The Effects of Serotonergic systems on Cognitive Flexibility and Perseverative Thinking: a comparison between SSRI, classical psychedelics, and acute tryptophan depletion in a Multilevel Meta-Analysis

Background: Serotonin has been implicated in cognitive flexibility and pathological perseverative thinking (PT), including rumination, worry, and obsessions. However, evidence remains fragmented across pharmacological manipulations, clinical populations, and outcome measures. This multilevel meta-analysis examined whether serotonergic interventions influence PT and cognitive flexibility. Methods: Preregistered and following PRISMA guidelines, we synthesized studies investigating three classes of serotonergic manipulations: acute tryptophan depletion (ATD), serotonin elevation via selective serotonin reuptake inhibitors (SSRIs), and classic serotonergic psychedelics. Three multilevel random-effects meta-analyses with cluster-robust variance estimation were conducted: (A) effects of ATD on cognitive flexibility (N = 266; 10 effect sizes), (B) effects of serotonin elevation on cognitive flexibility (N = 654; 15 effect sizes), and (C) effects of serotonin elevation on pathological perseverative thinking (N = 1,100; 20 effect sizes). Across analyses, the total sample comprised 2,030 participants and 45 effect sizes. Results: ATD did not significantly impair cognitive flexibility (g = 0.15, 95% CI [-0.07, 0.38], p = .23), and no moderation by task type, sex, or age was observed. Serotonin elevation similarly did not improve cognitive flexibility (g = -0.07, 95% CI [-0.36, 0.22], p = .63), with no significant performance differences emerging between SSRIs, classical psychedelics, or tryptophan enrichment. In contrast, serotonin elevation was associated with a significant medium-to-large reduction in perseverative thinking (g = -0.58, 95% CI [-0.76, -0.41], p < .001). Notably, while both pharmacological classes effectively reduced cognitive rigidity, SSRIs demonstrated a marginally smaller magnitude of symptom reduction compared to acute psilocybin interventions (p = .081). Furthermore, samples with a higher proportion of female participants showed larger reductions in perseverative thinking ({beta} = -1.86, p = .014), while worries exhibited marginally smaller reductions relative to obsessions ({beta} = 0.42, p = .055). Publication bias tests were non-significant across analyses. Conclusions: Serotonergic interventions robustly reduce perseverative thinking but do not consistently alter performance on laboratory measures of cognitive flexibility. These findings suggest that serotonin may influence cognitive-emotional rigidity and the subjective experience of repetitive thought more strongly than objective executive task performance. The dissociation between task-based and phenomenological outcomes aligns with contemporary models of serotonergic plasticity and highlights perseverative thinking as a potentially transdiagnostic therapeutic target of serotonergic interventions.