CannabinoidProductBoard

AnnualReport

November2017

Prepared by

Cannabinoid Product Board

Chair:KarenWilcoxPh.D.ErikChristensenM.D.

MichaelCrookstonM.D.,F.A.P.A.,F.A.S.A.M.GlenHansonDDS,Ph.D.

MarkMungerPharmD,FCCPEdReddM.D.

PerryRenshawM.D.,Ph.D.,M.B.A

Utah Cannabinoid Product Board

Cannabinoid Product Board Annual Report

Executive Summary November2017

AsmedicalandrecreationalmarijuanabecomeslegalizedacrosstheUnitedStates,theUtahLegislaturehastakenaproactiveapproachandin2017passedTheCannabinoidResearchAct,numberedasHB130.ThisactestablishedtheCannabinoidProductBoardandallowedfortheuseofCannabinoidproductsforresearch.ThepurposeoftheCannabinoidProductBoard(CPB)istoreviewavailableresearchandproviderecommendationstoprescribingphysiciansrelatedtotheuseofcannabinoidproductsfortreatingmedicalconditions,dosageamounts,andidentifyinginteractionswithothertreatments.TheBoardiscomposedofsevenmembers.Medicalresearchers,physicians,andthreeoftheBoardmembersarealsomembersoftheControlledSubstancesAdvisoryCommittee(CSAC).

TheBoardfirstmetinJune2017andbeganholdingmonthlymeetingstoreviewcannabinoidresearch.Annually,theBoardprovidesrecommendationstothelegislatureregardingtheirfindings.ThisreportcontainsthefindingandrecommendationsoftheBoardfromJunetoNovember2017.Below,thereaderwillfindthecriteriamatrixusedforanalyzingresearchaswellasthestudiesthathavebeenreviewedatthispoint.Otheractivitiesoftheboardareexplainedandlimitations,whichwereidentifiedthroughdiscussionandresearchreview,areoutlined.TheBoardhasmaderecommendationsaswellasidentifiednextstepsinthisreport.

KeyPoints:• TheBoardhaslimitedaccesstoinformation,

whichprovesdifficulttomakerecommendationsbasedonpublishedresearchalone.TheBoardwoulddefertorecommendationsfromtheFDA.

• TheBoardrecommendsexpandingthe10:1ratioofcannabidioltoTHCinstatutesothatmorestudiescanbeconsideredforreview.

• TheBoardisunabletorecommendappropriatedosagesortreatmentswithcannabinoidproductswithoutassuranceofqualityandconsistencythroughouttheresearch.

• TheBoardrecommendsthatcannabinoidproductmanufacturersadoptguidelinessimilartothosefromtheAmericanHerbalProductsAssociationforqualitycontrol.

• TheBoardacknowledgesthatthereiscurrentlynotenoughliteraturetomakeconclusionsaboutcannabidioleffectivenessforspecificdiseasestates.

• TheBoardrecommendsreviewingresearchregardingtheharmsassociatedwithcannabinoidproductsinadditiontothebenefitsofsuchproducts.

Utah Cannabinoid Product Board •

TableofContents

Introduction 1

Bylaws...................................................................................................................................2

Website.................................................................................................................................2

Organization 4

ProcessforReviewingandClassifyingResearch...................................................................4

ConclusiveEvidence:.............................................................................................................4

SubstantialEvidence:............................................................................................................5

ModerateEvidence:..............................................................................................................5

LimitedEvidence:..................................................................................................................5

NoorInsufficientEvidencetoSupporttheAssociation:......................................................5

Limitations 11

Scopeoftheboard..............................................................................................................11

Consistencyofproducts......................................................................................................11

Recommendations 13

NextSteps 14

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Introduction

TheCannabinoidProductBoardistheresultoftheCannabinoidResearchAct,sponsoredbyRep.BradDawandSen.EvanVickersduringthe2017GeneralLegislativeSession.TheCannabinoidResearchAct,numberedasHB130,madeseveralchangestothestatecode:

1. Allowtheprocessinganduseofcannabinoidproductsinacademicresearch;

2. Allowthepossessionofcannabinoidproductbysomeoneparticipatinginapprovedresearch;and

3. ThecreationoftheCannabinoidProductBoardandoutlinesitsduties.

TheCannabinoidResearchActreceivedwidesupportinthelegislature.ThebillreceivedunanimoussupportfromtheHouseHealthandHumanServicesCommitteeandreceivedonlytwonayvoteswhenontheHousefloor.IntheSenate,whereHB0130wasintroducedbySen.EvanVickers,theSenateHealthandHumanServicescommitteeapprovedthebill7-1,andpassedtheSenateasawhole27-1-1.Thelegislation,withitsamendments,passedtheconcurrencecalendarunanimously.Gov.HerbertsignedtheCannabinoidResearchActintolawonMarch25th.

TheCannabinoidResearchActdirectstheUtahDepartmentofHealth(UDOH)toformandfacilitatetheCannabinoidProductBoard.Asstatedinthelegislation,thepurposeoftheboardistoreviewavailableresearchrelatedtothehumanuseofcannabinoidproducts.Specificallytheboardisaskedtoevaluatethesafetyandefficacyofcannabinoidproductsintermsof:1)medicalconditionsthatrespondtocannabinoidproducts;2)dosageamountsandtheirmedicalforms;and3)interactionsbetweencannabinoidproductsandothertreatments.TheboardmayonlyreviewresearchthathasbeenapprovedbyanInstitutionalReviewBoard,orapproved/conductedbythefederalgovernment.

Fromthisresearch,theboardhasbeenaskedtodevelopprescribingguidelinesthatmaypotentiallybeusedbyphysiciansrecommendingcannabinoidproductstotheirpatients.TheboardisdirectedtoreportthefindingsoftheirevaluationinwritingtotheHealthandHumanServicesInterimCommitteebeforeNovember1stofeachyear.

ThelegislationoutlinesthattheCannabinoidProductBoardbemadeofthesevenmembers“…inconsultationwithaprofessionalassociationbasedinthestatethatrepresentsphysicians.”Threeoftheboardmembersmustbemedicalresearchersandfourmustbephysicians.ThreeoftheboardmembersmustalsobemembersoftheControlledSubstancesAdvisoryCommittee(CSAC).Thetermsofboardmembers,leadership,andvotingonrecommendationsarealsodiscussed.

TheExecutiveDirectorsOffice(EDO)ofUDOHbegantheprocessofidentifyingpotentialboardmembersandissuingappointmentsinApril,2017.

Thoseappointedinclude:

ErikChristensenM.D.* UtahDepartmentofHealthOfficeofMedicalExaminer

MichaelCrookstonM.D.,F.A.P.A.,F.A.S.A.M.

IntermountainMedicalGroup

GlenHansonDDS,Ph.D.*

UniversityofUtah,HealthSciencesCenter

MarkMungerPharm.D.*,F.C.C.P.,F.A.C.C.,F.H.F.S.A.

UniversityofUtah,HealthSciencesCenter

EdReddM.D. UtahLegislatorPerryRenshawM.D.,Ph.D.,M.B.A

UniversityofUtah,HealthSciencesCenter

KarenWilcoxPh.D. UniversityofUtah,HealthSciencesCenter

*CSACMembers

FacilitationoftheCannabinoidProductBoardwasdelegatedtotheTobaccoPreventionandControlProgramwithintheBureauofHealthPromotion.

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Bylaws

TheCannabinoidProductBoardadoptedbylawstodefinethestructureoftheBoardandtohelpguidetheBoardsdecisionsandoperations.ThebylawswereadaptedfromtheColoradoMedicalMarijuanaScientificAdvisoryCouncilbylawswithinclusionofrequirementsinH.B.130.Thebylawscontainthedutiesoftheboard,whicharedefinedas:

ARTICLEIV:DutiesoftheBoardSection1.TheBoardshall:1)Reviewanyavailableresearchrelatedtothehumanuseofacannabinoidproductthat:

a) wasconductedunderastudyapprovedbyanIRB,or

b) wasconductedorapprovedbythefederalgovernment

2)Basedontheresearch,theBoardshallevaluatethesafetyandefficacyofcannabinoidproducts,including:

a) medicalconditionsthatrespondtocannabinoidproducts

b) cannabinoiddosageamountsandmedicaldosageforms;and

c) interactionofcannabinoidproductswithothertreatments

3)BasedontheBoard’sevaluation,theBoardshalldevelopguidelinesforaphysicianrecommendingtreatmentwithacannabinoidproductthatincludesalistofmedicalconditions,ifany,thattheBoarddeterminesareappropriatefortreatmentwithacannabinoidproduct.

4)TheBoardshallsubmittheguidelinesto:a) thedirectoroftheDivisionofOccupationaland

ProfessionalLicensingb) theHealthandHumanservicesInterim

Committee5)TheBoardshallreporttheBoard’sfindingsbeforeNovember1ofeachyeartotheHealthandHumanServicesInterimCommittee.ThebylawscontaininformationregardingtheresponsibilitiesoftheDepartmentofHealthandhowmeetingsshouldbeconductedusingRobert’sRulesofOrder,aswellashowtodealwithconflictsofinterest.

Website

TheCannabinoidsProductBoarddevelopedafreepublicwebsiteforthepurposeoforganizingresearch,providingaplaceforpubliccommentandaddinganextralayeroftransparencytotheproceedingsoftheboard.Thewebsitecanbefoundat:https://sites.google.com/utah.gov/cpboard/.ThewebsitecontainsinformationofwhenandwheretheBoardmeetingswillbeheld,upcomingandpastagendas,andmeetingminutesforallCPBmeetings.Thewebsitealsocontainsasectionforresearch,whichhascopiesofalltheliteraturethatisbeingreviewedbytheboard.ThiswebsiteisalsoaplaceforthepublictointeractwiththeBoard.ThepubliccansubmitcommentsorquestionstotheBoard,whichtheBoardwillhavetheopportunitytorespondto.

*BelowarescreenshotsoftheUtahCannabinoidProductBoardWebsite

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OrganizationIntheinitialmeetingoftheCannabinoidProductBoard,theBoardvotedonselectingachairperson.KarenWilcox,Ph.D.whoisaprofessorandchairoftheDepartmentofPharmacology&ToxicologyattheUniversityofUtahwasselectedtobethechair.TheBoarddoesnothaveaco-chair,thoughthebylawsallowforoneifneededinthefuture.TheBoardhasdecidedtomeetmonthlyandwillcontinuetodosoasneeded.Thusfarfourboardmeetingshavebeenheld.Theagendaofatypicalboardmeetingconsistsofadministrativeitemssuchasapprovingthepreviousmeetingminutes,andreviewofpublishedresearch.Theresearcharticlesareassignedtomembersoftheboardtoreadandthentheyreportontheresearchatthemeeting.Afterpresentingtheresearch,eacharticleisdiscussedbytheBoard,andplacedintotheestablishedmatrixforscoring.TheresearchthatisreviewedisidentifiedprimarilybytheBoardinternbasedonthecriteriaforstudiesoutlinedinHB130.MembersoftheBoardalsobringrelevantresearchforwardfordiscussion.TheBoardisinterestedinhavingsubjectmatterexpertssuchasresearchersandpharmacologicalorganizationspresenttotheBoardandprovidefurtherinformationaboveandbeyondwhatresearchcanprovide.

ProcessforReviewingandClassifyingResearchTheCannabinoidProductBoardhasbeenaskedtoevaluatethesafetyandefficacyofcannabinoidproductsintermsof:1)medicalconditionsthatrespondtocannabinoidproducts;2)dosageamountsandtheirmedicalforms;and3)interactionsbetweencannabinoidproductsandothertreatments.AssuchtheBoardneededtocreateprocessesbywhichtheycouldsystematicallyreviewtheevidencewhichmetthecriteriaoutlinedinthestatue.TheBoardagreeduponusingthecategoriesusedbytheInstitutesofMedicinetocategorizeevidenceittheirbook“TheHealthEffectsofCannabisandCannabinoids:TheCurrentStateofEvidenceandRecommendationsforResearch”,toclassifystudyrecommendationsaswellastodeterminethelevelofevidenceforeachstudyreviewed.Itwasdecidedthatallresearchreviewedwouldbeputintoa

matrixthatidentifiesthespecificdiseasestateortopicthestudylookedat,studymethods(typeofstudy,samplesize,location),keyfindings,keylimitations,adeterminationofthelevelofevidenceaswellasagradingorclassificationoftherecommendations.Pleaseseeexamplebelow.UsingthismatrixasaguidetheBoardwouldsystematicallyworkthroughgradingeachpieceofevidence.TheBoardalsoinvitedrepresentativesfromvarioussuppliersofhighquality,pharmacygrade,cannabidialproductstopresenttotheBoardtogainabetterunderstandingoftheresearchbeingconductedandtheproductscurrentlyonthemarket.TheBoardadoptedstandardlanguagedevelopedbytheInstitutesofMedicinetocategorizetheweightofevidenceregardingwhethercannabinoiduseisaneffectiveorineffectivetreatmentforthespecifiedcondition.TheCategoriesandthegeneralparametersforthetypesofevidencesupportingeachcategoryarelistedbelow.1Theevidencecategoriessuggestthatthestudydesignwasappropriateforthelimitedconclusionsreachablebasedonthelimitationsinthedata.ItdoesnotindicatethattheBoardagreesordisagreeswithanyconclusionorrecommendation.

ConclusiveEvidence:Fortherapeuticeffects:Thereisstrongevidencefromrandomizedcontrolledtrialstosupporttheconclusionthatcannabinoidsareaneffectiveorineffectivetreatmentforthehealthendpointofinterest.Forotherhealtheffects:Thereisstrongevidencefromrandomizedcontrolledtrialstosupportorrefuteastatisticalassociationbetweencannabinoiduseandthehealthendpointofinterest.Forthislevelofevidence,therearemanysupportivefindingsfromgood-qualitystudieswithnocredibleopposingfindings.Afirmconclusioncanbemade,andthelimitationstotheevidence,includingchance,bias,andconfoundingfactors,canberuledoutwithreasonableconfidence.

1National Academies of Sciences, Engineering, and Medicine. 2017. Thehealtheffectsofcannabisandcannabinoids:Thecurrentstateofevidenceandrecommendationsforresearch.Washington, DC: The National Academies Press. doi: 10.17226/24625.

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SubstantialEvidence:Fortherapeuticeffects:ThereisstrongevidencetosupporttheconclusionthatcannabinoidsareaneffectiveorineffectivetreatmentforthehealthendpointofinterestForotherhealtheffects:Thereisstrongevidencetosupportorrefuteastatisticalassociationbetweencannabinoiduseandthehealthendpointofinterest.Forthislevelofevidence,thereareseveralsupportivefindingsfromgood-qualitystudieswithveryfewornocredibleopposingfindings.Afirmconclusioncanbemade,butminorlimitations,includingchance,bias,andconfoundingfactors,cannotberuledoutwithreasonableconfidence.

ModerateEvidence:Fortherapeuticeffects:Thereissomeevidencetosupporttheconclusionthatcannabinoidsareaneffectiveorineffectivetreatmentforthehealthendpointofinterest.Forotherhealtheffects:Thereissomeevidencetosupportorrefuteastatisticalassociationbetweencannabinoiduseandthehealthendpointofinterest.Forthislevelofevidence,thereareseveralsupportivefindingsfromgood-tofair-qualitystudieswithveryfewornocredibleopposingfindings.Ageneralconclusioncanbemade,butlimitations,includingchance,bias,andconfoundingfactors,cannotberuledoutwithreasonableconfidence.

LimitedEvidence:Fortherapeuticeffects:Thereisweakevidencetosupporttheconclusionthatcannabinoidsareaneffectiveorineffectivetreatmentforthehealthendpointofinterest.Forotherhealtheffects:Thereisweakevidencetosupportorrefuteastatisticalassociationbetweencannabinoiduseandthehealthendpointofinterest.Forthislevelofevidence,therearesupportivefindingsfromfair-qualitystudiesormixedfindingswithmostfavoringoneconclusion.Aconclusioncanbemade,butthereissignificantuncertaintyduetochance,bias,andconfoundingfactors.

NoorInsufficientEvidencetoSupporttheAssociation:Fortherapeuticeffects:Thereisnoorinsufficientevidencetosupporttheconclusionthatcannabinoidsareaneffectiveorineffectivetreatmentforthehealthendpointofinterest.Forotherhealtheffects:Thereisnoorinsufficientevidencetosupportorrefuteastatisticalassociationbetweencannabinoiduseandthehealthendpointofinterest.Forthislevelofevidence,therearemixedfindings,asinglepoorstudy,orhealthendpointhasnotbeenstudiedatall.Noconclusioncanbemadebecauseofsubstantialuncertaintyduetochance,bias,andconfoundingfactors.

ResearchReview:

TheresearchlistedinthematrixbelowwascompiledbytheCPBinternandreviewedbytheBoard.Theresearchpresentedwasidentifiedbyhavinga10:1ratioofcannabidioltoTHC.Thisratiolimitsthenumberofstudiesthatcanbereviewed,butthereviewprocessisongoingasstudiesthatmeetthiscriterionareidentified.

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TitleandAuthors Journal,Year(reference)

Methods(Typeofstudy,samplesize,study,location,etc.)

WeightofEvidenceCategory

KeyFindings KeyLimitations Comments(Industryties,etc.)

“TrialofCannabidiolforDrug-ResistantSeizureintheDravetSyndrome”,Devinsky,etal

NEnglJMed2017;376:2011-20.

DOI:10.1056/NEJMoa1611618

RandomizedControlledTrial;Double-blind,placebocontrolled

N=120

14-weektreatmentperiod

Dosagesof20mgperkgofbodyweightperdayofcannabidioloralsolutionorplaceboinadditiontostandardantiepileptictreatment.

Multinational:23centersintheU.S.andEurope

Sample:Children/youngadults(2-18yearsold)withtheDravetsyndrome(Epilepsydisorderassociatedwithdrug-resistantseizuresandhighmortalityrate)

Meanage:9.8yearsold

52%male

90%completedthetreatmentperiod

Conclusiveevidence

Cannabidiolresultedinagreaterreductioninconvulsive-seizurefrequencythanplaceboamongchildrenw/drug-resistanceDravetsyndrome.Cannabidiolgroup:-Decreaseinmedianfrequencyinconvulsiveseizurespermonthfrom12.4to5.9.-Percentageofpatientsw/atleasta50%reductioninconvulsive-seizurefrequency:43%.-5%becameseizurefree-Nosignificantreductioninnonconvulsiveseizures.-Adverseevents:diarrhea,vomiting,fatigue,pyrexia,somnolence,abnormalliver-functiontestresults.-Overallconditionimprovedbyatleastonecategoryonthe7-categoryCaregiverGlobalImpressionofChangeScale:62%Controlgroup:

Dataonconvulsiveseizures(numberandtype)wasrecordedeachdaybypatientsortheircaregivers.

ResultsofCaregiverGlobalImpressionofChangeareself-reportedona7-pointLikert-likescale.

Funded,designed,managed,monitored,andanalyzedbyGWPharmaceuticals

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-Decreaseinmedianfrequencyofseizurespermonthfrom14.9to14.1.-Percentageofpatientsw/atleasta50%reductioninconvulsive-seizurefrequency:27%.-Lessadverseeventsoccurred-0%becameseizurefree-Overallconditionimprovedbyatleastonecategoryonthe7-categoryCaregiverGlobalImpressionofChangeScale:34%Mediandifferencebetweencannabidiolgroupandplacebogroupinseizurefrequency:-22.8percentagepoints;95%CI,-41.1to-5.4;P=0.01

“Cannabidiolenhancesanandamidesignalingand

alleviatespsychoticsymptomsofschizophrenia”,Leweke,etal

TranslPsychiatry(2012)2,e94,doi:10.1038/tp.2012.15&2012MacmillanPublishersLimitedAllrightsreserved2158-3188/12

RandomizedClinicalTrial;therapeutic-exploratory(phaseII);Double-blind:cannabidiolvsamisulpride(apotentantipsychotic).

N=42

Sample:Age18-50yearsold;maleandfemale;alldiagnosedwithparanoidschizophrenia

Conclusiveevidence

Boththecannabidioltreatmentandamisulprideweresafeandequallyeffectiveatimprovingpsychoticsymptoms.

Cannabidioltreatment:-Superiorside-effectprofile:lessweightgainandlowerprolactinincrease-apredictorofgalactorrheaandsexual

Theprimarypharmacologicalmechanismthroughwhichcannabidiolexertsanipsychoticeffectsinnotyetclear.Thestudycouldnotexcludethatcannabidiolmayreducepsychoticsymptomsthroughcomplementaryor

ThestudywassupportedbygrantsfromtheStanleyMedicalResearchInstitute(FML)andtheNationalInstituteonDrugAbuse(DP).

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Location:DepartmentofPsychiatryandPsychotherapyoftheUniversityofCologne

Allpatientswerehospitalizedatbaselineandthroughday28afterrandomassignmenttotreatment.

Afterascreeningperiodofupto7daysandaminimumperiodof3antipsychotic-freedays,patientswererandomized(1:1)toreceiveeithercannabidioloramisulpridestartingwith200mgperdayeachandincreasedstepwiseby200mgperdaytoadailydoseof200mgfourtimesdaily(total800mgperday)eachwithinthefirstweek.Treatmentsweremaintainedforanother3weeks.

dysfunction.Well-tolerated-Significantincreaseinserumanandamidelevels,whichwassignificantlyassociatedwithclinicalimprovement.

evenalternativemechanismstoFAAHinhibition,includinginteractionswithserotonin5-HT1Areceptors,GPR55receptorsandtransientreceptorpotentialvanilloid-1receptors.TheresultsprovidearationaleforadditionalclinicaltestingofselectiveFAAHinhibitorsinschizophrenia.

“Safetyandpharmacokineticsoforalcannabidiolwhenadministeredconcomitantlywithintravenousfentanylinhumans”,Maninietal

JAddictMed.2015May-Jun;9(3):204–210.

doi:10.1097/ADM.0000000000000118

Double-blind,placebo-controlledcross-overstudyN=34(eachsubjecthadtwosessions;n=17)Sample:21-65yearsold;healthyvolunteerswithprioropioidexposure,regardlessofroute.Location:ClinicalResearchCenterinMountSinaiHospital

Moderateevidence

Cannabidioldoesnotexacerbateadverseeffectsassociatedwithintravenousfentanyladministration.Co-administrationofCBDandopioidswassafeandwelltolerated.Importantly,

Subjecttopotentialselectionbiasduetonotincludingparticipantsacrossallages,gender,andethnicbackgrounds.Self-reportingcouldhaveledtobias,but

ThestudywasfundedbyaresearchgrantfromtheNationalInstitutesofHealth.

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inNewYorkCityCannabidiol(CBD)wasorallyco-administeredwithintravenousfentanyl.Participantsadministeredeitherplacebo,400mgoralCBD,or800mgoralCBD.2sessions:Session1:.5mcg/Kg;Session2:1.0mcg/KgofIVfentanyl.Bloodsampleswereobtainedbeforeandafter400or800mgCBDpretreatment,followedbyasingle0.5(Session1)or1.0mcg/Kg(Session2)intravenousfentanyldose.Primaryoutcome:SystematicAssessmentforTreatmentEmergentEvents(SAFTEE)toassesssafetyandadverseeffects.Alsomeasured:CBDpeakplasmaconcentrations,timetoreachpeakplasmaconcentrationsandareaunderthecurve.

fentanylco-administrationdidnotproducerespiratorydepressionorcardiovascularcomplications.

thestudydidutilizeacombinationofself-reportingandobjectivemeasures(vitalsigns,urinetesting,bloodsampling).Participantswereexcludediftheyhadacurrentdiagnosisofdrugdependence(exceptnicotine)orapositivedrugscreen.

Thestudynotedthatit’spredictedthatCBDwouldhaveasignificanteffectoninhibitingheroin-seekingbehavior,butthattherearestilllargegapsofknowledgeaboutCBDactionsinthebrain.

“Low-DoseCannabidiolIsSafebutNotEffectiveintheTreatment

forCrohn’s

DigDisSci(2017)62:1615–1620

DOI10.1007/s10620-017-4540-z

RandomizedControlledTrial;placebo-controlled

N=19

Sample:18-75yearsoldwithaCrohn’sdiseaseactivityindex

InsufficientEvidencetoSupporttheAssociation

(small

CBDwasfoundtobesafetoadministertoCrohn’spatients,butdisplayednobeneficialeffects.

TheaverageCDAIbeforecannabidiolconsumptionwas337±108and308±

SmalldoseofCBDwasused.

Smallnumberofpatientsinthestudy.

Dosagewasgivenorally,whichmaybe

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Disease,aRandomizedControlledTrial”,Naftalietal.,

>200.11weremales.

Patientswererandomizedtoreceive10mgofcannabidiol(CBD)orallyorplacebotwicedaily.

samplesizeandsmalldosages)

96(p=NS)intheCBDandplacebogroups,respectively.After8weeksoftreatment,theindexwas220±122and216±121intheCBDandplacebogroups,respectively(p=NS).Hemoglobin,albumin,andkidneyandliverfunctiontestsremainedunchanged.Nosideeffectswereobserved.

lesseffectivethansmoking.

6patientsinthestudygroupwerecurrentsmokers,butnoneintheplacebogroupwere.SmokingisknowntobeharmfulinCrohn’sdisease.

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Limitations

Scopeoftheboard

UtahCode§26-61-202statesthatthepurposeoftheCannabinoidProductBoard(theBoard)istoreviewavailableresearchto“…evaluatethesafetyandefficacyofcannabinoidproducts…”IntheCannabinoidResearchActtheterm“cannabinoidproduct”isdefinedas:

“…aproductintendedforhumaningestionthat:

(i)containsanextractorconcentratethatis obtainedfromcannabis;

(iii)ispreparedinmedicinaldosageform;and

(iii)containsatleast10unitsofcannabidiolfor everyoneunitoftetrahydrocannabinol.”(UC§ 58-37-3.6(1)(a))

TheBoard,uponbeginningtoidentifyresearchtoreview,discoveredthattherearefewpublicallyavailableresearcharticleswhereintheadministeredproductmetthedefinitionof“cannabinoidproduct”asdefinedinstatecode.

Thelackofavailableresearchpreventstheboardfromconfidentlyfulfillingitspurposeofevaluatingsafetyandefficacyoftheseproducts.

Consistencyofproducts

ThepurposeoftheCannabinoidProductBoardinevaluatingthesafetyandefficacyofcannabinoidproductsissimilartothemissionoftheUnitedStatesFoodandDrugAdministration(FDA)insomuchthattheFDAseekstoensurethesafety,efficacy,andsecurityofdrugs,biologicalproducts,andmedicaldevicestoprotectthepublic.Toachieveitspurpose,theFDAhasputintoplaceregulationsforproductsdefinedaspharmaceuticals,botanicaldrugs,ordietarysupplements.Suchregulationsareknownbroadlyas

Chemistry,Manufacturing,&Controls(CMC)andCurrentGoodManufacturingPractices(cGMP).

DuringtheresearchanddevelopmentstageofanewpharmaceuticaltheFDArequirescompaniestocomplywithCMCguidancetobegrantedapproval.CMCsinvolvedocumentationof:

- Drugcomposition;- Manufacture;- Stabilityoftheactivesubstance;- Formulationoffinalproduct;- Appropriatevariationlimits;- Releasecriteria(qualitystandardsforwhenthe

drugcanbemadeavailable);and- Theresultsofanalyticaltesting.

Whenthepharmaceuticalbeingassessedisbotanicalinnatureandthushasmultiplecomponentsinthesameproduct,therequirementsofCMCschangeandalsoinclude:

- Authenticationofplantsource- Recordofplantspecimens- Historyofthelandusedtogrowtheplant

source- Awrittenandapprovedprocessofthegrowing

processincludingtheusechemicalsontheplantsource.

- Packaging- Andspecificationsoftheallowablelimitsof

potentiallyharmfulcontaminants.

WiththisinformationtheFDAcanassessanddecidewhethertheproducingcompanycanadequatelyandconsistentlyproduceawell-definedproductatahighstandard.

TheneedofCMCsisdifferentbasedontheintentoftheproduct.CMCsareneededforproductsthatareintendedforhumanusetotreatdisease(pharmaceuticals).Physiciansareinvolvedwiththeuse

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ofpharmaceuticalsandwhereinthephysicianprescribestheiruseanddose.CMCsarenotneededforproductsthatareinsteadintendedtosupplementdiettosupporthealth(dietarysupplements).Dietarysupplementsdonotrequireaphysician’sprescription.AsdietarysupplementsarenotintendedtobeusedtotreataspecificdiseasethestandardfortheirdevelopmentislessregulatedbytheFDAandiscomparabletotherequirementsoffoodproducts.

CurrentGoodManufacturingPracticesarethoseregulationsenforcedbytheFDAonceapharmaceuticalisonthemarkettoensurethatcompaniesproducesafe,consistent,andeffectiveproducts.Manyoftheseregulationsarefocusedonfacilitieswheremanufacturingandprocessingofpharmaceuticalsoccurtoensurethattheyareproperlydesigned,monitored,andcontrolled.Specifically,cGMPsrequire:

- Qualitymanagementsystem;- Useofhigh-qualityrawmaterials;- Operatingprocedures;- Qualitymonitoringandinvestigation;- Laboratorytesting;and- FDAinspections

cGMPsarerequiredforbothpharmaceuticalsanddietarysupplements.However,inthecaseofdietarysupplements,manufacturersareallowedtosettheirowncGMPspecificationswithoutFDAapprovalorauditing.Also,unlikeintheproductionofpharmaceuticalsthefacilitieswheredietarysupplementsareproducedneednotbelicensedbytheFDA.

AscannabinoidproductsareneitherpharmaceuticalsnordietarysupplementstherearenoCMCsorcGMPsfortheirdevelopmentorproductionfromtheFDA.ForthosestatesthathaveinstitutedasystemofmedicalcannabistherearesomevaryingrequirementstotryandpromotequalityhoweversuchregulationsdonotmeetthestandardsofCMCsorcGMPs.

Thelackofregulatorystandardsforcannabinoidproductsisimportantforseveralreasons.First,therearenoadequatecontrolstopreventthepresenceofharmfulproductconstituentsthatmayhavebeenintroducedtotheproducteitherthroughthegrowing,processing,ormanufacturingstages.Assuchitisdifficulttoevaluateaproductforside-effectsandinteractionswithothertreatments.Thisraisesethicalissuesiftheseproductsarerecommendedtotreatvulnerableindividuals.

Second,withoutCMCsorcGMPsitisdifficulttoensuretheconsistencyoftheend-product.Inconsistentproductmakesitdifficulttoevaluatetheefficacyofatreatment.Variationinthepotencyofactiveingredientsandotherproductcomponentsmeantryingtolinktheuseoftheproducttohealthbenefitsisnearimpossible.Likewise,whenphysiciansrecommendsuchproductstopatients,physicianswouldbeunabletorecommenddosageaseachbatchofthatproductmaydifferfromthelast.

ItistheopinionoftheBoardthatthelackofregulationoncannabinoidproductsraisesseriousquestionsregardingtheirqualityandreproducibilityintheacademicliteratureavailable.Withouttheassuranceofqualityandconsistency,theboardisunabletorecommenddiseasestateswhereincannabinoidproductscouldbeusedtotreat,orrecommendappropriatedosing.

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Recommendations

• TheBoardhashaveverylimitedaccesstotheinformationnecessarytomakerecommendationsregardingconditionsthatrespondtocannabinoidproducts,prescribingguidelines,anddruginteractions.Anexampleisthatsomeresearchstudiesdonotspecifyhowthecannabinoidproductwasprepared,orthereasoningbehindwhycertaindosageswereused.Alternatively,theFDAhasaccesstoamuchlargerbodyofinformationandanestablishedprocess,whichwouldmaketheirrecommendationsmoreaccurateandappropriate.Duetothisfact,theBoardwoulddefertorecommendationsfromtheFDA.

• ThescopeofwhattheBoardcanreviewasoutlinedinthestatuteisverynarrowandestablisheslimitstothe

cannabinoidproductsthatcanbetakenintoconsideration.Currently,a10:1ratioofcannabidioltoTHCiswhatisallowedinstatute.Whileconductingliteraturereviews,itisclearthattherearenotmanystudiesthatmeetthesecriteria.ThisseverelylimitsthenumberofstudiestheBoardcanreviewandtakeintoconsideration.TheBoardrecommendsexpandingtheratiobeyondthecurrentlimitationofa10:1ratioofcannabidioltoTHC.

• WhiletheBoardhasbeenmainlyfocusingonthepotentialbenefitsofcannabidiol,theBoardrecommendsalso

lookingintotheharmsassociatedwithcannabinoidproductsasthosefindingswillalsobeimportantforphysiciansprescribingtheseproducts.

• AstheBoardfocussesonspecificdiseasesforliteraturereview,itbecomesapparentthatinmostcasesthereis

notliteratureornotenoughliteraturetomakeconclusionsaboutcannabidioleffectiveness.TheBoardhighlyrecommendsnotmakingconclusionsbasedonasingleorveryfewstudies.

• ItistheopinionoftheBoardthatthelackofregulationorChemistry,Manufacturing,&Controls(CMC)and

CurrentGoodManufacturingPractices(cGMP)oncannabinoidproductsraisesseriousquestionsregardingtheirqualityandreproducibilityintheacademicliteratureavailable.Withouttheassuranceofqualityandconsistency,theboardisunabletorecommenddiseasestateswhereincannabinoidproductscouldbeusedtotreat,orrecommendappropriatedosing.

• TheBoardrecommendsthatcannabinoidproductmanufacturersadoptguidelinessimilartothosefromthe

AmericanHerbalProductsAssociationforcultivationandprocessing,manufacturingandrelatedoperations,laboratorypractice,anddispensingsothatresearchanddiseaseinteractionsareconsistent.

Utah Cannabinoid Product Board Page 14 of 14

NextSteps

• TheBoardwillcontinuetomeetmonthlyorasnecessarytoreviewresearcharticlesandutilizetheresearchmatrixtoclassifycannabinoidstudiesthatshowpromiseorharmforprescribingpurposes.

• Inadditiontoresearch,theBoardwillbringinexpertsfromavarietyofbackgroundstofurtheradvancethe

Board’sknowledgeofcannabinoidproductsandresearch.

• TheBoardhashiredanintern,Ms.KrisanaFinlay,whoisastudentattheUniversityofUtah,studyingpublicpolicyandpublichealth.Ms.Finlaywillassisttheboardinfindingandcompilingresearch,draftingreports,andassistingtheBoardwithvariousdutiesasassigned.