A randomized controlled trial of smell training and trigeminal nerve stimulation in the treatment of COVID-related persistent smell loss

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ABSTRACT COVID exposed the critical need for new and improved treatment interventions for chemosensory (i.e. smell and taste) dysfunction. Evidence indicates that COVID-related smell loss (SL) often endures well past recovery of the initial infection and is highly associated with other long COVID neuropsychiatric symptoms including impairments in mood, sleep, and cognition. To date, there are few interventions available to treat COVID-related persistent SL and its related impairments. While smell/olfactory training (ST) has emerged as a widely prescribed, front-line treatment for COVID-related persistent SL, rigorous study is required to determine its efficacy in long COVID. Moreover, given that ST is a lengthy treatment, requiring 12 weeks or longer of training, and is associated with slow improvement, non-compliance, drop-out, and modest effect size, additional study of adjunctive methods to improve its efficacy and speed of recovery are warranted. Here we propose the first study to investigate combinatorial trigeminal nerve stimulation (TNS) and ST in the treatment of post-COVID persistent SL and associated deficits in mood, sleep and cognitive impairment. Our previous work suggests that TNS, an easy-to-use and very safe form of non-invasive brain stimulation, increases olfactory sensitivity and has the potential to improve other symptoms of long COVID including mood, daytime sleepiness, and attention. Therefore, we will conduct a larger at-home, randomized, controlled trial of ST and determine whether TNS enhances the effects of ST in adults with COVID-related persistent SL. Our primary objectives are 1) to determine the efficacy of ST, compared to any natural gain in function, on olfactory-specific deficits (active ST versus sham ST), 2) to determine the TNS-enhanced effects of ST on olfactory-specific deficits (active TNS+ST versus active ST), and 3) to determine if TNS+ST, compared to ST, is also more efficacious in the treatment of other impairments (i.e. mood, sleep, and cognitive) associated with both SL and long COVID. While this research is focused on COVID-related persistent SL, the results will provide the necessary information to extend the study and use of ST and TNS to address wider chemosensory dysfunction. This line of investigation has the potential to make a substantial impact on how chemosensory dysfunction is treated and in turn significantly improve the current standard of care.