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.,! morphine,! oxycodone,! fentanyl,! or! codeine)! 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! heroin,! 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,! hydrocodone,! 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! (naloxone)! 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! buprenorphine! 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,!ketamine,!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) 2CTramadol HP1pos1(%) 0(0%) 21(6.5%) 01(0%) 01(0%) HP1ng/mg1(0.2)d 0 4.681(6.1) 0 0 Methadone HP1pos1(%) 0(0%) 11(3.2%) 01(0%) 01(0%) HP1ng/mg1(0.2)d 0 1.151(0.0) 0 0 ! ANOVAs!and!Chi2!for!frequency!distribution!(two2tailed).!Significant!p2values!(p<.05)!are!shown!in!bold.!! Data!for!Cluster!B!PD!was!missing!for!two!participants!of!the!control!group.!Substance!data!reported!for!participants!with! positive!substance!values.! *!Indicates!Sidak!post!hoc!p<.05!vs.!controls,!**!p<.01!vs!controls.!°!Indicates!Sidak!post!hoc!p<.05!vs.!3!substances!used,!! °°p<.01! vs.! 3! substances! used.! +! Indicates! Sidak! post! hoc! p<.05! vs.! 4! substances! used,! ++p<.01! vs.! 4! substances! used.! ^Indicates!Sidak!post!hoc!p<.05!vs.!5!substances!used,!^^!p<.01!vs.!5!substances!used.! ADHD:!attention2deficit/hyperactivity!disorder,!BDI:!Beck's!Depression!Inventory,!PSUSI:!polysubstance!use!severity!index! a!Alcohol!use!over!all!participants! b!Welch!test! c!WHO!definition!(2000)! d!Cut2off!values! !!
! 24! 2.4!RESULTS!! ! Original!research!paper!I! ! ! ! ! PSU!and!social!functioning!!! 2.4.2! Socio8cognitive!functioning% MASC% An!ANCOVA!corrected!for!age,!sex,!and!PSUSI!with!the!dependent!variable!ToM!correct!sum!score! revealed! no! differences! between! the! four! groups! and! no! linear! trend! (Table! 2).! Additional! linear! regression!analysis!including!demographic!and!clinical!variables!as!predictors!revealed!age!(β=2.39,! t=22.39,!p<.05)!as!the!only!significant!predictor!for!ToM!performances!(Table!S2a).! ! Table&2.&Results!of!socio2cognitive!functioning!(mean!and!SE)! controls 3)substances 4)substances 5)substances F df,%df p p%linear%contrast (n=$59) (n=31) (n=10) (n=6) MASCa $$$$$ToM$sum$correct 34.25$(1.5) 32.53$(1.5) 34.66$(2.5) 31.10$(3.7) 1.02 3,$99 0.385 0.648 METa Cognitive$empathy$CE 24.10$(1.4) 24.58$(1.4) 25.82$(2.4) 25.43$(3.5) 0.19 3,$99 0.905 0.722 Emotional$empathy$EE 5.42$(0.5) 4.86$(0.5) 3.30$(0.8)* 2.60$(1.2) 3.64 3,$99 0.015 0.049 $$$$$EEE 5.61$(0.5) 5.13$(0.5) 3.38$(0.8)* 2.80$(1.1)* 4.58 3,$99 0.005 0.040 $$$$$IEE 5.23$(0.5) 4.60$(0.5) 3.22$(0.8) 2.40$(1.3) 2.68 3,$99 0.051 0.068 CESa Global$CE$score 0.02$(0.2) $J0.09$(0.3) 0.28$(0.4) $J0.13$(0.6) 0.7 3,$99 0.556 0.973 SNQb Social$contacts 19.75$(0.8) 16.70$(1.1) 17.17$(1.9)$ 13.17$(2.6) 3.13 3,$99 0.029 0.029 ! ANCOVAs!corrected!for!age,!sex,!and!aPSUSI.! b!Data!for!one!participant!of!the!control!group!was!missing.! *!Indicates!Sidak!post!hoc!p<.05!vs.!3!substances!used.! EEE:! explicit! emotional! empathy,! IEE:! implicit! emotional! empathy,! PSUSI:! polysubstance! use! severity! index,! SNQ:! social! network!questionnaire,!ToM:!theory!of!mind! ! MET%&%CES% ANCOVAs!were!performed!for!the!dependent!variables!CE,!EE,!EEE,!IEE,!and!CES!with!the!fixed!factor! groups! (Table! 2).! The! results! revealed! differences! between! groups! in! EE! (p<.05)! with! a! significant! linear! trend! (p<.05)! showing! decreased! empathy! scores! with! an! increased! number! of! used! substances!(Figure!3).!No!differences!were!found!for!CE!and!the!global!cognitive!empathy!score!CES.! Sidak2corrected! pairwise! comparison! for! emotional! empathy! revealed! significant! differences! between!individuals!using!three!and!four!and!three!and!five!substances!(Table!2).!Cohen’s!d!yielded! substantial!differences!in!EEE,!IEE,!and!EE!mainly!for!individuals!using!more!than!three!substances! compared! to! controls! and! compared! to! individuals! using! three! substances! (Figure! 4).! Additional! linear!regression!models!revealed!no!significant!demographic!predictors!for!EE!and!CES!(Table!S2b!&! S2c).!
! !!
! 25! 2.4!RESULTS!! ! Original!research!paper!I! ! ! ! ! PSU!and!social!functioning!!! Social%Network%
ANCOVA! corrected! for! sex! and! age! was! conducted! for! analysing! differences! of! social! contacts! between!the!four!groups.!Results!revealed!a!significant!group!effect!and!a!linear!trend!(p<.05)!with! the! smallest! social! network! size! in! individuals! using! five! or! more! substances! (Table! 2).! Although! Sidak2corrected!pairwise!comparisons!revealed!no!significant!differences!between!groups,!the!effect! size! between! individuals! using! five! or! more! substances! and! controls! was! very! large! (d=1.01)! regarding! social! network! size! (Figure! 4).! Given! that! the! reduced! network! sizes! of! the! PSU! groups! might!have!been!biased!by!unemployment!status!(i.e.,!less!social!contacts!in!work2related!areas),!we! conducted!an!additional!ANCOVA!with!employment!status!as!a!covariate.!However,!the!main!effects! remained!significant!even!after!controlling!for!the!employment!status!(F(1,98)=2.89,!p=.039,!linear! trend!(p=.034).!Furthermore,!linear!regression!analysis!including!demographic!and!clinical!variables! as!predictors!revealed!age!as!the!only!significant!predictor!(β=2.36,!t=22.07,!p<.05)!for!social!network! size!(Table!S2d).!
EE" EEE" IEE" *" *" 6" *"
5"
4"
Emapthy"score" 3"
2"
1" Controls" 3"Substances" 4"Substances" 5"Substances" ! & Figure&3.!Means!and!standard!errors!of!emotional!empathy!(EE)!and!its!subscales!explicit!emotion!empathy!(EEE)! ! and!implicit!emotional!empathy!(IEE)!of!the!MET.! ! Corrected!for!age,!sex,!and!PSUSI.!*!Indicates!Sidak!post!hoc!p<.05.! !!
! 26! 2.4!RESULTS!! ! Original!research!paper!I! ! ! ! ! PSU!and!social!functioning!!! 2.4.3! Regression!models!
In!order!to!find!potential!substance2class!predictors!for!socio2cognitive!functioning,!we!used!multiple! regression! models! (forced! entry)! within! the! PSU! group! (n=47,! Table! S3).! Model! 1! concerned! the! estimation! for! the! effects! of! single! substance2class! parameters,! number! of! used! substances,! and! PSUSI! on! EE.! In! the! first! step,! dummy! coded! variables! with! the! most! frequently! used! substances! separated!for!their!neurochemical!classes!were!included!to!estimate!the!effects!of!single!substances! independently.!Therefore,!we!built!four!dummy!coded!substance2classes!of!alcohol!use!(n=27),!THC! use!(n=17),!stimulant!use!(n=45;!cocaine,!amphetamine,!methamphetamine,!and!methylphenidate),! and!empathogen!use!(n=36,!MDMA!and!2C2B).!Due!to!an!insufficient!number!of!ketamine!(n=6)!and! opioid! (n=4)! users,! we! did! not! include! these! substances! in! the! model.! In! a! second! step,! we! additionally! introduced! the! number! of! used! substance! and! in! a!third! step! the! variable! PSUSI.! The! analysis!revealed!no!significance!for!any!substance2class!parameter!(Table!S3).!The!number!of!used! substances!was!the!only!significant!predictor!for!EE!(β=2.47,!t=23.04,!p<.01;!Model!1).!Analogously,! the! same! regression! analysis! was! conducted! with! the! dependent! variable! SNQ! (Model! 2).! The! dummy! coded! THC! substance2class! revealed! statistical! significance! for! social! network! size! (β=.33,! t=2.08,!p<.05)!showing!more!social!contacts!(M=19.12,!SD=6.6)!than!stimulant!(M=16.33,!SD=6.8),! empathogen!(M=16.61,!SD=6.6),!and!alcohol!users!(M=16.44,!SD=7.3).!!
! 27! 2.4!RESULTS!! ! Original!research!paper!I! ! ! ! ! PSU!and!social!functioning!!! !
MET!EE! EEE! IEE! SNQ!
1.20!
1.00!
! 0.80! large effect ! ! 0.60! ! Cohen's(d( ! moderate! effect 0.40! ! ! ! small! 0.20! effect
0.00! 3!subst! 4!subst! 5!subst! 4!subst! 5!subst! 5!subst! vs! vs! vs! vs!3! vs!3! vs!4! controls! controls! controls! subst! subst! subst! ! & Figure&4.!Cohen’s!d!effect!sizes!for!comparisons!between!controls!and!PSU!subgroups.! ! EE:!emotional!empathy,!EEE:!explicit!emotional!empathy,!IEE:!implicit!emotional!empathy,!SNQ:!social! ! network!questionnaire,!subst:!substance! !
! 28! 2.5!DISCUSSION!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! 2.5! Discussion!
The! innovative! purpose! of! this! study! was! to! investigate! socio2cognitive! functioning! in! objectively! validated!stimulant!polysubstance!users!and!considering!the!number!of!used!substances!as!well!as! severity!of!PSU.!Our!results!revealed!decreased!performance!in!emotional!empathy!and!fewer!social! contacts! with! an! increased! number! of! used! substances.! However,! cognitive! empathy! was! largely! unaffected!by!PSU.!Additionally,!neither!overall!severity!of!PSU!(PSUSI)!nor!single!substance2classes! revealed!an!impact!on!emotional!empathy.!In!sum,!these!results!indicate!that!individuals!with!PSU! show!distinct!deficits!in!socio2cognitive!functioning,!which!are!worsening!with!the!number!of!used! substances.! ! Our!results!with!regard!to!the!performance!task!MET!are!consistent!with!the!study!by!Ferrari!et!al.! (2014)! demonstrating!self2reported!deficits!in!emotional!empathy!but!not!in!cognitive!empathy!in! individuals! with! PSU.! Furthermore,! the! authors! reported! sex! differences! revealing! deficits! of! cognitive!empathy!only!in!women!and!stronger!deficits!of!emotional!empathy!and!the!total!empathy! score!in!men.!However,!our!statistical!analyses!did!not!detect!a!significant!interaction!of!sex!and!PSU! on!EE.!The!present!results!are!also!in!accordance!with!previous!neuroimaging!findings!in!individuals! with!PSU!reporting!grey!matter!atrophy!found!in!regions!associated!with!emotional!empathy!such!as! the!ACC!(Fan!et!al.,!2011),!while!no!structural!differences!between!individuals!with!PSU!and!alcohol! users!were!reported!(Meyerhoff,!2017).!We!found!similar!deficits!in!emotional!empathy!related!to! stimulant!PSU!as!shown!for!alcohol!dependent!individuals!(Maurage!et!al.,!2011;!Mohagheghi!et!al.,! 2015)! and! also! for! pure! cocaine! users! (Preller! et! al.,! 2014).! Furthermore,! the! global! cognitive! empathy!score!(CES)!remained!unaffected!by!PSU.!Therefore,!we!could!not!replicate!the!findings!by! Fernandez2Serrano! et! al.! (2010)! and! Verdejo2Garcia! et! al.! (2007),! reporting! deficits! in! emotion! recognition,! which! is! one! important! facet! of! cognitive! empathy.! However,! crucial! differences! compared!to!our!study!sample!exist.!First,!their!PSU!group!was!defined!by!self2reports,!whereas!our! sample!was!objectively!validated!by!hair!and!urine!toxicology!because!self2reported!substance!use!is! often!biased!by!distorted!memories!or!social!desirability!(Harrison,!1997;!Latkin!et!al.,!2017;!Magura! &! Kang,! 1996;! Quednow! et! al.,! 2006).! Secondly,! only! two2group! comparisons! were! conducted! disregarding! the! number! of! used! substances.! Moreover,! Fernandez2Serrano! et! al.! (2010)! and! Verdejo2Garcia!et!al.!(2007)!used!the!Ekman!Faces!Test!assessing!only!emotion!recognition!in!faces,! whereas! the! MET! used! in! our! study! measures! emotion! recognition! in! complex! emotionally! laden! scenes!likely!engaging!processes!integrating!different!pathways!of!emotion!recognition.!Finally,!our! PSU! group! showed! much! less! opioid! consumption! compared! to! the! other! study! samples! because! opioid!use!was!an!exclusion!criterion!in!the!previous!studies!from!which!we!created!our!PSU!group.!
! 29! 2.5!DISCUSSION!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! Given!that!we!created!the!PSU!sample!out!of!excluded!participants!initially!recruited!for!cocaine!or! MDMA!use,!we!additionally!analysed!the!effects!of!stimulants,!empathogens,!THC,!and!alcohol!on! socio2cognitive!functioning.!However,!no!single!substance2class!indicator!was!identified!for!EE!and! CES.!One!possible!reason!for!this!could!be!that!impairments!in!individuals!with!PSU!rather!resulted! from!opposing!effects!of!different!substances!than!from!one!single!substance.!Accordingly,!findings! of!our!previous!studies!using!also!the!MET!and!MASC!revealed!deficits!of!emotional!and!cognitive! empathy!in!relatively!pure!cocaine!users,!whereas!MDMA!use!was!associated!with!superior!cognitive! empathy!(Preller!et!al.,!2014;!Wunderli!et!al.,!2017b).!Although!we!excluded!individuals!showing!one! primary!drug,!cocaine!and!MDMA!were!the!most!frequently!used!substances!and!the!most!common! combination!in!our!PSU!sample.!Therefore,!our!findings!might!result!from!the!opposing!effect!of!both! substances!and!additional!substance!use.!Furthermore,!individuals!showing!more!deficits!in!sharing! other’s!feelings!might!be!prone!to!use!more!substances,!which!leads!to!the!discussion!of!the!cause2 effect!relationship.! ! Although!severity!of!substance!use!in!individuals!with!PSU!was!discussed!as!a!potential!predictor!for! emotion!recognition!deficits!in!the!study!by!Fernandez2Serrano!et!al.!(2010),!our!severity!index!of! PSU!(PSUSI)!revealed!no!association!with!socio2cognitive!functioning.!However,!the!authors!reported! that!specifically!lifetime!quantity!of!cocaine!use!was!associated!with!socio2cognitive!deficits,!which! was!assessed!by!self2reports.!In!contrast,!the!PSUSI!of!our!study!was!an!estimation!of!severity!of!use! over!all!substances.!Therefore,!our!results!might!indicate!that!reported!deficits!of!PSU!were!rather! driven!by!the!number!of!used!substances!than!by!the!summed!severity!of!use!of!all!substances.! ! Our!findings!demonstrate!that!individuals!using!five!or!more!substances!revealed!the!fewest!social! contacts.!Moreover,!cannabis!users!showed!a!larger!social!network!than!stimulant,!empathogen,!and! moderate!to!heavy!alcohol!users.!Again,!this!finding!could!be!discussed!by!a!cause2effect!relationship! regarding! PSU! and! deficits! in! emotional! empathy.! Chronic! PSU! might! induce! impairments! in! experiencing! other’s! feelings! resulting! in! blunted! emotional! responses! in! given! situations,! which! could! lead! to! increased! interpersonal! conflicts! and! therefore! to! decreased! social! contacts.! Furthermore,! decreased! social! contacts! might! be! compensated! by! an! increased! use! of! additional! substances.!Alternatively,!deficits!in!emotional!empathy!might!reflect!a!predispositional!trait!(e.g.,!an! antisocial!or!psychopathic!personality)!causing!both,!a!decreased!social!network!and!PSU.!Analysis!of! the!SCID2II!Cluster!B!revealed!higher!scores!for!individuals!with!PSU!without!a!linear!trend!indicating! a!general!antisocial!and!psychopathic!behaviour!in!substance!users!independently!from!the!number! of! used! substances.! Similar! results! were! also! found! in! pure! cocaine! users! (Preller! et! al.,! 2014).! Furthermore,!individuals!with!psychopathic!PD!showed!similar!deficits!in!emotional!empathy!as!in!
! 30! 2.5!DISCUSSION!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! our! PSU! sample! (Blair,! 2005)! suggesting! that! PSU! might! facilitate! psychopathic! behaviour! or! that! individuals!with!psychopathic!traits!might!tend!to!show!PSU.! ! Our!results!indicate!that!individuals!with!PSU!show!preserved!cognitive!empathy!suggesting!that!the! ability! of! interpreting! and! recognising! emotions!of!others’!as!well!as!mentalising! behaviours! were! largely!unaffected!by!PSU.!However,!the!ability!of!subjectively!sharing!others’!emotions!was!impaired! in!the!PSU!subgroups!compared!to!controls,!which!is!important!for!building!meaningful!interpersonal! relationships!and!prosocial!behaviour!(Singer!&!Lamm,!2009).!Impaired!emotional!empathy!can!lead! to! severe! deficits! in! daily! life! interactions! especially! in! social! relationships.! Therefore,! our! results! indicate!a!stronger!implication!of!emotional!empathy!in!the!intervention!and!rehabilitation!of!PSU.! Improving! emotional! empathy! in! specific! intervention! programs! could! ameliorate! interpersonal! communication!in!daily!life!situations!and!within!social!relationships!but!also!during!psychotherapy.! Accordingly,!individuals!with!PSU!would!receive!a!broader!support!of!their!social!network,!which!in! turn! prevents! relapse! and! facilitate! a! positive! therapy! outcome! (Atadokht,! Hajloo,! Karimi,! &! Narimani,!2015;!Ellis!et!al.,!2004;!Havassy!et!al.,!1991).! ! This! study! shows! some! limitations.! First,! our! PSU! sample! was! dominated! by! individuals! using! stimulants!whereas!opioid!use!was!less!present!compared!to!other!PSU!studies!(Fernandez2Serrano! et!al.,!2010;!Ferrari!et!al.,!2014;!Verdejo2Garcia!et!al.,!2007).!This!is!based!on!the!fact!that!we!created! the!sample!out!of!former!excluded!participants!from!the!ZuCoSt2!and!MDMA!study!where!opioid!use! was!and!exclusion!criterion!(Hulka!et!al.,!2013;!Preller!et!al.,!2014;!Vonmoos!et!al.,!2013;!Wunderli!et! al.,!2017a).!Additionally,!we!could!not!include!opioids!and!ketamine!as!dummy!coded!variables!in!the! regression! model! due! to! small! sample! sizes.! Furthermore,! we! were! not! able! to! use! hair! concentration!as!a!variable!in!our!regression!model!because!they!were!not!normally!distributed!even! after!log2transformation.!Therefore,!the!substance2use!variables!were!dichotomised.!Secondly,!the! sample! size! for! the! groups! using! four! or! five! substances! was! relatively! small.! Therefore,! post2hoc! tests! mostly! did! not! reveal! significant! differences! between! PSU! subgroups.! However,! effect! sizes! showed!considerable!differences!in!social!contacts!and!emotional!empathy!for!the!subgroups.!Third,! pre2existing! differences! and! predispositions! cannot! be! fully! excluded! due! to! our! cross2sectional! design.!As!mentioned!before,!no!final!cause!statement!can!be!done.!Future!studies!should!address! this! limitation! conducting! longitudinal! studies! with! PSU! and! adding! more! specific! instruments! for! psychopathic!or!antisocial!personality!traits.! ! Taken!together,!our!findings!indicate!that!individuals!with!stimulant!PSU!show!discrete!impairments! in!emotional!empathy!with!unaffected!cognitive!empathy.!The!innovative!aspect!of!the!present!study!
! 31! 2.5!DISCUSSION!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! was!to!investigate!socio2cognitive!functioning!in!an!objectively!validated!PSU!sample!and!to!assess! cumulative! effects! by! the! number! of! used! substances.! Our! results! indicate! a! gradual! decrease! of! social! contacts! and! performances! in! emotional! empathy! related! to! an! increased! number! of! used! substances.! However,! the! ability! of! emotion! recognition,! mentalising! behaviour,! and! perspective2 taking!was!preserved.!Taken!together,!our!results!suggest!a!stronger!focus!on!emotional!empathy!in! psychotherapeutic!settings!for!future!interventions!and!rehabilitations!in!PSU.!
! 32! 2.6!SUPPLEMENTARY!MATERIAL!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! 2.6! Supplementary!material!
2.6.1! Methods!
Methods&S1:&Urine&and&hair&toxicology& Urine!toxicology!analyses!included!following!substances!with!cut2off!values!in!parentheses!(SAMHSA,! 2012):! amphetamine! (<300ng/ml),! benzodiazepine! (<200ng/ml),! tetrahydrocannabinol! (<50ng/ml),! cocaine! (<150ng/ml),! methadone! (<300ng/ml),! and! opiate! (<300ng/ml).! These! substances! were! assessed! by! a! semi2quantitative! enzyme! multiplied! immunoassay! method! using! a! Dimension! RXL! Max!(Siemens,!Erlangen,!Germany).! To! objectively! quantify! substance! use! over! the! last! six! months,! hair! samples! were! collected! and! analysed! with! liquid! chromatography2tandem! mass! spectrometry! (LC2MS/MS).! Proximal! hair! segments! with! a! length! of! up! to! six! cm! were! analysed.! The! following! compounds! were! assessed:! cocaine,! amphetamine,! methamphetamine,! MDMA,! methylphenidate,! morphine,! tramadol,! methadone,!codeine,!ketamine,!and!2C2B.! ! For!our!routine!protocol!a!three!step!washing!procedure!with!water!(2min!shaking,!15ml),!acetone! (2min,! 10ml)! and! finally! hexane! (2min,! 10ml)! of! hair! was! performed.! Then! the! hair! samples! were! dried! at! ambient! temperatures,! cut! into! small! snippets! and! extracted! in! two! steps,! first! with! methanol! (5ml,! 16h,! ultrasonication)! and! in! a! second! step! with! 3ml! MeOH! acidified! with! 50µl! hydrochloric!acid!33%!(3h,!ultrasonication).!The!extracts!were!dried!and!the!residue!reconstituted! with! 50µl! MeOH! and! 500µl! 0.2mM! ammonium! formate! (analytical! grade)! in! water.! As! internal! standards! deuterated! standards! of! the! following! compounds! were! used,! added! as! mixture! of! the! following!compounds:!cocaine2d3,!morphine2d3,!codeine2d3,!amphetamine2d6,!methamphetamine2 d9,! MDMA2d5,! methadone2d9,! methylphenidate2d9,! tramadol2d3.! All! deuterated! standards! were! from!ReseaChem!(Burgdorf,!Switzerland),!the!solvents!for!washing!and!extraction!were!of!analysis! grade!and!obtained!from!Merck!(Darmstadt,!Germany);!LC2solvents!were!of!HPLC!grade!and!were! obtained!from!Sigma!Aldrich!(Buchs,!Switzerland).! ! The! LC2MS/MS! apparatus! was! an! ABSciex! QTrap! 3200! (Analyst! software! Version! 1.5,! Turbo! V! ion! source!operated!in!the!ESI!mode,!gas!1,!nitrogen!(50psi);!gas!2,!nitrogen!(60psi);!ion!spray!voltage,! 3500V;!ion!source!temperature,!450°C;!curtain!gas,!nitrogen!(20psi)!collision!gas,!medium),!with!a! Shimadzu! Prominence! LC2system! (Shimadzu! CBM! 20! A! controller,! two! Shimadzu! LC! 20! AD! pumps! including!a!degasser,!a!Shimadzu!SIL!20!AC!autosampler!and!a!Shimadzu!CTO!20!AC!column!oven,! Shimadzu,!Duisburg,!Germany).!Gradient!elution!was!performed!on!a!separation!column!(Synergi!4µ! POLAR2RP! 80A,! 150x2.0! with! a! POLAR2RP! 4x2.0! Security! Guard! Cartridge,! (Phenomenex,!
! 33! 2.6!SUPPLEMENTARY!MATERIAL!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! Aschaffenburg,!Germany).!The!mobile!phase!consisted!of!1mM!ammonium!formate!buffer!adjusted! to!pH!3,5!with!formic!acid!(eluent!A)!and!acetonitrile!containing!1mM!ammonium!formate!and!1mM! formic!acid!(eluent!B).!The!analysis!was!performed!in!MRM!mode!with!two!transitions!per!analyte! and!one!transition!for!each!deuterated!internal!standard,!respectively.! ! Methods&S2:&Levels&of&substance&use&and&PSUSI& With!respect!to!the!classification!into!low!(1),!medium!(2),!and!severe!substance!use!(3),!hair!samples! of!all!recruited!participants!showing!positive!concentrations!for!the!most!consumed!substances![i.e.! cocaine!(n=111),!MDMA!(n=78),!and!amphetamine!(n=27)]!were!used!to!calculate!separation!values! for!three!equal!groups!in!relation!to!the!group!size.!In!order!to!be!able!to!compare!values!of!different! hair!samples,!we!normalised!them!by!dividing!substance!hair2concentrations!by!their!cut2off!values! (Cooper,!Kronstrand,!Kintz,!&!Society!of!Hair,!2012).!The!average!of!the!normalised!cut2off!values!in! the!three!equal!groups!were!used!for! the!final!classification!into!low!(1),!medium!(2),!and!severe! substance!use!(3)!with!respect!to!hair!concentration!(Table!S1).!Levels!of!substance!use!(1!to!3)!for! each!substance!were!summarised!to!the!PSU!severity!index!(PSUSI).! & Table&S1.&Classification!of!low,!medium,!and!high!substance!use! a)!
! Alcohol!consumption!levels!defined!by!WHO,!2000! b)!
! Cut2off!value!by!SAMHSA!(SAMHSA,!2012)! ! c)!
! *!For!normalisation,!hair!concentrations!were!divided!by!their!cut2off!values!reported!in!the!literature!(Cooper,!2012)! a!Example:!calculation!of!averaged!normalised!cut2off!value!for!low!(1)!level:!(3.7!+!1.8!+!4.3)/3!=!3.3!
! 34! 2.6!SUPPLEMENTARY!MATERIAL!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! 2.6.2! Results!
Table&S2.!Linear!regression!analyses!for!clinical!and!demographic!variables!predicting!socio2cognitive! functioning! ! a)!MASC! B SE#B β T&value p Constant 32.020 7.590 4.22 0.000 Sex &0.415 1.385 &0.046 &0.30 0.766 Age &0.199 0.083 &0.389 &2.39 0.022 YoE &0.112 0.421 &0.041 &0.27 0.792 Verbal#IQ 0.113 0.063 0.298 1.81 0.078 BDI#sum#score &0.122 0.114 &0.215 &1.07 0.291 ADHD&SR &0.058 0.082 &0.135 &0.71 0.483 Cluster#B &0.030 0.051 &0.098 &0.58 0.563 ! Dependent!variable:!ToM!sum!score.!Significant!p2values!are!shown!in!bold.! R2!=!0.247!and!F!=!1.78,!p!=!0.120.! N!=!47!individuals!with!PSU! The!data!met!the!assumption!of!independent!errors!(Durbin2Watson!value!=!1.62)!and!collinearity!(tolerance!values!>!0.5! and!VIF!>!1!&!!0.5! and!VIF!>1!&!<10)! ADHD:!attention2deficit/hyperactivity!disorder!BDI:!Beck's!Depression!Inventory,!YoE:!years!of!education.! !!
! 35! 2.6!SUPPLEMENTARY!MATERIAL!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!! c)!CES! B SE#B β T&value p Constant 0.054 1.135 0.05 0.962 Sex &0.324 0.207 &0.239 &1.56 0.126 Age &0.019 0.012 &0.240 &1.49 0.144 YoE &0.016 0.063 &0.040 &0.26 0.798 Verbal#IQ 0.018 0.009 0.306 1.88 0.068 BDI#sum#score &0.025 0.017 &0.291 &1.46 0.151 ADHD&SR 0.001 0.012 0.018 0.10 0.923 Cluster#B &0.014 0.008 &0.317 &1.91 0.064 ! Dependent!variable:!CES!z2score.!Significant!p2values!are!shown!in!bold.! R2!=!0.262!and!F!=1.93,!p!=!0.092.! N!=!47!individuals!with!PSU! The!data!met!the!assumption!of!independent!errors!(Durbin2Watson!value!=!2.25)!and!collinearity!(tolerance!values!>!0.5! and!VIF!>!1!&!<10)! ADHD:!attention2deficit/hyperactivity!disorder!BDI:!Beck's!Depression!Inventory,!YoE:!years!of!education.! ! ! ! d)!SNQ! B SE#B β T&value p Constant 16.328 12.891 1.27 0.213 Sex 1.606 2.351 0.113 0.68 0.499 Age &0.292 0.141 &0.359 &2.07 0.045 YoE 0.066 0.715 0.015 0.09 0.927 Verbal#IQ 0.085 0.106 0.140 0.80 0.428 BDI#sum#score &0.016 0.194 &0.018 &0.08 0.933 ADHD&SR &0.069 0.139 &0.101 &0.50 0.622 Cluster#B &0.074 0.086 &0.154 &0.86 0.396 ! Dependent!variable:!SNQ.!Significant!p2values!are!shown!in!bold.! R2!=!0.143!and!F!=.91,!p!=!0.512.! N!=!47!individuals!with!PSU! The!data!met!the!assumption!of!independent!errors!(Durbin2Watson!value!=!2.00)!and!collinearity!(tolerance!values!>!0.5! and!VIF!>1!&!<10)! ADHD:!attention2deficit/hyperactivity!disorder!BDI:!Beck's!Depression!Inventory,!YoE:!years!of!education.!
! 36! 2.6!SUPPLEMENTARY!MATERIAL!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!!
Table&S3.&Multiple!linear!regression!analyses!for!substance2classes!predicting!socio2cognitive!functioning!within! PSU!(n=47)! ! Model&1 B SE&B β T,value p R2&corr p#change&in&F Step#1 ,0.076 0.945
Constant 4.638 1.409 3.29 0.002 Stimulants 0.056 1.118 0.008 0.05 0.960 Empathogens 0.273 0.548 0.082 0.50 0.622 THC ,0.236 0.489 ,0.080 ,0.48 0.632 Alcohol ,0.123 0.479 ,0.043 ,0.26 0.799 Step#2 0.100 0.004 Constant 6.396 1.412 4.53 <0.001 Stimulants 0.854 1.055 0.122 0.81 0.423 Empathogens 0.788 0.529 0.236 1.49 0.144 THC ,0.089 0.449 ,0.030 ,0.20 0.844 Alcohol 0.319 0.462 0.111 0.69 0.494 Number&of&used& ,0.929 0.306 ,0.466 ,3.04 0.004 substances Step#3 0.098 0.347 Constant 5.981 1.479 4.04 <0.001 Stimulants 1.149 1.101 0.164 1.04 0.303 Empathogens 0.780 0.530 0.233 1.47 0.149 THC ,0.061 0.451 ,0.021 ,0.14 0.893 Alcohol 0.426 0.476 0.149 0.90 0.376 Number&of&used& ,1.231 0.441 ,0.618 ,2.79 0.008 substances PSUSI 0.151 0.159 0.199 0.95 0.347 ! Dependent!variable:!EE.!Significant!p2values!are!shown!in!bold.! Step!1:!R2=.017!and!F=0.19,!p=.945.! Step!2:!R2=.198!and!F=2.03,!p=.095.! Step!3:!R2=.216!and!F=1.83,!p=.117.! The!data!met!the!assumption!of!independent!errors!(Durbin2Watson!value!=!2.54)!and!collinearity!(tolerance!values!>!0.7! and!VIF!>!1!&!
! 37! 2.6!SUPPLEMENTARY!MATERIAL!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!!
Model&2 B SE&B β T,value p R2&corr p#change&in&F Step#1 0.024 0.292
Constant 15.686 6.316 2.48 0.017 Stimulants ,2.695 5.009 ,0.082 ,0.54 0.593 Empathogens 1.566 2.457 0.100 0.64 0.527 THC 4.555 2.190 0.329 2.08 0.044 Alcohol 0.970 2.149 0.072 0.45 0.654 Step#2 0.013 0.472 Constant 17.754 6.963 2.55 0.015 Stimulants ,1.756 5.201 ,0.053 ,0.34 0.737 Empathogens 2.172 2.609 0.138 0.83 0.410 THC 4.727 2.215 0.341 2.13 0.039 Alcohol 1.490 2.277 0.111 0.65 0.516 Number&of&used& ,1.093 1.507 ,0.117 ,0.73 0.472 substances Step#3 ,0.003 0.554 Constant 16.463 7.344 2.24 0.031 Stimulants ,0.838 5.464 ,0.025 ,0.15 0.879 Empathogens 2.148 2.630 0.136 0.82 0.419 THC 4.814 2.234 0.347 2.15 0.038 Alcohol 1.824 2.362 0.135 0.77 0.445 Number&of&used& ,2.035 2.190 ,0.217 ,0.93 0.358 substances PSUSI 0.470 0.788 0.132 0.60 0.554 ! Dependent!variable:!SNQ.!Significant!p2values!are!shown!in!bold.! Step!1:!R2=.109!and!F=1.28,!p=.292.! Step!2:!R2=.120!and!F=1.12,!p=.364.! Step!3:!R2=.128!and!F=0.98,!p=.452.! The!data!met!the!assumption!of!independent!errors!(Durbin2Watson!value!=!2.27)!and!collinearity!(tolerance!values!>!0.7! and!VIF!>!1!&!
! 38! 2.6!SUPPLEMENTARY!MATERIAL!! ! Original!research!paper!I!!! ! ! PSU!and!social!functioning!!!
! && Figure&S1a.&Distribution!of!alcohol!use!between!PSU!subgroups! ! ! & &
! && Figure&S1b.&Distribution!of!THC!over!all!positive!US!between!PSU!subgroups!! ! !! US:!urine!sample! ! ! 39! !
! ! ! ! ! Part!II! !
! 40! 3.1!ABSTRACT!! ! Original!research!paper!II!!! ! ! NMPOU!and!social!functioning!
3.! COGNITIVE!AND!SOCIO2COGNITIVE!FUNCTIONING! !! OF!CHRONIC!NON2MEDICAL!PRESCRIPTION! OPIOID!USERS3! ! 3.1! Abstract!
Non2medical!prescription!opioid!use!(NMPOU)!has!become!a!major!public!health!issue!in!the!U.S.! and!is!also!increasing!in!Europe.!However,!little!is!known!about!neuropsychological!consequences!of! NMPOU–specifically! regarding! social! cognition,! which! is! essential! for! social! functioning! and! treatability!of!opioid!dependence.!Previous!studies!with!heroin!users!or!opioid!substituted!patients! reported! deficits! in! a! variety! of! cognitive! functions! but! these! results! are! likely! confounded! by! comorbid!physical!and!psychiatric!diseases!or!adulteration!of!street!heroin.!Therefore,!the!purpose! of!the!present!study!was!to!investigate!social!and!non2social!cognition!in!a!relatively!pure!NMPOU! sample!taking!opioid!analgesics!or!antitussives.!We!assessed!23!individuals!with!NMPOU!objectively! confirmed! by! hair! analyses! and! 29! matched,! opioid2naïve,! healthy! controls! employing! a! comprehensive! neuropsychological! test! battery.! Significant! impairments! were! found! in! individuals! with! NMPOU! compared! to! controls! for! the! cognitive! domains! of! attention! (p=.004,! d=.80)! and! declarative! memory! (p=.022,! d=.64)! as! well! as! in! global! cognitive! empathy! (GCE;! p=.001,! d=0.90)! including! problems! with! emotion! recognition! from! faces,! voices,! and! complex! scenes.! Opioid! hair! concentrations!transformed!in!morphine!equivalents!were!negatively!correlated!with!GCE!(r=20.52,! p=.007)! indicating! dose2dependent! deficits.! Thus,! in! contrast! to! stimulant! users! displaying! deficits! primarily! in! emotional! empathy,! opioid! users! showed! selective! impairments! in! cognitive! empathy! with! dose2dependent! effects! suggesting! potential! opioid2induced! deficits! and! involvement! of! the! opioid2system! in! processes! of! cognitive! empathy.! Our! study! has! important! implications! for! future! interventions!of!opioid!dependence!targeting!social!functioning!and!consequently!enhancing!therapy! outcome!and!preventing!relapse.!
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 3!The!content!of!this!chapter!is!currently!under!review:! Kroll,!S.!L.;!Nikolic,!E.;!Bieri,!F.;!Baumgartner,!M.;!Soyka,!M.;!&!Quednow,!B.!B.!(2018).!Cognitive!and!! socio2cognitive!functioning!of!chronic!non2medical!prescription!opioid!users.!Psychopharmacology!(under!review)! ! 41! 4.1!ABSTRACT! ! Original!research!paper!III!!! ! ! NMPOU!and!social!pain!!
4.!!! ASSOCIATION!BETWEEN!NON2MEDICAL! PRESCRIPTION!OPIOID!USE!AND!PHYSIOLOGICAL! STRESS!RESPONSES!TO!SOCIAL!REJECTION4! ! 4.1! Abstract!
Non2medical!prescription!opioid!use!(NMPOU)!recently!increased!dramatically!especially!in!the!U.S.! Although! chronic! opioid! use! is! commonly! accompanied! with! deficits! in! social! functioning& and! dysregulation! of! the& hypothalamic2pituitary! adrenergic! (HPA)! stress! axis,!little!is!known!about!the! impact! of! NMPOU! on! responses! to! psychosocial! stress.! Therefore,! we! measured! physiological! responses!of!the!autonomic!nervous!system!and!the!HPA!axis!to!social!rejection!using!the!Cyberball! paradigm.! We! compared! 23! individuals! with! NMPOU,! objectively! confirmed! by! hair! and! urine! analyses,!with!29!matched,!opioid2naïve,!healthy!controls.!As!expected,!heart!rate!variability!(HRV)! increased!significantly!during!exclusion!within!controls,!while!in!the!NMPOU!group!only!a!trend!in! the! same! direction! was! found.! However,! HRV! increase! was! robustly! modulated! by! opioid! craving! indicating!worse!emotion!regulation!to!social!exclusion!specifically!in!NMPOU!individuals!with!high! craving!symptoms.!In!contrast,!skin!conductance!levels!(SCL)!upon!social!exclusion!revealed!no!group! differences.!Increased!plasma!levels!of!the!adrenocorticotropic!hormone!(ACTH)!and!cortisol!were! found! in! the! NMPOU! group! indicating! a! hyperreactivity! of! the! HPA! axis! to! social! rejection.! Behavioural! data! suggest! that! opioid! users! were! aware! of! being! excluded! but! less! emotionally! affected! by! the! rejection.! Moreover,! NMPOU! individuals! reported! a! smaller! social! network! size! compared!to!controls.!Present!findings!suggest!that!chronic!NMPOU!is!associated!with!dysfunctional! physiological!responses!to!psychosocial!stressors!such!as!social!rejection.!Additionally,!NMPOU!goes! along!with!an!abnormal!regulation!of!the!parasympathetic!nervous!system!specifically!under!opioid! craving!highlighting!its!potential!importance!in!relapse!prevention.! !
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 4!The!content!of!this!chapter!is!currently!submitted:! Kroll,!S.!L.;!Williams,!D.;!Thoma,!M.;!Staib,!M.;!Binz,!T.M.;!Baumgartner,!M.!R.;!Kirschbaum,!C.;!Thayer,!J.!F.;!&! Quednow,!B.!B.!(2018).!Association!between!non2medical!prescription!opioid!use!and!psychophysiological! stress!response!to!social!rejection.!Psychoneuroendocrinology!(submitted)! ! 65! 5.!GENERAL!DISCUSSION!
5.!GENERAL!DISCUSSION!
! The! aim! of! the! present! thesis! was! to! investigate! social! functioning! in! individuals! showing! distinct! patterns!of!chronic!substance!use.!The!study!presented!in!part!I!of!this!thesis!(chapter!2)!addressed! the! question! of! cumulative! drug! effects! with! respect! to! the! number! of! used! substances! on! social! cognition.!The!primary!goal!of!part!II!(chapter!3!and!4)!was!to!clarify!potential!predispositions!and! drug2induced! effects! of! chronic! opioid!use! with!the!focus!on!social!functioning! in! individuals! with! NMPOU.!Study!results!of!the!present!thesis!make!a!crucial!contribution!to!basic!addiction!research! and! might! provide! a! deeper! understanding! of! predispositions! and! consequences! of! chronic! substance!use!to!subsequently!improve!treatments!of!drug!addiction!and!to!prevent!relapse.!In!the! following,!I!will!summarise!the!main!results!of!the!three!studies!presented!in!this!thesis!and!discuss! strength!and!limitations!of!the!studies,!potential!clinical!implications,!and!perspectives!based!on!the! findings.! ! 5.1! Increased!number!of!used!substances!accompanied!with! ! decreased!social!functioning!
To!date,!only!few!studies!have!investigated!social!cognition!in!individuals!with!PSU!reporting!deficits! in!emotional!empathy!and!emotion!recognition!from!faces!(Fernandez2Serrano!et!al.,!2010;!Ferrari!et! al.,! 2014;! Verdejo2Garcia! et! al.,! 2007).! However,! these! studies! have! in! common! that! PSU! was! assessed! by! subjective! self2reports! and! that! the! number! of! used! substances! was! not! considered.! Therefore,! a! novel! aspect! of! the! study! presented! in! chapter! 2! (part! I)! was! the! creation! of! a! PSU! sample!based!on!objective!drug!use!data!detected!by!hair!and!urine!toxicology!and!the!separation! into!subgroups!related!to!the!number!of!substances!they!used.!The!results!of!this!study!confirmed! previous!findings!of!impaired!emotion!empathy!in!individuals!with!PSU!and!further!demonstrated,! for!the!first!time,!cumulative!adverse!effects!of!used!substances.!Similar!findings!were!shown!for!the! social! network! size! revealing! less! social! contacts! accompanied! by! an! increased! number! of! used! substances.!Interestingly,!neither!cognitive!empathy!assessed!directly!by!the!MET!and!MASC!nor!the! global!cognitive!empathy!index!(CES)!revealed!differences!between!the!control!group!and!the!PSU! subgroups!indicating!preserved!ability!of!understanding!other’s!feelings!and!mentalising!(ToM)!but! impaired!sharing!of!other’s!affective!state!in!individuals!with!stimulant!PSU.!This!is!consistent!with! the!findings!reported!by!Ferrari!et!al.!(2014)!postulating!deficits!of!emotional!empathy!but!preserved! cognitive! empathy! in! polysubstance! users! assessed! by! the! empathy! quotient! (EQ).! Although! the! authors!showed!that!women!with!PSU!revealed!higher!scores!in!cognitive!empathy!than!women!of!
! 87! 5.!GENERAL!DISCUSSION! the!control!group,!we!did!not!find!any!gender!effects!in!our!study.!Furthermore,!two!previous!studies! investigating!social!cognition!in!individuals!with!PSU!reported!deficits!in!cognitive!empathy!assessed! by!the!Ekman!Faces!Test!(Fernandez2Serrano!et!al.,!2010;!Verdejo2Garcia!et!al.,!2007).!As!mentioned! at! the! beginning! of! this! thesis! (chapter! 1.2.1),! cognitive! empathy! implies! emotion! recognition,! affective!ToM,!and!perspective!taking.!The!MET!and!the!MASC!used!in!our!study!measure!emotion! recognition!and!ToM!in!complex!emotionally!laded!scenes,!whereas!the!Ekman!Faces!Test!assesses! faces!emotion!perception.!Therefore,!different!emotion!recognition!processes!might!be!involved!in! these! tasks! providing! a! possible! explanation! for! our! different! results.! Furthermore,! deficits! in! emotional! empathy! were! associated! with! various! psychiatric! disorders! such! as! psychopathy! and! antisocial!personality!disorder!(chapter!1.2.1).!Therefore,!additional!statistical!analyses!for!the!SCID2II! Cluster! B! were! conducted! including! antisocial! personality! disorder! revealing! higher! scores! for! individuals! with! PSU! compared! to! controls.! However,! no! cumulative! drug! effects! were! found! indicating!general!antisocial!and!psychopathic!behaviour!in!substance!users!independently!from!the! number!of!used!substances.! ! The!assessment!of!the!social!network!size!can!be!interpreted!as!an!index!for!real2life!social!function.! The! study! results! indicate! that! an! increased! number! of! used! substances! is! accompanied! with! decreased!social!contacts.!The!present!finding!can!be!discussed!as!a!predisposition!in!polysubstance! users! suggesting! that! individuals! with! lower! social! contacts! might! be! prone! to! use! more! multiple! substances!or!as!a!consequence!of!PSU,!which!might!be!further!modulated!by!reported!deficits!in! emotional!empathy.! ! A!smaller!social!network!size!and!impaired!emotional!empathy!were!also!found!in!chronic!cocaine! users!in!previous!studies!of!our!research!group!(Preller!et!al.,!2014).!Given!that!the!PSU!sample!is! composed!of!excluded!subjects!initially!recruited!for!either!the!ZuCo2St!or!MDMA!study,!the!present! findings! might! result! rather! from! stimulant! drug! effects! than! from! cumulative! substance! use.! However,! regression! analysis! revealed! number! of! used! substances! as! the! only! predictor! for! emotional!empathy,!while!substance2class,!such!as!stimulants!or!empathogens,!was!not!significant.! Furthermore,!only!cannabis!use!was!positively!associated!with!social!contacts!but!again!no!stimulant! effect!was!observed.! ! Finally,! the! results! of! the! severity! index! of! PSU! (PSUSI)! indicated! that! reported! deficits! in! social! functioning!were!rather!driven!by!the!number!of!used!substances!than!by!the!severity!of!substance! use.!In!contrast,!Fernandez2Serrano!et!al.!(2010)!postulated!severity!of!substance!use!as!predictor!for! poorer!performances!in!emotion!recognition.!However,!the!authors!reported!that!the!results!were!
! 88! 5.!GENERAL!DISCUSSION! primarily!modulated!by!the!quantity!of!cocaine!use!and!severity!of!substance!use!was!assessed!by! self2reports! for! each! drug! separately,!whereas!the!PSUSI!of!our!study! represented! the! severity! of! substance!use!over!all!drugs!based!on!objective!data.! !!
! 89! 5.!GENERAL!DISCUSSION!
5.2! Impaired!cognitive!empathy!in!individuals!with!non2medical! ! prescription!opioid!use!
The! second! paper! of! this! thesis! aimed! to! investigate! chronic! effects! of! relatively! pure! opioid! use! primarily!on!social!cognition!but!also!on!cognitive!performance.!With!respect!to!the!lack!of!studies! examining! chronic! NMPOU! in!humans,!the!results!in!chapter!3!showed!for!the!first! time! distinct! socio2cognitive!and!cognitive!deficits!in!individuals!with!NMPOU,!objectively!confirmed!by!hair!and! urine! toxicology.! More! precisely,! chronic! opioid! users! revealed! impaired! cognitive! empathy! but! preserved! emotional! empathy! compared! to! controls! represented! by! poorer! performances! in! emotion!recognition!from!faces!and!prosody!and!understanding!of!others’!feelings!assessed!by!the! CATS!and!MET.!Deficits!in!emotion!perception!were!also!found!in!opioid2substituted!patients!with!a! history!of!heroin!dependence!(Kornreich!et!al.,!2003;!McDonald!et!al.,!2013).!However,!our!results! stand! in! contrast! to! the! recent! studies! by! Tomei! et! al.! (2017)! and! Stange! et! al.! (2017)! reporting! deficits!mainly!in!emotional!empathy!in!opioid2substituted!patients!assessed!by!self2reports.!Given! that!self2report!measurements!are!commonly!accompanied!by!response!biases!and!typically!poorly! correlated!with!more!complex!and!behavioural!empathy!paradigms!(Furnham!&!Henderson,!1982;! Stange!et!al.,!2017),!the!results!of!the!objective!computer2based!task!MET!used!in!our!study!may! provide! a! more! precise! indicator! for! emotional! and! cognitive! empathy.! However,! trait! empathy! assessed!by!self2reports!in!chapter!3!of!this!thesis!revealed!no!differences!between!the!NMPOU!and! control! group! suggesting! that! chronic! opioid! users! were! not! aware! of! their! deficits! and! further! supporting!the!response!bias!in!subjective!assessments.!Furthermore,!deficits!in!cognitive!empathy! was! positively! associated! with! higher! ME! concentrations! in! hairs! indicating! decreased! abilities! of! understanding! other’s! feelings! accompanied! by! increased! opioid! use.! Taken! together,! the! study! results! presented! in! chapter! 3! indicate! that! the! opioid! system! might! be! involved! in! processes! of! emotion! perception! and! mentalising! and! that! chronic! opioid! use! might! entail! neuroplastic! adaptations!in!specific!brain!structures!associated!with!cognitive!empathy!such!as!the!MCC!and!OFC! (Dvash!&!Shamay2Tsoory,!2014;!Fan!et!al.,!2011;!Nummenmaa!&!Tuominen,!2017).! ! Apart!from!the!assessments!of!social!functioning,!we!further!investigated!cognitive!performances!in! individuals! with! NMPOU.! Given! that! studies! examining! chronic! opioid! effects! on! cognitive! functioning! were! inconsistent! and! primarily! conducted! in! current! or! former! heroin! users,! opioid2 substituted!patients,!or!pain!patients,!who!are!biased!by!the!pain!factor!itself,!we!were!able!to!report! for!the!first!time!distinct!cognitive!impairments!in!individual!with!chronic!NMPOU.!With!respect!to!a! broad!range!of!opioid2related!cognitive!deficits!postulated!in!the!literature!(Baldacchino,!Armanyous,! Balfour,!Humphris,!&!Matthews,!2017;!Baldacchino!et!al.,!2012;!Kendall,!Sjøgren,!Pimenta,!Højsted,!
! 90! 5.!GENERAL!DISCUSSION!
&!Kurita,!2010),!the!study!results!presented!in!chapter!3!confirmed!only!inferior!performances!for! individuals! with! NMPOU! in! attention! and! declarative! memory! but! not! in! working! memory! and! executive! functioning.! However,! performances! of! former! or! current! heroin! users! are! commonly! accompanied! with! various! confounding! factors! such! as! psychiatric! comorbidities,! hypoxia2related! brain! injuries! after! opioid! overdoses,! drug! adulteration,! and! viral! infections! such! as! HCV! or! HIV,! which! could! contribute! to! already! existing! cognitive! deficits! independently.! Therefore,! the! study! results!in!chapter!3!might!provide!a!more!precise!indicator!for!chronic!opioid!effects!on!cognitive! performances.! ! Finally,! we! analysed! potential! associations! between! cognitive! performances! and! social! cognition! because! a! previous! study! revealed! cognitive! functioning! as! a! major! predictor! for! impaired! social! cognition! in! opioid2substitute! patients! (McDonald! et! al.,! 2013).! Although! individuals! with! NMPOU! revealed! inferior! performances! in! attention! and! declarative! memory! compared! to! controls,! only! executive!functioning!was!highly!correlated!with!the!global!cognitive!empathy!index!in!the!NMPOU! group.!Therefore,!we!considered!potential!modulatory!effects!of!executive!functioning!on!cognitive! empathy.! However,! our! results! of! inferior! performances! in! recognising! emotions! and! mentalising! remained!even!after!controlling!for!the!executive!domain,!although!the!effects!size!was!reduced!to!a! medium!effect.!!
! 91! 5.!GENERAL!DISCUSSION!
5.3! Dysfunctional!physiological!stress!response!to!social!rejection! ! in!non2medical!prescription!opioid!users!
The!last!paper!of!this!thesis!presented!in!chapter!4!addresses!the!question!of!altered!stress!response! to! social! pain! in! individuals! with! NMPOU! and! is! related! to! the! assumption! of! existing! neuronal! overlaps! between! physical! and! social! pain! processes.! Therefore,! we! assessed! behavioural! and! physiological! responses! to! social! rejection! using! the! Cyberball! paradigm! (Williams! &! Jarvis,! 2006).! Electrophysiological! measurements! were! conducted! to! assess! stress! response! of! the! ANS! using! vmHRV!as!an!index!for!parasympathetic!activity!and!spontaneous!fluctuation!of!the!SCL!as!an!index! for! sympathetic! activity.! Furthermore,!stress! response! of! the! HPA! axis! was! assessed! by!ACTH!and! cortisol! plasma! levels.! Although!the!NMPOU!and!control!group!revealed!no!differences!in!vmHRV! during!the!inclusion!and!exclusion!condition!in!the!Cyberball!task,!a!pronounced!increase!of!vmHRV! in!the!exclusion!condition!was!found!for!controls!and!a!trend!for!the!same!direction!in!individuals! with!NMPOU.!Based!on!the!findings!in!individuals!with!alcohol!abuse!by!Ingjaldsson!et!al.!(2003),!we! subdivided!the!NMPOU!group!by!a!median!split!on!a!craving!NRS!into!two!groups:!low/no!craver! (LowC)!and!high/medium!craver!(HiC).!Additional!statistical!analyses!revealed!that!HiC!showed!the! lowest!vmHRV!and!further!unchanged!vmHRV!from!inclusion!to!exclusion!condition,!whereas!LowC! revealed!a!similar!increase!of!vmHRV!to!exclusion!as!it!was!shown!for!controls.!This!is!in!line!with! previous! findings! of! individuals! with! alcohol! abuse! and! prescription! opioid! use! in! chronic! pain! patients!(Garland!et!al.,!2017;!Ingjaldsson!et!al.,!2003).!Because!vmHRV!is!associated!with!emotion! regulation!(Williams!et!al.,!2015),!these!results!might!indicate!a!better!adaptation!to!social!exclusion! in! LowC! and! controls! and! inferior! emotion! regulation! in! HiC.! Furthermore,! SCL! analyse! revealed! similar! spontaneous! fluctuation! during! exclusion! for! individuals! with! NMPOU! and! controls.! Taken! together,! the! electrophysiological! results! might! indicate! a! dysbalance! of! the! ANS! in! response! to! social!exclusion!indicated!by!regular!sympathetic!activity!but!abnormal!parasympathetic!activity!in! individuals!with!NMPOU!specifically!modulated!by!craving.! ! In!contrast!to!our!initial!hypothesis,!individuals!with!NMPOU!revealed!higher!ACTH!and!cortisol!levels! after!the!Cyberball!indicating!a!hyperreactivity!to!social!exclusion.!Acute!administration!of!opioids!by! contrast! entailed! stress2dampening! effects! indexed! by! decreased! cortisol! levels! and! behavioural! response!to!social!stress!(Bershad!et!al.,!2015;!Bershad!et!al.,!2016;!Vuong!et!al.,!2010).!Furthermore,! the! AUCi! for! ACTH! was! strongly! correlated! with! ME! hair! concentrations! indicating! a! higher! stress! response!of!the!HPA!axis!associated!with!increased!opioid!use.!Given!that!studies!investigating!opioid! effects!on!social!stress!in!humans!are!limited!and!differ!in! their!stress2induced! tasks!as!well!as!in! acute! versus! chronic! opioid! effects,! our! results! might! provide! for! the! first! time! evidence! for! an!
! 92! 5.!GENERAL!DISCUSSION! abnormal! activity! of! the! HPA! axis! in! response! to! social! pain! in! individuals! with! NMPOU.! Because! endogenous!opioids!such!as!β2endorphins!were!reported!to!inhibit!and!counteract!over2activation!of! the!HPA!axis!in!response!to!stress!(Bali!et!al.,!2015)!and!decreased!levels!of!endorphins!as!well!as! MOR! were! found! after! chronic! opioid! administration! in! rodents! (Sprouse2Blum! et! al.,! 2010),! observed! hyperreactivity! in! the! NMPOU! group! might! indicate! neuronal! adaptations! of! the! opioid! system! as! a! consequence! of! chronic! opioid! use! by! down2regulating! endogenous! opioid! release! resulting!in!hypersensibility!to!social!stress.!Vice!versa,!lower!availability!of!endorphins!might!be!a! predisposing! factor! in! individuals,! who! are! prone! to! use! opioids! for! counteracting! the! lack! of! endorphins,!which!subsequently!might!facilitate!initiation!and!maintenance!of!opioid!use.! ! In!contrast!to!the!hyperresponse!of!the!HPA!axis,!behavioural!results!of!the!Cyberball!task!indicate! that! individuals! with! NMPOU! were! less! affected! by! social! rejection,! whereas! controls! revealed! negative!changes!in!mood!after!social!exclusion.!However,!the!estimation!of!received!balls!during!the! Cyberball! and! feelings! of! inclusion! and! exclusion! were! similar! between! the! groups! indicating! that! opioid!users!were!aware!of!being!excluded!and!showed!preserved!perception!of!social!rejection.! ! In!line!with!the!BOTSA!suggesting!that!exogenous!opioids!might!replace!the!need!for!social!contacts! and!reduce!affiliative!behaviour,!individuals!with!NMPOU!revealed!a!smaller!social!network!size!than! controls.! However,! these! findings! can! be! also! discussed! as! a! consequence! of! deficits! in! cognitive! empathy! reported! in! the! study! before! (chapter! 3)! and! furthermore! as! a! predisposition! or! consequence!of!chronic!opioid!use.!Taken!together,!the!results!of!the!third!study!in!chapter!4!might! provide! evidence! that! the! endogenous! µ2opioid! system! plays! a! crucial! role! in! social! bonding! and! subsequently!in!social!rejection.!The!findings!can!be!interpreted!that!chronic!opioid!use!might!entail! perturbations!in!the!endogenous!opioid!system!and!therefore!supports!the!BOTSA!in!humans.! !!
! 93! 5.!GENERAL!DISCUSSION!
5.4! Strength!and!limitations!
All!three!studies!presented!in!this!thesis!share!some!important!strengths!and!limitations.!One!of!the! most! important! strengths! is! the! detection! and! confirmation! of! substance! use! by! hair! and! urine! analyses.!Therefore,!we!were!able!to!create!not!only!an!objective!validated!PSU!sample!for!the!first! time!in!part!I!of!this!thesis!but!also!to!confirm!relatively!pure!opioid!use!in!the!NMPOU!sample!of! part!II!and!further!to!exclude!subjects!showing!no!opioid!metabolites!in!hair!samples.!Given!that!the! validity!of!self2reported!drug!use!worsened!in!relation!to!the!increased!stigmatisation!of!the!used! substance!(Harrison,!1997),!objective!data!provide!a!more!precise!and!valid!estimation!of!illegal!drug! use.! Furthermore,! hair! toxicology! data! were! essential! for! the! severity! index! of! polysubstance! use! (PSUSI)!in!the!study!of!part!I!and!for!measuring!opioid2dose!associations!by!ME!in!hair!concentrations! in!both!studies!of!part!II.! ! A! further! important! strength! that! all! three! studies! in! this! thesis! have! in! common! is! the! strict! observance! of! inclusion! and! exclusion! criteria.! Participants! with! severe! psychiatric! or! physical! disorders!(e.g.,!schizophrenia,!eating!disorder,!obsessive2compulsive!disorder,!post2traumatic!stress! disorder,!or!HIC,!HCV,!chronic!pain,!brain!injuries,!etc.)!were!excluded!from!the!studies.!Especially!for! the! NMPOU! sample! in! part! II! of! this! thesis,! further! restrictions! were! set! with! respect! to! polysubstance!use.!Due!to!these!strict!criteria,!the!sample!size!of!the!NMPOU!group!was!quite!small.! However,!individuals!with!NMPOU!revealed!relatively!pure!opioid!use.! ! Further!advantages!over!all!three!studies!provide!the!well!matched!control!groups.!Therefore,!we! could! nearly! exclude! potential! gender,! age,! or! cognitive! effects! on! social! functioning,! which! are! commonly!associated!with!prosocial!behaviour!and!social!cognition!(Beadle!et!al.,!2015;!Cotter!et!al.,! 2018;!Kret!&!De!Gelder,!2012;!Miller!et!al.,!1991).!Furthermore,!cognitive!and!emotional!empathy!in! the!first!and!second!study!of!this!thesis!(chapter!2!and!3)!were!assessed!by!the!MET,!a!computer2 based!task!presenting!photos!of!people!in!complex!emotionally!charged!situations,!which!offers!a! greater!ecological!validity!than!subjective!self2reports.! ! The!advantage!of!the!third!study!was!the!assessment!of!physiological!stress!parameters.!Therefore,! we!could! objectively! investigate! potential!underlying!effects!of!chronic!opioid!use!on!social! stress! response.! Furthermore,! we! were! able! to! assess! and! compare! stress! parameters! of! both! stress! systems,!the!HPA!axis!and!the!ANS.! ! One!of!the!main!limitation!factor!in!all!three!studies!was!the!sample!size.!In!the!PSU!subgroups,!only! few! subjects! revealed! PSU! of! more! than! three! substances! and! the! sample! was! dominated! by!
! 94! 5.!GENERAL!DISCUSSION! stimulant! use,! whereas! opioid! use! was! less! prevalent.! As! mentioned! before,! due! to! our! strict! exclusion! criteria! and! also! to! difficult! accessibility! of! individuals! with! NMPOU! in! Switzerland,! the! NMPOU!sample!of!chapter!3!and!4!was!quite!small.!However,!Cohen’s!d!was!calculated!in!all!three! studies!to!overcome!this!limitation.! ! A!common!limitation!of!cross2sectional!studies!is!the!question!of!causality.!Results!presented!in!this! thesis! can! be! interpreted! as! drug2induced! effects! but! also! as! pre2existing! factors,! which! might! facilitate!PSU!or!NMPOU.!Therefore,!no!unequivocally!causal!conclusion!can!be!drawn!from!the!study! results! of! this! thesis.! However,! dose2related! opioid! effects! in! the! studies! of! part! II! might! indicate! opioid2induced!effects!on!cognitive!empathy!and!social!pain.!Furthermore,!animal!studies!revealed! particularly!deficits!in!prosocial!behaviour!as!well!as!reduced!β2endorphins!and!MOR!in!rodents!after! chronic! opioid! administration! indicating! that! also! our! findings! might! be! rather! opioid2induced! (Sprouse2Blum!et!al.,!2010;!Tomek,!Stegmann,!&!Olive,!2018).! ! The!final!limitation!concerns!the!Cyberball!paradigm!used!in!the!third!study!(chapter!4).!Due!to!our! study! design,! we! were! not! able! to! compare! behavioural,! SCL,! and! neuroendocrine! responses! between!the!inclusion!and!exclusion!condition.!Therefore,!we!cannot!absolutely!ensure,!if!present! results! were! distinctly! induced! by! social! exclusion! or! other! factors.! Given! that! the! control! group! showed!no!significant!stress!response!of!the!HPA!axis!to!social!exclusion,!one!might!assume!that!the! task!was!not!reliable!and!sensitive!enough.!However,!controls!revealed!negative!affect!changes!after! the!Cyberball,!which!can!be!interpreted!as!a!validity!index!for!the!task.!Furthermore,!cortisol!release! might!be!rather!caused!by!stressors!activating!the!need!for!power!such!as!fight!or!flight!than!the! need!for!affiliation,!which!might!explain!the!neuroendocrine!results!in!the!control!group!(Weik!et!al.,! 2017).! !!
! 95! 5.!GENERAL!DISCUSSION!
5.5! Clinical!implications!
The!results!of!the!present!thesis!do!not!only!contribute!to!basic!addiction!research!by!detecting!and! elucidating!potential!chronic!drug!effects,!but!also!might!entail!clinical!implications!with!the!aim!of! improving!interventions!as!well!as!therapy!outcome!and!reduce!relapse!in!individuals!with!PSU!and! NMPOU.! ! The! findings! of! the! first! study! presented! in! chapter! 2! indicate! a! gradual! decrease! of! emotional! empathy! and! social! contacts! related! to! an! increased! number! of! used! substances,! which! might! be! responsible!for!maintenance!and!relapse!of!stimulant!PSU!(Quednow,!2017).!Therefore,!therapeutic! interventions! of! PSU! should! target! these! deficits! and! try! to! improve! the! ability! to! share! other’s! affective!states!in!specific!training!programs!for!emotional!empathy.!Due!to!consistent!findings!of! structural!alterations!in!polysubstance!users!(Meyerhoff,!2017),!real2time!fMRI!biofeedback!targeting! cortical!and!subcortical!structures,!which!are!associated!with!emotional!empathy!(i.e.,!ACC,!insula,! amygdala;! chapter! 1.2.1),! might! further! support! and! ameliorate! current! psychotherapeutic! interventions! for! individuals! with! PSU! (Stoeckel,! Garrison,! Ghosh,! Wighton,! Hanlon,! Gilman! et! al.,! 2014).! Given! that! social! support! is! crucial! to! prevent! relapse! and! with! respect! to! the! gradual! decrease! of! social! contacts! related! to! an! increase! of! used! substances,! individual’s! social! network! including!family!members!should!be!involved!in!the!therapy.!Furthermore,!group!settings!might!be! appropriate!to!get!connected!with!other!people!and!to!improve!prosocial!behaviour!in!individuals! with!PSU.!With!respect!to!an!increase!of!socio2cognitive!deficits!by!using!more!substances,!therapy! programs!should!target!this!phenomenon!by!adapting!the!training!intensity!for!emotional!empathy! and! therefore! establishing! individualised! therapy! programs.! Furthermore,! psychoeducation! can! inform!people!about!the!worsening!effect!of!additional!substance!use!to!aid!the!prevention!of!PSU.!! ! The!findings!in!part!II!of!this!thesis!provide!several!clinical!implications!with!respect!to!prevention! and! intervention! of! chronic! opioid! use.! Although! it! is! still! unclear! to! what! extent! treatments! for! heroin!addiction!can!be!adapted!for!prescription!opioid!addiction,!NMPOU!is!often!treated!by!long2 term!or!lifetime!maintenance!with!opioid!substitution!therapy!(e.g.,!methadone!or!buprenorphine)! (Brady,!McCauley,!&!Back,!2016).!Additional!to!medical!detoxification,!our!results!suggest!a!stronger! focus!on!improvement!of!social!functioning!in!the!therapeutic!setting,!as!discussed!in!the!following.! ! First,! based! on! our! findings! in! chapter! 3,! future! therapeutic! intervention! of! opioid! dependence! should! consider! deficits! of! cognitive! empathy! in! specific! training! programs.! Given! that! a! similar! pattern! of! impaired! cognitive! empathy! but! preserved! or! even! elevated! emotional! empathy! was! found! for! individuals! with! ASD! (Blair,! 2005;! Smith,! 2009),! therapies! to! improve! social! skills! in!
! 96! 5.!GENERAL!DISCUSSION! individuals! with! NMPOU! might! be! adapted! for! trainings! targeting! ASD! such! as! social! skills! groups! training!programs!(Painter,!2006).!Based!on!the!assumption!that!deficits!in!social!cognition!preserve! the!vicious!circle!of!stimulant!drug!addiction!(Quednow,!2017),!impaired!abilities!in!understanding! other’s! feelings,! emotion! recognition,! and! mentalising! might! lead! to! dysfunctional! daily! life! interactions!particularly!in!social!relationships!but!also!in!therapist2patient!relationships!contributing! to!the!maintenance!and!relapse!in!individuals!with!NMPOU.!Given!that!high!opioid!receptor!density! was! found! in! brain! structures! associated! with! cognitive! empathy! (e.g.,!MCC,!insula,!and!OFC;! see! chapter! 1.1.2)! and! that! opioid! dependent! patients! revealed! also! altered! structural! and! functional! connectivity! of! the! insula! and! OFC! (Upadhyay! et! al.,! 2010),! real2time! fMRI! biofeedback! targeting! particularly! these! areas! might! improve! cognitive! empathy! and! subsequently! therapy! output! and! reduce!relapse.!As!mentioned!before,!because!social!support!was!previously!found!as!a!crucial!key! factor! to! prevent! relapse! (Ellis! et! al.,! 2004;! Havassy! et! al.,! 1991),! individuals! with! NMPOU! might! further! benefit! from! therapies! with! group! settings! and! from! involving! the! social! network! in! therapeutic!treatments.! ! Second,! psychotherapeutic! treatments! for! opioid! addiction! should! target! emotion! regulation! and! response!to!social!distress.!Based!on!the!results!reported!in!chapter!4,!particularly!high!opioid!craver! revealed! difficulties! in! emotion! regulation! indexed! by! low! and! unchanged! vmHRV.! Recent! studies! reported!positive!effects!of!vmHRV2biofeedback!on!emotional!outcome!as!well!as!in!substance!and! heroin!users!suggesting!vmHRV2biofeedback!as!an!efficient!treatment!for!opioid!dependence!(Eddie,! Vaschillo,!Vaschillo,!&!Lehrer,!2015;!Lin!et!al.,!2016;!Mather!&!Thayer,!2018).! Furthermore,!lower! vmHRV!is!associated!with!difficulties!in!impulsive!control!and!was!further!reported!to!predict!craving! in! alcohol! dependent! individuals! (Quintana! et! al.,! 2013;! Williams! et! al.,! 2015).! Therefore,! vmHRV! might!provide!a!biological!marker!for!treatment!response!and!outcome!and!further!contribute!to!the! development!of!more!individualised!psychotherapies!with!respect!to!treatment!intensity.!Moreover,! well2being! and! vmHRV! were! reported! to! be! increased! after! mindfulness! meditation! suggesting! mindfulness!training!programs!as!a!further!effective!treatment!component!for!opioid!addiction!and! specifically!in!individuals!with!high!opioid!craving!(Krygier,!Heathers,!Shahrestani,!Abbott,!Gross,!&! Kemp,!2013;!Park,!Oh,!Noh,!Kim,!&!Kim,!2018).! ! Third,!especially!the!results!from!the!third!study!of!this!thesis!might!provide!crucial!implications!for! preventing!NMPOU!particularly!for!clinical!practice!of!balancing!treatment!of!acute!and!chronic!pain! versus! inducing! a! risk! of! later! NMPOU.! As! mentioned! before,! vmHRV! is! associated! with! impulse! control! and! prediction! of! craving.! Therefore,! low! vmHRV! might! be! also! a! predisposing! factor! for! NMPOU! or! more! generally! for! drug! addiction! and! might! be! considered! in! prescription! of! opioid!
! 97! 5.!GENERAL!DISCUSSION! analgesics!in!the!future.!Furthermore,!in!chapter!5.3,!hyperreactivity!of!the!HPA!axis!in!individuals! with!NMPOU!was!discussed!as!a!potential!neuroadaptational!consequence!of!chronic!opioid!use!on! the! endogenous! opioid! system! indicating! a! down2regulation! of! endorphin! release.! However,! pre2 existing! lower! endorphin! levels! might! also! represent! a! predisposition! for! NMPOU! and! opioid! addiction.!Given!that!in!the!U.S!about!35.4%!of!individuals!with!NMPOU!received!analgesics!through! prescription!from!a!doctor!(SAMHSA,!2017)!and!up!to!86%!of!heroin!users!reported!NMPOU!before! initiating!heroin!use!(Compton!et!al.,!2016),!suggested!predispositions!might!yield!new!assessments! in! clinical! settings! regarding! the! treatment! of! pain! and! the! prescription! of! opioid! analgesics! to! prevent!NMPOU.!Finally,!psychoeducation!can!elucidate!and!inform!patients!about!potential!adverse! cognitive!and!socio2cognitive!effects!of!chronic!NMPOU.!!
! 98! 5.!GENERAL!DISCUSSION!
5.6! Outlook!
The! results! of! the! present! thesis! provide! evidence! for! distinct! deficits! in! social! functioning! in! individuals!with!chronic!drug!use.!Therefore,!fundamental!research!gaps!in!the!context!of!cumulative! PSU!and!chronic!NMPOU!could!be!filled.!However,!some!limitations!and!emerged!questions,!inspired! by!the!results!of!this!thesis,!should!be!addressed!in!future!continuative!studies.! ! Because!the!sample!size!in!both!parts!of!this!thesis!was!quite!small,!future!studies!should!address! this!limitation!and!try!to!replicate!our!findings!in!bigger!samples.!Furthermore,!based!on!the!theory! of!two!distinct!ToM!components!associated!with!activation!of!different!neuronal!systems!(affective! and!cognitive!ToM,!chapter!1.2.1)!(Dvash!&!Shamay2Tsoory,!2014),!subsequent!studies!investigating! affective!and!cognitive!ToM!could!elucidate!further!socio2cognitive!deficits!in!individuals!with!PSU! and! NMPOU.! Because! emotional! and! cognitive! empathy! were! also! associated! with! activation! of! different! neuronal! systems! (chapter! 1.2.1),! further! fMRI! studies!using! social! cognition! tasks! might! support! and! confirm! our! findings! of! distinct! socio2cognitive! deficits! in! individuals! with! PSU! and! NMPOU.! Therefore,! individuals! showing! an! increased! number! of! used! substances! should! reveal! decreased!neuronal!activity!of!cortical!and!subcortical!structures!associated!with!emotional!empathy! (e.g.,! ACC,! amygdala,! insula;! chapter! 1.2.1! and! 2.)! during! tasks! assessing! emotional! empathy.! Accordingly,! individuals! with! NMPOU! should! reveal! decreased! neuronal! activity! in! structures! associated! with! cognitive! empathy! (e.g.,! MCC,! OFC,! insula;! chapter! 1.2.1! and! 3.)! during! tasks! measuring!cognitive!empathy.! ! Various!research!questions!and!ideas!for!future!studies!derive!from!the!results!presented!in!chapter! 4,!which!can!be!extended!to!studies!investigating!effects!of!chronic!opioid!use!in!general.!Especially! PET! studies! using! the! MOR2selective! radiotracer! [11C]2carfentanil! could! elucidate! potential! neurochemical! adaptation! of! the! MOR! system! resulted! from! chronic! opioid! use.! In! line! with! the! BOTSA!and!reported!associations!of!the!OPRM1!G!allele!variant!with!heroin!use!(Mague!&!Blendy,! 2010),!individuals!with!chronic!opioid!use!should!reveal!lower!baseline!MOR!binding!potential!(BP)! than! healthy! controls! indicating! a! lower! MOR! density.! The! G! allele! of! the! OPRM1! A118G! polymorphism!is!associated!with!reduced!levels!of!MOR!mRNA!and!protein!(Zhang,!Wang,!Johnson,! Papp,!&!Sadee,!2005).!Furthermore,!the!G!allele!variant!was!more!frequently!found!in!heroin!but!also! in! substance! users! in! general! (Mague! &! Blendy,! 2010)! and! was! further! associated! with! avoidant! social! attachment! style,! higher! neuronal! activation! during! social! rejection,! and! greater! depressive! response!to!socially!painful!targeted!rejection!life!events!(Bonenberger,!Plener,!Groschwitz,!Gron,!&! Abler,! 2015;! Slavich,! Tartter,! Brennan,! &! Hammen,! 2014;! Troisi! et! al.,! 2011;! Way,! Taylor,! &! Eisenberger,! 2009).! Therefore,! hypothesised! lower! MOR! BP! in! individuals! with! chronic! opioid! use!
! 99! 5.!GENERAL!DISCUSSION! might!result!either!from!a!genetic!predisposition!of!the!OPRM1!polymorphism,!from!opioid2induced! receptor!internalisation!and!recycling,!or!from!both!(Zubieta,!Smith,!Bueller,!Xu,!Kilbourn,!Jewett!et! al.,!2001).!Animal!studies!have!already!shown!that!chronic!opioid!administration!led!to!an!inhibition! of!MOR!expression!and!reduced!endorphin!production!(Sprouse2Blum!et!al.,!2010).!In!line!with!these! results,! a! further! study! could! address! the! question! of! decreased! endorphin! availability! in! chronic! opioid! users,! which! might! modulate! stress! response! to! social! pain.! Increased! endorphin! release! during! social! rejection! was! found! in! healthy! humans! indicated! by! reduced! MOR! BP! for! the! tracer! [11C]2carfentanil!compared!to!baseline!BP!due!to!increased!binding!of!the!released!endorphins!on!the! MOR!sides!(Hsu!et!al.,!2013;!Zubieta!et!al.,!2001).!With!respect!to!the!results!shown!in!chapter!4!of! this!thesis,!the!observed!hyperreactivity!of!the!HPA!axis!in!response!to!social!rejection!in!the!NMPOU! group!was!discussed!as!a!potential!result!from!reduced!β2endorphin!levels.! Because!β2endorphins! show!a!high!binding!affinity!to!MOR!(Pasternak!&!Pan,!2013),!chronic!opioid!users!should!reveal!no! or!lower!differences!of!MOR!BP!between!baseline!and!social!rejection!compared!to!healthy!controls! indicating! decreased! endorphin! release! during! social! pain.! Furthermore,! studies! assessing! β2 endorphin!levels!directly!could!confirm!the!assumption!and!might!elucidate!potential!alterations!in! the!endogenous!opioid!system!in!chronic!opioid!users.!Individuals!with!chronic!alcohol!abuse!have! already! shown! a! decrease! of! β2endorphin! plasma! levels! (Zalewska2Kaszubska! &! Czarnecka,! 2005).! However,!because!endorphins!cannot!cross!the!blood2brain!barrier,!plasma!β2endorphin!levels!might! not! directly! represent! endogenous! opioid! release! and! availability! in! the! central! nervous! system! (Machin!&!Dunbar,!2011).!Therefore,!studies!assessing!β2endorphin!levels!in!cerebrospinal!fluid!(CSF)! via!lumbar!puncture!would!be!more!precisely!and!preferable.! ! Furthermore,! similar! findings! of! distinct! deficits! in! cognitive! empathy! in! individuals! with! chronic! NMPOU!(chapter!3)! were!also!reported!for!individuals!with!ASD! (Blair,!2005;!Smith,!2009).! In!line! with!this!association,!the!endogenous!opioid!excess!theory!of!autism,!initially!formulated!by!Sahley! and! Panksepp! (1987),! suggests! that! children! with! ASD! suffer! from! an! over2activation! of! the! endogenous!opioid!system!resulting!in!impaired!social!interaction!and!typical!stereotyped!behaviour.! As! mentioned! before,! chronic! opioid! administration! in! animals,! or! in! this! case! over2excess! of! endogenous! opioids,! might! result! in! neuroplastic! adaptations! such! as! MOR! internalisation! and! recycling,!reduced!endorphin!expression!as!a!negative!feedback!process,!or!both.!Therefore,!results! in!individuals!with!chronic!NMPOU!might!provide!a!drug2model!of!ASD!and!could!give!an!insight!in! the! development! and! course! of! ASD.! Vice! versa,! new! research! findings! of! ASD! might! support! the! understanding!of!the!underlying!mechanism!involved!in!chronic!opioid!use.! !
! 100! 5.!GENERAL!DISCUSSION!
Finally,!to!overcome!the!cross2sectional!study!design!and!address!the!question!of!causality,!further! longitudinal!studies!should!be!conducted!to!provide!a!better!interpretation!of!the!results!presented! in! this! thesis.! Therefore,! the! longitudinal! data! of! the! study! presented! in! part! II! might! give! first! insights! and! evidences! for! chronic! effects! of! NMPOU.! Especially! with! respect! to! increased! and! decreased! NMPOU,! data! of! the! follow2up! measurement! might! provide! crucial! information! about! stable!deficits!or!potential!recovery!of!social!functioning.!Furthermore,!because!vmHRV!is!association! with!impulse!control,!individuals!with!higher!vmHRV!and!a!better!adaptation!to!social!exclusion!in! the!cross2sectional!study!should!be!more!capable!of!decreasing!or!stopping!NMPOU!than!individuals! who!showed!lower!vmHRV!in!the!cross2sectional!study.! !
! 101! 6.!REFERENCES!
6.! REFERENCES!
!
Abu2Akel,!A.,!&!Shamay2Tsoory,!S.!(2011).!Neuroanatomical!and!neurochemical!bases!of!theory!of!mind.! Neuropsychologia,!49(11),!297122984.! Adolphs,!R.!(2002).!Neural!systems!for!recognizing!emotion.!Curr!Opin!Neurobiol,!12(2),!1692177.! American!Psychiatric!Association.!(1994).!Diagnostic!and!Statistical!Manual!of!Mental!Disorders:!DSM8IV!(4th! ed.).!Washington,!DC:!American!Psychiatric!Association!(APA).! American!Psychiatric!Association.!(2013).!Diagnostic!and!Statistical!Manual!of!Mental!Disorders:!DSM85!(5th! ed.).!Arlington,!VA:!American!Psychiatric!Association.! Anderson,!C.,!&!Keltner,!D.!(2002).!The!role!of!empathy!in!the!formation!and!maintenance!of!social!bonds.! Behav!Brain!Sci,!25(1),!21222.! Atadokht,!A.,!Hajloo,!N.,!Karimi,!M.,!&!Narimani,!M.!(2015).!The!role!of!family!expressed!emotion!and! perceived!social!support!in!predicting!addiction!relapse.!Int!J!High!Risk!Behav!Addict,!4(1),!e21250.! Bach,!D.!R.,!Daunizeau,!J.,!Kuelzow,!N.,!Friston,!K.!J.,!&!Dolan,!R.!J.!(2011).!Dynamic!causal!modeling!of! spontaneous!fluctuations!in!skin!conductance.!Psychophysiology,!48(2),!2522257.! Back,!S.!E.,!Gros,!D.!F.,!Price,!M.,!LaRowe,!S.,!Flanagan,!J.,!Brady,!K.!T.,!.!.!.!McCauley,!J.!L.!(2015).!Laboratory2 induced!stress!and!craving!among!individuals!with!prescription!opioid!dependence.!Drug!Alcohol! Depend,!155,!60267.! Badiani,!A.,!Belin,!D.,!Epstein,!D.,!Calu,!D.,!&!Shaham,!Y.!(2011).!Opiate!versus!psychostimulant!addiction:!the! differences!do!matter.!Nat!Rev!Neurosci,!12(11),!6852700.! Badiani,!A.,!Berridge,!K.!C.,!Heilig,!M.,!Nutt,!D.!J.,!&!Robinson,!T.!E.!(2018).!Addiction!research!and!theory:!a! commentary!on!the!Surgeon!General's!Report!on!alcohol,!drugs,!and!health.!Addict!Biol,!23(1),!325.! Baiamonte,!B.!A.,!Lee,!F.!A.,!Gould,!H.!J.,!3rd,!&!Soignier,!R.!D.!(2013).!Morphine2induced!cognitive!impairment! is!attenuated!by!induced!pain!in!rats.!Behav!Neurosci,!127(4),!5242534.! Baldacchino,!A.,!Armanyous,!M.,!Balfour,!D.!J.,!Humphris,!G.,!&!Matthews,!K.!(2017).!Neuropsychological! functioning!and!chronic!methadone!use:!A!systematic!review!and!meta2analysis.!Neurosci!Biobehav! Rev,!73,!23238.! Baldacchino,!A.,!Balfour,!D.!J.,!Passetti,!F.,!Humphris,!G.,!&!Matthews,!K.!(2012).!Neuropsychological! consequences!of!chronic!opioid!use:!a!quantitative!review!and!meta2analysis.!Neurosci!Biobehav!Rev,! 36(9),!205622068.! Bali,!A.,!Randhawa,!P.!K.,!&!Jaggi,!A.!S.!(2015).!Stress!and!opioids:!role!of!opioids!in!modulating!stress2related! behavior!and!effect!of!stress!on!morphine!conditioned!place!preference.!Neurosci!Biobehav!Rev,!51,! 1382150.! Bass,!E.!C.,!Stednitz,!S.!J.,!Simonson,!K.,!Shen,!T.,!&!Gahtan,!E.!(2014).!Physiological!stress!reactivity!and! empathy!following!social!exclusion:!a!test!of!the!defensive!emotional!analgesia!hypothesis.!Soc! Neurosci,!9(5),!5042513.! Baumeister,!R.!F.,!&!Leary,!M.!R.!(1995).!The!need!to!belong:!desire!for!interpersonal!attachments!as!a! fundamental!human!motivation.!Psychol!Bull,!117(3),!4972529.! Baumgartner,!U.,!Buchholz,!H.!G.,!Bellosevich,!A.,!Magerl,!W.,!Siessmeier,!T.,!Rolke,!R.,!.!.!.!Schreckenberger,!M.! (2006).!High!opiate!receptor!binding!potential!in!the!human!lateral!pain!system.!Neuroimage,!30(3),! 6922699.! Beadle,!J.!N.,!Sheehan,!A.!H.,!Dahlben,!B.,!&!Gutchess,!A.!H.!(2015).!Aging,!empathy,!and!prosociality.!J!Gerontol! B!Psychol!Sci!Soc!Sci,!70(2),!2152224.! Beauchaine,!T.!P.,!&!Thayer,!J.!F.!(2015).!Heart!rate!variability!as!a!transdiagnostic!biomarker!of! psychopathology.!Int!J!Psychophysiol,!98(2!Pt!2),!3382350.! Beck,!A.!T.,!Ward,!C.!H.,!Mendelson,!M.,!Mock,!J.,!&!Erbaugh,!J.!(1961).!An!inventory!for!measuring!depression.! Arch!Gen!Psychiatry,!4,!5612571.! Becker,!W.!C.,!Sullivan,!L.!E.,!Tetrault,!J.!M.,!Desai,!R.!A.,!&!Fiellin,!D.!A.!(2008).!Non2medical!use,!abuse!and! dependence!on!prescription!opioids!among!U.S.!adults:!psychiatric,!medical!and!substance!use! correlates.!Drug!Alcohol!Depend,!94(123),!38247.! Bernhardt,!B.!C.,!&!Singer,!T.!(2012).!The!neural!basis!of!empathy.!Annu!Rev!Neurosci,!35,!1223.! Bernstein,!M.!J.,!&!Claypool,!H.!M.!(2012).!Social!exclusion!and!pain!sensitivity:!why!exclusion!sometimes!hurts! and!sometimes!numbs.!Pers!Soc!Psychol!Bull,!38(2),!1852196.!
! 102! 6.!REFERENCES!
Berridge,!K.!C.,!Robinson,!T.!E.,!&!Aldridge,!J.!W.!(2009).!Dissecting!components!of!reward:!'liking',!'wanting',! and!learning.!Curr!Opin!Pharmacol,!9(1),!65273.! Bershad,!A.!K.,!Jaffe,!J.!H.,!Childs,!E.,!&!de!Wit,!H.!(2015).!Opioid!partial!agonist!buprenorphine!dampens! responses!to!psychosocial!stress!in!humans.!Psychoneuroendocrinology,!52,!2812288.! Bershad,!A.!K.,!Seiden,!J.!A.,!&!de!Wit,!H.!(2016).!Effects!of!buprenorphine!on!responses!to!social!stimuli!in! healthy!adults.!Psychoneuroendocrinology,!63,!43249.! Bertoux,!M.,!O'Callaghan,!C.,!Dubois,!B.,!&!Hornberger,!M.!(2016).!In!two!minds:!executive!functioning!versus! theory!of!mind!in!behavioural!variant!frontotemporal!dementia.!J!Neurol!Neurosurg!Psychiatry,!87(3),! 2312234.! Biernacki,!K.,!Terrett,!G.,!McLennan,!S.!N.,!Labuschagne,!I.,!Morton,!P.,!&!Rendell,!P.!G.!(2018).!Decision2 making,!somatic!markers!and!emotion!processing!in!opiate!users.!Psychopharmacology!(Berl),!235(1),! 2232232.! Blackhart,!G.!C.,!Eckel,!L.!A.,!&!Tice,!D.!M.!(2007).!Salivary!cortisol!in!response!to!acute!social!rejection!and! acceptance!by!peers.!Biol!Psychol,!75(3),!2672276.! Blair,!R.!J.!(2005).!Responding!to!the!emotions!of!others:!dissociating!forms!of!empathy!through!the!study!of! typical!and!psychiatric!populations.!Conscious!Cogn,!14(4),!6982718.! Bonenberger,!M.,!Plener,!P.!L.,!Groschwitz,!R.!C.,!Gron,!G.,!&!Abler,!B.!(2015).!Polymorphism!in!the!micro2opioid! receptor!gene!(OPRM1)!modulates!neural!processing!of!physical!pain,!social!rejection!and!error! processing.!Exp!Brain!Res,!233(9),!251722526.! Bora,!E.,!&!Zorlu,!N.!(2017).!Social!cognition!in!alcohol!use!disorder:!a!meta2analysis.!Addiction,!112(1),!40248.! Brady,!K.!T.,!McCauley,!J.!L.,!&!Back,!S.!E.!(2016).!Prescription!Opioid!Misuse,!Abuse,!and!Treatment!in!the! United!States:!An!Update.!Am!J!Psychiatry,!173(1),!18226.! Broseus,!J.,!Gentile,!N.,!&!Esseiva,!P.!(2016).!The!cutting!of!cocaine!and!heroin:!A!critical!review.!Forensic!Sci!Int,! 262,!73283.! Cacioppo,!S.,!Frum,!C.,!Asp,!E.,!Weiss,!R.!M.,!Lewis,!J.!W.,!&!Cacioppo,!J.!T.!(2013).!A!Quantitative!Meta2Analysis! of!Functional!Imaging!Studies!of!Social!Rejection.!Sci.!Rep.,!3.! Castellano,!F.,!Bartoli,!F.,!Crocamo,!C.,!Gamba,!G.,!Tremolada,!M.,!Santambrogio,!J.,!.!.!.!Carra,!G.!(2015).!Facial! emotion!recognition!in!alcohol!and!substance!use!disorders:!A!meta2analysis.!Neurosci!Biobehav!Rev,! 59,!1472154.! Castro,!D.!C.,!&!Berridge,!K.!C.!(2014).!Opioid!hedonic!hotspot!in!nucleus!accumbens!shell:!mu,!delta,!and!kappa! maps!for!enhancement!of!sweetness!"liking"!and!"wanting".!J!Neurosci,!34(12),!423924250.! Chapleau,!M.!W.,!&!Sabharwal,!R.!(2011).!Methods!of!assessing!vagus!nerve!activity!and!reflexes.!Heart!Fail! Rev,!16(2),!1092127.! Cochran,!G.,!Woo,!B.,!Lo2Ciganic,!W.!H.,!Gordon,!A.!J.,!Donohue,!J.!M.,!&!Gellad,!W.!F.!(2015).!Defining!Non2 Medical!Use!Of!Prescription!Opioids!within!Health!Care!Claims:!A!Systematic!Review.!Subst!Abus,!0.! Cohen,!J.!(1988).!Statistical!power!analysis!for!the!bevavioral!sciences!(Hillsdale!Ed.!2!ed.).!Hillsday,!New!Jersey:! Lawrence!Erlbaum!Associates.! Compton,!W.!M.,!Jones,!C.!M.,!&!Baldwin,!G.!T.!(2016).!Relationship!between!Nonmedical!Prescription2Opioid! Use!and!Heroin!Use.!N!Engl!J!Med,!374(2),!1542163.! Connor,!J.!P.,!Gullo,!M.!J.,!White,!A.,!&!Kelly,!A.!B.!(2014).!Polysubstance!use:!diagnostic!challenges,!patterns!of! use!and!health.!Curr!Opin!Psychiatry,!27(4),!2692275.! Cooper,!G.!A.,!Kronstrand,!R.,!Kintz,!P.,!&!Society!of!Hair,!T.!(2012).!Society!of!Hair!Testing!guidelines!for!drug! testing!in!hair.!Forensic!Sci!Int,!218(123),!20224.! Cotter,!J.,!Granger,!K.,!Backx,!R.,!Hobbs,!M.,!Looi,!C.!Y.,!&!Barnett,!J.!H.!(2018).!Social!cognitive!dysfunction!as!a! clinical!marker:!A!systematic!review!of!meta2analyses!across!30!clinical!conditions.!Neurosci!Biobehav! Rev,!84,!92299.! Craparo,!G.,!Gori,!A.,!Dell'Aera,!S.,!Costanzo,!G.,!Fasciano,!S.,!Tomasello,!A.,!&!Vicario,!C.!M.!(2016).!Impaired! emotion!recognition!is!linked!to!alexithymia!in!heroin!addicts.!PeerJ,!4,!e1864.! Cusi,!A.!M.,!Macqueen,!G.!M.,!Spreng,!R.!N.,!&!McKinnon,!M.!C.!(2011).!Altered!empathic!responding!in!major! depressive!disorder:!relation!to!symptom!severity,!illness!burden,!and!psychosocial!outcome.! Psychiatry!Res,!188(2),!2312236.! Darke,!S.!(2011).!The!Life!of!the!Heroin!User,!Typical!Beginnings,!Trajectories!and!Outcomes.!Cambridge:! Cambridge!University!Press.! Darke,!S.!(2013).!Pathways!to!heroin!dependence:!time!to!re2appraise!self2medication.!Addiction,!108(4),!6592 667.! Darke,!S.,!Sims,!J.,!McDonald,!S.,!&!Wickes,!W.!(2000).!Cognitive!impairment!among!methadone!maintenance! patients.!Addiction,!95(5),!6872695.!
! 103! 6.!REFERENCES!
Davis,!M.!H.!(1983).!Measuring!Individual2Differences!in!Empathy!2!Evidence!for!a!Multidimensional!Approach.!J! Pers!Soc!Psychol,!44(1),!1132126.! Decety,!J.,!&!Jackson,!P.!L.!(2004).!The!functional!architecture!of!human!empathy.!Behav!Cogn!Neurosci!Rev,! 3(2),!712100.! Del!Boca,!F.!K.,!&!Darkes,!J.!(2003).!The!validity!of!self2reports!of!alcohol!consumption:!state!of!the!science!and! challenges!for!research.!Addiction,!98!Suppl!2,!1212.! Derntl,!B.,!Finkelmeyer,!A.,!Toygar,!T.!K.,!Hulsmann,!A.,!Schneider,!F.,!Falkenberg,!D.!I.,!&!Habel,!U.!(2009).! Generalized!deficit!in!all!core!components!of!empathy!in!schizophrenia.!Schizophr!Res,!108(123),!1972 206.! Dvash,!J.,!&!Shamay2Tsoory,!S.!G.!(2014).!Theory!of!Mind!and!Empathy!as!Multidimensional!Constructs! Neurological!Foundations.!Top!Lang!Disord,!34(4),!2822295.! Dziobek,!I.,!Fleck,!S.,!Kalbe,!E.,!Rogers,!K.,!Hassenstab,!J.,!Brand,!M.,!.!.!.!Convit,!A.!(2006).!Introducing!MASC:!a! movie!for!the!assessment!of!social!cognition.!J!Autism!Dev!Disord,!36(5),!6232636.! Dziobek,!I.,!Preissler,!S.,!Grozdanovic,!Z.,!Heuser,!I.,!Heekeren,!H.!R.,!&!Roepke,!S.!(2011).!Neuronal!correlates!of! altered!empathy!and!social!cognition!in!borderline!personality!disorder.!Neuroimage,!57(2),!5392548.! Dziobek,!I.,!Rogers,!K.,!Fleck,!S.,!Bahnemann,!M.,!Heekeren,!H.!R.,!Wolf,!O.!T.,!&!Convit,!A.!(2008).!Dissociation! of!cognitive!and!emotional!empathy!in!adults!with!Asperger!syndrome!using!the!Multifaceted! Empathy!Test!(MET).!J!Autism!Dev!Disord,!38(3),!4642473.! Earleywine,!M.,!&!Newcomb,!M.!D.!(1997).!Concurrent!versus!simultaneous!polydrug!use:!prevalence,! correlates,!discriminant!validity,!and!prospective!effects!on!health!outcomes.!Exp!Clin! Psychopharmacol,!5(4),!3532364.! Eddie,!D.,!Kim,!C.,!Lehrer,!P.,!Deneke,!E.,!&!Bates,!M.!E.!(2014).!A!pilot!study!of!brief!heart!rate!variability! biofeedback!to!reduce!craving!in!young!adult!men!receiving!inpatient!treatment!for!substance!use! disorders.!Appl!Psychophysiol!Biofeedback,!39(324),!1812192.! Eddie,!D.,!Vaschillo,!E.,!Vaschillo,!B.,!&!Lehrer,!P.!(2015).!Heart!rate!variability!biofeedback:!Theoretical!basis,! delivery,!and!its!potential!for!the!treatment!of!substance!use!disorders.!Addict!Res!Theory,!23(4),!2662 272.! Eisenberger,!N.!I.!(2012).!The!pain!of!social!disconnection:!examining!the!shared!neural!underpinnings!of! physical!and!social!pain.!Nat!Rev!Neurosci,!13(6),!4212434.! Eisenberger,!N.!I.!(2015).!Social!pain!and!the!brain:!controversies,!questions,!and!where!to!go!from!here.!Annu! Rev!Psychol,!66,!6012629.! Ellis,!B.,!Bernichon,!T.,!Yu,!P.,!Roberts,!T.,!&!Herrell,!J.!M.!(2004).!Effect!of!social!support!on!substance!abuse! relapse!in!a!residential!treatment!setting!for!women.!Eval!Program!Plann,!27(2),!2132221.! EMCDDA.!(2002).!Annual!report!on!the!state!of!the!drugs!problem!in!the!European!Union!and!Norway.! Luxembourg:!Office!for!Official!Publications!of!the!European!Communities.! EMCDDA.!(2009).!Polydrug!Use:!Patterns!and!Responses.!Luxembourg:!Publications!Office!of!the!European! Union.! EMCDDA.!(2015).!European!Drug!Report!2015:!Trends!and!Developments.!Retrieved!from!Luxembourg:!! EMCDDA.!(2016).!Hospital!emergency!presentations!and!acute!drug!toxicity!in!Europe:!update!from!the!Euro8 DEN!Plus!research!group!and!the!EMCDDA.!Luxembourg:!Publications!Office!of!the!European!Union.! EMCDDA.!(2017).!European!Drug!Report!2017:!Trends!and!Developments.!Luxembourg:!Publications!Office!of! the!European!Union.! EMCDDA.!(2018).!European!Drug!Report!2018:!Trends!and!Developments.!Luxembourg:!Publications!Office!of! the!European!Union.! Eres,!R.,!Decety,!J.,!Louis,!W.!R.,!&!Molenberghs,!P.!(2015).!Individual!differences!in!local!gray!matter!density! are!associated!with!differences!in!affective!and!cognitive!empathy.!Neuroimage,!117,!3052310.! Ersche,!K.!D.,!Clark,!L.,!London,!M.,!Robbins,!T.!W.,!&!Sahakian,!B.!J.!(2006).!Profile!of!executive!and!memory! function!associated!with!amphetamine!and!opiate!dependence.!Neuropsychopharmacology,!31(5),! 103621047.! Fan,!Y.,!Duncan,!N.!W.,!de!Greck,!M.,!&!Northoff,!G.!(2011).!Is!there!a!core!neural!network!in!empathy?!An!fMRI! based!quantitative!meta2analysis.!Neurosci!Biobehav!Rev,!35(3),!9032911.! Faul,!F.,!Erdfelder,!E.,!Buchner,!A.,!&!Lang,!A.!G.!(2009).!Statistical!power!analyses!using!G*Power!3.1:!tests!for! correlation!and!regression!analyses.!Behav!Res!Methods,!41(4),!114921160.! Fernandez2Serrano,!M.!J.,!Lozano,!O.,!Perez2Garcia,!M.,!&!Verdejo2Garcia,!A.!(2010).!Impact!of!severity!of!drug! use!on!discrete!emotions!recognition!in!polysubstance!abusers.!Drug!Alcohol!Depend,!109(123),!57264.! Fernandez2Serrano,!M.!J.,!Perez2Garcia,!M.,!&!Verdejo2Garcia,!A.!(2011).!What!are!the!specific!vs.!generalized! effects!of!drugs!of!abuse!on!neuropsychological!performance?!Neurosci!Biobehav!Rev,!35(3),!3772406.!
! 104! 6.!REFERENCES!
Ferrari,!V.,!Smeraldi,!E.,!Bottero,!G.,!&!Politi,!E.!(2014).!Addiction!and!empathy:!a!preliminary!analysis.!Neurol! Sci,!35(6),!8552859.! Fields,!H.!L.!(2011).!Mu!Opioid!Receptor!Mediated!Analgesia!and!Reward.!In!G.!W.!Pasternak!(Ed.),!The!Opiate! Receptors!(second!ed.,!Vol.!23,!pp.!2392264).!New!York:!Humana!Press.! Frye,!C.!G.,!Wardle,!M.!C.,!Norman,!G.!J.,!&!de!Wit,!H.!(2014).!MDMA!decreases!the!effects!of!simulated!social! rejection.!Pharmacol!Biochem!Behav,!117,!126.! Furnham,!A.,!&!Henderson,!M.!(1982).!The!Good,!the!Bad!and!the!Mad!2!Response!Bias!in!Self2Report! Measures.!Pers!Indiv!Differ,!3(3),!3112320.! Gandolphe,!M.!C.,!Lecluyse,!B.,!Triquet,!C.,!Brunelle,!E.,!Duparcq,!J.!P.,!&!Nandrino,!J.!L.!(2018).!Mind!reading! abilities!in!opiate2dependent!patients:!An!exploratory!study.!Compr!Psychiatry,!83,!46252.! Garland,!E.!L.,!Bryan,!C.!J.,!Nakamura,!Y.,!Froeliger,!B.,!&!Howard,!M.!O.!(2017).!Deficits!in!autonomic!indices!of! emotion!regulation!and!reward!processing!associated!with!prescription!opioid!use!and!misuse.! Psychopharmacology!(Berl),!234(4),!6212629.! Garland,!E.!L.,!Froeliger,!B.,!Zeidan,!F.,!Partin,!K.,!&!Howard,!M.!O.!(2013).!The!downward!spiral!of!chronic!pain,! prescription!opioid!misuse,!and!addiction:!cognitive,!affective,!and!neuropsychopharmacologic! pathways.!Neurosci!Biobehav!Rev,!37(10!Pt!2),!259722607.! George,!O.,!&!Koob,!G.!F.!(2017).!Individual!differences!in!the!neuropsychopathology!of!addiction.!Dialogues! Clin!Neurosci,!19(3),!2172229.! Gilman,!J.!M.,!Curran,!M.!T.,!Calderon,!V.,!Schuster,!R.!M.,!&!Evins,!A.!E.!(2016).!Altered!Neural!Processing!to! Social!Exclusion!in!Young!Adult!Marijuana!Users.!Biol!Psychiatry!Cogn!Neurosci!Neuroimaging,!1(2),! 1522159.! Gonzalez2Liencres,!C.,!Shamay2Tsoory,!S.!G.,!&!Brune,!M.!(2013).!Towards!a!neuroscience!of!empathy:! ontogeny,!phylogeny,!brain!mechanisms,!context!and!psychopathology.!Neurosci!Biobehav!Rev,!37(8),! 153721548.! Guttman,!H.,!&!Laporte,!L.!(2002).!Alexithymia,!empathy,!and!psychological!symptoms!in!a!family!context.! Compr!Psychiat,!43(6),!4482455.! Han,!B.,!Compton,!W.!M.,!Blanco,!C.,!Crane,!E.,!Lee,!J.,!&!Jones,!C.!M.!(2017).!Prescription!Opioid!Use,!Misuse,! and!Use!Disorders!in!U.S.!Adults:!2015!National!Survey!on!Drug!Use!and!Health.!Ann!Intern!Med,! 167(5),!2932301.! Handelsman,!L.,!Cochrane,!K.!J.,!Aronson,!M.!J.,!Ness,!R.,!Rubinstein,!K.!J.,!&!Kanof,!P.!D.!(1987).!Two!new!rating! scales!for!opiate!withdrawal.!Am!J!Drug!Alcohol!Abuse,!13(3),!2932308.! Harada,!C.!N.,!Natelson!Love,!M.!C.,!&!Triebel,!K.!L.!(2013).!Normal!cognitive!aging.!Clin!Geriatr!Med,!29(4),!7372 752.! Harrison,!L.!(1997).!The!validity!of!self2reported!drug!use!in!survey!research:!an!overview!and!critique!of! research!methods.!NIDA!Res!Monogr,!167,!17236.! Havassy,!B.!E.,!Hall,!S.!M.,!&!Wasserman,!D.!A.!(1991).!Social!support!and!relapse:!commonalities!among! alcoholics,!opiate!users,!and!cigarette!smokers.!Addict!Behav,!16(5),!2352246.! Heatherton,!T.!F.,!Kozlowski,!L.!T.,!Frecker,!R.!C.,!&!Fagerstrom,!K.!O.!(1991).!The!Fagerstrom!Test!for!Nicotine! Dependence:!a!revision!of!the!Fagerstrom!Tolerance!Questionnaire.!Br!J!Addict,!86(9),!111921127.! Helmstaedter,!C.,!Lendt,!M.,!&!Lux,!S.!(2001).!VLMT.!Verbaler!Lern8!und!Merkfähigkeitstest!(Verbal!learning!and! memory!test).!Göttingen:!Beltz.! Henry,!J.!D.,!Mazur,!M.,!&!Rendell,!P.!G.!(2009).!Social2cognitive!difficulties!in!former!users!of! methamphetamine.!Br!J!Clin!Psychol,!48(Pt!3),!3232327.! Herman,!B.!H.,!&!Panksepp,!J.!(1978).!Effects!of!morphine!and!naloxone!on!separation!distress!and!approach! attachment:!evidence!for!opiate!mediation!of!social!affect.!Pharmacol!Biochem!Behav,!9(2),!2132220.! Hsu,!D.!T.,!Sanford,!B.!J.,!Meyers,!K.!K.,!Love,!T.!M.,!Hazlett,!K.!E.,!Wang,!H.,!.!.!.!Zubieta,!J.!K.!(2013).!Response! of!the!mu2opioid!system!to!social!rejection!and!acceptance.!Mol!Psychiatry,!18(11),!121121217.! Hulka,!L.!M.,!Preller,!K.!H.,!Vonmoos,!M.,!Broicher,!S.!D.,!&!Quednow,!B.!B.!(2013).!Cocaine!users!manifest! impaired!prosodic!and!cross2modal!emotion!processing.!Front!Psychiatry,!4,!98.! Hygge,!S.,!&!Hugdahl,!K.!(1985).!Skin!conductance!recordings!and!the!NaCl!concentration!of!the!electrolyte.! Psychophysiology,!22(3),!3652367.! Hynes,!C.!A.,!Baird,!A.!A.,!&!Grafton,!S.!T.!(2006).!Differential!role!of!the!orbital!frontal!lobe!in!emotional!versus! cognitive!perspective2taking.!Neuropsychologia,!44(3),!3742383.! Inagaki,!T.!K.,!Ray,!L.!A.,!Irwin,!M.!R.,!Way,!B.!M.,!&!Eisenberger,!N.!I.!(2016).!Opioids!and!social!bonding:! naltrexone!reduces!feelings!of!social!connection.!Soc!Cogn!Affect!Neurosci,!11(5),!7282735.! Ingjaldsson,!J.!T.,!Thayer,!J.!F.,!&!Laberg,!J.!C.!(2003).!Craving!for!alcohol!and!pre2attentive!processing!of!alcohol! stimuli.!Int!J!Psychophysiol,!49(1),!29239.!
! 105! 6.!REFERENCES!
Jobst,!A.,!Sabass,!L.,!Palagyi,!A.,!Bauriedl2Schmidt,!C.,!Mauer,!M.!C.,!Sarubin,!N.,!.!.!.!Padberg,!F.!(2015).!Effects! of!social!exclusion!on!emotions!and!oxytocin!and!cortisol!levels!in!patients!with!chronic!depression.!J! Psychiatr!Res,!60,!1702177.! Johnson,!K.!V.,!&!Dunbar,!R.!I.!(2016).!Pain!tolerance!predicts!human!social!network!size.!Sci!Rep,!6,!25267.! Kalivas,!P.!W.!(2009).!The!glutamate!homeostasis!hypothesis!of!addiction.!Nat!Rev!Neurosci,!10(8),!5612572.! Karjalainen,!K.,!Kuussaari,!K.,!Kataja,!K.,!Tigerstedt,!C.,!&!Hakkarainen,!P.!(2017).!Measuring!Concurrent! Polydrug!Use!in!General!Populations:!A!Critical!Assessment.!Eur!Addict!Res,!23(3),!1632169.! Karjalainen,!K.,!Lintonen,!T.,!&!Hakkarainen,!P.!(2017).!Illicit!drug!use!is!increasing!among!non2medical!users!of! prescription!drugs2Results!from!population2based!surveys!200222014.!Drug!Alcohol!Depend,!178,!4302 434.! Kelly,!M.,!McDonald,!S.,!&!Rushby,!J.!(2012).!All!alone!with!sweaty!palms22physiological!arousal!and!ostracism.! Int!J!Psychophysiol,!83(3),!3092314.! Kendall,!S.!E.,!Sjøgren,!P.,!Pimenta,!C.!A.!d.!M.,!Højsted,!J.,!&!Kurita,!G.!P.!(2010).!The!cognitive!effects!of!opioids! in!chronic!non2cancer!pain.!PAIN,!150(2),!2252230.! Kim,!Y.!T.,!Kwon,!D.!H.,!&!Chang,!Y.!(2011).!Impairments!of!facial!emotion!recognition!and!theory!of!mind!in! methamphetamine!abusers.!Psychiatry!Res,!186(1),!80284.! King,!A.!P.,!&!Liberzon,!I.!(2009).!Assessing!the!neuroendocrine!stress!response!in!the!functional!neuroimaging! context.!Neuroimage,!47(3),!111621124.! Kirby,!L.!G.,!Zeeb,!F.!D.,!&!Winstanley,!C.!A.!(2011).!Contributions!of!serotonin!in!addiction!vulnerability.! Neuropharmacology,!61(3),!4212432.! Kirschbaum,!C.,!Kudielka,!B.!M.,!Gaab,!J.,!Schommer,!N.!C.,!&!Hellhammer,!D.!H.!(1999).!Impact!of!gender,! menstrual!cycle!phase,!and!oral!contraceptives!on!the!activity!of!the!hypothalamus2pituitary2adrenal! axis.!Psychosom!Med,!61(2),!1542162.! Kirschbaum,!C.,!Pirke,!K.!M.,!&!Hellhammer,!D.!H.!(1993).!The!'Trier!Social!Stress!Test'22a!tool!for!investigating! psychobiological!stress!responses!in!a!laboratory!setting.!Neuropsychobiology,!28(122),!76281.! Koenig,!J.,!Jarczok,!M.!N.,!Warth,!M.,!Ellis,!R.!J.,!Bach,!C.,!Hillecke,!T.!K.,!&!Thayer,!J.!F.!(2014).!Body!mass!index! is!related!to!autonomic!nervous!system!activity!as!measured!by!heart!rate!variability22a!replication! using!short!term!measurements.!J!Nutr!Health!Aging,!18(3),!3002302.! Koob,!G.!F.,!&!Le!Moal,!M.!(1997).!Drug!abuse:!hedonic!homeostatic!dysregulation.!Science,!278(5335),!52258.! Koob,!G.!F.,!&!Volkow,!N.!D.!(2010).!Neurocircuitry!of!addiction.!Neuropsychopharmacology,!35(1),!2172238.! Kornreich,!C.,!Foisy,!M.!L.,!Philippot,!P.,!Dan,!B.,!Tecco,!J.,!Noel,!X.,!.!.!.!Verbanck,!P.!(2003).!Impaired!emotional! facial!expression!recognition!in!alcoholics,!opiate!dependence!subjects,!methadone!maintained! subjects!and!mixed!alcohol2opiate!antecedents!subjects!compared!with!normal!controls.!Psychiatry! Res,!119(3),!2512260.! Kreek,!M.!J.,!Levran,!O.,!Reed,!B.,!Schlussman,!S.!D.,!Zhou,!Y.,!&!Butelman,!E.!R.!(2012).!Opiate!addiction!and! cocaine!addiction:!underlying!molecular!neurobiology!and!genetics.!J!Clin!Invest,!122(10),!338723393.! Kret,!M.!E.,!&!De!Gelder,!B.!(2012).!A!review!on!sex!differences!in!processing!emotional!signals.! Neuropsychologia,!50(7),!121121221.! Kroll,!S.!L.,!Nikolic,!E.,!Bieri,!F.,!Baumgartner,!M.,!Soyka,!M.,!&!Quednow,!B.!B.!(2018a).!Cognitive!and!socio2 cognitive!functioning!of!chronic!non2medical!prescription!opioid!users.!Psychopharmacology!(Berl),! (under!review).! Kroll,!S.!L.,!Williams,!D.,!Thoma,!M.,!Staib,!M.,!Binz,!T.!M.,!Baumgartner,!M.!R.,!.!.!.!Quednow,!B.!B.!(2018b).! Association!between!non2medical!prescription!opioid!use!and!psychophysiological!stress!response!to! social!rejection.!Psychoneuroendocrinology,!(submitted).! Kroll,!S.!L.,!Wunderli,!M.!D.,!Vonmoos,!M.,!Hulka,!L.!M.,!Preller,!K.!H.,!Bosch,!O.!G.,!.!.!.!Quednow,!B.!B.!(2018c).! Social!functioning!in!stimulant!polysubstance!users.!Drug!Alcohol!Depend,!(accepted).! Kross,!E.,!Berman,!M.!G.,!Mischel,!W.,!Smith,!E.!E.,!&!Wager,!T.!D.!(2011).!Social!rejection!shares!somatosensory! representations!with!physical!pain.!Proc!Natl!Acad!Sci!U!S!A,!108(15),!627026275.! Krygier,!J.!R.,!Heathers,!J.!A.,!Shahrestani,!S.,!Abbott,!M.,!Gross,!J.!J.,!&!Kemp,!A.!H.!(2013).!Mindfulness! meditation,!well2being,!and!heart!rate!variability:!a!preliminary!investigation!into!the!impact!of! intensive!Vipassana!meditation.!Int!J!Psychophysiol,!89(3),!3052313.! Laborde,!S.,!Mosley,!E.,!&!Thayer,!J.!F.!(2017).!Heart!Rate!Variability!and!Cardiac!Vagal!Tone!in! Psychophysiological!Research!2!Recommendations!for!Experiment!Planning,!Data!Analysis,!and!Data! Reporting.!Front!Psychol,!8,!213.! Latkin,!C.!A.,!Edwards,!C.,!Davey2Rothwell,!M.!A.,!&!Tobin,!K.!E.!(2017).!The!relationship!between!social! desirability!bias!and!self2reports!of!health,!substance!use,!and!social!network!factors!among!urban! substance!users!in!Baltimore,!Maryland.!Addict!Behav,!73,!1332136.! Lehrl,!S.!(1999).!Mehrfachwahl8Wortschatz8Intelligenztest!(MWT8B)!(4th!ed.).!Göttingen:!Hogrefe.!
! 106! 6.!REFERENCES!
Lin,!I.!M.,!Ko,!J.!M.,!Fan,!S.!Y.,!&!Yen,!C.!F.!(2016).!Heart!Rate!Variability!and!the!Efficacy!of!Biofeedback!in! Heroin!Users!with!Depressive!Symptoms.!Clin!Psychopharmacol!Neurosci,!14(2),!1682176.! Linden,!M.,!Lischka,!A.2M.,!Popien,!C.,!&!Golombek,!J.!(2007).!Der!multidimensionale!Sozialkontakt!Kreis!(MuSK)! 2!ein!Interviewverfahren!zur!Erfassung!des!sozialen!Netzes!in!der!klinischen!Praxis.![The! Multidimensional!Social!Contact!Circle!(MuSK):!An!interview!for!the!assessment!of!the!social!network! in!clinical!practice].!Z!Med!Psychol,!16(3),!1352143.! Lintonen,!T.,!Ahlstrom,!S.,!&!Metso,!L.!(2004).!The!reliability!of!self2reported!drinking!in!adolescence.!Alcohol! Alcohol,!39(4),!3622368.! Lugoboni,!F.,!Levin,!F.!R.,!Pieri,!M.!C.,!Manfredini,!M.,!Zamboni,!L.,!Somaini,!L.,!.!.!.!Gruppo!InterSert! Collaborazione!Scientifica,!G.!(2017).!Co2occurring!Attention!Deficit!Hyperactivity!Disorder!symptoms! in!adults!affected!by!heroin!dependence:!Patients!characteristics!and!treatment!needs.!Psychiatry!Res,! 250,!2102216.! Lutz,!P.!E.,!&!Kieffer,!B.!L.!(2013).!The!multiple!facets!of!opioid!receptor!function:!implications!for!addiction.! Curr!Opin!Neurobiol,!23(4),!4732479.! Machin,!A.!J.,!&!Dunbar,!R.!I.!M.!(2011).!The!brain!opioid!theory!of!social!attachment:!a!review!of!the!evidence.! Behaviour,!148(9210),!98521025.! Mague,!S.!D.,!&!Blendy,!J.!A.!(2010).!OPRM1!SNP!(A118G):!involvement!in!disease!development,!treatment! response,!and!animal!models.!Drug!Alcohol!Depend,!108(3),!1722182.! Magura,!S.,!&!Kang,!S.!Y.!(1996).!Validity!of!self2reported!drug!use!in!high!risk!populations:!a!meta2analytical! review.!Subst!Use!Misuse,!31(9),!113121153.! Maier,!L.!J.,!Wunderli,!M.!D.,!Vonmoos,!M.,!Rommelt,!A.!T.,!Baumgartner,!M.!R.,!Seifritz,!E.,!.!.!.!Quednow,!B.!B.! (2015).!Pharmacological!Cognitive!Enhancement!in!Healthy!Individuals:!A!Compensation!for!Cognitive! Deficits!or!a!Question!of!Personality?!PLoS!One,!10(6),!e0129805.! Malik,!M.!(1996).!Heart!rate!variability.!Standards!of!measurement,!physiological!interpretation,!and!clinical! use.!Task!Force!of!the!European!Society!of!Cardiology!and!the!North!American!Society!of!Pacing!and! Electrophysiology.!Eur!Heart!J,!17,!3542381.! Martin,!C.!S.!(2008).!Timing!of!alcohol!and!other!drug!use.!Alcohol!Res!Health,!31(2),!96299.! Massey,!S.!H.,!Newmark,!R.!L.,!&!Wakschlag,!L.!S.!(2017).!Explicating!the!role!of!empathic!processes!in! substance!use!disorders:!A!conceptual!framework!and!research!agenda.!Drug!Alcohol!Rev.! Mather,!M.,!&!Thayer,!J.!(2018).!How!heart!rate!variability!affects!emotion!regulation!brain!networks.!Curr!Opin! Behav!Sci,!19,!982104.! Maurage,!F.,!de!Timary,!P.,!Tecco,!J.!M.,!Lechantre,!S.,!&!Samson,!D.!(2015).!Theory!of!mind!difficulties!in! patients!with!alcohol!dependence:!beyond!the!prefrontal!cortex!dysfunction!hypothesis.!Alcohol!Clin! Exp!Res,!39(6),!9802988.! Maurage,!P.,!Grynberg,!D.,!Noel,!X.,!Joassin,!F.,!Hanak,!C.,!Verbanck,!P.,!.!.!.!Philippot,!P.!(2011).!The!"Reading! the!Mind!in!the!Eyes"!test!as!a!new!way!to!explore!complex!emotions!decoding!in!alcohol! dependence.!Psychiatry!Res,!190(223),!3752378.! Maurage,!P.,!Joassin,!F.,!Philippot,!P.,!Heeren,!A.,!Vermeulen,!N.,!Mahau,!P.,!.!.!.!de!Timary,!P.!(2012).!Disrupted! regulation!of!social!exclusion!in!alcohol2dependence:!an!fMRI!study.!Neuropsychopharmacology,! 37(9),!206722075.! Mazza,!M.,!Tempesta,!D.,!Pino,!M.!C.,!Nigri,!A.,!Catalucci,!A.,!Guadagni,!V.,!.!.!.!Ferrara,!M.!(2015).!Neural! activity!related!to!cognitive!and!emotional!empathy!in!post2traumatic!stress!disorder.!Behav!Brain!Res,! 282,!37245.! McCauley,!J.!L.,!Killeen,!T.,!Gros,!D.!F.,!Brady,!K.!T.,!&!Back,!S.!E.!(2012).!Posttraumatic!Stress!Disorder!and!Co2 Occurring!Substance!Use!Disorders:!Advances!in!Assessment!and!Treatment.!Clin!Psychol8Sci!Pr,!19(3),! 2832304.! McDonald,!S.,!Darke,!S.,!Kaye,!S.,!&!Torok,!M.!(2013).!Deficits!in!social!perception!in!opioid!maintenance! patients,!abstinent!opioid!users!and!non2opioid!users.!Addiction,!108(3),!5662574.! Meyerhoff,!D.!J.!(2017).!Structural!Neuroimaging!in!Polysubstance!Users.!Curr!Opin!Behav!Sci,!13,!13218.! Miller,!P.!A.,!Bernzweig,!J.,!Eisenberg,!N.,!&!Fabes,!R.!A.!(1991).!The!development!and!socialization!of!prosocial! behavior.!In!R.!A.!Hinde!&!J.!Groebel!(Eds.),!Cooperation!and!Prosocial!Behaviour.!Cambridge:! Cambridge!University!Press.! Mintzer,!M.!Z.,!&!Johnson,!M.!W.!(2007).!Opioids.!In!A.!Kalechstein!&!W.!G.!van!Gorp!(Eds.),!Neuropsychology! and!Substance!Use.!New!York!and!London:!Taylor!&!Francis.! Mohagheghi,!A.,!Amiri,!S.,!Mousavi!Rizi,!S.,!&!Safikhanlou,!S.!(2015).!Emotional!intelligence!components!in! alcohol!dependent!and!mentally!healthy!individuals.!ScientificWorldJournal,!2015,!841039.! Moles,!A.,!Kieffer,!B.!L.,!&!D'Amato,!F.!R.!(2004).!Deficit!in!attachment!behavior!in!mice!lacking!the!mu2opioid! receptor!gene.!Science,!304(5679),!198321986.!
! 107! 6.!REFERENCES!
Moody,!L.,!Franck,!C.,!Hatz,!L.,!&!Bickel,!W.!K.!(2016).!Impulsivity!and!polysubstance!use:!A!systematic! comparison!of!delay!discounting!in!mono2,!dual2,!and!trisubstance!use.!Exp!Clin!Psychopharmacol,! 24(1),!30237.! Moor,!B.!G.,!Crone,!E.!A.,!&!van!der!Molen,!M.!W.!(2010).!The!Heartbrake!of!Social!Rejection:!Heart!Rate! Deceleration!in!Response!to!Unexpected!Peer!Rejection.!Psychol!Sci,!21(9),!132621333.! Mounteney,!J.,!Giraudon,!I.,!Denissov,!G.,!&!Griffiths,!P.!(2015).!Fentanyls:!Are!we!missing!the!signs?!Highly! potent!and!on!the!rise!in!Europe.!Int!J!Drug!Policy.! Mowbray,!O.!(2014).!The!moderating!role!of!social!networks!in!the!relationship!between!alcohol!consumption! and!treatment!utilization!for!alcohol2related!problems.!J!Subst!Abuse!Treat,!46(5),!5972601.! Musshoff,!F.,!&!Madea,!B.!(2006).!Review!of!biologic!matrices!(urine,!blood,!hair)!as!indicators!of!recent!or! ongoing!cannabis!use.!Ther!Drug!Monit,!28(2),!1552163.! Nielsen,!D.!A.,!&!Kreek,!M.!J.!(2012).!Common!and!specific!liability!to!addiction:!approaches!to!association! studies!of!opioid!addiction.!Drug!Alcohol!Depend,!123!Suppl!1,!S33241.! Novak,!S.!P.,!Hakansson,!A.,!Martinez2Raga,!J.,!Reimer,!J.,!Krotki,!K.,!&!Varughese,!S.!(2016).!Nonmedical!use!of! prescription!drugs!in!the!European!Union.!BMC!Psychiatry,!16,!274.! Nummenmaa,!L.,!Manninen,!S.,!Tuominen,!L.,!Hirvonen,!J.,!Kalliokoski,!K.!K.,!Nuutila,!P.,!.!.!.!Sams,!M.!(2015).! Adult!attachment!style!is!associated!with!cerebral!mu2opioid!receptor!availability!in!humans.!Hum! Brain!Mapp,!36(9),!362123628.! Nummenmaa,!L.,!&!Tuominen,!L.!(2017).!Opioid!system!and!human!emotions.!Br!J!Pharmacol.! Nutt,!D.!J.,!Lingford2Hughes,!A.,!Erritzoe,!D.,!&!Stokes,!P.!R.!(2015).!The!dopamine!theory!of!addiction:!40!years! of!highs!and!lows.!Nat!Rev!Neurosci,!16(5),!3052312.! Ornstein,!T.!J.,!Iddon,!J.!L.,!Baldacchino,!A.!M.,!Sahakian,!B.!J.,!London,!M.,!Everitt,!B.!J.,!&!Robbins,!T.!W.!(2000).! Profiles!of!cognitive!dysfunction!in!chronic!amphetamine!and!heroin!abusers.! Neuropsychopharmacology,!23(2),!1132126.! Painter,!K.!K.!(2006).!Social!skills!groups!for!children!and!adolescents!with!Asperger's!syndrome:!a!step8by8step! program.!London,!UK:!JKP!Resource!Materials.! Panksepp,!J.!(2003).!Neuroscience.!Feeling!the!pain!of!social!loss.!Science,!302(5643),!2372239.! Panksepp,!J.,!Bean,!N.!J.,!Bishop,!P.,!Vilberg,!T.,!&!Sahley,!T.!L.!(1980).!Opioid!blockade!and!social!comfort!in! chicks.!Pharmacol!Biochem!Behav,!13(5),!6732683.! Panksepp,!J.,!Herman,!B.,!Conner,!R.,!Bishop,!P.,!&!Scott,!J.!P.!(1978a).!Biology!of!Social!Attachments!2!Opiates! Alleviate!Separation!Distress.!Biol!Psychiatry,!13(5),!6072618.! Panksepp,!J.,!Herman,!B.!H.,!Vilberg,!T.,!Bishop,!P.,!&!DeEskinazi,!F.!G.!(1980).!Endogenous!opioids!and!social! behavior.!Neurosci!Biobehav!Rev,!4(4),!4732487.! Panksepp,!J.,!Vilberg,!T.,!Bean,!N.!J.,!Coy,!D.!H.,!&!Kastin,!A.!J.!(1978b).!Reduction!of!distress!vocalization!in! chicks!by!opiate2like!peptides.!Brain!Res!Bull,!3(6),!6632667.! Park,!H.,!Oh,!S.,!Noh,!Y.,!Kim,!J.!Y.,!&!Kim,!J.!H.!(2018).!Heart!Rate!Variability!as!a!Marker!of!Distress!and! Recovery:!The!Effect!of!Brief!Supportive!Expressive!Group!Therapy!With!Mindfulness!in!Cancer! Patients.!Integr!Cancer!Ther,!1534735418756192.! Pasternak,!G.!W.,!&!Pan,!Y.!X.!(2013).!Mu!opioids!and!their!receptors:!evolution!of!a!concept.!Pharmacol!Rev,! 65(4),!125721317.! Pennington,!D.!L.,!Durazzo,!T.!C.,!Schmidt,!T.!P.,!Abe,!C.,!Mon,!A.,!&!Meyerhoff,!D.!J.!(2015).!Alcohol!use! disorder!with!and!without!stimulant!use:!brain!morphometry!and!its!associations!with!cigarette! smoking,!cognition,!and!inhibitory!control.!PLoS!One,!10(3),!e0122505.! Pfabigan,!D.!M.,!Seidel,!E.!M.,!Wucherer,!A.!M.,!Keckeis,!K.,!Derntl,!B.,!&!Lamm,!C.!(2015).!Affective!empathy! differs!in!male!violent!offenders!with!high2!and!low2trait!psychopathy.!J!Pers!Disord,!29(1),!42261.! Platt,!B.,!Kamboj,!S.,!Morgan,!C.!J.,!&!Curran,!H.!V.!(2010).!Processing!dynamic!facial!affect!in!frequent! cannabis2users:!evidence!of!deficits!in!the!speed!of!identifying!emotional!expressions.!Drug!Alcohol! Depend,!112(122),!27232.! Preedy,!V.!R.!(2016).!Neuropathology!of!Drug!Addictions!and!Substance!Misuse!Volume!3:!General!Processes! and!Mechanisms,!Prescription!Medications,!Caffeine!and!Areca,!Polydrug!Misuse,!Emerging!Addictions! and!Non8Drug!Addictions:!Elsevier!Science!Publishing!Company!Incorporated.! Preller,!K.!H.,!Hulka,!L.!M.,!Vonmoos,!M.,!Jenni,!D.,!Baumgartner,!M.!R.,!Seifritz,!E.,!.!.!.!Quednow,!B.!B.!(2014).! Impaired!emotional!empathy!and!related!social!network!deficits!in!cocaine!users.!Addict!Biol,!19(3),! 4522466.! Prosser,!J.,!London,!E.!D.,!&!Galynker,!II.!(2009).!Sustained!attention!in!patients!receiving!and!abstinent! following!methadone!maintenance!treatment!for!opiate!dependence:!performance!and!neuroimaging! results.!Drug!Alcohol!Depend,!104(3),!2282240.!
! 108! 6.!REFERENCES!
Pruessner,!J.!C.,!Kirschbaum,!C.,!Meinlschmid,!G.,!&!Hellhammer,!D.!H.!(2003).!Two!formulas!for!computation! of!the!area!under!the!curve!represent!measures!of!total!hormone!concentration!versus!time2 dependent!change.!Psychoneuroendocrinology,!28(7),!9162931.! Quednow,!B.!B.!(2017).!Social!cognition!and!interaction!in!stimulant!use!disorders.!Curr!Opin!Behav!Sci,!13,!552 62.! Quednow,!B.!B.,!Jessen,!F.,!Kuhn,!K.!U.,!Maier,!W.,!Daum,!I.,!&!Wagner,!M.!(2006).!Memory!deficits!in!abstinent! MDMA!(ecstasy)!users:!neuropsychological!evidence!of!frontal!dysfunction.!J!Psychopharmacol,!20(3),! 3732384.! Quednow,!B.!B.,!Kuhn,!K.!U.,!Hoenig,!K.,!Maier,!W.,!&!Wagner,!M.!(2004).!Prepulse!inhibition!and!habituation!of! acoustic!startle!response!in!male!MDMA!('ecstasy')!users,!cannabis!users,!and!healthy!controls.! Neuropsychopharmacology,!29(5),!9822990.! Quello,!S.!B.,!Brady,!K.!T.,!&!Sonne,!S.!C.!(2005).!Mood!disorders!and!substance!use!disorder:!a!complex! comorbidity.!Sci!Pract!Perspect,!3(1),!13221.! Quintana,!D.!S.,!Guastella,!A.!J.,!McGregor,!I.!S.,!Hickie,!I.!B.,!&!Kemp,!A.!H.!(2013).!Heart!rate!variability!predicts! alcohol!craving!in!alcohol!dependent!outpatients:!further!evidence!for!HRV!as!a!psychophysiological! marker!of!self2regulation.!Drug!Alcohol!Depend,!132(122),!3952398.! Rapeli,!P.,!Fabritius,!C.,!Kalska,!H.,!&!Alho,!H.!(2011).!Cognitive!functioning!in!opioid2dependent!patients!treated! with!buprenorphine,!methadone,!and!other!psychoactive!medications:!stability!and!correlates.!BMC! Clin!Pharmacol,!11,!13.! Reay,!J.!L.,!Hamilton,!C.,!Kennedy,!D.!O.,!&!Scholey,!A.!B.!(2006).!MDMA!polydrug!users!show!process2specific! central!executive!impairments!coupled!with!impaired!social!and!emotional!judgement!processes.!J! Psychopharmacol,!20(3),!3852388.! Robinson,!T.!E.,!&!Berridge,!K.!C.!(1993).!The!neural!basis!of!drug!craving:!an!incentive2sensitization!theory!of! addiction.!Brain!Res!Brain!Res!Rev,!18(3),!2472291.! Roser,!P.,!Lissek,!S.,!Tegenthoff,!M.,!Nicolas,!V.,!Juckel,!G.,!&!Brune,!M.!(2012).!Alterations!of!theory!of!mind! network!activation!in!chronic!cannabis!users.!Schizophr!Res,!139(123),!19226.! Rösler,!M.,!Retz,!W.,!Retz2Junginger,!P.,!Thome,!J.,!Supprian,!T.,!Nissen,!T.,!.!.!.!Trott,!G.!E.!(2005).!Instrumente! zur!Diagnostik!der!Aufmerksamkeitsdefizit2/Hyperaktivitätsstörung!(ADHS)!im!Erwachsenenalter.!Der! Nervenarzt,!76(1),!1292130.! Sahley,!T.!L.,!&!Panksepp,!J.!(1987).!Brain!opioids!and!autism:!an!updated!analysis!of!possible!linkages.!J!Autism! Dev!Disord,!17(2),!2012216.! SAMHSA.!(2012).!Clinical!Drug!Testing!in!Primary!Care.!Rockville,!MD:!Substance!Abuse!and!Mental!Health! Services!Administration.! SAMHSA.!(2017).!Key!substance!use!and!mental!health!indicators!in!the!United!States:!Results!from!the!2016! National!Survey!on!Drug!Use!and!Health.!Retrieved!from!Rockville,!MD:! https://www.samhsa.gov/data/! Schaffer,!S.!G.,!Gregory,!A.,!Froming,!K.!B.,!Levy,!C.!M.,!&!Ekman,!P.!(2006)!Emotion!processing:!The! Comprehensive!Affect!Testing!System!User's!Manual.!Sanford,!FL:!Psychology!Software,!Inc.! Schaffer,!S.!G.,!Wisniewski,!A.,!Dahdah,!M.,!&!Froming,!K.!B.!(2009).!The!comprehensive!affect!testing!system2 abbreviated:!effects!of!age!on!performance.!Arch!Clin!Neuropsychol,!24(1),!892104.! Schmidt,!P.,!Haberthur,!A.,!&!Soyka,!M.!(2017a).!Cognitive!Functioning!in!Formerly!Opioid2Dependent!Adults! after!At!Least!1!Year!of!Abstinence:!A!Naturalistic!Study.!Eur!Addict!Res,!23(6),!2692275.! Schmidt,!T.!P.,!Pennington,!D.!L.,!Cardoos,!S.!L.,!Durazzo,!T.!C.,!&!Meyerhoff,!D.!J.!(2017b).!Neurocognition!and! inhibitory!control!in!polysubstance!use!disorders:!Comparison!with!alcohol!use!disorders!and!changes! with!abstinence.!J!Clin!Exp!Neuropsychol,!39(1),!22234.! Schweiger,!D.,!Stemmler,!G.,!Burgdorf,!C.,!&!Wacker,!J.!(2014).!Opioid!receptor!blockade!and!warmth2liking:! effects!on!interpersonal!trust!and!frontal!asymmetry.!Soc!Cogn!Affect!Neurosci,!9(10),!160821615.! Schweizerisches!Toxikologisches!Informationszentrum.!(2003).!Anhang!zum!Jahresbericht!2003.!Retrieved!from! Zürich:!http://toxinfo.ch/files/107/20032Anhang2JB2d22inkl2Tiere.pdf! Schweizerisches!Toxikologisches!Informationszentrum.!(2016).!Anhang!zum!Jahresbericht!2016.!Retrieved!from! Zürich:!http://toxinfo.ch/customer/files/638/20162Anhang2JB.pdf! Singer,!T.,!&!Lamm,!C.!(2009).!The!social!neuroscience!of!empathy.!Ann!N!Y!Acad!Sci,!1156(1),!81296.! Slavich,!G.!M.,!Tartter,!M.!A.,!Brennan,!P.!A.,!&!Hammen,!C.!(2014).!Endogenous!opioid!system!influences! depressive!reactions!to!socially!painful!targeted!rejection!life!events.!Psychoneuroendocrinology,!49,! 1412149.! Smith,!A.!(2006).!Cognitive!empathy!and!emotional!empathy!in!human!behavior!and!evolution.!Psychological! Record,!56(1),!3221.!
! 109! 6.!REFERENCES!
Smith,!A.!(2009).!The!Empathy!Imbalance!Hypothesis!of!Autism:!A!Theoretical!Approach!to!Cognitive!and! Emotional!Empathy!in!Autistic!Development.!Psychological!Record,!59(3),!4892510.! Smith,!E.!J.,!Marcum,!C.!S.,!Boessen,!A.,!Almquist,!Z.!W.,!Hipp,!J.!R.,!Nagle,!N.!N.,!&!Butts,!C.!T.!(2015).!The! relationship!of!age!to!personal!network!size,!relational!multiplexity,!and!proximity!to!alters!in!the! Western!United!States.!J!Gerontol!B!Psychol!Sci!Soc!Sci,!70(1),!91299.! Smyth,!B.!P.,!Barry,!J.,!Keenan,!E.,!&!Ducray,!K.!(2010).!Lapse!and!relapse!following!inpatient!treatment!of! opiate!dependence.!Ir!Med!J,!103(6),!1762179.! Soyka,!M.,!Lieb,!M.,!Kagerer,!S.,!Zingg,!C.,!Koller,!G.,!Lehnert,!P.,!.!.!.!Hennig2Fast,!K.!(2008).!Cognitive! functioning!during!methadone!and!buprenorphine!treatment:!results!of!a!randomized!clinical!trial.!J! Clin!Psychopharmacol,!28(6),!6992703.! Sprouse2Blum,!A.!S.,!Smith,!G.,!Sugai,!D.,!&!Parsa,!F.!D.!(2010).!Understanding!endorphins!and!their!importance! in!pain!management.!Hawaii!Med!J,!69(3),!70271.! Stange,!K.,!Kruger,!M.,!Janke,!E.,!Lichtinghagen,!R.,!Bleich,!S.,!Hillemacher,!T.,!&!Heberlein,!A.!(2017).!Positive! association!of!personal!distress!with!testosterone!in!opiate2addicted!patients.!J!Addict!Dis,!36(3),!1672 174.! Stoeckel,!L.!E.,!Garrison,!K.!A.,!Ghosh,!S.,!Wighton,!P.,!Hanlon,!C.!A.,!Gilman,!J.!M.,!.!.!.!Evins,!A.!E.!(2014).! Optimizing!real!time!fMRI!neurofeedback!for!therapeutic!discovery!and!development.!Neuroimage! Clin,!5,!2452255.! Tarvainen,!M.!P.,!Niskanen,!J.!P.,!Lipponen,!J.!A.,!Ranta2Aho,!P.!O.,!&!Karjalainen,!P.!A.!(2014).!Kubios!HRV22 heart!rate!variability!analysis!software.!Comput!Methods!Programs!Biomed,!113(1),!2102220.! Thayer,!J.!F.,!Ahs,!F.,!Fredrikson,!M.,!Sollers,!J.!J.,!3rd,!&!Wager,!T.!D.!(2012).!A!meta2analysis!of!heart!rate! variability!and!neuroimaging!studies:!implications!for!heart!rate!variability!as!a!marker!of!stress!and! health.!Neurosci!Biobehav!Rev,!36(2),!7472756.! Thayer,!J.!F.,!&!Lane,!R.!D.!(2009).!Claude!Bernard!and!the!heart2brain!connection:!further!elaboration!of!a! model!of!neurovisceral!integration.!Neurosci!Biobehav!Rev,!33(2),!81288.! Tomei,!A.,!Besson,!J.,!Reber,!N.,!Rougemont2Bucking,!A.,!&!Grivel,!J.!(2017).!Personal!distress!and!empathic! concern!in!methadone2maintained!patients.!J!Subst!Use,!22(1),!37241.! Tomek,!S.!E.,!Stegmann,!G.!M.,!&!Olive,!M.!F.!(2018).!Effects!of!heroin!on!rat!prosocial!behavior.!Addict!Biol.! Treede,!R.!D.,!Kenshalo,!D.!R.,!Gracely,!R.!H.,!&!Jones,!A.!K.!(1999).!The!cortical!representation!of!pain.!Pain,! 79(223),!1052111.! Troisi,!A.,!Frazzetto,!G.,!Carola,!V.,!Di!Lorenzo,!G.,!Coviello,!M.,!D'Amato,!F.!R.,!.!.!.!Gross,!C.!(2011).!Social! hedonic!capacity!is!associated!with!the!A118G!polymorphism!of!the!mu2opioid!receptor!gene! (OPRM1)!in!adult!healthy!volunteers!and!psychiatric!patients.!Soc!Neurosci,!6(1),!88297.! Troup,!L.!J.,!Bastidas,!S.,!Nguyen,!M.!T.,!Andrzejewski,!J.!A.,!Bowers,!M.,!&!Nomi,!J.!S.!(2016).!An!Event2Related! Potential!Study!on!the!Effects!of!Cannabis!on!Emotion!Processing.!PLoS!One,!11(2),!e0149764.! Uekermann,!J.,!Channon,!S.,!Winkel,!K.,!Schlebusch,!P.,!&!Daum,!I.!(2007).!Theory!of!mind,!humour!processing! and!executive!functioning!in!alcoholism.!Addiction,!102(2),!2322240.! Uekermann,!J.,!&!Daum,!I.!(2008).!Social!cognition!in!alcoholism:!a!link!to!prefrontal!cortex!dysfunction?! Addiction,!103(5),!7262735.! Uhlmann,!A.,!Ipser,!J.!C.,!Wilson,!D.,!&!Stein,!D.!J.!(2018).!Social!cognition!and!aggression!in!methamphetamine! dependence!with!and!without!a!history!of!psychosis.!Metab!Brain!Dis,!33(2),!5592568.! UNODC.!(2017).!World!Drug!Report!2017.!United!Nations:!United!Nations!publication.! Upadhyay,!J.,!Maleki,!N.,!Potter,!J.,!Elman,!I.,!Rudrauf,!D.,!Knudsen,!J.,!.!.!.!Borsook,!D.!(2010).!Alterations!in! brain!structure!and!functional!connectivity!in!prescription!opioid2dependent!patients.!Brain,!133(Pt!7),! 209822114.! van!der!Veen,!F.!M.,!van!der!Molen,!M.!W.,!Sahibdin,!P.!P.,!&!Franken,!I.!H.!(2014).!The!heart2break!of!social! rejection!versus!the!brain!wave!of!social!acceptance.!Soc!Cogn!Affect!Neurosci,!9(9),!134621351.! van!Holst,!R.!J.,!&!Schilt,!T.!(2011).!Drug2related!decrease!in!neuropsychological!functions!of!abstinent!drug! users.!Curr!Drug!Abuse!Rev,!4(1),!42256.! Verdejo2Garcia,!A.,!Rivas2Perez,!C.,!Vilar2Lopez,!R.,!&!Perez2Garcia,!M.!(2007).!Strategic!self2regulation,! decision2making!and!emotion!processing!in!poly2substance!abusers!in!their!first!year!of!abstinence.! Drug!Alcohol!Depend,!86(223),!1392146.! Volkow,!N.,!&!Li,!T.!K.!(2005).!The!neuroscience!of!addiction.!Nat!Neurosci,!8(11),!142921430.! Volkow,!N.!D.,!Baler,!R.!D.,!&!Goldstein,!R.!Z.!(2011).!Addiction:!pulling!at!the!neural!threads!of!social!behaviors.! Neuron,!69(4),!5992602.! Vonmoos,!M.,!Hulka,!L.!M.,!Preller,!K.!H.,!Jenni,!D.,!Baumgartner,!M.!R.,!Stohler,!R.,!.!.!.!Quednow,!B.!B.!(2013).! Cognitive!dysfunctions!in!recreational!and!dependent!cocaine!users:!role!of!attention2deficit! hyperactivity!disorder,!craving!and!early!age!at!onset.!Br!J!Psychiatry,!203(1),!35243.!
! 110! 6.!REFERENCES!
Vowles,!K.!E.,!McEntee,!M.!L.,!Julnes,!P.!S.,!Frohe,!T.,!Ney,!J.!P.,!&!van!der!Goes,!D.!N.!(2015).!Rates!of!opioid! misuse,!abuse,!and!addiction!in!chronic!pain:!a!systematic!review!and!data!synthesis.!Pain,!156(4),! 5692576.! Vuong,!C.,!Van!Uum,!S.!H.,!O'Dell,!L.!E.,!Lutfy,!K.,!&!Friedman,!T.!C.!(2010).!The!effects!of!opioids!and!opioid! analogs!on!animal!and!human!endocrine!systems.!Endocr!Rev,!31(1),!982132.! Walter,!H.!(2012).!Social!Cognitive!Neuroscience!of!Empathy:!Concepts,!Circuits,!and!Genes.!Emot!Rev,!4(1),!92 17.! Walter,!M.,!Gerber,!H.,!Kuhl,!H.!C.,!Schmid,!O.,!Joechle,!W.,!Lanz,!C.,!.!.!.!Borgwardt,!S.!J.!(2013).!Acute!effects!of! intravenous!heroin!on!the!hypothalamic2pituitary2adrenal!axis!response:!a!controlled!trial.!J!Clin! Psychopharmacol,!33(2),!1932198.! Watson,!D.,!Clark,!L.!A.,!&!Tellegen,!A.!(1988).!Development!and!validation!of!brief!measures!of!positive!and! negative!affect:!the!PANAS!scales.!J!Pers!Soc!Psychol,!54(6),!106321070.! Way,!B.!M.,!Taylor,!S.!E.,!&!Eisenberger,!N.!I.!(2009).!Variation!in!the!mu2opioid!receptor!gene!(OPRM1)!is! associated!with!dispositional!and!neural!sensitivity!to!social!rejection.!Proc!Natl!Acad!Sci!U!S!A,! 106(35),!15079215084.! Wechsler,!D.!(1997).!Wechsler!Memory!Scale!(Third!ed.).!San!Antonio.! Weik,!U.,!Ruhweza,!J.,!&!Deinzer,!R.!(2017).!Reduced!Cortisol!Output!during!Public!Speaking!Stress!in!Ostracized! Women.!Front!Psychol,!8,!60.! WHO.!(2000).!International!guide!for!monitoring!alcohol!consumption!and!related!harm:!Department!of! Mental!Health!and!Substance!Dependence.! Williams,!D.!P.,!Cash,!C.,!Rankin,!C.,!Bernardi,!A.,!Koenig,!J.,!&!Thayer,!J.!F.!(2015).!Resting!heart!rate!variability! predicts!self2reported!difficulties!in!emotion!regulation:!a!focus!on!different!facets!of!emotion! regulation.!Front!Psychol,!6,!261.! Williams,!K.!D.,!&!Jarvis,!B.!(2006).!Cyberball:!a!program!for!use!in!research!on!interpersonal!ostracism!and! acceptance.!Behav!Res!Methods,!38(1),!1742180.! Witt,!J.!A.,!Elger,!C.!E.,!&!Helmstaedter,!C.!(2015).!Adverse!cognitive!effects!of!antiepileptic!pharmacotherapy:! Each!additional!drug!matters.!Eur!Neuropsychopharmacol,!25(11),!195421959.! Wittchen,!H.!U.,!Wunderliche,!U.,!Gruschwitz,!S.,!&!Zaudig,!M.!(1997).!SKID8I.!Strukturiertes!Klinisches!Interview! für!DSM8IV!Achse!I:!Psychische!Störungen!(SCID8I.!Structured!Clinical!Interview!for!DSM8IV!Axes!I:! Mental!Disorders).!Göttingen:!Hogrefe.! Woo,!C.!W.,!Koban,!L.,!Kross,!E.,!Lindquist,!M.!A.,!Banich,!M.!T.,!Ruzic,!L.,!.!.!.!Wager,!T.!D.!(2014).!Separate! neural!representations!for!physical!pain!and!social!rejection.!Nat!Commun,!5,!5380.! Wunderli,!M.!D.,!Vonmoos,!M.,!Furst,!M.,!Schadelin,!K.,!Kraemer,!T.,!Baumgartner,!M.!R.,!.!.!.!Quednow,!B.!B.! (2017a).!Discrete!memory!impairments!in!largely!pure!chronic!users!of!MDMA.!Eur! Neuropsychopharmacol,!27(10),!9872999.! Wunderli,!M.!D.,!Vonmoos,!M.,!Treichler,!L.,!Zeller,!C.,!Dziobek,!I.,!Kraemer,!T.,!.!.!.!Quednow,!B.!B.!(2017b).! Social!cognition!and!interaction!in!chronic!users!of!3,42methylenedioxymethamphetamine!(MDMA,! "Ecstasy").!Int!J!Neuropsychopharmacol.! Younger,!J.!W.,!Chu,!L.!F.,!D'Arcy,!N.!T.,!Trott,!K.!E.,!Jastrzab,!L.!E.,!&!Mackey,!S.!C.!(2011).!Prescription!opioid! analgesics!rapidly!change!the!human!brain.!Pain,!152(8),!180321810.! Zalewska2Kaszubska,!J.,!&!Czarnecka,!E.!(2005).!Deficit!in!beta2endorphin!peptide!and!tendency!to!alcohol! abuse.!Peptides,!26(4),!7012705.! Zhang,!Y.,!Wang,!D.,!Johnson,!A.!D.,!Papp,!A.!C.,!&!Sadee,!W.!(2005).!Allelic!expression!imbalance!of!human!mu! opioid!receptor!(OPRM1)!caused!by!variant!A118G.!J!Biol!Chem,!280(38),!32618232624.! Zubieta,!J.!K.,!Smith,!Y.!R.,!Bueller,!J.!A.,!Xu,!Y.,!Kilbourn,!M.!R.,!Jewett,!D.!M.,!.!.!.!Stohler,!C.!S.!(2001).!Regional! mu!opioid!receptor!regulation!of!sensory!and!affective!dimensions!of!pain.!Science,!293(5528),!3112 315.! Zulauf,!C.!A.,!Sprich,!S.!E.,!Safren,!S.!A.,!&!Wilens,!T.!E.!(2014).!The!complicated!relationship!between!attention! deficit/hyperactivity!disorder!and!substance!use!disorders.!Curr!Psychiatry!Rep,!16(3),!436.! Zwolinski,!J.!(2008).!Biopsychosocial!responses!to!social!rejection!in!targets!of!relational!aggression.!Biol! Psychol,!79(2),!2602267.! Zwolinski,!J.!(2012).!Psychological!and!neuroendocrine!reactivity!to!ostracism.!Aggress!Behav,!38(2),!1082125.!
! 111! 7.!CURRICULUM!VITAE!
7.! CURRICULUM!VITAE! ! Sara!Liane!Kroll!
Date!of!birth:!! March!23rd!1985! Place!of!birth:!! Berlin,!Germany! Nationality:!! Finnish! Contact:! Drahtzugstrasse!8,!8008!Zurich,!Switzerland! E2Mail:!! [email protected]! ! ! Education!
09/2014!–!06/2018!! University!of!Zurich,!University!Hospital!for!Psychiatry!Zurich!(CH)! !!!! Experimental!and!Clinical!Pharmacopsychology! !!!! Doctoral!Student! ! 03/2007!–!06/2014!! University!of!Vienna!(AUT)! !!!! Social,!Cognitive!and!Affective!Neuroscience!Unit!(SCAN2Unit)! !!!! Diploma!of!Biological!Psychology!(MSc/!Mag.!rer.!nat.)! ! 08/1997!–!06/2004!! High!School:!Schadow!Gymnasium!Berlin!(D)! !!!! High!School!Degree!(Abitur)!
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