UTopiAH’s life expectancy and death rate are below the Marijuana states, which as of 2017, filled the top quintile state rankings. See Part 16. These parts contain the 2015 Drug Enforcement Agency’s response to a 2011 petition from the Governors of Washington and Rhode Island to legalize Marijuana, a DEA Schedule One Drug. . The letter is viewable at https://www.deadiversion.usdoj.gov/schedules/marijuana/Incoming_Letter_Department%20_HHS.pdf#search=marijuana.

Part 41 Marijuana Application Review of Published Clinical Studies March 19, 2015 Prepared by: U.S. Food and Drug Administration Center for Drug Evaluation and Research (FDA/CDER) Controlled Substance Staff (CSS)

[Continued from Part 40]

[See Part 39]

The Medical Application of Marijuana: A Review of Published Clinical Studies March 19, 2015 Prepared by: U.S. Food and Drug Administration Center for Drug Evaluation and Research (FDA/CDER) Controlled Substance Staff (CSS).

The Medical Application of Marijuana: A Review of Published Clinical Studies

Table of Contents
1. Introduction………………………………….… 7

2. Methods………………………………………….. 9

2.1 Define the Objective of the Review……….-……………………………..9

2.2 Define “Marijuana” ……………………….9

2.3 Define “Adequate and Well-Controlled Clinical Studies”………10

2.4 Search Medical Literature Databases and Identify Relevant Studies …………………………….10

2.5 Review and Analyze Qualifying Clinical Studies………………….13

[See Part 40]

3. Results and Discussion……………..……. 13

3.1 Neuropathic Pain…………………………13

3.1.1 Neuropathic Pain Associated with HIV-Sensory Neuropathy ……….13

3.1.2 Central and Peripheral Neuropathic Pain……………………………………17

3.2 Appetite Stimulation in HIV …………21

3.3 Spasticity in Multiple Sclerosis…………………………………………..24

3.4 Asthma………………………………………25

3.5 Glaucoma …………………………………..27

3.6 Conclusions………………………………..27

3.6.1 Conclusions for Chronic Neuropathic Pain…………………………….28

3.6.2 Conclusions for Appetite Stimulation in HIV …………………………28

3.6.3 Conclusions for Spasticity in M$………………………………………….28

3.6.4 Conclusions for Asthma……………………,………………………………..28

3.6.5 Conclusions for Glaucoma …………….29

3.7 Design Challenges for Future Studies ………………………………….29

3.7.1 Sample Size…………………………………..29·

3.7.2 Marijuana Dose Standardization …………………………………………..30

3.7.3 Acute vs. Chronic Therapeutic Marijuana Use ……………………….31

3.7.4 Smoking as a Route of Administration …………………………………..32

3.7.5 Difficulty in Blinding of Drug Conditions ……………………………..32

3.7.6 Prior Marijuana Experience ……………33

3.7.7 Inclusion and Exclusion Criteria…………………………………………..34

3.7.8 Number of Female Subjects……………35

Appendix (Tables)…………………………….. 39  [Excluded]

4. References
5. Marijuana and Medicine: Assessing the Science Base. Washington, D.C.: National Academy Press.

Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Sacchetti. McCune JM, and Schambelan M. 2003. Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo­ controlled clinical trial. Annals of Internal Medicine 139 (4): 258-266.

Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, and Petersen KL. 2007. Cannabis in painful HIV­ associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 68 (7): 515-521.

Appendino G, Chianese G, Taglialatela-Scafati 0. 2011. Cannabinoids: occurrence and medicinal chemistry. Curr Med Chem. 18(7):I085-99.

Barrett RL, Wiley JL, Balster RL, and Martin BR. 1995. Pharmacological specificity of /19-tetrahydrocannabinol discrimination in rats. Psychopharmacology 118(4): 419-424.

Chait LD, and Pierri J. 1989. Some physical characteristics of NIDA marijuana cigarettes. Addictive Behaviors 14 (1 ): 61-67.

Chang AE, Shiling DJ, Stillman RC, Godlberg NH, Seipp CA, Barofsky I, Simon RM, and Rosenberg SA. 1979. Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. Annals of Internal Medicine 91: 819-824.

Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, and Gouaux B.2012. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. Canadian Medical Association Journal 184 (10): 1143-1150.

Crane NA, Schuster RM, Fusar-Poli P, and Gonzalez R. 2012. Effects of Cannabis on Neurocognitive Functioning: Recent Advances, Neurodevelopmental Influences, and Sex Differences. Neuropsychology Review .

Crawford WJ, and Merritt JC. 1979. Effects of tetrahydrocannabinol on arterial and intraocular hypertension. International Journal of Clinical Pharmacology and biopharmacy 17 (5): 191-196.

Ellis RJ, ToperoffW, Vaida F, Van Den Brande G, Gonzales J, Gouaux B, Bentley H, and Atkinson JH. 2009. Smoked medicinal cannabis for

[Food and Drug Administration 36 March 19 2015

neuropathic pain in HlV: a randomized, crossover clinical trial. Neuropsychopharmacology 34 (3): 672-680.

Flom MC, Adams AJ, and Jones RT. 1975. Marijuana smoking and reduced pressure in human eyes: drug action or epiphenomenon? Investigative Ophthalmology 14(1): 52-55.

Foltin RW, Brady JV; and Fischamn MW. 1986. Behavioral analysis of marijuana effects on food intake in humans. Pharmacology Biochemistry and Behavior 25: 577-582.

Foltin RW, Fischman MW, and Byrne MF. 1988. Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite 11:1-14.

Greenberg HS, Wemess SA, Pugh JE, Andrus RO, Anderson DJ, and Domino EF. 1994. Short-term effects of smoking marijuana on balance in patients with

multiple sclerosis and normal volunteers. Clinical Pharmacology and Therapeutics 55 (3): 324-328.

Greenwald MK and Stitzer ML. 2000. Antinociceptive, subjective, and behavioral effects of smoked marijuana in humans. Drug and Alcohol Dependence 59: 261-275.

Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, and Foltin RW. 2007. Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep. Journal of Acquired Immune Deficiency Syndromes (1999) 45 (5): 545-554.

Haney M, Rabkin J, Gunderson E, and Foltin RW. 2005. Dronabinol and marijuana in HIV(+) marijuana smokers: acute effects on caloric intake and mood. Psychopharmacology 181 (1): 170-178.

Hill SY, Schwin R, Goodwin DW, and Powell BJ. 1974. Marihuana and pain. Journal of Pharmacology and Experimental Therapeutics 188(2): 415­ 418.

Jampel H. 2010. American glaucoma society position statement: marijuana and the treatment of glaucoma. Journal of Glaucoma 19 (2): 75-76.

Merritt JC, Crawford WJ, Alexander PC, Anduze AL, and Gelbart SS. 1980. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 87 (3): 222-228.

Milstein SL, MacCannell KL, Karr GW, and ClarkS. 1974. Marijuana produced changes in cutaneous sensitivity and affect: users and non-users. Pharmacology Biochemistry and Behavior 2:367-374.

[FDA                page 37  Marach]

Milstein SL, MacCannell K, Karr G, and ClarkS. 1975. Marijuana-produced changes in pain tolerance: Experiences and non-experienced subjects. Int. Pharmacopsychiat 10: 177-182.

Naftali T, Schleider LB, Dotan I, Lansky EP, Benjaminov FS, and KonikoffFM. 2013. Cannabis induces a clinical response in patients with Crohn’s disease: A prospective placebo-controlled study. Clinical Gastroenterology and Hepatology II: 1276-1280.

Russo E, Mathre ML, Byrne A, Velin R, Bach PJ, Sanchez-Ramos J, and Kirlin KA. 2002. Chronic Cannabis Use in the Compassionate Investigational New Drug Program: An Examination of Benefits and Adverse Effects of Legal Clinical Cannabis. Journal of Cannabis Therapeutics 2 (1): 3-57.

Soderpalm AHV, Schuster A, and de Wit H. 2001. Antiemetic efficacy of smoked marijuana subjective and behavioral effects on nausea induced by syrup of ipecac. Pharmacology Biochemistry and Behavior 69: 343-350.

Tashkin DP, Gliederer F, Rose J, Chang P, Hui KK, Yu JL, and Wu TC. 1991. Tar, CO and delta 9-THC delivery from the 1st and 2nd halves of a marijuana cigarette. Pharmacology Biochemistry and Behavior 40 (3): 657-661.

Tashkin DP, Shapiro BJ, Lee YE, Harper CE. 1975. Effects of smoked marijuana in experimentally induced asthma. American Review of Respiratory Disease 112: 377-386.

Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, Bentley H, Gouaux B, and Abramson I. 2007. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 107 (5): 785-796.

Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, Bennett GJ, and Collet JP. 2010. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. Canadian Medical Association Journall82 (14): E694-E701.

Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, and Fishman S. 2008. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 9 (6): 506-521.

Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, and Donaghe H. 2013. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 14(2):136-48.

[FDA    page 38  March]

Appendix Tables pages 39-49 [Excluded]

https://www.deadiversion.usdoj.gov/schedules/marijuana/Incoming_Letter_Department%20_HHS.pdf#search=marijuana

Addiction Research Center Inventory (ARCI)

adenosine triphosphate (ATP)

adrenocorticotropic hormone (ACTH),

biologics license application (BLA)

cannabinoid receptor type 1 (CB1)

cannabichromene (CBC)

cannabidiol (CBD)

cannabinol (CBN)

Conditioned place preference (CPP)

Controlled Substances Act (CSA)

Controlled Substance Staff, Center for Drug Evaluation and Research, FDA

delta 9-THC

Diagnostic and Statistical Manual (DSM-5)

Drug Abuse Warning Network (DAWN) SAMHSA

Emergency Department [ED]

FDA Center for Drug Evaluation and Research

Food and Drug Administration (FDA)

U.S. Department of Health and Human Services (HHS)

International Classification of Diseases (ICD-10

[Investigational new drug] IND

IQ Intelligence Quotient

Monitoring the Future (MTF) survey

National Institutes of Health’s National Institute on Drug Abuse (NIH/NIDA)

[National Survey on Drug Use and Health] (NSDUH)

[new drug application] NDA

NMDA antagonists; N-Methyl-D-aspartate -anesthetics that antagonize, or inhibit the action

Substance Abuse and Mental Health Services Administration (SAMHSA)

System to Retrieve Information from, Drug Evidence (STRIDE) DEA’s

tetrahydrocannabinol (THC)

Treatment Episode Data Set (TEDS) 2011

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