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ReportonDrugPerSeLimitsCanadianSocietyofForensicSciencesDrugsandDrivingCommitteeMembers:AmyPeaire,Ph.D.AngelaFilbert,M.Sc. D’ArcySmith,M.Sc.DougBeirness,Ph.D.,Vice-ChairEdithViel,B.Sc.RachelleWallage,M.Sc.,ChairSeptember2017

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TableofContentsExecutiveSummary..........................................................................................................................3Introduction.....................................................................................................................................5Tetrahydrocannabinol(THC).............................................................................................................7

Table1.PotentialCanadianperselimitsforTHC(ng/mL)andthecombinedoffenceofalcohol(mg/100mL)andTHC........................................................................................................................14References.........................................................................................................................................18

Cocaine...........................................................................................................................................23References.........................................................................................................................................24

Gammahydroxybutyrate(GHB)......................................................................................................26References.........................................................................................................................................28

Heroin/6-monoacetylmorphine(6-MAM)......................................................................................30References.........................................................................................................................................31

Ketamine........................................................................................................................................32References.........................................................................................................................................33

LysergicAcidDiethylamide(LSD)....................................................................................................34References.........................................................................................................................................35

Methamphetamine........................................................................................................................36References.........................................................................................................................................37

Phencyclidine(PCP)........................................................................................................................38References.........................................................................................................................................39

Psilocybin/Psilocin..........................................................................................................................40References.........................................................................................................................................41Table2.Recommendationsfordetectionorperselimitsforselecteddrugs................................42Endnotes............................................................................................................................................43

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ExecutiveSummary• Establishingadrugperselimitdoesnotimplyalldriversbelowthislimitarenotimpairedandall

driversabovethislimitareimpaired.• Impairmentcanbedefinedasadecreasedabilitytoperformacertaintask;thisdiffersfrom

intoxicationwhichcanbedescribedastheobservablesignsofdruguse.• Theprimarypsychoactivecompoundincannabisproductsistetrahydrocannabinol(THC).• THCimpairstheabilitytooperateamotorvehicle.• THCisthemostfrequentlyencountereddruginCanadiandrivers,afteralcohol.• THCandalcoholarefrequentlydetectedincombinationindrivers.• Althoughthescientificliteraturevaries,severalwell-controlledstudieswithsufficient

discriminatingpowerhavedemonstratedanincreasedcrashriskinTHC-positivedrivers.RiskswereincreasedforfatalcollisionsandwithelevatedTHCconcentrations.

• AvailableevidencesuggestssignificantlyincreasedrisksfordriverspositiveforalcoholandTHCincombination.

• Unlikealcohol,theeffectsofTHCdonotcorrelatewellwithTHCbloodconcentrations.• ImpairmentduetoTHCisrelatedtotheamount,therouteofadministration,thetimeelapsed

sinceuse,andinter-individualvariability.• ExistingperselimitsforTHCvarywidelybetweenjurisdictions.• TheTHCperselimitsconsideredbythiscommitteeare5ng/mLand2ng/mLinblood.• The5ng/mLTHCperselimitisbaseduponimpairmentconsiderations,whilethe2ng/mLTHC

perselimitisbaseduponpublicsafetyconsiderations.• Thiscommitteerecommendstheuseofdistinctbutcorrespondingperselimitsforplasmai.• Thiscommitteerecommendsacombinedoffenceof50mgofalcoholin100mLofbloodwhen

detectedincombinationwithTHCataconcentrationlessthanthelimitfortheTHCaloneoffence.

• MinimizingtimedelaysinsamplecollectioniscriticaltoimplementationofaneffectiveTHCperselimit.

• ConsiderationofTHCperselimitsiscomplicatedbythepotentialforprolongedTHCbloodconcentrationsinchronicusersalthoughthereisevidenceofresidualimpairmentinthispopulation.

• ThepotentialforpassiveexposuretoTHCresultinginconcentrationsatoraboveaperselimitisnotapracticalconcerninthecontextoftheconditionsthatwouldberequired,thelevelsdiscussedandtheinevitabletimedelaytosamplecollection.

• Cocaineisacentralnervoussystemstimulantwhichimpairstheabilitytooperateamotorvehicle.Cocaineissusceptibletodegradationinthebodyandinacollectiontube;therefore,timelycollection,preservativeandproperstorageconditions,andtimelyanalysisareimportant.Thiscommitteerecommendsacocaineperselimitof30ng/mLintheblood.Nolimitisrecommendedforbenzoylecgonine,theinactivebreakdownproductofcocaine.

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• Gammahydroxybutyrate(GHB)isadrugwhichdemonstratescentralnervoussystemdepressantactivityinadosedependentmanner.GHBimpairstheabilitytooperateamotorvehicle.GHBisalsoacompoundthatoccursnaturallyinthebodyatlowlevels,andassuch,theperselimitmustreflectaconcentrationaboveendogenouslevels.ThiscommitteerecommendsaGHBperselevelof10mg/Lintheblood.

• Heroinisanopioidanalgesicwhichhascentralnervoussystemdepressantproperties.Heroinimpairstheabilitytooperateamotorvehicle.Giventheextremelyshorttimeframeforheroindetectioninthebodyduetotherapidmetabolismofherointoitsactivemetabolite,6-monoacetylmorphine(6-MAM),thiscommitteerecommendszerotolerancefor6-MAMdetectionintheblood.

• Ketamineisadissociativeanaestheticwhichimpairstheabilitytooperateamotorvehicle.Thiscommitteerecommendszerotoleranceforketaminedetectionintheblood.

• LysergicAcidDiethylamide(LSD)isapotenthallucinogenwhichimpairstheabilitytooperateamotorvehicle.ThiscommitteerecommendszerotoleranceforLSDdetectionintheblood.LSDissusceptibletodegradationinacollectiontubeasitislightandheatlabile;therefore,properstorageconditionsandtimelyanalysisareimportant.

• Methamphetamineisacentralnervoussystemstimulantwhichimpairstheabilitytooperateamotorvehicle.Thiscommitteerecommendsamethamphetamineperselimitof50ng/mLintheblood.

• Phencyclidine(PCP)isadissociativeanaestheticwhichimpairstheabilitytooperateamotorvehicle.ThiscommitteerecommendszerotoleranceforPCPdetectionintheblood.

• Psilocybinisthecompoundpresentin‘magic’mushroomswhichareusedforhallucinogenicpurposes;psilocinistheprimarypsychoactivemetaboliteofpsilocybin.Psilocybin/psilocinimpairstheabilitytooperateamotorvehicle.Thiscommitteerecommendszerotoleranceforpsilocybinand/orpsilocinintheblood.

• Anydrugrecommendedforzerotoleranceinabloodsampleisalsorecommendedforzerotoleranceinaserumorplasmasample.

• Sincezerotolerancewillberelatedtothelimitsofthemethodologyemployed,thiscommitteerecommendsthattheprovincialandfederalgovernmentforensiclaboratorysystemsdevelopacommonlimitofdetectionfortheaforementioneddrugssoastoensurethecriminalcodeoffencewillnotvarybetweenjurisdictions.

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Introduction

Traditionallytheapproachtodrug-impaireddrivinginvestigationshasinvolvedthreecomponents:(i)observationofdrivingimpairment,(ii)evidenceofdruguse,whichvariesinnaturebutmayincludeevidenceofdrugsordrugparaphernaliainthemotorvehicle,signsandsymptomsofdruguse,and/ordrugfindingsfromabiologicalsamplecollectedfromtheaccuseddriver,and(iii)connectionofthedrugfindingstodrivingimpairment,typicallyprovidedbyatoxicologist.EvenwiththelegislativechangesimplementedonJuly2,2008whichprovidedfortheDrugEvaluationandClassificationProgram(DECP)withinCanada,theapproachtodrug-impaireddrivinginvestigationshaslargelycontinuedtoincorporatethesesamecomponents.Sincethattime,severalissueshavebecomeapparentwithuseoftheDECPastheprimarymeansbywhichtoaddressdrug-impaireddrivinginCanada.TheseincludethesubstantialcostandtimecommitmentsrequiredtotrainanofficertobecomeaDrugRecognitionExpert(DRE),thedifficultyinprovidingtherequisitenumberofDREofficersinageographicallydiverseandrelativelyunpopulatedcountrysuchasCanada,andthestrainplacedonpoliceservicesandforensiclaboratoriestomeettheincreasingdemandfortestimonybybothDREofficersandtoxicologists.Assuch,theutilityofadditionaltoolstohelpaddressdrug-impaireddrivinginCanadaneedstobeconsidered.

Whilemanyjurisdictionshaveintroducedperselimitstohelpwithdrug-impaireddrivingenforcement,todatetherehasnotbeenaconsistentapproachusedinthedevelopmentofthistypeoflegislation.Perselimitsspecifytheconcentrationofaparticulardruginthebloodorotherbodilyfluidatorabovewhichitisanoffencetooperateamotorvehicle,irrespectiveofanyobserveddrivingimpairment.Assuch,thecourtneedsonlytodetermineiftheindividual’sdrugconcentrationwasatorabovethespecifiedthresholdtodetermineguilt.InCanada,aperselimitofover80mgofalcoholin100mLofbloodhasbeeninplacesince1969.Thisperselimitissupportedbytheepidemiologicalrelationshipbetweenbloodalcoholconcentration(BAC)andcrashrisk,experimentalclosed-coursedrivingstudies,andlaboratorystudiesofalcohol-inducedimpairmentonspecificdriving-relatedtasksandfunctions.Unlikealcohol,oneofthechallengesformanypotentiallyimpairingdrugsisthatthereisnotcurrentlysubstantiveandconsistentscientificevidenceuponwhichtobaseperselimits.

Theinterestinutilizingaperseapproachisanattempttosimplifytheadjudicationprocess,facilitateenforcement,andenhancedeterrence.Together,thesefactorscanhaveapositiveimpactontrafficsafety.Researchhasdeterminedthatalcoholperselawsareassociatedwitha14%-15%reductioninalcohol-relatedfatalcrashes(Tippettsetal.,2005;Villavecesetal.,2003).Therelativesimplicityofperselaws,theirwidespreadacceptance,andthedemonstratedeffectivenessofalcoholperselaws,havebolsteredthecallthatsimilarlimitsbeestablishedforotherdrugsinCanada.

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In1985,aNationalInstituteonDrugAbuse(NIDA)sponsoredconsensusdevelopmentpanel(ConsensusReport,1985)stated“Inordertoestablishthatuseofadrugresultsinimpairmentofdrivingskillsandtojustifyatestingprogramtorespondtothishazard,certainfactsmustbeavailable.

1) Thedrugcanbedemonstratedinlaboratorystudiestoproduceadose-relatedimpairmentofskillsassociatedeitherwithdrivingorwithrelatedpsychomotorfunctions.

2) Concentrationsofthedrugand/oritsmetabolitesinbodyfluidscanbeaccuratelyandquantitativelymeasuredandrelatedtothedegreeofimpairmentproduced.

3) Suchimpairmentisconfirmedbyactualhighwayexperience.4) Simplebehavioraltests,suchascanbedoneattheroadsidebypoliceofficerswithmodesttraining,

canindicatethepresenceofsuchimpairmenttothesatisfactionofcourts.5) Arangeofconcentrationsofthedrugcanbeincorporatedinlawsrelatingtoimpaireddrivingas

ipsofactoevidence.

Thesecriteriahavebeenmetforethanol.Itisnotcertainthattheycanbemetforotherdrugsthatarenowofconcerntohighwaysafety."

Itremainschallengingtofulfillallfiveaforementionedcriteriaformanydrugsforseveralreasons:relevantlaboratorystudiesarelimitedinpartduetothemedicalandethicalissueswithadministeringillicitdrugsand/orprescriptiondrugstosubjectsattheelevatedlevelsdetectedinimpaireddrivingpopulations;interpretationofcrashandfatalitydataiscomplicatedbytheprevalenceofpoly-druguseinsuchcases.Furthercomplicationswiththesedatainclude:thepotentialfordrugconcentrationstoalterduetovariabletimelinessofsamplecollectionand,forfatalities,postmortemredistribution,choiceofsamplecollectionarea,and/orputrefactivechangesmayresultinaltereddrugconcentrationsbetweenthetimeofdeathandthetimeofsamplecollection.

Therearenumerousotherfactorsthatcomplicatetheconsiderationofperselimitsfordrugs.Manydrugsformoneormoreactivemetaboliteswhichmayremainpresentinthebodyforperiodsoftimebeyondthatoftheparentcompound,therebyextendingthedurationofactionofthedrug.Forexample,diazepammetabolizesintonordiazepam,temazepam,andoxazepam,allofwhichhavesimilarcentralnervoussystemdepressanteffectstodiazepam,andwhicheffectivelyprolongsthedurationofactiondespitethecontinuedmetabolismanddecliningconcentrationofdiazepam.Althoughmostdrugconcentrationsremainunchangedonceabloodsamplehasbeencollected,somedrugsbreakdowninbloodsamplesdespiteattemptstominimizethisdegradationthroughadditionofpreservativesandoptimizedstorageconditions.Forexample,cocainebreaksdownintoaninactivemetaboliteknownasbenzoylecgoninebothinthebodyandinthetesttubeaftersamplecollection,andassuch,itcanimpededeterminationofthecocaineconcentrationpresentatthetimeofsamplecollection.Anadditionalcomplicationtothedevelopmentofperselimitsisthetolerancewhichcandeveloptotheeffectsofcertaindrugs.Insuchsituations,theimpairmentproducedinanindividualatthestartofuseofthatdrugdiminisheswithregularuseovertime.Conversely,ifthatindividualincreasestheirdosage,doesnotmaintainaregulardosage,orrecommencesdruguseafteraperiodofabstinence,their

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tolerancetoparticulareffectsofthedrugmaybelessened.Diseaseorsignificanthealthalterationsmayalsoimpactanindividual’sdrugtolerance.Tofurthercomplicatematters,anindividualwhoistoleranttotheimpairingeffectsofagivendrugmayexperienceacertaindegreeofcross-tolerancetotheimpairingeffectsofrelateddrugs,evenatcommencementoftheiruse.Theextentofanysuchcross-tolerancecannotreliablybepredictedandcanvarywidelybetweenindividuals.Furthercomplicationsintherelationshipbetweendrugconcentrationsandimpairmentincludethatimpairmentofanindividualatagivenbloodconcentrationisdependentuponwhethertheyareintheacuteorwithdrawalphaseofdrugactionand,forthosedrugstowhichtolerancecandevelop,thattolerancemaybealteredbytheadministrationofothercompoundsthatcaninteractwiththedrugorwhichcanalteritsmetabolism.Thislattercomplicationisofconcerngiventhehighincidenceofmulti-druguseinthepopulation,includingtheconcomitantuseofover-the-counterdrugs,prescriptiondrugs,alcoholand/orillicitcompounds.

Despitethecomplicationsinherentindeterminingperselimitsfordrugs,therearecertaindrugsforwhichsuchlimitscanbereasonablyconsidered.Thisdocumentoutlines,alongwiththerelevantissuesforconsideration,specificdrugsthatarebeingproposedfornewlegislationtoassistwithdrug-impaireddrivinginvestigations.

Tetrahydrocannabinol(THC)

THCistheprimarypsychoactivecomponentofcannabisproducts.Cannabisproductsareavailableinmanyformsforadministrationincluding,butnotlimitedto,marijuana,hashish,andconcentrates(‘butter’,‘shatter’,‘oil’)whichcanbesmoked,ingested,andvapourized.Settingaperselimitforthisdrugisacontroversialexerciseformanyreasonswhichwillbeexamined.AslegalizationofcannabisinCanadaisimpending,THCperselimitsareofparticularimportance.THCimpairsanindividual’sabilitytooperateamotorvehicle;however,settingaperselimitdoesnotmeanthatalldriversbelowthatconcentrationarenotimpairedandalldriversabovethatconcentrationareimpaired.Determinationofaperselimitwhichaddressesbothpublicsafetyconcernsandminimizesthepotentialforanindividualtobe“wrongly”convictedofadrugged-drivingrelatedoffencecanbeconsideredanexerciseinselectingtheleastobjectionablealternative.Ultimately,thereareoptionsforfuturelegislation:continuedsupportandenhancementofStandardizedFieldSobrietyTests(SFST)andtheDECP,possibleinclusionofAdvanceRoadsideImpairedDrivingEnforcement(ARIDE),adoptionofaperselimitbasedonconcernsforroadsafety,oradoptionaperselimitbasedonimpairment.

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Epidemiology

RoadsideSurveys–DriversatRisk

Roadsidesurveysprovideauniquesourceofinformationonalcoholanddruguseamongthegeneraldrivingpopulation.Participatingdriversarenotselectedbasedontheirdrivingbehaviour,vehicletypeorcondition,orpersonalcharacteristics.Rather,roadsidesurveysareintendedtoprovidearepresentativesampleofdriversontheroadinanarea,ataparticulartimeofday,dayoftheweek,and,potentially,timeoftheyear.Althoughroadsidesurveyshavebeenconductedformanyyearstocollectinformationonalcoholusebydrivers,recentsurveyshavebeenabletogatherinformationondrugusethroughthecollectionoforalfluidsamplesfromdriversattheroadside.

IntheUnitedStates,aNationalRoadsideSurveyofalcoholanddrugusewasconductedin2013-2014(Berningetal.,2015).Driverswereselectedrandomlyat300locationsacrossthecontiguousUnitedStatesandaskedtoprovidebreath,oralfluidandbloodsamples.DatacollectionoccurredprimarilyonFridayandSaturdaynightsbetween10p.m.and3a.m.Intotal,7,881driversprovidedanoralfluidsample,and4,686agreedtoprovideabloodsample.Basedonoralfluidsamples,19.8%ofnight-timedriverstestedpositiveforpsychoactivedrugs.Basedonbloodsamples,21.2%ofnight-timedriverstestedpositiveforatleastonedrug.Overall,22.5%ofnight-timedriverswerepositivefordrugsinoralfluidand/orblood.Cannabiswasthemostcommonlydetectedsubstance,accountingforoverhalfofalldrug-positivecases(11.3%ofdriverswhoprovidedanoralfluidsample);a48%increasewasdocumentedforTHCpositiveweekendnighttimedriverswhencomparedtopreviousdatacollectionin2007.

InastudyconductedinBritishColumbia,Canada,breathandoralfluidsampleswerecollectedfromatotalof4,711randomlyselecteddriversonWednesdaythroughSaturdaynightsinJuneof2008,2010and2012(Beasleyetal.,2013).Ofthesedrivers,8.1%werepositivefordrugsonly,6.8%werepositiveforalcoholonly,and1.7%werepositiveforbothdrugsandalcohol.Cannabis,themostcommondrugfinding,wasdetectedin5.5%ofdrivers.AsimilarsurveyconductedinOntarioin2014found10.2%ofdriverstobepositivefordrugswhereasonly4.0%testedpositiveforalcohol.Cannabiswasdetectedin8.0%ofdrivers,representing69.1%ofalldrug-positivedrivers(Beirnessetal.,2015).

DrugUsebyDriversinvolvedinRoadCrashes

Numerousstudiesfromaroundtheworldhaveexaminedtheincidenceofdrugsandalcoholamongdriversinjuredorkilledincrashes.Inreviewingthesestudies,itisimportanttorecognizethattheyuseavarietyofmethods,populations,samplesizes,andcaseselectionmethods,whichcanaffecttheresultsofthestudy.Forexample,lowtestingratesamonginjuredanddeceaseddriversinmotorvehiclecollisionscontinuestoconfoundthesearchforavalidestimateoftheprevalenceofdruguseamongcrash-involveddrivers.Injurisdictionswheresuchtestingisnotrequired,driverswhoareinjuredincrashesarerarelytestedwithoutatleastsuspicionofdrugoralcoholuse.Thisrestrictstheabilityto

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reliablydeterminetheoverallprevalenceofdrugusebydriversinvolvedincrashes.InCanada,Stodutoetal.(1993)collecteddrugandalcoholdatafrom339driverstreatedatatraumacentreforinjuriessustainedinamotorvehiclecrash.Overall,35.5%ofthesedriverstestedpositiveforalcoholand41.3%testedpositiveforatleastonedrugotherthanalcohol.Cannabinoidswerethemostcommondrugfinding(14%)intheseinjureddrivers.In2012,33%offatallyinjureddriversinCanada(excludingBC)testedpositiveforalcoholand40%werepositivefordrugs(Brownetal.,2015).Cannabiswasthemostfrequentlydetecteddrugaccountingfor18.2%ofallcasesand45.5%ofdrug-positivecases(Brownetal.,2015).Foraone-yearperiodbetweenFebruary1,2011andJanuary31,2012,standardizedcomprehensivetestingwasperformedforallfatalmotorvehiclecollisionsdrivers,whodiedwithinhoursofthecollision,intheprovinceofOntario(Woodalletal.,2015).Ofthe252casesthatqualifiedforthestudy,12.2%werepositiveforalcoholonly,28.4%werepositivefordrugsonlyand15.3%werepositiveforboth;themostcommondrugfindingwascannabiswhichrepresented27%ofthedrugpositivecases.

RisksAssociatedwithDrugUsebyDrivers

Epidemiologicalstudiesattempttoquantifytheextenttowhichdrugsaredisproportionatelyrepresentedinroadcrashes.Casesaredefinedasdriversinvolved,injured,orkilledinroadcrashes.Thefrequencyofalcoholorotherdrugsdetectedinthecasesiscomparedtothefrequencyofdrugsand/oralcoholdetectedinacomparablecontrolgroupofdriverswhohaveeithernotbeeninvolvedincrashesorweredeemednotresponsibleforacrash.Theextenttowhichalcoholand/ordrugsaremorefrequentlydetectedincrashpopulationsthanincontrolpopulationsisanindicationofthedegreetowhichtheuseofpsychoactivesubstancespresentsanelevatedriskfordrivers.Thismethodhasbeeninstrumentalinunderstandingtherisksassociatedwithalcoholusebydrivers.Inaddition,bycomparingtheconcentrationofalcoholamongcasesandcontrols,itispossibletodeterminetherelativelikelihoodofcrashinvolvementatdifferentBACs(Blombergetal.,2009;Borkensteinetal.,1974).Comparableinformationwouldbebeneficialtoadiscussionofdrugperselimits.

Theapplicationofsuchcase-controlmethodstothestudyofcrashrisksfordriversusingdrugsissomewhatmorecomplexthanforalcohol.Incomparisontoalcohol,thetestingfordrugs,bothamongthecasesandthecontrols,ismoredifficult.Analysisfordrugsoccursinalaboratorysettingratherthanatroadsideoratapolicestation.Ideally,bloodfordruganalysisshouldbeobtainedfrombothcasesandcontrols,butobtainingtheneededcompliancefromcontrolscanbedifficultand,consequently,testingratesareoftenlowandattributingmeaningtothedataisproblematic.Amongcases,similarproblemsareexperiencedunlesstheindividualhasbeentakentohospitalwhereabloodsamplehasbeentakenorinfatalitiesinwhichpostmortembloodisavailable.Thenetresultisthattheestimatesofriskareoftenofquestionablevalidityandreliability.

Thesamplemediumusedtotestfordrugsisalsoanimportantconsideration.Foralcohol,BACscanbeeasilyandreliablydeterminedfrombreathsampleswhichcanbereadilyandunobtrusivelyobtained

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fromcontrolpopulations.Thisisnotthecasewithothertypesofpsychoactivesubstances,whichtypicallyrequirethattoxicologicaltestingbeconductedonotherbodilyfluids.Bloodsamplesareconsideredtobethemostrelevantandreliablesamplemediumfordeterminingtheconcentrationofactivedruginthedriver’sblood.However,duetotheinherentdifficultiesinobtainingbloodsamplesfromdriversatroadside,otherfluidsareoftenusedinstead.Althoughoverallestimatesofriskassociatedwithdrugusecanbecalculatedfromthesedata,quantifyingtheriskassociatedwithvariousdrugconcentrationsinsamplesotherthanbloodisnotrecommended.

Shouldasubstancebefoundtobeoverrepresentedincrashes,itisoftenassumedthatthemerepresenceofthesubstancewassufficienttohavecontributedtothecrash.Infact,thecase-controlapproachsimplyprovidesevidenceofanassociationbetweendrugsandcrashesanddoesnotdirectlyprovideevidencethatthesubstanceinducedadegreeofimpairmentsufficienttohavecontributedtothecrash.Otherfactorsassociatedwithdruguse,e.g.,characteristicsoftheperson,theirdrivingstyle,theircomfortlevelwithrisk,couldalsoexplaintheobservedassociation.Thisalsoappliestocase-controlstudiesconcerningtheroleofalcoholincrashes;however,foralcoholtherepeateddemonstrationofadose-dependentincreaseincrashriskcombinedwithacorrespondingdose-responserelationshipinexperimentalstudiesofimpairmentprovidesconvincingevidenceofthecontributoryroleofalcoholincrashes.Todate,manyepidemiologicalstudiesoftheroleofdrugsincrasheshavesimplydeterminedthepresenceorabsenceofparticulardrugsascomparedwiththosefewstudiesthathaveattemptedtodeterminetheextentofincreasedriskaccordingtotheconcentrationofTHCdetected(Drummeretal.,2004;Laumonetal.,2005).Inarecentreviewandmeta-analysisofstudiesassessingtherelativecollisionriskassociatedwiththeuseofcannabis,Asbridgeetal.(2012)identifiedninestudiesofsufficientqualitytobeincluded.Insevenofthesestudies,anincreasedriskofmotorvehiclecollisionwasfoundwhendrivershadconsumedcannabiswithinafewhourspriortothecollision.Thepooledresultsindicatedthatdriverspositiveforcannabisusewerealmosttwiceaslikely(OddsRatio=1.92,95%confidenceinterval=1.35-2.73)asdrugnegativedriverstobeinvolvedinacollision.Thisriskwasincreasedinstudiesoffatalcollisions.StudiesofcrashriskassociatedwithdrugusewerealsoconductedinseveralcountriesinEuropeaspartoftheDRUID(DrivingUndertheInfluenceofDrugs,AlcoholandMedicines)project(Gadegbekuetal.,2011;Thorsteinsdóttiretal.,2011;Helsetal.,2011).Thesestudiesvariedconsiderablyintermsoftheapproachandmethodsemployed.Driversweresampledfromdifferentpopulations,drugandalcoholanalysesdifferedasdidthesamplesanalyzed,andcomplianceratesandsamplesizesvaried.Consequently,theriskestimateshadlargeconfidenceintervalsandonlytwoofthethreeestimateswerestatisticallysignificant.

Amongthestudiesthathaveexaminedtheroleofcannabisincrashes,thereareseveralstudies(Drummeretal.,2004;Laumonetal.,2005;Longoetal.,2000;Muraetal.,2003)thataremethodologicallystrongerthantheothersbecausetheyallusedbloodsamplestospecificallytestforthepresenceoftheactiveingredientincannabis(THC)ratherthanitsinactivemetabolite(carboxy-THC).ThisisimportantbecauseindividualsfoundtohaveapositiveTHCbloodconcentrationaremost

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likelytobeundertheinfluenceofcannabis.Threeofthesestudiesreportedasignificantincreaseinriskassociatedwithcannabisuse;theLongostudy,whichspecificallyexaminedcrashculpability,determinednostatisticaldifferenceinculpabilityratesforTHC-positiveanddrug-freedrivers.Nevertheless,Longoetal.,didnotethatmostTHC-positivedriversintheirstudywereatextremelylowTHCconcentrations,anddidnotexcludethepossibilityofadverseeffectsatTHCconcentrationsgreaterthan2ng/mLinblood.Muraetal.(2003)employedacase-controlapproach,comparingasampleofinjureddriverswithasampleofotherpatientsalsoattendinghospitalinFranceandfounddriverswithTHCbloodconcentrationsgreaterthan1ng/mLwere2.5timesmorelikelytohavebeeninjuredinacrashthancontrols.Thesignificantincreaseinriskassociatedwithcannabisuse,however,wasrestrictedtothoseunder27yearsofage.Overtheageof27,therewererelativelyfewdriversandcontrolspositiveforTHCinthisstudy.Amongtheavailablestudies,thoseusingbothlargesamplesizesandrigorousmethodologyprovidethestrongestevidenceofincreasedcrashriskassociatedwithTHC.Thesestudiesareamongthoseincludedinthemeta-analysisbyAsbridgeetal.(2012)referredtopreviously.UsingresponsibilityanalysiswithsamplesoffatallyinjureddriversinAustralia,Drummeretal.(2004)reporteddriverswithTHClevelsgreaterthan5ng/mLwere6.6timesmorelikelytoberesponsibleforthecrashthandriverswhohadnotuseddrugsoralcohol.Laumonetal.(2005)reportedthattheriskofdriversbeingresponsibleforafatalmotorvehiclecollisionincreasedwithincreasingbloodTHCconcentrations;THCpositivedriverswithbloodconcentrationslessthan1ng/mLwere2.18timesmorelikelythandrug-freedriverstoberesponsibleforfatalmotorvehiclecollisions,withthatlikelihoodincreasingto4.72timesfordriverswithTHCbloodconcentrationsinexcessof5ng/mL.Inananalysisofdatafrom32,543driversbetweentheagesof20and49involvedinfatalcrashesintheUnitedStateswhoweretestedforcannabis,Bédardetal.(2007)founddriverspositiveforcannabisweresignificantlymorelikelythancontrolstohaveatleastonepotentiallyunsafedrivingactionrecordedinrelationtothecrash,suchasspeeding.

AmongthelimitednumberofrecentepidemiologicalstudiesthathavemeasuredTHCinbloodsamples,thereremainsadegreeofinconsistencyintheevidence.However,theweightoftheevidenceshowsthatcannabisuseisassociatedwithincreasedriskofcrashinvolvement.Inaddition,studiesthatdemonstrateadose-relatedincreaseinriskprovidestrongevidenceimplicatingcannabisasacausalfactorincrashes(Drummeretal.,2004;Laumonetal.,2005).

Theapparentinconsistencyoftheavailableepidemiologicalresultsmaybeattributable,inpart,tothevariabilityofthestudiesintermsoftheapproach(case-control,responsibilityanalysis),severityofcrash(injury,fatality),fluidtested(urine,oralfluid,blood),componentofcannabistested(THC,carboxy-THC),andsamplesize.Althoughthetotalnumberofdriversincludedinanystudymayappearlarge,theactualnumberwhotestpositiveforTHCistypicallysmall.Therelativelylowincidenceofcannabisdetectionamongdriversrenderstheresultssensitivetoevensmallvariationsinsamplingandcaseselection.Largescalestudiesusingrigorousandconsistentmethodsarenecessarytoprovideclearandunambiguousevidenceoftheincreasedriskofcrashesassociatedwithcannabisusebydrivers.

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Theconcomitantuseofalcoholandcannabishasalsobeenstudiedinthecontextofrelativerisk.Theavailableevidenceindicatesthattheuseofcannabisincombinationwithalcoholisassociatedwithhigherriskofcrashinvolvement.Amongthesmallnumberofstudiesthatspecificallyinvestigatedriverspositiveforbothcannabisandalcohol,significantlyincreasedrisksarereportedrelativetodriverswhoaredrug-free(Laumonetal.,2005;Longoetal.,2000),orrelativetothosewhoarepositiveforalcoholalone(Drummeretal.,2004).

PharmacologicalConsiderations

Pharmacology,thestudyofdrugs,canbedividedintopharmacokineticsandpharmacodynamics.Pharmacokineticssimplydefinediswhathappenstothedruginthebody(absorption,distributionandelimination);pharmacodynamicssimplydefinedishowthedrugaffectsthebody(impairmentandintoxication).ThechallengeindeterminingaperseconcentrationforTHCarisesfromtheuniquepharmacokineticsofthiscompound,aswellasthevariabilityinpharmacodynamics.THCcausesimpairmentinvariousfacultiesrequiredfortheoperationofamotorvehicleincludingdividedandconcentratedattention,vigilance,tracking,andexecutivefunctioning.Impairmentisadecreasedabilitytoperformatask,whereasintoxicationistheobservablesignsassociatedwithdruguse.TheeffectsofTHCarerelatedtotherouteofadministration,amountadministered,patternofadministration,thetimeelapsedsincelastuse,andinter-individualvariability.

Cannabisiscommonlyadministeredbysmoking.Duringcannabissmoking,THCisrapidlyabsorbedthroughthelungsanddistributedinthebody,resultinginpeakTHCconcentrationsduringactivesmoking.Uponcessationofsmoking,THCconcentrationseitherhavealreadystartedtodeclineorbegintodeclineshortlythereafter,withtherapidremovalofTHCfromthebloodviaredistributionintofattytissuesofthebody.ThisintenseTHCpeakandrapiddeclinewasdemonstratedin6individualssmokingamarijuanacigarette,witheither1.75%or3.55%THC,inwhommaximumplasmaconcentrationswerereachedaroundtheendofsmokingatameanof8.4minfromthestartofsmoking(Huestisetal.,1992).AdramaticdecreaseinTHCconcentrationwasobservedinthefirsthourpost-smokingandby4hoursthebloodTHCconcentrationsrangedfromnotdetectedto1.7ng/mLii(Huestisetal.,1992).NotethecigarettesinthisstudycontainedrelativelylowpercentagesofTHCascomparedtothecurrentproductsthatareavailable.AnimportantconceptwithrespecttotheeffectsofTHConthebrainand,therefore,cognitivefunctioningisthatTHCdemonstratescounter-clockwisehysteresis,whichmeansthatthesubjectiveeffectsofthedrugdonotcorrelatewiththeblooddrugconcentration(astheydowithalcohol).TherapidredistributionfromthebloodintofattytissuesresultsinlowTHCbloodconcentrationsdespitepersistingeffectsonthebrain.Therefore,individualsmaybeimpairedatwhatappearstobelowbloodconcentrations.Thepeakimpairingeffectsgenerallyoccurwithinthefirsthouraftersmokingacannabisproduct,andmaylastupto6hoursafteruse.

Inconjunctionwiththelegalizationofcannabisinmanystates,theavailabilityofdifferentproductscontainingcannabishasledtoincreasedoraladministration.Commercially-availableproducts

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containingTHCareavailableforingestion;alternately,cannabiscanbeaddedtobakedgoodsorotherfoodstuffsforconsumption.Ascomparedtosmokingcannabis,ingestionresultsinslowerabsorptionofTHCthroughthegastro-intestinaltractandintothebloodstream.TheimpactwillbeapotentiallylowerTHCconcentration,agreatercontributionofaTHCmetabolite,hydroxy-THC,tothepsychoactiveeffects,asloweronsetofeffects,andanincreaseinthedurationofactionwhencomparedtosmokingcannabis.TheeffectsoforalTHCgenerallyoccurwithinthefirsthourafterconsumptionbutmaytakelongertopeakeffectsandmaypersistfor6hoursormoreafteringestion.

TheTHCcontentofcannabisproductshasincreaseddramaticallyovertheyears.Cannabisproductsthathavebeensubjecttoextractiontechniquessuchas‘wax’,‘butter’,‘shatter’,‘concentrates’orwhateverterminologyisemployedmaybeofsuchahighpotencythat70%orgreaterispossible.Currently,researchpapersdealwithTHCconcentrationsmuchlowerthanthoseavailableforrecreationaluse.ThereisapaucityofliteratureontheimpactofthishighTHCcontentonindividuals;althoughlogicallytheeffectswouldbedosedependentandtheimpactwouldbetointensifytheestablishedeffectsofTHC,butalsotopossiblygiverisetonewsymptomologythathasnotgenerallybeenassociatedwithlowpotencycannabisuse.

ProposedLegalLimits

LegallimitsforTHCareusedinotherjurisdictions.Theconcentrationsfortheselimitsrangefromdetection(essentiallythelimitofdetectionofthemethodused)upto5ng/mLinabloodsample(Jones,2005;Vindenesetal.,2012;WolffandJohnston,2014;Wongetal.,2014).Table1illustratespossibleTHCperselimitsthathavebeendiscussedandconsideredbythiscommitteeforusewithinCanada.Thereareadvantagesanddisadvantagestoeachoftheconcentrationsbeingconsidered,namelyTHCconcentrationsof2and5ng/mLinblood.Basedonthesmokingrouteofadministration,therapiddeclineinTHCbloodconcentrationsandtheinevitabletimedelaytosamplecollection,manyindividualswouldbeexpectedtohavebloodTHCconcentrationsabove5ng/mLatthetimeoftheincidentbutforthoseconcentrationstobemuchlowerbythetimetheirbloodisdrawn.LoweringtheTHCperselimitwouldresultinmoreindividualsbeinginviolationofthistrafficsafetymeasure;forexample,aperselimitof2ng/mLwouldresultinalargernumberofcharges.However,thisisproblematicasheavyusersofcannabismayhaveresidualbloodTHClevelsbeyondatimeframetypicallyassociatedwiththedurationofactionfortheacutepsychoactiveeffectsandresultantdrivingimpairment.Theinevitableissueofthetimedelayinsamplecollection,passiveexposure,andtheimplicationsofchronicusewillbediscussed.Furthermore,sampletypeandinclusionofacombinedTHCandalcoholoffencewillbeaddressed.

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Table1.PotentialCanadianperselimitsforTHC(ng/mL)andthecombinedoffenceofalcohol(mg/100mL)andTHC.

SampleType THC-onlyConcentration THCConcentrationinCombinationwithAlcohol

AlcoholConcentrationinCombinationwithTHC

Blooda 5 <5 50

Bloodb 2 <2 50

Plasmaa 10 <10 60c

Plasmab 4 <4 60c

aCorrespondingbloodandplasmaTHCconcentrations;thatisifabloodTHClimitof5ng/mLisselectedthecorrespondingplasmalevelwouldbe10ng/mLbCorrespondingbloodandplasmaTHCconcentrations;thatisifabloodTHClimitof2ng/mLisselectedthecorrespondingplasmalevelwouldbe4ng/mLcWouldnotrequireaconversiontobloodsincethesampletypewouldbeplasma;therefore,itwouldbeplasmaalcoholconcentration.NoteserumandplasmawouldbeconsideredthesamematrixforthepurposesofTHCandalcoholconcentrations.TimeDelayinSampleCollectionInimpaireddrivinginvestigations,thetimeelapsedfromtheroadsideeventandsubsequentarresttocollectionofabloodsampleislikelytobeintherangeofhours.Collectionofabloodsamplethuseffectivelyconstitutesaraceagainstthepotentialforlostevidenceduetodrugmetabolismandre-distributionfollowingrecentuse.Thehighertheperselimit,thelesslikelyanindividualwouldmeetthatlimitastimepasses.WithimplementationofaTHCperselimitof5ng/mL,manyindividualsinitiallyabovethatlimitwouldfallbelowthatconcentrationafteranhourormoreofproceduralrequirementsinvolvedintheirarrest.Inastudyofadlibitumcannabissmoking,lessthan61%ofthesubjectshadabloodTHCconcentrationiiatorabove5ng/mLbeyond2hourspost-smoking.Thispercentagedecreasedto30%at4.1to8hourspost-smoking(Leeetal.,2015).Therefore,alowerlegallimit,i.e.,2ng/mLwouldreflectthedecreaseinbloodconcentrationstolevelslikelytobepresentatthetimeofsamplecollection.Itisimportanttonotethatbackextrapolationsofbloodconcentrations,routinelyperformedwithalcohol,arenotpossiblewithTHC.Thereistoomuchvariabilityintheabsorption,distributionandeliminationkineticsofTHCwithinthepopulation.Thismeanstheconcentrationdetectedatthetimeoftheanalysisisthetotalityoftheinformationthatwillbeavailable

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fromananalyticalperspective.ThehighertheTHCconcentration,themorelikelytherewasrecentadministration,andtimeofuseisanimportantfactorwhenconsideringimpairmentduetoTHC.However,duetotherelationshipofthepharmacokineticsandpharmacodynamicsofTHCanindividualcouldbeimpairedbelowboth2and5ng/mL.Therefore,intheinterestofpublicsafety,alegallimitof2ng/mLTHCinbloodwouldbethemoreprudentmeasure.However,iftheapproachistofocusontheincreasedlikelihoodofimpairmentduetocannabisuse,then5ng/mLTHCinbloodwouldbeamoreappropriateperselimit. DriverswhocometotheattentionofthepoliceasaresultoftheirdrivingbehaviourprovideanexampleofthepotentialchallengesassociatedwithproposedTHCperselimits.Inastudyof602driversarrestedforimpaireddrivingandwhohadpositiveTHCbloodconcentrationsintheabsenceofanyotherdrugsoralcoholfindings,THCconcentrationsrangedfrom1to47ng/mLwithamedianof5ng/mL(Loganetal.,2016).Thetimedelaybetweenarrestandblooddrawn,wherethisinformationwasavailable,wasamean,median,andmaximumof74minutes,61minutes,and3hoursand45minutes,respectively.Furthermore,theDREevaluationsperformedonthesedriverswereunabletodistinguishbetweentheclinicalobservationsandpsychomotorindicatorsofimpairmentfordriverswhoseTHCbloodconcentrationswouldlaterbedeterminedtobeeitheraboveorbelow5ng/mL.IntheyearfollowingtheimplementationofaTHClegallimitandgradedsanctionsinNorwayof1.3,3,and9ng/mL,thepercentageofdriversapprehendedonsuspicionofdruggeddrivingcaseswithTHCbloodconcentrationsabovetheselimitswere31.5%,19.0%,and5.4%,respectively(Vindenesetal.,2014).

ChronicUse

THCisalipophiliccompoundwhichmeansthatbloodconcentrationsrapidlydeclineasTHCpreferentiallydistributestolipid-richtissues.ThissameproclivityresultsinaslowreleaseofTHCfromthesetissuesandresultantlowlevelsofTHCdetectablewithinthebloodofchronicusersforprolongedperiodsoftime;thiswouldbefurtherexacerbatedbytheintensityoftheexposure.IndividualswhousecannabisproductsdailyormultipletimesthroughoutthedaymayhaveTHCbloodconcentrationsabovetheperselimitdespitehavinghadaperiodofcessationforhoursorpossiblydays.Inastudyof11occasionaland12heavycannabisusers,noneoftheoccasionaluserstestedpositiveatthebeginningofthestudypriortosmoking,andat8hoursaftersmokingacannabisproduct,allhadTHCconcentrationslessthan1ng/mLinbloodii.Incontrast,oneindividualwhowasachronicuserhadaTHCconcentrationgreaterthan5ng/mLinbloodiibothatthebeginningofthestudypriortosmoking,and8hoursaftersmokingaplacebocigarette(Toennesetal.,2008).Inthissamestudy,3ofthechronicusershadTHCbloodconcentrationsiiof2ng/mLorgreater8hoursaftersmokingacannabisproductdueto,atleastinpart,theresidualTHCpresentpriortosmoking.Inastudyofdailycannabisusers,bloodTHCconcentrationsapproximately6dayssincelastuserangedfromnotdetectableto4.2ng/mL;additionally,7of11subjectshadconcentrationsof2ng/mLorgreateratthistime(Odelletal.,2015).Inthissamestudy,9of21subjectshadTHCconcentrationsabove5ng/mLontheseconddaywhichwasatleast24hourssincereportedlastuse.Thus,theseindividualswouldhavebloodTHCconcentrations

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abovepotentialperselimitswellbeyondtheperiodduringwhichtheywouldbeexpectedtoexperiencetheacuteintoxicationandimpairingeffectsofcannabisadministration.However,thepotentialfordevelopmentofcognitivedeficitsduetochroniccannabisusebecomesarelevantdiscussionpointinthisdrivingpopulation.

Thereisevidencetosuggestthatrepeatedadministrationofcannabismayresultinimpairmentpasttheexpecteddurationofaction.ThismaybeduetoresidualTHCinthebrainhavingacontinuedimpact,withdrawaleffectsduetoabruptdiscontinuationofuse,oralterationsinbrainfunctioningassociatedwithyearsofcumulativecannabisexposure.Themechanismisdifficulttodetermineconsideringtheconfoundingissuesthatareinherentinretrospectivestudiesandtheethicalissuesthatareinherentinprospectivestudies.Regardless,thesedeficitsarepossiblyrelatedtodurationofuse,theagethattheindividualstartedcannabisuse,and/orfrequencyofuse(Bollaetal.,2002;Popeetal.,2003).Deficitsinmemory,learning,attention,andmanualdexterityhavebeenpostulatedtobeattributabletoregularcannabisuse(Bollaetal.,2002;PopeandYurgelun-Todd,1996).Whereasacuteeffectshavebeenpreviouslydefinedas0-6hoursaftersmokingcannabis,residualeffectsareconsideredtobethoseoccurring7hoursto20daysafterlastuse,andlongtermeffectsas3weeksorlongerafterlastuse(Creanetal.,2011).Chronic,heavyusebyindividualscanresultinenduringdeficitsforboththeresidualandlong-termcategories(Creanetal.,2011).Daystoweeksofdecreasedperformancearepossiblewithchronicheavycannabisusers(Bollaetal.,2002;Boskeretal.,2013;Popeetal.,2001).BaselineTHClevelsinchronicuserswithinaplacebogroupweredeterminedtobeashighasapproximately5.4ng/mLinbloodequivalentsii(Ramaekersetal.,2016).TheseusersstillperceivedasubjectivehighdespitenotbeinggivenactiveTHCinthestudy.Duringthecannabisadministrationpartofthisstudy,thesubjects,allcannabisusersbutofvaryingfrequency,demonstrateddecreasedabilitiesinexecutivefunctioning,impulsecontrol,attention,andpsychomotorfunctioning.Furthermore,itwasconsideredpossiblethatimpairmentofneurocognitivefunctioningofchronicuserscouldpersistbeyondtheinitialphaseofintoxication(Ramaekersetal.,2016).Thiscognitivedeclineislesslikelyasthefrequencyofcannabisusedeclinesandimprovementsarepossibleafteraperiodofabstinencefromcannabisproductssuggestingthesedeficitsarereversible(Popeetal.,2002).Theoriesthatthesedeficitscouldbepermanentarelikelyattributedtothoseindividualswhobeganchroniccannabisuseatearlyagesandmayhaveexperienceddeleteriouseffectsofcannabisonthedevelopingbrain.

ChronicusersalsoachievehigherTHCconcentrationsfromsmokingthesameTHCcontentinacigaretteascomparedtooccasionalusers,likelyduetothemoreefficientsmokingtechniquethattheyhaveacquiredwithexperience.Forexample,inastudyof12heavy(usemorethan4timesperweek)and12occasional(lessthan2timesperweek)users,themeanpeakTHCconcentrationaftersmokingwasapproximately2.5timeshigherinheavyuserscomparedtotheoccasionalusers(Theunissenetal.,2012).EvenaccountingfortheresidualTHCconcentrationspresentpriortosmokingthatwouldcontributetothefinalresultingTHClevel,chronicusersareabletocapturemoreoftheactiveingredientthroughtheinhalationprocess.

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PassiveInhalation/Exposure

AnotherissuewhichneedstobeconsiderediswhetherpassiveinhalationofcannabissmokecouldresultinTHCconcentrationsinthebloodthatwouldbeovertheperselimit.Someearlywork(Mørlandetal.,1985)suggestedthatTHCbloodconcentrationsachievedthroughpassiveinhalationcouldreachupto6.3ng/mLatthecessationofsmokingandthendroppedtocloseto0.5ng/mLby2hoursfromthestartofsmoking.Inmorerecentresearch,THCbloodequivalentiilevelsineightvolunteerspassivelyexposedtocannabissmokefor3hoursinabusyDutch“coffeeshop”werealllessthan0.5ng/mL(Röhrichetal.,2010).PeakTHCbloodconcentrationsrangedfrom1.2to5.6ng/mLin6individualspassivelyinhalingTHC(11.3%)smokefor1hourfrom6smokers(adlibitum);allindividualshadbloodconcentrationslessthan2ng/mLby1houraftertheendofexposure(Coneetal.,2015).Asubjectivedrugeffectwasreportedforthesenon-smokingsubjectsthatmimickedactiveTHCsmoking,althoughtoalessereffect(Coneetal.,2015).Thepassiveexposurestudiestendtobeextremeconditionswheresubjectsaresurroundedbymanyindividualssmokingcannabisinasmallspacewithalackofventilation;smokeisinhaledthroughproximityandlackoffreshair,andthesubjectsaresometimesofferedgogglesduetotheintensityofthesmokeandthepotentialforeyeirritationtobeexperienced.Thesearenotconditionstypicallyassociatedwithpassiveexposureandwereconsideredextremeornoxioussmokeconditionsthatareunlikelytobecasualencountersorunnoticed.TheriskofachievingaTHCconcentrationaboveaselectedperselimitfrompassiveinhalationislowconsideringtheconditionsrequiredtoachievesuchbloodconcentrationsandthetimedelaytosamplecollection.Furthermore,iftheexposureconditionsaresoextremethataresultantTHCconcentrationoccurs,theadministrationisarguablynolongerpassive,butratheractive.

SampleType

ThedistributionofTHCintotheredbloodcellsislimited,andtherefore,bloodandplasmaTHCconcentrationswillbedifferent.ForthepurposesofTHCconcentrations,plasmaandserumareconsideredtobeanequivalentmatrixandthetermplasmaisusedforsimplicity.BloodlevelsofTHCaretypicallylowerthanplasmalevelsandtherearerangesassociatedwiththeratiosofthesesampletypes.Inastudyof25subjectssmokingadlibituma6.8%THCcontainingcigaretteforupto10minutes,bloodandplasmasampleswerecomparedandblood-to-plasmaratiosrangingfrom0.31to1.1weredetermined,withamedianof0.68(Desrosiersetal.,2014);inanotherstudyoforalTHCadministrationinchronicusersoveran8dayperiod,blood-to-plasmaratiosrangedfrom0.3to1.7,withamedianof0.63whenallparticipants(n=196)andtimepointswerecombined(Karschneretal.,2012).TheNetherlandsAdvisoryCommitteerecommendedtheuseofseparateperselimitsinbloodandserumforTHC(Wongetal.,2014).Thisapproachwouldmakethemostsenseratherthantryingtodetermineanappropriateconversionfactorforserumorplasmasamplescommonlyobtainedfromahospitalbywarrant.Table1outlinestherecommendedplasmaconcentrationswhichcorrespondtoselectedpersebloodconcentrations.Forsimplicityandasaconservativeconversion,ablood-to-plasmaconversionof0.5wasusedtodetermineaplasmaequivalencyfromthebloodperselevel.

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THCandAlcohol

Inastudyofmaledrivers,thecombineddetectionofcannabisandalcoholindriverswasmorecommonthancannabisasthesoleintoxicant,andsimilarinoccurrencetoalcoholalone(Williamsetal.,1985).Thisobservationisacurrentconcernaspoly-druguseiscommonamongstdrug-impaireddrivers.ThecombineduseofTHCandalcoholisexpectedtoproduceatleastadditiveimpairmentofthefacultiesrequiredfortheoperationofamotorvehicle.ConsiderationofacombinedoffenceofalcoholandTHCperselimitswoulddependontheperselimitselectedforTHC.Table1outlinestheproposedlimitsforthecombinedpresenceofTHCandalcohol.AsthetechnologyexiststoquicklydetermineaBAC(orwithinarangeofBACs)attheroadside,andwiththepossibleimplementationoforalfluidscreeningtechnology,aBACwithinaspecifiedrangeandevidenceofrecentcannabisadministrationthroughapositiveoralfluidscreen,and/orotherobservationssuchassmellofburntcannabis,paraphernaliaorotherevidenceofcannabisuse,couldbeusedtodemandabloodsampleforthepurposesofthedualleveloffence.Furthermore,ifabloodsamplewasobtainedforTHCandtheconcentrationwasbelowtheperselimitforthesingledrugoffence,furtherexaminationattheforensiclaboratorycouldbeperformedforalcoholandthepossibilityoftheduallimitoffenceinvestigated.ThecombinationofTHCandalcoholcouldalsobeusedasanaggravatingfactorifadualoffenceisnotimplemented.

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Stoduto,G.,E.Vingilis,B.M.Kapur,W-J.Sheu,B.A.McLellan,andC.B.Liban.1993.AlcoholandDrugUseAmongMotorVehicleCollisionVictimsAdmittedtoaRegionalTraumaUnit:Demographic,InjuryandCrashCharacteristics.Accident,AnalysisandPrevention.25:411-420.

Theunissen,E.L.,G.F.Kauert,S.W.Toennes,M.R.Moeller,A.Sambeth,M.M.Blanchard,andJ.G.Ramaekers.2012.NeurophysiologicalFunctioningofOccasionalandHeavyCannabisUsersDuringTHCIntoxication.Psychopharmacology220:341-350.

Thorsteinsdóttir,K.,J.Mühlhäußer,L.Paul,S.Lottner,S.Schick,andW.Hell.2011.ResponsibilityStudy:PsychoactiveSubstancesAmongKilledDriversinGermany,Lithuania,HungaryandSlovakia.DrivingUndertheInfluenceofDrugs,AlcoholandMedicines,(DRUID)Deliverable2.3.4.Munich,Germany:LudwigMaximiliansUniversity.

Tippetts,A.S.,R.B.Voas,J.C.Fell,andJ.L.Nichols.2005.AMeta-analysisof.08BACLawsin19JurisdictionsintheUnitedStates.AccidentAnalysisandPrevention.37:149-161.

Toennes,S.W.,J.G.Ramaekers,E.L.Theunissen,M.R.Moeller,andG.F.Kauert.2008.ComparisonofCannabinoidPharmacokineticPropertiesinOccasionalandHeavyUsersSmokingaMarijuanaorPlaceboJoint.JournalofAnalyticalToxicology32:470-477.

Villaveces,A.,P.Cummings,T.D.Koepsell,F.P.Rivara,T.L.Lumley,andJ.Moffat.2003.AssociationofAlcohol-RelatedLawswithDeathsDuetoMotorVehicleandMotorcycleCrashesintheUnitedStates,1980-1997.AmericanJournalofEpidemiology.157:131-140.

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Vindenes,V.,D.Jordbru,A-B.Knapskog,E.Kvan,G.Mathisrud,L.Slørdal,andJ.Mørland.2012.ImpairmentBasedLegislativeLimitsforDrivingUndertheInfluenceofNon-AlcoholDrugsinNorway.ForensicScienceInternational.219:1-11.

Vindenes,V.,F.Boix,P.Koksæter,M.C.Strand,L.Bachs,J.Mørland,andH.Gjerde.2014.DruggedDrivingArrestsinNorwayBeforeandAftertheImplementationofPerSeLaw.ForensicScienceInternational.245:171-177.

Williams,A.F.,M.A.Peat,D.J.Crouch,J.K.Wells,andB.S.Finkle.1985.DrugsinFatallyInjuredYoungMaleDrivers.PublicHealthReports100:19-25.

Wolff,K.andA.Johnston.2014.CannabisUse:APerspectiveinRelationtotheProposedUKDrug-DrivingLegislation.DrugTestingandAnalysis.6:143-154.

Wong,K.,J.E.Brady,andG.Li.2014.EstablishingLegalLimitsforDrivingUndertheInfluenceofMarijuana.InjuryEpidemiology.1(26):1-8.

Woodall,K.L.,B.L.C.,Chow,A.Lauwers,andD.Cass.2015.ToxicologicalFindingsinFatalMotorVehicleCollisionsinOntario,Canada:One-YearStudy.JournalofForensicSciences.60(3):669-674.

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Cocaine

Cocaineisapotentcentralnervoussystem(CNS)stimulantdrugcommonlyusedforitseuphoriceffects.Typical routes of administration for cocaine and related compounds (e.g., crack) include insufflation(snorting),smoking,andinjection.Theonsetofeffectsisdependentontherouteofadministrationbutis rapid, fromseconds tominutes. The initialdesirable stimulanteffectsof cocaine includeeuphoria,excitation, talkativeness, reduced fatigue, and aheightened senseofwell-being. Someearly physicalsigns include pupil dilation, increases in heart rate, body temperature and blood pressure, tremors,rapidspeech, suppressionofappetite,and twitching (i.e., involuntarymovementof themuscles).Theintenseeuphoria is short-lived (up to30minutes),anddependenton therouteofadministrationanddose; the overall general stimulant effects may persist for up to 1 to 2 hours after administration(CouperandLogan,2014;VerstraeteandLegrand,2014).Theseeffectsmaybefollowedbya‘crash’ordysphoric phase which is characterized by agitation, irritability, anxiety, depression, craving, andparanoia. In order to delay the crash phase and maintain the more desirable stimulant effects ofcocaine,manyuserswill repeatedly administer thedrugover a periodof time ranging fromhours todays(i.e.,bingeuse).Evenduringabinge,theeuphoriceffectsaregraduallyreplacedbydysphoria,andwilleventuallyendwithacrashphasewhich ischaracterizedby intensefatigueandsedation.Chronichigh dose cocaine users may experience symptoms of toxic psychosis (i.e., cocaine induced exciteddelirium),whichischaracterizedbyparanoia,delirium,hallucinations,hyperthermia,extremeagitation,aggression,respiratoryarrest,andevensuddendeath(WetliandFishbain,1985).

Cocainehydrochlorideisananaestheticagent.Itisusedinverylimitedcircumstancesasananaestheticfor specific types of surgeries (e.g., eye, nose, and throat procedures). It is available in solution fortopicaluse.Systemicabsorptionwouldbeexpectedtobeminimal,andtheclearanceanddegradationof cocaine is rapid, which limits the possibility that this drug would persist in a blood sample.Nevertheless,outofanabundanceofcaution,patientswhohavebeenadministeredcocaineshouldbeadvisednottooperateamotorvehicleforaperiodof24hoursaftertheirprocedure.

Cocaine impairs the ability to operate a motor vehicle. Cocaine impairment can occur in both thestimulant and crash phases. The stimulant effect leads to an overestimation of abilities andunderestimationofriskassociatedwithaparticulardrivingaction.Thisincreasedrisk-takingbehaviourwhendrivinghasbeendocumentedtoincludespeeding,erraticdriving,andlossofcontrol(Siegel,1987;Isenschmid,2002;Jonesetal.,2008).Sinceapredominantsymptomafterbingeuseisexhaustionwithanincreasedneedtosleep, impairmentisalsoaconcernafterrepeatedadministrationofastimulant.Usersinthecrashstagemayhavedecreasedalertness,attention,andvigilance.Ithasbeensuggestedthat low dose stimulants may improve performance; however, the dose and pattern of use are nottypical of recreational cocaine use, and do not apply to drug abuse situations. In 20 cases of drivingunder the influence of drugs where no other psychoactive drugs were detected, cocaine blood

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concentrationsweredetectedat 80 to500ng/mL (Jonesetal., 2008). Observationsof thesedriversincludedagitation,enlargedpupils,incoherentspeech,andunsteadygait.

Cocainestability isofparticularconcern. Cocaineissusceptibletodegradationinthetesttubeduringstorage. Cocaine is also rapidly metabolized and has a short duration in the body. Therefore,considerations for decreasing the likelihood of cocaine breakdown include timely sample collection,storageatrefrigeratedtemperatureswithpreservativeaddedtothetesttube,andexpeditedanalysis.Benzoylecgonine is an inactive breakdown product of cocaine. It forms in the test tube and in thehumanbody.Benzoylecgonineisindicativeofcocaineuse.

Ofnote,somecountrieshavesetaperselimitforcocaineandbenzoylecgonine.Perselimitsforcocaineof 10 ng/mL and 24 ng/mL have been implemented in the United Kingdomiii (10 µg/L) and Norway(Vindenesetal.,2012),respectively.TheUKalsosetaperselimitforbenzoylecgonineof50ng/mL(50µg/L).

TheDrugsandDrivingCommitteerecommendsaperselimitforcocaineof30ng/mLinblood(Table2).TheCommitteerecommendsthat therebenoperse limit forbenzoylecgonine. The following factorswere considered when selecting aper selimit: analytical considerations, pharmacological properties,andestablishedperselevelselsewhere.Furthermore,thetimedelaytosamplecollectionandlackofanacceptable back extrapolation formula for drugs other than alcohol were important considerationswhenrecommendingaconcentration.

References

Couper,F.J.andB.K.Logan.Cocaine.April2014(revised).DrugandHumanPerformanceFactSheet.NationalHighwayTrafficSafetyAdministration.Pages19-24https://www.nhtsa.gov/sites/nhtsa.dot.gov/files/809725-drugshumanperformfs.pdf

Jones,A.W.,A.HolmgrenandF.C.Kugelberg.2008.ConcentrationsofCocaineanditsMajorMetaboliteBenzoylecgonineinBloodSamplesfromApprehendedDriversinSweden.ForensicScienceInternational.177:133-139.

Isenschmid,D.S.2002.Cocaine–EffectsonHumanPerformanceandBehavior.ForensicScienceReview.14(1/2):61-100.

Siegel,R.K.1987.CocaineUseandDrivingBehavior.AlcoholDrugsandDriving.3(1):1-8.

Verstraete,A.G.andS-A.Legrand.2014.DrugUse,ImpairedDrivingandTrafficAccidents,2ndEdition.EuropeanMonitoringCentreforDrugsandDrugAddiction(EMCDDA).60-63.

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Vindenes,V.,D.Jordbru,A-B.Knapskog,E.Kvan,G.Mathisrud,L.Slørdal,andJ.Mørland.2012.ImpairmentBasedLegislativeLimitsforDrivingUndertheInfluenceofNon-AlcoholDrugsinNorway.ForensicScienceInternational.219:1-11.

Wetli,C.V.andD.A.Fishbain.1985.Cocaine-InducedPsychosisandSuddenDeathinRecreationalCocaineUsers.JournalofForensicSciences.30(3):873-880.

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Gammahydroxybutyrate(GHB)

TheoriginofGHBcanbeexogenous(i.e.,adrug)orendogenous(i.e.,acompoundfoundnaturallyinthebody).Asadrug,GHBisacentralnervoussystem(CNS)depressant.Itismostcommonlyencounteredasa recreationaldrug,buthas limitedtherapeuticpotential forsomemedicalconditions (CouperandMarinetti,2002).TheinterpretationofGHBlevelsiscomplexandeffortshavebeenmadetoexplainthefactorsthathavebeenconsideredintheultimaterecommendation.

GHBisacompoundthatcanbeproducedendogenouslyinhealthyhumans,inelevatedconcentrationsdue toa raregeneticdisorder, andasapostmortemartifact.GHB is ametaboliteandaprecursorofgamma-amino butyric acid (GABA), an important inhibitory neurotransmitter (Couper andMarinetti,2002). Endogenous concentrations of GHB in blood are significantly lower than levels found afterexogenoususe. Typical concentrationsdetected in antemortemblood samples fromhumans arewellbelow 5mg/L. For example, in 240 blood samples GHB concentrations associatedwith endogenousproduction ranged from 0.17 to 1.51mg/L (Elian, 2002); in an examination of 6 blood samples, GHBoriginatingfromnormalphysiologicalprocesseswasdetectedatconcentrationsof0.5to2.3mg/L(Pauletal.,2006).Incontrast,oneindividualarrestedseventimesfordrivingundertheinfluenceofadrughadGHBconcentrationsof44to184mg/Linbloodsamplescollected1.5to2.5hoursaftercontactwithpolice(CouperandLogan,2004).Furthermore,in13subjectsarrestedforimpaireddriving,bloodGHBconcentrationsrangedfrom26to155mg/L(CouperandLogan,2001).ThereareafewpublicationsofnotewhereelevatedGHBhasbeenassociatedwith a rare genetic disorder, namely4-HydroxybutyricAciduriaorSuccinicSemialdehydeDehydrogenaseDeficiency(Divryetal.,1983;Rahbeenuetal.,1994).Individualswith this disorder tend to demonstratemental andmotor impairments early in life, haveseizuredisorders,andmayhavefamilymemberswiththesamedisorder(Divryetal.,1983;Rahbeenuetal.,1994).Theseindividualsareunlikelytobeoperatingamotorvehicle.ElevatedGHBconcentrationscanalsooccurinpostmortemsamples.Postmortemproductioninbloodisawell-establishedconceptinForensicToxicology,andassuch,interpretationofpostmortembloodlevelsisdistinctfromantemortemsamples.

Medical use of GHB in Canada is limited to specific conditions. Xyrem®iv is a drug available in liquidformulations for the treatment of narcolepsy. In other countries GHB may have wider uses as ananaestheticorhypnoticagent,ortoassistwithtreatmentofalcoholdependenceoropiatewithdrawal(Couper and Logan, 2014). GHB can also arise frommetabolism of 5-fluorouracil which is the activecompoundforsomecancertreatments(CouperandMarinetti,2002).

GHBcanoriginatethroughadministrationofGHB,orthroughmetabolismofgammabutyrolactone(GBL)or 1, 4-butanediol (1, 4-BD) (Couper andMarinetti, 2002). GBL is also aprecursor in the clandestinemanufacturingofGHB.GHBmayoccurinpowderformbutistypicallyavailableasaclear,viscousliquidwitha saltyand/or chemical taste.GHB isadministeredorally.EffectsofGHBconsumptionwillbegin

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shortlyafterabsorption(10to20minutes)andwillgenerally last for2to5hours(CouperandLogan,2014).GHBisrapidlymetabolizedandeliminated.DuetotheephemeralnatureofGHBeffectsandtherapidclearancefromtheblood,timelycollectionisof importance. GHBisunlikelytobedetectedinabloodsamplebeyond6to8hours(CouperandLogan,2014).

GHB is a powerful CNS depressant and its effects are dose dependent. As the administered doseincreasesandthepeakconcentrationofGHBcorrespondinglyrises, theCNSdepressanteffectswouldbeexpectedtoincrease.GHBusemayproducealargespectrumofsideeffectssuchasslow,slurredandincoherent speech,nausea, vomiting, sweating, incontinence, andhypothermia.Athigherdoses,GHBinducesprofoundsedation,astateofunconsciousness,andrespiratorydepressionwhichmayresultindeath.

GHB impairs the ability to operate amotor vehicle. Observations of GHB-intoxicated drivers includeerratic driving such as weaving, swerving, and ignoring road signs; physical indicia include lack ofbalance, decreased consciousness, and loss of coordination (Couper and Logan, 2001; Couper andLogan,2004).

Selectingaperse level forGHBmust incorporatea levelaboveendogenousandthereby indicativeofdruguse,butalsoalevellowenoughtobeofuseconsideringtherapidmetabolismofGHBinthebloodresulting in a quickly decreasing blood concentration between the incident and sample collection.Therefore, timelysamplecollection is imperative ifGHB is thedrugof interest. Therehasbeensomesuggestionthatacitrateadditivetothetesttubemayresult inanelevationoftheGHBconcentration(LeBeauetal.,2000).Withproperstorageconditionsandpreservative(notcitrate),GHBconcentrationsinantemortemsamplesarenotexpectedtoincreaseduringstorage(Beránkováetal.,2006;Jonesetal.,2015).

Ofnote,Norwayhasattempted toequatedrug levels toBACs thatareof relevance for theirdrinkinganddrivinglaws.AperselimithasbeenimplementedforGHBof10,300ng/mLwith2levelsofgradedsanctionsat30,900ng/mLand123,600ng/mLwhichtheyhaveequatedtoBACsof0.2,0.5and1.2g/L,respectively(Vindenesetal.,2012).TheseGHBlevelsconvertto10.3,30.9and123.6mg/LandtheBACsconvertto20,50and120mg/100mL.ThepercentageofcasesthatwereovertheGHBlimitsinthefirstyearafterimplementationwaslowat2.2%,1.7%and0.3%,respectively(Vindenesetal.,2014);thismaybeduetotheinherentdifficultyofGHBloss,orthelowprevalenceofGHBuse.

TheDrugsandDrivingCommitteerecommendsaperselimitforGHBof10mg/Linblood(Table2).Thefollowing factors were considered when selecting aper selimit: analytical considerations,pharmacological properties, and establishedper selevels elsewhere. Furthermore,the time delay tosample collection and lack of an acceptable back extrapolation formula for drugs other than alcoholwereimportantconsiderationswhenrecommendingaconcentration.

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ReferencesBeránková,K.,K.Mutňanská,andM.Balíková.2006.Gamma-HydroxybutyricAcidStabilityandFormationinBloodandUrine.ForensicScienceInternational.161:158-162.Couper,F.J.andB.K.Logan.2001.GHBandDrivingImpairment.JournalofForensicScience.46:919-923.

Couper,F.J.andB.K.Logan.2004.AddictedtoDrivingUndertheInfluence–aGHB/GBLCaseReport.JournalofAnalyticalToxicology.28:512-515.

Couper,F.J.andB.K.Logan.Gamma-hydroxybutyrate(GHB,GBLand1,4-BD).April2014(revised).DrugandHumanPerformanceFactSheet.NationalHighwayTrafficSafetyAdministration.Pages39-43https://www.nhtsa.gov/sites/nhtsa.dot.gov/files/809725-drugshumanperformfs.pdf

Couper,F.J.andL.J.Marinetti.2002.Gamma-Hydroxybutyrate(GHB)–EffectsonHumanPerformanceandBehavior.ForensicScienceReview.14(1/2):101-121.Divry,P.,P.Baltassat,M.O.Rolland,J.Cotte,M.Hermier,M.Duran,andS.K.Wadman.1983.ANewPatientwith4-hydroxybutyricAciduria,aPossibleDefectof4-AminobutyrateMetabolism.ClinicaChimicaActa.129:303-309.Elian,A.A.2002.DeterminationofEndogenousGamma-hydroxybutyricacid(GHB)LevelsinAntemortemUrineandBlood.ForensicScienceInternational.128:120-122.Jones,A.W.,S-A.Gladh,C.N.Windberg,andS.S.Johansen.2015.Stabilityofγ-HydroxybutyrateinBloodSamplesfromImpaireddriversafterStorageat4°CandComparisonofGC-FID-GBLandLC-MS-MSMethodsofAnalysis.JournalofAnalyticalToxicology.39:294-299.LeBeau,M.A.,M.A.Montgomery,R.A.Jufer,andM.L.Miller.2000.ElevatedGHBinCitrate-BufferedBlood.JournalofAnalyticalToxicology24:383-384.Paul,R.,L.Tsanaclis,R.Kingston,A.Berry,andA.Guwy.2006.GC-MS-MSDeterminationofGamma-HydroxybutyrateinBloodandUrine.JournalofAnalyticalToxicology.30:375-379.Rahbeeni,Z.,P.T.Ozand,M.Rashed,G.G.Gascon,M.AlNasser,A.AlOdaib,M.Amoudi,M.Nester,S.AlGarawiandJ.Brismar.1994.4-HydroxybutyricAciduria.Brain&Development.16(suppl.):64-71.

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Vindenes,V.,D.Jordbru,A-B.Knapskog,E.Kvan,G.Mathisrud,L.Slørdal,andJ.Mørland.2012.ImpairmentBasedLegislativeLimitsforDrivingUndertheInfluenceofNon-AlcoholDrugsinNorway.ForensicScienceInternational.219:1-11.

Vindenes,V.,F.Boix,P.Koksæter,M.C.Strand,L.Bachs,J.Mørland,andH.Gjerde.2014.DruggedDrivingArrestsinNorwayBeforeandAftertheImplementationofPerSeLaw.ForensicScienceInternational.245:171-177.

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Heroin/6-monoacetylmorphine(6-MAM)

Heroin (diacetylmorphine) is an opioid analgesic which has central nervous system (CNS) depressantproperties. Opioidanalgesicsareunitedbytheircommoneffectofpaincontrol.Heroinwasoriginallysynthesized in1874andusedtherapeuticallyasananalgesic,ananti-tussive (treatment forpersistentcoughs),andanantidiarrhealagent(StoutandFarrell,2003).ItisnolongerusedforthosepurposesinCanada, and other than the recent inclusion of heroin for the purposes of risk reduction in drugaddictionv,heroinisanillicitsubstance.Administrationismainlybyinjection(typicallyintravenous),butit can also be smoked, or insufflated (snorted). The effectsmost frequently reported are euphoria, afeeling of well-being, sedation, and a feeling of warmth and heaviness. The onset of effects aftersmokedor injectedheroin iswithinminutes,andcan lastup toapproximately4hours (Jenkinsetal.,1994). The onset of effects after insufflation of heroin is within several minutes, and has beendocumentedtolastforuptoapproximately8hours(Coneetal.,1993);thisdurationisduetotheactivemetabolitesformedthatcontributetotheoveralldrugeffect.

Heroinitself isnottypicallyanalyzedinbloodbecausethehalf-life isextremelyshort;heroinisalmostimmediatelybrokendownto6-MAM.6-MAMalsohasashorthalf-lifeandcanbepresentinthebloodfor up to approximately 2 hours after administration (Jenkinset al., 1994). However, thewindowofdetectionmaybesobriefthatimpaireddriversmaybenegativeinthebloodbutpositivefor6-MAMintheurineatthetimeofsamplecollection(Jonesetal.,2012).Asaresult,thedetectionof6-MAMintheblood is indicative of recent heroin use. 6-MAM is further metabolized to morphine, and the co-occurrenceof6-MAMandmorphine isexpectedafterheroinadministration. Thewindowfor6-MAMdetection isshortandcollectionofabloodsample inatimelymanner isessential foran investigationinto heroin use. Furthermore, 6-MAMmay be subject to degradation in the sample and during theextractionprocesswithfactorssuchasstoragetemperature,timeuntilanalysis,andfreeze/thawcyclesrelating to stability of the compound (Ropet al., 1994) and, therefore, storage conditions and timelyanalysisarealsoofimportance.

Heroinimpairstheabilitytooperateamotorvehicle.IndividualsundertheinfluenceofheroincanexperienceCNSdepressionrangingfrommoderatetosevereafterdrugadministration;theresultissedationandpsychomotorimpairment.Acommonobservationafterheroinuseistheindividualwillbe‘on-the-nod’implyinganalteredstateofconsciousness.

Duetothedeleteriousimpactuseofheroinwouldhaveonthefacultiesrequiredfortheoperationofamotorvehicle,theactivemetabolite,6-MAM,isrecommendedforzerotoleranceinabloodsample(Table2).Sincethismetaboliteisrecommendedforzerotolerance,theDrugsandDrivingCommitteealsorecommendsthatallforensiclaboratorieswithinthegovernmentsystemsattempttoconsolidateacut-offconcentrationfortheirmethodologies.Thiscommitteedoesnotmakearecommendationforthedetectionofheroinsincethisfindingisanunlikelyevent.

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References

Cone, E.J., B.A. Holicky, T.M. Grant, W.D. Darwin, and B.A. Goldberger. 1993. Pharmacokinetics andPharmacodynamicsofIntranasal“Snorted”Heroin.JournalofAnalyticalToxicology.17:327-337.

Jenkins, A.J., R.M. Keenan, J.E. Henningfield, and E.J. Cone. 1994. Pharmacokinetics andPharmacodynamicsofSmokedHeroin.JournalofAnalyticalToxicology.18:317-330.

Jones, A.W., A. Holmgren, and J. Ahlner. 2012. Concentrations of Free-Morphine in Peripheral BloodAfter Recent Use of Heroin in Overdose Deaths and in Apprehended Drivers. Forensic ScienceInternational.215:18-24.

Rop, P.P., F. Grimaldi, J. Burle, M.N. De Saint Leger, and A. Viala. 1994. Determination of 6-monoacetylmorphineandMorphineinPlasma,WholeBloodandUrineUsingHigh-PerformanceLiquidChromatographywithElectrochemicalDetection.JournalofChromatographyB.661:245-253.

Stout, P.R. and L.J. Farrell. 2003. Opioids – Effects on Human Performance and Behavior. ForensicScienceReview.15(1):29-60.

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Ketamine

Ketamineisadrugthatisclassifiedasadissociativeanaesthetic.Ketaminewasdevelopedasasurgicalalternativetophencyclidine(PCP)whichhadpotentialasananaestheticagentbutresultedinemergenceeffectsuponregainingconsciousnessthatincludedviolentandconfusedbehaviour.Ketamineisnotdevoidoftheseeffectsbuttheyaretypicallylesssevereinnature.Ketaminecanbeusedasapharmaceuticalagentinhumanandveterinarymedicine.Whenusedinsurgicalprocedurestoinduceanaesthesia,ketaminerapidlyproducesahypnoticstatethatischaracterizedbyprofoundanalgesia,unresponsivenesstocommands,andamnesia;however,thepatientcanbreathespontaneouslyandmayhavetheireyesopenduringthishypnoticstate.Patientsadministeredketamineinhospitalshouldbeadvisedtorefrainfromdrivingforaperiodof24hours.Duetoketamine’srapidclearancefromthebody,thistimeframeshouldbesufficienttoremovethedrugfromtheblood.

Ketamineisalsousedrecreationallyandisprimarilyadministeredbyinsufflation(snortedasadriedpowder)orinjection,andlesscommonly,byoraladministration(sometimesincombinationwithotherpsychoactivesubstances).Theonsetofeffectsdependsontherouteofadministration.Ingeneral,intramuscularinjection,insufflation,andoralingestionproduceeffectswithin2minutes,5to10minutes,and15to20minutes,respectively,afteradministration(Mozayani,2002).Ketamineisfastacting,quicklyeliminated,andgenerallyofshortduration;however,theeffectsofketamineusemaypersistforacoupleofhours(CouperandLogan,2014).Theeffectsofketaminearedoserelatedandatlargedosestheuserexperiencesanintensedetachmentfromreality(MorganandCurran,2011).Therapidonset,intensityoftheexperience,andshortdurationofactionmaylenditselftobingeuseofthisdrug(MorganandCurran,2011).

Ketamineimpairstheabilitytooperateamotorvehicle.Individualsundertheinfluenceofketaminemayexperiencemotorincoordination,out-of-bodyexperiences,agitation,hallucinations,andbeinatrance-likestate.Boththephysicalandpsychedelicexperiencesofketamineuseareinconsistentwiththementalacuityandmotorfunctioningessentialforroadsafety.

Duetothedeleteriousimpactuseofketaminewouldhaveonthefacultiesrequiredfortheoperationofamotorvehiclethisdrugisrecommendedforzerotoleranceinabloodsample(Table2).Sincethisdrugisrecommendedforzerotolerance,theDrugsandDrivingCommitteealsorecommendsthatallforensiclaboratorieswithinthegovernmentsystemsattempttoconsolidateacut-offconcentrationfortheirmethodologies.

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ReferencesCouper,F.J.andB.K.Logan.Ketamine.April2014(revised).DrugandHumanPerformanceFactSheet.NationalHighwayTrafficSafetyAdministration.Pages45-49https://www.nhtsa.gov/sites/nhtsa.dot.gov/files/809725-drugshumanperformfs.pdf

Morgan,C.J.A.andH.V.Currran.2011.KetamineUse:AReview.Addiction107:27-38.

Mozayani,A.2002.Ketamine–EffectsonHumanPerformanceandBehavior.ForensicScienceReview.14(1/2):123-131.

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LysergicAcidDiethylamide(LSD)

LSDisapotenthallucinogen,withsmalldosescausingvividhallucinations.LSDwasfirstsynthesizedin1938asaninvestigationaldrug.LSDisusedrecreationallyandnotavailableformedicaluseinCanada.LSD has low acute toxicitywhichmeans fatal intoxication due to LSD administration is very rare andunlikely.DeathsassociatedwithLSDuseareusuallyduetoinjuriesreceivedwhileundertheinfluenceof thedrug. ThehallucinogeniceffectsofLSDarecommonly referredtoas ‘trips’andtheeffectsareunpredictable varyingwith the amount ingested and the user’s personality,mood, expectations, andsurroundings.

The effects of LSD use can be classified into immediate and prolonged drug effects. LSD is typicallyadministeredorallyvia liquids, tablets,orblotterpaper squares. The immediateeffectsaregenerallyexperiencedwithin20to30minutes,peakat2to4hours,andreturntobaselineby6to8hoursafteradministration (Couper and Logan, 2014). In 5 patients admitted to hospital for LSD intoxication,common observations included hallucinations, agitation, and combative behaviours; symptomologyresolvedwithin 4 to 6 hours after admission other than one patientwhowas kept for evaluation ofacute psychosis (Blaho et al., 1997). The primary effect of LSD is perceptual distortion resulting intemporarypsychosis. Theperceptualdisturbancesincludesensorydistortion(visualandauditory)andhallucinations. Mood changes may also be experience by the user including euphoria, dysphoria,paranoia,anxiety,andpanic.FurthereffectsofLSDusearedizziness,confusion,agitation,hyperactivity,andhystericalbehavior.Subsequentunpredictablehallucinations,referredtoasflashbacks,mayoccurforweeksormonthsafterdruguse. Thesemaybe triggeredbyother factors suchas stress, fatigue,druguseoranxiety,andcanexacerbatepre-existingorunderlyingpsychosis.

LSDimpairstheabilitytooperateamotorvehicle.EvaluatingLSDinaclinicalsettingisdifficultinthatthe subjectmay become “too impaired” and unable to cooperatewith the study due to the intenseperceptualandphysicalchanges(Passieetal.,2008). Individualsunderthe intoxicatingeffectsofLSDare an extremely poor judge of their own abilities due to the mind-altering effects. Severepsychomotor,cognitive,andresidualeffectsareassociatedwithLSDuse.

Some analytical considerations of note are metabolism and stability of the compound, and storageconditions. LSD is susceptible to degradation in samples exposed to increased temperatures,fluorescentorultraviolet light (Lietal.,1998).Furthermore,LSD is taken insmalldosesand is rapidlymetabolizedwhichresultsinlowbloodconcentrationsandashorttimeframetodetectthedrug.Dueto these issues, ideal storage conditions are limited light exposure and refrigerated temperatures.Timelysamplecollectionandexpeditedanalysisarealsoimportantconsiderations.

Due to thedeleterious impactuseof LSDwouldhaveon the faculties required for theoperationofamotorvehiclethisdrugisrecommendedforzerotoleranceinabloodsample(Table2).Sincethisdrugis

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recommendedforzerotolerance,theDrugsandDrivingCommitteealsorecommendsthatall forensiclaboratories within the government systems attempt to consolidate a cut-off concentration for theirmethodologies.

References

Blaho,K.,K.Merigian,S.Winbery,S.A.Geraci,andC.Smartt.1997.ClinicalPharmacologyofLysergicAcidDiethylamide:CaseReportsandReviewoftheTreatmentofIntoxication.AmericanJournalofTherapeutics.4:211-221.

Couper, F.J. and B.K. Logan. Lysergic AcidDiethylamide (LSD). April 2014 (revised). Drug andHumanPerformance Fact Sheet. National Highway Traffic Safety Administration. Pages 51-54https://www.nhtsa.gov/sites/nhtsa.dot.gov/files/809725-drugshumanperformfs.pdf

Li,Z.,A.J.McNally,H.Wang,andS.J.Salamone.1998.StabilityStudyofLSDUnderVariousStorageConditions.JournalofAnalyticalToxicology.22:520-525.

Passie,T.,J.H.Halpern,D.O.Stichtenoth,H.M.Emrich,andA.Hintzen.2008.ThePharmacologyofLysergicAcidDiethylamide:AReview.CNSNeuroscienceandTherapeutics.14:295-314.

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MethamphetamineMethamphetamineisacentralnervoussystem(CNS)stimulantdrugcommonlyusedforitsabilitytoincreasealertness,relievefatigue,andforitseuphoricandstimulanteffects.Methamphetaminecanbeorallyingested,injected,insufflated(snorted),orsmoked.Whenmethamphetamineisinjected,smoked,orsnorted,theonsetofeffectsisrapid(i.e.,within10minutes).Whereasoraladministrationofmethamphetamineresultsinacomparativelydelayedonsetwithalessintensedrugexperience.Overallthedesiredeffectstypicallylast4to8hoursafterusebutmaypersistupto12hours(CouperandLogan,2014).Repeatedadministrationofmethamphetamine,toprolongthedrugeffectsandminimizethewithdrawaleffects,isacommonpatternofuseoftenreferredtoasbingeuse.Methamphetamineismetabolizedtoamphetaminewhichisanactivemetaboliteandcontributestosomeofthedrugeffects.Itiscommontodetectthepresenceofbothcompoundsinabloodsampleasaresultofmethamphetamineuse.Sinceephedrineand/orpseudoephedrineareusedintheillicitmanufactureofmethamphetamine,itisalsocommontodetectthesecompoundsincombinationwithmethamphetamine.

Theeffectsofmethamphetaminearedependentonthedose,patternofadministration,andtimeelapsedsincelastuse.Asthedoseincreases,theeffectswouldcorrespondinglyincreaseinintensity.Duringtheacuteintoxicationphase,physicaleffectsofmethamphetamineincluderapidmovementsandspeech,talkativeness,dilatedpupils,twitching(i.e.,involuntarymovementofmuscles),andincreasedheartrate,respirationrate,bodytemperatureandbloodpressure.Furthermore,theindividualmayexperienceinsomnia,lackofappetite,andaheightenedsenseofwell-being.SingledoseuseproducesCNSexcitationcharacterizedbyincreasedenergy,euphoria,andanelevatedsenseofconfidence;sedationmayfollowtheintensestimulantexperience.Bingeusemayoccuroverhoursordaysandisinitiallycharacterizedbytheaforementionedeffects,butisfrequentlyfollowedbyacrashphasewhichisaccompaniedbyanxiety,weakness,fatigue,nervousness,anddysphoria.Frequentrepeatedadministrationinabingepatternincreasesthepossibilityofpsychoticsymptomssuchasparanoiaandhallucinations.Intwostudiesofmethamphetamine-positivedriversconcentrationsrangedfrom<50ng/mLto9460ng/mL,andcommonobservationsincludedrapidandconfusedspeech,rapidpulse,agitation,paranoia,andviolent/aggressivebehaviours;erraticdriving,speeding,andweavingweresomeofthereporteddrivingobservations(Logan,1996;Lemos,2009).Ithasbeensuggestedthatlowdosestimulantsmayimproveperformance;however,thedoseandpatternofusearenottypicalofrecreationalmethamphetamineuse,anddonotapplytodrugabusesituations.

Therearepropertiesofmethamphetaminethatmaybeusedfortherapeuticbenefit.Thesepropertiesincludeappetitesuppression,nasaldecongestion,andfortreatmentofnarcolepsyandattentiondeficithyperactivitydisorder.Currently,thereisnoapprovedmedicaluseformethamphetamineinCanada;itisnotavailableover-the-counterorasaprescriptiondrug.However,methamphetamineisavailableinothercountriesformedicalpurposes(e.g.,DesoxynÒvi).Additionally,methamphetaminemayalsobe

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presentduetometabolismofselegilinevii,adrugavailablebyprescriptioninCanadausedfortreatmentofParkinson’sdisease.ThereareotherdrugsnotavailableinCanadawhichmayresultinthepresenceofmethamphetamineduetothemetabolismoftheparentdrug(Logan,2002).

Methamphetamineimpairstheabilitytooperateamotorvehicle.Impairmentbymethamphetamineresultsinlapsesinattentionandelevatedrisk-takingwhichleadstotheincreasedpotentialforerraticanddangerousdriving.Bloodconcentrationsofmethamphetaminewoulddependonthetimeelapsedsincelastadministrationaswellasthepatternofuse.Thebingepatternofuseformethamphetaminewillresultinelevatedconcentrationsofthisdrug,andclearanceofthedrugfromthebloodcouldtakehourstodays.Theimpactwouldbethattheuserwouldbeinastateofwithdrawalratherthanacutedrugadministration,butcontinuetohavedetectablemethamphetaminebloodconcentrations.Thesymptomologyassociatedwithmethamphetaminewithdrawal,suchashyper-somnolence,lackofenergyandoverallweakness,isalsoofconcerntoroadsafety.

Ofnote,somecountrieshavesetaperselimitformethamphetamine.AperselimitformethamphetaminehasbeenestablishedintheUnitedKingdomiiiandNorway(Vindenesetal.,2012)at10ng/mL(10µg/L)and45ng/mL,respectively.

The Drugs and Driving Committee recommends a per se limit formethamphetamine of 50 ng/mL inblood (Table 2). The following factors were considered when selecting aper selimit: analyticalconsiderations,pharmacologicalproperties, andestablishedper selevelselsewhere. Furthermore,thetimedelay to sample collection and lackof an acceptablebackextrapolation formula for drugsotherthanalcoholwereimportantconsiderationswhenrecommendingaconcentration.

ReferencesCouper, F.J. and B.K. Logan.Methamphetamine (and Amphetamine). April 2014 (revised). Drug andHuman Performance Fact Sheet. National Highway Traffic Safety Administration. Pages 61-65https://www.nhtsa.gov/sites/nhtsa.dot.gov/files/809725-drugshumanperformfs.pdf

Lemos,N.P.2009.MethamphetamineandDriving.ScienceandJustice.49:247-249.

Logan, B.K. 1996. Methamphetamine andDriving Impairment. Journal of Forensic Sciences. 41: 457-464.

Logan,B.K.2002.Methamphetamine–EffectsonHumanPerformanceandBehavior.ForensicScienceReview.14(1/2):133-151.

Vindenes,V.,D.Jordbru,A-B.Knapskog,E.Kvan,G.Mathisrud,L.Slørdal,andJ.Mørland.2012.ImpairmentBasedLegislativeLimitsforDrivingUndertheInfluenceofNon-AlcoholDrugsinNorway.ForensicScienceInternational.219:1-11.

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Phencyclidine(PCP)PCP, commonly referred to as ‘angel dust’, is a recreational drug that is categorized as a dissociativeanaesthetic.PCPwasfirstintroducedasapotentialsurgicalanaestheticagentduringthe1950s.PCPwasfoundtoinduceatrance-likestateinwhichanindividualcouldbeexposedtopainwithoutexperiencingtheactualsensationofpain.However,PCPwasquicklyremovedfromthemarketasitwasdeemedtohave unacceptable adverse effects, including emergence delirium in which patients coming out ofanaesthesiawouldexhibitagitation,disorientation,vividdreams,hallucinations,andemotionaldistress.PCPwasalsousedasaveterinaryanaesthetic,butthispracticehasalsobeendiscontinued.PCPisnotavailableformedicaluseinCanadaand,therefore,PCPiscurrentlyanillicitdrug.

TheroutesofadministrationforPCPincludeinhalation(smoking),insufflation(snorting),ingestionandinjection.PCPmaybeavailableinliquidorpowderforms.TheonsetofeffectsaftersmokedorinjectedPCPoccurswithinsecondstominutes,canbewithinseveralminutesaftersnorting,andcantake20to40minutes after oral ingestion (Mozayani, 2003). The effects of PCP generally last 4 to 8 hours butsomesymptomsmayextendforupto24hoursormore(Mozayani,2003).

TheeffectsofPCPcanincludefeaturesofacentralnervoussystem(CNS)depressant,aCNSstimulant,andahallucinogenicagent.RecreationaleffectscommonlyreportedafterusingPCPareeuphoria,andthefeelingofstrengthandinvulnerability.OthereffectsassociatedwithPCPuseincludedisorientation,out-of-body experiences, ataxia, drowsiness, agitation, hallucinations, and bizarre and/or violentbehaviour. The effects and duration of action of PCP on an individual depend on the route ofadministration, dose, presence of other psychoactive substances, underlying psychiatric disturbances,experiencewithPCP,andthesettingofthedrugadministration.

PCP impairs the ability to operate a motor vehicle. In 50 intoxicated drivers positive for PCP,observationsincludedstaggering,unsteadygait,blood-shoteyes,alteredspeechpatterns(thick,slowed,slurred),nystagmus,andblankstares (Clardyetal.,1979). PCPcancauseseverementalandphysicalimpairment.

DuetothedeleteriousimpactuseofPCPwouldhaveonthefacultiesrequiredfortheoperationofamotorvehiclethisdrugisrecommendedforzerotoleranceinabloodsample(Table2).Sincethisdrugisrecommendedforzerotolerance,theDrugsandDrivingCommitteealsorecommendsthatallforensiclaboratorieswithinthegovernmentsystemsattempttoconsolidateacut-offconcentrationfortheirmethodologies.

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References

Clardy, D.O., R.H. Cravey, B.J. MacDonald, S.J. Wiersema, D.S. Pearce, and J.L Ragle. 1979. ThePhencyclidine-IntoxicatedDriver.JournalofAnalyticalToxicology.3(6):238-241.

Mozayani, A. 2003. Phencyclidine – Effects on Human Performance and Behavior. Forensic ScienceReview.15(1):61-73.

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Psilocybin/Psilocin

Psilocybin,commonlyknownas‘magicmushrooms’,isanaturallyoccurringhallucinogeniccompound.Psilocybinmayeffectivelyactasapro-drugasitisrapidlyandextensivelymetabolizedintopsilocin,theprimarypsychoactivecompoundinthebody(Hasleretal.,1997).Typically,psilocybinmushroomsareingestedorally,eitherfresh,ordried.Theeffectsaredosedependent;however,thepotencyofthedrugisvariableandrelatedtogrowingconditions,speciesorvariant,origin,andageofthemushroom(vanAmsterdametal.,2011).Theonsetofpsychedeliceffectsoccurswithin20to40minutesofingestion,withmaximaleffectsoccurringwithin60to90minutes,andthedurationofactionmaypersistforupto6hourspost-ingestion(Hasleretal.,2004;vanAmsterdametal.,2011).

Althoughtherehavebeenacademicattemptstousepsilocybinforresearch,itisnotavailableformedicaluseinCanada,andisadrugusedforrecreationalpurposes.Usersconsumepsilocybinforthedesiredeffectsofrelaxation,giddiness,increasedenergy,euphoria,andthepsychedelic/mysticalexperience.Othereffectsincludeperceptualchanges,synaesthesia,andalterationofthoughtandtimesense.Sensorydistortionsmayincludeoneormoreofthefollowing:visualenhancements(e.g.,coloursbecomebrighter);visualdisturbances(e.g.,surfacesappeartomoveorproducewaves);alteredperceptionofrealevents,imagesandfaces;orhallucinations.Effectssuchasthesehavebeenassociatedwithanxietyandparanoiainpsilocybinusers.Althoughfataltoxicityisunlikely,psilocybinusehasbeenimplicatedinaccidentaldeathssuchasfallsorexposuretotheelements(vanAmsterdametal.,2011).

Psilocybinuseimpairstheabilitytooperateamotorvehicle.Individualsundertheinfluenceofthisdrugexperiencemind-alteringeffectsremovingthemfromtherealityofthesituation.Thepsychedelicexperienceswhichfollowpsilocybinuseareinconsistentwiththementalfunctioningrequiredforroadsafety.

Someanalyticalconsiderationsofnotearemetabolismandstabilityofthecompounds.Psilocin,theextensivelyandrapidlyproducedpsychoactivecomponent,maybelightandtemperaturesensitive,andmaynotbestableinaqueoussolutions(Bjornstadetal.,2009;Hasleretal.,1997).Therefore,storageconditionstoreducethepotentialdegradationofthecompoundandtimelyanalysisareofimportance.

Duetothedeleteriousimpactuseofpsilocybinwouldhaveonthefacultiesrequiredfortheoperationofamotorvehicle,boththeparent,psilocybin,anditsactivemetabolite,psilocin,arerecommendedforzerotoleranceinabloodsample.Detectionofpsilocybin,psilocinorbothwouldmakeouttheoffence.Sincethisdrugisrecommendedforzerotolerance(Table2),theDrugsandDrivingCommitteealsorecommendsthatallforensiclaboratorieswithinthegovernmentsystemsattempttoconsolidateacut-offconcentrationfortheirmethodologies.

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References

Björnstad,K.,O.Beck,andA.Helander.2009.AMulti-ComponentLC-MS/MSMethodforDetectionofTenPlant-DerivedPsychoactiveSubstancesinUrine.JournalofChromatographyB877:1162-1168.

Hasler,F.,D.Bourquin,R.Brenneisen,T.Bar,andF.S.Vollenweider.1997.DeterminationofPsilocinand4-hydroxyindole-3-aceticacidinPlasmabyHPLC-ECDandPharmacokineticProfilesofOralandIntravenousPsilocybininMan.PharmaceuticaActaHelvetiae72:175-184.

Hasler,F.,U.Grimberg,M.A.Benz,T.Huber,andF.X.Vollenweider.2004.AcutePsychologicalandPhysiologicalEffectsofPsilocybininHealthyHumans:aDouble-Blind,Placebo-ControlledDose-EffectStudy.Psychopharmacology172:145-156.

VanAmsterdam,J.,A.Opperhuizen,andW.vandenBrink.2011.HarmPotentialofMagicMushroomUse:AReview.RegulatoryToxicologyandPharmacology59:423-429.

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Table2.Recommendationsfordetectionorperselimitsforselecteddrugs.

DrugDetectionina

Blood/Serum/PlasmaSample

PerseLimitinaBloodSample

Cocaine 30ng/mL

Gammahydroxybutyrate(GHB) 10mg/L

Heroin(6-monoacetylmorphine*) ü

Ketamine ü

LysergicAcidDiethylamide(LSD) ü

Methamphetamine 50ng/mL

Phencyclidine(PCP) ü

Psilocybin/Psilocin ü

*6-monoacetylmorphine(6-MAM)detection;norecommendationforheroin

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Endnotes

iThetermsplasmaandserumareusedinterchangeablyforthepurposesofTHCandalcohol;althoughtechnicallydifferentsampletypes,theyareconsideredanequivalentmatrixforthepurposesofconversiontobloodvalues.iiConversiontobloodconcentrationsusingthemedianblood:plasmaratioof0.68(Desrosieretal.,2014).Manypapersexamineplasma/serumconcentrations.Theprimarysampletypeforfutureperselegislationwillbeblood;therefore,theconcentrationswereconvertedforeaseofcomparison.iiihttps://www.gov.uk/government/collections/drug-driving#table-of-drugs-and-limitsAccessedMarch2017ivXyremâCompendiumofPharmaceuticalsandSpecialties.CanadianPharmacistsAssociation,CPhAmonograph.Lastrevision:October2016.vhttp://www.gazette.gc.ca/rp-pr/p2/2016/2016-09-07/html/sor-dors239-eng.phpviDesoxynâU.S.Food&DrugAdministration(FDA).ID3734642.Lastrevision:April2015.

viiSelegiline.CompendiumofPharmaceuticalsandSpecialties.CanadianPharmacistsAssociation,CPhAmonograph.Lastrevision:November2011.