Monthly Archives: September 2018

Restored Self: A Phenomenological Study of Pain Relief by Cannabis.

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Pain Medicine

“OBJECTIVE:

To explore the subjective experience of pain relief by cannabis.

RESULTS:

Three key themes that emerged from the analysis were explored: 1) the Sigh of Relief, describing the corporal sensation of using cannabis, including a sense of relaxation and reduction in pain; 2) the Return to Normality, describing the comprehensive effect of using cannabis, including an increased ability to sleep, focus, and function; and 3) the Side Effects of using cannabis.

CONCLUSIONS:

We propose the term Restored Self to conceptualize the effect of medical cannabis. Restored Self is the experience of regaining one’s sense of self, sense of normality, and sense of control over one’s life.”

 https://www.ncbi.nlm.nih.gov/pubmed/30215782
https://academic.oup.com/painmedicine/advance-article-abstract/doi/10.1093/pm/pny176/5095910?redirectedFrom=fulltext

Oral cannabinoid-rich THC/CBD cannabis extract for secondary prevention of chemotherapy-induced nausea and vomiting: a study protocol for a pilot and definitive randomised double-blind placebo-controlled trial (CannabisCINV).

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BMJ Journals

“Chemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients receiving chemotherapy despite guideline-consistent antiemetic therapy. Trials using delta-9-tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events and flawed study design. Trials using cannabidiol-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids for this indication, nor has the potential economic impact of incorporating such regimens into the Australian healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of adding TN-TC11M, an oral THC/CBD extract to guideline-consistent antiemetics in the secondary prevention of CINV.

METHODS AND ANALYSIS:

The current multicentre, 1:1 randomised cross-over, placebo-controlled pilot study will recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic chemotherapy despite guideline-consistent antiemetics. Patients receive oral TN-TC11M (THC 2.5mg/CBD 2.5 mg) capsules or placebo capsules three times a day on day -1 to day 5 of cycle A of chemotherapy, followed by the alternative drug regimen during cycle B of chemotherapy and the preferred drug regimen during cycle C. The primary endpoint is the proportion of subjects attaining a complete response to CINV. Secondary and tertiary endpoints include regimen tolerability, impact on quality of life and health system resource use. The primary assessment tool is patient diaries, which are filled from day -1 to day 5. A subsequent randomised placebo-controlled parallel phase III trial will recruit a further 250 patients.

ETHICS AND DISSEMINATION:

The protocol was approved by ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.”

https://www.ncbi.nlm.nih.gov/pubmed/30209152

https://bmjopen.bmj.com/content/8/9/e020745

Cannabinoid 1 Receptor Signaling on Hippocampal GABAergic Neurons Influences Microglial Activity.

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“Microglia, the resident immune cells of the brain, play important roles in defending the brain against pathogens and supporting neuronal circuit plasticity. Chronic or excessive pro-inflammatory responses of microglia damage neurons, therefore their activity is tightly regulated.

Pharmacological and genetic studies revealed that cannabinoid type 1 (CB1) receptor activity influences microglial activity, although microglial CB1 receptor expression is very low and activity-dependent. The CB1 receptor is mainly expressed on neurons in the central nervous system (CNS)-with an especially high level on GABAergic interneurons.

Here, we determined whether CB1 signaling on this neuronal cell type plays a role in regulating microglial activity.

Our result suggests that CB1 receptor agonists can modulate microglial activity indirectly, through CB1 receptors on GABAergic neurons.

Altogether, we demonstrated that GABAergic neurons, despite their relatively low density in the hippocampus, have a specific role in the regulation of microglial activity and cannabinoid signaling plays an important role in this arrangement.”

https://www.ncbi.nlm.nih.gov/pubmed/30210289

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00295/full

Pharmaceutical potentialities of β-caryophyllene for drug delivery systems: a prospection.

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“The β-caryophyllene (BCP), a phytocannabinoid presents in various essential oils, demonstrated selective action on the CB2 endocannabinoid receptor and attracted considerable attention because of its several pharmacological activities. Despite this recognized potential, this hydrophobic compound is a volatile and acid-sensitive sesquiterpene that readily oxidizes when exposed to air, and has low bioavailability in oral formulations. Thus, the development of formulations that guarantee its stability and increase its bioavailability is a challenge for its use in the pharmaceutical field.

RESULTS:

The systems presented here may represent an interesting approach to overcome the limitations already mentioned for this terpene. These systems proved to be promising for improving solubility, stability and controlled release of this pharmacological relevant sesquiterpene. In the industrial field, some companies have filed patent applications for the commercial use of the BCP, however, the use of pharmaceutical formulations still appeared moderate.

CONCLUSION:

This prospective study evidenced the new perspectives related to BCP vectorization systems in the pharmaceutical and industrial marketing field and may serve as a basis for further research and pharmaceutical use of this powerful cannabinoid.”

https://www.ncbi.nlm.nih.gov/pubmed/30207226

http://www.eurekaselect.com/165376/article

“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

Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history.

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Journal of Ethnopharmacology

“Cannabis sativa L. (C. sativa) is an annual dioecious plant, which shares its origins with the inception of the first agricultural human societies in Asia. Over the course of time different parts of the plant have been utilized for therapeutic and recreational purposes, for instance, extraction of healing oils from seed, or the use of inflorescences for their psychoactive effects. The key psychoactive constituent in C. sativa is called Δ-9-tetrahydrocannabinol (D9-THC). The endocannabinoid system seems to be phylogenetically ancient, as it was present in the most primitive vertebrates with a neuronal network. N-arachidonoylethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG) are the main endocannabinoids ligands present in the animal kingdom, and the main endocannabinoid receptors are cannabinoid type-1 (CB1) receptor and cannabinoid type-2 (CB2) receptor.

AIM OF THE STUDY:

The review aims to provide a critical and comprehensive evaluation, from the ancient times to our days, of the ethnological, botanical, chemical and pharmacological aspects of C. sativa, with a vision for promoting further pharmaceutical research to explore its complete potential as a therapeutic agent.

RESULTS AND CONCLUSIONS:

A detailed comparative analysis of the available resources for C. sativa confirmed its origin and traditional spiritual, household and therapeutic uses and most importantly its popularity as a recreational drug. The result of several studies suggested a deeper involvement of phytocannabinoids (the key compounds in C. sativa) in several others central and peripheral pathophysiological mechanisms such as food intake, inflammation, pain, colitis, sleep disorders, neurological and psychiatric illness. However, despite their numerous medicinal benefits, they are still considered as a menace to the society and banned throughout the world, except for few countries. We believe that this review will help lay the foundation for promoting exhaustive pharmacological and pharmaceutical studies in order to better understand the clinical relevance and applications of non-psychoactive cannabinoids in the prevention and treatment of life-threatening diseases and help to improve the legal status of C. sativa.”

https://www.ncbi.nlm.nih.gov/pubmed/30205181

https://www.sciencedirect.com/science/article/pii/S0378874118316611?via%3Dihub

Understanding the endocannabinoid system as a modulator of the trigeminal pain response to concussion.

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“Post-traumatic headache is the most common symptom of postconcussion syndrome and becomes a chronic neurological disorder in a substantial proportion of patients.

This review provides a brief overview of the epidemiology of postconcussion headache, research models used to study this disorder, as well as the proposed mechanisms.

An objective of this review is to enhance the understanding of how the endogenous cannabinoid system is essential for maintaining the balance of the CNS and regulating inflammation after injury, and in turn making the endocannabinoid system a potential modulator of the trigeminal response to concussion.

The review describes the role of endocannabinoid modulation of pain and the potential for use of phytocannabinoids to treat pain, migraine and concussion.”

https://www.ncbi.nlm.nih.gov/pubmed/30202590

 https://www.futuremedicine.com/doi/10.2217/cnc-2017-0010

Heterogeneity of cannabinoid ligand-induced modulations in intracellular Ca2+ signals of mouse pancreatic acinar cells in vitro.

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“We recently reported that a CB2R agonist, GW405833 (GW), reduced both the ACh-induced Ca2+ oscillations and the L-arginine-induced Ca2+ signal enhancement in mouse pancreatic acinar cells, suggesting that GW-induced inhibition may prevent the pathogenesis of acute pancreatitis.

In this study, we aim to evaluate the effects of other cannabinoid ligands on Ca2+ signaling in acinar cells.

In conclusion, CB2R agonists play critical roles in modulating Ca2+ signals in mouse pancreatic acinar cells, while other cannabinoid ligands modulate Ca2+ oscillations in a heterogeneous manner through a CB receptor or non-CB-receptor mechanism.”

https://www.ncbi.nlm.nih.gov/pubmed/30202013

https://www.nature.com/articles/s41401-018-0074-y

Identification of novel mouse and rat CB1R isoforms and in silico modeling of human CB1R for peripheral cannabinoid therapeutics.

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“Targeting peripheral CB1R is desirable for the treatment of metabolic syndromes without adverse neuropsychiatric effects.

We previously reported a human hCB1b isoform that is selectively enriched in pancreatic beta-cells and hepatocytes, providing a potential peripheral therapeutic hCB1R target. It is unknown whether there are peripherally enriched mouse and rat CB1R (mCB1 and rCB1, respectively) isoforms.

In this study, we found no evidence of peripherally enriched rodent CB1 isoforms; however, some mCB1R isoforms are absent in peripheral tissues. We show that the mouse Cnr1 gene contains six exons that are transcribed from a single promoter. We found that mCB1A is a spliced variant of extended exon 1 and protein-coding exon 6; mCB1B is a novel spliced variant containing unspliced exon 1, intron 1, and exon 2, which is then spliced to exon 6; and mCB1C is a spliced variant including all 6 exons.

Using RNAscope in situ hybridization, we show that the isoforms mCB1A and mCB1B are expressed at a cellular level and colocalized in GABAergic neurons in the hippocampus and cortex. RT-qPCR reveals that mCB1A and mCB1B are enriched in the brain, while mCB1B is not expressed in the pancreas or the liver. Rat rCB1R isoforms are differentially expressed in primary cultured neurons, astrocytes, and microglia.

We also investigated modulation of Cnr1 expression by insulin in vivo and carried out in silico modeling of CB1R with JD5037, a peripherally restricted CB1R inverse agonist, using the published crystal structure of hCB1R.

The results provide models for future CB1R peripheral targeting.”

 https://www.ncbi.nlm.nih.gov/pubmed/30202012
https://www.nature.com/articles/s41401-018-0152-1

Role of Cannabinoids in Obesity.

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“Obesity is an increasing health problem worldwide. Its related comorbidities imply a high cost for the National Health System and diminish a patient’s life quality.

Adipose tissue is composed of three types of cells. White adipocytes are involved in fat storage and secretion of hormones. Brown adipocytes are involved in thermogenesis and caloric expenditure. Beige adipocytes are transitional adipocytes that in response to various stimuli can turn from white to brown and could be protective against the obesity, enhancing energy expenditure.

The conversion of white in beige adipose tissue is a potential new therapeutic target for obesity.

Cannabinoid receptors (CB) regulate thermogenesis, food intake and inflammation. CB1 ablation or inhibition helps reducing body weight and food intake. Stimulation of CB2 limits inflammation and promotes anti-obesity effects by reducing food intake and weight gain. Its genetic ablation results in adiposity development.

CB receptors are also responsible for transforming white adipose tissue towards beige or brown adipocytes, therefore their modulation can be considered potential anti-obesity target. CB1 principal localization in central nervous system represents an important limit. Stimulation of CB2, principally localized on peripheral cells instead, should facilitate the anti-obesity effects without exerting remarkable psychotropic activity.”

https://www.ncbi.nlm.nih.gov/pubmed/30201891

http://www.mdpi.com/1422-0067/19/9/2690

ANTINOCICEPTIVE TOLERANCE TO NSAIDS PARTIALLY MEDIATED VIA ENDOCANNABINOIDS IN ANTERIOR CINGULATE CORTEX OF RATS.

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“Pain is characterized as a complex experience, dependent not only on the regulation of nociceptive sensory systems but also on the activation of mechanisms that control emotional processes in limbic brain areas.

Non-opioid, non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used analgesics in the treatment of not-severe pain. We have recently shown that repeated doses result in tolerance to these drugs like opioids.

Here we investigated the central brain mechanisms of non-opioid induced antinociception in the non-acute pain models of rats, such as the ‘formalin test’ and a relation between administration of NSAIDs in the limbic brain area, – the anterior cingulated cortex (ACC), – and the endocannabinoid system.

The present data support the notion that endocannabinoids’ CB1 receptor contributes in part to antinociceptive effects of NSAIDs and probably involved in activation of the descending opioid modulatory system of pain.”

 https://www.ncbi.nlm.nih.gov/pubmed/30204109