The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids.

ijms-logo“Epilepsy is a neurological disorder that affects approximately 50 million people worldwide.

There is currently no definitive epilepsy cure. However, in recent years, medicinal cannabis has been successfully trialed as an effective treatment for managing epileptic symptoms, but whose mechanisms of action are largely unknown.

Lately, there has been a focus on neuroinflammation as an important factor in the pathology of many epileptic disorders. In this literature review, we consider the links that have been identified between epilepsy, neuroinflammation, the endocannabinoid system (ECS), and how cannabinoids may be potent alternatives to more conventional pharmacological therapies.

We review the research that demonstrates how the ECS can contribute to neuroinflammation, and could therefore be modulated by cannabinoids to potentially reduce the incidence and severity of seizures. In particular, the cannabinoid cannabidiol has been reported to have anti-convulsant and anti-inflammatory properties, and it shows promise for epilepsy treatment.

There are a multitude of signaling pathways that involve endocannabinoids, eicosanoids, and associated receptors by which cannabinoids could potentially exert their therapeutic effects. Further research is needed to better characterize these pathways, and consequently improve the application and regulation of medicinal cannabis.”

https://www.ncbi.nlm.nih.gov/pubmed/31810321

https://www.mdpi.com/1422-0067/20/23/6079

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The Effectiveness of Topical Cannabidiol Oil in Symptomatic Relief of Peripheral Neuropathy of the Lower Extremities.

“Peripheral neuropathy can significantly impact the quality of life for those who are affected, as therapies from the current treatment algorithm often fail to deliver adequate symptom relief. There has, however, been an increasing body of evidence for the use of cannabinoids in the treatment of chronic, noncancer pain. The efficacy of a topically delivered cannabidiol (CBD) oil in the management of neuropathic pain was examined in this four-week, randomized and placebo-controlled trial.

RESULTS:

The study population included 62.1% males and 37.9% females with a mean age of 68 years. There was a statistically significant reduction in intense pain, sharp pain, cold and itchy sensations in the CBD group when compared to the placebo group. No adverse events were reported in this study.

CONCLUSIONS:

Our findings demonstrate that the transdermal application of CBD oil can achieve significant improvement in pain and other disturbing sensations in patients with peripheral neuropathy. The treatment product was well tolerated and may provide a more effective alternative compared to other current therapies in the treatment of peripheral neuropathy.”

https://www.ncbi.nlm.nih.gov/pubmed/31793418

http://www.eurekaselect.com/177080/article

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Does Integrative Medicine Reduce Prescribed Opioid Use for Chronic Pain? A Systematic Literature Review.

Image result for pain medicine journal“Chronic pain (CP) is a major public health problem. Many patients with CP are increasingly prescribed opioids, which has led to an opioid crisis.

Integrative medicine (IM), which combines pharmacological and complementary and alternative medicine (CAM), has been proposed as an opioid alternative for CP treatment.

The majority of the studies showed that opioid use was reduced significantly after using IM. Cannabinoids were among the most commonly investigated approaches in reducing opioid use, followed by multidisciplinary approaches, cognitive-behavioral therapy, and acupuncture. The majority of the studies had limitations related to sample size, duration, and study design.

CONCLUSIONS:

There is a small but defined body of literature demonstrating positive preliminary evidence that the IM approach including CAM therapies can help in reducing opioid use. As the opioid crisis continues to grow, it is vital that clinicians and patients be adequately informed regarding the evidence and opportunities for IM/CAM therapies for CP.”

https://www.ncbi.nlm.nih.gov/pubmed/31755962

https://academic.oup.com/painmedicine/advance-article-abstract/doi/10.1093/pm/pnz291/5637803?redirectedFrom=fulltext

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Potential new therapies against a toxic relationship: neuroinflammation and Parkinson’s disease.

 Image result for ovid journal“Parkinson’s disease (PD) is a neurodegenerative disorder classically associated with motor symptoms, but several nonmotor disturbances appear decades before the clinical diagnosis of the disease.

A variety of hypotheses exist to explain the onset of PD, and neuroinflammation is one of the most investigated processes. In fact, strong evidence suggests that PD begins with an inflammatory process; currently, however, no anti-inflammatory therapy is clinically employed to alleviate the typical motor and the prodromal disturbances such as olfactory loss, cognitive impairments, depression and anxiety, sleep disturbances, and autonomic disorders.

In fact, the classical dopaminergic therapies are not effective in alleviating these symptoms and there is no other specific therapy for these outcomes. Therefore, in this review, we will discuss novel potential pharmacological therapeutic strategies focusing on cannabinoids, caffeine, melatonin, and dietary compounds, which could act as adjuvants to regular PD therapy.

These described chemicals have been extensively investigated as anti-inflammatory agents possibly promoting beneficial effects on nonmotor symptoms of PD. The investigation of the inflammatory process at different stages of PD progression should give us a better view of the therapeutic scenario and could improve our understanding of the mechanisms of this disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31703030

https://insights.ovid.com/crossref?an=00008877-201912000-00008

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Targeting the cannabinoid receptor CB2 in a mouse model of l-dopa induced dyskinesia.

Neurobiology of Disease“L-dopa induced dyskinesia (LID) is a debilitating side-effect of the primary treatment used in Parkinson’s disease (PD), l-dopa. Here we investigate the effect of HU-308, a cannabinoid CB2 receptor agonist, on LIDs.

Utilizing a mouse model of PD and LIDs, induced by 6-OHDA and subsequent l-dopa treatment, we show that HU-308 reduced LIDs as effectively as amantadine, the current frontline treatment. Furthermore, treatment with HU-308 plus amantadine resulted in a greater anti-dyskinetic effect than maximally achieved with HU-308 alone, potentially suggesting a synergistic effect of these two treatments. Lastly, we demonstrated that treatment with HU-308 and amantadine either alone, or in combination, decreased striatal neuroinflammation, a mechanism which has been suggested to contribute to LIDs.

Taken together, our results suggest pharmacological treatments with CB2 agonists merit further investigation as therapies for LIDs in PD patients. Furthermore, since CB2 receptors are thought to be primarily expressed on, and signal through, glia, our data provide weight to suggestion that neuroinflammation, or more specifically, altered glial function, plays a role in development of LIDs.”

https://www.ncbi.nlm.nih.gov/pubmed/31669673

“Collectively, our findings suggest CB2 agonists offer a putative target to treat LIDs, with efficacy comparable to the frontline treatment amantadine. Our study suggests that targeting glial function may be an important strategy for developing therapies for treating LIDs, a major unmet need for PD patients.”

https://www.sciencedirect.com/science/article/pii/S0969996119303213?via%3Dihub

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Cannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative?

 Publication Cover“Understanding how the body regulates pain is fundamental to develop rational strategies to combat the growing prevalence of chronic pain states, opioid dependency, and the increased financial burden to the medical care system.

Pain is the most prominent reason why Americans seek medical attention and extensive literature has identified the importance of the endocannabinoid pathway in controlling pain. Modulation of the endocannabinoid system offers new therapeutic opportunities for the selective control of excessive neuronal activity in several pain conditions (acute, inflammatory, chronic, and neuropathic).

Cannabinoids have a long history of medicinal use and their analgesic properties are well documented; however, there are major impediments to understanding cannabinoid pain modulation.

One major issue is the presence of psychotropic side effects associated with D9-tetrahydrocannabinol (THC) or synthetic derivatives, which puts an emphatic brake on their use. This dose-limiting effect prevents the appropriate degree of analgesia .

Animal studies have shown that the psychotropic effects are mediated via brain cannabinoid type 1 (CB1) receptors, while analgesic activity in chronic pain states may be mediated via CB1R action in the spinal cord, brainstem, peripheral sensory neurons, or immune cells.

The development of appropriate therapies is incumbent on our understanding of the role of peripheral versus central endocannabinoid-driven analgesia. Recent physiological, pharmacological, and anatomical studies provide evidence that one of the main roles of the endocannabinoid system is the regulation of gamma-aminobutyric acid (GABA) and/or glutamate release.

This article will review this evidence in the context of its implications for pain. We first provide a brief overview of CB1R’s role in the regulation of nociception, followed by a review of the evidence that the peripheral endocannabinoid system modulates nociception.

We then look in detail at regulation of central-mediated analgesia, followed up with evidence that cannabinoid mediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions. Finally, we discuss cannabinoid action on non-neuronal cells in the context of inflammation and direct modulation of neurons.

This work stands to reveal long-standing controversies in the cannabinoid analgesia area that have had an impact on failed clinical trials and implementation of therapeutics targeting this system.”

https://www.ncbi.nlm.nih.gov/pubmed/31596190

https://www.tandfonline.com/doi/abs/10.1080/15504263.2019.1668100?journalCode=wjdd20

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Δ9-Tetrahydrocannabinol Derivative-Loaded Nanoformulation Lowers Intraocular Pressure in Normotensive Rabbits.

“Δ9-Tetrahydrocannabinol-valine-hemisuccinate, a hydrophilic prodrug of Δ9-tetrahydrocannabinol, synthesized with the aim of improving the ocular bioavailability of the parent molecule, was investigated in a lipid-based nanoparticle dosage form for ocular delivery.

RESULTS:

A peak intraocular pressure (IOP) drop of 30% from baseline was observed in rabbits treated with SLNs loaded with Δ9-tetrahydrocannabinol-valine-hemisuccinate at 90 minutes. Treated eyes of rabbits receiving Δ9-tetrahydrocannabinol-valine-hemisuccinate SLNs had significantly lower IOP than untreated eyes until 360 minutes, whereas the group receiving the emulsion formulation showed a drop in IOP until 90 minutes only. In comparison to marketed pilocarpine and timolol maleate ophthalmic solutions, Δ9-tetrahydrocannabinol-valine-hemisuccinate SLNs produced a greater effect on IOP in terms of both intensity and duration. In terms of tissue concentrations, significantly higher concentrations of Δ9-tetrahydrocannabinol-valine-hemisuccinate were observed in iris-ciliary bodies and retina-choroid with SLNs.

CONCLUSION:

Δ9-Tetrahydrocannabinol-valine-hemisuccinate formulated in a lipid-based nanoparticulate carrier shows promise in glaucoma pharmacotherapy.

TRANSLATIONAL RELEVANCE:

Glaucoma therapies usually focus on decreased aqueous humor production and increased outflow. However, such therapy is not curative, and there lies a need in preclinical research to focus efforts on agents that not only affect the aqueous humor dynamics but also provide neuroprotection. Historically, there have been bench-scale studies looking at retinal ganglion cell death post-axonal injury. However, for a smooth translation of this in vitro activity to the clinic, animal models examining IOP reduction, i.e., connecting the neuroprotective activity to a measurable outcome in glaucoma management (IOP), need to be investigated. This study investigated the IOP reduction efficacy of cannabinoids for glaucoma pharmacotherapy in a normotensive rabbit model, bringing forth a new class of agents with the potential of IOP reduction and improved permeation to the back of the eye, possibly providing neuroprotective benefits in glaucoma management.”

https://www.ncbi.nlm.nih.gov/pubmed/31588378

“THC has been demonstrated to be effective in glaucoma management, helping to lower IOP in human subjects after smoking marijuana; however, the molecule fails to manifest a similar effect when dosed topically. This research explores molecular bioengineering and formulation-based strategies to improve the ocular bioavailability of THC, facilitating the molecule to translate into a dosage form capable of demonstrating a desired IOP-lowering effect even on topical application. These studies suggest that formulation development efforts along with prodrug derivatization can effectively improve the overall ocular bioavailability of THC. Thus, THC-VHS represents a potential new therapy option for the treatment and management of glaucoma by virtue of its superiority in lowering IOP when compared to antiholinergic and beta blockers, as studied in this model.”
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Comparative studies of endocannabinoid modulation of pain.

Philosophical Transactions of the Royal Society B: Biological Sciences cover image

“Cannabinoid-based therapies have long been used to treat pain, but there remain questions about their actual mechanisms and efficacy. From an evolutionary perspective, the cannabinoid system would appear to be highly conserved given that the most prevalent endogenous cannabinoid (endocannabinoid) transmitters, 2-arachidonyl glycerol and anandamide, have been found throughout the animal kingdom, at least in the species that have been analysed to date. This review will first examine recent findings regarding the potential conservation across invertebrates and chordates of the enzymes responsible for endocannabinoid synthesis and degradation and the receptors that these transmitters act on. Next, comparisons of how endocannabinoids modulate nociception will be examined for commonalities between vertebrates and invertebrates, with a focus on the medicinal leech Hirudo verbana. Evidence is presented that there are distinct, evolutionarily conserved anti-nociceptive and pro-nociceptive effects. The combined studies across various animal phyla demonstrate the utility of using comparative approaches to understand conserved mechanisms for modulating nociception. This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.”

https://www.ncbi.nlm.nih.gov/pubmed/31544609

https://royalsocietypublishing.org/doi/10.1098/rstb.2019.0279

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Medical cannabis for chronic pain: can it make a difference in pain management?

 “Globally, chronic pain is a major therapeutic challenge and affects more than 15% of the population. As patients with painful terminal diseases may face unbearable pain, there is a need for more potent analgesics.

Although opioid-based therapeutic agents received attention to manage severe pain, their adverse drug effects and mortality rate associated with opioids overdose are the major concerns.

Evidences from clinical trials showed therapeutic benefits of cannabis, especially delta-9-tetrahydrocannabinol and cannabinoids reduced neuropathic pain intensity in various conditions. Also, there are reports on using combination cannabinoid therapies for chronic pain management.

The association of cannabis dependence and addiction has been discussed much and the reports mentioned that it can be comparatively lower than other substances such as nicotine and alcohol.

More countries have decided to legalise the medicinal use of cannabis and marijuana.

Healthcare professionals should keep themselves updated with the changing state of medical cannabis and its applications.”

https://www.ncbi.nlm.nih.gov/pubmed/31535218

https://link.springer.com/article/10.1007%2Fs00540-019-02680-y

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Endocannabinoid Signaling in the Central Amygdala and Bed Nucleus of the Stria Terminalis: Implications for the Pathophysiology and Treatment of Alcohol Use Disorder.

Alcoholism: Clinical and Experimental Research banner“High rates of relapse are a chronic and debilitating obstacle to effective treatment of alcohol use disorder (AUD); however, no effective treatments are available to treat symptoms induced by protracted abstinence.

In the first part of this two-part review series, we examine the literature supporting the effects of alcohol exposure within the extended amygdala (EA) neural circuitry.

In part two, we focus in on a potential way to combat negative affect associated with AUD, by exploring the therapeutic potential of the endogenous cannabinoid (eCB) system.

The eCB system is a potent modulator of neural activity in the brain, and its ability to mitigate stress and negative affect has long been an area of interest for developing novel therapeutics.

This review details the recent advances in our understanding of eCB signaling in two key regions of the EA, the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), and their role in regulating negative affect.

Despite an established role for EA eCB signaling in reducing negative affect, few studies have examined the potential for eCB-based therapies to treat AUD-associated negative affect.

In this review, we present an overview of studies focusing on eCB signaling in EA and cannabinoid modulation on EA synaptic activity. We further discuss studies suggesting dysregulation of eCB signaling in models of AUD and propose that pharmacological augmentation of eCB could be a novel approach to treat aspects of AUD.

Lastly, future directions are proposed to advance our understanding of the relationship between AUD-associated negative affect and the EA eCB system that could yield new pharmacotherapies targeting negative affective symptoms associated with AUD.”

https://www.ncbi.nlm.nih.gov/pubmed/31373708

https://onlinelibrary.wiley.com/doi/abs/10.1111/acer.14159

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