Association Between Inflammatory Cytokines, Executive Function, and Substance Use in Patients With Opioid Use Disorder and Amphetamine-Type Stimulants Use Disorder

Abstract

Background: Long-term opioid and amphetamine-type stimulants (ATS) abuse may affect immunological function and impair executive function. We aimed to determine whether biomarkers of inflammation and executive function were associated with substance use in individuals with opioid use disorder (OUD) and ATS use disorder (ATSUD). The interactions between these biomarkers were also explored.

Methods: We assessed plasma cytokines [tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-8, IL-6, transforming growth factor (TGF)-β1, brain-derived neurotrophic factor (BDNF), and executive function in terms of the Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT) in OUD and ATSUD patients and healthy controls (HC). OUD and ATSUD patients were followed for 12 weeks, and their urine morphine and amphetamine tests, cytokine levels, and executive function were repeatedly measured.

Results: We enrolled 483 patients and 145 HC. Plasma TNF-α, CRP, IL-8, IL-6, and BDNF levels and most subscale scores on the WCST and CPT significantly differed between OUD and ATSUD patients and HC. Increased TNF-α levels and more perseveration error on the WCST were significantly associated with more urine drug-positive results and less abstinence. Plasma IL-6 and CRP levels were significantly negatively correlated with WCST and CPT performance.

Conclusion: OUD and ATSUD patients had more inflammation and worse executive function than HC. Inflammatory markers and WCST performance were associated with their urinary drug results, and higher inflammation was associated with poor executive function. Studies on regulating the inflammatory process and enhancing executive function in OUD and ATSUD are warranted.

Keywords: Opioid use disorder; amphetamine-type stimulants use disorder; brain-derived neurotrophic factor; cytokines; executive function.

Figure 1.

Significant differences in cytokine and BDNF levels between OUD and ATSUD patients and HC by MANCOVA. Covarying for age and sex. *P < .05; **P < .001. Abbreviations: ATSUD, amphetamine-type stimulants use disorder; BDNF, brain-derived neurotrophic factor; CRP, C-reactive protein; HC, healthy controls; IL-6, interleukin-6; IL-8, interleukin-8; MANCOVA, multivariate analysis of covariance; OUD, opioid use disorder; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis factor α.

Figure 2.

Significant differences in WCST performance between OUD and ATSUD patients and HC by MANCOVA. Covarying for age, sex, and years of education. *P < .05; **P < .001. Abbreviations: ATSUD, amphetamine-type stimulants use disorder; CL, conceptual level; HC, healthy controls; MANCOVA, multivariate analysis of covariance; NCC, number of completed categories; OUD, opioid use disorder; PE, perseveration error; TCC, trials to complete the first category; TNE, total number error; WCST, Wisconsin card sorting test.

Figure 3.

Significant differences in CPT performance between OUD and ATSUD patients and HC by MANCOVA. Covarying for age, sex, and years of education. *P < .05; **P < .001. Abbreviations: ATSUD, amphetamine-type stimulants use disorder; CPT, Continuous Performance Test; C-TS, commission T-score; HC, healthy controls; HRTSE-TS, HRT standard error T-score; HRT-TS, hit reaction time T-score; MANCOVA, multivariate analysis of covariance; O-TS, omission T-score; OUD, opioid use disorder.

Figure 4.

A significant positive correlation between changes in log IL-6 levels and WCST PE performance. Covarying for age, sex, years of education and substance use, visits, psychiatric comorbidities, and treatment group. Abbreviations: IL-6, interleukin-6; PE, perseveration error; WCST, Wisconsin card sorting test.

Figure 5.

A significant positive correlation between changes in log IL-6 levels and WCST TCC performance. Covarying for age, sex, years of education and substance use, visits, psychiatric comorbidities, and treatment group. Abbreviations: IL-6, interleukin-6; TCC, trials to complete the first category; WCST, Wisconsin card sorting test.

Figure 6.

A significant positive correlation between changes in log CRP levels and CPT O-TS performance. Covarying for age, sex, years of education and substance use, visits, psychiatric comorbidities, and treatment group. Abbreviations: CRP, C-reactive protein; CPT, Continuous Performance Test; O-TS, omission T-score.