The cannabinoid system: from the point of view of a chemist

doi:10.1017/CBO9780511543630.003

1 - The cannabinoid system: from the point of view of a chemist

Published online by Cambridge University Press: 07 December 2009

Raphael Mechoulam and

Lumir Hanuš

Edited by

David Castle and

Robin Murray

Show author details

Raphael Mechoulam: Affiliation:
Hebrew University Medical Faculty, Israel
Lumir Hanuš: Affiliation:
Hebrew University Medical Faculty, Israel
David Castle: Affiliation:
Mental Health Research Institute, Melbourne
Robin Murray: Affiliation:
Institute of Psychiatry, London

Book contents

Get access

Summary

This book is about cannabis (marijuana) and psychotic illnesses; more specifically, it outlines how our increasing understanding of cannabis itself, the effects of cannabis on the brain and psychic functions and of the cannabinoid system can inform our understanding of the relationships between cannabis and psychosis. This chapter serves as an introduction to this topic, with a brief historical overview of the psychic effects of cannabis, followed by an exposition on the cannabinoid system.

Cannabis and mental illness

J. J. Moreau, the first nineteenth-century psychiatrist with an interest in psychopharmacology, described in great detail his experiments with hashish (Moreau, 1973). He took the drug himself and asked his students to follow his example. He also administered it to his patients. By modern standards the doses used were enormously high. The effects on one of his assistants, who swallowed 16 g of an extract – presumably containing several hundred milligrams of tetrahydrocannabinol (THC), which we know today to be the major psychotropic principal of cannabis – were intense agitation, incoherence, delirium and hallucinations. On the basis of numerous such experiments, Moreau declared that ‘there is not a single, elementary manifestation of mental illness that cannot be found in the mental changes caused by hashish, from simple manic excitement to frenzied delirium, from the feeblest impulse, the simplest fixation, the merest injury to the senses, to the most irresistible drive, the wildest delirium, the most varied disorders of feelings’.

Information

Type: Chapter
Information: Marijuana and Madness
Psychiatry and Neurobiology
, pp. 1 - 18

DOI: https://doi.org/10.1017/CBO9780511543630.003 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2004

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Abadji, V., Lin, S., Taha, G.et al. (1994). (R)-methanandamide: a chiral novel anandamide possessing higher potency and metabolic stability. J. Med. Chem, 37, 1889–1893CrossRef Google Scholar PubMed

Adams, R. (1941–1942). Marihuana. Harvey Lect., 37, 168–197Google Scholar

Beltramo, M., Stella, N., Calignano, A.et al. (1997). Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science, 227, 1094–1097CrossRef Google Scholar

Ben-Shabat, S., Fride, E., Sheskin, T.et al. (1998). An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol., 353, 23–31CrossRef Google Scholar PubMed

Bisogno, T., Hanuš, L., Petrocellis, L.et al. (2001). Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br. J. Pharmacol., 135, 845–852CrossRef Google Scholar

Boger, D. L., Henriksen, S. J. and Cravatt, B. F. (1998). Oleamide: an endogenous sleep-inducing lipid and prototypical member of a new class of biological signaling molecules. Curr. Pharm. Design, 4, 303–314Google Scholar PubMed

Breivogel, C. S., Griffin, G., Di Marzo, V. and Martin, B. R. (2001). Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol. Pharmacol., 60, 155–163CrossRef Google Scholar

Carlini, E. A. and Cunha, J. M. (1981). Hypnotic and antiepileptic effects of cannabidiol. J. Clin. Pharmacol., 21, 417S–427SCrossRef Google Scholar PubMed

Carlini, E. A., Leite, J. R., Tanhauser, M. and Bernardi, A. C. (1973). Cannabidiol and Cannabis sativa extract protect mice and rats against convulsive agents. J. Pharm. Pharmacol., 25, 664–665CrossRef Google Scholar PubMed

Consroe, P. (1998). Brain cannabinoid system as targets for the therapy of neurological disorders. Neurobiol. Dis., 5, 534–551CrossRef Google Scholar PubMed

Cunha, J. M., Carlini, E. A., Pereira, A. E.et al. (1980). Chronic administration of CBD to healthy volunteers and epileptic patients. Pharmacologia, 21, 175–185Google Scholar PubMed

Deutsch, D. G., Ueda, N. and Yamamoto, S. (2002). The fatty acid amide hydrolase (FAAH). Prostaglandins Leukot. Essent. Fatty Acids, 66, 201–210CrossRef Google Scholar

Devane, W. A., Dysarz, F. A., Johnson, M. R., Melvin, L. S. and Howlett, A. C. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol., 34, 605–613Google Scholar PubMed

Devane, W. A., Breuer, A., Sheskin, T.et al. (1992a). A novel probe for the cannabinoid receptor. J. Med. Chem., 35, 2065–2069CrossRef Google Scholar

Devane, W. A., Hanu, L., Breuer, A.et al. (1992b). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 258, 1946–1949CrossRef Google Scholar

Di Marzo, V., Petrocellis, L., Bisogno, T. and Melck, D. (1999). Metabolism of anandamide and 2-arachidonoylglycerol: an historical overview and some recent developments. Lipids, 34, S319–S325CrossRef Google Scholar PubMed

Di Marzo, V., Petrocellis, L., Fezza, F., Ligresti, A. and Bisogno, T. (2002). Anandamide receptors. Prostaglandins Leukot. Essent. Fatty Acids, 66, 377–391CrossRef Google Scholar PubMed

Donovan, M. (1845). On the physical and medicinal qualities of Indian hemp (Cannabis indica). Dublin J. Med. Sci., 26, 368–402CrossRef Google Scholar

Elphick, M. R. and Egertova, M. (2001). The neurobiology and evolution of cannabinoid signalling. Philos. Trans. R. Soc. Lond., 356, 381–408CrossRef Google Scholar PubMed

Feigenbaum, J. J., Bergman, F., Richmond, S. A.et al. (1989). Nonpsychotropic cannabinoid acts as a functional N-methyl-d-asparate (NMDA) receptor blocker. Proc. Natl Acad. Sci. USA, 86, 9584–9587CrossRef Google Scholar

Felder, C. C. and Glass, M. (1998). Cannabinoid receptors and their endogenous agonists. Annu. Rev. Pharmacol. Toxicol., 38, 179–200CrossRef Google Scholar PubMed

Field, B. I. and Arndt, R. R. (1980). Cannabinoid compounds in South African Cannabis sativa L. J. Pharm. Pharmacol., 32, 21–24CrossRef Google Scholar PubMed

Ford, W. R., Honan, S. A., White, R. and Hiley, C. R. (2002). Evidence of a novel site mediating anandamide-induced negative inotropic and coronary vasodilator responses in rat isolated hearts. Br. J. Pharmacol., 135, 1191–1198CrossRef Google Scholar

Fowler, J. J. and Jacobsson, S. O. P. (2002). Cellular transport of anandamide, 2-arachidonoylgly cerol and palmitoylethanolamide – targets for drug development?Prostaglandin Leukot. Essent. Fatty Acids, 66, 193–200CrossRef Google Scholar

Fowler, C. J., Jonsson, K. O. and Tiger, G. (2001). Fatty acid amide hydrolase: biochemistry, pharmacology, and therapeutic possibilities for an enzyme hydrolyzing anandamide, 2-arachidonoylglycerol, palmitoylethanolamide, and oleamide. Biochem. Pharmacol., 62, 517–526CrossRef Google Scholar PubMed

Gaoni, Y. and Mechoulam, R. (1964). Isolation, structure and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc., 86, 1646CrossRef Google Scholar

Gerard, C. M., Mollereau, C., Vassart, G. and Parmentier, M. (1991). Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem. J., 279 (Pt 1), 129–134CrossRef Google Scholar PubMed

Gerth, C. W., Schultze-Lutter, F., Mauss, C.et al. (2002). The natural cannabinoid cannabidiol in the treatment of acute schizophrenia. Schizophr. Res. (Suppl.), 53, 192, B113Google Scholar

Giuffrida, A., Beltramo, M. and Piomelli, D. (2001). Mechanisms of endocannabinoid inactivation: biochemistry and pharmacology. J. Pharmacol. Exp. Ther., 298, 7–14Google Scholar PubMed

Grinspoon, L. and Bakalar, J. B. (1997). Marihuana, the Forbidden Medicine. New Haven, CT: Yale University Press

Guimaraes, F. S., Chiaretti, T. M., Graeff, F. G. and Zuardi, A. W. (1990). Antianxiety effect of cannabidol in the elevated plus-maze. Psychopharmacology, 100, 558–559CrossRef Google Scholar

Hanu, L., Gopher, A., Almog, S. and Mechoulam, R. (1993). Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor. J. Med. Chem., 36, 3032–3034CrossRef Google Scholar

Hanuš, L., Breuer, A., Tchilibon, S.et al. (1999). HU-308: a specific agonist for CB2, a peripheral cannabinoid receptor. Proc. Natl Acad. Sci. USA, 96, 14228–14233CrossRef Google Scholar

Hanuš, L., Abu-Lafi, S., Fride, E.et al. (2001). 2-Arachidonyl glyceryl ether, a novel endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl Acad. Sci. USA, 98, 3662–3665CrossRef Google Scholar

Hillard, C. J. (2000). Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostagladins Other Lipid Mediat., 61, 3–18CrossRef Google Scholar

Howlett, A. C. (1998). The CB1 cannabinoid receptor in the brain. Neurobiol. Dis., 5, 405–416CrossRef Google Scholar

Howlett, A. C. and Fleming, R. M. (1984). Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol. Pharmacol., 26, 532–538Google Scholar PubMed

Howlett, A. C., Champion, T. M., Wilken, G. H. and Mechoulam, R. (1990). Stereochemical effects of 11-OH-Δ8-tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor. Neuropharmacology, 29, 161–165CrossRef Google Scholar

Huffman, J. W. (2000). The search for selective ligands for the CB2 receptor. Curr. Pharm. Des., 6, 1323–1337CrossRef Google Scholar PubMed

Kaminski, N. E., Abood, M. E., Kessler, F. K., Martin, B. R. and Schatz, A. R. (1992). Identification of a functionally relevant cannabinoid receptor on mouse spleen cells that is involved in cannabinoid-mediated immune modulation. Mol. Pharmacol., 42, 736–742Google Scholar PubMed

Knoller, N., Levi, L., Shoshan, I.et al. (2002). Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled phase II clinical trial. Crit. Care Med., 30, 548–554CrossRef Google Scholar PubMed

Kozak, K. R. and Marnett, L. J. (2002). Oxidative metabolism of endocannabinoids. Prostaglandins Leukot. Essent. Fatty Acids, 66, 211–220CrossRef Google Scholar PubMed

Kunos, G., Jarai, Z., Varga, K.et al. (2000). Cardiovascular effects of endocannabinoids – the plot thickens. Prostaglandins Other Lipid Mediat., 61, 71–84CrossRef Google Scholar PubMed

Lan, R., Liu, Q., Fan, P.et al. (1999). Structure–activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J. Med. Chem., 42, 769–776CrossRef Google Scholar PubMed

Leweke, F. M., Schneider, U., Radwan, M., Schmidt, E. and Emrich, H. M. (2000). Different effects of nabilone and cannabidiol in binocular depth inversion in man. Pharmacol. Biochem. Behav., 66, 175–181CrossRef Google Scholar PubMed

Lutz, B. (2002). Molecular biology of cannabinoid receptors. Prostaglandin Leukot. Essent. Fatty Acids, 66, 123–142CrossRef Google Scholar PubMed

Maccarrone, M., Valensise, H., Bari, M.et al. (2000). Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet, 355, 1326–1329CrossRef Google Scholar PubMed

Maccarrone, M., Pauselli, R., Rienzo, M. D. and Finazzi-Agro, A. (2002). Binding, degradation and apoptotic activity of stearoylethanolamide in rat C6 glioma cells. Biochem. J., 15, 137–144CrossRef Google Scholar

Malfait, A. M., Gallily, R., Sumariwalla, P. F.et al. (2000). The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc. Natl Acad. Sci. USA, 97, 9561–9566CrossRef Google Scholar PubMed

Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. and Bonner, T. I. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 346, 561–564CrossRef Google Scholar PubMed

Mechoulam, R. (1973). Cannabinoid chemistry. In Marijuana Chemistry, Metabolism, Pharmacology and Clinical Effects, ed. R. Mechoulam, pp. 1–99. New York: Academic Press

Mechoulam, R. (1986). The pharmacohistory of Cannabis sativa. In Cannabinoids as Therapeutic Agents, pp. 1–19. Boca Raton, FL. CRC Press

Mechoulam, R. and Edery, H. (1973). Structure–activity relationships in the cannabinoid series. In Marijuana Chemistry, Metabolism, Pharmacology and Clinical Effects, ed. R. Mechoulam, pp. 101–136. New York: Academic Press

Mechoulam, R. and Hanuš, L. (2002). Cannabidiol: an overview of some chemical and pharmacological aspects. Part I. Chemical aspects. Chem. Phys. Lipids, 121, 35–43CrossRef Google Scholar PubMed

Mechoulam, R. and Shvo, Y. (1963). The structure of cannabidiol. Tetrahedron, 19, 2073–2078CrossRef Google Scholar PubMed

Mechoulam, R., Shani, A., Edery, H. and Grunfeld, Y. (1970). The chemical basis of hashish activity. Science, 169, 611–612CrossRef Google Scholar PubMed

Mechoulam, R., Feigenbaum, J. J., Lander, N.et al. (1988). Enantiomeric cannabinoids: stereo-specificity of psychotropic activity. Experientia, 44, 762–764CrossRef Google Scholar

Mechoulam, R., Ben-Shabat, S., Hanuš, L.et al. (1995). Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to the peripheral cannabinoid receptors. Biochem. Pharmacol., 50, 83–90CrossRef Google Scholar

Mechoulam, R., Fride, E. and Di Marzo, V. (1998). Endocannabinoids. Eur. J. Pharmacol., 359, 1–18CrossRef Google Scholar PubMed

Moreau, J-J. (1973). Hashish and Mental Illness. Translated from the French original (1845). New York: Raven Press

Munro, S., Thomas, K. L. and Abu-Shaar, M. (1993). Molecular characterization of a peripheral receptor for cannabinoids. Nature, 365, 61–65CrossRef Google Scholar PubMed

Onaivi, E. S., Green, M. R. and Martin, B. R. (1990). Pharmacological characterization of cannabinoids in the elevated plus maze. J. Pharmacol. Exp. Ther., 253, 1002–1009Google Scholar PubMed

O'Shaugnessy, W. B. (1841). Cannabis. In The Bengal Dispensatory and Pharmacopoeia, pp. 579–604. Calcutta: Bishop's College Press

O'Shaugnessy, W. B. (1843). On the Cannabis indica or Indian hemp. Pharmacol. J. Trans., 2, 594–595Google Scholar

Ottani, A. and Giuliani, D. (2001). HU 210: a potent tool for investigations of the cannabinoid system. CNS Drug Rev., 7, 131–45CrossRef Google Scholar PubMed

Panikashvili, D., Simeonidou, C., Ben-Shabat, S.et al. (2001). An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature, 413, 527–531CrossRef Google Scholar PubMed

Parker, L. A., Mechoulam, R. and Schlievert, C. (2002). Cannabidiol, a non-psychoactive component of cannabis, and its dimethylheptyl homolog suppress nausea in an experimental model with rats. Neuroreport, 13, 567–570CrossRef Google Scholar

Pertwee, R. G. and Ross, R. A. (2002). Cannabinoid receptors and their ligands. Prostaglandins Leukot. Essent. Fatty Acids, 66, 101–121CrossRef Google Scholar PubMed

Pertwee, R. G., Stevenson, L. A., Elrick, D. B., Mechoulam, R. and Corbett, A. D. (1992). Inhibitory effects of certain enantiomeric cannabinoids in the mouse vas deferens and the myenteric plexus preparation of guinea-pig small intestine. Br. J. Pharmacol., 105, 980–984CrossRef Google Scholar PubMed

Pickens, J. T. (1981). Sedative activity of cannabis in relation to its delta-1-trans-tetrahydrocannabinol and cannabidiol content. Br. J. Pharmacol., 72, 649–656CrossRef Google Scholar

Piomelli, D., Giuffrida, A., Calignano, A. and Fonseca, F. R. (2000). The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol. Sci., 21, 218–223CrossRef Google Scholar PubMed

Porter, A. C., Sauer, J. M., Knierman, M. D.et al. (2002). Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J. Pharmacol. Exp. Ther., 301, 1020–1024CrossRef Google Scholar PubMed

Reynolds, J. R. (1890). Therapeutic uses and toxic effects of Cannabis indica. Lancet, 1, 637–638CrossRef Google Scholar

Rinaldi-Carmona, M., Barth, F., Heaulme, M.et al. (1994). SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett., 350, 240–244CrossRef Google Scholar PubMed

Rinaldi-Carmona, M., Barth, F., Millan, J.et al. (1998). SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther., 284, 644–650Google Scholar PubMed

Rottanburg, D., Robins, A. H., Ben-Arie, O., Teggin, A. and Elk, R. (1982). Cannabis-associated psychosis with hypomanic features. Lancet, 2, 1364–1366CrossRef Google Scholar PubMed

Schlicker, E. and Kathmann, M. (2001). Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci., 22, 565–572CrossRef Google Scholar PubMed

Schmid, H. H. (2000). Pathways and mechanisms of N-acylethanolamine biosynthesis: can anandamide be generated selectively?Chem. Phys. Lipids, 108, 71–87CrossRef Google Scholar PubMed

Schmid, H. H. O. and Berdyshev, E. V. (2002). Cannabinoid receptor-inactive N-acylethanolamines and other fatty acid amides: metabolism and function. Prostaglandins Leukot. Essent. Fatty Acids, 66, 363–376CrossRef Google Scholar PubMed

Shohami, E. and Mechoulam, R. (2000). Dexanabinol (HU-211): a non-psychotropic cannabinoid with neuroprotective properties. Drug Dev. Res., 50, 211–2153.0.CO;2-G>CrossRef Google Scholar

Srivastava, M. D., Srivastava, B. I. and Brouhard, B. (1998). Delta-9-tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology, 40, 179–185CrossRef Google Scholar PubMed

Sugiura, T., Kondo, S., Sukagawa, A.et al. (1995). 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun., 215, 89–97CrossRef Google Scholar PubMed

Sugiura, T., Kobayashi, Y., Oka, S. and Waku, K. (2002). Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot. Essent. Fatty Acids, 66, 173–192CrossRef Google Scholar PubMed

Todd, A. R. (1946). Hashish. Experientia, 2, 55–60CrossRef Google Scholar

Turkanis, S. A., Cely, W., Olsen, D. M. and Karler, R. (1974). Anticonvulsant properties of cannabidiol. Res. Commun. Chem. Pathol. Pharmacol., 8, 231–246Google Scholar PubMed

Turner, C. E., Elsohly, M. A. and Boeren, E. G. (1980). Constituents of Cannabis sativa L. XVII. A review of the natural constituents. J. Nat. Prod., 43, 169–234CrossRef Google Scholar PubMed

Stelt, M., van-Kuik, J. A., Bari, M.et al. (2002). Oxygenated metabolites of anandamide and 2-arachidonylglycerol: conformational analysis and interaction with cannabinoid receptors, membrane transporter, and fatty acid amide hydrolase. J. Med. Chem., 45, 3709–3720CrossRef Google Scholar PubMed

Wachtel, S. R., ElSohly, M. A., Ross, S. A., Ambre, J. and 'de Wit, H. (2002). Comparison of the subjective effects of Δ9-tetrahydrocannabinol and marijuana in humans. Psychopharmacology, 161, 331–339Google Scholar PubMed

Wagner, J. A., Varga, K., Jarai, Z. and Kunos, G. (1999). Mesenteric vasodilation mediated by endothelial anandamide receptors. Hypertension, 33, 429–434CrossRef Google Scholar PubMed

Wallace, M. J., Wiley, J. L., Martin, B. R. and DeLorenzo, R. J. (2001). Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. Eur. J. Pharmacol., 28, 51–57CrossRef Google Scholar

Watzl, B., Scuderi, P. and Watson, R. R. (1991). Marijuana components stimulate human peripheral blood mononuclear cell secretion of interferon-gamma and suppress interleukin-1 alpha in vitro. Int. J. Immunopharmacol., 13, 1091–1097CrossRef Google Scholar PubMed

Zuardi, A. W., Shirakawa, I., Finkelfarb, E. and Karniol, I. G. (1982). Action of cannabidiol on the anxiety and other effects produced by delta-9-THC in normal subjects. Psychopharmacology, 76, 245–250CrossRef Google Scholar PubMed

Zuardi, A. W., Rodrigues, J. A. and Cunha, J. M. (1991). Effects of cannabidiol in animal models predictive of antipsychotic activity. Psychopharmacology, 104, 260–264CrossRef Google Scholar PubMed

Zuardi, A. W., Morais, S. L., Guimaraes, F. S. and Mechoulam, R. (1995). Antipsychotic effect of cannabidiol. J. Clin. Psychiatry, 56, 485–486Google Scholar PubMed

Zuardi, A. W., Guimaraes F. S., Guimaraes, V. M. C. and Del Bel, E. A. (2002). Cannabidiol: possible therapeutic application. In Cannabis and Cannabinoids, ed. F. Grotenhermen and E. Russo, pp. 359–369. New York: Haworth Press

Accessibility standard: Unknown

Accessibility compliance for the PDF of this book is currently unknown and may be updated in the future.