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Section 2) Pharmacology.

Contrary to prior assertions by the DEA, the chemistry, toxicology, and pharmacology of marijuana has been subjected to extensive study and peer review, and have been well-characterized in scientific literature.

The effects of marijuana smoke on the lungs have been extensively studied. While marijuana smoke has more tar and carbon monoxide than tobacco smoke, in several other areas marijuana smoke is demonstrably less harmful than tobacco smoke, as in effect on small airway function, effect on bronchoalveolar lavage (BAL) macrophages, effect on phagocytic behavior or the respiratory burst of human pulmonary alveolar macrophages, and oxidant release of pulmonary alveolar macrophages. The tar in marijuana smoke can be reduced by filtration (such as with a waterpipe), and many gas-phase cytotoxins in the smoke are water soluble. The carbon monoxide levels produced by marijuana smoke are influenced by breathholding, which provides a diminishing return in contributions to plasma levels of the drug’s active ingredient and thus can be reduced by changes in smoking techniques. Efforts to promote safer marijuana use through the use of waterpipes and changes in smoking habits are impossible under existing, schedule 1 based, policy.

The absorption of THC from marijuana smoke is well characterized, and variables such as dosage stability, route of administration, bioavailability, puff volume, THC content, and breathholding time have all been investigated for their effect on absorption.

The pharmacology, toxicology, and chemistry of marijuana and its constituent chemicals have been published in scientific journals, and structure activity relationships for the cannabinoids have been established and correlated with animal tests. A stable pharmacological profile of the substance’s effects is available, as is epidemiological data on the incidence and prevalence of minor side effects. The substance has a well-established and extremely low toxicity. There are no cases of overdose on record.

This knowledge allows scientists to make valid assertions about marijuana on the basis of research on its separate constituent parts.

Prior hypotheses that marijuana’s mechanism of action involved cell membrane perturbation have been abandoned by the scientific community on two grounds, 1) extremely serious problems with method affect the validity of findings supporting the hypotheses, and 2) a receptor-based mechanism of action has been determined, localized, and characterized over the last seven years.

References Cited in Section 2.

Agurell, S., Hallden, M., et al., “Pharmacokinetics and Metabolism of D1-Tetrahydrocannabinol and other cannabinoids with emphasis on man.” Pharmacological Reviews. 38(1):21-43, 1986.

Azorlosa, J., Greenwald, M, Stitzer, M., “Marijuana Smoking: Effects of Varying Puff Volume and Breathhold Duration.” Journal of Pharmacology and Experimental Therapeutics 272:560-569. 1995.

Azorlosa, J., Heishman, S., et al., “Marijuana Smoking: Effect of Varying D9-Tetrahydrocannabinol Content and Number of Puffs.” Journal of Pharmacology and Experimental Therapeutics. 261:114-122. 1992.

Barbers, R.G., Evans, M.J., Gong, H., and Tashkin, D.P., “Enhanced Alveolar Monocytic Phagocyte (Macrophage) Proliferation in Tobacco and Marijuana Smokers.” Am Rev Respir Dis. 143:1092-1095, 1991.

Dewey, W., “Cannabinoid Pharmacology.” Pharmacological Reviews. 38(1):151-178, 1986.

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.

Hollister, L., “Peregrinations Among Drugs of Dependence: Nathan B. Eddy Memorial Award Lecture.” In: Problems of Drug Dependence, 1989. Proceedings of the 49th Annual Scientific Meeting, The Committee on Problems of Drug Dependence, Inc. Harris, L. (ed.), National Institute on Drug Abuse Research Monograph 95. (Washington, D.C.: U.S. Govt. Print. Off.,) 1990. pg. 36-43.

Huber, G., First, M., Grubner, O., “Marijuana and Tobacco Smoke Gas-Phase Cytotoxins.” Pharmacology Biochemistry & Behavior. 40:629-636, 1991.

Huestis, M., Sampson, A., et al., “Characterization of the absorption phase of marijuana smoking.” Clin Pharmacol Ther. 52:31-41, 1992.

Kemmerich, B., Rossing TH, Pennington, JE., “Comparative oxidative microbicidal activity of human blood monocytes and alveolar macrophages and activation by recombinant gamma interferon.” Am Rev. Respir. Dis. 136:266-70, 1987. Cited in Sherman et al. (1991).

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

Martin, B., Bloom, A., Howlett, A., Welch, S., “Cannabinoid Action in the Central Nervous System”. In: Problems of Drug Dependence, 1988. Proceedings of the 49th Annual Scientific Meeting, The Committee on Problems of Drug Dependence, Inc. Harris, L. (ed.), National Institute on Drug Abuse Research Monograph 90. (Washington, D.C.: U.S. Govt. Print. Off.,) 1988. pg.. 275-283.

Mathre, M.L., “A Survey on Disclosure of Marijuana Use to Health Care Professionals.” Journal of Psychoactive Drugs. 20(1):117-120, Jan-Mar 1988.

Mechoulam, R., “Chemistry of Cannabis.” Handbook Exp. Pharmacol. 55:119-134, 1981.

Mechoulam, R. “Marijuana chemistry” Science 168 (3936):1159-66. 1973.

Perez-Reyes, M., White, W.R., et al. “The Pharmacologic Effects of Daily Marijuana Smoking in Humans.” Pharmacology Biochemistry & Behavior. 40:691 – 694, 1991.

Polen, M., Sidney, S. et al., “Health Care Use by Frequent Marijuana Smokers Who Do Not Smoke Tobacco.” Western Journal of Medicine. 158:596-601, May 1993.

Razdan, R. “Structure-Activity Relationships in Cannabinoids.” Pharmacological Reviews. 38(1):75 – 149, 1986.

Sherman, M.P., Campbell, L.A., Gong, H., Roth, M.D., and Tashkin, D.P., “Antimicrobial and Respiratory Burst Characteristics of Pulmonary Alveolar Macrophages Recovered from Smokers of Marijuana Alone, Smokers of Tobacco Alone, Smokers of Marijuana and Tobacco, and Nonsmokers. Am Rev Respir Dis. 144:1351-1356, 1991.

Sherman, M.P., Roth, M.D., et al., “Marijuana Smoking, Pulmonary Function, and Lung Macrophage Oxidant Release.” Pharmacology Biochemistry & Behavior. 40:663-669, 1991.

Tashkin, D.P., “Is Frequent Marijuana Smoking Harmful to Health?” Western Journal of Medicine. 158:635-637, 1993.

Tashkin, D.P., “Pulmonary Complications of Smoked Substance Abuse.” Western Journal of Medicine; 152:525-530, May 1990

Tashkin, D.P., Coulson, V. et al., “Respiratory Symptoms and Lung Function in Habitual Heavy Smokers of Marijuana Alone, Smokers of Marijuana and Tobacco, Smokers of Tobacco Alone, and Nonsmokers.” Am Rev Respir Dis . 135:209-216, 1987

Tashkin, D.P., Gliederer, F., et al., “Effects of Varying Marijuana Smoking Profile on Deposition of Tar and Absorption of CO and Delta-9-THC.” Pharmacology Biochemistry & Behavior. 40:651-656, 1991.

Tashkin, D.P., Gliederer, F., et al. “Tar, CO, and D9-THC Delivery From the 1st and 2nd Halves of a Marijuana Cigarette” Pharmacology Biochemistry & Behavior. 40:657-661, 1991.

Tashkin, D.P., Simmons, M., Chang, P., Liu, H., Coulson, A., “Effect of Smoked Substance Abuse on Nonspecific Airway Hyperresponsiveness.” Am Rev Respir Dis , 147: 97-103, 1993.

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)

Wu, H., Wright, R., Catherine, S., & Tashkin, D.P., “Effects of Smoked Marijuana of Varying Potency on Ventilatory Drive and Metabolic Rate” Am Rev Respir Dis 146:716-721. 1992.

Wu, T.C., Tashkin, D.P., et al., “Pulmonary Hazards of Smoking Marijuana as Compared with Tobacco.” N. Engl. J. Med. 318:347-351; 1988.