Efficacy and safety of tradipitant in motion sickness: a systematic review and meta-analysis.

BACKGROUND: Motion sickness affects up to 30% of the general population, yet the three pharmacological agents currently approved in the United States, dimenhydrinate, meclizine, and scopolamine carry significant sedative and cognitive liabilities and offer incomplete protection against vomiting. Tradipitant, a selective neurokinin-1 receptor antagonist, has been evaluated across three randomized controlled trials for motion sickness prevention, but no pooled quantitative synthesis of this evidence exists. This study aimed to evaluate the efficacy and safety of tradipitant versus placebo in adults with a documented history of motion sickness. METHODS: PubMed, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov were searched from inception through March 25, 2026, following PRISMA guidelines (PROSPERO: CRD420261332049). Eligible studies were RCTs enrolling adults aged 18 years or older with documented motion sickness history. Binary outcomes were pooled as RRs using the Mantel-Haenszel method; continuous outcomes as MDs. Random-effects and fixed-effect models were applied to all outcomes. RESULTS: Three RCTs enrolling 808 participants were included, with two trials rated low risk of bias and one receiving some concerns. For vomiting incidence (primary outcome; 3 RCTs, n = 807), tradipitant significantly reduced vomiting risk versus placebo (RR 0.42, 95% CI 0.33 to 0.53; p-value < 0.0001; I² = 0%), with consistent dose-stratified estimates at 170 mg (n = 466; RR 0.38, 95% CI 0.28 to 0.53; p-value < 0.0001; I² = 0%) and 85 mg (n = 341; RR 0.46, 95% CI 0.32 to 0.65; p-value < 0.0001; I² = 0%), and a rough sea conditions pooled RR of 0.39 (95% CI 0.29 to 0.54). Nausea severity (3 RCTs, n = 491) showed no significant difference (SMD - 0.05, 95% CI - 0.24 to 0.13; p = 0.5846; I² = 0%; GRADE: Low). MSAQ total score (n = 488) was MD 1.43 (95% CI - 5.89 to 8.75; p = 0.4896; I² = 0%), MSAQ-GI subscale (n = 488) was MD - 3.14 (95% CI - 7.94 to 1.66; p = 0.1063; I² = 0%), and PGI-S score (n = 490) was MD - 0.18 (95% CI - 0.37 to 0.02; p = 0.0603; I² = 0%), none reaching significance. Any TEAE (n = 807) was significantly higher with tradipitant (RR 1.94, 95% CI 1.20 to 3.13; p = 0.0185; I² = 4.8%). However, individual adverse events did not reach significance: headache RR 1.45 (95% CI 0.85 to 2.50; p = 0.1283; I² = 0%), fatigue RR 2.23 (95% CI 0.78 to 6.36; p = 0.0940; I² = 0%), and somnolence RR 1.69 (95% CI 0.68 to 4.22; p = 0.1839; I² = 20.5%). CONCLUSION: Tradipitant significantly reduced vomiting incidence at both doses and across sea conditions, with negligible heterogeneity and stable sensitivity analyses. Although no significant improvement was observed in nausea or broader symptom burden, tradipitant was associated with a higher overall treatment-emergent adverse event rate than placebo. These findings support characterizing tradipitant as a selective vomiting prophylactic agent in the context of motion sickness; the absence of significant effects on nausea severity, MSAQ total and GI subscale scores, and PGI-S indicates that tradipitant should not be expected to provide comprehensive relief from the full symptomatic burden of motion sickness.