Background <p>Substance use disorder (SUD) is a debilitating neuropsychiatric condition characterized by persistent compulsive drug use and associated cognitive and psychiatric impairments. Emerging evidence suggests that neuroinflammatory pathways contribute to the pathophysiology of SUD. However, the relationships between neuroinflammatory-related biomarkers and psychiatric symptomatology in SUD remain poorly understood. This study aimed to investigate neuroinflammatory-related biomarkers and their association with psychiatric symptom changes in individuals with SUD.</p> Methods <p>Participants with SUD (<i>N</i> = 100) at three local facilities in the North West Province of South Africa were enrolled. At baseline and following three weeks of treatment, psychiatric symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Serum levels of superoxide dismutase (SOD), glutathione (GSH), glutathione disulphide (GSSG), tryptophan, kynurenine (KYN), kynurenic acid (KYNA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), cortisol and serum S100 calcium-binding protein B (S100B) were measured.</p> Results <p>Over the 3-week treatment period BPRS scores and serum levels of tryptophan, 5-HT, 5-HIAA, KYN, KYNA, cortisol and GSH decreased, whereas SOD, S100B and GSSG levels increased. Baseline BPRS correlated with baseline serum levels of 5-HIAA, KYNA and GSSG. A decrease in BPRS correlated with baseline levels of 5HIAA, KYN and KYNA, as well as with 3-week changes in levels of select biomarkers (∆tryptophan, ∆5-HT, ∆5-HIAA, ∆KYN, ∆KYNA, ∆GSSG and ∆cortisol).</p> Conclusion <p>The results suggest that baseline 5-HIAA, KYN and KYNA may predict psychiatric symptom improvement whereas tryptophan, 5-HT, 5-HIAA, KYN, KYNA, GSSG and cortisol may explain the neurobiological basis of changed psychiatric symptomatology.</p>