Medical Marijuana: Pros Medical Marijuana: Pros and Consand Cons

A “Prescription” for Trouble?A “Prescription” for Trouble?

Elizabeth ‘Libby’ Stuyt, MDElizabeth ‘Libby’ Stuyt, MDUniversity of Colorado, Department of PsychiatryUniversity of Colorado, Department of Psychiatry

Medical Director, Circle ProgramMedical Director, Circle Program

Colorado Mental Health Institute at PuebloColorado Mental Health Institute at Pueblo

2012 Colorado Behavioral Healthcare Council 2012 Colorado Behavioral Healthcare Council

Annual Training Conference, Sept 28, 2012Annual Training Conference, Sept 28, 2012

ConflictsConflicts

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

CannabisCannabis Complex alkaloid mixture of more than Complex alkaloid mixture of more than

400 compounds derived from the 400 compounds derived from the Cannabis sativa plantCannabis sativa plant

60 different compounds described with 60 different compounds described with activity on the cannabinergic systemactivity on the cannabinergic system

Most abundant cannabinoids are Most abundant cannabinoids are Delta-9 tetrahydrocannabinol (most Delta-9 tetrahydrocannabinol (most

psychoactive)psychoactive) CannabidiolCannabidiol Cannabinol Cannabinol

Cannabinergic systemCannabinergic system Two main cannabis receptorsTwo main cannabis receptors CB1–present throughout CNSCB1–present throughout CNS

HippocampusHippocampus CortexCortex Olfactory areas Olfactory areas Basal gangliaBasal ganglia CerebellumCerebellum Spinal cordSpinal cord

CB2 – located peripherally, CB2 – located peripherally, linked with immune systemlinked with immune system

SpleenSpleen macrophagesmacrophages

History of MarijuanaHistory of Marijuana

6000 BC – Cannabis seeds used as 6000 BC – Cannabis seeds used as food in Chinafood in China

4000 BC – Textiles made of hemp in 4000 BC – Textiles made of hemp in ChinaChina

2727 BC – first recorded medicinal 2727 BC – first recorded medicinal use in Chinese Pharmacopoeia use in Chinese Pharmacopoeia

1400 BC to AD – trade moves product 1400 BC to AD – trade moves product through India, Mediterranean through India, Mediterranean countries, Europe – numerous countries, Europe – numerous medicinal uses reported medicinal uses reported

History of MarijuanaHistory of Marijuana

1378 – Emir of the Ottoman Empire 1378 – Emir of the Ottoman Empire makes the first edict against eating makes the first edict against eating hashish or smoking cannabis – 1hashish or smoking cannabis – 1stst “War “War on Drugs”on Drugs”

1798 – Napoleon declared total 1798 – Napoleon declared total prohibition on marijuana after realizing prohibition on marijuana after realizing much of the Egyptian lower class were much of the Egyptian lower class were habitual smokershabitual smokers

1868 – Egypt – 11868 – Egypt – 1stst modern country to modern country to outlaw cannabis ingestionoutlaw cannabis ingestion

1890 – Hashish made illegal in Turkey1890 – Hashish made illegal in Turkey

History of MarijuanaHistory of Marijuana

Introduced to North America in 1600s by Introduced to North America in 1600s by Puritans – Hemp for ropes, sails, clothing; Puritans – Hemp for ropes, sails, clothing; cannabis a common ingredient in cannabis a common ingredient in medicines, sold openly in pharmaciesmedicines, sold openly in pharmacies

1937 – Marijuana Tax Act – transfer of 1937 – Marijuana Tax Act – transfer of cannabis illegal throughout US except for cannabis illegal throughout US except for medicinal and industrial use, expensive medicinal and industrial use, expensive excise tax and detailed logs required excise tax and detailed logs required

1969 – found to be unconstitutional since 1969 – found to be unconstitutional since it violated 5it violated 5thth Amendment privilege against Amendment privilege against self-recriminationself-recrimination

History continuedHistory continued 1970 – Controlled Substance Act – 1970 – Controlled Substance Act –

classified cannabis as having:classified cannabis as having: High abuse potentialHigh abuse potential No medical useNo medical use Not safe to use under medical supervisionNot safe to use under medical supervision

1975 – FDA establishes Compassionate 1975 – FDA establishes Compassionate Use Program for Medical Marijuana – Use Program for Medical Marijuana – Glaucoma, Multiple Sclerosis, CancerGlaucoma, Multiple Sclerosis, Cancer

1986 – Dronabinol placed into Schedule II 1986 – Dronabinol placed into Schedule II by DEAby DEA

2003 – Canada – 12003 – Canada – 1stst country in world to country in world to offer medical marijuana to patientsoffer medical marijuana to patients

Compassionate Use – not based Compassionate Use – not based on any research on any research

Glaucoma - #1 cause of blindnessGlaucoma - #1 cause of blindness 1992 – American Academy of 1992 – American Academy of

Ophthalmology’s Committee on Drugs – Ophthalmology’s Committee on Drugs – no scientific verifiable evidence that the no scientific verifiable evidence that the use of marijuana is safe and effective in use of marijuana is safe and effective in the treatment of glaucomathe treatment of glaucoma

1997 – NEI – no studies have 1997 – NEI – no studies have demonstrated that marijuana can safely demonstrated that marijuana can safely and effectively lower IOP any more than and effectively lower IOP any more than a variety of drugs on the marketa variety of drugs on the market

GlaucomaGlaucoma

1999 – Institute of Medicine – although 1999 – Institute of Medicine – although IOP can be reduced by using IOP can be reduced by using cannabinoids and marijuana, the cannabinoids and marijuana, the effect is too short lived and requires effect is too short lived and requires too high doses.too high doses.

There are too many side effects to There are too many side effects to recommend lifelong use in the recommend lifelong use in the treatment of glaucomatreatment of glaucoma

Would have to smoke 10-12 joints per Would have to smoke 10-12 joints per 24 hours to maintain low IOP through 24 hours to maintain low IOP through out the dayout the day

IndicationsIndications

Dronabinol (Marinol) and nabilone Dronabinol (Marinol) and nabilone (Cesamet) indicated for chemotherapy-(Cesamet) indicated for chemotherapy-induced nausea and vomitinginduced nausea and vomiting

Dronabinol (Marinol) approved for HIV-Dronabinol (Marinol) approved for HIV-associated anorexiaassociated anorexia

Sativex (oromucosal spray) conditionally Sativex (oromucosal spray) conditionally approved for neuropathic pain in multiple approved for neuropathic pain in multiple sclerosis and cancer painsclerosis and cancer pain

Herbal smoked marijuana – found to be Herbal smoked marijuana – found to be safe and effective for HIV-associated safe and effective for HIV-associated disordersdisorders

CanadaCanada

Four cannabinoid products availableFour cannabinoid products available Herbal cannabis extract, “Sativex”, delta-Herbal cannabis extract, “Sativex”, delta-

9-THC and cannabidiol in oromucosal 9-THC and cannabidiol in oromucosal sprayspray

Dronabinol synthetic delta-9-THC, Dronabinol synthetic delta-9-THC, “Marinol”“Marinol”

Nabilone synthetic derivative of delta-9-Nabilone synthetic derivative of delta-9-THC, “Cesamet”THC, “Cesamet”

Herbal form of cannabis – “medical Herbal form of cannabis – “medical marijuana” marijuana”

Research IssuesResearch Issues MJ is a Schedule I drug – a barrier to conducting MJ is a Schedule I drug – a barrier to conducting

prospective RCTs, DB w/ placeboprospective RCTs, DB w/ placebo Studies are short - two weeks average, ranging from a few Studies are short - two weeks average, ranging from a few

hours to one yearhours to one year Most studies conducted with oral TCH preps rather than Most studies conducted with oral TCH preps rather than

smoked cannabissmoked cannabis Most studies exclude anyone with a history of major Most studies exclude anyone with a history of major

psychiatric disorder other than depression and/or history of psychiatric disorder other than depression and/or history of substance abusesubstance abuse

Most studies done to date:Most studies done to date: Short in length (average two weeks)Short in length (average two weeks) Small N (lacking power)Small N (lacking power) Retrospective in natureRetrospective in nature Confounded by uncontrolled variablesConfounded by uncontrolled variables

Concomitant tobacco useConcomitant tobacco use Comorbid illnessesComorbid illnesses

Studies of Effects on PainStudies of Effects on Pain

Lit review of cannabinoids given by any route Lit review of cannabinoids given by any route for treatment of painfor treatment of pain Campbell et al. BMJ 2001;323:1-6Campbell et al. BMJ 2001;323:1-6

9 RCTs, 222 patients, 5 trials cancer pain; 2 9 RCTs, 222 patients, 5 trials cancer pain; 2 chronic non-malignant pain; 2 post-operative chronic non-malignant pain; 2 post-operative pain; none evaluated cannabispain; none evaluated cannabis

““Cannabinoids are no more effective than Cannabinoids are no more effective than codeine in controlling pain and have codeine in controlling pain and have depressant effects on the CNS that limit their depressant effects on the CNS that limit their use. In acute postoperative pain they should use. In acute postoperative pain they should not be used. Before cannabinoids can be not be used. Before cannabinoids can be considered for treating spasticity and considered for treating spasticity and neuropathic pain, further valid randomized neuropathic pain, further valid randomized controlled studies are needed.”controlled studies are needed.”

Side Effects of CannabisSide Effects of Cannabis

Most of our knowledge about the Most of our knowledge about the negative effects of marijuana come negative effects of marijuana come from recreational usefrom recreational use

Literature review of safety studies of Literature review of safety studies of medical cannabinoids over past 40 medical cannabinoids over past 40 years – 23 RCTs (median exposure to years – 23 RCTs (median exposure to cannabinoids 2 weeks, range 8 hrs to cannabinoids 2 weeks, range 8 hrs to 12 months) Wang et al. CMAJ 12 months) Wang et al. CMAJ 2008;17:1669-16782008;17:1669-1678

Side EffectsSide Effects

4779 adverse events reported in 4779 adverse events reported in those assigned to the interventionthose assigned to the intervention

96.6% were not serious96.6% were not serious 164 serious events – no different 164 serious events – no different

from controls (RR) 1.04from controls (RR) 1.04 Rate of nonserious events higher Rate of nonserious events higher

among those assigned medical among those assigned medical cannabinoids than controls (RR)1.86 cannabinoids than controls (RR)1.86 – dizziness most common event– dizziness most common event

Studies with Smoked CannabisStudies with Smoked Cannabis Double-blind, placebo controlled, Double-blind, placebo controlled,

crossover trial of smoked cannabis crossover trial of smoked cannabis for the short term treatment of for the short term treatment of neuropathic pain associated with HIV neuropathic pain associated with HIV – five study phases over 7 weeks – – five study phases over 7 weeks – five days of active or placebo five days of active or placebo smoking with washout periodssmoking with washout periods

Participants had documented HIV, Participants had documented HIV, neuropathic pain refractory to a least neuropathic pain refractory to a least two previous analgesics, 5 or higher two previous analgesics, 5 or higher on pain scale on pain scale (Ellis et al. (Ellis et al. Neuropyschopharmacology 2009;34:672-680)Neuropyschopharmacology 2009;34:672-680)

Studies of Smoked CannabisStudies of Smoked Cannabis

Four smoking sessions per day, titrating dose Four smoking sessions per day, titrating dose (1-8% THC) to achieve maximum tolerable (1-8% THC) to achieve maximum tolerable dosedose

Exclusion criteriaExclusion criteria Current substance use disorderCurrent substance use disorder Lifetime history of dependence on cannabisLifetime history of dependence on cannabis Concurrent use of medication with Concurrent use of medication with

cannabinoidscannabinoids Previous psychosis with or intolerance to Previous psychosis with or intolerance to

cannabinoids cannabinoids

ResultsResults ““significantly reduced neuropathic pain significantly reduced neuropathic pain

intensity compared to placebo”intensity compared to placebo” 46% with cannabis reported a 46% with cannabis reported a ≥≥ 30% 30%

reduction in pain versus 18% with placeboreduction in pain versus 18% with placebo Another study with almost identical Another study with almost identical

outcomes – 52% vs 24%, >30% reduction outcomes – 52% vs 24%, >30% reduction in pain with 3 smoking sessions/dayin pain with 3 smoking sessions/day (Abrams et al. Neurology 2007:68:515-521)(Abrams et al. Neurology 2007:68:515-521)

““All patients were required to have prior All patients were required to have prior experience smoking marijuana so they experience smoking marijuana so they would know how to inhale and what would know how to inhale and what neuropsychological effects to expect”neuropsychological effects to expect”

More Studies of Smoked CannabisMore Studies of Smoked Cannabis Ware et al. CMAJ. 2010;E694-E701.Ware et al. CMAJ. 2010;E694-E701.

N=21N=21 Inclusion CriteriaInclusion Criteria

Outpatients with > 3 month hx neuropathic Outpatients with > 3 month hx neuropathic painpain

Pain caused by physical trauma or surgeryPain caused by physical trauma or surgery Pain intensity > 4 (0 to 10 scale)Pain intensity > 4 (0 to 10 scale)

Randomized, double-blind, placebo-controlled, Randomized, double-blind, placebo-controlled, four-period crossover design four-period crossover design

THC concentration = 0, 2.5%, 6% or 9.4% THC concentration = 0, 2.5%, 6% or 9.4% Three daily dosages x 5 daysThree daily dosages x 5 days 9 day washout period.9 day washout period.

Participants Participants advisedadvised not to drive a vehicle or not to drive a vehicle or operate heavy machinery while on study drugoperate heavy machinery while on study drug

Ware et al. CMAJ. 2010;E694-E701(cont)Ware et al. CMAJ. 2010;E694-E701(cont)

Average daily pain intensity:Average daily pain intensity: 5.4 on 9.4% THC cannabis 5.4 on 9.4% THC cannabis 6.1 on Placebo(0% THC)6.1 on Placebo(0% THC) (p=0.023;difference = 0.7, 95% CI 0.02-1.4)(p=0.023;difference = 0.7, 95% CI 0.02-1.4)

No difference observed between 2.5%, 6%, 0%No difference observed between 2.5%, 6%, 0% The reduction is modest when compared with The reduction is modest when compared with

that from other drugs for neuropathic pain that from other drugs for neuropathic pain such as gabapentin or pregabalinsuch as gabapentin or pregabalin

A “joint” with a 9.4% THC content would A “joint” with a 9.4% THC content would impair the majority of usimpair the majority of us

Dose-dependent effects of smoked cannabis on Capsaicin-Dose-dependent effects of smoked cannabis on Capsaicin-induced pain and hyperalgesia in healthy volunteersinduced pain and hyperalgesia in healthy volunteers

(Wallace et al. Anesthesiology. 2007;107:785-796)(Wallace et al. Anesthesiology. 2007;107:785-796)

Randomized, double-blinded, placebo-Randomized, double-blinded, placebo-controlled, crossover designcontrolled, crossover design

High dose training session, 15 subjectsHigh dose training session, 15 subjects 100 mg capsaicin injected 100 mg capsaicin injected

intradermally ventral forearm – intradermally ventral forearm – spontaneous painspontaneous pain

Stroking and von Frey hair stimulation Stroking and von Frey hair stimulation – elicited pain– elicited pain

Low dose 2% THC, medium dose Low dose 2% THC, medium dose 4%THC, high dose 8% THC4%THC, high dose 8% THC

ResultsResults Capsaicin injections induced spontaneous Capsaicin injections induced spontaneous

and elicited pain in all subjectsand elicited pain in all subjects No difference in pain perception between No difference in pain perception between

any of the cannabis doses and placebo any of the cannabis doses and placebo during early (right arm) courseduring early (right arm) course

Low dose did not differ from placebo at Low dose did not differ from placebo at any time pointany time point

During late course (left arm) medium dose During late course (left arm) medium dose subjects reported decreased pain subjects reported decreased pain sensation, high dose subjects reported sensation, high dose subjects reported increased perception of pain – consistent increased perception of pain – consistent with other reports that chronic delivery of with other reports that chronic delivery of cannabinoids can cause thermal cannabinoids can cause thermal hyperalgesiahyperalgesia

So To ReviewSo To Review

Marijuana (smoked/oral) used as a Marijuana (smoked/oral) used as a therapeutic, not recreational agent, is a therapeutic, not recreational agent, is a drugdrug as defined by the FDA as defined by the FDA

All new drugs must be scientifically All new drugs must be scientifically evaluated before they may be allowed to evaluated before they may be allowed to enter the stream of interstate commerceenter the stream of interstate commerce

The drug does not have to be proven The drug does not have to be proven superior to already approved drugs, its superior to already approved drugs, its benefits must outweigh the risks when benefits must outweigh the risks when used for the purpose for which it has been used for the purpose for which it has been approvedapproved

The fact that it is a botanical does The fact that it is a botanical does not preclude scientific investigationnot preclude scientific investigation

Digitalis purpurea – fox glove - CHFDigitalis purpurea – fox glove - CHF Papaver somniferum – opium poppyPapaver somniferum – opium poppy Atropa belladonna – nightshade -IBSAtropa belladonna – nightshade -IBS Ephedra sinica – ephedrine - Ephedra sinica – ephedrine -

hypotensionhypotension Salix alba – willow tree - ASASalix alba – willow tree - ASA Taxis brevifolia – Pacific Yew tree – Taxis brevifolia – Pacific Yew tree –

breast cancerbreast cancer

DEA – Scheduling Drugs depends on:DEA – Scheduling Drugs depends on:

Does the drug have a currently accepted Does the drug have a currently accepted medical use in the United States?medical use in the United States?

What is the drug’s safety under medical What is the drug’s safety under medical supervision?supervision?

What is its addiction liability?What is its addiction liability? Is there a potential for significant diversion Is there a potential for significant diversion

for illegal use?for illegal use? Are individuals using it on their own Are individuals using it on their own

initiative or only on physician’s initiative or only on physician’s prescription?prescription?

Is the drug similar in its pharmacology to Is the drug similar in its pharmacology to other controlled drugs?other controlled drugs?

““Rocky Mountain High”Rocky Mountain High”ColoradoColorado

November 2000 November 2000

Coloradoans passed Amendment 20 Coloradoans passed Amendment 20

Colorado Department of Public Health and Colorado Department of Public Health and Environment was tasked with implementing Environment was tasked with implementing and administrating the Medical Marijuana and administrating the Medical Marijuana Registry program Registry program

March 2001 March 2001

Colorado Board of Health approved rules and Colorado Board of Health approved rules and regulations regulations

June 2001June 2001

MMJ Registry began accepting applications for MMJ Registry began accepting applications for Registry Identification Cards. Registry Identification Cards.

The Flood Gates OpenedThe Flood Gates Opened

February 2009 February 2009 Obama administration indicated that Medical Obama administration indicated that Medical

Marijuana prosecution would have low priorityMarijuana prosecution would have low priority October 2009 October 2009

Obama administration will not seek to arrest Obama administration will not seek to arrest medical marijuana users and suppliers as long medical marijuana users and suppliers as long as they conform to state laws as they conform to state laws

Applications increased dramaticallyApplications increased dramatically September 2009 – 3,523 applications September 2009 – 3,523 applications

received/monthreceived/month December 2009 – 10,585 applications December 2009 – 10,585 applications

received/monthreceived/month

Storefront “Medical” Marijuana Storefront “Medical” Marijuana dispensaries sprouted like weeds! dispensaries sprouted like weeds!

Marijuana GrowersMarijuana Growers CaregiversCaregivers Legal Legal Doctors making recommendations ($$$$)Doctors making recommendations ($$$$) Grow LightsGrow Lights VaporizersVaporizers PipesPipes EdiblesEdibles Advertising (Westword has gone “green”)Advertising (Westword has gone “green”) FestivalsFestivals Delivery ServicesDelivery Services

September 30, 2009 June 30, 2012 19,691 new patient 19,691 new patient

applications receivedapplications received 17,356 patients with valid 17,356 patients with valid

ID cardsID cards 73% male, average age 73% male, average age

40, 8 minors <1840, 8 minors <18 57% in the Denver/metro 57% in the Denver/metro

areaarea 67% have designated 67% have designated

primary care-giverprimary care-giver Over Over 800800 different different

physiciansphysicians have signed for have signed for patients in Coloradopatients in Colorado

184,002 new patient 184,002 new patient applications receivedapplications received

99,960 patients with Valid 99,960 patients with Valid ID cardsID cards

68% male, average age 68% male, average age 42, 47 minors <1842, 47 minors <18

56% in the Denver/metro 56% in the Denver/metro areaarea

54% have designated 54% have designated primary care-giverprimary care-giver

Over Over 900900 different different physiciansphysicians have signed for have signed for patients in Coloradopatients in Colorado

Conditions (as of June 2012)

Condition # of Patients Percentage

Cachexia 1,215 1%

Cancer 2,583 3%

Glaucoma 1,021 1%

HIV/AIDS 632 1%

Muscle Spasms 17,286 17%

Seizures 1,708 2%

Severe Pain 93,679 94%

Severe Nausea 11,567 12%

Rules and RegulationsRules and Regulations

““Patient will be deemed to have established an Patient will be deemed to have established an affirmative defense to such allegation” affirmative defense to such allegation” (possession of marijuana) where:(possession of marijuana) where:

Patient was previously diagnosed by a Patient was previously diagnosed by a physician as having a debilitating medical physician as having a debilitating medical conditioncondition

Patient was advised by his or her physician, in Patient was advised by his or her physician, in the context of a bona fide physician-patient the context of a bona fide physician-patient relationship, that the patient might benefit relationship, that the patient might benefit from the medical use of marijuana in from the medical use of marijuana in connection with a debilitating medical connection with a debilitating medical conditioncondition

Conditions considered debilitatingConditions considered debilitating

CachexiaCachexia Severe PainSevere Pain Severe NauseaSevere Nausea SeizuresSeizures Persistent Muscle SpasmsPersistent Muscle Spasms Any other medical condition Any other medical condition

approved by the state health agencyapproved by the state health agency

Lobbying for New ConditionsLobbying for New Conditionsunsuccessful so far:unsuccessful so far:

AsthmaAsthma AtherosclerosisAtherosclerosis Crohn’s DiseaseCrohn’s Disease Diabetes MellitusDiabetes Mellitus Hepatitis CHepatitis C Hypertension Hypertension

MRSAMRSA Rheumatoid Rheumatoid

ArthritisArthritis

Opioid DependenceOpioid Dependence PTSDPTSD Bipolar DisorderBipolar Disorder Anxiety DisordersAnxiety Disorders DepressionDepression Tourette’s DisorderTourette’s Disorder

Rules and RegulationsRules and Regulations

Patient may engage in the medical use Patient may engage in the medical use of marijuana with no more marijuana of marijuana with no more marijuana than is medically necessary to address than is medically necessary to address a debilitating medical conditiona debilitating medical condition

No more than 2 ounces and no more No more than 2 ounces and no more than six plants, 3 or fewer being maturethan six plants, 3 or fewer being mature

No patient shall engage in medical use No patient shall engage in medical use of marijuana in plain view of, or in a of marijuana in plain view of, or in a place open to, the general publicplace open to, the general public

Problems with the physiciansProblems with the physicians

In the fall of 2009 @ 900 doctors had In the fall of 2009 @ 900 doctors had written approval letters (7% of written approval letters (7% of licensed MDs)licensed MDs)

15 doctors – 72% of forms15 doctors – 72% of forms 5 doctors – 50 % of forms5 doctors – 50 % of forms One doctor signed 3,500 in a two day One doctor signed 3,500 in a two day

periodperiod

SB 109 - 2010SB 109 - 2010

Defines a bona fide relationshipDefines a bona fide relationship Physician must have an unrestricted Physician must have an unrestricted

medical and DEA licensemedical and DEA license Addresses physician conflict of interest Addresses physician conflict of interest

– physician can not be employed by – physician can not be employed by the dispensarythe dispensary

Allows CMB to examine care of Allows CMB to examine care of providersproviders

Two physicians need to independently Two physicians need to independently examine those < 21.examine those < 21.

ImplicationsImplications

The vast majority of these patients The vast majority of these patients don’t have debilitating illnesses don’t have debilitating illnesses

The majority of the patients are young The majority of the patients are young males who will be exposed to the long males who will be exposed to the long term effects of cannabis exposureterm effects of cannabis exposure

Studies conducted are all short termStudies conducted are all short term Therefore their risks may be the same Therefore their risks may be the same

as for recreational users and/or addictsas for recreational users and/or addicts

Therefore Physicians Therefore Physicians Recommending Medical MarijuanaRecommending Medical Marijuana

Will need to get a thorough history - Will need to get a thorough history - medically, psychiatrically and substance medically, psychiatrically and substance abuse – keep a chart and have a abuse – keep a chart and have a patient/physician relationshippatient/physician relationship

Will need to attempt to decide what level Will need to attempt to decide what level of marijuana use is most appropriateof marijuana use is most appropriate

Will need to recommend patients not drive Will need to recommend patients not drive etc. when under the influenceetc. when under the influence

Will need to follow patients closely for side Will need to follow patients closely for side effects and unintended consequenceseffects and unintended consequences

Marijuana use and Cancer riskMarijuana use and Cancer risk

Marijuana smoke contains several of Marijuana smoke contains several of the same carcinogens and co-the same carcinogens and co-carcinogens as tobacco smokecarcinogens as tobacco smoke

Benzo[Benzo[αα]pyrene, a procarcinogenic ]pyrene, a procarcinogenic polycyclic aromatic hydrocarbon, is polycyclic aromatic hydrocarbon, is present in marijuana tar at higher present in marijuana tar at higher concentrations than in tobacco tarconcentrations than in tobacco tar

Marijuana smoking involves Marijuana smoking involves inhalation of 3 times the amount of inhalation of 3 times the amount of tar as tobacco smoketar as tobacco smoke

Cancer Studies involving MarijuanaCancer Studies involving Marijuana

Studies are small in number and are Studies are small in number and are retrospective in natureretrospective in nature

Confounded by concomitant use of Confounded by concomitant use of tobaccotobacco

Confounded by underreporting of Confounded by underreporting of marijuana use because such use is marijuana use because such use is often illegaloften illegal

Cannabis use and risk of Lung Cannabis use and risk of Lung Cancer Cancer Aldington et al. Eur Respir J. 2008;31:280-286Aldington et al. Eur Respir J. 2008;31:280-286

Case-controlled study of lung cancer in Case-controlled study of lung cancer in adults adults << 55yrs of age in New Zealand 55yrs of age in New Zealand

79 cases of lung cancer and 324 controls79 cases of lung cancer and 324 controls Risk of lung cancer increased 8% for each Risk of lung cancer increased 8% for each

joint-yr (1 joint/day for one year) of joint-yr (1 joint/day for one year) of cannabis smoking after adjustment for cannabis smoking after adjustment for confounding variables including tobaccoconfounding variables including tobacco

Risk increased 7% for each pack-yr Risk increased 7% for each pack-yr tobacco tobacco

““Long-term cannabis use increases risk of Long-term cannabis use increases risk of lung cancer in young adults”lung cancer in young adults”

Head and Neck CancersHead and Neck Cancers

Retrospective, case-controlled study, Retrospective, case-controlled study, 173 proven cases of head and neck 173 proven cases of head and neck cancer and 176 controls matched with cancer and 176 controls matched with respect to age, sex, race, education, respect to age, sex, race, education, tobacco, alcohol usetobacco, alcohol use

Risk of cancer 2.6 fold greater in Risk of cancer 2.6 fold greater in cannabis users than non-userscannabis users than non-users

3-fold greater increase in those 3-fold greater increase in those << 55 yrs 55 yrs Zhang et al. Cancer Epidemiol Biomark Zhang et al. Cancer Epidemiol Biomark

Prev 1999;8:1071-1078.Prev 1999;8:1071-1078.

Other CancersOther Cancers

In a cohort study – among non-tobacco In a cohort study – among non-tobacco smokers, ever-marijuana smokers had smokers, ever-marijuana smokers had increased risk for prostate cancer - increased risk for prostate cancer - RR=3.1, and cervical cancer - RR=1.4 RR=3.1, and cervical cancer - RR=1.4 Sidney et al. Cancer Causes Control 1997;8:722-728.Sidney et al. Cancer Causes Control 1997;8:722-728.

Another cohort study found an Another cohort study found an increased risk of malignant primary increased risk of malignant primary adult-onset glioma for ever-marijuana adult-onset glioma for ever-marijuana smokers – RR=1.9 smokers – RR=1.9 Efird et al. J Neurooncol Efird et al. J Neurooncol 2004;68:57-692004;68:57-69

Metabolism of MarijuanaMetabolism of Marijuana

Massive first pass metabolism via the oral Massive first pass metabolism via the oral route – only 10-20% reaches systemic route – only 10-20% reaches systemic circulation unchanged – takes 30 – 60 circulation unchanged – takes 30 – 60 minutes to achieve an effect – key side minutes to achieve an effect – key side effect on CNS can be dysphoria rather effect on CNS can be dysphoria rather than euphoriathan euphoria

Via the lungs – onset of action within Via the lungs – onset of action within seconds – “high” experienced with serum seconds – “high” experienced with serum concentration of 3 ng/ml, produced by as concentration of 3 ng/ml, produced by as little as 2-3 mg D9THC, average “joint” little as 2-3 mg D9THC, average “joint” contains 0.5 – 1.0 g of cannabiscontains 0.5 – 1.0 g of cannabis

Routes of AdministrationRoutes of Administration

““Where there’s smoke, there’s harm”, Where there’s smoke, there’s harm”, “There is no future in smoking marijuana as “There is no future in smoking marijuana as a conventional medicine” Janet Joy PhDa conventional medicine” Janet Joy PhD

Until there is an alternative, for a small Until there is an alternative, for a small segment of the population – there is a segment of the population – there is a modestmodest clinical benefit of smoked marijuana clinical benefit of smoked marijuana

Sound theoretical reasons for intrathecal or Sound theoretical reasons for intrathecal or epidural cannabinoids – may produce spinal epidural cannabinoids – may produce spinal cord analgesia without effects on cerebral cord analgesia without effects on cerebral receptors that are associated with receptors that are associated with psychotropic effectspsychotropic effects

Marijuana and Cognitive ImpairmentMarijuana and Cognitive Impairment

Use of 4 joints or more per week Use of 4 joints or more per week resulted in a decrement in mental test resulted in a decrement in mental test performance, subjects who smoked performance, subjects who smoked regularly for a decade or more did the regularly for a decade or more did the worst worst Messinis et al. Neurology 2006;66:737Messinis et al. Neurology 2006;66:737

Long-term marijuana users were Long-term marijuana users were impaired 70% of the time on a decision impaired 70% of the time on a decision making test, compared to 55% for making test, compared to 55% for short-term users and 8% for non-usersshort-term users and 8% for non-users

Marijuana and Cognitive ImpairmentMarijuana and Cognitive Impairment

Heavy marijuana use (daily for at least Heavy marijuana use (daily for at least one month) is associated with residual one month) is associated with residual neuropsychological effects even after neuropsychological effects even after a day of supervised abstinence from a day of supervised abstinence from the drugthe drug Harrison et al. JAMA 1996;275:521 Harrison et al. JAMA 1996;275:521

Unknown whether this is due to Unknown whether this is due to residue of drug in the brain, residue of drug in the brain, withdrawal effects or frank neurotoxic withdrawal effects or frank neurotoxic effect of the drugeffect of the drug

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Fre

qu

en

cy

SampleNumberSampleNumber

11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717

ScrScrScrScrBasBasFemale 1 PresentFemale 1 Present

ScrScrFemale 2 PresentFemale 2 Present

ScrScr

Source: Fiorino and PhillipsSource: Fiorino and Phillips

SEXSEX

Natural Rewards Elevate Dopamine LevelsNatural Rewards Elevate Dopamine LevelsNatural Rewards Elevate Dopamine LevelsNatural Rewards Elevate Dopamine Levels

00100100200200300300400400500500600600700700800800900900

1000100011001100

00 11 22 33 44 5 hr5 hr

Time After AmphetamineTime After Amphetamine

% o

f B

as

al

Re

lea

se

% o

f B

as

al

Re

lea

se

DADADOPACDOPACHVAHVA

AccumbensAccumbens AMPHETAMINEAMPHETAMINE

00

100100

150150

200200

250250

00 11 22 3 hr3 hrTime After NicotineTime After Nicotine

% o

f B

as

al

Re

lea

se

% o

f B

as

al

Re

lea

se

AccumbensAccumbensCaudateCaudate

NICOTINENICOTINE

Source: Di Chiara and ImperatoSource: Di Chiara and Imperato

Effects of Drugs on Dopamine LevelsEffects of Drugs on Dopamine LevelsEffects of Drugs on Dopamine LevelsEffects of Drugs on Dopamine Levels

THC/Marijuana

00

100100

150150

200200

250250

00 11 22 33 44 5hr5hrTime After MorphineTime After Morphine

% o

f B

as

al

Re

lea

se

% o

f B

as

al

Re

lea

se

AccumbensAccumbens

0.50.51.01.02.52.51010

Dose (mg/kg)Dose (mg/kg)

MORPHINEMORPHINE

Effects of Drug Use on the Effects of Drug Use on the HippocampusHippocampus

Drugs of abuse are potent negative Drugs of abuse are potent negative regulators of adult neurogenesis in regulators of adult neurogenesis in the hippocampusthe hippocampus

Chronic administration of opiates, Chronic administration of opiates, THC, ethanol or nicotine decreases THC, ethanol or nicotine decreases hippocampal function, decreasing hippocampal function, decreasing ability of adult brain to adapt to new ability of adult brain to adapt to new informationinformation

Regional Brain Abnormalities Associated Regional Brain Abnormalities Associated

with Long-term heavy Cannabis Usewith Long-term heavy Cannabis Use Arch Gen Arch Gen

Psychiatry 2008;65:694-701Psychiatry 2008;65:694-701

15 long term (>10 years) and heavy (>5 15 long term (>10 years) and heavy (>5 joints daily) cannabis using men compared joints daily) cannabis using men compared with 16 age matched non using controls by with 16 age matched non using controls by MRIs of brainsMRIs of brains

Cannabis users had bilaterally reduced Cannabis users had bilaterally reduced hippocampal and amygdala volumes p=.001hippocampal and amygdala volumes p=.001

Increase in positive symptoms (psychotic) Increase in positive symptoms (psychotic) p<.001p<.001

Significantly worse performance on Significantly worse performance on measures of verbal learning p<.001measures of verbal learning p<.001

Multiple Sclerosis and Cannabis: A Multiple Sclerosis and Cannabis: A cognitive and psychiatric studycognitive and psychiatric study

10 subjects with MS and current 10 subjects with MS and current cannabis users compared with 40 cannabis users compared with 40 subjects with MS who did not use subjects with MS who did not use cannabiscannabis

psychiatric diagnosis higher in cannabis psychiatric diagnosis higher in cannabis users p=0.04users p=0.04

Slower mean performance time on SDMT Slower mean performance time on SDMT (index of information processing speed, (index of information processing speed, working memory and sustained working memory and sustained attention) in the cannabis users p=0.006attention) in the cannabis users p=0.006

Neurology 2008;71:164-169Neurology 2008;71:164-169

Marijuana and DrivingMarijuana and Driving Laboratory tests and driving studies show Laboratory tests and driving studies show

that cannabis may acutely impair several that cannabis may acutely impair several driving-related skills in a dose related fashiondriving-related skills in a dose related fashion

Effects between individuals vary more than Effects between individuals vary more than for alcohol because of tolerance, differences for alcohol because of tolerance, differences in smoking technique, and different in smoking technique, and different absorptions of THCabsorptions of THC Sewell et al. Am J Addictions Sewell et al. Am J Addictions 2009;18:185-193.2009;18:185-193.

More pronounced with highly automatic More pronounced with highly automatic driving functions; less with complex tasks driving functions; less with complex tasks that require conscious control – opposite that require conscious control – opposite from that seen with alcoholfrom that seen with alcohol

Effects of Marijuana Intoxication and Effects of Marijuana Intoxication and Pilot PerformancePilot Performance Am J Psychiatry 1985;142:1325-1329Am J Psychiatry 1985;142:1325-1329

Ten experienced licensed private pilots Ten experienced licensed private pilots trained for 8 hours on a flight trained for 8 hours on a flight stimulator landing taskstimulator landing task

Each smoked a THC cigarette (19 mg)Each smoked a THC cigarette (19 mg) 24 hours later their mean performance 24 hours later their mean performance

on the flight task showed trends on the flight task showed trends toward impairment in all variables, toward impairment in all variables, some tasks showed significant some tasks showed significant impairmentimpairment

Despite the deficits, the pilots reported Despite the deficits, the pilots reported no awareness of impaired performanceno awareness of impaired performance

Marijuana and Mental IllnessMarijuana and Mental Illness

Study in Australia tracked 1600 girls for 7 Study in Australia tracked 1600 girls for 7 yearsyears Arseneault et al. BMJ 2002;325:1212 Arseneault et al. BMJ 2002;325:1212

Those who used marijuana every day were 5 Those who used marijuana every day were 5 times more likely to suffer from depression times more likely to suffer from depression and anxiety than non-usersand anxiety than non-users

Teenage girls who used the drug a least once Teenage girls who used the drug a least once a week were twice as likely to develop a week were twice as likely to develop depression than those who did not usedepression than those who did not use

Cannabis use increased the risk of developing Cannabis use increased the risk of developing schizophrenia symptoms – specific to schizophrenia symptoms – specific to cannabis and early onset – prior to age 15cannabis and early onset – prior to age 15

Risk of PsychosisRisk of Psychosis

Increased by 40% in people who Increased by 40% in people who have used cannabishave used cannabis Cohen et al. Australian Cohen et al. Australian New Zealand J Psychiatry 2008;42:357-368.New Zealand J Psychiatry 2008;42:357-368.

Dose-response effect leading to an Dose-response effect leading to an increased risk of 50-200% in the increased risk of 50-200% in the most frequent usersmost frequent users

Approximately 14% of psychotic Approximately 14% of psychotic outcomes in young people would not outcomes in young people would not have occurred if cannabis had not have occurred if cannabis had not been consumedbeen consumed

Early Cannabis use associated with Early Cannabis use associated with psychosis related outcomes in young psychosis related outcomes in young

adults adults Arch Gen Psych 2010;67Arch Gen Psych 2010;67

Sibling pair analysis within a Sibling pair analysis within a prospective birth cohort in Australiaprospective birth cohort in Australia

3801 young adults – cannabis use 3801 young adults – cannabis use and 3 psychosis-related outcomes and 3 psychosis-related outcomes (nonaffective psychosis, (nonaffective psychosis, hallucinations, and Delusional hallucinations, and Delusional Inventory score)Inventory score)

Early cannabis use is associated with Early cannabis use is associated with psychosis-related outcomes in young psychosis-related outcomes in young adultsadults

Marijuana and SchizophreniaMarijuana and Schizophreniadouble-edged sworddouble-edged sword

Low doses may improve frontal lobe Low doses may improve frontal lobe functioning by acutely increasing blood flow to functioning by acutely increasing blood flow to cortices concerned with cognition, mood and cortices concerned with cognition, mood and perception – increasing availability and perception – increasing availability and utilization of dopamineutilization of dopamine

Continued use depresses cerebral flow and Continued use depresses cerebral flow and high doses augment mesolimbic dopamine high doses augment mesolimbic dopamine release, opposing therapeutic effects of release, opposing therapeutic effects of antipsychotic drugs and exacerbating antipsychotic drugs and exacerbating psychosis psychosis

It also suppresses PFC dopamine utilization It also suppresses PFC dopamine utilization resulting in cognitive dysfunctionresulting in cognitive dysfunction

SpiceSpice

Synthetic cannabinoids AM694 and HU210 Synthetic cannabinoids AM694 and HU210 found in Spice products are 500 to 600 times found in Spice products are 500 to 600 times more potent than the THC found in more potent than the THC found in traditional marijuanatraditional marijuana

The THC in high potency marijuana and The THC in high potency marijuana and Spice products are potentially harmful to Spice products are potentially harmful to embryonic development as early as 2 weeks embryonic development as early as 2 weeks after conceptionafter conception

Utero exposure to THC linked to Utero exposure to THC linked to anencephaly, ADHD, Depression, Aggressionanencephaly, ADHD, Depression, Aggression

Rats exposed to nicotine as adolescents self-Rats exposed to nicotine as adolescents self-administer more nicotine than rats exposed as administer more nicotine than rats exposed as

adults adults Levin ED et al. Psychopharm 2000;169:141-149Levin ED et al. Psychopharm 2000;169:141-149

Rats First Exposed to Nicotine in Adolescence Rats First Exposed to Nicotine in Adolescence Show Greater Sensitization to Cocaine Than Show Greater Sensitization to Cocaine Than

Rats First Exposed as AdultsRats First Exposed as Adults

Sources: Collins et al, 2004, Levin et al, 2003, NIDA Notes v19.2

*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.

Marijuana and AddictionMarijuana and Addiction

Approximately 10% of regular marijuana Approximately 10% of regular marijuana users become addicted to itusers become addicted to it But this is old data, based on marijuana But this is old data, based on marijuana

with less THC concentrationswith less THC concentrations Some medicinal marijuana blends, ie Some medicinal marijuana blends, ie

“Connie Chung” strain contain 20 times “Connie Chung” strain contain 20 times more THC than marijuana found 40 years more THC than marijuana found 40 years agoago

Compared with 15% for alcohol, 32% for Compared with 15% for alcohol, 32% for nicotine and 26% for opiatesnicotine and 26% for opiates

The number of adults with The number of adults with substance use disorders is substance use disorders is

trending upward and expected trending upward and expected to double by the year 2020to double by the year 2020

Colorado ranks 5Colorado ranks 5thth in the nation in the nation for adolescent marijuana use.for adolescent marijuana use.

Pros and Cons of MarijuanaPros and Cons of Marijuana

Not associated with Not associated with deathdeath

Not as addicting as Not as addicting as other drugsother drugs

ModestModest benefit benefit demonstrated for demonstrated for smallsmall segment of segment of the population in the population in short term useshort term use

Marked negative Marked negative cognitive effectscognitive effects

Very dangerous to Very dangerous to adolescent brain adolescent brain development and development and occurrence of occurrence of mental illnessmental illness

Cancer riskCancer risk Driving impairmentDriving impairment

What’s the going rate?What’s the going rate?

One joint weighs @ One joint weighs @ 0.9 grams with 0.9 grams with 3.56% THC (Abrams 3.56% THC (Abrams study)study)

0.9 g = 0.03 oz0.9 g = 0.03 oz ¼ oz = 7.1 g¼ oz = 7.1 g 1 oz = 28 g1 oz = 28 g 1 oz = 31 joints; at 3 1 oz = 31 joints; at 3

joints per day – need joints per day – need 3 oz per month3 oz per month

$900/month$900/month

The Hippocratic OathThe Hippocratic Oath

First……….do no harmFirst……….do no harm

The practice of medicine is a The practice of medicine is a privilegeprivilege……. not a right!……. not a right!

Malignant versus Non-malignantMalignant versus Non-malignant

There is definitely a place for Medical There is definitely a place for Medical Marijuana when people are suffering Marijuana when people are suffering with terminal conditionswith terminal conditions Cachexia – appetite stimulantCachexia – appetite stimulant Nausea – secondary to chemotherapyNausea – secondary to chemotherapy Pain – mild improvement Pain – mild improvement

Neither opioid medications nor Neither opioid medications nor medical marijuana is the answer for medical marijuana is the answer for chronic, non-malignant painchronic, non-malignant pain

Physician MotivesPhysician Motives

Financial incentives and/or personal Financial incentives and/or personal political views should not influence political views should not influence treatment recommendationstreatment recommendations

Conflicts of interest – ethically/legally Conflicts of interest – ethically/legally proscribedproscribed Investment in dispensariesInvestment in dispensaries ““kickbacks for referrals”kickbacks for referrals”

Societal CostsSocietal Costs Public SafetyPublic Safety

Cognitive impairment in safety sensitive positionsCognitive impairment in safety sensitive positions Workplace accidentsWorkplace accidents Driving and AccidentsDriving and Accidents

National Transportation Safety BoardNational Transportation Safety Board Studied 182 fatal truck accidents in 1999Studied 182 fatal truck accidents in 1999 Just as many accidents were caused by drivers Just as many accidents were caused by drivers

impaired by MJ as by drivers impaired by Etohimpaired by MJ as by drivers impaired by Etoh Increased criminal activity?Increased criminal activity?

A large percentage of those arrested for crimes A large percentage of those arrested for crimes test positive for MJtest positive for MJ

Nationwide 40% of adult males tested positive for Nationwide 40% of adult males tested positive for MJ at the time of their arrestMJ at the time of their arrest

Societal CostsSocietal Costs

Sending the wrong message to Sending the wrong message to children?children? Soda “pot”Soda “pot” Edibles (colorful cookies, cupcakes, Edibles (colorful cookies, cupcakes,

candy)candy) ““It’s organic, green, natural”It’s organic, green, natural” Wellness ads (promoting MJ)Wellness ads (promoting MJ) Case Example: Peanut Butter “spiced” Case Example: Peanut Butter “spiced”

with MJwith MJ

Case Vignette Case Vignette Denver Post – December 2009Denver Post – December 2009

44-year-old female, grandmother and 44-year-old female, grandmother and advocate for medical marijuana – used the advocate for medical marijuana – used the drug for chronic back pain most of her lifedrug for chronic back pain most of her life

Gave her 3-year-old grandson a peanut Gave her 3-year-old grandson a peanut butter cookie made with cannabis butterbutter cookie made with cannabis butter

The next day she had trouble rousing the The next day she had trouble rousing the boy and called an ambulanceboy and called an ambulance

Police seized the jar of cannabis butter Police seized the jar of cannabis butter and the boy had the drug in his systemand the boy had the drug in his system

A week later the grandmother took her A week later the grandmother took her own lifeown life

In the End – Prevention is KeyIn the End – Prevention is Key