Dopamine D2/D3 receptor partial agonists reduce craving in substance use disorders: a systematic review and meta-analysis

Introduction

Substance use disorders (SUD) affect hundreds of millions of people globally. Dopaminergic dysregulation, particularly at the dopamine D2 and D3 receptors, is a core neurobiological mechanism across addictions. Higher craving levels are associated with worse prognosis [1], making craving a relevant therapeutic target. Dopamine D2/D3 receptor partial agonists (D2/D3 PAs), including aripiprazole, brexpiprazole, and cariprazine, may function as dopamine stabilizers and have shown preliminary potential to reduce craving, especially in dual-diagnosis populations.

Aims

To investigate the efficacy of dopamine D2/D3 receptor partial agonists in reducing craving in substance use disorders.

Methods

This systematic review and meta-analysis followed PRISMA 2020 guidelines and was prospectively registered in PROSPERO (CRD420251232201). Eligibility followed the Population, Intervention, Comparator, Outcome (PICO) framework. Studies reporting on (P) patients with SUD treated with (I) aripiprazole, brexpiprazole, and cariprazine (D2/D3 PAs) were included in our analysis if they provided data on craving scales or Positive and Negative Syndrome Scale (PANSS) scores. A systematic search of 3 databases in November 2025 identified 5585 records. Duplicates were removed, titles and abstracts were screened independently by two reviewers (AL and HP) using a predefined protocol, followed by a full-text review. Inter-rater reliability was very high (κ = 0.84 and κ = 0.94, respectively). Discrepancies were resolved by consensus with a third party. Forward and backward citation chasing was performed. For the statistical synthesis, a random-effects model was applied; single-arm results are reported as before-after mean differences with 95% confidence intervals.

Results

Twenty-five full-text articles were included in the systematic review.

Of the included articles, 12 were included in the meta-analysis for the primary outcome, change on the Visual Analogue Scale (VAS) for craving. The pooled analysis showed a mean reduction of 3.24 points in craving [95% CI, 2.06 to 4.42], based on 281 participants. Subgroup analysis by the most common substance in each article’s population revealed an even higher, significant reduction in craving in cannabis use disorder dominant populations, with a mean reduction of 5.29 points on the VAS. For the Positive and Negative Syndrome Scale (PANSS) positive subscale, based on 6 eligible articles reporting on 177 patients, we found a pooled mean reduction of 9.91 points [95% CI 2.29 to 17.53]. As for the PANSS negative subscale, based on 5 included studies, we found a pooled mean reduction of 7.74 points [95% CI 0.79 to 14.68]. These results show that the D2/D3 PAs may be effective in dual-diagnosis populations, emphasizing their potential role in reducing both positive and negative symptoms in schizophrenia spectrum disorders.

Conclusions

Current evidence suggests that D2/D3 PAs may reduce craving in the SUD population, with notable reduction in cannabis use disorder populations. Furthermore, D2/D3 PAs may be effective in dual-diagnosis populations and may have clinically significant efficacy in reducing the severity of negative symptoms. Clinicians may consider these medications as an option in schizophrenia spectrum disorder patients with concurrent SUD to target both pathologies simultaneously.

References

Vafaie, N., Kober, H., 2022. Association of drug cues and craving with drug use and relapse, a systematic review and meta-analysis. JAMA Psychiatry 79 (7), 641–650. http://dx.doi.org/10.1001/jamapsychiatry.2022.1240.