Nabiximols for the Treatment of Cannabis Dependence: A Randomized Clinical Trial.

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“This study demonstrates that cannabinoid agonist treatment, in this case using nabiximols, in combination with psychosocial interventions is a safe approach for reducing cannabis use among individuals with cannabis dependence who are seeking treatment.”   https://www.ncbi.nlm.nih.gov/pubmed/31305874
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2737918
“nabiximols: An herbal preparation containing a defined quantity of specific cannabinoids formulated for oromucosal spray administration with potential analgesic activity. Nabiximols contains a standardized extract of tetrahydrocannabinol (THC), the non-psychoactive cannabinoid cannabidiol (CBD), other minor cannabinoids, flavonoids, and terpenes from two cannabis plant varieties.” https://www.cancer.gov/publications/dictionaries/cancer-drug/def/nabiximols
“Cannabis treatment counters addiction: First study of its kind. Trial shows cannabis replacement therapy can be effective” https://www.sciencedaily.com/releases/2019/07/190715114247.htm

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Cannabis sativa L. extract and cannabidiol inhibit in vitro mediators of skin inflammation and wound injury.

Publication cover image“The present study investigates the potential effect of a Cannabis sativa L. ethanolic extract standardized in cannabidiol as antiinflammatory agent in the skin. The extract inhibited the release of mediators of inflammation involved in wound healing and inflammatory processes occurring in the skin. Cannabis extract and cannabidiol showed different effects on the release of interleukin-8 and vascular endothelial growth factor, which are both mediators whose genes are dependent on NF-κB. Our findings provide new insights into the potential effect of Cannabis extracts against inflammation-based skin diseases.” https://www.ncbi.nlm.nih.gov/pubmed/31250491

https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.6400

“The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757311/

“The endocannabinoid system of the skin. A potential approach for the treatment of skin disorders” https://www.sciencedirect.com/science/article/abs/pii/S0006295218303484

Cannabinoid system in the skin – a possible target for future therapies in dermatology.”   https://www.ncbi.nlm.nih.gov/pubmed/19664006

“Extracts of the hemp plant cannabis are traditionally used as a popular remedy against inflammation.” https://medicalxpress.com/news/2007-06-cannabinoids-human-body-anti-inflammatory-effect.html

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The heterogeneity and complexity of Cannabis extracts as antitumor agents

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“The Cannabis plant contains over 100 phytocannabinoids and hundreds of other components. The biological effects and interplay of these Cannabis compounds are not fully understood and yet influence the plant’s therapeutic effects.

Here we assessed the antitumor effects of whole Cannabis extracts, which contained significant amounts of differing phytocannabinoids, on different cancer lines from various tumor origins.

Our results show that specific Cannabis extracts impaired the survival and proliferation of cancer cell lines as well as induced apoptosis.

Our findings showed that pure (-)-Δ9trans-tetrahydrocannabinol (Δ9-THC) did not produce the same effects on these cell lines as the whole Cannabis extracts. Furthermore, Cannabis extracts with similar amounts of Δ9-THC produced significantly different effects on the survival of specific cancer cells.

In addition, we demonstrated that specific Cannabis extracts may selectively and differentially affect cancer cells and differing cancer cell lines from the same organ origin. We also found that cannabimimetic receptors were differentially expressed among various cancer cell lines and suggest that this receptor diversity may contribute to the heterogeneous effects produced by the differing Cannabis extracts on each cell line.

Our overall findings indicate that the effect of a Cannabis extract on a specific cancer cell line relies on the extract’s composition as well as on certain characteristics of the targeted cells.”

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=26983

“Many previous reports highlight and demonstrate the anti-tumor effects of cannabinoids. In the last decade, accumulating evidence has indicated that phytocannabinoids might have antitumor properties. A number of in vitro and in vivo studies have demonstrated the effects of phytocannabinoids on tumor progression by interrupting several characteristic features of cancer. These studies suggest that specific cannabinoids such as Δ9-THC and CBD induce apoptosis and inhibit proliferation in various cancer cell lines.”

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=26983&path%5B%5D=85698

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Aplicaciones terapéuticas por acción de los cannabinoides.

“The interest on cannabinoids became evident between the 1940 and 1950 decades. Although the active substance of the plant was not known, a series of compounds with cannabinomimetic activity were synthesized, which were investigated in animals and clinically. The most widely tested was Δ6a, 10a-THC hexyl. Δ6a, 10a-THC dimethylheptyl (DMHP) antiepileptic effects were studied in several children, with positive results being obtained in some cases. DMHP differs from sinhexyl in that its side chain is DMHP instead of n-hexyl. The first cannabinoid isolated from Cannabis sativa was cannabinol, although its structure was correctly characterized several years later. Cannabidiol was isolated some years later and was subsequently characterized by Mechoulam and Shvo. In 2013, the National Academy of Medicine and the Faculty of Medicine of the National Autonomous University of Mexico, through the Seminar of Studies on Entirety, decided to carry out a systematic review on a subject that is both complex and controversial: the relationship between marijuana and health. In recent years, studies have been conducted with cannabis in several diseases: controlled clinical trials on spasticity in multiple sclerosis and spinal cord injury, chronic, essentially neuropathic, pain, movement disorders (Gilles de Latourette, dystonia, levodopa dyskinesia), asthma and glaucoma, as well as non-controlled clinical trials on Alzheimer’s disease, neuroprotection, intractable hiccups, epilepsy, alcohol and opioid dependence and inflammatory processes.”

https://www.ncbi.nlm.nih.gov/pubmed/31219471

http://gacetamedicademexico.com/frame_esp.php?id=310

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Antitumor Cannabinoid Chemotypes: Structural Insights.

Image result for frontiers in pharmacology“Cannabis has long been known to limit or prevent nausea and vomiting, lack of appetite, and pain. For this reason, cannabinoids have been successfully used in the treatment of some of the unwanted side effects caused by cancer chemotherapy.

Besides their palliative effects, research from the past two decades has demonstrated their promising potential as antitumor agents in a wide variety of tumors.

Cannabinoids of endogenous, phytogenic, and synthetic nature have been shown to impact the proliferation of cancer through the modulation of different proteins involved in the endocannabinoid system such as the G protein-coupled receptors CB1, CB2, and GRP55, the ionotropic receptor TRPV1, or the fatty acid amide hydrolase (FAAH).

In this article, we aim to structurally classify the antitumor cannabinoid chemotypes described so far according to their targets and types of cancer. In a drug discovery approach, their in silico pharmacokinetic profile has been evaluated in order to identify appropriate drug-like profiles, which should be taken into account for further progress toward the clinic.

This analysis may provide structural insights into the selection of specific cannabinoid scaffolds for the development of antitumor drugs for the treatment of particular types of cancer.” https://www.ncbi.nlm.nih.gov/pubmed/31214034

“The first report on the antitumor activity of phytocannabinoids was published over four decades ago. During these last years, significant research has been focused on the therapeutic potential of cannabinoids to manage palliative effects in cancer patients. Besides such palliative applications, some cannabinoids have shown anticancer properties. Since inflammation is a common risk factor for cancer, and some cannabinoids have shown anti-inflammatory properties, they could play a role in chemoprevention.” https://www.frontiersin.org/articles/10.3389/fphar.2019.00621/full
“Antitumor effects of THC.” http://www.ncbi.nlm.nih.gov/pubmed/11097557
“Antitumor effects of cannabidiol” http://www.ncbi.nlm.nih.gov/pubmed/14617682
“Anti-tumour actions of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/30019449
“Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer.” https://www.ncbi.nlm.nih.gov/pubmed/29940172
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The origins of cannabis smoking: Chemical residue evidence from the first millennium BCE in the Pamirs.

 Science Advances: 5 (6)“Cannabis is one of the oldest cultivated plants in East Asia, grown for grain and fiber as well as for recreational, medical, and ritual purposes. It is one of the most widely used psychoactive drugs in the world today, but little is known about its early psychoactive use or when plants under cultivation evolved the phenotypical trait of increased specialized compound production. The archaeological evidence for ritualized consumption of cannabis is limited and contentious. Here, we present some of the earliest directly dated and scientifically verified evidence for ritual cannabis smoking. This phytochemical analysis indicates that cannabis plants were burned in wooden braziers during mortuary ceremonies at the Jirzankal Cemetery (ca. 500 BCE) in the eastern Pamirs region. This suggests cannabis was smoked as part of ritual and/or religious activities in western China by at least 2500 years ago and that the cannabis plants produced high levels of psychoactive compounds.”

https://www.ncbi.nlm.nih.gov/pubmed/31206023

https://advances.sciencemag.org/content/5/6/eaaw1391

“Earliest evidence for cannabis smoking discovered in ancient tombs”  https://www.nationalgeographic.com/culture/2019/06/earliest-evidence-cannabis-marijuana-smoking-china-tombs/

“The First Evidence of Smoking Pot Was Found in a 2,500-Year-Old Pot”  https://www.smithsonianmag.com/smart-news/2500-year-old-chinese-cemetery-offers-earliest-physical-evidence-cannabis-smoking-180972410/

“Earliest Evidence of People “Smoking” Weed Found in 2,500-Year-Old Chinese Pots”  https://www.sciencealert.com/ancient-pots-from-china-reveal-humans-smoking-cannabis-2-500-years-ago

“Oldest evidence of marijuana use discovered in 2500-year-old cemetery in peaks of western China” https://www.sciencemag.org/news/2019/06/oldest-evidence-marijuana-use-discovered-2500-year-old-cemetery-peaks-western-china

“Cannabis use for medicinal purposes dates back at least 3,000 years.”  https://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#section/_7

“Cannabis has been used for medicinal purposes for thousands of years.” https://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq

“The use of Cannabis for medicinal purposes dates back to ancient times.” http://www.cancer.gov/about-cancer/treatment/cam/patient/cannabis-pdq#section/all

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Cannabidiol Overcomes Oxaliplatin Resistance by Enhancing NOS3- and SOD2-Induced Autophagy in Human Colorectal Cancer Cells.

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“Although oxaliplatin is an effective chemotherapeutic drug for colorectal cancer (CRC) treatment, patients often develop resistance to it. Therefore, a new strategy for CRC treatment is needed.

The purpose of this study was to determine the effect of cannabidiol(CBD), one of the components of the cannabis plant, in overcoming oxaliplatin resistance in CRC cells.

Taken together, these results suggest that elevated phosphorylation of NOS3 is essential for oxaliplatin resistance. The combination of oxaliplatin and CBD decreased NOS3 phosphorylation, which resulted in autophagy, by inducing the overproduction of ROS through mitochondrial dysfunction, thus overcoming oxaliplatin resistance.”

https://www.ncbi.nlm.nih.gov/pubmed/31195721

https://www.mdpi.com/2072-6694/11/6/781

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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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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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Should Oncologists Recommend Cannabis?

“Cannabis is a useful botanical with a wide range of therapeutic potential. Global prohibition over the past century has impeded the ability to study the plant as medicine. However, delta-9-tetrahydrocannabinol (THC) has been developed as a stand-alone pharmaceutical initially approved for the treatment of chemotherapy-related nausea and vomiting in 1986. The indication was expanded in 1992 to include treatment of anorexia in patients with the AIDS wasting syndrome. Hence, if the dominant cannabinoid is available as a schedule III prescription medication, it would seem logical that the parent botanical would likely have similar therapeutic benefits. The system of cannabinoid receptors and endogenous cannabinoids (endocannabinoids) has likely developed to help us modulate our response to noxious stimuli. Phytocannabinoids also complex with these receptors, and the analgesic effects of cannabis are perhaps the best supported by clinical evidence. Cannabis and its constituents have also been reported to be useful in assisting with sleep, mood, and anxiety. Despite significant in vitro and animal model evidence supporting the anti-cancer activity of individual cannabinoids-particularly THC and cannabidiol (CBD)-clinical evidence is absent. A single intervention that can assist with nausea, appetite, pain, mood, and sleep is certainly a valuable addition to the palliative care armamentarium. Although many healthcare providers advise against the inhalation of a botanical as a twenty-first century drug-delivery system, evidence for serious harmful effects of cannabis inhalation is scant and a variety of other methods of ingestion are currently available from dispensaries in locales where patients have access to medicinal cannabis. Oncologists and palliative care providers should recommend this botanical remedy to their patients to gain first-hand evidence of its therapeutic potential despite the paucity of results from randomized placebo-controlled clinical trials to appreciate that it is both safe and effective and really does not require a package insert.”

https://www.ncbi.nlm.nih.gov/pubmed/31161270

https://link.springer.com/article/10.1007%2Fs11864-019-0659-9

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