Clinical Treatment of Cannabis Use Disorders in … Legalization and Youth: #9 - Clinical Treatment of Cannabis Use Disorders California Society of Addiction Medicine :

MarijuanaLegalizationandYouth: #9-ClinicalTreatmentofCannabisUseDisordersBriefingsforCaliforniaPolicyMakers 1 Banys&CermakRev22July2016

File:9.TreatmentofCUD,Banys&CermakRev2016-07-22.docx 1 CaliforniaSocietyofAddictionMedicine

ClinicalTreatmentofCannabisUseDisordersinAdolescents

PeterBanys,MD,MScTimmenCermak,MD

ExecutiveSummary:

Thereisnouniquetreatmentmodalityforthetreatmentofdependenceoncannabis.Forthemostpart,researchoutcomesstudieshavetestedthesametreatmentmethodsthathavebeenpreviouslydeveloped for other addictive drugs, including 12-step meetings, psychotherapy, cognitive-behavioraltreatments,andmotivationalinterviewing.Youthstudiesrightlyfavorapproachesthatinclude a strong family component. All appear to produce moderate short-term benefits andsignificant rates of relapse (best understood as part of the natural history of any addictiontreatment).And,althoughanumberofpharmaceuticalshavebeentestedtoreducecravingand/orrelapse,nonehavebeenapprovedforuseincannabisdependenceorwithdrawal.

At this time in history, we have more research literature on reasonably effective psychosocialtreatmentinterventionsthanorganizedtreatmentvenuesforadolescentsinCalifornia.Inthemain,adolescents resist treatment for marijuana use, and often require persistent family, school, orjudicial leverage. In California there are few organized treatment resources for adolescents introublewithmarijuana.Mostoften,schoolcounselors,pediatricians,andchildpsychiatristsserveas consultantsanddefacto psychotherapists foryouth in trouble. Inparentaldefiance situations,families with means often resort to a forced passage through an extended wilderness program.These programs are generally in remote rural areaswhere youth can be sequestered from theirusualpeersforoneormoremonthsandcanbesocializedintoprinciplesofrecoveryusingmethodsthatoftenresembleablendofOutwardBoundandbootcamp.Somefamilieswillhavethemeanstocontinuetheirchild’streatmentinequallyisolatedtherapeuticboardingschools;otherswillreturntothehomeenvironmentwheretherearescantorganizedtreatmentorgroupsupportresources.

Itisourthesisthatthegreatestrisksofyoung-onsetmarijuanausearetoeducationandlearning,because school years are particularly vulnerable to many kinds of psychosocial disruptions. Aminority of regular (10-19days/mo.) andheavy (>20days/mo.) userswill transition tomeetingcriteriafordependenceforsomeperiodoftime.

Thisbriefingsummarizestheoptionsandchallengesforthiscohortofthemostseverelyaffected.



CriteriaforaCannabisUseDisorder:

Marijuanause,evenheavyuse, isnot thesameasaclinicaldiagnosisofaCannabisUseDisorder(CUD). For most youthful users marijuana dependence will be a self-limiting process [1]. And,unfortunatelythereisonlyasmallliterature,describedbelow,studyingthetransitionfromregularrecreational use to dependent use. Neither the amounts, nor the frequency, of cannabinoidconsumptionarepresumptiveevidenceforaDSM-VCannabisUseDisorder.DSM-VClinicalcriteriaemphasizeconsequences.

Although heavy users of marijuana are at a higher risk for developing a CUD, especially if theyinitiate use in early teen years, the majority do not go on to a lifelong course of dependence(addiction).Mostteenswhoareregularandheavyusersofmarijuanawilltransitionouttolowornoregularuseintheir20’sand30’s.EuropeandatafromEMCDDA(EuropeanMonitoringCentreforDrugsandDrugAddiction) has found that 20-50% of near-daily users will transition tomeetingdependencecriteria[2].DatafromtheChristchurchcohortinNewZealandfindthatthemajorityofheavyusers transitionoutbytheir late20’sandearly30’s(pleaserefer toEpidemiologybriefingformoredetails).

DSM-V altered the framework for diagnosis. The DSM-IV distinction between abuse anddependencewasdroppedinfavorofdiagnosingCannabisUseDisorderonacontinuumofseverityfromnodiagnosis(0-1diagnosticcriteria)tomild(2-3criteria),moderate(4-5criteria)andsevere(6ormorecriteria)[3].Thischangeunfortunatelyusesthesameterm(disorder)forlightweightaswell as heavyweight problems. In addition, DSM-IV criteria were changed slightly, dropping“recurrentlegalproblems”andadding“craving.”Thesechangesleadtosomedifficultycomparingrecent researchwith earlierwork. Furthermore,manyolder studieshave categorized subjects intermsof frequencyofuse (generallydefining20daysofusepermonthasheavyuse), leading toadditionaldifficulty comparing results.Webelieve thatdaysofuse in thepriormonth remainsavaluablemetricthatisnotcapturedinDSM-V.

Among themost common symptoms seen in the first 21days of cannabiswithdrawal are anger,irritability, anxiety, restlessness, decreased appetite, sleep difficulties, dream rebound, diversephysical complaints, and depressed mood [4, 5]. And it is well-established that daily users will

DSM-VCriteriaforaSubstanceUseDisorderTheDiagnosticandStatisticalManual5definesasubstanceusedisorderasthepresenceofatleast2of11criteria,whichareclusteredinfourgroups:

ImpairedControl:1. Takingmoreorforlongerthanintended,2. Unsuccessfuleffortstostoporcutdownuse,3. Spendingagreatdealoftimeobtaining,

using,orrecoveringfromuse,4. Cravingforsubstance.

RiskyUse:1. Recurrentuseinhazardoussituations,2. Continuedusedespitephysicalor

psychologicalproblemsthatarecausedorexacerbatedbysubstanceuse.

SocialImpairment:1. Failuretofulfillmajorobligationsduetouse,2. Continuedusedespiteproblemscausedor

exacerbatedbyuse,3. Importantactivitiesgivenuporreduced

becauseofsubstanceuse.

PharmacologicDependence:1. Tolerancetoeffectsofthesubstance,2. Withdrawal symptoms when not using or

usingless.



continuetoexcretemetabolitesandtestpositiveforcannabisforamonthormoreaftercessation,althoughtheclinicalsignificanceofthishasnotbeenestablished.

ScreeningInstruments:

Screening instrumentsarenotnecessarilydiagnostic tools,but suchbrief instrumentsdohelp todetermine whichmarijuana usersmight benefit frommore thorough diagnostic assessments. Ingeneral,screeningtoolsarebetteratscoringfrequencyofusethanconsequencesofchronicuse.

Piontek and colleagues have reviewed psychometric properties of several commonly usedscreening instruments [6-9].TheSDS (SeverityofDependenceScale) is a general scale fordiversedrugs and there are conflicting opinions about its utility for adolescents [10, 11]. The CUDIT-R(CannabisUseDisordersIdentificationTest-Revised)[12]hasbeentestedingeneralpopulationsandspecificuser samples.Althoughnotadiagnostic instrumentperse, theCUDIT-R8-itemscreeningtooldistinguishesbetweendifferentlevelsofcannabisuseandratesproblemseverity,andthismayfacilitatematchingofpatientstotreatmentintensity.TheCAST(CannabisAbuseScreeningTest)[7]hasbeentested inFrenchadolescents.TheCUPIT(CannabisUseProblemsIdentificationTest) [13]wasdevelopedinAustraliawithadolescentsandadults.

Atthepresenttime,wehaveinsufficientexperiencewiththesescreeningtoolstorecommendoneoveranother.

EpidemiologyofCannabisUseDisorders&TreatmentNeeds:

NationalData: The2013NationalSurveyofDrugUseandHealthbySAMHSA[14]reportedthat1.76million(7.1%)of12-17yearoldsusedmarijuanaduringthepastmonth. In2013,amongallyouthsaged12to17,anestimated4.8%hadusedmarijuanaforthefirsttimewithinthepastyear.Anestimated1.4millionfirst-timepastyearmarijuanausersinitiatedpriortotheageof18.

CaliforniaData:ThetableonthefollowingpagecombinesCaliforniaHealthyKidsSurvey(CHKS)datafrom2011-13withtheDepartmentofEducation’sestimatesofprojectedenrollmentfor2015-16.Themostsignificantsurveyfindingisthatin2015-16,beforeanylegalizationinitiative,6.1%of11th gradersarealreadyheavyusers,usingmarijuana20ormoredayseachmonth, andanother2.9%areregularusers,using10-19dayseachmonth.(Pleaserefertoourepidemiologybriefingformore details about adolescent youth patterns in California.)Webelieve that risks to educationalprogressaremuchgreaterthanrisksforpersistentaddictionorbraindamage.Marijuanauseisoneofmanyfactorsthatareclearlyassociatedwithdecrementsinschoolperformance.Atpresentitisnotpossibletoteaseoutrelativecausalityamongotherassociatedfactorssuchasalcoholanddruguse,familyandpeer-groupeffects,andculture.

California offers remarkably fewpublic resources for treatment ofbonafide severe cannabis usedisorder (addiction/dependence). There are few treatment facilities that specialize in adolescenttreatment of substance abuse. One example is Thunder Road Adolescent Treatment Center inOakland1,butmostsuchprogramsareunstablyfundedbycombinationsofgrants,insurance,andprivate pay. For-profit residential substance abuse facilities developed for adults, and oftenstructuredwithspa-likeamenities,sometimesofferresidentialtracksforadolescents.Such28-dayor longer programs typically do not satisfy cost-effectiveness criteria. Their costs can be

1http://www.altabatessummit.org/thunderroad/



astonishinglyhigh, and their longer termoutcomesare toutedbutpoorlydocumented.The truthaboutthenaturalhistoryofthetreatmentofanyaddiction,includingteenagecannabisdependence,is that relapse is a predictable, expectable part of the course. “I can have just one” is the mostfrequentpathwaytoaslip.Whatisneededtomaintainabstinenceandpromoterecovery,andwhatismostlymissing,isgroupsupportsystemsinthehomecommunity.

EstimatedMarijuanaUseinCaliforniaHighSchools2015-16:

Familieswithmeansmayinitiallyrelyonamonthormoreinawildernessprogram,mostofwhichareinremoteruralsettings(tointerferewithrunningaway).Suchprogramsofferextendedforcedseparationsfromfamilyandpeersandemphasizeself-relianceactivitiessuchascampingtofostergreater sense of responsibility and altruistic activities such as peer collaboration. They aresomething of a blend of Outward Bound, ropes courses, and boot camp—all in the service ofsocializationintoaworkingconceptofrecoveryandabstinence.Thisis,ofcourse,onlyaninitiationoftreatment.

Free self-help and group support services in the community such Ala-Teen2emphasize alcoholproblems;and,adultself-helpprogramsaretypicallyuncomfortablesettingsforyouth.AlaTeenisfor childrenofalcoholics todealwith the impactofparental addiction.However, in some localesthere are YPAA groups (YoungPeople inAA). They have names like MCYPAA (Marin Co. YPAA),SACYPAA (SacramentoYPAA).The SouthLosAngeles group (SLACYPAA)often refers to “alcoholandotherformsofalcohol”inordertoincludedrugs.

Sustainedtreatmentsupportremainsdifficulttofind,inpart,becausesolittleisofferedwithintheschoolsystem.Onceagain,thereisahugedisparitybetweenresourcesavailableforfamilieswith

2http://www.al-anon.org/for-alateen



means and thosewithout. Thosewith insurancemay turn to pediatricians or child psychiatristswhotypicallyonlyofferindividualcounseling,oftenwithnoexpertiseinaddiction.

JuvenileJusticeinCalifornia:Thejuvenilejusticesystemremainsamajorproviderofservicesforyouthwithoutmeans,butoutcomesdataarehardtofind.TheCaliforniaDivisionofJuvenileJustice(DJJ), previously known as the California Youth Authority (CYA), is a division of the CaliforniaDepartment of Corrections and Rehabilitation (CDCR) that provides education, training, andtreatmentservicesforCalifornia'smostseriousyouthoffenders.TheDJJmaintains11correctionalfacilities, 4 conservation camps and 2 residential drug treatment programs. Following severecriticisms of youth prison conditions and a court order, the legislature mandated a majorreorganization.

Havingsaidthat,mostsubstanceabuseservicesareactuallyofferedaspartofacommunity-basedprobationsystem—butwehavenotbeenabletofinddataonmethodsandoutcomes.WedoknowthatinCaliforniamostjuvenilemarijuanaarrestsareplea-bargainedandaremorelikelytoleadtoprobationthanincarceration.AsnotedintheMitigationofLegalHarmsbriefing,itisnotclearwhysomeyouth continue tobe chargedwithmisdemeanorswhileothers are chargedwith infractionfines(possessionoflessthanoneounceofmarijuanabecameaninfractionoffensein2011).

And,atthiswriting,wehaveinsufficientknowledgetomeaningfullycommentonwhatconstitutes“treatment”inthisadjudicatedsystem.

InsuranceCoverageinCalifornia:InDecember2014,theCaliforniaSocietyofAddictionMedicine(CSAM) published a consumer guide and scorecard for substance abuse coverage in Californiaunder the Affordable Care Act bronze plans in Covered California3. This scorecard did notspecificallyanalyzeresourcesavailableforyouthsubstanceabusetreatment.

SignificantCUDTreatmentStudies:

There are several comprehensive reviews of treatmentforCannabisUseDisorders[15-19].Thesesummarizethestill-limited research on a variety of methods. Ofparticular note are materials from Australia’s NationalCannabis Prevention and Information Centre (NCPIC)4, ascientifically soundandbalancedresource.Analogous inthe U.S. are NIH’s NIDA website5and the SAMHSAwebsite6.

In our opinion, the single best present-day guide toclinical treatment is the 115 page guide developed forNCPICbyCopeland,Frewen,andElkins[15].

Severalwell-controlled studies are highlighted below tofurther inform the nature of the transitions from heavyusetodependence,alittle-studied,butimportanttopic,tobetter understand the frequency and risk factors for 3http://www.csam-asam.org/sites/default/files/pdf/csam_guide-scorecard-dec2014.pdf4NCPIC:https://ncpic.org.au/5NIDA:http://www.nih.gov/news/health/jun2014/nida-04.htm)6SAMHSA:(http://www.samhsa.gov/atod/cannabis)



relapsefromabstinence,andtoemphasizetheneedfortreatmentmethodsthatengagethefamily.

Transition fromuse todependence: NationalHouseholdSurvey2001: Chen et al. (2005) [20]analyzed adult and adolescent data from the 2000-2001 National Household Survey to bettercharacterize the risks of cannabis dependence. They looked at 3,352 respondents who initiatedcannabisuseintheprior2years.Approximately3.9%ofrecent-onsetusersdevelopeddependencewithin24months.Riskswereincreasedforonsetbeforelate-adolescence,forlowincome,andforpoly-drugusepriortocannabisinitiation.

Netherlands2013:InvanderPoletal.’slargeDutchtransitionstudyofsixhundred18-30yearoldregularusers,36.7%ofthemtransitionedoverthreeyearstomeetingdiagnosticcriteriaforDSM-IVdependenceoncannabis[21,22].Thestudyevaluatedvulnerabilityfactorspreviouslyidentifiedingeneral studiesof illicitdruguseandstress factors thought tobeassociatedwithdependence.Remarkably,cannabisexposurevariableswerenotpredictiveofthetransitionfromnon-dependentto dependent cannabis use. They also unexpectedly found that none of the sociodemographicvariablespredictedcannabisdependence,exceptlivingalone.Thebaselinecannabisusevariablesthatdidpredictcannabisdependenceincludedadiagnosisof12-monthabuse,numberoflifetimeCUDsymptoms,continualsmokingandusingindaytime,andcopingmotivesforuse.Lifetimeandcurrent mental disorders were frequent in both family members and participants but thesedisorders were not predictive. Smoking marijuana as a coping strategy emerged as a majorpredictivefactor.

Thisimpliesthatinayoungadultpopulation,acutestressfuleventsarestrongerpredictorsofdependencethanthepresenceofrelativelystablevulnerabilityfactors.Amajorfinancialproblemwasthestrongestpredictoramongallnegativelifeevents.Also,livingalonewasastrongpredictor….[22]

Transitionbackfromabstinencetorelapse:TheNationalEpidemiologicalSurveyofAlcoholandRelatedConditions (NESARC)analyzed theoddsof relapseof anon-treatmentpopulation of2,350adults (18 and over) [23]. The relapse to a CUDwas only 6.6% over a 3.6 year window. Majordepressivedisorderwas identifiedasapredictive factor for relapse.The investigators concludedthat,“TheoddsofCUDrelapsefoundinourstudyaremuchlowerthanthosereportedinstudiesofclinical samples possibly due to lower average severity of CUD, less psychiatric comorbidity andhealthissues,andlessexposuretohigh-riskenvironments,amongcommunityratherthanclinicalsamples[23]p.131”.

Moore and Budney [24] studied 82 adults intreatment who had achieved at least twoweeks ofabstinence.Seventy-onepercentrelapsedatleastonceduringthefirst6monthsofcare.

CannabisYouthStudy(CYT),USA2004:SAMHSAtestedfiveshort-termoutpatientinterventionmodelsinfoursitesforadolescentswithCUDs[25,26].Sixhundredyoung(ages15-16)cannabisuserswerepredominatelywhitemales.Thefiveformsoftreatmentofferedinseveralcombinationsand intensities were (1) Motivational Enhancement Therapy (MET), (2) Cognitive BehavioralTreatment (CBT), offered in 5 or 12 session doses, (3) Adolescent Community ReinforcementApproach(ACRA),(4)MultidimensionalFamilyTherapy(MDFT),and(5)FamilySupportNetwork(FSN).

Allfiveinterventionsdemonstratedstatisticallysignificantpre-posttreatmentimprovementsover12monthsasmeasuredbydaysofabstinenceandthepercentofadolescentsinrecovery(nouseorabuse/dependenceproblemsandlivinginthecommunity).Clinicaloutcomesweredisappointinglysimilaracrossmodalitiesandconditions.Indeed,theCannabisYouthTreatmentStudyalsoshowed



that, while the initial intervention was often effective, half of the adolescents experiencedintermittentrelapseoneormoretimesafterdischarge.Two-thirdsstillreportedsubstanceuseorrelated problems at 12-month follow-up. The study’s authors concluded that cannabis diagnosesarebestunderstoodaschronicconditionsrequiringaneedtofocusmoreonlong-termmonitoringandcare.

Multidimensional FamilyTherapy (MDFT), Europe2013: In 2011, TheEuropeanMonitoringCenter forDrugs andDrugAddiction (EMCDDA 2013) reported that over 109,000 cannabis andcannabis-associatedproblemcaseswerereportedbyoutpatienttreatmentservicesintheEuropeanUnion[27].Cannabiswassecondonlytoheroin.Europeaninvestigators,havingreviewedtheCYTandotherstudies,decidedonalargemulti-sitetrialofMDFTasthemostpromisingoftheavailableinterventionsandtesteditagainstindividualpsychotherapy(IP)acommoninterventioninEurope[28-30].

Thetrans-national trialwascalledthe InternationalNeedforCannabisTreatment (INCANT)study.Study participants (n=450) were recruited at outpatient secondary level addiction, youth, andforensic care clinics in Brussels, Berlin, Paris, The Hague, and Geneva. Participants wereadolescents(ages13-18)witharecentcannabisusedisorder.Bothmethodsworked,butover12months,MDFToutperformedindividualpsychotherapyinreducingdrug-usingdaysandretainingsubjectsintreatment.

ClinicalChallenges:Adultheavyusersusuallyestablish therapeuticcontact themselves(often inresponse to a partner’s pressure), but for adolescents, the parents are more likely to make theinitialcontactwithaclinician.Mostheavymarijuanausersarenotreluctanttodiscusstheiruseiftheir rationales for use are explored rather than attacked. The principles of motivationalinterviewing (MI) provide excellent guidelines for initiating dialogue about a patient’smarijuanause [31, 32]. MI elicits behavior change by helping patients explore and resolve their latentambivalence. It accepts that patients are at different levels of readiness for change and is non-judgmental and non-adversarial. The motivation to change arises from patients’ articulation ofwarded-off ambivalent feelings, usually related to real-world consequences of use. MotivationalInterviewingtechniquesrequireclinicianstoengageinactivedialogue[33,34].Evensinglesessioninterventionshavedemonstratedsignificantdeclines incannabisuseat threemonth follow-up inbothadultsandadolescents[35].

TypicalPatternsofRationalization: Several common themes run throughpatients'denial thatmarijuanacancauseproblems.Generallyspeaking,mostheavyuserswillstate that theycanquitany time they so desire, that marijuana is beneficial for them, that authorities and parents arehypocritesgiven theirownuseofalcoholandpills,and that theynoticenodifference in functionwhentheyquitforafewdays.

• “EveryoneIknowusesweed.”• “Itcan’tbeharmful–it’snaturalandorganic.”• “Nooneeverdiedfromamarijuanaoverdose.”• “Itmakesmefeelbetter.Ifeelmoreawareofthingsaroundme”• “Ithelpsmestudyboringsubjects”• “Ihaveamedicalmarijuanacard,andIhavearighttotreatmymood.”

Individual assessment and treatment depends on developing a non-confrontational therapeuticrelationship, beginning with eliciting the patient’s experience with marijuana, often initiallypresentedby the adolescent as entirelypositive. Inevitably therehavebeen somepersonal costsand getting to them will evoke the cognitive dissonance that is needed to drive change. The



principles of motivational interviewing respect patients’ ambivalence and encourage them towrestlewiththeirownpositiveandnegativefacts.

MedicationStudiesforTreatmentofCUD:

Thereisasmallamountofresearchonmedications,includingoralTHC[36],toreducesymptomsofcannabiswithdrawal, and somemedicationsmay help in the short-term. However, there are noapprovedmedstoreducecravingortoreducetheoddsofrelapse.

Currently [April 2015], no medications are indicated for the treatment of marijuana usedisorder,butresearchisactiveinthisarea.Becausesleepproblemsfeatureprominentlyinmarijuanawithdrawal,somestudiesareexaminingtheeffectivenessofmedicationsthataidinsleep.Medicationsthathaveshownpromiseinearlystudiesorsmallclinicaltrialsincludethe sleepaid zolpidem(Ambien®), ananti-anxiety/anti-stressmedicationcalledbuspirone(BuSpar®), and an anti-epileptic drug called gabapentin (Horizant®, Neurotin®) that mayimprove sleep and, possibly, executive function. Other agents being studied include thenutritional supplementN-acetylcysteine and chemicals called FAAH inhibitors,whichmayreduce withdrawal by inhibiting the breakdown of the body’s own cannabinoids. Futuredirections include the study of substances called allostericmodulators that interact withcannabinoidreceptorstoinhibitTHC’srewardingeffects.

http://www.drugabuse.gov/publications/research-reports/marijuana/available-treatments-marijuana-use-disorders

Two of themedications that have been reported of value in treating cannabis dependencewereadministered in the context of structured psychosocial treatment. N-acetylcysteine (NAC), aresearch compound, that is available over the counter, more than doubled the odds of havingnegativeurinecannabinoidtestsascomparedwithplacebo,withbenefitsdetectablewithinaweekof treatment initiation [37]. For cannabis dependent patients who have discontinued use,gabapentin substantially reducedwithdrawal symptoms [38]. Sleepandmooddisturbanceswerereduced, aswas craving. Executive functionswere improvedwithin the firstweek, an importantfactor in patients’ ability to make effective use of treatment. Such small studies have not beenwidelyvalidated;and,neithermedicationisapprovedforuseintreatingcannabisusedisorders.

MarijuanaLegalizationandYouth: #9-ClinicalTreatmentofCannabisUseDisordersBriefingsforCaliforniaPolicyMakers 9 Banys&Cermak23May2015


ENDNOTES:1. Farmer,R.F.,etal.,Naturalcourseofcannabisusedisorders.PsycholMed,2015.45(1):p.63-72.

BACKGROUND:Despite its importance as a public health concern, relatively little is known about the naturalcourseofcannabisusedisorders(CUDs).Theprimaryobjectiveofthisresearchwastoprovidedescriptivedataontheonset,recoveryandrecurrencefunctionsofCUDsduringthehigh-riskperiodsofadolescence,emergingadulthoodandyoungadulthoodbasedondatafromalargeprospectivecommunitysample.METHOD:Probands(n=816) fromtheOregonAdolescentDepressionProject(OADP)participated in fourdiagnosticassessments(T1-T4)betweentheagesof16and30years,duringwhichcurrentandpastCUDswereassessed.RESULTS:TheweightedlifetimeprevalenceofCUDswas19.1%withanaverageonsetageof18.6years.Althoughgenderwasnotsignificantly related to theageof initialCUDonset,menweremore likely tobediagnosedwitha lifetimeCUD. Of those diagnosed with a CUD episode, 81.8% eventually achieved recovery during the study period.Women achieved recovery significantly more quickly than men. The recurrence rate (27.7%) was relativelymodest,andmost likely tooccurwithinthe first36months followingtheoffsetof the firstCUDepisode.CUDrecurrence was uncommon after 72 months of remission and recovery. CONCLUSIONS: CUDs are relativelycommon, affecting about one out of five persons in the OADP sample prior to the age of 30 years. Eventualrecovery from index CUD episodes is the norm, although about 30%of thosewith a CUD exhibit a generallypersistentpatternofproblematicuseextending7yearsorlonger.

2. EMCDDA,Cannabis.AnnualReport2009:TheStateoftheDrugsProbleminEurope2009, EuropeanMonitoringCentreforDrugsandDrugAbuse:Lisbon.p.38-47.

3. Compton, W.M., et al., Crosswalk between DSM-IV dependence and DSM-5 substance use disorders for opioids,cannabis,cocaineandalcohol.DrugAlcoholDepend,2013.132(1-2):p.387-90.

BACKGROUND:AscertainingagreementbetweenDSM-IVandDSM-5isimportanttodeterminetheapplicabilityof treatments forDSM-IVconditions topersonsdiagnosedaccording to theproposedDSM-5.METHODS:DatafromanationallyrepresentativesampleofUSadultswereused tocompareconcordanceofpast-yearDSM-IVopioid, cannabis, cocaineandalcoholdependencewithpast-yearDSM-5disorders at thresholdsof3+,4+,5+and6+positiveDSM-5criteriaamongpast-yearusersofopioids(n=264),cannabis(n=1622),cocaine(n=271)and alcohol (n=23,013). Substance-specific 2 x 2 tables yielded overall concordance (kappa), sensitivity,specificity,positivepredictivevalues(PPV)andnegativepredictivevalues(NPV).RESULTS:ForDSM-IValcohol,cocaine and opioid dependence, optimal concordance occurred when 4+ DSM-5 criteria were endorsed,corresponding to the threshold for moderate DSM-5 alcohol, cocaine and opioid use disorders. MaximalconcordanceofDSM-IVcannabisdependenceandDSM-5cannabisusedisorderoccurredwhen6+criteriawereendorsed,correspondingtothethresholdforsevereDSM-5cannabisusedisorder.Attheseoptimalthresholds,sensitivity, specificity, PPV and NPV generally exceeded 85% (>75% for cannabis). CONCLUSIONS: Overall,excellentcorrespondenceofDSM-IVdependencewithDSM-5substanceusedisorderswasdocumentedinthisgeneralpopulationsampleofalcohol,cannabis,cocaineandopioidusers.ApplicabilityoftreatmentstestedforDSM-IVdependenceissupportedbytheseresultsforthosewithaDSM-5alcohol,cocaineoropioidusedisorderofatleastmoderateseverityorseverecannabisusedisorder.Furtherresearchisneededtoprovideevidenceforapplicabilityoftreatmentsforpersonswithmildersubstanceusedisorders.

4. Allsop,D.J.,etal.,Quantifyingtheclinicalsignificanceofcannabiswithdrawal.PLoSOne,2012.7(9):p.e44864.

BACKGROUND AND AIMS: Questions over the clinical significance of cannabis withdrawal have hindered itsinclusionasadiscretecannabisinducedpsychiatricconditionintheDiagnosticandStatisticalManualofMentalDisorders(DSMIV).Thisstudyaimstoquantifyfunctionalimpairmenttonormaldailyactivitiesfromcannabiswithdrawal,andlooksatthefactorspredictingfunctionalimpairment.Inadditionthestudyteststheinfluenceof functional impairment from cannabiswithdrawal on cannabis use during and after an abstinence attempt.METHODS ANDRESULTS: A volunteer sample of 49 non-treatment seeking cannabis userswhomet DSM-IVcriteria for dependence provided daily withdrawal-related functional impairment scores during a one-weekbaselinephaseandtwoweeksofmonitoredabstinencefromcannabiswithaonemonthfollowup.Functionalimpairment from withdrawal symptoms was strongly associated with symptom severity (p=0.0001).Participantswithmoreseverecannabisdependencebeforetheabstinenceattemptreportedgreaterfunctionalimpairment from cannabis withdrawal (p=0.03). Relapse to cannabis use during the abstinence period wasassociatedwithgreaterfunctionalimpairmentfromasubsetofwithdrawalsymptomsinhighdependenceusers.Higherlevelsoffunctionalimpairmentduringtheabstinenceattemptpredictedhigherlevelsofcannabisuseatone month follow up (p=0.001). CONCLUSIONS: Cannabis withdrawal is clinically significant because it isassociatedwithfunctionalimpairmenttonormaldailyactivities,aswellasrelapsetocannabisuse.Samplesizein the relapse group was small and the use of a non-treatment seeking population requires findings to be



replicated in clinical samples. Tailoring treatments to targetwithdrawal symptoms contributing to functionalimpairmentduringaquitattemptmayimprovetreatmentoutcomes.

5. Budney,A.J.andJ.R.Hughes,Thecannabiswithdrawalsyndrome.CurrOpinPsychiatry,2006.19(3):p.233-8.

PURPOSE OF REVIEW: The demand for treatment for cannabis dependence has grown dramatically. Themajority of thepeoplewho enter the treatment havedifficulty in achieving andmaintaining abstinence fromcannabis. Understanding the impact of cannabis withdrawal syndrome on quit attempts is of obviousimportance.Cannabis,however,haslongbeenconsidereda'soft'drug,andmanycontinuetoquestionwhetheronecantrulybecomedependentoncannabis.Skepticismistypicallyfocusedonwhethercannabisusecanresultin 'physiological' dependence or withdrawal, and whether withdrawal is of clinical importance. RECENTFINDINGS: The neurobiological basis for cannabis withdrawal has been established via discovery of anendogenous cannabinoid system, identification of cannabinoid receptors, and demonstrations of precipitatedwithdrawalwithcannabinoidreceptorantagonists.Laboratorystudieshaveestablishedthereliability,validity,andtimecourseofacannabiswithdrawalsyndromeandhavebeguntoexploretheeffectofvariousmedicationson suchwithdrawal. Reports from clinical samples indicate that the syndrome is common among treatmentseekers.SUMMARY:Aclinicallyimportantwithdrawalsyndromeassociatedwithcannabisdependencehasbeenestablished.Additional researchmustdeterminehowcannabiswithdrawalaffects cessationattemptsand thebestwaytotreatitssymptoms.

6. Legleye, S., D. Piontek, and L. Kraus, PsychometricpropertiesoftheCannabisAbuseScreeningTest(CAST) inaFrenchsampleofadolescents.DrugAlcoholDepend,2011.113(2-3):p.229-35.

PURPOSE: Psychometric and screening properties of the Cannabis Abuse Screening Test (CAST) wereinvestigatedusingDSM-IVdiagnosesofcannabisdependence(CD)andcannabisusedisorders(CUD)asexternalcriteria. Performance of the binary and the full version of the CASTwere compared.METHODS: The sampleconsistedof2566Frenchadolescentsaged17whoreportedcannabisuse12monthspriortothesurvey.TheMunich Composite International Diagnostic Interview (M-CIDI) was used as a gold standard for DSM-IVdiagnoses. Internal consistency (Cronbach's alpha), construct validity (exploratory and confirmatory factoranalyses, correlation of CAST scores with related variables), and criterion validity (Receiver OperatingCharacteristic analyses) were assessed. RESULTS: Both CAST versions were unidimensional and Cronbach'salphawas0.748forthebinaryand0.775forthefullversion.HighandcomparableAUCvaluesindicateagoodabilityofbothtestversionstodiscriminatebetweenindividualswithandwithoutaclinicaldiagnosis.Basedonbalancedsensitivityandspecificity,theoptimalcut-offscoresforCDandCUDwere2forthebinaryand3or4for the full version. While both versions largely overestimated CD prevalence, CUD prevalence was slightlyunderestimated.CONCLUSIONS:ThebinaryandthefullversionoftheCASTareequallyusefulforscreeningforcannabis-relateddisorders.Bothclinicalandresearchapplicationsof thescalearepossible.TheCASTmaybeusedforestimatingCUDprevalenceratherthanCDprevalence.Theultimatechoiceofthecut-offdependsonthepurposeofthespecificstudyusingtheCAST.

7. Legleye,S.,etal.,AvalidationoftheCannabisAbuseScreeningTest(CAST)usingalatentclassanalysisoftheDSM-IVamongadolescents.IntJMethodsPsychiatrRes,2013.22(1):p.16-26.

ThispaperexploredthelatentclassstructureoftheDiagnosticandStatisticalManualofMentalDisorders,4thEdition (DSM-IV) (assessed with the Munich Composite International Diagnostic Interview). Secondly, thescreeningpropertiesoftheCannabisAbuseScreeningTest(CAST)inadolescentswereassessedwithclassicaltest theory using the latent class structure as empirical gold standard. The sample comprised 3266 Frenchcannabisusersaged17to19fromthegeneralpopulation.Threelatentclassesofcannabisuserswereidentifiedreflecting a continuumof problem severity: non-symptomatic,moderate and severe.Gender-specific analysesshowed thebestmodel fit, althoughresultswerealmost identical in the total sample.The latentclassesweregood predictors of daily cannabis use, number of joints per day and age of first experimentation. The CASTshowedgoodscreeningpropertiesforthemoderate/severeclass(areaunderreceiveroperatingcharacteristiccurve>0.85)andverygoodforthesevereclass(0.90). Itwasmoresensitiveforboys,morespecific forgirls.Although structural equivalence across gender was rejected, results suggest small gender differences in thelatentstructureoftheDSM-IV.TheperformanceoftheCASTinscreeningforthelatentclassstructurewasgoodandsuperiortothoseobtainedwiththeclassicalDSM-IVdiagnoses.

8. Piontek,D.,L.Kraus,andD.Klempova,Shortscalestoassesscannabis-relatedproblems:areviewofpsychometricproperties.SubstAbuseTreatPrevPolicy,2008.3:p.25.

AIMS:Thepurposeofthispaperistosummarizethepsychometricpropertiesoffourshortscreeningscalestoassess problematic forms of cannabis use: Severity of Dependence Scale (SDS), Cannabis Use DisordersIdentificationTest (CUDIT), CannabisAbuseScreeningTest (CAST) andProblematicUseofMarijuana (PUM).METHODS: A systematic computer-based literature search was conducted within the databases of PubMed,



PsychINFOandAddictionAbstracts.Atotalof12publicationsreportingmeasuresofreliabilityorvaliditywereidentified:8concerningSDS,2concerningCUDITandoneconcerningCASTandPUM.Studiesspannedadultandadolescentsamplesfromgeneralandspecificuserpopulationsinanumberofcountriesworldwide.RESULTS:Allscreeningscalestendedtohavemoderatetohighinternalconsistency(Cronbach'salpharangingfrom.72to.92).Test-retestreliabilityanditemtotalcorrelationhavebeenreportedforSDSwithacceptableresults.Resultsof validation studies varied depending on study population and standards used for validity assessment, butgenerally sensitivity, specificity and predictive power are satisfactory. Standard diagnostic cut-off points thatcanbegeneralized todifferentpopulationsdonotexist foranyscale.CONCLUSION:Shortscreeningscales toassess dependence and other problems related to the use of cannabis seem to be a time and cost savingopportunity toestimateoverallprevalencesof cannabis-relatednegative consequencesand to identify at-riskpersonspriortousingmoreextensivediagnosticinstruments.Nevertheless,furtherresearchisneededtoassesstheperformanceofthetestsindifferentpopulationsandincomparisontobroadercriteriaofcannabis-relatedproblemsotherthandependence.

9. Piontek, D., et al.,ThevalidityofDSM-IVcannabisabuseanddependencecriteriainadolescentsandthevalueofadditionalcannabisuseindicators.Addiction,2011.106(6):p.1137-45.

AIMS: This study assessed the validity of DSM-IV cannabis abuse and dependence criteria in an adolescentgeneral population sample and evaluated the usefulness of additional cannabis use indicators. DESIGN ANDSETTING:Datacamefromthe2008SurveyonHealthandConsumptionduringtheDayofDefensePreparation(ESCAPAD), a cross-sectional self-administered survey conducted in France. PARTICIPANTS: The analyticalsample comprised 3641 adolescents aged 17-19 years who reported cannabis use in the past 12 months.MEASUREMENTS: To assess DSM-IV criteria of cannabis abuse and dependence, the Munich CompositeInternationalDiagnosticInterview(M-CIDI)wasused.Asadditionalcannabisuseindicators,dailyuse,usewhenalone and use before midday were assessed. Confirmatory factor analyses and two-parameter logistic itemresponsetheory(IRT)modelswererun.DifferentialitemfunctioningwasassessedusingtheIRTlog-likelihoodratioapproach.RESULTS:Aone-factormodelcomprisingbothabuseanddependencecriteriashowedthebestfit to the data. Abuse item legal problems showed the greatest severity, whereas dependence itemslarger/longerandtolerancewerefoundleastsevere.Discriminatorypowerwaslowestforimpairedcontrolandlegalproblems.Additionalcannabisuse indicators increased theprecisionof theoverallDSM-IVcriterionset.Gender-based differential item functioning was observed for items tolerance, withdrawal and use beforemidday.CONCLUSION:ThecurrentDSMconceptualizationwithtwodistinctandgradeddiagnosticclasseshaslimitedvalidityamongadolescents.Inforthcomingrevisionsoftheclassificationsystem,severalexistingcriteriashouldberevisedordropped,newindicatorsofsubstanceusedisordersshouldbeincludedandgendershouldbeconsidered.

10. Martin,G.,etal.,TheSeverityofDependenceScale(SDS)inanadolescentpopulationofcannabisusers:reliability,validityanddiagnosticcut-off.DrugAlcoholDepend,2006.83(1):p.90-3.

The Severity ofDependence Scale (SDS) is a five-item scale that has been reported to be a reliable and validscreeninginstrumentfordependenceandameasureofdependenceseverityinadultsacrossseveralsubstanceclasses.Todatenodatahavebeenreportedonitsperformanceinapopulationofadolescentcannabisusers.Thecurrent study assessed the psychometric properties of the SDS in a community sample of 14-18-year-oldadolescent cannabis users (n=100). Internal consistency (alpha=0.83) and test-retest coefficients (ICC=0.88)werehighandaprincipalcomponentsanalysisofthescalefoundallitemstoloadonasinglefactor.TotalSDSscorecorrelatedsignificantlywith frequencyofcannabisuseandnumberofDSM-IVdependencecriteriamet,indicatinggoodconcurrentvalidity.ReceiverOperatingCharacteristiccurveanalysiswasusedtodeterminethemostappropriateSDScut-offscoreforuseasanindicatorofcannabisdependence,withoptimaldiscriminationatanSDSscoreof4.ThesefindingsindicatethattheSDSisareliableandvalidmeasureofseverityofcannabisdependence among adolescents, has high diagnostic utility, and that an SDS score of 4may be indicative ofcannabisdependence.

11. vanderPol,P.,etal.,ReliabilityandvalidityoftheSeverityofDependenceScalefordetectingcannabisdependenceinfrequentcannabisusers.IntJMethodsPsychiatrRes,2013.22(2):p.138-43.

TheSeverityofDependenceScale (SDS)measureswith five items thedegreeofpsychologicaldependenceonseveralillicitdrugs,includingcannabis.Itspsychometricpropertieshavenotyetbeenexaminedinyoungadultfrequent cannabis users, an eminently high-risk group for cannabis dependence. Internal consistency andcriterion validity of the SDS were investigated within an enriched community based sample of 577 Dutchfrequent (>/= three days per week in the past 12 months) cannabis users between 18-30 years. Criterionvalidity was tested against the Composite International Diagnostic Interview (CIDI) 3.0 DSM-IV diagnosiscannabis dependence, and psychometric properties were assessed separately for males and females and forethnicsubgroups.PrincipalcomponentanalysisshowedthatallitemsofthescaleloadedonasinglefactorandreliabilityoftheSDStotalscorewasgood(Cronbach'salpha=0.70).However,criterionvalidityagainsttheCIDI



diagnosiscannabisdependencewaslow:areaundercurve(AUC)was0.68(95%confidenceinterval:0.64-0.73)andattheoptimaldifferentiatingcut-off(SDS>/=4),sensitivitywas61.3%andspecificity63.5%.Resultsweresimilar for subgroups on gender and ethnicity. While internal consistency of the SDS is good, its use as ascreenertodifferentiatebetweendependenceandnon-dependencewithinpopulationsofyoungadultfrequentcannabisusersisnotrecommended.

12. Adamson,S.J.,etal.,Animprovedbriefmeasureofcannabismisuse:theCannabisUseDisordersIdentificationTest-Revised(CUDIT-R).DrugAlcoholDepend,2010.110(1-2):p.137-43.

BACKGROUND: Cannabis is widely used and significant problems are associated with heavier consumption.When a cannabis misuse screening tool, the CUDIT, was originally published it was noted that although itperformedwelltherewasconcernaboutindividualitems.METHODS:144patientsenrolledinaclinicaltrialforconcurrentdepressionandsubstancemisusewereadministeredanexpandedCUDIT,containingtheoriginal10itemsand11candidatereplacementitems.Allpatientswereassessedforacurrentcannabisusedisorderwiththe SCID. RESULTS: A revised CUDIT-R was developed containing 8 items, two each from the domains ofconsumption, cannabisproblems(abuse),dependence,andpsychological features.Although thepsychometricadequacy of the original CUDIT was confirmed, the CUDIT-R was shorter and had equivalent or superiorpsychometric properties. High sensitivity (91%) and specificity (90%)were achieved. CONCLUSIONS: The 8-itemCUDIT-Rhasimprovedperformanceovertheoriginalscaleandappearswellsuitedtothetaskofscreeningforproblematiccannabisuse.Itmayalsohavepotentialasabriefroutineoutcomemeasure.

13. Bashford, J., R. Flett, and J. Copeland, The Cannabis Use Problems Identification Test (CUPIT): development,reliability,concurrentandpredictivevalidityamongadolescentsandadults.Addiction,2010.105(4):p.615-25.

AIMS:TodescribetheempiricalconstructionandinitialvalidationoftheCannabisUseProblemsIdentificationTest (CUPIT), a brief self-report screening instrument for detection of currently and potentially problematiccannabisuse.DESIGN:Inathree-phaseprospectivedesignanitempoolofcandidatequestionswasgeneratedfroma literature review and extensive expert consultation. TheCUPIT internal structure, cross-sectional andlongitudinal psychometric properties were then systematically tested among heterogeneous past-year users.PARTICIPANTS:Volunteerparticipantswere212high-riskadolescents(n=138)andadults(n=74)aged13-61years frommultiple community settings. MEASUREMENTS: The comprehensive assessment battery includedseveral established measures of cannabis-related pathology for CUPIT validation, with DSM-IV/ICD-10diagnoses of cannabis use disorders as criterion standard. FINDINGS: Sixteen items loading highly on twosubscales derived fromprincipal components analysis exhibited good to excellent test-retest (0.89-0.99) andinternal consistency reliability (0.92,0.83), andhighly significantability todiscriminatediagnostic subgroupsalong the severity continuum(non-problematic, risky,problematicuse).Twelvemonths later,baselineCUPITscores demonstrated highly significant longitudinal predictive utility for respondents' follow-up diagnosticgroupmembership. Receiver operating characteristic (ROC) analysis identified a CUPIT score of 12 to be theoptimalcut-pointformaximizingsensitivityforbothcurrentlydiagnosablecannabisusedisorderandthoseatrisk ofmeeting diagnostic criteria in the following 12months. CONCLUSIONS: The CUPIT is a brief cannabisscreener that is reliable,validandacceptable foruseacrossdiversecommunitysettingsandconsumersofallages.TheCUPIThasclearpotentialtoassistwithachievementofpublichealthgoalstoreducecannabis-relatedharmsinthecommunity.

14. SAMHSA.Resultsfromthe2013NationalSurveyonDrugUseandHealth:SummaryofNationalFindings.NSDUHSeriesH-48,HHSPublNo(SMA)14-48632014SAMHSA;Thisreportpresentsdetailedresultsfromthe2013NationalSurveyonDrugUseandHealth(NSDUH),anannualsurveysponsoredbytheSubstanceAbuseandMentalHealthServicesAdministration(SAMHSA).Thesurveyistheprimarysourceofinformationontheuseofillicitdrugs,alcohol,andtobaccointhecivilian,noninstitutionalizedpopulationoftheUnitedStatesaged12 years old or older. Approximately 67,500persons are interviewed inNSDUH each year. Unless otherwisenoted,allcomparisonsinthisreportthataredescribedusingtermssuchas"increased,""decreased,"or"morethan"arestatisticallysignificantatthe.05level.

15. Copeland,J.,A.Frewen,andK.Elkins.Managementofcannabisusedisorderandrelatedissues(NCPICAustralia).2009 National Cannabis Prevention and Information Centre; Available from:https://ncpic.org.au/media/1594/management-of-cannabis-use-disorder-and-related-issues-a-clinicians-guide.pdf

16. Copeland,J.andW.Swift,Cannabisusedisorder:epidemiologyandmanagement.IntRevPsychiatry,2009.21(2):p.96-103.

Thispaperprovidesanoverviewoftheepidemiologyofcannabisuse,cannabisusedisordersanditstreatment.Cannabisisthemostcommonlyusedillicitdruginternationally.Whileuseisdecreasinginthedevelopedworld,itappearstobestableorincreasingindevelopingcountriesandsomeindigenouscommunities.Earlyinitiation



and regularadolescentusehavebeen identifiedasparticular risk factors for laterproblematic cannabis (andotherdrug)use, impairedmentalhealth,delinquency, lowereducational achievement, risky sexualbehaviourandcriminaloffendinginarangeofstudies.Itisestimatedthatapproximatelyoneintenpeoplewhohadeverusedcannabiswillbecomedependentwithriskincreasingmarkedlywithfrequencyofuse.Therehasbeenanincrease in the proportion of treatment provided for cannabis use. There are as yet no evidence-basedpharmacotherapiesavailableforthemanagementofcannabiswithdrawalandcraving.Relativelybriefcognitivebehavioural therapy and contingency management have the strongest evidence of success, and structured,family-based interventions,providepotent treatmentoptions foradolescents.Withcriminally involvedyoungpeople and those with severe, persistent mental illness, longer and more intensive therapies provided byinterdisciplinaryteamsmayberequired.

17. McRae,A.L.,A.J.Budney, andK.T.Brady,Treatmentofmarijuanadependence:areviewoftheliterature. J SubstAbuseTreat,2003.24(4):p.369-76.

Until recently, relatively little research has focused on the treatment of marijuana abuse or dependence;however,marijuanausedisordersarenowreceivingincreasedattention.Thispaperreviewstheinitialclinicaltrials evaluating the efficacy of outpatient treatments for adult marijuana dependence. Findings from fivecontrolledtrialsofpsychotherapeutic interventionssuggestthatthisdisorderappearsresponsivetothesametypesoftreatmentasothersubstancedependencies.Moreover,theseinitialstudiessuggestthatmanypatientsdonotshowapositivetreatmentresponse,indicatingthatmarijuanadependenceisnoteasilytreated.Strengthsand weaknesses of the data are presented. Preliminary data from less controlled studies relevant to thetreatmentofmarijuanadependencearediscussedtosuggest futureresearchareas.Althoughveryfewstudiesontreatmentformarijuanaabuseanddependencehavebeencompleted,theinitialreportsidentifypromisingtreatmentapproachesanddemonstrateaneedformoreresearchonthedevelopmentofeffectiveinterventions.

18. NIDAPrinciplesofDrugAddictionTreatment:AResearch-BasedGuide.2009.

19. Budney,A.J.,etal.,Marijuanadependenceanditstreatment.AddictSciClinPract,2007.4(1):p.4-16.

The prevalence of marijuana abuse and dependence disorders has been increasing among adults andadolescents in the United States. This paper reviews the problems associated with marijuana use, includinguniquecharacteristicsofmarijuanadependence,andtheresultsof laboratoryresearchandtreatmenttrialstodate.Italsodiscusseslimitationsofcurrentknowledgeandpotentialareasforadvancingresearchandclinicalintervention.

20. Chen, C.Y., M.S. O'Brien, and J.C. Anthony, Who becomes cannabis dependent soon after onset of use?EpidemiologicalevidencefromtheUnitedStates:2000-2001.DrugAlcoholDepend,2005.79(1):p.11-22.

Inthispaperweestimatetheriskofbecomingcannabisdependentwithin24monthsafterfirstuseofcannabisandexaminesubgroupvariationinthisrisk.ThestudyestimatesarebasedontheNationalHouseholdSurveyonDrug Abuse conducted during 2000-2001, with a representative sample of U.S. residents ages 12 and older(n=114,241).Atotalof3352respondentswerefoundtohaveusedcannabisforthefirsttimewithinaspanofupto 24 months prior to assessment. An estimated 3.9% of these recent-onset users developed a cannabisdependencesyndromeduringtheintervalsincefirstuse(medianintervaldurationapproximately12months).Excessriskofcannabisdependencewasfoundforthosewithcannabisonsetbeforelate-adolescence,thosewithfamilyincomelessthanUSdollars20,000,andthosewhohadusedthreeormoredrugsbeforethefirstuseofcannabis(i.e.,tobacco,alcohol,andotherdrugs).Whilethesefindingsgenerallysupportpreviousstudyresults,thisstudy'sfocusonrecent-onsetusersmorecloselyapproximatesprospectiveandlongitudinalresearchontheincidence (risk) of becoming cannabisdependent soonafter onset of cannabisuse, removing the influenceofuserswithlong-sustainedorpersistentcannabisdependencedevelopedyearsago.

21. vanderPol,P.,etal.,TheDutchCannabisDependence(CanDep)studyonthecourseoffrequentcannabisuseanddependence:objectives,methodsandsamplecharacteristics.IntJMethodsPsychiatrRes,2011.20(3):p.169-81.

ThispaperpresentsanoverviewoftheprospectivecohortdesignoftheDutchCannabisDependence(CanDep)study,whichinvestigates(i)thethree-yearnaturalcourseoffrequentcannabisuse(>/=threedaysperweekinthepast12months)andcannabisdependence;and(ii)thefactorsinvolvedinthetransitionfromfrequentnon-dependent cannabis use to cannabis dependence, and remission from dependence. Besides its scientificrelevance, this knowledge may contribute to improve selective and indicated prevention, early detection,treatmentandcannabispolicies.Thesecondaryobjectivesaretheidentificationoffactorsrelatedtotreatmentseekingand thevalidationof self reportmeasuresof cannabisuse.BetweenSeptember2008andApril2009,baselinedatawerecollectedfrom600frequentcannabisuserswithanaverageageof22.1years,predominantlymale(79.3%)andanaveragecannabisusehistoryof7.1years;42.0%fulfilleda(12-monthDSM-IV)diagnosisofcannabisdependence.Theresponseratewas83.7%afterthefirstfollowupat18months.Thesecondandlastfollow-up is planned at 36 months. Computer assisted personal interviews (CAPI) were conducted which



covered: cannabisuse (includingdetailed assessments of exposure,motives foruse andpotencypreference);use of other substances; DSM-IV internalizing and externalizing mental disorders; treatment seeking;personality;lifeevents;socialsupportandsocialfunctioning.

22. van der Pol, P., et al.,Predictingthetransitionfromfrequentcannabisusetocannabisdependence:athree-yearprospectivestudy.DrugAlcoholDepend,2013.133(2):p.352-9.

BACKGROUND: Frequent cannabis users are at high risk of dependence, stillmost (near) daily users are notdependent.Itisunknownwhysomefrequentusersdevelopdependence,whereasothersdonot.Thisstudyaimstoidentifypredictorsof first-incidenceDSM-IVcannabisdependenceinfrequentcannabisusers.METHODS:Aprospective cohort of frequent cannabis users (aged 18-30, n=600) with baseline and two follow-upassessments (18 and 36months)was used. Only participantswithout lifetime diagnosis of DSM-IV cannabisdependenceatbaseline(n=269)wereselected.IncidenceofDSM-IVcannabisdependencewasestablishedusingtheCompositeInternationalDiagnosticInterviewversion3.0.Variablesassessedaspotentialpredictorsofthedevelopmentofcannabisdependenceincludedsociodemographicfactors,cannabisusevariables(e.g.,motives,consumptionhabits,cannabisexposure),vulnerabilityfactors(e.g.,childhoodadversity,familyhistoryofmentaldisordersorsubstanceuseproblems,personality,mentaldisorders),andstress factors(e.g., lifeevents,socialsupport).RESULTS:Three-yearcumulativeincidenceofcannabisdependencewas37.2%(95%CI=30.7-43.8%).Independentpredictorsofthefirstincidenceofcannabisdependenceincluded:livingalone,copingmotivesforcannabisuse,numberandtypeofrecentnegativelifeevents(majorfinancialproblems),andnumberandtypeofcannabis use disorder symptoms (impaired control over use). Cannabis exposure variables and stablevulnerabilityfactorsdidnotindependentlypredictfirstincidenceofcannabisdependence.CONCLUSIONS:Inahighriskpopulationofyoungadultfrequentcannabisusers,currentproblemsaremoreimportantpredictorsoffirst incidence cannabis dependence than the level and type of cannabis exposure and stable vulnerabilityfactors.

23. Florez-Salamanca, L., et al., Probabilityandpredictorsof cannabisusedisorders relapse: resultsof theNationalEpidemiologicSurveyonAlcoholandRelatedConditions(NESARC).DrugAlcoholDepend,2013.132(1-2):p.127-33.

BACKGROUND:Thisstudyaims toestimate theoddsandpredictorsofCannabisUseDisorders (CUD)relapseamongindividuals inremission.METHODS:Analysesweredoneonthesubsampleof individualswith lifetimehistory of a CUD (abuse or dependence) who were in full remission at baseline (Wave 1) of the NationalEpidemiological Survey of Alcohol andRelated Conditions (NESARC) (n=2350). Univariate logistic regressionmodelsandhierarchical logistic regressionmodelwere implemented toestimateoddsof relapseand identifypredictors of relapse at 3 years follow up (Wave 2). RESULTS: The relapse rate of CUDwas 6.63% over anaverageof3.6yearfollow-upperiod.Inthemultivariablemodel,theoddsofrelapsewereinverselyrelatedtotime in remission,whereashavingahistoryof conductdisorderoramajordepressivedisorderafterWave1increased the risk of relapse. CONCLUSIONS:Our findings suggest thatmaintenance of remission is themostcommon outcome for individuals in remission from a CUD. Treatment approaches may improve rates ofsustainedremissionofindividualswithCUDandconductdisorderormajordepressivedisorder.

24. Moore, B.A. and A.J. Budney, Relapse in outpatient treatment formarijuanadependence. J Subst Abuse Treat,2003.25(2):p.85-9.

Thecurrentstudyprovidesaninitialexaminationof lapseandrelapsetomarijuanauseamong82individualswhoachievedat least2weeksofabstinenceduringoutpatient treatment formarijuanadependence.Seventy-onepercentusedmarijuanaatleastonce(i.e.,lapsed)within6monthsofinitialabstinence,averaging73days(SD=50)till lapsing.Similarly,71%ofthosewholapsed,relapsedtoheavierusedefinedasat least4daysofmarijuana use in any 7-day period. Early lapses were more strongly associated with consequent relapse.Previous studies have noted thatmarijuana-dependent outpatients experience difficulty initiating abstinencefrom marijuana much as do those dependent on other substances. The present data suggest that thesesimilaritiesextendtodifficultymaintainingabstinence.

25. Dennis,M., et al.,TheCannabisYouthTreatment(CYT)Study:mainfindingsfromtworandomizedtrials. J SubstAbuseTreat,2004.27(3):p.197-213.

Thisarticlepresentsthemainoutcomefindingsfromtwointer-relatedrandomizedtrialsconductedatfoursitestoevaluate theeffectivenessandcost-effectivenessof fiveshort-termoutpatient interventions foradolescentswith cannabis use disorders. Trial 1 compared five sessions of Motivational Enhancement Therapy plusCognitive Behavioral Therapy (MET/CBT) with a 12-session regimen of MET and CBT (MET/CBT12) andanother that included family education and therapy components (Family Support Network [FSN]). Trial IIcompared the five-session MET/CBT with the Adolescent Community Reinforcement Approach (ACRA) andMultidimensionalFamilyTherapy(MDFT).The600cannabisuserswerepredominatelywhitemales,aged15-



16.AllfiveCYTinterventionsdemonstratedsignificantpre-posttreatmentduringthe12monthsafterrandomassignment to a treatment intervention in the two main outcomes: days of abstinence and the percent ofadolescents in recovery (no use or abuse/dependence problems and living in the community). Overall, theclinicaloutcomeswerevery similaracross sitesandconditions;however, after controlling for initial severity,themostcost-effectiveinterventionswereMET/CBT5andMET/CBT12inTrial1andACRAandMET/CBT5inTrial2. It ispossible that thesimilarresultsoccurredbecauseoutcomesweredrivenmorebygeneral factorsbeyond the treatment approaches tested in this study; or because of shared, general helping factors acrosstherapiesthathelptheseteensattendtoanddecreasetheirconnectiontocannabisandalcohol.

26. Compton, W.M. and B. Pringle, Services researchonadolescentdrug treatment.Commentaryon "TheCannabisYouthTreatment(CYT)Study:mainfindings fromtworandomizedtrials". J Subst Abuse Treat, 2004.27(3): p.195-6.

OneconclusionwecandrawfromthiseffortisthatbtreatmentworksQ—thatis,treatmentcanreducecannabisuse and support recovery. All five interventions have fairly consistent results on clinical outcomes, whethermeasuredintermsofdaysofabstinenceorrecoveryatthe3-,6-,9-and12-monthfollowuppoints.Evenamoresophisticated analysis, based on random regression models of alternative continuous measures of outcome,demonstrates similar results. In thesemorecomplexanalyses, somevariationappearsamong the treatments,buttheresultsstillimplygeneraleffectivenessofalltheinterventionswithoutconsistentdifferencesacrossthesites.

27. Hoch, E., et al., CANDIS treatment program for cannabis use disorders: findings from a randomized multi-sitetranslationaltrial.DrugAlcoholDepend,2014.134:p.185-93.

BACKGROUND: Ina recentpaper,we reported theefficacyofamodular cognitive-behavioral intervention fortreatingadolescentsandadultswithcannabisusedisorders(CUD).Inthisstudy,weexaminetheoutcomeofthisinterventionaftertranslatingitintoclinicalpractice.METHODS:Amulti-site,randomizedcontrolledtrialof279treatment seekers with ICD-10 cannabis use disorders aged 16- 63 years was conducted in 11 outpatientaddictiontreatmentcentersinGermany.PatientswererandomlyassignedtoanActiveTreatment(AT,n=149)orDelayedTreatmentControl(DTC,n=130).Treatmentconsistedof10sessionsoffullymanualizedindividualpsychotherapythatcombinedCognitive-BehavioralTherapy,MotivationalEnhancementTherapyandproblem-solvingtraining.Assessmentswereconductedatbaseline,duringeachtherapysession,atpost-treatmentandatthreeandsixmonthfollow-ups.RESULTS:Atpostassessment53.3%ofATpatientsreportedabstinence(46.3%negative urine screenings) compared to 22% of DTC patients (17.7% negative drug screenings) (p<0.001,Intention-to-treat analysis). AT patients improved in the frequency of cannabis use, number of cannabisdependence criteria, severity of dependence, as well as number and severity of cannabis-related problems.Effect sizes were moderate to high. While abstinence rates in the AT group decreased over the 3-month(negative urine screenings: 32.4%) and 6-month (negative urine screenings: 35.7%) follow-up periods, theeffectsinsecondaryoutcomesweremaintained.CONCLUSIONS:Theinterventioncansuccessfullybetranslatedtoandappliedinclinicalpractice.Ithasthepotentialtoimproveaccesstoevidence-basedcareforchronicCUDpatients.

28. Rigter, H., et al., Multidimensional family therapy lowers the rate of cannabis dependence in adolescents: arandomisedcontrolledtrialinWesternEuropeanoutpatientsettings.DrugAlcoholDepend,2013.130(1-3):p.85-93.

BACKGROUND:Noticingalackofevidence-basedprogrammesfortreatingadolescentsheavilyusingcannabisinEurope,governmentrepresentativesfromBelgium,France,Germany,TheNetherlands,andSwitzerlanddecidedto have U.S.-developedmultidimensional family therapy (MDFT) tested in their countries in a trans-nationaltrial, called the International Need for Cannabis Treatment (INCANT) study. METHODS: INCANT was a 2(treatment condition)x5 (time) repeated measures intent-to-treat randomised effectiveness trial comparingMDFTto IndividualPsychotherapy(IP).Dataweregatheredatbaselineand3,6,9and12months thereafter.Study participantswere recruited at outpatient secondary level addiction, youth, and forensic care clinics inBrussels,Berlin,Paris,TheHague,andGeneva.Participantswereadolescentsfrom13through18yearsofagewitharecentcannabisusedisorder.85%wereboys;40%wereofforeigndescent.One-thirdhadbeenarrestedforacriminaloffenceinthepast3months.Threeprimaryoutcomeswereassessed:(1)treatmentretention,(2)prevalence of cannabis use disorder and (3) 90-day frequency of cannabis consumption. RESULTS: PositiveoutcomeswerefoundinboththeMDFTandIPconditions.MDFToutperformedIPonthemeasuresoftreatmentretention(p<0.001)andprevalenceofcannabisdependence(p=0.015).MDFTreducedthenumberofcannabisconsumptiondaysmorethanIPinasubgroupofadolescentsreportingmorefrequentcannabisuse(p=0.002).CONCLUSIONS: Cannabis use disorder was responsive to treatment. MDFT exceeded IP in decreasing theprevalenceofcannabisdependence.MDFTisapplicableinWesternEuropeanoutpatientsettings,andmayshowmoderatelygreaterbenefitsthanIPinyouthwithmoreseveresubstanceuse.



29. Rigter,H.,etal.,INCANT:atransnationalrandomizedtrialofmultidimensionalfamilytherapyversustreatmentasusualforadolescentswithcannabisusedisorder.BMCPsychiatry,2010.10:p.28.

BACKGROUND:In2003,thegovernmentsofBelgium,France,Germany,theNetherlandsandSwitzerlandagreedthat therewasaneed inEurope fora treatmentprogramme foradolescentswithcannabisusedisordersandother behavioural problems. Based on an exhaustive literature review of evidence-based treatments and aninternational expertsmeeting,Multidimensional Family Therapy (MDFT)was selected for a pilot study first,which was successful, and then for a joint, transnational randomized controlled trial named INCANT(INternational CAnnabis Need for Treatment). METHODS/DESIGN: INCANT is a randomized controlled trial(RCT)withanopen-label,parallelgroupdesign.ThisstudycomparesMDFTwithtreatmentasusual(TAU)atandacrosssitesinBrussels,Berlin,Paris,TheHagueandGeneva.Assessmentsareatbaselineandat3,6,9and12monthsafterrandomization.Aminimumof450casesintotalisrequired;siteswillrecruit60caseseachinBelgium and Switzerland, and a maximum of 120 each in France, Germany and the Netherlands.Eligible forINCANTareadolescentsfrom13through18yearsofagewithacannabisusedisorder(dependenceorabuse),with at least one parent willing to take part in the treatment. Randomization is concealed to, and thereforebeyondcontrolby, theresearcher/siterequesting it.Randomization isstratifiedastogender,ageand levelofcannabis consumption.Assessments focus on substance use; mental function; behavioural problems; andfunctioningregardingfamily,school,peersandleisuretime.Foroutcomeanalyses,thestudywillusestateoftheartlatentgrowthcurvemodellingtechniques,includingallrandomizedparticipantsaccordingtotheintention-to-treatprinciple.INCANThasbeenapprovedby the appropriate ethicalboards inBelgium,France,Germany,theNetherlands,Switzerland,andtheUniversityofMiamiMillerSchoolofMedicine. INCANTis fundedbythe(federal)Ministries ofHealth ofBelgium,Germany, theNetherlands, Switzerland, andbyMILDT: theMissionInterministerielledeLutteContralaDrogueetdeToximanie,France.DISCUSSION:Untilrecently,cannabisusedisorders in adolescents were not viewed in Europe as requiring treatment, and the co-occurrence of suchdisorders with other mental and behavioural problems was underestimated. This has changed now.Initially,therewasdoubtthataRCTwouldbefeasibleintreatmentsectorsandcountrieswithnoexperienceinthistypeofstudy. INCANThasproventhatsuchdoubtsareunjustified.Governmentsandtreatmentsites fromthe fiveparticipating countries agreedona sound studyprotocol, and the INCANT trial isnowunderwayasplanned.TRIALREGISTRATION:ISRCTN51014277.

30. Rowe,C.,etal.,ImplementationfidelityofMultidimensionalFamilyTherapyinaninternationaltrial.JSubstAbuseTreat,2013.44(4):p.391-9.

Implementation fidelity, a critical aspect of clinical trials research that establishes adequate delivery of thetreatmentasprescribedintreatmentmanualsandprotocols,isalsoessentialtothesuccessfulimplementationofeffectiveprogramsintonewpracticesettings.Althoughinfrequentlystudiedinthedrugabusefield,strongerimplementation fidelity has been linked to better outcomes in practice but appears to be more difficult toachieve with greater distance from model developers. In the INternational CAnnabis Need for Treatment(INCANT) multi-national randomized clinical trial, investigators tested the effectiveness of MultidimensionalFamilyTherapy (MDFT) incomparison to individualpsychotherapy (IP) inBrussels,Berlin,Paris,TheHague,and Genevawith 450 adolescentswith a cannabis use disorder and their parents. This study reports on theimplementation fidelity ofMDFT across these fiveWestern European sites in terms of treatment adherence,doseandprogramdifferentiation,anddiscussespossibleimplicationsforinternationalimplementationefforts.

31. Arkowitz, H.,W.R.Miller, and S. Rollnick,Motivationalinterviewinginthetreatmentofpsychologicalproblems.Secondedition.ed.Applicationsofmotivationalinterviewing.2015,NewYork:TheGuilfordPress.pagescm.

32. Miller, W.R. and S. Rollnick, Motivational interviewing : helping people change. 3rd ed. Applications ofmotivationalinterviewing.2013,NewYork,NY:GuilfordPress.xii,482p.

33. Gray,E., J.McCambridge,and J.Strang,Theeffectivenessofmotivationalinterviewingdeliveredbyyouthworkersinreducingdrinking,cigaretteandcannabissmokingamongyoungpeople:quasi-experimentalpilotstudy.AlcoholAlcohol,2005.40(6):p.535-9.

AIM: To test whether a single session of Motivational Interviewing (MI) focussing on drinking alcohol, andcigarette and cannabis smoking, would successfully lead to reductions in use or problems. METHODS:Naturalistic quasi-experimental study, in 162 young people (mean age 17 years) who were daily cigarettesmokers,weeklydrinkersorweeklycannabissmokers,comparing59receivingMIwith103non-interventionassessment-only controls. MI was delivered in a single session by youth workers or by the first author.Assessmentwasmadeofchangesinself-reportedcigarette,alcohol,cannabisuseandrelatedindicatorsofriskand problems between recruitment and after 3 months by self-completion questionnaire. RESULTS: 87% ofsubjects (141of162)were followedup.Themost substantial evidenceofbenefitwasachieved in relation toalcoholconsumption,withthosereceivingMIdrinkingonaveragetwodayspermonthlessthancontrolsafter3months.Weaker evidences of impact on cigarette smoking, andno evidenceof impact on cannabis use,were



obtained.CONCLUSIONS:EvidenceofeffectivenessforthedeliveryofMIbyyouthworkersinroutineconditionshasbeenidentified.However, theextentofbenefit ismuchmoremodestthanpreviously identifiedinefficacystudies.

34. McCambridge, J., et al.,EncouragingGPalcoholintervention:pilotstudyofchange-orientatedreflectivelistening(CORL).AlcoholAlcohol,2004.39(2):p.146-9.

AIMS:To test the feasibility of delivery andpotential value of a briefmotivational enhancement interventiontargetingGPsinrelationtoalcoholasapublichealthissue,andtocomparedataobtainedwithsimilarattemptstoinfluenceGPinterventionwithdrugusers.METHOD:21GPswhowerenotinvolvedinthetreatmentofdrugdependence received a telephone-administered 'change-orientated reflective listening' (CORL) intervention,basedonMotivationalInterviewing,withaninformationaladjunct.Assessmentsweremadeatbaselineandat2-3monthsofactivityandwillingnesstodeliverspecifiedalcohol-relatedinterventions,plusoveralltherapeuticcommitment andmotivation.Qualitativedatawasobtained.RESULTS:Therewasno changeover time in thesample as a whole, with very modest evidence of benefit among individual practitioners. Comparisons withcannabisanddrugmisuseinterventiontargetssuggestthatitmaybemoredifficulttoalterviewsoninterveningwith drinkers. CONCLUSIONS: Further attempts are needed to influence practitioner motivation, based onimprovedunderstandingofGPviewsonthedeliveryofalcoholinterventions.

35. McCambridge, J. and J. Strang, The efficacy of single-session motivational interviewing in reducing drugconsumptionandperceptionsofdrug-relatedriskandharmamongyoungpeople:resultsfromamulti-siteclusterrandomizedtrial.Addiction,2004.99(1):p.39-52.

AIM:Totestwhetherasinglesessionofmotivational interviewing(discussingalcohol, tobaccoandillicitdruguse)wouldleadsuccessfullytoreductioninuseofthesedrugsorinperceptionsofdrug-relatedriskandharmamongyoungpeople.DESIGN:Cluster randomized trial, allocating200youngpeople in thenatural groups inwhichtheywererecruitedtoeithermotivationalinterviewing(n=105)ornon-interventioneducation-as-usualcontrol condition (n=95).SETTING:Ten furthereducationcollegesacross innerLondon.PARTICIPANTS:Twohundredyoungpeople(agerange16-20years)currentlyusingillegaldrugs,withwhomcontactwasestablishedthrough peers trained for the project. INTERVENTION: The interventionwas adapted from the literature onmotivationalinterviewingintheformofa1-hoursingle-sessionface-to-faceinterviewstructuredbyaseriesoftopics.MEASUREMENTS:Changesinself-reportedcigarette,alcohol,cannabisandotherdruguseandinarangeofdrug-specificperceptionsandotherindicatorsofriskandharm.Measurementatrecruitmentandfollow-upinterview3monthslater.FINDINGS:Agoodfollow-uprate(89.5%;179of200)wasachieved.Incomparisontothecontrolgroup,thoserandomizedtomotivationalinterviewingreducedtheirofuseofcigarettes,alcoholandcannabis,mainly throughmoderationofongoingdruguserather thancessation.Effect sizeswere0.37 (0.15-0.6), 0.34 (0.09-0.59) and 0.75 (0.45-1.0) for reductions in the use of cigarettes, alcohol and cannabis,respectively. For both alcohol and cannabis, the effect was greater among heavier users of these drugs andamong heavier cigarette smokers. The reduced cannabis use effect was also greater among youth usuallyconsideredvulnerableorhigh-riskaccordingtoothercriteria.Changewasalsoevidentinvariousindicatorsofriskandharm,butnotaswidelyasthechanges indrugconsumption.CONCLUSIONS:Thisstudyprovidesthefirst substantialevidenceofnon-treatmentbenefit tobederivedamongyoungpeople involved in illegaldruguseinreceiptofmotivationalinterviewing.Thetargetingofmultipledruguseinagenericfashionamongyoungpeoplehasalsobeensupported.

36. Vandrey,R.,etal.,Thedoseeffectsofshort-termdronabinol(oralTHC)maintenanceindailycannabisusers.DrugAlcoholDepend,2013.128(1-2):p.64-70.

BACKGROUND: Prior studies have separately examined the effects of dronabinol (oral THC) on cannabiswithdrawal, cognitiveperformance, and theacuteeffectsof smokedcannabis.A single studyexamining theseclinicallyrelevantdomainswouldbenefitthecontinuedevaluationofdronabinolasapotentialmedicationforthe treatment of cannabis use disorders. METHODS: Thirteen daily cannabis smokers completed a within-subjectcrossoverstudyandreceived0,30,60and120mgdronabinolperdayfor5consecutivedays.Vitalsignsand subjective ratingsof cannabiswithdrawal, cravingand sleepwereobtaineddaily; outcomesunderactivedose conditions were compared to those obtained under placebo dosing. On the 5th day of medicationmaintenance, participants completed a comprehensive cognitive performance battery and then smoked fivepuffs of cannabis for subjective effects evaluation. Each dronabinol maintenance period occurred in acounterbalanced order andwas separated by 9 days of ad libitum cannabis use. RESULTS: Dronabinol dose-dependentlyattenuatedcannabiswithdrawalandresultedinfewadversesideeffectsordecrementsincognitiveperformance. Surprisingly, dronabinol did not alter the subjective effects of smoked cannabis, but cannabis-inducedincreasesinheartratewereattenuatedbythe60and120mgdoses.CONCLUSIONS:Dronabinol'sabilityto dose-dependently suppress cannabiswithdrawalmay be therapeutically beneficial to individuals trying tostop cannabis use. The absence of gross cognitive impairment or side effects in this study supports safety of



dosesupto120mg/day.Continuedevaluationofdronabinolintargetedclinicalstudiesofcannabistreatment,usinganexpandedrangeofdoses,iswarranted.

37. Gray,K.M.,etal.,Adouble-blindrandomizedcontrolledtrialofN-acetylcysteineincannabis-dependentadolescents.AmJPsychiatry,2012.169(8):p.805-12.

OBJECTIVE: Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine (NAC), viaglutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substancedependence.TheauthorsinvestigatedNACasanovelcannabiscessationtreatmentinadolescents,avulnerablegroup for whom existing treatments have shown limited efficacy. METHOD: In an 8-week double-blindrandomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (ages 15-21 years;N=116)receivedNAC(1200mg)orplacebotwicedailyaswellasacontingencymanagementinterventionandbrief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negativeweeklyurinecannabinoidtestresultsduringtreatmentamongparticipantsreceivingNACcomparedwiththosereceiving placebo, in an intent-to-treat analysis. The primary tolerability measure was frequency of adverseevents, compared by treatment group. RESULTS: Participants receiving NAC had more than twice the odds,compared with those receiving placebo, of having negative urine cannabinoid test results during treatment(odds ratio=2.4, 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were notstatistically significant.NACwaswell tolerated,withminimal adverse events. CONCLUSIONS:This is the firstrandomizedcontrolledtrialofpharmacotherapyforcannabisdependence inanyagegrouptoyieldapositiveprimary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy tocomplementpsychosocialtreatmentforcannabisdependenceinadolescents.

38. Mason, B.J., et al., A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use,withdrawal and executive function deficits in cannabis-dependent adults. Neuropsychopharmacology, 2012.37(7):p.1689-98.

There are no FDA-approved pharmacotherapies for cannabis dependence. Cannabis is themost widely usedillicitdrugintheworld,andpatientsseekingtreatmentforprimarycannabisdependencerepresent25%ofallsubstance use admissions.We conducted a phase IIa proof-of-concept pilot study to examine the safety andefficacyofacalciumchannel/GABAmodulatingdrug,gabapentin,forthetreatmentofcannabisdependence.A12-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 50 unpaid treatment-seekingmaleandfemaleoutpatients,aged18-65years,diagnosedwithcurrentcannabisdependence.Subjectsreceivedeithergabapentin(1200mg/day)ormatchedplacebo.Manual-guided,abstinence-orientedindividualcounselingwasprovidedweeklytoallparticipants.Cannabisusewasmeasuredbyweeklyurinetoxicologyandby self-reportusing theTimelineFollowback Interview.Cannabiswithdrawal symptomswere assessedusingthe MarijuanaWithdrawal Checklist. Executive function wasmeasured using subtests from the Delis-KaplanExecutiveFunctionSystem.Relativetoplacebo,gabapentinsignificantlyreducedcannabisuseasmeasuredbothbyurinetoxicology(p=0.001)andbytheTimelineFollowbackInterview(p=0.004),andsignificantlydecreasedwithdrawal symptoms as measured by the Marijuana Withdrawal Checklist (p<0.001). Gabapentin was alsoassociated with significantly greater improvement in overall performance on tests of executive function(p=0.029). This POC pilot study provides preliminary support for the safety and efficacy of gabapentin fortreatmentofcannabisdependencethatmeritsfurtherstudy,andprovidesanalternativeconceptualframeworkfortreatmentofaddictionaimedatrestoringhomeostasisinbrainstresssystemsthataredysregulatedindrugdependenceandwithdrawal.

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