Background: Rodatristat ethyl (RE) is a prodrug for rodatristat (R), a peripheral inhibitor of tryptophan hydroxylase (TPH). TPH isoform 1 is over expressed in lungs of pulmonary arterial hypertension (PAH) patients resulting in enhanced serotonin production and pulmonary arterial remodeling. R did not reduce brain 5HT in healthy nor PAH model rats. Here we predict potential for RE to reduce CNS 5HT in humans and report incidence of mood changes in healthy human subjects. Methods: Maximal exposure (Cmax) of pharmacologically active unbound R (Ru) in human brain was predicted from PK and QWBA data in rat, in vitro tissue binding, and PK in healthy human subjects. Cumulative mood-related safety data including nervous system, psychiatric disorders, and Columbia-Suicide Severity Rating Scale assessments were collated from Phase 1 studies in healthy adults administered repeat 100mg-800mg BID doses (14-16 days). Results: Predicted steady-state Ru Cmax in human brain was 0.22/0.34ng/mL (300mg/600mg BID) reflecting sub-pharmacological levels of only 4.4% and 6.8% of the CNS TPH isoform 2 IC50 (5ng/mL). In 89 healthy subjects, incidence of total nervous system disorder AEs was 19.1% (dizziness or headache) for RE, and 20.0% (dizziness, headache, somnolence) for placebo.  Psychiatric disorders were limited to anxiety in 2 (2.2%) RE-treated subjects. No RE treated subjects (0/53) reported suicidal ideation, suicidal behavior, or self-injurious behavior without suicidal intent. Conclusion: RE is predicted to have low risk for impacting brain 5HT consistent with no changes in mood or suicidal ideation in healthy subjects.