Tag Archives: Cannabinoids

Bioactive spirans and other constituents from the leaves of Cannabis sativa f. sativa.

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“In this paper, 17 compounds (1-17) were isolated from the leaves of Hemp (Cannabis sativa f. sativa). Among the isolates, two were determined to be new spirans: cannabispirketal (1), and α-cannabispiranol 4′-O-β-D-glucopyranose (2) by 1D and 2D NMR spectroscopy, LC-MS, and HRESIMS. The known compounds 7, 8, 10, 13, 15, and 16 were isolated from Hemp (C. sativa f. sativa) for the first time. Furthermore, compounds 8 and 13 were isolated from the nature for the first time. All isolated compounds were evaluated for cytotoxicity on different tissue-derived passage cancer cell lines through cell viability and apoptosis assay. Among these compounds, compounds 5, 9 and 16 exhibited a broad-spectrum antitumor effect via inhibiting cell proliferation and promoting apoptosis. These results obtained have provided valuable clues to the understanding of the cytotoxic profile for these isolated compounds from Hemp (C. sativa f. sativa).”

https://www.ncbi.nlm.nih.gov/pubmed/27848262

High-resolution crystal structure of the human CB1 cannabinoid receptor.

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“The human cannabinoid G-protein-coupled receptors (GPCRs) CB1 and CB2 mediate the functional responses to the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG), as well as the widely consumed plant (phyto)cannabinoid Δ9-tetrahydrocannabinol (THC)1. The cannabinoid receptors have been the targets of intensive drug discovery efforts owing to the therapeutic potential of modulators for controlling pain2, epilepsy3, obesity4, and other maladies. Although much progress has recently been made in understanding the biophysical properties of GPCRs, investigations of the molecular mechanisms of the cannabinoids and their receptors have lacked high-resolution structural data. We used GPCR engineering and lipidic cubic phase (LCP) crystallization to determine the structure of the human CB1 receptor bound to the inhibitor taranabant at 2.6 Å resolution. The extracellular surface of CB1, including the highly conserved membrane-proximal amino-terminal (N-terminal) region, is distinct from other lipid-activated GPCRs and forms a critical part of the ligand binding pocket. Docking studies further demonstrate how this same pocket may accommodate the cannabinoid agonist THC. Our CB1 structure provides an atomic framework for studying cannabinoid receptor function, and will aid the design and optimization of cannabinoid system modulators for therapeutic ends.”

 https://www.ncbi.nlm.nih.gov/pubmed/27851727

Survey of herbal cannabis (marijuana) use in rheumatology clinic attenders with a rheumatologist confirmed diagnosis.

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“Cannabinoids may hold potential for the management of rheumatic pain.

Arthritis, often self-reported, is commonly cited as the reason for the use of medicinal herbal cannabis (marijuana). We have examined the prevalence of marijuana use among 1000 consecutive rheumatology patients with a rheumatologist-confirmed diagnosis and compared in an exploratory manner the clinical characteristics of medicinal users and nonusers.

Current marijuana use, medicinal or recreational, was reported by 38 patients (3.8%; 95% CI: 2.8-5.2). Ever use of marijuana for medical purposes was reported by 4.3% (95% CI: 3.2-5.7), with 28 (2.8%; 95% CI: 1.9-4.0) reporting current medicinal use. Current medicinal users had a spectrum of rheumatic conditions, with over half diagnosed with osteoarthritis. Medicinal users were younger, more likely unemployed or disabled, and reported poorer global health. Pain report and opioid use was greater for users, but they had similar physician global assessment of disease status compared with nonusers.

Medicinal users were more likely previous recreational users, with approximately 40% reporting concurrent recreational use. Therefore, less than 3% of rheumatology patients reported current use of medicinal marijuana. This low rate of use in patients with a rheumatologist-confirmed diagnosis is in stark contrast to the high rates of severe arthritis frequently reported by medicinal marijuana users, especially in Canada. Familiarity with marijuana as a recreational product may explain use for some as disease status was similar for both groups.”

https://www.ncbi.nlm.nih.gov/pubmed/27842047

Cannabinoid receptor ligand bias: implications in the central nervous system.

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“The G protein-coupled cannabinoid receptors CB1, CB2, GPR18, and GPR55 regulate neurotransmission, pain, and inflammation and have been intensively investigated as potential drug targets. Each of these GPCRs is coupled to multiple effector proteins mediating divergent cellular signals. The ligand bias of cannabinoid-targeted compounds is only beginning to be quantified. Research into cannabinoid bias is now revealing correlations between bias in cell culture and functional outcomes in vivo. We present an example study of cannabinoid bias in the context of Huntington disease. In future, an understanding of cannabinoid receptor structure and quantification of ligand bias will optimize drug selection matched to patient population and disease.”

https://www.ncbi.nlm.nih.gov/pubmed/27835801

A cannabinoid link between mitochondria and memory.

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“Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB1 receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1 receptors signal through intra-mitochondrial Gαi protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects ofcannabinoids. Thus, the G protein-coupled mtCB1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.”

https://www.ncbi.nlm.nih.gov/pubmed/27828947

Cannabinoid CB1 Receptors Are Localized in Striated Muscle Mitochondria and Regulate Mitochondrial Respiration.

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“The cannabinoid type 1 (CB1) receptor is widely distributed in the brain and peripheral organs where it regulates cellular functions and metabolism. In the brain, CB1 is mainly localized on presynaptic axon terminals but is also found on mitochondria (mtCB1), where it regulates cellular respiration and energy production. Likewise, CB1 is localized on muscle mitochondria, but very little is known about it. The aim of this study was to further investigate in detail the distribution and functional role of mtCB1 in three different striated muscles.

Immunoelectron microscopy for CB1 was used in skeletal muscles (gastrocnemius and rectus abdominis) and myocardium from wild-type and CB1 -KO mice. Functional assessments were performed in mitochondria purified from the heart of the mice and the mitochondrial oxygen consumption upon application of different acute delta-9-tetrahydrocannabinol (Δ9-THC) concentrations (100 nM or 200 nM) was monitored. About 26% of the mitochondrial profiles in gastrocnemius, 22% in the rectus abdominis and 17% in the myocardium expressed CB1. Furthermore, the proportion of mtCB1 versus total CB1 immunoparticles was about 60% in the gastrocnemius, 55% in the rectus abdominis and 78% in the myocardium. Importantly, the CB1 immunolabeling pattern disappeared in muscles of CB1 -KO mice.

Functionally, acute 100 nM or 200 nM THC treatment specifically decreased mitochondria coupled respiration between 12 and 15% in wild-type isolated mitochondria of myocardial muscles but no significant difference was noticed between THC treated and vehicle in mitochondria isolated from CB1 -KO heart. Furthermore, gene expression of key enzymes involved in pyruvate synthesis, tricarboxylic acid (TCA) cycle and mitochondrial respiratory chain was evaluated in the striated muscle of CB1 -WT and CB1 -KO. CB1 -KO showed an increase in the gene expression of Eno3, Pkm2, and Pdha1, suggesting an increased production of pyruvate. In contrast, no significant difference was observed in the Sdha and Cox4i1 expression, between CB1 -WT andCB1 -KO.

In conclusion, CB1 receptors in skeletal and myocardial muscles are predominantly localized in mitochondria. The activation of mtCB1 receptors may participate in the mitochondrial regulation of the oxidative activity probably through the relevant enzymes implicated in the pyruvate metabolism, a main substrate for TCA activity.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078489/

Tetrahydrocannabinol:Cannabidiol Oromucosal Spray for Multiple Sclerosis-Related Resistant Spasticity in Daily Practice.

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“Tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex®) is an add-on therapy for moderate-to-severe multiple sclerosis (MS)-related drug-resistant spasticity (MSS).

In everyday clinical practice, THC:CBD oromucosal spray provided symptomatic relief of MSS and related troublesome symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/27732980

Cannabinoids in the Management of Musculoskeletal or Rheumatic Diseases.

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“The endocannabinoid system impacts pain and inflammation with potential for therapeutic effect on patients with rheumatic diseases. The current treatment options include the herbal product derived from the plant Cannabis sativa, as well as pharmaceutical preparations. The legalization of medicinal cannabis (marijuana) in many jurisdictions and widespread public advocacy has propelled an interest in use either by prescription or self-medication. In this review, we examine current evidence for efficacy and adverse effects of any cannabinoid product in rheumatic conditions. The evidence to date is scant and precludes making recommendations for the use of cannabinoid preparations in rheumatology patients. In particular, the risks of herbal cannabis in patients are not well defined. Anecdote and advocacy cannot supersede sound evidence.”

https://www.ncbi.nlm.nih.gov/pubmed/27832442

The cannabinoid receptor CB1 contributes to the development of ectopic lesions in a mouse model of endometriosis.

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“Does signaling via the cannabinoid (CB1) receptor play a role in the pathogenesis of endometriosis in a mouse model?

The expression of components of the endocannabinoid system has been demonstrated in both mouse and human uteri. CB1 receptors are expressed in human epithelial and stromal cell lines derived from eutopic endometrium and deep infiltrating endometriosis nodules.

This was a randomized study in a mouse model of endometriosis.

We provide evidence that endocannabinoid signaling via CB1 receptor plays a role in the development of endometriosis in a mouse model.

However, the relative contribution of the CB1-mediated signaling pathways active in inflammatory, uterine and peritoneal cells remains to be ascertained. Since the study was performed in a mouse model, the significance of the findings in the human system warrants further investigation.

Clarifying the function and regulation of CB1 and its molecular interactions with endogenous ligands, and how endocannabinoids levels are regulated in women with endometriosis, represent critical areas of research for the potential development of a novel medical treatment of the disease.”

https://www.ncbi.nlm.nih.gov/pubmed/27821707

Clinical trials of medicinal cannabis for appetite-related symptoms from advanced cancer: a survey of preferences, attitudes and beliefs among patients willing to consider participation.

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“Australian clinical trials are planned to evaluate medicinal cannabis in a range of clinical contexts.

To explore the preferences, attitudes and beliefs of patients eligible and willing to consider participation in a clinical trial of medicinal cannabis for poor appetite and appetite-related symptoms from advanced cancer.

A cross-sectional anonymous survey was administered from July to December 2015 online and in eight adult outpatient palliative care and/or cancer services. Respondents were eligible if they were ≥18 years, had advanced cancer and poor appetite/taste problems/weight loss and might consider participating in a medicinal cannabis trial. Survey items focused on medicinal rather than recreational cannabis use and did not specify botanical or pharmaceutical products. Items asked about previous medicinal cannabis use and preferences for delivery route and invited comments and concerns.

RESULTS:

There were 204 survey respondents, of whom 26 (13%) reported prior medicinal cannabis use. Tablets/capsules were the preferred delivery mode (n = 144, 71%), followed by mouth spray (n = 84, 42%) and vaporiser (n = 83, 41%). Explanations for preferences (n = 134) most commonly cited convenience (n = 66; 49%). A total of 82% (n = 168) of respondents indicated that they had no trial-related concerns, but a small number volunteered concerns about adverse effects (n = 14) or wanted more information/advice (n = 8). Six respondents volunteered a belief that cannabis might cure cancer, while two wanted assurance of efficacy before participating in a trial.

CONCLUSION:

Justification of modes other than tablets/capsules and variable understanding about cannabis and trials will need addressing in trial-related information to optimise recruitment and ensure that consent is properly informed.”

https://www.ncbi.nlm.nih.gov/pubmed/27530738