Assessment of Efficacy and Tolerability of Medicinal Cannabinoids in Patients With Multiple Sclerosis: A Systematic Review and Meta-analysis.

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“Cannabinoids have antispastic and analgesic effects; however, their role in the treatment of multiple sclerosis (MS) symptoms is not well defined.

OBJECTIVE:

To conduct a systematic review and meta-analysis to assess the efficacy and tolerability of medicinal cannabinoids compared with placebo in the symptomatic treatment of patients with MS.

STUDY SELECTION:

Randomized, double-blind, and placebo-controlled trials evaluating the effect of medicinal cannabinoids by oral or oromucosal route of administration on the symptoms of spasticity, pain, or bladder dysfunction in adult patients with MS.

RESULTS:

Seventeen selected trials including 3161 patients were analyzed. Significant findings for the efficacy of cannabinoids vs placebo were SMD = -0.25 SD (95% CI, -0.38 to -0.13 SD) for spasticity (subjective patient assessment data), -0.17 SD (95% CI, -0.31 to -0.03 SD) for pain, and -0.11 SD (95% CI, -0.22 to -0.0008 SD) for bladder dysfunction. Results favored cannabinoids. Findings for tolerability were RR = 1.72 patient-years (95% CI, 1.46-2.02 patient-years) in the total adverse events analysis and 2.95 patient-years (95% CI, 2.14-4.07 patient-years) in withdrawals due to adverse events. Results described a higher risk for cannabinoids. The serious adverse events meta-analysis showed no statistical significance.

CONCLUSIONS AND RELEVANCE:

The results suggest a limited efficacy of cannabinoids for the treatment of spasticity, pain, and bladder dysfunction in patients with MS. Therapy using these drugs can be considered as safe.”

https://www.ncbi.nlm.nih.gov/pubmed/30646241

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2706499

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Cannabinoid CB1 receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior.

 Image result for nature medicine“Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world’s population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular mechanisms through which BLA neurons modulate depressive behavior are largely uncharacterized. Here, in mice, we identified that BLA cholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement via D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and that chronic social defeat selectively potentiated excitatory transmission of the CCKBLA-D2NAc circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor (CB1R). Knockdown of CB1R in the CCKBLA-D2NAc circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCKBLA-D2NAc circuit or administration of synthetic cannabinoids in the NAc was sufficient to produce antidepressant-like effects. Overall, our studies reveal the circuit and molecular mechanisms of depression.”

https://www.ncbi.nlm.nih.gov/pubmed/30643290

https://www.nature.com/articles/s41591-018-0299-9

“Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.”  https://www.ncbi.nlm.nih.gov/pubmed/20332000

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Crystal Structure of the Human Cannabinoid Receptor CB2.

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“The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases.

Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257’s unexpected opposing functional profile of CB2 antagonism versus CB1 agonism.

Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.”

https://www.ncbi.nlm.nih.gov/pubmed/30639103

https://linkinghub.elsevier.com/retrieve/pii/S0092867418316258

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Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex.

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“Cannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting heterotrimeric G protein Gi. Activation of CB1-Gi signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of Giactivation by CB1.

Here, we present the structure of the CB1-Gi signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities.”

https://www.ncbi.nlm.nih.gov/pubmed/30639101

https://linkinghub.elsevier.com/retrieve/pii/S0092867418315654

“Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.”   https://www.ncbi.nlm.nih.gov/pubmed/20332000

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Cannabis and Mood Disorders.

 “The present review will provide an overview of the neurobiology, epidemiology, clinical impact, and treatment of cannabis use disorder (CUD) in mood disorders.

Patients with mood disorders including major depressive disorder (MDD) and bipolar disorder (BD) have higher rates of cannabis use, and CUD compared to the general population. Reasons for this association are not clear, nor are the putative therapeutic effects of cannabis use, or its components delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), in these illnesses.

Cannabis use may be associated mood disorders, but more research is needed to increase our understanding of the mechanisms for this association, and to develop more effective treatments for this comorbidity.”

https://www.ncbi.nlm.nih.gov/pubmed/30643708

https://link.springer.com/article/10.1007%2Fs40429-018-0214-y

“Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.”   https://www.ncbi.nlm.nih.gov/pubmed/20332000

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∆9-Tetrahydrocannabinol, a major marijuana component, enhances the anesthetic effect of pentobarbital through the CB1 receptor.

 “∆9 Tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), major psychoactive constituents of marijuana, induce potentiation of pentobarbital-induced sleep in mice.

We have elucidated the mechanism of enhancement of the anesthetic effect of pentobarbital by cannabinoids.

These results suggest that binding of ∆9-THC to the CB1 receptor is involved in the synergism with pentobarbital, and that potentiating effect of CBD with pentobarbital may differ from that of ∆9-THC. We successfully demonstrated that ∆9-THC enhanced the anesthetic effect of pentobarbital through the CB1 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/30636988

“The pharmacological results indicate the effect of ∆9-THC co-administered with pentobarbital was a synergistic, but not additive, action in mice. Further evidence suggests the CB1 receptor plays an important role as a trigger in potentiating pentobarbital-induced sleep by ∆9-THC.”

https://link.springer.com/article/10.1007%2Fs11419-018-0457-2

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Assessing the impact of cannabis use on trends in diagnosed schizophrenia in the United Kingdom from 1996 to 2005.

Schizophrenia Research

“The study cohort comprised almost 600,000 patients each year, representing approximately 2.3% of the UK population aged 16 to 44. Between 1996 and 2005 the incidence and prevalence of schizophrenia and psychoses were either stable or declining. Explanations other than a genuine stability or decline were considered, but appeared less plausible. In conclusion, this study did not find any evidence of increasing schizophrenia or psychoses in the general population from 1996 to 2005.”

https://www.ncbi.nlm.nih.gov/pubmed/19560900

https://www.sciencedirect.com/science/article/pii/S0920996409002692?via%3Dihub

“The incidence and prevalence of patients showing schizophrenic syndromes are unchanged or have even fallen while the use of cannabis has increased enormously. We must conclude that either previous schizophrenic illnesses have become much less common or that cannabis schizophrenia is rare and perhaps it may not even exist.” https://www.bmj.com/content/325/7374/1183/rapid-responses

“Cannabis use appears to be neither a sufficient nor a necessary cause for psychosis.”  https://www.ncbi.nlm.nih.gov/pubmed/14754822

“The current data do not support low to moderate lifetime cannabis use to be a major contributor to psychosis or poor social and role functioning in high-risk youth.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459073/

“Multiple reports indicate no rise in psychosis accompanies increases in pot use rates” http://potfacts.ca/multiple-reports-indicate-no-rise-in-psychosis-accompanies-increases-in-pot-use-rates/

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Cannabis and Turmeric as Complementary Treatments for IBD and Other Digestive Diseases.

 “Complementary therapies for inflammatory bowel disease (IBD) have earned growing interest from patients and investigators alike, with a dynamic landscape of research in this area. In this article, we review results of the most recent studies evaluating the role of cannabis and turmeric for the treatment of IBD and other intestinal illnesses.

RECENT FINDINGS:

Cannabinoids are well-established modulators of gut motility and visceral pain and have demonstrated anti-inflammatory properties. Clinical trials suggest that there may be a therapeutic role for cannabinoid therapy in the treatment of IBD, irritable bowel syndrome (IBS), nausea and vomiting, and GI motility disorders. Recent reports of serious adverse effects from synthetic cannabinoids highlight the need for additional investigation of cannabinoids to establish their efficacy and safety. Turmeric trials have demonstrated some promise as adjuvant treatment for IBD, though not in other GI disease processes. Evidence suggests that the use of cannabis and turmeric is potentially beneficial in IBD and IBS; however, neither has been compared to standard therapy in IBD, and thus should not be recommended as alternative treatment for IBD. For cannabis in particular, additional investigation regarding appropriate dosing and timing, given known adverse effects of its chronic use, and careful monitoring of potential bleeding complications with synthetic cannabinoids are imperative.”

https://www.ncbi.nlm.nih.gov/pubmed/30635796

https://link.springer.com/article/10.1007%2Fs11894-019-0670-0

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Preclinical safety and efficacy of cannabidivarin for early life seizures.

Neuropharmacology

“A significant proportion of neonatal and childhood seizures are poorly controlled by existing anti-seizure drugs (ASDs), likely due to prominent differences in ionic homeostasis and network connectivity between the immature and mature brain. In addition to the poor efficacy of current ASDs, many induce apoptosis, impair synaptic development, and produce behavioral deficits when given during early postnatal development.

There is growing interest in new targets, such as cannabidiol (CBD) and its propyl analog cannabidivarin (CBDV) for early life indications. While CBD was recently approved for treatment of refractory childhood epilepsies, little is known about the efficacy or safety of CBDV.

Here, we addressed this gap through a systematic evaluation of CBDV against multiple seizure models in postnatal day (P) 10 and 20 animals. We also evaluated the impact of CBDV on acute neurotoxicity in immature rats.

CBDV (50-200 mg/kg) displayed an age and model-specific profile of anticonvulsant action.

Finally, CBDV treatment generally avoided induction of neuronal degeneration in immature rats.

Together, the efficacy and safety profile of CBDV suggest it may have therapeutic value for early life seizures.”

https://www.ncbi.nlm.nih.gov/pubmed/30633929

https://www.sciencedirect.com/science/article/pii/S0028390818306786?via%3Dihub

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Cannabis sativa L. and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer.

 Related image“In the last decades, a lot of attention has been paid to the compounds present in medicinal Cannabis sativa L., such as Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), and their effects on inflammation and cancer-related pain.

The National Cancer Institute (NCI) currently recognizes medicinal C. sativa as an effective treatment for providing relief in a number of symptoms associated with cancer, including pain, loss of appetite, nausea and vomiting, and anxiety.

Several studies have described CBD as a multitarget molecule, acting as an adaptogen, and as a modulator, in different ways, depending on the type and location of disequilibrium both in the brain and in the body, mainly interacting with specific receptor proteins CB1 and CB2.

CBD is present in both medicinal and fibre-type C. sativa plants, but, unlike Δ9-THC, it is completely nonpsychoactive. Fibre-type C. sativa (hemp) differs from medicinal C. sativa, since it contains only few levels of Δ9-THC and high levels of CBD and related nonpsychoactive compounds.

In recent years, a number of preclinical researches have been focused on the role of CBD as an anticancer molecule, suggesting CBD (and CBD-like molecules present in the hemp extract) as a possible candidate for future clinical trials.

CBD has been found to possess antioxidant activity in many studies, thus suggesting a possible role in the prevention of both neurodegenerative and cardiovascular diseases. In animal models, CBD has been shown to inhibit the progression of several cancer types. Moreover, it has been found that coadministration of CBD and Δ9-THC, followed by radiation therapy, causes an increase of autophagy and apoptosis in cancer cells. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models.

These activities seem to involve also alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity.

In the light of all these findings, in this review we explore the effects and the molecular mechanisms of CBD on inflammation and cancer processes, highlighting also the role of minor cannabinoids and noncannabinoids constituents of Δ9-THC deprived hemp.”

https://www.ncbi.nlm.nih.gov/pubmed/30627539

https://www.hindawi.com/journals/bmri/2018/1691428/

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