Skip to main content

Role of Cannabinoids in Pain Management

Abstract

It is a curious fact that we owe a great deal of our insight into pharmacological treatment of pain to the plant world. Willow bark from Salix spp. led to development of aspirin and eventual elucidation of the analgesic effects of prostaglandins and their role in inflammation. The opium poppy (Papaver somniferum) provided the prototypic narcotic analgesic morphine, the first alkaloid discovered, and stimulated the much later discovery of the endorphin and enkephalin systems. Similarly, the pharmacological properties of cannabis (Cannabis sativa) prompted the isolation of Δ9-tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis, in 1964. It is this breakthrough that subsequently prompted the more recent discovery of the body’s own cannabis-like system, the endocannabinoid system (ECS), which modulates pain under physiological conditions.

Keywords

  • Neuropathic Pain
  • Chronic Neuropathic Pain
  • Peripheral Neuropathic Pain
  • Central Neuropathic Pain
  • Sidestream Smoke

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, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-1-4614-1560-2_18
  • Chapter length: 17 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   219.00
Price excludes VAT (USA)
  • ISBN: 978-1-4614-1560-2
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Hardcover Book
USD   279.99
Price excludes VAT (USA)
Fig. 18.1
Fig. 18.2

References

  1. Di Marzo V, Bisogno T, De Petrocellis L. Endocannabinoids and related compounds: walking back and forth between plant natural products and animal physiology. Chem Biol. 2007;14(7):741–56.

    PubMed  CrossRef  CAS  Google Scholar 

  2. Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86:1646–7.

    CAS  CrossRef  Google Scholar 

  3. Pate D. Chemical ecology of cannabis. J Int Hemp Assoc. 1994;2:32–7.

    Google Scholar 

  4. Di Marzo V, Melck D, Bisogno T, De Petrocellis L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 1998;21(12):521–8.

    PubMed  CrossRef  Google Scholar 

  5. Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389–462.

    PubMed  CAS  CrossRef  Google Scholar 

  6. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384(6604):83–7.

    PubMed  CAS  CrossRef  Google Scholar 

  7. Dinh TP, Freund TF, Piomelli D. A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. Chem Phys Lipids. 2002;121(1–2):149–58.

    PubMed  CAS  CrossRef  Google Scholar 

  8. Gulyas AI, Cravatt BF, Bracey MH, et al. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci. 2004;20(2):441–58.

    PubMed  CAS  CrossRef  Google Scholar 

  9. Mangieri RA, Piomelli D. Enhancement of endocannabinoid signaling and the pharmacotherapy of depression. Pharmacol Res. 2007;56(5):360–6.

    PubMed  CAS  CrossRef  Google Scholar 

  10. Howlett AC, Johnson MR, Melvin LS, Milne GM. Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model. Mol Pharmacol. 1988;33(3):297–302.

    PubMed  CAS  Google Scholar 

  11. Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA. 1999;96(10):5780–5.

    PubMed  CAS  CrossRef  Google Scholar 

  12. Wilson RI, Nicoll RA. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature. 2001;410(6828):588–92.

    PubMed  CAS  CrossRef  Google Scholar 

  13. Ibrahim MM, Porreca F, Lai J, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci USA. 2005;102(8):3093–8.

    PubMed  CAS  CrossRef  Google Scholar 

  14. Guindon J, Hohmann AG. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol. 2008;153(2):319–34.

    PubMed  CAS  CrossRef  Google Scholar 

  15. Pacher P, Mechoulam R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res. 2011;50:193–211.

    PubMed  CAS  CrossRef  Google Scholar 

  16. Racz I, Nadal X, Alferink J, et al. Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain. J Neurosci. 2008;28(46):12136–45.

    PubMed  CAS  CrossRef  Google Scholar 

  17. Guindon J, Hohmann AG. The endocannabinoid system and pain. CNS Neurol Disord Drug Targets. 2009;8(6):403–21.

    PubMed  CAS  CrossRef  Google Scholar 

  18. Fankhauser M. History of cannabis in Western medicine. In: Grotenhermen F, Russo EB, editors. Cannabis and cannabinoids: pharmacology, toxicology and therapeutic potential. Binghamton: Haworth Press; 2002. p. 37–51.

    Google Scholar 

  19. Russo EB. History of cannabis as medicine. In: Guy GW, Whittle BA, Robson P, editors. Medicinal uses of cannabis and cannabinoids. London: Pharmaceutical Press; 2004. p. 1–16.

    Google Scholar 

  20. Russo EB. History of cannabis and its preparations in saga, science and sobriquet. Chem Biodivers. 2007;4(8):2624–48.

    Google Scholar 

  21. Mechoulam R. The pharmacohistory of Cannabis sativa. In: Mechoulam R, editor. Cannabinoids as therapeutic agents. Boca Raton: CRC Press; 1986. p. 1–19.

    Google Scholar 

  22. Russo E. Cannabis treatments in obstetrics and gynecology: a historical review. J Cannabis Ther. 2002;2(3–4):5–35.

    CrossRef  Google Scholar 

  23. Russo EB. Hemp for headache: an in-depth historical and scientific review of cannabis in migraine treatment. J Cannabis Ther. 2001;1(2):21–92.

    CrossRef  Google Scholar 

  24. Russo EB. The role of cannabis and cannabinoids in pain management. In: Cole BE, Boswell M, editors. Weiner’s pain management: a practical guide for clinicians. 7th ed. Boca Raton: CRC Press; 2006. p. 823–44.

    Google Scholar 

  25. Russo EB. Cannabis in India: ancient lore and modern medicine. In: Mechoulam R, editor. Cannabinoids as therapeutics. Basel: Birkhäuser Verlag; 2005. p. 1–22.

    CrossRef  Google Scholar 

  26. ABC News, USA Today, Stanford Medical Center Poll. Broad experience with pain sparks search for relief. 9 May 2005.

    Google Scholar 

  27. Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008;4(1):245–59.

    PubMed  CAS  Google Scholar 

  28. Russo EB. The solution to the medicinal cannabis problem. In: Schatman ME, editor. Ethical issues in chronic pain management. Boca Raton: Taylor & Francis; 2006. p. 165–94.

    Google Scholar 

  29. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113(1–2):9–19.

    PubMed  CrossRef  Google Scholar 

  30. Tyler VE. Phytomedicines in Western Europe: potential impact on herbal medicine in the United States. In: Kinghorn AD, Balandrin MF, editors. Human medicinal agents from plants (ACS symposium, No. 534). Washington, D.C.: American Chemical Society; 1993. p. 25–37.

    CrossRef  Google Scholar 

  31. Russo EB. Handbook of psychotropic herbs: a scientific analysis of herbal remedies for psychiatric conditions. Binghamton: Haworth Press; 2001.

    Google Scholar 

  32. Food and Drug Administration. Guidance for industry: botanical drug products. In: Services UDoHaH, editor. US Government; 2004. p. 48. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070491.pdf.

  33. Walker JM, Hohmann AG. Cannabinoid mechanisms of pain suppression. Handb Exp Pharmacol. 2005;168:509–54.

    PubMed  CAS  CrossRef  Google Scholar 

  34. Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics. 2009;6(4):713–37.

    PubMed  CAS  CrossRef  Google Scholar 

  35. Richardson JD, Aanonsen L, Hargreaves KM. SR 141716A, a cannabinoid receptor antagonist, produces hyperalgesia in untreated mice. Eur J Pharmacol. 1997;319(2–3):R3–4.

    PubMed  CAS  CrossRef  Google Scholar 

  36. Walker JM, Huang SM, Strangman NM, Tsou K, Sanudo-Pena MC. Pain modulation by the release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci. 1999;96(21):12198–203.

    PubMed  CAS  CrossRef  Google Scholar 

  37. Walker JM, Hohmann AG, Martin WJ, Strangman NM, Huang SM, Tsou K. The neurobiology of cannabinoid analgesia. Life Sci. 1999;65(6–7):665–73.

    PubMed  CAS  CrossRef  Google Scholar 

  38. Martin WJ, Hohmann AG, Walker JM. Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist: correlation between electrophysiological and antinociceptive effects. J Neurosci. 1996;16:6601–11.

    PubMed  CAS  Google Scholar 

  39. Hohmann AG, Martin WJ, Tsou K, Walker JM. Inhibition of noxious stimulus-evoked activity of spinal cord dorsal horn neurons by the cannabinoid WIN 55,212-2. Life Sci. 1995;56(23–24):2111–8.

    PubMed  CAS  CrossRef  Google Scholar 

  40. Richardson JD, Aanonsen L, Hargreaves KM. Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol. 1998;345(2):145–53.

    PubMed  CAS  CrossRef  Google Scholar 

  41. Strangman NM, Walker JM. Cannabinoid WIN 55,212-2 inhibits the activity-dependent facilitation of spinal nociceptive responses. J Neurophysiol. 1999;82(1):472–7.

    PubMed  CAS  Google Scholar 

  42. Rahn EJ, Makriyannis A, Hohmann AG. Activation of cannabinoid CB(1) and CB(2) receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats. Br J Pharmacol. 2007;152:765–77.

    PubMed  CAS  CrossRef  Google Scholar 

  43. Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain. 1998;75(1):111–9.

    PubMed  CAS  CrossRef  Google Scholar 

  44. Karsak M, Gaffal E, Date R, et al. Attenuation of allergic contact dermatitis through the endocannabinoid system. Science. 2007;316(5830):1494–7.

    PubMed  CAS  CrossRef  Google Scholar 

  45. Luongo L, Palazzo E, Tambaro S, et al. 1-(2′,4′-Dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice. Neurobiol Dis. 2010;37(1):177–85.

    PubMed  CAS  CrossRef  Google Scholar 

  46. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA. 1998;95(14):8268–73.

    PubMed  CAS  CrossRef  Google Scholar 

  47. Burstein S, Levin E, Varanelli C. Prostaglandins and cannabis. II. Inhibition of biosynthesis by the naturally occurring cannabinoids. Biochem Pharmacol. 1973;22(22):2905–10.

    PubMed  CAS  CrossRef  Google Scholar 

  48. Fimiani C, Liberty T, Aquirre AJ, Amin I, Ali N, Stefano GB. Opiate, cannabinoid, and eicosanoid signaling converges on common intracellular pathways nitric oxide coupling. Prostaglandins Other Lipid Mediat. 1999;57(1):23–34.

    PubMed  CAS  CrossRef  Google Scholar 

  49. Stott CG, Guy GW, Wright S, Whittle BA. The effects of cannabis extracts Tetranabinex & Nabidiolex on human cyclo-oxygenase (COX) activity. Paper presented at: Symposium on the Cannabinoids, Clearwater, June 2005.

    Google Scholar 

  50. 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):845–52.

    PubMed  CAS  CrossRef  Google Scholar 

  51. Russo EB, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses. 2006;66(2):234–46.

    PubMed  CAS  CrossRef  Google Scholar 

  52. Morgan CJ, Curran HV. Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis. Br J Psychiatry. 2008;192(4):306–7.

    PubMed  CrossRef  Google Scholar 

  53. Morgan CJ, Freeman TP, Schafer GL, Curran HV. Cannabidiol attenuates the appetitive effects of delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology. 2010;35(9):1879–85.

    PubMed  CAS  CrossRef  Google Scholar 

  54. Morgan CJ, Schafer G, Freeman TP, Curran HV. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study. Br J Psychiatry. 2010;197(4):285–90.

    PubMed  CrossRef  Google Scholar 

  55. Malfait AM, Gallily R, Sumariwalla PF, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci USA. 2000;97(17):9561–6.

    PubMed  CAS  CrossRef  Google Scholar 

  56. Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci USA. 2006;103(20):7895–900.

    PubMed  CAS  CrossRef  Google Scholar 

  57. McHugh D, Hu SS, Rimmerman N, et al. N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neurosci. 2010;11:44.

    PubMed  CrossRef  CAS  Google Scholar 

  58. Dmitrieva N, Nagabukuro H, Resuehr D, et al. Endocannabinoid involvement in endometriosis. Pain. 2010;151(3):703–10.

    PubMed  CAS  CrossRef  Google Scholar 

  59. Izzo AA, Camilleri M. Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects. Gut. 2008;57(8):1140–55.

    PubMed  CAS  CrossRef  Google Scholar 

  60. Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther. 2010;126(1):21–38.

    PubMed  CAS  CrossRef  Google Scholar 

  61. Shen M, Piser TM, Seybold VS, Thayer SA. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci. 1996;16(14):4322–34.

    PubMed  CAS  Google Scholar 

  62. Nicolodi M, Volpe AR, Sicuteri F. Fibromyalgia and headache. Failure of serotonergic analgesia and N-methyl-D-aspartate-mediated neuronal plasticity: their common clues. Cephalalgia. 1998;18 Suppl 21:41–4.

    PubMed  Google Scholar 

  63. Russo EB. Clinical endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol Lett. 2004;25(1–2):31–9.

    PubMed  CAS  Google Scholar 

  64. Russo E. Cannabis for migraine treatment: the once and future prescription? An historical and scientific review. Pain. 1998;76(1–2):3–8.

    PubMed  CAS  CrossRef  Google Scholar 

  65. Spadone C. Neurophysiologie du cannabis [neurophysiology of cannabis]. Encéphale. 1991;17(1):17–22.

    PubMed  CAS  Google Scholar 

  66. Akerman S, Holland PR, Goadsby PJ. Cannabinoid (CB1) receptor activation inhibits trigeminovascular neurons. J Pharmacol Exp Ther. 2007;320(1):64–71.

    PubMed  CAS  CrossRef  Google Scholar 

  67. Akerman S, Kaube H, Goadsby PJ. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. J Pharmacol Exp Ther. 2003;309(1):56–63.

    CrossRef  CAS  Google Scholar 

  68. Akerman S, Kaube H, Goadsby PJ. Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1 receptors. Br J Pharmacol. 2004;142:1354–60.

    PubMed  CAS  CrossRef  Google Scholar 

  69. Manzanares J, Corchero J, Romero J, Fernandez-Ruiz JJ, Ramos JA, Fuentes JA. Chronic administration of cannabinoids regulates proenkephalin mRNA levels in selected regions of the rat brain. Brain Res Mol Brain Res. 1998;55(1):126–32.

    PubMed  CAS  CrossRef  Google Scholar 

  70. Cichewicz DL, Martin ZL, Smith FL, Welch SP. Enhancement of mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification. J Pharmacol Exp Ther. 1999;289(2):859–67.

    PubMed  CAS  Google Scholar 

  71. Cichewicz DL, Welch SP. Modulation of oral morphine antinociceptive tolerance and naloxone-precipitated withdrawal signs by oral delta 9-tetrahydrocannabinol. J Pharmacol Exp Ther. 2003;305(3):812–7.

    PubMed  CAS  CrossRef  Google Scholar 

  72. Cichewicz DL, McCarthy EA. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther. 2003;304(3):1010–5.

    PubMed  CAS  CrossRef  Google Scholar 

  73. Calhoun SR, Galloway GP, Smith DE. Abuse potential of dronabinol (Marinol). J Psychoactive Drugs. 1998;30(2):187–96.

    PubMed  CAS  CrossRef  Google Scholar 

  74. Clermont-Gnamien S, Atlani S, Attal N, Le Mercier F, Guirimand F, Brasseur L. Utilisation thérapeutique du delta-9-tétrahydrocannabinol (dronabinol) dans les douleurs neuropathiques réfractaires. The therapeutic use of D9-tetrahydrocannabinol (dronabinol) in refractory neuropathic pain. Presse Med. 2002;31(39 Pt 1):1840–5.

    PubMed  Google Scholar 

  75. Attal N, Brasseur L, Guirimand D, Clermond-Gnamien S, Atlami S, Bouhassira D. Are oral cannabinoids safe and effective in refractory neuropathic pain? Eur J Pain. 2004;8(2):173–7.

    PubMed  CAS  CrossRef  Google Scholar 

  76. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ. 2004;329(7460):253.

    PubMed  CAS  CrossRef  Google Scholar 

  77. Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106(1–2):169–72.

    PubMed  CAS  CrossRef  Google Scholar 

  78. Neff GW, O’Brien CB, Reddy KR, et al. Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease. Am J Gastroenterol. 2002;97(8):2117–9.

    PubMed  CrossRef  Google Scholar 

  79. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain. 2008;9(3):254–64.

    PubMed  CAS  CrossRef  Google Scholar 

  80. Toth C, Au S. A prospective identification of neuropathic pain in specific chronic polyneuropathy syndromes and response to pharmacological therapy. Pain. 2008;138(3):657–66.

    PubMed  CrossRef  Google Scholar 

  81. Rintala DH, Fiess RN, Tan G, Holmes SA, Bruel BM. Effect of dronabinol on central neuropathic pain after spinal cord injury: a pilot study. Am J Phys Med Rehabil. 2010;89(10):840–8.

    PubMed  CrossRef  Google Scholar 

  82. Lemberger L, Rubin A, Wolen R, et al. Pharmacokinetics, metabolism and drug-abuse potential of nabilone. Cancer Treat Rev. 1982;9(Suppl B):17–23.

    PubMed  CrossRef  Google Scholar 

  83. Notcutt W, Price M, Chapman G. Clinical experience with nabilone for chronic pain. Pharm Sci. 1997;3:551–5.

    CAS  Google Scholar 

  84. Berlach DM, Shir Y, Ware MA. Experience with the synthetic cannabinoid nabilone in chronic noncancer pain. Pain Med. 2006;7(1):25–9.

    PubMed  CrossRef  Google Scholar 

  85. Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain: Les effets de la nabilone, un cannabinoide synthetique, sur la douleur postoperatoire. Can J Anaesth. 2006;53(8):769–75.

    PubMed  CrossRef  Google Scholar 

  86. Maida V. The synthetic cannabinoid nabilone improves pain and symptom management in cancer patietns. Breast Cancer Res Treat. 2007;103(Part 1):121–2.

    Google Scholar 

  87. Wissel J, Haydn T, Muller J, et al. Low dose treatment with the synthetic cannabinoid nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. J Neurol. 2006;253(10):1337–41.

    PubMed  CAS  CrossRef  Google Scholar 

  88. Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ. 2008;336(7637):199–201.

    PubMed  CAS  CrossRef  Google Scholar 

  89. Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008;9(2):164–73.

    PubMed  CAS  CrossRef  Google Scholar 

  90. Ware MA, Fitzcharles MA, Joseph L, Shir Y. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth Analg. 2010;110(2):604–10.

    PubMed  CAS  CrossRef  Google Scholar 

  91. Bestard JA, Toth CC. An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy. Pain Pract. 2011;11:353–68. Epub 2010 Nov 18.

    PubMed  CrossRef  Google Scholar 

  92. Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA. 2003;290(13):1757–62.

    PubMed  CAS  CrossRef  Google Scholar 

  93. Dyson A, Peacock M, Chen A, et al. Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat. Pain. 2005;116(1–2):129–37.

    PubMed  CAS  CrossRef  Google Scholar 

  94. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68(7):515–21.

    PubMed  CAS  CrossRef  Google Scholar 

  95. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008;9(6):506–21.

    PubMed  CAS  CrossRef  Google Scholar 

  96. Wallace M, Schulteis G, Atkinson JH, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology. 2007;107(5):785–96.

    PubMed  CrossRef  Google Scholar 

  97. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34(3):672–80.

    PubMed  CAS  CrossRef  Google Scholar 

  98. Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182(14):E694–701.

    PubMed  Google Scholar 

  99. Wade DT, Makela PM, House H, Bateman C, Robson PJ. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler. 2006;12:639–45.

    PubMed  CAS  CrossRef  Google Scholar 

  100. Tashkin DP. Smoked marijuana as a cause of lung injury. Monaldi Arch Chest Dis. 2005;63(2):93–100.

    PubMed  CAS  Google Scholar 

  101. Tashkin DP, Simmons MS, Sherrill DL, Coulson AH. Heavy habitual marijuana smoking does not cause an accelerated decline in FEV1 with age. Am J Respir Crit Care Med. 1997;155(1):141–8.

    PubMed  CAS  Google Scholar 

  102. Hashibe M, Morgenstern H, Cui Y, et al. Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study. Cancer Epidemiol Biomarkers Prev. 2006;15(10):1829–34.

    PubMed  CAS  CrossRef  Google Scholar 

  103. Grinspoon L, Bakalar JB. Marihuana, the forbidden medicine. Rev. and exp. edn. New Haven: Yale University Press; 1997.

    Google Scholar 

  104. Moir D, Rickert WS, Levasseur G, et al. A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions. Chem Res Toxicol. 2008;21(2):494–502.

    PubMed  CAS  CrossRef  Google Scholar 

  105. Singh R, Sandhu J, Kaur B, et al. Evaluation of the DNA damaging potential of cannabis cigarette smoke by the determination of acetaldehyde derived N2-ethyl-2′-deoxyguanosine adducts. Chem Res Toxicol. 2009;22(6):1181–8.

    PubMed  CAS  CrossRef  Google Scholar 

  106. Joy JE, Watson SJ, Benson Jr JA. Marijuana and medicine: assessing the science base. Washington D.C.: Institute of Medicine; 1999.

    Google Scholar 

  107. Gieringer D. Marijuana waterpipe and vaporizer study. MAPS Bull. 1996;6(3):59–66.

    Google Scholar 

  108. Gieringer D. Cannabis “vaporization”: a promising strategy for smoke harm reduction. J Cannabis Ther. 2001;1(3–4):153–70.

    CrossRef  Google Scholar 

  109. Storz M, Russo EB. An interview with Markus Storz. J Cannabis Ther. 2003;3(1):67–78.

    CrossRef  Google Scholar 

  110. Gieringer D, St. Laurent J, Goodrich S. Cannabis vaporizer combines efficient delivery of THC with effective suppression of pyrolytic compounds. J Cannabis Ther. 2004;4(1):7–27.

    CAS  CrossRef  Google Scholar 

  111. Hazekamp A, Ruhaak R, Zuurman L, van Gerven J, Verpoorte R. Evaluation of a vaporizing device (Volcano) for the pulmonary administration of tetrahydrocannabinol. J Pharm Sci. 2006;95(6):1308–17.

    PubMed  CAS  CrossRef  Google Scholar 

  112. Van der Kooy F, Pomahacova B, Verpoorte R. Cannabis smoke condensate I: the effect of different preparation methods on tetrahydrocannabinol levels. Inhal Toxicol. 2008;20(9):801–4.

    PubMed  CrossRef  CAS  Google Scholar 

  113. Bloor RN, Wang TS, Spanel P, Smith D. Ammonia release from heated ‘street’ cannabis leaf and its potential toxic effects on cannabis users. Addiction. 2008;103(10):1671–7.

    PubMed  CrossRef  Google Scholar 

  114. Zuurman L, Roy C, Schoemaker RC, et al. Effect of intrapulmonary tetrahydrocannabinol administration in humans. J Psychopharmacol (Oxford, England). 2008;22(7):707–16.

    CAS  CrossRef  Google Scholar 

  115. Pomahacova B, Van der Kooy F, Verpoorte R. Cannabis smoke condensate III: the cannabinoid content of vaporised Cannabis sativa. Inhal Toxicol. 2009;21(13):1108–12.

    PubMed  CAS  CrossRef  Google Scholar 

  116. Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME, Benowitz NL. Vaporization as a smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther. 2007;82(5):572–8.

    PubMed  CAS  CrossRef  Google Scholar 

  117. Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clinical pharmacology and therapeutics. 2011;90(6):844–51.

    Google Scholar 

  118. Earleywine M, Barnwell SS. Decreased respiratory symptoms in cannabis users who vaporize. Harm Reduct J. 2007;4:11.

    PubMed  CrossRef  Google Scholar 

  119. Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet. 2003;362(9395):1517–26.

    PubMed  CAS  CrossRef  Google Scholar 

  120. Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry. 2005;76(12):1664–9.

    PubMed  CAS  CrossRef  Google Scholar 

  121. Ernst G, Denke C, Reif M, Schnelle M, Hagmeister H. Standardized cannabis extract in the treatment of postherpetic neuralgia: a randomized, double-blind, placebo-controlled cross-over study. Paper presented at: international association for cannabis as medicine, Leiden, 9 Sept 2005.

    Google Scholar 

  122. Holdcroft A, Maze M, Dore C, Tebbs S, Thompson S. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology. 2006;104(5):1040–6.

    PubMed  CAS  CrossRef  Google Scholar 

  123. McPartland JM, Russo EB. Cannabis and cannabis extracts: greater than the sum of their parts? J Cannabis Ther. 2001;1(3–4):103–32.

    CAS  CrossRef  Google Scholar 

  124. de Meijer E. The breeding of cannabis cultivars for pharmaceutical end uses. In: Guy GW, Whittle BA, Robson P, editors. Medicinal uses of cannabis and cannabinoids. London: Pharmaceutical Press; 2004. p. 55–70.

    Google Scholar 

  125. Guy GW, Robson P. A phase I, double blind, three-way crossover study to assess the pharmacokinetic profile of cannabis based medicine extract (CBME) administered sublingually in variant cannabinoid ratios in normal healthy male volunteers (GWPK02125). J Cannabis Ther. 2003;3(4):121–52.

    CAS  CrossRef  Google Scholar 

  126. Karschner EL, Darwin WD, McMahon RP, et al. Subjective and physiological effects after controlled Sativex and oral THC administration. Clin Pharmacol Ther. 2011;89(3):400–7.

    PubMed  CAS  CrossRef  Google Scholar 

  127. Karschner EL, Darwin WD, Goodwin RS, Wright S, Huestis MA. Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin Chem. 2011;57(1):66–75.

    PubMed  CAS  CrossRef  Google Scholar 

  128. Russo EB, Etges T, Stott CG. Comprehensive adverse event profile of Sativex. 18th annual symposium on the cannabinoids. Vol Aviemore, Scotland: International Cannabinoid Research Society; 2008. p. 136.

    Google Scholar 

  129. Barnes MP. Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain. Expert Opin Pharmacother. 2006;7(5):607–15.

    PubMed  CAS  CrossRef  Google Scholar 

  130. Pérez J. Combined cannabinoid therapy via na oromucosal spray. Drugs Today. 2006;42(8):495–501.

    PubMed  CrossRef  CAS  Google Scholar 

  131. Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003;17:18–26.

    Google Scholar 

  132. Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 “N of 1” studies. Anaesthesia. 2004;59:440–52.

    PubMed  CrossRef  Google Scholar 

  133. Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain. 2004;112(3):299–306.

    PubMed  CrossRef  Google Scholar 

  134. Rog DJ, Nurmiko T, Friede T, Young C. Randomized controlled trial of cannabis based medicine in central neuropathic pain due to multiple sclerosis. Neurology. 2005;65(6):812–9.

    PubMed  CrossRef  Google Scholar 

  135. Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 2007;133(1–3):210–20.

    PubMed  CAS  CrossRef  Google Scholar 

  136. Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler. 2004;10(4):434–41.

    PubMed  CAS  CrossRef  Google Scholar 

  137. Blake DR, Robson P, Ho M, Jubb RW, McCabe CS. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford). 2006;45(1):50–2.

    CAS  CrossRef  Google Scholar 

  138. Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage. 2010;39(2):167–79.

    PubMed  CrossRef  Google Scholar 

  139. Russo EB, Guy GW, Robson PJ. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers. 2007;4(8):1729–43.

    PubMed  CAS  CrossRef  Google Scholar 

  140. Lynch ME, Young J, Clark AJ. A case series of patients using medicinal marihuana for management of chronic pain under the Canadian Marihuana Medical Access Regulations. J Pain Symptom Manage. 2006;32(5):497–501.

    PubMed  CrossRef  Google Scholar 

  141. Janse AFC, Breekveldt-Postma NS, Erkens JA, Herings RMC. Medicinal gebruik van cannabis: PHARMO instituut. Institute for Drug Outcomes Research; 2004.

    Google Scholar 

  142. Gorter RW, Butorac M, Cobian EP, van der Sluis W. Medical use of cannabis in the Netherlands. Neurology. 2005;64(5):917–9.

    PubMed  CrossRef  Google Scholar 

  143. Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med. 2004;10:6.

    Google Scholar 

  144. Topol EJ. Failing the public health – rofecoxib, Merck, and the FDA. N Engl J Med. 2004;10:6.

    Google Scholar 

  145. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42(4):327–60.

    PubMed  CAS  CrossRef  Google Scholar 

  146. 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):276–82.

    PubMed  CAS  Google Scholar 

  147. Wright S. GWMS001 and GWMS0106: maintenance of blinding. London: GW Pharmaceuticals; 2005.

    Google Scholar 

  148. Clark P, Altman D. Assessment of blinding in phase III Sativex spasticity studies. GW Pharmaceuticals; 2006.

    Google Scholar 

  149. Samaha AN, Robinson TE. Why does the rapid delivery of drugs to the brain promote addiction? Trends Pharmacol Sci. 2005;26(2):82–7.

    PubMed  CAS  CrossRef  Google Scholar 

  150. Jones RT, Benowitz N, Bachman J. Clinical studies of cannabis tolerance and dependence. Ann N Y Acad Sci. 1976;282:221–39.

    PubMed  CAS  CrossRef  Google Scholar 

  151. Budney AJ, Hughes JR, Moore BA, Vandrey R. Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry. 2004;161(11):1967–77.

    PubMed  CrossRef  Google Scholar 

  152. Smith NT. A review of the published literature into cannabis withdrawal symptoms in human users. Addiction. 2002;97(6):621–32.

    PubMed  CrossRef  Google Scholar 

  153. Solowij N, Stephens RS, Roffman RA, et al. Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA. 2002;287(9):1123–31.

    PubMed  CrossRef  Google Scholar 

  154. Schoedel KA, Chen N, Hilliard A, et al. A randomized, double-blind, placebo-controlled, crossover study to evaluate the abuse potential of nabiximols oromucosal spray in subjects with a history of recreational cannabis use. Hum Psychopharmacol. 2011;26:224–36.

    PubMed  CAS  Google Scholar 

  155. Russo EB, Mathre ML, Byrne A, et al. Chronic cannabis use in the Compassionate Use Investigational New Drug Program: an examination of benefits and adverse effects of legal clinical cannabis. J Cannabis Ther. 2002;2(1):3–57.

    CrossRef  Google Scholar 

  156. Fride E, Russo EB. Neuropsychiatry: schizophrenia, depression, and anxiety. In: Onaivi E, Sugiura T, Di Marzo V, editors. Endocannabinoids: the brain and body’s marijuana and beyond. Boca Raton: Taylor & Francis; 2006. p. 371–82.

    Google Scholar 

  157. Aragona M, Onesti E, Tomassini V, et al. Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study. Clin Neuropharmacol. 2009;32(1):41–7.

    PubMed  CAS  Google Scholar 

  158. Degenhardt L, Hall W, Lynskey M. Testing hypotheses about the relationship between cannabis use and psychosis. Drug Alcohol Depend. 2003;71(1):37–48.

    PubMed  CrossRef  Google Scholar 

  159. Macleod J, Davey Smith G, Hickman M. Does cannabis use cause schizophrenia? Lancet. 2006;367(9516):1055.

    PubMed  CrossRef  Google Scholar 

  160. Macleod J, Hickman M. How ideology shapes the evidence and the policy: what do we know about cannabis use and what should we do? Addiction. 2010;105:1326–30.

    PubMed  CrossRef  Google Scholar 

  161. Hickman M, Vickerman P, Macleod J, et al. If cannabis caused schizophrenia–how many cannabis users may need to be prevented in order to prevent one case of schizophrenia? England and Wales calculations. Addiction. 2009;104(11):1856–61.

    PubMed  CrossRef  Google Scholar 

  162. Zuardi AW, Guimaraes FS. Cannabidiol as an anxiolytic and antipsychotic. In: Mathre ML, editor. Cannabis in medical practice: a legal, historical and pharmacological overview of the therapeutic use of marijuana. Jefferson: McFarland; 1997. p. 133–41.

    Google Scholar 

  163. Russo EB. Taming THC: potential cannabis synergy and ­phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163:1344–64.

    PubMed  CAS  CrossRef  Google Scholar 

  164. Cabral G. Immune system. In: Grotenhermen F, Russo EB, editors. Cannabis and cannabinoids: pharmacology, toxicology and therapeutic potential. Binghamton: Haworth Press; 2001. p. 279–87.

    Google Scholar 

  165. Katona S, Kaminski E, Sanders H, Zajicek J. Cannabinoid influence on cytokine profile in multiple sclerosis. Clin Exp Immunol. 2005;140(3):580–5.

    PubMed  CAS  CrossRef  Google Scholar 

  166. Abrams DI, Hilton JF, Leiser RJ, et al. Short-term effects of cannabinoids in patients with HIV-1 infection. A randomized, placbo-controlled clinical trial. Ann Intern Med. 2003;139:258–66.

    PubMed  CAS  Google Scholar 

  167. Stott CG, Guy GW, Wright S, Whittle BA. The effects of cannabis extracts Tetranabinex and Nabidiolex on human cytochrome P450-mediated metabolism. Paper presented at: Symposium on the Cannabinoids, Clearwater, 27 June 2005.

    Google Scholar 

  168. Stott CG, Ayerakwa L, Wright S, Guy G. Lack of human cytochrome P450 induction by Sativex. 17th annual symposium on the cannabinoids. Saint-Sauveur, Quebec: International Cannabinoid Research Society; 2007. p. 211.

    Google Scholar 

  169. Grotenhermen F, Leson G, Berghaus G, et al. Developing limits for driving under cannabis. Addiction. 2007;102(12):1910–7.

    PubMed  CrossRef  Google Scholar 

  170. Hohmann AG, Suplita 2nd RL. Endocannabinoid mechanisms of pain modulation. AAPS J. 2006;8(4):E693–708.

    PubMed  CAS  CrossRef  Google Scholar 

  171. Clapper JR, Moreno-Sanz G, Russo R, et al. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat Neurosci. 2010;13:1265–70.

    PubMed  CAS  CrossRef  Google Scholar 

  172. Schlosburg JE, Blankman JL, Long JZ, et al. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat Neurosci. 2010;13(9):1113–9.

    PubMed  CAS  CrossRef  Google Scholar 

  173. Yu XH, Cao CQ, Martino G, et al. A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain. Pain. 2010;151(2):337–44.

    PubMed  CAS  CrossRef  Google Scholar 

  174. Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009;30(10):515–27.

    PubMed  CAS  CrossRef  Google Scholar 

  175. Wirth PW, Watson ES, ElSohly M, Turner CE, Murphy JC. Anti-inflammatory properties of cannabichromene. Life Sci. 1980;26(23):1991–5.

    PubMed  CAS  CrossRef  Google Scholar 

  176. Davis WM, Hatoum NS. Neurobehavioral actions of cannabichromene and interactions with delta 9-tetrahydrocannabinol. Gen Pharmacol. 1983;14(2):247–52.

    PubMed  CAS  CrossRef  Google Scholar 

  177. Ligresti A, Moriello AS, Starowicz K, et al. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther. 2006;318(3):1375–87.

    PubMed  CAS  CrossRef  Google Scholar 

  178. De Petrocellis L, Starowicz K, Moriello AS, Vivese M, Orlando P, Di Marzo V. Regulation of transient receptor potential channels of melastatin type 8 (TRPM8): effect of cAMP, cannabinoid CB(1) receptors and endovanilloids. Exp Cell Res. 2007;313(9):1911–20.

    PubMed  CrossRef  CAS  Google Scholar 

  179. Gauson LA, Stevenson LA, Thomas A, Baillie GL, Ross RA, Pertwee RG. Cannabigerol behaves as a partial agonist at both CB1 and CB2 receptors. 17th annual symposium on the cannabinoids. Vol Saint-Sauveur, Quebec: International Cannabinoid Research Society; 2007, p. 206.

    Google Scholar 

  180. Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG. Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br J Pharmacol. 2010;159(1):129-41.

    PubMed  CAS  CrossRef  Google Scholar 

  181. Banerjee SP, Snyder SH, Mechoulam R. Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes. J Pharmacol Exp Ther. 1975;194(1):74–81.

    PubMed  CAS  Google Scholar 

  182. Evans FJ. Cannabinoids: the separation of central from peripheral effects on a structural basis. Planta Med. 1991;57(7):S60–7.

    CAS  CrossRef  Google Scholar 

  183. Evans AT, Formukong E, Evans FJ. Activation of phospholipase A2 by cannabinoids. Lack of correlation with CNS effects. FEBS Lett. 1987;211(2):119–22.

    PubMed  CAS  CrossRef  Google Scholar 

  184. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199–215.

    PubMed  CAS  CrossRef  Google Scholar 

  185. Hill AJ, Weston SE, Jones NA, et al. Delta-tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats. Epilepsia. 2010;51(8):1522–32.

    PubMed  CAS  CrossRef  Google Scholar 

  186. Bolognini D, Costa B, Maione S, et al. The plant cannabinoid delta9-tetrahydrocannabivarin can decrease signs of inflammation and inflammatory pain in mice. Br J Pharmacol. 2010;160(3):677–87.

    PubMed  CAS  CrossRef  Google Scholar 

  187. Mehmedic Z, Chandra S, Slade D, et al. Potency trends of delta(9)-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci. 2010;55:1209–17.

    PubMed  CAS  CrossRef  Google Scholar 

  188. King LA, Carpentier C, Griffiths P. Cannabis potency in Europe. Addiction. 2005;100(7):884–6.

    PubMed  CrossRef  Google Scholar 

  189. Potter DJ, Clark P, Brown MB. Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci. 2008;53(1):90–4.

    PubMed  CrossRef  Google Scholar 

  190. Potter D. Growth and morphology of medicinal cannabis. In: Guy GW, Whittle BA, Robson P, editors. Medicinal uses of cannabis and cannabinoids. London: Pharmaceutical Press; 2004. p. 17–54.

    Google Scholar 

  191. Rao VS, Menezes AM, Viana GS. Effect of myrcene on nociception in mice. J Pharm Pharmacol. 1990;42(12):877–8.

    PubMed  CAS  CrossRef  Google Scholar 

  192. Lorenzetti BB, Souza GE, Sarti SJ, Santos Filho D, Ferreira SH. Myrcene mimics the peripheral analgesic activity of lemongrass tea. J Ethnopharmacol. 1991;34(1):43–8.

    PubMed  CAS  CrossRef  Google Scholar 

  193. Basile AC, Sertie JA, Freitas PC, Zanini AC. Anti-inflammatory activity of oleoresin from Brazilian Copaifera. J Ethnopharmacol. 1988;22(1):101–9.

    PubMed  CAS  CrossRef  Google Scholar 

  194. Tambe Y, Tsujiuchi H, Honda G, Ikeshiro Y, Tanaka S. Gastric cytoprotection of the non-steroidal anti-inflammatory sesquiterpene, beta-caryophyllene. Planta Med. 1996;62(5):469–70.

    PubMed  CAS  CrossRef  Google Scholar 

  195. Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA. 2008;105(26):9099–104.

    PubMed  CAS  CrossRef  Google Scholar 

  196. Gil ML, Jimenez J, Ocete MA, Zarzuelo A, Cabo MM. Comparative study of different essential oils of Bupleurum gibraltaricum Lamarck. Pharmazie. 1989;44(4):284–7.

    PubMed  CAS  Google Scholar 

  197. Re L, Barocci S, Sonnino S, et al. Linalool modifies the nicotinic receptor-ion channel kinetics at the mouse neuromuscular junction. Pharmacol Res. 2000;42(2):177–82.

    PubMed  CAS  CrossRef  Google Scholar 

  198. Gregg, L.C, Jung, K.M., Spradley, J.M., Nyilas, R., Suplita II, R.L., Zimmer, A., Watanabe, M., Mackie, K., Katona, I., Piomelli, D. and Hohmann, A.G. (2012) Activation of type-5 metabotropic glutamate receptors and diacylglycerol lipase-alpha initiates 2-arachidonoylglycerol formation and endocannabinoid-mediated analgesia in vivo. The Journal of Neuroscience, in press [DOI:10.1523/JNEUROSCI.0013-12.2012].

    Google Scholar 

  199. Kavia R, De Ridder D, Constantinescu C, Stott C, Fowler C. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler. 2010;16(11):1349–59.

    PubMed  CAS  CrossRef  Google Scholar 

  200. Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438–49.

    Google Scholar 

  201. Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clinical pharmacology and therapeutics. 2011;90(6):844–51.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ethan B. Russo M.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2013 American Academy of Pain Medicine

About this chapter

Cite this chapter

Russo, E.B., Hohmann, A.G. (2013). Role of Cannabinoids in Pain Management. In: , et al. Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1560-2_18

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-1560-2_18

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-1559-6

  • Online ISBN: 978-1-4614-1560-2

  • eBook Packages: MedicineMedicine (R0)