Tag Archives: Cannabinoids

Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice.

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British Journal of Pharmacology

“Cannabis extracts and several cannabinoids have been shown to exert broad anti-inflammatory activities in experimental models of inflammatory CNS degenerative diseases.

Clinical use of many cannabinoids is limited by their psychotropic effects. However, phytocannabinoids like cannabidiol (CBD), devoid of psychoactive activity, are, potentially, safe and effective alternatives for alleviating neuroinflammation and neurodegeneration.

Treatment with CBD during disease onset ameliorated the severity of the clinical signs of EAE.

CBD, a non-psychoactive cannabinoid, ameliorates clinical signs of EAE in mice, immunized against MOG. Suppression of microglial activity and T-cell proliferation by CBD appeared to contribute to these beneficial effects.”

https://www.ncbi.nlm.nih.gov/pubmed/21449980

“In summary, we have shown that CBD administered to MOG-immunized C57BL/6 mice, at the onset of EAE disease, reduced the severity of the clinical signs of EAE. CBD treatment was accompanied by diminished axonal loss and inflammation (infiltration of T cells and microglial activation). Moreover, CBD prevented proliferation of myelin-specific T cells in vitro. These observations suggest that CBD may have potential for alleviating MS-like pathology.” http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01379.x/full

“Study Shows Cannabidiol (CBD) Improves MS-Like Symptoms”  http://www.prohealth.com/library/showarticle.cfm?libid=31211

The current state and future perspectives of cannabinoids in cancer biology.

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Cancer Medicine

“To date, cannabinoids have been allowed in the palliative medicine due to their analgesic and antiemetic effects, but increasing number of preclinical studies indicates their anticancer properties. Cannabinoids exhibit their action by a modulation of the signaling pathways crucial in the control of cell proliferation and survival. Many in vitro and in vivo experiments have shown that cannabinoids inhibit proliferation of cancer cells, stimulate autophagy and apoptosis, and have also a potential to inhibit angiogenesis and metastasis. In this review, we present an actual state of knowledge regarding molecular mechanisms of cannabinoids’ anticancer action, but we discuss also aspects that are still not fully understood such as the role of the endocannabinoid system in a carcinogenesis, the impact of cannabinoids on the immune system in the context of cancer development, or the cases of a stimulation of cancer cells’ proliferation by cannabinoids. The review includes also a summary of currently ongoing clinical trials evaluating the safety and efficacy of cannabinoids as anticancer agents.”

https://www.ncbi.nlm.nih.gov/pubmed/29473338

http://onlinelibrary.wiley.com/doi/10.1002/cam4.1312/abstract

Exogenous Cannabinoid Efficacy: Merely a Pharmacokinetic Interaction?

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Clinical Pharmacokinetics

“Endocannabinoid pharmacology is now relatively well understood with a number of endocannabinoids and endogenous cannabinoid neurotransmitters identified and the pharmacokinetics relatively well ascertained.

Further, the cannabinoid receptors are now molecularly and pharmacologically characterised and the cell processes involved in endocannabinoid transcription, synthesis, post-translational modification and protein expression are reported.

Endogenous cannabinoids have been shown to have key roles in immune and pain pathways and neuro-behavioural signalling including appetite regulation. Significant recent interest has thus been shown in understanding these pathways to guide the development of agents that inhibit the natural catabolism of endogenous cannabinoids to modify pain and appetite, and to synthesise antagonists for the treatment of disease such as obesity.

This research is concurrent with the renewed clinical interest in exogenous cannabinoids and their use in disease. However, the complex pharmacology and physiological effects of exogenous cannabinoids, either as individual components or in combination, as extracts or via administration of the whole plant in humans, are less well known.

Yet as with all other therapeutics, including those derived from plants, knowledge of the pharmacokinetics and dynamics of the complete plant, the individual chemical molecules and their synthetic versions, including formulations and excipients is a standard part of drug development.

This article covers the key pharmacological knowledge required to guide further exploration of the toxicity and efficacy of different cannabinoids and their formulations in blinded placebo-controlled studies.”

https://www.ncbi.nlm.nih.gov/pubmed/28921125

https://link.springer.com/article/10.1007%2Fs40262-017-0599-0

Cannabidiol Regulates Long Term Potentiation Following Status Epilepticus: Mediation by Calcium Stores and Serotonin.

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“Epilepsy is a devastating disease, with cognitive and emotional consequences that are not curable.

In recent years, it became apparent that cannabinoids help patients to cope with epilepsy.

We have studied the effects of cannabidiol (CBD) on the ability to produce long term potentiation (LTP) in stratum radiatum of CA1 region of the mouse hippocampus.

Exposure to seizure-producing pilocarpine reduced the ability to generate LTP in the slice.

Pre-exposure to CBD prevented this effect of pilocarpine.

Furthermore, CBD caused a marked increase in ability to generate LTP, an effect that was blocked by calcium store antagonists as well as by a reduction in serotonin tone. Serotonin, possibly acting at a 5HT1A receptor, or fenfluramine (FFA), which causes release of serotonin from its native terminals, mimicked the effect of CBD.

It is proposed that CBD enhances non-NMDA LTP in the slice by facilitating release of serotonin from terminals, consequently ameliorating the detrimental effects of pilocarpine.”

 https://www.ncbi.nlm.nih.gov/pubmed/29467619
https://www.frontiersin.org/articles/10.3389/fnmol.2018.00032/full

Time-dependent effect of phytocannabinoid treatments in fat cells.

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“The objectives of this paper is to investigate, demonstrate, and compare the mechanism of action of phytocannabinoids as antidiabetic and anti-obesity agents in preadipocytes and adipocytes, relative to rosiglitazone and metformin.

Briefly, cannabis extract, Δ9 -tetrahydrocannabinol and cannabidiol (in very low dosages) were shown to promote glucose uptake higher or to equivalent levels, reduce fat accumulation, and reverse the insulin-resistant state of 3T3-L1 cells more effectively, relative to rosiglitazone and metformin. The phytocannabinoids had a more pronounced effect in preadipocytes undifferentiated model rather than the differentiated model. They induced a protective effect at the mitochondrial level by preventing overactivity of the succinate dehydrogenase pathway (p < .01), unlike rosiglitazone, through activation of the glycerol-3-phosphate dehydrogenase shuttling system. An increase in oxygen consumption and an increased expression of beta to alpha adrenoceptors (p < .05) in treated cells were noted.

These findings contribute toward understanding the mechanism of action of phytocannabinoids in fat cells and highlight the antidiabetic and anti-obesity properties of various phytocannabinoids that could potentially support the treatment of obesity-related insulin resistance.”

https://www.ncbi.nlm.nih.gov/pubmed/29464872

Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability.

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“Cannabinoids combined with opioids produce synergistic antinociceptive effects, decreasing the lowest effective antinociceptive opioid dose (i.e., opioid-sparing effects) in laboratory animals.

Although pain patients report greater analgesia when cannabis is used with opioids, no placebo-controlled studies have assessed the direct effects of opioids combined with cannabis in humans or the impact of the combination on abuse liability.

This double-blind, placebo-controlled, within-subject study determined if cannabis enhances the analgesic effects of low dose oxycodone using a validated experimental model of pain and its effects on abuse liability.

Cannabis enhances the analgesic effects of sub-threshold oxycodone, suggesting synergy, without increases in cannabis’s abuse liability. These findings support future research into the therapeutic use of opioid-cannabinoid combinations for pain.”

 https://www.ncbi.nlm.nih.gov/pubmed/29463913
https://www.nature.com/articles/s41386-018-0011-2

The Role of Cannabinoid Receptor 1 in the Immunopathology of Respiratory Syncytial Virus.

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Mary Ann Liebert, Inc. publishers

“Endocannabinoid system plays an important role in pathophysiologic processes such as immune functions and impacts on disease severity.

Our previous study showed that cannabinoid receptor 2 (CB2) affects clinical course of respiratory syncytial virus (RSV) infection. In this study, we investigated the role of cannabinoid receptor 1 (CB1) in RSV immunopathology and its therapeutic potential in mice model.

This study and our previous finding indicated that endocannabinoid signaling regulates the inflammatory response to RSV infection, and is a potential therapeutic candidate for alleviation of RSV-associated immunopathology.”

https://www.ncbi.nlm.nih.gov/pubmed/29461930

http://online.liebertpub.com/doi/10.1089/vim.2017.0098

Sex differences in antinociceptive response to Δ-9-tetrahydrocannabinol and CP 55,940 in the mouse formalin test.

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“Cannabinoids have shown promise for the treatment of intractable pain states and may represent an alternative pharmacotherapy for pain management.

A growing body of clinical evidence suggests a role for sex in pain perception and in cannabinoid response.

We examined cannabinoid sensitivity and tolerance in male and female mice expressing a desensitization-resistant form (S426A/S430A) of the cannabinoid type 1 receptor (CB1R).

Mice were assessed for acute and inflammatory nociceptive behaviors in the formalin test following pretreatment with either vehicle or mixed CB1R/CB2R agonists, Δ-9-tetrahydrocannabinol ([INCREMENT]-THC) (1-6 mg/kg) or CP 55,940 (0.06-0.2 mg/kg). Tolerance to the effects of 6 mg/kg [INCREMENT]-THC or 0.1 mg/kg CP 55,940 was examined by the formalin test following chronic daily dosing.

Female mice showed decreased sensitivity to the effects of [INCREMENT]-THC and CP 55,940 compared with male mice. The S426A/S430A mutation increased the attenuation of nociceptive behaviors for both agonists in both sexes. Female mice displayed delayed tolerance to [INCREMENT]-THC compared with male mice, whereas the S426A/S430A mutation conferred a delay in tolerance to [INCREMENT]-THC in both sexes. Male S426A/S430A mutant mice also display resistance to tolerance to CP 55,940 compared with wild-type controls.

This study demonstrates sex and genotype differences in response for two different cannabinoid agonists. The results underscore the importance of including both male and female mice in preclinical studies of pain and cannabinoid pharmacology.”

https://www.ncbi.nlm.nih.gov/pubmed/29461336

https://insights.ovid.com/crossref?an=00001756-900000000-98413

Limited Access to a High Fat Diet Alters Endocannabinoid Tone in Female Rats.

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“Emerging evidence suggest an impaired endocannabinoid activity in the pathophysiology of binge eating disorder (BED). Herein, we investigated whether endocannabinoid tone could be modified as a consequence of dietary-induced binge eating in female rats.

For this purpose, brain levels of the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), as well as two endocannabinoid-like lipids, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), were assessed in different brain areas involved in the hedonic feeding (i.e., prefrontal cortex, nucleus accumbens, amygdala, hippocampus, and hypothalamus).

The brain density of cannabinoid type-1 receptors (CB1) was also evaluated. Furthermore, we determined plasma levels of leptin, ghrelin, and corticosterone hormones, which are well-known to control the levels of endocannabioids and/or CB1 receptors in the brain.

To induce binge eating behavior, rats were subject to an intermittent and limited access to a high fat diet (HFD) (margarine). Three experimental groups were used, all with ad libitum access to chow: control (CTRL), with no access to margarine; low restriction (LR), with 2 h margarine access 7 days/week; high restriction (HR), with 2 h margarine access 3 days/week. Bingeing was established when margarine intake in the HR group exceeded that of the LR group.

Our results show that, compared to CTRL, AEA significantly decreased in the caudate putamen, amygdala, and hippocampus of HR group. In contrast, 2-AG significantly increased in the hippocampus while OEA decreased in the hypothalamus. Similar to the HR group, AEA and OEA decreased respectively in the amygdala and hypothalamus and 2-AG increased in the hippocampus of LR group. Moreover, LR group also had AEA decreased in the prefrontal cortex and increased in the nucleus accumbens. In both groups we found the same reduction of CB1 receptor density in the prefrontal cortex compared to CTRL. Also, LR and HR groups showed alterations in both ghrelin and corticosterone levels, while leptin remained unaltered.

In conclusion, our findings show a modified endocannabinoid tone due to margarine exposure, in several brain areas that are known to influence the hedonic aspect of food. Even if not uniquely specific to binge eating, margarine-induced changes in endocannabinoid tone could contributes to the development and maintenance of this behavior.”

https://www.ncbi.nlm.nih.gov/pubmed/29456490

https://www.frontiersin.org/articles/10.3389/fnins.2018.00040/full

Cannabinoids prevent depressive-like symptoms and alterations in BDNF expression in a rat model of PTSD.

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“Posttraumatic stress disorder (PTSD) is a debilitating condition highly comorbid with depression. The endocannabinoid (eCB) system and brain-derived neurotrophic factor (BDNF) are suggestively involved in both disorders.

We examined whether cannabinoids can prevent the long-term depressive-like symptoms induced by exposure to the shock and situational reminders (SRs) model of PTSD. The CB1/2 receptor agonist WIN55,212-2 (0.5 mg/kg; i.p.), the fatty acid hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg, i.p.) or vehicle were administered 2 h after severe shock.

Cannabinoids prevented the shock/SRs-induced alterations in social recognition memory, locomotion, passive coping, anxiety-like behavior, anhedonia, fear retrieval, fear extinction and startle response as well as the decrease in BDNF levels in the hippocampus and prefrontal cortex (PFC). Furthermore, significant correlations were found between depressive-like behaviors and BDNF levels in the brain.

The findings suggest that cannabinoids may prevent both depressive- and PTSD-like symptoms following exposure to severe stress and that alterations in BDNF levels in the brains’ fear circuit are involved in these effects.”

https://www.ncbi.nlm.nih.gov/pubmed/29458190

https://www.sciencedirect.com/science/article/pii/S027858461731000X