Tag Archives: therapeutic

Is cannabis treatment for anxiety, mood, and related disorders ready for prime time?

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Depression and Anxiety

“Anxiety and related disorders are the most common mental conditions affecting the North American population. Despite their established efficacy, first-line antidepressant treatments are associated with significant side effects, leading many afflicted individuals to seek alternative treatments. Cannabis is commonly viewed as a natural alternative for a variety of medical and mental health conditions. Currently, anxiety ranks among the top five medical symptoms for which North Americans report using medical marijuana. However, upon careful review of the extant treatment literature, the anxiolytic effects of cannabis in clinical populations are surprisingly not well-documented. The effects of cannabis on anxiety and mood symptoms have been examined in healthy populations and in several small studies of synthetic cannabinoid agents but there are currently no studies which have examined the effects of the cannabis plant on anxiety and related disorders. In light of the rapidly shifting landscape regarding the legalization of cannabis for medical and recreational purposes, it is important to highlight the significant disconnect between the scientific literature, public opinion, and related policies. The aim of this article is to provide a comprehensive review of the current cannabis treatment literature, and to identify the potential for cannabis to be used as a therapeutic intervention for anxiety, mood, and related disorders. Searches of five electronic databases were conducted (PubMed, MEDLINE, Web of Science, PsychINFO, and Google Scholar), with the most recent in February 2017. The effects of cannabis on healthy populations and clinical psychiatric samples will be discussed, focusing primarily on anxiety and mood disorders.”  https://www.ncbi.nlm.nih.gov/pubmed/28636769   http://onlinelibrary.wiley.com/doi/10.1002/da.22664/abstract

“The endocannabinoid system and the treatment of mood and anxiety disorders. Collectively, both clinical and preclinical data argue that cannabinoid receptor signalling may be a realistic target in the development of a novel class of agent for the pharmacotherapy of mood and anxiety disorders.”  https://www.ncbi.nlm.nih.gov/pubmed/19839936

The cannabinoid system and pain.

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“Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28625720

http://www.sciencedirect.com/science/article/pii/S002839081730285X

Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years.

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“Cannabis extracts have been used for centuries, but its main active principle ∆9-tetrahydrocannabinol (THC) was identified about 50 years ago. Yet, it is only 25 years ago that the first endogenous ligand of the same receptors engaged by the cannabis agents was discovered. This “endocannabinoid (eCB)” was identified as N-arachidonoylethanolamine (or anandamide (AEA)), and was shown to have several receptors, metabolic enzymes and transporters that altogether drive its biological activity. Here I report on the latest advances about AEA metabolism, with the aim of focusing open questions still awaiting an answer for a deeper understanding of AEA activity, and for translating AEA-based drugs into novel therapeutics for human diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28611591

http://journal.frontiersin.org/article/10.3389/fnmol.2017.00166/full

Endocannabinoid System in Neurodegenerative Disorders.

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Journal of Neurochemistry

“Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid (EC) system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs.”

https://www.ncbi.nlm.nih.gov/pubmed/28608560

http://onlinelibrary.wiley.com/doi/10.1111/jnc.14098/abstract

Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders.

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“Beneficial effects of cannabidiol (CBD) have been described for a wide range of psychiatric disorders, including anxiety, psychosis, and depression. The mechanisms responsible for these effects, however, are still poorly understood. Similar to clinical antidepressant or atypical antipsychotic drugs, recent findings clearly indicate that CBD, either acutely or repeatedly administered, induces plastic changes. For example, CBD attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation and the decrease in the number of parvalbumin-positive GABA neurons in a pharmacological model of schizophrenia. More recently, it was found that CBD modulates cell fate regulatory pathways such as autophagy and others critical pathways for neuronal survival in neurodegenerative experimental models, suggesting the potential benefit of CBD treatment for psychiatric/cognitive symptoms associated with neurodegeneration. These changes and their possible association with CBD beneficial effects in psychiatric disorders are reviewed here.”

https://www.ncbi.nlm.nih.gov/pubmed/28588483

http://journal.frontiersin.org/article/10.3389/fphar.2017.00269/full

Medicinal Uses of Marijuana and Cannabinoids

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“In the past two decades, there has been increasing interest in the therapeutic potential of cannabis and single cannabinoids, mainly cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC). THC and cannabis products rich in THC exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). Since 1975, 140 controlled clinical trials using different cannabinoids or whole-plant preparations for the treatment of a large number of disorders and symptoms have been conducted. Results have led to the approval of cannabis-based medicines [dronabinol, nabilone, and the cannabis extract nabiximols (Sativex®, THC:CBD = 1:1)] as well as cannabis flowers in several countries. Controlled clinical studies provide substantial evidence for the use of cannabinoid receptor agonists in cancer chemotherapy induced nausea and vomiting, appetite loss and cachexia in cancer and HIV patients, neuropathic and chronic pain, and in spasticity in multiple sclerosis. In addition, there is also some evidence suggesting a therapeutic potential of cannabis-based medicines in other indications including Tourette syndrome, spinal cord injury, Crohn’s disease, irritable bowel syndrome, and glaucoma. In several other indications, small uncontrolled and single-case studies reporting beneficial effects are available, for example in posttraumatic stress disorder, attention deficit hyperactivity disorder, and migraine. The most common side effects of THC and cannabis-based medicines rich in THC are sedation and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. In recent years there is an increasing interest in the medical use of CBD, which exerts no intoxicating side effects and is usually well-tolerated. Preliminary data suggest promising effects in the treatment of anxiety disorders, schizophrenia, dystonia, and some forms of epilepsy. This review gives an overview on clinical studies which have been published over the past 40 years.”

http://www.tandfonline.com/doi/abs/10.1080/07352689.2016.1265360?needAccess=true&journalCode=bpts20

“Review Identifies 140 Controlled Clinical Trials Related to Cannabis”  http://blog.norml.org/2017/06/04/review-identifies-140-controlled-clinical-trials-related-to-cannabis/

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

GPR3 and GPR6, novel molecular targets for cannabidiol.

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“GPR3 and GPR6 are members of a family of constitutively active, Gs protein-coupled receptors. Previously, it has been reported that GPR3 is involved in Alzheimer’s disease whereas GPR6 plays potential roles in Parkinson’s disease.

GPR3 and GPR6 are considered orphan receptors because there are no confirmed endogenous agonists for them. However, GPR3 and GPR6 are phylogenetically related to the cannabinoid receptors.

In this study, the activities of endocannabinoids and phytocannabinoids were tested on GPR3 and GPR6 using a β-arrestin2 recruitment assay. Among the variety of cannabinoids tested, cannabidiol (CBD), the major non-psychoactive component of marijuana, significantly reduced β-arrestin2 recruitment to both GPR3 and GPR6. In addition, the inhibitory effects of CBD on β-arrestin2 recruitment were concentration-dependent for both GPR3 and GPR6, with a higher potency for GPR6.

These data show that CBD acts as an inverse agonist at both GPR3 and GPR6 receptors. These results demonstrate for the first time that both GPR3 and GPR6 are novel molecular targets for CBD.

Our discovery that CBD acts as a novel inverse agonist on both GPR3 and GPR6 indicates that some of the potential therapeutic effects of CBD (e.g. treatment of Alzheimer’s disease and Parkinson’s disease) may be mediated through these important receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/28571738

http://www.sciencedirect.com/science/article/pii/S0006291X17310744

Activation of CB2 receptor system restores cognitive capacity and hippocampal Sox2 expression in a transgenic mouse model of Alzheimer’s disease.

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“Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by neuroinflammation, extensive deposits of amyloid-β aggregates, and loss of memory and cognitive abilities. The brains of patients with AD show increased expression of cannabinoid receptor type 2 (CB2) receptors and glial markers. CB2 receptors act as a negative feedback regulator; when activated by a CB2agonist, they can help limit the extent of the neuroinflammatory response and the subsequent development of neuronal damage in the central nervous system. In a double transgenic APP/PS1 mice model of AD, we evaluated the effect of MDA7, a CB2 agonist, on several neuropathological conditions of AD including amyloid deposition, inflammatory reaction, Sox2 (sex-determining region Y-box 2) expression, and spatial memory. Activation of microglia CB2 receptors by MDA7 suppressed neuroinflammation, demonstrated by decreased immunosignal of Iba1 in the hippocampal CA1 and dentate gyrus (DG) areas, promoted clearance of amyloid plaques in the DG area, restored Sox2 expression, and promoted recovery of the neuronal synaptic plasticity in hippocampal CA1. In addition, treatment with MDA7 improved the behavioral performance in the Morris water maze in APP/PS1mice. Collectively, these findings suggest that MDA7 has a potential therapeutic effect in the setting of AD.”

https://www.ncbi.nlm.nih.gov/pubmed/28551012

http://www.sciencedirect.com/science/article/pii/S0014299917303758

Endocannabinoids modulate apoptosis in endometriosis and adenomyosis.

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“Adenomyosis that is a form of endometriosis is the growth of ectopic endometrial tissue within the muscular wall of the uterus (myometrium), which may cause dysmenorrhea and infertility. Endocannabinoid mediated apoptotic mechanisms of endometriosis and adenomyosis are not known. We hypothesized that the down regulation of endocannabinoid receptors and/or alteration in their regulatory enzymes may have a direct role in the pathogenesis of endometriosis and adenomyosis through apoptosis.

Endocannabinoid receptors CB1 and CB2, their synthesizing and catabolizing enzymes (FAAH, NAPE-PLD, DAGL, MAGL) and the apoptotic indexes were immunohistochemically assessed in endometriotic and adenomyotic tissues. Findings were compared to normal endometrium and myometrium. Endometrial adenocarcinoma (Ishikawa) and ovarian endometriosis cyst wall stromal (CRL-7566) cell lines were furthermore cultured with or without cannabinoid receptor agonists. The IC50 value for CB1 and CB2 receptor agonists was quantified. Cannabinoid agonists on cell death were investigated by Annexin-V/Propidium iodide labeling with flow cytometry. CB1 and CB2 receptor levels decreased in endometriotic and adenomyotic tissues compared to the control group (p=0,001 and p=0,001). FAAH, NAPE-PLD, MAGL and DAGL enzyme levels decreased in endometriotic and adenomyotic tissues compared to control (p=0,001, p=0,001, p=0,001 and p=0,002 respectively). Apoptotic cell indexes both in endometriotic and adenomyotic tissues also decreased significantly, compared to the control group (p=0,001 and p=0,001). CB1 and CB2 receptor agonist mediated dose dependent fast anti-proliferative and pro-apoptotic effects were detected in Ishikawa and ovarian endometriosis cyst wall stromal cell lines (CRL-7566).

Endocannabinoids are suggested to increase apoptosis mechanisms in endometriosis and adenomyosis. CB1 and CB2 antagonists can be considered as potential medical therapeutic agents for endometriosis and adenomyosis.”

https://www.ncbi.nlm.nih.gov/pubmed/28549792

http://www.sciencedirect.com/science/article/pii/S0065128116303154