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
medRxiv June 22, 2026 Roi Basch, Maya Cohen, Leehe Peled‐avron
Serotonin-boosting treatments, such as SSRIs and psychedelics, consistently reduce repetitive negative thoughts like rumination, worry, and obsessions, but do not reliably improve performance on lab tests of cognitive flexibility. A meta-analysis of 2,030 participants across 45 effect sizes found that acute tryptophan depletion did not impair cognitive flexibility, and serotonin elevation did not enhance it. However, serotonin elevation produced a medium-to-large reduction in pathological perseverative thinking. The effect was stronger in samples with more female participants, and psilocybin showed a marginally larger reduction than SSRIs. The findings suggest serotonin's role in emotional and cognitive rigidity is distinct from its effects on objective executive function.