What other names is Marijuana known by?
Anashca, Banji, Bhang, Blunt, Bud, Cannabis, Cannabis sativa, Charas, Dope, Esrar, Gaga, Ganga, Grass, Haschisch, Hash, Hashish, Herbe, Huo Ma Ren, Joint, Kif, Marie-Jeanne, Mariguana, Marijuana Médicale, Marihuana, Mary Jane, Medical Marijuana, Pot, Sawi, Sinsemilla, Weed.
What is Marijuana?
Marijuana is an herb. It contains chemicals called cannabinoids that affect the central nervous system. Cannabinoids are found in the highest concentration in the leaves and flowers, the parts of the herb that are used to make medicine.
Some people take marijuana extract by mouth or as a spray to be applied under the tongue for pain and symptoms of multiple sclerosis.
Some people inhale marijuana for medicinal purposes. Marijuana is smoked for nausea, glaucoma, appetite stimulation, to reduce swelling of mucous membranes, for leprosy, fever, dandruff, hemorrhoids, obesity, asthma, urinary tract infections, cough, anorexia associated with weight loss in AIDS patients, nerve pain, and multiple sclerosis. It is also inhaled to weaken the immune system after kidney transplant to lessen the chance of transplant rejection. In addition, marijuana is smoked to reduce symptoms amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease).
Some people use marijuana recreationally to create a sense of well-being or to alter the senses. It is either taken by mouth or smoked (inhaled).
Avoid confusion with hemp, a distinct variety of Cannabis sativa cultivated for its fiber and seeds, which contains less than 1% THC.
In the U.S., marijuana is classified as a Schedule I controlled substance, making possession illegal. Some states, such as California, Washington, Oregon, Arizona, and others, have legalized or decriminalized the use of medical marijuana, despite objections from the federal government. Some countries such as Canada also permit the use of medical marijuana.
Possibly Effective for.
- HIV/AIDS-related weight loss. Smoking marijuana seems to stimulate the appetite of people with AIDS. Marijuana cigarettes can also cause weight gain in people with HIV who are also taking indinavir (Crixivan) or nelfinavir (Viracept).
- Multiple sclerosis (MS). Applying a specific spray containing marijuana extract (Sativex, GW Pharmaceuticals) under the tongue seems to improve some self-reported symptoms of multiple sclerosis, including muscle spasms, need to urinate, and nerve pain. In the UK, this product is approved as a prescription medicine to treat muscle spasms in people with MS. In Canada, this product is approved to treat nerve pain in people with MS. This product is not available as a prescription medicine in the US. Also, some conflicting evidence suggests that this product does not significantly improve muscle spasms, nor does it reduce the need to urinate or tremors in MS patients. There are conflicting results regarding the effects of marijuana extract when taken by mouth. One small study shows that taking a specific marijuana extract (Cannador, Society for Clinical Research) by mouth reduces self-reported muscle stiffness and muscle spasms in people with MS. However, other studies show that taking marijuana extract by mouth does not significantly improve muscle spasms, the ability to walk, or tremors in people with MS. Early research shows that smoking marijuana may reduce muscle spasms, pain in the arms and legs, and tremors in people with MS.
- Nerve pain. Early research shows that smoking marijuana three times a day might reduce nerve pain caused by HIV and other conditions.
Insufficient Evidence to Rate Effectiveness for.
- Amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease). Early research shows that patients with ALS who use marijuana might have improvements in some symptoms, including depression, appetite, spasms, and drooling.
- Weight loss in people with advanced cancer (cachexia). Early research shows that taking marijuana extract by mouth does not improve appetite in people with cachexia.
- Glaucoma. Smoking marijuana seems to reduce pressure inside the eye in people with glaucoma. However, this effect seems to last for only 3-4 hours. Also, smoking marijuana seems to decrease blood flow to the nerve that transmits visual information from the eye to the brain. This might increase vision loss in people with glaucoma. So far, it is not known if marijuana can improve sight in people with glaucoma.
- Rheumatoid arthritis (RA). Some research suggests that using a specific mouth spray containing marijuana extract (Sativex, GW Pharmaceuticals) can decrease morning pain and improve sleep in people with RA. However, it does not seem to improve joint stiffness in the morning or overall pain severity.
- Preventing organ rejection after kidney transplants.
- Urinary infections.
- Other conditions.
More evidence is needed to rate marijuana for these uses.
How does Marijuana work?
Marijuana contains chemicals that work by binding to specific sites in the brain and on the nerves.
Are there safety concerns?
Marijuana extract is POSSIBLY SAFE when used as a standardized spray (Sativex, GW Pharmaceuticals) that is applied under the tongue.
Marijuana is POSSIBLY UNSAFE when smoked. Smoking marijuana is associated with an increased the risk of developing lung cancer. Also, some reports suggest that smoking marijuana might cause air-filled cavities to form within lung tissue. These air-filled cavities can cause symptoms such as chest pressure, soreness, and difficulty breathing.
Smoking marijuana or using mouth sprays containing marijuana extract can cause headache, dizziness, drowsiness, dry mouth, nausea, and paranoid thinking. Smoking marijuana might also increase appetite, cause coughs, increase heart rate, increase or decrease blood pressure, and impair mental functioning. Some reports suggest that smoking marijuana may also increase the risk of acute coronary syndrome, heart attack, and/or swelling of walls of the arteries (arteritis). However, in many cases, people who experienced these events after smoking marijuana had other risk factors for heart-related events such as smoking cigarettes or being overweight.
Special Precautions & Warnings:
Breast-feeding: Using marijuana, either by mouth or by inhalation is LIKELY UNSAFE during breast-feeding. The dronabinol (THC) in marijuana passes into breast milk and extensive marijuana use during breast-feeding may result in slowed development in the baby.
Bipolar disorder: Using marijuana might worsen manic symptoms in people with bipolar disorder.
Heart disease: Marijuana might cause rapid heartbeat, short-term high blood pressure. It might also increase the risk of a having heart attack.
A weakened immune system: Cannabinoids in marijuana can weaken the immune system, which might make it more difficult for the body to fight infections.
Depression: Marijuana use, especially frequent use, might worsen symptoms of depression.
Multiple sclerosis: Taking marijuana by mouth might worsen some symptoms of multiple sclerosis.
Lung diseases: Long-term use of marijuana can make lung problems worse. Regular, long-term marijuana use has been associated with lung cancer and also with several cases of an unusual type of emphysema, a lung disease.
Schizophrenia: Using marijuana might worsen symptoms of schizophrenia.
Stroke: Using marijuana after having a stroke might increase the risk of having a second stroke.
Surgery: Marijuana affects the central nervous system. It might slow the central nervous system too much when combined with anesthesia and other medications during and after surgery. Stop using marijuana at least 2 weeks before a scheduled surgery.
Are there any interactions with medications?
The body breaks down antipyrine to get rid of it. Some chemicals in marijuana might decrease how quickly the body breaks down antipyrine. This might increase antipyrine levels in the body and increase its effects and side effects.
Disulfiram (Antabuse)Interaction Rating: Moderate Be cautious with this combination.Talk with your health provider.
Taking marijuana with disulfiram (Antabuse) might cause you to feel irritated, nervous, jittery, and excited. Doctors call this hypomania.
Fluoxetine (Prozac)Interaction Rating: Moderate Be cautious with this combination.Talk with your health provider.
Taking marijuana with fluoxetine (Prozac) might cause you to feel irritated, nervous, jittery, and excited. Doctors call this hypomania.
Medications changed by the liver (Cytochrome P450 2E1 (CYP2E1) substrates)Interaction Rating: Moderate Be cautious with this combination.Talk with your health provider.
Some medications are changed and broken down by the liver. Marijuana might increase how quickly the liver breaks down some medications. Using marijuana along with some medications that are broken down by the liver might decrease the effects of some medications. Before using marijuana talk to your healthcare provider if you take any medications that are changed by the liver.
Some medications changed by the liver include acetaminophen, chlorzoxazone (Parafon Forte), ethanol, theophylline, and anesthetics such as enflurane (Ethrane), halothane (Fluothane), isoflurane (Forane), methoxyflurane (Penthrane).
Medications changed by the liver (Cytochrome P450 3A4 (CYP3A4) substrates)Interaction Rating: Moderate Be cautious with this combination.Talk with your health provider.
Some medications are changed and broken down by the liver. Marijuana might decrease how quickly the liver breaks down some medications. Using marijuana along with some medications that are broken down by the liver might increase the effects and side effects of some medications. Before using marijuana talk to your healthcare provider if you take any medications that are changed by the liver.
Some medications changed by liver include lovastatin (Mevacor), clarithromycin (Biaxin), cyclosporine (Neoral, Sandimmune), diltiazem (Cardizem), estrogens, indinavir (Crixivan), triazolam (Halcion), and others.
Medications moved by pumps in cells (P-glycoprotein Substrates)Interaction Rating: Moderate Be cautious with this combination.Talk with your health provider.
Some medications are moved by pumps into cells. Marijuana might make these pumps less active and increase how much of some medications get absorbed by the body. This might increase the side effects of some medications.
Some medications that are moved by these pumps include etoposide, paclitaxel, vinblastine, vincristine, vindesine, ketoconazole, itraconazole, amprenavir, indinavir, nelfinavir, saquinavir, cimetidine, ranitidine, diltiazem, verapamil, corticosteroids, erythromycin, cisapride (Propulsid), fexofenadine (Allegra), cyclosporine, loperamide (Imodium), quinidine, and others.
Medications that slow blood clotting (Anticoagulant / Antiplatelet drugs)Interaction Rating: Moderate Be cautious with this combination.Talk with your health provider.
Marijuana might slow blood clotting. Taking marijuana extracts along with medications that also slow clotting might increase the chances of bruising and bleeding.
Sedative medications (Barbiturates)Interaction Rating: Moderate Be cautious with this combination.Talk with your health provider.
Marijuana might cause sleepiness and drowsiness. Medications that cause sleepiness are called sedatives. Taking marijuana along with sedative medications might cause too much sleepiness.
Sedative medications (CNS depressants)Interaction Rating: Moderate Be cautious with this combination.Talk with your health provider.
Marijuana might cause sleepiness and drowsiness. Medications that cause sleepiness are called sedatives. Taking marijuana along with sedative medications might cause too much sleepiness.
TheophyllineInteraction Rating: Moderate Be cautious with this combination.Talk with your health provider.
Taking marijuana might decrease the effects of theophylline. But there isn’t enough information to know if this is a big concern.
Warfarin (Coumadin)Interaction Rating: Minor Be cautious with this combination.Talk with your health provider.
Using marijuana might increase the effects of warfarin (Coumadin). Smoking marijuana while taking warfarin (Coumadin) might increase the chance of bruising and bleeding.
Dosing considerations for Marijuana.
The following doses have been studied in scientific research:
- For multiple sclerosis: One to five capsules containing marijuana extract standardized to contain tetrahydrocannabinol 2.5 mg and cannabinol 0.8 to 1.8 mg (Cannador, Society for Clinical Research, Berlin, Germany) has been taken twice daily for 12 weeks.
AS A MOUTH SPRAY:
- For multiple sclerosis: A specific marijuana extract product (Sativex, GW Pharmaceuticals, Salisbury, UK), standardized to contain 2.7 mg of tetrahydrocannabinol (THC) and 2.5 mg of cannabidiol per spray, has been used daily for up to 2 years.
Natural Medicines Comprehensive Database rates effectiveness based on scientific evidence according to the following scale: Effective, Likely Effective, Possibly Effective, Possibly Ineffective, Likely Ineffective, and Insufficient Evidence to Rate (detailed description of each of the ratings).
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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Abrams, D. I., Jay, C. A., Shade, S. B., Vizoso, H., Reda, H., Press, S., Kelly, M. E., Rowbotham, M. C., and Petersen, K. L. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2-13-2007;68(7):515-521. View abstract.
Agarwal, N., Pacher, P., Tegeder, I., Amaya, F., Constantin, C. E., Brenner, G. J., Rubino, T., Michalski, C. W., Marsicano, G., Monory, K., Mackie, K., Marian, C., Batkai, S., Parolaro, D., Fischer, M. J., Reeh, P., Kunos, G., Kress, M., Lutz, B., Woolf, C. J., and Kuner, R. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat.Neurosci. 2007;10(7):870-879. View abstract.
Ahmedzai, S., Carlyle, D. L., Calder, I. T., and Moran, F. Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy. Br.J.Cancer 1983;48(5):657-663. View abstract.
Aigner, M., Treasure, J., Kaye, W., and Kasper, S. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of eating disorders. World J.Biol.Psychiatry 2011;12(6):400-443. View abstract.
Aldington, S., Harwood, M., Cox, B., Weatherall, M., Beckert, L., Hansell, A., Pritchard, A., Robinson, G., and Beasley, R. Cannabis use and risk of lung cancer: a case-control study. Eur.Respir.J 2008;31(2):280-286. View abstract.
Aldington, S., Williams, M., Nowitz, M., Weatherall, M., Pritchard, A., McNaughton, A., Robinson, G., and Beasley, R. Effects of cannabis on pulmonary structure, function and symptoms. Thorax 2007;62(12):1058-1063. View abstract.
Ames, F. R. and Cridland, S. Anticonvulsant effect of cannabidiol. S.Afr.Med.J. 1-4-1986;69(1):14. View abstract.
Amtmann, D., Weydt, P., Johnson, K. L., Jensen, M. P., and Carter, G. T. Survey of cannabis use in patients with amyotrophic lateral sclerosis. Am.J.Hosp.Palliat.Care 2004;21(2):95-104. View abstract.
Anstead, M. I. Kuhn R. J. Martyn D. Craigmyle L. Kanga J. F. Dronabinol, an effective and safe appetite stimulant in cystic fibrosis [abstract]. Pediatr.Pulm. 2003;Suppl. 25:343.
Armstrong, M. J. and Miyasaki, J. M. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. Neurology 8-7-2012;79(6):597-603. View abstract.
Asbridge, M., Hayden, J. A., and Cartwright, J. L. Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis. BMJ 2012;344:e536. View abstract.
Ashton, C. H. Adverse effects of cannabis and cannabinoids. Br.J.Anaesth. 1999;83(4):637-649. View abstract.
Attal, N., Cruccu, G., Haanpaa, M., Hansson, P., Jensen, T. S., Nurmikko, T., Sampaio, C., Sindrup, S., and Wiffen, P. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur.J.Neurol. 2006;13(11):1153-1169. View abstract.
Attal, N., Mazaltarine, G., Perrouin-Verbe, B., and Albert, T. Chronic neuropathic pain management in spinal cord injury patients. What is the efficacy of pharmacological treatments with a general mode of administration? (oral, transdermal, intravenous). Ann.Phys.Rehabil.Med. 2009;52(2):124-141. View abstract.
Baastrup, C. and Finnerup, N. B. Pharmacological management of neuropathic pain following spinal cord injury. CNS.Drugs 2008;22(6):455-475. View abstract.
Bachs, L. and Morland, H. Acute cardiovascular fatalities following cannabis use. Forensic Sci.Int. 12-27-2001;124(2-3):200-203. View abstract.
Bagshaw, S. M. and Hagen, N. A. Medical efficacy of cannabinoids and marijuana: a comprehensive review of the literature. J.Palliat.Care 2002;18(2):111-122. View abstract.
Baldinger, R., Katzberg, H. D., and Weber, M. Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease. Cochrane.Database.Syst.Rev. 2012;4:CD004157. View abstract.
Barnes, M. P. Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain. Expert.Opin.Pharmacother. 2006;7(5):607-615. View abstract.
Beaulieu, P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can.J.Anaesth. 2006;53(8):769-775. View abstract.
Ben Amar, M. and Potvin, S. Cannabis and psychosis: what is the link? J Psychoactive Drugs 2007;39(2):131-142. View abstract.
Berlach, D. M., Shir, Y., and Ware, M. A. Experience with the synthetic cannabinoid nabilone in chronic noncancer pain. Pain Med. 2006;7(1):25-29. View abstract.
Berman, J. S., Symonds, C., and 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. View abstract.
Berry, E. M. and Mechoulam, R. Tetrahydrocannabinol and endocannabinoids in feeding and appetite. Pharmacol.Ther. 2002;95(2):185-190. View abstract.
Berryman, S. H., Anderson, R. A., Jr., Weis, J., and Bartke, A. Evaluation of the co-mutagenicity of ethanol and delta 9-tetrahydrocannabinol with Trenimon. Mutat.Res 1992;278(1):47-60. View abstract.
Beshay, M., Kaiser, H., Niedhart, D., Reymond, M. A., and Schmid, R. A. Emphysema and secondary pneumothorax in young adults smoking cannabis. Eur.J Cardiothorac.Surg. 2007;32(6):834-838. View abstract.
Blake, D. R., Robson, P., Ho, M., Jubb, R. W., and McCabe, C. S. 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. View abstract.
Brady, C. M., DasGupta, R., Dalton, C., Wiseman, O. J., Berkley, K. J., and Fowler, C. J. An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Mult.Scler. 2004;10(4):425-433. View abstract.
Callaway, J., Schwab, U., Harvima, I., Halonen, P., Mykkanen, O., Hyvonen, P., and Jarvinen, T. Efficacy of dietary hempseed oil in patients with atopic dermatitis. J Dermatolog.Treat. 2005;16(2):87-94. View abstract.
Cappelli, F., Lazzeri, C., Gensini, G. F., and Valente, S. Cannabis: a trigger for acute myocardial infarction? A case report. J Cardiovasc.Med.(Hagerstown.) 2008;9(7):725-728. View abstract.
Carter, G. T. and Rosen, B. S. Marijuana in the management of amyotrophic lateral sclerosis. Am.J.Hosp.Palliat.Care 2001;18(4):264-270. View abstract.
Carter, G. T. and Ugalde, V. Medical marijuana: emerging applications for the management of neurologic disorders. Phys.Med.Rehabil.Clin.N.Am. 2004;15(4):943-54, ix. View abstract.
Chan, H. S., Correia, J. A., and MacLeod, S. M. Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: a double-blind, crossover trial. Pediatrics 1987;79(6):946-952. View abstract.
Chang, A. E., Shiling, D. J., Stillman, R. C., Goldberg, N. H., Seipp, C. A., Barofsky, I., and Rosenberg, S. A. A prospective evaluation of delta-9-tetrahydrocannabinol as an antiemetic in patients receiving adriamycin and cytoxan chemotherapy. Cancer 4-1-1981;47(7):1746-1751. View abstract.
Chang, A. E., Shiling, D. J., Stillman, R. C., Goldberg, N. H., Seipp, C. A., Barofsky, I., Simon, R. M., and Rosenberg, S. A. Delata-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. A prospective, randomized evaluation. Ann.Intern.Med. 1979;91(6):819-824. View abstract.
Chatterjee, A., Almahrezi, A., Ware, M., and Fitzcharles, M. A. A dramatic response to inhaled cannabis in a woman with central thalamic pain and dystonia. J.Pain Symptom.Manage. 2002;24(1):4-6. View abstract.
Chinuck, R. S., Fortnum, H., and Baldwin, D. R. Appetite stimulants in cystic fibrosis: a systematic review. J.Hum.Nutr.Diet. 2007;20(6):526-537. View abstract.
Cichewicz, D. L. and McCarthy, E. A. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J.Pharmacol.Exp.Ther. 2003;304(3):1010-1015. View abstract.
Clark, A. J., Ware, M. A., Yazer, E., Murray, T. J., and Lynch, M. E. Patterns of cannabis use among patients with multiple sclerosis. Neurology 6-8-2004;62(11):2098-2100. View abstract.
Collin, C., Davies, P., Mutiboko, I. K., and Ratcliffe, S. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur.J.Neurol. 2007;14(3):290-296. View abstract.
Collin, C., Ehler, E., Waberzinek, G., Alsindi, Z., Davies, P., Powell, K., Notcutt, W., O’Leary, C., Ratcliffe, S., Novakova, I., Zapletalova, O., Pikova, J., and Ambler, Z. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol.Res. 2010;32(5):451-459. View abstract.
Colls, B. M., Ferry, D. G., Gray, A. J., Harvey, V. J., and McQueen, E. G. The antiemetic activity of tetrahydrocannabinol versus metoclopramide and thiethylperazine in patients undergoing cancer chemotherapy. N.Z.Med.J. 6-25-1980;91(662):449-451. View abstract.
Cone, L. A., Greene, D. S., and Helm, N. A. Use of nabilone in the treatment of chemotherapy-induced vomiting in an outpatient setting. Cancer Treat.Rev. 1982;9 Suppl B:63-70. View abstract.
Consroe, P., Kennedy, K., and Schram, K. Assay of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humans. Pharmacol Biochem.Behav. 1991;40(3):517-522. View abstract.
Consroe, P., Laguna, J., Allender, J., Snider, S., Stern, L., Sandyk, R., Kennedy, K., and Schram, K. Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol Biochem.Behav. 1991;40(3):701-708. View abstract.
Cotter, J. Efficacy of Crude Marijuana and Synthetic Delta-9-Tetrahydrocannabinol as Treatment for Chemotherapy-Induced Nausea and Vomiting: A Systematic Literature Review. Oncol.Nurs.Forum 5-1-2009;36(3):345-352. View abstract.
Crawford, S. M. and Buckman, R. Nabilone and metoclopramide in the treatment of nausea and vomiting due to cisplatinum: a double blind study. Med.Oncol.Tumor Pharmacother. 1986;3(1):39-42. View abstract.
Crippa, J. A., Zuardi, A. W., Garrido, G. E., Wichert-Ana, L., Guarnieri, R., Ferrari, L., Azevedo-Marques, P. M., Hallak, J. E., McGuire, P. K., and Filho, Busatto G. Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology 2004;29(2):417-426. View abstract.
Crippa, J. A., Zuardi, A. W., Martin-Santos, R., Bhattacharyya, S., Atakan, Z., McGuire, P., and Fusar-Poli, P. Cannabis and anxiety: a critical review of the evidence. Hum.Psychopharmacol. 2009;24(7):515-523. View abstract.
Croxford, J. L. Therapeutic potential of cannabinoids in CNS disease. CNS.Drugs 2003;17(3):179-202. View abstract.
Cunha, J. M., Carlini, E. A., Pereira, A. E., Ramos, O. L., Pimentel, C., Gagliardi, R., Sanvito, W. L., Lander, N., and Mechoulam, R. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 1980;21(3):175-185. View abstract.
Cunningham, D., Bradley, C. J., Forrest, G. J., Hutcheon, A. W., Adams, L., Sneddon, M., Harding, M., Kerr, D. J., Soukop, M., and Kaye, S. B. A randomized trial of oral nabilone and prochlorperazine compared to intravenous metoclopramide and dexamethasone in the treatment of nausea and vomiting induced by chemotherapy regimens containing cisplatin or cisplatin analogues. Eur.J.Cancer Clin.Oncol. 1988;24(4):685-689. View abstract.
Curtis A, Mitchell I Patel S Ives N Rickards H. A pilot study using nabilone for symptomatic treatment in Huntington’s disease. Mov Disord 2009;24(2254):2259.
Curtis, A., Clarke, C. E., and Rickards, H. E. Cannabinoids for Tourette’s Syndrome. Cochrane.Database.Syst.Rev. 2009;(4):CD006565. View abstract.
D’Souza, D. C., Perry, E., MacDougall, L., Ammerman, Y., Cooper, T., Wu, Y. T., Braley, G., Gueorguieva, R., and Krystal, J. H. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 2004;29(8):1558-1572. View abstract.
Dalzell, A. M., Bartlett, H., and Lilleyman, J. S. Nabilone: an alternative antiemetic for cancer chemotherapy. Arch.Dis.Child 1986;61(5):502-505. View abstract.
Darmani, N. A. The potent emetogenic effects of the endocannabinoid, 2-AG (2-arachidonoylglycerol) are blocked by delta(9)-tetrahydrocannabinol and other cannnabinoids. J Pharmacol Exp.Ther. 2002;300(1):34-42. View abstract.
Davis, M. P. Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain. Expert.Opin.Investig.Drugs 2008;17(1):85-95. View abstract.
de Jong, F. A., Engels, F. K., Mathijssen, R. H., van Zuylen, L., Verweij, J., Peters, R. P., and Sparreboom, A. Medicinal cannabis in oncology practice: still a bridge too far? J Clin Oncol. 5-1-2005;23(13):2886-2891. View abstract.
Degenhardt, L., Roxburgh, A., and McKetin, R. Hospital separations for cannabis- and methamphetamine-related psychotic episodes in Australia. Med J Aust. 4-2-2007;186(7):342-345. View abstract.
Dempster, B. Clinical study report: a multi centre randomised, double blind, placebo controlled, parallel group comparison of the effects of cannabis based medicine standardised extracts over 4 weeks, in patients with chronic refractory pain due to multiple sclerosis or other defects of neurological function. GW Pharma Ltd Study Code: GWPS0105 2003;
Dewey, W. L. Cannabinoid pharmacology. Pharmacol.Rev. 1986;38(2):151-178. View abstract.
Einhorn, L. H., Nagy, C., Furnas, B., and Williams, S. D. Nabilone: an effective antiemetic in patients receiving cancer chemotherapy. J.Clin.Pharmacol. 1981;21(8-9 Suppl):64S-69S. View abstract.
Einhorn, L. Nabilone: an effective antiemetic agent in patients receiving cancer chemotherapy. Cancer Treat.Rev. 1982;9 Suppl B:55-61. View abstract.
Ekert, H., Waters, K. D., Jurk, I. H., Mobilia, J., and Loughnan, P. Amelioration of cancer chemotherapy-induced nausea and vomiting by delta-9-tetrahydrocannabinol. Med.J.Aust. 12-15-1979;2(12):657-659. View abstract.
Ellis, E. F., Moore, S. F., and Willoughby, K. A. Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin. Am.J.Physiol 1995;269(6 Pt 2):H1859-H1864. View abstract.
Ellis, R. J., Toperoff, W., Vaida, F., van den Brande, G., Gonzales, J., Gouaux, B., Bentley, H., and Atkinson, J. H. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009;34(3):672-680. View abstract.
Fairbairn, J. W. and Pickens, J. T. The oral activity of delta’-tetrahydrocannabinol and its dependence on prostaglandin E2. Br.J Pharmacol 1979;67(3):379-385. View abstract.
Fajardo, L. L. Association of spontaneous pneumomediastinum with substance abuse. West J Med 1990;152(3):301-304. View abstract.
Finnerup, N. B., Otto, M., McQuay, H. J., Jensen, T. S., and Sindrup, S. H. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 12-5-2005;118(3):289-305. View abstract.
Fiorentini, A., Volonteri, L. S., Dragogna, F., Rovera, C., Maffini, M., Mauri, M. C., and Altamura, C. A. Substance-induced psychoses: a critical review of the literature. Curr.Drug Abuse Rev. 2011;4(4):228-240. View abstract.
Formukong, E. A., Evans, A. T., and Evans, F. J. The inhibitory effects of cannabinoids, the active constituents of Cannabis sativa L. on human and rabbit platelet aggregation. J.Pharm.Pharmacol. 1989;41(10):705-709. View abstract.
Fox, A., Kesingland, A., Gentry, C., McNair, K., Patel, S., Urban, L., and James, I. The role of central and peripheral Cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain 2001;92(1-2):91-100. View abstract.
Fox, P., Bain, P. G., Glickman, S., Carroll, C., and Zajicek, J. The effect of cannabis on tremor in patients with multiple sclerosis. Neurology 4-13-2004;62(7):1105-1109. View abstract.
Frank, B., Serpell, M. G., Hughes, J., Matthews, J. N., and Kapur, D. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ 1-26-2008;336(7637):199-201. View abstract.
Frytak, S., Moertel, C. G., O’Fallon, J. R., Rubin, J., Creagan, E. T., O’Connell, M. J., Schutt, A. J., and Schwartau, N. W. Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. A comparison with prochlorperazine and a placebo. Ann.Intern.Med. 1979;91(6):825-830. View abstract.
Gallily, R., Even-Chena, T., Katzavian, G., Lehmann, D., Dagan, A., and Mechoulam, R. Gamma-irradiation enhances apoptosis induced by cannabidiol, a non-psychotropic cannabinoid, in cultured HL-60 myeloblastic leukemia cells. Leuk.Lymphoma 2003;44(10):1767-1773. View abstract.
Genetic Risk and Outcome in Psychosis (GROUP) Investigators. Evidence that familial liability for psychosis is expressed as differential sensitivity to cannabis: an analysis of patient-sibling and sibling-control pairs. Arch.Gen.Psychiatry 2011;68(2):138-147. View abstract.
George, M., Pejovic, M. H., Thuaire, M., Kramar, A., and Wolff, J. P. [Randomized comparative trial of a new anti-emetic: nabilone, in cancer patients treated with cisplatin]. Biomed.Pharmacother. 1983;37(1):24-27. View abstract.
Gloss, D. and Vickrey, B. Cannabinoids for epilepsy. Cochrane.Database.Syst.Rev. 2012;6:CD009270. View abstract.
Gong, H., Jr., Tashkin, D. P., Simmons, M. S., Calvarese, B., and Shapiro, B. J. Acute and subacute bronchial effects of oral cannabinoids. Clin Pharmacol Ther. 1984;35(1):26-32. View abstract.
Gorter, R. W., Butorac, M., Cobian, E. P., and van der, Sluis W. Medical use of cannabis in the Netherlands. Neurology 3-8-2005;64(5):917-919. View abstract.
Gralla, R. J., Tyson, L. B., Bordin, L. A., Clark, R. A., Kelsen, D. P., Kris, M. G., Kalman, L. B., and Groshen, S. Antiemetic therapy: a review of recent studies and a report of a random assignment trial comparing metoclopramide with delta-9-tetrahydrocannabinol. Cancer Treat.Rep. 1984;68(1):163-172. View abstract.
Green, A. J. and De-Vries, K. Cannabis use in palliative care – an examination of the evidence and the implications for nurses. J.Clin.Nurs. 2010;19(17-18):2454-2462. View abstract.
Green, K., Kearse, E. C., and McIntyre, O. L. Interaction between delta-9-tetrahydrocannabinol and indomethacin. Ophthalmic Res. 2001;33(4):217-220. View abstract.
Gross, H., Ebert, M. H., Faden, V. B., Goldberg, S. C., Kaye, W. H., Caine, E. D., Hawks, R., and Zinberg, N. A double-blind trial of delta 9-tetrahydrocannabinol in primary anorexia nervosa. J.Clin.Psychopharmacol. 1983;3(3):165-171. View abstract.
Grotenhermen, F. Cannabis-associated arteritis. Vasa 2010;39(1):43-53. View abstract.
Grotenhermen, F. Pharmacology of cannabinoids. Neuro.Endocrinol.Lett. 2004;25(1-2):14-23. View abstract.
Guzman, M. Cannabinoids: potential anticancer agents. Nat.Rev.Cancer 2003;3(10):745-755. View abstract.
Hagenbach, U., Luz, S., Ghafoor, N., Berger, J. M., Grotenhermen, F., Brenneisen, R., and Mader, M. The treatment of spasticity with Delta9-tetrahydrocannabinol in persons with spinal cord injury. Spinal Cord. 2007;45(8):551-562. View abstract.
Hall, W. and Solowij, N. Adverse effects of cannabis. Lancet 11-14-1998;352(9140):1611-1616. View abstract.
Harvey, D. J. and Mechoulam, R. Metabolites of cannabidiol identified in human urine. Xenobiotica 1990;20(3):303-320. View abstract.
Harvey, D. J., Samara, E., and Mechoulam, R. Comparative metabolism of cannabidiol in dog, rat and man. Pharmacol Biochem.Behav. 1991;40(3):523-532. View abstract.
Harvey, D. J., Samara, E., and Mechoulam, R. Urinary metabolites of cannabidiol in dog, rat and man and their identification by gas chromatography-mass spectrometry. J Chromatogr. 1-2-1991;562(1-2):299-322. View abstract.
Hays, H. Marijuana for the management of proximal mytonic myopathy. J.Pain Symptom.Manage. 2001;21(4):267-269. View abstract.
Herman, T. S., Einhorn, L. H., Jones, S. E., Nagy, C., Chester, A. B., Dean, J. C., Furnas, B., Williams, S. D., Leigh, S. A., Dorr, R. T., and Moon, T. E. Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy. N.Engl.J.Med. 6-7-1979;300(23):1295-1297. View abstract.
Herman, T. S., Jones, S. E., Dean, J., Leigh, S., Dorr, R., Moon, T. E., and Salmon, S. E. Nabilone: a potent antiemetic cannabinol with minimal euphoria. Biomedicine. 1977;27(9-10):331-334. View abstract.
Holland, M. L., Panetta, J. A., Hoskins, J. M., Bebawy, M., Roufogalis, B. D., Allen, J. D., and Arnold, J. C. The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells. Biochem.Pharmacol 4-14-2006;71(8):1146-1154. View abstract.
Hollister, L. E. Interactions of cannabis with other drugs in man. NIDA Res.Monogr 1986;68:110-116. View abstract.
Holmes, S. D., Lipshultz, L. I., and Smith, R. G. Effect of cannabinoids on human Sertoli cell function in vitro. Arch Androl 1983;11(3):245-251. View abstract.
Howard, J., Anie, K. A., Holdcroft, A., Korn, S., and Davies, S. C. Cannabis use in sickle cell disease: a questionnaire study. Br.J.Haematol. 2005;131(1):123-128. View abstract.
Hung, O., Lynch, M. E., and Clark, A. J. Cannabinoids and pain management. Can.J.Anaesth. 2006;53(8):743-746. View abstract.
Hutcheon, A. W., Palmer, J. B., Soukop, M., Cunningham, D., McArdle, C., Welsh, J., Stuart, F., Sangster, G., Kaye, S., Charlton, D., and . A randomised multicentre single blind comparison of a cannabinoid anti-emetic (levonantradol) with chlorpromazine in patients receiving their first cytotoxic chemotherapy. Eur.J.Cancer Clin.Oncol. 1983;19(8):1087-1090. View abstract.
Indlekofer, F., Piechatzek, M., Daamen, M., Glasmacher, C., Lieb, R., Pfister, H., Tucha, O., Lange, K. W., Wittchen, H. U., and Schutz, C. G. Reduced memory and attention performance in a population-based sample of young adults with a moderate lifetime use of cannabis, ecstasy and alcohol. J Psychopharmacol. 2009;23(5):495-509. View abstract.
Iskedjian, M., Bereza, B., Gordon, A., Piwko, C., and Einarson, T. R. Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain. Curr.Med.Res Opin. 2007;23(1):17-24. View abstract.
James, J. S. Marijuana safety study completed: weight gain, no safety problems. AIDS Treat.News 8-4-2000;(348):3-4. View abstract.
Jochimsen, P. R., Lawton, R. L., VerSteeg, K., and Noyes, R., Jr. Effect of benzopyranoperidine, a delta-9-THC congener, on pain. Clin.Pharmacol.Ther. 1978;24(2):223-227. View abstract.
Johansson, R., Kilkku, P., and Groenroos, M. A double-blind, controlled trial of nabilone vs. prochlorperazine for refractory emesis induced by cancer chemotherapy. Cancer Treat.Rev. 1982;9 Suppl B:25-33. View abstract.
Johnson JR, Potts R. Cannabis-based medicines in the treatment of cancer pain: A randomised, doubleblind, parallel group, placebo controlled, comparative study of the efficacy, safety and tolerability of Sativex and Tetranabinex in patients with cancerrelated pain. British Pain Society. 2005;
Jones, S. E., Durant, J. R., Greco, F. A., and Robertone, A. A multi-institutional Phase III study of nabilone vs. placebo in chemotherapy-induced nausea and vomiting. Cancer Treat.Rev. 1982;9 Suppl B:45-48. View abstract.
Jordan, K., Roila, F., Molassiotis, A., Maranzano, E., Clark-Snow, R. A., and Feyer, P. Antiemetics in children receiving chemotherapy. MASCC/ESMO guideline update 2009. Support.Care Cancer 2011;19 Suppl 1:S37-S42. View abstract.
Kapur D. Shall we be using cannabis for pain control? Progress in Palliative Care 2003;11:248-250.
Karst, M., Salim, K., Burstein, S., Conrad, I., Hoy, L., and Schneider, U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 10-1-2003;290(13):1757-1762. View abstract.
Killestein, J., Hoogervorst, E. L., Reif, M., Kalkers, N. F., van Loenen, A. C., Staats, P. G., Gorter, R. W., Uitdehaag, B. M., and Polman, C. H. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 5-14-2002;58(9):1404-1407. View abstract.
Kluin-Neleman, J. C., Neleman, F. A., Meuwissen, O. J., and Maes, R. A. delta 9-Tetrahydrocannabinol (THC) as an antiemetic in patients treated with cancerchemotherapy; a double-blind cross-over trial against placebo. Vet.Hum.Toxicol. 1979;21(5):338-340. View abstract.
Knoller, N., Levi, L., Shoshan, I., Reichenthal, E., Razon, N., Rappaport, Z. H., and Biegon, A. Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial. Crit Care Med. 2002;30(3):548-554. View abstract.
Krenn, H., Daha, L. K., Oczenski, W., and Fitzgerald, R. D. A case of cannabinoid rotation in a young woman with chronic cystitis. J.Pain Symptom.Manage. 2003;25(1):3-4. View abstract.
Krishnan, S., Cairns, R., and Howard, R. Cannabinoids for the treatment of dementia. Cochrane.Database.Syst.Rev. 2009;(2):CD007204. View abstract.
Kumar, R. N., Chambers, W. A., and Pertwee, R. G. Pharmacological actions and therapeutic uses of cannabis and cannabinoids. Anaesthesia 2001;56(11):1059-1068. View abstract.
Lakhan, S. E. and Rowland, M. Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review. BMC.Neurol. 2009;9:59. View abstract.
Lane, M., Vogel, C. L., Ferguson, J., Krasnow, S., Saiers, J. L., Hamm, J., Salva, K., Wiernik, P. H., Holroyde, C. P., Hammill, S., and . Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. J.Pain Symptom.Manage. 1991;6(6):352-359. View abstract.
Laqueille, X. [Is cannabis a vulnerability factor in schizophrenic disorders]. Arch Pediatr. 2009;16(9):1302-1305. View abstract.
Large, M., Sharma, S., Compton, M. T., Slade, T., and Nielssen, O. Cannabis use and earlier onset of psychosis: a systematic meta-analysis. Arch.Gen.Psychiatry 2011;68(6):555-561. View abstract.
Le Bec, P. Y., Fatseas, M., Denis, C., Lavie, E., and Auriacombe, M. [Cannabis and psychosis: search of a causal link through a critical and systematic review]. Encephale 2009;35(4):377-385. View abstract.
Le Guen, P. Y., Gestin, S., Plat, E., Quehe, P., and Bressollette, L. [Renal and spleen infarction after massive consumption of cannabis and cocaine in a young man]. J.Mal Vasc. 2011;36(1):41-44. View abstract.
Lee, M. H. and Hancox, R. J. Effects of smoking cannabis on lung function. Expert.Rev.Respir.Med. 2011;5(4):537-546. View abstract.
Lee, S. Y., Oh, S. M., Lee, S. K., and Chung, K. H. Antiestrogenic effects of marijuana smoke condensate and cannabinoid compounds. Arch.Pharm Res 2005;28(12):1365-1375. View abstract.
Leizer C, Ribnicky D, Poulev A, Dushenkov S, and Raskin I. The composition of hemp seed oil and its potential as an important source of nutrition. Journal of Nutraceuticals, Functional & Medical Foods 2000;2(4):35-53.
Levitt, D. G. Heterogeneity of human adipose blood flow. BMC.Clin Pharmacol 2007;7:1. View abstract.
Levitt, M. Nabilone vs. placebo in the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Cancer Treat.Rev. 1982;9 Suppl B:49-53. View abstract.
Levy, R., Schurr, A., Nathan, I., Dvilanski, A., and Livne, A. Impairment of ADP-induced platelet aggregation by hashish components. Thromb.Haemost. 12-31-1976;36(3):634-640. View abstract.
Li, J. H. and Lin, L. F. Genetic toxicology of abused drugs: a brief review. Mutagenesis 1998;13(6):557-565. View abstract.
Li, M. C., Brady, J. E., DiMaggio, C. J., Lusardi, A. R., Tzong, K. Y., and Li, G. Marijuana use and motor vehicle crashes. Epidemiol.Rev. 2012;34(1):65-72. View abstract.
Lucas, V. S., Jr. and Laszlo, J. delta 9-Tetrahydrocannabinol for refractory vomiting induced by cancer chemotherapy. JAMA 3-28-1980;243(12):1241-1243. View abstract.
Lynch, M. E. and Campbell, F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br.J.Clin.Pharmacol. 2011;72(5):735-744. View abstract.
Lynch, M. E. and Clark, A. J. Cannabis reduces opioid dose in the treatment of chronic non-cancer pain. J.Pain Symptom.Manage. 2003;25(6):496-498. View abstract.
Maas, A. I., Murray, G., Henney, H., III, Kassem, N., Legrand, V., Mangelus, M., Muizelaar, J. P., Stocchetti, N., and Knoller, N. Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 2006;5(1):38-45. View abstract.
Machado Rocha, F. C., Stefano, S. C., De Cassia, Haiek R., Rosa Oliveira, L. M., and Da Silveira, D. X. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur.J Cancer Care (Engl.) 2008;17(5):431-443. View abstract.
Martin-Sanchez, E., Furukawa, T. A., Taylor, J., and Martin, J. L. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med 2009;10(8):1353-1368. View abstract.
Massi, P., Vaccani, A., Bianchessi, S., Costa, B., Macchi, P., and Parolaro, D. The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol.Life Sci. 2006;63(17):2057-2066. View abstract.
Massi, P., Vaccani, A., Ceruti, S., Colombo, A., Abbracchio, M. P., and Parolaro, D. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp.Ther. 2004;308(3):838-845. View abstract.
Matheson, S. L., Shepherd, A. M., Laurens, K. R., and Carr, V. J. A systematic meta-review grading the evidence for non-genetic risk factors and putative antecedents of schizophrenia. Schizophr.Res. 2011;133(1-3):133-142. View abstract.
Maurer, M., Henn, V., Dittrich, A., and Hofmann, A. Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur.Arch.Psychiatry Clin.Neurosci. 1990;240(1):1-4. View abstract.
McCabe, M., Smith, F. P., Macdonald, J. S., Woolley, P. V., Goldberg, D., and Schein, P. S. Efficacy of tetrahydrocannabinol in patients refractory to standard antiemetic therapy. Invest New Drugs 1988;6(3):243-246. View abstract.
McGrath, J., Welham, J., Scott, J., Varghese, D., Degenhardt, L., Hayatbakhsh, M. R., Alati, R., Williams, G. M., Bor, W., and Najman, J. M. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch Gen.Psychiatry 2010;67(5):440-447. View abstract.
McKallip, R. J., Jia, W., Schlomer, J., Warren, J. W., Nagarkatti, P. S., and Nagarkatti, M. Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol.Pharmacol 2006;70(3):897-908. View abstract.
Mechoulam, R. and Carlini, E. A. Toward drugs derived from cannabis. Naturwissenschaften 1978;65(4):174-179. View abstract.
Meiri, E., Jhangiani, H., Vredenburgh, J. J., Barbato, L. M., Carter, F. J., Yang, H. M., and Baranowski, V. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr.Med.Res.Opin. 2007;23(3):533-543. View abstract.
Meyer, M. J., Megyesi, J., Meythaler, J., Murie-Fernandez, M., Aubut, J. A., Foley, N., Salter, K., Bayley, M., Marshall, S., and Teasell, R. Acute management of acquired brain injury part II: an evidence-based review of pharmacological interventions. Brain Inj. 2010;24(5):706-721. View abstract.
Mills, R. J., Yap, L., and Young, C. A. Treatment for ataxia in multiple sclerosis. Cochrane.Database.Syst.Rev. 2007;(1):CD005029. View abstract.
Minozzi, S., Davoli, M., Bargagli, A. M., Amato, L., Vecchi, S., and Perucci, C. A. An overview of systematic reviews on cannabis and psychosis: discussing apparently conflicting results. Drug Alcohol Rev. 2010;29(3):304-317. View abstract.
Moore, T. H., Zammit, S., Lingford-Hughes, A., Barnes, T. R., Jones, P. B., Burke, M., and Lewis, G. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 7-28-2007;370(9584):319-328. View abstract.
Moore, T. M., Stuart, G. L., Meehan, J. C., Rhatigan, D. L., Hellmuth, J. C., and Keen, S. M. Drug abuse and aggression between intimate partners: a meta-analytic review. Clin.Psychol.Rev. 2008;28(2):247-274. View abstract.
Moulin, D. E., Clark, A. J., Gilron, I., Ware, M. A., Watson, C. P., Sessle, B. J., Coderre, T., Morley-Forster, P. K., Stinson, J., Boulanger, A., Peng, P., Finley, G. A., Taenzer, P., Squire, P., Dion, D., Cholkan, A., Gilani, A., Gordon, A., Henry, J., Jovey, R., Lynch, M., Mailis-Gagnon, A., Panju, A., Rollman, G. B., and Velly, A. Pharmacological management of chronic neuropathic pain – consensus statement and guidelines from the Canadian Pain Society. Pain Res.Manag. 2007;12(1):13-21. View abstract.
Muller-Vahl, K. R., Schneider, U., Koblenz, A., Jobges, M., Kolbe, H., Daldrup, T., and Emrich, H. M. Treatment of Tourette’s syndrome with Delta 9-tetrahydrocannabinol (THC): a randomized crossover trial. Pharmacopsychiatry 2002;35(2):57-61. View abstract.
Muller-Vahl, K. R., Schneider, U., Prevedel, H., Theloe, K., Kolbe, H., Daldrup, T., and Emrich, H. M. Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J.Clin.Psychiatry 2003;64(4):459-465. View abstract.
Mushtaq, F., Mondelli, V., and Pariante, C. M. The metabolic implications of long term cannabis use in patients with psychosis. Epidemiol.Psichiatr.Soc. 2008;17(3):221-226. View abstract.
Namaka, M., Leong, C., Grossberndt, A., Klowak, M., Turcotte, D., Esfahani, F., Gomori, A., and Intrater, H. A treatment algorithm for neuropathic pain: an update. Consult Pharm. 2009;24(12):885-902. View abstract.
Narang, S., Gibson, D., Wasan, A. D., Ross, E. L., Michna, E., Nedeljkovic, S. S., and Jamison, R. N. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J.Pain 2008;9(3):254-264. View abstract.
Nawrot, T. S., Perez, L., Kunzli, N., Munters, E., and Nemery, B. Public health importance of triggers of myocardial infarction: a comparative risk assessment. Lancet 2-26-2011;377(9767):732-740. View abstract.
Neidhart, J. A., Gagen, M. M., Wilson, H. E., and Young, D. C. Comparative trial of the antiemetic effects of THC and haloperidol. J.Clin.Pharmacol. 1981;21(8-9 Suppl):38S-42S. View abstract.
Niamatali, C., Fallon, S. D., and Egan, E. L. Nabilone in the management of prochlorperazine resistant cancer chemotherapy induced emesis. Ir.Med.J. 1984;77(9):276-277. View abstract.
Niederle, N., Schutte, J., and Schmidt, C. G. Crossover comparison of the antiemetic efficacy of nabilone and alizapride in patients with nonseminomatous testicular cancer receiving cisplatin therapy. Klin.Wochenschr. 4-15-1986;64(8):362-365. View abstract.
Niiranen, A. and Mattson, K. Antiemetic efficacy of nabilone and dexamethasone: a randomized study of patients with lung cancer receiving chemotherapy. Am.J.Clin.Oncol. 1987;10(4):325-329. View abstract.
No author. Nabilone and high-dose metoclopramide: anti-emetics for cancer chemotherapy. Drug Ther.Bull. 2-10-1984;22(3):9-11. View abstract.
Noel, B., Ruf, I., and Panizzon, R. G. Cannabis arteritis. J Am.Acad.Dermatol. 2008;58(5 Suppl 1):S65-S67. View abstract.
Notcutt W. Cannabis and pain control. European Journal of Palliative Care 2004;11:6-230.
Notcutt, W., Price, M., Miller, R., Newport, S., Phillips, C., Simmons, S., and Sansom, C. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia 2004;59(5):440-452. View abstract.
Noyes, R., Jr., Brunk, S. F., Avery, D. A., and Canter, A. C. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther. 1975;18(1):84-89. View abstract.
Nurmikko, T. J., Serpell, M. G., Hoggart, B., Toomey, P. J., Morlion, B. J., and Haines, D. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain 12-15-2007;133(1-3):210-220. View abstract.
Ohlsson, A., Lindgren, J. E., Andersson, S., Agurell, S., Gillespie, H., and Hollister, L. E. Single-dose kinetics of deuterium-labelled cannabidiol in man after smoking and intravenous administration. Biomed.Environ Mass Spectrom. 1986;13(2):77-83. View abstract.
Orr, L. E. and McKernan, J. F. Antiemetic effect of delta 9-tetrahydrocannabinol in chemotherapy-associated nausea and emesis as compared to placebo and compazine. J.Clin.Pharmacol. 1981;21(8-9 Suppl):76S-80S. View abstract.
Orr, L. E., McKernan, J. F., and Bloome, B. Antiemetic effect of tetrahydrocannabinol. Compared with placebo and prochlorperazine in chemotherapy-associated nausea and emesis. Arch.Intern.Med. 1980;140(11):1431-1433. View abstract.
Payne, R. J. and Brand, S. N. The toxicity of intravenously used marihuana. JAMA 7-28-1975;233(4):351-354. View abstract.
Penetar, D. M., Kouri, E. M., Gross, M. M., McCarthy, E. M., Rhee, C. K., Peters, E. N., and Lukas, S. E. Transdermal nicotine alters some of marihuana’s effects in male and female volunteers. Drug Alcohol Depend. 8-1-2005;79(2):211-223. View abstract.
Perez-Reyes, M., Burstein, S. H., White, W. R., McDonald, S. A., and Hicks, R. E. Antagonism of marihuana effects by indomethacin in humans. Life Sci. 1991;48(6):507-515. View abstract.
Perras, C. Sativex for the management of multiple sclerosis symptoms. Issues Emerg.Health Technol. 2005;(72):1-4. View abstract.
Petro, D. J. and Ellenberger, C., Jr. Treatment of human spasticity with delta 9-tetrahydrocannabinol. J.Clin.Pharmacol. 1981;21(8-9 Suppl):413S-416S. View abstract.
Phillips, R. S., Gopaul, S., Gibson, F., Houghton, E., Craig, J. V., Light, K., and Pizer, B. Antiemetic medication for prevention and treatment of chemotherapy induced nausea and vomiting in childhood. Cochrane.Database.Syst.Rev. 2010;(9):CD007786. View abstract.
Phillips, T. J., Cherry, C. L., Cox, S., Marshall, S. J., and Rice, A. S. Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials. PLoS.One. 2010;5(12):e14433. View abstract.
Pinsger, M., Schimetta, W., Volc, D., Hiermann, E., Riederer, F., and Polz, W. [Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain–a randomized controlled trial]. Wien.Klin.Wochenschr. 2006;118(11-12):327-335. View abstract.
Pittler, M. H. and Ernst, E. Complementary therapies for neuropathic and neuralgic pain: systematic review. Clin J Pain 2008;24(8):731-733. View abstract.
Pomeroy, M., Fennelly, J. J., and Towers, M. Prospective randomized double-blind trial of nabilone versus domperidone in the treatment of cytotoxic-induced emesis. Cancer Chemother.Pharmacol. 1986;17(3):285-288. View abstract.
Priestman, S. G., Priestman, T. J., and Canney, P. A. A double-blind randomised cross-over comparison of nabilone and metoclopramide in the control of radiation-induced nausea. Clin.Radiol. 1987;38(5):543-544. View abstract.
Priestman, T. J. and Priestman, S. G. An initial evaluation of Nabilone in the control of radiotherapy-induced nausea and vomiting. Clin.Radiol. 1984;35(4):265-266. View abstract.
Rabin, R. A., Zakzanis, K. K., and George, T. P. The effects of cannabis use on neurocognition in schizophrenia: a meta-analysis. Schizophr.Res. 2011;128(1-3):111-116. View abstract.
Redmond, W. J., Goffaux, P., Potvin, S., and Marchand, S. Analgesic and antihyperalgesic effects of nabilone on experimental heat pain. Curr.Med.Res.Opin. 2008;24(4):1017-1024. View abstract.
Reece, A. S. Chronic toxicology of cannabis. Clin Toxicol.(Phila) 2009;47(6):517-524. View abstract.
Richards, B. L., Whittle, S. L., and Buchbinder, R. Neuromodulators for pain management in rheumatoid arthritis. Cochrane.Database.Syst.Rev. 2012;1:CD008921. View abstract.
Rog, D. J., Nurmikko, T. J., and Young, C. A. 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. View abstract.
Rog, D. J., Nurmikko, T. J., Friede, T., and Young, C. A. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 9-27-2005;65(6):812-819. View abstract.
Sallan, S. E., Cronin, C., Zelen, M., and Zinberg, N. E. Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. N.Engl.J.Med. 1-17-1980;302(3):135-138. View abstract.
Sheidler, V. R., Ettinger, D. S., Diasio, R. B., Enterline, J. P., and Brown, M. D. Double-blind multiple-dose crossover study of the antiemetic effect of intramuscular levonantradol compared to prochlorperazine. J.Clin.Pharmacol. 1984;24(4):155-159. View abstract.
Sheweita, S. A. Narcotic drugs change the expression of cytochrome P450 2E1 and 2C6 and other activities of carcinogen-metabolizing enzymes in the liver of male mice. Toxicology 9-30-2003;191(2-3):133-142. View abstract.
Skrabek, R. Q., Galimova, L., Ethans, K., and Perry, D. Nabilone for the treatment of pain in fibromyalgia. J.Pain 2008;9(2):164-173. View abstract.
Staquet, M., Gantt, C., and Machin, D. Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Clin.Pharmacol.Ther. 1978;23(4):397-401. View abstract.
Steele, N., Gralla, R. J., Braun, D. W., Jr., and Young, C. W. Double-blind comparison of the antiemetic effects of nabilone and prochlorperazine on chemotherapy-induced emesis. Cancer Treat.Rep. 1980;64(2-3):219-224. View abstract.
Strasser, F., Luftner, D., Possinger, K., Ernst, G., Ruhstaller, T., Meissner, W., Ko, Y. D., Schnelle, M., Reif, M., and Cerny, T. 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. 7-20-2006;24(21):3394-3400. View abstract.
Svendsen, K. B., Jensen, T. S., and Bach, F. W. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 7-31-2004;329(7460):253. View abstract.
Sweet, D. L., Miller, N. J., Weddington, W., Senay, E., and Sushelsky, L. delta 9-Tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. A pilot study. J.Clin.Pharmacol. 1981;21(8-9 Suppl):70S-75S. View abstract.
Teasell, R. W., Mehta, S., Aubut, J. A., Foulon, B., Wolfe, D. L., Hsieh, J. T., Townson, A. F., and Short, C. A systematic review of pharmacologic treatments of pain after spinal cord injury. Arch.Phys.Med.Rehabil. 2010;91(5):816-831. View abstract.
Tetrault, J. M., Crothers, K., Moore, B. A., Mehra, R., Concato, J., and Fiellin, D. A. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch.Intern.Med. 2-12-2007;167(3):221-228. View abstract.
Thaera, G. M., Wellik, K. E., Carter, J. L., Demaerschalk, B. M., and Wingerchuk, D. M. Do cannabinoids reduce multiple sclerosis-related spasticity? Neurologist. 2009;15(6):369-371. View abstract.
Tomida, I., Azuara-Blanco, A., House, H., Flint, M., Pertwee, R. G., and Robson, P. J. Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study. J Glaucoma. 2006;15(5):349-353. View abstract.
Trembly B, Sherman M. Double-blind clinical study of cannabidiol as a secondary anticonvulsant. Marijuana ’90 International Conference on Cannabis and Cannabinoids 1990;2:5.
Tucker, P. Substance misuse and early psychosis. Australas.Psychiatry 2009;17(4):291-294. View abstract.
Ungerleider, J. T., Andrysiak, T., Fairbanks, L., Goodnight, J., Sarna, G., and Jamison, K. Cannabis and cancer chemotherapy: a comparison of oral delta-9-THC and prochlorperazine. Cancer 8-15-1982;50(4):636-645. View abstract.
Vaccani, A., Massi, P., Colombo, A., Rubino, T., and Parolaro, D. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br.J Pharmacol 2005;144(8):1032-1036. View abstract.
Vaney, C., Heinzel-Gutenbrunner, M., Jobin, P., Tschopp, F., Gattlen, B., Hagen, U., Schnelle, M., and Reif, M. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult.Scler. 2004;10(4):417-424. View abstract.
Vidal, C., Fuente, R., Iglesias, A., and Saez, A. Bronchial asthma due to Cannabis sativa seed. Allergy 1991;46(8):647-649. View abstract.
Voirin, N., Berthiller, J., Benhaim-Luzon, V., Boniol, M., Straif, K., Ayoub, W. B., Ayed, F. B., and Sasco, A. J. Risk of lung cancer and past use of cannabis in Tunisia. J Thorac.Oncol. 2006;1(6):577-579. View abstract.
Volicer, L., Stelly, M., Morris, J., McLaughlin, J., and Volicer, B. J. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease. Int.J.Geriatr.Psychiatry 1997;12(9):913-919. View abstract.
Wada, J. K., Bogdon, D. L., Gunnell, J. C., Hum, G. J., Gota, C. H., and Rieth, T. E. Double-blind, randomized, crossover trial of nabilone vs. placebo in cancer chemotherapy. Cancer Treat.Rev. 1982;9 Suppl B:39-44. View abstract.
Wade, D. T., Collin, C., Stott, C., and Duncombe, P. Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis. Mult.Scler. 2010;16(6):707-714. View abstract.
Wade, D. T., Makela, P., Robson, P., House, H., and 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):434-441. View abstract.
Wade, D. T., Robson, P., House, H., Makela, P., and Aram, J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin.Rehabil. 2003;17(1):21-29. View abstract.
Ward, A. and Holmes, B. Nabilone. A preliminary review of its pharmacological properties and therapeutic use. Drugs 1985;30(2):127-144. View abstract.
Weber, M., Goldman, B., and Truniger, S. Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: a randomised, double-blind crossover trial. J.Neurol.Neurosurg.Psychiatry 2010;81(10):1135-1140. View abstract.
Wilsey, B., Marcotte, T., Tsodikov, A., Millman, J., Bentley, H., Gouaux, B., and Fishman, S. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J.Pain 2008;9(6):506-521. View abstract.
Wissel, J., Haydn, T., Muller, J., Brenneis, C., Berger, T., Poewe, W., and Schelosky, L. D. 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):1337-1341. View abstract.
Woolridge, E., Barton, S., Samuel, J., Osorio, J., Dougherty, A., and Holdcroft, A. Cannabis use in HIV for pain and other medical symptoms. J Pain Symptom.Manage. 2005;29(4):358-367. View abstract.
Yamamoto, I., Watanabe, K., Narimatsu, S., and Yoshimura, H. Recent advances in the metabolism of cannabinoids. Int J Biochem.Cell Biol 1995;27(8):741-746. View abstract.
Zammit, S., Moore, T. H., Lingford-Hughes, A., Barnes, T. R., Jones, P. B., Burke, M., and Lewis, G. Effects of cannabis use on outcomes of psychotic disorders: systematic review. Br.J Psychiatry 2008;193(5):357-363. View abstract.
Zhu, H. J., Wang, J. S., Markowitz, J. S., Donovan, J. L., Gibson, B. B., Gefroh, H. A., and Devane, C. L. Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana. J Pharmacol Exp.Ther. 2006;317(2):850-857. View abstract.
Zimmerman, S. and Zimmerman, A. M. Genetic effects of marijuana. Int J Addict. 1990;25(1A):19-33. View abstract.
Zuardi, A. W., Crippa, J. A., Hallak, J. E., Moreira, F. A., and Guimaraes, F. S. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz.J Med Biol Res 2006;39(4):421-429. View abstract.
Zuardi, A. W., Hallak, J. E., Dursun, S. M., Morais, S. L., Sanches, R. F., Musty, R. E., and Crippa, J. A. Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol. 2006;20(5):683-686. View abstract.
Zuardi, A. W., Shirakawa, I., Finkelfarb, E., and Karniol, I. G. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl) 1982;76(3):245-250. View abstract.
Advances in Hemp Research. Ed. P. Ranalli. Binghamton, NY: Haworth Press, Inc., 1999.
Andre CM, Hausman JF, Guerriero G. Cannabis sativa: The Plant of the Thousand and One Molecules. Front Plant Sci. 2016 Feb 4;7:19. View abstract.
Astley, S. J. and Little, R. E. Maternal marijuana use during lactation and infant development at one year. Neurotoxicol.Teratol. 1990;12(2):161-168. View abstract.
Baker D, Pryce G, Croxford JL, et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 2000;404:84-7. View abstract.
Barber PA, Pridmore HM, Krishnamurthy V, et al. Cannabis, ischemic stroke, and transient ischemic attack: a case-control study. Stroke. 2013 Aug;44(8):2327-9.
Beaconsfield P, Ginsburg J, Rainsbury R. Marihuana smoking. Cardiovascular effects in man and possible mechanisms. N Engl J Med. 1972 Aug 3;287(5):209-12. View abstract.
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;10:89-97.. View abstract.
Benowitz, N. L. and Jones, R. T. Cardiovascular and metabolic considerations in prolonged cannabinoid administration in man. J Clin Pharmacol 1981;21(8-9 Suppl):214S-223S. View abstract.
Botanical.Com A Modern Herbal. www.botanical.com (Accessed 31 July 1999).
Brady CM, DasGupta R, Dalton C, et al. An open-label study of cannabis-based extracts for bladder dysfuntion in advanced multiple sclerosis. Mult Scler 2004;10(4):425-33. View abstract.
Briggs GB, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1998.
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;323:13-6.. View abstract.
Carlini EA, Cunha JM. Hypnotic and antiepileptic effects of cannabidiol. J Clin Pharmacol 1981;21(8-9 Suppl):417S-27S. View abstract.
Clark SC, Greene C, Karr GW, MacCannell KL, Milstein SL. Cardiovascular effects of marihuana in man. Can J Physiol Pharmacol. 1974 Jun;52(3):706-19. View abstract.
Clark SC. Marihuana and the cardiovascular system. Pharmacol Biochem Behavior. 1975;3(2):299-306.
Combemale P, Consort T, Denis-Thelis L, et al. Cannabis arteritis. Br J Dermatol. 2005;152(1):166-9. View abstract.
Consroe P, Musty R, Rein J, et al. The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur Neurol 1997;38:44-8.. View abstract.
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 Medicine 2000;6:313-9. View abstract.
Gibbs M, Winsper C, Marwaha S, et al. Cannabis use and mania symptoms: a systematic review and meta-analysis. J Affect Disord. 2015;171:39-47. View abstract.
Goldschmidt RH, Dong BJ. Treatment of AIDS and HIV-related conditions: 2000. J Am Board Fam Pract 2000;13:274-98.
Gowran A, McKayed K, Campbell VA. The cannabinoid receptor type 1 is essential for mesenchymal stem cell survival and differentiation: implications for bone health. Stem Cells Int. 2013;2013:796715. View abstract.
Greenberg I, Kuehnle J, Mendelson JH, Bernstein JG. Effects of Marihuana use on body weight and caloric intake in humans. Psychopharmacol. 1976;49:79-84.
Guy GW, Stott CG. “The development of Sativex – a natural cannabis-based medicine.” Ed. R Mechoulam. Cannabinoids as Therapeutics. Basel, Switzerland: Birkhauser Verlag, 2005. 231-263.
Hackam DG. Cannabis and stroke: systematic appraisal of case reports. Stroke. 2015;46(3):852-6. View abstract.
Hancock-Allen JB, Barker L, VanDyke M, Holmes DB. Notes from the Field: Death Following Ingestion of an Edible Marijuana Product–Colorado, March 2014. MMWR Morb Mortal Wkly Rep. 2015;64(28):771-2. View abstract.
Harris A, Siesky B, Wirostko B. Cerebral blood flow in glaucoma patients. J Glaucoma. 2013;22 Suppl 5:S46-8. View abstract.
Hebel SK, ed. Drug Facts and Comparisons. 52nd ed. St. Louis: Facts and Comparisons, 1998.
Henquet C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ. 2005;330(7481):11. View abstract.
Ince B, Benbir G, Yuksel O, et al. Both hemorrhagic and ischemic stroke following high doses of cannabis consumption. Presse Med. 2015;44(1):106-7. View abstract.
Johnson MA, Robin P, Smith RP, Morrisona D, et al. Large lung bullae in marijuana smokers. Thorax 2000;55:340-2.. View abstract.
Johnson, E. M. Substance abuse and women’s health. Public Health Rep. 1987;102(4 Suppl):42-48. View abstract.
Jouanjus E, Lapeyre-Mestre M, Micallef J; French Association of the Regional Abuse and Dependence Monitoring Centres (CEIP-A) Working Group on Cannabis Complications. Cannabis use: signal of increasing risk of serious cardiovascular disorders. J Am Heart Assoc. 2014 Apr 23;3(2):e000638. View abstract.
Kavia RB, De Ridder D, Constantinescu CS, et al. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler 2010;16(11):1349-59. View abstract.
Klein TW, Newton CA, Nakachi N, Friedman H. Delta 9-tetrahydrocannabinol treatment suppresses immunity and early IFN-gamma, IL-12, and IL-12 receptor beta 2 responses to Legionella pneumophila infection. J Immunol 2000;164:6461-6.. View abstract.
Lev-Ran S, Roerecke M, Le Foll B, et al. The association between cannabis use and depression: a systematic review and meta-analysis of longitudinal studies. Psychol Med. 2014;44(4):797-810. View abstract.
Marijuana Use by Middle-Aged Adults Linked to Increased Risk of MI. www.medscape.com/reuters/prof/2000/03/03.03/ep03030b.html (Accessed 3 March 2000).
Marinol [package insert]. [package insert]. Marietta, GA: Unimed Pharmaceuticals, Inc; 2006.
Marinol Prescribing Information. Solvay Pharmaceuticals, Rev March 2008. Available at: http://www.solvaypharmaceuticals-us.com/static/wma/pdf/1/3/2/5/0/004InsertText500012RevMar2008.pdf (Accessed 2 July 2009).
McLoughlin BC, Pushpa-Rajah JA, Gillies D, et al. Cannabis and schizophrenia. Cochrane Database Syst Rev. 2014 Oct 14;10:CD004837. View abstract.
Merritt JC, Crawford WJ, Alexander PC, et al. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmol 1980;87:222-8.. View abstract.
Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE. Triggering myocardial infarction by marijuana. Circulation. 2001;103(23):2805-9. View abstract.
Notcutt W, Langford R, Davies P, et al. A placebo-controlled, parallel group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex (nabiximols). Mult Scler 2012;18(2):219-28. View abstract.
Novotna A, Mares J, Ratcliffe S, et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex), as add-on therapy, in subjects with refractory spasticity cause by multiple sclerosis. Eur J Neurol 2011;18(9):1122-31. View abstract.
Overview. GW Pharmaceuticals Web site. Available at: http://www.gwpharm.com/about-us-overview.aspx. Accessed: May 31, 2015.
Ozyurt S, Muderrisoglu F, Ermete M, Afsar F. Cannabis-induced erythema multiforme-like recurrent drug eruption. Int J Dermatol. 2014;53(1):e22-3. View abstract.
Pellinen, P., Honkakoski, P., Stenback, F., Niemitz, M., Alhava, E., Pelkonen, O., Lang, M. A., and Pasanen, M. Cocaine N-demethylation and the metabolism-related hepatotoxicity can be prevented by cytochrome P450 3A inhibitors. Eur.J Pharmacol 1-3-1994;270(1):35-43. View abstract.
Piomelli D. Pot of gold for glioma therapy. Nat Med 2000;6:255-6.
Reece AS. Severe multisystem dysfunction in a case of high level exposure to smoked cannabis. BMJ Case Rep. 2009;2009. pii: bcr08.2008.0798. View abstract.
Sallan SE, Zinberg NE, Frei E III. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 1975;293:795-7. View abstract.
Sansone RA, Sansone LA. Marijuana and body weight. Innov Clin Neurosci. 2014;11(7-8):50-4.View abstract.
Semple DM, McIntosh AM, Lawrie SM. Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol. 2005;19(2):187-94. View abstract.
Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J Neurol 2013;260(1):285-95. View abstract.
Sidney S. Cardiovascular Consequences of Marijuana Use. J Clin Pharmacol. 2002;42(11 Suppl):64S-70S.View abstract.
Solowij N, Stephens RS, Roffman RA, et al. Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA 2002;287:1123-31.. View abstract.
Tramer MR, Carroll D, Campbell FA, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001;323:16-21.. View abstract.
Tyrey L. Delta 9-Tetrahydrocannabinol: a potent inhibitor of episodic luteinizing hormone secretion. J Pharmacol Exp Ther 1980;213:306-8. View abstract.
Wade DT, Makela PM, House H, et al. Long-term use of a cannabis-based treatment in spasticity and other symptoms in multiple sclerosis. Mult Scler 2006;12(5):639-45. View abstract.
Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 2010;182:e694-e701. View abstract.
Westover AN, McBride S, Haley RW. Stroke in young adults who abuse amphetamines or cocaine: a population-based study of hospitalized patients. Arch Gen Psychiatry. 2007 Apr;64(4):495-502. View abstract.
Yadav V, Bever C Jr, Bowen J, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2014;82(12):1083-92. View abstract.
Yamreudeewong W, Wong HK, Brausch LM, Pulley KR. Probable interaction between warfarin and marijuana smoking. Ann Pharmacother 2009;43:1347-53. View abstract.
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;362:1517-26.. View abstract.
Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG; MUSEC Research Group. Multiple sclerosis and extract of cannabis: results of the MUSEC trial. J Neurol Neurosurg Psychiatry. 2012;83(11):1125-32. View abstract.
Zhu LX, Sharma S, Stolina M, et al. Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol 2000;165:373-80.. View abstract.
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Diuretic Effects of Cannabinoids
In vivo effects of cannabinoid (CB) agonists are often assessed using four well-established measures: locomotor activity, hypothermia, cataleptic-like effects, and analgesia. The present studies demonstrate that doses of CB agonists that produce these effects also reliably increase diuresis. Diuretic effects of several CB agonists were measured in female rats over 2 hours immediately after drug injection, and results were compared with hypothermic effects. Direct-acting CB1 agonists, including Δ 9 -tetrahydrocannabinol, WIN 55,212 [R-(1)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate], AM2389 [9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol], and AM4054 [9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol], produced dose-dependent increases in diuresis and decreases in colonic temperature, with slightly lower ED50 values for diuresis than for hypothermia. The highest doses of cannabinoid drugs yielded, on average, 26–32 g/kg urine; comparable effects were obtained with 10 mg/kg furosemide and 3.0 mg/kg trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50-488). Methanandamide (10.0 mg/kg) had lesser effect than other CB agonists, and the CB2 agonist AM1241 [1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole], the anandamide transport inhibitor AM404, and the CB antagonist rimonabant did not have diuretic effects. In further studies, the diuretic effects of the CB1 agonist AM4054 were similar in male and female rats, displayed a relatively rapid onset to action, and were dose-dependently antagonized by 30 minutes pretreatment with rimonabant, but not by the vanilloid receptor type I antagonist capsazepine, nor were the effects of WIN 55,212 antagonized by the CB2 antagonist AM630 [(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)]. These data indicate that cannabinoids have robust diuretic effects in rats that are mediated via CB1 receptor mechanisms.
Cannabinoid CB1 receptor ligands often are studied for their ability to concomitantly produce four effects in mice; decreases in locomotor activity, hypothermia, antinociception, and immobility (Martin et al., 1991; Wiley et al., 2007; Wiley et al., 2012). Δ 9 -Tetrahydrocannabinol (THC) and related compounds also induce diuresis, but this has received scant attention, even though early clinical reports of the effects of cannabis in humans included anecdotal observations of increases in diuresis (Allentuck and Bowman, 1942; Parker and Wrigley, 1947; Stockings, 1947). In one such study, voiding rates in human subjects were specifically measured, with urine volumes averaging 320% of control values following cannabis ingestion (Ames, 1958). In a subsequent study in hydrated rats, oral Δ 9 -THC was found to produce diuretic effects equivalent to or greater than those of hydrochlorothiazide (Sofia et al., 1977). Surprisingly, the diuretic effects of cannabinoids were not studied further until reports began to appear that suggested symptoms of urinary urgency and incontinence in patients with multiple sclerosis were attenuated after cannabis use (Consroe et al., 1997). A more recent pilot study with cannabis extracts confirmed the earlier findings of decreased urinary frequency and urine volume, and led to speculation that cannabinoids may be useful in treating cystitis or other lower urinary tract dysfunction (Brady et al., 2004; Apostolidis, 2012). These results contrast with the earlier reports and suggest that cannabinoids may have mixed effects on diuresis or that the observed effect—diuretic or anti-diuretic—may vary in different patient populations.
Despite the paucity of data regarding exogenous cannabinoids and diuresis, a role for endocannabinoids, particularly anandamide, in urinary function has been identified. As with the effects of cannabis, both increases and decreases in urine loss have been reported with anandamide, and mechanisms through which these different effects are mediated appear to be complex. Endocannabinoids influence the release of urine through multiple mechanisms that may include vanilloid receptor type I (TRPV1) or cannabinoid CB1 and CB2 receptors, which are all found throughout the lower urinary tract (Avelino and Cruz, 2006; Tyagi et al., 2009; Strittmatter et al., 2012). For example, anandamide may increase bladder contractility, especially in inflamed tissues; these effects are blocked by coadministration of capsazepine, indicating involvement of TRPV1 receptors (Dinis et al., 2004; Avelino and Cruz, 2006). On the other hand, increasing levels of anandamide after local administration of a fatty acid amide hydrolase inhibitor also lead to decreased contractility of normal bladder tissue–effects that are antagonized by CB1 and CB2 selective antagonists (Strittmatter et al., 2012). Such opposing actions have led to the suggestion that the net regulatory effects of anandamide on bladder function result from a balance of CB1, CB2, and TRPV1 effects (Dinis et al., 2004; Avelino and Cruz, 2006).
In addition to their complex actions on urine storage and release, endocannabinoids may increase urine production by both peripheral and central actions. Thus, direct infusion of methanandamide into the renal medulla increases urine flow rate, suggesting that endocannabinoids alter urine production at the level of the kidney (Li and Wang, 2006). Work from other laboratories suggests that both anandamide and 2-arachidonylglycerol, released from the hypothalmus, may modulate the release of hypophysial hormones, including vasopressin (Di et al., 2005; Soya et al., 2005). In keeping with data from these separate studies, it is worth noting that Sofia and colleagues (Sofia et al.,1971) similarly suggested that the diuretic actions of oral Δ 9 -THC were mediated both peripherally and within the central nervous system. In summary, exogenous and endogenous cannabinoids clearly modulate urinary function, although their effects and the mechanisms mediating these effects may differ depending on the site of action and the experimental conditions.
Many synthetic cannabinoid ligands have been developed in the past 20 years, including compounds such as CP55,940 and WIN55,212 (Devane et al., 1988; Compton et al., 1992); however, potential diuretic effects of these drugs have not been previously evaluated. The present studies were undertaken to compare the net diuretic effects of systemic administration of cannabinoid agonists in conscious rats. Results show that CB1 agonists dose-dependently increase diuresis concomitantly with hypothermic effects, and further studies with the nonselective agonist AM4054 (Thakur et al., 2012) reveal that these effects are antagonized by rimonabant. Overall, our data indicate that diuresis is a CB1-mediated effect that may serve as a reliable and objective physiologic measure of cannabinoid action in rats; the circumstances under which these results represent a potential therapeutic benefit or potential liability of cannabinoids remain to be determined.
Materials and Methods
Adult female Sprague-Dawley rats (Charles River, Wilmington, MA) weighing 200–350 g and adult male Sprague-Dawley rats weighing 530–770 g were used. Animals were group-housed in a climate-controlled vivarium with a 12-hour light/dark cycle (lights on at 7 AM ). Subjects had unrestricted access to food and water outside experimental sessions. All studies were approved by the McLean Hospital and Northeastern University Institutional Animal Care and Use Committees.
After initial exposure to handling procedures, rats were placed in customized restraint devices made of polyvinyl chloride tubing. Individual absorbent pads, placed in each restraint device, were weighed before and after the experiment; the difference in pad weight was recorded as the weight (in grams) of voided urine. Unless otherwise noted, sessions lasted 2 hours.
After initial exposure to handling procedures, thermal probes (YSI, No. 401) were inserted rectally to a depth of 7 cm, 30 minutes before drug administration. The probes were secured to the tails with porous tape, and the animals were placed in individual chambers measuring 30 × 12 × 12 cm. Two baseline temperature readings were recorded before drug injection, and temperature was recorded every 30–60 minutes for 6 hours after injection. The change in temperature was determined for each rat by subtracting temperature readings from the mean of the 2 baseline measures.
Δ 9 -THC and rimonabant were obtained from the National Institute on Drug Abuse (Rockville, MD); sodium pentobarbital and furosemide were purchased from Sigma-Aldrich (St. Louis, MO), capsazepine and WIN-55-212 were purchased from Tocris Bioscience (Ellisville, MO), and U50,488 was obtained from the Upjohn Company (Kalamazoo, MI; now Pfizer Inc.). AM4054, AM2389, AM404, AM630, and methanandamide were synthesized at Northeastern University, as previously described (Abadji et al., 1994; Beltramo et al., 1997; Nikas et al., 2010; Thakur et al., 2012), and AM1241 was a generous gift of MAK Scientific (West Mystic, CT). Pentobarbital and U50,488 were dissolved in saline; furosemide was dissolved in 1% 1N NAOH and sterile water. All other compounds were prepared in 20% ethanol, 20% alkamuls-620 (Rhone-Poulenc, Princeton, NJ), and 60% saline and were further diluted with saline. Except where noted, injections were delivered subcutaneously in volumes of 1 ml/kg body weight; drug doses are expressed in terms of the weight of the free base. At least three days separated each drug test.
(A) Diuretic effects produced by p.o. injection of water (n = 12). (B) Diuretic effects produced by furosemide or U50-488 (n = 6). Abscissae: Volumes of water (A) or doses of drug (B) in milligrams per kilogram bodyweight; points to the left, above 0 or sal represent effects obtained after s.c. saline injection. Ordinates: Urine volume expressed as grams per kilogram bodyweight. Symbols and associated vertical lines represent the mean and S.E.M.; asterisks indicate values significantly different from saline control; *P 9 -THC; WIN 55,212; AM4054; and AM2389 increased urine output in a dose-dependent manner, with maxima of 26–32 g/kg urine after the highest doses ( Fig. 2 ). Likewise, each of the cannabinoid agonists significantly and dose-dependently decreased temperature. When the data are expressed as a percentage of a maximum effect (35 g/kg urine or −6°C; not shown), the dose-effect functions for each of the four agonists across the two procedures are parallel. ED50 values calculated from these functions reveal an order of potency of AM2389 ≥ AM4054 > Win55,212 ≥ Δ 9 -THC for diuretic and hypothermic effects. Differences in potency across the two effects were small; however, for all four drugs, diuretic effects occurred at slightly lower doses than did hypothermic effects ( Table 1 ). To evaluate potential sex differences in the diuretic effects of cannabinoids, the effects of AM4054 were compared in male and female rats; AM4054 significantly increased diuresis in both male and female rats, with no evidence of significant sex differences ( Table 2 ).
Effects of AM4054; Δ 9 -THC; AM2389; WIN 55,212; and rimonabant on diuresis (top) and hypothermia (bottom) (n=6 per drug); points above V represent the effects of vehicle, averaged from all groups. Bottom ordinate represents peak hypothermic effects obtained within 6 hours after drug injections and are expressed as a change from baseline values (mean, 38.55°C; range, 37.60-39.01°C); other details as in Fig 2 .
ED50 values (in mg/kg) and 95% confidence interval for diuretic and hypothermic effects in female rats (n = 6)
|Variable||AM4054||Δ 9 -THC||WIN55,212||AM2389|
Voided urine in female and male rats (n = 6) after injection of saline or AM4054
Values given are the mean (±S.E.M.) in grams per kilogram bodyweight.
|0.03 mg/kg||0.1 mg/kg||0.3 mg/kg|
|Female||4.1 (± 1.0)||13.0 (± 1.9)||22.0 (± 4.4)||23.9 (± 6.4)|
|Male||4.6 (± 3.1)||9.2 (± 3.6)||23.0 (± 2.3)||21.7 (± 4.1)|
In contrast to the effects of the cannabinoid agonists, the cannabinoid antagonist rimonabant had neither diuretic nor hypothermic effects ( Fig. 2 ). Rimonabant also did not have antidiuretic effects in rats that had been preloaded with 10.0–30.0 ml/kg water ( Table 3 ). Although diuresis was slightly increased after 0.3 mg/kg rimonabant in rats prehydrated with 30.0 ml/kg water, this effect was not dose-related and further increases in dose to 1.0 and 3.0 mg/kg did not reveal any significant increase in diuresis. Among other cannabinergic drugs that were evaluated for diuretic effects, only methanandamide increased voided urine and, these effects were observed only with a single dose, 10 mg/kg. In contrast to other CB1 agonists displaying intermediate effects, a 3-fold increase in dose, to 30 mg/kg of methanandamide, did not correspondingly increase urine output but, instead, reduced diuresis to control levels. The remaining drugs, including the CB2 selective cannabinoid agonist AM1241 and the endocannabinoid transport inhibitor AM404, were without effect on urine output ( Table 4 ).
Effects of rimonabant on urine loss in female rats (n = 6–11) after preloading with 10 or 30 ml/kg water
Values given are the mean ± S.E.M. (in grams per kilogram bodyweight).
|0. 3 mg/kg||1.0 mg/kg||3.0 mg/kg|
|10 ml/kg H2O||6.2 ± 1.3||8.3 ± 2.5||5.2 ± 1.2||10.9 ± 1.3|
|30 ml/kg H2O||28.4 ± 2.7||39.6 ± 5.8 *||21.8 ± 1.5||29.8 ± 1.9|
ND, not determined.
Time course of diuretic and hypothermic effects of saline, 0.1–0.3 mg/kg AM4054, and 10 mg/kg furosemide (n=6 per drug). Abscissae: Time since injection (in minutes); other details as in Fig 2 .
Rimonabant antagonized the diuretic effects of AM4054; 0.1, 1.0, and 3.0 mg/kg rimonabant produced 5–15-fold rightward shifts of the AM4054 dose-effect function, suggesting that competitive interactions occur between the drugs ( Fig. 4 and Table 5 ). However, the effects of AM4054 were not diminished by 0.3 mg/kg rimonabant, suggesting that a more complex relationship than simple competitive antagonism underlies the diuretic effects of these drugs given in combination. The effects of 0.1–0.3 mg/kg AM4054 after pretreatment with 0.3 mg/kg rimonabant were redetermined in another groups of rats, and again, there was no attenuation of the diuretic effects of AM4054. To further evaluate contributions of other receptor systems, the effects of ∼ED50 doses AM4054 and WIN 55,212 were re-determined in the presence of the TRPV1 antagonist capsazepine or the CB2 antagonist AM630, respectively. Results show that a 15-minute pretreatment with 10.0 mg/kg capsazepine did not enhance or reduce the effects of 0.1 mg/kg AM4054 ( Fig. 5A ) and a 30-minute pretreatment with 10.0 mg/kg AM630 did not alter the effects of 3.0 mg/kg WIN 55,212 ( Fig. 5B ).
Effects of AM4054 alone (open symbols) or after 30-minutes pretreatment with rimonabant; other details as in Fig 2 .
ED50 values with 95% confidence intervals (CI; in mg/kg) and potency ratios for AM4054-induced diuresis after 30 minutes pretreatment with rimonabant
|Treatment||ED||95% CI||Potency Ratio|
|+0.1 mg/kg rimonabant||0.44||0.24–2.00||4.7|
|+0.3 mg/kg rimonabant||ND||ND||ND|
|+1.0 mg/kg rimonabant||1.07||0.68–2.66||11.6|
|+3.0 mg/kg rimonabant||1.36||ND||14.7|
ND, not determined.
(A) Diuretic effects after injection of vehicle, 0.1 mg/kg AM4054, or 0.1 mg/kg AM4054 after a 15-minute pretreatment with 10 mg/kg capsazepine. (B) Diuretic effects after injection of vehicle; 3.0 mg/kg WIN 55,212; or 3.0 mg/kg WIN 55,212 after a 30-minute pretreatment with 10 mg/kg AM630; other details as in Fig 2 .
Products of the cannabis plant were used as diuretics in ancient India, and early laboratory studies on the effects of cannabis or Δ 9 -THC reported that phytocannabinoids increase amounts of voided urine in both rats and humans (Ames, 1958; Sofia et al., 1977; Touw, 1981). However, recent advances in cannabinoid pharmacology, including the development of synthetic cannabinoid agonists, have neglected further study of the diuretic effects of cannabinoids. The present studies demonstrate that synthetic cannabinoid agonists can dose-dependently increase diuresis in rats. Similar effects were obtained with the cannabinoids Δ 9 -THC, AM2389, and AM4054 and with an aminoalkylindole, WIN55,212; thus, the effects are not unique to a particular chemical class (Compton et al., 1992; Nikas et al., 2010; Thakur et al., 2012). The diuretic effects produced by cannabinoids are comparable to those of the loop diuretic furosemide and the κ-opioid agonist U50,488. The effects of all four cannabinoid agonists were dose-related for all drugs, and moderate diuresis appeared at lower doses. However, the maximum diuretic effects of the four compounds were rather high and corresponded to the effect of preloading rats with 30.0 ml/kg water. It remains to be determined whether diuresis represents a potential new therapeutic use for cannabinoids or, instead, an additional clinical liability. Nevertheless, the present studies clearly show that urine output provides an easily obtained physiologic measure of the effects of CB1 agonists and, consequently, a robust and objective metric with which to assess the effects of novel cannabinoid agonists.
Hypothermia is one of four measures commonly used to describe the effects of novel cannabinoid agonists in vivo (Martin et al., 1991; Wiley et al., 2007) and was included in the present study as an objective comparative measure of cannabinoid effects. Hypothermia has been characterized previously as a CB1 receptor–mediated effect, based on evidence that decreases in body temperature produced by Δ 9 -THC; CP55,940; and WIN 55,212 are blocked by the CB1-selective antagonist rimonabant and, furthermore, that CB1 receptor knockout mice do not exhibit cannabinoid-produced hypothermia (Rinaldi-Carmona et al., 1994; Compton et al., 1996; Zimmer et al., 1999; De Vry et al., 2004; McMahon and Koek, 2007). Of the drugs studied here, Δ 9 -THC and AM4054 have equal affinity for CB1 and CB2 receptors; AM2389 is CB1 receptor-preferring, with ∼25-fold higher affinity at CB1, compared with CB2 receptors; and WIN 55,212 is CB2 receptor–preferring, with ∼20-fold higher affinity at CB2, compared with CB1 receptors (Felder et al., 1995; Nikas et al., 2010; Thakur et al., 2012). Despite their different selectivities for CB1 and CB2 receptors, the four drugs produced diuresis and hypothermia with the same order of potency, suggesting that the effects are mediated by the same receptor. Given the evidence that hypothermia is mediated by CB1 receptors, it is therefore likely that diuresis is also a CB1 receptor–mediated effect. Antagonism studies with rimonabant provide more evidence that the diuretic effects of cannabinoids in rats are mediated primarily by CB1 receptors. Thus, AM4054-induced diuresis was antagonized by doses of rimonabant similar to those used to antagonize numerous behavioral effects of Δ 9 -THC and other cannabinoid ligands, including suppression of locomotor activity, antinociception, catalepsy, hypothermia, discriminative stimulus effects, and self-administration (Wiley et al., 2001; Järbe et al., 2005; Justinova et al., 2005; McMahon, 2006; McMahon and Koek, 2007).
Although it is likely that the mechanisms underlying cannabinoid-induced diuresis primarily involve CB1 receptor activation, a role for other pharmacological mechanisms cannot be completely dismissed. Antagonism of diuresis by rimonabant was generally dose-related, with the exception that 0.3 mg/kg rimonabant did not alter the position of the AM4054 dose-response function. These results were surprising because this dose of rimonabant has previously been shown to attenuate the analgesic, cataleptic, and hypothermic effects of cannabinoid agonists in mice and rats (De Vry et al., 2004; McMahon and Koek, 2007). Rimonabant has been described as an inverse agonist producing effects opposite to those of cannabinoid agonists (e.g., potentiating smooth muscle contractions, stimulating adenylyl cyclase, and decreasing GTPγS binding) (Meschler et al., 2000; Sim-Selley et al., 2001; Makwana et al., 2010). Inverse agonist activity might explain a lack of a stepwise, competitive interaction between AM4054 and rimonabant, although there is little evidence of inverse agonist effects of rimonabant in vivo. For example, in the present studies, one might predict that an inverse agonist would have antidiuretic effects; however, in rats preloaded with either 10 or 30 ml/kg water, there was no evidence of any antidiuretic activity of rimonabant. Indeed, in one instance, rimonabant—of note, with the same dose of 0.3 mg/kg–unexpectedly increased the amount of voided urine. When coupled with the biphasic effects obtained with methanandamide, our results suggest that the diuretic effects of cannabinoids involve more than simple direct agonist effects at one receptor type. Other potential targets for cannabinoid activity include direct effects on CB2 receptors or alteration of endocannabinoid activity. A role for both CB1 and CB2 receptors and TRPV1 receptors has been implicated in mediating the effects of endocannabinoids on bladder contractility (Dinis et al., 2004; Walczak et al., 2009; Strittmatter et al., 2012); furthermore, at least one report has suggested that endocannabinoids alter urine production through a noncannabinoid, nonvanilloid mechanism in rats (Li and Wang, 2006). At present, we have no explanation for these results, although our data with the selective CB2 ligands AM1241 and AM630, the TRPV1 antagonist capsazepine, and the endocannabinoid transport inhibitor AM404 do not support a major role for any of these systems in exocannabinoid-induced diuresis.
In the present report, the loss of urine is referred to as diuresis, as opposed to micturition; however, it is unclear whether cannabinoids increase urine production, stimulate the release of urine from the bladder, or both. Nonetheless, the present data suggest that the effects reported here represent more than simple micturition, as the highest doses of cannabinoids resulted in urine loss within 2 hours that is similar to 24-hour urine loss in untreated female Sprague-Dawley rats [unpublished observations and (Powers, 2001)]. The rapidity with which cannabinoids produce their full diuretic effects was surprising. Although many effects of cannabinoids appear within minutes and are measured within the first hour after drug injection (Martin et al., 1991; Wiley et al., 2007), it often takes several hours for cannabis-related drugs to reach their peak effects (Davis et al., 1973; Schlosburg et al., 2009). The present findings indicate that maximum diuresis preceded the peak hypothermic effects of cannabinoids, which occurred more than 2 hours after injection. The fast onset of diuresis, coupled with the marginally lower doses required for diuretic than hypothermic effects, suggest that fluid loss may contribute to the hypothermic effects of cannabinoid drugs. However, the finding that pentobarbital-induced hypothermia is not altered by coadministration of furosemide and the lack of hypothermia after furosemide alone demonstrates that hypothermic and diuretic effects can occur separately. The clear separation of diuresis and hypothermia after noncannabinoid treatment may distinguish diuresis from other behavioral measures of cannabinoid activity. Thus, cannabinoid effects commonly measured in previous studies—catalepsy, decreased locomotion, antinociception, and hypothermia—are difficult to view as completely separate phenomena. Three of the four measures involve decreased movement, and consequently, the different assays are often treated as one basic measure, referred to as the tetrad test or cannabinoid tetrad (Bosier et al., 2010; Brents et al., 2012). The finding that cannabinoids also dose-dependently increase diuresis importantly provides a separate and independent physiologic response that can serve as a robust and reliable measure of CB1-mediated actions.
In conclusion, the present results demonstrate that behaviorally active doses of exogenous cannabinoids also produce profound diuretic effects in female and male rats. These results suggest that diuresis may occur separately, yet simultaneously, with other measures of cannabinoid activity in laboratory animals and, perhaps, in humans. Antagonism of cannabinoid diuretic effects by rimonabant, coupled with a lack of effect of non-CB1 ligands, indicates that these effects are mediated primarily by CB1 receptors; however, other mechanisms may contribute to these physiologic effects. The implications of these findings currently are poorly understood, although a better understanding of mechanisms and sites of action by which cannabinoids increase urine loss may lead to the rational development of novel cannabinergic medications.
The authors thank Jared Martin and Joseph B. Anderson for excellent technical assistance.
Diuretic Effects of Cannabinoids Abstract In vivo effects of cannabinoid (CB) agonists are often assessed using four well-established measures: locomotor activity, hypothermia, cataleptic-like