Early diagnosis of susceptibility to psychoactive substance (PAS) use and addiction is a pressing problem of addictology. The development of PAS dependence involves a reward system that also plays a key role in the modulation of nociception. The PRDM12 gene associated with congenital insensitivity to pain is involved in neurogenesis and affects the properties of nerve cells. Objective: to comparatively assess pain sensitivity in mental and behavioral disorders caused by the use of PASs in healthy individuals and subjects with their occasional uses according to the genotype of rs10121864 in the PRDM12 gene. Patients and methods. Examinations were made in 103 patients with addiction to PAS (F1x.2), in 114 apparently healthy individuals (a control group) and in 36 subjects who occasionally used PASs (a risk group). The pain sensitivity threshold and pain tolerance were determined by tensoalgometry; a subjective assessment of pain thresholds was made using a visual analogue scale. Genotyping was performed using the PRDM12 rs10121864 polymorphism. Results and discussion. The distribution of the genotypes of PRDM12 rs101218 was statistically significantly different in the comparison groups. Odds ratio (OR) calculation showed that in the subjects who occasionally used PASs, the risk of their dependence was several times greater than that in carriers of the mutant A allele (OR, 2.52; 95% confidence interval (CI), 1.42–4.50) of rs10121864 and its homozygous genotype AA (OR, 6.66; 95% CI, 1.50–29.54) and in those of alternative genotypes. The PRDM12 was also found to be associated with the parameter of subjective assessment of pain sensitivity in PAS-dependent subjects. Thus, this parameter was significantly lower in the carriers of the mutant A allele than in those of the GG genotype. Conclusion. The A allele and AA genotype of PRDM12 rs10121864 were established to be associated with the risk of PAS dependence and with the parameter of subjective perception of the upper pain threshold.