11/18/2013
Gilbert Fanciullo, MD, MS
December 5, 2013
 None
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11/18/2013
 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 
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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
Amendment to NH HB 573‐FN
 May 31, 2012‐ Governor signed HD 5389 making CT 
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the 17th State…
Went into effect October 1, 2012
Predict system will be up and running by 2014
Cancer, glaucoma, HIV, Parkinson's disease, MS, SCI causing spasticity, epilepsy, wasting syndrome, Crohns disease, PTSD
Department of Consumer Protection can add additional conditions
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 Only pharmacists can open dispensaries
 Licensed producers can apply after submitting a $25K 
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fee
License will cost $75K/year (proposed)
Patients and caregivers
Very strict approach
Maine, Massachusetts, Connecticut, New Hampshire, Vermont, Rhode Island
And/or
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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
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 CB1 receptor discovered in 1980 by Pfizer is the major 
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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
 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
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 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
 “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
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 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
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 ∆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)
 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)
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 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)
 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)
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 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  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 ∆9‐THC has shown significant antidepressant activity
 Inconsistent results looking at CBD
2003)
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 ∆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
 ∆9‐THC increases HR, slightly increases supine BP, 
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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
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 “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)
 Montecucco F and Di Marzo V 2012
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 (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
 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)
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 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
 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.
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 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
 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 14
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 “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”
 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.
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 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
 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
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 Clear correlation between number of medical marijuana licenses and marijuana toxicosis seen at veterinary hospitals (Meola et al J Vet Emerg Crit 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
 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!
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Nicotine
Heroin Cocaine Alcohol
Marijuana
32%
23%
17%
15%
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 Saf 2011.
 Not for early use
 Not for pregnant women
 Not for driving
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 Chemotherapy induced nausea and vomiting
 Glaucoma
 Pain
 Appetite
 Spasticity
 Parkinson disease
 Anxiety
 Adults relatively immune to behavioral or brain morphological changes
 In the Netherlands, cost at grower level for 1 gram of dry 
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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)
Varieties with 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)
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 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)
 Evidence
 Preference sensitive care
 Supply sensitive care
 Wennberg JE. Tracking Medicine: A researchers quest to understand health care. Oxford University Press, 2010.
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 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)
 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
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 Evidence based guidelines do not exist
 Risks
 Benefits
 Risk stratification
 Dosage
 Use at work
 Use when driving
 Use in pregnancy
 Monitoring
 Use prudence, shared decision making,
caution
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