Endogenous and synthetic cannabinoids induce the downregulation of cannabinoid CB1 receptor in retina.

Experimental Eye Research

“Endogenous and synthetic cannabinoids have been shown to provide neuroprotection to retinal neurons in acute animal models of retinopathy.

Chronic exposure to cannabinoid receptor (CB1R) agonists has been reported to induce downregulation of the CB1R in brain and behavioral tolerance.

The aim of this study was to investigate the effect of subchronic/chronic cannabinoid administration on CB1R downregulation in normal rat retina, its downstream prosurvival signaling and subsequent effect on retinal neuroprotection against AMPA excitotoxicity.

This study provides novel information regarding agonist-induced CB1R downregulation in rat retina after subchronic/chronic cannabinoid treatment, and its effect on downstream prosurvival signaling and neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/31199905

https://www.sciencedirect.com/science/article/pii/S0014483519301216?via%3Dihub

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The Important Role of the Endocannabinoid System and the Endocannabinoidome in Gut Health.

Image result for Altern Ther Health Med journal “The endocannabinoid system is an endogenous pathway comprised of the cannabinoid receptors 1 and 2 (CB1 and CB2), their endogenous ligands known as endocannabinoids, and the enzymes responsible for their synthesis and degradation. The endocannabinoidome extends this system to include other receptors such as TRPV1, PPARα, GPR55 and 5-HT1A. An extensive amount of research is now linking the endocannabinoidome to intestinal health through fascinating mechanisms that include endocannabinoid receptor expression in the gut and interplay with the intestinal microbiota. A dysregulated endocannabinoid system may lead to inflammatory bowel disease and colon cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/31202201

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The Endocannabinoid System and its Modulation by Cannabidiol (CBD).

Image result for Altern Ther Health Med. “The endocannabinoid system (ECS) is an extensive endogenous signaling system with multiple elements, the number of which may be increasing as scientists continue to elucidate its role in human health and disease. The ECS is seemingly ubiquitous in animal species and is modulated by diet, sleep, exercise, stress, and a multitude of other factors, including exposure to phytocannabinoids, like Cannabidiol (CBD). Modulating the activity of this system may offer tremendous therapeutic promise for a diverse scope of diseases, ranging from mental health disorders, neurological and movement disorders, pain, autoimmune disease, spinal cord injury, cancer, cardiometabolic disease, stroke, TBI, osteoporosis, and others.”

https://www.ncbi.nlm.nih.gov/pubmed/31202198

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Dramatic response to Laetrile and cannabidiol (CBD) oil in a patient with metastatic low grade serous ovarian carcinoma.

Gynecologic Oncology Reports

“Complimentary alternative medicine use is common in women with gynecologic cancers. Cannabinoid receptors are potential therapeutic targets in ovarian cancer. Communication with patients is critical regarding use of alternative therapies.”  https://www.ncbi.nlm.nih.gov/pubmed/31193514

In this case report, we present the case of a female patient who demonstrated disease response after declining standard therapy and taking a combination of Laetrile and CBD oil. Previous clinical trials in humans have demonstrated no therapeutic effect in cancer patients taking Laetrile. However, basic science studies have identified cannabinoid receptors in ovarian cancer as potential therapeutic targets for cannabinoid use in treating malignancy.

In this case report, we highlight a dramatic response to combination Laetrile and CBD oil in a patient with widely metastatic Low grade serous ovarian cancer (LGSOC).

Laetrile is a semi-synthetic version of amygdaline, a chemical compound found in plants and fruit seeds. Both Laetrile and amygdaline contain cyanide within a common structural component. Theoretically, Laetrile has anti-cancer effects when cyanide is released via enzymatic degradation. However, a Cochrane review published in 2015 found no randomized or quasi randomized control trials supporting the use of Laetrile in cancer patients. Further, they argued that due to the risk of cyanide poisoning, Laetrile use should be discouraged in patients seeking the compound for alternative cancer therapy. Concerns for toxicity in combination with inability to demonstrate clinical efficacy led to an effective ban on the substance by the FDA in the 1980s. Nevertheless, the substance remains available for purchase in variable formulations commercially.

Cannabidiol (CBD) is a compound naturally derived from the cannabis plant.

The anti-cancer effects of CBD have been evaluated predominantly in the laboratory setting. Interestingly, ovarian cancer cell lines express GPR55, a target that is inhibited indirectly by CBD and that plays a role in prostate and ovarian cancer cell proliferation. Mouse model studies have also demonstrated cannabinoids inhibit tumor cell growth and induce apoptosis in gliomas, lymphomas, prostate, breast, lung, skin, and pancreatic cancer cells.”

https://www.sciencedirect.com/science/article/pii/S2352578919300517?via%3Dihub

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Selective modulation of the cannabinoid type 1 (CB1) receptor as an emerging platform for the treatment of neuropathic pain.

“Neuropathic pain is caused by a lesion or dysfunction in the nervous system, and it may arise from illness, be drug-induced or caused by toxin exposure. Since the discovery of two G-protein-coupled cannabinoid receptors (CB1 and CB2) nearly three decades ago, there has been a rapid expansion in our understanding of cannabinoid pharmacology. This is currently one of the most active fields of neuropharmacology, and interest has emerged in developing cannabinoids and other small molecule modulators of CB1 and CB2 as therapeutics for neuropathic pain. This short review article provides an overview of the chemotypes currently under investigation for the development of novel neuropathic pain treatments targeting CB1 receptors.”

Graphical abstract: Selective modulation of the cannabinoid type 1 (CB1) receptor as an emerging platform for the treatment of neuropathic pain
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[Cannabis for medical purposes and its prescription].

“Since 10 March 2017, physicians have been allowed to prescribe cannabis to patients with serious illnesses and in the absence of alternative therapies. Patients can obtain it as dried flowers or extracts in standardised pharmaceutical quality by prescription (narcotic prescription, except for cannabidiol) in pharmacies. When prescribing, physicians have to take a few things into account. The first step is to decide which therapeutic effects are to be achieved and which is the most suitable cannabis product. Cannabis for medical use must meet the requirements for pharmaceutical quality. An identity check must be carried out in the pharmacy on the basis of the monographs of the German Pharmacopoeia (DAB) or the German Pharmaceutical Codex/New Prescription Form (DAC/NRF). For the production of prescription drugs, e.g. capsules, drops or inhalates, there are also corresponding monographs for the preparation of prescription drugs. These standardised, quality-assured prescription formulas should be given preference in the case of a medical prescription. When prescribing an oral or inhalative form of application, it should be noted that the onset and duration of action are very different. Also, due to the complex pharmacology of cannabinoids, interindividual genetic differences in the metabolisation of ∆9-tetrahydrocannabinol (THC), the individual structure and function of the cannabinoid receptors, as well as differences in receptor density and distribution, the dosage and frequency of application must be individually determined. Last but not least, the dosage also depends on the type of disease and individual susceptibility to side effects. When prescribed for the first time, a creeping dosage with a very low initial dose is recommended.”

https://www.ncbi.nlm.nih.gov/pubmed/31187182

https://link.springer.com/article/10.1007%2Fs00103-019-02970-6

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Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer’s Disease.

The American Journal of Geriatric Psychiatry

“Nabilone may be an effective treatment for agitation.”

https://www.ncbi.nlm.nih.gov/pubmed/31182351

https://www.sciencedirect.com/science/article/pii/S1064748119303550?via%3Dihub

“Nabilone (marketed as Cesamet) is a synthetic form of delta-9-tetrahydrocannabinol (Δ⁹-THC), the primary psychoactive component of cannabis (marijuana). Although structurally distinct from THC, nabilone mimics THC’s structure and pharmacological activity through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors, however it is considered to be twice as active as Δ⁹-THC. Nabilone is approved by the FDA for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.” https://www.drugbank.ca/drugs/DB00486

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The oncogenic role of CB2 in the progression of non-small-cell lung cancer.

Biomedicine & Pharmacotherapy

“Several studies have verified the important role of cannabinoid and cannabinoid receptor agonists in tumor progression. However, little is known about the precise role of CB2 expression level in the progression of non-small-cell lung cancer (NSCLC).

The expression of CB2 in NSCLC tissues and corresponding paracancerous tissues was examined using immunohistochemical staining assay.

CONCLUSION:

Our data suggested that targeting CB2 may inhibit the growth and survival of NSCLC cells, which the Akt/mTOR/P70S6K pathway may be involved in. These results confer the pro-oncogenic role of CB2 in the progression of NSCLC, thus improving our understanding of CB2 in tumor progression.”

https://www.ncbi.nlm.nih.gov/pubmed/31176172

https://www.sciencedirect.com/science/article/pii/S0753332219321341?via%3Dihub

“Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC.”  https://www.ncbi.nlm.nih.gov/pubmed/21097714

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The cannabinoid receptor 2 agonist, β-caryophyllene, improves working memory and reduces circulating levels of specific proinflammatory cytokines in aged male mice.

Behavioural Brain Research“Age-related cognitive decline has been associated with proinflammatory cytokines, yet the precise relationship between cognitive decline and cytokine load remains to be elucidated. β-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist with established anti-inflammatory effects that is known to improve memory and increase lifespan. It is of interest to explore the potential of BCP to reduce age-related cognitive decline and proinflammatory cytokine load. In this study, we assessed changes in circulating cytokines across the lifespan, memory performance in young and aged mice, and the effects of BCP on memory function and cytokine load. The plasma levels of 12 cytokines were assessed in male Swiss-Webster mice at 3, 12, and 18 months of age using multiplexed flow cytometry. Working memory was compared in 3 and 12 month-old mice using spontaneous alternations. A dose-response function (100-300 mg/kg, subchronic administration) for BCP-induced memory restoration was determined in 3 and 12 month-old mice. Finally, the effects on cytokine levels of the peak memory enhancing dose of BCP was assessed in 18 month-old mice. Circulating levels of several cytokines significantly increased with age. Multilinear regression analysis showed that IL-23 levels were most strongly associated with age. Aged mice showed deficits in working memory and higher levels of IL-23, both of which were reversed by BCP treatment. BCP appears to reverse age-associated impairments in memory and modulates cytokine production. IL-23 may play a significant role in the aging process, and future research should determine whether it has utility as a biomarker for novel anti-aging therapeutics.”

https://www.ncbi.nlm.nih.gov/pubmed/31173795

https://www.sciencedirect.com/science/article/pii/S0166432819304516?via%3Dihub

“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

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

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Novel CB1-ligands maintain homeostasis of the endocannabinoid-system in ω3- and ω6-long chain-PUFA deficiency.

The Journal of Lipid Research“Mammalian ω3- and ω6-PUFAs are synthesized from essential fatty acids (EFAs) or supplied by the diet. PUFAs are constitutive elements of membrane-architecture and precursors of lipid signaling molecules. EFAs and long chain PUFAs are precursors in the synthesis of endocannabinoid-ligands of the Gi/o-protein coupled cannabinoid receptors 1 and 2 in the endocannabinoid-system, which critically regulates energy homeostasis, as metabolic signaling system in hypothalamic neuronal circuits, and behavioral parameters. We utilized the auxotrophic fatty acid desaturase 2 deficient (fads2-/-) mouse, deficient in long chain PUFA-synthesis, to follow the age dependent dynamics of the PUFA pattern in the CNS-phospholipidome in unbiased dietary studies of three cohorts on sustained long chain PUFA-free, ω6-arachidonic and ω3-docosahexaenoic acid supplemented diets and their impact on the precursor pool of CB1 ligands. We discovered the transformation of eicosa-all cis-5,11,14-trienoic acid, uncommon in mammalian lipidomes, into two novel endocannabinoids, 20:35,11,14-ethanolamide and 2-20:35,11,14-glycerol, acting as ligands of CB1 in HEK293-cells. Labeling experiments excluded a Δ8-desaturase activity and proved the position-specificity of FADS2. The fads2 -/- mutant might serve as an unbiased model in vivo in the development of novel CB1-agonists and antagonists.”

https://www.ncbi.nlm.nih.gov/pubmed/31167809

http://www.jlr.org/content/early/2019/06/05/jlr.M094664

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