What Constitutes Best Medical Practice with Medical Marijuana?

1. What Constitutes Best Medical Practice with Medical Marijuana? Gilbert Fanciullo, MD, MS October 19, 2014

2. Conflict of interest disclosure • None

3. Introduction • Vermont Medical Marijuana Committee • Editorial • Fanciullo GF, Journal of Opioid Management, 2009 • Most widely used recreational substance in the world • 123,890 registered marijuana users in the State of Colorado (2.1% cancer, 94.3% severe or chronic pain) • 250,000-300,000 in California • In Canada, 10% of patients with non cancer chronic pain use marijuana for pain relief • Katz and Fanciullo, about the same in 2005

4. Endocannabinoid system (ECS) • General strategy of action is to help cells, tissues and organs re-establish physiological steady state after acute or chronic perturbations of homeostasis • Ubiquitous and pleiotropic (Pleiotropy occurs when one gene influences multiple phenotypic traits) • ECS major focus for drug developers because can develop drugs that can target several disorders at the same time (e.g., depression and pain) Hill AJ, et al. Phytocannabinoids as novel therapeutic agents in CNS disorders. Pharmacology and Therapeutics 133(2012)79-97. Montecucco F and Di Marzo V. At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction. Trends in Pharmacological Sciences 33(6):2012;331-340

5. Endocannabinoid system • CB1 receptor discovered in 1980 by Pfizer is the major binding site for ∆9-THC (partial agonist) • Use of ∆9-THC limited by psychoactivity • Anti-obesity agent rimonabant CB1 receptor antagonist (taken off market in 2008- depression and suicidality) • CB2 receptor identified in 1993 • Cannabidiol (CBD) has low affinity for CB1 or CB2 receptors and has been shown to antagonize the actions of synthetic cannabinoid (CB) ligands at CB1 and CB2 receptors

6. Phytocannabinoids (pCB) • Lipid soluble chemicals present in the resin secreted from trichomes (small hair from the epidermis of a plant)that are abundantly produced by female plants of Cannabis sativa • Two major pCBs are ∆9-THC and CBD, both derived from cannabigerol • pCBs unique to cannabis and numbering >100 (plus >500 non-CB constituents) • Plant can be genetically manipulated to alter ratios of pCBs produced

7. Phytocannabinoids • Initially exploited to increase amount of intensely psycho-active ∆9-THC • Currently solely horticultural techniques are being used to develop “chemovars” (cloned plants), “legitimate” medicinal products • Processes follow FDA botanical guidelines producing standardized cannabis extracts used in Sativex • Sativex (1:1 mixture of ∆9-THC: CBD) first drug licensed (UK, Canada, Spain, Germany, Denmark, New Zealand) using cannabis extracts indicated for pain and spasticity in MS

8. Phytocannabinoids • “Importantly, modulation of ratios of pCBs in different SCEs (Standardized Cannabis Extracts) may not only offer therapeutic potential dependent on the nature of the target disease, but also provide a valuable intellectual property model to justify pharmaceutical industry development of cannabis-based medicines.” (Hill AJ et al) • pCBs can also activate non-CB metabotropic G-protein coupled receptors • CBD is a 5-HT1A agonist • CBG is a 5-HT1A antagonist and α2-adrenoceptor antagonist

9. Phytocannabinoids • pCBs are known to protect neurons from neurotoxic stimuli or neuro-degeneration via a range of properties which may include ligand action at CB receptors, innate antioxidant properties and effects on the immune system • CBD has been shown to be anti-inflammatory • pCBs have effects on receptors, ion channels and enzymes that (may) enable them to achieve therapeutic aims

11. pCBs in epilepsy • ∆9-THC exhibits contradictory pro and anti-convulsant activity in clinical cases and that combined with psychotropic side effects make it undesirable (Wade et al 2006, Davis & Ramsey 1949) • CBD is the only non ∆9-THC pCB to have been investigated as an anticonvulsant in human subjects (Carlini & Cunha 1981, Trembley & Sherman 1990) • It is anticonvulsant when used alone and enhanced the anticonvulsant effects of phenytoin and phenobarbital but diminished the effects of chlordiazepoxide, clonazepam, trimethadione and ethosuxamide (Consroe & Wolkin 1977) • There is no evidence of pro-convulsant activity • Compelling evidence to support further investigation • Similar effects with ∆9-THCV (tetrahydrocannabivarin) (Hill et al 2010)

12. pCBs and neurodegenerative disease • MS • Pathological basis is creation of inflammatory, demyelinating lesions in the CNS • ∆9-THC controls spasticity in a mouse model of MS via a CB1 mechanism (Baker et al 2000) • Marinol(synthetic ∆9-THC)and Cannador (2.5:1.25 mg ∆9-THC:CBD SCE (Standardized Cannabis Extract)) studied in randomized, placebo controlled trial showing neither drug effected Ashworth scores but clearly showed improvement in patient reported pain and spasticity (Zajicek J, et al. Lancet 362;1517-1526)

13. pCBs and neurodegenerative disease • Can pCBs alter the progression of MS? • CUPID Study (Cannabinoid Use in Progressive Inflammatory Brain Disease)in progress. Three year study with 493 patients randomized to placebo v. ∆9-THC (Clinical Neurology Research Group, 2009) • Parkinson’s disease • Evidence of efficacy ∆9-THC is mixed • Administration of ∆9-THCV to the 6-OHDA Parkinsonism model in rats has been shown to improve motor performance (Garcia et al 2011)

14. pCBs and neurodegenerative disease • Huntington’s disease • Double blind, randomized, placebo controlled, crossover trial in 15 patients showed no effect of CBD on chorea severity (Cosroe et al 1991) • Double blind, randomized, placebo controlled, crossover trial of Nabilone (∆9-THC )in 37 patients showed no significant effect (Curtis et al 2009)

15. Affective disorders • Anxiety • While cannabis may be anxiogenic in otherwise healthy cohorts, there are clear indications of anxiolytic effects in sufferers of anxiety disorders (Hill 2012) • Results from animal studies suggest that CBD has anxiolytic potential (Restel et al 2009, Guimaraes et al 1990, Pistovcakova 2006, etc) • Anxiogenic and anxiolytic effects of cannabis may be offset against the anxiolytic effects of CBD supporting the idea that CBD can usefully ameliorate the unwanted side effects of ∆9-THC

16. Affective disorders • Depression • Cannabis ingestion is associated with an with an increased incidence of bipolar disorder and depression (Jarvis et al 2008, van Rossum et al 2009) • However, in patients with advanced cancer (Regelson et al 1976), MS (Svendsen et al 2004), and chronic pain (Wade et al 2003)∆9-THC has shown significant antidepressant activity • Inconsistent results looking at CBD

17. Feeding • ∆9-THC shows a degree of over-eating far exceeding any other available appetite stimulants (Hill 2012) • ∆9-THC SCE has shown clearly less appetite stimulation than ∆9-THC alone (Farrimond et al 2010) • This implies that understanding the composition of SCE is critical and may lead to the identification of a pCB that antagonizes the stimulating effect of ∆9-THC and may be useful as an appetite suppressant

18. Cardiovascular effects of ECS • ∆9-THC increases HR, slightly increases supine BP, and can on occasion produce orthostatic hypotension likely in a dose dependent fashion (Jones RT 2002) • CO increases, PVR decreases, maximum exercise performance decreases • Tolerance appears rapidly • With repeated exposure, orthostatic hypotension disappears, HR slows, exercise performance increases, blood volume increases • MI and stroke associated with the use of cannabis have been reported

19. Cardiovascular effects of ECS • “Relatively rare case reports of adverse cardiovascular events associated with marijuana use may simply represent coincidental events and a consequence of the large number of people who use marijuana. However, marijuana smoking by older people, particularly those with some degree of coronary artery or cerebrovascular disease, may pose greater risks because of the increased cardiac work, increased catecholamine's, increased carboxyhemoglobin levels, and possibly episodes of intense postural hypotension, particularly when relatively nontolerant individuals are exposed to potent marijuana” (Jones RT. J Clin Pharm 2002;42:58S-63S)

20. Montecucco F and Di Marzo V 2012

21. Cardiovascular effects of ECS • (a) Myocardial ischemia and reperfusion injury is represented by a heart section showing a necrotic zone with infiltrating inflammatory cells. It has been shown that activation of the CB2 receptor reduces infarct size and arrhythmia complications in rodent models • (b) The potential role of ECBs on arrhythmias in the apparently healthy heart are unknown • (c) Doxorubicin induced cardiotoxity (d) Cirrhotic cardiomyopathy (e) Diabetic cardiomyopathy. For these disorders, CB1 antagonism represents a promising strategy for reducing cardiac injury

22. Smoked cannabis for neuropathic pain: a randomized controlled trial Ware MA, et al. CMAJ 2010 • 23 patients with post surgical or post traumatic neuropathic pain • Randomly assigned 4 potencies ∆9-THC (0%,2.5%, 6%, 9.4%) • Capsules (25 mg) of assigned potency placed in bowel; inhaled 5 sec; held in lungs 5 seconds. Three times daily for 5 days • Statistically significant difference between 0% and 9.4% but very modest (Average daily pain 0%-6.1, 9.4% 5.4)

23. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover trialEllis RJ, et al. Neuropsychopharmacology2009 • 34 refractory subjects with distal sensory predominant polyneuropathy • 4% ∆9-THC which could be titrated downward as low as 1% or upward as high as 8% all on day 1. Participants titrated to target dose (smoked as much as they needed at each session). • 4 daily smoking sessions separated by 90-120 minutes for 5 consecutive days • 2 week washout and 5 days active drug v. 5 days placebo

24. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover trialEllis RJ, et al. Neuropsychopharmacology2009 • 2 subjects withdrew- one with acute cannabis related delirium and one with intractable smoking related cough • Used DDS scale- 21 points • Cannabis use reduced DDS by 3.3 points, NNT to achieve 30% pain reduction was 3.5.

25. The intersection between cannabis and cancer in the US.Critical Reviews in Oncology/Hematology 2012 • Cannabis smoke is carcinogenic and mutagenic in rodents • Contains the same carcinogens as tobacco smoke at up to 50% higher concentration and with 3x the tar in cigarettes • Despite this, it has been difficult, even with effort, to strongly correlate cannabis use with the development of human cancers • Epidemiologic data for head and neck squamous cell carcinoma (HNSCC) are inconsistent

26. The intersection between cannabis and cancer in the US.Critical Reviews in Oncology/Hematology 2012 • Three studies have found increased risk HNSCC • Ever users had 2.6 fold increased risk (Zhang et al 1999) • Heavy smokers in Northern Africa had odds ratio 2.62 (Feng et al 2009) • HPV+ HNSCC was associated with marijuana use but not HPV-HNSCC (Gillison et al 2008) • INHANCE consortium looked at over 4000 HNSCC patients compared to 5000 controls (Rosenblatt et al 2004, Hashibe et al 2006, Berthiller et al 2009) • No link between cannabis use and HNSCC was found when controlling for alcohol and tobacco use

27. The intersection between cannabis and cancer in the US.Critical Reviews in Oncology/Hematology 2012 • “At this point the majority of studies do not support the hypothesis that smoked cannabis is strongly associated with an increased risk of HNSCC once tobacco and alcohol intake are controlled”

28. Marijuana use and risk of lung cancer: a 40 year cohort studyCallaghan, Allebeck and Sidorchuk. Cancer Causes Control (2013) 24 • Population based cohort study (n = 49,321) • 18-21 year old men assessed for marijuana use at the time of military conscription in Sweden in 1969-70 and tracked fro incidence of lung cancer until 2009 • 10.5% (5,156) reported lifetime use and 1.7% (831) reported heavy use (more than 50 times) • After statistical adjustment for alcohol, tobacco, respiratory conditions and socioeconomic status, heavy cannabis use was associated with more than a twofold risk of developing lung cancer (hazard ratio 2.12, 95%)

29. Marijuana use and risk of lung cancer: a 40 year cohort studyCallaghan, Allebeck and Sidorchuk. Cancer Causes Control (2013) 24 • Many weaknesses- e.g., did not look at marijuana, alcohol or tobacco use after conscription; conscripts gave non-anonymous reports of marijuana use; 91% of heavy users smoked cigarettes • One other cohort study showed no increased risk (Sidney et al, 1997) and seven case control studies show inconsistent results

30. Marijuana use and mortalityAm J Public Health 1997 • The development of other cancers has been inconsistently associated with cannabis use. A study of 65,855 members of a U.S. health management organization (HMO) that classified members as experimenters (six or fewer lifetime usages), former users, or current users found no increased risk of HNSCC, lung, colorectal, melanoma, or breast cancers in current or former cannabis smokers versus never smokers or experimenters when controlled for tobacco use, alcohol intake, and socioeconomic status.

31. Safety • State medical cannabis laws bypass the usual FDA approval process- marijuana has been used since the beginning of recorded history • Post marketing surveillance studies have been ongoing for generations • Ideally elements identified and proper sequence of drug testing followed

32. Risks- largely defined by lowest levels of scientific evidence • Glass beads in France; Talcosis in Germany • Case reports of MI and arrhythmias • Case reports of Stroke (59 cases in world literature) (Wolff 2012) • Chronic bronchitis, reduced lung density, lung cysts anecdotally reported • Earlier age of onset of psychosis Reece AS. Chronic toxicology of cannabis. Clinical Toxicology, 2009

33. Risks • Clear correlation between number of medical marijuana licenses and marijuana toxicosis seen at veterinary hospitals (Meola et al J Vet EmergCrit Care 2012) • ∆9-THC toxicosis in dogs can cause considerable morbidity • Onset 30-60 minutes after ingestion • Urinary incontinence, CNS depression, ataxia, tremors, death • Gastric lavage with activated charcoal and intralipid therapy

34. Risks • Prenatal cannabis exposure associated with • Negative impact on school achievement (Goldschmidt et al 2011) • Teratogenic on developing brain • Fetal growth reduction (Gray et al 2010) • Many findings discrepant • Marijuana use is associated with an increased risk of being involved in a motor vehicle crash and a fatal MVA • Daily use of marijuana does not impair motivation (Smucker Barnwell 2006)- controversial • Addiction, abuse, misuse, diversion!

35. Lifetime Dependence Risk • Nicotine 32% • Heroin 23% • Cocaine 17% • Alcohol 15% • Marijuana 9% • Adult age of initiation, low to moderate use, use for therapeutic rather than recreational, of marijuana appears to be protective against dependency Robson P. Exp Op Drug Saf2011.

36. Risks • Not for early use • Not for pregnant women • Not for driving

37. Benefits • Chemotherapy induced nausea and vomiting • Glaucoma • Pain • Appetite • Spasticity • Parkinson disease • Anxiety • Adults relatively immune to behavioral or brain morphological changes

38. Forensic literature • In the Netherlands, cost at grower level for 1 gram of dry cannabis buds is 3-4.25 Є. One ounce = 28 grams. One Є = $1.31. One ounce, at the grower level, in the Netherlands, sells for $110. Unknown in U.S. • ∆9-THC concentration in Dutch marijuana is in the 15-20% range. Varieties: Super Skunk (nederwiet) 14.3%; White Widow 11.7%, etc(Vanhove et al Forensic Science International 2011) • Varietieswith high ∆9-THC content have low or absent CBD content • Cannabis consumption in the Netherlands is lower than would be expected in an unrestricted market, perhaps because prices have remained high • US States that legalized medical marijuana had higher rates of marijuana use. Use increased 1.92 times (Cerda et al Drug and Alcohol Dependence 2012)

39. Forensic literature • In the U.S. retail cost per ounce is @$280 compared to @$196 in the Netherlands (MacCoum RJ Addiction 2011) • How many joints are there in an ounce of marijuana? • Each joint contains 0.3-0.5 grams, 28/0.4= 70! (Kilmer et al Bringing perspective to illicit markets: estimating the size of the US marijuana market Drug and Alcohol Dependence 2011)

40. How is treatment provided? • Evidence • Preference sensitive care • Supply sensitive care • Wennberg JE. Tracking Medicine: A researchers quest to understand health care. Oxford University Press, 2010.

41. Conundrum • Marijuana's relegation to Schedule I status seems irrational- opioids, cocaine, amphetamine are Schedule II • Should people go to jail for possession of marijuana? • Not likely a pharmacological equivalent will be available within the next decade (or two)

42. Little about Cannabis is Straightforward! • Physicians and the general public are in agreement that marijuana shows promise in combating diverse medical problems • Medical use and recreational use are not two discreet elements- patrons of medical marijuana clinics are ¾ male and recreationally familiar • Doctors and Nurses become both healers and scofflaws (a person who fails to comply with a law that is difficult to enforce effectively) • There are no Guidelines

43. Guidelines • Evidence based guidelines do not exist • Risks • Benefits • Risk stratification • Dosage • Use at work • Use when driving • Use in pregnancy • Monitoring

44. Responsibility • Use prudence, shared decision making, caution