Section 3) Scientific knowledge on marijuana's mechanism of action.

Most popular assertions about marijuana's affect on the human body and brain are based on what is now viewed by the scientific community as a discredited hypothesis.

The discovery of a cannabinoid receptor system in the human body began a scientific revolution that radically altered contemporary knowledge about marijuana's effects on the body and brain.

The cannabinoid receptor system accounts for almost all of marijuana's characteristic effects, as well as the substance's low toxicity.

The receptor has also been cloned, an endogenous ligand has been identified, and an antagonist has also been discovered. A structure-activity relationship for the ligand has also been established.

The cannabinoid receptor system responds to continued exposure to marijuana by reducing the number of receptors available for binding; the discovery of this tolerance mechanism for marijuana discredits the prior hypothesis that tolerance to marijuana resulted from a desensitization of brain cells, and supports the assertion that tolerance to marijuana does not contribute to a dangerous dependence liability.

The existence of the cannabinoid receptor system has clarified concern over marijuana's possible effects on the immune system, giving credence to claims that such effects pose no threat to human health.

The existence of the receptor system explains why marijuana has never been proven to cause brain damage.

The discovery of the receptor system and the resulting research provides great promise for development of a new class of effective pharmaceutical drugs, and may enable scientists to learn more about the chemistry of emotions.

These new research findings contradict many of the DEA's on-record findings of fact about marijuana, findings which have been used in the past to block reconsideration of marijuana's scheduling status.

References Cited in Section 3.

Abood, M.E., and Martin, B.R., "Neurobiology of Marijuana Abuse," Trends in Pharmacological Sciences 13:201-206, 1992

Childers, S.R., Sexton, T., Roy, M.B., "Effects of Anandamide on Cannabinoid Receptors in Rat Brain Membranes." Biochemical Pharmacology. 47:711-715, 1994.

Compton, D.R., Rice, K.C., et al., "Cannabinoid Structure-Activity Relationships: Correlation of Receptor Binding and in Vivo Activities." Journal of Pharmacology and Experimental Therapeutics. 265:218-226. 1993.

Devane, W.A., Dysarz, F.A., et al., "Determination and Characterization of a Cannabinoid Receptor in Rat Brain." Molecular Pharmacology 34:605-613.

Devane, W.A., Hanus, L, et al., "Isolation and structure of a brain constituent that binds to the cannabinoid receptor." Science. 258:1946-1949, 1992.

Di Marzo, V., Fontana, A., et al., "Formation and inactivation of endogenous cannabinoid anandamide in central neurons." Nature. 372:686-691. 1994.

Fride, E., Barg, J., et al., "Low Doses of Anandamides Inhibit Pharmacological Effects of D9-Tetrahydrocannabinol." Journal of Pharmacology and Experimental Therapeutics. 272:699-707, 1995.

Harvey, D.J., Paton, W.D.M., Marihuana '84, "Final Summary." In Harvey, D.J., Paton, W.D.M., Nahas, G. (eds.), Marihuana '84: Proceedings of the Oxford Symposium on Cannabis. (Washington, D.C.: IRL Press,) 1985. (Satellite Symposium on Cannabis, 3rd, 1984, Oxford, England; International Congress of Pharmacology, 9th, 1984, London, England.) pg. 734.

Herkenham, M., "Cannabinoid Receptor Localization in Brain: Relationship to Motor and Reward Systems," P.W. Kalivas and H.H. Samson (eds.), The Neurobiology of Drug and Alcohol Addiction, Annals of the American Academy of Sciences. 654:19-32, 1992.

Herkenham, M., Lynn, A.B., et al., "Cannabinoid Receptor Localization in Brain," Proceedings of the National Academy of Sciences, 87:1932-1936, 1990.

Hollister, L.E. "Marijuana and Immunity." Journal of Psychoactive Drugs. Vol. 20(1):3-8, 1988.

Hollister, L.E. "Health Aspects of Cannabis", Pharmacological Reviews, 38(1):1-20, 1986.

Howlett, A.C., Bidaut-Russell, M, Devane, W., Melvin, L., Johnsons, M., & Herkenham, M., "The Cannabinoid Receptor: Biochemical, Anatomical, and Behavioral Characterization." Trends in Neuroscience 13:10, 420-423, 1990.

Johnson, M.R., Rice, K.C., Howlett, A., Melvin, L.S., and Herkenham, M. "The Cannabinoid Receptor-Pharmacologic Identification, Anatomical Localization and Cloning." In: Problems of Drug Dependence, 1991. Proceedings of the 53th Annual Scientific Meeting, The Committee on Problems of Drug Dependence, Inc. Harris, L. (ed.), National Institute on Drug Abuse Research Monograph 119. (Washington, D.C.: U.S. Govt. Print. Off.,) 1992. pg. 86-90.

Koob, G.B. and Bloom, F.E., "Cellular and molecular mechanisms of drug dependence." Science, 242:715-723, 1988. Cited in Oviedo, et al (1993) and in Pratt (1992).

Lichtman, A.H., Martin, B.R., "Spinal and Supraspinal Components of Cannabinoid-Induced Antinociception." Journal of Pharmacology and Experimental Therapeutics. 258:517-523, 1991.

Lynn, A.B., and Herkenham, M., "Localization of Cannabinoid Receptors and Nonsaturable High-Density Cannabinoid Binding Sites in Peripheral Tissues of the Rat: Implications for Receptor-Mediated Immune Modulation by Cannabinoids" Journal of Pharmacology and Experimental Therapeutics, 268(3):1612-1623, 1993.

Martin, B.R., "Marijuana." In Bloom, F., Kupfer, D. (eds.), Psychopharmacology: The Fourth Generation of Progress, (New York: Raven Press,) 1995. pg. 1757-1765.

Martin, B.R. "Cellular Effects of Cannabinoids." Pharmacological Reviews 38(1):45-74, 1986.

Matsuda, L., Lolait, S., et al., "Structure of a cannabinoid receptor and functional expression of the cloned cDNA." Nature 346:561-564, 1990.

Mechoulam, R., "Interview with Professor Raphael Mechoulam, Codiscoverer of THC", The International Journal of the Addictions, 21(4&5), 579-587, 1986. (The interview was conducted by Stanley Einstein in Jerusalem on January 14, 1985.)

Mechoulam, R., Devane, W.A., Breuer, A., and Zahalka, J., "A Random Walk Through A Cannabis Field", Pharmacology, Biochemistry, & Behavior, 40:461-464, 1991.

Melvin, L.S., Milne, G.M., et al., "Structure-Activity Relationships for Cannabinoid Receptor-Binding and Analgesic Activity: Studies of Bicyclic Cannabinoid Analogs." Molecular Pharmacology. 44: 1008-1015, 1993.

Nahas, G. (1976) Keep Off The Grass: A Scientist's Documented Account of Marijuana's Destructive Effects. (New York: Readers Digest Press,) 1976.

Nahas, G. Marihuana in Science and Medicine. (New York: Raven Press,) 1984.

Nahas, G., Frick, H.C., Brill, H., Drug Abuse in the Modern World: A Perspective for the Eighties: An International Symposium Held at the College of Physicians and Surgeons of Columbia University. (New York: Pergamon Press,) 1981.

Nahas, G., Keep Off The Grass -- 5th rev. and enl. ed. (Middlebury, VT: P.S. Eriksson,) 1990.

Nahas, G., Marihuana-Deceptive Weed. (New York: Raven Press,) 1973.

Nahas, G.G., Sucia-Foca, N., et al., "Inhibition of cellular mediated immunity in marijuana smokers." Science. 183:419-420, 1974. Cited in Lynn and Herkenham (1993).

Oviedo, A., Glowa, J, and Herkenham, M., "Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study." Brain Research, 616:293-302, 1993.

Paton, W.D.M., "Concluding Summary". In Nahas, G., Paton, W.D.M., Braude, M.C. (eds.), Marihuana: Biological Effects: Analysis, Metabolism, Cellular Responses, Reproduction, and Brain: Proceedings of the Satellite Symposium on Marihuana, 7th International Congress Of Pharmacology. (New York: Pergamon Press,) 1979. (International Congress of Pharmacology, 7th, 1978, Paris. Also known as Rheims Conference.) pg. 736.

Paton, W.D.M., "Concluding Summary." In Nahas, G., Paton, W.D.M., Idanpaan-Heikkila, J. (eds.), Marihuana: Chemistry, Biochemistry, and Cellular Effects. (New York: Springer-Verlag,) 1976. (Proceedings of the Satellite Symposium on Marihuana of the 6th International Congress of Pharmacology held July 26-27, 1975 in Helinski, Finland.) pg. 552.

Pertwee, R.G., "The Evidence for the Existence of Cannabinoid Receptors." General Pharmacology. 29(4):811-824, 1993.

Pertwee, R.G., "The Central Neuropharmacology of Psychotropic Cannabinoids." Pharmac. Ther. 36:189-261, 1988.

Pratt, J.A., "Psychotropic Drug Tolerance and Dependence: Common Underlying Mechanisms?" In Pratt, J.A. (ed.) The Biological Bases of Drug Tolerance and Dependence. (London: Academic Press,) 1991.

Prescott, W.R., Gold, L.H., Martin, B.R., "Evidence for separate neuronal mechanisms for the discriminative stimulus and catalepsy induced by D9-THC in the rat." Psychopharmacology. 107:117-124, 1992.

Richardson, S., Mirasedeghi, S., Lynn, A., Johnson, M.R., Melvin, L.S., Herkenham, M., and Rice, K., "Synthetic and Biological Studies of Potential Affinity Ligands for the Cannabinoid Receptor Based on CP-55,244." In: Problems of Drug Dependence, 1990. Proceedings of the 52th Annual Scientific Meeting, The Committee on Problems of Drug Dependence, Inc. Harris, L. (ed.), National Institute on Drug Abuse Research Monograph 105. (Washington, D.C.: U.S. Govt. Print. Off.,) 1990. pg. 140 - 146.

Rinaldi-Carmona, M., Barth, F., et al., "SR141716A, a potent and selective antagonist of the brain cannabinoid receptor." FEBS Letters 350:240 - 244, 1994.

Rodriguez De Foncesa, F., Gorriti, M., et al., "Downregulation of Rat Brain Cannabinoid Binding Sites After Chronic D9-Tetrahydrocannabinol Treatment." Pharmacology, Biochemistry, and Behavior. 47:33-40, 1994.

Smith, P.B., Compton, D.R., et al., "The Pharmacological Activity of Anandamide, a Putative Endogenous Cannabinoid, in Mice." Journal of Pharmacology and Experimental Therapeutics. 270:219-227, 1994.

Smith, P.B., Welch, S.P., Martin, B.R., "Interactions between D9-Tetrahydrocannabinol and Kappa Opiods in Mice." Journal of Pharmacology and Experimental Therapeutics. 268:1381-1387, 1994.

Thomas, B., Compton, D., Martin, N., "Characterization of the Lipophilicity of Natural and Synthetic Analogs of D9-Tetrahydrocannabinol and Its Relationships to Pharmacological Potency." Journal of Pharmacology and Experimental Therapeutics . 255(2):624-630, 1990.

Thomas, B., Wie, X., Martin, B., "Characterization and Autoradiographic Localization of the Cannabinoid Binding Site in Rat Brain Using [3H]11-OH-D9-THC-DMH." Journal of Pharmacology and Experimental Therapeutics . 263(3):1383-1390, 1992

U.S. Department of Health and Human Services, (1991) Drug Abuse and Drug Abuse Research, the Third Triennial Report to Congress From the Secretary, Department of Health and Human Services. (Washington, D.C.: U.S. Govt. Print. Off.,) 1991. (DHHS Publication No. (ADM)91-1704.) pg. 138 - 140.

U.S. Department of Justice, Drug Enforcement Administration, Docket No. 86-22. Schedules of Controlled Substances; Hearing on Petition to Reschedule Marijuana and its Components. 51 Fed. Reg. 22,946 (1986)

U.S. Department of Justice, Drug Enforcement Administration, Docket No. 86-22. Marijuana Scheduling Petition, Denial of Petition. 54 Fed. Reg. 53,787 (1989)

U.S. Department of Justice, Drug Enforcement Administration, Docket No. 86-22. Marijuana Scheduling Petition, Denial of Petition; Remand. 57 Fed. Reg. 10,499 (1992)

Wert, R.C., Raulin, M.L., "The Chronic Cerebral Effects of cannabis Use. I. Methodological Issues and Neurological Findings." International Journal of the Addictions, 21(6), 605-628, 1986.

Wert, R.C., Raulin, M.L., "The Chronic Cerebral Effects of cannabis Use. II. Psychological Findings and Conclusions." International Journal of the Addictions, 21(6), 629-642, 1986.