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Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor.

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“The cannabinoid CB1 receptor is a G protein coupled receptor and plays an important role in many biological processes and physiological functions.

A variety of CB1 receptor agonists and antagonists, including endocannabinoids, phytocannabinoids, and synthetic cannabinoids, have been discovered or developed over the past 20 years.

In 2005, it was discovered that the CB1 receptor contains allosteric site(s) that can be recognized by small molecules or allosteric modulators.

A number of CB1 receptor allosteric modulators, both positive and negative, have since been reported and importantly, they display pharmacological characteristics that are distinct from those of orthosteric agonists and antagonists.

Given the psychoactive effects commonly associated with CB1 receptor agonists and antagonists/inverse agonists, allosteric modulation may offer an alternate approach to attain potential therapeutic benefits while avoiding inherent side effects of orthosteric ligands.

This review details the complex pharmacological profiles of these allosteric modulators, their structure-activity relationships, and efforts in elucidating binding modes and mechanisms of actions of reported CB1 allosteric modulators.

The ultimate development of CB1 receptor allosteric ligands could potentially lead to improved therapies for CB1-mediated neurological disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/27879006

Highest-resolution model to date of brain receptor behind marijuana’s high

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“Researchers at UT Southwestern Medical Center report the most detailed 3-D structure to date of the brain receptor that binds and responds to the chemical at the root of marijuana’s high.

Their high-resolution structure of the human cannabinoid receptor 1 (CB1) and its binding site for the chemical tetrahydrocannabinol (THC) should lead to a better understanding of how marijuana affects the brain.

The research also could aid discovery of new treatments for conditions that target the receptor, said Dr. Daniel Rosenbaum, Assistant Professor of Biophysics and Biochemistry at UT Southwestern.”

https://www.sciencedaily.com/releases/2016/11/161116131935.htm

Bioactive spirans and other constituents from the leaves of Cannabis sativa f. sativa.

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“In this paper, 17 compounds (1-17) were isolated from the leaves of Hemp (Cannabis sativa f. sativa). Among the isolates, two were determined to be new spirans: cannabispirketal (1), and α-cannabispiranol 4′-O-β-D-glucopyranose (2) by 1D and 2D NMR spectroscopy, LC-MS, and HRESIMS. The known compounds 7, 8, 10, 13, 15, and 16 were isolated from Hemp (C. sativa f. sativa) for the first time. Furthermore, compounds 8 and 13 were isolated from the nature for the first time. All isolated compounds were evaluated for cytotoxicity on different tissue-derived passage cancer cell lines through cell viability and apoptosis assay. Among these compounds, compounds 5, 9 and 16 exhibited a broad-spectrum antitumor effect via inhibiting cell proliferation and promoting apoptosis. These results obtained have provided valuable clues to the understanding of the cytotoxic profile for these isolated compounds from Hemp (C. sativa f. sativa).”

https://www.ncbi.nlm.nih.gov/pubmed/27848262

High-resolution crystal structure of the human CB1 cannabinoid receptor.

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“The human cannabinoid G-protein-coupled receptors (GPCRs) CB1 and CB2 mediate the functional responses to the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG), as well as the widely consumed plant (phyto)cannabinoid Δ9-tetrahydrocannabinol (THC)1. The cannabinoid receptors have been the targets of intensive drug discovery efforts owing to the therapeutic potential of modulators for controlling pain2, epilepsy3, obesity4, and other maladies. Although much progress has recently been made in understanding the biophysical properties of GPCRs, investigations of the molecular mechanisms of the cannabinoids and their receptors have lacked high-resolution structural data. We used GPCR engineering and lipidic cubic phase (LCP) crystallization to determine the structure of the human CB1 receptor bound to the inhibitor taranabant at 2.6 Å resolution. The extracellular surface of CB1, including the highly conserved membrane-proximal amino-terminal (N-terminal) region, is distinct from other lipid-activated GPCRs and forms a critical part of the ligand binding pocket. Docking studies further demonstrate how this same pocket may accommodate the cannabinoid agonist THC. Our CB1 structure provides an atomic framework for studying cannabinoid receptor function, and will aid the design and optimization of cannabinoid system modulators for therapeutic ends.”

 https://www.ncbi.nlm.nih.gov/pubmed/27851727

Non-violent drug users should face no penalty—a call from the Global Commission on Drug Policy

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“We urgently need pragmatic reform to develop effective and humane drug policies, including regulated drug markets, because prohibition has failed, write Ruth Dreifuss and Pavel Bém

The failures of prohibition—the attempt to eliminate illicit drugs for non-medical purposes through measures such as criminalisation or militarisation—and other repressive drug strategies are well documented. Over the past 50 years, they have been unable to curb either supply or demand at global or local levels. In fact, drug use, production, and trafficking, and concern about the issue among the general public, grow ever higher, while prohibition continues to exact a tragic toll on individuals and societies. Effective and humane drug policies are needed more urgently than ever.

This urgency can be felt both at the local level, where cities struggle to cope with drug use directly, and at the international level, with growing criticism of an outdated drug control system built on three United Nations conventions. Even though these conventions do not specifically insist on harsh punishment for drug use, national interpretation has favoured prohibitive approaches, with many harmful consequences.

The commission takes this a logical step further and calls for governments to regulate all illicit drugs. This would curb a massive revenue stream for organised crime, worth an estimated $320bn (£260bn; €290bn).7 It would also allow further research to inform policy and facilitate restriction of drug use—for example, setting the age of the user, maximum quantities allowed for sale or possession, and where drugs can be used. And it could help to shift perceptions from considering drugs as inherently “evil” to a more pragmatic mindset in which scientific evidence, not ideology, drives drug policy.”

http://www.bmj.com/content/355/bmj.i5921

“British Medical Journal calls for legalisation of drugs”  http://www.independent.co.uk/news/uk/crime/war-on-drugs-british-medical-journal-heroin-cannabis-cocaine-a7417171.html

 “War on drugs has failed says one of the world’s top medical journals”  http://www.mirror.co.uk/news/uk-news/war-drugs-british-medical-journal-9260434

“The war on drugs has failed and doctors should lead calls for change, says BMJ”  http://medicalxpress.com/news/2016-11-war-drugs-doctors-bmj.html

“The war on drugs has failed: doctors should lead calls for drug policy reform”  http://www.bmj.com/content/355/bmj.i6067

Medical cannabis and mental health: A guided systematic review

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“This review considers the potential influences of the use of cannabis for therapeutic purposes (CTP) on areas of interest to mental health professionals, with foci on adult psychopathology and assessment. We identified 31 articles relating to the use of CTP and mental health, and 29 review articles on cannabis use and mental health that did not focus on use for therapeutic purposes. Results reflect the prominence of mental health conditions among the reasons for CTP use, and the relative dearth of high-quality evidence related to CTP in this context, thereby highlighting the need for further research into the harms and benefits of medical cannabis relative to other therapeutic options. Preliminary evidence suggests that CTP may have potential for the treatment of PTSD, and as a substitute for problematic use of other substances. Extrapolation from reviews of non-therapeutic cannabis use suggests that the use of CTP may be problematic among individuals with psychotic disorders. The clinical implications of CTP use among individuals with mood disorders are unclear. With regard to assessment, evidence suggests that CTP use does not increase risk of harm to self or others. Acute cannabis intoxication and recent CTP use may result in reversible deficits with the potential to influence cognitive assessment, particularly on tests of short-term memory.

Cannabis use does not appear to increase risk of harm to self or others.”

http://www.sciencedirect.com/science/article/pii/S0272735816300939

“Marijuana could help treat drug addiction, mental health, study suggests”  https://www.sciencedaily.com/releases/2016/11/161116102847.htm

“Marijuana may help combat substance abuse, mental health disorders”  http://www.medicalnewstoday.com/articles/314159.php

“Medical cannabis may help treat mental health problems and opioid addiction”  http://www.news-medical.net/news/20161116/Medical-cannabis-may-help-treat-mental-health-problems-and-opioid-addiction.aspx

The central cannabinoid receptor type-2 (CB2) and chronic pain.

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“Cannabinoid receptor type-2 (CB2, CB2 Receptor, or CB2-R) mediates analgesia, via two mechanisms. CB2 receptors contained in peripheral immune tissue mediates analgesia by altering cytokine profiles, and thus has little adverse effects on central nervous systems. CB2 is also expressed in the neurons and glial cells of the Central Nervous System (CNS). This neuronal expression may also contribute to pain attenuation. The CB2 receptor has been proposed as a potential target in treating chronic pain of several etiologies.”

https://www.ncbi.nlm.nih.gov/pubmed/27842450

The combination of β-caryophyllene, baicalin and catechin synergistically suppresses the proliferation and promotes the death of RAW267.4 macrophages in vitro.

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“β-caryophyllene, which is a constituent of many essential oils, has been known to be a selective agonist of the cannabinoid receptor type-2 and to exert cannabimimetic anti-inflammatory effects in animals.

On the whole, this study demonstrates that the combination of β-caryophyllene, baicalin and (+)-catechin exerts synergistic suppressive effects on macrophages in vitro.

This composition may be a useful as an anti-inflammatory treatment strategy.”

https://www.ncbi.nlm.nih.gov/pubmed/27840942

A cannabinoid link between mitochondria and memory.

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“Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB1 receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1 receptors signal through intra-mitochondrial Gαi protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects ofcannabinoids. Thus, the G protein-coupled mtCB1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.”

https://www.ncbi.nlm.nih.gov/pubmed/27828947

Cannabinoid CB1 Receptors Are Localized in Striated Muscle Mitochondria and Regulate Mitochondrial Respiration.

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“The cannabinoid type 1 (CB1) receptor is widely distributed in the brain and peripheral organs where it regulates cellular functions and metabolism. In the brain, CB1 is mainly localized on presynaptic axon terminals but is also found on mitochondria (mtCB1), where it regulates cellular respiration and energy production. Likewise, CB1 is localized on muscle mitochondria, but very little is known about it. The aim of this study was to further investigate in detail the distribution and functional role of mtCB1 in three different striated muscles.

Immunoelectron microscopy for CB1 was used in skeletal muscles (gastrocnemius and rectus abdominis) and myocardium from wild-type and CB1 -KO mice. Functional assessments were performed in mitochondria purified from the heart of the mice and the mitochondrial oxygen consumption upon application of different acute delta-9-tetrahydrocannabinol (Δ9-THC) concentrations (100 nM or 200 nM) was monitored. About 26% of the mitochondrial profiles in gastrocnemius, 22% in the rectus abdominis and 17% in the myocardium expressed CB1. Furthermore, the proportion of mtCB1 versus total CB1 immunoparticles was about 60% in the gastrocnemius, 55% in the rectus abdominis and 78% in the myocardium. Importantly, the CB1 immunolabeling pattern disappeared in muscles of CB1 -KO mice.

Functionally, acute 100 nM or 200 nM THC treatment specifically decreased mitochondria coupled respiration between 12 and 15% in wild-type isolated mitochondria of myocardial muscles but no significant difference was noticed between THC treated and vehicle in mitochondria isolated from CB1 -KO heart. Furthermore, gene expression of key enzymes involved in pyruvate synthesis, tricarboxylic acid (TCA) cycle and mitochondrial respiratory chain was evaluated in the striated muscle of CB1 -WT and CB1 -KO. CB1 -KO showed an increase in the gene expression of Eno3, Pkm2, and Pdha1, suggesting an increased production of pyruvate. In contrast, no significant difference was observed in the Sdha and Cox4i1 expression, between CB1 -WT andCB1 -KO.

In conclusion, CB1 receptors in skeletal and myocardial muscles are predominantly localized in mitochondria. The activation of mtCB1 receptors may participate in the mitochondrial regulation of the oxidative activity probably through the relevant enzymes implicated in the pyruvate metabolism, a main substrate for TCA activity.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078489/