Association of Cannabinoid Administration With Experimental Pain in Healthy Adults: A Systematic Review and Meta-analysis.

Image result for jama psychiatry “Cannabinoid drugs are widely used as analgesics, but experimental pain studies have produced mixed findings. The analgesic properties of cannabinoids remain unclear.

OBJECTIVE:

To conduct a systematic review and meta-analysis of the association between cannabinoid drug administration and experimental pain outcomes in studies of healthy adults.

CONCLUSIONS AND RELEVANCE:

Cannabinoid drugs may prevent the onset of pain by producing small increases in pain thresholds but may not reduce the intensity of experimental pain already being experienced; instead, cannabinoids may make experimental pain feel less unpleasant and more tolerable, suggesting an influence on affective processes. Cannabis-induced improvements in pain-related negative affect may underlie the widely held belief that cannabis relieves pain.”

https://www.ncbi.nlm.nih.gov/pubmed/30422266

https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2701671

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The Endocannabinoid System and Oligodendrocytes in Health and Disease.

 Image result for frontiers in neuroscience“Cannabinoid-based interventions are being explored for central nervous system (CNS) pathologies such as neurodegeneration, demyelination, epilepsy, stroke, and trauma. As these disease states involve dysregulation of myelin integrity and/or remyelination, it is important to consider effects of the endocannabinoid system on oligodendrocytes and their precursors. In this review, we examine research reports on the effects of the endocannabinoid system (ECS) components on oligodendrocytes and their precursors, with a focus on therapeutic implications. Cannabinoid ligands and modulators of the endocannabinoid system promote cell signaling in oligodendrocyte precursor survival, proliferation, migration and differentiation, and mature oligodendrocyte survival and myelination. Agonist stimulation of oligodendrocyte precursor cells (OPCs) at both CB1 and CB2 receptors counter apoptotic processes via Akt/PI3K, and promote proliferation via Akt/mTOR and ERK pathways. CB1 receptors in radial glia promote proliferation and conversion to progenitors fated to become oligodendroglia, whereas CB2 receptors promote OPC migration in neonatal development. OPCs produce 2-arachidonoylglycerol (2-AG), stimulating cannabinoid receptor-mediated ERK pathways responsible for differentiation to arborized, myelin basic protein (MBP)-producing oligodendrocytes. In cell culture models of excitotoxicity, increased reactive oxygen species, and depolarization-dependent calcium influx, CB1 agonists improved viability of oligodendrocytes. In transient and permanent middle cerebral artery occlusion models of anoxic stroke, WIN55212-2 increased OPC proliferation and maturation to oligodendroglia, thereby reducing cerebral tissue damage. In several models of rodent encephalomyelitis, chronic treatment with cannabinoid agonists ameliorated the damage by promoting OPC survival and oligodendrocyte function. Pharmacotherapeutic strategies based upon ECS and oligodendrocyte production and survival should be considered.”

https://www.ncbi.nlm.nih.gov/pubmed/30416422

https://www.frontiersin.org/articles/10.3389/fnins.2018.00733/full

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Cannabis, cannabinoids and the endocannabinoid system – is there therapeutic potential for inflammatory bowel disease?

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“Cannabis sativa and its extracts have been used for centuries both medicinally and recreationally. There is accumulating evidence that exogenous cannabis and related cannabinoids improve symptoms associated with inflammatory bowel disease such as pain, loss of appetite, and diarrhoea. In vivo, exocannabinoids have been demonstrated to improve colitis, mainly in chemical models. Exocannabinoids signal through the endocannabinoid system, an increasingly understood network of endogenous lipid ligands and their receptors, together with a number of synthetic and degradative enzymes and the resulting products. Modulating the endocannabinoid system using pharmacological receptor agonists, genetic knockout models, or inhibition of degradative enzymes have largely shown improvements in colitis in vivo. Despite these promising experimental results, this has not translated into meaningful benefits for human IBD in the few clinical trials which have been conducted to date. The largest study to date being limited by poor medication tolerance due to the Δ9-tetrahydrocannabinol component. This review article synthesises the current literature surrounding the modulation of the endocannabinoid system and administration of exocannabinoids in experimental and human IBD. Findings of clinical surveys and studies of cannabis use in IBD are summarised. Discrepancies in the literature are highlighted together with identifying novel areas of interest.”

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Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis.

Journal of Pharmacology and Experimental Therapeutics

“Phytocannabinoids modulate inflammatory responses by regulating the production of cytokines in several experimental models of inflammation.

Cannabinoid type-2 (CB2) receptor activation was shown to reduce the production of the monocyte chemotactic protein-2 (MCP-2) chemokine in polyinosinic-polycytidylic acid [poly-(I:C)]-stimulated human keratinocyte (HaCaT) cells, an in vitro model of allergic contact dermatitis (ACD).

We investigated if nonpsychotropic cannabinoids, such as cannabidiol (CBD), produced similar effects in this experimental model of ACD.

We show that in poly-(I:C)-stimulated HaCaT cells, CBD elevates the levels of AEA and dose-dependently inhibits poly-(I:C)-induced release of MCP-2, interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α in a manner reversed by CB2 and TRPV1 antagonists 6-iodopravadoline (AM630) and 5′-iodio-resiniferatoxin (I-RTX), respectively, with no cytotoxic effect.

This is the first demonstration of the anti-inflammatory properties of CBD in an experimental model of ACD.”

https://www.ncbi.nlm.nih.gov/pubmed/29632236

http://jpet.aspetjournals.org/content/365/3/652.long

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Anti-inflammatory agents for smoking cessation? Focus on cognitive deficits associated with nicotine withdrawal in male mice.

 Brain, Behavior, and Immunity

“Nicotine withdrawal is associated with cognitive deficits including attention, working memory, and episodic memory impairments.

Treatment with the non-psychoactive cannabinoid cannabidiol abolished memory impairment of nicotine withdrawal and microglia reactivity, reduced the expression of IL1β and IFNγ in the hippocampus and the prefrontal cortex, respectively, and normalized Ki67 levels. The nonsteroidal anti-inflammatory drug indomethacin also prevented cognitive deficits and microglial reactivity during withdrawal.

These data underline the usefulness of anti-inflammatory agents to improve cognitive performance during early nicotine abstinence.”

https://www.ncbi.nlm.nih.gov/pubmed/30391635

https://www.sciencedirect.com/science/article/pii/S0889159118302599?via%3Dihub

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Pain and Depression: A Systematic Review.

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“Pain comorbid with depression is frequently encountered in clinical settings and often leads to significant impaired functioning. Given the complexity of comorbidities, it is important to address both pain and depressive symptoms when evaluating treatment options.

Overall, studies suggested that pain and depression are highly intertwined and may co-exacerbate physical and psychological symptoms. These symptoms could lead to poor physical functional outcomes and longer duration of symptoms. An important biochemical basis for pain and depression focuses on serotonergic and norepinephrine systems, which is evident in the pain-ameliorating properties of serotonergic and norepinephrine antidepressants.

Alternative pharmacotherapies such as ketamine and cannabinoids appear to be safe and effective options for improving depressive symptoms and ameliorating pain. In addition, cognitive-behavioral therapy may be a promising tool in the management of chronic pain and depression.

CONCLUSION:

The majority of the literature indicates that patients with pain and depression experience reduced physical, mental, and social functioning as opposed to patients with only depression or only pain. In addition, ketamine, psychotropic, and cognitive-behavioral therapies present promising options for treating both pain and depression.”

https://www.ncbi.nlm.nih.gov/pubmed/30407234

https://insights.ovid.com/crossref?an=00023727-201811000-00005

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Cannabis and the Anxiety of Fragmentation-A Systems Approach for Finding an Anxiolytic Cannabis Chemotype.

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“Cannabis sativa is a medicinal herb with a diverse range of chemotypes that can exert both anxiolytic and anxiogenic effects on humans. Medical cannabis patients receiving organically grown cannabis from a single source were surveyed about the effectiveness of cannabis for treating anxiety.

Patients rated cannabis as highly effective overall for treating anxiety with an average score of 8.03 on a Likert scale of 0 to 10 (0 = not effective, 10 = extremely effective).

Patients also identified which strains they found the most or least effective for relieving their symptoms of anxiety. To find correlations between anxiolytic activity and chemotype, the top four strains voted most and least effective were analyzed by HPLC-MS/MS to quantify cannabinoids and GC-MS to quantify terpenes. Tetrahydrocannabinol (THC) and trans-nerolidol have statistically significant correlations with increased anxiolytic activity.

Guiaol, eucalyptol, γ-terpinene, α-phellandrene, 3-carene, and sabinene hydrate all have significant correlations with decreased anxiolytic activity. Further studies are needed to better elucidate the entourage effects that contribute to the anxiolytic properties of cannabis varieties.”

https://www.ncbi.nlm.nih.gov/pubmed/30405331

https://www.frontiersin.org/articles/10.3389/fnins.2018.00730/full

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Efficacy of cannabinoids in paediatric epilepsy.

Developmental Medicine & Child Neurology banner

“There are hundreds of compounds found in the marijuana plant, each contributing differently to the antiepileptic and psychiatric effects. Cannabidiol (CBD) has the most evidence of antiepileptic efficacy and does not have the psychoactive effects of ∆9 -tetrahydrocannabinol. CBD does not act via cannabinoid receptors and its antiepileptic mechanism of action is unknown. Despite considerable community interest in the use of CBD for paediatric epilepsy, there has been little evidence for its use apart from anecdotal reports, until the last year. Three randomized, placebo-controlled, double-blind trials in Dravet syndrome and Lennox-Gastaut syndrome found that CBD produced a 38% to 41% median reduction in all seizures compared to 13% to 19% on placebo. Similarly, CBD resulted in a 39% to 46% responder rate (50% convulsive or drop-seizure reduction) compared to 14% to 27% on placebo. CBD was well tolerated; however, sedation, diarrhoea, and decreased appetite were frequent. CBD shows similar efficacy to established antiepileptic drugs. WHAT THIS PAPER ADDS: Cannabidiol (CBD) shows similar efficacy in the severe paediatric epilepsies to other antiepileptic drugs. Careful down-titration of benzodiazepines is essential to minimize sedation with adjunctive CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/30402932

https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.14087

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New insights on atherosclerosis: A cross-talk between endocannabinoid systems with gut microbiota.

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“The incidence of atherosclerosis is increasing rapidly all over the world. Inflammatory processes have outstanding role in coronary artery disease (CAD) etiology and other atherosclerosis manifestations. Recently attentions have been increased about gut microbiota in many fields of medicine especially in inflammatory diseases like atherosclerosis. Ineffectiveness in gut barrier functions and subsequent metabolic endotoxemia (caused by rise in plasma lipopolysaccharide levels) is associated with low-grade chronic inflammation i.e. a recognized feature of atherosclerosis. Furthermore, the role of trimethylamine-N-oxide (TMAO), a gut bacterial metabolite has been suggested in atherosclerosis development. On the other hand, the effectiveness of gut microbiota modulation that results in TMAO reduction has been investigated. Moreover, considerable evidence supports a role for the endocannabinoid system (ECS) in atherosclerosis pathology which affects gut microbiota, but their effects on atherosclerosis are controversial. Therefore, we presented some evidence about the relationship between gut microbiota and ECS in atherosclerosis. We also presented evidences that gut microbiota modulation by pre/probiotics can have significant influence on the ECS.

Even though there are many questions which have been unanswered, studies demonstrated that mucosal barrier function disruption and subsequent gut microbiota-derived endotoxemia could contribute to cardiometabolic diseases pathogenesis. As well, number of studies revealed that TMAO in systemic circulation can activate macrophages which lead to cholesterol accumulation and subsequent foam cells formation in atherosclerotic lesions. On the other hand, accumulating evidence proposes that ECS involved in many physiological processes that are related to maintenance of gut-barrier function and inflammation regulation. Hence, although present literature review provides beneficial evidence in support of crosstalk between ECS and gut microbiota, additional studies are needed to clarify whether gut microbiota modulation can alter ECS tone and inflammation levels or not.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203867/

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Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis.

 Image result for drugs journal“Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.

OBJECTIVE:

The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.

METHODS:

Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).

RESULTS:

Four trials involving 550 patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1-31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8-28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07-2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55-8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28-7.41; p = 0.657) and 4.20 (95% CI 1.82-9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87-16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22-12.86; p = 0.626) and 6.89 (95% CI 2.28-20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11-1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.

CONCLUSIONS:

Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.”

https://www.ncbi.nlm.nih.gov/pubmed/30390221

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