Category Archives: Multiple Sclerosis (MS)

(-)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis.

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“(-)-β-caryophyllene (BCP), a cannabinoid receptor type 2 (CB2)-selective phytocannabinoid, has already been shown in precedent literature to exhibit both anti-inflammatory and analgesic effects in mouse models of inflammatory and neuropathic pain.

Herein, we endeavored to investigate the therapeutic potential of BCP on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). Furthermore, we sought to demonstrate some of the mechanisms that underlie the modulation BCP exerts on autoimmune activated T cells, the pro-inflammatory scenery of the central nervous system (CNS), and demyelination.

Our findings demonstrate that BCP significantly ameliorates both the clinical and pathological parameters of EAE. In addition, data hereby presented indicates that mechanisms underlying BCP immunomodulatory effect seems to be linked to its ability to inhibit microglial cells, CD4+ and CD8+ T lymphocytes, as well as protein expression of pro-inflammatory cytokines. Furthermore, it diminished axonal demyelination and modulated Th1/Treg immune balance through the activation of CB2 receptor.

Altogether, our study represents significant implications for clinical research and strongly supports the effectiveness of BCP as a novel molecule to target in the development of effective therapeutic agents for MS.” https://www.ncbi.nlm.nih.gov/pubmed/28368293

“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

Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex®): A Review in Multiple Sclerosis-Related Spasticity.

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“Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (THC/CBD, Sativex®, nabiximols) is available in numerous countries worldwide for the treatment of multiple sclerosis (MS)-related moderate to severe spasticity in patients who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.

Twelve weeks’ therapy with THC/CBD improved MS-related spasticity in patients with an inadequate response to other anti-spasticity agents who had undergone a successful initial trial of THC/CBD therapy, according to the results of a pivotal phase 3 trial.

Improvements in spasticity were maintained in the longer term with THC/CBD with no evidence of dose tolerance, and results of real-world studies confirm the effectiveness of THC/CBD in everyday clinical practice.

Improvements in health-related quality of life and activities of daily living were also seen with THC/CBD.

THC/CBD is generally well tolerated; adverse effects such as dizziness may occur whilst the THC/CBD dosage is being optimized.

THC/CBD has low abuse potential and a low risk of psychoactive effects.

In conclusion, THC/CBD oromucosal spray is a useful option for the treatment of MS-related spasticity not completely relieved with current anti-spasticity medication.”

https://www.ncbi.nlm.nih.gov/pubmed/28293911

Cannabinoids therapeutic use: what is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others?

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“The complexity of the endocannabinoid (eCB) system is becoming better understood and new drivers of eCB signaling are emerging. Modulation of the activities of the eCB system can be therapeutic in a number of diseases.

Research into the eCB system has been paralleled by the development of agents that interact with cannabinoid receptors. In this regard it should be remembered that herbal cannabis contains a myriad of active ingredients, and the individual cannabinoids have quite distinct biological activities requiring independent studies.

This article reviews the most important current data involving the eCB system in relation to human diseases, to reflect the present (based mainly on the most used prescription cannabinoid medicine, THC/CBD oromucosal spray) and potential future uses of cannabinoid-based therapy.

Expert commentary: From the different therapeutic possibilities, THC/CBD oromucosal spray has been in clinical use for approximately five years in numerous countries world-wide for the management of multiple sclerosis (MS)-related moderate to severe resistant spasticity.

Clinical trials have confirmed its efficacy and tolerability.

Other diseases in which different cannabinoids are currently being investigated include various pain states, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and epilepsy. The continued characterization of individual cannabinoids in different diseases remains important.”

https://www.ncbi.nlm.nih.gov/pubmed/28276775

Implication of cannabinoids in neurological diseases.

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“1. Preparations from Cannabis sativa (marijuana) have been used for many centuries both medicinally and recreationally. 2. Recent advances in the knowledge of its pharmacological and chemical properties in the organism, mainly due to Delta(9)-tetrahydrocannabinol, and the physiological roles played by the endocannabinoids have opened up new strategies in the treatment of neurological and psychiatric diseases. 3. Potential therapeutic uses of cannabinoid receptor agonists include the management of spasticity and tremor in multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, cancer, and vasodilation that accompanies advanced cirrhosis. CB(1) receptor antagonists have therapeutic potential in Parkinson’s disease. 4. Dr. Julius Axelrod also contributed in studies on the neuroprotective actions of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/16699878

“Medical marijuana: emerging applications for the management of neurologic disorders.” https://www.ncbi.nlm.nih.gov/pubmed/15458761

Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis

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“The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS).

Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo.

Implications This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.”

https://www.ncbi.nlm.nih.gov/pubmed/28189366

Modulation of Human Peripheral Blood Mononuclear Cell Signaling by Medicinal Cannabinoids.

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“Medical marijuana is increasingly prescribed as an analgesic for a growing number of indications, amongst which terminal cancer and multiple sclerosis.

In this study we aimed to investigate the immune-cell modulatory properties of medical cannabis.

Healthy volunteers were asked to ingest medical cannabis, and kinome profiling was used to generate comprehensive descriptions of the cannabis challenge on inflammatory signal transduction in the peripheral blood of these volunteers.

Results were related to both short term and long term effects in patients experimentally treated with a medical marijuana preparation for suffering from abdominal pain as a result of chronic pancreatitis or other causes.

The results reveal an immunosuppressive effect of cannabinoid preparations via deactivation of signaling through the pro-inflammatory p38 MAP kinase and mTOR pathways and a concomitant deactivation of the pro-mitogenic ERK pathway. However, long term cannabis exposure in two patients resulted in reversal of this effect.

While these data provide a powerful mechanistic rationale for the clinical use of medical marijuana in inflammatory and oncological disease, caution may be advised with sustained use of such preparations.”

https://www.ncbi.nlm.nih.gov/pubmed/28174520

http://journal.frontiersin.org/article/10.3389/fnmol.2017.00014/full

Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation.

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“Microglial cells are important mediators of the immune response in the CNS. The phytocannabinoid, cannabidiol (CBD), has been shown to have central anti-inflammatory properties, and the purpose of the present study was to investigate the effects of CBD and other phytocannabinoids on microglial phagocytosis.

CONCLUSIONS AND IMPLICATIONS:

The TRPV-dependent phagocytosis-enhancing effect of CBD suggests that pharmacological modification of TRPV channel activity could be a rational approach to treating neuroinflammatory disorders involving changes in microglial function and that CBD is a potential starting point for future development of novel therapeutics acting on the TRPV receptor family.”

https://www.ncbi.nlm.nih.gov/pubmed/24641282

Cannabinoids for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: a systematic review and meta-analysis.

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“To systematically review all available evidence on efficacy and safety of cannabinoids for treating neurogenic lower urinary tract dysfunction (NLUTD) in patients with multiple sclerosis (MS).

:Preliminary data imply, that cannabinoids might be an effective and safe treatment option for NULTD in patients with MS.”

https://www.ncbi.nlm.nih.gov/pubmed/28058780

Potent immunomodulatory activity of a highly selective cannabinoid CB2 agonist on immune cells from healthy subjects and patients with multiple sclerosis.

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“COR167, a novel CB2-selective high affinity agonist, was found to significantly inhibit, in a dose-dependent manner, the proliferation of both peripheral blood mononuclear cells and myelin basic protein-reactive T cell lines from normal healthy subjects and patients with relapsing-remitting multiple sclerosis (MS). In MS, a significantly higher inhibition was observed in patients on treatment with disease modifying drugs compared to those naive to treatment. The inhibitory activity of COR167 was exerted through a mixed mechanism involving atypical and incomplete shift of Th1 phenotype towards Th2 phenotype associated with slight reduction of IL-4 and IL-5 as well as strongly reduced levels of Th17-related cytokines. COR167 was also able to reduce in vitro migration of stimulated immunocompetent cells through human brain endothelium associated with a significant reduction of levels of several chemokines. These findings demonstrate that COR167 exerts potent immunomodulatory effects and confirm the cannabinoid CB2 receptor as a novel pharmacological target to counteract neuroinflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/28041663

An observational postmarketing safety registry of patients in the UK, Germany, and Switzerland who have been prescribed Sativex® (THC:CBD, nabiximols) oromucosal spray.

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“The global exposure of Sativex® (Δ9-tetrahydrocannabinol [THC]:cannabidiol [CBD], nabiximols) is estimated to be above 45,000 patient-years since it was given marketing approval for treating treatment-resistant spasticity in multiple sclerosis (MS).

An observational registry to collect safety data from patients receiving THC:CBD was set up following its approval in the UK, Germany, and Switzerland, with the aim of determining its long-term safety in clinical practice.

Twice a year, the Registry was opened to prescribing physicians to voluntarily report data on patients’ use of THC:CBD, clinically significant adverse events (AEs), and special interest events. The Registry contains data from 941 patients with 2,213.98 patient-years of exposure.

Within this cohort, 60% were reported as continuing treatment, while 83% were reported as benefiting from the treatment. Thirty-two percent of patients stopped treatment, with approximately one third citing lack of effectiveness and one quarter citing AEs.

Psychiatric AEs of clinical significance were reported in 6% of the patients, 6% reported falls requiring medical attention, and suicidality was reported in 2%. Driving ability was reported to have worsened in 2% of patients, but improved in 7%.

AEs were more common during the first month of treatment. The most common treatment-related AEs included dizziness (2.3%) and fatigue (1.7%).

There were no signals to indicate abuse, diversion, or dependence.

The long-term risk profile from the Registry is consistent with the known (labeled) safety profile of THC:CBD, and therefore supports it being a well-tolerated and beneficial medication for the treatment of MS spasticity.

No evidence of new long-term safety concerns has emerged.”

https://www.ncbi.nlm.nih.gov/pubmed/27956834