The analgesic potential of cannabinoids

Jaseena Elikottil, MBBS; Pankaj Gupta, MD; Kalpna Gupta, PhD

doi:10.5055/jom.2009.0034

Authors

Jaseena Elikottil, MBBS
Pankaj Gupta, MD
Kalpna Gupta, PhD

DOI:

https://doi.org/10.5055/jom.2009.0034

Keywords:

pain, cannabinoid, opioid, marijuana, cannabis

Abstract

Historically and anecdotally cannabinoids have been used as analgesic agents. In recent years, there has been an escalating interest in developing cannabis-derived medications to treat severe pain. This review provides an overview of the history of cannabis use in medicine, cannabinoid signaling pathways, and current data from preclinical as well as clinical studies on using cannabinoids as potential analgesic agents. Clinical and experimental studies show that cannabis-derived compounds act as antiemetic, appetite modulating, and analgesic agents. However, the efficacy of individual products is variable and dependent upon the route of administration. As opioids are the only therapy for severe pain, analgesic ability of cannabinoids may provide a much-needed alternative to opioids. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis-based medications deserves serious consideration to alleviate the suffering of patients due to severe pain.

Author Biographies

Jaseena Elikottil, MBBS

Department of Medicine, Minneapolis VA Medical Center, Minneapolis, Minnesota.

Pankaj Gupta, MD

Hematology/Oncology Section, Department of Medicine, Minneapolis VA Medical Center, Minneapolis, Minnesota.

Kalpna Gupta, PhD

Division of Hematology, Oncology and Transplantation and the Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota.

References

Demuth DG, Molleman A: Cannabinoid signalling. Life Sci. 2006; 78(6): 549-563.

Booth M: Cannabis: A History, 1st ed. New York: Thomas Dunne Books, 2004.

Mikuriya TH: Marijuana in medicine: Past, present and future. Calif Med. 1969; 110(1): 34-40.

Zuardi AW: History of cannabis as a medicine: A review. Rev Bras Psiquiatr. 2006; 28(2): 153-157.

Brown RT, Zuelsdorff M, Fleming M: Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag. 2006; 2(3): 137-146.

Davis MP, Lasheen WP, Gamier P: Practical guide to opioids and their complications in managing cancer pain. What oncologists need to know. Oncology (Williston Park). 2007; 21(10): 1229-1238; discussion 1238.

Chang G, Chen L, Mao J: Opioid tolerance and hyperalgesia. Med Clin North Am. 2007; 91(2): 199-211.

Ballantyne JC, Shin NS: Efficacy of opioids for chronic pain: A review of the evidence. Clin J Pain. 2008; 24(6): 469-478.

Svizenska I, Dubovy P, Sulcova A: Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures–A short review. Pharmacol Biochem Behav. 2008; 90(4): 501-511.

Gong JP, Onaivi ES, Ishiguro H, et al.: Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. Brain Res. 2006; 1071(1): 10-23.

Kano M, Ohno-Shosaku T, Hashimotodani Y, et al.: Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009; 89(1): 309-380.

Guzman M, Sanchez C, Galve-Roperh I: Control of the cell survival/death decision by cannabinoids. J Mol Med. 2001; 78(11): 613-625.

Ryan D, Drysdale AJ, Lafourcade C, et al.: Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci. 2009; 29(7): 2053-2063.

Howlett AC, Breivogel CS, Childers SR, et al.: Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004; 47 (Suppl 1):345-358.

Sawzdargo M, Nguyen T, Lee DK, et al.: Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. Brain Res Mol Brain Res. 1999; 64(2): 193-198.

Starowicz K, Nigam S, Di Marzo V: Biochemistry and pharmacology of endovanilloids. Pharmacol Ther. 2007; 114(1): 13-33.

Ozaita A, Puighermanal E, Maldonado R: Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain. J Neurochem. 2007; 102(4): 1105-1114.

Molina-Holgado F, Pinteaux E, Heenan L, et al.: Neuroprotective effects of the synthetic cannabinoid HU-210 in primary cortical neurons are mediated by phosphatidylinositol 3-kinase/AKT signaling. Mol Cell Neurosci. 2005; 28(1): 189-194.

Lee YM, Uhm KO, Lee ES, et al.: AM251 suppresses the viability of HepG2 cells through the AMPK (AMP-activated protein kinase)-JNK (c-Jun N-terminal kinase)-ATF3 (activating transcription factor 3) pathway. Biochem Biophys Res Commun. 2008; 370(4): 641-645.

Greenhough A, Patsos HA, Williams AC, et al.: The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. Int J Cancer. 2007; 121(10): 2172-2180.

Ellert-Miklaszewska A, Kaminska B, Konarska L: Cannabinoids down-regulate PI3K/Akt and Erk signalling pathways and activate proapoptotic function of Bad protein. Cell Signal. 2005; 17(1): 25-37.

Caffarel MM, Moreno-Bueno G, Cerutti C, et al.: JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008; 27(37): 5033-5044.

Carracedo A, Gironella M, Lorente M, et al.: Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res. 2006; 66(13): 6748-6755.

Gustafsson K, Christensson B, Sander B, et al.: Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma. Mol Pharmacol. 2006; 70(5): 1612-1620.

Carracedo A, Lorente M, Egia A, et al.: The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell. 2006; 9(4): 301-312.

Sarnataro D, Pisanti S, Santoro A, et al.: The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism. Mol Pharmacol. 2006; 70(4): 1298-1306.

Jeong HJ, Kim SJ, Moon PD, et al.: Antiapoptotic mechanism of cannabinoid receptor 2 agonist on cisplatin-induced apoptosis in the HEI-OC1 auditory cell line. J Neurosci Res. 2007; 85(4): 896-905.

Khasabova IA, Khasabov SG, Harding-Rose C, et al.: A decrease in anandamide signaling contributes to the maintenance of cutaneous mechanical hyperalgesia in a model of bone cancer pain. J Neurosci. 2008; 28(44): 11141-11152.

Hamamoto DT, Giridharagopalan S, Simone DA: Acute and chronic administration of the cannabinoid receptor agonist CP 55,940 attenuates tumor-evoked hyperalgesia. Eur J Pharmacol. 2007; 558(1-3): 73-87.

Elmes SJ, Winyard LA, Medhurst SJ, et al.: Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. Pain. 2005; 118(3): 327-335.

Quartilho A, Mata HP, Ibrahim MM, et al.: Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology. 2003; 99(4): 955-960.

Nackley AG, Makriyannis A, Hohmann AG: Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience. 2003; 119(3): 747-757.

Siegling A, Hofmann HA, Denzer D, et al.: Cannabinoid CB(1) receptor upregulation in a rat model of chronic neuropathic pain. Eur J Pharmacol. 2001; 415(1): R5-R7.

Lim G, Sung B, Ji RR, et al.: Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats. Pain. 2003; 105(1-2): 275-283.

Zhang J, Hoffert C, Vu HK, et al.: Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci. 2003; 17(12): 2750-2754.

Liang YC, Huang CC, Hsu KS: The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain. Neuropharmacology. 2007; 53(1): 169-177.

Guindon J, Desroches J, Dani M, et al.: Pre-emptive antinociceptive effects of a synthetic cannabinoid in a model of neuropathic pain. Eur J Pharmacol. 2007; 568(1-3): 173-176.

Yamamoto W, Mikami T, Iwamura H: Involvement of central cannabinoid CB2 receptor in reducing mechanical allodynia in a mouse model of neuropathic pain. Eur J Pharmacol. 2008; 583(1): 56-61.

Dogrul A, Gul H, Yildiz O, et al.: Cannabinoids blocks tactile allodynia in diabetic mice without attenuation of its antinociceptive effect. Neurosci Lett. 2004; 368(1): 82-86.

Pascual D, Goicoechea C, Suardiaz M, et al.: A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats. Pain. 2005; 118(1-2): 23-34.

Rahn EJ, Makriyannis A, Hohmann AG: Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats. Br J Pharmacol. 2007; 152(5): 765-777.

Vera G, Chiarlone A, Cabezos PA, et al.: WIN 55,212-2 prevents mechanical allodynia but not alterations in feeding behaviour induced by chronic cisplatin in the rat. Life Sci. 2007; 81(6): 468-479.

Rahn EJ, Zvonok AM, Thakur GA, et al.: Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats. J Pharmacol Exp Ther. 2008; 327(2): 584-591.

Comelli F, Giagnoni G, Bettoni I, et al.: Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: Mechanisms involved. Phytother Res. 2008; 22(8): 1017-1024.

Clayton N, Marshall FH, Bountra C, et al.: CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain. 2002; 96(3): 253-260.

Burgos E, Pascual D, Isabel Martin M, et al.: Antinociceptive effect of the cannabinoid agonist, WIN 55,212-2, in the orofacial and temporomandibular formalin tests. Eur J Pain. 2009 (in press); doi: 10.1016/j.ejpain.2009.02.003.

Kehl LJ, Hamamoto DT, Wacnik PW, et al.: A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain. Pain. 2003; 103(1-2): 175-186.

Hanus L, Breuer A, Tchilibon S, et al.: HU-308: A specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci USA. 1999; 96(25): 14228-14233.

Guerrero AV, Quang P, Dekker N, et al.: Peripheral cannabinoids attenuate carcinoma-induced nociception in mice. Neurosci Lett. 2008; 433(2): 77-81.

Potenzieri C, Harding-Rose C, Simone DA: The cannabinoid receptor agonist, WIN 55, 212-2, attenuates tumor-evoked hyperalgesia through peripheral mechanisms. Brain Res. 2008; 1215: 69-75.

Smith PA, Selley DE, Sim-Selley LJ, et al.: Low dose combination of morphine and delta9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. Eur J Pharmacol. 2007; 571(2-3): 129-137.

Wilson AR, Maher L, Morgan MM: Repeated cannabinoid injections into the rat periaqueductal gray enhance subsequent morphine antinociception. Neuropharmacology. 2008; 55(7): 1219-1225.

Jan CR, Schneider AS: Sodium-dependent calcium efflux from adrenal chromaffin cells following exocytosis. Possible role of secretory vesicle membranes. J Biol Chem. 1992; 267(14): 9695-9700.

Cox ML, Haller VL, Welch SP: Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat. Eur J Pharmacol. 2007; 567(1-2): 125-130.

Cichewicz DL, McCarthy EA: Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther. 2003; 304(3): 1010-1015.

Smith FL, Cichewicz D, Martin ZL, et al.: The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol. Pharmacol Biochem Behav. 1998; 60(2): 559-566.

Yesilyurt O, Dogrul A, Gul H, et al.: Topical cannabinoid enhances topical morphine antinociception. Pain. 2003; 105(1-2): 303-308.

Cichewicz DL, Welch SP, Smith FL: Enhancement of transdermal fentanyl and buprenorphine antinociception by transdermal delta9-tetrahydrocannabinol. Eur J Pharmacol. 2005; 525(1-3): 74-82.

Paquette J, Olmstead MC: Ultra-low dose naltrexone enhances cannabinoid-induced antinociception. Behav Pharmacol. 2005; 16(8): 597-603.

Crain SM, Shen KF: Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment. Proc Natl Acad Sci USA. 1995; 92(23): 10540-10544.

Shen KF, Crain SM: Ultra-low doses of naltrexone or etorphine increase morphine’s antinociceptive potency and attenuate tolerance/dependence in mice. Brain Res. 1997; 757(2): 176-190.

Williams J, Haller VL, Stevens DL, et al.: Decreased basal endogenous opioid levels in diabetic rodents: Effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception. Eur J Pharmacol. 2008; 584(1): 78-86.

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): 3093-3098.

Ledent C, Valverde O, Cossu G, et al.: Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science. 1999; 283(5400): 401-404.

Castane A, Robledo P, Matifas A, et al.: Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice. Eur J Neurosci. 2003; 17(1): 155-159.

Naef M, Curatolo M, Petersen-Felix S, et al.: The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain. 2003; 105(1-2): 79-88.

Seeling W, Kneer L, Buchele B, et al.: Delta(9)-tetrahydrocannabinol and the opioid receptor agonist piritramide do not act synergistically in postoperative pain. Anaesthesist. 2006; 55(4): 391-400.

Saboory E, Derchansky M, Ismaili M, et al.: Mechanisms of morphine enhancement of spontaneous seizure activity. Anesth Analg. 2007; 105(6): 1729-1735, table of contents.

Wallace MJ, Blair RE, Falenski KW, et al.: The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J Pharmacol Exp Ther. 2003; 307(1): 129-137.

Wallace MJ, Wiley JL, Martin BR, et al.: Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. Eur J Pharmacol. 2001; 428(1): 51-57.

Blair RE, Deshpande LS, Sombati S, et al.: Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus. J Pharmacol Exp Ther. 2006; 317(3): 1072-1078.

Porreca F, Ossipov MH: Nausea and vomiting side effects with opioid analgesics during treatment of chronic pain: Mechanisms, implications, and management options. Pain Med. 2009; 10(4): 654-662.

Slatkin NE: Cannabinoids in the treatment of chemotherapyinduced nausea and vomiting: Beyond prevention of acute emesis. J Support Oncol. 2007; 5(5 Suppl 3): 1-9.

Sontineni SP, Chaudhary S, Sontineni V, et al.: Cannabinoid hyperemesis syndrome: Clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse. World J Gastroenterol. 2009; 15(10): 1264-1266.

Pattinson KT: Opioids and the control of respiration. Br J Anaesth. 2008; 100(6): 747-758.

Gardell LR, King T, Ossipov MH, et al.: Opioid receptormediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery. Neurosci Lett. 2006; 396(1): 44-49.

Chu LF, Angst MS, Clark D: Opioid-induced hyperalgesia in humans: Molecular mechanisms and clinical considerations. Clin J Pain. 2008; 24(6): 479-496.

Weber ML, Farooqui M, Nguyen J, et al.: Morphine induces mesangial cell proliferation and glomerulopathy via kappa-opioid receptors. Am J Physiol Renal Physiol. 2008; 294(6): F1388-F1397.

Arerangaiah R, Chalasani N, Udager AM, et al.: Opioids induce renal abnormalities in tumor-bearing mice. Nephron Exp Nephrol. 2007; 105(3): e80-e89.

Pan H, Mukhopadhyay P, Rajesh M, et al.: Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death. J Pharmacol Exp Ther. 2009; 328(3): 708-714.

Gupta K, Kshirsagar S, Chang L, et al.: Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res. 2002; 62(15): 4491-4498.

Bifulco M, Laezza C, Gazzerro P, et al.: Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (review). Oncol Rep. 2007; 17(4): 813-816.

Beaulieu P: Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth. 2006; 53(8): 769-775.

Kraft B, Frickey NA, Kaufmann RM, et al.: Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers. Anesthesiology. 2008; 109(1): 101-110.

Beaulieu P, Ware M: Reassessment of the role of cannabinoids in the management of pain. Curr Opin Anaesthesiol. 2007; 20(5): 473-477.

Mechoulam R, Hanu L: The cannabinoids: An overview. Therapeutic implications in vomiting and nausea after cancer chemotherapy, in appetite promotion, in multiple sclerosis and in neuroprotection. Pain Res Manag. 2001; 6(2): 67-73.

Davis MP: Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain. Expert Opin Investig Drugs. 2008; 17(1): 85-95.

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): 352-359.

Kogan NM, Mechoulam R: Cannabinoids in health and disease. Dialogues Clin Neurosci. 2007; 9(4): 413-430.

Strasser F, Luftner D, Possinger K, et al.: Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: A multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol. 2006; 24(21): 3394-3400.

Woolridge E, Barton S, Samuel J, et al.: Cannabis use in HIV for pain and other medical symptoms. J Pain Symptom Manage. 2005; 29(4): 358-367.

Corless IB, Lindgren T, Holzemer W, et al.: Marijuana effectiveness as an HIV self-care strategy. Clin Nurs Res. 2009; 18(2): 172-193.

Pollmann W, Feneberg W: Current management of pain associated with multiple sclerosis. CNS Drugs. 2008; 22(4): 291-324.

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): 1517-1526.

Rog DJ, Nurmikko TJ, Friede T, et al.: Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005; 65(6): 812-819.

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.

Killestein J, Hoogervorst EL, Reif M, et al.: Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology. 2002; 58(9): 1404-1407.

Rog DJ, Nurmikko TJ, Young CA: Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: An uncontrolled, open-label, 2-year extension trial. Clin Ther. 2007; 29(9): 2068-2079.

Russo EB, Guy GW, Robson PJ: Cannabis, pain, and sleep: Lessons from therapeutic clinical trials of Sativex, a cannabisbased medicine. Chem Biodivers. 2007; 4(8): 1729-1743.

Hartrick CT, Kovan JP, Shapiro S: The numeric rating scale for clinical pain measurement: A ratio measure? Pain Pract. 2003; 3(4): 310-316.

Galer BS, Jensen MP: Development and preliminary validation of a pain measure specific to neuropathic pain: The Neuropathic Pain Scale. Neurology. 1997; 48(2): 332-338.

Herndon RM: Handbook of Neurological Rating Scales, 2nd ed. New York: Demos Medical Publishing, 2006.

Iskedjian M, Bereza B, Gordon A, et al.: Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain. Curr Med Res Opin. 2007; 23(1): 17-24.

Maida V, Ennis M, Irani S, et al.: Adjunctive nabilone in cancer pain and symptom management: A prospective observational study using propensity scoring. J Support Oncol. 2008; 6(3): 119-124.

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): 254-264.

Holdcroft A, Maze M, Dore C, et al.: A multicenter doseescalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology. 2006; 104(5): 1040-1046.

Buggy DJ, Toogood L, Maric S, et al.: Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain. 2003; 106(1-2): 169-172.

Skrabek RQ, Galimova L, Ethans K, et al.: Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008; 9(2): 164-173.

Blake DR, Robson P, Ho M, et al., 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): 50-52.

Bruera E, Kuehn N, Miller MJ, et al.: The Edmonton Symptom Assessment System (ESAS): A simple method for the assessment of palliative care patients. J Palliat Care. 1991; 7(2): 6-9.

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): 672-680.

Abrams DI, Jay CA, Shade SB, et al.: Cannabis in painful HIV-associated sensory neuropathy: A randomized placebocontrolled trial. Neurology. 2007; 68(7): 515-521.

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): 506-521.

Nurmikko TJ, Serpell MG, Hoggart B, et al.: Sativex successfully treats neuropathic pain characterised by allodynia: A randomised, double-blind, placebo-controlled clinical trial. Pain. 2007; 133(1-3): 210-220.

Frank B, Serpell MG, Hughes J, et al.: 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.

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(5): 440-452.

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.

Campbell FA, Tramer MR, Carroll D, et al.: Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ. 2001; 323(7303): 13-16.

Howard J, Anie KA, Holdcroft A, et al.: Cannabis use in sickle cell disease: A questionnaire study. Br J Haematol. 2005; 131(1): 123-128.

Ballas SK: Pain management of sickle cell disease. Hematol Oncol Clin North Am. 2005; 19(5): 785-802.

Smith WR, Penberthy LT, Bovbjerg VE, et al.: Daily assessment of pain in adults with sickle cell disease. Ann Intern Med. 2008; 148(2): 94-101.

Shord SS, Chew L, Villano J: Evaluation of opioid induced nausea and vomiting in sickle cell disease. Am J Hematol. 2008; 83(3): 196-199.

Burstein SH, Zurier RB: Cannabinoids, endocannabinoids, and related analogs in inflammation. AAPS J. 2009; 11(1): 109-119.

Nath KA, Grande JP, Croatt AJ, et al.: Transgenic sickle mice are markedly sensitive to renal ischemia-reperfusion injury. Am J Pathol. 2005; 166(4): 963-972.

Montecucco F, Lenglet S, Braunersreuther V, et al.: CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol. 2009; 46(5): 612-620.

Defer N, Wan J, Souktani R, et al.: The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy. FASEB J. 2009; 23(7): 2120-2130.

Hillard CJ: Role of cannabinoids and endocannabinoids in cerebral ischemia. Curr Pharm Des. 2008; 14(23): 2347-2361.

Zhang M, Martin BR, Adler MW, et al.: Modulation of cannabinoid receptor activation as a neuroprotective strategy for EAE and stroke. J Neuroimmune Pharmacol. 2009; 4(2): 249-259.

Aldington S, Harwood M, Cox B, et al.: Cannabis use and cancer of the head and neck: Case-control study. Otolaryngol Head Neck Surg. 2008; 138(3): 374-380.

Aldington S, Harwood M, Cox B, et al.: Cannabis use and risk of lung cancer: A case-control study. Eur Respir J. 2008; 31(2): 280-286.

Voirin N, Berthiller J, Benhaim-Luzon V, et al.: Risk of lung cancer and past use of cannabis in Tunisia. J Thorac Oncol. 2006; 1(6): 577-579.

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): 1829-1834.

Bluhm EC, Daniels J, Pollock BH, et al.: Maternal use of recreational drugs and neuroblastoma in offspring: A report from the Children’s Oncology Group (United States). Cancer Causes Control. 2006; 17(5): 663-669.

Wehner FC, van Rensburg SJ, Thiel PG: Mutagenicity of marijuana and Transkei tobacco smoke condensates in the Salmonella/microsome assay. Mutat Res. 1980; 77(2): 135-142.

Busch FW, Seid DA, Wei ET: Mutagenic activity of marihuana smoke condensates. Cancer Lett. 1979; 6(6): 319-324.

Van Went GF: Mutagenicity testing of 3 hallucinogens: LSD, psilocybin and delta 9-THC, using the micronucleus test. Experientia. 1978; 34(3): 324-325.

Zimmerman AM, Stich H, San R: Nonmutagenic action of cannabinoids in vitro. Pharmacology. 1978; 16(6): 333-343.

National Toxicology Program: NTP Toxicology and Carcinogenesis Studies of 1-Trans-Delta(9)-Tetrahydrocannabinol (CAS No. 1972-08-3) in F344 Rats and B6C3F1 Mice (Gavage Studies). Natl Toxicol Program Tech Rep Ser. 1996; 446: 1-317.

Chan PC, Sills RC, Braun AG, et al.: Toxicity and carcinogenicity of delta 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice. Fundam Appl Toxicol. 1996; 30(1): 109-117.

McKallip RJ, Lombard C, Fisher M, et al.: Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood. 2002; 100(2): 627-634.

Kogan NM, Blazquez C, Alvarez L, et al.: A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells. Mol Pharmacol. 2006; 70(1): 51-59.

Galanti G, Fisher T, Kventsel I, et al.: Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells. Acta Oncol. 2008; 47(6): 1062-1070.

Sarfaraz S, Afaq F, Adhami VM, et al.: Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res. 2005; 65(5): 1635-1641.

Schneider M: Puberty as a highly vulnerable developmental period for the consequences of cannabis exposure. Addict Biol. 2008; 13(2): 253-263.

Hall W, Degenhardt L: Cannabis use and the risk of developing a psychotic disorder. World Psychiatry. 2008; 7(2): 68-71.

Luzi S, Morrison PD, Powell J, et al.: What is the mechanism whereby cannabis use increases risk of psychosis? Neurotox Res. 2008; 14(2-3): 105-112.

Harvey MA, Sellman JD, Porter RJ, et al.: The relationship between non-acute adolescent cannabis use and cognition. Drug Alcohol Rev. 2007; 26(3): 309-319.

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. 2008; 32(1): 41-47.

Maldonado R: Study of cannabinoid dependence in animals. Pharmacol Ther. 2002; 95(2): 153-164.

Hutcheson DM, Tzavara ET, Smadja C, et al.: Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydrocannabinol. Br J Pharmacol. 1998; 125(7): 1567-1577.

Hasin DS, Keyes KM, Alderson D, et al.: Cannabis withdrawal in the United States: Results from NESARC. J Clin Psychiatry. 2008; 69(9): 1354-1363.

DeSanty KP, Dar MS: Cannabinoid-induced motor incoordination through the cerebellar CB(1) receptor in mice. Pharmacol Biochem Behav. 2001; 69(1-2): 251-259.

Dar MS: Cerebellar CB(1) receptor mediation of delta(9)-THC-induced motor incoordination and its potentiation by ethanol and modulation by the cerebellar adenosinergic A(1) receptor in the mouse. Brain Res. 2000; 864(2): 186-194.