Role of the endocannabinoid system in neurological disorders.

International Journal of Developmental Neuroscience

“Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that begins in infancy. Although the etiology and pathogenesis are poorly understood, many studies have shown that ASD is closely related to structural and functional defects in the nervous system, especially synaptic transmission. The endocannabinoid (eCB) system is an important regulatory system of the central nervous system that regulates neurotransmission and synaptic plasticity and plays an important role in emotional and social responses and cognitive function. The relationship between eCB system and ASD has attracted increasing attention from scholars. In this review, we discuss the complex lipid signaling network of the eCB system, intracellular transport pathways, abnormal expression and association with various neurological diseases, and direct and indirect evidence for the link between eCB and ASD. Collectively, the findings to date indicate that the eCB system plays a key role in the pathophysiology of ASD and can provide new insights into potential interventions and rehabilitation strategies for ASD.”

https://www.ncbi.nlm.nih.gov/pubmed/30858029

https://www.sciencedirect.com/science/article/abs/pii/S0736574818302995?via%3Dihub

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Are cannabis users less likely to gain weight? Results from a national 3-year prospective study.

International Journal of Epidemiology

“Pre-clinical studies indicate increased food intake and weight gain as cannabinoid effects. Cross-sectional epidemiological studies, however, indicate lower prevalence of obesity among cannabis users. Here, we aim to study the weight-gain research question in the prospectively conducted National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

RESULTS:

At W2, 77% of the participants never used cannabis, 18% had discontinued use (‘quit’), 3% were initiates and 2% were persistent users. Estimated W1-to-W2 BMI change shows an increase for all subgroups. Compared with never-users (reference), inverse slope estimates and attenuated change (%) in BMI between W1 and W2 are seen for cannabis-use subgroups: quitters [β = -0.81; 95% confidence interval (CI) = -1.01, -0.60], initiates (β = -0.97; 95% CI = -1.36, -0.57) and persistent users (β = -1.26; 95% CI = -1.81, -0.72).

CONCLUSION:

This new prospective study builds from anecdotes, pre-clinical studies and cross-sectional evidence on inverse associations linking cannabis use and obesity and shows an inverse cannabis-BMI increase association. Confirmatory studies with rigorous cannabis and BMI assays will be needed.”

https://www.ncbi.nlm.nih.gov/pubmed/30879064

https://academic.oup.com/ije/advance-article-abstract/doi/10.1093/ije/dyz044/5382155?redirectedFrom=fulltext

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Cannabimimetic plants: are they new cannabinoidergic modulators?

“Phytochemicals and secondary metabolites able to interact with the endocannabinoid system (Cannabimimetics) have been recently described in a broad range of plants and fruits. These findings can open new alternative avenues to explore for the development of novel therapeutic compounds. The cannabinoids regulate many physiological and pathological functions in both animals and plants. Cannabis sativa is the main plant that produces phytocannabinoids inside resins capable to defend the plant from the aggression of parasites and herbivores. Animals produce anandamide and 2-arachidonoyl glycerol, which thanks to binding with main receptors such as type-1 cannabinoid receptor (CB1R) and the type-2 cannabinoid receptor (CB2R) are involved in inflammation processes and several brain functions. Endogenous cannabinoids, enzymes for synthesis and degradation of cannabinoids, and CB1R and CB2R constitute the endocannabinoid system (ECS). Other plants can produce cannabinoid-like molecules such as perrottetinene extracted from Radula perrottetii, or anandamide and 2-arachidonoyl glycerol extracted from some bryophytes. Moreover, several other secondary metabolites can also interact with the ECS of animals and take the name of cannabimimetics. These phytoextracts not derived from Cannabis sativa can act as receptor agonists or antagonist, or enzyme inhibitors of ECS and can be involved in the inflammation, oxidative stress, cancer, and neuroprotection. Finally, given the evolutionary heterogeneity of the cannabimimetic plants, some authors speculated on the fascinating thesis of the evolutionary convergence between plants and animals regarding biological functions of ECS. The review aims to provide a critical and complete assessment of the botanical, chemical and therapeutic aspects of cannabimimetic plants to evaluate their spread in the world and medicinal potentiality.”

https://www.ncbi.nlm.nih.gov/pubmed/30877436

https://link.springer.com/article/10.1007%2Fs00425-019-03138-x

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Analyzing the role of cannabinoids as modulators of Wnt/β-catenin signaling pathway for their use in the management of neuropathic pain.

Bioorganic & Medicinal Chemistry Letters

“Neuropathic pain is a debilitating form of treatment-resistant chronic pain caused by damage to the nervous system. Cannabinoids have been known for suppressing neuropathic pain by modulating the endo cannabinoid system. Since the canonical Wnt/β-catenin signaling has recently been implicated in pain sensation, we investigated the impact of major cannabinoids (1-6) from the leaves of Cannabis sativa and an epoxy derivative of compound 2, here upon referred to as 2a, on modulating Wnt/β-catenin signaling pathway. The results presented in this study show that compound 1, 2 and 2a exhibited potent inhibitory activity against Wnt/β-catenin pathway in a dose-dependent manner. Compound 2a was seen to inhibit this pathway at slightly lower concentrations than its parent molecule 2, under similar conditions. Taken together, compound 1, 2 and 2a, by virtue of their inhibition of Wnt/β-catenin signaling pathway, could be developed as effective neuroprotective agents for the management of neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/30871771

https://www.sciencedirect.com/science/article/pii/S0960894X19301428?via%3Dihub

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CBD as the New Medicine in the Pain Provider’s Armamentarium.

“As providers who currently treat some chronic pain patients with CBD oil as part of a multimodal analgesic treatment regimen, we have found great benefit of this new weapon recently being utilized in our armamentarium. As mentioned in the article, the current political climate surrounding CBD is both vague and ever-changing, which can and does impact treatment and subsequent patient outcomes as pain medicine providers. If we want to make cannabis and CBD into a legitimate medicinal treatment, there must be more regulations on CBD oil production and accurate labeling. Patients will continue to seek CBD oil as an additional option to treat their chronic pain as it gains popularity, so it is our duty as providers to protect them and ensure they have safe options of this new medication to choose from.”
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Beneficial and deleterious effects of cannabinoids in the brain: the case of ultra-low dose THC.

Publication Cover

“This article reviews the neurocognitive advantages and drawbacks of cannabinoid substances, and discusses the possible physiological mechanisms that underlie their dual activity. The article further reviews the neurocognitive effects of ultra-low doses of ∆9-tetrahydrocannabinol (THC; 3-4 orders of magnitude lower than the conventional doses) in mice, and proposes such low doses of THC as a possible remedy for various brain injuries and for the treatment of age-related cognitive decline.”

https://www.ncbi.nlm.nih.gov/pubmed/30864864

https://www.tandfonline.com/doi/abs/10.1080/00952990.2019.1578366?journalCode=iada20

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β-Caryophyllene, a Natural Sesquiterpene, Attenuates Neuropathic Pain and Depressive-Like Behavior in Experimental Diabetic Mice.

 View details for Journal of Medicinal Food cover image“Neuropathic pain (NP) is associated with chronic hyperglycemia and emotional disorders such as depression in diabetic patients, complicating the course of treatment. Drugs currently used to treat NP have undesirable side effects, so research on other natural sources has been required.

β-caryophyllene (BCP), a natural sesquiterpene found in some food condiments and considered an agonist to cannabinoid receptor type 2, could have potential therapeutic effects to treat conditions such as NP and emotional disorders. For this reason, we assessed whether BCP modulates nociception, anxiety, and depressive-like behavior in streptozotocin (STZ)-induced experimental diabetic BALB/c female mice.

BCP was orally chronic administrated (10 mg/kg/60 μL). Pain developed with STZ was evaluated with von Frey filament test, SMALGO®, and hot plate test. Anxiety and depression-like behavior were assessed by marbles test, forced swim test, and tail suspension test. BCP significantly reduced glycemia in experimental diabetic mice. The pain was also mitigated by BCP administration. Depression-like behavior assessed with tail suspension test was attenuated with orally chronic BCP administration. Substance P and cytokines such as interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) were also attenuated with BCP administration. NP was positively correlated with substance P and IL-6 and IL-1β release.

Our data using an orally chronic BCP administration in the STZ challenged mice to suggest that glycemia, diabetes-related NP, and depressive-like behavior could be prevented/reduced by dietary BCP.”

https://www.ncbi.nlm.nih.gov/pubmed/30864870

https://www.liebertpub.com/doi/10.1089/jmf.2018.0157

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

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Cannabidiol enhances the passage of lipid nanocapsules across the blood-brain barrier both in vitro and in vivo.

 Molecular Pharmaceutics“Diseases affecting the central nervous system (CNS) should be regarded as a major health challenge due to the current lack of effective treatments given the hindrance to brain drug delivery imposed by the blood-brain barrier (BBB). Since efficient brain drug delivery should not solely rely on passive targeting, active targeting of nanomedicines into the CNS is being explored. The present study is devoted to the development of lipid nanocapsules (LNCs) decorated with non-psychotropic cannabinoids as pioneering non-immunogenic brain targeting molecules and to the evaluation of their brain targeting ability both in vitro and in vivo. Noticeably, both the permeability experiments across the hCMEC/D3 cell-based in vitro BBB model and the biodistribution experiments in mice consistently demonstrated that the highest brain targeting ability was achieved with the smallest-sized cannabinoid-decorated LNCs. Importantly, the enhancement in brain targeting achieved with the conjugation of CBD to LNCs outperformed by 6-fold the enhancement observed for the G-Technology® (the main brain active strategy that has already entered clinical trials for the treatment of CNS diseases) As the transport efficiency across the BBB certainly determines the efficacy of the treatments for brain disorders, small cannabinoid-decorated LNCs represent auspicious platforms for the design and development of novel therapies for CNS diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/30865462

https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.8b01344

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Cannabinoid Use in Patients With Gastroparesis and Related Disorders: Prevalence and Benefit.

 

Image result for Am J Gastroenterol.

“Gastroparesis (Gp) can be a challenging disorder to manage due to the paucity of treatment options. We do not know how frequently patients with Gp symptoms resort to cannabinoids to address their symptoms. This study (i) determines the prevalence of cannabinoid use in patients with Gp symptoms, (ii) describes the patients with Gp symptoms using cannabinoids, and (iii) assesses the patients’ perceived benefit of cannabinoids for Gp symptoms.

METHODS:

Consecutive outpatients with symptoms suggestive of Gp seen on follow-up at our academic center from June 2018 to September 2018 filled out questionnaires on their symptoms and the current treatments.

RESULTS:

Of 197 patients, nearly half (n = 92, 46.7%) reported current (35.5%) or past (11.2%) use of cannabinoids, including tetrahydrocannabinol (n = 63), dronabinol (n = 36), and/or cannabidiol (n = 16). Of these, most perceived improvement in Gp symptoms from cannabinoids (93.5% with tetrahydrocannabinol, 81.3% with cannabidiol, and 47.2% with dronabinol). Cannabinoids were used most commonly via smoking (n = 46). Patients taking cannabinoids were younger (41.0 ± 15.4 vs 48.0 ± 15.9 years; P < 0.01) and had a higher Gastroparesis Cardinal Symptom Index total score (3.4 ± 1.0 vs 2.8 ± 1.3; P < 0.01) compared with patients with no history of cannabinoid use.

CONCLUSIONS:

A third of patients with Gp symptoms actively use cannabinoids for their chronic symptoms. Most of these patients perceive improvement in their symptoms with cannabinoids. Patients taking cannabinoids were younger and more symptomatic than those not taking cannabinoids. Further studies on the efficacy and safety of cannabinoids in Gp will be useful.”

https://www.ncbi.nlm.nih.gov/pubmed/30865015

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Perspectives on the Role of Endocannabinoids in Autism Spectrum Disorders.

 Logo of nihpa

“Autism spectrum disorders (ASDs) are diagnosed on the basis of three behavioral features, namely, (1) deficits in social communication, (2) absence or delay in language and (3) stereotypy. The consensus regarding the neurological pathogenesis of ASDs is aberrant synaptogenesis and synapse function. Further, it is now widely accepted that ASD is neurodevelopmental in nature, placing emphasis on derangements occurring at the level of intra- and intercellular signaling during corticogenesis. At present, there is an ever-growing list of mutations in putative susceptibility genes in affected individuals, preventing effective transformation of knowledge gathered from basic science research to the clinic. In response, the focus of ASD biology has shifted toward the identification of cellular signaling pathways that are common to various ASD-related mutations in hopes that these shared pathways may serve as more promising treatment targets than targeting individual genes or proteins. To this end, the endogenous cannabinoid (endocannabinoid, eCB) system has recently emerged as a promising therapeutic target in the field of ASD research. The eCB system is altered in several neurological disorders, but the role of these bioactive lipids in ASD etiology remains poorly understood. In this perspective, we review current evidence linking eCB signaling to ASDs and put forth the notion that continued focus on eCBs in autism research may provide valuable insight into pathophysiology and treatment strategies. In addition to its role in modulating transmitter release at mature synapses, the eCB signaling system plays important roles in many aspects of cortical development, and disruption of these effects of eCBs may also be related to ASD pathophysiology.”

https://www.ncbi.nlm.nih.gov/pubmed/30854511

“Advances in our understanding of eCB actions will undoubtedly facilitate pharmacological interventions and further, provide patients the best quality of life possible.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407886/

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