2D:4D ratio, affective lability, and impulsivity in men with cannabinoid and methamphetamine use disorders: A comparative analysis with healthy controls.

The second-to-fourth digit ratio (2D:4D) is considered a non-invasive marker of prenatal androgen exposure and has been proposed as a developmental indicator of behavioral vulnerability; however, findings in substance use disorders remain inconsistent. This study aimed to examine whether 2D:4D ratios are associated with substance use disorders and to compare their relative contribution with psychological factors, including affective lability, impulsivity, and anxiety. In this cross-sectional case-control study, male participants with cannabinoid use disorder (CUD; n = 47), methamphetamine use disorder (MUD; n = 48), and healthy controls (n = 53) were included. The mean age of participants was 32.7±8.95 years. All participants were assessed using the Structured Clinical Interview for DSM-5 (SCID-5), Affective Lability Scale-18 (ALS-18), Barratt Impulsiveness Scale-11 (BIS-11), and Generalized Anxiety Disorder-7 (GAD-7). The 2D:4D ratio was measured with a digital caliper by two trained psychiatrists, and 2D:4D ratios and right-left differences (Dr-I) were calculated. No significant group differences were observed in left or right 2D:4D ratios or Dr-I; however, a consistent trend toward lower 2D:4D values, particularly for right-hand 2D:4D, was observed in the CUD and MUD groups compared with controls. In contrast, affective lability, impulsivity, and anxiety scores were significantly elevated in both patient groups (p <0.05). In univariate logistic regression analyses, affective lability, impulsivity, anxiety, and lower right-hand 2D:4D were associated with substance use disorder; however, right-hand 2D:4D showed the weakest association among these predictors. In the multivariate model, lower right-hand 2D:4D, impulsivity, lower educational attainment, and smoking remained independently associated with substance use disorder. These findings suggest that while 2D:4D may reflect a distal developmental vulnerability, psychological factors, particularly impulsivity, have a more direct and clinically relevant role in substance use disorders. Incorporating the assessment of impulsivity into clinical evaluation and intervention strategies may improve risk identification and treatment planning.