ORIGINAL INVESTIGATION

Drug-related cues exacerbate decision making and increasecraving in heroin addicts at different abstinence times

Gui-Bin Wang & Xiao-Li Zhang & Li-Yan Zhao &

Li-Li Sun & Ping Wu & Lin Lu & Jie Shi

Received: 29 September 2011 /Accepted: 9 December 2011 /Published online: 30 December 2011# Springer-Verlag 2011

AbstractRationale Relapse is a persistent problem in the managementof addiction. Drug-related cues are powerful instigators ofrelapse. Impulsive decision making may contribute to relapsethrough a poorly considered assessment of the consequencesof drug use. Drug cues robustly increase subjective craving,which is frequently associated with relapse.Objective The present study explored the effects of drug-related cues on decision making and craving in heroin addictsat different abstinence times: 1, 3, 12, and 24 months.Methods The 75 male participants were given 5 min expo-sure to neutral and drug-associated cues while decisionmaking performance, craving, blood pressure, heart rate,and emotional state pre- and post-exposure were assessed.The Iowa Gambling Task was used to evaluate decisionmaking ability in heroin addicts.Results Drug-related cues exacerbated impulsive decisionmaking and increased craving, heart rate, and systolic pressurein heroin addicts at all abstinence times.Conclusions Drug-related cues aggravated decision makingand increased craving in former heroin addicts who hadbeen drug-free for 1–24 months, which might have significantclinical implications for the prevention of relapse.

Keywords Drug-related cues . Decision making . Craving .

Heroin addicts . Different abstinence times

Introduction

Relapse is a critical challenge in the treatment of drugaddiction (Stewart 2008; Witkiewitz and Marlatt 2007).Exposure to drug-related cues is a common relapse trigger(Kosten et al. 2006; Sinha and Li 2007). Neuroimagingstudies suggest that cognitive processes, such as impulsivity,mediate the triggering effects of cues (Li et al. 2008; Sripadaet al. 2010; Volkow et al. 2007). Impulsivity, which refers toa category of behaviors that encompass deficits in the abilityto delay immediate gratification for future larger rewardsand response inhibition, is a complex, multifaceted con-struct in terms of component processes and neural substrates(Crews and Boettiger 2009; Evenden 1999). Behavioraltasks, such as decision making, response inhibition, andreflective impulsivity, can be used to measure impulsivity,and drug abusers performed poorly on these tasks (Clark etal. 2006; Yucel et al. 2007). The Iowa Gambling Task (IGT)(Bechara et al. 1994) was specifically developed to assessand quantify decision making ability by simulating real-lifedecisions under ambiguous conditions (Brand et al. 2007).However, the effects of drug-related cues on decisionmaking in heroin addicts at different abstinence timeshave received little attention.

Drug-related cues robustly increase subjective cravingand, to a lesser extent, physiological indices (Bedi et al.2011; Carter and Tiffany 1999; Shi et al. 2009). Craving is apredictor of relapse and treatment outcome (Gordon et al.2006; Marissen et al. 2007; Paliwal et al. 2008; Rohsenow etal. 2007; Rohsenow et al. 1994). How cue-induced cravingchanges with abstinence in heroin addicts has not beeninvestigated.

We recently found a difference in decision making defi-cits between short-term (3 to 30 days), long-term (3 months

Gui-Bin Wang and Xiao-Li Zhang contributed equally to this work.

G.-B. Wang :X.-L. Zhang : L.-Y. Zhao : L.-L. Sun : P. Wu :L. Lu : J. Shi (*)National Institute on Drug Dependence, Peking University,Beijing 100191, Chinae-mail: shijie@bjmu.edu.cn

Psychopharmacology (2012) 221:701–708DOI 10.1007/s00213-011-2617-5

to 1 year), and protracted (2 years) abstinence, and psy-chosocial stress-impaired decision making in all groupsof former heroin addicts (Zhang et al. 2011). The present studyinvestigated the effects of drug-related cues on the impairmentof decision making performance in heroin addicts at differentabstinence times (1, 3, 12, and 24 months). The time course ofcue-induced psychological craving and physiological indiceswere also measured.

Materials and methods

Subjects

A total of 75 male participants, aged 20 to 45 years, wererecruited from the Addiction Treatment and RehabilitationCenter, Guangdong Province, China, in which the patientshad no chance to find and use any illicit drug. The addictswere sent to the center on the last-use-heroin day andprovided urine sample for kind of drugs abused verifi-cation before admitting. The subjects were abstinentfrom heroin for 1 month (n018), 3 months (n018),12 months (n020), and 24 months (n019). Prior toenrollment, all of the subjects were screened using theStructured Clinical Interview for the Diagnostic andStatistical Manual of Mental Disorders, 4th edition(DSM-IV). All of the subjects had a history of DSM-IV diagnosis of opiate dependence and did not have anycurrent medical illness that required pharmacologicaltreatment or any other substance use disorder with theexception of nicotine dependence. Other exclusion cri-teria included a history of head injury, a severe mentalillness, psychosis, and neurological disorders. The studywas approved by the Peking University Research EthicsBoard. The study’s procedures and risks were discussedthoroughly with each participant, and all participantsprovided written informed consent and received mone-tary compensation for participating in the study.

Questionnaires and neuropsychological measures

Barratt Impulsiveness Scale The subjects were adminis-tered the Chinese version of the Barratt ImpulsivenessScale, 11th edition (BIS-11), a validated 30-item question-naire that conceptualizes impulsiveness in three maindimensions (Patton et al. 1995). The BIS-11 contains threesubscales: attention impulsiveness, motor impulsiveness,and non-planning impulsiveness. The Chinese version ofthe BIS-11 was shown to have good internal consistencyand test–retest reliability by Medical Psychological Re-search Centre of the Second Xiangya Hospital, China(Zhang et al. 2011)

Working memory (digit-span test) Working memory wasassessed using the digit-span test (Wechsler 1987), whichhas two sections: forward (simple attention) and back-ward (concentration, complex attention). The partici-pants repeated digits told to them by a rater. On theforward subtest, the participants simply repeated thestrings until they failed to correctly repeat an entire trial(composed of two strings of identical length). On thebackward subtest, the participants were required to repeat thedigit string in the reverse order until they failed bothstrings in a trial. The score is expressed as the numberof digits achieved forward and backward.

d2 Test of attention/psychomotor speed From a series of “d”and “p” letters with one or two dashes above and/or beloweach letter, the participants were asked to mark the “d”accompanied with two dashes as quickly and accurately aspossible. A summary test score represented the total numberof correctly marked “d” letters minus the number of errors(Zhang et al. 2011).

Iowa Gambling Task We used the original card version ofthe IGT to evaluate decision making performance. The taskwas administered according to the procedure described inprevious studies (Bechara et al. 1994, 2000b). In the task,the participants were presented with four different decks ofcards and asked to select one card at a time, with thegoal of maximizing their “jackpot” over 100 cardchoices. Unbeknownst to the subjects, two of the fourdecks were “advantageous”; gains from these deckswere relatively modest, but losses were also modest sothat consistently choosing these decks would result inan overall gain in the jackpot. The other two deckswere “disadvantageous”; gains from these decks werehigh, but the losses were even higher so that consistent-ly choosing these decks would result in an overall lossfrom the jackpot. The outcome measure for this task was theIGT Net Score (total number of selections from “advanta-geous” decks minus “disadvantageous” decks, [C + D] −[A + B]). Healthy individuals gradually switch their prefer-ence toward the advantageous decks (C and D) and away fromthe disadvantageous decks (A and B).

Emotional State Ratings We used an abbreviated version ofthe Differential Emotion Scale (DES) to assess specificnegative, positive, and neutral emotional states at varioustime points. The standard DES instructions were used, ask-ing the subjects to rate on a single 5-point Likert scale theextent to which 25 emotional words described the wayhe presently felt. The ratings were attributed to each ofthe fear, anger, joy, sadness, and neutral/relaxed statesand summed to generate the scores for each emotional state(Sinha et al. 1999).

702 Psychopharmacology (2012) 221:701–708

Visual Analog Scale Craving was also assessed by a 10-pointvisual analog scale (VAS), in which participants marked 1 (“notat all”) to 10 (“extremely high”) in response to the question,“How much do you feel the urge to use heroin?” Cravingratings were obtained at baseline and immediately after expo-sure to the neutral or heroin videotape (Sinha et al. 1999).

Cardiovascular measures

Systolic and diastolic blood pressure was measured with anarm cuff connected to a 9062D monitor (Baozhong Biotech-nology Company, Beijing, China). Heart rate was measuredcontinuously with a fingertip pulse sensor connected to anSD-700 monitor (Shi et al. 2009).

Procedures

Upon arrival, the experimental procedure was explained tothe participants. Following a 15-min adaptation time, eachsubject completed the following questionnaires: HamiltonAnxiety Scale (HAM-A; which had 14 items rated on a 5-

point scale), Beck Depression Inventory (BDI; which wasused to assess the severity of depression), the BIS-11, andneuropsychological tests (working memory and d2 test ofattention). As Table 1 shows, the subjects were presentedwith a heroin-related video or neutral video in random order,and IGT was administered at pre- and post-heroin cueand pre- and post-neutral cue time points. The measurementscollected before and after the cues included heart rate, bloodpressure, and emotional ratings. There are about 20min of freetime between two cue sessions. The participants were allowedto leave the laboratory when their systolic blood pressure andheart rate returned to baseline levels.

Data analysis

All of the data were analyzed with SPSS version 13.0(Chicago, IL, USA). One-way analyses of variance(ANOVA) were used for between-group comparisons ofdemographic characteristics (age, years of education, dura-tion of heroin use, typical dose), neuropsychological task

Table 1 Schedule for laboratory session

Time Event/activity

−0:45 min Participant arrival, written informed consent given

−0:30 min Demographic characteristic collection, measures of HAMA, BDI, BIS, working memory, and attention

Cue session 1

0:00 min Baseline period, online measurement of heart rate, blood pressure, emotion ratings, IGT, and craving

0:10 min Cue 1 presentation

0:15 min Online measurement of heart rate, blood pressure, emotion ratings, IGT, and craving

0:25 min 20-min free time

Cue session 2

0:45 min Online measurement of heart rate, blood pressure, emotion ratings, IGT, and craving

0:55 min Cue 2 presentation

0:60 min Online measurement of heart rate, blood pressure, emotion ratings, IGT, and craving

Table 2 Demographic and clinical characteristics of the participants

Characteristics 1 month (n018) 3 months (n018) 12 months (n020) 24 months (n019) p value

Age (years) 31.17±6.62 31.94±4.90 32.90±5.32 33.89±4.74 0.46

Education (years) 7.56±2.18 7.33±2.28 7.30±2.54 7.68±2.16 0.95

Time of heroin use (years) 8.18±3.39 8.21±3.62 8.45±3.85 9.00±4.66 0.92

Average dose 0.90±0.54 1.01±0.58 0.88±0.51 0.74±0.40 0.44

HAMA score 4.28±1.74 3.44±1.54 5.45±3.41 5.42±3.36 0.07

BDI-11 score 15.78±6.03 9.33±5.04 10.88±8.08 9.18±4.04 0.002

Working memory

Forward condition 7.11±0.90 7.06±0.73 7.00±1.12 7.16±1.26 0.97

Backward condition 4.50±0.71 4.39±0.01 4.80±1.11 4.58±0.84 0.49

D2 test of attention 163.56±47.32 164.00±24.62 168.40±32.40 175.58±38.03 0.72

Psychopharmacology (2012) 221:701–708 703

performance (working memory and d2 test of attention),psychiatric symptoms, including anxiety, depression, andimpulsivity, IGT baseline and final scores, and physiologicalmeasures. The reactivity to heroin-related cues vs. neu-tral cues was analyzed with two-way ANOVA, with thebetween-subjects factor group (1, 3, 12, and 24 months)and within-subjects factor cue (cue, neutral). Paired t test wasused to compare within-session change scores (post-cueminus pre-cue), including IGT score, craving score, andphysiological measures, for heroin cues vs. neutral cues.

Results

Demographics

The demographic and clinical characteristics of the partic-ipants are shown in Table 2. Of the 75 participants enrolledin the study, no significant differences were found in age,education, heroin use, HAMA score, working memory (bothforward and backward conditions), and d2 test of attentionin the groups with different abstinence times. However, the1-month group had higher BDI scores than the other threegroups (F3,7105.484, p00.002).

Self-reported impulsivity on the BIS-11 in heroin addicts

Table 3 shows self-reported impulsivity on the BIS-11 in thefour groups of heroin addicts. No significant differenceswere found among the four groups in attention impulsivity,motor impulsivity, non-planning impulsivity, and BIS-11total scores.

Effects of heroin-related cues on the IGT and cravingin heroin addicts at different abstinence times

The participants’ IGT scores before cue presentations in-creased with abstinence (F3,71010.635, p<0.001) and the1-month group had the lowest IGT performance (Fig. 1a).The ratings of craving decreased with abstinence (F3,710

4.011, p<0.05), and the 1- and 3 month groups reportedhigher craving (Fig. 1b). IGT performance was poorer afterheroin cue exposure in all of the groups (F1,142027.021, p<

0.001; 1-month group—t1702.785, p00.013; 3-monthgroup—t1703.484, p00.003; 12-month group—t1903.984,p00.062; 24-month group—t1802.692, p00.015), but nodifferences were found between the four groups (Fig. 2a).Cue exposure induced craving in all four groups (F1,1420

55.653, p<0.001; 1-month group—t170−3.296, p00.004;3-month group—t170−2.741, p00.014; 12-month group—t190−4.566, p<0.001; 24-month group—t180−3.699, p00.002), and the groups did not differ in cue-induced craving(Fig. 2b). The IGT score at the end of heroin cue in the fourgroups increased with abstinence (F3,7105.271, p00.002),and the 1-month group performed the worst on the IGT

Table 3 Self-reported impulsiv-ity on the BIS-11 in heroinaddicts at differentabstinence times

Scale/subscale 1 month (n018) 3 months (n018) 12 months (n020) 24 months(n019)

p value

BIS-Attention 19.11±3.74 18.78±3.33 17.77±2.75 17.82±2.24 0.52

BIS-Motor 27.06±4.70 25.56±3.42 25.90±5.13 23.90±3.94 0.15

BIS-Non-planning 29.39±5.19 29.00±3.63 27.60±6.51 27.41±4.00 0.65

BIS-Total 75.56±11.40 73.33±7.83 71.53±9.23 70.18±6.27 0.31

a IGT score (C+D)-(A+B)%

10 ***#

10

5 **5 **

0

1 3 12 24 -5

Cu

e S

essi

on

Bas

elin

eC

ue

Ses

sio

n B

asel

ine

Abstinence Months

Abstinence Months

b Craving

3

2 * *

1

01 3 12 24

0

Fig. 1 Effects of length of abstinence on baseline IGT performanceand heroin craving. a IGT score baseline. b Craving score baseline.*p<0.05, **p<0.01, ***p<0.001, compared with 1-month group; #p<0.05, ##p<0.01, compared with 3-month group;%p<0.05, comparedwith 12-month group. Error bars show standard error of the mean

704 Psychopharmacology (2012) 221:701–708

(Fig. 3a). No significant differences were found in thecraving scores after drug cue exposure at different absti-nence times (F3,7100.891, p00.45; Fig. 3b).

Effects of heroin-related cues on heart rate and bloodpressure in addicts at four different abstinence times

Heart rate and systolic blood pressure significantly in-creased after viewing the heroin-related video in all of thegroups (heart rate—F1,1420214.909, p<0.001; systolicblood pressure—F1,142065.600, p<0.001; Fig. 4a, b), butdiastolic blood pressure did not change (F1,14203.262, p00.073; Fig. 4c).

Effects of heroin-related cues on emotional statein heroin addicts at different abstinence times

Heroin-related cues led to significant decreases in joyand relaxed states in all four groups (all p<0.05) butdid not affect fear, anger, sadness, and neutral states(Table 4).

Discussion

The present study showed that drug-related cues exacerbatedthe decision-making deficiency in heroin addicts at abstinencetimes from 1 m to 24 m, concomitant with increased craving,heart rate, systolic blood pressure, and decreased positiveemotions.

Participants’ IGT scores increased before cue presenta-tions with abstinence. Decision making is thought to involveareas of the brain involved in emotion (e.g., amygdala,ventromedial prefrontal cortex [vmPFC]), and memory(e.g., hippocampus, dorsolateral prefrontal cortex [dlPFC]);(Cho et al. 2010; Gupta et al. 2010). Neuroimaging studiesshowed that dysfunction of the prefrontal neural networkmay underlie the poor decisions characteristic of addicts(Bolla et al. 2003, 2005; Liu et al. 2009; Tanabe et al.2007), and the present study suggested that functional re-covery of the PFC occurs with abstinence in heroin addicts.The heroin-related cues unmasked the latent impairment ofdecision making in long-term abstinent addicts (3, 12, and24 months), which may play an important role in the vul-nerability to relapse. The former addicts who were abstinentfor 1 and 3 months made more disadvantageous choices on

IGTa

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essi

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nd

-10

Craving

6

b6

44

2

0

1 3 1 21 3 12 24

1 3 1 21 3 12 240

Abstinence Months

Abstinence Months

Fig. 3 IGT performance and craving after exposure to heroin-relatedcues in addicts. a IGT score at end of cue session. b Craving score atend of cue session. *p<0.05, compared with 1-month group; #p<0.05,compared with 3-month group. Error bars show standard error ofthe mean

IGTscore((C+D)-(A+B))a 5 Neutral Cue5

Heroin Cue

00

-5

-10 1 3 12 24

Ch

ang

e P

re-P

ost

Cu

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han

ge

Pre

-Po

st C

ue

Abstinence Months

Cravingb3

2

11

0

1 3 12 24-1 1 3 12 24

Abstinence Months

Fig. 2 Effects of exposure to heroin-related cues and neutral cues onIGT performance and craving in heroin addicts at different abstinencetimes. a Change Pre-Post IGT score. b Change Pre-Post craving score.Error bars show standard error of the mean

Psychopharmacology (2012) 221:701–708 705

the IGT than the addicts who were drug-free for 24 months.Impulsive decision making was shown to predispose indi-viduals to a high-risk of relapse (Bowden-Jones et al. 2006;Perry and Carroll 2008), suggesting that the addicts whowere abstinent for a shorter period of time were at a greaterrisk for relapse.

Drug-related cues induced craving even when the addictswere abstinent for 24 months, highlighting the sensitivity ofaddicts relapse to drug use. Previous studies found thatlimbic and frontal region activation was associated withcue-induced craving (Childress et al. 1999; Volkow et al. T

able4

Emotionalstateratin

gsin

heroin

addictsatdifferentabstinence

times.(pre-con,

pre-neutralcueexpo

sure;po

st-con

,post-neutralcueexpo

sure;pre-cue,pre-heroin

cueexpo

sure;po

st-cue,

post-heroincueexpo

sure)*p

<0.05

,comparedwith

Pre-cue

1mon

th(n018

)3mon

ths(n018

)

Pre-con

Post-con

Pre-cue

Post-cue

Pre-con

Post-con

Pre-cue

Post-cue

Fear

7.27

±2.55

7.67

±2.28

7.68

±2.39

6.75

±3.33

7.01

±2.37

6.60

±2.54

7.74

±2.45

7.09

±4.20

Ang

er7.52

±3.43

7.23

±3.68

7.41

±3.23

8.84

±3.83

7.41

±3.50

7.43

±2.54

7.84

±3.60

7.78

±3.53

Joy

9.11

±4.54

9.59

±3.13

9.21

±2.70

8.24

±2.65

*8.26

±4.21

8.45

±4.57

8.91

±4.37

7.99

±5.22

*

Sadness

8.47

±2.84

8.50

±2.64

7.88

±3.25

7.58

±3.38

8.87

±4.14

8.91

±3.96

9.48

±4.19

9.48

±4.74

Neutral

10.50±3.99

10.67±3.45

10.67±4.13

10.39±4.68

11.09±4.13

10.30±3.64

8.91

±3.32

9.13

±3.66

Relaxed

10.83±4.25

11.89±5.01

11.16±5.12

10.46±4.67

*11.52±4.02

12.16±4.00

13.13±3.83

11.52±3.76

*

12mon

ths(n020

)24

mon

ths(n019

)

Pre-con

Post-con

Pre-cue

Post-cue

Pre-con

Post-con

Pre-cue

Post-cue

Fear

7.37

±3.55

6.67

±2.28

6.78

±2.29

7.50

±2.45

6.51

±1.37

7.00

±2.54

5.74

±2.45

7.09

±4.20

Ang

er7.72

±3.43

7.33

±3.68

7.11

±3.03

6.83

±2.81

7.61

±3.50

7.83

±3.54

7.48

±3.00

7.78

±3.53

Joy

10.11±5.54

9.39

±4.13

9.44

±3.65

8.91

±4.70

*9.28

±4.25

9.55

±4.27

9.91

±3.37

8.09

±3.22

*

Sadness

8.17

±3.84

7.50

±2.62

7.44

±3.05

7.28

±3.49

8.87

±4.14

8.91

±3.96

8.48

±4.19

8.48

±4.74

Neutral

9.50

±3.99

9.67

±3.45

9.67

±4.13

9.39

±3.68

10.09±4.13

10.30±3.64

9.91

±3.32

10.13±3.66

Relaxed

11.38±4.35

12.99±5.21

12.61±5.12

10.06±4.76

*12

.52±4.02

14.61±4.00

15.13±3.83

11.52±3.76

*

HRa

Neutral Cue

Heroin Cue

5

10

00

-5 1 3 12 24

1 3 12 24

Ch

ang

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Cu

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han

ge

Pre

-Po

st C

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(m

mH

g)

Ch

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Cu

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mm

Hg

)

Abstinence Months

SPb

15

10

5

0

-5

-5

-10

Abstinence Months

Abstinence Months

DP

15

c

10

5

0

5

0

1 3 12 241 3 12 24

Fig. 4 Effects of exposure to heroin-related cues and neutral cues onheart rate, systolic blood pressure, and diastolic blood pressure inheroin addicts at different abstinence times. a Heart rate. b Systolicblood pressure. c Diastolic blood pressure. Error bars show standarderror of the mean

706 Psychopharmacology (2012) 221:701–708

2010; Wang et al. 1999), and increased striatal dopaminewas involved in cue-induced craving (Volkow et al. 2006).The present results suggested the latent impairment of theaforementioned brain regions over an extended abstinenceperiod in addicts, and manipulating the activity of theseregions may have therapeutic effects.

The participants in the four groups showed no differencesin working memory or attention, suggesting that decisionmaking may be independent of cognitive intelligence andattention impairment. The depression rating in the 1-monthgroup was higher than the other three groups, suggestingmore serious depression in short-term abstinent addicts.Emotional ratings during cue exposure indicated that thesubjects responded to heroin-related cues. The changes inemotional state also indicated that the cues inhibited positiveaffect, which may be the basis for increased ratings of heroincraving. The affective consequences of depression and lowpositive affect may cause abstinent addicts to face significantobstacles in their attempt to remain drug-free (Reitzel et al.2010). Therefore, incorporating interventions designed todecrease depression and increase positive affect duringabstinence may be beneficial to addiction treatment.

The present study has some limitations that should beconsidered. First, repeated administration of the IGT couldlead to practice effects. However, no such effects were seenin patients with vmPFC lesions (Bechara et al. 2000a) whowere behaviorally similar to individuals with substance-usedisorders in some respects, such as choosing immediaterewards and ignoring future consequences (Bechara 2005).Practice effects in our study were mitigated by the crossoverdesign. Second, we used a separate group to represent eachabstinence time period rather than an ideal within-subjectsdesign in which decision making performance is assessedlongitudinally in one group of former addicts. Therefore, wecannot exclude the possibility that decision making amonggroups are born different. Third, we did not evaluate theeffects of heroin-related cues on decision making in healthyindividuals. Therefore, we cannot conclude that the deleteriouseffects on the IGT were specific to addicts. Fourth, only menwere enrolled in the present study, and possible sex differencesneed to be examined in future studies.

Cue exposure is among the major determinants ofrelapse in abstinent heroin addicts. The present studydemonstrated deleterious effects of drug-related cues ondecision making and craving in both short-term andlong-term abstinent addicts and suggests that a high riskof relapse precipitated by cues may persist for at least24 months after abstinence.

Acknowledgments This work was supported in part by the NationalBasic Research Program of China (no. 2009CB522000), Natural ScienceFoundation of Beijing Municipality (no. 7092058), and Natural ScienceFoundation of China (no. 81000571 and 91132719).

Conflict of interest The authors declare that they do not have anyconflicts of interest (financial or otherwise) related to the datapresented in this manuscript.

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