Chemistry of Cannabis

  • R. Mechoulam
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 55 / 3)

Abstract

The aim of this chapter is to present a short summary of cannabinoid1 chemistry with emphasis on those aspects which have pharmacological relevance. A comprehensive chemical review is beyond the scope of this handbook. Since 1964, when the active principle of cannabis, Δ 1-tetrahydrocannabinol (Δ 1-THC), was identified (Gaoni and Mechoulam, 1964a), nearly 5,000 scientific articles on cannabis, Δ 1-THC and other cannabinoids have appeared; approximately 1,000 of these articles are chemically oriented. For this reason alone the present review will have to be selective.

Keywords

High Pressure Liquid Chromatographic Annotate Bibliography Cannabis Sativa Tetrahedron Letter Absolute Stereochemistry 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Adams, R., Baker, B.R., Wearn, R.B.: Synthesis of cannabinol, l-hydroxy-3n-amyl-6,6,9- trimethyl-6-dibenzopyran. J. Am. Chem. Soc. 62, 2204–2207 (1940)Google Scholar
  2. Agurell, S., Gustafsson, B., Holmstedt, B., Leander, K., Lindgren, J.-E., Nilsson, I., Sandberg, F., Asberg, M.: Quantitation of Δ 1-THC in plasma from cannabis smokers. J. Pharm. Pharmacol. 25, 554–558 (1973)PubMedGoogle Scholar
  3. Archer, R.A.: The cannabinoids: Therapeutic potential. Ann. Rep. Med. Chem. 9, 253–259 (1974)Google Scholar
  4. Ben-Zvi, Z., Mechoulam, R., Burstein, S.: Identification through synthesis of an active Δ6- THC metabolite. J. Am. Chem. Soc. 92, 3468 (1970)PubMedGoogle Scholar
  5. Bercht, C.A.L., Lousberg, R.J.J.C., Küppers, F.J.E.M., Salemink, C.A.: Cannabicitran: A new naturally occurring tetracyclic diether from Lebanese Cannabis sativa. Phytochemistry 13, 619–621 (1974)Google Scholar
  6. Bhargava, N.H.: Potential therapeutic applications of naturally occurring and synthetic cannabinoids. Gen. Pharmacol. 9, 195–213 (1978)PubMedGoogle Scholar
  7. Braude, M.C., Szara, S. (eds.): The pharmacology of marihuana. New York: Raven 1976Google Scholar
  8. Burstein, S.H.: Labeling and metabolism of the THC’s. In: Marijuana. Chemistry, pharmacology, metabolism and clinical effects. Mechoulam, R. (ed.), pp. 167–190. New York, London: Academic Press 1973Google Scholar
  9. Burstein, S.H., Menezes, F., Williamson, E., Mechoulam, R.: Metabolism of Δ6-THC, an active marihuana constituent. Nature 225, 87–88 (1970)PubMedGoogle Scholar
  10. Cais, M., Dani, S., Josephy, Y., Modiano, A., Gershon, H., Mechoulam, R.: Studies of cannabinoid metabolites - a free radical immunoassay. FEBS Lett. 55, 257–260 (1975)PubMedGoogle Scholar
  11. Chan, W.R., Magnus, K.E., Watson, H.A.: The structure of cannabitriol. Experientia 32, 283 (1976)PubMedGoogle Scholar
  12. Claussen, U., Spulak, F. v., Körte, F.: Cannabichromene, ein neuer Haschisch Inhaltstoff. Tetrahedron 22, 1477–1479 (1966)Google Scholar
  13. Cohen, S., Stillman, R.C. (eds.): The therapeutic potential of marihuana. New York: Plenum 1976Google Scholar
  14. Crombie, L., Ponsford, R., Shani, A., Yagnitinsky, B., Mechoulam, R.: Photochemical produc-tion of cannabicyclol from cannabichromene. Tetrahedron Letters 55, 5771–5772 (1968)PubMedGoogle Scholar
  15. Crombie, W.M.L.: The analysis of cannabis. In: Cannabis and health. Graham, J.D.P. (ed.) pp. 21–41. London: Academic Press 1976Google Scholar
  16. Cunha, I.M., Carlini, E.A., Pereira, A.E., Ramos, O.L., Gagliardi, R., Sanvito, W.L., Lander, N., Mechoulam, R.: Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21, 175–185 (1980)PubMedGoogle Scholar
  17. El-Feraly, F.S., Elsohly, M.A., Boeren, E.G., Turner, C.E., Ottersen, T., Aasen, A.: Crystal and molecular structure of cannabispiran and its correlation to dehydrocannabispiran. Tetrahedron 33, 2373–2387 (1977)Google Scholar
  18. Fairbairn, J.W.: The pharmacognosy of Cannabis. In: Cannabis and Health. Graham, J.D.P. (ed.), pp. 3–19. London: Academic 1976Google Scholar
  19. Fairbairn, J.W., Liebman, J.A.: The cannabinoid content of Cannabis sativa L. grown in England. J. Pharm. Pharmacol. 26, 413–419 (1974)PubMedGoogle Scholar
  20. Fenimore, D.C., Freeman, R.R., Loy, P.R.: Determination of zl9-THC in blood by electron capture gas chromatography. Anal. Chem. 45, 2331–2335 (1973)Google Scholar
  21. Foltz, R., Fentiman, A.F., Leighty, E.G., Walter, J.L., Drewes, H.R., Schwartz, W.E., Page, T.F.Jr., Truitt, E.F.Jr.: Metabolite of ¿18-THC: Identification and synthesis. Science 168, 844–855 (1970)Google Scholar
  22. Forrest, I.S., Green, D.E., Rose, S.D., Skinner, G.C., Torres, D.M.: Fluorescentlabeled cannabinoids. Res. Commun. Chem. Pathol. Pharmacol. 2, 787–792 (1971)PubMedGoogle Scholar
  23. Gaoni, R., Mechoulam, R.: Isolation, structure and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86, 1646–1647 (1964a)Google Scholar
  24. Gaoni, Y., Mechoulam, R.: The structure and synthesis of cannabigerol. Proc. Chem. Soc. 82, (1964b)Google Scholar
  25. Gaoni, Y., Mechoulam, R.: Cannabichromene, a new active principle in hashish. Chem. Commun. 20 (1966)Google Scholar
  26. Garrett, E.R., Hunt, C.A.: Picogram analysis of THC and application to biological fluids. J. Pharm. Sci. 62, 1211–1214 (1973)PubMedGoogle Scholar
  27. Garrett, E.R., Hunt, C.A.: Physiochemical properties, solubility and protein binding of Δ 9- THC. J. Pharm. Sci. 63, 1056–1064 (1974)PubMedGoogle Scholar
  28. Garrett, E.R., Hunt, C.A.: Separation and analysis of Δ 9-THC in biological fluids using HPLC and GLC. J. Pharm. Sci. 66, 20–26 (1977)PubMedGoogle Scholar
  29. Garrett, E.R., Tsau, J.J.: Stability of THC’s. J. Pharm. Sci. 63, 1563–1574 (1974)PubMedGoogle Scholar
  30. Gill, E.W., Jones, G.: Brain levels of Δ 1-THC and its metabolites in mice. Biochem. Pharmacol. 21, 2237–2248 (1972)PubMedGoogle Scholar
  31. Gross, S.J., Soares, J.R.: Validated direct blood Δ 9-THC radioimmune quantitation. J. Anal. Toxicol. 2, 98–100 (1978)Google Scholar
  32. Grotte, H., Spiteller, G.: Neue Cannabinoide. J. Chromatogr. 154, 13–23 (1978)Google Scholar
  33. Hartley, J.P.R., Nogrady, S.G., Seaton, A., Graham, J.D.P.: Bronchodilator effect of Δ 1-THC. Br. J. Clin. Pharmacol. 5, 523–525 (1978)PubMedGoogle Scholar
  34. Harvey, D.J., Martin, B.R., Paton, W.D.M.: Identification of metabolites of Δ1 and Δ6-THC containing a reduced double bond. J. Pharm. Pharmacol. 29, 495–497 (1977a)PubMedGoogle Scholar
  35. Harvey, D.J., Martin, B.R., Paton, W.D.M.: Identification of di and tri-substituted hydroxy and ketone metabolites of Δ 1-THC in mouse liver. J. Pharm. Pharmacol. 29, 482–486 (1977b)PubMedGoogle Scholar
  36. Herman, T.S., Jones, S.E., Dean, J., Leigh, S., Dorr, R., Moon, T.E., Salmon, S.E.: Nabilone, a potent antiemetic cannabinol with minimal euphoria. Biomedicine 27, 331–334 (1977)PubMedGoogle Scholar
  37. Hivley, R.L., Mosher, W.A., Hoffmann, F.W.: Isolation of A6-THC from marijuana. J. Am. Chem. Soc. 88, 1832–1833 (1966)Google Scholar
  38. Hoellinger, H., Nam, N.H., Decauchereux, J.F., Pichat, L.: Synthese de Δ8 et Δ 9-THC deuteries et trities. J. Label. Compounds Radiopharm. 13, 401–415 (1977)Google Scholar
  39. Karniol, I.G., Carlini, E.A.: The content of A9-THC does not explain all biological activity of some Brazilian marihuana samples. J. Pharm. Pharmacol. 24, 833–835 (1972)PubMedGoogle Scholar
  40. Knaus, E.E., Coutts, R.T., Kozakoff, C.W.: The separation, identification and quantitation of cannabinoids and their derivatives using HPLC. J. Chromatogr. Sci. 14, 525–530 (1976)PubMedGoogle Scholar
  41. Körte, F., Haag, M., Claussen, U.: Tetrahydrocannabinol carboxylic acid, a component of hashish. Angew. Chem. [Engl.]. 4, 872 (1965)Google Scholar
  42. Lawrence, D.K., Gill, E.W.: The effects of Δ 1-THC and other cannabinoids on spin labeled liposomes and their relationship to mechanisms of general anesthesia. Mol. Pharmacol. 11, 595–602 (1975)PubMedGoogle Scholar
  43. Leighty, E.G., Fentiman, A.F.Jr., Foltz, R.L.: Long-retained metabolites of Δ9 and Δ 8-THC identified as novel fatty acid conjugates. Res. Commun. Chem. Pathol. Pharmacol. 14, 13–28 (1976)Google Scholar
  44. Lemberger, L.: The pharmacokinetic of Δ 9-THC and its metabolites. In: Marihuana. Chemistry, biochemistry and cellular effects. Nahas, G.G. (ed.), pp. 169–178. Berlin, Heidelberg, New York: Springer 1976Google Scholar
  45. Lemberger, L., Rubin, A.: Physiologic disposition of drugs of abuse. New York: Spectrum 1976Google Scholar
  46. Levy, S., Yagen, B., Mechoulam, R.: Identification of a C-glucuronide of Δ6-THC in a mouse liver. Science 200, 1391–1392 (1978)PubMedGoogle Scholar
  47. Lyle, M.A., Pallante, S., Head, K., Fenselau, C.: Synthesis and characterization of glucuronides of cannabinol, cannabidiol, Δ 9-THC and Δ 8-THC. Biomed. Mass. Spectrom 4, 190–196 (1977)PubMedGoogle Scholar
  48. Martin, B., Agurell, S., Nordqvist, M., Lindgren, J.-E.: Dioxygenated metabolites of cannabidiol formed by rat liver. J. Pharm. Pharmacol. 28, 603–608 (1976)PubMedGoogle Scholar
  49. Martin, B.R., Harvey, D.J., Paton, W.D.M.: Biotransformation of cannabidiol in mice. Identification of new acid metabolites. Drug. Metab. Dispos. 5, 259–267 (1977)PubMedGoogle Scholar
  50. Martin, B.R., Carney, J.M., Balster, R.L., Harris, L.S.: Behavioral activity, distribution and metabolism of 3H-Δ 9-THC in monkey brain following an intraventricular injection. Fed. Proc. 37, 164 (1978)Google Scholar
  51. McCallum, N.K., Eastwood, M.E.: In vivo binding of Δ 1-THC and CBN to rat serum proteins. J. Pharm. Pharmacol. 30, 384–386 (1978)PubMedGoogle Scholar
  52. McCallum, N.K., Gugelmann, A., Brenninkmeijer, C.A.M., Mechoulam, R.: Isotope effect studies in the dehydrogenation of Δ 1-THC in the rat. Experientia 33, 1012–1014 (1977)PubMedGoogle Scholar
  53. McCallum, N.K., Cairns, E.R., Ferry, D.G., Wong, R.J.: A simple GLC method for routine Δ 1-THC analyses of blood and brain. J. Anal. Toxicol. 2, 89–92 (1978)Google Scholar
  54. Mechoulam, R. (ed.): Marijuana. Chemistry, pharmacology, metabolism and clinical effects. New York, London: Academic 1973Google Scholar
  55. Mechoulam, R., Carlini, E.A.: Toward drugs derived from Cannabis. Naturwissenschaften 65, 174–179 (1978)PubMedGoogle Scholar
  56. Mechoulam, R., Gaoni, Y.: Recent advances in the chemistry of hashish. In: Fortschritte Chemisch Organischer Naturstoffe. Zechmeister, L. (ed.), Vol. 25, pp. 175–213. Wien: Springer 1967aGoogle Scholar
  57. Mechoulam, R., Gaoni, Y.: The absolute configuration of Δ 1-THC. Tetrahedron Letters 12, 1109–1111 (1967b)PubMedGoogle Scholar
  58. Mechoulam, R., Shvo, Y.: The structure of cannabidiol. Tetrahedron 19, 2073–2078 (1963)Google Scholar
  59. Mechoulam, R., Ben-Zvi, Z., Gaoni, Y.: On the nature of the Beam test. Tetrahedron 24, 5615 - 5624 (1968)PubMedGoogle Scholar
  60. Mechoulam, R., Ben-Zvi, Z., Yagnitinsky, B., Shani, A.: A new THC acid, Tetrahedron Letters 28, 2339–2341 (1969)Google Scholar
  61. Mechoulam, R., Braun, P., Gaoni, Y.: A stereospecific synthesis of Δ 1-THC and Δ 1(6)-THC. J. Am. Chem. Soc. 89, 4552–4554 (1967)PubMedGoogle Scholar
  62. Mechoulam, R., Braun, P., Gaoni, Y.: Syntheses of Δ 1-THC and related cannabinoids. J. Am. Chem. Soc. 94, 6159–6165 (1972)PubMedGoogle Scholar
  63. Mechoulam, R., McCallum, N.K., Burstein, S.: Recent advances in the chemistry and biochemistry of Cannabis. Chem. Rev. 76, 75–112 (1976)Google Scholar
  64. Mechoulam, R., Shani, A., Edery, H., Grunfeld, Y.: Chemical basis of hashish activity. Science 169, 611–612 (1970)PubMedGoogle Scholar
  65. Nahas, G.G.: Marihuana - deceptive weed. New York: Raven 1972Google Scholar
  66. Nahas, G.G. (ed.): Marihuana. Chemistry, biochemistry and cellular effects. Berlin, Heidelberg, New York: Springer 1976Google Scholar
  67. Nakano, S., Gillespie, H.K., Hollister, L.E.: A model for evaluation of antianxiety drugs with the use of experimentally induced stress: comparison of nabilone with diazepam. Clin. Pharmacol. Ther. 23, 54–62 (1978)PubMedGoogle Scholar
  68. Nilsson, I.M., Agurell, S., Nilsson, J.L.G., Ohlsson, A., Sandberg, F., Wahlqvist, M.: Δ 1-THC: Structure of a major metabolite. Science 168, 1228–1229 (1970)PubMedGoogle Scholar
  69. Novotny, M., Lee, M.L.: Detection of marijuana smoke in the atmosphere of a room. Experi- entia 29, 1038–1039 (1973)Google Scholar
  70. Pallante, S., Lyle, M.A., Fenselau, C.: Synthesis and characterization of glucuronides of 5′-OH-Δ 9-THC and 11-OH-Δ 9-THC. Drug Met. Dispos. 6, 389–395 (1978)Google Scholar
  71. Pars, H.G., Razdan, R.K., Howes, J.F.: Potential therapeutic agents derived from the cannabinoid nucleus. Adv. Drug Res. 11, 97–189 (1977)PubMedGoogle Scholar
  72. Paton, W.D.M.: Pharmacology of marijuana. Annu. Rev. Pharmacol. 15, 191–220 (1975)PubMedGoogle Scholar
  73. Petrzilka, T., Haefliger, W., Sikemeier, C.: Synthese von Haschisch - Inhaltsstoffen. Helv. Chim. Acta 52, 1102–1134 (1969)Google Scholar
  74. Pitt, C.G., Hobbs, D.T., Schran, H., Twine, C.E.Jr., Williams, D.L.: The synthesis of deuterium, carbon-14 and carrier-free tritium labeled cannabinoids. J. Label. Compounds Radiopharm. 11, 551–575 (1975)Google Scholar
  75. Razdan, R.K.: Recent advances in the chemistry of cannabinoids. Prog. Org. Chem. 8, 78–101 (1973)Google Scholar
  76. Razdan, R.K., Dalzell, H.C., Handrick, G.R.: A simple one-step synthesis of Δ 1-THC from p- mentha-2,8-diene-1 -ol and olivetol. J. Am. Chem. Soc. 96, 5860–5865 (1974)PubMedGoogle Scholar
  77. Razdan, R.K., Howes, J.F., Uliss, D.B., Dalzell, H.C., Handrick, G.R., Dewey, W.L.: 8ß-Hydroxymethyl-Δ 1-THC, a novel physiologically active analog of Δ 1-THC. Experientia 32, 416–417 (1976a)PubMedGoogle Scholar
  78. Razdan, R.K., Terris, B.Z., Pars, H.G., Plotnikoff, N.P., Dodge, P.W., Dren, A.T., Kyncl, J., Somani, P.: Drugs derived from cannabinoids. 2. Basic esters of N- and carbocyclic analogs. J. Med. Chem. 19, 454–461 (1976b)PubMedGoogle Scholar
  79. Rosenfeld, J.: The simultaneous determination of A9- THC and 1 l-hydroxy-zl9-THC in plasma. Anal. Lett. 10, 917–930 (1977)Google Scholar
  80. Rosenthal, D., Harvey, T.M., Bursey, J.T., Brine, D.R., Wall, M.E.: Comparison of GC-MS methods for the determination of Δ 9-THC in plasma. Biomed. Mass. Spectrom 5, 312–316 (1978)PubMedGoogle Scholar
  81. Sallan, S.E., Zinberg, N.E., Frei, E.: Antiemetic effect of Δ 9-THC in patients receiving cancer chemotherapy. N. Engl. J. Med. 293, 795–797 (1975)PubMedGoogle Scholar
  82. Schou, J., Steentoft, A., Worm, K., Andersen, J.M., Nielsen, E.: Highly sensitive method for gas chromatography of THC and CBN. Acta Pharmacol. Toxicol. (Kbh). 30, 480–482 (1971)Google Scholar
  83. Segelman, A.B., Segelman, F.P., Star, A.E., Wagner, H., Seligman, O.: Structure of two C- diglycosyl-flavones from Cannabis sativa. Phytochemistry 17, 824–826 (1978)Google Scholar
  84. Shani, A., Mechoulam, R.: Photochemical reactions of CBD. Tetrahedron 27, 601–606 (1971)Google Scholar
  85. Shani, A., Mechoulam, R.: Cannabielsoic acids. Isolation and synthesis by a novel oxidative cyclization. Tetrahedron 30, 2437–2446 (1974)Google Scholar
  86. Shoyama, Y., Hirano, H., Nishioka, I.: Synthesis of cannabigerorcinic-carboxyl-14C acid, can- nabigerovarinic-carboxyl-14C-acid and cannabichromevarinic-carboxyl-14C-acid. J. Label. Comp. Radiopharm. 14, 835–842 (1978)Google Scholar
  87. Smith, R.M., Vaughan, C.G.: High pressure liquid chromatography of Cannabis. J. Chromatogr. 129, 347–354 (1976)PubMedGoogle Scholar
  88. Spronck, H.J., Salemink, C.A.: Isolation and synthesis of olivetol derivatives formed in the pyrolysis of CBD. Ree. Trav. Chim. Bays-Bas. 97, 187–190 (1978)Google Scholar
  89. Spulak, F. v., Claussen, U., Fehlhaber, H.W., Körte, F.: Cannabidiolcarbonsaure-tetra hydro- cannabitriol-ester, ein neuer Haschisch-Inhaltsstoff. Tetrahedron 24, 5379–5383 (1968)Google Scholar
  90. Staquet, M., Gantt, C., Machin, D.; Effect of a nitrogen analog of THC on cancer pain. Clin. Pharmacol. Ther. 23, 397–401 (1978)PubMedGoogle Scholar
  91. Tamir, I., Mechoulam, R., Meyer, A.Y.: Cannabidiol and phenytoin, a structural comparison. J. Med. Chem. 23, 220–223 (1980)PubMedGoogle Scholar
  92. Teale, J.D., Forman, E.J., King, L.J., Piall, E.M., Marks, V.J.: The development of a radio immunoassay for cannabinoids in blood and urine. J. Pharm. Pharmacol. 21, 465–472 (1975)Google Scholar
  93. Turner, C.E., Hsu, M.H., Knopp, J.E., Schiff, P.L., Slatkin, D.J.: Isolation of cannabisativine, an alkaloid from Cannabis sativa L. J. Pharm. Sci. 65, 1084–1085 (1976)PubMedGoogle Scholar
  94. Valle, J.R., Viera, J.E.V., Aucelio, J.G., Valio, I.F.M.: Influence of photoperiodism on canna- binoid content of Cannabis sativa L. Bull. Narcotics 30 /1, 67–68 (1978)Google Scholar
  95. Vinson, J.A. (ed.): Cannabinoid analysis in physiological fluids. Washington, D.C.: American Chemical Society 1979Google Scholar
  96. Vinson, J.A., Patel, D.D., Patel, A.H.: Detection of THC in blood and serum using a fluores-cent derivative and TLC. Anal. Chem. 49, 163–165 (1977)PubMedGoogle Scholar
  97. Wahlqvist, M., Nilsson, I.M., Sandberg, F., Agurell, S., Granstrand, B.: Binding of Δ 1-TRC to human plasma proteins. Biochem. Pharmacol. 19, 2579–2589 (1970)PubMedGoogle Scholar
  98. Wall, M.E., Brine, D.R., Brine, G.A., Pitt, G.G., Freudenthal, R.I., Christensen, A.D.: Isolation, structure and biological activity of several metabolites of zl9-THC. J. Am. Chem. Soc. 92, 3466–3468 (1970)PubMedGoogle Scholar
  99. Wall, M.E., Brine, D.R., Perez-Reyes, M.: Metabolism of cannabinoids in man. In: The pharmacology of marihuana. Braude, M.C., Szara, S. (eds.), pp. 93–113. New York: Raven 1976Google Scholar
  100. Waller, C.W., Johnson, J.J., Buelke, J., Turner, C.E.: Marihuana: An annotated bibliography. New York: MacMillan 1976Google Scholar
  101. Williams, P.L., Moffat, A.C., King, L.J.: Combined HPLC and radio immunoassay for the quantitation of Δ 9-THC and some of its metabolites in human plasma. J. Chromatogr. 155, 273–283 (1978)PubMedGoogle Scholar
  102. Willette, R.E. (ed.): Cannabinoid assays in humans. Rockville: National Institute on Drug Abuse 1976Google Scholar
  103. Wollner, H.J., Matchett, J.R., Levine, J., Loewe, S.: Isolation of a physiologically active tetrahydrocannabinol from Cannabis sativa resin. J. Am. Chem. Soc. 64, 26–29 (1942)Google Scholar
  104. Yagen, B., Levy, S., Mechoulam, Ben-Zvi, Z.: Synthesis and enzymatic formation of a C-glucuronide of Δ6-THC. J. Am. Chem. Soc. 99, 6444–6446 (1977)Google Scholar
  105. Yisak, W., Agurell, S., Lindgren, J.-E., Widman, M.: In vivo metabolites of CBN identified as fatty acid conjugates. J. Pharm. Pharmacol. 30, 462–463 (1978)PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1982

Authors and Affiliations

  • R. Mechoulam

There are no affiliations available

Personalised recommendations