Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch

Year: 2018

Association of polysubstance and non-medical prescription opioid use with alterations in social functioning from a behavioural and psychophysiological perspective

Kroll, Sara L

Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-152956 Dissertation Published Version

Originally published at: Kroll, Sara L. Association of polysubstance and non-medical prescription opioid use with alterations in social functioning from a behavioural and psychophysiological perspective. 2018, University of Zurich, Faculty of Arts. ! ! ! Association!of!polysubstance!and!non2medical! prescription!opioid!use!with!alterations!in!social! functioning!from!a!behavioural!and! psychophysiological!perspective! ! ! ! ! ! ! Thesis!(cumulative!thesis)! ! Presented!to!the!Faculty!of!Arts!and!Social!Sciences! ! of!the!University!of!Zurich! ! for!the!Degree!of!Doctor!of!Philosophy! ! ! ! ! by!Sara!Liane!Kroll! ! ! ! ! Accepted!in!the!Spring!Term!2018! ! on!the!Recommendation!of!the!Doctoral!Committee:! ! Prof.!Dr.!rer.!nat.!Boris!Quednow!(main!advisor)! ! Prof.!Dr.!rer.!nat.!Lutz!Jäncke! ! ! ! ! Zurich,!2018! ! ! !

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! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! Homo!sum,!humani!nil!a!me!alienum!puto! ! –!Terenz!! (Heautontimorumenos!77)! ! !

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! ACKNOWLEDGEMENT!

! First!and!foremost,!I!want!to!thank!Prof.!Dr.!Boris!Quednow,!principal!supervisor!of!my!PhD!steering! committee,!for!giving!me!the!opportunity!to!work!autonomously!on!this!interesting!and!challenging! topic.!I!am!grateful!for!his!trust!and!expertise!he!offered!in!the!last!years.!I!would!like!to!extend!my! gratitude!to!Prof.!Dr.!Lutz!Jäncke!for!supporting!my!thesis!and!being!a!member!of!my!PhD!steering! committee.! ! Further,! I! want! to! thank! all! current! and! former! lab! members! and! colleagues! for! their! support,! refreshing!lunch!times,!and!after2lunch!walks!around!the!PUK:!Matthias,!Michi,!Sarah,!both!Monikas! (Näff!and!Visentini),!Bruno,!Anni!as!well!as!Etna!and!Hannes.!Special!thanks!go!to!Tom!and!Lukasz!for! inspiring!and!interesting!discussions!during!the!lunch2walks!and!feeding!the!lambs!especially!in!the! second!year!of!my!PhD.! ! I!am!deeply!thankful!to!all!my!friends!close!by!but!also!abroad!for!supporting!me!the!last!years.!I! want!to!point!out!Lisi!for!nice!dinners!at!home!and!for!interesting!discussions!about!our!PhDs;!Nathi,! Michi,!and!Pascale!for!our!weekly!Jour!Fix!meetings!and!for!taking!my!mind!off!things;!Anna,!Kirstin,! Laura,!Karina,!Juli,!Elli,!and!Nadine!for!their!fabulous!support!by!phone!and!for!being!always!there!for! me.! ! Finally,! I! want! to! thank! my! family.! My! deep! gratitude! goes! to! my! mother! Marita! and! her! unconditional!support!and!belief!in!me!without!any!doubt!since!day!one.!Furthermore,!I!am!deeply! thankful! to! my! love! Max! for! listening! patiently! to! all! my! problems! and! ideas,! for! providing!me!a! shoulder,!when!I!needed!it,!and!for!supporting!my!career!and!me!in!every!respect.! !!

! I ABSTRACT!

! In!recent!years,!polysubstance!use!(PSU)!occurred!more!frequently!than!monosubstance!use!and!also! non2medical! prescription! opioid! use! (NMPOU;! e.g.,! ,! ,! ,! or! )! provides!a!serious!public!health!concern.!However,!only!few!studies!examined!social!functioning!in! individuals! with! PSU! and! opioid! use! revealing! confounding! factors! and! inconsistent! results.! Social! cognition!such!as!empathy,!theory!of!mind,!or!emotion!perception!is!crucial!for!daily!life!interactions! (e.g.,!social!relationships!or!in!therapist2patient!relationships).!Therefore,!this!thesis!aims!to!clarify! alterations!of!social!functioning!in!individuals!with!stimulant!PSU!and!NMPOU.! ! Part!I!of!the!thesis!addresses!the!question!of!potential!cumulative!effects!of!stimulant!PSU!on!social! functioning.! The! results! show! a! gradual! decrease! of! emotional! empathy! and! social! network! size! related!to!an!increased!number!of!used!substances.! ! Part!II!of!the!thesis!reports!two!studies!assessing!social!functioning!in!individuals!with!NMPOU.!The! findings! posit! distinct! deficits! of! cognitive! empathy! and! emotion! recognition! in! individuals! with! NMPOU!as!well!as!hyperreaction!of!endocrine!stress!parameters!to! social! rejection.! Furthermore,! high!opioid!craver!showed!poorer!emotion!regulation!during!social!exclusion.! ! The! thesis! contributes! to! basic! addiction! research! and! provides! clinical! implications! aiming! to! improve!interventions!as!well!as!therapy!outcome!and!to!reduce!relapse!in!individuals!with!PSU!and! NMPOU.! !!

! II! ZUSAMMENFASSUNG!

! In!den!letzten!Jahren!wurde!vermehrt!ein!Anstieg!des!Konsums!multipler!Substanzen!(PSU)!sowie!des! nicht2medizinischen! Gebrauchs! von! verschreibungspflichtigen! Opioiden!(NMPOU;! z.B.! Morphin,! Oxycodon,! Fentanyl! oder! Codein)! berichtet.! Bis! dato! befassten! sich! wenige! Studien! mit! sozialen! Funktionen! bei! Personen! mit! PSU! und! Opioidkonsum.! Soziale! Kognitionen! wie!Empathie! und! Emotionswahrnehmung! sind! v.a.! bei! alltäglichen! Interaktionen! wichtig! (z.B.! in! sozialen! und! Therapeuten2Patienten2Beziehungen).! Die! vorliegende! Arbeit! soll! deswegen! zu! einem! besseren! Verständnis!der!sozialen!Funktionen!bei!Personen!mit!PSU!und!NMPOU!beitragen.! ! Part!I!der!Arbeit!befasst!sich!mit!kumulierten!Substanzeffekten!bei!Personen!mit!PSU!auf!die!sozialen! Funktionen.!Die!Ergebnisse!zeigen!eine!graduelle!Verschlechterung!der!emotionalen!Empathie!sowie! eine!reduzierte!soziale!Netzwerkgrösse!bei!vermehrtem!Substanzkonsum.! ! ! Part! II! der! Arbeit! berichtet! zwei! Studien,! die! soziale! Funktionen! bei! Personen! mit! NMPOU! untersuchte.! Die! Ergebnisse! zeigen! distinkte! Defizite! in! der! kognitiven! Empathie! und! Emotionserkennung! sowie! eine! Hyperreaktion! endokriner! Stressparameter! auf! sozialen! Ausschluss! bei! Opioidkonsumenten.! Zudem! berichteten! Personen! mit!starkem! Opioidcraving! eine! schlechtere! Emotionsregulation!auf!sozialen!Ausschluss.! ! Diese! Arbeit! dient! der! Grundlagenforschung! und! bietet! klinische! Implikationen! für! verbesserte! Interventionen,!Therapieergebnisse!und!zur!Verhinderung!von!Rückfällen!bei!Personen!mit!PSU!und! NMPOU.!

! III !

CONTENTS!

1.! THEORETICAL!BACKGROUND!...... !1! 1.1! General!introduction!of!addiction!...... !1! 1.1.1! Polysubstance!use!...... !3! 1.1.2! Non8medical!prescription!opioid!use!...... !4! 1.2! General!introduction!of!social!functioning!...... !6! 1.2.1! Empathy!and!emotion!perception!...... !6! 1.2.2! Social!bonding:!the!Brain!Opioid!Theory!of!Social!Attachment!...... !7! 1.3! Social!functioning!in!substance!users!...... !9! 1.4.! Study!subjects!...... !11! 1.4.1! Sample!of!stimulant!polysubstance!users!...... !11! 1.4.2! Sample!of!non8medical!prescription!opioid!users!...... !11! 1.5! Thesis!structure!...... !12!

2.! SOCIO2COGNITIVE!FUNCTIONING!IN!STIMULANT!POLYSUBSTANCE!USERS!...... !14! 2.1! Abstract!...... !14! 2.2! Introduction!...... !15! 2.3! Methods!...... !18! 2.3.1! Recruitment!and!participants!...... !18! 2.3.2! PSU!sample!...... !18! 2.3.3! Clinical!Assessment!...... !19! 2.3.4! Drug!assessment!...... !20! 2.3.5! Socio8cognitive!assessment!...... !21! 2.3.6! Statistical!analysis!...... !21! 2.4! Results!...... !23! 2.4.1! Demographic!characteristics!...... !23! 2.4.2! Socio8cognitive!functioning!...... !25! 2.4.3! Regression!models!...... !27! 2.5! Discussion!...... !29! 2.6! Supplementary!material!...... !33! 2.6.1! Methods!...... !33! 2.6.2! Results!...... !35!

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3.! COGNITIVE!AND!SOCIO2COGNITIVE!FUNCTIONING!OF!CHRONIC!NON2MEDICAL! ! PRESCRIPTION!OPIOID!USERS!...... !41! 3.1! Abstract!...... !41! 3.2! Introduction!...... !42! 3.3! Methods!...... !45! 3.3.1! Participants!...... !45! 3.3.2! Procedure!...... !45! 3.3.3! Assessment!of!social!cognition!and!trait!empathy!...... !46! 3.3.4! Assessments!of!neurocognitive!functioning!...... !47! 3.3.5! Statistical!analyses!...... !47! 3.4! Results!...... !49! 3.4.1! Demographic!characteristics!and!drug!use!...... !49! 3.4.2! Assessments!of!social!functioning!...... !49! 3.4.3! Assessment!of!neurocognitive!functioning!...... !52! 3.4.4! Demographic!predictors!...... !53! 3.4.5! Correlation!analyses:!morphine!equivalents!hair!concentration!...... !53! 3.4.6! Correlation!analyses:!social!and!non8social!cognition!...... !54! 3.5! Discussion!...... !55! 3.6! Supplementary!material!...... !59! 3.6.1! Methods!...... !59! 3.6.2! Results!...... !61!

4.! ASSOCIATION!BETWEEN!NON2MEDICAL!PRESCRIPTION!OPIOID!USE!AND! ! PHYSIOLOGICAL!STRESS!RESPONSES!TO!SOCIAL!REJECTION!...... !65! 4.1! Abstract!...... !65! 4.2! Introduction!...... !66! 4.3! Methods!...... !68! 4.3.1! Participants!...... !68! 4.3.2! Procedure!...... !68! 4.3.3! Behavioural!assessments!...... !69! 4.3.4! Physiological!stress!responses!to!social!rejection!...... !69! 4.3.5! Statistical!Analyses!...... !71! 4.4! Results!...... !73! 4.4.1! Demographic!characteristics!and!drug!use!...... !73!

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4.4.2! Physiological!stress!response!...... !73! 4.4.3! Behavioural!assessments!...... !76! 4.4.4! Correlation!analyses:!morphine!equivalents!hair!concentration!and!! !! opioid!use!...... !78! 4.5! Discussion!...... !79! 4.6! Supplementary!material!...... !84! 4.6.1! Methods!...... !84! 4.6.2! Results!...... !84!

5.! GENERAL!DISCUSSION!...... !87! 5.1! Increased!number!of!used!substances!accompanied!with!!decreased!social! ! functioning!...... !87! 5.2! Impaired!cognitive!empathy!in!individuals!with!non2medical!!prescription!! ! opioid!use!...... !90! 5.3! Dysfunctional!physiological!stress!response!to!social!rejection!!in!non2medical! ! prescription!opioid!users!...... !92! 5.4! Strength!and!limitations!...... !94! 5.5! Clinical!implications!...... !96! 5.6! Outlook!...... !99!

6.! REFERENCES!...... !102!

7.! CURRICULUM!VITAE!...... !112!

! ! 1.!THEORETICAL!BACKGROUND!

1.! THEORETICAL!BACKGROUND!

! 1.1 General!introduction!of!addiction!

Addiction!is!commonly!defined!as!a!chronic!and!relapsing!disorder!characterised!by!the!compulsion! to!seek!and!take!the!drug!despite!negative!consequences,!the!loss!of!control!in!restricting!drug!use,! and!occurrence!of!negative!affects!after!discontinuing!drug!intake!(Koob!&!Volkow,!2010).!It!can!be! diagnosed!by!the!Diagnostic!and!Statistical!Manual!of!the!American!Psychiatric!Association!(DSM25)! measuring!substance!use!disorder!(SUD)!on!a!continuum!from!mild!to!severe!(American!Psychiatric! Association,!2013).!Globally,!the!past2year!prevalence!of!drug!use!for!2015!was!estimated!by!5.3%! (255!million!people)!of!which!over!11%!(about!29.5!million!people)!were!reported!to!suffer!from!SUD! (UNODC,!2017).!Cannabis!was!the!most!common!used!illegal!substance!worldwide!with!an!annual! prevalence!of!3.8%!followed!by!amphetamines!(0.77%),!opioids!(0.73%),!ecstasy!(0.45%),!and!cocaine! (0.35%).!Also!in!Europe,!the!past2year!prevalence!rate!was!the!highest!for!cannabis!(5.2%)!followed! by! opioids! (0.83%),! cocaine! (0.74%),! ecstasy! (0.69%),! and! amphetamines! (0.45%)! (UNODC,! 2017).! With!respect!to!a!drug2induced!mortality!rate!of!over!9000!deaths!for!2016!in!Europe,!substance!use! causes! severe! physical! harm! (EMCDDA,! 2018).! Furthermore,! data! from! hospital! emergency! departments!reported!that!polysubstance!use!(the!use!of!more!than!one!substance,!chapter!1.1.1)! was!most!frequently!associated!with!drug!toxicity!presentations!shown!in!38%!of!cases!followed!by! opioid2induced!toxicity!presentations!reported!in!24%!of!cases!(EMCDDA,!2016).!With!respect!to!the! many! harms! inflicted! by! drugs,! it! is! important! to! investigate! predispositions! and! sequelae! of! substance! use! to! understand! why! people! initiate! and! maintain! drug! use! despite! negative! consequences! and! to! subsequently! prevent! drug! addiction! and! relapse! as! well! as! to! improve! therapeutic! treatments! of! substance! use.! For! the! sake! of! a! better! understanding,! I! will! start! this! thesis! with! the! introduction! of! two! major! addiction! theories! explaining! the! transition! from! recreational!drug!use!to!addiction!followed!by!more!detailed!information!about!polysubstance!use! and! non2medical! prescription! opioid! use! as! well! as! key! terms! of! social! functioning! and! its! link! to! substance!use.! ! Over! the! last! decades,! several! theories! of! addiction! have! been! postulated! and! modified! from! the! initial! dopamine! theory! of! addiction! considering! the! assumption! that! drug! reward! is! not! only! mediated! by! the! dopamine! but! also! by! the! opioid! system! especially! in! opioid! use! (Badiani,! Belin,! Epstein,!Calu,!&!Shaham,!2011;!Nutt,!Lingford2Hughes,!Erritzoe,!&!Stokes,!2015).!Two!major!models! of! addiction! progression! have! been! established! with! the! focus! on! drug! reward.! (1)! The! incentive2 sensitisation!model!of!addiction!postulated!at!least!two!psychological!components!of!reward:!“liking”! ! 1! 1.!THEORETICAL!BACKGROUND!

(i.e.! hedonic! impact! associated! with! μ2opioid! system! in! the! nucleus! accumbens! [NA]),! “wanting”! (incentive! salience,! motivation! associated! with! dopamine! and! opioid! system! in! the! NA),! and! also! “learning”!(predictive!associations!and!cognitions)!(Berridge,!Robinson,!&!Aldridge,!2009;!Castro!&! Berridge,!2014;!Robinson!&!Berridge,!1993).!The!model!posits!that!repeated!drug!exposure!entails! neuronal! adaptations! in! the! brain! reward! and! learning! systems! causing! hypersensitivity! (sensitisation)! to! drug! and! drug2associated! stimuli! resulting! in! compulsive! drug! “wanting”! effects.! The!authors!further!hypothesised!that!incentive!salience!can!occur!independently!from!the!hedonic! drug!effect!and!that!during!the!transition!from!casual!drug!use!to!compulsive!addiction,!drug!“liking”! decreases,!whereas!drug!“wanting”!increases!(Berridge!et!al.,!2009;!Robinson!&!Berridge,!1993).!(2)! The!second!major!addiction!model,!initially!formulated!by!Koob!and!Le!Moal!(1997),!characterises! the!development!of!drug!addiction!in!three!stages!by!a!transition!from!impulsivity!to!compulsivity! and! from! positive! to! negative! reinforcement! (George! &! Koob,! 2017;! Koob! &! Volkow,! 2010).! The! authors!highlighted!that!impulsivity!occurred!mainly!at!the!beginning!of!addiction!progression!in!the! binge/intoxication!stage!(1.!stage)!indicated!by!positive!reinforcement!effects!of!the!drug!(rewarding! effects)!and!mediated!by!dopamine!and!opioid!transmission!in!the!ventral!tegmental!area!(VTA)!and! NA.!The!model!reported!a!transition! from! impulsivity! to! compulsivity!in! the! two! later! stages.! The! withdrawal/negative! affect! stage!(2.! stage)! is! described! by! a! negative! emotional! state! and! stress! modulated! by! decreased! rewarding! drug! effects! and! increased! stress! response! during! abstinence.! The!authors!further!posited!that!negative!reinforcement!entails!drug!seeking!and!craving!to!avoid! withdrawal! and! facilitates! chronic! relapse! even! after! prolonged! abstinence! represented! in! the! preoccupation/anticipation!stage!(3.!stage)!(George!&!Koob,!2017;!Koob!&!Volkow,!2010).! ! With!respect!to!maintenance!and!relapse!of!substance!use,!impairments!of!social!cognition!(such!as! empathy! and! emotion! perception,! chapter! 1.2)! in! chronic! stimulant! users! were! suggested! to! be! associated! with! preserving! the! vicious! circle! of! drug! addiction! (Quednow,! 2017).! Therefore,! inadequate! prosocial! behaviour! and! deficits! in! social! cognition! might! play! a! crucial! role! in! maintenance!of!addictive!behaviour!and!relapse!of!drug!use,!which!is!the!underlying!assumption!of! this!thesis.! ! Apart! from! the! involvement! of! the! dopamine! and! opioid! system! in! addiction! transition,! further! neurotransmitter!systems!were!discussed!playing!a!crucial!role!in!the!development!of!drug!addiction.! In!recent!years,!the!serotonin!system!was!associated!with!impulsivity!and!comorbidity!of!affective! disorders!in!chronic!substance!users!(Kirby,!Zeeb,!&!Winstanley,!2011)!and!the!glutamate!system!was! reported!to!play!a!crucial!role!in!addiction!memory!(Kalivas,!2009).!However,!most!of!the!addiction! theories! share! the! general! perspective! of! a! unitary! addiction! progression! disregarding! distinct!

! 2! 1.!THEORETICAL!BACKGROUND! substance2specific! neuroadaptations! and! differences! in! the! transition! to! addiction! (Badiani! et! al.,! 2011;!Badiani,!Berridge,!Heilig,!Nutt,!&!Robinson,!2018).! ! Three!major!risk!factors!are!reported!to!facilitate!the!liability!to!develop!drug!addiction:!(1)!genetic! risk! factor,! (2)! environmental! aspects! (e.g.,! external! stressors,! drug! access! and! cues,! social! background,!etc.),!and!(3)!drug2related!neurobiological!alterations,!which!might!result!in!abnormal! behaviour! and! entail! maintenance! of! drug! use! (Nielsen!&!Kreek,!2012;!Volkow!&!Li,!2005).! With! respect!to!the!last!risk!factor,!it!is!important!to!investigate!and!to!understand!the!underlying!drug2 specific!changes!of!the!brain!and!subsequently!of!behaviour!in!chronic!substance!users!to!burst!the! maintenance!of!drug!use.!Given!that!inadequate!social!interaction!and!cognition!might!increase!the! risk! for! initiating,! maintenance,! and! relapse! of! drug! use! (Ellis,! Bernichon,! Yu,! Roberts,! &! Herrell,! 2004;!Havassy,!Hall,!&!Wasserman,!1991;!Quednow,!2017;!Volkow,!Baler,!&!Goldstein,!2011),! the! focus!of!the!present!thesis!was!to!investigate!social!functioning!in!chronic!substance!users!and!to! find!potential!and!distinct!drug2induced!alterations.! ! 1.1.1! Polysubstance!use!

According!to!the!Diagnostic!and!Statistical!Manual!of!Mental!Disorders!(DSM2IV),!polysubstance!use! (PSU)!was!initially!diagnosed!by!the!use!of!at!least!three!substances!(beside!caffeine!and!nicotine)! within! the! same! 122months! period! (American! Psychiatric! Association,! 1994).! After! the! diagnosis! criteria! for! PSU! have! been! removed! in! the! DSM25! (American! Psychiatric! Association,! 2013),! inconsistent!and!broad!variations!of!PSU!definitions!were!found!in!the!literature.!The!most!common! definition!of!PSU!is!the!use!of!more!than!one!psychotropic!substance!simultaneously,!on!the!same! occasion,!or!concurrently,!on!separate!occasions!(Connor,!Gullo,!White,!&!Kelly,!2014;!Earleywine!&! Newcomb,!1997).!In!recent!years,!PSU!was!reported!as!a!more!frequent!pattern!of!drug!use!than! monosubstance! use! accompanied! with! serious! health! and! social! consequences! (Karjalainen,! Kuussaari,! Kataja,! Tigerstedt,! &! Hakkarainen,! 2017;! Martin,! 2008).! In! Europe,! 57%! of! clients! in! treatment!have!reported!using!at!least!one!additional!drug!of!whom!33%!reported!one!secondary! drug,!20%!two,!and!the!rest!have!reported!to!use!three!or!more!additional!drugs!(EMCDDA,!2009).! The!most!common!drug!combination!among!PSU!clients!entering!outpatient!and!inpatient!treatment! centres! for! the! first! time! is! cocaine! together! with! alcohol! and/or! cannabis! (11.5%),! followed! by! cannabis! combined! with! alcohol! (11.2%),! and! stimulants! (other! than! cocaine)! accompanied! with! alcohol!and/or!cannabis!use!(7.3%)!(EMCDDA,!2009).!Consecutive!and!especially!simultaneous!PSU! poses! severe! health! problems! with! regard! to! psychological! (e.g.,! depression! or! anxiety)! and! physiological!disorders!and!may!result!in!an!increased!risk!of!intoxication,!injury,!and!death!(Connor! et! al.,! 2014;! EMCDDA,! 2009).! The! major! reasons! for! PSU! were! reported! due! to! cumulate! or!

! 3! 1.!THEORETICAL!BACKGROUND! complement!drug!effects,!to!counteract!negative!effects!such!as!craving!and!withdrawal,!and!PSU! might!further!represent!the!drugs’!availability,!fashion,!or!prescribing!policy!of!the!country!(Connor! et!al.,!2014;!EMCDDA,!2009).! ! 1.1.2! Non8medical!prescription!opioid!use!

Non2medical! prescription! opioid! use! (NMOU)! is! defined! as! the! use! of! opioids1! other! than! ,! either!without!any!medical!indications!and!prescriptions!taken!only!for!the!experience!and!feelings!it! caused!or!that!were!taken!more!frequently!and/or!in!a!higher!dose!than!it!was!initially!prescribed! (Cochran,!Woo,!Lo2Ciganic,!Gordon,!Donohue,!&!Gellad,!2015;!Han,!Compton,!Blanco,!Crane,!Lee,!&! Jones,! 2017).! Prescription! opioids! consist! of! opioid! analgesics! such! as! morphine,! oxycodone,! fentanyl,! ,! or! codeine.! In! the! last! two! decades,! NMPOU! increased! dramatically! worldwide,!reaching!epidemic!dimensions!in!the!United!Sates!(U.S.).!The!past2year!prevalence!rate! for! NMPOU! in! the! U.S.! was! recently! reported! by! 37.8%! (Han! et! al.,! 2017).! Among! these,! 12.5%! showed! prescription! opioid! misuse! of! which! 16.7%! revealed! a! prescription! opioid! use! disorder.! Additionally,! a! recent! meta2analysis! postulated! that! 21228%! of! chronic! pain! patients! treated! with! opioid!analgesics!have!shown!an!opioid!misuse!and!8212%!developed!an!opioid!use!disorder!(Vowles,! McEntee,!Julnes,!Frohe,!Ney,!&!van!der!Goes,!2015).!Also!in!Europe,!NMPOU!increased!recently!as! seen!by!the!treatment!entrants!citing!opioids!other!than!heroin!as!a!primary!drug!reported!by!20%!in! 2017,!which!have!more!than!doubled!from!2015!(EMCDDA,!2015,!2018).!A!European!survey!including! five! countries! (Germany,! Denmark,! Great! Britain,! Sweden,! and! Spain)! has! estimated! a! lifetime! prevalence!of!13.5%!and!a!past2year!prevalence!of!5%!for!NMPOU!in!Europe!with!the!highest!rates! reported!in!Great!Britain!and!Spain!(Novak,!Hakansson,!Martinez2Raga,!Reimer,!Krotki,!&!Varughese,! 2016).!In!Switzerland,!cases!of!opioid2induced!intoxication!almost!tripled!from!53!cases!in!2003!to! 147! cases! in! 2016! (Schweizerisches! Toxikologisches! Informationszentrum,! 2003,! 2016).! However,! exact!data!regarding!prescription!opioid!use!and!misuse!are!missing!so!far,!especially!for!Europe.! ! Opioids! cause! the! highest! harm! potential! of! all! psychotropic! substances! reporting! opioid2related! death!in!84%!of!fatal!overdoses!(EMCDDA,!2018).!Furthermore,!the!mortality!rate!caused!by!drug! overdose!is!meanwhile!higher!for!NMPOU!than!heroin!showing!an!increase!from!2012!to!2015!by! 265%!in!the!U.S.!(UNODC,!2017).!Moreover,!up!to!86%!of!heroin!users!in!the!U.S.!reported!NMPOU! before!initiating!heroin!use!indicating!a!transition!from!prescription!opioid!to!heroin!use!due!to!its! better!availability!and!lower!costs!(Compton,!Jones,!&!Baldwin,!2016).! !

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 1!For!sake!of!simplicity,!in!the!following!the!term!opioid!includes!opiates!as!well!(UNODC,!2017).! ! 4! 1.!THEORETICAL!BACKGROUND!

Apart!from!drug2induced!harm!caused!by!opioid!misuse,!it!is!important!to!differentiate!NMPOU!from! opioid!analgesic!use!in!cancer!and!chronic!non2cancer!pain!therapies.!Physical!pain!can!be!subdivided! into!two!neurobiological!components:!(1)!the!sensory!component!is!associated!with!activations!of! the! posterior! insula! (PI),! primary! and! secondary! somatosensory! cortices! (SI! and! SII)! encoding! localisation,!quality,!and!intensity!of!pain.!(2)!The!affective!component!is!associated!with!activations! of!the!dorsal!anterior!cingulate!cortex!(dACC)!and!the!anterior!insula!(AI)!encoding!unpleasant!and! distressing!feelings!of!pain!(Treede,!Kenshalo,!Gracely,!&!Jones,!1999).!Most!of!the!analgesics!bind! with! high! affinity! on! the! μ2opioid! receptor! (MOR)! mediating! antinociceptive! effects! due! to! its! activation! and! subsequent! inhibition! of! neuronal! signalling! (Fields,! 2011).! High! opioid! receptor! density!was!reported!in!cortical!and!subcortical!regions!such!as!NA,!ACC,!midcingulate!cortex!(MCC),! insula,!and!orbitofrontal!cortex!(OFC)!(Baumgartner,!Buchholz,!Bellosevich,!Magerl,!Siessmeier,!Rolke! et!al.,!2006;!Lutz!&!Kieffer,!2013;!Machin!&!Dunbar,!2011;!Nummenmaa!&!Tuominen,!2017).!Under! correct! indication! and! if! adequately! used,! opioid! analgesics! are! one! of! the! most! important! components!in!the!therapy!of!severe!physical!pain.!However,!MOR!activation!is!also!associated!with! reward!and!feelings!of!“high”!(chapter!1.1),!which!entails!its!high!abuse!liability.! !!

! 5! 1.!THEORETICAL!BACKGROUND!

1.2! General!introduction!of!social!functioning!

The! ability! of! mentalising,! recognising,! and! sharing! other’s! feelings! is! crucial! for! a! better! understanding! and! prediction! of! others’! mental! state! promoting! prosocial! behaviour! (Decety! &! Jackson,!2004;!Singer!&!Lamm,!2009).!Furthermore,!adequate!prosocial!behaviour!is!important!for! successful!social!interaction!and!for!creating!as!well!as!preserving!interpersonal!bonds!(Anderson!&! Keltner,!2002).!These!abilities!can!be!subsumed!into!the!umbrella!term!of!social!cognition,!which!is! important! for! optimal! social! functioning.! Deficits! in! social! cognition! were! reported! in! diverse! psychiatric! disorders! including! drug! addiction,! which! might! increase! the! risk! for! initiating,! maintenance,!and!relapse!of!drug!use!(Ellis!et!al.,!2004;!Havassy!et!al.,!1991;!Volkow!et!al.,!2011).! Because!empathy,!emotion!recognition,!and!social!bonding!are!key!components!of!social!cognition! and!crucial!for!social!functioning,!I!will!address!these!social!skills!in!more!detail!in!the!following.! ! 1.2.1! Empathy!and!emotion!perception!

Empathy!is!a!multidimensional!construct!comprising!a!cognitive!and!affective!component.!Cognitive! empathy!contains!the!ability!of!understanding!other’s!emotional!state,!whereas!emotional!empathy! implies! sharing! other’s! feelings! through! observation! or! imagination! and! requires! the! ability! of! perspective!taking!as!well!as!self/other!distinction!(Blair,!2005;!Singer!&!Lamm,!2009;!Walter,!2012).! Cognitive! empathy! can! be! equated! with! affective! theory! of! mind! (ToM;! thinking! about! feelings,! whereas! cognitive! ToM! contains! thinking! about! thoughts)! (Dvash! &! Shamay2Tsoory,! 2014)! and! involves! emotion! perception! (i.e.! emotion! recognition! in! faces! or! prosody)! as! well! as! perspective! taking! (Adolphs,! 2002;! Walter,! 2012).! In! literature,! neuronal! activation! during! cognitive! empathy! were! found! in! the! AI,! anterior! MCC,! medial! prefrontal! cortex! (mPFC),! and! OFC! as! well! as! the! amygdala! in! emotion! recognition,! while! emotional! empathy! is! associated! with! activation! in! the! anterior!cingulate!cortex!(ACC),!insula,!and!amygdala!(Adolphs,!2002;!Dvash!&!Shamay2Tsoory,!2014;! Fan,! Duncan,! de! Greck,! &! Northoff,! 2011).! Distinct! deficits! in! both! components! of! empathy! have! been! demonstrated! in! various! psychiatric,! developmental,! and! neurological! disorders! (Cotter,! Granger,! Backx,! Hobbs,! Looi,! &! Barnett,! 2018).! Impaired! cognitive! empathy! has! been! commonly! reported! in! patients! with! schizophrenia,! autism! spectrum! disorder! (ASD),! borderline! personality! disorder,!and!bipolar!disorder!(Blair,!2005;!Gonzalez2Liencres,!Shamay2Tsoory,!&!Brune,!2013;!Smith,! 2006).!Inferior!performances!of!emotional!empathy!were!primarily!associated!with!psychopathy!and! antisocial!personality!disorder!(Blair,!2005;!Smith,!2006).!Furthermore,!deficits!in!emotional!and/or! cognitive!empathy!were!frequently!reported!in!substance!use!disorder,!which!I!will!discuss!in!more! detail! in! chapter! 1.3! (Castellano,! Bartoli,! Crocamo,! Gamba,! Tremolada,! Santambrogio! et! al.,! 2015;! Massey,!Newmark,!&!Wakschlag,!2017;!Quednow,!2017).!

! 6! 1.!THEORETICAL!BACKGROUND!

1.2.2! Social!bonding:!the!Brain!Opioid!Theory!of!Social!Attachment!

From! an! evolutionary! view,! engaging! in! social! relationships! has! various! survival! and! reproductive! advantages! such! as! social! support! and! protection! as! well! as! access! to! potential! mating! partners.! Furthermore,! social! bonds! are! positively! associated! with! well2being,! stress2management,! and! the! course!of!addiction!and!relapse!(Bernstein!&!Claypool,!2012;!Ellis!et!al.,!2004).!Accordingly,!the!need! for! social! relationships! was! reported! as! motivationally! relevant! as! the! need! for! food! and! water! (Baumeister!&!Leary,!1995).! ! Various! neuropeptides,! such! as! oxytocin,! vasopressin,! dopamine,!and!serotonin,! have! been! linked! with!social!bonding!especially!with!the!onset!of!social!relationships,!while!endogenous!opioids!might! play! a! crucial! role! in! the! maintenance! of! social! bonds! and! is! associated! with! affiliative! behaviour! (Machin!&!Dunbar,!2011).!This!assumption!was!initially!formulated!by!Panksepp,!Herman,!Conner,! Bishop,!and!Scott!(1978a)!in!the!“Brain!Opioid!Theory!of!Social!Attachment”!(BOTSA).!The!BOTSA!is! based! on! parallels! observed! in! individuals! with! an! addiction! to! a! relationship! (i.e.,! love)! and! with! opioid!addiction!showing!similar!behaviour,!which!can!be!differentiated!in!three!distinct!phases:!(1)! euphoria!followed!by!addiction,!(2)!tolerance,!which!is!reflected!in!the!relationship!by!the!move!from! romantic!to!companionate!love,!and!(3)!withdrawal,!when!the!object!or!subject!of!dependence!is! removed!suggesting!that!social!withdrawal!elicit!similar!symptoms!as!opioid!withdrawal!(Machin!&! Dunbar,! 2011).! Accordingly,! the! BOTSA! proposes! that! social! contacts! and! interaction! results! in! release!of!endogenous!opioids!mediating!pleasant!feelings,!whereas!social!isolation!and!separation! entails!low!endogenous!opioid!levels!causing!opioid!withdrawal!effects,!which!leads!to!an!increased! motivation! to! seek! social! contacts! and! maintenance! of! social! bonds! (Panksepp! et! al.,! 1978a;! Panksepp,!Herman,!Vilberg,!Bishop,!&!DeEskinazi,!1980).!First!evidences!for!the!BOTSA!came!from! animal! studies! investigating! MOR! agonists! (morphine)! and! antagonists! ()! in! chicks,! rats,! puppies,! and! guinea! pigs! (Herman! &! Panksepp,! 1978;! Panksepp,! Bean,! Bishop,! Vilberg,! &! Sahley,! 1980;!Panksepp!et!al.,!1978a;!Panksepp,!Vilberg,!Bean,!Coy,!&!Kastin,!1978b).!Maternal!separated! infant! animals! revealed! reduced! distress! vocalisation! under! the! effect! of! morphine,! whereas! naloxone! increased! them.! Furthermore,! MOR! gene! (OPRM1)! knockout! mice! revealed! decreased! isolation!calls!after!maternal!separation!(Moles,!Kieffer,!&!D'Amato,!2004).!Analogously,!evidence!for! the! BOTSA! in! humans! was! found! in! genetic! and! positron! emission! tomography! (PET)! studies! reporting!an!association!of!social!attachment!style!with!the!OPRM1!polymorphism!as!well!as!with! MOR! activation! in! the! amygdala,! AI,! ACC,! thalamus,! mPFC,! and! OFC! (Hsu,! Sanford,! Meyers,! Love,! Hazlett,!Wang!et!al.,!2013;!Nummenmaa,!Manninen,!Tuominen,!Hirvonen,!Kalliokoski,!Nuutila!et!al.,! 2015;!Troisi,!Frazzetto,!Carola,!Di!Lorenzo,!Coviello,!D'Amato!et!al.,!2011).!Moreover,!administration! of!a!MOR!antagonist!induced!reduction!in!feelings!of!affiliation!and!connection!(Inagaki,!Ray,!Irwin,!

! 7! 1.!THEORETICAL!BACKGROUND!

Way,! &! Eisenberger,! 2016;! Schweiger,! Stemmler,! Burgdorf,! &! Wacker,! 2014).! Behavioural! studies! indirectly! support! the! BOTSA! in! humans! reporting! an! association! between! endogenous! opioid! release!indexed!by!an!increased!pain!threshold!and!affiliative!behaviour!as!well!as!social!network!size! (Johnson! &! Dunbar,! 2016;! Machin! &! Dunbar,! 2011).! Further! support! comes! from! studies! investigating! social! pain! (i.e.,! social! exclusion,! rejection,! or! ostracism)! in! humans! assuming! that! feelings!of! social!pain! is!equivalent! to! feelings!of!separation!distress!in!animals!mentioned!before! (Eisenberger,! 2015;! Panksepp,! 2003).!Various! neuroimaging! studies! indicate! a! neuronal! overlap! between!social!pain!and!physical!pain!(chapter!1.1.2)!through!the!MOR!system!reporting!activation! in!the!dACC,!AI,!PI,!and!SII!during!social!rejection!commonly!measured!by!the!Cyberball!paradigm,!a! virtual! ball2tossing! game! (Eisenberger,! 2015;! Hsu! et! al.,! 2013;! Kross,! Berman,! Mischel,! Smith,! &! Wager,! 2011;! Williams! &! Jarvis,! 2006).! Therefore,! strong! evidence! exists,! suggesting! that! the! endogenous! opioid! system! might! play! a! crucial! role! in! social! bonding! and! consequently! in! social! rejection.! !!

! 8! 1.!THEORETICAL!BACKGROUND!

1.3! Social!functioning!in!substance!users!

Drug!addiction!is!often!found!to!be!accompanied!by!deficits!in!social!cognition.!The!main!findings!of! social!functioning!alterations!in!chronic!substance!users!are!presented!in!Table!1.!Strong!evidence! comes! particularly! from! studies! investigating! stimulant! users.! In! recent! years,! results! from! our! research!group!revealed!various!impairments!of!social!functioning!in!chronic!stimulant!users.!Distinct! deficits!in!emotional!empathy,!ToM,!emotion!recognition!from!prosody!and!from!fearful!and!angry! faces!were!found!in!cocaine!users!(Quednow,!2017).!Furthermore,!chronic!cocaine!users!revealed!a! smaller! social! network! size! and! less! prosocial! behaviour! (Hulka,! Preller,! Vonmoos,! Broicher,! &! Quednow,!2013;!Preller,!Hulka,!Vonmoos,!Jenni,!Baumgartner,!Seifritz!et!al.,!2014).!Similar!deficits!in! ToM!(Uhlmann,!Ipser,!Wilson,!&!Stein,!2018),!emotion!recognition!and!emotional!empathy!were!also! found! in! methamphetamine! users,! while! non2medical! methylphenidate! users! showed! less! social! contacts! and! impaired! emotion! recognition! from! complex! scenes! (Quednow,! 2017).! In! contrast,! investigation!of!chronic!3,42methylendioxymethamphetamine!(MDMA,!ecstasy)!use!yielded!superior! cognitive!and!preserved!emotional!empathy!(Wunderli,!Vonmoos,!Treichler,!Zeller,!Dziobek,!Kraemer! et!al.,!2017b).!Furthermore,!acute!administration!of!MDMA!decreased!perception!of!social!rejection! (Frye,! Wardle,! Norman,! &! de! Wit,! 2014).! Studies! examining! individuals! with! alcohol! use! disorder! revealed!primarily!deficits!in!emotional!empathy,!ToM,!and!emotion!recognition!(Kornreich,!Foisy,! Philippot,!Dan,!Tecco,!Noel!et!al.,!2003;!Massey!et!al.,!2017;!Maurage,!de!Timary,!Tecco,!Lechantre,!&! Samson,! 2015;! Maurage,! Joassin,! Philippot,! Heeren,! Vermeulen,! Mahau! et! al.,! 2012)! as! well! as! a! smaller! social! network! size! (Mowbray,! 2014)! and! dysregulated! neuronal! activation! in! response! to! social!pain!but!no!significant!differences!in!feelings!of!exclusion!compared!to!controls!(Maurage!et! al.,! 2012).! Less! evidence! of! drug! effects! on! social! cognition! derives! from! chronic! cannabis! users.! Neuroimaging!and!electrophysiological!studies!revealed!altered!physiological!response!to!social!pain! (Gilman,!Curran,!Calderon,!Schuster,!&!Evins,!2016)!and!during!task!performances!of!empathy!and! ToM!with!an!increased!reaction!time!to!identify!facial!emotions!(Platt,!Kamboj,!Morgan,!&!Curran,! 2010;! Roser,! Lissek,! Tegenthoff,! Nicolas,! Juckel,! &! Brune,! 2012;! Troup,! Bastidas,! Nguyen,! Andrzejewski,!Bowers,!&!Nomi,!2016).! Analogously,!there!are! only!few! studies! investigating! social! cognition! in! individuals! with! opioid! dependence.! Deficits! in! emotion! recognition! were! found! for! opioid2substituted!patients!using!objective!computer2based!tasks!(Kornreich!et!al.,!2003;!McDonald,! Darke,! Kaye,! &! Torok,! 2013).! Furthermore,!studies!measuring!empathy!by!a!subjective!self2rating! questionnaire,! the! Interpersonal! Reactivity! Index! (IRI)! (Davis,! 1983),! reported! less! emotional! empathy!in!opioid2substituted!patients!compared!to!a!healthy!controls!group!(Stange,!Kruger,!Janke,! Lichtinghagen,!Bleich,!Hillemacher!et!al.,!2017;!Tomei,!Besson,!Reber,!Rougemont2Bucking,!&!Grivel,! 2017).! A! recent! study! by! Gandolphe,! Lecluyse,! Triquet,! Brunelle,! Duparcq,! and! Nandrino! (2018)! reported!impaired!ToM!performances!in!opioid!substituted!patients.!To!the!best!of!my!knowledge,!

! 9! 1.!THEORETICAL!BACKGROUND! no! studies! exist! investigating! social! pain! in! individuals! with! opioid! dependence! so! far.! However,! acute! effects! of! the! partial! MOR! agonist! ! on! social! pain! were! examined! in! healthy! subjects!reporting!an!opioid2induced!decrease!in!perception!of!social!exclusion!(Bershad,!Seiden,!&! de! Wit,! 2016).! Furthermore,! buprenorphine! administration! reduced! stress! response! to! the! Trier! Social!Stress!Test!(TSST)!(Kirschbaum,!Pirke,!&!Hellhammer,!1993)!indicated!by!subjective!self2ratings! and! attenuated! cortisol! levels! (Bershad! et! al.,! 2016).! For! individuals! with! prescription! opioid! dependence,!neither!subjective!nor!physiological!differences!in!cortisol!levels!and!heart!rate!were! found!compared!to!healthy!controls!after!the!TSST!(Back,!Gros,!Price,!LaRowe,!Flanagan,!Brady!et!al.,! 2015).! ! Limited!studies!exist!investigating!social!cognition!in!individuals!with!PSU.!Consistent!deficits!were! reported! for! emotion! recognition! from! faces! in! polysubstance! users! (Fernandez2Serrano,! Lozano,! Perez2Garcia,! &! Verdejo2Garcia,! 2010;! Verdejo2Garcia,! Rivas2Perez,! Vilar2Lopez,! &! Perez2Garcia,! 2007).!However,!the!study!by!Ferrari,!Smeraldi,!Bottero,!and!Politi!(2014)!found!impairments!only!in! emotional!empathy,!whereas!cognitive!empathy!remained!unaffected!measured!by!a!subjective!self2 rating! scale.! Recently,! a! neuroimaging! study! in! individuals! with! PSU! postulated! pronounced! structural! alterations! in! the! OFC! and! ACC,! which! are! associated! with! social! cognition! (Meyerhoff,! 2017).! ! Table&1!Social!functioning!in!chronic!substance!users! S-mulant(users2( Domains(of(social( Alcohol( !! !! MDMA3( Cannabis4( Opioid(users5( 1 Cocaine( Methamphetamine( Non2medical( PSU6( func-oning( users ( users( users( (subs&tuted)! !! users( users( methylphenidate(users(

a a,c b a a,b c c a a,b,c( d a d Cogni-ve(empathy( ((((((((((((( ( !!!!!!!!!! ,!!!!! ( !!!!!!!!!!!!!!!!!!!!!!!!!! ! !!!!!!!!!!!!!!!!!!! ,!!!! ! !!!!!!!!!!!!!! ! !!!!!!!!!!(!!!) ! !!!!!!!!! ,!!!!!!! ! !!!!!!!! ,!!!!!!!! !

d d Emo-onal(empathy( !!!!!!!!!!!!!!!!!! !!!!!!!!!!(!!)! !!!!!!!!!!!!!!!!! ! (((((((((((((( !!

Theory(of(mind( !!!!!!!!!!!!!!!!!!!!! !!!!!!!!!!!!!!!!!!!!(!!)! !!!!!!!!!!!!!!!!!!!! ((((((((((((H( e e Social(pain((Cyberball)!!!!!!!(!!)! ((((((((((((H( ((((((((((((((((((((((H( (((((((((((((((((((((((H( (((((((((!!) ( !!!!!!!!!!(!!)! ((((((((((((!!) ( !!!!!!!!!!!!H(

Social(network(size( ((((((((((((((((((((((H( (((((((((((H( (((((((((((((H( ((((((((((((((H( ((((((((((((H( ! !!:!reported!impairment,!!!!!!:!reported!superiority,!!!!!!!!:!unchanged,!():!reported!indications;!PSU:!polysubstance!users.! 1! For! review! see! Massey! et! al.! (2017)! and! Bora! and! Zorlu! (2017),! for! social! pain! see! Maurage! et! al.! (2012),! for! social!!!!! network!size!see!Mowbray!(2014).! 2!For!review!see!Quednow!(2017),!for!ToM!in!methylphenidate!users!see!Uhlmann!et!al.!(2018).! 3!See!Wunderli!et!al.!(2017b)!and!Frye!et!al.!(2014).! 4!See!e.g.,!Troup!et!al.!(2016),!Roser!et!al.!(2012),!and!Gilman!et!al.!(2016).! 5!See!e.g.,!McDonald!et!al.!(2013),!Stange!et!al.!(2017),!Gandolphe!et!al.!(2018),!and!Bershad!et!al.!(2016).! 6!See!e.g.,!Fernandez2Serrano!et!al.!(2010)!and!Ferrari!et!al.!(2014).! a!Emotion!recognition!from!faces.! b!Emotion!recognition!from!prosody.! c!Emotion!recognition!from!complex!scenes.! d!Subjective!self2reports.! e!Acute!effects.! !!

! 10! 1.!THEORETICAL!BACKGROUND!

1.4.! Study!subjects!

Study!samples!presented! in! this! thesis!contain! subjects!who!participated!in!two!separate!projects! conducted! at! the! University! Hospital! for! Psychiatry! in! Zurich.! One! study! was! conducted! with! exclusively! polysubstance! users,! while! two! studies! comprised! a! sample! of! relatively! pure! opioid! analgesic!users.! ! 1.4.1! Sample!of!stimulant!polysubstance!users!

The! study! presented! in! chapter! 2! investigated! social! functioning! in! polysubstance! users! by! considering! the! number! of! substances! that! were! used.! Subjects! of! the! PSU! sample! initially! participated!in!the!Zurich!Cocaine!Cognition!Study!(ZuCo2St)!and!MDMA!study!and!were!excluded! afterwards!due!to!polysubstance!use!(Hulka!et!al.,!2013;!Preller!et!al.,!2014;!Vonmoos,!Hulka,!Preller,! Jenni,!Baumgartner,!Stohler!et!al.,!2013;!Wunderli!et!al.,!2017b).!In!accordance!to!the!DSM2IV,!PSU! was! defined! as! the! use! of! three! psychotropic! substances! including! at! least! two! illegal! drugs! objectively!detected!by!hair!and!urine!toxicology!and!alcohol!as!the!only!legal!substance!(for!details! see! chapter! 2.).! With! respect! to! the! number! of! used! substances,! the! final! PSU! sample! comprised! three! subgroups! with! individuals! using! three! (n=31),! four! (n=10),! and! five! (n=6)! substances.! Furthermore,!subjects!of!the!matched!drug2naïve!control!group!(n=59)!were!also!selected!from!the! two! studies! mentioned! before.! Given! that! individuals! of! the! present! PSU! sample! were! initially! recruited!for!the!ZuCo2St!or!MDMA!study!and!that!opioid!use!was!an!exclusion!criteria,!most!of!the! participants!showed!primarily!stimulant!use.!Therefore,!the!group!was!named!stimulant!PSU.! ! 1.4.2! Sample!of!non8medical!prescription!opioid!users!

Chapter!3!and!4!present!cross2sectional!results!of!a!larger!longitudinal!case2control!study!as!part!of! my!PhD!project!investigating! potential! neuropsychological! and! psychophysiological!predispositions! and!consequences!of!chronic!NMPOU.!Initially,!59!subjects!participated!in!the!cross2sectional!part!of! the! study! of! which! seven! participants! were! excluded:! one! participant! due! to! insufficient! effort! in! socio2cognitive!tasks,!two!participants!of!the!NMPOU!group!due!to!negative!hair!and!urine!toxicology! for!opioids,!and!four!participants!due!to!chronic!pain.!The!final!sample!comprised!23!individuals!with! NMPOU!and!29!subjects!in!the!control!group!and!both!groups!were!matched!by!age,!sex,!years!of! education,!verbal!IQ,!and!smoking!status.! !!

! 11! 1.!THEORETICAL!BACKGROUND!

1.5! Thesis!structure!

The! focus! of! the! present! thesis! lies! on! social! functioning! in! chronic! substance! users.! Within! the! context!of!two!different!studies!and!study!samples,!this!thesis!is!structured!in!two!parts.!The!first! part! (part! I)! includes! chapter! 2! and! considers! predispositions! and! drug! effects! of! PSU! on! social! functioning.!Several!studies!demonstrated!strong!evidence!for!altered!socio2cognitive!functioning!in! monosubstance! users! specifically! for! stimulant! use! (chapter! 1.3).! However,! only! few! studies! exist! investigating! social! cognition! in! individuals! with! PSU! reporting! deficits! in! emotion! recognition,! emotional!empathy,!and!structural!alterations!in!the!OFC!and!ACC!(Fernandez2Serrano!et!al.,!2010;! Ferrari!et!al.,!2014;!Meyerhoff,!2017;!Verdejo2Garcia!et!al.,!2007).!Because!PSU!was!assessed!by!self2 reports! and! potential! cumulative! effects! of! multiple! substance! use! were! disregarded! so! far,! the! innovative!aspect!of!the!study!in!chapter!2!was!the!creation!of!an!objectively!validated!PSU!sample! and!the!consideration!of!the!number!of!used!substances!by!subdividing!the!PSU! group! into!three! subgroups.! ! The! second! part! (part! II)! of! this! thesis! contains! chapter! 3! and! 4! and! addresses! the! question! of! potential!predispositions!and!drug!effects!of!chronic!opioid!use!in!individuals!with!NMPOU!with!the! focus! on! social! functioning.! The! few! and! inconsistent! findings! of! impaired! social! functioning! in! chronic!opioid!users!comprised!mainly!participants!showing!a!current!or!previous!history!of!heroin! dependence! (Back! et! al.,! 2015;! Kornreich! et! al.,! 2003;! McDonald! et! al.,!2013;!Stange!et!al.,!2017;! Tomei! et! al.,! 2017).! For! this! population,! it! is! difficult! to! attribute! the! reported! findings! to! pharmacological!opioid!effects!due!to!confounding!factors!commonly!associated!with!heroin!use!or! opioid!substitution!such!as!polysubstance!use,!non2compliance,!monetary!motivation,!injection!use,! and!lifestyle!factors!(e.g.,!poor!dietary!habits,!brain!injury!due!to!drug!overdoses!or!drug!adulterants,! viral! infections! such! as! hepatitis! C! [HCV]! and! human! immune2deficiency! virus! [HIV]),! which! may! contribute!to!cognitive!impairments!independently!(Darke,!2011,!2013;!Mintzer!&!Johnson,!2007).! Therefore,! the! advantage! of! the! studies! presented! in! part! II! of! this! thesis! is! the! investigation! of! relatively! pure! chronic! opioid! users! objectively! confirmed! by! hair! and! urine! analyses.! Chapter! 3! considers! potential! effects! of! chronic! opioid! use! on! emotional! empathy,! cognitive! empathy,! and! emotion!recognition,!whereas!chapter!4!focus!on!the!BOTSA!investigating!potential!behavioural!and! physiological!effects!of!chronic!NMPOU!on!social!pain.! ! The!final!chapter!5!contains!a!general!discussion!of!the!results!presented!in!chapter!2!to!4,!strength! and!limitations!of!the!studies,!and!clinical!implications!as!well!as!an!outlook!inspired!by!the!study! results.! !

! 12! !

! ! ! ! ! Part!I! !

! 13! 2.1!ABSTRACT! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!

2.! SOCIO2COGNITIVE!FUNCTIONING!IN!STIMULANT! POLYSUBSTANCE!USERS2! ! 2.1! Abstract!

Background:&Using!more!than!one!psychotropic!substance!is!accompanied!with!increased!risks!for! psychiatric! and! physical! disorders.! Accordingly,! deficits! in! basal! cognitive! functions! have! been! consistently! associated! with! polysubstance! use! (PSU),! whereas! little! is! known! about! potential! impairments! in! more! complex! socio2cognitive! skills,! which! are! relevant! for! daily2life! functioning.! Therefore,! we! investigated! the! effects! of! toxicological! validated! stimulant! PSU! on! social! cognition! under!consideration!of!potential!cumulative!effects.! ! Methods:&We!compared!socio2cognitive!performances!of!47!individuals!with!stimulant!PSU!with!59! matched!stimulant2naïve!controls!using!the!Multifaceted!Empathy!Test!(MET)!and!the!Movie!for!the! Assessment!of!Social!Cognition!(MASC).!Additionally,!social!network!size!was!assessed!by!the!Social! Network! Questionnaire! (SNQ).! Hair! and! urine! testing! was! employed! to! categorise! three! PSU! subgroups!(3,!4,!and!≥5!substances!used)!and!to!ensure!drug!abstinence!in!controls.! ! Results:&Individuals!with!stimulant!PSU!showed!lower!emotional!empathy!(MET)!and!a!smaller!social! network! (SNQ)! compared! to! controls! (both! with! linear! trends! for! increasing! number! of! used! substances:!p<.05).!In!contrast,!cognitive!empathy!(MET!and!MASC)!was!largely!unaffected!by!PSU.! Additional!linear!regression!analyses!within!PSU!individuals!revealed!number!of!used!substances!as! the!best!predictor!for!inferior!performance!in!emotional!empathy!(p<.01),!while!severity!of!the!use! of!single!substances!or!substance2classes!did!not!show!a!significant!impact.! ! Conclusion:! These! findings! demonstrate! cumulative! adverse! effects! of! stimulant! PSU! on! an! important! facet! of! socio2cognitive! functioning.! Therefore,! emotional! empathy! deficits! should! be! targeted!in!future!interventions!and!rehabilitations!for!individuals!with!PSU.!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 2!The!content!of!this!chapter!is!reported:! Kroll,!S.!L.;!Wunderli,!M.!D.;!Vonmoos,!M.;!Hulka,!L.!M.;!Preller,!K.!H.;!Bosch,!O.!G.;!Baumgartner,!M.;!&!! Quednow,!B.!B.!(2018).!Social!functioning!in!stimulant!polysubstance!users.!Drug!Alcohol!Depend! ! 14! 2.2!INTRODUCTION! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning! 2.2! Introduction!

The! use! of! more! than! one! psychotropic! substance,! concurrently! or! consecutively,! is! termed! polysubstance!use!(PSU)!(EMCDDA,!2002;!Meyerhoff,!2017).!PSU!was!previously!diagnosed!according! to!the!Diagnostic!and!Statistical!Manual!of!Mental!Disorders!(DSM2IV)!by!the!use!of!at!least!three! substances! (excluding! caffeine! and! nicotine)! within! the! same! 122month! period.! However,! this! definition!has!recently!been!removed!in!the!DSM25!(American!Psychiatric!Association,!1994,!2013).! ! Three!main!reasons!for!PSU!are!commonly!reported:!(1)!it!can!induce!cumulative!or!complementary! effects,!(2)!it!can!compensate!negative!effects!of!other!drugs,!and!(3)!it!can!reflect!the!replacement! of!a!drug!by!another!drug!due!to!low!prices,!availability,!or!fashion!(EMCDDA,!2009;!Preedy,!2016).! While! the! frequency! of! monosubstance! use! is! decreasing! over! the! last! years,! PSU! instead! has! become!a!serious!and!increasing!public!health!concern!with!regard!to!psychological!(e.g.,!depression! or!anxiety)!and!physiological!illnesses!accompanied!by!an!increased!risk!of!intoxication,!injury,!and! death!(Connor!et!al.,!2014;!Karjalainen,!Lintonen,!&!Hakkarainen,!2017;!Martin,!2008).!Accordingly,! 38%!of!drug2related!hospital!emergency!presentations!in!Europe!were!reported!to!be!caused!by!PSU! (EMCDDA,!2016).! ! Recently,!neurocognitive!effects!of!PSU!have!been!investigated!intensively!indicating!an!increased! interest!in!this!research!field!of!substance!use.!The!study!by!Schmidt,!Pennington,!Cardoos,!Durazzo,! and!Meyerhoff!(2017b)!investigated!neurocognitive!functioning!in!individuals!with!PSU!and!alcohol! use!disorders!(AUD).!The!PSU!group!revealed!inferior!performances!in!auditory2verbal!memory!and! learning,!inhibitory!control!of!impulsivity,!decision2making,!and!global!cognition!compared!to!AUD! (Schmidt!et!al.,!2017b).!This!is!in!line!with!previous!findings!of!behavioural!and!neuroimaging!studies! investigating!cognition!in!individuals!with!PSU!and!reporting!similar!deficits!in!cognitive!efficiency,! attention,!memory,!and!delayed!discounting!(Connor!et!al.,!2014;!Fernandez2Serrano,!Perez2Garcia,! &!Verdejo2Garcia,!2011;!Moody,!Franck,!Hatz,!&!Bickel,!2016;!Pennington,!Durazzo,!Schmidt,!Abe,! Mon,!&!Meyerhoff,!2015).! ! Apart!from!consistently!reported!neurocognitive!impairments!of!PSU,!little!is!known!about!its!socio2 cognitive!sequelae.!Social!cognition!includes!prosocial!and!interpersonal!behaviour!such!as!empathy! and!emotion!recognition,!which!are!crucial!for!daily2life!interactions!(Singer!&!Lamm,!2009;!Walter,! 2012).!Empathy!is!a!multidimensional!construct!subdivided!in!at!least!two!components:!1)!cognitive! empathy! is! characterised! by! the! ability! to! understand! the! feelings! of! others! without! necessarily! experiencing!them!and!involves!perspective2taking,!also!called!Theory2of2Mind!(ToM),!and!emotion! recognition;!2)!emotional!empathy!means!to!subjectively!experience!the!others’!feelings!(Decety!&!

! 15! 2.2!INTRODUCTION! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning! Jackson,!2004;!Eres,!Decety,!Louis,!&!Molenberghs,!2015;!Walter,!2012).!Deficits!in!empathy!have! been! demonstrated! in! various! psychiatric! diseases! such! as! autism! (Blair,! 2005;! Dziobek,! Rogers,! Fleck,! Bahnemann,! Heekeren,! Wolf! et! al.,! 2008),! schizophrenia! (Derntl,! Finkelmeyer,! Toygar,! Hulsmann,! Schneider,! Falkenberg! et! al.,! 2009),! depression! (Cusi,!Macqueen,!Spreng,!&!McKinnon,! 2011),!psychopathy!(Blair,!2005;!Pfabigan,!Seidel,!Wucherer,!Keckeis,!Derntl,!&!Lamm,!2015),!and!in! individuals! with! substance! use! disorders! (Quednow,! 2017;! Reay,! Hamilton,! Kennedy,! &! Scholey,! 2006;!Uekermann!&!Daum,!2008).!More!specifically,!alcohol!dependence!is!associated!with!deficits!in! emotional!empathy,!emotion!recognition,!and!humour!processing!(Kornreich!et!al.,!2003;!Maurage! et! al.,! 2015;! Maurage,! Grynberg,! Noel,! Joassin,! Hanak,! Verbanck! et! al.,! 2011;! Mohagheghi,! Amiri,! Mousavi! Rizi,! &! Safikhanlou,! 2015;! Uekermann,! Channon,! Winkel,! Schlebusch,! &! Daum,! 2007).! Studies! with! chronic! methamphetamine! users! consistently! demonstrated! deficits! in! emotion! recognition! and! ToM! (Henry,! Mazur,! &! Rendell,! 2009;! Kim,! Kwon,! &! Chang,! 2011).! Furthermore,! previous!studies!of!our!group!revealed!deficits!in!emotion!recognition,!ToM,!and!emotional!empathy! in! cocaine! users,! whereas! non2medical! methylphenidate! users! mainly! showed! impairments! in! cognitive!empathy!(Hulka!et!al.,!2013;!Maier,!Wunderli,!Vonmoos,!Rommelt,!Baumgartner,!Seifritz!et! al.,!2015;!Preller!et!al.,!2014).! In! contrast,! chronic! 3,42methylenedioxymethamphetamine!(MDMA)! users!showed!superior!cognitive!empathy!accompanied!by!unaffected!emotional!empathy!(Wunderli! et!al.,!2017b).!Studies!investigating!opioid2related!effects!reported!impairments!in!social!perception! in! substituted! patients! (Kornreich! et! al.,! 2003;! McDonald! et! al.,! 2013).! Finally,! neuroimaging! and! electrophysiological! studies! with! chronic! cannabis! users! revealed! altered! physiological! response! during!task!performances!of!ToM!and!empathy!(Platt!et!al.,!2010;!Roser!et!al.,!2012;!Troup!et!al.,! 2016).! ! Although!PSU!is!clinically!highly!relevant,!studies!investigating!social!cognition!in!individuals!with!PSU! are!limited!to!date.!The!study!by!Ferrari!et!al.!(2014)!demonstrated!reduced!emotional!empathy!with! preserved!cognitive!empathy!in!addicted!PSU!patients!compared!to!controls!using!a!subjective!self2 rating!scale!of!the!empathy!quotient.!These!effects!were!specifically!pronounced!for!males!with!PSU.! Furthermore,!deficits!in!recognition!of!facial!emotion!expressions!were!reported!for!individuals!with! PSU!using!a!computer2based!Ekman!Faces!Test!(Fernandez2Serrano!et!al.,!2010;!Verdejo2Garcia!et!al.,! 2007).!Moreover,!a!recent!neuroimaging!review!by!Meyerhoff!(2017)!reported!consistent!findings!in! individuals!with!PSU!regarding!structural!alterations!in!the!orbitofrontal!cortex!(OFC)!and!anterior! cingulate! cortex! (ACC),! which! are! associated! with! ToM! and! empathy! (Abu2Akel! &! Shamay2Tsoory,! 2011;!Bernhardt!&!Singer,!2012;!Fan!et!al.,!2011).! !

! 16! 2.2!INTRODUCTION! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning! In!sum,!studies!investigating!socio2cognitive!functioning!in!individuals!with!PSU!mainly!focused!on! emotion!recognition!or!subjective!self2rating!scales!for!empathy.!Therefore,!our!aim!was!to!assess! emotional! and! cognitive! empathy! with! complex! stimuli! in! situational! contexts! using! performance! tasks.!Furthermore,!only!two2group!analyses!were!conducted!so!far!comparing!polysubstance!users! with!controls!while!disregarding!cumulative!effects!of!multiple!substances.!Based!on!the!study!by! Witt,!Elger,!and!Helmstaedter!(2015)!reporting!decreased!cognitive!performance!with!an!increased! number!of!consumed!antiepileptics,!we!created!a!42group!design!for!our!study!(three!PSU!subgroups! vs.! healthy! controls)! in! order! to! consider! the! number! of! used! substances.! Although! studies! investigating!PSU!differ!with!respect!to!their!classifications,!they!all!have!in!common!that!PSU!was! assessed!by!self2reports.!Because!it!is!well2known!that!self2reports!in!substance!users!are!distorted! by!social!desirability!biases!and!memory!alterations!(Latkin,!Edwards,!Davey2Rothwell,!&!Tobin,!2017;! Magura!&!Kang,!1996;!Quednow,!Jessen,!Kuhn,!Maier,!Daum,!&!Wagner,!2006),!a!further!innovative! aspect!of!our!study!was!to!investigate!an!objectively!validated!PSU!sample!based!on!hair!and!urine! toxicology!analyses.!Given!that!deficits!of!emotional!empathy!have!been!shown!for!a!variety!of!single! substance!users!as!well!as!for!PSU!assessed!only!by!self2reports,!we!hypothesised!that!an!increased! number! of! used! substances! goes! along! with! decreased! performances! in! emotional! empathy! accompanied! by! increased! impairments! in! real2life! social! functioning! reflected! in! a! smaller! social! network!size.! !

! 17! 2.3!METHODS!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! 2.3! Methods!

2.3.1! Recruitment!and!participants!

Participants! in! our! PSU! and! control! groups! were! initially! recruited! and! assessed! for! our! previous! cocaine!(Zurich!Cocaine!Cognition!Study,!ZuCoSt2)!(Hulka!et!al.,!2013;!Preller!et!al.,!2014;!Vonmoos!et! al.,! 2013)! and! MDMA! studies! (Wunderli,! Vonmoos,! Furst,! Schadelin,! Kraemer,! Baumgartner! et! al.,! 2017a).! The! present! PSU! sample! was! composed! of! individuals! who! were! excluded! from! these! previous! studies! because! of! PSU.! Participants! were! initially! recruited! through! flyers! in! addiction! centres!and!hospitals,!advertisements!in!local!newspapers,!internet!platforms,!and!word!of!mouth.! All!participants!were!tested!at!the!Psychiatric!Hospital!of!the!University!of!Zurich,!aged!between!18! and!60!years,!had!proficiency!in!German!language,!and!showed!no!severe!physical,!neurological,!and! psychiatric!disorders!according!to!DSM2IV!with!exception!of!substance!abuse/dependence,!attention! deficit! hyperactivity! disorder! (ADHD),! and! history! of! depression! for! the! PSU! sample.! Specific! exclusion!criteria!for!the!control!group!were!positive!urine!or!hair!toxicology!and!a!medium!to!high! alcohol! risk! level! (see! 2.3.2.).! All! participants! were! asked! to! abstain! from! illegal! substances! for! at! least!72!hours!and!from!alcohol!24!hours!prior!to!the!measurement.!The!study!was!approved!by!the! Ethic!Committee!of!the!Canton!Zurich.!All!participants!provided!written!informed!consent!and!were! compensated!for!their!participation.! ! 2.3.2! PSU!sample!

Referring! to! DSM2IV! criteria,! we! defined! PSU! as! the! consumption! of! at! least! three! psychotropic! substances!within!the!last!six!months,!including!alcohol!as!the!only!legal!drug!and!excluding!tobacco! use.!Objective!data!were!used!to!get!a!precise!and!valid!estimation!of!illegal!drug!use!and!to!avoid! social! desirability! in! subjective! questionnaires.! According! to! the! social! desirability! hypothesis,! Harrison!(1997)!postulated!that!the!validity!of!self2reported!substance!use!decreases!in!relation!to! the!increase!in!stigmatisation!of!the!substance!that!is!used.!Alcohol!is!a!legal!drug,!which!is!socially! recognised!with!low!stigmatisation!compared!to!illegal!substances.!Therefore,!alcohol!was!the!only! drug! for! which! no! objective! validation! was! collected,! as! we! believed! that! our! subjective! data! of! alcohol!use!were!less!biased!than!illegal!drug!use!(Del!Boca!&!Darkes,!2003;!Lintonen,!Ahlstrom,!&! Metso,!2004).! Based! on! the! World! Health! Organisation! (WHO,! 2000),!we!defined!three!groups!of! alcoholic!risk!consumption!levels!for!men!and!women!respectively!with!low!(1),!medium!(2),!and!high! (3)!risk!alcohol!consumption!levels!(Table!S1a).!Low!level!of!alcohol!consumption!was!not!considered! for!the!number!of!used!substances!in!the!PSU!subgroups.!Chronic!cannabis!use!was!confirmed!by! urine! analyses! because! participants! were! asked! to! abstain! from! illegal! substances! for! at! least! 72! hours! and! the! window! of! detection! for! THC! in! urine! samples! is! up! to! more! than! three! weeks! in!

! 18! 2.3!METHODS!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! frequent! cannabis! users! (Musshoff! &! Madea,! 2006).! Additional! psychotropic! substance! use! (e.g.,! cocaine,!MDMA,!amphetamines,!opioids,!,!2,52dimethoxy242bromophenethylamine![2C2B])! was! quantified! by! hair! analyses.! For! urine! samples,! delta292tetrahydrocannabinol! (THC)! concentrations!of!at!least!50!ng/ml!were!considered!positive!(Methods!S1).!Three!equal!groups!in! relation! to! the! group! size! were! calculated! over! all! positive! urine! samples! of! initially! recruited! participants!(n=60)!to!differentiate!again!between!low!(1),!medium!(2),!and!high!(3)!substance!use! (Table!S1b).!The!same!procedure!was!performed!with!hair!samples!to!differentiate!between!three! levels!of!substance!use!severity!for!each!illegal!substance!(see!Methods!S2!&!Table!S1c).!The!average! of!the!normalised!cocaine,!MDMA,!and!amphetamine!hair!values!was!used!to!define!the!final!cut2off! values!for!low!(1),!medium!(2),!and!severe!(3)!substance!use!(Table!S1c).!Furthermore,!a!PSU!severity! index!(PSUSI)!over!all!substances!was!calculated!by!summarising!the!severity!levels!low!(1),!medium! (2),!high!(3)!of!used!substances.!

!

Because! participants! were! initially! recruited! for! our! previous! studies! investigating! cocaine! and! MDMA!users,!participants!were!excluded!if!they!revealed!consumption!of!less!than!three!substances! or!high!severity!level!(level!3)!of!only!one!single!substance!accompanied!with!low!levels!(level!1)!of! additional! substances! indicating! a! primary! drug! of! choice.! Our! final! sample! comprised! three! subgroups!of!PSU!using!three!(n=31),!four!(n=10),!and!five!or!more!substances!(n=6)!and!59!controls! (Fig.!1).!The!groups!were!carefully!matched!for!age,!verbal!IQ,!years!of!education,!and!tobacco!use.! Data!from!the!healthy!stimulant2naïve!controls!of!the!present!study!has!already!been!published!in! previous! papers! including! the! ZuCoSt2! and! MDMA! study! (Vonmoos! et! al.,! 2013;! Wunderli! et! al.,! 2017a).!However,!our!PSU!sample!does!not!contain!any!cocaine!user!included!in!previous!ZuCo2St! publications!(e.g.,!Vonmoos!et!al.,!2013)!but!revealed!an!overlap!of!42.6%!with!the!MDMA!polydrug! sample!reported!in!the!study!by!Wunderli!et!al.!(2017a).! ! 2.3.3! Clinical!Assessment!

The! Structured! Clinical! Interview! for! Axis2I! DSM2IV! disorders! (SCID! I)! was! conducted! by! trained! psychologists.! Furthermore,! participants! completed! the! DSM2IV! self2rating! questionnaire! assessing! Axis2II! personality! disorders! (SCID! II).! Because! cocaine! use! was! previously! associated! with! higher! scores!in!antisocial!and!narcissistic!personality!disorder!(PD)!domains!(Preller!et!al.,!2014),!Cluster!B! PD! including! antisocial,! borderline,! histrionic,! and! narcissistic! PD! was! calculated.! To! control! for! potential!mood!or!attention!differences!between!groups,!the!Beck!Depression!Inventory!(BDI)!(Beck,! Ward,!Mendelson,!Mock,!&!Erbaugh,!1961)!and!the!Attention!Deficit!Hyperactivity!Disorder!(ADHD)! self2rating!scale!(ADHD2SR)!(Rösler,!Retz,!Retz2Junginger,!Thome,!Supprian,!Nissen!et!al.,!2005)!were!

! 19! 2.3!METHODS!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! conducted.! Premorbid! verbal! IQ! was! estimated! by! the! Mehrfachwahl2Wortschatz2Intelligenztest! (Lehrl,!1999),!which!is!a!standardised!German!vocabulary!test.! ! 2.3.4! Drug!assessment!

Substance! use! over! the! last! six! months! was! assessed! by! means! of! a! structured! and! standardised! interview! for! psychotropic! drug! consumption! (Quednow,! Kuhn,! Hoenig,! Maier,! &! Wagner,! 2004).! Additionally,!illegal!substance!use!over!the!last!six!months!was!examined!by!6cm2hair!samples,!which! were!segmented!into!two!3cm2hair!parts!and!analysed!separately.!The!average!concentration!of!both! hair!segments!was!calculated!and!used!for!the!final!analyses.!Twenty!individuals!(34%)!in!the!control! and!13!(28%)!in!the!PSU!group!had!only!one!hair!segment!due!to!insufficient!hair!length.!In!these! cases,! only! the! single! values! were! introduced! in! the! analyses.! Hair! samples! were! taken! from! the! posterior! vertex! region! of! the! head! to! assess! the! concentration! of! 11! common! drugs! and! their! metabolites! by! liquid! chromatography2tandem! mass! spectroscopy! (LC2MS/MS).! Additionally,! urine! analyses!were!conducted!by!semi2quantitative!enzyme!multiplied!immunoassays!in!order!to!assess! cannabis!use!(Methods!S1).! !

Completed neuropsychological assessment with HS & US and without physical or psychiatric diseases (n=339)

Controls (n=118) Substance user (n=221) • Negative HS & US • Positive HS & US

Excluded (n=59) Excluded (n=174) • Matching for age, sex, • < 3 Substances used (n=170) YoE, and tobacco (2 substances detected in US (n=41) & HS + alcohol use levels > 1) • Alcohol use level > 1 • PSU with primary substance (n=18) use of: Cocaine (n=1) MDMA (n=3)

Final controls (n=59) Final PSU (n=47) 3 substances (n=31) 4 substances (n=10) 5 substances (n=6) ! Figure&1.!Flow!diagram!of!the!final!study!sample.! HS:!hair!samples,!PSU:!polysubstance!use,!US:!urine!samples,!YoE:!years!of!education.! !!

! 20! 2.3!METHODS!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! 2.3.5! Socio8cognitive!assessment! MASC% The! Movie! for! Assessment! of! Social! Cognition! (MASC)! is! a! 152minute! video2based! task! with! the! intention!of!assessing!mental!and!emotional!perspective2taking!(ToM),!which!is!a!facet!of!cognitive! empathy,!with!an!ecological!valid!method!(Dziobek,!Fleck,!Kalbe,!Rogers,!Hassenstab,!Brand!et!al.,! 2006).! During! the! video,! participants! were! asked! about! the! characters’! feelings,! thoughts,! and! intentions.!Four!response!alternatives!were!presented!with!one!correct!answer!and!three!distractors.! ! MET% The! Multifaceted! Empathy! Test! (MET)! is! a! computer2based! task! comprising! 40! pictures! showing! people! in! distinct! positive! and! negative! emotional! situations! (Dziobek! et! al.,! 2008).! Based! on! the! multidimensional! construct! of! empathy,! the! MET! distinguishes! between! emotional! and! cognitive! empathy.!Emotional!empathy!(EE)!is!subdivided!into!explicit!emotional!empathy!(EEE)!assessed!by! ratings! of! the! participants’! empathic! concern,! and! implicit! emotional! empathy! (IEE)! measured! by! ratings!of!the!participants’!arousal!on!a!92point!Likert!scale.!Cognitive!empathy!(CE)!was!measured!by! presenting!four!response2alternatives!from!which!the!participant!had!to!choose!one!emotion,!which! fits!the!best!to!the!person’s!mental!state!on!the!picture.! ! Additionally,!we!constructed!a!global!cognitive!empathy!domain!score!(CES)!including!z2transformed! CE! and! MASC! data! based! on! means! and! standard! deviations! of! the! control! group! according! to! Wunderli!et!al.!(2017b).! & SNQ% Furthermore,!participants’!social!contacts!were!measured!by!the!Social!Network!Size!Questionnaire! (SNQ,!for!details!see!Preller!et!al.,!2014).!The!number!of!personal!contacts!during!the!previous!four! weeks!in!specific!life!areas!(household,!family,!work!or!education,!friends,!neighbours,!and!others)! were!named!and!subsumed!to!the!total!network!size.! ! 2.3.6! Statistical!analysis!

Statistical!analyses!were!performed!by!SPSS!23.0!for!Mac.!Frequency!data!were!analysed!by!means! of! Pearson’s! χ2! test.! To! determine! quantitative! differences! between! groups,! analyses! of! variance! (ANOVA)!and!covariance!(ANCOVA)!with!the!four!groups!as!fixed!factor!(three!PSU!subgroups!and! controls)!were!used!to!control!for!age!and!sex!because!of!differences!in!sex!distribution!between!our! groups!and!associations!with!prosocial!behaviour!(Beadle,!Sheehan,!Dahlben,!&!Gutchess,!2015;!Kret! &!De!Gelder,!2012;!Miller,!Bernzweig,!Eisenberg,!&!Fabes,!1991).!Furthermore,!the!severity!index!of! ! 21! 2.3!METHODS!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! PSU!(PSUSI)!was!introduced!as!an!additional!covariate!for!the!MET!and!MASC!due!to!differences!of! the!PSUSI!between!the!groups!and!because!of!putative!association!between!severity!of!substance! use! and! emotion! recognition! in! individuals! with! PSU! (Fernandez2Serrano! et! al.,! 2010).! Sidak2 corrected!post!hoc!analyses!and!linear!group!contrasts!for!trend!analysis!were!performed!regarding! the!number!of!used!substances.!Multiple!linear!regression!analyses!(forced!entry)!were!conducted!to! estimate! potential! single! substance2class! effects! (alcohol,! THC,! stimulants,! and! empathogens,! see! 2.4.3)!on!socio2cognitive!functioning!over!all!individuals!with!PSU!(n=47).!Further!linear!regression! analyses! within! the! PSU! subgroups! were! used! to! determine! potential! associations! of! clinical! and! demographic!variables!on!socio2cognitive!functioning.!Cohen’s!d!effect!sizes!were!calculated!by!the! means!and!pooled!standard!deviations!of!the!four!groups!(Cohen,!1988).!The!confirmatory!statistical! comparisons!were!carried!out!on!a!significance!level!of!p<.05!(two2tailed).!

! 22! 2.4!RESULTS!! ! Original!research!paper!I! ! ! ! ! PSU!and!social!functioning!!! 2.4! Results!

2.4.1! Demographic!characteristics!

Because! of! our! matching! procedure,! groups! did! not! differ! with! regard! to! verbal! IQ,! years! of! education,!age,!and!smoking!behaviour!(Table!1).!However,!individuals!using!five!or!more!substances! showed!a!different!sex!distribution!compared!to!the!other!PSU!subgroups!with!more!females!than! males!in!this!group.!Individuals!with!PSU!scored!higher!than!controls!on!the!BDI!and!ADHD2SR!sum! scores!as!substance!use!disorder!is!commonly!associated!with!depression!and!ADHD!(Quello,!Brady,! &!Sonne,!2005;!Zulauf,!Sprich,!Safren,!&!Wilens,!2014).!Furthermore,!Cluster!B!PD!was!significantly! higher! in! polysubstance! users! (p<.001)! compared! to! controls! but! no! linear! trend! was! detectable! (p=.158).! Means! of! alcohol! consumption! in! gram! and! substance! concentrations! in! hair! and! urine! samples!are!shown!in!Table!1.!The!distribution!of!substance!use!between!PSU!subgroups!are!shown! in!Figure!2.!The!most!frequently!used!substances!over!all!PSU!subgroups!were!cocaine!(83%),!MDMA! (76.6%),! alcohol! (57.4%! moderate! or! high! use,! Figure! S1a),! amphetamine! (40.4%),! and! cannabis! (36.2%;! Figure! S1b).! The! most! common! substance! combinations! over! all! PSU! subgroups! were! cocaine2MDMA2alcohol!(29.8%)!and!cocaine2MDMA2amphetamine!(25.5%).!As!intended,!the!control! group!showed!only!low!levels!of!alcohol!consumption!and!no!objectively!quantified!illegal!substance! use.!

!! & Figure&2.&Distribution!of!substance!use!over!all!positive!hair!concentrations!between!PSU!subgroups.! ! MPH:!methylphenidate.!!

! 23! 2.4!RESULTS!! ! Original!research!paper!I! ! ! ! ! PSU!and!social!functioning!!!

Table&1.!Demographic,!clinical,!and!substance!use!data!(means!and!standard!deviations)! Controls 3)substances 4)substances 5)substances value df p (n=59) (n=31) (n=10) (n=6) Female/male 16/43 16/25 14/6 15/1 χ21=110.64 3 0.014 Age 30.981(9.3) 29.901(8.9) 29.61(7.6) 24.331(4.0) F1=11.05 3,1102 0.372 Years1of1education 10.511(1.8) 10.321(1.7) 10.101(1.7) 11.001(1.7) F1=10.41 3,1102 0.744 Verbal1IQ 105.341(10.0) 103.031(11.5) 104.91(12.5) 100.831(5.9) F1=10.57 3,1102 0.637 Employment1(y/n) 50/9 123/8 18/2 14/2 χ21=12.16 3 0.539 BDI1sum1score 3.661(4.0) 7.391(5.5)* 7.81(10.2) 10.171(11.3) F1=14.91 3,1102 0.003 ADHDOSR 6.361(4.2) 15.101(9.3)** 12.21(6.1) 15.51(16.4)* F1=111.61 3,1102 <0.001 SCID1II 111111Cluster1B 18.351(12.6) 30.801(15.1)** 31.091(9.8)* 26.721(16.3) F1=17.06 3,100 <0.001 Smoker1(y/n)1 44/15 128/3 19/1 16/0 χ21=15.43 3 0.143 Cigarettes/week1(only1smokers) 73.241(64.7) 93.081(67.4) 138.441(75.5)* 92.381(30.9) F1=12.61 3,183 0.057 Alcohol1g/weeka 76.881(59.8) 260.381(263.3)** 298.101(102.0)** 234.671(145.9) F1=119.25b 3,115.4 <0.001 PSUSI 0.971(0.2) 6.551(1.4)**++^^ 8.201(1.1)**°°^^ 10.331(1.4)**°°++ F1=1465.58 3,1102 <0.001 Alcohol MediumOhighc1(%) 0(0%) 151(48.4%) 81(80%) 41(66.7%) Gram/week 426.521(292.8) 311.081(110.0) 295.001(143.1) THC HP1pos1(%) 0(0%) 121(38.7%) 31(30%) 21(33.3%) UP1ng/ml1(50)d 0 117.581(126.8) 99.001(33.8) 218.501(188.8) Cocaine HP1pos1(%) 0(0%) 251(80.6%) 81(80%) 61(100%) HP1ng/mg1(0.5)d 0 7.451(8.12) 22.081(44.3) 9.291(13.7) MDMA HP1pos1(%) 0(0%) 221(71%) 81(80%) 61(100%) HP1ng/mg1(0.2)d 0 6.461(11.6) 4.231(7.1) 8.121(12.3) Amphetamine HP1pos1(%) 0(0%) 71(22.6%) 71(70%) 51(83.3%) HP1ng/mg1(0.2)d 0 0.581(0.6) 0.791(0.6) 5.731(6.9) Methamphetamine HP1pos1(%) 0(0%) 01(0%) 11(10%) 11(16.7%) HP1ng/mg1(0.2)d 0 0 0.731(0.0) 0.491(0.0) Methylphenidate HP1pos1(%) 0(0%) 61(19.4%) 11(10%) 01(0%) HP1ng/mg1(0.02)d 0 0.121(0.1) 0.071(0.0) 0 Ketamine HP1pos1(%) 0(0%) 21(6.5%) 11(10%) 31(50%) HP1ng/mg1(0.1)d 0 0.421(0.1) 0.381(0.0) 0.351(0.4) 2C