Study Limitations
impaired functional status from long COVID, neuroinflammation, fatigue
This study has limitations relating to enrollment, interventions, and assessment. The population affected by olfactory loss and other manifestations of long-COVID is heterogeneous, variously suffering from fatigue, cognitive, and respiratory symptom clusters [The weighted randomization scheme increased exposure of participants to a putative gold standard, but this approach contributed to smaller size of remaining groups and modest reduction in statistical power; the failure to detect any significant demographic associations should be interpreted accordingly. The analysis also did not incorporate serological or radiological biomarkers to assess changes in neuroinflammation or pharmacokinetic analysis, both are areas for future research.Nearly 1 in 5 of participants enrolled in this study dropped out before completion. This attrition introduces a risk of bias, since individuals who dropped out of the study might differ from those who completed the study. Our analysis did not find differences in baseline olfactory function or response to therapy between those who dropped out vs. those who completed the study. However, there was a lower rate of attrition in the once daily um-PEA–LUT alone group compared to other groups. Taking a supplement once a day is less burdensome than taking a supplement twice daily or combining the supplement olfactory training, which may partly explain this finding. We did not systematically collect data on reasons for dropout from the study. Possible contributors include logistical hurdles of the trial, impaired functional status from long COVID, perceived lack of benefit, perceived lack of need to complete the study if recovered, or interactions between these factors.Olfactory outcomes were performed with the validated Sniffin’ Sticks test using odor identification measures to maximize feasibility of serial assessments, consistent with prior work showing only a small effect of olfactory training on the threshold subtest for odor detection [In assessing olfactory recovery, the analysis was limited to use of “I” (odor identification) instead of the full TDI battery (odor threshold, identification, and discrimination), which was a deviation from the original clinical trial protocol. This modification resulted in less comprehensive analysis than the full TDI battery, and the rigor of odor identification in our study falls short of the internationally accepted standard of the University of Pennsylvania Smell Identification Test (UPSIT), which offers extensive normative data and a broad range of 40 or more odorants spanning a wide spectrum of olfactory stimuli. In the long-COVID population, which often experiences brain fog or other cognitive manifestations, participant fatigue and sustained attention were significant concerns. The abridged assessment based on identification is limiting and relied on use of clinically significant difference of three points compared to a difference of five points for the full TDI Battery; we cannot assess whether the single treatment with um-PEA–LUT might improve threshold or detection. Additional studies using TDI or UPSIT are needed to corroborate findings and determine generalizability to larger populations. In addition, limitations relating to blinding, randomization, and attrition increased risk of bias. Assignment to placebo vs. supplement was blinded for patients, clinicians, and statistician, but there was no patient blinding for once-daily vs. twice-daily supplement or for whether olfactory training was performed. In addition, a significant portion of patients enrolled did not complete the study, contributing to imbalance between the experimental groups in gender distribution and olfactory function.