Dopamine Receptor Modulation in Co-Occurring Disorders: Potential of Cariprazine and D3 Receptor Activity

Objective: Substance use disorders (SUDs) frequently co-occur with serious mental illness (SMI) and remain undertreated, in part due to limited pharmacologic options for many substances. Dopamine receptor-modulating agents (DRMAs), particularly antipsychotics with partial agonist activity, have been investigated for their potential to influence craving, reward processing, and relapse. This commentary reviews the evolving evidence for dopamine receptor modulation in SUDs, with particular emphasis on second-generation antipsychotics (SGAs) and the D3-preferring partial agonist cariprazine. Methods: A narrative review of preclinical, clinical, and observational literature was conducted, focusing on dopamine receptor antagonists and partial agonists studied in populations with SUDs, including individuals with co-occurring SMI. Particular attention was given to pharmacologic mechanisms involving D2 versus D3 receptor activity and to emerging evidence regarding cariprazine. Results: Early studies of first-generation antipsychotics, characterized by potent and sustained D2 receptor antagonism, generally demonstrated limited benefit or worsening of substance use outcomes. SGAs have shown more heterogeneous effects, likely reflecting variability in receptor-binding profiles and study methodologies. Increasing evidence highlights the role of the dopamine D3 receptor in substance-related motivation, reward, and cue reactivity. Cariprazine, the only currently approved antipsychotic with high affinity and preferential activity at the D3 receptor, has demonstrated potential benefits across preclinical models, case reports, and observational studies. Reported improvements include reductions in substance use, craving, and relapse-particularly for stimulant and cannabis use disorders-alongside improvements in psychiatric symptoms and functioning. However, most clinical evidence remains limited to small samples, non-randomized designs, and variable outcome measures. Conclusions: Dopamine receptor modulation, particularly targeting the D3 receptor, represents a promising but still emerging strategy for the treatment of SUDs, especially in individuals with co-occurring psychiatric disorders. Cariprazine's unique pharmacologic profile and broad clinical indications position it as a compelling candidate for further investigation. Rigorous randomized controlled trials using standardized substance use outcomes are needed to clarify its efficacy and role in integrated treatment models for dual diagnosis populations.