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TheRoleofthePhysicianinMedicalMarijuana

PresidentsActionCommitteeonMedicalMarijuanaoftheAmericanSocietyofAddiction Medicine.Membersofthecommittee: AndreaG.Barthwell,MD,FASAM,Cochair,ASAMPresidentsActionCommitteeonMedical Marijuana;MedicalandScientificPolicyAdvisor,CenterforLawfulAccessandDeterrence; President,TwoDreamsOuterBanks,Corolla,NorthCarolina LouisE.Baxter,Sr.,MD,PresidentofASAM;Member,ASAMPresidentsActionCommittee onMedicalMarijuana; TimmenCermak,MD,Member,ASAMPresidentsActionCommitteeonMedicalMarijuana; RobertDuPont,MD,Cochair,ASAMPresidentsActionCommitteeonMedicalMarijuana; MarkL.Kraus,MD,FASAM,Member,ASAMPresidentsActionCommitteeonMedical Marijuana;AssistantClinicalProfessorofMedicine,YaleUniversitySchoolofMedicine, NewHaven,Connecticut;primarycaregeneralinternalmedicine/addictionmedicine, WestsideMedicalGroup,P.C.,Waterbury,Connecticut;andChiefMedicalOfficer, ConnecticutCounselingCenters,Danbury,Connecticut PetrosLevounis,MD,FASAM,Member,ASAMPresidentsActionCommitteeonMedical Marijuana;Director,TheAddictionInstituteofNewYorkChief;DivisionofAddiction PsychiatryandAssociateChairforClinicalServices,St.Luke'sandRooseveltHospitals; AssociateClinicalProfessorofPsychiatry,ColumbiaUniversityCollegeofPhysicians& Surgeons,NewYork,NewYork Basedonaliteraturereview,consensusdiscussions,andafieldreview,theAction Committeedevelopedaseriesoffindings,conclusionsandrecommendationsregardingthe therapeuticvalueofsmokedmarijuanaandtheroleofphysiciansintheprescribingof marijuanaformedicinalpurposes. September2010

ABSTRACT
laggedbehindthatofothermodernmedications.Therecentdiscoveryandelucidationof theendocannabinoidreceptorsystem,coupledwithimprovementsintechnologyandnew researchtools,hasfacilitatedanalytical,pharmacological,andotherpreclinicalresearch. Theconundruminmanystatesisthatliberalcannabisdistributiontopatientswithvarious medicalconditionsoccursinasettingwherelittlescientificevidenceexiststoguidethis processinarational,ethicalmannertoprotectpatienthealthandsafety.Thepurposeof thisreviewistoexaminethecircumstancesthatledtothissituationandexplorethe scientificissuesinvolvedinmovingtowardaresolution.Italsosetsoutrecommendations toassistphysiciansincopingwiththeseissuesandproposespolicyrecommendationsfor considerationthat,ifadopted,couldreducethepotentialformoreproblemsinthefuture. Results:Reviewfindingsindicatethatinordertothinkclearlyaboutmedicalmarijuana, onemustdistinguishfirstbetween1)thetherapeuticpotentialsofspecificchemicalsfound inmarijuanathataredeliveredincontrolleddosesbynontoxicdeliverysystems,and2) smokedmarijuana.Second,onemustconsiderthedrugapprovalprocessinthecontextof publichealth,notjustformedicalmarijuanabutalsoforallmedicinesandespeciallyfor controlledsubstances.Controlledsubstancesaredrugsthathaverecognizedabuse potential.Marijuanaishighonthatlistbecauseitiswidelyabusedandamajorcauseof drugdependenceintheUnitedStatesandaroundtheworld.Whenphysiciansrecommend useofscheduledsubstances,theymustexercisegreatcare.Thecurrentpatternof medicalmarijuanauseintheUnitedStatesisfarfromthatstandard. Conclusions:Allcannabisbasedandcannabinoidmedicationsshouldbesubjectedtothe rigorousscrutinyoftheFederalFoodandDrugAdministration(FDA)regulatoryprocess. Thisprocessprovidesimportantprotectionsforpatients,makingmedicationsavailable onlywhenthey:1)arestandardizedbyidentity,purity,potencyandquality;2)are accompaniedbyadequatedirectionsforuseintheapprovedmedicalindication;and3) haverisk/benefitprofilesthathavebeendefinedinwellcontrolledclinicaltrials. KeyWords:cannabis,cannabinoidmedication,medicalmarijuana
Objectives:Researchintothetherapeuticpotentialofcannabisandcannabinoidshas

ExecutiveSummary
Researchintothetherapeuticpotentialofcannabisandcannabinoidshaslagged behindthatofothermodernmedications.Therecentdiscoveryandelucidationofthe endocannabinoidreceptorsystem,coupledwithimprovementsintechnologyandnew researchtools,hasfacilitatedanalytical,pharmacological,andotherpreclinicalresearch. Clinicalresearchisalsoincreasing,althoughonlyasmallnumberofcontrolledstudies meetingmodernscientificstandardshavebeenpublished. Allcannabisbasedandcannabinoidmedicationsshouldbesubjectedtothe rigorousscrutinyoftheFederalFoodandDrugAdministration(FDA) 1 regulatoryprocess. Thisprocessprovidesimportantprotectionsforpatients,makingmedicationsavailable onlywhenthey:1)arestandardizedbyidentity,purity,potencyandquality;2)are accompaniedbyadequatedirectionsforuseintheapprovedmedicalindication;and3) haverisk/benefitprofilesthathavebeendefinedinwellcontrolledclinicaltrials.TheFDA hassetforththecriteriathatmustbemetifabotanicallybasedmedicationistoachieve marketingapprovalthroughthisprocess. AllmajormedicalorganizationssupporttheFDAapprovalprocess.Boththe AmericanMedicalAssociation(AMA)andtheAmericanCollegeofPhysicians(ACP)have rejectedtheuseofstatelegislativeenactmentstodeterminewhetheramedicationshould bemadeavailabletopatients.TheInstituteofMedicinehasalsorejectedthisapproachand hascalledforfurtherresearchintothedevelopmentofnonsmoked,reliabledelivery systemsforcannabisderivedandcannabinoidmedications.Rigorousresearchisneeded bettertounderstandthesignificanceofdifferentcannabinoidformulationsandratios, methodsofadministration,anddoseresponserelationships.Cannabishasarangeof effects,someofwhichmaybedisturbingtopatientswithseriousmedicalconditions, adverselyimpacttheircognitiveskills,orimpairtheirlungfunction.Sucheffectsshouldbe betterunderstood,particularlyinthecontextofchronicmedicaluse. Medicalmarijuana,currentlydistributedpursuanttostatelegislation,doesnot accordwithcriticallyimportantaspectsofthemodernscientificmodel.Itlacksquality controlandstandardization;canbecontaminatedwithpesticidesandmicrobes;anddoes notassurepatientsareliableandreproducibledose.Increasedcannabispotencyheightens theriskofadverseevents,especiallyamongcannabisnavepatients,aswellasthedangers ofdependenceandaddiction.Therearenoeffectiveriskmanagementmeasurestoprevent diversionandabuse,especiallybyadolescents. Thepracticeofmedicinemustbeevidencebased;allmedicalinterventionsshould bejustifiedbyhighqualitydata.Despitethepaucityofrigorousscientificdata, dispensariesarenowdistributingcannabisandcannabisproductstolargenumbersof

1SomeindividualscriticizetheFDAasanimperfect,flawedsystem,butitsprocessisthestandardfor

medicationapprovalintheUnitedStates.Thereisnorationaleforcarvingoutlargescaleexceptionstothis reviewprocess.Anyrationaleofferedlosescurrencywhenoneconsidersthepotentialharmassociatedwith increasingtheavailabilityofasubstancewithahighabuseliability.

individuals.Yetphysicians,whoarethegatekeepersofthisprocessunderstatelaw,have inadequateinformationonwhichtobasetheirjudgmentiftheychoosetodiscusscannabis asatreatmentoptionwiththeirpatients.Physiciansshouldcarefullyconsidertheirethical andprofessionalresponsibilitiesbeforeissuingacannabisrecommendationtoapatient.A physicianshouldnotadviseapatienttoseekatreatmentoptionaboutwhichthephysician hasinadequateinformationregardingcomposition,dose,sideeffects,orappropriate therapeutictargetsandpatientpopulations.

Introduction
Duringthepast40years,popularinterestinthetherapeuticpotentialofcannabis hassignificantlyincreased,propagatedbywidespreadmediaattention.Because cannabinoidresearchposesspecialchallenges,datafromsuchresearchhaveaccumulated slowlyandonlyrecentlyhavegainedsubstantialattentionwithinthescientificandmedical communities.Theconundruminmanystatesis:liberalcannabisdistributiontopatients withvariousmedicalconditions;littlescientificevidenceexiststoguidethisprocessina rational,ethicalmannerwhichensurespatienthealthandsafety.Thisreportwillexamine thecircumstancesthatledtothissituationandexplorethescientificissuesinvolvedin movingtowardaresolution.Itwillalsosetoutrecommendationstoassistphysiciansin copingwiththeseissuesandproposepolicyrecommendationsforconsiderationthatare intendedtoreducethepotentialformoreproblemsinthefuture. ModernHistoryofCannabisinMedicine Intheearlypartofthe19thcentury,theEuropeanmedicalcommunitybecame awareofthetherapeuticpotentialofcannabisbasedmedications.Dr.William OShaughnessy,anIrishphysician,conductedclinicalandnonclinicalworkinIndiawith cannabispreparationsanduponhisreturntoEngland,theresultsofhisstudiesbecame widelyknown.AcrossEuropeandNorthAmericainterestincreasedinthetherapeutic potentialofthesematerials.(OShaughnessyWB,1973)Pharmacistsandearly pharmaceuticalcompanies(HamiltonHC,LescohierAW&PerkinsRA,1913)developed oralcannabisextractsandtinctures 2 forvariousmedicalconditions.Thesecannabis preparationswereunstableandunreliable,however,becauseunlikeopiates,cannabinoids arelipid,ratherthanwatersoluble,andsensitivetodegradationbyheatandlight(Garrett ER,HuntCA,1974).Becauseofthesecharacteristics,andthelimitedtechnologyavailable atthetime,theactiveingredientsincannabispreparationswereunknown,the preparationslackedstandardization,andpatientresponsewasvariable(WaltonRP,1928).

2Historically,cannabiswasusedfortherapeuticpurposesprimarilyintheformofteas,extracts,tinctures

(grainsofhemp/hashishresindissolvedinalcohol)notinsmokedform.Onlyinrarecases,involving respiratoryconditionswascannabisinhaled.Inthe1800s,thecompositionofthisresinwouldhavebeen abouthalfTHCandCBD(ofitsprimarycannabinoids).(RussoEB,2007).Seediscussionbelow.

ReportsoftenblametheenactmentofthefederalMarihuanaTaxActof1937,which imposedadministrativelimitationsontheprescriptionofcannabispreparations, 3 forthe contractionintheuseofmarijuanainmedicine.Themainreasonsforthisdisappearance werethevariablepotencyofcannabisextracts,theerraticandunpredictableindividual responses,theintroductionofsyntheticandmorestablepharmaceuticalsubstitutessuch asaspirin,chloralhydrateandbarbiturates,andtherecognitionofimportantadverse effectssuchasanxietyandcognitiveimpairment(FankhauserM,2002).Accordingly, cannabispreparationsgraduallyfelloutofusebythemedicalprofession. 4 Asone prominentphysicianin1938noted(WaltonRP,1938) 5 : ThetherapeuticapplicationofCannabisismoreamatterofhistorythanofpresent daypractice.Syntheticanalgesicsandhypnoticshavealmostentirelydisplaced thesepreparationsfromtheiroriginalfieldofapplication.Thenewersyntheticsare moreeffectiveandreliableand,inaddition,havebeenmoreintensivelyexploitedby commercialinterestsThedrughascertainremarkablepropertiesandifits chemicalstructureweredeterminedandsyntheticvariationsdeveloped,some ofthesemightprovetobeparticularlyvaluable,bothastherapeuticagentsandas experimentaltools(WaltonRP,1938). Waltonspredictionstodayremainbothhopefulandelusive. Becauseofthetechnologicalchallengesinvolvedincannabinoidformulationand research,itwasnotuntil1964thattheprimarypsychoactiveingredientincannabis,delta 9tetrahydrocannabinol(THC),wasidentifiedandsynthesized(MechoulamR&GaoniY, 1965).Coincidentally,popularinterestinsmokedcannabisbegantoincreasesignificantly. Anumberofindividualsreportedthatsmokingcannabisforrecreationalpurposesseemed toalleviatesomeoftheirmedicalsymptoms.Interestgrewinfindingtherapeuticusesfor smokedcannabis.Moreadvancedtechnologyinthe1800sandearly1900smighthave madearangeofcannabinoidmedicationssimilartothatofmodernopiatesavailable, andcannabissmokingmighthavebeenrelegatedtotherealmofnondependent,non

wouldhaveontheavailabilityofcannabispreparationsbutacknowledgedthatsuchpreparationswerelittle used: Cannabisatthepresenttimeisslightlyusedformedicinalpurposes,butitwouldseem worthwhiletomaintainitsstatusasamedicinalagentforsuchpurposesasitnowhas.Thereis apossibilitythatarestudyofthedrugbymodernmeansmayshowotheradvantagesto bederivedfromitsmedicinaluse. 4Asimilarsituationoccurredinthetreatmentofcancerchemotherapyinducednauseaandvomiting.Inthe 1970sand1980s,therewasconsiderableinterestinusingsmokedcannabisandoralTHCforthese conditions,sinceexistingtreatmentswereinadequateforcontrolofemesis.Anumberofstatedepartmentsof healthconductedopenlabelstudiescomparingsmokedmarijuana,oralTHC,andexistingantiemetics. Followingthedevelopmentofmoreeffectiveantiemeticagentssuchasthe5HTreceptorantagonists interestinusingoralTHCandsmokedcannabistopreventacutevomitingwaned.(CouncilonScientific AffairsReport6,2001). 5Ataboutthattime,Dr.WaltonwasProfessorandHeadoftheDepartmentofPharmacologyand Therapeutics,MedicalCollegeofSouthCarolina,Charleston,S.C.,andwroteandpublishedoncannabisin 1938.
3TheAMACommitteeonLegislativeActivitiesexpressedconcernaboutthenegativeimpactthattheAct

medicaluseforpleasure(McCarbergWH&BarkinRL,2007). 6 Thus,thelaginthe technologicalcapabilitiesofmodernscienceprobablycontributedtothecontroversyof medicalmarijuana.Thattechnologyhasnowarrived,andtheeraofmoderncannabinoid medicationdevelopmentiswellonitsway. TheBasisforCannabinoidTherapeutics Momentumfordevelopingcannabinoidmedicationsgainedforceonlyafterthe discoveryofendocannabinoidreceptors(MunroS,ThomasKL,&AbuShaarM,1993; HowlettAC,1995)andthebrainsendogenouscannabinoidligandsinthelate1980sand early1990s(DevaneWA,HanusL,BreuerAetal,1992).Thesemonumentaldiscoveries, parallelintheirbasicframeworktothediscoveryofthebrainsendogenousmorphinelike neuralsystem(theendorphins),transformedthefocusofresearchfrommarijuanatothe brainitself.Thesediscoveriesmarkedthedawnofcannabinoidneuroscience. Wenowunderstandthatanextensivesystemofnerveswithinthebrain communicatewitheachotherusingthesamebasicchemistryfoundinmarijuana.Whilewe areonlybeginningtounraveltheroletheendocannabinoidsystemplaysinoverallbrain function,RaphaelMechoulamhasdeclaredthatThecannabinoidreceptorsarefoundin higherconcentrationsthananyotherreceptorinthebrainandtheendocannabinoid systemactsessentiallyinjustabouteveryphysiologicalsystemthatpeoplehavelooked into,soitappearstobeaverycentralsystem(BrownD,20052006). Cannabinoidtype1(CB1)receptorsaredistributedthroughoutthebrain,where theyareconcentratedinthehippocampus,amygdala,basalganglia,cerebellum,nucleus accumbensandcortex(anterior>posterior).Cannabinoidtype2(CB2)receptorsare generallylocatedperipherally(HerkenhamM,LynnAB,LittleMD,etal,1990).Tonic activitywithintheendocannabinoidsystemiscontinuouslymodulatingahugevarietyof physiologicalandbrainfunctions,includingshorttermmemory,learning,appetite, anxiety/fear,pain,andspontaneousmotoractivity. Twoaspectsoftheendocannabinoidsystemareimportantfromtheaddiction medicineperspective.First,CB1receptorsandendocannabinoidligandsareheavily concentratedinthenucleusaccumbensthefinalcommonpathwayactivatedbydrugsof addictionintheRewardCenter.Frequentfloodingofthesereceptorsbytheingestionof exogenouscannabinoidsisinpartresponsibleforthedevelopmentofdependence(Budney A,HughesJR,MooreBA,etal,2004).Alsocontributingtowithdrawalsymptomsisthe downregulationofcannabinoidreceptorsbyupto60%inresponsetoexogenous cannabinoids(RomeraJ,1997). CB1knockoutmice,whichhavevirtuallynocannabinoidactivityinthecentral nervoussystem(CNS),havebeenusedtoassesstheoverallroleofourendocannabinoid

6Unlikecannabis,themedicinalandrecreationalformsofopiumwereclearlydistinct.Hadmedical

technologybeenadvancedenoughatthattimetoallowcannabinoidstobeidentified,formulated,and delivered,themedicalmarijuanamovementwouldprobablynothaveoccurred.Aswiththeopiumpoppy, prescriptioncannabinoidmedicationsandcrudeherbalcannabiswouldhavebeenusedinverydifferent venues.

system.Withoutafunctioningcannabinoidsystemduetoageneticallyinducedlackof CB1receptors,knockoutmicedemonstrateincreasedmemories(MarsicanoG,WotjakCT, AzadSC,etal,2002),decreasedextinctionofaversivememories,failuretoselfadminister morphineandasignificantlyincreasedmortalityfromawidevarietyofcauses(Chhatwal JP,DavisM,etal,2005). THCandsimilarmoleculesinmarijuanaareabletoaffectthebrainonlybecause theymimicournaturalneurotransmitters,floodingreceptorsiteswithstimulation.Allthe cannabinoidbasedareasofthebrainaresubsequentlyactivatedbeyondnormal physiologicallevels.Thisisgenerallyenjoyableformostpeople,butnotwithout consequencesformany.Smokingmarijuanaessentiallyreachesintothebrainand increasestheactivityofonespecificsubsetofneuronalactivityliketurninguparheostat thatcontrolsthebrainsendocannabinoidactivity. Thequestionofwhetherthereismedicinalvalueinstimulating,orreducing,activity incannabinoidbasedportionsofthebraindependsonthreethings: 1. Specificareasofthebrainwherecannabinoidchemistryisconcentratedandthe functionsservedbytheseareas; 2. Thespecificdiseaseandsymptomsbeingtreated;and 3. Sideeffectsproducedbythetreatmentessentiallyamedicalcost/benefit analysis. Inadditiontherearealsocannabinoidreceptors(CB2)foundthroughoutthebody, onnerves,bloodcells,onorgans,andthroughoutallstagesofembryonicdevelopment.The potentialforcannabinoidtherapeuticsmustalsolookatthedirectimpactofstimulatingor antagonizingthesereceptorsaswell. Thepotentialvalueofanycannabinoidmedicationdependsonmodifying physiologicfunctionsthatarenaturallycontrolledbyourbodysinternalcannabinoid system.Givenallthefunctionsthataremodulatedbyendocannabinoidchemistry,itis likelythateitherstimulatingorblockingportionsofthisubiquitousneuronalsubsystem hasthepotentialforrelievingthesufferingcausedbydisease.Thebasicneuroscienceof ourendocannabinoidsystemthusprovidestheAmericanSocietyofAddictionMedicines (ASAM)perspectiveonthemosteffectiveframeworkformedicalizingcannabinoid therapeutics. A.ASAMrecognizesthatarolehasbeenestablishedforthebodysnaturalcannabinoid chemistryinregulatingmanyfacetsofmemory,pain,emotions,appetites,motor activity,digestion,attention,higherorderexecutivefunctions,reward/addiction,the immunesystem,andreproductiveactivity. B.Multipleillnessesaffectingthesefunctions,suchasdementia,chronicpain,anxiety, posttraumaticshockdisorder(PTSD),wastingsyndrome,spasticity,diarrhea,irritable bowelsyndrome,thenausea/vomitingofchemotherapyandapplicationsstillbeing exploredinresearchlabs,arelikelytobenefitfrommedicationsbasedonourbodys inherentcannabinoidchemistry.

C.Thenewcannabinoidmedicationsbeingdevelopedwillrangefromonesthatdirectly stimulatecannabinoidreceptorstoonesthatprolongtheeffectofournatural cannabinoidchemistry(similartohowmostantidepressantswork)toonesthatblock thereceptorsinordertoreducetheactivityofourcannabinoidsystem.Medications arealsobeingdevelopedthatcantargetonlyportionsofourcannabinoidsystem withoutaffectingthewholesystem(forexample,reducingpaininthebodywithout affectingthebrain)(IbrahimMM,DengH,etal,2003;QuartilhoA,MataHP,etal, 2003). Theexcitingdiscoveriessummarizedaboveregardingtheendocannabinoidsystem havestimulatedpreclinicalresearch: Thisevolutionhasfollowedthesameprinciplesastheevolutionofdrug therapyingeneral.Thedirectionhasbeenawayfromcrudesubstancesofvariable composition,stability,andpotency,towardthedevelopmentofprogressivelymore selectivelyactivepurecompoundsthatpermitdosagethatismorepreciseand reducedriskofunwantedsideeffects.(VarvelSA,WiseLE,etal,2007)25 Afteradelayofoveracentury,wearenowonthecuspofanewerainwhichmany cannabinoidproductscouldbecomepartofthephysiciansarmamentarium.Anumberof cannabinoidproductsarealreadyindevelopment.Severalareplantderived(Sativex, Cannador);othersaresyntheticanalogues(ChatwalJP,2005)orligandsattheCB2rather thantheCB1receptor(MarsicanoG,Wotjak,etal,2002;ChhatwalJP,DavidM,Maguschak KA,etal,2005;VarvelSA,WiseLE,etal,2007);stillothersinvolvenewdeliverysystems forTHC.Itwilltaketimeforthisresearchtoevolveintoarangeofprescription medications.Thedurationandcomplexityofthisdevelopmentprocessis,however, necessarytoensurethataproductspharmacologyandrisk/benefitprofileareadequately understoodandsuchpreparationscanmeetFDAstandardsofconsistency,safetyand efficacybeforetheproductisdistributedtopatients. MedicalMarijuanaintheUnitedStates FifteenstatesandtheDistrictofColumbiahavecurrentlyenactedlawsthatpermit theuseofcannabisformedicaluse.Someofthelawshavebeenpassedbypopularvote throughtheinitiativeprocess;statelegislativebodieshavepromulgatedafew.Thefirstof theselawspassedin1996.Afterhavingfailedforseveralyearstoobtainalegislative enactment,cannabisadvocatestooktheissuetothepeopleofCaliforniathroughthe initiativeprocess. 7 Inmostofthesestates,individualpatientsand/ortheirdesignated

7TherewereseveralmedicalmarijuanabillsintroducedintotheCalifornialegislature,beginningin1994, e.g.,SB1364,AB2933,AB1529,AB2120,buttheyeitherdidnotpassorwerevetoedbytheGovernor. Coincidentally,thesebillsfollowedimmediatelyontheheelsofthefinaldispositionofapetitionfiledbythe NationalOrganizationfortheReformofMarijuanaLaws(NORML),whichwasfiledin1972shortlyafter

caregiversmaycultivatecannabisformedicalpurposes.Somestatesplacelimitsonthe medicalconditionsthatcanqualifyforlegalprotection,(e.g.,Washington,NewJersey,New Mexico).Afewpermitthedistributionofcannabisbycertaintypesofdispensaries,(e.g., RhodeIsland,NewJersey,andNewMexico).Withoutexception,allofthestatelawsmake physiciansthegatekeepers,thatis,apatientcannotqualifytousecannabisformedical purposesunlessaphysicianhasrecommendedtheuseofcannabisforthatperson. 8 Asageneralrule,theselawsdonotcreatenewrightsunderstatelaw;rather,they allowapatient(anddesignatedcaregivers)toraisehis/herpersonalmedicaluse/ cultivationasanaffirmativedefenseiftheindividualisarrestedandchargedwithviolation ofcertainstatecriminallawspertainingtocannabis. 9 Inthefirstfewyearsfollowingtheenactmentofthefirstmedicalmarijuanalaws, individualpatientsandtheirdesignatedcaregiversprimarilyconductedcultivation. Accordingly,thelawshadlimitedapplication,andresearchmighthavebeenableto provideimportantdatabeforewidespreaduseoccurred.Now,however,thesituationhas changeddramaticallyanddispensarieshaveproliferatedatarapidrate.Manyphysicians haveopenedpracticesbasedexclusivelyonissuingcannabisrecommendations(see furtherdiscussionbelow).Asaresult,thousandsofpersons,withdiversemedical conditions(and/ornonmedicalreasons),areusingcannabis,despitethefactthatresearch hasnotkept(andcannotkeep)pacewithsuchrapidlyexpandinguseforthemyriadof conditionsthatcannabisisreportedtotreat. ReportsfromExpertBodies Theearlymedicalmarijuanainitiativesgarneredwidespreadmediacoverage, publicinterest,andcontroversy.Asaresult,anumberofexpertbodiesexaminedthedata relatingtothetherapeuticpotentialofcannabisandcannabinoids. NationalInstitutesofHealth In1997,theNationalInstitutesofHealth(NIH)hostedaworkshopatwhichmedical expertsdiscussedthepotentialmedicalusesofsmokedcannabis.Thisgroupreviewedthe

CongressplacedmarijuanainScheduleIoftheControlledSubstancesActin1970.NORMLinitiallysoughtto removemarijuanaentirelyfromtheCSAor,alternatively,placemarijuanainScheduleV,NORMLv.Ingersoll, 497F.2d654(D.C.Cir.1974),butagreedthatUStreatyobligationsdidnotpermitthatcourseofactionfor cannabisandcannabisresin.NORMLv.DEA,559F.2d735(D.C.Cir.1977)fn.43.Subsequently,NORML soughttomovemarijuanatoScheduleII.ThatpetitionwasdeniedbyDEAand,after22yearsoflitigation,the DEAdenialwasupheldbythefederalcourts.ACTv.DEA,15F.3d1131(D.C.Cir.1994). 8Since1)nomarijuanabasedproducthasbeenapprovedbytheFDA,and2)marijuanaisaScheduleI substanceunderfederallaw,aphysiciancannotprescribe,norcanapharmacistdispense,suchaproduct. Instead,physiciansmayrecommendthemedicaluseofcannabistoaspecificpatient.InMichigan,for example,aphysicianmustcertifythatthepatientislikelytoreceivemedicalbenefitfromtheuseofcannabis. 9Forexample,theCaliforniaSupremeCourthasruledthatCalifornia'slawsconferonlyalimitedimmunity whichoperatesbydecriminalizingconductthatotherwisewouldbecriminal.Peoplev.Mower28Cal.4th 457,472;122Cal.Rptr.2d326(2002).

literatureandconductedhearingsrelatingtothetherapeuticusesofcannabistotreat conditionsincluding:analgesia,neurologicalandmovementdisorders,nauseaand vomitingassociatedwithcancerchemotherapy,glaucoma,andappetite stimulation/cachexia(NationalInstitutesofHealth,1997).Foranumberofthese conditions,thegroupconcludedthattherewouldonlybelimitedvalueinpursuingfurther researchintosmokedcannabis,becauseeffectivetreatmentswerealreadyavailable. However,theydidrecommendnewcontrolledstudiesonsmokedcannabissincecurrent researchdidnotprovidedefinitiveanswersonitsrisk/benefitprofile.Theconsensuswas thatintheseresearchstudies,smokedcannabismustmeetthesamestandardsasother medicationsintermsofeffectivenessandsafety. Giventhatdelta9tetrahydrocannabinol(dronabinol,thegenericandMarinol)is marketedtotreatnauseaandvomitingassociatedwithchemotherapyandappetite stimulationinAIDSpatients,theexpertgroupsuggestedthattheeffectsofsmoked cannabisontheseconditionsbeevaluatedandstudiedtodrawcomparisonsbetween smokedcannabisandsyntheticTHC. ExpertsalsospecificallysuggestedthatNIHuseitsresourcestodevelopasmoke freeinhaleddeliverysystemforcannabisorTHCtoeliminatethenegativehealtheffectsof smokinginresearchtrials. InstituteofMedicineReport In1997,theWhiteHouseOfficeofNationalDrugControlPolicy(ONDCP)requested thattheInstituteofMedicine(IOM)conductareviewofthescientificevidenceregarding thepotentialhealthbenefitsandrisksofcannabisanditscomponentcannabinoids.In 1999,theIOMissuedthereportCannabisandMedicine:AssessingtheScienceBasethat becamethefoundationofstudyintomedicalmarijuana(JoyJE,Watson,Jr.SJ&Benson JA,1999).IOMmadeaseriesofrecommendationspertainingtotheuseofcannabisin medicaltreatmentthatrevolvearoundtheneedformoreresearchandevaluation. Ititsreport,IOMmadethefollowingrecommendations(JoyJE,Watson,Jr.SJ& BensonJA,1999): Recommendation1:Researchshouldcontinueintothephysiologicaleffectsof syntheticandplantderivedcannabinoidsandthenaturalfunctionofcannabinoids foundinthebody.Becausedifferentcannabinoidsappeartohavedifferenteffects, cannabinoidresearchshouldinclude,butnotberestrictedto,effectsattributableto THCalone. Recommendation2:Clinicaltrialsofcannabinoiddrugsforsymptommanagement shouldbeconductedwiththegoalofdevelopingrapidonset,reliable,andsafe deliverysystems.

Recommendation3:Psychologicaleffectsofcannabinoidssuchasanxietyreduction andsedation,whichcaninfluencemedicalbenefits,shouldbeevaluatedinclinical trials. Recommendation4:Studiestodefinetheindividualhealthrisksofsmoking marijuanashouldbeconducted,particularlyamongpopulationsinwhichcannabis useisprevalent. Recommendation5:Clinicaltrialsofmarijuanauseformedicalpurposesshouldbe conductedunderthefollowinglimitedcircumstances:trialsshouldinvolveonly shorttermmarijuanause(lessthansixmonths),shouldbeconductedinpatients withconditionsforwhichthereisreasonableexpectationofefficacy,shouldbe approvedbyinstitutionalreviewboards,andshouldcollectdataaboutefficacy. Recommendation6:Shorttermuseofsmokedmarijuana(lessthansixmonths)for patientswithdebilitatingsymptoms(suchasintractablepainorvomiting)must meetthefollowingconditions: o failureofallapprovedmedicationstoprovidereliefhasbeendocumented, o thesymptomscanreasonablybeexpectedtoberelievedbyrapidonset cannabinoiddrugs, o suchtreatmentisadministeredundermedicalsupervisioninamannerthat allowsforassessmentoftreatmenteffectiveness,and o Involvesanoversightstrategycomparabletoaninstitutionalreviewboard processthatcouldprovideguidancewithin24hoursofasubmissionbya physiciantoprovidemarijuanatoapatientforaspecifieduse. TheIOMclearlystatedthatthepurposeofshorttermstudieswithsmokedcannabis wouldserve,atbest,aspreliminarysupportforthedevelopmentofcannabisbasedor cannabinoidmodernmedications.Thegoalofclinicaltrialsofsmokedcannabiswould notbetodevelopcannabisasalicenseddrug,butrathertoserveasafirststep towardthepossibledevelopmentofnonsmokedrapidonsetcannabinoiddelivery systems(emphasisadded)(JoyJE,Watson,Jr.SJ,&BensonJA,1999).Specifically,IOM stressedthatthereislittlefutureinsmokedmarijuana. TheIOMacknowledgedthat,untilanonsmokedrapidonsetcannabinoiddrugdelivery systembecameavailable,therewasnoclearalternativeforpeoplesufferingfromchronic conditionsthatmightberelievedbysmokedcannabis.TheIOMsuggestedthatone possibleapproachwouldbetotreatpatientsasnof1clinicaltrials,inwhichpatients arefullyinformedoftheirstatusasexperimentalsubjectsusingaharmfuldrugdelivery system.Itrecommendedthattheirconditioniscloselymonitoredanddocumentedunder medicalsupervision,therebyincreasingtheknowledgebaseoftherisksandbenefitsof marijuanauseundersuchconditions.Underthecurrentsystemofcannabisdistribution bydispensaries,withlimitedoversightbyphysicians,thesepatientprotectionsanddata collectionfunctionsarewhollyabsent.

ProfessionalOrganizations AmericanMedicalAssociation Inboth1997(CouncilonScientificAffairsReport10,1997)and2001,theAMA issuedreportsonthescientificdatarelevanttothemedicalutilityofcannabis(Councilon ScientificAffairsReport6,2001).InNovember2009,theAMAsCouncilonScienceand PublicHealth(CSAPH)revisedseveralofitspolicystatementsoncannabis.The organizationretaineditspreviousrecommendationsfor:1)furtheradequateandwell controlledstudiesintocannabisandcannabinoids;2)urgingtheNIHtofacilitategrants applicationsfor,andtheconduct,ofsuchtrials;and3)permittingfreeandunfettered exchangeofinformationontreatmentalternativesbetweenphysiciansandpatients,which shouldnotsubjecteitherpartytocriminalsanctions. IntheExecutiveSummary,CSAPHnotedthatshorttermclinicaltrialssuggestthat smokedcannabishasefficacyincertainmedicalconditions(aconclusionpresumably furtheranalyzedinthebodyofthereport,whichhasnotyetbeenpublished).Inits Recommendation,AMAurgedthatcannabissstatusasascheduleIdrugbereviewed. Thepurposeofsuchreviewwouldbetoascertainwhetherreschedulingcouldfacilitatethe conductofclinicalresearchandthedevelopmentofcannabinoidbasedmedicinesand alternatedeliverymethods.AMAemphasizedthatthisrecommendationshouldnotbe viewedasanendorsementofstatebasedmedicalcannabisprograms,legalizationof marijuanaorthatscientificevidenceonthetherapeuticuseofcannabismeetsthecurrent standardforaprescriptiondrugproduct(CouncilonScienceandPublicHealthReport3, 2009).Thereportstressedthepatchworkofstatebasedsystemsthathavebeen establishedformedicalmarijuanaiswoefullyinadequateinestablishingeven rudimentarysafeguardsthatnormallywouldbeappliedtotheappropriateclinicaluseof psychoactivesubstances.Thefutureofcannabinoidbasedmedicineliesintherapidly evolvingfieldofbotanicaldrugsubstance 10 development,aswellasthedesignof moleculesthattargetvariousaspectsoftheendocannabinoidsystem. 11 AmericanCollegeofPhysicians

In2008,theAmericanCollegeofPhysicians(ACP)HealthandPublicPolicy Committee(HPPC)composedapositionpaperonthemedicalusesofcannabisthat followedtheleadsetforthbyIOM.Theirpositionsinclude(AmericanCollegeofPhysicians, 2008):

10Forthemeaningofbotanicaldrugsubstance,seediscussionoftheFDABotanicalGuidance,below.

At its 2010 Interim Meeting, the AMA House of Delegates voted to amend current policy by urging the creationofa"special"scheduleforcannabis(ratherthanmovingcannabistoScheduleII),forthepurposeof facilitatingclinicalresearch.http://www.amaassn.org/assets/meeting/2010i/i10annotatedk.pdf.

11

Position1:ACPsupportsprogramsandfundingforrigorousscientificevaluationof thepotentialtherapeuticbenefitsofmedicalmarijuanaandthepublicationofsuch findings. o Position1a:ACPsupportsincreasedresearchforconditionswherethe efficacyofmarijuanahasbeenestablishedtodetermineoptimaldosageand routeofdelivery. o Position1b:Medicalmarijuanaresearchshouldnotonlyfocuson determiningdrugefficacyandsafetybutalsoondeterminingefficacyin comparisonwithotheravailabletreatments. Position2:ACPencouragestheuseofnonsmokedformsofTHCthathaveproven therapeuticvalue. Position3:ACPsupportsthecurrentprocessforobtainingfederalresearchgrade cannabis. Position4(asamended): 12 ACPurgesanevidencebasedreviewofmarijuanas statusasaScheduleIcontrolledsubstancetodeterminewhetheritshouldbe reclassifiedtoadifferentschedule.Thisreviewshouldconsiderthescientific findingsregardingmarijuanassafetyandefficacyinsomeclinicalconditionsaswell asevidenceonthehealthrisksassociatedwithmarijuanaconsumption,particularly initssmokedform. Position5:ACPstronglysupportsexemptionfromfederalcriminalprosecution;civil liability;orprofessionalsanctioning,suchaslossoflicensureorcredentialing,for physicianswhoprescribeordispensemedicalmarijuanainaccordancewithstate law.Similarly,ACPstronglyurgesprotectionfromcriminalorcivilpenaltiesfor patientswhousemedicalmarijuanaaspermittedunderstatelaws.

Inanaddendumtothepositionpaper,ACPaddressedconcernsraisedthatitwas promotingsmokedmarijuanaasmedicine.Inthisresponse,ACPstatesthatithasnot advocatedforthelongtermuseofsmokedmarijuana;rather,thepaperexplicitlydiscusses theharmassociatedwithchronicuseofsmokedmarijuanaandstressestheneedfor developmentofnonsmokedformsofcannabinoiddeliverysystemsstrictlyfortherapeutic purposessupportedbytheevidence(AmericanCollegeofPhysicians,2008).ACPalso stressedthatitsharestheconcernsexpressedbysomeaboutstateballotinitiativesor legislationthatcanunderminethefederalregulatorystructureforassessingthesafetyand efficacyofnewdrugsbeforesuchdrugscanbeapprovedfortherapeuticuse. AmericanNursesAssociation InDecember2008,theAmericanNursesAssociation(ANA)publishedthefollowing statementonmarijuana:

12ACPsoriginalrecommendationseemedtosuggestthatitwascallingforthereclassificationofcannabis

intoamoreappropriateschedule.Afterreceivingextensivecommentaryonthispoint,ACPclarifiedits positiontostatethattheevidencemeritsareviewofcannabissScheduleIclassification,butanychangeto thatclassificationshouldoccuronlyifthereviewestablishedthattheevidencewassufficienttojustifythe change.

TheAmericanNursesAssociationsupports(AmericanNursesAssociation,2008): Theeducationofregisterednursesandotherhealthcarepractitionersregarding appropriateevidencebasedtherapeuticuseofmarijuanaincludingthosenon smokedformsofdelta9tetrahydrocannabinol(THC)thathaveproventobe therapeuticallyefficacious. Protectionfromcriminalorcivilpenaltiesforpatientsusingmedicalmarijuanaas permittedunderstatelaws. Exemptionfromcriminalprosecution;civilliability;orprofessionalsanctioning, suchaslossoflicensureorcredentialing,forhealthcarepractitionerswhoprescribe, dispenseoradministermedicalmarijuanainaccordancewithstatelaw. ReclassificationofmarijuanasstatusfromaScheduleIcontrolledsubstanceintoa lessrestrictivecategory. Confirmationofthetherapeuticefficacyofmedicalmarijuana.

TheFederalPosition TheControlledSubstancesAct(CSA) AllcontrolledsubstancesareassignedtooneoffiveschedulesundertheControlled SubstancesAct(CSA),dependingontheirmedicalusefulnessandtheirpotentialfor abuse. 13 Cannabis/marijuana,ibogaine,mescaline,andpeyotearebotanicalhallucinogens listedinScheduleI.ScheduleIsubstancesarethosesaidtohave: Ahighpotentialforabuse; NocurrentlyacceptedmedicaluseintreatmentintheUS 14 ;and

substanceisassigned: 1. Itsactualorrelativepotentialforabuse 2. Scientificevidenceofitspharmacologicaleffects 3. Thestateofcurrentscientificknowledgeregardingthedrug 4. Itshistoryandcurrentpatternofabuse 5. Thescope,duration,andsignificanceofabuse 6. What,ifany,riskthereistopublichealth 7. Itspsychicorphysiologicaldependenceliability 8. Whetherthesubstanceisanimmediateprecursorofasubstancealreadyundercontrol 21U.S.C.sec.811. 14 In a proceeding which seeks to move a drug from Schedule I to Schedule II, the DEA will examine the followingfactorsindeterminingwhetherthedrughasacurrentlyacceptedmedicaluse: 1.Thedrugschemistrymustbeknownandreproducible; 2.Theremustbeadequatesafetystudies; 3.Theremustbeadequateandwellcontrolledstudiesprovingefficacy; 4.Thedrugmustbeacceptedbyqualifiedexperts;and 5.Thescientificevidencemustbewidelyavailable. See Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131 (D.C.Cir. 1994). 14 See 57 F.R. 10499,10506. AccordingtotheDEA,afailuretomeetanyofthefactorsprecludesadrugfromhavingacurrentlyaccepted medicaluse.57Fed.Reg.at10507.OnlyaproductgoingthroughtheFDAprocesscouldmeetallthesecriteria.
13Thefollowingfactors,oftenreferredtoastheeightfactoranalysis,determinethescheduletowhicha

Alackofacceptedsafetyforuseundermedicalsupervision(21USCsec.812(c) (ScheduleI(c)).

SubstancesinScheduleIIhave: Ahighpotentialforabuse; AcurrentlyaccepteduseintreatmentintheUSoracurrentlyacceptedmedicaluse withsevererestrictions;and Abuseofthesubstancemayleadtoseverepsychologicalorphysiological dependence(21USCsec.812(c)(ScheduleII(a)). 15 Opium,poppystraw,concentrateofpoppystraw,andcocaleavesarebotanicalmaterials listedinScheduleII.AtthetimetheCSAwasenactedin1970,modernprescription medicationsderivedfromthesebotanicalstartingmaterialshadalreadybeenapprovedfor marketingbytheFDA. SubstancesinScheduleImayonlybeusedinresearchstudiesbyinvestigatorswho 1)haveprotocolsthathavebeenapprovedbytheFDAand2)havereceivedresearch registrationsfromtheDrugEnforcementAdministration(DEA).Therefore,allpossession, cultivation,distribution,etc.,ofcannabis,evenifpermittedundervariousstatemedical marijuanalaws,continuestobeillegalunderfederallaw.Aphysician,however,hasaFirst AmendmentrightunderthefederalConstitutiontoprovideapatientwithbonafide medicaladvice,whichmayincluderecommendingtheuseofcannabisformedical purposes,solongasthephysiciandoesnothingaffirmativelytoaidorabetapatientin obtainingcannabis(Conantv.Walters,2002). 16 FederalDepartmentsandAgencies Onanumberofoccasionssince1996,theDrugEnforcementAdministrationhas closedcannabisdispensaries(USv.OaklandCannabisBuyersCooperative,2001)In October2009,thefederalDepartmentofJustice(DOJ)issuedguidelinestoprosecutors (U.S.DepartmentofJustice,2009)that,despitethepublicitytheseguidelinesreceived suggestingthattheObamaadministrationwaspermissivetowardsmedicalmarijuana, areactuallyquitenarrow.Attheoutset,theprovisionsstressthatmarijuanaisa dangerousdrug.Theyconfirmthe(alreadyexisting)policythatfederalprosecution prioritiesshouldbefocusedonsignificant 17 traffickers,notsmallscaleindividualusers. Hence,U.S.attorneysareadvisednottoprosecutepatientswithcancerorotherserious illnesseswhoareusingcannabisaspartofarecommendedtreatmentregimenconsistent

1521USCsec.812(c)(ScheduleII(a)).SubstancesinSchedulesIIIVhavedecreasinglevelsofabusepotential

#1315,TheCompassionateUseActof1996:TheMedicalMarijuanaInitiative(Jan.2010) http://www.cmanet.org/bookstore/freeoncall2.cfm/CMAOnCall1315.pdf?call_number=1315&CFID=745764 &CFTOKEN=27566287(accessedFeb.18,2010). 17Note:thistermisbroaderthanmajor.

16Foramoredetaileddescriptionofthisissue,seeCaliforniaMedicalAssociation,CMAONCALL,document

andaresubjecttolesserdegreesofcontrol.

withstatelaworcaregiversinclearandunambiguouscompliancewithstatelawwho providecannabistosuchpatients(CaliforniaAttorneyGeneral,2008).Commercial enterprises,however,andthoseentitieswhosenonprofitmedicalmarijuanadistribution activitiesaremerelyapretextforforprofitendeavors,aresubjecttoprosecution. 18 SubsequenttotheissuanceoftheseDOJguidelines,theDEAissuedastatement: Theseguidelinesdonotlegalizemarijuana.Itisnotthepracticeorpolicyof DEAtotargetindividualswithseriousmedicalconditionswhocomplywith statelawsauthorizingtheuseofmarijuanaformedicalpurposes.Consistent withtheDOJguidelines,wewillcontinuetoidentifyandinvestigateany criminalorganizationorindividualwhounlawfullygrows,markets,or distributesmarijuanaorotherdangerousdrugs(DrugEnforcement Administration,2009). Similarly,theDirectorofONDCPstressed: TheDepartmentofJustice'sguidelinesstrikeabalancebetweenefficientuse oflimitedlawenforcementresources,andatoughstanceagainstthose whoseviolationsofstatelawjeopardizepublichealthandsafetyEnforcing thelawagainstthosewhounlawfullymarketandsellmarijuanaforprofit willcontinuetobeanenforcementpriorityfortheU.S.government(Officeof NationalDrugControlPolicy,2009). TheDepartmentofTransportation(DOT)alsoemphasizedthattheguidelines wouldnotimpacttheDOTsdrugtestingprogram:TheDepartmentofTransportations DrugandAlcoholTestingRegulation49CFRPart40,at40.151(e)doesnotauthorize medicalmarijuanaunderastatelawtobeavalidmedicalexplanationforatransportation employeespositivedrugtestresult(DOT,MedicalMarijuanaGuidelines,2009) Inlightofthesestatements,thecurrentpositionofthefederalgovernmentis uncertain.Nevertheless,largelybecauseofexaggeratedmediareports,theObama administrationisviewedaslenienttowardmedicalmarijuana.Thishasbeenfollowedby proliferationofdispensarieswhichresultsinvirtuallyunrestricteddistributionof cannabis. ModernMedicationsandtheFDAApprovalProcess InearlierdaysinWesternmedicine,herbsandotherbotanicalproductswere commontreatmentoptionsandremainsoinmanydevelopingcountries.Bytheendofthe 20thcentury,however,thesecrudebotanicalmixturesandpreparationshadbeenreplaced

18Theguidelinesalsoallowprosecutionofthosedistributionactivitiesthatmaybeconsistentwithstatelaw

(incaseastatedecidestopassveryliberallegislation),ifnecessarytoserveimportantfederalinterests.

bymodernmedicationswhichwerecharacterizedbystandardized,purifiedproducts whoseactiveingredients(AIs)wereoftenofsyntheticorigin. FolkRemedies Useplantproductswhosecompositionis uncertainandunregulated. ModernMedicines Usehighlypurifiedordefined medications,oftencomprisingsynthetic chemicals. Treatpoorlydefinedillnessesorsymptom Treatspecificillnesses. withunknownbasis(e.g.coughfromTB, influenza,oretc.). Arebasedonlittleunderstandingofthe Elucidatethenatureoftheillnesses. pathophysiologyofthedisordersbeing treated. Arebasedonlittleunderstandingofthe Usemedicinesthathavearecognized roleofmedicineinthetherapy. effectonpathologicalprocesses;often understandthemechanismofaction. Areusedininconsistentandhardto Areadministeredincontrolleddoses; quantifyamounts. deliverysystemprovidespredictabledose overdefinedperiodoftime. Eventhosemedicationsthatonceoriginatedinbotanicalmaterial,e.g.,digitalis, wereultimatelycomprisedofsyntheticAIs.Dosageformsanddeliverysystemswere carefullytestedtodeliveradiscrete,reproducibledose.Theeverincreasingsophistication andrigoroftheFDAapprovalprocesscontributedtothistrend. Thatapprovalprocesshasbeendevelopedoverthepastcenturytoprotectpatient safetyandwelfare.Itpromotesthequality,safety,andefficacyofmedications,andis supportedbyallmajormedical/healthcareorganizations.Extensivepreclinicalandclinical testingtheresultsofwhicharepublishedinpeerreviewedjournalsprovidesarobust bodyofriskbenefitandpharmacologicaldata,onwhichphysiciansdependinorderto makeinformedprescribingdecisions.Theregistrationandinspectionproceduresensure thatthemanufacturingprocessisconductedinaccordancewithvalidatedqualitycontrol toolsandmeasures.Manufacturerspromotionalactivitiesarelimitedtothoseclaims supportedbythemedicationslabel.Medicationsareprescribedanddispensedunderthe closesupervisionoflicensedhealthcareproviders,primarilyphysiciansandpharmacists. Inaddition,theFDAhasrecentlyindicatedthatmedications,bothwithandwithout abusepotential,mustdevelopspecialplanstoidentify,evaluate,andmitigatethe medicationsrisks(DepartmentofHealthandHumanServices,FoodandDrug Administration,2010).Suchplansmustinclude,whererelevant,therisksofabuseand diversion(DepartmentofHealthandHumanServices,FoodandDrugAdministration, 2009).

Bycontrast,herbalproductsandotherdietarysupplementsaresubjecttoafar lesserdegreeofsupervision.Compositionandqualityareuncertain;clinicaldataonsafety andefficacyarelimited;andphysiciansgenerallydonotfeelqualifiedtoopineabout specificproductsrisksandbenefitsforparticularmedicalconditions(DietarySupplement HealthandEducationActof1994).VariousscholarshavesuggestedthattheFDAshould morestringentlyregulatemanydietarysupplements(CohenPJ,2005).Generally,dietary supplementsareingestedorallyandlackabusepotential. 19 Despitethereducedlevelofregulatoryscrutinyandqualityassurance,public interestinbotanicallyderivedtreatmentscontinuestorise.Acknowledgingsuchinterest, andthefactthattechnologyhasimprovedsignificantlyinrecentdecades,theFDAissueda 2004guidancedocumentthatsetsforththeprinciplestowhichpharmaceutical manufacturersmustadherewhendevelopingprescriptionmedicationsderivedfrom complexbotanicalmaterial(FoodandDrugAdministration,2004).TheGuidancepermits someleniencyinthebiochemicalcharacterizationofaprospectivebotanicalagentduring theearlystagesofresearch;however,atthepointofadvancedclinicalresearch(PhaseIII), orNewDrugApplication(NDA),amedicationmustmeetallstandardsforanewchemical entity(NCE). Thedocumentidentifiesthreestagesofdevelopmentforabotanicallyderived medication:1)BotanicalRawMaterial(BRM),2)BotanicalDrugSubstance(BDS)and3) BotanicalDrugProduct(BDP).BRMisthefreshorprocessed(e.g.,cleaned,frozen,dried,or sliced)partofasinglespeciesofplantorafreshorprocessedalgaormacroscopicfungus. BDSispreparedfrombotanicalrawmaterialsbyoneormoreofthefollowingprocesses: pulverization,decoction,expression,aqueousextraction,ethanolicextraction,orother similarprocess.Itmaybeavailableinavarietyofphysicalforms,suchaspowder,paste, concentratedliquid,juice,gum,syrup,oroil.BDPisabotanicalproductthatisintended foruseasadrug,i.e.,afinisheddrugproductthatispreparedfromabotanicaldrug substance.Botanicaldrugproductsareavailableinavarietyofdosageforms,suchas solutions(e.g.,teas),powders,tablets,capsules,elixirs,andtopicals. In2006,theFDArejectedthecontentionthatsmokedherbalcannabisisasafeand effectivemedication.FDAstatedthat: ApastevaluationbyseveralDepartmentofHealthandHumanServices (DHHS)agencies,includingtheFoodandDrugAdministration(FDA), SubstanceAbuseandMentalHealthServicesAdministration(SAMHSA)and NationalInstituteforDrugAbuse(NIDA),concludedthatnosoundscientific studiessupportedmedicaluseofmarijuanafortreatmentintheUnited States,andnoanimalorhumandatasupportedthesafetyorefficacyof marijuanaforgeneralmedicaluse.Ifadrugproductistobemarketed, disciplined,systematic,scientificallyconductedtrialsarethebestmeansto

19OnDecember30,2003,theFDAannounceditsintentiontobanthemarketingofephedra(FDA,2004).

obtaindatatoensurethatdrugissafeandeffectivewhenusedasindicated. EffortsthatseektobypasstheFDAdrugapprovalprocesswouldnotserve theinterestsofpublichealthbecausetheymightexposepatientstounsafe andineffectivedrugproducts.FDAhasnotapprovedsmokedmarijuanafor anyconditionordiseaseindication(FoodandDrugAdministration,2006). ThisstatementdoesnotimplythatFDAwillrejectallcannabisbasedmedications.Indeed, onecannabisderivedmedication,Sativex,isenteringintoPhaseIIItrialsinaccordance withtheGuidance(GWPharmaceuticals,2006). MedicalMarijuanaandtheModernMedicationModel Thestatusofmedicalmarijuanacontrastssharplywiththecriticallyimportant aspectsofthemodernmedicationmodel.First,crudeherbalcannabisisnota homogeneousmaterial;thetermmedicalmarijuanathereforedoesnotrefertoasingle, consistentsubstanceorentity.Thecompositionofherbalmaterial,includingitsTHC content,varieswidelydependingonthestrain,cultivation,storage,andharvesting practices,etc.Theopiumpoppycansimilarlyvaryincomposition.Opiumcanberichin morphine,thebaine,ororipavine(DrugEnforcementAdministration,2008).Themethods ofherbalcannabisadministrationsmoked/vaporized,bakedgoods,teas,infusedhoneys, elixirs,candies,etc.alsodonotensurethatapatientreceivesanidentifiable, standardized,andhencereproducible,dose.Patientsthereforecannotbecertainthatthey willexperiencethesamedegreeofbenefitorextentofsideeffectsfromtimetotime. Patients,particularlythoseunfamiliarwithcannabis,maybeunwittinglydosed excessively,andincurfrighteningorseverelyunpleasanteffects.Forexample,inamedia report,onepatientwithadvancedcanceringested1/8teaspoonofcannabisinfusedhoney thatshehadpurchasedatadispensary.Afterafewhours,shewashallucinating,toodizzy andconfusedtodressherselfforadoctor'sappointment.Thencamevomitingfarworse thanherstomachupsetbeforeshetookthedrug(MathewsAW,2010). Second,qualitycontrolmechanismsaregenerallyabsent.Asaresult,cannabis productsmaybecontaminatedwithmicrobes. 20 Certainpathogens,suchasaflatoxins,are notdestroyedbyheat(asinsmokingorvaporizing)andareincreasinglybeingrecognized asanunderestimatedsourceofneurologicaltoxicityorinfectionssuchasaspergillosis. Individualswhoareusingantiinflammatorysteroidsorhavecompromisedimmune systemsareespeciallyvulnerabletosuchinfections(HazekampA,2006).Heavymetals andpesticidesmayalsobepresent.Cannabissamplesrecentlytestedfromdispensariesin

20Anumberofbacteriathatarepathogenictohumanshavebeenfoundoncannabis,including:Salmonella muenchen,Klebsiellapneumoniae,Euterobactercloacae,E.agglomerans,Streptococcus(GroupD), Thermoactinomycescandidus,T.vulgaris,Micropolysporafaeni,Aspergillusfumigatus,A.niger,A.flavus,A. tamarri,A.sulphureus,A.repens,Penicilliumchrysogenum,P.italicum,Rhizopusstolonifer,Alternaria alternata,Curvularialunata,andHistoplasmuscapsulatum.Seegenerally,McPartlandJM.Contaminantsand adulterantsinherbalCannabis,inCannabisandCannabinoidsPharmacology,ToxicologyandTherapeutic Potential(GrotenhermenF&RussoEeds.)(HaworthPressNewYork)2002.

LosAngelescontainedpesticidelevels170timesgreaterthanthatpermittedforherbal products(Peoplev.HempFactoryV,2009). 21 Themanufacturersoftheseproductshave essentiallynoaccountability,andtheFDAdoesnotinspecttheirmanufacturingfacilities. Patientsinjuredbyharmfulproductshavenolegalrecourse. Third,distributionofcannabisproductsdoesnottakeplacewithinthemonitored andregulatedchannelsofsupplyforpharmaceuticals,butratherthroughdispensaries. Theseproductsarenotlabeledwithcontentinformation,orwithwarningsand instructionsforproperuse,despitethefactthatthisisarequirementforallmedical productsunderbothstateandfederallaw(CaliforniaShermanFood,Drug,andCosmetic Act).Dispensarypersonnelwhoarenotlicensedmedicalpractitionersoffermedicaladvice concerningtheefficacyorappropriatenessofvariousproducts. Finally,appropriatephysiciansupervisionisvirtuallyunavailable.Asindicated above,allstatemedicalmarijuanalawsplacephysiciansinanuntenablepositiononthe onehand,beingappointedthegatekeepersofapatientsaccesstocannabis;ontheother, havingnoaccesstotheinformationnecessarytoprovidemeaningfuladviceand supervision.Reliabledataessentialtoaphysiciansabilitytoassessatreatmentoption arenotbeinggeneratedbytheexistingsystemofdistributionanduse.Thereisno mechanismforcollectingdatareflectingefficacyoradverseevents;therefore,themedical communityisprecludedfromknowingwhetherspecificmedicalconditionsarebeing improved,towhatextent,andinwhichpercentageorsubgroupofpatients,norwhether therearecontraindications,drugdruginteractions,etc. ItisnotsurprisingthatinsessionsatnationalmedicalconferencesdescribingNew TherapeuticDevelopments,herbalcannabisisalmostnevermentioned,despiteits prominenceinthemedia.Withoutafoundationofrigorousdata,developedinclinicaltrials ofproperlengthanddesign,andpublishedinpeerreviewedjournals,nocannabisproduct canevergainentranceintothephysiciansarmamentariumandtherebybecomeavailable topatientsasalegitimateoptionamongvarioustreatmentchoices.Therefore,ifit continuesinitspresentform,thecurrentcannabisdistributionsystemhasthe unfortunateevenironiceffectofpreventingthevastmajorityofpatients,whowishtobe abletoobtainmeaningfulguidance,advice,andsupervisionfromtheirtreatingphysicians, fromobtainingaccesstocannabisbasedmedications. Physiciansshouldcarefullyconsidertheirethicalandprofessionalresponsibilities beforeissuingacannabisrecommendationtoapatient.Aphysicianshouldnotadvisea patienttoseekatreatmentoptionaboutwhichthephysicianhasinadequateinformation regardingcomposition,dose,sideeffects,orappropriatetherapeutictargetsandpatient populations.Statemedicalboardshaveindicatedthatphysicianswhodiscusscannabis withapatientmustadheretotherelevantstandardofcareandfollowthebasic

21In2005,acannabisadvocatediedfromaneurologicalconditionbelievedtohaveresultedfromhandling

cannabiscontaminatedbypesticides,whichwasbeingdistributedthroughcannabisdispensaries.(GardnerF, 2005.)

professionaltenetsofgoodpatientcare:aphysicalexamination,medicalhistory,reviewof pastmedicaltreatments,developmentofatreatmentplan,followupandcontinuing oversight(MedicalBoardofCalifornia,2004).Failuretodosomayresultinafindingof unprofessionalconductandsignificantsanctions,includinglicensesuspensionor revocation(MedicalBoardofCalifornia,2009).Aphysiciansprofessionalliabilitycoverage mayalsonotextendtoharmresultingfromapatientsuseofcannabisuponthephysicians recommendation(EducatingVoices,2003). Thislackofeffectivephysicianoversightposesoneofthegreatestdangersto patientsinthesystembywhichcannabisismadeavailableforostensiblemedicaluse. Theimpactofthisabsenceofprofessionalmonitoringisexacerbatedbythefactthatthe potencyofcannabisherbalmaterialandcannabisproductshasrisensignificantlyoverthe lastfewdecades. 22 Suchincreasedpotencymayheightentheriskofaddiction(National CenteronAddictionandSubstanceAbuse,2008).Thisisparticularlyproblematicinlightof thefactthat,increasingly,adolescentsareobtainingcardswhichenablethemtopurchase andusecannabiswithlegalimpunity.Anumberofadolescentpsychiatristshaveexpressed concernattherapidlyincreasingnumberofyoungpatientswhoentertreatmentfor cannabisdependencebutwhohavecardsfacilitatingtheircontinueduse(ThurstoneC, 2010).Furthermore,severalstudieshaverevealedthataverylargepercentageof individualshavesoughtcannabiscardsinordertotreatanxietyordepression,ratherthan nausea/vomitingfromcancerchemotherapy,HIV,orpainandthatalmostallofthose applicantsinitiatedcannabisorothersubstanceuseduringadolescence(GardnerF,2006; OConnellTJ&BouMatarCB,2007).Suchindividualsrequireclosephysicianssupervision toensurethattheyarenotdevelopingormaintainingcannabisdependence,ratherthan attemptingtoalleviateamedicalcondition.Finally,individualswhosmokeorvaporize highpotencycannabisarelikelytoexperienceintoxication,sinceinhalationrapidlyraises plasmaandbrainlevelsofTHC(HuestisMA,HenningfieldJE,ConeEJ,1002;HuestisMA, 2007).Thismaypreventbothphysiciansandpatientsfromidentifyingdiseaseprogression andhinderpatientsfromobtainingappropriatetreatment(MedicalBoardofCalifornia, 2004) 23 . WhatHasBeenTriedinOtherCountries? BothCanadaandtheNetherlandshavegovernmentsupervisedprogramsfor distributingcannabisformedicaluse.InCanada,courtrulingsmandatedthatthe governmentestablishaprocedurethroughwhichpatientscouldqualifytocultivateand possesscannabisformedicalpurposes.Subsequently,thegovernmentwasrequireditself

22TheUniversityofMississippihasbeenanalyzingtheTHClevelsofseizedcannabisforover30years.Inthat period,thoselevels(fordomesticcannabisseizures)haveincreasedfromanaverageof1.7%to13%.See UniversityofMississippiMarijuanaPotencyMonitoringProject, www.whitehousedrugpolicy.gov/publications/pdf/mpmp_report_104.pdf. 23Thephysicianshoulddeterminethatmedicalmarijuanauseisnotmaskinganacuteortreatable progressivecondition,orthatsuchusewillleadtoaworseningofthepatientscondition.

toestablisharegulatedsourceofsupply(HealthCanada,MarihuanaMedicalAccess Regulations,2001). Physicianshavevoicedseriousconcernsaboutthissystem.TheCanadianMedical Association(CMA)stated: Physiciansarenotinapositiontocounselpatientsregardingtheuseof marijuana.Specifically,theyareunabletoprovidethoroughandnecessary informationregardingsuchissuesasproperdosage,marijuana'sinteraction withotherdrugsoritsimpactonotherpreexistingmedicalconditions Lackofinformationontheindications,risksandbenefitsofmedicinal marijuanahinders[aphysicians]abilitytoinformproperlypatientsandhas thepotentialtothreatenthepatientphysicianrelationship.CMAdoesnot supportphysicianscontrollingaccesstosubstancesforwhichroutine premarketregulatoryreviewofsafety,purityandefficacy,asrequired forcurrentprescriptiondrugs,hasnotoccurred.(CanadianMedical Association,2001) PhysiciansforaSmokeFreeCanadaconcurred: First,sincemarijuanahasnotbeenthoroughlytestedasamedicine,most physiciansarefamiliarneitherwithitspotentialbenefits(ifany),norwith thedosagerequiredtoachievethosebenefits.Second,whenapatientis requestingsmokedmarijuana,therisksassociatedwithsmoking,coupled withthelackofclinicalknowledgeaboutspecificbenefits,makeany accurateapproximationoftherisktobenefitratiooftreatmentimpossible (PhysiciansforaSmokeFreeCanada,2002). TheCanadianMedicalProtectiveAssociationvoicedthesameobjections: Giventhefactthatmanyphysicianswouldnothavethenecessaryknowledgeabout theeffectiveness,risksorbenefitsofmarijuana,webelieveitisunreasonableto makephysicians[the]gatekeepersinthisprocess(WharryS,2002;Canadian MedicalProtectiveAssociation,2008). In2005,theMarihuanaMedicalAccessRegulations(MMAR)regulationswere revisedtoremovetherequirementthatphysiciansrecommendaspecificdailydose,form androuteofadministration.However,physiciansarestillrequiredtoindicate,intheir medicaldeclaration,thedailyamount,form,androuteofadministrationthattheapplicant intendstouse.Althoughphysiciansnolongermuststatethatthebenefitsofcannabis outweightherisks,applicantsmuststilldeclarethattheyhavediscussedtheriskswiththe physicianwhosignsthemedicaldeclaration.CMPAnotesthattheamendedRegulations representanimprovement,butdonotaddressalltheCMAsandCMPAspreviously expressedconcerns. 24

24CMPAadvisestheirmemberstoobtainareleasefromliabilityfromapatientforwhomthephysicianhas

approvedtheuseofcannabis.

UndertheHealthCanadaprogram,cultivationisrequiredtobeconductedunder GoodManufacturingPractices.Furthermore,inordertoensurethatthemicrobialcontent remainsatacceptablelevels,thecannabisisirradiatedbeforeitisprovidedtopatients (HealthCanada,ProductInformationSheet,2008;HazekampA,2006). 25 Thedried cannabishasaTHClevelof12.52%.HealthCanadaprovidesinformationtoboth physiciansandtopatientsconcerningtheuseofcannabis,includingpotentialsideeffects (HealthCanada,ProductInformationSheet,2008).Nevertheless,thesystemisfoundering. Anestimated400,0001,000,000Canadiansusecannabisforselfidentifiedmedical purposes,butapproximately4,029personshavegovernmentauthorizationstopossess cannabis.Fewerthan20%ofthoseaccesscannabisfromHealthCanada. 26 Detractorsof theprogramclaim,amongotherthings,thatthegovernmentauthorizationprocessistoo lengthyandcumbersome;relativelyfewphysicianswillsignthenecessaryform;andthe qualityofthecannabisisnotsatisfactory(althoughitisonaverage12%THC).They furtherclaimthatpatientswishtoselectdifferentstrainsforvariousmedicalconditions; anddosinglimitsconfinepatientsto5gramsaday,unlessaphysicianiswillingtoexplaina patientsneedforahigherdailyintake(BelleIsleL,HathawayA,2007;CanwestNews Service,2010).Asaresult,patientsobtaintheircannabisandtheirinformationaboutthe medicalusesofcannabisandcannabisproductsfromdifferentcompassionclubs. Inadditiontocriticismsfromhealthcareprovidersandpatients,Canadahasalso incurredareprimandfromtheInternationalNarcoticsControlBoard(INCB),which believesthatCanadaisoperatingoutsideofitsobligationsunderinternationaltreaties.In theaftermathoftheINCBsstatement,governmentalauthoritieshaveundertakento reviewtheCanadianprogram(EdwardsS,2010). ThesituationinCanadademonstratesthatevengovernmentsupervisedcannabis cultivationanddistributionprogramsarenotsufficienttoenablecannabistobecomea legitimatemedicationthatphysiciansare(orshouldbe)comfortableprescribing.Inorder forcannabisbasedmedicationstobecomebroadlyavailabletopatientsthroughtheir treatingphysicians,thosemedicationsmustgothroughtheconventionaldomestic medicationapprovalprocesses. ExistingResearch:WhatDoWeKnowandWhatDoWeStillNeedtoDetermine? IssuesforAdditionalResearch Considerableanalyticalandpreclinicalresearchandclinicalinvestigationshave beenconductedwithcannabinoidagonists,antagonists,andothercompoundsthataffect

25TheNetherlandshasasimilarprogram.Thatcannabis,too,isirradiatedtoreducemicrobiallevels. 26AsofJune2009,4029personswereauthorizedtopossesscannabis,and2841personswereauthorizedto

cultivatecannabisformedicalpurposes(2360ofwhichholdapersonaluseproductionlicense;481holda designatedpersonproductionlicense).However,only798arecurrentlyobtainingcannabisfromHealth Canada;891haveobtainedseedsforcultivation;and188personshavereceivedboth.http://www.hc sc.gc.ca/dhpmps/marihuana/stat/_2009/junejuineng.php

thecannabinoidreceptorsystem.Inexaminingsuchresearch,itisessentialtoavoid drawingexcessivelybroadconclusionsaboutthebenefitsandrisksofsmokedcannabisin humansfromtheresultsofpublishedstudiesinvolvingotherpreparationsandother researchsettings. 27 Forexample,preclinicalresearchstudyingsyntheticTHC,invitroorin vivo,mayofferintriguingpossibilitiesforfutureclinicalresearch,butitiscertainlynot determinativeofthebenefit/adverseeventprofileofsmokedcannabis(orTHC)inhumans. EvidencethatTHCcaninhibitmalignanttumorgrowthinrodentsdoesnotmean,oreven suggest,thatsmokingcannabiscanpreventorcurecancer(GuzmanM,2003).Suchstudies provideatbestafoundationforpursuingsmallpilotstudiesofacannabinoidformulation inhumans(GuzmanM,etal,2006).TheeffectsofpureoralTHCmaydiffersignificantly fromthatofsmokedcannabis,becauseofboththeformulationandtheverydifferentmode ofdelivery.Evendifferentnonsmokedcannabinoidformulationsmayexertnotably disparateeffects,dependingonthecannabinoidcompositionandthemethodof administration.Finally,theeffectsofcannabisorcannabinoidsinexperimentalpain modelsmaynotindicatehowpatientswithchronicpainconditionswouldrespond:The respectivemechanismsunderlyingthewholevarietyofchronicpainsyndromesmay considerablydifferfromacutenociception(HazekampA&GrotenhermenF,2010). Currentresearchreportsandreviewsrarelyacknowledgethatthecompositionand cannabinoidprofileofmodernherbalcannabismaybeverydifferentfromthatwhich existedcenturiesorevendecadesago.Althoughdiscussionsofcannabiscommonlybegin withtheclaimthatcannabishasbeenusedtherapeuticallyforhundreds,ifnotthousands, ofyears,theseresearchreportsorreviewsfailtopointoutthatthecannabisplanthas beensignificantlymodifiedoverthatperiodthroughbreedingtechniquesandmodern cultivationpractices.Thewidespreaduseofsinsemilla(thebudoftheunfertilizedfemale plant),coupledwithsophisticatedindoorcultivationprojects,haveinmanycases increasedTHClevelsconsiderablyabovethosepresentincannabiseven40yearsago. Inaddition,selectivebreedingtechniqueshaveresultedincannabisplantsalmost totallydevoidofcannabidiol(CBD),anonpsychoactivecannabinoidwithimportant therapeuticpotential.Inthepast,aharvestofwildcannabiswouldhaveoftenbeen composedofapproximatelyhalfTHCandhalfCBD(ofitsmajorcannabinoids)(PotterDJ, ClarkP,BrownMB,2008).Inanimalmodelsandsomehumanstudies,CBDhasbeenshown tohaveanalgesic,antipsychotic,anticonvulsant,neuroprotectiveproperties(Mechoulam R,MaximillianP,MurilloRodriquezE,etal,1974;RussoE,GuyGW,2006;PertweeRG, 2004).ThereisalsoevidencethatCBDmaymitigatesomeofthenegativeeffectsofTHC, suchaspsychoactivity(KarniolIG,CarliniEA,1973;KarniolIG,ShirakawaI,KasinskiN,et al,1974).NumerousreportshaveconfirmedthatCBDisalmostentirelyabsentfrom modernblackmarketcannabis(PotterDJ,ClarkP,BrownMB,2008).Becauseofthese trends,modernherbalcannabisavailableindispensariesmayhaveverydifferenteffects thanthosereportedcenturiesorevendecadesago.TheabsenceofCBD,coupledwith higherlevelsofTHC,mayhaveadverseeffectsonpatients,particularlyinchronicuse

27Casestudies,surveys,andnoncontrolledstudiesarebeyondthescopeofthisreportandwillnotbe

examined.

(DiFortiM,etal,2009;SterlingE,2010).Moreresearchisneededtoelucidatetheeffectsof differentcannabinoid(especiallyTHC:CBD)ratios. Doseresponserelationshipsalsorequirefurtherresearch.Cannabinoidsareknown toexhibitbiphasiceffects,i.e.,alowerdosemayrelieveasymptombutahigherdosemay exacerbateit(HealthCanada,InformationforHealthCareProfessionals,2003).Aclinical studyofsmokedcannabisinexperimentalpainillustratesthiswell(WallaceM,etal,2007). Furthermore,sincepatientsvarywidelyintheirresponsetocannabinoids,inadequate dosingortitration,e.g.,theuseoffixeddosesmaycauseaclinicalstudytobenegative, eveniftheinvestigativeagentmightotherwisehavebeenexpectedtohavetherapeutic value(StrassserF,etal,2006). Themethodofmedicationdeliverymayalsomarkedlyaffectboththeextentof efficacyandrangeofsideeffects.TheIOMhasstatedthatoraldronabinolhaslow bioavailabilityandaprolongedonsetofaction,makingitextremelydifficultforpatientsto adjusttheirdose(JoyJE,Watson,Jr.SJ,&BensonJA,1999).Psychoactivity,ofteninthe formofdysphoria,isaproblemandmaypreventapatientfromconsumingadoselarge enoughtohavetherapeuticeffect.Ithasbeenreportedthatsomecannabisdispensaries prepareelixirs,honeys,bakedgoods,andcandies,buttherearenoreliabledatatoindicate whetherthesepreparationsaremoreefficaciousand/orbettertoleratedthanoral dronabinol. Differentsubgroupsofpatientsmayhavedifferentresponsestocannabisand cannabinoids.Patientswithdebilitatingand/orchronicmedicalconditions,elderly patients,andthosewhoarecannabisnavemaybemoresensitivetoCNSandotherside effects.Inaddition,thereisevidenceofagenderdifferenceinresponsivenessto cannabinoids,particularlywithregardtoanalgesia(HazekampA&GrotenhermenF, 2010). ResultsofControlledClinicalTrials Cannabinoidresearchbothpreclinicalandclinicalhasincreasedalmost exponentiallyinthepast20years.Anumberofthoroughreviewshavebeenpublished whichdescribethesestudies(JoyJE,Watson,Jr.SJ&BensonJA,1999;BenAmarM.,2006; RussoEB,2008;HazekampA&GrotenhermenF,2010;HealthCanada,Informationfor HealthCareProfessionals,2003).Unfortunately,mostliteraturereviewsstructuretheir analysesbythetypeofdiseasestate,ratherthanthespecifictypeofcannabisor cannabinoidinterventionthatwasusedtostudythatdiseasestate.Forthereasonsstated above,thishastheresultofcreatingconfusionanduncertainty,sincedifferentcannabis andcannabinoidpreparations(withdifferentformulationsanddosageforms)mayhave differenteffects.Therefore,thebriefsummaryofrecentstudiesdescribedbelowwillfocus onthetypeofcannabisorcannabinoidmedication.Inalimitednumberofstudies,two suchmedicationswerecomparedagainstplacebo.Insuchcases,thestudiesaregenerally mentionedtwice.

OralCannabinoidPreparations Dronabinol Dronabinol(synthetic)isthebestknownoralcannabinoidpreparation. 28 TheFDA approveditin1985fortreatmentofnauseaandvomitingassociatedwithcancer chemotherapyinpatientswhohadfailedadequatelytorespondtoexistingantiemetic treatments,andin1992foranorexiaassociatedwithweightlossinpatientswithAIDS.It showedefficacyinearlystudiesbycomparisontothenavailableantiemetics(Councilon ScientificAffairsReport6,2001).Ithasnot,however,beencomparedwithmorerecent antiemeticmedications,whichhavemuchbetterefficacy.Onestudyhasshownefficacyin delayedchemotherapyinducednauseaandvomitingcomparabletoondansetron,although thecombinationofdronabinolandondansetrondidnotprovidebenefitbeyondthat observedwitheitheragentalone(MeiriE,etal,2007).Itdidnotshowefficacyinatrial comparinganoralcannabisextract(Cannador),THCandplaceboonappetiteandquality oflifeinpatientswithcancerrelatedanorexiacachexiasyndromeandwasnotmore efficaciousthanmegestrolacetate(JatoiA,etal,2002;StrasserF,etal,2006).Forastudy investigatingdronabinolandsmokedcannabisonviralloadandfoodintakeinHIVpositive patients,seediscussionbelow. StudiesofMarinolasananalgesicand/orantispasmodichave beenmixed.Early studiesfounditefficaciousinreducingcancerpainatdosesof10,15,and20mg.butside effectswereprominent(NoyesJrR,BrunkSF,AveryDH,CanterA,1975).Ithasbeenfound effective in central neuropathic pain in multiple sclerosis, but not in postoperative pain (BuggyDJ,ToogoodL,MaricS,etal,2003;SvendsenKB,JensenTS,&BachFW,2004).The Institute of Medicine has stated that, "It is well recognized that Marinol's oral route of administration hampers its effectiveness because of slow absorption and patients' desire formorecontroloverdosing"(JoyJE,WatsonJr.SJ,&BensonJA,1999). Inalargetrialofpatientswithmultiplesclerosis,dronabinol 29 didnotshow objectiveimprovementinspasticitymeasuredontheAshworthscale,theprimary endpoint.Therewasobjectiveimprovementinmobilityandsubjectiveimprovementsin spasticity,spasm,painandsleepquality(ZajicekJ,etal,2003).Inaoneyearfollowup, patientsshowedasmallobjectiveimprovementinspasticity,aswellashighlysignificant subjectiveimprovementsinspasticity,spasm,pain,tirednessandsleep(ZajicekJ,etal, 2005). Cesamet Cesamet(Nabilone)isasyntheticcannabinoidanaloguethatisbelievedtobe morepotentthanTHC.Itisapprovedforthetreatmentofnauseaandvomitingassociated

28ThebrandednameisMarinol.InScheduleIIIoftheCSA,thesubstanceisdefinedas:dronabinol (synthetic)insesameoilandencapsulatedinasoftgelatincapsuleinaUSFoodandDrugAdministration approvedproduct.21CFRsec.1308.13(g)(1).GenericversionsofMarinolarenowonthemarket. 29Thisstudycompareddronabinol,Cannadorandplacebo.

withcancerchemotherapyinpatientswhohavefailedadequatelytorespondtoavailable antiemetics.Inonesmallstudy,ithasbeenshowntoreducespasticityrelatedpainin patientswithuppermotorneuronsyndrome(WisselJ,etal,2006).Inacontrolledstudyof patientsundergoingvarioussurgicalprocedures,highdoseNabiloneinthepresenceof morphinePCAwasassociatedwithanincreaseinpainscores(BeaulieuP,2006). Cannador Cannadorisanoralcannabisextract(encapsulated),withreportedlya2:1ratioof THCtoCBD.ItisunderinvestigationinEuropebytheInstituteforClinicalResearch.Ina studycomparingCannadorwithdronabinolandplaceboonappetiteandqualityoflifein patientswithcancerrelatedanorexiacachexiasyndrome,nodifferenceswerefound betweenCannador,THCorplacebo(StrasserF,etal,2006).Inalargestudyofpatients withmultiplesclerosis,itdidnotshowobjectiveimprovementinspasticitymeasuredon theAshworthscale,althoughtherewassubjectiveimprovementsinspasticity,spasm,pain andsleepquality(ZajicekJ,etal,2003).Inaoneyearfollowup,patientsshowedasmall objectiveimprovementinspasticity,aswellashighlysignificantsubjectiveimprovements inspasticity,spasm,pain,tirednessandsleep(ZajicekJ,etal,2005). Inanalgesicstudies,Cannadorhasshownamodestdosedependentdecreasein rescueanalgesiarequirementsinpostoperativepain(HoldcroftA,MazeM,2006). Smoked/vaporizedHerbalCannabis In2003,acontrolledresidentialstudyfoundthatbothsmokedcannabisand dronabinolhadbeneficialeffectsonappetiteandweightgaininHIVpositivepatientson stableantiretroviraltherapy.Inthecourseofthe21daytreatmentperiod,therewasno adverseeffectonviralloadorthenumberofCD4+andCD8+lymphocytes,nordidthetwo formsofcannabinoidsinterferewiththeproteaseinhibitorstakenbythepatients(Abrams DJ,etal,2003).Asubsequentstudydemonstratedthatbothsmokedcannabisand dronabinolincreasedfoodintakeinexperiencedcannabissmokers,althoughthisincrease paralleledincreasedratingsofintoxication(HanleyM,RabkinJ,GundersonE,FoltinRW, 2005). In1999,theCenterforMedicinalCannabisResearch(CMCR)wasestablished pursuanttolegislationcommissioningtheUniversityofCaliforniatoestablisharesearch programtoinvestigatethetherapeuticpotentialofcannabisandcannabinoids.Overthe courseofthenexttenyears,CMCRapprovedandfundedfifteenclinicalstudies,including sevencontrolledclinicaltrials,ofwhichfivehavecompletedandtwoareongoing(Center forMedicalCannabisResearch,2010).Fiveclinicalstudieshavebeenpublishedinpeer reviewedjournals.Threeofthesestudiesinvolvedneuropathicpain;afourthinvolved experimentalpain,andoneinvolvedapilotstudyforacannabisdeliverydevice(Abrams DI,etal,2007;WilseyB,etal,2008;EllisRJ,etal,2009). Thesestudieshaveprovidedpreliminaryevidenceofanalgesicefficacywhich suggestthatfurthertrialsofcannabisderivedandcannabinoidmedicationsinneuropathic

painofvariousoriginsshouldbepursuedtoidentifydesirablecannabisbasedor cannabinoidformulationsandmodesofdelivery.Theresultsofthesestudiescannot, however,besaidtoprovethatsmokedcannabisshouldbemadeavailabletopatients withchronicpainconditions.Eachstudywasconductedinasmallnumberofpatientsand wasofveryshortduration.Inalmostallcases,thepatientswerecannabisexperienced. Indeed,inonestudy,theauthorsnotedthatonlycannabisexperiencedpatientswere enteredintothestudyinordertoreducetheriskofadversepsychoactiveeffectsinnave individuals(WilseyB,etal,2008).Therefore,therisk/benefitprofileinthesepatients particularlytheincidenceofadverseCNSeventscannotbegeneralizedtocannabisnaive patients.Infact,inonestudy,anincidentofacutecannabisinducedpsychosisoccurredin acannabisnavepatient,resultinginhiswithdrawalfromthestudy(EllisRJ,etal,2009). Evenamongcannabisexperiencedpatients,thelevelofadverseeventswasnotable; inonestudy,cognitiveimpairmentwasespeciallyprominent(WilseyB,etal,2008).This couldsuggestthataninhalationmodeofdeliverymaynotbeoptimal.Suchrapiddelivery ofTHCmaynotbenecessaryinpatientswithchronicconditions,solongasthedosage formenablespatientstotitratetheirdosingleveltoindividualbenefit/tolerabilityover severaldays.Thecannabisavailableinthesestudieswasamaximumof8%THC.Inone study,cannabisofonly3.5%generatedasignificantCNSsideeffectprofile(AbramsDI,et al,2007).SuchCNSsideeffectswouldnodoubtbeevenmoreprevalentifpatientswereto usehigherpotencycannabis,suchasthatavailableindispensaries.Finally,the effectivenessoftheblindingissubjecttoquestion,sincethepatientswerecannabis experiencedandcouldbeexpectedtobeabletodistinguishactivefromplacebo.IntheEllis study,blindingwasevaluated;93%ofthosepatientsassignedtoreceivecannabis accuratelyguessedthattheywereonactivemedication,whereasthepatientsassignedto placebogenerallydidnotguesscorrectly(EllisRJ,etal,2009). Theresultsofthesestudies,whilequiteinteresting,constituteatmosttheearly stagesofcannabinoidmedicationdevelopment.Neithertheefficacynortheadverseevents intheseshorttermacutestudiescanbeextrapolatedtochronicuse.Alone,theycouldnot formthebasisofFDAapproval,norofcannabisrescheduling. Oromucosal/sublingualCannabisderivedPreparations Sativex(nabiximols)isabotanicallyderivedcannabisextractwithadefined1:1 ratioofTHCtoCBDanddeliveredasanoromucosalspray. 30 Sativexhasshownpositive resultsasanadjunctivetreatmentincontrolledstudiesinvolvingpatients(withpreviously intractablesymptomswhoremainedonalltheirexistingmedications)withbrachialplexus avulsion(BermanJS,SymondsC,BirchR,2004),centralneuropathicpaininmultiple sclerosis(RogDJ,NurmilloT,FriedeT,etal,2005),spasticityinmultiplesclerosis(Collins C,DaviesP,MutibokoIK,RatcliffeS,2007),rheumatoidarthritis(BlakeDR,etal,2006), peripheralneuropathicpain(NurmikkoTJ,SerpellMC,HoggartB,etal,2007),andpain associatedwithadvancedcancer(JohnsonJR,BurnellNugentM,LossignolD,etal,2010).

30SativexisproducedbyGWPharmaceuticalsintheUK.NabixomolsistheUSAdoptedName(USAN).

Interestingly,inthecancerpainstudy,nabiximolsshowedstatisticallysignificantanalgesic effectcomparedwithplacebo,whereasaTHCpredominantextractdidnot.Thismay suggestthattheTHC:CBDformulationhasadifferenttherapeuticimpactcomparedtoTHC withoutCBD. Symptomreliefwithnabiximolswasmaintainedinlongtermstudies,withoutthe needfordoseescalation(WadeDT,MakelaPM,HouseH,etal,2006).Patientswho abruptlywithdrewfromnabiximolsdidnotexhibitacannabiswithdrawalsyndrome (BudneyAJ&HughesJR,2006)oranywithdrawalsymptomsrequiringtreatment. Intoxicationscoresremainedlow,evenduringdosetitration(WadeDT,MakelaPM,House H,etal,2006).Sativexdoesnotinducepsychopathologyorimpaircognitionincannabis navepatientswithmultiplesclerosis(AragonaM,etal,2009).Bycontrast,smoked cannabisproducescognitiveimpairmentinpatientswithMultipleSclerosis(GhaffaroO andFeinsteinA,2008). SativexisapprovedintheUK,Spain,NewZealand,andCanadaasanadjunctive treatmentforspasticityinmultiplesclerosisandmaybeavailablesoonthereafterinother EuropeanUnioncountriesunderharmonizedrecognitionprocedures.Canadahasalso approveditundertheNoticeofCompliancewithConditions(NOC/c)asanadjunctive treatmentforneuropathicpaininmultiplesclerosisandforpainassociatedwithadvanced cancerpain.IntheUnitedStates,itisundergoingadvancedclinicalstudiesinpatientswith advancedcancerwhosepainhasnotbeenadequatelyrelievedbystrong(StepIII)opioids. AreTherePrincipledReasonsforExemptingCannabisfromtheQuality,Safety,and EfficacyRequirementsoftheModernMedicationModel? IsCannabisBenign?RisksandSideEffects Cannabisisnotaharmlessherb.AccordingtotheIOM,itisapowerfuldrugwith avarietyofeffects(JoyJE,Watson,Jr.SJ&BensonJA,1999).Tobesure,allmedications havepotentialsideeffects,someofthemquiteserious.Duringthecourseofcontrolled clinicaltrials(bothpreandpostmarketing),manyofthesesideeffectsareidentified,and amedicationsbenefit/riskprofilecantherebybeassessed,bybothregulatoryauthorities andthemedicalprofession.Ongoingphysiciansupervisionallowstheseriskstobe managed,e.g.,bydoseadjustment,discontinuationoftreatment,orrotation to/augmentationbyanalternateoradditionalmedication.Medicationlabelsandinserts apprisepatientsofprobablesideeffects.Forexample,patientsshouldbewarnedofthe risksofdrivingoroperatingheavymachinerywhileundertheinfluenceofcannabinoids (U.S.NationalHighwayTrafficSafetyAdministration,2004;BeirnessDJ&PorathWaller AM,2009). 31 Cannabisproductsdistributedbydispensarieslackthisinformation. Anumberofsideeffectsmaybeofparticularconcernwhencannabisisusedin significantamountsdaily,overalongperiod,insmokedform,bypatientswithdebilitating

31Inhalationofcannabisproducesdeficitsintracking,reactiontime,visualfunction,anddividedattention.

medicalconditions.TheacuteeffectsofpureTHCandhighTHCcannabisthatarerelevant tomedicaluseincludeintoxication(includingdysphoria),anxiety(includingpanicattacks), hallucinationsandotherpsychoticlikesymptoms,somnolence,confusion,psychomotor impairment,cognitiveimpairment,dizziness,orthostatichypotension,drymouth 32 ,and tachycardia(JoyJE,Watson,Jr.SJ&BensonJA,1999).Inclinicaltrialsofcannabinoid medications,patientswithpreexistingseriousmentaldisorders,significanthepaticor renalimpairment,epilepsy,cardiacconditions,orpriorsubstanceabuse/dependenceare typicallyexcluded.Nevertheless,patientswiththeseconditionsareroutinelyaddedtothe "membershiplists"ofdispensaries. TheIOMrecognizedthattheseacutesideeffectsarewithintheriskstoleratedfor manymedicationsJoyJE,Watson,Jr.SJ&BensonJA,1999).Asnotedabove,however,the sideeffectsofothermedicationshavebeenidentifiedbymeansofextensivetestingand examinationinbothnonclinical/preclinicalandPhaseIIIIclinicaltrials,includinglarge doubleblind,placebocontrolledstudies.Theacutesideeffectsofsmokedcannabishave notbeenfullyelucidatedthroughsuchcomprehensivetesting.Asaresultofthese potentialsideeffects,whichmaymoreseverelyimpacttheelderlyorthosewithhepaticor immuneimpairment,itisimperativethatspecificcannabisandcannabinoidmedications arestudiedinparticularmedicalconditionsandpatientpopulations,andpatientsusing suchmedicationsinclinicalpracticeshouldbeproperlysupervisedbytheirtreating physicians.Underthecurrentsysteminthe15statesthathavemedicalmarijuanalaws, noneofthisdatacollectionandphysiciansupervisionistakingplaceaccordingto regulatorystandards. Thechroniceffectsofinhaledcannabisareofspecialconcerninthecontextof medicaluse.Thesechroniceffectscanbeplacedintoseveralcategories:theeffectsof chronicsmokingandtheeffectsofinhaledTHC.Patientsoftenuse15gramsadayof cannabis;thisrepresents18cannabiscigarettes(ComeauP,2007).Theremaining patientsinthefederalCompassionateUseProgramareprovidedwith300cannabis cigarettespermonth. 33 Cannabissmokecontainsmanyofthecomponentsoftobaccosmoke.Smokinga cannabiscigarettecandepositasmuchasfourtimestheamountoftarinthelungs, comparedtosmokingatobaccocigarette(WuTC,TashkinDP,DjahedB,RoseJE,1988). Thiseffectresultsfromthefactthatcannabiscigaretteslackfiltersandcannabissmokers inhalemoredeeplyandholdtheirbreathlongerthantobaccosmokersholdtheirs(JoyJE,

33TheNationalInstituteonDrugAbuse(NIDA)suppliescannabistoseveralpatientsunderasinglepatient socalledcompassionateuseInvestigationalNewDrugApplications(IND).In1978,aspartofalawsuit settlementbytheDepartmentofHealthandHumanServices(DHHS),NIDAbegansupplyingcannabisto patientswhosephysicianappliedforandreceivedsuchanINDfromtheFDA.In1992,theSecretary[of HealthandHumanServices]terminatedthispractice,butdecidedthatNIDAshouldcontinuetosupplythose patientswhowerereceivingcannabisatthetime. http:/www.drugabuse.gov/about/organization/nacda/MarijuanaStatement.html 32Drymouthcancausegumdisease,toothdecay,andmouthinfections,suchasthrush.

Watson,Jr.SJ&BensonJA,1999).Thereisnodoubtthatchroniccannabissmokingis harmfultothelungs(TashkinDP,2005;DiplockJandPlecasD,2009). 34 Theinhalationofcannabisalsoposesariskofabuseanddependency.AstheIOM stated:Adolescents,particularlythosewithconductdisorders,andpeoplewithpsychiatric disorders,orproblemswithsubstanceabuseappeartobeatgreatriskformarijuana dependencethanthegeneralpopulation.Heavycannabisuseinadolescenceisassociated withavarietyofneurocognitivedeficits(SchweinsburgAD,BrownSA&TapertSF,2008). Thehighpotencycannabisnowdistributedbydispensariescouldexacerbatetheserisks. Thefactthatadolescentshavereadyaccesstocannabiscards,withoutmeaningful physiciansupervision,isparticularlyproblematic. Theseconcernsarenotvitiatedbyvaporization,currentlypopularwithcannabis advocates.First,therearewidevarietiesofvaporizersavailableforpurchaseonthe internetandatcannabisdispensaries,althoughtheFDAhasapprovednoneofthemasa medicaldevice.Theyvarysignificantlyintheextenttowhichtheyreducetoxic combustionproducts.Eventhemostsophisticatedvaporizer,theVolcano 35 ,hasnotbeen demonstratedtoeliminateallpolyaromatichydrocarbons,atleastathighertemperatures (GieringerD,St.LaurentJ&GoodrichS,2004).Evenatlowertemperatures,ammoniaand acetaldehydehavealsonotbeenshowntobeeliminated(RussoE,2006;BloorRN,Wang TS,SpanelP,&SmithD,2008). 36 Bycontrast,carbonmonoxidedoesnotappeartobe releasedbyvaporizationwiththeVolcano(AbramsDI,etal,2007). Second,theproductsofvaporizationaredependentonthequalityandcomposition oftheunderlyingherbalmaterial.Ifthatmaterialisnothighlystandardized,the compositionofthevaporwillbeuncertain.Becausethesedeviceshavenotbeenfully testedthroughtheFDAprocessitisuncertainwhetherherbalmaterialcontaminatedwith pesticidesormicrobeswouldtransmitthesecontaminantsintothevapor.Unlessthe vaporizerdevicehasalockoutmechanism,variabilityinintraandinterpatientinhalation patternsmaymakeitunlikelythataknownandreproducibledosewillbedelivered. Third,vaporizationdoesnotimprovethesideeffectprofileexhibitedbysmoked cannabis,includingitspsychoactiveeffects.Likesmoking,vaporizationcausesTHCplasma levelstoriseabruptly(MillerJ,MeuwsenI,ZumBrunnenT,&deVriesM,2005).Rapid deliveryofTHCtotheplasmaandbrainincreasesthelikelihoodofintoxicationandabuse liability,andmaypromotedependency(SamahaAN&RobinsonTE,2005).Again,such

officiallistofknowncarcinogens.See,TomarRS,BeaumontJ,HsiehJCY.EvidenceontheCarcinogenicityof MarijuanaSmoke.http://www.oehha.ca.gov/prop65/public_meetings/pdf/cicslides060509.pdf 35TheVolcanoisproducedbyStorz&BickelGmbH&Co.KGinGermany.http://www.storz bickel.com/vaporizer/storzbickelcompanyvaporizermanufacturer.html. 36ItisimportantthattheFDAassessmedicaldevicesthatdelivervaporizationproductstothelungs.TheFDA hasrecentlywarnedconsumersaboutthedangersoftoxicandcarcinogenicchemicalscontainedinelectronic cigarettes,toutedasasmokefreeandlessharmfulalternativetosmoking.FDA,FDANewsRelease,FDAand PublicHealthExpertsWarnAboutElectronicCigarettes. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm173222.htm


34In2009,CaliforniasOfficeofEnvironmentalHealthHazardAssessmentaddedcannabissmoketoits

rapiddeliveryisprobablynotnecessaryforpatientswithchronicconditionssolongasthe dosageformenablessuchpatientstotitratetheirdoseadequatelyandpredictably(Russo E,2006). 37 Forexample,rapidonsetopioidmedications,suchasbuccalfentanyl,are prescribedforpatientswithbreakthroughpain,notwithchronicpersistentpain.Infact, patientswithsuchpersistentpainareoftenplacedonextendedreleaseopioidmedications oncetheirindividualdailydoseisestablishedthroughshorttermreleasemedications. Finally,whencannabisjointsorvaporizersareshared,dangerouspathogenscanbe spreadamongstseriouslyillpatients(ZanoccoV,2005). CouldaCannabisPreparationAchieveFDAApproval? Asindicatedabove,theFDAhassetforththerequirementsforthedevelopmentofa botanicallybasedprescriptionmedication.Thoseagencyrecommendationsrequirethat highlystandardizedcannabisherbalmaterial(BotanicalRawMaterial)bedevelopedintoa BotanicalDrugSubstanceandultimatelyintoaBotanicalDrugProduct.Underthe Guidancedocument,itmaybechallengingforherbalmaterialevenifstandardizedtobe approved,sincetheherbalmaterialmustalsobeincorporatedintoadefinedand reproducibledosageform.AstheAMAreportrecognized,Thefutureofcannabinoidbased medicineliesintherapidlyevolvingfieldofbotanicaldrugsubstancedevelopment,as wellasthedesignofmoleculesthattargetvariousaspectsoftheendocannabinoidsystem (AmericanMedicalAssociation,2009).Smokedcannabisparticularlyforchronicuse wouldnodoubtposerisksthatwouldbeunacceptabletotheagency.Improvementsin vaporizationtechnologywouldneedtooccurinorderfullytoeliminatealltoxic combustionproductsandensureastandardizedandpredictabledose. Noneofthisisimpossible.Therefore,theobviousquestionarises:why,asapolicy matter,shouldherbalcannabisbeexemptedfromthemodernmedicationmodel?Many newpromisingmedicationsareunderinvestigation,andsufferingpatientsunderstandably seektoobtainaccesstothemasearlyaspossible.TheFDAhasestablishedfasttrack procedures 38 tofacilitatethisaccess,andcompassionateaccessthroughTreatmentINDsis oftenavailableduringlatestagemedicationdevelopment. 39 BoththeFDAandthefederal courts,however,haveconcludedthatseriouslyilleventerminallyillpatientswillnot benefitonbalancefromproductsthathavenotcompletedthevastmajorityofsteps leadingtoanapprovedmedication(AbigailAlliance,2008).Inshort,theconceptof medicalnecessityisnotsufficienttooverridetheprovisionsoftheFood,Drugand

37Inhaledcannabishasashorterdurationofactionthatoralorotherdosageforms. 39TheFDAmayapproveuseofaninvestigationaldrugbypatientsnotpartoftheclinicaltrialsforthe treatmentofseriousorimmediatelylifethreateningdisease[s]ifthereexistsnocomparableor satisfactoryalternativedrugorothertherapy,ifthedrugisunderinvestigationinacontrolledclinicaltrials, andifthedrugssponsorisactivelypursuingmarketingapprovaloftheinvestigationaldrugwithdue diligence.21C.F.R.sec.312.34. 3821C.F.R.secs.312.80,312.10,314.500.

CosmeticAct(AbigailAlliance,2008)ortheControlledSubstancesAct(UnitedStatesv. OaklandCannabisBuyersCooperative,2001). AllowingcannabistocircumventtherequirementsoftheFDAprocesssetsa dangerousprecedentforthefuture.Forexample,herbalproductscalledSpice,Skunk, andSencearecurrentlybecomingpopularintheU.S.andEurope.Theseproductscontain herbalpreparationsthatareenrichedwithsyntheticcannabinoids,suchasHU210, whichismuchmorepotentthanTHC.Thesesyntheticcannabinoidshavebeendevelopedover


thepast30yearsforresearchpurposestoinvestigatetheendocannabinoidreceptorsysteminnon humanstudies.AlthoughthesecompoundshaveTHClikeproperties,theyaremuchmorepotent thanTHC.Productscontainingthesesyntheticcannabinoidsaremarketedas"legal"alternativesto cannabisandarebeingsoldovertheinternetandintobaccoandsmokeshops,drugparaphernalia shops,andconveniencestores.CouldSpiceadvocatesinthefuturecontendthatthese

products,too,shouldbemadeavailabletopatientsandotherconsumerswithoutbeing testedthroughtheFDAprocess?Thisis,indeed,adangerouslyslipperyslope. 40 TheSignificanceofScheduling BoththeAMAandACPhaverecentlyquestionedthestatusofcannabissplacementin ScheduleIoftheControlledSubstancesAct. 41 ScheduleIIsubstancesare,forthemostpart, subjecttothesamerestrictionsandrequirementsundertheControlledSubstancesAct, includingmanufacturingandprocurementquotas,securitymeasures,recordkeeping, import/exportpermits,etc.Itmaybeuseful,therefore,toexaminewhatthereschedulingof cannabis(presumablytoScheduleII)wouldandwouldnotachieve.Cannabisadvocates commonlyurgethatcannabisberescheduledsothatitcanbemadeavailabletopatientson prescription.Reschedulingherbalcannabisalonewouldnot,however,besufficienttocreate amedicationthatphysicianscouldprescribeandpharmacistscoulddispense.Inordertobe prescribable,anyparticularmedicationmusthavesuccessfullycompletedtheFDAapproval process.TheFDAdoesnotapprovebulksubstances,suchascannabis(orrawopiumorcoca leaves),formarketinganddirectprescription.Therefore,aspecificcannabisderived medicationwouldhavetobedevelopedinaccordancewithFDAstandards,whichwould requirethatitbestandardized,formulated,tested,andadministeredinanappropriate deliverysystem.InorderforaScheduleIIsubstancetobemadeavailablebyprescription,it

TheDEAhasrecentlyactedonanemergencybasistoplacefivesuchcompoundsinScheduleI.DOJ,DEA, "SchedulesofControlledSubstances:TemporaryPlacementofFiveSyntheticCannabinoidsintoScheduleI," 75 Fed. Reg. 71636 (Nov. 24, 2010). This action will make possessing and selling these chemicals or the products that contain them illegal in the U.S. for at least one year while the DEA and the United States Department of Health and Human Services (DHHS) further study whether these chemicals and products shouldbepermanentlycontrolled.
41NotecannabisisassignedtoScheduleIundermoststatecontrolledsubstanceslaws,includingCalifornias.

40

mustbecontainedinoneormorespecificdosageforms,asisthecaseforopium.Eachand everyoneofsuchdosageformsmustpassFDAmuster(RussoE,2006). 42 FDAapprovalofaspecificcannabisBotanicalDrugProductwouldconstitutecurrently acceptedmedicaluseintheUS,therebyallowingthatmedicationtoberescheduledinto ScheduleIIorbelow(Grinspoonv.DEA,1984). 43 SuchFDAapproval,however,wouldnot necessarilyrequirethereschedulingofbulkcannabis,despitethefactthatopiumandcoca leavesareinScheduleII.AlthoughtheControlledSubstancesActschedulesapplytoclassesof substances,ratherthanspecificmedications,precedenthasdevelopedfordifferential scheduling.Forexample,syntheticdronabinol,inaspecificFDAapprovedformulation,is listedinScheduleIII,whilepureTHCinanyotherformremainsinScheduleI. 44 Similarly, Xyrem,anapprovedtreatmentfornarcolepsy,isclassifiedinScheduleIII,whilestreet versionsofGHBremaininScheduleI(NeumanA,2004).Therefore,ifsuchaspecificcannabis medicationwereapprovedbytheFDAandrescheduledbytheDEA,bulkherbalcannabis couldstillremaininScheduleI. Reschedulingofcannabiswouldalsonotallowpharmaciststocompoundcannabis productsforlargenumbersofpatients.TheFDAhasissuednumerouswarninglettersto compoundingpharmacists,emphasizingthat: ThedrugsthatpharmacistscompoundarenotFDAapprovedandlackan FDAfindingofsafetyandefficacy,however,FDAhaslongrecognizedthe importantpublichealthfunctionservedbytraditionalpharmacy compounding.FDAregardstraditionalcompoundingastheextemporaneous combining,mixing,oralteringofingredientsbyapharmacistinresponsetoa physician'sprescriptiontocreateamedicationtailoredtothespecialized needsofanindividualpatient.SeeThompsonv.WesternStatesMedical Center,535U.S.357,36061(2002).Traditionalcompoundingtypicallyis usedtopreparemedicationsthatarenotavailablecommercially,suchas adrugforapatientwhoisallergictoaningredientinamassproduced productordiluteddosagesforchildren. Throughtheexerciseofenforcementdiscretion,FDAhistoricallyhasnot takenenforcementactionsagainstpharmaciesengagedintraditional pharmacycompounding.Rather,FDAhasdirecteditsenforcementresources

contendthatreschedulingwouldmakecannabisprescribabletopatients.GettmanJ.FrequentlyAsked QuestionsaboutMedicalCannabisandRescheduling.http://www.drugscience.org/lib/freq_qst.html. 43Asnotedabove,fn14,delineatingthecriteriathatmustbemetinorderforasubstancetohaveacurrently acceptedmedicaluseintheUS.Thesecriteriacanonlybesatisfiedbyarobustbodyofscientificdata,notby theenactmentofstatelawsthatdecriminalizetheuseofcannabisformedicalpurposes.USDepartmentof Justice,DEA,lettertoCarlOlsen(Dec.19,2008)(denyingapetitionforrescheduling). http://www.iowamedicalmarijuana.org/petitions/pdfs/dea_20081219.pdf 44TheDEAhasrecentlyissuedaNoticeofProposedRulemaking(NPRM)proposingtotransfercertain genericdronabinolproductstoScheduleIII.DOJ,DEA,"ListingofApprovedDrugProductsContaining DronabinolinScheduleIII,"75Fed.Reg.67054(Nov.1,2010).
42Interestingly,oneprominentcannabisadvocate,whohasfiledcannabisreschedulingactions,doesnot

againstestablishmentswhoseactivitiesraisethekindsofconcernsnormally associatedwithadrugmanufacturerandwhosecompoundingpractices resultinsignificantviolationsofthenewdrug,adulteration,ormisbranding provisionsoftheFDCA(FDA,CompliancePolicyGuide,2002;FDA,Warning Letter,2006). Reschedulingcannabiswouldnotautomaticallyreduceorotherwiseaffect federalcriminalpenaltiesforpossessionortrafficking.Thesestatutesprovide specificpenaltiesformarijuanaorforpossessingacontrolledsubstancewithouta lawfulprescription. 45 Suchstatuteswouldrequireseparateamendmentinorderfor existingpenaltiestobemodified,andthisamendmentprocesswouldinvolve differentpolicyfactorsandconsiderations. Cannabisreschedulingwouldalsonotnecessarilyallowtheestablishmentof additionalcannabiscultivationfacilitiestoproducecannabisforresearchpurposes.The UnitedStatesisasignatorytotheSingleConventiononNarcoticDrugs1961.Thattreaty requiresthatcannabiscultivatedwithintheU.S.bordersmustbedeliveredtoanational agency.IntheUS,thenationalagencyistheNationalInstituteonDrugAbuse(NIDA).NIDA hastheexclusiveauthorityoverimporting,exporting,wholesaletrading,andmaintaining stocks(SingleConventiononNarcoticDrugs,1961). 46 OnlytheUniversityofMississippi, undercontractwithNIDA,currentlycultivatescannabisforresearchpurposes(NIDA, 1997).ThemandatesofthetreatyarenotaffectedbycannabissschedulingunderUS domesticlaw. 47 Thereisonerespect,however,inwhichthereschedulingofcannabiscouldfacilitate research.Ifaphysicianinvestigatorpossessesaregistration(theCSAtermforalicense)to dispenseanFDAapprovedScheduleIIcontrolledsubstance,heorshemayconduct researchonanyScheduleIIsubstance,asacoincidentactivitytohis/herregistrationto dispense,withouttheneedtoobtainaseparateresearchregistrationfromtheDEA.(Of course,anysuchresearchwouldstillneedtobeapprovedbytheFDAandanappropriate institutionalreviewboard,aswellasperhapsbyastateregulatorybody. 48 Bycontrast,a separateregistrationisrequiredforScheduleIresearch. 49 Inaddition,eachregistrationis protocolspecific.IfaresearcherwishestoconductadifferentstudyonthesameScheduleI substance,he/shemustobtainaseparateregistration.Furthermore,aScheduleII practitionerregistrationmustberenewedeverythreeyears;whereasaScheduleI researchregistrationmustberenewedannually.Thus,anydelaysassociatedwith obtainingandrenewingaScheduleIresearchregistrationcouldbeobviatedbythe reschedulingofcannabistoScheduleII.Thissituation,however,couldalsoberesolvedbya morelimitedstatutoryandregulatorychangethatpermittedpractitionerswithScheduleII

45See,e.g.,21U.S.C.secs.841,844. 46Thereisanexceptionforstocksheldbymanufacturersofpharmaceuticalpreparations.Art.23,para.2(e). 47ForfullerdiscussionoftherequirementsoftheSingleConvention,seeDepartmentofJustice,DEA,LyleE. 4821U.S.C.sec.823(f);21C.F.R.secs.1301.13. 4921C.F.R.sec.1301.18.

Craker;DenialofApplication,74Fed.Reg.2101(Jan.14,2009).

registrationstoconductScheduleIcannabis/cannabinoidresearchasacoincidentactivity totheirexistingregistrations.

Conclusions
Cognitivedissonanceisatermthataptlydescribesthecurrentapproachto medicalmarijuana.Scientistsrecognizethepublichealthharmsoftobaccosmokingand urgeouryoungpeopletorefrainfromthepractice,yetmostcannabisconsumersuse smokingastheirpreferreddeliverymechanism.Thepracticeofmedicineisincreasingly evidencebased,yetsomephysiciansarewillingtoconsiderrecommendingcannabisto theirpatients,despitethefactthattheylackeventhemostrudimentaryinformationabout thematerialcurrentlybeingconsumedbypatients(composition,quality,anddose,andno controlledstudiesprovideinformationonitsbenefitandsafetyofitsuseinchronic medicalconditions).Pharmaceuticalcompaniesareresponsiblefortheharmscausedby contaminatedorotherwisedangerousproductsandtobaccocompaniescanbeheld accountableforharmscausedbycigarettes,yet,dispensariesdistributecannabisproducts aboutwhichverylittleareknown,includingtheirsource.Effortsarebeingmadetostem theepidemicofprescriptiondrugabuse,includingFDAmandatedriskmanagementplans requiredforprescriptionmedications,yetcannabisdistributionsitesproliferateinmany states,virtuallywithoutregulation. Inordertothinkclearlyaboutmedicalmarijuana,onemustdistinguishfirst between1)thetherapeuticpotentialsofspecificchemicalsfoundinmarijuanathatare deliveredincontrolleddosesbynontoxicdeliverysystems,and2)smokedmarijuana. Second,onemustconsiderthedrugapprovalprocessinthecontextofpublichealth, notjustformedicalmarijuanabutalsoforallmedicinesandespeciallyforcontrolled substances.Controlledsubstancesaredrugsthathaverecognizedabusepotential. Marijuanaishighonthatlistbecauseitiswidelyabusedandamajorcauseofdrug dependenceintheUnitedStatesandaroundtheworld.Whenphysiciansrecommenduse ofscheduledsubstances,theymustexercisegreatcare.Thecurrentpatternofmedical marijuanauseintheUnitedStatesisfarfromthatstandard. Ifanycomponentsofmarijuanaareevershowntobebeneficialtotreatanyillness thenphysiciansshouldprescribethosecomponentsbynontoxicroutesofadministrationin controlleddosesjustallothermedicinesareintheU.S. Inorderforphysicianstofulfilltheirprofessionalobligationstopatients,andin orderforpatientstobeofferedthehighstandardofmedicalcarethatwehavecometo expectintheUnitedStates,cannabisbasedmedicationsmustmeetthesameexacting standardsthatweapplytootherprescriptionmedicines.MembersoftheAmericanSociety ofAddictionMedicinearephysicianswithexpertiseinaddictionmedicinewithknowledge specifictotherisksassociatedwiththeuseofsubstanceswithhighabusepotential.ASAM muststandstronglybehindthestandardthatanyclinicaluseofacontrolledsubstance

mustmeethighstandardstoprotectthepatientandthepublic;theapprovalofmedical marijuanadoesnotmeetthisstandard.

Recommendations
ASAMassertsthatcannabis,cannabisbasedmedications,andcannabisdeliverydevices shouldbesubjecttothesamestandardsthatareapplicabletootherprescription medicationsandmedicaldevicesandthatthesemedicationsordevicesshouldnotbe distributedorotherwiseprovidedtopatientsunlessanduntilsuchmedicationsordevices havereceivedmarketingapprovalfromtheFoodandDrugAdministration. ASAMrecommendsitsmembersandotherphysicianorganizationsandtheirmembers rejectresponsibilityforprovidingaccesstocannabisandcannabisbasedmedicationsuntil suchtimethatthesematerialsreceivemarketingapprovalfromtheFoodandDrug Administration. ASAMrejectssmokingasameansofdrugdeliverysinceitisinherentlyunsafe. ASAMsupportstheneedforfederalregulatorystandardsfordrugapprovaland distribution.ASAMrecognizesthatstatescanenactlimitationsthataremorerestrictive butrejectstheconceptthatstatescouldenactmorepermissiveregulatorystandards. ASAMdiscouragesstateinterferenceinthefederalmedicationapprovalprocess. ASAMrejectsaprocesswherebyStateandlocalballotinitiativesapprovemedicines becausetheseinitiativesarebeingdecidedbyindividualsnotqualifiedtomakesuch decisions(baseduponacarefulsciencebasedreviewofsafetyandefficacy, standardizationandformulationfordosing,orprovideameansforaregulated,closed systemofdistributionformarijuanawhichisaCNSdrugwithabusepotential). ASAMassertsthatphysicianorganizationsoperatinginstateswherephysiciansareplaced inthegatekeepingrolehaveanobligationtohelplicensingauthoritiesassurethat physicianswhochoosetodiscussthemedicaluseofcannabisandcannabisbasedproducts withpatients: Adheretotheestablishedprofessionaltenetsofproperpatientcare,including o Historyandgoodfaithexaminationofthepatient; o Developmentofatreatmentplanwithobjectives;

o Provisionofinformedconsent 50 ,includingdiscussionofrisks,sideeffects,and potentialbenefits; o Periodicreviewofthetreatmentsefficacy; o Consultation,asnecessary;and o Proper record keeping that supports the decision to recommend the use of cannabis Haveadequatetraininginidentifyingsubstanceabuseandaddiction 52 . Notissuearecommendationunlessthephysicianhasadequateinformation regardingthecompositionanddoseofthecannabisproduct; Ensurethattheissuanceofrecommendationsisnotadisproportionatelylarge(or evenexclusive)aspectoftheirpractice; Haveabonafidephysicianpatientrelationshipwiththepatient,i.e.,shouldhavea preexistingandongoingrelationshipwiththepatientasatreatingphysician 51 ;

Acknowledgements
ThispaperwaswrittenbyaPresidentsActionCommitteeonMedicalMarijuanaofthe AmericanSocietyofAddictionMedicine.Membersofthecommitteewere:AndreaG. Barthwell,MD,andRobertDuPont,MD,Cochairs,LouisE.Baxter,Sr.,MD,Presidentof ASAM,TimmenCermak,MD,PetrosLevounis,MD,andMarkKraus,MDmembers.The ASAMBoardofDirectorsacceptedtherecommendationsatitsannualmeetingApril2010 andrequestedexpertfieldreviewfromASAMsBoardofDirectors,ASAMsPublicPolicy Committee,ASAMsChaptersCouncil,andASAMsMembershipCommittee.Comments weresubmittedbyinterestedmembersandincorporatedintothisfinalversionSeptember 2010.

50Ifaphysicianrecommendstheuseofcannabisforaminor,parentsand/orlegalguardiansmustbefully informedofthepotentialrisksandbenefitsofsuchuseandmustconsenttothatuse. 51Thisprovisionmaybemodifiediftheprescribingphysicianisabonafideconsultantbroughtintothecare ofapatientbythephysicianwithwhomthepatienthasarelationship.Thisfurtherdefineshowtoviewand evaluatetheactionsofthephysicianwhoholdsher/himselfoutasanexpertincannabismedicalcarewho hasnoconnectiontotheprimaryphysicianofthepatientforwhomcrudecannabisisrecommended. 52ThisisparticularlygermanetotheASAMwhichconsistsofphysiciansknowledgeableindrugabuseand addictionandwhoadvocatetoensurethatallphysicianshavetheknowledgetomanageCNSmedications responsiblyinthegeneralpatientpopulationandcanidentifyandtreatorreferfortreatmentcasesofabuse anddependencetopsychoactivesubstances.

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