Doc, will you sign my medical marijuana card? Daniel W. Bowles, MD Fellow in Hematology/Medical Oncology General Internal Medicine i Grand Rounds September 21, 2010
Disclosures Skeptical about marijuana before researching this topic I serve on the State of Colorado MMAC
Why this topic? How many times have you been asked? What do you think about medical marijuana? Will you sign my card? I know this guy
Questions Does it help with symptoms, esp. nausea, anorexia, or pain? Is it better than our other meds? Will it make my patient s illness worse? What s the legal l situation ti in Colorado?
Outline Basics Timeline in history Discuss its role in symptom control Review effects on specific diseases Examine legal issues in Colorado
Basics: The Plant Cannabis sativa Highly adaptable 3-5 month life cycle Grows 15 cm/day Germinates within 6 days Requires little water Grows almost anywhere
Routes of administration Marijuana: Dried portions of the plant, esp. leaves and flowers Hashish: Resin from female flowers. Smash: Liquid concentrate of cannabis oil extracted from resin with solvents (acetone, gas, etc.) Hemp: Stalks and fibers of the plant. Contains <1% THC of recreational plants
Physiology Δ9-tetrahydrocannabinol (THC) Over 60 other known cannabinoids (cannabidiol-cbd) CR1:CNS, GI tract 9THC 11-hydroxy-THC CR2: peripheral, immune cells GABA, histamine, dopamine, p prostaglandins, opioids
Physiology CNS Low-grade euphoria Loss of inhibition Sensory changes Concentration changes Memory loss
History Native to temperate zones of Central Asia. One of the first plants cultivated by humans. Earliest recorded appearance of hemp in Taiwan 10,000-3,000 BC. Medicinal properties recognized 3000 BC, became a mainstay of Chinese medicine. Psychoactive effects recognized by 600 BC. Referenced in Taoism, Buddhism, the Vedas, the,,, Bible, the Koran.
Early History in North America 1606: Cannabis sativa first planted in Nova Scotia 1700 s: Hemp a mainstay of early American agriculture 1800s: Cannabis use not explicitly frowned upon
Modern History in North America 1920 s Harry Ainslinger and the Federal Bureau of Narcotics Linked with crime, promiscuity, etc. 1930 s s-1940s Marijuana Tax Act (1937) requires registration and taxes Dr. Woodward from the AMA opposes
Modern History in North America 1950-1960 s 1960 McCarthy and harsh penalties Hippies/counter culture 1970 s-1980 s Research into marijuana Renewed interest in medical uses
Medical Cannabis in the US 1750-1942: Present in pharmacies as antibiotic and analgesic 1850: US pharmacopoeia states myriad uses Late 1880s: Trend towards synthetics drugs 1942: Removed from pharmacopoeia 1967: All forms illegal by 1967 (US ratified a UN resolution) 1970: Made a schedule I substance 1970s-1980 s: interest in cannabinoids as therapy
Synthetic Cannabinoids in Medicine i Nabilone (Cesamet ) approved in 1985, marketed in 2006 Dronabinol (Marinol, 9-THC) approved in 1986 Levonantradol Sativex (THC and CBD). Approved in Canada
Do cannabinoids effectively relieve symptoms?
Colorado statistics as of December 31, 2009 Reported Condition Number of Patients Percent of Patients Reporting Condition Reporting Condition** Cachexia 700 2% Cancer 908 2% Glaucoma 382 1% HIV/AIDS 296 1% Muscle Spasms 12,077 29% Seizures 764 2% Severe Pain 37,912 92% Severe Nausea 6,696 16% http://www.cdphe.state.co.us/hs/medicalmarijuana/statistics.html
Cachexia (2%) Will cannabinoids help my patients gain or Will cannabinoids help my patients gain or maintain weight?
469 patients Megestrol acetate t 800 mg/d, oral dronabinol 2.5 mg twice a day, or both Multicenter trial US trial JCO 2002; 20: 567-573.
Fig 1. Megestrol acetate improved (1) appetite, (2) physician-reported weight, (3) patient-reported weight, and (4) FAACT QOL score (Fisher's exact test, PP <.001,.02,.04, and.009, respectively). The UNISCALE found no significant differences in QOL. Bars represent 95% confidence intervals. Jatoi, A. et al. J Clin Oncol; 20:567-573 2002 Copyright American Society of Clinical Oncology
Only difference in AEs is impotence JCO 2002; 20: 567-573.
243 patients Cannabis extract (2.5 mg THC/1mg CBD) vs. THC vs. placebo 6 week trial Performed in Switzerland and Germany
Fig 2. Changes in visual analog scale (VAS) scores from baseline for appetite in the intent-to-treat population Strasser, F. et al. J Clin Oncol; 24:3394-3400 2006 Copyright American Society of Clinical Oncology
Fig 3. Changes in visual analog scale (VAS) scores from baseline for quality of life (QOL) in the intent-totreat population Strasser, F. et al. J Clin Oncol; 24:3394-3400 2006 Copyright American Society of Clinical Oncology
JCO 2006; 24: 3394-3400.
139 pts: dronabinol 2.5mg bid vs. placebo 38% vs. 8% improve appetite e (p=0.05) 05) NS lessn nausea, improved mood
Cachexia conclusions Cannabinoids do not improve anorexia or QOL in advanced cancer Megesterol acetate is more effective in alleviating cachexia in cancer Cannabinoids id may improve appetite in HIV/AIDS No clear data on medical marijuana
Nausea/vomiting (16%) Will cannabinoids help keep my patient from Will cannabinoids help keep my patient from feeling nauseated and vomiting?
Chemo-induced nausea/vomiting (CINV) First studies performed in the mid-1970 s Most compare synthetic cannabinoids and pre-1990 s anti-emetics One study of smoked marijuana: 78% positive response NEJM 1975;293:795-7. NY State J Med 1988; 525-527.
198 reports whittled to 30 evaluable trials Efficacy data on 1366 patients Average trial size was 46 patients 83% of trials used a cross over design Nabilone (16), dronabinol (13), levonantradol l (1) All evaluated acute CINV BMJ 2001; 323: 1-8
Copyright 2001 BMJ Publishing Group Ltd. Tramer, M. R et al. BMJ 2001;323:16
Copyright 2001 BMJ Publishing Group Ltd. Tramer, M. R et al. BMJ 2001;323:16
BMJ 2001; 323: 1-8
Curr Med Res Opin 2007; 23: 533 Delayed CINV
CINV conclusions Cannabinoids are more effective than older anti-emetics (e.g. Compazine) Cannabinoids have more side effects than older anti-emetics Cannabinoids id have little role in chronic CINV Little data about smoked marijuana
Non-chemo N/V
Muscle spasms (29%) 36%-43% of patients with MS report use Neurology 2004;62:2098-100. Multiple Sclerosis 2006;12:646 651. Lancet 2003;362:1517-20.
CAMS trial 630 pts at 33 sites Oral cannabis extracts vs. 9THC vs. placebo Lancet 2003;362:1517-20.
Sativex in MS No difference in Ashworth scores Approved in UK in 2010 Eur. J. Neurol. 2007;14:290 296.
Severe pain (92%) Will cannabinoids help relieve my patient s Will cannabinoids help relieve my patient s pain?
9 single-dose trials Cross-over designs, single dose studies Cannabinoids id as effective as codeine 50-120 mg Adverse events were common Problems: does not address smoked products, chronic use, adjunctive use BMJ 2001; 323: 1-6
Acute pain Smoked marijuana results in modest dose dependent relief in normal subjects Oral extract without effect Anesthesiology. 2007;107:785-96. Anesthesiology. 2008;109:101-10.
Neuropathic pain CT-3 (11-THC-oic) better than placebo for neuropathic pain (JAMA, 2003) Dronabinol > placebo in MS-central pain cross- over trial (BMJ, 2003) Sativex >placebo in MS (Neurology, 2005) Smoked cannabis > placebo in HIV neuropathy (BMJ, 2007) Nabilone < dihydrocodeine in neuropathic pain (5% v. 19% relief) with more toxicity (BMJ, 2008) JAMA 2003;290:1757. BMJ. 2004;329:253. Neurol. 2005;65:812-9. Neurol 2007; 68:515-21. BMJ 2008; 336. 199
Prospective observational trial Single center in Canada 112 patients J Support Oncol 2008; 6: 119-124
J Support Oncol 2008; 6: 119-124
J Support Oncol 2008; 6: 119-124
Sativex and chronic cancer pain Phase IIb double-blinded blinded RCT Opiates +/- self-titrated Sativex in 3 dose ranges Superior to placebo at low and moderate doses (p < 0.05) 05) Similar number of patients with AEs with low and moderate doses Phase III completed and being analyzed http://www.gwpharm.com/phase%20iib%20cancer%20pain%20trial%20data.aspx
Pain conclusions Cannabinoids have modest analgesic effects in the acute setting More effective than placebo for neuropathic pain in HIV and MS Cannabinoids id may decrease opiate needs and serve as complementary meds Role in chronic, non-neuropathic pain is unknown
Will cannabinoids make the illness worse?
Marijuana and cancer risk No clear increase in all cancer risk No clear association with lung cancer No clear association with head and neck cancers Increased concern for fungal infections Cancer Causes Control 1997;8:722. Lancet Oncol 2005;6:35. Cancer Epidemiol 1999:8:1071. Cancer Prev Res 2009;2:759. Arch Intern Med. 2006;166:1359-67.
Marijuana hyperemesis Chronic, heavy marijuana a use Improves with cessation of MJ Confused with chronic vomiting syndrome
Marijuana and other diseases Lung disease: Dose-dependant decrease in lung fucntion Schizophrenia: earlier presentation, worse psychosis Hepatitis C: increased steatosis t Thorax. 2007;62:1058-63. Am J Psychiatry. 2010;167:987-93. Gastroenterology. 2008;134:432-9.
What s the status of medical marijuana in Colorado?
Physician Attitudes 1991, 54% of H/O MDs favored prescription MJ 2005 survey 994/2227 responses 36.1% agree with legalization, li 26% neutral, 37.8% opposed Internists t more likely l to approve than addiction med, psychiatry, or family medicine JCO 1991;9:1314-9. J. Addict. Dis. 2005;24:87-93
NEJM 2010; 362: 1453
NEJM 2010; 362: 1453
Federal status Schedule I drug: no currently acceptable medical use 2005: Gonzales v. Raich confirmed that federal law enforcement can make arrests despite state laws October 2009: Department of Justice says federal resources should not be used to prosecute those in compliance with state laws NEJM 2010; 362: 1453
Legal Marijuana in Colorado 2000: Voters pass amendment 20 to legalize medical marijuana 2 oz. and 6 plants Patient and caregiver free from prosecution Dispensaries not established Summer 2009: Board of Health liberalized caregiver definition iti commercial dispensaries NEJM 2010; 362: 1453 http://online.wsj.com/article/sb10001424052748704784904575111692045223482.html
Green Rush 2000-2008: 2008: 2000 medical marijuana cards approved 2009: At least 43,000(!) approved by 12/09 August 2009: 270 applications/day February 2010: 1000 applications/day At least 230 dispensaries in Denver http://www.westword.com/2009-02-05/news/medical-marijuana-has-become-a-growth-industry-in-colorado/ http://www.cdphe.state.co.us/hs/medicalmarijuana/statistics.html
Getting a card Can be prescribed by any licensed physician in Colorado $90 application fee
Colorado registry demographics 74% male Average age is 40 years >1000 different physician i prescribers Reported Condition Number of Patients Reporting Condition Percent of Patients Reporting Condition** Cachexia 700 2% Cancer 908 2% Glaucoma 382 1% HIV/AIDS 296 1% Muscle Spasms 12,077 29% Seizures 764 2% Severe Pain 37,912 92% Severe Nausea 6,696 16% http://www.cdphe.state.co.us/hs/medicalmarijuana/statistics.html. Accessed 9/14/10.
Slow your roll House Bill 1284 and Senate Bill 109 passed in 2010 Dispensaries must have state and local licenses Dispensaries grow 70% of what they sell Cannot stay open past 7PM May be eligible for taxation Physicians need a bona fide relationship. Can report violations to CBME http://www.cdphe.state.co.us/hs/medicalmarijuana/statistics.html. Accessed 9/14/10.
Medical marijuana in Colorado conclusions Use is growing rapidly Regulations changing rapidly Probably bl safe to prescribe
Conclusions Modestly effective in pain and in acute CINV Not effective in cancer-related cachexia Better than placebo in pain control Little data about symptom control with smoked marijuana
Medical cannabis conclusions Marijuana is not strongly correlated with cancer development Cannabinoids may have a role in cancer treatment Colorado is on the forefront f of dynamic medical marijuana issue