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Cbd capsules or cbd spray or drops for anxiety medication

Mechoulam R



  • Mechoulam R
  • Cannabinoid pharmacology: the first 66 years
  • raphael mechoulam
  • Raphael Mechoulam (Hebrew: רפאל משולם ) (born ) is an Israeli organic chemist and professor of Medicinal Chemistry at the Hebrew University of. A Total Synthesis of dl-Δ1-Tetrahydrocannabinol, the Active Constituent of Hashish1. R. Mechoulam, and Y. Gaoni. J. Am. Chem. Soc., , 87 (14), pp –. Y. Gaoni, and R. Mechoulam. J. Am. Chem. Soc., , 86 (8), pp – DOI: /jaa Publication Date: April ACS Legacy Archive.

    Mechoulam R

    Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP-activated protein kinase Faseb Journal. Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson's disease: Functional roles and therapeutic opportunities Gli endocannabinoidi: Endothelial-mediated regulation of cerebral microcirculation Journal of Physiology and Pharmacology.

    Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. Cannabidiol, a constituent of Cannabis sativa, modulates sleep in rats. Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling Molecular Pharmacology. The chemistry of endocannabinoids. Journal of Endocrinological Investigation.

    Cannabidiol lowers incidence of diabetes in non-obese diabetic mice Autoimmunity. A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells Molecular Pharmacology.

    Endocannabinoids, feeding and suckling - From our perspective International Journal of Obesity. N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties. Peripheral cannabinoid receptor, CB2, regulates bone mass. The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines Neurobiology of Disease. Deltatetrahydrocannabinol and cannabidiol, but not ondansetron, interfere with conditioned retching reactions elicited by a lithium-paired context in Suncus murinus: An animal model of anticipatory nausea and vomiting.

    Endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice. Cns and Neurological Disorders. Hippocampal cannabinoid-1 receptor upregulation upon endothelin-B receptor deficiency: Toward an anandamide transporter. Differential response to acute and repeated stress in cannabinoid CB 1 receptor knockout newborn and adult mice Behavioural Pharmacology.

    Therapeutic opportunities through modulation of the endocannabinoid system. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: Effects of the endocannabinoid noladin ether on body weight, food consumption, locomotor activity, and cognitive index in mice.

    CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition. Cannabinoids in models of chronic inflammatory conditions Phytochemistry Reviews. Pain reduction and lack of psychotropic effects with ajulemic acid: Comment on the article by Sumariwalla et al [4] multiple letters Arthritis and Rheumatism.

    Synthesis and antitumor activity of quinonoid derivatives of cannabinoids. Journal of Medicinal Chemistry. The promise of advances in the field of endocannabinoids. Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. A comparative analysis of the potential of cannabinoids and ondansetron to suppress cisplatin-induced emesis in the Suncus murinus house musk shrew Psychopharmacology.

    Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus house musk shrew Psychopharmacology. Gamma-irradiation enhances apoptosis induced by cannabidiol, a non-psychotropic cannabinoid, in cultured HL myeloblastic leukemia cells. Cannabidiol - Transdermal delivery and anti-inflammatory effect in a murine model Journal of Controlled Release. Stout guards of the central nervous system.

    Science New York, N. Short-term fasting and prolonged semistarvation have opposite effects on 2-AG levels in mouse brain Brain Research. The CB1 cannabinoid receptor agonist, HU, reduces levodopa-induced rotations in 6-hydroxydopamine-lesioned rats. Drug-induced hypothermia reduces ischemic damage: Effects of the cannabinoid HU Stroke. Cannabis and alcohol - A close friendship Trends in Pharmacological Sciences. Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice: Effects of cannabinoids on lithium-induced conditioned rejection reactions in a rat model of nausea Psychopharmacology.

    Antioxidant properties of the vasoactive endocannabinoid, 2-arachidonoyl glycerol 2-AG Acta Neurochirurgica, Supplementum. An overview of some chemical and pharmacological aspects. Chemical aspects Chemistry and Physics of Lipids. Activation of cannabinoid receptors decreases the area of ischemic myocardial necrosis Bulletin of Experimental Biology and Medicine. Endogenous cannabinoids improve myocardial resistance to arrhythmogenic effects of coronary occlusion and reperfusion: A possible mechanism Bulletin of Experimental Biology and Medicine.

    An overview of some pharmacological aspects Journal of Clinical Pharmacology. Comparison of the enzymatic stability and intraocular pressure effects of 2-arachidonylglycerol and noladin ether, a novel putative endocannabinoid Investigative Ophthalmology and Visual Science.

    Tetrahydrocannabinol and endocannabinoids in feeding and appetite Pharmacology and Therapeutics. Increase of the heart arrhythmogenic resistance and decrease of the myocardial necrosis zone during activation of cannabinoid receptors Povyshenie ustoichivosti serdtsa k aritmogennym vozdeistviiam i umen'shenie zony ishemicheskogo nekroza miokarda pri aktivatsii kannabinoidnykh retseptorov Rossiiskii Fiziologicheskii Zhurnal Imeni I.

    Discovery of endocannabinoids and some random thoughts on their possible roles in neuroprotection and aggression Prostaglandins Leukotrienes and Essential Fatty Acids. International Union of Pharmacology. Classification of cannabinoid receptors. Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats Neuroreport.

    Endocannabinoids and neuroprotection Science's Stke: Signal Transduction Knowledge Environment. Noladin ether, a putative novel endocannabinoid: Inactivation mechanisms and a sensitive method for its quantification in rat tissues Febs Letters. Cannabinoids and brain injury: Therapeutic implications Trends in Molecular Medicine. Lipids in neural function: Therapeutic implications in vomiting and nausea after cancer chemotherapy, in appetite promotion, in multiple sclerosis and in neuroprotection Pain Research and Management.

    Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide British Journal of Pharmacology.

    An endogenous cannabinoid 2-AG is neuroprotective after brain injury Nature. Suppressors of cancer cell proliferation from fig Ficus carica resin: Isolation and structure elucidation Journal of Natural Products. Critical role of the endogenous cannabinoid system in mouse pup suckling and growth European Journal of Pharmacology. A hunger for cannabinoids Nature.

    Involvement of central and peripheral cannabinoid receptors in the regulation of heart resistance to arrhythmogenic effects of epinephrine Bulletin of Experimental Biology and Medicine.

    A historical overview of chemical research on cannabinoids Chemistry and Physics of Lipids. Human brain capillary endothelium: The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis Proceedings of the National Academy of Sciences of the United States of America.

    Looking back at cannabis research Current Pharmaceutical Design. A submicron emulsion of HU, a synthetic cannabinoid, reduces intraocular pressure in rabbits Graefe's Archive For Clinical and Experimental Ophthalmology.

    Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice European Journal of Pharmacology. Synthesis of a primary metabolite of cannabidiol Organic Letters.

    A nonpsychotropic cannabinoid with neuroprotective properties Drug Development Research. PADMA, a traditional tibetan herbal preparation inhibits the respiratory burst in human neutrophils, the killing of epithelial cells by mixtures of oxidants and pro-inflammatory agonists and peroxidation of lipids.

    Discovery and characterization of endogenous cannabinoids. From gan-zi-gun-nu to anandamide and 2-arachidonoylglycerol: The ongoing story of cannabis Natural Product Reports. Recent advances in Cannabinoid research Jungste fortschritte in der Cannabinoid-forschung Forschende Komplementarmedizin. A new radioligand for positron emission tomographic studies of cannabinoid receptors Journal of Labelled Compounds and Radiopharmaceuticals.

    Trick or treat from food endocannabinoids? Carbachol, an acetylcholine receptor agonist, enhances production in rat aorta of 2-arachidonoyl glycerol, a hypotensive endocannabinoid European Journal of Pharmacology. Biphasic effects of anandamide Pharmacology Biochemistry and Behavior. Binding to cannabinoid receptors and inhibition of adenylylcyclase Journal of Medicinal Chemistry.

    The sleep inducing factor oleamide is produced by mouse neuroblastoma cells Biochemical and Biophysical Research Communications. Anandamide may mediate sleep induction [6] Nature. Todd's achievement [6] Nature. Structural requirements for binding of anandamide-type compounds to the brain cannabinoid receptor Journal of Medicinal Chemistry. Cytokine production in the brain following closed head injury: Endogenous cannabinoid ligands Advances in Experimental Medicine and Biology.

    Endogenous and synthetic cannabinoids: Recent advances Cns Drug Reviews. The structure of senegenic acid, a nortriterpene artifact from Polygala senega. The Journal of Organic Chemistry. The synthesis of hydroxyalpha-testosterone.

    Mechoulam R , Parker L. Mechoulam R , Parker LA. For the in vivo bioassay of cannabinoids, one of these was to exploit the apparent ability of animals to discriminate between the subjective effects of psychotropic cannabinoids and those of noncannabinoids or of cannabinoids that lack psychotropic activity. Another in vivo strategy, devised in Billy Martin's laboratory at Virginia Commonwealth University, was to compare the ability of a test compound to produce four effects in a group of mice: One or other of these effects can be produced by a wide range of noncannabinoids.

    Consequently, at least some degree of selectivity can be achieved by subjecting animals to all four tests. One of the first in vitro strategies used to distinguish cannabinoid receptor agonists from other ligands was to perform bioassays either with cells that had been transfected with CB 1 or CB 2 receptors or with membranes obtained from these cells.

    For validating a particular bioassay, it also proved helpful to establish whether a correlation existed between the potencies exhibited by a set of cannabinoids or by a pair of enantiomeric cannabinoids for displacing a radioligand from CB 1 binding sites and the pharmacological potencies shown by the same compounds in the bioassay under investigation. Once cannabinoid receptors had been discovered, it became important to establish whether mammalian tissues also produce a cannabinoid receptor agonist or whether these receptors are targets only for plant cannabinoids and their synthetic cousins.

    The search for an endogenous cannabinoid had begun. One likely candidate was isolated from pig brain by Bill Devane, who was now working in Jerusalem with Raphael Mechoulam Devane et al.

    To establish whether this endogenous ligand would activate CB 1 receptors, a few micrograms were sent to Aberdeen where it was found that this test material did indeed share the ability of CB 1 receptor agonists to inhibit electrically evoked contractions of the mouse isolated vas deferens Devane et al. Moreover, it produced this inhibitory effect in a naloxone-insensitive manner and with an EC 50 value that approximated to its CB 1 K i value, a finding that is in line with its subsequent classification as a CB 1 receptor partial agonist reviewed in Howlett et al.

    Evidence that anandamide was acting through CB 1 receptors in the vas deferens was initially obtained by demonstrating that tissues rendered tolerant to established CB 1 receptor agonists but not to noncannabinoid inhibitors of electrically evoked contractions such as clonidine or opioid receptor agonists reviewed in Pertwee, also exhibit tolerance to anandamide Pertwee et al.

    It was subsequently confirmed that anandamide is active in other established bioassays for cannabinoid receptor agonists reviewed in Pertwee, ; and, once the first CB 1 -selective antagonist, SRA, had been developed see below , that anandamide is susceptible to antagonism by this ligand Rinaldi-Carmona et al. It was fortuitous that the first isolated tissue experiments with the minute amounts of anandamide that had been extracted from pig brain were not carried out with the guinea-pig MPLM preparation, then also being used in Aberdeen for the bioassay of cannabinoids, as it subsequently became apparent that anandamide is rapidly metabolized by this guinea-pig preparation but not by the mouse vas deferens Pertwee et al.

    The discovery of anandamide was followed by reports that mammalian tissues contain a number of other fatty acid derivatives that behave as endogenous cannabinoids reviewed in Di Marzo et al. Apart from anandamide, the most investigated of these has been 2-arachidonoyl glycerol Figure 2. They are then metabolized intracellularly, anandamide by fatty acid amide hydrolase and 2-arachidonoyl glycerol mainly by monoacylglycerol lipase reviewed in Di Marzo et al.

    Most of the endogenous cannabinoids that have so far been identified are high- or low-efficacy cannabinoid receptor agonists. All these compounds proved to be agonists for both CB 1 and CB 2 receptors that bind more or less equally well to each receptor type but that vary in their CB 1 and CB 2 affinities and relative intrinsic activities.

    Agonists that activate CB 1 receptors or CB 2 receptors selectively have also been developed. One other major advance prompted by the discovery of cannabinoid receptors was the development of selective cannabinoid receptor antagonists reviewed in Howlett et al.

    The availability of selective CB 1 and CB 2 receptor antagonists and agonists has greatly facilitated research into the pharmacology of cannabinoids. These antagonists seem to lack the apparent ability of ligands such as SRA to reduce the degree of any constitutive activity exhibited by CB 1 receptors reviewed in Pertwee, a.

    A common property of all cannabinoid receptor agonists and antagonists currently used as experimental tools is one of high lipophilicity and low or negligible water solubility. This necessitates the use of a vehicle such as dimethyl sulphoxide, Tween or ethanol, which may itself produce pharmacological changes or influence the free concentration of a cannabinoid at its site of action.

    This practical difficulty prompted an exploration of the possibility of developing a water-soluble cannabinoid receptor agonist, leading to the synthesis by Raj Razdan of O, a classical cannabinoid that is readily soluble in water and yet almost as potent as CP as a CB 1 and CB 2 receptor agonist Pertwee et al. It is now generally accepted that, in contrast to 2-arachidonoyl glycerol and established non-eicosanoid cannabinoids, anandamide can activate not only CB 1 and CB 2 receptors but also vanilloid TRPV1 receptors reviewed in Ross, In addition, evidence has recently emerged that the orphan G-protein-coupled receptor, GPR55, is a cannabinoid receptor see, e.

    This should be borne in mind when selecting a cannabinoid receptor agonist for use as a pharmacological tool or potential medicine. Also, the possibility still remains that cannabinoids produce some of their effects by inducing structure-dependent perturbations of membrane lipids as proposed by Edward Gill and David Lawrence see above. One other recent finding of note is that the CB 1 receptor has an allosteric site Price et al.

    However, a fuller elucidation of the mechanisms that underlie the development of this tolerance had to await the discovery of cannabinoid receptors. It then became possible to establish, at least for effects mediated by cannabinoid CB 1 receptors, that internalization of these receptors with or without their subsequent degradation, decreases in CB 1 receptor protein synthesis, and reductions in the efficiency of CB 1 receptor signalling desensitization can all contribute to the development of tolerance to agonists for these receptors.

    Interestingly, the extent to which any one of these mechanisms is involved in the production of this tolerance seems to be brain area-dependent and also to be influenced by agonist efficacy. Not much is presently known about tolerance to effects mediated by cannabinoid CB 2 receptors. The discovery of this system has had a major impact on cannabinoid research which now focuses not only on the pharmacology of phytocannabinoids and their synthetic analogues but also on the pharmacology of the endocannabinoids, on the physiological and pathological events that trigger their release and subsequent cellular uptake and metabolism, and on the roles that endocannabinoids and their pharmacological targets play in both health and disease.

    In some of these disorders, for example, multiple sclerosis, certain types of pain, cancer, schizophrenia, post-traumatic stress disorders, some intestinal and cardiovascular diseases, excitotoxicity and traumatic head injury, this upregulation of the endocannabinoid system may cause a reduction in the severity of symptoms or a slowing of disease progression.

    However, there are other disorders, for example, impaired fertility in women, obesity, cerebral injury in stroke, endotoxaemic shock, cystitis, ileitis and paralytic ileus, in which the unwanted effects appear to result from an upregulation of the endocannabinoid system, suggesting that this system has its own pathology and possibly also that it sometimes mediates unwanted effects because it is being influenced by pathological events taking place in some other system from which it receives input.

    Research into the therapeutic potential of individual cannabinoids began in the s, ironically at a time when tincture of cannabis had just been withdrawn as a medicine in the U.

    Although this research programme was never completed, it did generate an important set of novel cannabinoid receptor agonists that played a major role in the discovery of the CB 1 receptor see above. More recently, attention has again focused on the possibility of using cannabinoids as analgesics. Attention is also being directed at other therapeutic applications for cannabinoid receptor agonists that include the relief of other kinds of pain, the management of the spasms and spasticity of multiple sclerosis, and the treatment of intestinal disorders and of certain kinds of cancer.

    In addition, there is now considerable interest in developing new strategies that might improve the benefit to risk ratio of cannabinoid receptor agonists reviewed in Pertwee, c. Potential strategies include the administration of. Potential clinical strategies for the management of disorders in which an increased production of anandamide may lead to a reduction in the intensity of unwanted signs and symptoms reviewed in Pertwee c.

    These strategies rely on augmentation of apparent anandamide-mediated protective effects through inhibition of the cellular uptake of anandamide, through inhibition of its intracellular metabolism by fatty acid amide hydrolase or through allosteric enhancement of anandamide-induced CB 1 receptor activation.

    Since the discovery of CB 1 receptors and the subsequent development of SRA by Sanofi in , there has also been considerable interest in the therapeutic potential of competitive CB 1 receptor antagonists for the management of disorders in which the endocannabinoid system appears to induce undesirable symptoms following its upregulation see above. Indeed, SRA rimonabant will most likely soon be licensed for use as an antiobesity agent Van Gaal et al. Allosteric CB 1 receptor antagonists have potential as medicines too, as do CB 2 receptor inverse agonists since evidence has recently emerged that these can ameliorate inflammation by inhibiting immune cell migration reviewed in Pertwee, c.

    Finally, some pharmacologically active cannabinoids that do not activate or block CB 1 or CB 2 receptors also have therapeutic potential. Among these are the phytocannabinoid, CBD, which, for example, possesses anti-inflammatory, anti-oxidant and neuroprotective properties reviewed in Pertwee, b ; Robson, These advances owe much to:. The challenge now is to continue investigations into the physiological and pathophysiological roles of the endocannabinoid system and to identify and implement the best strategies for exploiting what emerges from this research, in the clinic.

    Another important objective is to extend current knowledge about the pharmacology, firstly of endocannabinoids, and secondly of cannabinoid receptors and their exogenous agonists, inverse agonists and neutral antagonists when these are administered acutely or chronically. It will also be important to characterize proposed non-CB 1 , non-CB 2 , non-TRPV1 targets for cannabinoids more completely, to elucidate the pharmacology of cannabinoid receptor allosteric sites more fully, to seek out and explore the pharmacology of any as yet unidentified endocannabinoids or pharmacological targets for cannabinoids, to follow-up early indications that cannabinoid receptors may exist as homodimers or form heterodimers or oligomers with one or more other class of coexpressed receptor reviewed in Pertwee, b and to continue the task of exploring the pharmacology of plant cannabinoids.

    National Center for Biotechnology Information , U. Journal List Br J Pharmacol v. Published online Jan 9. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC.

    Abstract Research into the pharmacology of individual cannabinoids that began in the s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Cannabis, cannabinoids, endocannabinoids, cannabinoid receptor agonists, cannabinoid receptor antagonists, anandamide, 2-arachidonoyl glycerol, autoprotection, autoimpairment.

    The discovery of cannabinoids Cannabis is one of the first plants to have been used as a medicine, for religious ceremonies and recreationally, the first accounts of its use for these purposes stretching back years reviewed in Mechoulam, Open in a separate window.

    Table 1 Plant-derived cannabinoids phytocannabinoids.

    Cannabinoid pharmacology: the first 66 years

    Prof Raphael Mechoulam Professor Raphael Mechoulam R. Mechoulam (ed ) Cannabinoids as Therapeutics, Birkhauser Verlag, Basel. Y. Gaoni, R. MechoulamIsolation, structure and partial synthesis of an active P.J. Little, D.R. Compton, R. Mechoulam, R.R. MartinStereochemical effects of. It was also in Mechoulam's laboratory, in , that (±)-Δ9-THC and [PubMed ]; MECHOULAM R. Cannabinoid chemistry Marijuanaed.

    raphael mechoulam



    Prof Raphael Mechoulam Professor Raphael Mechoulam R. Mechoulam (ed ) Cannabinoids as Therapeutics, Birkhauser Verlag, Basel.


    Y. Gaoni, R. MechoulamIsolation, structure and partial synthesis of an active P.J. Little, D.R. Compton, R. Mechoulam, R.R. MartinStereochemical effects of.


    It was also in Mechoulam's laboratory, in , that (±)-Δ9-THC and [PubMed ]; MECHOULAM R. Cannabinoid chemistry Marijuanaed.


    Mechoulam R(1), Parker LA, Gallily R. Author information: (1)Deportment of Medicinal Chemistry and Natural Products, Hebrew University of Jerusalem, Israel.


    , Soni D, Smoum R, Breuer A, Mechoulam R, Steinberg D. Effect of the synthetic cannabinoid HU on quorum sensing and on the production of quorum.


    Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. E Fride, R Mechoulam. European journal of pharmacology .

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