Central Aspects of Nausea and Vomiting in GI Disorders.

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“Nausea and vomiting result from continuous interactions among gastrointestinal, central nervous system, and autonomic nervous system. Despite being closely associated, central pathways of nausea and vomiting appear to be at least partly different and nausea is no longer considered only a penultimate step of vomiting. Although our understanding of central pathways of nausea has improved over the last one decade, it is still very basic.

Afferent pathways from gastrointestinal tract via vagus, vestibular system, and chemoreceptor trigger zone project to nucleus tractus solitarius which, in turn, relays the signal to central pattern generator initiating multiple downstream pathways. This central nausea pathway appears to be under constant modulation by autonomic nervous system and cerebral cortex.

There is also some evidence that central pathway of chronic nausea is different from that of acute nausea and closely resembles that of neuropathic pain. This improved understanding has modified the way we can approach the treatment of acute and chronic nausea.

While conventional therapies such as antiemetics (antiserotoninergic, antihistaminic, antidopaminergic) and prokinetics are commonly used to manage acute nausea, they are not as effective in improving chronic nausea.

Recently, neuromodulators such as tricyclic antidepressants, gabapentin, olanzapine, benzodiazepines, and cannabinoids have been shown to have antinausea effect.

There is a need to study the utility of these drugs in managing chronic functional nausea. Improving our understanding of central and peripheral circuitry of nausea will allow us to better utilize the currently available drugs and develop new therapeutic options.”

https://www.ncbi.nlm.nih.gov/pubmed/27734216

A New Study Suggests Cannabis Could Treat Cervical Cancer

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“A new study suggests that cannabis might be useful in treating cervical cancer.

Through in vitro, or test tube/petri dish, analysis, researchers from the biochemistry department at North-West University in Potchefstroom, South Africa found that the non-psychotropic cannabinoid, or chemical compound, CBD (cannabidiol), taken from a Cannabis sativa extract, could hold anticarcinogenic properties. They pointed out that cannabis acted on the cancerous cells through apoptosis, or a process of cell death, causing only the cancerous cells to kill themselves, and inhibiting their growth.

Cervical cancer is no longer a leading cause of death as much as it used to be in the United States, thanks in large part to the widespread use of pap smears, but it’s still a widespread threat. And in Sub-Saharan Africa, it kills 250,000 women every year. “This makes it the most lethal cancer amongst black women and calls for urgent therapeutic strategies,” the study’s authors wrote in the BMC Complementary and Alternative Medicine journal. “In this study we compare the anti-proliferative effects of crude extract of Cannabis sativa and its main compound cannabidiol on different cervical cancer cell lines.”

It will take much more research before cannabis can be integrated into official cervical cancer treatments in sub-Saharan Africa. But earlier studies also shows that cannabis has been useful in treating not only the symptoms of cancer and chemotherapy, but also the cancer itself.

One study from the journal of Current Clinical Pharmacology found that cannabis served as a preventative agent, reducing inflammation, which researchers also said was useful in reducing the likelihood of cancer. Another study from Oncology Hematology also noted cannabis’ anti-cancer effects, explaining how the plant’s cannabinoids inhibited tumor growth in vitro, such as in a petri dish or test tube, and in vivo, or a living organism.

A handful of other studies have also looked into cannabis as a treatment specifically for cervical cancer. Another from the University Hospital in Geneva, Switzerland, found that the cannabinoids, including the body’s own endocannabinoids, offered “attractive opportunities for the development of novel potent anticancer drugs.”

With that said, often medical marijuana is ingested via capsules, tinctures, vaporizable oils, and other non-smokeable, more pharmaceutical-style forms. Should cannabis eventually become approved for cervical cancer treatment in Africa, it may be up for debate whether whole plant therapy (in which all the cannabinoids work synergistically through the “entourage effect”) or specific cannabinoid therapy is best.”

http://motherboard.vice.com/read/a-new-study-suggests-cannabis-could-treat-cervical-cancer

Dendritic Cell Regulation by Cannabinoid-Based Drugs.

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“Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered.

Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory diseases.

Moreover, as we discuss here, additional studies also indicates that these drugs have immunosuppressive and anti-inflammatory properties including modulation of immune cell function.

Thus, manipulation of the endocannabinoid system in vivo may provide novel therapeutic strategies against inflammatory disorders.

At least two types of cannabinoid receptors, cannabinoid 1 and cannabinoid 2 receptors are expressed on immune cells such as dendritic cells (DC). Dendritic cells are recognized for their critical role in initiating and maintaining immune responses.

Therefore, DC are potential targets for cannabinoid-mediated modulation.

Here, we review the effects of cannabinoids on DC and provide some perspective concerning the therapeutic potential of cannabinoids for the treatment of human diseases involving aberrant inflammatory processes.”

https://www.ncbi.nlm.nih.gov/pubmed/27713374

Cannabinoids and Dementia: A Review of Clinical and Preclinical Data.

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“The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia.

We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD).

Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro.

However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce.

While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia.

Further research is needed, including in vivo models of dementia and human studies.”

https://www.ncbi.nlm.nih.gov/pubmed/27713372

Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3

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“Spinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression.

Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortemcerebellum of patients affected by autosomal-dominant hereditary ataxias suggest that targeting the endocannabinoid signaling system may be a promising therapeutic option.

Our goal was to investigate the status of the endocannabinoid signaling system in a transgenic mouse model of SCA-3, in the two CNS structures most affected in this disease –cerebellum and brainstem-.

These animals exhibited progressive motor incoordination, imbalance, abnormal gait, muscle weakness, and dystonia, in parallel to reduced in vivobrain glucose metabolism, deterioration of specific neuron subsets located in the dentate nucleus and pontine nuclei, small changes in microglial morphology, and reduction in glial glutamate transporters.

Concerning the endocannabinoid signaling, our data indicated no changes in CB2 receptors. By contrast, CB1 receptors increased in the Purkinje cell layer, in particular in terminals of basket cells, but they were reduced in the dentate nucleus.

We also measured the levels of endocannabinoid lipids and found reductions in anandamide and oleanolamideoyleth in the brainstem. These changes correlated with an increase in the FAAH enzyme in the brainstem, which also occurred in some cerebellar areas, whereas other endocannabinoid-related enzymes were not altered.

Collectively, our results in SCA-3 mutant mice confirm a possible dysregulation in the endocannabinoid system in the most important brain structures affected in this type of ataxia, suggesting that a pharmacological manipulation addressed to correct these changes could be a promising option in SCA-3.”

http://www.sciencedirect.com/science/article/pii/S0306452216305012

The Potential Role of Cannabinoids in Modulating Serotonergic Signaling by Their Influence on Tryptophan Metabolism.

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“Phytocannabinoids present in Cannabis plants are well known to exert potent anti-inflammatory and immunomodulatory effects.

Previously, we have demonstrated that the psychoactive D9-tetrahydrocannabinol (THC) and the non-psychotropic cannabidiol (CBD) modulate mitogen-induced Th1-type immune responses in peripheral blood mononuclear cells (PBMC).

The suppressive effect of both cannabinoids on mitogen-induced tryptophan degradation mediated by indoleamine-2,3-dioxygenase (IDO), suggests an additional mechanism by which antidepressive effects of cannabinoids might be linked to the serotonergic system.

Here, we will review the role of tryptophan metabolism in the course of cell mediated immune responses and the relevance of cannabinoids in serotonergic signaling.

We conclude that in particular the non-psychotropic CBD might be useful for the treatment of mood disorders in patients with inflammatory diseases, since this cannabinoid seems to be safe and its effects on activation-induced tryptophan degradation by CBD were more potent as compared to THC.”

Brain CB₂ Receptors: Implications for Neuropsychiatric Disorders.

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“Although previously thought of as the peripheral cannabinoid receptor, it is now accepted that the CB₂ receptor is expressed in the central nervous system on microglia, astrocytes and subpopulations of neurons.

Expression of the CB₂ receptor in the brain is significantly lower than that of the CB₁ receptor. Conflicting findings have been reported on the neurological effects of pharmacological agents targeting the CB₂ receptor under normal conditions.

Under inflammatory conditions, CB₂ receptor expression in the brain is enhanced and CB2 receptor agonists exhibit potent anti-inflammatory effects. These findings have prompted research into the CB₂ receptor as a possible target for the treatment of neuroinflammatory and neurodegenerative disorders.

Neuroinflammatory alterations are also associated with neuropsychiatric disorders and polymorphisms in the CB₂ gene have been reported in depression, eating disorders and schizophrenia. This review will examine the evidence to date for a role of brain CB₂ receptors in neuropsychiatric disorders.”

Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex.

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“Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression.

The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy.

Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC.

Although double-blind, placebo-controlled trials are still necessary, these findings suggest that cannabidiol may be an effective and well-tolerated treatment option for patients with refractory seizures in TSC.”

https://www.ncbi.nlm.nih.gov/pubmed/27696387

Vascular Dysfunction in a Transgenic Model of Alzheimer’s Disease: Effects of CB1R and CB2R Cannabinoid Agonists.

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“There is evidence of altered vascular function, including cerebrovascular, in Alzheimer’s disease (AD) and transgenic models of the disease.

Indeed vasoconstrictor responses are increased, while vasodilation is reduced in both conditions. β-Amyloid (Aβ) appears to be responsible, at least in part, of alterations in vascular function.

Cannabinoids, neuroprotective and anti-inflammatory agents, induce vasodilation both in vivo and in vitro.

We have demonstrated a beneficial effect of cannabinoids in models of AD by preventing glial activation.

In this work we have studied the effects of these compounds on vessel density in amyloid precursor protein (APP) transgenic mice, line 2576, and on altered vascular responses in aortae isolated ring.

In summary, we have confirmed and extended the existence of altered vascular responses in Tg APP mice.

Moreover, our results suggest that treatment with cannabinoids may ameliorate the vascular responses in AD-type pathology.”

Turning Down the Thermostat: Modulating the Endocannabinoid System in Ocular Inflammation and Pain.

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“The endocannabinoid system (ECS) has emerged as an important regulator of both physiological and pathological processes. Notably, this endogenous system plays a key role in the modulation of pain and inflammation in a number of tissues.

The components of the ECS, including endocannabinoids, their cognate enzymes and cannabinoid receptors, are localized in the eye, and evidence indicates that ECS modulation plays a role in ocular disease states.

Of these diseases, ocular inflammation presents a significant medical problem, given that current clinical treatments can be ineffective or are associated with intolerable side-effects. Furthermore, a prominent comorbidity of ocular inflammation is pain, including neuropathic pain, for which therapeutic options remain limited.

Recent evidence supports the use of drugs targeting the ECS for the treatment of ocular inflammation and pain in animal models; however, the potential for therapeutic use of cannabinoid drugs in the eye has not been thoroughly investigated at this time.

This review will highlight evidence from experimental studies identifying components of the ocular ECS and discuss the functional role of the ECS during different ocular inflammatory disease states, including uveitis and corneal keratitis.

Candidate ECS targeted therapies will be discussed, drawing on experimental results obtained from both ocular and non-ocular tissue(s), together with their potential application for the treatment of ocular inflammation and pain.”

https://www.ncbi.nlm.nih.gov/pubmed/27695415