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Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice.

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British Journal of Pharmacology

“Cannabis extracts and several cannabinoids have been shown to exert broad anti-inflammatory activities in experimental models of inflammatory CNS degenerative diseases.

Clinical use of many cannabinoids is limited by their psychotropic effects. However, phytocannabinoids like cannabidiol (CBD), devoid of psychoactive activity, are, potentially, safe and effective alternatives for alleviating neuroinflammation and neurodegeneration.

Treatment with CBD during disease onset ameliorated the severity of the clinical signs of EAE.

CBD, a non-psychoactive cannabinoid, ameliorates clinical signs of EAE in mice, immunized against MOG. Suppression of microglial activity and T-cell proliferation by CBD appeared to contribute to these beneficial effects.”

https://www.ncbi.nlm.nih.gov/pubmed/21449980

“In summary, we have shown that CBD administered to MOG-immunized C57BL/6 mice, at the onset of EAE disease, reduced the severity of the clinical signs of EAE. CBD treatment was accompanied by diminished axonal loss and inflammation (infiltration of T cells and microglial activation). Moreover, CBD prevented proliferation of myelin-specific T cells in vitro. These observations suggest that CBD may have potential for alleviating MS-like pathology.” http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01379.x/full

“Study Shows Cannabidiol (CBD) Improves MS-Like Symptoms”  http://www.prohealth.com/library/showarticle.cfm?libid=31211

Single-Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology.

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Clinical Pharmacology in Drug Development

“Cannabidiol (CBD) is the main nonpsychoactive component of the cannabis plant. It has been associated with antiseizure, antioxidant, neuroprotective, anxiolytic, anti-inflammatory, antidepressant, and antipsychotic effects.

PTL101 is an oral gelatin matrix pellets technology-based formulation containing highly purified CBD embedded in seamless gelatin matrix beadlets. Study objectives were to evaluate the safety and tolerability of PTL101 containing 10 and 100 mg CBD, following single administrations to healthy volunteers and to compare the pharmacokinetic profiles and relative bioavailability of CBD with Sativex oromucosal spray (the reference product) in a randomized, crossover study design.

Administration of PTL101 containing 10 CBD, led to a 1.7-fold higher Cmax and 1.3-fold higher AUC compared with the oromucosal spray. Tmax following both modes of delivery was 3-3.5 hours postdosing. CBD exhibited about a 1-hour lag in absorption when delivered via PTL101. A 10-fold increase in the dose resulted in an ∼15-fold increase in Cmax and AUC. Bioavailability of CBD in the 10-mg PTL101 dose was 134% relative to the reference spray.

PTL101 is a pharmaceutical-grade, user-friendly oral formulation that demonstrated safe and efficient delivery of CBD and therefore could be an attractive candidate for therapeutic indications.”

https://www.ncbi.nlm.nih.gov/pubmed/29125702

http://onlinelibrary.wiley.com/doi/10.1002/cpdd.408/abstract

Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol.

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Neurobiology of Aging

“This study was designed to test our hypothesis that an ultra-low dose of delta-9 tetrahydrocannabinol (THC) reverses age-dependent cognitive impairments in old mice and to examine the possible biological mechanisms that underlie this behavioral effect. These findings suggest that extremely low doses of THC that are devoid of any psychotropic effect and do not induce desensitization may provide a safe and effective treatment for cognitive decline in aging humans.”  https://www.ncbi.nlm.nih.gov/pubmed/29107185

“Cognitive decline is an integral aspect of aging. The idea that age-related cognitive decline can be reversed and that the old brain can be revitalized is not new. It has been previously suggested that the endocannabinoid system is part of an antiaging homeostatic defense system.  In previous studies, we have shown that ultra-low doses of tetrahydrocannabinol (THC, the main psychotropic ingredient in cannabis) protected young mice from cognitive impairments that were evoked by various insults. In the present study, we tested our hypothesis that a single ultra-low dose of THC can reverse age-dependent cognitive decline in mice. Here, we show that a single extremely low dose of THC devoid of any psychotropic activity can trigger an endogenous compensatory mechanism that improves cognitive functioning in old mice and that this effect lasts for at least several weeks. Since THC in high doses (dronabinol, 1–10 mg) is already approved for medical treatments in humans, and since its safety profile is well characterized, we believe that the initiation of clinical trials with ultra-low doses of THC designed to reverse cognitive decline in elderly patients should be straightforward.”  http://www.sciencedirect.com/science/article/pii/S0197458017303214

“Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol. These findings suggest that extremely low doses of THC that are devoid of any psychotropic effect and do not induce desensitization may provide a safe and effective treatment for cognitive decline in aging humans.”   http://www.neurobiologyofaging.org/article/S0197-4580(17)30321-4/fulltext

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Dronabinol Is a Safe Long-Term Treatment Option for Neuropathic Pain Patients.

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“Treatment of neuropathic pain (NP) symptoms associated with multiple sclerosis (MS) is frequently insufficient. Yet, cannabis is still rarely offered for treatment of pain. This clinical trial aimed at showing the positive benefit-risk ratio of dronabinol. Two hundred forty MS patients with central NP entered a 16-weeks placebo-controlled phase-III study followed by a 32-weeks open-label period. One hundred patients continued therapy for overall up to 119 weeks. Primary endpoint was change of pain intensity on the 11-point Numerical Rating Scale over a 16-weeks treatment period. Safety was assessed on the basis of adverse reactions (ARs), signs of dependency and abuse. Pain intensity during 16-weeks dronabinol and placebo treatment was reduced by 1.92 and 1.81 points without significant difference in between (p = 0.676). Although the proportion of patients with ARs was higher under dronabinol compared to placebo (50.0 vs. 25.9%), it decreased during long-term use of dronabinol (26%). No signs of drug abuse and only one possible case of dependency occurred. The trial results demonstrate that dronabinol is a safe long-term treatment option.” https://www.ncbi.nlm.nih.gov/pubmed/29073592

“Overall, this trial demonstrated the long-lasting therapeutic potential, the good tolerability and favourable safety profile of dronabinol – especially in terms of drug abuse and dependency. Based on the presented results, there is no special focus on the harm caused by dronabinol treatment. Although the statistical proof of efficacy for dronabinol versus placebo treatment is pending, physicians should consider the potential benefits of the multifactorial effects of dronabinol.” https://www.karger.com/Article/FullText/481089

Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.

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“Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a non-euphoria producing constituent of cannabis that has the potential to relieve pain.

The aim of this study was to determine if CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy.

The therapeutic and prophylactic effects of peripheral CBD (100-300μg) were assessed. In end stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (p<0.0001; n=8). Acute, transient joint inflammation was reduced by local CBD treatment (p<0.0001; n=6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (p<0.0001; n=8), and was also found to be neuroprotective (p<0.05; n=6-8).

The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints.

These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28885454             https://insights.ovid.com/crossref?an=00006396-900000000-99152

Cannabis and intractable chronic pain: an explorative retrospective analysis of Italian cohort of 614 patients.

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“Despite growing interest in the therapeutic use of cannabis to manage chronic pain, only limited data that address these issues are available. In recent years, a number of nations have introduced specific laws to allow patients to use cannabis preparations to treat a variety of medical conditions. In 2015, the Italian government authorized the use of cannabis to treat several diseases, including chronic pain generally, spasticity in multiple sclerosis, cachexia and anorexia among AIDS and cancer patients, glaucoma, Tourette syndrome, and certain types of epilepsy. We present the first snapshot of the Italian experience with cannabis use for chronic pain over the initial year of its use.

METHODS:

This is a retrospective case series analysis of all chronic pain patients treated with oral or vaporized cannabis in six hubs during the initial year following the approval of the new Italian law (December 2015 to November 2016). We evaluated routes of administration, types of cannabis products utilized, dosing, and effectiveness and safety of the treatment.

RESULTS:

As only one of the six centers has extensively used cannabinoids for intractable chronic pain (614 patients of 659), only the population from Azienda Ospedaliero Universitaria Pisana (Pisa) was considered. Cannabis tea was the primary mode of delivery, and in almost all cases, it was used in association with all the other pain treatments. Initial and follow-up cannabinoid concentrations were found to vary considerably. At initial follow-up, 76.2% of patients continued the treatment, and <15% stopped the treatment due to side effects (none of which were severe).

CONCLUSION:

We present the first analysis of Italian clinical practice of the use of cannabinoids for a large variety of chronic pain syndromes. From this initial snapshot, we determined that the treatment seems to be effective and safe, although more data and subsequent trials are needed to better investigate its ideal clinical indication.”

https://www.ncbi.nlm.nih.gov/pubmed/28579820

https://www.dovepress.com/cannabis-and-intractable-chronic-pain-an-explorative-retrospective-ana-peer-reviewed-article-JPR

[Therapeutic potential of Cannabis sativa].

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SciELO - Scientific Electronic Library Online

“Cannabis sativa (marihuana) is considered an illicit drug due to its psychoactive properties. Recently, the Chilean government opened to the use cannabis in the symptomatic treatment of some patients. The biological effects of cannabis render it useful for the complementary treatment of specific clinical situations such as chronic pain. We retrieved scientific information about the analgesic properties of cannabis, using it as a safe drug. The drug may block or inhibit the transmission of nervous impulses at different levels, an effect associated with pain control. Within this context and using adequate doses, forms and administration pathways, it can be used for chronic pain management, considering its effectiveness and low cost. It could also be considered as an alternative in patients receiving prolonged analgesic therapies with multiple adverse effects.”

 https://www.ncbi.nlm.nih.gov/pubmed/28548193
http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0034-98872017000300010&lng=en&nrm=iso&tlng=en

Cannabis in Inflammatory Bowel Diseases: from Anecdotal Use to Medicalization?

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“Inflammatory bowel diseases (IBD) are disorders of chronic intestinal inflammation of unknown etiology. The basic pathophysiological process is that of immune mediated inflammation affecting the intestinal tract. This process is dependent on and governed by both genetic and environmental factors. There are two distinct forms of IBD – ulcerative colitis and Crohn’s disease.

There is no curative medical treatment. Furthermore, over 30% of patients, and over 70% with Crohn’s disease, will need surgical intervention for their disease. Thus, it comes as no surprise that many patients will turn to complementary or alternative medicine at some stage of their disease. Recent information reveals that between 16% and 50% of patients admit to having tried marijuana for their symptoms.

There is a long list of gastrointestinal symptoms that have been reported to be relieved by cannabis. These include anorexia, nausea, abdominal pain, diarrhea, gastroparesis – all of which can be part of IBD. These effects are related to the fact that the gastrointestinal tract is rich in cannabinoid (CB) receptors and their endogenous ligands, comprising together the endocannabinoid system (ECS).

In conclusion, use of cannabis is common in IBD, and it seems to be mostly safe. Accumulating preliminary data from human studies support a beneficial role of cannabinoids in IBD.”

https://www.ima.org.il/FilesUpload/IMAJ/0/228/114217.pdf

https://www.ima.org.il/imaj/ViewArticle.aspx?aId=4045

https://www.ncbi.nlm.nih.gov/pubmed/28457058

Low-Dose Cannabidiol Is Safe but Not Effective in the Treatment for Crohn’s Disease, a Randomized Controlled Trial.

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“Cannabidiol (CBD) is an anti-inflammatory cannabinoid shown to be beneficial in a mouse model of IBD. Lacking any central effect, cannabidiol is an attractive option for treating inflammatory diseases. In this study of moderately active Crohn’s disease, CBD was safe but had no beneficial effects. This could be due to lack of effect of CBD on Crohn’s disease, but could also be due to the small dose of CBD, the small number of patients in the study, or the lack of the necessary synergism with other cannabinoids.”  https://www.ncbi.nlm.nih.gov/pubmed/28349233

“Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. We performed a prospective trial to determine whether cannabis can induce remission in patients with Crohn’s disease. Complete remission was achieved by 5 of 11 subjects in the cannabis group and 1 of 10 in the placebo group. A short course (8 weeks) of THC-rich cannabis produced significant clinical, steroid-free benefits to 10 of 11 patients with active Crohn’s disease, compared with placebo, without side effects.”  https://www.ncbi.nlm.nih.gov/pubmed/23648372

Cannabinoids – a new weapon against cancer?

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“Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent.

The isolation and characterization of the structure of one of the main active ingredients of cannabis – Δ9 – tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine.

Many scientific studies indicate the potential use of cannabinoids in the fight against cancer.

Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo-angiogenesis and the ability of cells to metastasize.

The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors.

Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future.”

 https://www.ncbi.nlm.nih.gov/pubmed/28100841