Second Cannabinoid Receptor Has the Yin to the First Receptor’s Yang

“Understanding the diverse effects that cannabis has on the human body is imperative if we hope to take advantage of its medicinal properties to treat various disorders. As such, elucidating the molecular structure of the receptors that bind endocannabinoids is a critical step toward developing selective drugs that can differentiate between the two known receptors—CB1 and CB2—for these molecules. Since the structure of the CB1 receptor was resolved a few years ago, an international team of researchers led by scientists at the iHuman Institute within ShanghaiTech University has just published the crystal structure of the human type 2 cannabinoid receptor, CB2.

Findings from the new study—published recently in Cell through an article titled “Crystal Structure of the Human Cannabinoid Receptor CB2”—should be helpful in the development of drugs against inflammatory, neurodegenerative, and other diseases. The study authors compared the newly discovered structure to that of the CB1 receptor, deeming the two receptors to be the “yin and yang” of the human endocannabinoid system.”

“Crystal Structure of the Human Cannabinoid Receptor CB1” https://www.cell.com/fulltext/S0092-8674(16)31385-X
“Crystal Structure of the Human Cannabinoid Receptor CB2” https://www.cell.com/cell/pdf/S0092-8674(18)31625-8.pdf
“This study compares newly discovered structures to those of the CB1 receptor, and deems the two receptors to be the Yin and Yang of the human endocannabinoid system, which is a signalling system that regulates biological processes such as pain, immune function, metabolism, and neuronal activities among others.” https://www.worldhealth.net/news/ying-yang-second-cannabinoid-receptor/
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Complete biosynthesis of cannabinoids and their unnatural analogues in yeast

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“Cannabis sativa L. has been cultivated and used around the globe for its medicinal properties for millennia. Some cannabinoids, the hallmark constituents of Cannabis, and their analogues have been investigated extensively for their potential medical applications. Certain cannabinoid formulations have been approved as prescription drugs in several countries for the treatment of a range of human ailments. However, the study and medicinal use of cannabinoids has been hampered by the legal scheduling of Cannabis, the low in planta abundances of nearly all of the dozens of known cannabinoids, and their structural complexity, which limits bulk chemical synthesis. Here we report the complete biosynthesis of the major cannabinoids cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, cannabidiolic acid, Δ9-tetrahydrocannabivarinic acid and cannabidivarinic acid in Saccharomyces cerevisiae, from the simple sugar galactose. To accomplish this, we engineered the native mevalonate pathway to provide a high flux of geranyl pyrophosphate and introduced a heterologous, multi-organism-derived hexanoyl-CoA biosynthetic pathway. We also introduced the Cannabis genes that encode the enzymes involved in the biosynthesis of olivetolic acid, as well as the gene for a previously undiscovered enzyme with geranylpyrophosphate:olivetolate geranyltransferase activity and the genes for corresponding cannabinoid synthases. Furthermore, we established a biosynthetic approach that harnessed the promiscuity of several pathway genes to produce cannabinoid analogues. Feeding different fatty acids to our engineered strains yielded cannabinoid analogues with modifications in the part of the molecule that is known to alter receptor binding affinity and potency. We also demonstrated that our biological system could be complemented by simple synthetic chemistry to further expand the accessible chemical space. Our work presents a platform for the production of natural and unnatural cannabinoids that will allow for more rigorous study of these compounds and could be used in the development of treatments for a variety of human health problems.”

https://www.nature.com/articles/s41586-019-0978-9

“Yeast can produce THC, CBD, novel cannabinoids”  https://www.upi.com/Science_News/2019/02/28/Yeast-can-produce-THC-CBD-novel-cannabinoids/4411551303863/

“Yeast produce low-cost, high-quality cannabinoids”  https://www.eurekalert.org/pub_releases/2019-02/uoc–ypl022419.php

“Engineered yeast can brew up the active ingredients in cannabis plants”  https://www.newscientist.com/article/2195103-engineered-yeast-can-brew-up-the-active-ingredients-in-cannabis-plants/

“High grade cannabis chemicals produced using brewing yeast”  https://www.independent.co.uk/news/science/cannabis-drug-produced-yeast-marijuana-thc-cbd-medicine-california-a8799576.html

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Crystal Structure of the Human Cannabinoid Receptor CB2

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“The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257’s unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.”
“Study reveals the structure of the 2nd human cannabinoid receptor”   HTTPS://MIPT.RU/ENGLISH/NEWS/STUDY_REVEALS_THE_STRUCTURE_OF_THE_2ND_HUMAN_CANNABINOID_RECEPTOR
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The Association between Cannabis Product Characteristics and Symptom Relief

Scientific Reports

“Across product characteristics, only higher THC levels were independently associated with greater symptom relief and prevalence of positive and negative side effects. In contrast, CBD potency levels were generally not associated with significant symptom changes or experienced side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/30804402

https://www.nature.com/articles/s41598-019-39462-1

“Notorious psychoactive chemical THC more important for therapeutic effects in cannabis than previously believed. Contrary to popular media-reports and scientific dogma, the psychoactive chemical, tetrahydrocannabinol or “THC,” showed the strongest correlation with therapeutic relief and far less evidence for the benefits of relying on the more socially acceptable chemical, cannabidiol or “CBD.””  https://news.unm.edu/news/notorious-psychoactive-chemical-thc-more-important-for-therapeutic-effects-in-cannabis-than-previously-believed

“THC more important for therapeutic effects in cannabis than previously believed”  https://medicalxpress.com/news/2019-02-thc-important-therapeutic-effects-cannabis.html

“THC found more important for therapeutic effects in cannabis than originally thought” https://www.sciencedaily.com/releases/2019/02/190226112353.htm

“Study: Patients Find More Relief In Marijuana‘s Physchoactive Compound THC Than In CBD.https://www.forbes.com/sites/javierhasse/2019/02/27/study-patients-find-more-relief-in-marijuanas-physchoactive-compound-thc-than-in-cbd/#384ee158717a

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Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: a report of three cases

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“Epidermolysis bullosa (EB) is a genetic blistering disorder characterized by intense pain related to disease pathology and care‐based interventions.

Opioid‐based therapies underpin pain care in EB; however, they are unable to provide adequate analgesia in a significant proportion of patients.

Cannabinoid‐based medicines (CBMs) have been studied increasingly for pain conditions of various aetiologies and pose as a novel dimension for pain care in EB.

We present three patients with EB who were prescribed pharmaceutical‐grade sublingually administered CBMs comprising tetrahydrocannabinol and cannabidiol.

All three patients reported improved pain scores, reduced pruritus and reduction in overall analgesic drug intake.”

https://www.ncbi.nlm.nih.gov/pubmed/30347109

https://onlinelibrary.wiley.com/doi/full/10.1111/bjd.17341

“Cannabinoids Could Help Manage EB-related Pain, Study Suggests”  https://epidermolysisbullosanews.com/2019/02/08/cannabinoids-could-help-manage-eb-related-pain-study-suggests/

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WHO proposes rescheduling cannabis to allow medical applications

Image result for the bmj journal“The World Health Organization has proposed rescheduling cannabis within international law to take account of the growing evidence for medical applications of the drug, reversing its position held for the past 60 years that cannabis should not be used in legitimate medical practice.”

https://www.bmj.com/content/364/bmj.l574

“WHO RECOMMENDS RESCHEDULING #CANNABIS IN INTERNATIONAL LAW FOR FIRST TIME IN HISTORY. The World Health Organization has suggested that cannabis should be downgraded, or “rescheduled,” given the mounting evidence showing that the drug could prove beneficial in treating a number of health problems. This marks a significant change in WHO’s position, which for the last 60 years has said that cannabis should not be used in medicine, according to an article in the BMJ.” https://www.newsweek.com/who-recommends-rescheduling-cannabis-international-law-first-time-history-1324613
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Synthetic Cannabinoid Activity Against Colorectal Cancer Cells

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“Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, and new therapeutic strategies are still required. Here we screened a synthetic cannabinoid library to identify compounds that uniformly reduce the viability of seven CRC cell lines.

We identified 10 compounds from the library that were able to reduce cell viability of CRC cell lines.

Conclusion: We identified three families of cannabinoid compounds that reduce CRC cell viability through a noncanonical receptor mechanism. Future modification of these compounds may lead to the development of novel therapies to treat this disease.”

https://www.liebertpub.com/doi/10.1089/can.2018.0065

“Cannabinoid compounds may inhibit growth of colon cancer cells”  https://news.psu.edu/story/557660/2019/02/06/research/cannabinoid-compounds-may-inhibit-growth-colon-cancer-cells

“CANNABIS COMPOUNDS SLOW COLON CANCER IN THE LAB”  https://www.futurity.org/cannabinoids-colon-cancer-1975272/

“Synthetic cannabis may stop colorectal cancer from growing, study suggests”  https://www.dailymail.co.uk/health/article-6674275/Synthetic-cannabis-stop-colorectal-cancer-growing-study-suggests.html

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Marijuana smoking and markers of testicular function among men from a fertility centre

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“Men who had ever smoked marijuana had significantly higher sperm concentration than men who had never smoked marijuana after adjusting for potential confounders.

These findings are not consistent with a deleterious effect of marijuana on testicular function.”

https://www.ncbi.nlm.nih.gov/pubmed/30726923

https://academic.oup.com/humrep/advance-article-abstract/doi/10.1093/humrep/dez002/5307080?redirectedFrom=fulltext

“SMOKING MARIJUANA APPEARS TO UP MEN’S SPERM COUNT—TO THE SURPRISE OF SCIENTISTS” https://www.newsweek.com/smoking-marijuana-appears-men-sperm-count-surprise-scientists-1318138

“Cannabis Smoking Associated With Higher Sperm Count, Study Finds”  https://www.bloomberg.com/news/articles/2019-02-06/cannabis-smoking-associated-with-higher-sperm-count-study-finds

“Smoking cannabis has unexpectedly been linked to greater fertility in men.” https://www.independent.ie/world-news/north-america/smoking-cannabis-can-make-men-more-fertile-say-scientists-37787137.html

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A Cost-Effectiveness Model for Adjunctive Smoked Cannabis in the Treatment of Chronic Neuropathic Pain

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“A recent meta-analysis affirmed the benefit of medicinal cannabis for chronic neuropathic pain, a disabling and difficult-to-treat condition. As medicinal cannabis use is becoming increasingly prevalent among Americans, an exploration of its economic feasibility is warranted. We present this cost-effectiveness analysis of adjunctive cannabis pharmacotherapy for chronic peripheral neuropathy.

A growing body of scientific literature demonstrates reproducible efficacy of cannabis in the treatment of several medical conditions, including chronic neuropathic pain. Clinical trials of oral, smoked, and vaporized cannabis and cannabinoids have all demonstrated analgesic benefit of medicinal cannabis in the treatment of this costly and disabling condition. A recent meta-analysis of individual patient data from five randomized controlled trials of inhaled cannabis demonstrated pain relief comparable to gabapentin. Treatment guidelines for neuropathic pain recommend consideration of cannabinoids as third-line agents.

As recently proposed willingness-to-pay thresholds for the United States health marketplace range from $110,000 to $300,000 per QALY, cannabis appears cost-effective when augmenting second-line treatment for painful neuropathy. Further research is warranted to explore the long-term benefit of smoked cannabis and standardization of its dosing for chronic neuropathic pain.”

https://www.liebertpub.com/doi/10.1089/can.2018.0027

“New study analyzes cost effectiveness of smoked cannabis to treat chronic neuropathic pain” https://www.eurekalert.org/pub_releases/2019-01/mali-nsa012919.php

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Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy.

Scientific Reports

“There has been a dramatic increase in the number of children diagnosed with autism spectrum disorders (ASD) worldwide. Recently anecdotal evidence of possible therapeutic effects of cannabis products has emerged.

The aim of this study is to characterize the epidemiology of ASD patients receiving medical cannabis treatment and to describe its safety and efficacy.

We analysed the data prospectively collected as part of the treatment program of 188 ASD patients treated with medical cannabis between 2015 and 2017. The treatment in majority of the patients was based on cannabis oil containing 30% CBD and 1.5% THC. Symptoms inventory, patient global assessment and side effects at 6 months were primary outcomes of interest and were assessed by structured questionnaires.

After six months of treatment 82.4% of patients (155) were in active treatment and 60.0% (93) have been assessed; 28 patients (30.1%) reported a significant improvement, 50 (53.7%) moderate, 6 (6.4%) slight and 8 (8.6%) had no change in their condition. Twenty-three patients (25.2%) experienced at least one side effect; the most common was restlessness (6.6%).

Cannabis in ASD patients appears to be well tolerated, safe and effective option to relieve symptoms associated with ASD.”

https://www.ncbi.nlm.nih.gov/pubmed/30655581

https://www.nature.com/articles/s41598-018-37570-y

“Medical cannabis is an effective, well-tolerated, and most importantly, a safe treatment for autism in children, helping to reduce a range of symptoms in those with the condition, a new study finds.” https://www.studyfinds.org/cannabis-safe-effective-treatment-autism-young-children/

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