Author Archives: adminoacido

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Practical considerations in medical cannabis administration and dosing.

Category : Dolor

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Practical considerations in medical cannabis administration and dosing.

Eur J Intern Med. 2018 Jan 04;:

Authors: MacCallum CA, Russo EB

Abstract
Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.

PMID: 29307505 [PubMed – as supplied by publisher]

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Cannabis and Pediatric Inflammatory Bowel Disease: Change Blossoms a Mile High.

Category : Antiinflamatorio

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Cannabis and Pediatric Inflammatory Bowel Disease: Change Blossoms a Mile High.

J Pediatr Gastroenterol Nutr. 2017 Feb;64(2):265-271

Authors: Hoffenberg EJ, Newman H, Collins C, Tarbell S, Leinwand K

Abstract
The trend toward decriminalization of cannabis (marijuana) continues sweeping across the United States. Colorado has been a leader of legalization of medical and recreational cannabis use. The growing public interest in the medicinal properties of cannabis and its use by patients with a variety of illnesses including inflammatory bowel disease (IBD) makes it important for pediatric gastroenterologists to understand this movement and its potential effect on patients. This article describes the path to legalization and “medicalization” of cannabis in Colorado and the public perception of safety despite the known adverse health effects of use. We delineate the mammalian endocannabinoid system and our experience of caring for children and adolescents with IBD in an environment of increasing awareness and acceptance of its use. We then summarize the rationale for considering that cannabis may have beneficial and harmful effects for patients with IBD. Finally, we highlight the challenges federal laws impose on conducting research on cannabis in IBD. The intent of this article is to inform health care providers about the issues around cannabis use and research in adolescents and young adults with IBD.

PMID: 27579692 [PubMed – indexed for MEDLINE]

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Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts.

Category : Antiinflamatorio

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Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts.

Arch Oral Biol. 2017 Dec 06;87:79-85

Authors: Abidi AH, Presley CS, Dabbous M, Tipton DA, Mustafa SM, Moore BM

Abstract
OBJECTIVES: Approximately 65 million adults in the US have periodontitis, causing tooth loss and decreased quality of life. Cannabinoids modulate immune responses, and endocannabinoids are prevalent during oral cavity inflammation. Targets for intervention in periodontal inflammation are cannabinoid type 1 and 2 receptors (CB1R, CB2R), particularly CB2R because its levels increase during inflammation. We previously demonstrated that SMM-189 (CB2R inverse agonist) decreased pro-inflammatory cytokine production in primary microglial cells. The hypothesis of this study was that cannabinoids anandamide (AEA), HU-308 (CB2R selective agonist), and SMM-189 decrease pro-inflammatory IL-6 and MCP-1 production by primary human periodontal ligament fibroblasts (hPDLFs) stimulated with P. gingivalis LPS, TNF-α, or IL-1β.
DESIGN: Cytotoxic effects of cannabinoid compounds (10-4-10-6.5 M), LPS (1-1000 ng/ml), TNFα (10 ng/ml) and IL-1β (1 ng/ml) were assessed by measuring effects on cellular dehydrogenase activity. IL-6 and MCP-1 production were measured using Mesoscale Discovery (MSD) Human Pro-Inflammatory IL-6 and MSD Human Chemokine MCP-1 kits and analyzed using MSD Sector 2400 machine.
RESULTS: EC50 values for AEA, SMM-189, and HU-308 were 16 μM, 13 μM, and 7.3 μM respectively. LPS (1 μg/ml), TNF-α (10 ng/ml), and IL-1β (1 ng/ml) increased IL-6 and MCP-1 production, which were inhibited by AEA, SMM-189, and HU-308. AEA alone significantly increased IL-6, but not MCP-1 levels, but the other cannabinoids alone had no effect.
CONCLUSION: The effective inhibition of LPS, TNF-α, IL-1β stimulated IL-6 and MCP-1 production by CB2R ligands in hPDLFs suggests that targeting the endocannabinoid system may lead to development of novel drugs for periodontal therapy, aiding strategies to improve oral health.

PMID: 29274621 [PubMed – as supplied by publisher]

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Sex and age specific effects of delta-9-tetrahydrocannabinol during the periadolescent period in the rat: The unique susceptibility of the prepubescent animal.

Category : Antiinflamatorio

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Sex and age specific effects of delta-9-tetrahydrocannabinol during the periadolescent period in the rat: The unique susceptibility of the prepubescent animal.

Neurotoxicol Teratol. 2016 Nov – Dec;58:88-100

Authors: Silva L, Black R, Michaelides M, Hurd YL, Dow-Edwards D

Abstract
Adolescents who use marijuana are more likely to exhibit anxiety, depression, and other mood disorders, including psychotic-like symptoms. Additionally, the age at onset of use and the stress history of the individual can affect responses to cannabis. To examine the effect of early life experience on adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we exposed adolescent (postnatal day (P) 29-38) male and female rats, either shipped from a supplier or born in our vivarium, to once daily injections of 3mg/kg THC. Our findings suggest that males are more sensitive to the anxiolytic and antidepressant effects of THC, as measured by the elevated plus maze (EPM) and forced swim test (FST), respectively, than females. Exposure to the FST increased plasma corticosterone levels, regardless of drug treatment or origin and females had higher levels than males overall. Shipping increased THC responses in females (acoustic startle habituation) and in males (latency to immobility in FST). No significant effects of THC or shipping on pre-pulse inhibition were observed. Due to differences in timing of puberty in males and females during the P29-38 period of THC treatment, we also dosed female rats between P21-30 (pre-puberty) and male rats between P39-48 (puberty). Pre-pubertal animals showed reductions in anxiety on the EPM, an effect that was not seen in animals treated during puberty. These results suggest that both sexes are more susceptible to changes in emotional behavior when THC exposure occurs just prior to the onset of puberty. Within the animals dosed from P29-38, THC increased cannabinoid receptor 1 (CB1R) mRNA expression and tended to decrease CP55,940 stimulated [35S]GTPγS binding in the central amygdala only of females. Therefore, early stress enhances THC responses in males (in FST) and females (ASR habituation), THC alters CB1R expression and function in females only and prepubescent rats are generally more responsive to THC than pubertal rats. In summary, THC and stress interact with the developing endocannabinoid system in a sex specific manner during the peri-pubertal period.

PMID: 26898326 [PubMed – indexed for MEDLINE]

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Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells.

Category : Antiinflamatorio

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Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells.

United European Gastroenterol J. 2017 Dec;5(8):1108-1115

Authors: Gigli S, Seguella L, Pesce M, Bruzzese E, D’Alessandro A, Cuomo R, Steardo L, Sarnelli G, Esposito G

Abstract
Background: Clostridium difficile toxin A is responsible for colonic damage observed in infected patients. Drugs able to restore Clostridium difficile toxin A-induced toxicity have the potential to improve the recovery of infected patients. Cannabidiol is a non-psychotropic component of Cannabis sativa, which has been demonstrated to protect enterocytes against chemical and/or inflammatory damage and to restore intestinal mucosa integrity.
Objective: The purpose of this study was to evaluate (a) the anti-apoptotic effect and (b) the mechanisms by which cannabidiol protects mucosal integrity in Caco-2 cells exposed to Clostridium difficile toxin A.
Methods: Caco-2 cells were exposed to Clostridium difficile toxin A (30 ng/ml), with or without cannabidiol (10-7-10-9 M), in the presence of the specific antagonist AM251 (10-7 M). Cytotoxicity assay, transepithelial electrical resistence measurements, immunofluorescence analysis and immunoblot analysis were performed in the different experimental conditions.
Results: Clostridium difficile toxin A significantly decreased Caco-2 cells’ viability and reduced transepithelial electrical resistence values and RhoA guanosine triphosphate (GTP), bax, zonula occludens-1 and occludin protein expression, respectively. All these effects were significantly and concentration-dependently inhibited by cannabidiol, whose effects were completely abolished in the presence of the cannabinoid receptor type 1 (CB1) antagonist, AM251.
Conclusions: Cannabidiol improved Clostridium difficile toxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of the CB1 receptor.

PMID: 29238589 [PubMed]

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Treasure Hunt

Category : Noticias

Nine ways that scientists are targeting the endocannabinoid system with synthetic drugs and isolates
By Martin A. Lee On December 13, 2017

In recent years, cannabis has been at the center of one of the most important developments in modern science, which has significantly advanced our understanding of health and disease.

Research on marijuana’s effects led directly to the discovery of a major biochemical signaling system in the human body – the endocannabinoid system – which plays a pivotal role in regulating a wide range of physiological processes that affect our mood, our blood pressure, our bone density, our metabolism, our intestinal fortitude, our energy level, how we experience pain, stress, hunger, and much more.

“By using a plant that has been around for thousands of years, we discovered a new physiological system of immense importance,” says Israeli scientist Raphael Mechoulam. “We wouldn’t have been able to get there if we had not looked at the plant.”

Described by Mechoulam as “a medicinal treasure trove,” cannabis contains more than 100 unique biologically active compounds known as “cannabinoids,” including tetrahydrocannabinol (THC) and cannabidiol (CBD). THC causes the high that cannabis is famous for, CBD does not; both have important therapeutic attributes.

In addition to phytocannabinoids produced by the plant, there are endogenous cannabinoids – marijuana-like molecules – that occur naturally in the human brain and body. And there are also synthetic cannabinoids created by pharmaceutical researchers, who are developing new medicines that target the endocannabinoid system for therapeutic benefit.

Some of these novel synthetic compounds activate the same cannabinoid receptors – CB1 and CB2 – in the brain and body that respond pharmacologically to THC and other cannabis components.1

Medical scientists are also experimenting with synthetic drugs designed to improve “endocannabinoid tone” without binding directly to cannabinoid receptors.

Here are nine strategies that scientists are currently pursuing in an effort to harness the healing potential of the endocannabinoid system:

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Marinol

1. Single-molecule plant cannabinoids

Dronabinol, marketed in pill form as Marinol, is a single-molecule THC extract combined with sesame oil. It got fast-tracked for approval by the Food and Drug Administration in 1985 in response to rising patient demand for medical marijuana.

Other THC preparations are also on the FDA’s radar, including Syndros, a liquid THC drug produced by Insys. But patented single-molecule THC is a poor substitute for whole plant cannabis.

Even though it is highly psychoactive and potentially dysphoric, pharmaceutical THC is legally accessible in all 50 states as a prescription medication.

Cannabidiol, unlike pure THC, is not yet legal in all 50 states. But CBD will soon become a legal pharmaceutical, as the FDA is poised to approve Epidiolex, a botanically derived anti-seizure medication produced by GW Pharmaceuticals. Epidiolex is pure CBD with a dash of cannabidivarin (CBDV), a “minor” cannabinoid that also has potent anti-epileptic properties.

Along with the imminent advent of pharmaceutical CBD, several R&D firms have begun to harvest single-molecule cannabinoids, such as CBDV, from a yeast substrate. As this biotechnology improves, drug developers and pharmacists will have access to numerous single-molecule cannabis compounds.

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Image Credit: Bryan Satalino

2. Synthetic cannabinoid analogs

Scientists have created synthetic analogs of plant cannabinoids for research purposes and for commercial sale and distribution. Nabilone, a synthetic THC analog, was developed by Eli Lilly and Co. as a treatment for chemotherapy-induced nausea and vomiting.

Marketed under the trade name Cesamet, this synthetic cannabinoid is used as an adjunct therapy for chronic pain management in Canada and other countries. Clinical trials of Nabilone have indicated some effectiveness for fibromyalgia, Parkinson’s, PTSD-related nightmares, irritable bowel disease, and multiple sclerosis.

Researchers are using various synthetic analogs to investigate the biochemical pathways and molecular mechanisms of the endocannabinoid system. Some of these compounds (such as WIN55,212-2 and CP55,940) bind to both cannabinoid receptors – CB1 and CB2 – much like THC. Other experimental drugs target only one type of cannabinoid receptor and not the other. 2

A cannabinoid agonist binds to a cell receptor and causes it to initiate a signaling cascade that modulates various physiological processes and protects neurons against toxic insults. A cannabinoid antagonist binds to a cell receptor and prevents it from signaling.

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Image Credit: Bryan Satalino

3. Synthetic cannabinoid antagonists

Cannabinoid CB1 receptors, which mediate the psychoactive effects of THC, are concentrated in the brain and central nervous system. When THC binds to CB1, it can make a person feel stoned – and hungry. The “munchies,” scientists confirmed, are linked to stimulation of CB1 receptors in areas of the brain that regulate hunger and satiety. If activated, CB1 receptors induce appetite; if blocked, they reduce it.

SR141716,” a synthetic CB1 antagonist developed by the French pharmaceutical giant Sanofi-Aventis, was initially utilized as a research tool: By blocking CB1 and monitoring which functions were altered, scientists advanced their understanding of the endocannabinoid system.

Sanofi strategists believed they had invented the perfect diet pill, and they promoted SR141716 as an appetite suppressant in Europe. But the diet drug, sold as “Rimonabant,” proved to be too blunt an instrument. Before long, the synthetic CB1 antagonist was pulled from circulation because of dangerous side effects – high blood pressure, nausea, vomiting, anxiety, mood swings, depression, headaches, seizures, sleep disorders, and a heightened risk of suicide.

If nothing else, the CB1 antagonist debacle provided vivid evidence that a well-functioning endocannabinoid system is essential for good health.3

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4. Peripherally restricted CB1 agonists

Cannabinoid CB1 receptors, the most prevalent protein receptors in the human brain, influence many neurological functions, including marijuana’s mood-altering effects. CB1 receptors are also expressed in the enteric nervous system (the gut), the liver, kidneys, heart and other peripheral organs.

Stimulating CB1 receptors can deliver significant therapeutic benefits, but THC’s psychoactivity limits its medical utility, according to Big Pharma catechism, which defines the CB1-mediated marijuana “high” as an adverse side effect that drug designers should avoid if they hope to win regulatory approval of their patented synthetic novelties.

So pharmaceutical researchers have created peripherally-restricted CB1 agonists (such as AZ11713908) that only activate CB1 receptors outside the central nervous system, but don’t cross the blood-brain barrier.

A peripherally restricted CB1 agonist won’t cause side effects such as disconcerting dysphoria or useless euphoria. But such a compound has never been approved for therapeutic use by the FDA.

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Researchers studying impact on CB2 receptors in animals

5. Selective CB2 agonists

Scientists have been hot on the trail of another type of synthetic cannabinoid – a “selective CB2 agonist” – that will bypass the brain while acting on the peripheral nervous system, where CB2 receptors are concentrated. CB2 receptors regulate immune function, pain perception, and inflammation.

Tinkering with synthetic compounds (such as HU 308 and JWH 133) that selectively stimulate CB2 receptors raises the prospect of healing without the high because CB2 receptors are localized primarily outside the brain and thus do not induce psychoactivity.

Cannabinoid researchers have their eyes on the ultimate prize, the pharmaceutical Holy Grail – a non-addictive painkiller bereft of adverse side effects. Animal experiments focusing on the CB2 receptor initially showed promise.

Thus far, however, drug companies have not been able to synthesize clinically effective CB2-selective compounds, though not for lack of trying. “If drug discovery is a sea, then CB2 is a rock that is surrounded by shipwrecked-projects,” remarked Italian scientist Giovanni Appendino.

Image

Nanoemulsions

6. Water-soluble cannabinoids

In their natural form, plant cannabinoids and endocannabinoids are oily, hydrophobic substances that don’t dissolve in water. But these lipid molecules can be structurally altered so that they become water soluble without diminishing their therapeutic attributes.

Scientists have developed several ways of synthesizing water-compatible derivatives of THC and other cannabinoids that are more bioavailable and thus potentially more potent than their oily, naturally-occurring counterparts.

The first water-soluble version of THC was created in 1972. Subsequent research found that water-friendly cannabinoid derivatives can lower intraocular pressure in rabbits. A water-soluble cannabinoid ester, “O-1057,” exhibited stronger analgesic properties than THC in preclinical experimentation.

Internet retailers are claiming to sell water-soluble CBD formulated as a nanoemulsion. Pure CBD delivered via nanotechnology is supposed to provide exceptionally high bioavailability and remedial effect compared to a hydrophobic CBD oil extract.

But a CBD isolate typically requires a much higher dose for therapeutic efficacy than a whole plant CBD-rich concentrate – and this factor may cancel out the alleged advantages of nanoemulsified single-molecule CBD.

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ZCZ011 {Image source Wikipedia}

7. Allosteric cannabinoid receptor modulators

Because direct, full-on stimulation of cannabinoid receptors in the brain may trigger undesirable psychoactive effects, scientists have developed synthetic compounds that change the shape of the CB1 receptor and influence how it signals without causing a THC-like high. These compounds, known as allosteric modulators, can either amplify or decrease a receptor’s ability to transmit a signal.

A “positive allosteric modulator” increases the potency and/or efficacy of CB1 receptor activation by anandamide and 2AG (the two main endogenous cannabinoids), thereby boosting the protective effects of the endocannabinoid system.

Scientists at the University of Aberdeen in Scotland have synthesized a positive allosteric modulator of CB1 to treat pain and neurological disorders. When researchers at Virginia Commonwealth University tested this experimental drug (“ZCZ011”) on mice, it reduced inflammatory pain by magnifying the CB1 receptor’s response to anandamide.

But allosteric effects are rarely consistent across species, which significantly impedes drug development in this area.4

 

Image

The brain on cannabis

8. Inhibitors of endocannabinoid metabolizing enzymes

Medical scientists are experimenting with synthetic designer drugs to enhance endocannabinoid tone without binding directly (or allosterically) to cannabinoid receptors.

Pharmacological augmentation of endocannabinoid signaling can be achieved by inhibiting fatty acid amide hydrolase (FAAH) and/or monoglycerol lipase (MAGL), the catabolic enzymes that break down the brain’s own marijuana-like molecules, anandamide and 2AG, respectively.

Simply put, less FAAH and MAGL means more anandamide and 2AG, resulting in greater cannabinoid receptor activity throughout the body. Drugs that suppress endocannabinoid-metabolizing enzymes indirectly boost cannabinoid receptor signaling, causing a natural high without the vivid psychoactive effects associated with synthetic and plant-based CB1 agonists.

Preclinical research suggests that indirect modulation of endocannabinoid signaling could become a treatment option for various inflammatory conditions and stress-related disorders. FAAH and MAGL inhibition have been shown to ease pain, anxiety, colitis, hypertension, opiate withdrawal, diarrhea and arthritis in animal models.

While drug developers investigate synthetic FAAH-inhibitors (such as URB597) and MAGL-inhibitors (such as JZL 184), one need look no further than the kitchen spice rack for phytonutrients that regulate endocannabinoid tone by inhibiting the same catabolic enzymes. Nutmeg, one of many culinary spices that interact with the endocannabinoid system, inhibits the breakdown of both anandamide and 2AG, the brain’s own marijuana.

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AM404 {Image source Wikipedia}

9. Endocannabinoid reuptake inhibitors

Another way to augment endocannabinoid tone entails delaying the reuptake of anandamide and 2AG. Scientists have synthesized reuptake inhibitors (such as AM404) that target transport molecules known as fatty acid binding proteins. These membrane-penetrating fatty acid binding proteins facilitate the intracellular transport and reuptake of endogenous cannabinoids.

By blocking access to these critical transport molecules, synthetic reuptake inhibitors increase endocannabinoid levels in the brain’s synapses. This results in heightened cannabinoid receptor signaling and endocannabinoid-induced protective effects.

THC and CBD also inhibit endocannabinoid reuptake. Enhancing endocannabinoid tone via reuptake inhibition may be a key mechanism whereby plant cannabinoids confer protective effects against seizures and neurodegeneration, as well as many other health benefits.

Fool’s gold?

Despite repeated setbacks, the possibility of healing without the high persists as an idée fixe among cannabinoid scientists and pharmaceutical researchers.

The lack of success with selective CB2 agonists, peripherally restricted CB1 agonists, allosteric modulators, CB1 antagonists and other non-euphoric cannabinoids underscores the challenges and limitations of synthetic, monomolecular medicine that targets a single protein receptor while forsaking whole plant synergies.

Synthetic CBD analogs are also in development. By tweaking the mother molecule and removing, adding or editing a molecular side chain, pharmaceutical researchers hope to create a marketable compound that is more potent and more effective than botanical CBD.

But a CBD isolate is not inherently superior to a whole plant CBD-rich extract. Preclinical studies that compare the efficacy of single-molecule CBD and full spectrum CBD-rich oil concentrates indicate that CBD solo is effective only at precise, high doses – whereas whole plant CBD-rich extracts have a much wider and safer therapeutic window and are effective at significantly lower doses. Problematic drug interactions are also much likelier with high dose single-molecule CBD.

Regulatory policy should not privilege single-molecule meds over full spectrum cannabis remedies. Patients are best served by having access to a wide range of cannabinoid-based therapeutic options, including artisanal whole plant preparations and synthetic isolates, if and when they become available.


Martin A. Lee is the director of Project CBD and the author of Smoke Signals: A Social History of Marijuana – Medical, Recreational and Scientific.


Footnotes

  1. Only four cannabis compounds bind directly to either one or both cannabinoid receptors. THC activates CB1 and CB2. Cannabinol (CBN), a THC breakdown component, activates the CB1 receptor, though with less potency than THC. Tetrahydracannabivarin (THCV), the propyl variant of THC, binds to both cannabinoid receptors, activating CB2 while blocking CB1. And beta caryophyllene, an aromatic terpene found in many cannabis strains, green leafy vegetables, and common kitchen spices, activates CB2. Other cannabinoids, including CBD, interact with the endocannabinoid system indirectly without binding like lock and key to a cannabinoid receptor.
  2. Developed as a research tool to study that endocannabinoid system, JWH-018 is a synthetic cannabinoid compound that activates the CB1 receptor but not CB2. After the formula for this potent CB1 agonist was published in the scientific literature, JWH-018 surfaced as a street drug known as “Spice” or “K2.” Media accounts typically mischaracterize Spice as “synthetic marijuana.”
  3. U.S. government scientists have not given up entirely on Rimonabant. The fact that this compound blocks the euphoric effects of cannabis is a big plus to the National Institute on Drug Abuse, which has sponsored research on utilizing CB1 blockers to treat various addictions, including “cannabis dependence.”
  4. Canadian scientists have identified CBD as a “negative allosteric modulator” of the CB1 receptor based on in vitro research. This means that CBD, when administered in combination with THC, will alter the shape of the CB1 receptor in a way that weakens its binding affinity for THC. As a negative allosteric modulator of CB1, CBD lowers the ceiling on THC’s psychoactivity, which might be why people don’t feel as high when using CBD-rich cannabis as compared to a THC-infused product.

Sources

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• Ignatowska-Jankowska BM, Baillie GL, Kinsey S, Crowe M, Ghosh S, et al. A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects. Neuropsychopharmacology. 2015 Dec;40(13):2948-59. PubMed PMID: 26052038; PubMed Central PMCID: PMC4864630.
• Mitjavila J, Yin D, Kulkarni PM, Zanato C, Thakur GA, et al. Enantiomer-specific positive allosteric modulation of CB1 signaling in autaptic hippocampal neurons. Pharmacol Res. 2017 Nov 20;PubMed PMID: 29158048.
O’Hearn S, Diaz P, Wan BA, DeAngelis C, Lao N, et al. Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies. Ann Palliat Med. 2017 Aug 31;PubMed PMID: 29156899.
• Pertwee RG, Gibson TM, Stevenson LA, Ross RA, Banner WK, et al. O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties. Br J Pharmacol. 2000 Apr;129(8):1577-84. PubMed PMID: 10780961; PubMed Central PMCID: PMC1572002.
• Schindler CW, Scherma M, Redhi GH, Vadivel SK, Makriyannis A, et al. Self-administration of the anandamide transport inhibitor AM404 by squirrel monkeys. Psychopharmacology (Berl). 2016 May;233(10):1867-77. PubMed PMID: 26803499; NIHMSID: NIHMS754451; PubMed Central PMCID: PMC4846479.
• Wasilewski A, Misicka A, Sacharczuk M, Fichna J. Modulation of the endocannabinoid system by the fatty acid amide hydrolase, monoacylglycerol and diacylglycerol lipase inhibitors as an attractive target for secretory diarrhoea therapy. J Physiol Pharmacol. 2017 Aug;68(4):591-596. PubMed PMID: 29151076.
• Yu XH, Cao CQ, Martino G, Puma C, Morinville A, et al. A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain. Pain. 2010 Nov;151(2):337-44. PubMed PMID: 20696525.

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Hypothalamic-pituitary-adrenal axis measures and cognitive abilities in early psychosis: Are there sex differences?

Category : Antiinflamatorio

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Hypothalamic-pituitary-adrenal axis measures and cognitive abilities in early psychosis: Are there sex differences?

Psychoneuroendocrinology. 2016 Oct;72:54-62

Authors: Labad J, Gutiérrez-Zotes A, Creus M, Montalvo I, Cabezas Á, Solé M, Ortega L, Algora MJ, Sánchez-Gistau V, Vilella E

Abstract
INTRODUCTION: Measures of hypothalamic-pituitary-adrenal (HPA) axis activity such as increased diurnal cortisol levels or a blunted cortisol awakening response (CAR) have been associated with cognitive impairments in people with psychotic disorders. We aimed to explore whether there are sex differences in the relationship between HPA axis measures and cognition in early psychosis (EP).
METHODS: 60 EP outpatients and 50 healthy subjects (HS) were assessed with the MATRICS Consensus Cognitive Battery. Saliva cortisol levels were determined at the neuropsychological assessment and on another day at 6 sampling times: awakening; 30′ and 60′ post-awakening; and 10:00h, 23:00h and 10:00h the day after the administration of 0.25mg of dexamethasone, which occurred at 23:00h. Three HPA axis measures were calculated: CAR, cortisol diurnal slope and cortisol suppression ratio of the dexamethasone suppression test (DST). Multiple linear regression analyses were conducted to explore the relationship between HPA axis measures and cognitive tasks while adjusting for covariates (education level, smoking, cannabis use, and cortisol levels at the cognitive assessment). Interactions between female sex, EP diagnosis and HPA axis measures were examined.
RESULTS: An increased CAR was associated with a poorer cognitive performance in EP women in processing speed and verbal memory. In contrast, a more flattened diurnal cortisol slope was associated with poorer functioning in the spatial working memory of EP women. DST suppression ratio was associated with better visual memory, without sex differences.
CONCLUSIONS: Our study suggests that there are sex differences in the relationship between HPA axis measures and cognitive abilities in EP.

PMID: 27344379 [PubMed – indexed for MEDLINE]

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Cannabinoids for epilepsy: What do we know and where do we go?

Category : Epilepsia

Cannabinoids for epilepsy: What do we know and where do we go?

Epilepsia. 2017 Dec 06;:

Authors: Brodie MJ, Ben-Menachem E

Abstract
Over the past decade there has been an increasing interest in using cannabinoids to treat a range of epilepsy syndromes following reports of some remarkable responses in individual patients. The situation is complicated by the fact that these agents do not appear to work via their attachment to endogenous cannabinoid receptors. Their pharmacokinetics are complex, and bioavailability is variable, resulting in difficulty in developing a suitable formulation for oral delivery. Drug interactions also represent another complication in their everyday use. Nevertheless, recent randomized, placebo-controlled trials with cannabidiol support its efficacy in Dravet and Lennox-Gastaut syndromes. Further placebo-controlled studies are underway in adults with focal epilepsy using cannabidivarin. The many unanswered questions in the use of cannabinoids to treat epileptic seizures are briefly summarized in the conclusion.

PMID: 29214639 [PubMed – as supplied by publisher]

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Systematic review: interventions for abdominal pain management in inflammatory bowel disease.

Category : Antiinflamatorio

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Systematic review: interventions for abdominal pain management in inflammatory bowel disease.

Aliment Pharmacol Ther. 2017 Jul;46(2):115-125

Authors: Norton C, Czuber-Dochan W, Artom M, Sweeney L, Hart A

Abstract
BACKGROUND: Abdominal pain is frequently reported by people with inflammatory bowel disease (IBD), including in remission. Pain is an under-treated symptom.
AIM: To systematically review evidence on interventions (excluding disease-modifying interventions) for abdominal pain management in IBD.
METHODS: Databases (MEDLINE, EMBASE, PsycInfo, CINAHL, Scopus, Cochrane Library) were searched (February 2016). Two researchers independently screened references and extracted data.
RESULTS: Fifteen papers were included: 13 intervention studies and two cross-sectional surveys. A variety of psychological, dietary and pharmacological interventions were reported. Four of six studies reported pain reduction with psychological intervention including individualised and group-based relaxation, disease anxiety-related Cognitive Behavioural Therapy and stress management. Both psychologist-led and self-directed stress management in inactive Crohn’s disease reduced pain compared with controls (symptom frequency reduction index=-26.7, -11.3 and 17.2 at 6-month follow-up, respectively). Two dietary interventions (alcoholic drinks with high sugar content and fermentable carbohydrate with prebiotic properties) had an effect on abdominal pain. Antibiotics (for patients with bacterial overgrowth) and transdermal nicotine patches reduced abdominal pain. Current and past cannabis users report it relieves pain. One controlled trial of cannabis reduced SF-36 and EQ-5D pain scores (1.84 and 0.7, respectively). These results must be treated with caution: data were derived from predominantly small uncontrolled studies of moderate to low quality.
CONCLUSIONS: Few interventions have been tested for IBD abdominal pain. The limited evidence suggests that relaxation and changing cognitions are promising, possibly with individualised dietary changes. There is a need to develop interventions for abdominal pain management in IBD.

PMID: 28470846 [PubMed – indexed for MEDLINE]

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