ImportanceMeniere disease accounts for up to 15% of new vestibular diagnoses,; however, the optimal treatment has yet to be identified. A conservative treatment that would reduce or stop the vertigo episodes has not been identified.ObjectiveTo determine the efficacy of a serotonin-norepinephrine reuptake inhibitor, venlafaxine, compared to placebo in treating patients with Meniere disease.Design, Setting, and ParticipantsThis was a randomized, double-blind, placebo-controlled, crossover pilot study spanning 22 weeks of follow-up. The clinical trial took place at a single-center tertiary referral center in Charleston, South Carolina. Participants were eligible if they were 18 years or older, had definite Meniere disease criteria as defined by Barany criteria, had at least 2 episodes in the last month, had not received intratympanic gentamycin, skull base surgery, or radiation therapy to the head or neck, not currently taking diuretics for Meniere disease, not currently taking oral steroids, and not currently taking serotonin-modulating medication. Patients were enrolled between February 2020 and September 2023.InterventionsPatients received either 1 venlafaxine tablet, 37.5 mg, taken daily by mouth for 8 weeks or 1 placebo tablet taken daily by mouth for 8 weeks. Group 1 received placebo during phase 1 of the trial and venlafaxine in phase 2 of the trial. Group 2 received venlafaxine during phase 1 of the trial and placebo in phase 2 of the trial.Main Outcomes and MeasuresThe main outcomes included the number of episodes and scores on the following scales: Dizziness Handicap Inventory, Neuropsychological Vertigo Inventory, Meniere Disease Patient-Oriented Symptom Index, 20-Item Short Form Health Survey, Penn State Worry Questionnaire, Cognitive Failure Questionnaire.ResultsA total of 182 patients were screened, and 40 participants with Meniere disease enrolled in the trial. The mean (SD) age of participants was 56.6 (14.3) years, and 22 (55%) were female. Participants had a mean (SD) of 13.8 (10.1) episodes per phase at baseline, 5.4 (4.4) episodes (Δ8.4) during the venlafaxine phase, and 5.0 (4.6) episodes (Δ8.8) during the placebo phase. No significant difference was identified between venlafaxine and placebo groups in the number of episodes or quality-of-life metrics.Conclusions and RelevanceThis randomized clinical trial failed to identify a difference between venlafaxine and placebo in number of episodes and other quality-of-life metrics. Future studies may benefit from different dosing regimens, larger cohorts, and longer lengths of therapy.Trial RegistrationClinicalTrials.gov Identifier: NCT04218123