Marijuana: What Does The Evidence Show? Allen C. Bowling, MD, PhD Physician Associate Colorado Neurological Institute (CNI)

Marijuana:Marijuana:What Does The Evidence Show?What Does The Evidence Show?

Allen C. Bowling, MD, PhDAllen C. Bowling, MD, PhD

Physician AssociatePhysician Associate

Colorado Neurological Institute (CNI)Colorado Neurological Institute (CNI)

Marijuana and Neurological Marijuana and Neurological DiseaseDisease

Increasing legalization and availability Increasing legalization and availability Neurologically relevant medical studiesNeurologically relevant medical studies BUT huge challenges for public and BUT huge challenges for public and

professionals:professionals:– Emotional responseEmotional response– Political/media/business interestsPolitical/media/business interests– Difficult to find objective safety and Difficult to find objective safety and

effectiveness informationeffectiveness information

Marijuana InformationMarijuana Information

“Cannabis is effective for treating epilepsy, Parkinson’s disease, depression, and migraine.”

“[In MS], numerous studies have reported improvement in tremor, sexual dysfunction,…vision dimness, dysfunctions of walking and balance (ataxia), and memory loss.”

“Research has shown that medical marijuana…can alleviate symptoms of Tourette’s.”

SummarySummary Basics of MarijuanaBasics of Marijuana The EvidenceThe Evidence

– Scientific studiesScientific studies– Clinical studiesClinical studies

• MS, epilepsy, Parkinson’s disease and other MS, epilepsy, Parkinson’s disease and other movement disordersmovement disorders

• Pain, anxiety, sleepPain, anxiety, sleep

– SafetySafety

Information ResourcesInformation Resources

States with Medical/Recreational States with Medical/Recreational Marijuana (Illegal at Federal Level)Marijuana (Illegal at Federal Level)

Proposed Marijuana Bills/Initiatives Proposed Marijuana Bills/Initiatives in 2014in 2014

Medical Marijuana in Colorado:Medical Marijuana in Colorado:“Approved Conditions”“Approved Conditions”

““persistent muscle spasms, persistent muscle spasms, including those that are including those that are characteristic of multiple sclerosis”characteristic of multiple sclerosis”

““seizures, including those that are seizures, including those that are characteristic of epilepsy”characteristic of epilepsy”

““severe pain”severe pain”

Variability of Marijuana Plants Variability of Marijuana Plants and Products and Products

Two major “subspecies”Two major “subspecies”– Cannabis sativa: Cannabis sativa: mainly THCmainly THC– Cannabis indica: Cannabis indica: THC and THC and

CBDCBD

Many different hybrids Other variables

– Growing and storage– State of maturity– Processing/formulation

Forms of MarijuanaForms of Marijuana LeafLeaf

– Smoked, eaten (“edibles”), vaporizedSmoked, eaten (“edibles”), vaporized

Plant resin: “hashish”Plant resin: “hashish”– Smoked, eatenSmoked, eaten

Oil extractsOil extracts– Nabiximols (Sativex), Cannador, many others that Nabiximols (Sativex), Cannador, many others that

are unregulated and non-standardizedare unregulated and non-standardized

Single molecule preparationsSingle molecule preparations– THC: Marinol, dronabinolTHC: Marinol, dronabinol– Chemical variant of THC: Cesamet, nabiloneChemical variant of THC: Cesamet, nabilone

““Cannabinoids”Cannabinoids”

Many different potentially active molecules: – THC: delta-9-

tetrahydrocannabinol– CBD: cannabidiol– About 60 others

MarijuanaMarijuana

ActionsActions– CB1 receptorsCB1 receptors

• Nerve cellsNerve cells• ““Homeostasis”Homeostasis”

– CB2 receptorsCB2 receptors• Immune cellsImmune cells

–Multiple other effectsMultiple other effects--Antioxidant, excitotoxicity, calcium fluxAntioxidant, excitotoxicity, calcium flux

““Endocannabinoids”Endocannabinoids” Analagous to endorphinsAnalagous to endorphins Two main endocannabinoidsTwo main endocannabinoids

– AnandamideAnandamide• 100 times 100 times less less potent potent

than THCthan THC• ? “endorphin high”? “endorphin high”

– 2-AG 2-AG

Full range of functions Full range of functions unknownunknown




– 2-AG 2-AG


THC




– 2-AG 2-AG


THC

Anandamide

SummarySummary Basics of MarijuanaBasics of Marijuana The EvidenceThe Evidence

– Scientific studiesScientific studies– Clinical studiesClinical studies

• MS, epilepsy, Parkinson’s disease and other MS, epilepsy, Parkinson’s disease and other movement disordersmovement disorders

• Pain, anxiety, sleepPain, anxiety, sleep

– SafetySafety

Information ResourcesInformation Resources

Neurological Relevance:Neurological Relevance:Scientific StudiesScientific Studies

Nerve Cell FunctionNerve Cell Function– Normalizes release of Normalizes release of manymany different different

neurotransmittersneurotransmitters

Nerve Cell SurvivalNerve Cell Survival– Promotes survival by Promotes survival by manymany

mechanismsmechanisms

Immune System FunctionImmune System Function– Anti-inflammatory effectAnti-inflammatory effect

Neurological Relevance:Neurological Relevance:Clinical StudiesClinical Studies

Multiple SclerosisMultiple Sclerosis EpilepsyEpilepsy Parkinson’s Disease and Other Parkinson’s Disease and Other

Movement DisordersMovement Disorders PainPain Sleep DisordersSleep Disorders AnxietyAnxiety

AAN Classification Scheme:AAN Classification Scheme:Classes of Controlled TrialsClasses of Controlled Trials

Class IClass I– Randomized, controlled, objective outcomeRandomized, controlled, objective outcome– Extra criteria: concealed allocation, primary Extra criteria: concealed allocation, primary

outcome clearly defined, exclusion and outcome clearly defined, exclusion and inclusion criteria clearly defined, adequate inclusion criteria clearly defined, adequate accounting for dropouts and crossoversaccounting for dropouts and crossovers

Class II: Class II: lacks one criterionlacks one criterion

Class III: Class III: all other controlled trials with all other controlled trials with independent outcome assessmentindependent outcome assessment

Review of Alternative Review of Alternative Medicine and MSMedicine and MS

Summary of evidence-based guideline: Summary of evidence-based guideline: complementary and alternative medicine in complementary and alternative medicine in multiple sclerosis. multiple sclerosis. Neurology Neurology 2014;82:1-10.2014;82:1-10.

Report of the Guideline Development Committee Report of the Guideline Development Committee of the American Academy of Neurologyof the American Academy of Neurology– Yadav, Bever, Bowen, Bowling, Weinstock-Guttman, Yadav, Bever, Bowen, Bowling, Weinstock-Guttman,

Cameron, Bourdette, Gronseth, NarayanaswamiCameron, Bourdette, Gronseth, Narayanaswami

Medline search: 1970-Sept 2013Medline search: 1970-Sept 2013

Review of Marijuana and Review of Marijuana and Neurological DisordersNeurological Disorders

Systematic review: Efficacy and safety of medical Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders. marijuana in selected neurologic disorders. Neurology Neurology 2014;82:1556-1563.2014;82:1556-1563.

Report of the Guideline Development Committee of the Report of the Guideline Development Committee of the American Academy of NeurologyAmerican Academy of Neurology– Koppel, Brust, Fife, Bronstein, Youssof, Gronseth, GlossKoppel, Brust, Fife, Bronstein, Youssof, Gronseth, Gloss

Medline search: 1948-Jan 2013Medline search: 1948-Jan 2013 DisordersDisorders

– MS: spasticity, pain, bladder dyfunction, tremorMS: spasticity, pain, bladder dyfunction, tremor– Dyskinesias: Huntington’s disease, levodopa-induced in Dyskinesias: Huntington’s disease, levodopa-induced in

Parkinson’s diseaseParkinson’s disease– Cervical dystonia, tics of Tourette syndrome, epilepsyCervical dystonia, tics of Tourette syndrome, epilepsy

Studies of Marijuana and Studies of Marijuana and Neurologic ConditionsNeurologic Conditions

Class I Class II Class III TOTALMS 6 4 9 19

Epilepsy 0 0 0 0

Parkinson’s 1 0 1 2

Huntington’s 1 1 1 3

Tourette 0 1 1 2

Dystonia 0 0 1 1

MS: Two Recent ReviewsMS: Two Recent Reviews

The largest and most convincing research Formulations

– THC: 4– Oral cannabis extract (Cannador): 8– Nabiximols (Sativex): 8– Smoked: 2

MS: Two Recent ReviewsMS: Two Recent Reviews

Some level of effectiveness– “Subjective spasticity,” pain

• Cannador, Nabiximols, THC

– Urinary frequency• Nabiximols

Probably ineffective– Objective spasticity, tremor

• Cannador, Nabiximols, THC

Insufficient data: smoked

EpilepsyEpilepsy Marijuana and THC: anti-convulsant or pro-Marijuana and THC: anti-convulsant or pro-

convulsant?convulsant? CBD: appears anti-convulsantCBD: appears anti-convulsant No Class I, II, or III studiesNo Class I, II, or III studies 2 Class IV with no benefit, many anecdotes2 Class IV with no benefit, many anecdotes Survey of 19 parents, CBD-enrichedSurvey of 19 parents, CBD-enriched

– 84% improved: 11% seizure-free, 42% with more than 84% improved: 11% seizure-free, 42% with more than 80% decrease 80% decrease

– Porter, Porter, Epilepsy & Behav Epilepsy & Behav 2013;29:574-577.2013;29:574-577.

Parkinson’s DiseaseParkinson’s Disease

2 studies: one class I, one class III2 studies: one class I, one class III CBD extract not effective for CBD extract not effective for

“dyskinesia”“dyskinesia” Class IV studyClass IV study

– ““Open label,” smokedOpen label,” smoked– Improvement in tremor, rigidity, and Improvement in tremor, rigidity, and

bradykinesiabradykinesia

Huntington’s Disease and Huntington’s Disease and OthersOthers

Huntington’sHuntington’s– 3 studies: Classes I, II, III3 studies: Classes I, II, III– Nabilone possibly effective for chorea, Nabilone possibly effective for chorea,

but inconsistent results and limited but inconsistent results and limited studiesstudies

Tourette and DystoniaTourette and Dystonia– Very limited studiesVery limited studies– No conclusions possibleNo conclusions possible

PainPain 18 controlled trials in pain18 controlled trials in pain

– Classes I, II, and IIIClasses I, II, and III

FormulationsFormulations– Smoked: 4Smoked: 4– Extract: 7Extract: 7– THC: 2THC: 2– Nabilone: 4Nabilone: 4– Unique molecule: 1Unique molecule: 1

Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Brit J Clin Pharmacol 2011;72:735-744.

PainPain

15/18 reported improvement in pain15/18 reported improvement in pain– Especially central and peripheral nerve painEspecially central and peripheral nerve pain– For painful HIV neuropathy, possibly the For painful HIV neuropathy, possibly the

most effective treatmentmost effective treatment– Also fibromyalgia and rheumatoid arthritisAlso fibromyalgia and rheumatoid arthritis

4/18 also reported improvement in sleep4/18 also reported improvement in sleep No controlled studies in headache, No controlled studies in headache,

including migraineincluding migraine

Sleep DisordersSleep Disorders

39 clinical studies39 clinical studies– Quality: extremely variable, generally poorQuality: extremely variable, generally poor

FormulationsFormulations– Smoked: 7Smoked: 7– THC or Nabilone: 14THC or Nabilone: 14– Cannador or Nabiximols: 14Cannador or Nabiximols: 14– Other oral form: 4Other oral form: 4

Gates PJ, et al. The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep Med Rev 2014;1-11.

Sleep DisordersSleep Disorders

Impossible to make firm conclusionsImpossible to make firm conclusions– Many different conditions and formulationsMany different conditions and formulations

General observationsGeneral observations– ““Recreational use”Recreational use”

• May interrupt sleep cycle and cause non-restful May interrupt sleep cycle and cause non-restful sleepsleep

– Use with condition that interrupts sleepUse with condition that interrupts sleep• May improve sleep quality and decrease night-May improve sleep quality and decrease night-

time disturbancestime disturbances

AnxietyAnxiety A very complicated story!A very complicated story! Marijuana use is significantly higher in those Marijuana use is significantly higher in those

with anxietywith anxiety ParadoxesParadoxes

– Limited use: may cause relaxation but also panic, Limited use: may cause relaxation but also panic, paranoia, and psychosisparanoia, and psychosis

– Regular useRegular use• Short-term: may decrease anxietyShort-term: may decrease anxiety• Long-term: may Long-term: may increaseincrease anxiety and anxiety and decreasedecrease

effectiveness of anxiety medseffectiveness of anxiety medsTambaro S, et al. Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge

and future perspectives. Recent Patents CNS Drug Discov 2012;7:25-40.

AnxietyAnxiety

Variable effects may be due to Variable effects may be due to different componentsdifferent components– Marijuana and THCMarijuana and THC

• Modest doses: decreased anxietyModest doses: decreased anxiety• High doses: panic, psychosis, phobiaHigh doses: panic, psychosis, phobia

– CBDCBD• More consistent anti-anxiety effectMore consistent anti-anxiety effect

Marijuana:Marijuana:Side EffectsSide Effects

Generally well tolerated in neurological Generally well tolerated in neurological clinical trialsclinical trials

No risk of lethal overdose (unlike alcohol)No risk of lethal overdose (unlike alcohol) No clear increase in risk of COPD or No clear increase in risk of COPD or

cancer of lung, head, and neck (?anti-cancer of lung, head, and neck (?anti-cancer effect)cancer effect)

Marijuana:Side EffectsMarijuana:Side EffectsCONFIDENCE

Addiction High

Decreased achievement High

Motor vehicle accidents High

Chronic bronchitis High

Abnormal brain development Medium

Progression to other drugs Medium

Schizophrenia Medium

Depression or anxiety Medium

Volkow et al, Adverse health effects of marijuana use. New Eng J Med 2014;370:2219-2227.

Marijuana: Neurologically Marijuana: Neurologically Relevant Side EffectsRelevant Side Effects

Dizziness, impaired balance, Dizziness, impaired balance, incoordination, visual difficulties, incoordination, visual difficulties, seizures, leg weakness, sedation, seizures, leg weakness, sedation, lightheadedness, psychosis, lightheadedness, psychosis, hallucinations, associated with hallucinations, associated with strokes (and heart attacks)strokes (and heart attacks)

Also, interactions with many Also, interactions with many neurological medsneurological meds

MRI Changes: CognitionMRI Changes: Cognition

Recent MS studyRecent MS study– Users had more Users had more

cognitive cognitive impairment and impairment and more more abnormalities on abnormalities on functional MRIfunctional MRI

– Limitations of Limitations of studystudy

– Pavisian B, et al. Effects of cannabis on cognition in patients with MS. Neurol 2014;82:1879-1887.

MRI Changes: CognitionMRI Changes: Cognition

?Neurotoxicity?Neurotoxicity– ““Meta-analysis”--14 studiesMeta-analysis”--14 studies– Consistently smaller Consistently smaller

hippocampus size in usershippocampus size in users• Is cannabis neurotoxic for the Is cannabis neurotoxic for the

healthy brain? A meta-analytic healthy brain? A meta-analytic review of structural brain review of structural brain alterations in non-psychotic alterations in non-psychotic users, Rocchetti et al, users, Rocchetti et al, Psych Psych Clin Neurosci Clin Neurosci 2013;67:483-492.2013;67:483-492.

MRI Changes: Addiction?MRI Changes: Addiction? Amygdala and Nucleus Accumbens: emotion and Amygdala and Nucleus Accumbens: emotion and

motivationmotivation

• Cannabis use is quantitatively associated with nucleus accumbens and Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational user, Gilman et al, amygdala abnormalities in young adult recreational user, Gilman et al, J J Neurosci Neurosci 2014;34:5529-5538.2014;34:5529-5538.

Marijuana:Marijuana:Uncertain Potency and PurityUncertain Potency and Purity

Study of edibles in Colorado (2014)• N=13• No products contained the amount of THC on label• 1 product with 50% more• 3 products with 0.2-0.4%

Colorado labelling• “Warning: There may be health risks associated with the

consumption of this product…The product was produced without regulatory oversight for health, safety, or efficacy…The marijuana product contained within this package has not been tested for potency, consume with caution. The marijuana product contained within this package has not been tested for contaminants.”

Unanswered Questions, Unanswered Questions, Unresolved IssuesUnresolved Issues

Many studies are with standardized Many studies are with standardized preparations—not available in the USpreparations—not available in the US

Products that are availableProducts that are available– Many are non-standardized, non-regulated, Many are non-standardized, non-regulated,

and high in THCand high in THC

How to translate research studies with How to translate research studies with oral preparations to smoked products?oral preparations to smoked products?

Unanswered Questions, Unanswered Questions, Unresolved IssuesUnresolved Issues

Are some hybrids more effective or safer?Are some hybrids more effective or safer? What dose, frequency, and preparation?What dose, frequency, and preparation? ““Combination therapy” with meds?Combination therapy” with meds? Relative safety and effectiveness of Relative safety and effectiveness of

marijuana vs conventional meds or marijuana vs conventional meds or procedures?procedures?

Future DirectionsFuture Directions

Studies of specific strainsStudies of specific strains– Low, medium, and high THCLow, medium, and high THC– Significant differences: anxiety, appetite, othersSignificant differences: anxiety, appetite, others– Brunt et al, 2014, Brunt et al, 2014, J Clin PsychopharmJ Clin Psychopharm

Increase endocannabinoid levelsIncrease endocannabinoid levels– Many possibilitiesMany possibilities– Promising studies in animalsPromising studies in animals– Pryce et al, 2013, Pryce et al, 2013, Mult Scler JMult Scler J

SummarySummary Thousands of yearsThousands of years of human use, but scientific of human use, but scientific

understanding and evidence-based medical use understanding and evidence-based medical use is in its is in its infancyinfancy

Extremely complex pharmacologyExtremely complex pharmacology Dozens of potentially active compoundsDozens of potentially active compounds Complex neurological conditions Complex neurological conditions Limited safety informationLimited safety information Thoughtful, evidence-based risk:benefit analysisThoughtful, evidence-based risk:benefit analysis

Summary:Summary:Examples of UseExamples of Use

MSMS– Reasonable?—moderate-severe disability Reasonable?—moderate-severe disability

with severe pain and/or spasticitywith severe pain and/or spasticity– Unreasonable—college student, rare spasmsUnreasonable—college student, rare spasms

EpilepsyEpilepsy– Reasonable?—severe seizure disorder not Reasonable?—severe seizure disorder not

treatable with meds, surgery is next optiontreatable with meds, surgery is next option– Unreasonable—2 seizures, never taken medsUnreasonable—2 seizures, never taken meds

Information SourcesInformation Sources

Objective, updated, user-friendly Objective, updated, user-friendly information resource for general information resource for general public and professionalspublic and professionals

Information SourcesInformation Sources

Objective, updated, user-friendly Objective, updated, user-friendly information resource for general information resource for general public and professionalspublic and professionals

–DOES NOT EXIST!DOES NOT EXIST!

States with Medical/Recreational States with Medical/Recreational Marijuana (Illegal at Federal Level)Marijuana (Illegal at Federal Level)

Information ResourcesInformation Resources Lay articlesLay articles

– King ME. Medical marijuana: King ME. Medical marijuana: hype or hope? hype or hope? Momentum Momentum Fall 2014, pp. 28-35.Fall 2014, pp. 28-35.

– Bowling AC. Marijuana and Bowling AC. Marijuana and MS—an unfinished story. MS—an unfinished story. Momentum Momentum Fall 2010, pp. 33-Fall 2010, pp. 33-35. 35.

BookBook– Iversen LL. Iversen LL. The Science of The Science of

Marijuana. Marijuana. Oxford Univ. Oxford Univ. Press: 2010.Press: 2010.

ReferencesReferences Books

– Bowling AC. Optimal Health With Multiple Sclerosis: A Guide to Integrating Lifestyle, Alternative, and Conventional Medicine. New York: Demos, 2014.

– Bowling AC. Complementary and alternative medicine: practical considerations. In Rae-Grant A, Fox R, Bethoux F, eds. Multiple Sclerosis and Related Disorders: Diagnosis, Medical Management, and Rehabilitation. New York: Demos, 2013, 243-249.

– Iversen LL. The Science of Marijuana. New York: Oxford University Press, 2008.

– Jellin JM, Gregory PJ, Batz F, et al. Pharmacist’s Letter/ Prescriber’s Letter Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Faculty, 2014.

ReferencesReferences

Journal Articles– Aggarwal SK. Cannabinergic pain medicine. Clin J Pain 2013;29:162-171.– Anon. Adverse effects of marijuana. Prescrire Int 2011;20:18-23.– Baca R. Labels fudge THC levels: with no standard for testing, buyers

can’t trust items’ potency. Denver Post 2014 March 9:1A, 17A.– Baker D, et al. The therapeutic potential of cannabis. Lancet Neurol

2003;2:291–298.– Borgelt LM, et al. The pharmacologic and clinical effects of medical

cannabis. Pharmacother 2013;33:195-209.– Bowling AC. Cannabinoids in MS—are we any closer to knowing how

best to use them? Mult Scler 2006; 12:523-525.– Bowling AC. Worthless weed or pot of gold? Int J MS Care

2004;5:138,166.– Bowling AC. Marijuana and MS—an unfinished story. Momentum, Fall

2010, 33-35.

ReferencesReferences– Corey-Bloom J, et al. Smoked cannabis for spasticity in multiple sclerosis: a

randomized, placebo-controlled trial. CMAJ 2012;184:1143-1150.– Devinsky O, et al. Cannabidiol: pharmacology and potential therapeutic role in

epilepsy and other neuropsychiatric conditions. Epilepsia 2014;55:791-802.– Gates PJ, et al. The effects of cannabinoid administration on sleep: a systematic

review of human studies. Sleep Med Rev 2014;1-11.– Gilman JM, et al. Cannabis use is quantitatively associated with nucleus accumbens

and amygdala abnormalities in young adult recreational users. J Neurosci 2014;34:5529-5538.

– Gordon AJ, et al. Medical consequences of marijuana use: a review of current literature. Curr Psych Rep 2013;15:419.

– Greenberg HS, et al. Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers. Clin Pharmacol Ther 1994;55:324-328.

– Kedzior KK, Laeber LT. A positive association between anxiety disorders and cannabis use or cannabis use disorders in the general population—a meta-analysis of 31 studies. BMC Psychiatr 2014;14:136.

– King ME. Medical marijuana: hype or hope? Momentum Fall 2014:28-35.

ReferencesReferences– Koppel BS, et al. Systematic review: efficacy and safety of medical marijuana in

selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurol 2014;82:1556-1563.

– Lotan I, et al. Cannabis (medical marijuana) treatment of motor and non-motor symptoms of Parkinson disease: an open-label observational study. Clin Neuropharm 2014;37:41-44.

– Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Brit J Clin Pharmacol 2011;72:735-744.

– Pavisian B, et al. Effects of cannabis on cognition in patients with MS. Neurol 2014;82:1879-1887.

– Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epil Behav 2013;29:574-577.

– Pryce G, et al. Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors. Mult Scler J 2013;19:1896-1904.

– Rocchetti M, et al. Is cannabis neurotoxic for the healthy brain? A meta-analytical review of structural brain alterations in non-psychotic users. Psychiatr Clin Neurosci 2013;67:483-492.

ReferencesReferences– Secades-Villa R, et al. Probability and predictors of the cannabis gateway effect:

a national study. Int J Drug Policy 2014; 10.1016/j.drugpo.2014.07.011– Tambaro S, et al. Cannabinoid-related agents in the treatment of anxiety

disorders: current knowledge and future perspectives. Recent Patents CNS Drug Discov 2012;7:25-40.

– Thomas G, et al. Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know. Amer J Cardiol 2014;113:187-190.

– Volkow ND, et al. Adverse health effects of marijuana use. New Eng J Med 2014;370:2219-2227.

– Yadav V, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurol 2014;82:1-10.

– Zajicek JP, Apostu VI. Role of cannabinoids in multiple sclerosis. CNS Drugs 2011;25:187-201.

– Zajicek J, et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomized, placebo-controlled trial. Lancet Neurol 2013;12:857-865.

ReferencesReferences

– Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003;362:1517–1526.

– Zajicek J, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neursurg Psych 2005;76:1664–1669.

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Marijuana: What Does The Evidence Show? Allen C. Bowling, MD, PhD Physician Associate Colorado Neurological Institute (CNI)