The Endocannabinoid System
The long history of medicinal cannabis use posed a mystery to researchers, clinicians and patients: How could the compounds contained in one plant possess therapeutic properties for such a wide variety of human diseases and physical ailments?
This mystery began to unravel in 1964, when tetrahydrocannabinol, or THC, the main psychoactive chemical in cannabis was isolated and synthesized by Raphael Mechoulam and colleagues in Israel. Subsequently, in 1988, Allyn Howlett and colleagues discovered the cannabinoid receptor in the brain. This receptor called CB1was a precise match for the unique chemicals called cannabinoids found in the cannabis plant (phytocannabinoids). This initial discovery led to scientists hypothesizing that humans are "wired" for cannabis. The CB1receptors have been found in the brain in areas that control the coordination of movement, emotions, memory, reduction of pain, reward systems, and reproduction, yet are almost absent in the brain stem (which affects our vital functions such as breathing). It appears that cannabinoid receptors, which modulate other neurotransmitter function in a retrograde “on demand” fashion are present in far higher concentrations in the brain than any other receptor. While the CB1 receptors are primarily found in the central nervous system, a second type, CB2, discovered in 1993, are found primarily in the immune system, GI tract, liver, spleen, kidney, bones, heart, and peripheral nervous system. In fact, the CB2 receptor appears to be up-regulated whenever there is tissue pathology.
The first endogenous cannabinoid, arachidonylethanolamide or Anandamide (a Sanskrit word meaning blissful amide) was found in Dr. Mechoulam's labratory in Israel in 1992. This discovery built on the idea that when receptors were found there had to be an endogenous ligand that would be the key to its use. Back in Mechoulam's lab a second endocannabinoid called 2-arachidonylglycerol (2-AG) was discovered in 1995.
These discoveries of the cannabinoid receptors, endocannabinoids and the related enzymes make up what is now called the endocannabinoid system and it seems to be essential in most if not all physiological systems. The endocannabinoid system is essential to life and it relates messages that affect how we relax, eat, sleep, forget and protect as noted by the Italian researcher, Vincenzo Di Marzo.
To understand that this system of life exists within your body and brain is to understand the remakable and various therapeutic applications of cannabis.
Faculty Presentations on the Endocannabinoid System
Video - Cannabinoid System in Neuroprotection, Raphael Mechoulam, PhD - Professor at Hebrew University in Jerusalem, Dr. Mechoulam gives a brief history of Medical Cannabis, then describes the role of Cannabinoids as anti-inflammatory for arthritis, as neuroprotectant for brain injury and as a possible treatment for PTSD. Presented at the Third Clinical Conference on Cannabis Therapeutics, May, 2004 in Charlottesville, VA. Dr. Mechoulam first isolated THC in 1964.
Video - Holistic Biochemistry of Cannabinoids, by Robert Melamede, PhD -Dr. Melamede, Associate Professor and Biology Chairman, Biology Department, University of Colorado, explains how the Endocannabinoid System functions as a "Global Homeostatic Regulator", balancing several organ systems. He theorizes that, "Free Radicals are the Friction of Life. Endocannabinoids are the Oil of Life."
Centonze, D., Finazzi-Agro, A., Bernardi, G., & Maccarrone, M. (2007). The endocannabinoid system in targeting inflammatory neurodegenerative diseases. Trends in Pharmacological Science, 28(4) 180-187.
Di Marzo V. (2008). Targeting the endocannabinoid system: to enhance or reduce? Nat Rev. Drug Discov. 7:438-55.
Hajrasouliha AR, Tavakoli S, Ghasemi M, Jabehdar-Maralani P, Sadeghipour H, Ebrahimi F & Dehpour AR. (2008). Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart. European Journal of Pharmacology. 579:246-52.
Hiley CR. (2009). Endocannabinoids and the heart. Journal of Cardiovascular Pharmacology. 0(0):1-10.
Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G & Piomelli D. (2005). An endocannabinoid mechanism for stress-induced analgesia
Idris et al (2005). Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nature Medicine. 11:774-9.
Itai B. (2007). Regulation of skeletal remodeling by the endocannabinoid system. Annals of the New York Academy of Sciences.
Kress M & Kuner R. (2009). Mode of action of cannabinoids on nociceptive nerve endings. Exp. Brain Res. Doi 10.1007/s00221-009-1762-0
Lever IJ, Robinson M, Cibelli M, Paule C, Santha P, Yee L, Hunt SP, Cravatt BF, Elphick MR, Nagy I & Rice ASC. (2009). Localization of the endocannabinoid-degrading enzyme fatty acid amide hydrolase in rat dorsal root ganglion cells and its regulation after peripheral nerve injury. The Journal of Neuroscience. 29(12): 3766-80.
Mach, R., Montecucco, F. & Steffens, S. (2008). Cannabinoid receptors in acute and chronic complications of atherosclerosis. British Journal of Pharmacology. 153: 290-298.
Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgänsberger, Di Marzo V & Lutz B. (2002). The endogenous cannabinoid system controls extinction of aversive memories. Nature. 418:530-4.
Ofek et al (2006). Peripheral cannabinoid receptor, CB2, regulates bone mass. Proceedings of the National Academy of Sciences of the United States of America. 103:696-701.
Pacher P & Steffens S. (2009). The emerging role of the endocannabinoid system in cardiovascular disease. Semin Immunopathol. doi 10.1007/s00281-009-0145-8
Palazuelos, J., Davoust, N., Julien, B., Hatterer, E., Aguado, T., Mechoulam, R., Benito, C., Romero, J., Silva, A., Guzmán, M., Nataf, S. & Galve-Roperh, I. (2008). The CB2 cannabinoid receptor controls myeloid progenitor trafficking. The Journal of Biological Chemistry. 283(19): 13320-13329.
Panikashvile D, Mechoulam R, Beni SM, Alexandrovich A & Shohami E. (2005). CB1 cannabinoid receptors are involved in neuroprotection via NF-?B inhibition. Journal of Cerebral Blood Flow & Metabolism. 25: 477-84.
Pertwee, R. G. (2004). Receptors and pharmacodynamics:natural and synthetic cannabinoids and endocannabinoids. In G. W. Guy, B. A. Whittle & P. Robson (Eds.), Medicinal uses of cannabis and cannabinoids. (pp. 103-140). London: Pharmaceutical Press.
Pertwee, R. G. (2005). The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids. Aaps J, 7(3), E625-654.
Pertwee, R. G. (2006). Cannabinoid pharmacology: the first 66 years. Br J Pharmacol, 147 Suppl 1, S163-171.
Sagredo, O., Garcia-Arencibia, M., de Lago, E., Finette, S., Decio, A. & Fernandez-Ruiz, J. (2007). Cannabinoids and neuroprotection in basal ganglia disorders. Molecular Neurobiology. 36: 82-91.
Sarzani R. (2008). Endocannabinoids, blood pressure and the human heart. Journal of Neuroendocrinology. 20(Suppl.1):58-62.
Shouman B, Fontaine RH, Baud O, Schwendimann L, Keller M, et.al. (2006). Endocannabinoids potently protect the newborn brain against AMPA-kainate receptor-mediated excitotoxic damage. Br J Pharmacol., 148(4), 442-51.
Karanian DA, Brown QB, Makriyannis A, Kosten TA & Bahr BA. (2005). Dual modulationof endocannabinoid transport and fatty acid amide hydrolase protects against excitotoxicity. The Journal of Neuroscience. 25(34): 7813-20.
Nyilas R, Gregg LC, Mackie K, Watanabe M, Zimmer A, Hohmann AG & Katona I. (2009). Molecular architecture of endocannabinoid signaling at nociceptive synapses mediating analgesia. European Journal of Neuroscience. 29: 1964-78.