Clinical Pharmacokinetics

, Volume 42, Issue 4, pp 327–360

Pharmacokinetics and Pharmacodynamics of Cannabinoids

Review Article Drug Disposition

Abstract

Δ9-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for nonreceptor-dependent mechanisms.

Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15–30 minutes, and taper off within 2–3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30–90 minutes, reach their maximum after 2–3 hours and last for about 4–12 hours, depending on dose and specific effect.

At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs.

Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.

References

  1. 1.
    Loewe S. Cannabiswirkstoffe und Pharmakologie der Cannabinole. Archiv Experimentelle Pathologie Pharmakologie 1950; 211: 175–93Google Scholar
  2. 2.
    Dewey WL. Cannabinoid pharmacology. Pharmacol Rev 1986; 38(2): 151–78PubMedGoogle Scholar
  3. 3.
    Hollister LE. Health aspects of cannabis. Pharmacol Rev 1986; 38: 1–20PubMedGoogle Scholar
  4. 4.
    Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of the active constituent of hashish. J Am Chem Soc 1964; 86: 1646–7CrossRefGoogle Scholar
  5. 5.
    Devane WA, Dysarz III FA, Johnson MR, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34(5): 605–13PubMedGoogle Scholar
  6. 6.
    Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258(5090): 1946–9PubMedCrossRefGoogle Scholar
  7. 7.
    Razdan RK. Structure-activity relationships in cannabinoids. Pharmacol Rev 1986; 38: 75–149PubMedGoogle Scholar
  8. 8.
    Pate D. Taxonomy of cannabinoids. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 15–26Google Scholar
  9. 9.
    ElSohly MA. Chemical constituents of cannabis. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 27–36Google Scholar
  10. 10.
    Field BI, Arndt RR. Cannabinoid compounds in South African Cannabis sativa L. J Pharm Pharmacol 1980; 32(1): 21–4PubMedCrossRefGoogle Scholar
  11. 11.
    Pitts JE, Neal JD, Gough TA. Some features of Cannabis plants grown in the United Kingdom from seeds of known origin. J Pharm Pharmacol 1992; 44(12): 947–51PubMedCrossRefGoogle Scholar
  12. 12.
    Rowan MG, Fairbairn JW. Cannabinoid patterns in seedlings of Cannabis sativa L. and their use in the determination of chemical race. J Pharm Pharmacol 1977; 29(8): 491–4PubMedCrossRefGoogle Scholar
  13. 13.
    Harvey DJ. Characterization of the butyl homologues of deltal tetrahydrocannabinol, cannabinol and cannabidiol in samples of cannabis by combined gas chromatography and mass spectrometry. J Pharm Pharmacol 1976; 28(4): 280–5PubMedCrossRefGoogle Scholar
  14. 14.
    Vree TB, Breimer DD, van Ginneken CA, et al. Identification in hashish of tetrahydrocannabinol, cannabidiol and cannabinol analogues with a methyl side-chain. J Pharm Pharmacol 1972; 24(1): 7–12PubMedCrossRefGoogle Scholar
  15. 15.
    ElSohly MA, Ross SA, Mehmedic Z, et al. Potency trends of Δ9-THC and other cannabinoids in confiscated marijuana from 1980–1997. J Forensic Sci 2000; 45(1): 24–30PubMedGoogle Scholar
  16. 16.
    Brenneisen R. Psychotrope drogen: II. Bestimmung der Cannabinoide in Cannabis sativa L. und in Cannabisprodukten mittels Hochdruckflüssigkeitschromatographie (HPLC). Pharm Acta Helv 1984; 59: 247–59PubMedGoogle Scholar
  17. 17.
    Baker PB, Taylor BJ, Gough TA. The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products. J Pharm Pharmacol 1981; 33(6): 369–72PubMedCrossRefGoogle Scholar
  18. 18.
    Garrett ER, Hunt CA. Physiochemical properties, solubility, and protein binding of Δ9-tetrahydrocannabinol. J Pharm Sci 1974; 63(7): 1056–64PubMedCrossRefGoogle Scholar
  19. 19.
    Mechoulam R. Chemistry of cannabis. Handbook Exp Pharmacol 1981; 53: 119–34Google Scholar
  20. 20.
    Thomas BF, Compton DR, Martin BR. Characterization of the lipophilicity of natural and synthetic analogs of delta 9-tetrahydrocannabinol and its relationship to pharmacological potency. J Pharmacol Exp Ther 1990; 255(2): 624–30PubMedGoogle Scholar
  21. 21.
    Johnson JR, Jennison TA, Peat MA, et al. Stability of delta 9-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC in blood and plasma. J Anal Toxicol 1984; 8(5): 202–4PubMedGoogle Scholar
  22. 22.
    NN Monographs: Dronabinol capsules 2.5/5 or 10mg (NRF 22.7.); oily dronabinol drops 2.5% (NRF 22.8). In: Bundesvereinigung Deutscher Apothekerverbände, editor. Neues Rezepturformularium (NRF), Loose-Leaf Collection of 2001. Eschborn, Germany: Govi-Verlag Pharmazeutischer Verlag / Stuttgart, Germany: Deutscher Apotheker-Verlag, 2001Google Scholar
  23. 23.
    Agurell S, Leander K. Stability, transfer and absorption of cannabinoid constituents of cannabis (hashish) during smoking. Acta Pharm Suec 1971; 8(4): 391–402PubMedGoogle Scholar
  24. 24.
    Fairbairn JW, Liebmann JA, Rowan MG. The stability of cannabis and its preparations on storage. J Pharm Pharmacol 1976; 28: 1–7PubMedCrossRefGoogle Scholar
  25. 25.
    Brenneisen R, Egli A, Elsohly MA, et al. The effect of orally and rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther 1996; 34(10): 446–52PubMedGoogle Scholar
  26. 26.
    Stinchcomb A, Challapalli P, Harris K, et al. Optimization of in vitro experimental conditions for measuring the percutaneous absorption of Δ9-THC, cannabidiol, and WIN55,212-2 [abstract]. 2001 Symposium on the Cannabinoids. Burlington (VT): International Cannabinoid Research Society, 2001: 161Google Scholar
  27. 27.
    Guy GW, Flint ME. A phase one study of sublingual Cannabis based medicinal extract. 2000 Symposium on the Cannabinoids. Burlington (VT): International Cannabinoid Research Society: 2000, 115Google Scholar
  28. 28.
    Merritt JC, Olsen JL, Armstrong JR, et al. Topical delta 9-tet-rahydrocannabinol in hypertensive glaucomas. J Pharm Pharmacol 1981; 33(1): 40–1PubMedCrossRefGoogle Scholar
  29. 29.
    Lichtman AH, Peart J, Poklis JL, et al. Pharmacological evaluation of aerosolized cannabinoids in mice. Eur J Pharmacol 2000; 399(2–3): 141–9PubMedCrossRefGoogle Scholar
  30. 30.
    Williams SJ, Hartley JP, Graham JD. Bronchodilator effect of delta1-tetrahydrocannabinol administered by aerosol of asthmatic patients. Thorax 1976; 31(6): 720–3PubMedCrossRefGoogle Scholar
  31. 31.
    Wall ME, Sadler BM, Brine D, et al. Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol, in men and women. Clin Pharmacol Ther 1983; 34(3): 352–63PubMedCrossRefGoogle Scholar
  32. 32.
    Hunt CA, Jones RT. Tolerance and disposition of tetrahydrocannabinol in man. J Pharmacol Exp Ther 1980; 215(1): 35–44PubMedGoogle Scholar
  33. 33.
    Kelly P, Jones RT. Metabolism of tetrahydrocannabinol in frequent and infrequent marijuana users. J Anal Toxicol 1992; 16(4): 228–35PubMedGoogle Scholar
  34. 34.
    Brenneisen R. Pharmakokinetik. In: Grotenhermen F, editor. Cannabis und Cannabinoide. Pharmakologie, Toxikologie und Therapeutisches Potenzial. Göttingen: Hans Huber Verlag, 2001: 87–92Google Scholar
  35. 35.
    Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids: I. absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol 1992; 16(5): 276–82PubMedGoogle Scholar
  36. 36.
    Chiang CW, Barnett G. Marijuana effect and delta-9-tetrahy-drocannabinol plasma level. Clin Pharmacol Ther 1984; 36(2): 234–8PubMedCrossRefGoogle Scholar
  37. 37.
    Hollister LE, Gillespie HK, Ohlsson A, et al. Do plasma concentrations of delta 9-tetrahydrocannabinol reflect the degree of intoxication? J Clin Pharmacol 1981; 21 (8–9 Suppl.): 171S–7SPubMedGoogle Scholar
  38. 38.
    Lindgren JE, Ohlsson A, Agurell S, et al. Clinical effects and plasma levels of delta 9-tetrahydrocannabinol (delta 9-THC) in heavy and light users of cannabis. Psychopharmacology 1981; 74(3): 208–12PubMedCrossRefGoogle Scholar
  39. 39.
    Ohlsson A, Lindgren JE, Wahlen A, et al. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther 1980; 28(3): 409–16PubMedCrossRefGoogle Scholar
  40. 40.
    Perez-Reyes M, Di Guiseppi S, Davis KH, et al. Comparison of effects of marihuana cigarettes to three different potencies. Clin Pharmacol Ther 1982; 31(5): 617–24PubMedCrossRefGoogle Scholar
  41. 41.
    Sporkert F, Pragst F, Ploner CJ, et al. Pharmacokinetic investigation of delta-9-tetrahydrocannabinol and its metabolites after single administration of 10mg Marinol in attendance of a psychiatric study with 17 volunteers. Poster at the 39th Annual International Meeting, International Association of Forensic Toxicologists; 2001 Aug 26–30; Prague, Czech RepublicGoogle Scholar
  42. 42.
    Ohlsson A, Lindgren JE, Wahlen A, et al. Single dose kinetics of deuterium labelled Δ1-tetrahydrocannabinol in heavy and light cannabis users. Biomed Mass Spectrom 1982; 9(1): 6–10PubMedCrossRefGoogle Scholar
  43. 43.
    Davis KH, McDaniell JA, Cadwell LW, et al. Some smoking characteristics of marijuana cigarettes. In: Agurell S, Dewey WL, Willette RE, editors. The cannabinoids: chemical, pharmacologic and therapeutic aspects. New York: Academic Press, 1984: 245–61Google Scholar
  44. 44.
    Timpone JG, Wright DJ, Li N, et al. The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome. AIDS Res Hum Retroviruses 1997; 13(4): 305–15PubMedCrossRefGoogle Scholar
  45. 45.
    Law B, Mason PA, Moffat AC, et al. Forensic aspects of the metabolism and excretion of cannabinoids following oral ingestion of cannabis resin. J Pharm Pharmacol 1984; 36(5): 289–94PubMedCrossRefGoogle Scholar
  46. 46.
    Frytak S, Moertel CG, Rubin J. Metabolic studies of delta-9-tet-rahydrocannabinol in cancer patients. Cancer Treat Rep 1984; 68(12): 1427–31PubMedGoogle Scholar
  47. 47.
    Harvey DJ. Metabolism and pharmacokinetics of the cannabinoids. In: Watson RR, editor. Biochemistry and physiology of substance abuse. Vol III. Boca Raton (FL): CRC Press, 1991: 279–365Google Scholar
  48. 48.
    Lemberger L, Weiss JL, Watanabe AM, et al. Delta-9-tetrahydrocannabinol. Temporal correlation of the psychologic effects and blood levels after various routes of administration. N Engl J Med 1972; 286(13): 685–8PubMedCrossRefGoogle Scholar
  49. 49.
    Chiang CW, Barnett G, Brine D. Systemic absorption of delta 9-tetrahydrocannabinol after ophthalmic administration to the rabbit. J Pharm Sci 1983; 72(2): 136–8PubMedCrossRefGoogle Scholar
  50. 50.
    ElSohly MA, Stanford DF, Harland EC, et al. Rectal bioavailability of delta-9-tetrahydrocannabinol from the hemisuccinate ester in monkeys. J Pharm Sci 1991; 80(10): 942–5PubMedCrossRefGoogle Scholar
  51. 51.
    Notcutt W, Price M, Miller R, et al. Medicinal cannabis extracts in chronic pain: (5) cognitive function and blood cannabinoid levels. 2001 Congress on Cannabis and the Cannabinoids. Cologne, Germany: International Association for Cannabis as Medicine; 28Google Scholar
  52. 52.
    Touitou E, Fabin B, Dany S, et al. Transdermal delivery of tetrahydrocannabinol. Int J Pharm 1988; 43: 9–15CrossRefGoogle Scholar
  53. 53.
    Leuschner JT, Harvey DJ, Bullingham RE, et al. Pharmacokinetics of delta 9-tetrahydrocannabinol in rabbits following single or multiple intravenous doses. Drug Metab Dispos 1986; 14(2): 230–8PubMedGoogle Scholar
  54. 54.
    Widman M, Agurell S, Ehrnebo M, et al. Binding of (+)- and (−)-Δ1- tetrahydrocannabinols and (−)-7-hydroxy-Δ1-tetrahydrocannabinol to blood cells and plasma proteins in man. J Pharm Pharmacol 1974; 26(11): 914–6PubMedCrossRefGoogle Scholar
  55. 55.
    Fehr KO, Kalant H. Fate of 14C-delta1-THC in rat plasma after intravenous injection and smoking. Eur J Pharmacol 1974; 25(1): 1–8PubMedCrossRefGoogle Scholar
  56. 56.
    Wahlqvist M, Nilsson IM, Sandberg F, et al. Binding of delta1-tetrahydrocannabinol to human plasma proteins. Biochem Pharmacol 1970; 19(9): 2579–84PubMedCrossRefGoogle Scholar
  57. 57.
    Lemberger L, Tamarkin NR, Axelrod J, et al. Delta-9-tetrahydrocannabinol: metabolism and disposition in long-term marihuana smokers. Science 1971; 173(991): 72–4PubMedCrossRefGoogle Scholar
  58. 58.
    Barnett G, Chiang CW, Perez-Reyes M, et al. Kinetic study of smoking marijuana. J Pharmacokinet Biopharm 1982; 10(5): 495–506PubMedGoogle Scholar
  59. 59.
    Brewster ME, Pop E, Foltz RL, et al. Clinical pharmacokinetics of escalating i.v. doses of dexanabinol (HU-211), a neuroprotectant agent, in normal volunteers. Int J Clin Pharmacol Ther 1997; 35(9): 361–5PubMedGoogle Scholar
  60. 60.
    Sticht G, Käferstein H. Grundbegriffe, toxikokinetik und toxikodynamik. In: Berghaus G, Krüger HP, editors. Cannabis im Straßenverkehr. Stuttgart: Gustav Fischer, 1998: 1–11Google Scholar
  61. 61.
    Ryrfeldt A, Ramsay CH, Nilsson IM, et al. Whole-body auto radiography of Δ1-tetrahydrocannabinol and Δ1 (6)-tetrahydrocannabinol in mouse: pharmacokinetic aspects of Δ1-tetrahydrocannabinol and its metabolites. Acta Pharm Suec 1973; 10(1): 13–28PubMedGoogle Scholar
  62. 62.
    Ho BT, Fritchie GE, Kralik PM, et al. Distribution of tritiated-1 delta 9-tetrahydrocannabinol in rat tissues after inhalation. J Pharm Pharmacol 1970; 22(7): 538–9PubMedCrossRefGoogle Scholar
  63. 63.
    Gill EW, Jones G. Brain levels of Δ1-tetrahydrocannabinol and its metabolites in mice: correlation with behaviour, and the effect of the metabolic inhibitors SKF 525A and piperonyl butoxide. Biochem Pharmacol 1972; 21(16): 2237–48PubMedCrossRefGoogle Scholar
  64. 64.
    Chiang CN, Rapaka RS. Pharmacokinetics and disposition of cannabinoids. NIDA Res Monogr 1987; 79: 173–88PubMedGoogle Scholar
  65. 65.
    Perez-Reyes M, Simmons J, Brine D, et al. Rate of penetration of Δ9-tetrahydrocannabinol and 11-hydroxy-Δ9-tetrahydrocannabinol to the brain of mice. In: Nahas GG, editor. Marihuana: chemistry, biochemistry, and cellular effects. New York: Springer, 1976: 179–85Google Scholar
  66. 66.
    Agurell S, Nilsson IM, Ohlsson A, et al. On the metabolism of tritium-labelled, 1-tetrahydrocannabinol in the rabbit. Biochem Pharmacol 1970; 19(4): 1333–9PubMedCrossRefGoogle Scholar
  67. 67.
    Johansson E, Noren K, Sjovall J, et al. Determination of delta 1-tetrahydrocannabinol in human fat biopsies from marihuana users by gas chromatography-mass spectrometry. Biomed Chromatogr 1989; 3(1): 35–8PubMedCrossRefGoogle Scholar
  68. 68.
    Kreuz DS, Axelrod J. Delta-9-tetrahydrocannabinol: localization in body fat. Science 1973; 179(71): 391–3PubMedCrossRefGoogle Scholar
  69. 69.
    Harvey DJ, Leuschner JT, Paton WD. Gas chromatographic and mass spectrometric studies on the metabolism and phar-macokinetics of delta 1-tetrahydrocannabinol in the rabbit. J Chromatogr 1982; 239: 243–50PubMedCrossRefGoogle Scholar
  70. 70.
    Haggerty GC, Deskin R, Kurtz PJ, et al. The pharmacological activity of the fatty acid conjugate 11-palmitoyloxy-delta 9-tetrahydrocannabinol. Toxicol Appl Pharmacol 1986; 84(3): 599–606PubMedCrossRefGoogle Scholar
  71. 71.
    Leighty EG, Fentiman Jr AF, Foltz RL. Long-retained metabolites of Δ9- and Δ8-tetrahydrocannabinols identified as novel fatty acid conjugates. Res Commun Chem Pathol Pharmacol 1976; 14(1): 13–28PubMedGoogle Scholar
  72. 72.
    Blackard C, Tennes K. Human placental transfer of can nabinoids [letter]. N Engl J Med 1984; 311: 797PubMedGoogle Scholar
  73. 73.
    Abrams RM, Cook CE, Davis KH, et al. Plasma delta-9-tetra-hydrocannabinol in pregnant sheep and fetus after inhalation of smoke from a marijuana cigarette. Alcohol Drug Res 1985–1986; 6: 361–9PubMedGoogle Scholar
  74. 74.
    Bailey JR, Cunny HC, Paule MG, et al. Fetal disposition of delta 9-tetrahydrocannabinol (THC) during late pregnancy in the rhesus monkey. Toxicol Appl Pharmacol 1987; 90: 315–21PubMedCrossRefGoogle Scholar
  75. 75.
    Hutchings DE, Martin BR, Gamagaris Z, et al. Plasma concentrations of delta-9-tetrahydrocannabinol in dams and fetuses following acute or multiple prenatal dosing in rats. Life Sci 1989; 44(11): 697–701PubMedCrossRefGoogle Scholar
  76. 76.
    Martin BR, Dewey WL, Harris LS, et al. 3H-delta 9-tetrahydrocannabinol distribution in pregnant dogs and their fetuses. Res Commun Chem Pathol Pharmacol 1977; 17: 457–70PubMedGoogle Scholar
  77. 77.
    Boskovic R, Klein J, Woodland C, et al. The role of the placenta in variability of fetal exposure to cocaine and cannabinoids: a twin study. Can J Physiol Pharmacol 2001; 79(11): 942–5PubMedCrossRefGoogle Scholar
  78. 78.
    Chao FC, Green DE, Forrest IS, et al. The passage of 14C-delta 9-tetrahydrocannabinol into the milk of lactating squirrel monkeys. Res Commun Chem Pathol Pharmacol 1976; 15: 303–17PubMedGoogle Scholar
  79. 79.
    Perez-Reyes M, Wall ME. Presence of delta 9-tetrahydrocannabinol in human milk. N Engl J Med 1982; 307: 819–20PubMedCrossRefGoogle Scholar
  80. 80.
    Matsunaga T, Iwawaki Y, Watanabe K, et al. Metabolism of delta 9-tetrahydrocannabinol by cytochrome P450 isozymes purified from hepatic microsomes of monkeys. Life Sci 1995; 56(23–24): 2089–95PubMedCrossRefGoogle Scholar
  81. 81.
    Narimatsu S, Watanabe K, Matsunaga T, et al. Cytochrome P-450 isozymes involved in the oxidative metabolism of delta 9-tetrahydrocannabinol by liver microsomes of adult female rats. Drug Metab Dispos 1992; 20(1): 79–83PubMedGoogle Scholar
  82. 82.
    Watanabe K, Matsunaga T, Yamamoto I, et al. Involvement of CYP2C in the metabolism of cannabinoids by human hepatic microsomes from an old woman. Biol Pharm Bull 1995; 18(8): 1138–41PubMedCrossRefGoogle Scholar
  83. 83.
    Alozie SO, Martin BR, Harris LS, et al. 3H-delta 9-Tetrahydrocannabinol, 3H-cannabinol and 3H-cannabidiol: penetration and regional distribution in rat brain. Pharmacol Biochem Behav 1980; 12(2): 217–21PubMedCrossRefGoogle Scholar
  84. 84.
    Borys HK, Karler R. Cannabidiol and delta 9-tetrahydrocannabinol metabolism: in vitro comparison of mouse and rat liver crude microsome preparations. Biochem Pharmacol 1979; 28(9): 1553–9PubMedCrossRefGoogle Scholar
  85. 85.
    Harvey DJ, Brown NK. Comparative in vitro metabolism of the cannabinoids. Pharmacol Biochem Behav 1991; 40(3): 533–40PubMedCrossRefGoogle Scholar
  86. 86.
    Grotenhermen F. Review of unwanted actions of cannabis and THC. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 233–48Google Scholar
  87. 87.
    Harvey DJ, Paton WDM. Examination of the metabolites of Δ1-tetrahydrocannabinol in mouse, liver, heart and lung by combined gas chromatography and mass spectrometry. In: Nahas GG, editor. Marihuana: chemistry, biochemistry and cellular effects. New York: Springer-Verlag, 1976: 93–107Google Scholar
  88. 88.
    Nakazawa K, Costa E. Metabolism of delta 9-tetrahydrocannabinol by lung and liver homogenates of rats treated with methylcholanthrene. Nature 1971; 234(5323): 48–9PubMedCrossRefGoogle Scholar
  89. 89.
    Widman M, Nordqvist M, Dollery CT, et al. Metabolism of delta1-tetrahydrocannabinol by the isolated perfused dog lung. Comparison with in vitro liver metabolism. J Pharm Pharmacol 1975; 27(11): 842–8PubMedCrossRefGoogle Scholar
  90. 90.
    Wall ME. The in vivo and in vitro metabolism of tetrahydrocannabinol. Ann N Y Acad Sci 1971; 191: 23–9CrossRefGoogle Scholar
  91. 91.
    Widman M, Halldin M, Martin B. In vitro metabolism of tetrahydrocannabinol by rhesus monkey liver and human liver. Adv Biosci 1978; 22-23: 101–3PubMedGoogle Scholar
  92. 92.
    Leighty EG. Metabolism and distribution of cannabinoids in rats after different methods of administration. Biochem Pharmacol 1973; 22(13): 1613–21PubMedCrossRefGoogle Scholar
  93. 93.
    Johansson E, Halldin MM, Agurell S, et al. Terminal elimination plasma half-life of delta 1-tetrahydrocannabinol (delta 1-THC) in heavy users of marijuana. Eur J Clin Pharmacol 1989; 37(3): 273–7PubMedCrossRefGoogle Scholar
  94. 94.
    Schwartz RH, Hayden GF, Riddile M. Laboratory detection of marijuana use: experience with a photometric immunoassay to measure urinary cannabinoids. Am J Dis Child 1985; 139(11): 1093–6PubMedGoogle Scholar
  95. 95.
    Ellis Jr GM, Mann MA, Judson BA, et al. Excretion patterns of cannabinoid metabolites after last use in a group of chronic users. Clin Pharmacol Ther 1985; 38(5): 572–8PubMedCrossRefGoogle Scholar
  96. 96.
    Huestis MA, Cone EJ. Urinary excretion half-life of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol in humans. Ther Drug Monit 1998; 20(5): 570–6PubMedCrossRefGoogle Scholar
  97. 97.
    Johansson E, Halldin MM. Urinary excretion half-life of delta 1-tetrahydrocannabinol-7-oic acid in heavy marijuana users after smoking. J Anal Toxicol 1989; 13(4): 218–23PubMedGoogle Scholar
  98. 98.
    Halldin MM, Andersson LK, Widman M, et al. Further urinary metabolites of delta 1-tetrahydrocannabinol in man. Arzneimittel Forschung 1982; 32(9): 1135–8PubMedGoogle Scholar
  99. 99.
    Halldin MM, Carlsson S, Kanter SL, et al. Urinary metabolites of delta 1-tetrahydrocannabinol in man. Arzneimittel Forschung 1982; 32(7): 764–8PubMedGoogle Scholar
  100. 100.
    Williams PL, Moffat AC. Identification in human urine of delta 9-tetrahydrocannabinol-11-oic acid glucuronide: a tetrahydrocannabinol metabolite. J Pharm Pharmacol 1980; 32(7): 445–8PubMedCrossRefGoogle Scholar
  101. 101.
    Alburges ME, Peat MA. Profiles of delta 9-tetrahydrocannabinol metabolites in urine of marijuana users: preliminary observations by high performance liquid chromatographyradioimmunoassay. J Forensic Sci 1986; 31(2): 695–706PubMedGoogle Scholar
  102. 102.
    Wall ME, Perez-Reyes M. The metabolism of delta 9-tetrahydrocannabinol and related cannabinoids in man. J Clin Pharmacol 1981; 21 (8–9 Suppl.): 178S–89SPubMedGoogle Scholar
  103. 103.
    Manno JE, Manno BR, Kemp PM, et al. Temporal indication of marijuana use can be estimated from plasma and urine concentrations of Δ9-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol, and 11-nor-Δ9-tetrahydrocannabinol9-carboxylic acid. J Anal Toxicol 2001; 25(7): 538–49PubMedGoogle Scholar
  104. 104.
    Mikes F, Hofmann A, Waser PG. Identification of (-)-delta 9-6a,10a-trans-tetrahydrocannabinol and two of its metabolites in rats by use of combination gas chromatography-mass spectrometry and mass fragmentography. Biochem Pharmacol 1971; 20(9): 2469–76PubMedCrossRefGoogle Scholar
  105. 105.
    Harder S, Rietbrock S. Concentration-effect relationship of delta-9-tetrahydrocannabiol and prediction of psychotropic effects after smoking marijuana. Int J Clin Pharmacol Ther 1997; 35(4): 155–9PubMedGoogle Scholar
  106. 106.
    Robbe HWJ. Influence of marijuana on driving. Maastricht: Institut for Human Psychopharmacology, University of Limburg, 1994Google Scholar
  107. 107.
    Barnett G, Licko V, Thompson T. Behavioral pharmacokinetics of marijuana. Psychopharmacology 1985; 85(1): 51–6PubMedCrossRefGoogle Scholar
  108. 108.
    Cocchetto DM, Owens SM, Perez-Reyes M, et al. Relationship between plasma delta-9-tetrahydrocannabinol concentration and pharmacologic effects in man. Psychopharmacology 1981; 75(2): 158–64PubMedCrossRefGoogle Scholar
  109. 109.
    Nyoni EC, Sitaram BR, Taylor DA. Determination of delta 9-tetrahydrocannabinol levels in brain tissue using high-performance liquid chromatography with electrochemical detection. J Chromatogr B Biomed Appl 1996; 679(1–2): 79–84PubMedCrossRefGoogle Scholar
  110. 110.
    McIsaac W, Fritchie G, Idanpaan-Heikkila J, et al. Distribution of marihuana in monkey brain and concomitant behavioural effects. Nature 1971; 230(5296): 593–4PubMedCrossRefGoogle Scholar
  111. 111.
    Ohlsson A, Widman M, Carlsson S, et al. Plasma and brain levels of delta 6-THC and seven monooxygenated metabolites correlated to the cataleptic effect in the mouse. Acta Pharmacol Toxicol (Copenh); 1980; 47(4): 308–17CrossRefGoogle Scholar
  112. 112.
    Law B, Moffat AC. The influence of the metabolism and elimination of cannabinoids on forensic analysis and interpretation. In: Harvey DJ, editor. Marijuana’ 84: Proceedings of the Oxford Symposium on Cannabis. Oxford: IRL Press Limited, 1985: 197–204Google Scholar
  113. 113.
    McBurney LJ, Bobbie BA, Sepp LA. GC/MS and EMIT analyses for delta 9-tetrahydrocannabinol metabolites in plasma and urine of human subjects. J Anal Toxicol 1986; 10(2): 56–64PubMedGoogle Scholar
  114. 114.
    Daldrup TH. Cannabis im Straßenverkehr. Final report commissioned by the Ministry of Economy, Technology and Traffic of North Rhine-Westphalia. Düsseldorf: University of Düsseldorf, 1996Google Scholar
  115. 115.
    Hanson V, Buonarati M, Baselt R, et al. Comparison of 3H- and 125I-radioimmunoassay and gas chromatography/mass spectrometry for the determination of Δ9-tetrahydrocannabinol and cannabinoids in blood and serum. J Anal Toxicol 1983; 7: 96–102PubMedGoogle Scholar
  116. 116.
    Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids: II. models for the prediction of time of marijuana exposure from plasma concentrations of delta 9-te trahydrocannabinol (THC) and 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH). J Anal Toxicol 1992; 16(5): 283–90PubMedGoogle Scholar
  117. 117.
    Agurell S, Halldin M, Lindgren JE, et al. Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 1986; 38(1): 21–43PubMedGoogle Scholar
  118. 118.
    Ohlsson A, Lindgren JE, Andersson S, et al. Single dose kinetics of cannabidiol in man. In: Agurell S, Dewey WL, Willette R, editors. The cannabinoids: chemical, pharmacologic, and therapeutic aspects. New York: Academic Press, 1984: 219–25Google Scholar
  119. 119.
    Agurell S, Carlsson S, Lindgren JE, et al. Interactions of delta 1-tetrahydrocannabinol with cannabinol and cannabidiol following oral administration in man: assay of cannabinol and cannabidiol by mass fragmentography. Experientia 1981; 37(10): 1090–2PubMedCrossRefGoogle Scholar
  120. 120.
    Consroe P, Laguna J, Allender J, et al. Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol Biochem Behav 1991; 40(3): 701–8PubMedCrossRefGoogle Scholar
  121. 121.
    Harvey DJ, Mechoulam R. Metabolites of cannabidiol identified in human urine. Xenobiotica 1990; 20(3): 303–20PubMedCrossRefGoogle Scholar
  122. 122.
    Wall ME, Brine DR, Perez-Reyes M. Metabolism of cannabinoids in man. In: Braude MC, Szara S, editors. Pharmacology of marihuana. New York: Raven Press, 1976: 93–113Google Scholar
  123. 123.
    Lemberger L, Rubin A, Wolen R, et al. Pharmacokinetics, metabolism and drug-abuse potential of nabilone. Cancer Treat Rev 1982; 9 Suppl. B: 17–23PubMedCrossRefGoogle Scholar
  124. 124.
    Rubin A, Lemberger L, Warrick P, et al. Physiologic disposition of nabilone, a cannabinol derivative, in man. Clin Pharmacol Ther 1977; 22(1): 85–91PubMedGoogle Scholar
  125. 125.
    Sullivan HR, Kau DL, Wood PG. Pharmacokinetics of nabilone, a psychotropically active 9-ketocannabinoid, in the dog. Utilization of quantitative selected ion monitoring and deuterium labeling. Biomed Mass Spectrom 1978; 5(4): 296–301PubMedCrossRefGoogle Scholar
  126. 126.
    Sullivan HR, Hanasono GK, Miller WM, et al. Species specificity in the metabolism of nabilone: relationship between toxicity and metabolic routes. Xenobiotica 1987; 17(4): 459–68PubMedCrossRefGoogle Scholar
  127. 127.
    Bornheim LM, Grillo MP. Characterization of cytochrome P450 3A inactivation by cannabidiol: possible involvement of cannabidiol-hydroxyquinone as a P450 inactivator. Chem Res Toxicol 1998; 11(10): 1209–16PubMedCrossRefGoogle Scholar
  128. 128.
    Jaeger W, Benet LZ, Bornheim LM. Inhibition of cyclosporine and tetrahydrocannabinol metabolism by cannabidiol in mouse and human microsomes. Xenobiotica 1996; 26(3): 275–84PubMedCrossRefGoogle Scholar
  129. 129.
    Watanabe K, Arai M, Narimatsu S, et al. Self-catalyzed inactivation of cytochrome P-450 during microsomal metabolism of cannabidiol. Biochem Pharmacol 1987; 36(20): 3371–7PubMedCrossRefGoogle Scholar
  130. 130.
    Yamamoto I, Watanabe K, Narimatsu S, et al. Recent advances in the metabolism of cannabinoids. Int J Biochem Cell Biol 1995; 27(8): 741–6PubMedCrossRefGoogle Scholar
  131. 131.
    Bornheim LM, Kim KY, Li J, et al. Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain. Drug Metab Dispos 1995; 23(8): 825–31PubMedGoogle Scholar
  132. 132.
    Hunt CA, Jones RT, Herning RI, et al. Evidence that cannabidiol does not significantly alter the pharmacokinetics of tetrahydrocannabinol in man. J Pharmacokinet Biopharm 1981; 9(3): 245–60PubMedGoogle Scholar
  133. 133.
    Bornheim LM, Everhart ET, Li J, et al. Induction and genetic regulation of mouse hepatic cytochrome P450 by cannabidiol. Biochem Pharmacol 1994; 48(1): 161–71PubMedCrossRefGoogle Scholar
  134. 134.
    Watanabe K, Arai M, Narimatsu S, et al. Effect of repeated administration of 11-hydroxy-delta 8-tetrahydrocannabinol, an active metabolite of delta 8-tetrahydrocannabinol, on the hepatic microsomal drug-metabolizing enzyme system of mice. Biochem Pharmacol 1986; 35(11): 1861–5PubMedCrossRefGoogle Scholar
  135. 135.
    Costa B, Parolaro D, Colleoni M. Chronic cannabinoid, CP-55,940, administration alters biotransformation in the rat. Eur J Pharmacol 1996; 313(1–2): 17–24PubMedCrossRefGoogle Scholar
  136. 136.
    Hollister LE, Gillespie H. Interactions in man of delta-9-tetra-hydrocannabinol: II. cannabinol and cannabidiol. Clin Pharmacol Ther 1975; 18(1): 80–3PubMedGoogle Scholar
  137. 137.
    Zuardi AW, Shirakawa I, Finkelfarb E, et al. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology 1982; 76(3): 245–50PubMedCrossRefGoogle Scholar
  138. 138.
    Karniol IG, Shirakawa I, Kasinski N, et al. Cannabidiol interferes with the effects of delta 9-tetrahydrocannabinol in man. Eur J Pharmacol 1974; 28(1): 172–7PubMedCrossRefGoogle Scholar
  139. 139.
    Petitet F, Jeantaud B, Reibaud M, et al. Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of Δ9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci 1998; 63(1): PL1–6PubMedCrossRefGoogle Scholar
  140. 140.
    De Petrocellis L, Melck D, Bisogno T, et al. Finding of the endocannabinoid signalling system in Hydra, a very primitive organism: possible role in the feeding response. Neuroscience 1999; 92(1): 377–87PubMedCrossRefGoogle Scholar
  141. 141.
    Bueb JL, Lambert DM, Tschirhart EJ. Receptor-independent effects of natural cannabinoids in rat peritoneal mast cells in vitro. Biochim Biophys Acta 2001; 1538(2–3): 252–9PubMedCrossRefGoogle Scholar
  142. 142.
    Hampson A. Cannabinoids as neuroprotectants against ischemia. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 101–10Google Scholar
  143. 143.
    Ralevic V, Kendall DA. Cannabinoids inhibit pre- and postjunctionally sympathetic neurotransmission in rat mesenteric arteries. Eur J Pharmacol 2002; 444(3): 171–81PubMedCrossRefGoogle Scholar
  144. 144.
    Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci 1995; 56(23–24): 2097–102PubMedCrossRefGoogle Scholar
  145. 145.
    Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74(2): 129–80PubMedCrossRefGoogle Scholar
  146. 146.
    Pertwee RG. Sites and mechanisms of action. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 73–88Google Scholar
  147. 147.
    Schweitzer P. Cannabinoids decrease the K+ M-current in hippocampal CA1 neurons. J Neurosci 2000; 20: 51–8PubMedGoogle Scholar
  148. 148.
    Glass M, Felder CC. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci 1997; 17: 5327–33PubMedGoogle Scholar
  149. 149.
    Galiègue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 1995; 232: 54–61PubMedCrossRefGoogle Scholar
  150. 150.
    Breivogel CS, Griffin G, Di Marzo V, et al. Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol 2001; 60(1): 155–63PubMedGoogle Scholar
  151. 151.
    Di Marzo V, Breivogel CS, Tao Q, et al. Levels, metabolism, and pharmacological activity of anandamide in CB (1) cannabinoid receptor knockout mice: evidence for non-CB (1), non-CB (2) receptor-mediated actions of anandamide in mouse brain. J Neurochem 2000; 75(6): 2434–44PubMedCrossRefGoogle Scholar
  152. 152.
    Pertwee RG. Evidence for the presence of CB1 cannabinoid receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid receptors. Life Sci 1999; 65: 597–605PubMedCrossRefGoogle Scholar
  153. 153.
    Recht LD, Salmonsen R, Rosetti R, et al. Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid. Biochem Pharmacol 2001; 62(6): 755–63PubMedCrossRefGoogle Scholar
  154. 154.
    Sanchez C, de Ceballos ML, del Pulgar TG, et al. Inhibition of glioma growth in vivo by selective activation of the CB2 cannabinoid receptor. Cancer Res 2001; 61(15): 5784–9PubMedGoogle Scholar
  155. 155.
    Giuffrida A, Beltramo M, Piomelli D. Mechanisms of endocannabinoid inactivation: biochemistry and pharmacology. J Pharmacol Exp Ther 2001; 298(1): 7–14PubMedGoogle Scholar
  156. 156.
    Sugiura T, Kondo S, Sukagawa A, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 1995; 215(1): 89–97PubMedCrossRefGoogle Scholar
  157. 157.
    De Petrocellis L, Melck D, Bisogno T, et al. Endocannabinoids and fatty acid amides in cancer, inflammation and related disorders. Chem Phys Lipids 2000; 108(1–2): 191–209PubMedCrossRefGoogle Scholar
  158. 158.
    Di Marzo V. ’Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochim Biophys Acta 1998; 1392(2–3): 153–75PubMedGoogle Scholar
  159. 159.
    Cravatt BF, Demarest K, Patricelli MP, et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci U S A 2001; 98(16): 9371–6PubMedCrossRefGoogle Scholar
  160. 160.
    Abadji V, Lin S, Gihan T, et al. (R)-Methanandamide: a chiral novel anandamide possessing higher potency and metabolic stability. J Med Chem 1994; 37: 1889–93PubMedCrossRefGoogle Scholar
  161. 161.
    Pertwee RG. Pharmacology of cannabinoid receptor ligands. Curr Med Chem 1999; 6: 635–64PubMedGoogle Scholar
  162. 162.
    Walker JM, Huang SM, Strangman NM, et al. Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci U S A 1999; 96(21): 12198–203PubMedCrossRefGoogle Scholar
  163. 163.
    Baker D, Pryce G, Croxford JL, et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J 2001; 15(2): 300–2PubMedGoogle Scholar
  164. 164.
    Siegling A, Hofmann HA, Denzer D, et al. Cannabinoid CB1 receptor upregulation in a rat model of chronic neuropathic pain. Eur J Pharmacol 2001; 415(1): R5–7PubMedCrossRefGoogle Scholar
  165. 165.
    Izzo AA, Fezza F, Capasso R, et al. Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br J Pharmacol 2001; 134(3): 563–70PubMedCrossRefGoogle Scholar
  166. 166.
    Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001; 410(6830): 822–5PubMedCrossRefGoogle Scholar
  167. 167.
    Darmani NA. Delta-9-tetrahydrocannabinol differentially suppresses cisplatin-induced emesis and indices of motor function via cannabinoid CB (1) receptors in the least shrew. Pharmacol Biochem Behav 2001; 69(1–2): 239–49PubMedCrossRefGoogle Scholar
  168. 168.
    Leweke FM, Giuffrida A, Wurster U, et al. Elevated endogenous cannabinoids in schizophrenia. Neuroreport 1999; 10(8): 1665–9PubMedCrossRefGoogle Scholar
  169. 169.
    Beaulieu P, Bisogno T, Punwar S, et al. Role of the endogenous cannabinoid system in the formalin test of persistent pain in the rat. Eur J Pharmacol 2000; 396(2–3): 85–92CrossRefGoogle Scholar
  170. 170.
    Adams IB, Martin BR. Cannabis: pharmacology and toxicology in animals and humans. Addiction 1996; 91(11): 1585–614PubMedCrossRefGoogle Scholar
  171. 171.
    Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002Google Scholar
  172. 172.
    Hall W, Solowij N, Lemon J. The health and psychological consequences of cannabis use. Canberra: Commonwealth Department of Human Services and Health, Monograph Series No. 25, 1994Google Scholar
  173. 173.
    House of Lords Select Committee on Science and Technology. Cannabis: the scientific and medical evidence. London: The Stationery Office, 1998Google Scholar
  174. 174.
    Joy JE, Watson SJ, Benson JA, editors. Marijuana and medicine: assessing the science base. Washington, DC: Institute of Medicine, National Academy Press, 1999Google Scholar
  175. 175.
    Kalant H, Corrigal W, Hall W, et al., editors. The health effects of cannabis. Toronto (ON): Centre for Addiction and Mental Health, 1999Google Scholar
  176. 176.
    Sulcova E, Mechoulam R, Fride E. Biphasic effects of anandamide. Pharmacol Biochem Behav 1998; 59(2): 347–52PubMedCrossRefGoogle Scholar
  177. 177.
    Thompson GR, Rosenkrantz H, Schaeppi UH, et al. Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys. Toxicol Appl Pharmacol 1973; 25(3): 363–72PubMedCrossRefGoogle Scholar
  178. 178.
    Bachs L, Morland H. Acute cardiovascular fatalities following cannabis use. Forensic Sci Int 2001; 124(2–3): 200–3PubMedCrossRefGoogle Scholar
  179. 179.
    Mittleman MA, Lewis RA, Maclure M, et al. Triggering myocardial infarction by marijuana. Circulation 2001; 103(23): 2805–9PubMedCrossRefGoogle Scholar
  180. 180.
    Pope HJ. Cannabis, cognition, and residual confounding. JAMA 2002; 287(9): 1172–4PubMedCrossRefGoogle Scholar
  181. 181.
    Solowij N, Stephens RS, Roffman RA, et al. Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA 2002; 287(9): 1123–31PubMedCrossRefGoogle Scholar
  182. 182.
    Lyketsos CG, Garrett E, Liang KY, et al. Cannabis use and cognitive decline in persons under 65 years of age. Am J Epidemiol 1999; 149(9): 794–800PubMedCrossRefGoogle Scholar
  183. 183.
    Pope Jr HG, Gruber AJ, Hudson JI, et al. Neuropsychological performance in long-term cannabis users. Arch Gen Psychiatry 2001; 58(10): 909–15PubMedCrossRefGoogle Scholar
  184. 184.
    Russo E, Mathre ML, Byrne A, et al. Chronic cannabis use in the compassionate investigational new drug program: an examination of benefits and adverse effects of legal medical cannabis. J Cannabis Ther 2002; 2(1): 3–57CrossRefGoogle Scholar
  185. 185.
    Fried PA, Watkinson B, Gray R. Differential effects on cognitive functioning in 9- to 12-year olds prenatally exposed to cigarettes and marihuana. Neurotoxicol Teratol 1998; 20(3): 293–306PubMedCrossRefGoogle Scholar
  186. 186.
    Solowij N, Grenyer BFS. Long term effects of cannabis on psyche and cognition. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 299–312Google Scholar
  187. 187.
    Mattes RD, Shaw LM, Engelman K. Effects of cannabinoids (marijuana) on taste intensity and hedonic ratings and salivary flow of adults. Chem Senses 1994; 19(2): 125–40PubMedCrossRefGoogle Scholar
  188. 188.
    Freemon FR. Effects of marihuana on sleeping states. JAMA 1972; 220(10): 1364–5PubMedCrossRefGoogle Scholar
  189. 189.
    Lissoni P, Resentini M, Mauri R, et al. Effects of tetrahydrocannabinol on melatonin secretion in man. Horm Metab Res 1986; 18(1): 77–8PubMedCrossRefGoogle Scholar
  190. 190.
    Wachtel SR, ElSohly MA, Ross SA, et al. Comparison of the subjective effects of delta (9)-tetrahydrocannabinol and marijuana in humans. Psychopharmacology 2002; 161(4): 331–9PubMedCrossRefGoogle Scholar
  191. 191.
    Hampson RE, Deadwyler SA. Cannabinoids, hippocampal function and memory. Life Sci 1999; 65: 715–23PubMedCrossRefGoogle Scholar
  192. 192.
    Heyser CJ, Hampson RE, Deadwyler SA. Effects of delta-9-tet-rahydrocannabinol on delayed match to sample performance in rats: alterations in short-term memory associated with changes in task specific firing of hippocampal cells. J Pharmacol Exp Ther 1993; 264(1): 294–307PubMedGoogle Scholar
  193. 193.
    Slikker Jr W, Paule MG, Ali SF, et al. Behavioral, neurochemical and neurohistochemical effects of chronic marijuana smoke exposure in the nonhuman primate. In: Myrphy L, Bartke A, editors. Marijuana/cannabinoids: neurobiology and neurophysiology. Boca Raton (FL): CRC Press, 1992: 219–73Google Scholar
  194. 194.
    Kelly TH, Foltin RW, Emurian CS, et al. Performance-based testing for drugs of abuse: dose and time profiles of marijuana, amphetamine, alcohol, and diazepam. J Anal Toxicol 1993; 17(5): 264–72PubMedGoogle Scholar
  195. 195.
    Perez-Reyes M. The psychologic and physiologic effects of active cannabinoids. In: Nahas G, Sutin KM, Harvey DJ, et al. Marihuana and medicine. Totowa (NJ): Humana Press, 1999: 245–52Google Scholar
  196. 196.
    Sañudo-Peña MC, Tsou K, Walker JM. Motor actions of cannabinoids in the basal ganglia output nuclei. Life Sci 1999; 65: 703–13PubMedCrossRefGoogle Scholar
  197. 197.
    Pertwee R. In vivo interactions between psychotropic cannabinoids and other drugs involving central and peripheral neurochemical mediators. In: Myrphy L, Bartke A, editors. Marijuana/cannabinoids: neurobiology and neurophysiology. Boca Raton (FL): CRC Press, 1992: 165–218Google Scholar
  198. 198.
    Domino EF. Cannabinoids and the cholinergic system. In: Nahas G, Sutin KM, Harvey DJ, et al., editors. Marihuana and medicine. Totowa (NJ): Humana Press, 1999: 223–6Google Scholar
  199. 199.
    Fan P. Cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons. J Neurophysiol 1995; 73(2): 907–10PubMedGoogle Scholar
  200. 200.
    Müller-Vahl KR, Kolbe H, Schneider U, et al. Movement disorders. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 205–14Google Scholar
  201. 201.
    Musty RE, Consroe P. Spastic disorders. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 195–204Google Scholar
  202. 202.
    Tashkin DP, Levisman JA, Abbasi AS, et al. Short-term effects of smoked marihuana on left ventricular function in man. Chest 1977; 72(1): 20–6PubMedCrossRefGoogle Scholar
  203. 203.
    Benowitz NL, Jones RT. Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. Clin Pharmacol Ther 1975; 18(3): 287–97PubMedGoogle Scholar
  204. 204.
    Formukong EA, Evans AT, Evans FJ. The inhibitory effects of cannabinoids, the active constituents of Cannabis sativa L., on human and rabbit platelet aggregation. J Pharm Pharmacol 1989; 41(10): 705–9PubMedCrossRefGoogle Scholar
  205. 205.
    O’Leary DS, Block RI, Koeppel JA, et al. Effects of smoking marijuana on brain perfusion and cognition. Neuropsychopharmacology 2002; 26(6): 802–16PubMedCrossRefGoogle Scholar
  206. 206.
    Wagner JA, Varga K, Kunos G. Cardiovascular actions of cannabinoids and their generation during shock. J Mol Med 1998; 76(12): 824–36PubMedCrossRefGoogle Scholar
  207. 207.
    Wagner JA, Jarai Z, Batkai S, et al. Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB1 receptors. Eur J Pharmacol 2001; 423(2–3): 203–10PubMedCrossRefGoogle Scholar
  208. 208.
    Van Klingeren B, Ten Ham M. Antibacterial activity of Δ9-tetrahydrocannabinol and cannabidiol. Antonie Van Leeuwenhoek 1976; 42(1–2): 9–12PubMedCrossRefGoogle Scholar
  209. 209.
    Lancz G, Specter S, Brown HK. Suppressive effect of delta-9-tetrahydrocannabinol on herpes simplex virus infectivity in vitro. Proc Soc Exp Biol Med 1991; 196(4): 401–4PubMedGoogle Scholar
  210. 210.
    Pate D. Glaucoma and cannabinoids. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 215–24Google Scholar
  211. 211.
    Colasanti BK. A comparison of the ocular and central effects of delta 9-tetrahydrocannabinol and cannabigerol. J Ocul Pharmacol 1990; 6(4): 259–69PubMedCrossRefGoogle Scholar
  212. 212.
    Murphy L. Hormonal system and reproduction. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 289–98Google Scholar
  213. 213.
    Tahir SK, Trogadis JE, Stevens JK, et al. Cytoskeletal organization following cannabinoid treatment in undifferentiated and differentiated PC12 cells. Biochem Cell Biol 1992; 70(10–11): 1159–73PubMedCrossRefGoogle Scholar
  214. 214.
    De Petrocellis L, Melck D, Palmisano A, et al. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci U S A 1998; 95(14): 8375–80PubMedCrossRefGoogle Scholar
  215. 215.
    Melck D, De Petrocellis L, Orlando P, et al. Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology 2000; 141(1): 118–26PubMedCrossRefGoogle Scholar
  216. 216.
    Galve-Roperh I, Sanchez C, Cortes ML, et al. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 2000; 6(3): 313–9PubMedCrossRefGoogle Scholar
  217. 217.
    Cabral G. Immune system. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 279–88Google Scholar
  218. 218.
    Melamede R. Possible mechanisms in autoimmune diseases. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 111–22Google Scholar
  219. 219.
    Evans AT, Formukong EA, Evans FJ. Actions of cannabis constituents on enzymes of arachidonate metabolism: anti-inflammatory potential. Biochem Pharmacol 1987; 36(12): 2035–7PubMedCrossRefGoogle Scholar
  220. 220.
    Sofia RD, Nalepa SD, Harakal JJ, et al. Anti-edema and analgesic properties of Δ9-tetrahydrocannabinol (THC). J Pharmacol Exp Ther 1973; 186(3): 646–55PubMedGoogle Scholar
  221. 221.
    Hembree III WC, Nahas GG, Zeidenberg P, et al. Changes in human spermatozoa associated with high dose marihuana smoking. Adv Biosci 1978; 22–23: 429–39PubMedGoogle Scholar
  222. 222.
    Chang MC, Berkery D, Schuel R, et al. Evidence for a can nabinoid receptor in sea urchin sperm and its role in blockade of the acrosome reaction. Mol Reprod Dev 1993; 36(4): 507–16PubMedCrossRefGoogle Scholar
  223. 223.
    Williams CM, Kirkham TC. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology 1999; 143(3): 315–7PubMedCrossRefGoogle Scholar
  224. 224.
    Williams CM, Kirkham TC. Observational analysis of feeding induced by delta (9)-THC and anandamide. Physiol Behav 2002; 76(2): 241–50PubMedCrossRefGoogle Scholar
  225. 225.
    Shook JE, Burks TF. Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents. J Pharmacol Exp Ther 1989; 249(2): 444–9PubMedGoogle Scholar
  226. 226.
    McCallum RW, Soykan I, Sridhar KR, et al. Delta-9-tetrahydrocannabinol delays the gastric emptying of solid food in humans: a double-blind, randomized study. Aliment Pharmacol Ther 1999; 13(1): 77–80PubMedCrossRefGoogle Scholar
  227. 227.
    Coruzzi G, Adami M, Coppelli G, et al. Inhibitory effect of the cannabinoid receptor agonist WIN 55,212-2 on pentagastrin-induced gastric acid secretion in the anaesthetized rat. Naunyn Schmiedebergs Arch Pharmacol 1999; 360(6): 715–8PubMedCrossRefGoogle Scholar
  228. 228.
    Adami M, Frati P, Bertini S, et al. Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach. Br J Pharmacol 2002; 135(7): 1598–606PubMedCrossRefGoogle Scholar
  229. 229.
    Lemberger L, Crabtree RE, Rowe HM. 11-Hydroxy-Δ9-tetra-hydrocannabinol: pharmacology, disposition, and metabolism of a major metabolite of marihuana in man. Science 1972; 177(43): 62–4PubMedCrossRefGoogle Scholar
  230. 230.
    Perez-Reyes M, Timmons M, Lipton M, et al. Intravenous injection in man of delta-9- tetrahydrocannabinol and 11-OH-delta-9-tetrahydrocannabinol. Science 1972; 177(49): 633–5PubMedCrossRefGoogle Scholar
  231. 231.
    Karler R, Turkanis SA. Different cannabinoids exhibit different pharmacological and toxicological properties. NIDA Res Monogr 1987; 79: 96–107PubMedGoogle Scholar
  232. 232.
    Burstein SH, Audette CA, Doyle SA, et al. Antagonism to the actions of platelet activating factor by a nonpsychoactive cannabinoid. J Pharmacol Exp Ther 1989; 251(2): 531–5PubMedGoogle Scholar
  233. 233.
    Burstein SH. The cannabinoid acids: nonpsychoactive derivatives with therapeutic potential. Pharmacol Ther 1999; 82(1): 87–96PubMedCrossRefGoogle Scholar
  234. 234.
    Doyle SA, Burstein SH, Dewey WL, et al. Further studies on the antinociceptive effects of delta 6-THC-7-oic acid. Agents Actions 1990; 31(1–2): 157–63PubMedCrossRefGoogle Scholar
  235. 235.
    Burstein S, Hunter SA, Latham V, et al. A major metabolite of delta 1-tetrahydrocannabinol reduces its cataleptic effect in mice. Experientia 1987; 43(4): 402–3PubMedCrossRefGoogle Scholar
  236. 236.
    Zuardi AW, Guimarães FS, Guimarães VMC, et al. Cannabidiol: possible therapeutic application. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 359–70Google Scholar
  237. 237.
    Karler R, Turkanis SA. The cannabinoids as potential antiepileptics. J Clin Pharmacol 1981; 21 (8–9 Suppl.): 437S–48SPubMedGoogle Scholar
  238. 238.
    Consroe P, Sandyk R, Snider SR. Open label evaluation of cannabidiol in dystonic movement disorders. Int J Neurosci 1986; 30(4): 277–82PubMedCrossRefGoogle Scholar
  239. 239.
    Parker LA, Mechoulam R, Schlievert C. Cannabidiol, a nonpsychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats. Neuroreport 2002; 13(5): 567–70PubMedCrossRefGoogle Scholar
  240. 240.
    Malfait AM, Gallily R, Sumariwalla PF, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral antiarthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A 2000; 97(17): 9561–6PubMedCrossRefGoogle Scholar
  241. 241.
    Colasanti BK, Brown RE, Craig CR. Ocular hypotension, ocular toxicity, and neurotoxicity in response to marihuana extract and cannabidiol. Gen Pharmacol 1984; 15(6): 479–84PubMedCrossRefGoogle Scholar
  242. 242.
    Baek SH, Kim YO, Kwag JS, et al. Boron trifluoride etherate on silica-A modified Lewis acid reagent (VII): antitumor activity of cannabigerol against human oral epitheloid carcinoma cells. Arch Pharm Res 1998; 21(3): 353–6PubMedCrossRefGoogle Scholar
  243. 243.
    Fride E, Barg J, Levy R, et al. Low doses of anandamides inhibit pharmacological effects of delta 9-tetrahydrocannabinol. J Pharmacol Exp Ther 1995; 272(2): 699–707PubMedGoogle Scholar
  244. 244.
    Archer RA, Stark P, Lemberger L. Nabilone. In: Mechoulam R, editor. Cannabinoids as therapeutic agents. Boca Raton: CRC Press, 1986: 85–103Google Scholar
  245. 245.
    Little PJ, Compton DR, Mechoulam R, et al. Stereochemical effects of 11-OH-Δ8-THC-dimethylheptyl in mice and dogs. Pharmacol Biochem Behav 1989; 32: 661–6PubMedCrossRefGoogle Scholar
  246. 246.
    Ottani A, Giuliani D. Hu 210: a potent tool for investigations of the cannabinoid system. CNS Drug Rev 2001; 7(2): 131–45PubMedCrossRefGoogle Scholar
  247. 247.
    Titishov N, Mechoulam R, Zimmerman AM. Stereospecific effects of (−)- and (+)-7-hydroxy-delta-6-tetrahydrocannabinol-dimethylheptyl on the immune system of mice. Pharmacology 1989; 39(6): 337–49PubMedCrossRefGoogle Scholar
  248. 248.
    Mechoulam R, Shohami E. HU-211: cannabinoid neuroprotective agent. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 389–400Google Scholar
  249. 249.
    Burstein S. Therapeutic potential of ajulemic acid (CT3). In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 381–8Google Scholar
  250. 250.
    Jain AK, Ryan JR, McMahon FG, et al. Evaluation of intramuscular levonantrodol and placebo in acute postoperative pain. J Clin Pharmacol 1981; 21 (8–9 Suppl.): 320S–6SPubMedGoogle Scholar
  251. 251.
    Citron ML, Herman TS, Vreeland F, et al. Antiemetic efficacy of levonantradol compared to delta-9-tetrahydrocannabinol for chemotherapy-induced nausea and vomiting. Cancer Treat Rep 1985; 69: 109–12PubMedGoogle Scholar
  252. 252.
    Lucraft HH, Palmer MK. Randomized clinical trial of levonantradol and chlorpromazine in the prevention of radiotherapy-induced vomiting. Clin Radiol 1982; 33(6): 621–2PubMedCrossRefGoogle Scholar
  253. 253.
    Showalter VM, Compton DR, Martin BR, et al. Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J Pharmacol Exp Ther 1996; 278(3): 989–99PubMedGoogle Scholar
  254. 254.
    Melvin LS, Milne GM, Johnson MR, et al. Structure-activity relationships for cannabinoid receptor-binding and analgesic activity: studies of bicyclic cannabinoid analogs. Mol Pharmacol 1993; 44(5): 1008–15PubMedGoogle Scholar
  255. 255.
    Beltramo M, Stella N, Calignano A, et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 1997; 277(5329): 1094–7PubMedCrossRefGoogle Scholar
  256. 256.
    Jaggar SI, Hasnie FS, Sellaturay S, et al. The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain. Pain 1998; 76(1–2): 189–99PubMedCrossRefGoogle Scholar
  257. 257.
    Terranova J-P, Storme J-J, Lafon N, et al. Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716. Psychopharmacology 1996; 126: 165–72PubMedCrossRefGoogle Scholar
  258. 258.
    Huestis MA, Gorelick DA, Heishman SJ, et al. Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 2001; 58(4): 322–8PubMedCrossRefGoogle Scholar
  259. 259.
    Di Marzo V, Hill MP, Bisogno T, et al. Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson’s disease. FASEB J 2000; 14(10): 1432–8PubMedCrossRefGoogle Scholar
  260. 260.
    Müller-Vahl KR, Schneider U, Emrich HM. Nabilone increases choreatic movements in Huntington’s disease. Mov Disord 1999; 14(6): 1038–40PubMedCrossRefGoogle Scholar
  261. 261.
    Romero J, Garcia-Palomero E, Castro JG, et al. Effects of chronic exposure to Δ9-tetrahydrocannabinol on cannabinoid receptor binding and mRNA levels in several rat brain regions. Brain Res Mol Brain Res 1997; 46(1–2): 100–8PubMedCrossRefGoogle Scholar
  262. 262.
    Jones RT, Benowitz N, Bachman J. Clinical studies of cannabis tolerance and dependence. Ann N Y Acad Sci 1976; 282: 221–39PubMedCrossRefGoogle Scholar
  263. 263.
    Stefanis C. Biological aspects of cannabis use. NIDA Res Monogr 1978; 19: 149–78PubMedGoogle Scholar
  264. 264.
    Bass CE, Martin BR. Time course for the induction and maintenance of tolerance to Delta (9)-tetrahydrocannabinol in mice. Drug Alcohol Depend 2000; 60(2): 113–9PubMedCrossRefGoogle Scholar
  265. 265.
    Luthra YK, Esber HJ, Lariviere DM, et al. Assessment of tolerance to immunosuppressive activity of delta 9-tetrahydrocannabinol in rats. J Immunopharmacol 1980; 2(2): 245–56PubMedCrossRefGoogle Scholar
  266. 266.
    Miczek KA, Dixit BN. Behavioral and biochemical effects of chronic delta 9-tetrahydrocannabinol in rats. Psychopharmacology (Berl) 1980; 67(2): 195–202CrossRefGoogle Scholar
  267. 267.
    Smith CG, Almirez RG, Berenberg J, et al. Tolerance develops to the disruptive effects of delta 9-tetrahydrocannabinol on primate menstrual cycle. Science 1983; 219(4591): 1453–5PubMedCrossRefGoogle Scholar
  268. 268.
    Di Marzo V, Berrendero F, Bisogno T, et al. Enhancement of anandamide formation in the limbic forebrain and reduction of endocannabinoid contents in the striatum of Δ9-tetrahydrocannabinol-tolerant rats. J Neurochem 2000; 74(4): 1627–35PubMedCrossRefGoogle Scholar
  269. 269.
    Rubino T, Vigano D, Massi P, et al. Changes in the cannabinoid receptor binding, G protein coupling, and cyclic AMP cascade in the CNS of rats tolerant to and dependent on the synthetic cannabinoid compound CP55,940. J Neurochem 2000; 75(5): 2080–6PubMedCrossRefGoogle Scholar
  270. 270.
    Abood ME, Sauss C, Fan F, et al. Development of behavioral tolerance to delta 9-THC without alteration of cannabinoid receptor binding or mRNA levels in whole brain. Pharmacol Biochem Behav 1993; 46(3): 575–9PubMedCrossRefGoogle Scholar
  271. 271.
    Rubino T, Vigano D, Costa B, et al. Loss of cannabinoid-stimulated guanosine 5′-O- (3-[35S]thiotriphosphate) binding without receptor down-regulation in brain regions of anandamide-tolerant rats. J Neurochem 2000; 75(6): 2478–84PubMedCrossRefGoogle Scholar
  272. 272.
    Georgotas A, Zeidenberg P. Observations on the effects of four weeks of heavy marihuana smoking on group interaction and individual behavior. Compr Psychiatry 1979; 20(5): 427–32PubMedCrossRefGoogle Scholar
  273. 273.
    Anthony JC, Warner LA, Kessler RC. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol 1994; 2: 244–68CrossRefGoogle Scholar
  274. 274.
    Kleiber D, Soellner R, Tossmann P. Cannabiskonsum in der Bundesrepublik Deutschland: Entwicklungstendenzen, Konsummuster und Einflußfaktoren. Bonn: Federal Ministry of Health, 1997Google Scholar
  275. 275.
    Roques B. Problemes posées par la dangerosité des drogues. Rapport du professeur Bernhard Roques au Secrétaire d’Etat à la Santé. Paris, 1998Google Scholar
  276. 276.
    Calhoun SR, Galloway GP, Smith DE. Abuse potential of dronabinol (Marinol®). J Psychoactive Drugs 1998; 30(2): 187–96PubMedCrossRefGoogle Scholar
  277. 277.
    British Medical Association. Therapeutic uses of cannabis. Amsterdam: Harwood Academic Publishers, 1997Google Scholar
  278. 278.
    Grinspoon L, Bakalar JB. Marihuana, the forbidden medicine. New Haven (CT): Yale University Press, 1993Google Scholar
  279. 279.
    Grotenhermen F. Review of therapeutic effects. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids: pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 123–42Google Scholar
  280. 280.
    Mathre ML, editor. Cannabis in medical practice: a legal, historical and pharmacological overview of the therapeutic use of marijuana. Jefferson (NC): McFarland & Co, 1997Google Scholar
  281. 281.
    Mechoulam R, editor. Cannabinoids as therapeutic agents. Boca Raton: CRC Press, 1986Google Scholar
  282. 282.
    Dansak DA. As an antiemetic and appetite stimulant in cancer patients. In: Mathre ML, editor. Cannabis in medical practice: a legal, historical and pharmacological overview of the therapeutic use of marijuana. Jefferson (NC): McFarland & Co, 1997: 69–83Google Scholar
  283. 283.
    Lane M, Vogel CL, Ferguson J, et al. Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. J Pain Symptom Manage 1991; 6(6): 352–9PubMedCrossRefGoogle Scholar
  284. 284.
    Sallan SE, Cronin C, Zelen M, et al. Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. N Engl J Med 1980; 302(3): 135–8PubMedCrossRefGoogle Scholar
  285. 285.
    Beal JE, Olson R, Lefkowitz L, et al. Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manage 1997; 14(1): 7–14PubMedCrossRefGoogle Scholar
  286. 286.
    Plasse TF, Gorter RW, Krasnow SH, et al. Recent clinical experience with dronabinol. Pharmacol Biochem Behav 1991; 40(3): 695–700PubMedCrossRefGoogle Scholar
  287. 287.
    Beal JE, Olson R, Laubenstein L, et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 1995; 10(2): 89–97PubMedCrossRefGoogle Scholar
  288. 288.
    Jatoi A, Windschitl HE, Loprinzi CL, et al. Dronabinol versus megestrol acetate versus combination therapy for cancerassociated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol 2002; 20(2): 567–73PubMedCrossRefGoogle Scholar
  289. 289.
    Soderpalm AH, Schuster A, de Wit H. Antiemetic efficacy of smoked marijuana: subjective and behavioral effects on nausea induced by syrup of ipecac. Pharmacol Biochem Behav 2001; 69(3–4): 343–50PubMedCrossRefGoogle Scholar
  290. 290.
    Maurer M, Henn V, Dittrich A, et al. Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur Arch Psychiatry Neurol Sci 1990; 240(1): 1–4CrossRefGoogle Scholar
  291. 291.
    Petro DJ. Marihuana as a therapeutic agent for muscle spasm or spasticity. Psychosomatics 1980; 21(1): 81–5PubMedGoogle Scholar
  292. 292.
    Killestein J, Hoogervorst EL, Reif M, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 2002; 58(9): 1404–7PubMedCrossRefGoogle Scholar
  293. 293.
    Martyn CN, Illis LS, Thom J. Nabilone in the treatment of multiple sclerosis [letter]. Lancet 1995; 345(8949): 579PubMedCrossRefGoogle Scholar
  294. 294.
    Meinck HM, Schonle PW, Conrad B. Effect of cannabinoids on spasticity and ataxia in multiple sclerosis. J Neurol 1989; 236(2): 120–2PubMedCrossRefGoogle Scholar
  295. 295.
    Petro DJ, Ellenberger Jr C. Treatment of human spasticity with delta 9-tetrahydrocannabinol. J Clin Pharmacol 1981; 21 (8–9 Suppl.): 413S–6SPubMedGoogle Scholar
  296. 296.
    Ungerleider JT, Andyrsiak T, Fairbanks L, et al. Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Adv Alcohol Subst Abuse 1987; 7(1): 39–50PubMedCrossRefGoogle Scholar
  297. 297.
    Elsner F, Radbruch L, Sabatowski R. Tetrahydrocannabinol zur Therapie chronischer Schmerzen [Tetrahydrocannabinol for treatment of chronic pain]. Schmerz 2001; 15(3): 200–4PubMedCrossRefGoogle Scholar
  298. 298.
    Notcutt W, Price M, Miller R, et al. Medicinal cannabis extracts in chronic pain: (2) comparison of two patients with back pain and sciatica. Congress on Cannabis and the Cannabinoids. Cologne: International Association for Cannabis as Medicine, 2001Google Scholar
  299. 299.
    Notcutt W, Price M, Miller R, et al. Medicinal cannabis extracts in chronic pain: (3) comparison of two patients with multiple sclerosis. Congress on Cannabis and the Cannabinoids. Cologne: International Association for Cannabis as Medicine, 2001Google Scholar
  300. 300.
    Noyes Jr R, Brunk SF, Avery DAH, et al. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 1975; 18(1): 84–9PubMedGoogle Scholar
  301. 301.
    Noyes Jr R, Brunk SF, Baram DA, et al. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 1975; 15(2–3): 139–43PubMedGoogle Scholar
  302. 302.
    Clifford DB. Tetrahydrocannabinol for tremor in multiple sclerosis. Ann Neurol 1983; 13(6): 669–71PubMedCrossRefGoogle Scholar
  303. 303.
    Fox SH, Kellett M, Moore AP, et al. Randomised, double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor stimulation in the treatment of dystonia. Mov Disord 2002; 17(1): 145–9PubMedCrossRefGoogle Scholar
  304. 304.
    Hemming M, Yellowlees PM. Effective treatment of Tourette’s syndrome with marijuana. J Psychopharmacol 1993; 7: 389–91PubMedCrossRefGoogle Scholar
  305. 305.
    Müller-Vahl KR, Schneider U, Kolbe H, et al. Treatment of Tourette’s syndrome with delta-9-tetrahydrocannabinol [letter]. Am J Psychiatry 1999; 156(3): 495PubMedGoogle Scholar
  306. 306.
    Müller-Vahl KR, Schneider U, Koblenz A, et al. Treatment of Tourette’s syndrome with Δ9-tetrahydrocannabinol (THC): a randomized crossover trial. Pharmacopsychiatry 2002; 35(2): 57–61PubMedCrossRefGoogle Scholar
  307. 307.
    Sandyk R, Awerbuch G. Marijuana and Tourette’s syndrome [letter]. J Clin Psychopharmacol 1998; 8: 844Google Scholar
  308. 308.
    Sieradzan KA, Fox SH, Hill M, et al. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology 2001; 57(11): 2108–11PubMedCrossRefGoogle Scholar
  309. 309.
    Hartley JP, Nogrady SG, Seaton A. Bronchodilator effect of delta1-tetrahydrocannabinol. Br J Clin Pharmacol 1978; 5(6): 523–5PubMedCrossRefGoogle Scholar
  310. 310.
    Tashkin DP, Shapiro BJ, Frank IM. Acute effects of smoked marijuana and oral Δ9-tetrahydrocannabinol on specific airway conductance in asthmatic subjects. Am Rev Respir Dis 1974; 109(4): 420–8PubMedGoogle Scholar
  311. 311.
    Crawford WJ, Merritt JC. Effects of tetrahydrocannabinol on arterial and intraocular hypertension. Int J Clin Pharmacol Biopharm 1979; 17(5): 191–6PubMedGoogle Scholar
  312. 312.
    Hepler RS, Frank IR. Marihuana smoking and intraocular pressure [letter]. JAMA 1971; 217(10): 1392PubMedCrossRefGoogle Scholar
  313. 313.
    Hepler RS, Petrus RJ. Experiences with administration of marihuana to glaucoma patients. In: Cohen S, Stillman RC, editors. The therapeutic potential of marihuana. New York: Plenum Medical Book, 1976: 63–75CrossRefGoogle Scholar
  314. 314.
    Merritt JC, Crawford WJ, Alexander PC, et al. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 1980; 87(3): 222–8PubMedGoogle Scholar
  315. 315.
    Schnelle M, Grotenhermen F, Reif M, et al. Ergebnisse einer standardisierten Umfrage zur medizinischen Verwendung von Cannabisprodukten im deutschen Sprachraum, [Results of a standardized survey on the medical use of cannabis products in the German-speaking area]. Forsch Komplementarmed [Res Complementary Med] 1999: 36Google Scholar
  316. 316.
    Gordon E, Devinsky O. Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy. Epilepsia 2001; 42(10): 1266–72PubMedCrossRefGoogle Scholar
  317. 317.
    Gilson I, Busalacchi M. Marijuana for intractable hiccups [letter]. Lancet 1998; 351(9098): 267PubMedCrossRefGoogle Scholar
  318. 318.
    Grinspoon L, Bakalar JB. The use of cannabis as a mood stabilizer in bipolar disorder: anecdotal evidence and the need for clinical research. J Psychoactive Drugs 1998; 30(2): 171–7PubMedCrossRefGoogle Scholar
  319. 319.
    Mikuriya TH. Cannabis substitution: an adjunctive therapeutic tool in the treatment of alcoholism. Med Times 1970; 98(4): 187–91PubMedGoogle Scholar
  320. 320.
    Volicer L, Stelly M, Morris J, et al. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 1997; 12(9): 913–9PubMedCrossRefGoogle Scholar
  321. 321.
    Ralevic V, Kendall DA. Cannabinoid inhibition of capsaicinsensitive sensory neurotransmission in the rat mesenteric arterial bed. Eur J Pharmacol 2001; 418(1–2): 117–25PubMedCrossRefGoogle Scholar
  322. 322.
    Jacobsson SO, Wallin T, Fowler CJ. Inhibition of rat C6 glioma cell proliferation by endogenous and synthetic cannabinoids: relative involvement of cannabinoid and vanilloid receptors. J Pharmacol Exp Ther 2001; 299(3): 951–9PubMedGoogle Scholar
  323. 323.
    Guzman M, Sanchez C, Galve-Roperh I. Control of the cell survival/death decision by cannabinoids. J Mol Med 2001; 78(11): 613–25PubMedCrossRefGoogle Scholar
  324. 324.
    Izzo AA, Pinto L, Borrelli F, et al. Central and peripheral cannabinoid modulation of gastrointestinal transit in physiological states or during the diarrhoea induced by croton oil. Br J Pharmacol 2000; 129(8): 1627–32PubMedCrossRefGoogle Scholar
  325. 325.
    Calignano A, Katona I, Desarnaud F, et al. Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature 2000; 408(6808): 96–101PubMedCrossRefGoogle Scholar
  326. 326.
    Carley DW, Paviovic S, Janelidze M, et al. Functional role for cannabinoids in respiratory stability during sleep. Sleep 2002; 25(4): 391–8PubMedGoogle Scholar
  327. 327.
    Pryor GT, Husain S, Mitoma C. Acute and subacute interactions between delta-9-tetrahydrocannabinol and other drugs in the rat. Ann N Y Acad Sci 1976; 281: 171–89PubMedCrossRefGoogle Scholar
  328. 328.
    Kosel BW, Aweeka FT, Benowitz NL, et al. The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. AIDS 2002; 16(4): 543–50PubMedCrossRefGoogle Scholar
  329. 329.
    Zullino DF, Delessert D, Eap CB, et al. Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int Clin Psychopharmacol 2002; 17(3): 141–3PubMedCrossRefGoogle Scholar
  330. 330.
    Hollister LE. Interactions of marihuana and Δ9-THC with other drugs. In: Nahas G, Sutin KM, Harvey DJ, et al., editors. Marihuana and medicine. Totowa (NJ): Humana Press, 1999: 273–7Google Scholar
  331. 331.
    Sutin KM, Nahas GG. Physiological and pharmacological interactions of marihuana (Δ9-THC) with drugs and anesthetics. In: Nahas G, Sutin KM, Harvey DJ, et al., editors. Marihuana and medicine. Totowa (NJ): Humana Press, 1999: 253–71Google Scholar
  332. 332.
    Brody S, Preut R. Cannabis, tobacco, and caffeine use modify the blood pressure reactivity protection of ascorbic acid. Pharmacol Biochem Behav 2002; 72(4): 811–6PubMedCrossRefGoogle Scholar
  333. 333.
    Welch SP, Eads M. Synergistic interactions of endogenous opioids and cannabinoid systems. Brain Res 1999; 848(1–2): 183–90PubMedCrossRefGoogle Scholar
  334. 334.
    Koe BK, Milne GM, Weissman A, et al. Enhancement of brain [3H]flunitrazepam binding and analgesic activity of synthetic cannabimimetics. Eur J Pharmacol 1985; 109(2): 201–12PubMedCrossRefGoogle Scholar
  335. 335.
    Moss DE, Manderscheid PZ, Montgomery SP, et al. Nicotine and cannabinoids as adjuncts to neuroleptics in the treatment of Tourette syndrome and other motor disorders. Life Sci 1989; 44(21): 1521–5PubMedCrossRefGoogle Scholar
  336. 336.
    Perez-Reyes M, Burstein SH, White WR, et al. Antagonism of marihuana effects by indomethacin in humans. Life Sci 1991; 48(6): 507–15PubMedCrossRefGoogle Scholar
  337. 337.
    Green K, Kearse EC, McIntyre OL. Interaction between delta-9-tetrahydrocannabinol and indomethacin. Ophthalmic Res 2001; 33(4): 217–20PubMedCrossRefGoogle Scholar
  338. 338.
    Mechoulam R, Hanus L, Fride E. Towards cannabinoid drugs: revisited. Prog Med Chem 1998; 35: 199–243PubMedCrossRefGoogle Scholar
  339. 339.
    Bisogno T, Hanus L, De Petrocellis L, et al. 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 2001; 134(4): 845–52PubMedCrossRefGoogle Scholar

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© Adis International Limited 2003

Authors and Affiliations

  1. 1.Nova-InstitutHürthGermany

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