medications for OCD. In this study, we review evidence from both animal and human studies that suggests that the ECS may play a role in OCD and related disorders. We also describe findings from studies in which cannabinoid drugs were shown to impact symptoms of these conditions.

Recent studies in both humans and animals have shown a critical role for the ECS in anxiety, stress, fear, and repetitive/habitual behaviors. Moreover, many patients with OCD who use cannabis anecdotally report that it improves their symptoms and reduces anxiety.

Conclusions: An emerging body of evidence suggests that the ECS plays a role in OCD symptoms and may be a target for the development of novel medications. Further exploration of this topic through well-designed human trials is warranted.”

https://www.liebertpub.com/doi/10.1089/can.2018.0049

“Can cannabinoids help treat obsessive-compulsive disorder?”  https://eurekalert.org/pub_releases/2019-05/mali-cch053119.php

Modulation of the Endocannabinoid System as a Potential Anticancer Strategy.

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 Image result for frontiers in pharmacology“Currently, the involvement of the endocannabinoid system in cancer development and possible options for a cancer-regressive effect of cannabinoids are controversially discussed. In recent decades, a number of preclinical studies have shown that cannabinoids have an anticarcinogenic potential. Therefore, especially against the background of several legal simplifications with regard to the clinical application of cannabinoid-based drugs, an extended basic knowledge about the complex network of the individual components of the endocannabinoid system is required. The canonical endocannabinoid system consists of the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol as well as the Gi/o protein-coupled transmembrane cannabinoidreceptors CB1 and CB2. As a result of extensive studies on the broader effect of these factors, other fatty acid derivatives, transmembrane and intracellular receptors, enzymes and lipid transporters have been identified that contribute to the effect of endocannabinoids when defined in the broad sense as “extended endocannabinoid system.” Among these additional components, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid-binding protein family, additional cannabinoid-activated G protein-coupled receptors such as GPR55, members of the transient receptor family, and peroxisome proliferator-activated receptors were identified as targets for possible strategies to combat cancer progression. Other endocannabinoid-related fatty acids such as 2-arachidonoyl glyceryl ether, O-arachidonoylethanolamine, N-arachidonoyldopamine and oleic acid amide showed an effect via cannabinoid receptors, while other compounds such as endocannabinoid-like substances exert a permissive action on endocannabinoid effects and act via alternative intracellular target structures. This review gives an overview of the modulation of the extended endocannabinoid system using the example of anticancer cannabinoid effects, which have been described in detail in preclinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31143113

“In addition to the palliative effects of cannabinoid compounds in cancer treatment, the endocannabinoid system provides several targets for systemic anticancer treatment. Accordingly, preclinical studies suggest cannabinoids inhibit cancer progression via inhibition of cancer cell proliferation, neovascularization, invasion and chemoresistance, as well as induction of apoptosis, autophagy and increase of tumor immune surveillance.”

https://www.frontiersin.org/articles/10.3389/fphar.2019.00430/full

Medical Cannabis: Effects on Opioid and Benzodiazepine Requirements for Pain Control.

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SAGE Journals

“The objective of this study was to determine if the use of medical cannabis affects the amount of opioids and benzodiazepines used by patients on a daily basis.

METHODS:

This single-center, retrospective cohort study evaluated opioid and benzodiazepine doses over a 6-month time period for patients certified to use medical cannabis for intractable pain. All available daily milligram morphine equivalents (MMEs) and daily diazepam equivalents (DEs) were calculated at baseline and at 3 and 6 months.

RESULTS:

A total of 77 patients were included in the final analysis. There was a statistically significant decrease in median MME from baseline to 3 months (-32.5 mg; P = 0.013) and 6 months (-39.1 mg; P = 0.001). Additionally, there was a non-statistically significant decrease in median DE at 3 months (-3.75 mg; P = 0.285) and no change in median DE from baseline to 6 months (-0 mg; P = 0.833). Conclusion and Relevance: Over the course of this 6-month retrospective study, patients using medical cannabis for intractable pain experienced a significant reduction in the number of MMEs available to use for pain control. No significant difference was noted in DE from baseline. Further prospective studies are warranted to confirm or deny the opioid-sparing effects of medical cannabis when used to treat intractable pain.”

https://www.ncbi.nlm.nih.gov/pubmed/31129977

https://journals.sagepub.com/doi/abs/10.1177/1060028019854221?journalCode=aopd

Prolonged Cannabidiol Treatment Lacks on Detrimental Effects on Memory, Motor Performance and Anxiety in C57BL/6J Mice.

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Image result for frontier in behavioral neuroscience“The Cannabis plant contains more than 100 currently known phytocannabinoids. Regarding the rising consumption of the non-psychotropic phytocannabinoid cannabidiol (CBD) in people’s everyday life (e.g., beauty products, food and beverages), the importance of studies on the influence of CBD on healthy humans and rodents is evident. Therefore, the behavioral profile of CBD was investigated with a battery of behavioral tests, including motor, anxiety, and memory tests after prolonged CBD treatment. Adult C57Bl/6J wildtype (WT) mice were daily intraperitoneally injected with 20 mg/kg CBD for 6 weeks starting at two different points of ages (3 months and 5 months) to compare the influence of prolonged CBD treatment with a washout period (former group) to the effects of long term CBD treatment (current group). Our results show that CBD treatment does not influence motor performance on an accelerating Rotarod test, while it also results in a lower locomotor activity in the open field (OF). No influence of CBD on spatial learning and long term memory in the Morris Water Maze (MWM) was observed. Memory in the Novel Object Recognition test (NORT) was unaffected by CBD treatment. Two different anxiety tests revealed that CBD does not affect anxiety behavior in the Dark-Light Box (DLB) and OF test. Although, anxiety is altered by current CBD treatment in the Elevated Plus Maze (EPM). Moreover, CBD-treated C57Bl/6J mice showed an unaltered acoustic startle response (ASR) compared to vehicle-treated mice. However, current CBD treatment impairs prepulse inhibition (PPI), a test to analyze sensorimotor gating. Furthermore, prolonged CBD treatment did not affect the hippocampal neuron number. Our results demonstrate that prolonged CBD treatment has no negative effect on the behavior of adult C57Bl/6J mice.”

https://www.ncbi.nlm.nih.gov/pubmed/31133833

https://www.frontiersin.org/articles/10.3389/fnbeh.2019.00094/full

Cannabinoid Receptor 1 Blockade Attenuates Obesity and Adipose Tissue Type 1 Inflammation Through miR-30e-5p Regulation of Delta-Like-4 in Macrophages and Consequently Downregulation of Th1 Cells.

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 Image result for frontier in immunology“Obesity is characterized by chronic low-grade inflammation that contributes to development of cardiometabolic disorders. Cannabinoid receptor 1 (CB1) antagonists attenuate diet-induced obesity (DIO) and related inflammation, although the precise anti-inflammatory mechanisms involved have not been fully explored. In the current study we used a mouse model of DIO intervention to determine the microRNA (miRNA, miR)-mediated anti-obesity and anti-inflammatory effects of the CB1 antagonist, AM251. DIO mice that were fed high-fat diet (HFD) for 12 weeks were treated with AM251 (10 mg/kg) for an additional 4 weeks. HFD + AM251 mice experienced rapid and prolonged weight loss and reduced inflammatory M1 adipose tissue macrophage (ATM) infiltration. To investigate miRNA-mediated regulation of ATMs, F4/80+ cells from stromal vascular fractions (SVF) of epididymal fat were subjected to miR microarray analysis. Several miRs were differentially expressed in AM251-treated mice that were independent of calorie restriction. Prominently, miR-30e-5p was upregulated in ATMs from HFD + AM251 mice while the miR-30e-5p target, DLL4, was downregulated. Consistent with a decrease in DLL4-Notch signaling, fat storage and pro-inflammatory cytokine/chemokine expression was reduced following AM251 treatment. Furthermore, we found that AM251-treated macrophages can suppress DLL4-mediated Th1 polarization in CD4+ T cells. Together these data demonstrate that blocking CB1 receptors leads to upregulation of miR-30e-5p and down regulation of DLL4 in ATMs, which in turn suppress DLL4-Notch signaling-induced polarization of inflammatory Th1 cells and adipocyte energy storage. This combined effect of ATMs and T cells leads to an anti-inflammatory state and attenuation of DIO. These data support therapeutic potential of miR-30 in the treatment of cardiometabolic disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31134094

https://www.frontiersin.org/articles/10.3389/fimmu.2019.01049/full

Retrograde activation of CB1R by muscarinic receptors protects against central organophosphorus toxicity.

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Neuropharmacology“The acute toxicity of organophosphorus-based compounds is primarily a result of acetylcholinesterase inhibition in the central and peripheral nervous systems. The resulting cholinergic crisis manifests as seizure, paralysis, respiratory failure and neurotoxicity. Though overstimulation of muscarinic receptors is the mechanistic basis of central organophosphorus (OP) toxicities, short-term changes in synapse physiology that precede OP-induced seizures have not been investigated in detail. To study acute effects of OP exposure on synaptic function, field excitatory postsynaptic potentials (fEPSPs) were recorded from Schaffer collateral synapses in the mouse hippocampus CA1 stratum radiatum during perfusion with various OP compounds. Administration of the OPs paraoxon, soman or VX rapidly and stably depressed fEPSPs via a presynaptic mechanism, while the non-OP proconvulsant tetramethylenedisulfotetramine had no effect on fEPSP amplitudes. OP-induced presynaptic long-term depression manifested prior to interictal spiking, occurred independent of recurrent firing, and did not require NMDA receptor currents, suggesting that it was not mediated by activity-dependent calcium uptake. Pharmacological dissection revealed that the presynaptic endocannabinoid type 1 receptor (CB1R) as well as postsynaptic M1 and M3 muscarinic acetylcholine receptors were necessary for OP-LTD. Administration of CB1R antagonists significantly reduced survival in mice after a soman challenge, revealing an acute protective role for endogenous CB1R signaling during OP exposure. Collectively these data demonstrate that the endocannabinoid system alters glutamatergic synaptic function during the acute response to OP acetylcholinesterase inhibitors.”

https://www.ncbi.nlm.nih.gov/pubmed/31132436

“CB1R activation represents a novel therapy to mitigate acute OP toxicity”

https://www.sciencedirect.com/science/article/pii/S002839081930190X?via%3Dihub