Medical and Legalized MarijuanaMedical and Legalized Marijuana From pain relief to recreational use… Schoen W. Kruse, Ph.D. Assistant Dean Associate Professor of Pharmacology Kansas

Medical and Legalized Marijuana From pain relief to recreational use…

Schoen W. Kruse, Ph.D. Assistant Dean Associate Professor of Pharmacology Kansas City University

Dr.White,aprac.cingfamilyphysicianinKansasCity,MO,walksintoanexamina.onroomandmeetsa31y/ofemalenamedRachel.Rachelhasa3yearhistoryofmul.plesclerosis(MS).ShewasborninKC,MOandnowlivesinCalifornia.Shehasbeenintownvisi.ngfamilyandfriendsforthepast2weeks.

Rachel’sMSiscategorizedastheprimaryprogressiveMS(PPMS)type,inwhichthediseaseprogressesfromtheonsetwithoccasionalplateaus,temporaryminorimprovements,andacuterelapses.Overthecourseofherdisease,shehastakentheimmunosuppressivetherapiescyclosporine,methotrexate,cyclophosphamide,interferon,andsteroids.

MostofthetreatmentsRachelhastriedhavetemporarilyhalteddiseaseprogression,buttheyhavenotresultedinlong-termsymptommanagement.Asaresult,Rachelhasbecomereliantonmedicalmarijuanaforsymptommanagement,whichhasofferedtheonlyconsistentreliefofhersymptoms.Ratherthanfly,shedrovetoKCsothatcouldbringmarijuanaonhertriptocontrolhersymptoms.

RachelarrivesinDr.White’sofficeindistressbecausehersupplyofmedicalmarijuanawasexhaustedbyhernephewandhisfriends(theyfoundthedruginhertravelbagandtookitandsmokedit).SheissufferingandislookingtoDr.Whiteforhelp.

Ethical LegalClinical

SessionObjec.vesAUeraVendingtheCMEsessiononMedicalandLegalizedMarijuana,youwillbeableto:

1. Compareandcontrasttheknowneffectsoftetrahydrocannabinol(THC)andcannabidiol(CBD).

2. Iden.fysymptomsthatmayberelievedbytreatmentwithmarijuanaorothercannabinoids

3. Iden.fyapplicablemedicalmarijuanalawsinstatesinwhichyouhaveamedicallicense.

Exogenouscannabinoids• ExtractedfromthemarijuanaplantCannabissa(vaorCannabisindica

• Over100cannabinoidshavebeeniden.fiedinthemarijuanaplant

Tetrahydrocannabinol(THC)• Majorpsychoac.vecomponentinmarijuana• Cannabissa(va

Cannabidiol(CBD)• Doesn’tproduceanyofthepsychoac.veeffectsofTHC• Doesn’tmakeyouhigh,paranoid,hallucinate• Cannabisindica

www.thcdigest.com/indica-vs-sa.va

Receptorsthatbindexogenouscannabinoids

CB1receptors• CNSneuronsinthebasalganglia,limbicsystem,cerebellum,cortex• Ac.va.oncausespsychotropiceffects,dependence,andcogni.veimpairment

CB2receptors• Distribu.onpredominantlyincellsand.ssuesoftheimmunesystem(thymus,tonsils,B&Tlymphocytes,macrophages,monocytes,NKcells)• Expressedinmicroglialcells(CNSversionofimmunecells)duringvariousstatesofinflamma.on• Ac.va.onlargelydevoidofpsychotropiceffects

Serotoninreceptors,GPR-55,TRVP1receptor,others…

EffectsofTHCandCBD

THC• CB1andCB2receptorpar.alagonist• ResponsesstronglyinfluencedbothbytheexpressionlevelandsignalingefficiencyofCB1/CB2receptorsandbyongoingendogenouscannabinoidrelease

CBD• HighpotencyasanantagonistofCB1/CB2receptoragonistsinCB1-andCB2-expressingcellsor.ssues• Antagonistac.onshelpsexplainitsabilitytoinhibitevokedimmunecellmigra.on• MaypreventTHCfromac.ngasagonist(hallucinogeniceffects)

Whatarethecomponentsofmarijuana?

• THClevelshaverisenconsistentlysincethemid1990s• Asthedesireformarijuanawithhighhallucinogeniceffectsincreased,CBDlevelsdecreased

Heterogeneityinthecomposi.onofmarijuanaseizedinCalifornia

CBDmaybetherealstar• CBDhasgainedpar.cularinterestrecentlyasacons.tuentinthemedica.onSa.vex,whichhasbeenfoundtoalleviatespas.cityassociatedwithMS,cancerpaininopioid-treatedpa.ents,andmarijuanawithdrawal

• CBDisunderinves.ga.oninassortedclinicaltrialsasanan.-epilep.c

• PreclinicalstudiesreportedthatCBDelicitsan.convulsant,an.-inflammatory,andan.-tumorgeniceffects.

• hVp://www.ncbi.nlm.nih.gov/pubmed

Clinicalcondi.onswithsymptomsthatmayberelievedbytreatmentwithmarijuanaorothercannabinoids

• Marijuanacancauseatransientdecreaseinintraocularpressure(1970s,1980s)

• Other,standardtreatmentsarecurrentlymoreeffec.ve

• Moreresearchisneededtoestablishwhethermoleculesthatmodulatetheendocannabinoidsystemmaynotonlyreduceintraocularpressurebutalsoprovideaneuroprotec.vebenefitinpa.entswithglaucoma

Glaucoma

• Treatmentofthenauseaandvomi.ngassociatedwithchemotherapywasoneofthefirstmedicalusesofTHCandothercannabinoids

• THCisaneffec.vean.eme.cagentinpa.entsundergoingchemotherapy,butpa.entsoUenstatethatmarijuanaismoreeffec.veinsuppressingnausea

• Other,uniden.fiedcompoundsinmarijuanamayenhancetheeffectofTHC(asappearstobethecasewithTHCandCBD)

• Paradoxically,increasedvomi.ng(hyperemesis)hasbeenreportedwithrepeatedmarijuanause

Nausea

• Smokedoringestedcannabisimprovesappe.teandleadstoweightgainandimprovedmoodandqualityoflifeamongpa.entswithAIDS

• However,thereisnolong-termorrigorousevidenceofasustainedeffectofcannabisonAIDS-relatedmorbidityandmortality,withanacceptablesafetyprofile,thatwouldjus.fyitsincorpora.onintocurrentclinicalprac.ceforpa.entswhoarereceivingeffec.vean.retroviraltherapy

• Datafromthefewstudiesthathaveexploredthepoten.altherapeu.cvalueofcannabinoidsforthispa.entpopula.onareinconclusive

AIDS-associatedanorexiaandwas.ngsyndrome

• Marijuanahasbeenusedtorelievepainforcenturies

• Studieshaveshownthatcannabinoidsac.ngthroughcentralCB1receptorsandpossiblyperipheralCB1andCB2receptorsplayimportantrolesinmodelingnocicep.veresponsesinvariousmodelsofpain

• Marijuanahasbeenshowntobeeffec.veinameliora.ngneuropathicpainatverylowlevelsofTHC(1.29%)

• Bothmarijuanaanddronabinol(synthesizedTHC)decreasepain,butdronabinolmayleadtolonger-las.ngreduc.onsinpainsensi.vityandlowerra.ngsofrewardingeffects

Chronicpain

• THCandCBDhavesubstan.alan.-inflammatoryeffectsbecauseoftheirabilitytoinduceapoptosis,inhibitcellprolifera.on,andsuppresscytokineproduc.on

• CBDhasaVractedpar.cularinterestasanan.-inflammatoryagentbecauseofitslackofpsychoac.veeffects

• AnimalmodelshaveshownthatCBDisapromisingcandidateforthetreatmentofrheumatoidarthri.sandforinflammatorydiseasesofthegastrointes.naltract(e.g.,ulcera.vecoli.sandCrohn'sdisease)

Inflamma.on

• Nabiximols(Sa.vex),anoromucosalspraythatdeliversamixofTHCandCBD,appearstobeaneffec.vetreatmentforneuropathicpain,disturbedsleep,andspas.cityinpa.entswithmul.plesclerosis

• Sa.vexisavailableintheUnitedKingdom,Canada,andseveralothercountriesandiscurrentlybeingreviewedinphase3trialsintheUnitedStatesinordertogainapprovalfromtheFoodandDrugAdministra.on

• TheNa.onalMul.pleSclerosissocietysupportstherightsofpeoplewithMStoworkwiththeirMShealthcareproviderstoaccessmarijuanaformedicalpurposesinaccordancewithlegalregula.onsinthosestateswheresuchusehasbeenapproved(www.na.onalmssociety.org)

Mul.plesclerosis

• Inarecentsmallsurveyofparents(19families)whousemarijuanawithahighCBDcontenttotreatepilep.cseizuresintheirchildren:• 11%reportedcompletefreedomfromseizures• 42%reportedareduc.onofmorethan80%inseizurefrequency• 32%(6families)reportedareduc.onof25to60%inseizurefrequency

• Althoughsuchreportsarepromising,insufficientsafetyandefficacydataareavailableontheuseofcannabisbotanicalsforthetreatmentofepilepsy

• ThereisincreasingevidenceoftheroleofCBDasanan.epilep.cinanimalmodels

Epilepsy

• 80totalstudiesforcannabidiol(CBD)• 132totalstudiesfortetrahydrocannabinol(THC)

• Condi.onsinvolved• Epilepsy• Substanceabuse• Pain• Autoimmunediseases• Demyelina.ngdiseases• Mul.plesclerosis• Psychiatricdisorders

• www.clinicaltrials.gov

Clinicaltrials

LevelofConfidenceintheEvidenceforAdverseEffectsofMarijuanaonHealthandWell-Being

NEJM370;23.2014

Comparedtoadverseeffectsfromcurrenttherapyop.ons?





Backtoourcase…

Ethical LegalClinical

Marijuanainthe1600-1800s

www.pbs.org,9/9/2015

Americanproduc.onofhempwasencouragedbythegovernmentinthe17thcenturyfortheproduc.onofrope,sails,andclothing

In1619theVirginiaAssemblypassedlegisla.onrequiringeveryfarmertogrowhemp.HempwasallowedtobeexchangedaslegaltenderinPennsylvania,Virginia,andMaryland

Domes.cproduc.onflourishedun.laUertheCivilWar,whenimportsandotherdomes.cmaterialsreplacedhempformanypurposes

Inthelatenineteenthcentury,marijuanabecameapopularingredientinmanymedicinalproductsandwassoldopenlyinpublicpharmacies

Briefhistoryofmarijuanaregula.on

www.pbs.org,9/9/2015www.ncsl.org,8/11/2015

1906PureFoodandDrugActrequiringlabelingofanycannabisinOTCremedies

1930Crea.onoftheFederalBureauofNarco.cs

1932UniformStateNarco.cActencouragingstategovernmentstocontrolrisinguseofmarijuana

1936ReeferMadnesspropagandafilmaboutthedangersofmarijuanause

1937Marijuanataxactcriminalizingmarijuanaexceptauthorizedmedicalandindustrialuses

1951-56BoggsActandNarco.csControlActsetmandatorysentencesformarijuana-relatedoffenses

1968Crea.onoftheBureauofNarco.csandDangerousDrugs

1970ControlledSubstancesActeliminatedmandatoryfederalsentencesforpossessionofsmallamounts;marijuanaisaScheduleIsubstance

1973Crea.onoftheDrugEnforcementAgency

1986An.-DrugAbuseActins.tutesmandatorysentencesfordrug-relatedcrimes

1996MedicaluselegalizedinCalifornia

2009Memotofederalprosecutorsencouragingthemnottoprosecutepeoplewhodistributemarijuanaformedicalpurposesinaccordancewithstatelaw

Federalperspec.ve–amixedmessage?MarijuanaisaScheduleIsubstanceundertheControlledSubstancesAct• Consideredtohaveahighpoten.alfordependencyandnoacceptedmedicaluse• Distribu.onofmarijuanaisafederaloffense.

October2009• ObamaAdministra.onsendsamemotofederalprosecutorsencouragingthemnottoprosecutepeoplewhodistributemarijuanaformedicalpurposesinaccordancewithstatelaw

August2013• USDOJannouncesupdatetotheirmarijuanaenforcementpolicy• USDOJexpectsstateslikeCOandWAtocreate"strong,state-basedenforcementefforts....andwilldefertherighttochallengetheirlegaliza.onlawsatthis.me."• USDOJreservestherighttochallengethestatesatany.metheyfeelit'snecessary.

www.ncsl.org8/11/2015

Whatislegalandwhatisnot?

Na.onalConferenceofStateLegislatures–www.ncsl.org• Statemedicalmarijuana/cannabisprogramlaws• Limitedaccessmarijuanaproductlaws(lowTHC/highCBD)• Linkstolegaldocumenta.on• Statevs.federalperspec.ve

MarijuanaPolicyProject–www.mpp.org• Federalandstatepolicies• Ballotini.a.ves

Statemedicalmarijuana/cannabisprogramlaws

23states,theDistrictofColumbiaandGuamnowallowforcomprehensivepublicmedicalmarijuanaandcannabisprograms

Comprehensiveprogram• Protec.onfromcriminalpenal.esforusingmarijuanaforamedicalpurpose• Accesstomarijuanathroughhomecul.va.on,dispensariesorsomeothersystemthatislikelytobeimplemented• Itallowsavarietyofstrains,includingthosemorethan"lowTHC"• Itallowseithersmokingorvaporiza.onofsomekindofmarijuanaproducts,plantmaterialorextract


Statemedicalmarijuana/cannabisprogramlaws

Alaska,Connec.cut,Delaware,DC,Guam,Hawaii,Illinois,Maine,Maryland,MassachuseVs,Minnesota,Montana,Nevada,NewHampshire,NewJersey,NewMexico,NewYork,Oregon,RhodeIsland,Vermont,Washington www.ncsl.org

8/11/2015

StateStatutoryLanguage(year)

Pa:entRegistryorIDcards AllowsDispensaries

SpecifiesCondi:ons

RecognizesPa:entsfromotherstates

StateAllowsforRetailSales/AdultUse

Arizona Proposi.on203(2010)

Yes Yes Yes Yes

Colorado Amendment20(2000)

Yes Yes Yes No Amendment64(2012)

California Proposi.on215(1996)SB420(2003)

Yes Yes(coopera.vesandcollec.ves)

No

Michigan Proposal1(2008) Yes Notinstatelaw,butlocali.esmaycreateordinancestoallowthemandregulatethem.

Yes Yes

Variabilityfromstatetostate“Seriousmedicalcondi.on":• Acquiredimmunedeficiencysyndrome(AIDS)• Anorexia• Arthri.s• Cachexia• Cancer• Chronicpain• Glaucoma• Migraine• Severenausea

• Persistentmusclespasms,including,butnotlimitedto,spasmsassociatedwithmul.plesclerosis• Seizures,including,butnotlimitedto,seizuresassociatedwithepilepsy.• Anyotherchronicorpersistentmedicalsymptomthateither:(A)Substan.allylimitstheabilityofthepersontoconductoneormoremajorlifeac.vi.esasdefinedintheAmericanswithDisabili.esActof1990.(B)Ifnotalleviated,maycauseseriousharmtothepa.ent'ssafetyorphysicalormentalhealth.

Variabilityfromstatetostate“Debilita.ngmedicalcondi.on":• Cancer• mul.plesclerosis• HIV• AIDS• Thetreatmentofthesecondi.ons,ifthediseaseorthetreatmentresultsinsevere,persistent,andintractablesymptoms;OR

• adisease,medicalcondi.on,oritstreatmentthatischronic,debilita.ng,andproducessevere,persistent,andoneormoreofthefollowingintractablesymptoms:

• Cachexiaorwas.ngsyndrome• Severepain• Severenausea• Seizures

Limitedaccessmarijuanaproductlaws

17statesallowuseof"lowTHC,highcannabidiol(CBD)"productsformedicalreasonsinlimitedsitua.onsorasalegaldefense


State

ProgramNameandStatutoryLanguage(year)

Pa:entRegistryorIDcards

DispensariesorSourceofProduct(s) SpecifiesCondi:ons

RecognizesPa:entsfromotherstates

Defini:onofProductsAllowed

AllowsforLegalDefense

AllowedforMinors

Missouri HB2238(2014)

Yes Yes,createscannabidioloilcarecentersandcul.va.onandproduc.onfacili.es/laboratories.

Yes,intractableepilepsythathasnotrespondedtothreeormoreothertreatmentop.ons.

No "Hempextracts"equalorlessthan.3%THCandatleast5%CBDbyweight.

Yes Yes

Alabama,Florida,Georgia,Iowa,Kentucky,Louisiana,Mississippi,NorthCarolina,Oklahoma,SouthCarolina,Tennessee,Texas,Utah,Virginia,Wisconsin,Wyoming

VariabilityfromstatetostateState SpecifiesCondi:ons Defini:onofProductsAllowed

Missouri Yes,intractableepilepsythathasnotrespondedtothreeormoreothertreatmentop.ons.

"Hempextracts"equalorlessthan.3%THCandatleast5%CBDbyweight.

Alabama Yes,debilita.ngepilep.ccondi.onsorlife-threateningseizures. ExtractsthatarelowTHC=below3%THC

Florida Yes,cancer,medicalcondi.onorseizuredisordersthatchronicallyproducessymptomsthatcanbealleviatedbylow-THCproducts

CannabiswithlowTHC=below.8%THCandabove10%CBDbyweight

Georgia Yes,endstagecancer,ALS,MS,seizuredisorders,Crohn's,mitochondrialdisease,Parkinson's,SickleCelldisease

CannabisoilswithlowTHC=below5%THCandatleastanequalamountofCDB.

Iowa Yes,intractableepilepsy "Cannabidiol-anon-psychoac.vecannabinoid"thatcontainsbelow3%THC,nomorethan32oz,andessen.allyfreefromplantmaterial.

Kentucky Intractableseizuredisorders No,only"cannabidiol"






Backtoourcase…

SessionObjec.vesAUeraVendingtheCMEsessiononMedicalandLegalizedMarijuana,youwillbeableto:

1. Compareandcontrasttheknowneffectsoftetrahydrocannabinol(THC)andcannabidiol(CBD).

2. Iden.fysymptomsthatmayberelievedbytreatmentwithmarijuanaorothercannabinoids

3. Iden.fyapplicablemedicalmarijuanalawsinstatesinwhichyouhaveamedicallicense.

References1.  BurgdorfJR,KilmerB,PaculaRL.Heterogeneityinthecomposi.onofmarijuanaseizedinCalifornia.

DrugAlcoholDepend.2011Aug1;117(1):59-61.2.  Cabral,GAandGriffin-Thomas,L.EmergingroleofthecannabinoidreceptorCB2inimmuneregula.on:

Therapeu.cprospectsforneuroinflamma.on.ExpertReviewsinMolecularMedicine11,No.1(2009):e3.

3.  Cabral,GA,Rogers,TJ,Lichtman,AH.TurningOveraNewLeaf:CannabinoidandEndocannabinoidModula.onofImmuneFunc.on.JNeuroimmunePharmacol.2015;10(2):193–203.

4.  CasareV,D.Stoned.CurrentPublishing.2015.5.  Na.onalConferenceofStateLegislatureswebsite(www.ncsl.org)6.  MarijuanaPolicyProjectwebsite(www.mpp.org)7.  Pertwee,RG.ThediverseCB1andCB2receptorpharmacologyofthreeplantcannabinoids:delta-9-

tetrahydrocannabinol,cannabidiol,anddelta-9-tetrahydrocannabivarin.Bri(shJournalofPharmacology153,199-215.2008.

8.  VolkowND,BalerRD,ComptonWM,WeissSR.Adversehealtheffectsofmarijuanause.NEnglJMed.2014;370(23):2219–2227.

9.  Whi.ng,PF,et.al.CannabinoidsforMedicalUse:Asystema.creviewandmeta-analysis.JAMA.2015;313(24):2456-2473.

Documents

Medical and Legalized MarijuanaMedical and Legalized Marijuana From pain relief to recreational use… Schoen W. Kruse, Ph.D. Assistant Dean Associate Professor of Pharmacology Kansas