DMSO Dual-Route Therapy for Refractory Tinnitus in Long-COVID and Post-COVID-19 Vaccine Injury

Subjective non-pulsatile tinnitus is a common and often debilitating symptom in patients with post-acute sequelae of SARS-CoV-2 (PASC, long-COVID) and post-COVID-19 vaccine injury. Mechanisms are thought to include neuroinflammation, microvascular dysfunction, oxidative stress, and mitochondrial impairment within cochlear and central auditory pathways. A substantial proportion of patients remain highly symptomatic despite standard therapies such as sound therapy, cognitive behavioral approaches, antidepressants, and corticosteroids. No FDA-approved curative pharmacologic therapy exists for chronic subjective tinnitus. Dimethyl sulfoxide (DMSO) is a tree-derived solvent with anti-inflammatory, antioxidant, vasodilatory, and penetration-enhancing properties. A foundational open-label study in the 1970s reported that DMSO-based formulations combined with vasoactive and anti-inflammatory agents improved or resolved subjective tinnitus in most treated patients, but this approach has not been systematically evaluated in modern refractory PASC or vaccine-injury cohorts. This pilot trial modernizes that historical concept using current compounding standards and telemedicine-enabled follow-up. This is a prospective, single-arm, open-label pilot study of approximately 20 adults with refractory subjective tinnitus attributed to PASC or post-COVID-19 vaccine injury. All participants receive a dual-route regimen for 30 days: (1) a DMSO-based otic liquid instilled into the external auditory canal every 4 days, and (2) a DMSO-based transdermal cream applied once daily to the bilateral mastoid regions, periauricular skin, and upper posterior neck. Both formulations are compounded by a licensed pharmacy according to protocol specifications. Standard tinnitus counseling and sound therapy are allowed, but no new tinnitus-specific medications may be started during the 30-day treatment window. The primary objective is to estimate the proportion of participants achieving at least a 50% reduction in Tinnitus Handicap Inventory (THI) score from baseline to Day 30. Secondary objectives include changes in THI score at later time points, visual analog scale (VAS) ratings of tinnitus loudness, annoyance, sleep interference, and concentration, patient global impression of change, and VAS measures of concomitant symptoms such as vertigo, insomnia, headache, and fatigue. Safety and tolerability are assessed by monitoring adverse events, including expected DMSO-related effects such as transient odor or skin irritation. Exploratory measures may include changes in tympanic membrane temperature and audiometric parameters where available. Screening and informed consent are performed via telemedicine, followed by a required baseline in-person ENT evaluation with otoscopy, audiometry, and completion of the THI and other questionnaires. During the 30-day treatment period, participants have regular telemedicine check-ins and complete electronic questionnaires through a secure, HIPAA-compliant REDCap-based platform. Follow-up assessments occur at approximately 6 and 12 months to evaluate durability of tinnitus response and longer-term safety. As a pilot study, analyses are descriptive and use paired pre- and post-treatment comparisons to generate effect-size estimates and feasibility data for future controlled trials.