Elizabeth ‘Libby’ Stuyt, MD
University of Colorado, Department of Psychiatry
Medical Director, Circle Program
Colorado Mental Health Institute at Pueblo
2012 Colorado Behavioral Healthcare Council
Annual Training Conference, Sept 28, 2012

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The Circle Program is now funded in part by Medical Marijuana Tax proceeds

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Complex alkaloid mixture of more than
400 compounds derived from the
Cannabis sativa plant
60 different compounds described with activity on the cannabinergic system
Most abundant cannabinoids are
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Delta-9 tetrahydrocannabinol (most psychoactive)
Cannabidiol
Cannabinol

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Two main cannabis receptors
CB1–present throughout CNS
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Hippocampus
Cortex
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Olfactory areas
Basal ganglia
Cerebellum
Spinal cord
CB2 – located peripherally, linked with immune system
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Spleen
 macrophages

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6000 BC – Cannabis seeds used as food in
China
4000 BC – Textiles made of hemp in China
2727 BC – first recorded medicinal use in
Chinese Pharmacopoeia
1400 BC to AD – trade moves product through India, Mediterranean countries,
Europe – numerous medicinal uses reported

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1378 – Emir of the Ottoman Empire makes the first edict against eating hashish or smoking cannabis – 1 st “War on Drugs”
1798 – Napoleon declared total prohibition on marijuana after realizing much of the
Egyptian lower class were habitual smokers
1868 – Egypt – 1 st modern country to outlaw cannabis ingestion
1890 – Hashish made illegal in Turkey

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Introduced to North America in 1600s by
Puritans – Hemp for ropes, sails, clothing; cannabis a common ingredient in medicines, sold openly in pharmacies
1937 – Marijuana Tax Act – transfer of cannabis illegal throughout US except for medicinal and industrial use, expensive excise tax and detailed logs required
1969 – found to be unconstitutional since it violated 5 th Amendment privilege against selfrecrimination

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1970 – Controlled Substance Act – classified cannabis as having:
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High abuse potential
No medical use
Not safe to use under medical supervision
1975 – FDA establishes Compassionate Use
Program for Medical Marijuana – Glaucoma,
Multiple Sclerosis, Cancer
1986 – Dronabinol placed into Schedule II by
DEA
2003 – Canada – 1 st country in world to offer medical marijuana to patients

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Glaucoma - #1 cause of blindness
1992 – American Academy of
Ophthalmology’s Committee on Drugs – no scientific verifiable evidence that the use of marijuana is safe and effective in the treatment of glaucoma
1997 – NEI – no studies have demonstrated that marijuana can safely and effectively lower IOP any more than a variety of drugs on the market

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1999 – Institute of Medicine – although
IOP can be reduced by using cannabinoids and marijuana, the effect is too short lived and requires too high doses.
There are too many side effects to recommend lifelong use in the treatment of glaucoma
Would have to smoke 10-12 joints per 24 hours to maintain low IOP through out the day

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Dronabinol (Marinol) and nabilone (Cesamet) indicated for chemotherapy-induced nausea and vomiting
Dronabinol (Marinol) approved for HIVassociated anorexia
Sativex (oromucosal spray) conditionally approved for neuropathic pain in multiple sclerosis and cancer pain
Herbal smoked marijuana – found to be safe and effective for HIV-associated disorders

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Four cannabinoid products available
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Herbal cannabis extract, “Sativex”, delta-9-
THC and cannabidiol in oromucosal spray
Dronabinol synthetic delta-9-THC, “Marinol”
Nabilone synthetic derivative of delta-9-THC,
“Cesamet”
Herbal form of cannabis – “medical marijuana”

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MJ is a Schedule I drug – a barrier to conducting prospective RCTs,
DB w/ placebo
Studies are short - two weeks average, ranging from a few hours to one year
Most studies conducted with oral TCH preps rather than smoked cannabis
Most studies exclude anyone with a history of major psychiatric disorder other than depression and/or history of substance abuse
Most studies done to date:
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Short in length (average two weeks)
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Small N (lacking power)
Retrospective in nature
Confounded by uncontrolled variables
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Concomitant tobacco use
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Comorbid illnesses

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Lit review of cannabinoids given by any route for treatment of pain
Campbell et al. BMJ 2001;323:1-6
9 RCTs, 222 patients, 5 trials cancer pain; 2 chronic non-malignant pain; 2 post-operative pain; none evaluated cannabis
“Cannabinoids are no more effective than codeine in controlling pain and have depressant effects on the CNS that limit their use. In acute postoperative pain they should not be used.
Before cannabinoids can be considered for treating spasticity and neuropathic pain, further valid randomized controlled studies are needed.”

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Most of our knowledge about the negative effects of marijuana come from recreational use
Literature review of safety studies of medical cannabinoids over past 40 years –
23 RCTs (median exposure to cannabinoids 2 weeks, range 8 hrs to 12 months) Wang et al. CMAJ 2008;17:1669-
1678

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4779 adverse events reported in those assigned to the intervention
96.6% were not serious
164 serious events – no different from controls (RR) 1.04
Rate of nonserious events higher among those assigned medical cannabinoids than controls (RR)1.86 – dizziness most common event

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Double-blind, placebo controlled, crossover trial of smoked cannabis for the short term treatment of neuropathic pain associated with HIV – five study phases over 7 weeks – five days of active or placebo smoking with washout periods
Participants had documented HIV, neuropathic pain refractory to a least two previous analgesics, 5 or higher on pain scale
(Ellis et al. Neuropyschopharmacology
2009;34:672-680)

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Four smoking sessions per day, titrating dose (1-
8% THC) to achieve maximum tolerable dose
Exclusion criteria
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Current substance use disorder
Lifetime history of dependence on cannabis
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Concurrent use of medication with cannabinoids
Previous psychosis with or intolerance to cannabinoids

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“significantly reduced neuropathic pain intensity compared to placebo”
46% with cannabis reported a ≥ 30% reduction in pain versus 18% with placebo
Another study with almost identical outcomes –
52% vs 24%, >30% reduction in pain with 3 smoking sessions/day (Abrams et al. Neurology
2007:68:515-521)
“All patients were required to have prior experience smoking marijuana so they would know how to inhale and what neuropsychological effects to expect”

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Ware et al. CMAJ. 2010;E694-E701.
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N=21
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Inclusion Criteria
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Outpatients with > 3 month hx neuropathic pain
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Pain caused by physical trauma or surgery
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Pain intensity > 4 (0 to 10 scale)
Randomized, double-blind, placebo-controlled, fourperiod crossover design
THC concentration = 0, 2.5%, 6% or 9.4%
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Three daily dosages x 5 days
9 day washout period.
Participants advised not to drive a vehicle or operate heavy machinery while on study drug

Ware et al. CMAJ. 2010;E694-E701(cont)
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Average daily pain intensity:
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5.4 on 9.4% THC cannabis
6.1 on Placebo(0% THC)
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(p=0.023;difference = 0.7, 95% CI 0.02-1.4)
No difference observed between 2.5%, 6%, 0%
The reduction is modest when compared with that from other drugs for neuropathic pain such as gabapentin or pregabalin
A “joint” with a 9.4% THC content would impair the majority of us

Dose-dependent effects of smoked cannabis on Capsaicininduced pain and hyperalgesia in healthy volunteers
(Wallace et al. Anesthesiology. 2007;107:785-796)
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Randomized, double-blinded, placebocontrolled, crossover design
High dose training session, 15 subjects
100 mg capsaicin injected intradermally ventral forearm – spontaneous pain
Stroking and von Frey hair stimulation – elicited pain
Low dose 2% THC, medium dose 4%THC, high dose 8% THC

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Capsaicin injections induced spontaneous and elicited pain in all subjects
No difference in pain perception between any of the cannabis doses and placebo during early
(right arm) course
Low dose did not differ from placebo at any time point
During late course (left arm) medium dose subjects reported decreased pain sensation, high dose subjects reported increased perception of pain – consistent with other reports that chronic delivery of cannabinoids can cause thermal hyperalgesia

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Marijuana (smoked/oral) used as a therapeutic, not recreational agent, is a drug as defined by the FDA
All new drugs must be scientifically evaluated before they may be allowed to enter the stream of interstate commerce
The drug does not have to be proven superior to already approved drugs, its benefits must outweigh the risks when used for the purpose for which it has been approved

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Digitalis purpurea – fox glove - CHF
Papaver somniferum – opium poppy
Atropa belladonna – nightshade -IBS
Ephedra sinica – ephedrine - hypotension
Salix alba – willow tree - ASA
Taxis brevifolia – Pacific Yew tree – breast cancer

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Does the drug have a currently accepted medical use in the United States?
What is the drug’s safety under medical supervision?
What is its addiction liability?
Is there a potential for significant diversion for illegal use?
Are individuals using it on their own initiative or only on physician’s prescription?
Is the drug similar in its pharmacology to other controlled drugs?

November 2000
Coloradoans passed Amendment 20
Colorado Department of Public Health and
Environment was tasked with implementing and administrating the Medical Marijuana Registry program
March 2001
Colorado Board of Health approved rules and regulations
June 2001
MMJ Registry began accepting applications for
Registry Identification Cards.

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February 2009
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Obama administration indicated that Medical Marijuana prosecution would have low priority
October 2009
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Obama administration will not seek to arrest medical marijuana users and suppliers as long as they conform to state laws
Applications increased dramatically
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September 2009 – 3,523 applications received/month
December 2009 – 10,585 applications received/month

Storefront “Medical” Marijuana dispensaries sprouted like weeds!

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Marijuana Growers
Caregivers
Legal
Doctors making recommendations ($$$$)
Grow Lights
Vaporizers
Pipes
Edibles
Advertising (Westword has gone “green”)
Festivals
Delivery Services

September 30, 2009 June 30, 2012
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19,691 new patient applications received
17,356 patients with valid ID cards
73% male, average age 40, 8 minors <18
57% in the Denver/metro area
67% have designated primary care-giver
Over 800 different physicians have signed for patients in
Colorado
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184,002 new patient applications received
99,960 patients with Valid ID cards
68% male, average age 42, 47 minors <18
56% in the Denver/metro area
54% have designated primary care-giver
Over 900 different physicians have signed for patients in
Colorado

Condition
Cachexia
Cancer
Glaucoma
HIV/AIDS
Muscle Spasms
Seizures
Severe Pain
Severe Nausea
# of Patients
1,215
2,583
1,021
632
17,286
1,708
93,679
11,567
Percentage
1%
3%
1%
1%
17%
2%
94%
12%

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“Patient will be deemed to have established an affirmative defense to such allegation”
(possession of marijuana) where:
Patient was previously diagnosed by a physician as having a debilitating medical condition
Patient was advised by his or her physician, in the context of a bona fide physician-patient relationship, that the patient might benefit from the medical use of marijuana in connection with a debilitating medical condition

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Cachexia
Severe Pain
Severe Nausea
Seizures
Persistent Muscle Spasms
Any other medical condition approved by the state health agency

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Asthma
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Opioid Dependence
Atherosclerosis
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PTSD
Crohn’s Disease
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Bipolar Disorder
Diabetes Mellitus
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Anxiety Disorders
Hepatitis C
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Depression
Hypertension Tourette’s Disorder
MRSA
Rheumatoid Arthritis

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Patient may engage in the medical use of marijuana with no more marijuana than is medically necessary to address a debilitating medical condition
No more than 2 ounces and no more than six plants, 3 or fewer being mature
No patient shall engage in medical use of marijuana in plain view of, or in a place open to, the general public

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In the fall of 2009 @ 900 doctors had written approval letters (7% of licensed
MDs)
15 doctors – 72% of forms
5 doctors – 50 % of forms
One doctor signed 3,500 in a two day period

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Defines a bona fide relationship
Physician must have an unrestricted medical and DEA license
Addresses physician conflict of interest – physician can not be employed by the dispensary
Allows CMB to examine care of providers
Two physicians need to independently examine those < 21.

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The vast majority of these patients don’t have debilitating illnesses
The majority of the patients are young males who will be exposed to the long term effects of cannabis exposure
Studies conducted are all short term
Therefore their risks may be the same as for recreational users and/or addicts

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Will need to get a thorough history - medically, psychiatrically and substance abuse – keep a chart and have a patient/physician relationship
Will need to attempt to decide what level of marijuana use is most appropriate
Will need to recommend patients not drive etc. when under the influence
Will need to follow patients closely for side effects and unintended consequences

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Marijuana smoke contains several of the same carcinogens and co-carcinogens as tobacco smoke
Benzo[α]pyrene, a procarcinogenic polycyclic aromatic hydrocarbon, is present in marijuana tar at higher concentrations than in tobacco tar
Marijuana smoking involves inhalation of 3 times the amount of tar as tobacco smoke

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Studies are small in number and are retrospective in nature
Confounded by concomitant use of tobacco
Confounded by underreporting of marijuana use because such use is often illegal

Aldington et al. Eur Respir J. 2008;31:280-286
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Case-controlled study of lung cancer in adults <
55yrs of age in New Zealand
79 cases of lung cancer and 324 controls
Risk of lung cancer increased 8% for each jointyr (1 joint/day for one year) of cannabis smoking after adjustment for confounding variables including tobacco
Risk increased 7% for each pack-yr tobacco
“Long-term cannabis use increases risk of lung cancer in young adults”

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Retrospective, case-controlled study, 173 proven cases of head and neck cancer and
176 controls matched with respect to age, sex, race, education, tobacco, alcohol use
Risk of cancer 2.6 fold greater in cannabis users than non-users
3-fold greater increase in those < 55 yrs
Zhang et al. Cancer Epidemiol Biomark
Prev 1999;8:1071-1078.

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In a cohort study – among non-tobacco smokers, ever-marijuana smokers had increased risk for prostate cancer -
RR=3.1, and cervical cancer - RR=1.4
Sidney et al. Cancer Causes Control 1997;8:722-728.
Another cohort study found an increased risk of malignant primary adult-onset glioma for ever-marijuana smokers –
RR=1.9
Efird et al. J Neurooncol 2004;68:57-69

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Massive first pass metabolism via the oral route
– only 10-20% reaches systemic circulation unchanged – takes 30 – 60 minutes to achieve an effect – key side effect on CNS can be dysphoria rather than euphoria
Via the lungs – onset of action within seconds –
“high” experienced with serum concentration of
3 ng/ml, produced by as little as 2-3 mg D9THC, average “joint” contains 0.5 – 1.0 g of cannabis

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“Where there’s smoke, there’s harm”, “There is no future in smoking marijuana as a conventional medicine” Janet Joy PhD
Until there is an alternative, for a small segment of the population – there is a benefit of smoked marijuana modest clinical
Sound theoretical reasons for intrathecal or epidural cannabinoids – may produce spinal cord analgesia without effects on cerebral receptors that are associated with psychotropic effects

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Use of 4 joints or more per week resulted in a decrement in mental test performance, subjects who smoked regularly for a decade or more did the worst
Messinis et al. Neurology 2006;66:737
Long-term marijuana users were impaired
70% of the time on a decision making test, compared to 55% for short-term users and 8% for non-users

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Heavy marijuana use (daily for at least one month) is associated with residual neuropsychological effects even after a day of supervised abstinence from the drug
Harrison et al. JAMA 1996;275:521
Unknown whether this is due to residue of drug in the brain, withdrawal effects or frank neurotoxic effect of the drug

200
FOOD
NAc shell
200
SEX
150 150
100
50
Empty
Box Feeding
0
0 60 120
Time (min)
Source: Di Chiara et al.
180
100
5
ScrScr
Bas Female 1 Present
Scr Scr
Female 2 Present
Sample 1 2 3 4 5 6 7 8
Number
9 10 11 12 13 14 15 16 17
Mounts
Intromissions
Ejaculations
0
Source: Fiorino and Phillips
15
10

250
200
150
100
1100
1000
900
800
700
600
500
400
300
200
100
0
0
Accumbens
AMPHETAMINE
DA
DOPAC
HVA
1 2 3 4
Time After Amphetamine
5 hr
NICOTINE
Accumbens
Caudate
250
Accumbens
200
150
100
0
0
MORPHINE
Dose (mg/kg)
0.5
1.0
2.5
10
1 2 3 4
Time After Morphine
5hr
THC/Marijuana
0
0 1 2 3 hr
Time After Nicotine
Source: Di Chiara and Imperato

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Drugs of abuse are potent negative regulators of adult neurogenesis in the hippocampus
Chronic administration of opiates, THC, ethanol or nicotine decreases hippocampal function, decreasing ability of adult brain to adapt to new information

Regional Brain Abnormalities Associated
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 with Long-term heavy Cannabis Use
Arch Gen
Psychiatry 2008;65:694-701
15 long term (>10 years) and heavy (>5 joints daily) cannabis using men compared with 16 age matched non using controls by MRIs of brains
Cannabis users had bilaterally reduced hippocampal and amygdala volumes p=.001
Increase in positive symptoms (psychotic) p<.001
Significantly worse performance on measures of verbal learning p<.001

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10 subjects with MS and current cannabis users compared with 40 subjects with MS who did not use cannabis psychiatric diagnosis higher in cannabis users p=0.04
Slower mean performance time on SDMT
(index of information processing speed, working memory and sustained attention) in the cannabis users p=0.006
Neurology 2008;71:164-169

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Laboratory tests and driving studies show that cannabis may acutely impair several drivingrelated skills in a dose related fashion
Effects between individuals vary more than for alcohol because of tolerance, differences in smoking technique, and different absorptions of
THC Sewell et al. Am J Addictions 2009;18:185-193.
More pronounced with highly automatic driving functions; less with complex tasks that require conscious control – opposite from that seen with alcohol

Am J Psychiatry 1985;142:1325-1329
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Ten experienced licensed private pilots trained for 8 hours on a flight stimulator landing task
Each smoked a THC cigarette (19 mg)
24 hours later their mean performance on the flight task showed trends toward impairment in all variables, some tasks showed significant impairment
Despite the deficits, the pilots reported no awareness of impaired performance

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Study in Australia tracked 1600 girls for 7 years
Arseneault et al. BMJ 2002;325:1212
Those who used marijuana every day were 5 times more likely to suffer from depression and anxiety than non-users
Teenage girls who used the drug a least once a week were twice as likely to develop depression than those who did not use
Cannabis use increased the risk of developing schizophrenia symptoms – specific to cannabis and early onset – prior to age 15

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Increased by 40% in people who have used cannabis
Cohen et al. Australian New Zealand
J Psychiatry 2008;42:357-368.
Dose-response effect leading to an increased risk of 50-200% in the most frequent users
Approximately 14% of psychotic outcomes in young people would not have occurred if cannabis had not been consumed

Arch Gen Psych 2010;67
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Sibling pair analysis within a prospective birth cohort in Australia
3801 young adults – cannabis use and 3 psychosis-related outcomes (nonaffective psychosis, hallucinations, and Delusional
Inventory score)
Early cannabis use is associated with psychosis-related outcomes in young adults

double-edged sword
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Low doses may improve frontal lobe functioning by acutely increasing blood flow to cortices concerned with cognition, mood and perception
– increasing availability and utilization of dopamine
Continued use depresses cerebral flow and high doses augment mesolimbic dopamine release, opposing therapeutic effects of antipsychotic drugs and exacerbating psychosis
It also suppresses PFC dopamine utilization resulting in cognitive dysfunction

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Synthetic cannabinoids AM694 and HU210 found in Spice products are 500 to 600 times more potent than the THC found in traditional marijuana
The THC in high potency marijuana and Spice products are potentially harmful to embryonic development as early as 2 weeks after conception
Utero exposure to THC linked to anencephaly,
ADHD, Depression, Aggression

Rats exposed to nicotine as adolescents selfadminister more nicotine than rats exposed as adults Levin ED et al. Psychopharm 2000;169:141-149

Rats First Exposed to Nicotine in Adolescence
Show Greater Sensitization to Cocaine Than
Rats First Exposed as Adults
*Activity level after cocaine administration was measured by counting the number of times in 10 minutes each rat crossed light beams projected in a grid across its cage.
Sources: Collins et al, 2004, Levin et al, 2003, NIDA Notes v19.2

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Approximately 10% of regular marijuana users become addicted to it
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But this is old data, based on marijuana with less THC concentrations
Some medicinal marijuana blends, ie “Connie
Chung” strain contain 20 times more THC than marijuana found 40 years ago
Compared with 15% for alcohol, 32% for nicotine and 26% for opiates

th

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Not associated with death
Not as addicting as other drugs
Modest benefit demonstrated for small segment of the population in short term use
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Marked negative cognitive effects
Very dangerous to adolescent brain development and occurrence of mental illness
Cancer risk
Driving impairment

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One joint weighs @
0.9 grams with 3.56%
THC (Abrams study)
0.9 g = 0.03 oz
¼ oz = 7.1 g
1 oz = 28 g
1 oz = 31 joints; at 3 joints per day – need
3 oz per month
$900/month

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There is definitely a place for Medical
Marijuana when people are suffering with terminal conditions
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Cachexia – appetite stimulant
Nausea – secondary to chemotherapy
Pain – mild improvement
Neither opioid medications nor medical marijuana is the answer for chronic, nonmalignant pain

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Financial incentives and/or personal political views should not influence treatment recommendations
Conflicts of interest – ethically/legally proscribed
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Investment in dispensaries
“kickbacks for referrals”

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Public Safety
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Cognitive impairment in safety sensitive positions
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Workplace accidents
Driving and Accidents
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National Transportation Safety Board
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Studied 182 fatal truck accidents in 1999
Just as many accidents were caused by drivers impaired by MJ as by drivers impaired by Etoh
Increased criminal activity?
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A large percentage of those arrested for crimes test positive for MJ
Nationwide 40% of adult males tested positive for
MJ at the time of their arrest

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Sending the wrong message to children?
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Soda “pot”
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Edibles (colorful cookies, cupcakes, candy)
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“It’s organic, green, natural”
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Wellness ads (promoting MJ)
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Case Example: Peanut Butter “spiced” with MJ

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44-year-old female, grandmother and advocate for medical marijuana – used the drug for chronic back pain most of her life
Gave her 3-year-old grandson a peanut butter cookie made with cannabis butter
The next day she had trouble rousing the boy and called an ambulance
Police seized the jar of cannabis butter and the boy had the drug in his system
A week later the grandmother took her own life