Psychiatry · Medical Literature
The Impact of Citicoline/Phosphatidylserine Supplementation on Cognitive Performance and Executive Functions in Mental Disorders: A Systematic Review of Controlled Trials.
Abstract
Citicoline and phosphatidylserine (PS) have been proposed as potential neuroprotective and cognitive-enhancing agents; however, evidence of their therapeutic impact across populations with mental disorders remains limited. This systematic review aimed to evaluate the effects of citicoline and PS, administered as monotherapy or adjunctive treatment, on cognitive performance in children, adolescents, and adults with mental disorders. A systematic review of 11 included studies was conducted following PRISMA guidelines. Databases searched were PubMed/MEDLINE, Scopus, Web of Science, and Cochrane CENTRAL through October 2025. Ten studies were randomized controlled trials (RCTs), and one was a non-randomized controlled trial (non-RCT). Methodological quality and risk of bias were evaluated using the RoB 2 and ROBINS-I tools. Five studies focused on children with ADHD, and the remaining studies included adults with mood disorders, alcohol and substance use disorders, and schizophrenia. Regarding ADHD, PS-containing supplementation produced significant improvements in attention and impulsivity in three studies, whereas two studies found no significant differences. A single study in schizophrenia reported significant improvements in verbal free recall but no global cognitive gains. Results for alcohol and substance use disorders, as well as mood disorders were mixed. Two studies revealed selective benefits in cognitive performance, while the others showed none. Overall, findings were heterogeneous and inconsistent across diagnostic groups. Given methodological limitations and high risk of bias, current evidence does not support citicoline or PS-containing compounds as effective cognitive enhancers in mental disorders. Consequently, these agents should be positioned as adjunctive or investigational rather than as evidence-based treatments.
Clinical relevance
Cognitive impairment is a transdiagnostic feature of major psychiatric conditions including ADHD, schizophrenia, mood disorders, and substance use disorders, for which few well-tolerated pharmacological options exist. This systematic review addresses the clinical gap surrounding nutraceutical cognitive enhancers—specifically citicoline and phosphatidylserine (PS)—which are increasingly used in practice despite limited high-quality evidence. Given the growing patient and clinician interest in adjunctive neuroprotective strategies, a rigorous appraisal of the controlled trial literature is timely and directly relevant to prescribing decisions.
Key findings
1. The systematic review included 11 controlled trials (10 RCTs, 1 non-RCT) identified across PubMed/MEDLINE, Scopus, Web of Science, and Cochrane CENTRAL through October 2025, following PRISMA guidelines with formal risk-of-bias assessment via RoB 2 and ROBINS-I tools. 2. Five studies examined pediatric ADHD populations: PS-containing supplementation demonstrated significant improvements in attention and impulsivity in 3 of these studies, while the remaining 2 studies found no statistically significant differences versus control conditions. 3. In schizophrenia (single study), PS supplementation yielded significant improvement in verbal free recall specifically, but no statistically significant gains in global cognitive functioning were observed. 4. In alcohol and substance use disorders, as well as mood disorders (remaining studies), results were mixed: 2 studies identified selective domain-specific cognitive benefits, while the others showed no significant cognitive benefit over control. 5. Overall findings were characterized by significant heterogeneity and inconsistency across all diagnostic groups, precluding pooled meta-analytic conclusions. 6. Methodological limitations—including high risk of bias across studies as assessed by standardized tools—were pervasive, undermining the strength and generalizability of any positive signals observed.
Practice implications
Clinicians should not routinely recommend citicoline or phosphatidylserine-containing compounds as evidence-based cognitive enhancers for patients with ADHD, schizophrenia, mood disorders, or substance use disorders, given the heterogeneous, inconsistent, and methodologically compromised evidence base. If considered at all, these agents should be framed explicitly as adjunctive or investigational options—particularly PS supplementation in pediatric ADHD where the most consistent (though not uniform) signal exists—with clear communication to patients and families about the current lack of robust efficacy data. Future adoption into practice should be contingent on adequately powered, low-bias RCTs with standardized cognitive outcome measures across well-defined psychiatric populations.