Olfactory training for COVID-19–related smell loss: the smell trial

Background Olfactory dysfunction (OD) after SARS-CoV-2 infection is common and can be prolonged and disabling, but evidence for effective treatments remains limited. We aimed to evaluate the efficacy and safety of 12-week olfactory training (OT) in adults with post-COVID-19 OD. Methods In this single-centre, randomized, controlled, assessor-blinded trial, adults aged ≥18 years with ≥3 months of ongoing OD after SARS-CoV-2-infection and impairment on Sniffin’ Sticks identification (SSI) testing were randomly assigned to 12 weeks of OT or no intervention. Because the protocol was developed during the pandemic under contemporaneous infection-control recommendations, olfactory testing was performed by drawing an odor line on single-use filter paper strips without directly presenting the reusable Sniffin’ Stick pen under the nose. This procedure was feasible for SSI and Sniffin’ Stick discrimination (SSD), but not for the Threshold assessment, which therefore was omitted. A prespecified modified Sniffin’ Sticks total score (mSST; SSI + SSD) was used as primary outcome; primary endpoint was change in mSST from baseline to 12 weeks. Results Seventy-seven participants were screened through October 31, 2024. Of these, 70 were randomly assigned, and 68 completed the randomised phase and were included in the per-protocol analysis (OT n = 38; no intervention n = 30). OT improved mSST compared with natural course, with a significant time-by-group interaction (F(1,66) = 29.95, p < 0.001; partial η²=0.31). Significant interactions were also observed for SSI and SSD scores (both p < 0.001; partial η²=0.27 and 0.19, respectively). Protocol-defined clinically relevant improvement in mSST occurred in 22/38 (57.9%) in the OT compared with 2/30 (6.7%) participants in the control group (φ = 0.53, p < 0.001). Clinician-rated and patient-reported global improvement also favoured OT. Subgroup analyses showed consistent treatment effects among participants with OD lasting >6 and >12 months. Participants from the control group who subsequently underwent OT during the exploratory extension phase showed significant improvements in mSST, SSI, and SSD scores. No serious adverse events occurred. Conclusions Twelve weeks of structured OT produced significant and clinically relevant improvements in psychophysical olfactory outcomes in adults with post-COVID-19 OD. The exploratory extension phase further supported improvement after delayed training initiation. OT appears to be a safe, practical, and scalable treatment option for post-COVID-19 OD. Trial registration Trial registration number: NCT05421221; URL: https://clinicaltrials.gov/study/NCT05421221 ; Trial registration date: 13 June 2022.