DavidCasarettMDMAProfessorofMedicineChiefofPalliativeCare

DukeUniversity

Conflictsofinterest

• SAB,CurioWellnessandPalliatech• Noconsultingorspeakingforthe

pharmaceuticalindustry

ViewsdonotreflecttheopinionsofDukeUniversityorDukeHealth

Marijuana:Medicationorweed?

IwroteStoned forJudith…

3Surprises• There’sascienceofhow

cannabisworks• Cannabishasrealpotential

benefits(andrisks)• There’sawidegap

betweenenthusiasmformedicalcannabisandtheevidencesupportingit

Surprise#1:Thereisascienceofhowmarijuanaworks

Surprise#1:There’sascienceofhowcannabisworks

• Tetrahydrocannabinol (THC)• Cannabidiol (CBD)• (Andmanyother

cannabinoids)

Ms.Sativa:Upcloseandpersonal

Cannabissativa/indica:what’sthedifference?

Sativa strains:OftenhigherTHCconcentrationsIndica strains:GenerallylowerTHCandhigherCBDBUT:Speciesdon’treallypredictTHC/CBDlevels

Thescienceofcannabinoidreceptors

THC:CB1andCB2receptors,mostlyinthebrain,plusreproductivesystem

CBD:Otherreceptors,mostlyintheimmunesystem,plusmicroglialcellsinthebrain

Othercannabinoids…Otherreceptors…

Cannabisisnature’swayofhackingtheendocannabinoidsystem

• Anandamide,the“BlissMolecule”

• 2-AG• Manymore

Surprise#1BThere’sascienceofhowtouse

marijuana

Absorptionandmetabolism• Concentration(THC)– flower=2-10%– hash>30%– shatter>80%

• Bioavailability– PO=10-20%;Inhaled=30-50%– BUT:Wide(10-fold)inter-individualvariability(inhaled)

Advantageofsmoking:fastuptake

WilliamO’Shaughnessy,goats,andtinctures

Edibles

Thescienceofedibles

• Cannabinoidsaresolubleinalcoholandlipids:

• Alcohol-based(infusedgrainEtOH)

• Lipid-based(Brownies)

Thefutureofcannabisdeliverysystems?

Surprise#2:Cannabisdoeshaverealmedicalbenefits(andrisks)

“Thebestmedicinethedrugcompaniesdon’twantyoutoknow

about.”-DispensaryownerinSanDiego

Potentialusesinstatelaws:

• Nausea• Chronicpain• Anxiety• PTSD• Anorexia/weightloss• Insomnia• Pediatricepilepsy• Andmanymore…

Howmuchevidenceisthereofmedicalbenefit?

Answer:Notasmuchaswe’dlike

• Moderate evidence:– Neuropathicpain– Spasticity

• Weak evidence:– Nausea–Weightgaininthesettingofchronic,seriousillness(AIDS,cancer)

– Sleep

Neuropathicpain

• GoodRCTdata*• Evidenceofeffectivenessasadjuvanttoopioids(Abrams,2011,ClinPharmTher)

*Abrams,Neurology,2007;Lynch,BrJClin Pharm,2011(Systematicreview);Wilsey,JPain,2008)

• Strengths– RCT– Placebocontrol– Blinded– Low- andhigh-dosegroupstoexaminedoseeffects

• Weaknesses– 39subjects– Imperfectblinding

vImperfectblindingandsmallsizemadethisa“lowquality”study

Blinding:TheAchillesheelofmedicalcannabisresearch

• Amongpatientsassignedfirstto“active”marijuana,14/15(93%)guessedcorrectly

Curescancer?

“Risks?Marijuanadoesn’thaveanyrisks—it’saflower.Notlike

morphine.”

-DispensaryownerinDenver

Risks?

Knownrisks• Drivingimpairment*• Addiction*• Hyperemesissyndrome

Possiblerisks• Myocardialinfarction• Stroke• Schizophrenia• (Psychoticepisodes)• Long-termcognitivedysfunction

• NOT:Cancer,lungdisease

(Pulmonaryrisks)

• VeryminorPFTchanges– IncreasedFVC– DecreasedFEV1andFEV1/FVCforveryheavyusers

– Nocancerrisk(Tashkin,AnnalsATS,2013)

Contaminants

Cardiovascularrisks

• Theoreticalrisk:– IncreasedHR– Orthostasis– Increasedclotting(invitro)

– Hx studies(Aronow andCassidy,NEJM,1974)

• ButnoevidenceofincreasedriskofstrokeorMI

N=3882;Mittleman,Circulation,2001

Weedandwheels

• Slowreactiontimes• Distraction• Lackoffocus• Poorsaliencedetection• Fieldsobrietytestnothelpful

Addiction

Addiction

Compton,JAMA,2003

“Other”

• Infertility• Gynecomastia• Recurrentherpes• Koro• Pneumothorax• Etc

Risks

• Afewrisksareknown• Manyarespeculative• Everyonehasanaxetogrind

• Casereportsarecommonandcanbemisleading

So…Medicationorweed?

• Significantbenefits• Realrisks

“Whatisaweed?Aplantwhosevirtueshaveneverbeendiscovered.”

-RalphWaldoEmerson

Themedicalmarijuanaenthusiasm-evidencegap

Howmuchevidenceofbenefitandsafetyisenough?

Forpatientsandphysicians:• Oneortwosmallstudies

• Ideallyacontrolledtrial• Anecdote

Forresearchersandpolicymakers:• Multiplelargecontrolledtrials

• Placebocontrols• Rigorousblinding• Large-scalesafetystudies

Ifenthusiasmformedicalmarijuanahasoutstrippedtheevidencesupportingitsuse,that’softenbecausepeoplearedissatisfiedwiththemedicalcarethey’rereceiving.

Thanks• ZachKlein,HeatherDespres,

NathanPollack,BobMelamede,JohnMorley,OrrinDevinsky,DonaldTashkin, BarthWilsey,JonathanGavrin,SteveLankenau,TeriFranklin,MarinaGoldman,ChristineRabinak,DonaldAbrams,RaphaelMechoulam,ClintWerner,LarryGidaley…andSashatheWonderDog