Gilbert Fanciullo, MD, MSOctober 19, 2014

What Constitutes Best Medical Practice with Medical Marijuana?

None

Conflict of interest disclosure

Vermont Medical Marijuana CommitteeEditorial

Fanciullo GF, Journal of Opioid Management, 2009Most widely used recreational substance in the

world123,890 registered marijuana users in the State of

Colorado (2.1% cancer, 94.3% severe or chronic pain)

250,000-300,000 in CaliforniaIn Canada, 10% of patients with non cancer chronic

pain use marijuana for pain reliefKatz and Fanciullo, about the same in 2005

Introduction

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

Endocannabinoid system (ECS)

CB1 receptor discovered in 1980 by Pfizer is the major binding site for ∆9-THC (partial agonist)

Use of ∆9-THC limited by psychoactivityAnti-obesity agent rimonabant CB1 receptor

antagonist (taken off market in 2008- depression and suicidality)

CB2 receptor identified in 1993Cannabidiol (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

Endocannabinoid system

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

Phytocannabinoids (pCB)

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

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 receptorsCBD is a 5-HT1A agonistCBG is a 5-HT1A antagonist and α2-adrenoceptor

antagonist

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-inflammatorypCBs have effects on receptors, ion channels

and enzymes that (may) enable them to achieve therapeutic aims

Phytocannabinoids

∆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 activityCompelling evidence to support further investigation

Similar effects with ∆9-THCV (tetrahydrocannabivarin) (Hill

et al 2010)

pCBs in epilepsy

MSPathological 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)

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 diseaseEvidence of efficacy ∆9-THC is mixedAdministration of ∆9-THCV to the 6-OHDA

Parkinsonism model in rats has been shown to improve motor performance (Garcia et al 2011)

pCBs and neurodegenerative disease

Huntington’s diseaseDouble 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)

pCBs and neurodegenerative disease

AnxietyWhile 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

Affective disorders

DepressionCannabis 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

Affective disorders

∆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

Feeding

∆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 rapidlyWith 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

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)

Cardiovascular effects of ECS

Montecucco F and Di Marzo V 2012

(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

Cardiovascular effects of ECS

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)

Smoked cannabis for neuropathic pain: a randomized controlled trial

Ware MA, et al. CMAJ 2010

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

Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover trial

Ellis RJ, et al. Neuropsychopharmacology 2009

2 subjects withdrew- one with acute cannabis related delirium and one with intractable smoking related cough

Used DDS scale- 21 pointsCannabis use reduced DDS by 3.3 points,

NNT to achieve 30% pain reduction was 3.5.

Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover trialEllis RJ, et al. Neuropsychopharmacology 2009

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

The intersection between cannabis and cancer in the US.

Critical Reviews in Oncology/Hematology 2012

Three studies have found increased risk HNSCCEver 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

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”

The intersection between cannabis and cancer in the US.

Critical Reviews in Oncology/Hematology 2012

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%)

Marijuana use and risk of lung cancer: a 40 year cohort study

Callaghan, 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

Marijuana use and risk of lung cancer: a 40 year cohort study

Callaghan, Allebeck and Sidorchuk. Cancer Causes Control (2013) 24

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.

Marijuana use and mortalityAm J Public Health 1997

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

Safety

Glass beads in France; Talcosis in GermanyCase reports of MI and arrhythmiasCase reports of Stroke (59 cases in world

literature) (Wolff 2012) Chronic bronchitis, reduced lung density,

lung cysts anecdotally reportedEarlier age of onset of psychosis

Reece AS. Chronic toxicology of cannabis. Clinical Toxicology, 2009

Risks- largely defined by lowest levels of scientific evidence

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 morbidityOnset 30-60 minutes after ingestionUrinary incontinence, CNS depression, ataxia,

tremors, deathGastric lavage with activated charcoal and

intralipid therapy

Risks

Prenatal cannabis exposure associated withNegative impact on school achievement (Goldschmidt

et al 2011) Teratogenic on developing brain Fetal growth reduction (Gray et al 2010)

Many findings discrepantMarijuana 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!

Risks

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 Saf 2011.

Lifetime Dependence Risk

Not for early useNot for pregnant womenNot for driving

Risks

Chemotherapy induced nausea and vomitingGlaucomaPainAppetiteSpasticityParkinson diseaseAnxietyAdults relatively immune to behavioral or

brain morphological changes

Benefits

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)

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)

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)

Forensic literature

EvidencePreference sensitive careSupply sensitive care

Wennberg JE. Tracking Medicine: A researchers quest to understand health care. Oxford University Press, 2010.

How is treatment provided?

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)

Conundrum

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

Little about Cannabis is Straightforward!

Evidence based guidelines do not existRisksBenefitsRisk stratificationDosageUse at workUse when drivingUse in pregnancyMonitoring

Guidelines

Use prudence, shared decision making, caution

Responsibility