Cannabinoids and their medicinal potential

Deepika Tikoo, Geeta Sharma, Meenakshi Gupta


Cannabis sativa L preparations have been used therapeutically since many years. Inspite of their medicinal value, the danger of its abusive potential led to the ban on its use in clinical practice in many countries. The recent research and in depth knowledge about the cannabinoid system which throw a light on their disease management potential has paved way for the cannabinoids to become a new therapeutic focus of attention. Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors which include CB1, predominantly expressed in the brain and CB2 which is primarily found in the cells of the immune system. Despite the addictive properties of cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases such as anorexia, pain, inflammation, obesity, cardiovascular disorders, neurodegenerative diseases, cancer, gastrointestinal diseases, hepatic disorders, skin related diseases, respiratory disorders like asthma and eye diseases like glaucoma have suggested cannabinoid agonists/ antagonists/ cannabinoids related compounds as potential treatment options.  Developments of new specific ligands for the cannabinoid receptors are now underway and it needs to be seen, if in future, they can prove to be a boon for the medical world. The paper reviews the current understanding of the cannabinoid receptors, their ligands and their possible role in various diseases supported by preclinical and clinical studies.


Cannabinoids, cannabinoid receptors, clinical practice

Full Text:



Hiley CR. Endocannabinoids and the Heart. J Cardiovasc Pharmacol 2009;53(4):267-76.

Rang HP, Dale MM, Ritter JM, Flower RJ. Cannabinoids. In: Rang HP, Dale MM, Ritter JM, Flower RJ, eds. Rang and Dale’s Pharmacology 6th edition. Philadelphia: Churchill Livingstone Elsevier; 2007:248-55.

Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmaco Rev 2002;54:161-202.

De Petrocellis L, Cascio MG, Di Marzo V. The endocannabinoid system: a general view and latest additions. Br J Pharmacol 2004;141:765-74.

O’Sullivan S. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 2007;152:576-82.

Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 2005;310:329-32.

Seely KA, Prather PL, James LP, Moran JH. Marijuana based drugs: Innovative therapeutics or designer drugs of Abuse? Mol Interv 2011;11(1):36-51.

Pacher P, Batkai S and Kunos G. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacol Rev 2006;58(3):389-462.

Gonsiorek W, Lunn C, Fan X, Narula S, Lundell D, Hipkin RW. Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Mol Pharmacol 2000;57:1045-50.

Goparaju SK, Ueda N, Yamaguchi H, Yamamoto S. Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand. FEBS Lett 1998;422:69-73.

Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 2002;99:10819-24.

Dinh TP, Freund TF, Piomelli D. A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. Chem Phys Lipids 2002;121:49.

Witkamp RF. Current and future drug targets in weight management. Pharm Res 2011;28:1792-818.

Grant I, Cahn BR. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges. Clin Neurosci Res 2005;5(2-4):185-99.

Kogan NM, Mechoulam R. Cannabinoids in health and disease. Dialogues Clin Neurosci 2007;9:413-30.

Tramer MR, Campbell FA, Reynolds JM, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001;323:16-21.

Cluny NL, Vemuri VK, Chambers AP, Limebeer CL, Bedard H, Wood JT et al. A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents. Br J Pharmacol 2010;161:629-42.

Witkamp RF. Current and future drug targets in weight management. Pharm Res 2011;28:1792-818.

Cabral GA and Thomas LG. Cannabinoids as therapeutic agents for ablating neuroinflammatory disease. Endocr Metab Immune Disord Drug Targets 2008;8(3):159-72.

Pacher P, Batkai S, Kunos G. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacol Rev 2006;58(3):389-462.

Benito C, Romero JP, Tolon RM, Clemente D, Docagne F, Hillard CJ et al. Cannabinoid CB1 and CB2 Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis. J Neurosci 2007;27(9):2396-402.

Scotter EL, Abood ME, Glass M. The endocannabinoid system as a target for the treatment of neurodegenerative disease. Br J Pharmacol 2010;160:480-98.

Sheng WS, Hu S, Min X, Cabral GA, Lokensgard JR, Peterson PK. Synthetic cannabinoid WIN55, 212–212 inhibits generation of inflammatory mediators by IL-1β-stimulated human astrocytes. Glia 2005;49:211-9.

Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Makriyannis A et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J 2001;15(2):300-2.

Ligresti A, Cascio MG, Pryce G, Kulasegram S, Beletskaya I, Petrocellis LD. New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis. Br J Pharmacol 2006;147:83-91.

Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem 2009;1(7):1333-49.

Zajicek JP, Wright DE, Vickery PJ, Ingram WM, Reilly SM et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 2005;76:1664-9.

Greenberg HS, Werness SA, Pugh JE, Andrus RO, Anderson DJ, Domino EF. Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers. Clin Pharmacol Ther 1994;55(3):324-8.

Gerdeman G, Lovinger DM. CB1 Cannabinoid Receptor Inhibits Synaptic Release of Glutamate in Rat Dorsolateral Striatum. J Neurophysiol 2001;85:468-71.

Brotchie JM. CB1 cannabinoid receptor signaling in Parkinson's disease. Curr Opin Pharmacol 2003;3:54-61.

Eubanks LM, Rogers CJ, Beuscher AE, Koob GF, Olson AJ, Dickerson TJ et al. A molecular link between the active component of marijuana and Alzheimer's disease pathology. Mol Pharm 2006;3:773-7.

Ehrhart J, Obregon D, Mori T, Hou H, Sun N, Bai Y et al. Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J Neuroinflammation 2005;2:29.

Sharma HL, Sharma KK. Antipsychotic drugs. In: Sharma HL, Sharma KK, eds. Principles of Pharmacology 2nd edition. Hyderabad: Paras Medical Publisher; 2011:451-60.

Ujike H, Morita Y. New perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia. J Pharmacol Sci 2004;96:376-81.

Turner WM, Tsuang MT. Impact of Substance Abuse on the Course and Outcome of Schizophrenia. Schizophr Bull 1990;16(1):87-95.

Johns A. Psychiatric effects of cannabis. Br J Pharmacol 2001;178:116-22.

D’Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu Y et al. The Psychotomimetic Effects of Intravenous Delta-9- Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis. Neuropharmacology 2004;29:1558-72.

Basu D, Malhotra A, Varma VK.Cannabis related psychiatric syndromes: A selective review. Indian J Psychiat 1994;36(3):121-8.

Giuffrida A, Leweke FM, Gerth CW, Schreiber D, Koethe D, Faulhaber J et al. Cerebrospinal Anandamide Levels are Elevated in Acute Schizophrenia and are Inversely Correlated with Psychotic symptoms. Neuropharmacology 2004;29:2108-14.

De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V. Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis 2003;2:5.

Marco EM, Gutierrez MSG, Silva FJB, Moreira FA, Guimaraes F, Manzanares J. Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects. Front Behav Neurosci 2011;5:63.

Haller J, Bakos N, Szirmay M, Ledent C, Freund TF. The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety. Eur J Neurosci 2002;16(7):1395.

Gaal LV, Sunyer XP, Despres JP, McCarthy C, Scheen A. Efficacy and Safety of Rimonabant for Improvement of Multiple Cardiometabolic Risk Factors in Overweight/Obese Patients. Pooled 1-year data from the Rimonabant in Obesity (RIO) program. Diabetes Care 2008;31 Suppl 2:S229-40.

Martin WJ, Hohmann AG, Walker JM. Suppression of Noxious Stimulus-Evoked Activity in the Ventral Posterolateral Nucleus of the Thalamus by a Cannabinoid Agonist: Correlation between Electrophysiological and Antinociceptive Effects. J Neurosci 1996;16(20):6601-11.

Bushlin I, Rozenfeld R and Devi LA. Cannabinoid-opioid interactions during neuropathic pain and analgesia. Curr Opin Pharmacol 2010;10(1):80-6.

Iskedjian M, Bereza B, Gordon A, Piwko C, Einarson TR. Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain. Curr Med Res Opin 2007;23:17-24.

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

Batkai S, Pacher P, Hyiaman DO, Radaeva S, Liu J, White JH. Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension. Circulation 2004;110(14):1996-2002.

Liu J, Gao B, Mirshahi F, Sanyal AJ, Khanolkar AD, Makriyannis A. Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 2000;346:835-40.

Gebremedhin D, Lange AR, Campbell WB, Hillard CJ, Harder DR. Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am J Physiol 1999;276(6 Pt 2):H2085-93.

Lake KD, Martin BR, Kunos G, Varga K. Cardiovascular Effects of Anandamide in Anesthetized and Conscious Normotensive and Hypertensive Rats. Hypertension 1997;29:1204-10.

Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Huestis MA. The cannabinoid CB1 receptor antagonist rimonabant attenuates the hypotensive effect of smoked marijuana in male smokers. Am Heart J 2006;151(3):754.e1-754.e5.

Rajesh M, Mukhopadhyay P, Bátkai S, Haskó G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Pacher P. CB2-receptor stimulation attenuates TNF-a-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol 2007;293:H2210-8.

Filippo CD, Rossi F, Rossi S, D’Amico M. Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia-reperfusion injury: involvement of cytokine/chemokines and PMN. J Leukoc Biol 2004;75:453-9.

Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Drel VR et al. Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Heart Circ Physiol 2007;293(1):H610-9.

Bifulco M, Laezza C, Pisanti S, Gazzerro P. Cannabinoids and cancer: pros and cons of an antitumor strategy. Br J Pharmacol 2006;148:123-35.

Sanchez C, de Ceballos ML, del Pulgar TG, Rueda D,Corbacho C, Velasco G, Galve-roperh I, Huffman JW, Ramon YCS and Guzman M. Inhibition of glioma growth in vivo by selective activation of the cb(2) cannabinoid receptor. Cancer Res 2001;61:5784-9.

Maccarrone M, Lorenzon T, Bari M, Melino G, Finazzi-Agro A. Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J Biol Chem 2000;275(41):31938-45.

De Petrocellis L, Melck D, Palmisano A, Bisogno T, Laezza C, Bifulco M and Dimarzo V. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci U.S.A 1998;95:8375-80.

Mckallip RJ, Nagarkatti M and Nagarkatti PS. Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol 2005;174:3281-9.

Hamelers IHL, Vanschaik RFMA, Sussenback JS and Steenbergh PH. 17b-Estradiol responsiveness of MCF-7 laboratory strains is dependent on an autocrine signal activating the IGF type I receptor. Cancer Cell Int 2003;3:10-20.

Melck D, De petrocellis L, Orlando P, Bisogno T, Laezza C, Bifulco M and Dima rzo V. Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology 2000;141:118-26.

Patsos HA, Hicks DJ, Dobson RR, Greenhough A, Woodman N, Lane JD et al. The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: A possible role for cyclooxygenase 2. Gut 2005;54:1741-50.

Carracedo A, Gironella M, Lorente M, Garcia S, Guzman M, Velasco M et al. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res 2006;66:6748-55.

Sarfaraz S, Afaq F, Adhami VM, Malik A, Mukhtar H. Cannabinoid receptor agonist-induced apoptosis of human prostate cancer cells LNCaP proceeds through sustained activation of ERK1/2 leading to G1 cell cycle arrest. J Biol Chem 2006;281:39480-91.

Mallat A, Lotersztajn S. Endocannabinoids and Their Receptors in the Liver. Am J Physiol Gastrointest Liver Physiol 2008;294:G9-G12.

Cluny NL, Vemuri VK, Chambers AP, Limebeer CL, Bedard H, Wood JT et al. A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents. Br J Pharmacol 2010;161:629-42.

Tam J, Vemuri VK, Liu J, Batkai S, Mukhopadhyay B, Godlewski G et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest 2010;120:2953-66.

Mallat A, Clerc FT, Deveaux V, Manin S and Lotersztajn S. The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings. Br J Pharmacol 2011;163:1432-40.

Teixeira-Clerc F, Belot MP, Manin S, Deveaux V, Cadoudal T, Chobert MN et al. Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration. J Hepatology 2010;52(3):1046-59.

Munoz-Luque J, Ros J, Fernandez-Varo G, Tugues S, Morales-Ruiz M, Alvarez CE et al. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats. J Pharmacol Exp Ther 2008;324:475-83.

Massa F, Marsicano G, Hermann H, Cannich A, Monory K, Cravatt BF et al. The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest 2004;113:1202-9.

Kunos G, Pacher P. Cannabinoids cool the intestine. Nat Med 2004;10(7):678-9.

Pertwee RG. Cannabinoids and the gastrointestinal tract. Gut 2001;48:859-67.

Schicho R, Storr M. Alternative targets within the endocannabinoid system for future treatment of gastrointestinal diseases. Can J Gastroenterol 2011;25(7):377-83.

Beaumont H, Jensen J, Carlsson A, Ruth M, Lehmann A, Boeckxstaens G. Effect of delta 9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans. Br J Pharmacol 2009;156:153-62.

Grider JR, Mahavadi S, Li Y, Qiao LY, Kuemmerle JF, Murthy KS et al. Modulation of motor and sensory pathways of the peristaltic reflex by cannabinoids. Am J Physiol Gastrointest Liver Physiol 2009;297:G539-49.

Coutts AA, Pertwee RG. Inhibition by cannabinoid receptor agonists of acetylcholine release from the guinea-pig myenteric plexus. Br J Pharmacol 1997;121:1557-66.

Hinds NM, Ullrich K, Smid SD. Cannabinoid 1 (CB1) receptors coupled to cholinergic motorneurones inhibit neurogenic circular muscle contractility in the human colon. Br J Pharmacol 2006;148:191-9.

Wang A, Liao X, Xiong L, Peng S, Xiao Y, Liu S et al. The clinical overlap between functional dyspepsia and irritable bowel syndrome based on Rome III criteria. BMC Gastroenterol 2008;8:43.

Izzo AA, Fezza F, Capasso R, Bisogno T, Pinto L, Luvone T et al. Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br J Pharmacol 2001;134:563-70.

Guagnini F, Valenti M, Mukenge S, Matias I, Bianchetti A, Palo SD et al. Neural contractions in colonic strips from patients with diverticular disease: role of endocannabinoids and substance P. Gut 2006;55:946-53.

Adami M, Frati P, Bertini S, Narla AK, Brown DR, De Caro G et al. Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach. Br J Pharmacol 2002;135:1598-606.

Coruzzi G, Adami M, Coppelli G, Frati P, Soldani G. Inhibitory effect of the cannabinoid receptor agonist WIN 55,212-2 on pentagastrin-induced gastric acid secretion in the anaesthetized rat. Naunyn Schmiedebergs Arch Pharmacol 1999;360(6):715-8.

Biro T, Toth BI, Hasko G, Paus R and Pal P. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol 2009;30(8):411-20.

Akhmetshina A, et al. The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis. Arthritis Rheum 2009;60:1129-36.

Kamei J, Yoshikawa Y, Saitoh A. Effect of N-arachidonoyl-(2-methyl-4-hydroxyphenyl) amine (VDM11), an anandamide transporter inhibitor, on capsaicin-induced cough in mice. Cough 2006;2:2.

Jan TR, Farraj AK, Harkema JR, Kaminski NE. Attenuation of the ovalbumin-induced allergic airway response by cannabinoid treatment in A/J mice. Toxicol Appl Pharmacol 2003;188:24.

Pate DW, Jarvinen K, Urtti A, Jarho P, Jarvinen T. Ophthalmic arachidonylethanolamide decreases intraocular pressure in normotensive rabbits. Curr Eye Res 1995;14:791.

Straiker A, Stella N, Piomelli D, Mackie K, Karten HJ, Maguire G. Cannabinoid CB1 receptors and ligands in vertebrate retina: Localization and function of an endogenous signaling system. Proc Natl Acad Sci USA 1999;96(25):14565-70.

Straiker AJ, Maguire G, Mackie K, Lindsey J. Localization of cannabinoid CB1 receptors in the human anterior eye and retina. Investig Ophthalmol Vis Sci 1999;40:2442-8.

Song ZH, Slowey CA. Involvement of cannabinoid receptors in the intraocular pressure-lowering effects of WIN55212-2. J Pharmacol Exp Ther 2000;292:136-9.

Chien FY, Wang RF, Mittag TW, Podos SM. Effect of WIN 55212-2, a cannabinoid receptor agonist, on aqueous humor dynamics in monkeys. Arch Ophthalmol 2003;121:87-90.

Liou GI,El-Remessy EB, Ibrahim AS, Caldwell RB, Khalifa YM, Gunes A et al. Cannabidiol As a Putative Novel Therapy for Diabetic Retinopathy: A Postulated Mechanism of Action as an Entry Point for Biomarker-Guided Clinical Development. Curr Pharmacogenomics Person Med 2009;7(3):215-22.