Δ9-tetrahydrocannabinol (THC) is present in the body between smoking sessions in occasional non-daily cannabis users

D 9-tetrahydrocannabinol (THC) is present in the body between smoking sessions in occasional non-daily cannabis users

J. Mørland

*, J.G. Bramness

aNorwegianInstituteofPublicHealth,POBox222Skøyen0213,N-0403Oslo,Norway

bInstituteofClinicalMedicine,UniversityofOslo,POBox1072,Blindern,N-0316Oslo,Norway

cNorwegianNationalAdvisoryUnitonConcurrentSubstanceAbuseandMentalHealthDisorders,InnlandetHospitalTrust,Ottestad,Norway

dInstituteofClinicalMedicine,UiT-TheArcticUniversityofNorway,Tromsø,Norway

ARTICLE INFO Articlehistory:

Received7October2019

Receivedinrevisedform4February2020 Accepted8February2020

Availableonline28February2020 Keywords:

Cannabis

Tetrahydrocannabinol Pharmacokinetics Accumulation

ABSTRACT

Background:THCcanbemeasuredinblooduptoamonthafterlastintakeinheavycannabisusers.The cognitivedeficitsduringabstinencehavebeenhypothesizedtobeatleastinpartduetoresidualTHCin brain.TowhichextentTHCaccumulationwilloccurafteroccasionalcannabisusehasgainedlimited attention.Weaimed topredictTHC-levelsbetweensmokingsessionsinnon-dailyaswellasdaily cannabisusersandtocomparethesepredictionswithpublishedTHClevels.

Methods:Predictionswerebasedonpharmacokineticprinciplesondrugaccumulationafterrepeated dosing,appliedtodifferentcannabissmokingpatterns,usingdatafromathree-compartmentmodelfor THCpharmacokineticsandresultsontheterminaleliminationhalf-lifeofTHCinhumans.Wesearched theliteratureforTHCmeasurementswhichcouldbecomparedwiththesepredictions.Wefoundnosuch resultsfromcontrolledstudiesoflong-termrepeatedcannabisconsumptionofknownTHCamounts.

Thirteenpublishedstudiescontained,however,enoughinformationoncannabisuseandresultsfrom THC-measurementstomaketentativecomparisonswiththepredictions.

Results:ThepredictionsofTHC-plasmalevelspresentafterdifferentcannabissmokingpatternsassuming terminaleliminationhalf-livesofTHCof21.5horlonger,hadsomesupportinpublishedTHClevels measured in individuals self-reporting their cannabis consumption. We found no consistent discrepanciesbetweenthepredictionsandreportedTHCplasmalevelsafternon-dailyordailycannabis use.ThepredictionsindicatethatTHCmightbepresentinplasmabetweensmokingsessionsaboveusual analyticallimitswhensmokingeverythirdandsecondday,andat lowerlevelsafteronceweekly smoking.

Conclusions:ThestudyindicatesthatTHCmightbepresentcontinuouslyeveninnon-dailysmokersat lowlevels,evenifthesmokingoccasionsareseparatedbyaweek.Thisisdifferentfromalcohol,where ethanolhasdisappearedafteraday.FromatoxicologicalpointofviewthepersistanceofTHCinthebrain, raisesquestionswhetherthisshouldbegivenmoreattentionaswithothertoxicologicalthinkingwhere long-termpresenceofbioactivesubstancesgivesrisetoconcern.Therearesomeuncertaintiesinthis analysis, and controlled studies on THC-accumulation accompanying different use patterns seem warranted.

©2020ElsevierB.V.Allrightsreserved.

1.Background

With rapidly changing legislation across the world on recreationaland medicinal use of cannabis, increased use can beexpected[1].Thereisalsoapublictendencytoviewcannabis as less dangerous than in the past [2] and such views might further lead to increased use [3]. Cannabis use can result in

various degrees of acute intoxication with cognitive and psychomotor impairment. Chronic use might be related to long-term effects on cognition, brain structure, psychiatric disordersandcannabisusedisorders[4,5].Thecognitivedeficits during early abstinence in chronic daily users have been hypothesizedtobeatleastinpartduetoresidualTHCinbrain [6,7]asTHCcanbemeasuredinbloodforuptoamonthafterlast intake insuch users[8,9].Thisprolonged THC-eliminationhas beenreportedrelatedtoyearsofpriorcannabisuse[9],andhas been suggested to represent gradual transfer into the blood streamfromstorageinadiposetissue[6,10].

* Correspondingauthorat:NorwegianInstituteofPublicHealth,Oslo,Norway.

E-mailaddress:jorg.morland@medisin.uio.no(J. Mørland).

http://dx.doi.org/10.1016/j.forsciint.2020.110188 0379-0738/©2020ElsevierB.V.Allrightsreserved.

ContentslistsavailableatScienceDirect

Forensic Science International

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a te / fo r s c i i n t

Most cannabis users are not daily smokers [11,12] and the questionwhetheroccasionalrecreationalsmokingcanleadtoTHC accumulationbetweensmokingsessionshasonlygainedlimited researchattention.MountingTHClevelsinbloodhavenotbeen expectedinoccasionalusersastherearenumerousobservationsof arapiddeclineofbloodTHCconcentrationsaftersmoking,with thedetection limit of usualanalytical methods reachedwithin 612h[6,13].Eliminationhalf-lives(T1/2)determinedfromblood THC concentration measurements during the hours following smokinghaveaccordinglybeenbelow2h[14–19].

The pharmacokinetics of THC is, however, complex and different multiple compartment models have been suggested [19,20]. Recently, Heuberger and co-workers [21] developed a more complete population pharmacokinetic model of THC, representing a three compartment model, based on detailed analysis of several previous unpublished and published [22]

experimental studies. Heuberger’s paper suggests that THC regardless of route of intake and intake frequency has a fast initialandintermediateT1/2,butanapparentterminalT1/2thatis about21.5h.OtherpreviousstudieshavealsoreportedT1/2inthe orderof1836h[15,23,24].Onestudywithbloodsamplingforan extendedperiodofatleast10daysafterTHCadministrationeven reportedameanterminalT1/2of4.3daysindailycannabisusers [25].

Whetherthereisashort(fewhours)orlong(days)T_1/2ofTHC wouldgreatlyinfluencethepossibilityofTHCtobeingpresentin thebodyofrecreationalcannabisusersbetweencannabisintake episodes.

Inthepresentstudy,wefirstwantedtodevelopamodelthat couldpredictTHC-levelsinplasmapresentbetweenintakeswith certainpatternsofrepeatedrecreationalcannabisuse.Knowledge of drug half-life and dosing frequency gives the possibility to calculateextentofdrugaccumulation[26]afterrepeateddosing.

Recreationalnon-dailyuseofcannabisdoesnotoccurwithgreat regularity but estimates of the THC-levels present in blood betweenintakes were performedfor individuals withsmoking patternsofe.g.onceaweek,everythirdandeverysecondday.

Thesecondpurposeofthepresentstudywastocomparethe predictionsfromthepharmacokineticmodelwithpublisheddata fromuserswithlong-termrepeatedsmokingofcannabis,tothe extent that such data could be retrieved from the existing literature.

2.Methods

2.1.PredictionofplasmaTHClevelsafterdifferentrepeatedcannabis usepatterns

If a drug is eliminated accordingto first-orderkinetics, the amountofdruginthebodywillincreaseuntilasteadystate(a plateau level) is reached after a period corresponding to

approximately5timesT1/2.Atthisplateau,theamountofdrug dosedperintervalisequaltotheamountofdrugeliminatedduring thatinterval.Foranydrugwithmultipledosing,theaccumulated amount of the drug in the body at plateau conditions can be calculatedaccordingtotheexpression[26]:

AI¼ 1 1e^kt

Kistheeliminationconstantofthedruginquestion(k¼⁰T1^:693=2), and

t

AIistheaccumulationindex,i.e.theratiobetweentheamount ofdruginthebodyatplateauanygiventimeafterthelastdoseand theamountofdruginthebodyatthesametimeafterasingledose.

Afterdistributionequilibrium is attained, theAI would alsobe validforcirculatingdrugconcentrations.

To apply this general pharmacokinetic principle of drug accumulation toTHC aftercannabis use, a certain regularityof smoking a given dose was postulated. We did this for the prediction of THC concentrations after cannabis used once a week,2–3timesperweek(everythirdday),everysecondday,once everyday,andtwiceeveryday.Dailysmoking(onceortwice)was included among the predictions for the purpose of possible comparisonwithmorepublisheddata(seebelow).Thepharma- cokineticmodelofHeubergerandco-workers[21]indicatesthat thedistributionofTHCisfinalizedat12haftersmokingandthe terminal phase is reached at this time. Wethus calculated the expectedTHCconcentrationsinplasma12haftersmokinguntil thenextintake.Wedecidedtousesmokingofadoseof54mgTHC thestandarddoseinourcalculations.Thisallowedustousesome ofthepredictionscalculatedbyHeuberger’sgroup[21].Thisdose isprobablyhigherthanoftenusedbyoccasionalusers,about25 mgTHCandclosertothatacceptedbyexperiencedusers,3554 mg[15,21,27].Thus,weobtainedarepresentationofnearmaximal accumulationobtainablebydifferentsmokingpatterns.Basedon previousstudies[24,28]weassumedthattherewasnodifference interminalTHChalf-lifebetweenlightandheavycannabisusers.

InthepresentpredictionsweusedboththeTHCterminalhalf-life of21.5h[21]andthemeanvalueof4.3daysasfoundbyJohansson andco-workers[25].Thesehalf-livescoverroughlytherangeof published elimination half-lives of THC from studies with sampling periods longer than 1224 h. The results of the predictionsareshowninTable1.

2.2.PublisheddataonTHClevelsincannabisuserswithlong-term repeatedintake

Tocollectstudieswithdatathatcouldbecomparedwiththe calculatedpredictedTHClevels,wesearchedOvidMedlineand PubMedforrelevantstudies.Weusedthesearchterms“cannabis or cannabinoid or marijuana or THC” and “accumulation or excretion or disposition or half-life or pharmacokinetics or

Table1

Theeffectofdifferentdosingintervalsonaccumulationindex(AI)andcalculationsoftypicalpredictedTHCplasmaconcentrations(95%predictioninterval)[21],12hafter smoking54mgTHC,andatnextintake,assumingterminalT1/2of21.5hor4.3days,respectively.

T1/2=21.5h T1/2=4.3days

Patternofuse AccumulationIndex(AI) THCplasmaconcentrations(ng/ml) AccumulationIndex(AI) THCplasmaconcentrations(ng/ml)

12haftersmoking Atnextintake 12haftersmoking Atnextintake

Infrequent 1.00 1.2(0.6–3.0) 1.00 1.2(0.6–3.0)

Onceaweek 1.01 1.2(0.6–3.0) 0.01(0.0-0.02) 1.48 1.8(0.9–4.4) 0.7(0.3–1.6)

Everythirdday 1.11 1.3(0.7–3.3) 0.2(0.1-0.5) 2.61 3.1(1.6–7.8) 2.1(1.1–5.2)

Everysecondday 1.27 1.4(0.7–3.6) 0.4(0.2–1.1) 3.64 4.4(2.2–10.9) 3.5(1.7–8.6)

Oncedaily 1.87 2.2(1.1–5.6) 1.5(0.7–3.8) 6.71 8.1(4.0–20.1) 7.5(3.7–18.6)

Twicedaily 3.13 3.8(1.9–9.4) 3.8(1.9–9.4) 12.83 15.4(7.7–38.5) 15.4(7.7–38.5)

concentrationinblood/plasma/serum”, restrictingthesearch to humanstudiesintheEnglishlanguage.Fromtheretrievedpapers, weselectedthose,whichhadsomeinformationonthefrequencies ofuseofcannabisinthesubjectsandsomemeasureofTHC-levels inwholeblood(B),serum(S)orplasma(P).Wealsosearchedthe publications’referencelistsforadditionalpublications.Thesearch ledto13scientificpublicationswiththiskindofinformation.

Wefoundnocontrolledstudies ofTHC-levelsobtainedafter long-termrepeatedsmokingofcannabiswithknownamountsof THC.Weuseddatafromsomestudies,whereTHCconcentrations inbloodorplasmaweremeasuredinpeoplewhohadself-reported their consumption of cannabis in the preceding period. Other studies where THC was administered for pharmacodynamics/

kineticpurposestopeoplewithdifferentpriorcannabisconsump- tion,thebaselinelevelsrelatedtopreviousself-reportedcannabis intake,werealsousedforcomparisonwiththepredictionmodel.

TheresultsarepresentedinTable2.

3.Results

3.1.PredictionofplasmaTHClevelsafterdifferentrepeatedcannabis usepatterns

Table1showsthecalculatedaccumulationindices(AIs)andthe predictedTHC-plasmalevelsbetweenintakes aftercertainnon- dailycannabisusepatterns.Forcomparison,Table1 alsoshows dataforinfrequentsmokingandtwopatternsofdailysmoking.

The AIs increased with increasing frequency of use. The differencebetween use once a week and every third or every

seconddaywasabout10%or25%,respectivelywhenT1/2wasset to21.5h.Correspondingdifferenceswerearound70%or145%, respectivelywhenaT1/2of4.3dayswasapplied(column1and4, Table 1).ThesedifferenceswerereflectedinTHClevelspresent betweenintakesforthethreedifferentsmokingpatterns(oncea week,everythirdorsecondday).

Based ona T1/2of21.5 htheTHCplasmaconcentrationwas below1ng/ml24hafterthelastsmokingforallthreenon-daily smokingpatterns(notshowninTable1)anddecreasedtoplasma levelsbelow0,5ng/mlatnextintake(column3,Table1).Asmost routineanalyticalmethodsforplasmaTHChaveLOQsof0.5or1 ng/ml,nofindingofTHCintheperiodbetweenintakeswouldoften occur.Butevenfortheleastfrequentpattern(onceaweek),some THCwaspresentinplasma.

Based on a T1/2 of 4.3 days the THC plasma levels were substantiallyhigherandwouldinmostcasesexceptforsmoking onceaweek,beabovetheanalyticalLOQsduringthewholeperiod betweenintakes(column6,Table1).

3.2.ComparisonofpredictedandpublisheddataonTHClevelsin cannabisuserswithlong-termrepeatedintake

Table 2 summarizes data from 13 studies with data on both long-termrepeated cannabis consumptionand measure- mentsofTHC-levelsinwholeblood(B),serum(S)orplasma(P) afterdistributionequilibriumofthelastdosewasreached.The studiesarelistedaccordingtointakeofcannabis:onceaweek, everythirdday,everysecondday,onceadayorseveraltimesper day.

Table2

Datafrom13studiesmeasuringTHClevelsinblood/plasma/serumafterprecedinglong-termrepeatedcannabisuse.Abbreviationsabouttime:w:weeks,d:days,h:hours.

Abbreviationsonstatistics:me:mean,md:median,r:range,SE:standarderror,SD:standarddeviation,95CI:95%confidenceinterval.Abbreviationsaboutsamplematrix:S:

serum,P:plasma,B:wholeblood.

Reference Groupsize,amountandfrequency

ofcannabisuse

Timebetweenlastsmoking andbloodsampling

MeasuredTHC conc.ng/ml

THCconc.^ginplasma ng/ml

Smokingonceaweek

Skopp&Pötsch,2008[41] N=6,upto1joint/w 36(24–48)hme(r) S:0(0–1.4)md(r) 0(0–1.4)md(r) Ramaekersetal.2016[39] N=5^a,10-15occasions/3months,i.e.0.8-1.2

occasions/w

Notspecified S:0(0–1)md(r)^a 0(0–1)md(r) Smokingeverythirdday

Hartmanetal.2015^c[42] N=32,upto2–3occasions/w 2(0.3–4)dmd(r) P:0.9md^b 0.9md

Hartmanetal.2016^c[43] N=19,upto2–3occasions/w 2(0.3–4)dmd(r) B:(0–6.3)(r) 0-9.7r Smokingeverysecondday

Skopp&Pötsch,2008[41] N=15,uptoonejoint/d,i.e.3–4joints/w(?) 36(24–48)hme(r) S:0.3(0–2.6)md(r) 0.3(0–2.6)md(r) Hjorthøyetal.2012[29] N=88,onaverage40.4(3.24SE)jointson13.8(0.76

SE)d/month

1dmd P:4.1(0.76)me(SE) 4.1(0.76)me(SE) Smokingoncedaily

Skopp&Pötsch,2008[41] N=16,morethan1joint/d 36(24–48)hme(r) S:1.3(0–6.4)md(r) 1.3(0–6.4)md(r) Toenessetal.2008^c[15];Ramaekers

etal.2009^c[44]

N=12,using340(86)timesme(SD)peryear,2 jointson7(4–25)md(r)occasionslastweek

Onenight(8h?)+4hafter smokingplacebo

S:2.8(3.4)me(SD) 2.8(3.4)me(SD) Smithetal.2018[30] N=16,using0.30(0.22)gme(SD)cannabisper

occasion,on1.3(0.8)me(SD)dailyoccasions

Atleast12h B:1.2(1.5)me(SD) 1.8(2.3)me(SD) Smokingmultipletimesdaily

Odelleta.2016[40] N=21,dailyusing4–6joints,or20(5–50)bongs,or2 (0.5–4)gheads,md(r)

25.5(12–31)h^dmd(r) B:2(1–13)md(r) 3.1(1.5–20)md(r) Desrosiersetal.2014[27] N=14,using4.5(1.5–21)joints/d,md(r)forthelast

14(11–14)d,md(r)

22(19–41)hmd(r) P:4.8(3.3–6.3)me (95%CI)^e

4.8(3.3–6.3)me (95CI) Schwopeetal.2011[45] N=10,using5(1–12)joints/d,md(r);forthelast11

(8–14)d,md(r)

65(39–116)hmd(r) P:1.6(0–7.3)md(r) 1.6(0–7.3)md(r) Bergamashietal.2013^c[8];Karschner

etal.2016^c[9]

N=28,using9(1–30)joints/d,md(r);forthelast14 (11–14)d,md(r)

Atleast24h P:2.7(0–8.7)^fmd(r) 2.7(0–8.7)md(r) Smithetal.2018[30] N=10,using0,62(0.36)gme(SD)cannabisper

occasionon2.7(0.93)me(SD)dailyoccasions

Atleast12h B:2.3(2.9)me(SD) 3.5(4.5)me(SD)

aApproximatenumbersfromfig.1and4[39].

b Calculatedfromdataafterplacebosmoking,theirsupplementarytable5[42].

cThetwopaperspresentdifferentaspectsofthesamestudy.

d Timetofirstbloodsampleafter12hsincesmoking[40].

eDatafromsupplementarydatatable1e[27].

f Datafromday1,thedayafteradmissionday[8,9].

g Conversionfactorfrombloodtoplasma:x1.54[45,46];serumtoplasmaratioequals1.0.

TwostudiesinTable2reportedTHClevelsfromsmokingoncea week,representing11individuals.For5ofthesethetimebetween smokingandbloodsamplingwasunknown,fortheother6itwas between24and48h.Thehighestvaluewas1.4ng/ml,butinmost cases,theTHCconcentrationwasbelowtheLOQof1ng/ml.These resultswerecompatiblewiththepredictionsinTable1.

Two studies presented THC-levels from 32 people smoking everythird day or less often (Table 2). The time between last smokingandbloodsamplingwas2days(median,witharangeof 0.3–4days).ThemeasuredTHCplasmalevelsrangedfrom0to9.7 ng/ml.Thehighestvaluewassomewhathigherthanthehighest predictedTHC-level.

TwostudiesmeasuredTHClevelsfrom103individualssmoking everysecondday(Table2).Themediantimesincelastsmoking was24hormore.Thestudywiththemostdetaileddescriptionof cannabisconsumptionandmostparticipants[29]reportedamean THCplasmaconcentrationof 4.1 ng/mlfor theperiod between smoking occasionscompatible with the predictionsin Table 1, column5and6,i.e.thosebasedonaterminalTHCT1/2of4.3days.

Tendifferentstudiesonsmokerswithintakesonceormultiple timesdailywithtimesbetweenlastsmokingandbloodsampling from12to116hwerecollected(Table2).ThemedianormeanTHC plasmalevelswererangingfrom1.3–4.8 ng/ml,withindividual valuesrangingfrom0to20ng/ml.Thehighestindividualvalues recorded were compatible with the predictions presented in column5and6inTable1.

4.Discussion

The present predictions of THC-plasma levels present after differentcannabissmokingpatternsassumingterminalelimina- tionhalf-livesof THCof 21.5hor longer,had somesupportin publishedTHClevelsmeasuredinindividualsself-reportingtheir cannabis consumption. We found no consistent discrepancies betweenthepredictionsandreportedTHCplasmalevelsafternon- daily or daily cannabis use, supporting the reliability of the predictions.It is therefore reason to assume that THC will be presentinplasmaandorgansinequilibriumwithbloodase.g.the brain,betweensmokingsessionsinnon-dailyusers.

Inaccurate reporting of smoking frequency in the published studiescannot beexcluded. Deliberate over- orunderreporting may, however, be less of a problem than expected, as several studiescomparingself-reportandTHC-biometricshaveconcluded thatself-reportcanbequitereliable[30,31]

Itcouldbearguedthatsomeofthehighervaluesmeasured fittedwithpredictionsduetotheinclusionofTHCresultsfrom samplestakenbeforeadistributionperiodof812hafterlast smokinghadpassed.Thisseemshoweververyunlikelygiventhe informationin thedifferentpapers.Ontheotherhand,forall consumption patterns we observed some deviations as severalpublishedindividualTHC-levelswerelowerthanthose predicted. In some instances, the broad range of smoking frequenciesincludedinthegroupthuscontaininglessfrequent smokingthanthepatternusedtodefinethegroup,couldexplain this.

Anotherfactorthatwouldgiverisetolowermeasuredlevels thanthosepredictedwasintakeoflowerdosesthanthedose(54 mg) THC used in the predictions, although this dose was considered to represent a medium-strong marihuana cigarette [21].NoneofthestudiesinTable2reportedtheamountofTHC consumedperdose, occasionorday.In general,theknowledge about doses of THC smoked by different individuals is quite limited. A recent Spanish study estimated a “median joint” to consistof260mgmarihuanaandtocontain7mgTHC[12].The mediannumberofjointssmokedperoccasionwere3givingan intakeof 21mg peroccasion. Otherstudieshave estimatedan

averagemarihuanajointweighing320mg[11]ortobewithinthe 3500mgrange[32].Ameta-analysisfoundincreasingmeanTHC contentinherbalcannabisovertheyears,reachingabout10%in 2010[33].Thus,ajointof320mgwouldcontainabout32mgTHC.

Howeverallthesestudiesshowedlargevariationsinjointsizeand THCcontent,inadditionsmokersoftentitratetheabsorbeddose byadjustingthewaytheysmokeaccordingtotheinfluencethey experience during smoking [6], and considerable individual variationintheamountabsorbedmightbeexpected[13,14,27].

Asitispossiblethatthedoseusedinthepredictionswasinthe upperendoftheusualdoserange,thepredictedTHCplasmalevels mightprobablybesomewhathigher thanthoseusually experi- encedbynon-dailysmoking.Themostlikelylevelspredictedfor thosesmokingonceaweek(Table1)didgenerallynotexceed2ng/

mlduringtheperioduntilnextsmoking.THCconcentrationsin plasma below 2 ng/ml probablydo not inflict psychomotor or neurocognitiveimpairment,butconcentrationsfrom25ng/ml might[34].Therelations betweenpharmacodynamicand phar- macokineticparametersare,however,limited[28].Somestudies have shown a rough concentration effect relationship for THC levelsinplasma[34–37],whileothershavenot[13].Toleranceto certaineffects ofTHCasa possibleconsequenceofchronicuse havebeen suggestedin somestudies[38],but is not foundby others[39].Itmightthereforebedifficulttorelatecertaincognitive orpsychomotoreffectstothelevelsofTHCbeingpresentbetween smoking sessions for once a week smokers. The chances of persistent cognitive impairment would probably be higher for thosesmokingeverythirdorsecondday,withhigheraccumulated THClevels.Ontheotherhand,developmentoftolerancemight obscuresucheffects.

However,ifweassumethatTHCwillbepresentcontinuouslyin non-dailysmokers,evenifthesmokingoccasionsareseparatedby aweek,wefaceasituationquitedifferentfromthatpresentamong thosedrinkingalcoholonceaweekandwhereethanolhasleftthe bodyafteraday.Fromatoxicologicalpointofviewthepersistent presenceof a psychoactivesubstance (THC)in thebrain,raises questionswhetherthisshouldbegivenmoreattentionasisthe caseelsewhereintoxicologicalthinking.

Presently, itis probably somewhat speculativeto conclude thatTHChasaterminalhalf-lifeofdaysinallusers,whichcould resultin accumulationof THC andpossible chronicimpairing effectsinregularuserswhousecannabisonlyonceoracoupleof daysperweek.Thereare,however,asdiscussedabove,several indicationsthatthiscouldbethecase.AlsoroughestimatesofT

1/2ofTHCfromdatapresentedbyOdellandco-workers[40]and Bergamaschiandco-workers[8]indicatevaluesofmorethan4 daysandaround6days,respectively.Ourcurrentunderstanding ofthepharmacokineticsofTHCmaybelessthancomprehensive.

There is a great need for controlled studies clarifying the accumulationofTHCafterrepeatedcannabissmoking.Smoking frequency,inparticular,shouldbeaddressedinsuchstudies,as this is a critical variable for accumulation. This was recently indicatedinastudywherethefrequencyratherthanamountof cannabis used in the last month correlated better with subsequent blood THC measurements [30]. Because cannabis potencyanduseinmany partsof theworldis increasing,itis fundamental to evaluate the risk of possible neurocognitive impairmentofperiodslastingsubstantiallylongerthanthehours ofacuteinebriation.

DeclarationofCompetingInterest

JMhasreceivedremunerationfromtheNorwegianDepartment ofTransportation,fromNorwegiancourtsandpoliceforreportson THCpharmacokineticsandeffectsrelatedtodrivingbehaviour.JGB doesnothaveanyconflictsofintereststodeclare.

Acknowledgments

Thispaperwaswrittenwiththeuseofinternalfundingonly.

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