It is well known that alcohol can diminish individual health from the fetus to old age. Alcohol affects a wide range of structures and processes in the central nervous system. Associated with personality characteristics, is causal factor for injuries, absenteeism, many somatic diseases, as well some types of cancers (1). Alcohol contributes in about 100 million disability-adjusted life-years across the world, while some data show there were more than 60 million cases of alcohol use disorder (AUD) globally (2). The fact that the treatment process is very difficult and complex, and that there are still no sufficiently effective psychopharmaceuticals that would guarantee the reduction of cravings and the establishment of permanent abstinence, is of additional concern. Cravings refers to the subjective need and desire to use substances. Further, the individual experience of cravings is perceived to be the first aspect of and driving force behind substance use. Unfortunately, there are still no specific guidelines for the effective pharmacological treatment of cravings (3).

The role of dopamine D2 and D3 receptors in addictive diseases is the subject of many years of research (4). D2 receptors are linked with mesocortical and mesohippocampal dopamine systems, the D3 receptors are connected with the ventral forebrain mesolimbic system (5). That position of the D3 receptors is very suitable to influence reward, emotion, motivation and drug seeking and relapse mechanisms. Psychoactive substances increase dopamine in the nucleus accumbens, a major component of the reward system, due to expression of D3 receptors in this specific localization, there is huge interest about the potential role of D3 receptors in drug reward and addictive processes. Antagonism or partial agonism of DRD3 has been shown to reduce the alcohol deprivation effect (6). Some results indicate that a year of voluntary alcohol drinking and in high alcohol drinking was connected with higher D3 gene expression in the striatum (7).

Among many psychotropic medications, cariprazine actually preferentially binds to D3 receptors, and its binding is stronger than that of any other antipsychotic, and even that of dopamine itself (8). Considering the very high affinity of dopamine for D3 receptors, the otherwise low affinities of antipsychotics, with the exception of cariprazine, render them incapable of blocking D3 receptors in the presence of dopamine in the living brain (9).

In the cases presented above, cariprazine was used outside of its approved and clinically studied indications. Nevertheless, the consistent achievement of full abstinence across all four patients suggests that it may have potential relevance in the management of alcohol use disorder (AUD).

There were no possible side effects of cariprazine treatment in any of the cases.

The first case involved a patient with a lifelong history of alcoholism who had failed multiple prior pharmacological treatments. Only after initiating cariprazine did he achieve stable abstinence, without experiencing adverse effects. A similar pattern appears in Case 4: despite many years of alcohol dependence and unsuccessful attempts with olanzapine and quetiapine, abstinence was reached only after cariprazine was introduced. The two other cases involve younger patients with shorter disease duration, where cariprazine was equally successful in treating AUD. Notably, the patient in Case 2 remained on 1.5 mg/day; all others showed greater improvements in abstinence after increasing the dose from 1.5 mg to 3 mg/day.

The potential role of cariprazine in reducing alcohol or substance use may relate to its very high affinity for D3 receptors (10, 11) which are abundant in the brain’s reward circuitry and are deeply involved in addiction pathophysiology (11–13). This could imply that cariprazine can show the effects usually associated with D3 partial agonism, which are improvements in the domain of negative, cognitive and depressive symptoms, as well as in the sphere of motivation and reward (14). Beyond the cases reported here, supporting evidence comes from preclinical studies: in animal models, cariprazine reduced the rewarding effects of cocaine and prevented relapse, and the abuse preventing potency of cariprazine was ~20-fold higher than that of aripiprazole (15). Preliminary clinical observations also suggest that cariprazine may be useful for patients with comorbid substance use disorders. A real-world evidence study and various case reports are available to underscore cariprazine’s efficacy on addiction symptoms (16–21). In a study by Szerman et al, authors examined the use of cariprazine for treating dual disorders, specifically comorbid substance use disorder (SUD) and schizophrenia (20). Cariprazine treatment led to significant improvements in schizophrenia symptoms, along with a decrease of cannabis use (20). These findings are further supported by case reports describing cariprazine’s efficacy in reducing the craving and substance use in patients consuming methamphetamine, cocaine, cannabis, alcohol and tobacco (19–24). In consequence, current guidelines suggest cariprazine and other partial agonists as first line treatment in maintenance settings and as second line in acute settings of substance use disorder comorbidities (12, 22, 23). In a functional MRI study examining brain responses to brief cocaine-related cues (500 ms), a group of cocaine-dependent patients treated with cariprazine 3 mg/day (n = 4) was compared with an unmedicated, demographically similar control group (n = 14). The findings showed that cariprazine markedly reduced cue-induced limbic activation in the treated patients (24).

Across all four cases, a marked improvement in depressive symptoms was observed. Although each patient had been treated with antidepressants for many years, meaningful improvement occurred only after the introduction of cariprazine. It remains uncertain to what extent this improvement reflects the direct pharmacological properties of cariprazine, the effects of sustained alcohol abstinence, or an interaction of both factors. Nevertheless, the antidepressant effects of cariprazine are well documented in the literature, and the medication is approved for bipolar depression as well as for adjunctive treatment of major depressive disorder in the United States and other countries (25). Its efficacy has been demonstrated in four bipolar depression studies and in several MDD add-on studies, all of which confirmed significant improvements in depressive symptoms (26). The antidepressant properties of cariprazine are thought to arise primarily from its partial agonism at dopamine D3 and D2 receptors, serotonin 5-HT1A receptors, and its antagonistic activity at 5-HT2B and 5-HT2A receptors (27).

The Cases 1 and 2, belong to the so called category of AUD without comorbid psychosis, so the clinical rationale for the prescribing of antipsychotics in the context of AUD lies in their above mentioned effects at dopamine D3 and D2 receptors. Many studies suggest that atypical antipsychotic agents may be beneficial for the treatment of alcohol dependence, as olanzapine (28, 29) and quetiapine (30, 31).

In Case 3, psychotic features—including delusions, occasional auditory hallucinations, and suicidal ideation—resolved completely within one month of starting cariprazine, alongside full abstinence. It is not surprising that cariprazine alleviated positive symptoms such as delusions and hallucinations, given its well-established efficacy in schizophrenia. Cariprazine’s antipsychotic effects have been demonstrated across six clinical studies, and subgroup analyses specifically examining positive symptom domains consistently show significant improvements (26). Real world effectiveness studies further support these findings (16, 32–35).

In the presented cases patients also improved related to their cognitive functioning, according to improvements in the area of remembering, speaking and overall communication, as well understanding and especially better concentrating. Consecutively, better cognitive functioning resulted in less feel of exhaustion, less stressed and reduction of depressive symptoms. The dopamine D3 receptor has been identified as a key target for cognitive enhancement, and cariprazine’s partial agonism at D3 is thought to contribute to potential cognitive benefits. This effect has been supported by subgroup analyses from several clinical studies, indicating that cariprazine may indeed improve cognitive performance in relevant patient populations (29). Further, beside the many advantages of randomized controlled trials (RCTs), one of the biggest concerns is generalizability, as populations involved in these trials can significantly diverge from those seen in actual clinical practices (36). Similarly, patients with AUD are excluded of clinical trials, and the therapeutic product does not seem feasible in real-world settings for these population (37, 38). Therefore, in psychiatry, especially in the field of addiction, information from evidence-based medicine, such as case reports, are highly valuable. The most recent and relevant studies of Schröder et colleagues (39–41), were focused in the possibility of alcohol–medication interactions, and shown that a significant number of patients with AUD receive medications with the potential to interact with alcohol. The use of interaction checks to assess the appropriateness of medications for the addiction setting could be beneficial in improving medications safety for the patients with AUD.

Our cases show that cariprazine could represent a potential successful strategy in patients with severe AUD and other psychiatric diagnoses. Some psychiatric symptoms in these patients were partially resolved with other medications, but only cariprazine decreased cravings for alcohol. This fact could contribute potentially to the rationale for cautiously using cariprazine off‐label for AUD in patients without comorbidities, who have not responded to other medications such as naltrexone, quetiapine, olanzapine. Additional fact, that cariprazine is associated with fewer metabolic side effects compared to other antipsychotics, could positively influence the compliance (42). However, in the future, well conducted and highly controlled studies are needed to explore a potential cariprazine’s role and its place in the management of alcohol dependence.