Lecture: Medical Marijuana Long term effects and interac ons with common medicines Neuropharamacology of the brain with cannabis

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1 Lecture: Medical Marijuana Long term effects and interac ons with common medicines Neuropharamacology of the brain with cannabis William Morrone, DO Robert Piccinini, DO

4 Endocannabinoids in Disease and Therapeutics Robert G.G. Piccinini, D.O., dfacn Exogenous Cannabinoids The plant Cannabis Sativa, the source of cannabis is native to central Asia In the 1830 s a physician serving the British Crown introduced to England Cannabis entered The Dispensatory of the United States of Americain Its primary use was for the alieviation of pain and spasticity In 1964 Raphael Mechoulam isolated delta-9- tetrahydrocannabinol and cannabidiol 1

5 Receptors and Signal Transduction Discovery of the u-receptor launched a search for cannabinoid receptors, however the search was stalled because of its nonspecific binding The cannabinoid receptor can activate different G protein subtypes. They are the most common GPCRs in the brain but are unevenly distributed. CB 1 is principal located in the nervous system. CB 2 is primarily associated with cells governing immune function: leukocytes, splenocytes and microglia. Endogenous Cannabinoids The first endogenous cannabinoid, anandamide (AEA) was discovered by Mechoulam in 1992 the discovery of 2-arachidonoylglycerol (2-AG) occurred shortly thereafter. Both AEA and 2-AG endocannabinoids are metabolites of arachidonic acid. They do not resemble THC but nonetheless fit the CB 1 and CB 2 binding pockets Within the central nervous system, the endocannabinoid system acts as a negative feedback mechanism to dampen synaptic release of classic neurotransmitters. 2

6 Embryology and Development The CB 1 receptors have been detected in mouse embryos as early as the second day of gestation. The endocannabinoid system organizes a broad array of developmental processes in the embryonic brain Once stem cells commit to neurogenesis, endocannabinoids regulate neuronal migration and synaptogenesis. 3

7 Neuroprotection Anti-inflammatory, antioxidant, and antispasmodic properties of THC and Cannabidiol MS, Huntington disease, ALS, Parkinson, Epilepsy Alzheimer Disease Schizophrenia Autonomic Function and Immunity Endocannabinoids and THC affect autonomic outflow through the peripheral and central nervous systems. Cannabinoids provide antihypertensive benefits in humans Sympathetic nerve terminals contain CB 1 Inflammation and Connective Tissues: Activation of CB 2 suppresses proinflammatory cytokines Apoptosis: CB 1 -mediated 4

Nociception and Pain Research on the effects of endocannabinoids has focused on the following four areas: 1. Peripheral terminal of nociceptors 2.

8 Nociception and Pain Research on the effects of endocannabinoids has focused on the following four areas: 1. Peripheral terminal of nociceptors 2. The Dorsal horn 3. The descending pain inhibitory pathway 4. Supratentorial sites Peripheral terminals of C-fiber nociceptors contain receptors for activators and sensitizers 5

9 Hunger and Feeding Marijuana-enhanced hunger and feeding is a behavior that teleologically begins in utero. The endocannabinoid system modulates cell metablism Biological Oscillators Cardiac Pulse Rate Thoracic respiration Gastrointestinal motility and peristalsis Enhancing the Endocannabinoid System Lifestyle modification Pharmaceutical approaches OMT 6

References McPartland, JM The Endocannabinoid System: An Osteopthic Perspective. JAOA October 1, 2008 vol 108 no 10 585-600 Mechoulam R. The pharmacohistory of Cannabis sativa.

New York: Appleton and Company; 1915 Fishbein M. Federal regulation of medicinal use of cannabis. JAMA. 1937; 108: 1543-1544 Okie S. Medical marijuana and the supreme Court.

10 References McPartland, JM The Endocannabinoid System: An Osteopthic Perspective. JAOA October 1, 2008 vol 108 no Mechoulam R. The pharmacohistory of Cannabis sativa. In: Mechoulam R,ed. Cannabinoids as Therapuetic Agents. Boca Raton,FLA CRC press 1986 Osler W. Mcrae T. The Principal and Praactice of Medicine. New York: Appleton and Company; 1915 Fishbein M. Federal regulation of medicinal use of cannabis. JAMA. 1937; 108: Okie S. Medical marijuana and the supreme Court. N Engl J Med. 2005; Glass M, Dragunow M, Faul RL Cannabinoid receptor in the human brain: a detailed anatonmical and qualitative autoradiographic study in the fetal neonatal and adult human brain. Neuroscience 1997;

The Endocannabinoid System

The Endocannabinoid System Think of this system as the wizard behind the curtain. It underlies all the other systems, including the Autonomic Nervous System. Overall it influences well-being and the perception