Gilbert Fanciullo, MD, MS
October 19, 2014
 None
 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



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
 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
 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
 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
 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
 ∆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)
 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. ∆9THC (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)
 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
2003) ∆9-THC has shown significant antidepressant
activity
 Inconsistent results looking at CBD
 ∆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,




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
 “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
 (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)
 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.
 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
 “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”
 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%)
 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
 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.
 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
 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
Barnwell 2006)- controversial
 Addiction, abuse, misuse, diversion!
(Smucker





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
 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




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)
 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.
 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
 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