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Original Articles

Cognitive Functions and Impact of Plasma BDNF in Chronic Heroin Users

Soliman, Alaa MD, PhD; Zaki, Nivert MD, PhD; El-Ghonemy, Soheir H. MD, PhD; El Ghamry, Reem MD, PhD; Shorub, Eman MD, PhD; Farag, Mahmoud MD, PhD

Author Information
Addictive Disorders & Their Treatment: June 2021 - Volume 20 - Issue 2 - p 98-108
doi: 10.1097/ADT.0000000000000218
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Abstract

Addiction to drugs is characterized as a compulsive behavior, including drug seeking, drug use, and drug cravings, but it is also considered as a disorder of altered cognition.1 Studies have indicated that abusing drugs may alter the normal structure in brain regions and influence functions that induce cognitive shifts and promote continued drug use. Continued drug use causes cognitive deficits that aggravate the difficulty of establishing sustained abstinence.1,2 Opioid dependence is a chronic complex disorder and a severe public health problem caused by a combination of environmental, biological, and genetic factors.3,4 Opioids produce selective adaptations in very specific brain regions, and, consequently, this leads to cognitive dysfunctions related to problem solving, impulse control, purposeful behavior, collection maintenance, using flexible procedures, selective attention, attentive control, initiation and self-assessment, using feedback to adjust responses, vigilance and controlling irrelevant information to the task at hand, working memory, emotional control, and behavior inhibition.5,6 Recent evidence suggests that long-term opioid use causes cognitive deficits and might intensify dependence and contribute to relapses. These effects will aggravate the burden of rehabilitation in heroin-dependent patients and reduce their prognosis to a great degree.7,8 However, the pathophysiological mechanisms underlying these cognitive deficits associated with long-term heroin use are still not well-understood. Therefore, investigating neurobiological changes in heroin-dependent individuals has great potential to improve the understanding of the disease and help to improve their overall outcome.6,9

Experimental and clinical data suggest that brain-derived neurotrophic factor (BDNF) plays an important role in the pathogenesis of many psychiatric disorders that are characterized by declined cognitive functions.10 Reduced BDNF levels may play a role in the pathophysiology of cognitive impairment in chronic heroin users.11 The aim of the current study was to assess the cognitive dysfunction in patients with chronic heroin use and to explore any relation to BDNF plasma level. In addition, a trial was carried out to examine the correlation of cognitive dysfunction and severity of heroin use.

SUBJECTS AND METHODS

Study Design

A case-control naturalistic cross-sectional study was performed in the inpatient unit and outpatient clinics of Institute of Psychiatry, Ain Shams University, located in Cairo, Egypt.

Subjects

All opioid-dependent patients diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV)12 visiting the outpatient clinics for follow-up or who were admitted to the inpatient unit in the Institute of Psychiatry, Faculty of Medicine, Ain Shams University Hospitals, fulfilling inclusion and exclusion criteria were registered for further assessment to be recruited in the study later after the detoxification period. Accordingly, the study was conducted during the period spanning from March 1, 2014 to March 31, 2016, taking almost 24 months.

A total of 50 male patients with chronic heroin dependence were selected (case group) and were compared with the control group consisting of frequency-matched 38 healthy volunteers with no past or current history of any substance dependence (confirmed by toxicological screen) or psychiatric disorders. Control cases were selected from employees in Institute of Psychiatry, Ain Shams University Hospitals, and relatives or friends of attendings in the hospital waiting area, frequency matched with the patients’ group.

Male patients were selected, aged between 18 and 55 years, with heroin use as a main substance of use for at least 1 year before enrollment in the study with the condition that their use of other substances did not fulfill the criteria of dependence. Patients should have received at least technical school education to assure average level of intelligence. However, those patients who were illiterate or those with any comorbid psychiatric, neurological, or medical disorders were excluded. We also excluded those who refused to participate or withdraw during the interview.

Ethical Consideration

Ethical approval for the study was granted from Ethics Research Committee of Faculty of Medicine, Ain Shams University. An informed consent was taken from all patients after being informed in detail about the study and about what they were asked to do. Patients were ensured about the confidentiality of information and that the participation in the study was completely voluntary and that they had the freedom to withdraw from the assessment at anytime.

Procedures

The subjects were assessed clinically, including psychiatric history and mental status examination for registration, and they completed the following:

  • For confirming diagnosis of opioid dependence Structured Clinical Interview for DSM-IV (SCID-I)12—Arabic form13 was used.
  • Assessment of case group to determine severity of their drug dependence using Addiction Severity Index (ASI)14—Arabic form15 was applied.
  • Cognitive function assessment:
  • Wechsler Adults Intelligence Scale (WAIS)16 was used to measure intellectual performance. Its verbal scales measure general knowledge, language, reasoning, and memory skills, while its performance scales measure spatial, sequencing, and problem-solving skills.
  • Wechsler Memory Scale (WMS)17 was applied to measure different memory functions and its 5 Index scores (auditory memory, visual memory, visual working memory, immediate memory, and delayed memory) were estimated.
  • Wisconsin Card Sorting Test (WCST)—computerized version18 has been considered a measure of executive function.

Measuring plasma BDNF level via enzyme-linked immunosorbent assay kit.19

Statistical Analysis

Data collected were reviewed, coded, and analyzed using SPSS (Statistical Package for Social Sciences), version 17 (SPSS Inc., Chicago, IL).20 Numerical data were presented as mean and SD values. Categorical data were presented as frequencies and percentages. Comparison between groups was carried out using χ2 test, and the Student t test was used to assess the statistical significance of the difference between 2 study group means; P-value is presented, and the threshold of significance is fixed at the 5% level.

RESULTS

The demographic characteristics of the study sample are summarized in Table 1. On assessment of drug severity profile using ASI among case group, 33 (66%) were severe, while 17 (34%) were moderate, which is expected, as our Institute hosts mostly the severe conditions in its catchment area. As regards duration of drug dependence, among the participants of the case group, 46 (92%) had a history of <10 years, and only 4 (8%) reported a history of >10 years (Figs. 1, 2).

TABLE 1 - Sociodemographic Data of Case and Control Groups
Group [n (%)]
Data Cases (n=50) Control (n=38) t Test Significance
Age (mean±SD) (y) 29.4±6.2 30.3±6.5 0.4 Nonsignificant
Marital status
 Single 31 (62) 23 (60) χ2=0.831 Nonsignificant
 Married 16 (32) 13 (34.2)
 Divorced 2 (4) 2 (5.3)
 Widowed 1 (2) 0 (0)
Education
 Technical 20 (40) 9 (23.6) 0.02 Significant
 Secondary 7 (14) 19 (50)
 University 23 (46) 10 (26.4)
Occupation
 Unemployed 8 (16) 0 (0) 0.111 Nonsignificant
 Employed 42 (84) 38 (100)

FIGURE 1
FIGURE 1:
Drug severity distribution within the sample. ASI indicates Addiction Severity Index.
FIGURE 2
FIGURE 2:
Duration of heroin dependence.

WAIS, WMS, and WCST scores showed statistically significant differences between the studied groups (P<0.001) (Tables 2, 3). Details of WAIS subscale showed that the case group scored lower on verbal (similarities, arithmetic, digit span, and comprehensive parameters) and performance (digit symbol, block design, and picture complete parameters). On WMS subscales, the case group scored lower than the control group with statistical significance in visual, verbal, immediate memory, and concentration parameters (P<0.001), while WCST did not show significance between the studied groups, yet the case group performed worse, specifically in preservative response and preservative errors. This means that the case group performed worse than the control group across the cognitive domain scores of total intellectual functions, logical reasoning, executive function, learning, memory, and perception.

TABLE 2 - Comparison of WAIS Subtests Across Case and Control Groups
Group (Mean±SD)
Data Case (n=50) Control (n=38) P (t Test) Significance
WAIS Total Score 95.90±8.411 111.00±13.27 0.001 Yes
WAIS Performance 98.88±9.255 111.58±12.30 0.001 Yes
WAIS Verbal 95.22±10.056 111.08±14.91 0.001 Yes
Performance IQ
 Digital symbol 10.96±2.15 13.11±2.87 0.001 Yes
 Block design 8.56±2.04 10.42±2.57 0.001 Yes
 Picture completed 8.84±1.29 10.58±1.70 0.001 Yes
Verbal IQ
 Similarities 9.26±1.93 11.18±3.02 0.001 Yes
 Arithmetic 7.34±2.42 9.68±3.23 0.01 Yes
 Digit span 7.32±2.12 10.18±2.9 0.001 Yes
 Comprehensive 11.90±1.72 14.84±2.07 0.001 Yes
IQ indicates intelligence quotient; WAIS, Wechsler Adults Intelligence Scale.

TABLE 3 - Comparison of WMS and WCST Subtests Across Case and Control Groups
Group (Mean±SD)
Data Case (n=50) Control (n=38) P (t Test) Significance
WMS
 Visual backward 5.88±1.881 5.66±1.16 0.4 No
 Visual forward 7.26±2.49 8.26±1.85 0.04 Yes
 Digit span backward 5.06±1.82 5.58±1.32 0.1 No
 Digit span forward 6.18±2.36 7.47±1.50 0.09 Yes
 Visual paired association 2 3.38±1.61 5.05±1.22 0.001 Yes
 Visual paired association 1 6.58±3.69 10.42±4.45 0.001 Yes
 Verbal paired association 2 5.62±1.48 6.68±1.52 0.002 Yes
 Verbal paired association1 4.24±4.24 12.245±4.05 0.001 Yes
WCST
 Preservative response 19.56±15.40 8.68±5.71 0.001 Yes
 Preservative errors 17.58±13.43 8.29±5.00 0.001 Yes
 Conceptual level responses 61.22±14.97 67.24±3.52 0.01 Yes
 Category completed 5.16±1.51 5.92±0.35 0.003 Yes
WCST indicates Wisconsin Card Sorting Test; WMS, Wechsler Memory Scale.

On exploring the impact of duration of drug dependence on cognitive function within the case group, results showed that those with longer duration over 10 years have positive correlation with the WAIS performance subscale (P=0.004) and negative correlation with the WCST conceptual level (P=0.005); otherwise, no statistical significance was found on other subscales between both groups (Table 4).

TABLE 4 - Relation Between Duration of Heroin Use and Cognitive Function Subtests Among Case Group
Duration of Heroin Dependence
Cognitive Function Tests <10 y ≥10 y P (t Test) Significance
WAIS
 Total score 95.50±8.56 97.50±5.20 0.3 No
 Performance 98.09±9.16 108.00±4.62 0.039 Yes
 Verbal 95.15±10.42 96.00±4.62 0.873 No
WMS
 Visual backward 5.87±1.96 6.00±0.00 0.896 No
 Visual forward 8.00±2.47 10.50±1.73 0.06 No
 Digit span backward 5.15±1.78 4.00±2.31 0.229 No
 Digit span forward 7.28±2.44 6.00±0.00 0.302 No
 Visual paired association 2 3.46±1.60 2.50±1.73 0.260 No
 Visual paired association 1 6.67±3.70 5.50±4.04 0.548 No
 Verbal paired association 2 5.59±1.54 6.00±0.00 0.598 No
 Verbal paired association1 12.00±4.34 15.00±1.15 0.178 No
WCST
 Preservative response 19.00±14.66 26.00±24.25 0.389 No
 Preservative errors 17.11±12.85 23.00±20.78 0.406 No
 Conceptual level responses 62.72±13.28 44±24.25 0.01 Yes
 Category completed 5.26±1.42 4.00±2.31 0.112 No
WAIS indicates Wechsler Adults Intelligence Scale; WCST, Wisconsin Card Sorting Test; WMS, Wechsler Memory Scale.

On assessment of drug severity impact (Table 5) on cognitive function domains, significant positive correlation of drug severity with picture-completed subscale of performance intelligence quotient (IQ) was detected (P=0.001), which was reflected on total performance IQ as well (P=0.013). Furthermore, we found a positive correlation between drug severity and verbal similarity subscale (P=0.018). Whereas, when correlating drug severity with WMS, significant negative correlation was detected between addiction severity with digit span forward (P=0.000), and visual backward (P=0.048) subscales. Moreover, assessing drug severity profile with WCST revealed significant negative correlation on conceptual level and category completed (P=0.009 and 0.035, respectively).

TABLE 5 - Relation Between Addiction Severity and Cognitive Function Subtests Among Case Group
ASI
Cognitive Function Tests Moderate Severe P (t Test) Significance
WAIS
 Total score 94.24±8.96 96.76±8.12 0.320 No
 Performance 94.82±8.78 100.97±8.91 0.025 Yes
 Verbal 95.18±11.54 95.24±9.39 0.983 No
WMS
 Visual backward 6.41±2.37 5.61±1.54 0.153 No
 Visual forward 8.41±2.72 8.09±2.42 0.672 No
 Digit span backward 5.82±2.01 4.67±1.61 0.032 Yes
 Digit span forward 8.76±2.82 6.36±1.60 <0.001 Yes
 Visual paired association 2 3.53±1.59 3.30±1.65 0.643 No
 Visual paired association 1 5.88±3.55 6.94±3.77 0.344 No
 Verbal paired association 2 5.53±1.42 5.67±1.53 0.760 No
 Verbal paired association1 10.88±3.69 12.94±4.39 0.105 No
WCST
 Preservative response 14.47±7.22 22.18±17.78 0.044 Yes
 Preservative errors 13.06±5.94 19.91±15.57 0.038 Yes
 Conceptual level responses 68.29±10.02 57.58±15.91 0.01 Yes
 Category completed 5.71±0.77 4.88±1.73 0.097 No
ASI indicates Addiction Severity Index; WAIS, Wechsler Adults Intelligence Scale; WCST, Wisconsin Card Sorting Test; WMS, Wechsler Memory Scale.

Statistical significance was shown between case and control groups with regard to plasma BDNF level (P<0.001) where the case group was >3-fold higher with mean level 33.3±18.45 compared with 5.6±1.55 in the control group (Fig. 3).

FIGURE 3
FIGURE 3:
Brain-derived neurotrophic factor mean level.

On exploring the relationship between plasma BDNF with duration and severity of drug dependence, the results showed that there was no statistical significance within the case group, yet those with longer duration have lower plasma BDNF levels, and a higher level was detected in participants with a severe addiction index (Table 6).

TABLE 6 - Relation Between BDNF Level and Duration of Heroin Use and Addiction Severity in Case Group
Data BDNF Level t Test P
Duration
 <10 y 33.60±19.14 0.110 0.742
 >10 y 30.38±8.38
ASI
 Moderate 31.47±20.76 0.260 0.613
 Severe 34.30±17.45
ASI indicates Addiction Severity Index; BDNF, brain-derived neurotrophic factor.

Correlation study for cognitive functions’ scores and plasma BDNF levels of case and control groups revealed no statistical significance (Table 7).

TABLE 7 - Correlation Between BDNF and Cognitive Function Subtests Among Case Group
BDNF
Pearson Correlation
Cognitive Function Tests Case Group Control Group P Significance
WAIS
 Total score 0.048 0.210 0.742 No
 Performance −0.059 0.199 0.682 No
 Verbal 0.111 0.198 0.444 No
WMS
 Visual backward −0.127 0.094 0.378 No
 Visual forward 0.025 0.000 0.864 No
 Digit span backward −0.021 0.296 0.884 No
 Digit span forward −0.175 0.246 0.224 No
 Visual paired association 2 −0.142 0.010 0.325 No
 Visual paired association 1 −0.047 0.049 0.748 No
 Verbal paired association 2 0.175 0.223 0.224 No
 Verbal paired association 1 0.022 0.103 0.880 No
WCST
 Preservative response 0.015 −0.194 0.919 No
 Preservative errors 0.019 −0.171 0.895 No
 Conceptual level responses 0.063 0.140 0.663 No
 Category completed 0.021 0.261 0.885 No
BDNF indicates brain-derived neurotrophic factor; WAIS, Wechsler Adults Intelligence Scale; WCST, Wisconsin Card Sorting Test; WMS, Wechsler Memory Scale.

DISCUSSION

Substance use disorder (SUD) is one of the most complicated problems that face not only medical professionals but the whole community. This results from the enormous personal, social, and economic costs of such a disorder. Moreover, SUD is considered a preventable illness and cause of death in our country and other countries.21 The Egyptian Ministry Of Health published an epidemiologic study for the prevalence of SUDs and revealed that 1.6% of the Egyptian population suffers from SUD, and 10% of them are addicted to opioid drugs; they add that the lifetime prevalence of any substance use varies between 7.25% and 14.5%.22,23

Many abused drugs lead to changes in endogenous BDNF expression in neural circuits responsible for addictive behaviors. BDNF is a known molecular mediator of memory consolidation processes, evident at both behavioral and neurophysiological levels.24 Moreover, elevated levels of BDNF in the ventral tegmental area were proved to increase the likelihood of becoming dependent on opiates, such as heroin and morphine. BDNF also intensified the characteristic behavioral effects of drug use, and it induced changes in the brain consistent with drug dependence and subsequent withdrawal.25 Our study demonstrated significant impairment in cognitive functions in chronic heroin-dependent patients compared with frequency-matched healthy controls, as measured by WAIS, WMS, and WCST. In addition, our findings are largely consistent with previous studies for negative effect of chronic opiates on brain regions and poor impact on cognitive functions.26–28 Similarly, Latvala et al29 found that SUD was associated with poorer verbal intellectual ability, vocabulary subtest, and slower psychomotor processing, as measured with the WAIS-Revised digit symbol subtest. However, this is not concordant with Strang and Gurling30 who reported that daily use of high doses of heroin on a long-term basis did not produce any deleterious effect on cognitive functioning, which was linked to small sample size in their study. Meanwhile, our work showed, in terms of individual test performance, that chronic heroin-dependent patients suffer from impairment in executive functions, especially evident in high preservative errors and decreased ability of concept formation, as detected by WCST. This is in agreement with Brand et al31 who concluded that opiate dependents may have cognitive dysfunctions particularly within the spectrum of executive functioning and emotional processing. Such dysfunctions can also compromise daily decisions, making them more prone to risk-taking behaviors. In addition, Martins and colleagues32,33 suggested that chronic drug use may severely damage executive functions, especially those associated with response prevention and decision-making, and these damages are accompanied by malfunctions in the frontal gyrus and frontal lobe. Learning and memory impairments appear quite consistently in chronic heroin patients, specifically the visual, verbal, and immediate memory. This is in congruence with other studies that reported a negative effect of chronic opiates on brain regions related to learning and memory, such as the frontal cortex, emphasizing the notion that addiction to heroin drug is linked to significant attention deficits and inadequate performance on memory tasks.34 Meanwhile, Lu et al6 reported that the heroin addicts were found to have an increased number of perseveration errors and rotations in their drawings and constricted use of space of paper when compared with the nonopiate addicts.

In our study, we aimed at investigating cognitive dysfunction in a sample of patients diagnosed with opioid dependence disorder and exploring the relation of plasma BDNF level with their scores. The results largely replicated those obtained in previous studies for memory and executive functions. Patients with longer duration showed more impairment in most of the test subscales. However, patients with longer duration of use (≥10 y) had less impaired performance IQ than those with shorter durations (≤10 y). This may be explained by the fact that the slight impairment in some of the cognitive functions with longer durations may represent compensatory adaptation that can help the drug dependent to deal with accumulating problems that arise in his daily living events and to continue drug use as well against obstacles. Medina et al35 suggested that the abuse of multiple substances over a long period of time potentially produces long-lasting neuropsychological impairment with minimal recovery of functioning even after maintained abstinence. In addition, Latvala et al29 used WAIS to measure IQ, and they found that patients with regular use have better performance in the test than those with occasional use.

As regards the disease severity, interestingly, the more severe the heroin dependence was, the less impaired performance IQ and verbal similarities were. The possible explanation might be that addiction as a disease needs tools to exist and progress, and performance IQ and verbal similarities are components of these tools. On the contrary, the more severe the drug dependence was, the more impaired memory and executive functions were (especially attention and concentration function of memory, plus concept formation and cognitive flexibility of executive functions), and this impairment is suspected to cause continued drug use as well. This suggests that smart people are more able to intellectualize their drug use and more capable of deceiving themselves and others, which leads to more severe addiction profile.36–38

It is worth mentioning that our results revealed that plasma BDNF level is higher than that of controls by >3-fold. This may be the result of increased production of BDNF in ventral tegmental area and the hippocampus, which is accused in shifting the person from dopamine-independent to dopamine-dependent state. In addition, increased BDNF expression may counteract the effect of chronic opiate use on neurons. Therefore, it is likely that increased BDNF expression occurs as a compensatory response to neuronal insult.25

Our study replicates the results of Heberlein et al,38 who found BDNF serum levels were significantly increased in the opiate-dependent patients, as compared with healthy controls. Add on BDNF serum levels were significantly associated with craving for heroin, which contributes in dependence syndrome. Similarly, Zhang et al,39 reported that baseline serum BDNF levels were significantly higher in heroin addicts compared with controls, and there was no difference in serum BDNF levels among heroin addicts at baseline and 1 month after heroin cessation.

In contrast, Francesco et al10 found decreased serum levels of the nerve growth factor and BDNF compared with healthy controls in opiate-dependent patients, and this may be explained by their relatively small sample size (n=15). In addition, factors such as nicotine use, alcohol consumption, depression, and stress have all been reported to influence serum BDNF levels. Therefore, these factors may also explain part of the discrepancy of the results. In addition, Shiou-Lan et al40 studied plasma BDNF level in patients with methadone maintenance treatment (MMT) compared with healthy controls; they found decreased BDNF level in MMT patients than in controls. We could understand the difference within this study due to older age of the patients where BDNF was noticed to be negatively correlated with age; in addition, most of the heroin-dependent patients were on MMT before the study began, and the effect of long-term MMT on plasma BDNF levels needs to be further examined.

Examining the relation between BDNF level and duration of heroin use, our study revealed that BDNF level is lower in patients with longer duration (10 y and more) than in those with shorter duration (<10 y); however, it is not statistically significant. The downregulation of peripheral BDNF levels in long-term heroin-dependent patients represents the possible downregulation of central nervous system BDNF, and this observation could explain the slight improvement reported in cognitive functions in patients with longer duration of use. This could be understood as a compensatory adaptation that helps the drug dependent to deal with accumulating problems that arise in his daily living events and to continue drug use as well against obstacles.

In accordance with Shiou-Lan et al,40 plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 y) users had significantly lower plasma BDNF levels than did short-term (<5 y) users.

Our study elicited that BDNF plasma level is higher within the patients’ group with severe ASI scores than those with moderate scores. However, the difference was not statistically significant. Similarly, Heberlein et al38 found that BDNF level increased with increased craving severity.

Meanwhile, our results could not prove statistical significance between BDNF level and cognitive functions in the studied groups, yet the correlations tend to be positive, especially in normal persons (control group). That is quite expected, as BDNF is known with its neurotrophic action and synaptogenesis. Various studies reported the importance of BDNF and its role in building up proper cognitive functions and ensuring healthier neurons.41 Although we do not have available data concerned with the relation between BDNF and cognitive functions in normal persons, it seems that the adequate amount that is needed to deliver the specific function of BDNF differs from one person to another, and any decrease or increase below or above that limit could indicate pathologic changes.42

CONCLUSIONS

Chronic heroin-dependent patients statistically differed from healthy controls on measures of cognitive dysfunction and plasma BDNF level, which suggests that heroin induces and hires brain BDNF to establish a neuronal adaptation in areas related to addictive behaviors, such as the reward center and memory, at the expense of other brain areas/functions. Therapeutic approaches respecting these findings may help in improvement of heroin-dependent patients’ overall outcome.

Clinical Implications

Patients with heroin dependency have significant cognitive dysfunction that may influence their engagement in treatment programs and lead to frequent relapses. We recommend routine screening for cognitive functions in drug-dependent patients and taking into account the impact on their daily functioning, employment, and relationships to improve their outcome and their quality of life. Moreover, the possibility of utilization of BDNF plasma level in preventing relapses could be considered.

Limitations

To our knowledge, our study is considered one of only few studies that are concerned with the relation between chronic heroin dependence and cognitive function with BDNF plasma level. Yet, being cross-sectional in nature, it made it difficult to infer causality in relationship. In addition, recruiting patients with only heroin dependency was quite difficult, which made us include only those with heroin use as a main substance of dependency for at least 1 year, which was reflected in the small sample size, and we could not exclude the impact of previously used drugs on cognitive function that may have reduced statistical power, and potentially increased the occurrence of type II errors.

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Keywords:

cognitive dysfunction; heroin; intelligence; memory

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