A clinical and mechanistic study on traditional Chinese medicine herbs used in olfactory training

Olfactory dysfunction (OD) is a prevalent condition with limited treatment options, severely impairing patients' quality of life. Olfactory training (OT) using conventional odorants provides limited benefit. Traditional Chinese Medicine (TCM) herbs with complex odors may offer novel OT agents, but their mechanism and clinical value remain unclear.

In a prospective, open-label, parallel-controlled clinical observation, 73 OD patients (TCM-OT group: n = 36; control group: n = 37) received either 3-month TCM-based OT (6 herbs) or mometasone furoate nasal spray. Olfactory function was assessed by olfactory identification test (OIT), visual analog scale (VAS), and quality-of-life questionnaire (QOD). Volatile profiles of the six herbs were characterized by GC-MS. We then performed systematic functional screening of 16 major herb odorants and 4 common chemical odorants (eugenol, citronellal, phenylethyl alcohol, eucalyptol) against ~ 400 human olfactory receptors (hORs) using luciferase assays. Results were combined with public database entries (M2OR, OlfactionBase) to compare OR activation patterns. Molecular docking and molecular dynamics (MD) simulations were performed for (-)-Borneol, a representative active component, against its responsive ORs.

TCM-OT significantly improved the primary outcome (OIT) compared with control (mean improvement 11.31 ± 6.30 vs. 6.22 ± 4.99, p < 0.001, Cohen's d = 1.150). Secondary outcomes (VAS and QOD) showed trends favoring TCM-OT but did not reach statistical significance after Bonferroni correction. Greater benefit was observed in younger patients. Herb odorants displayed higher chemical diversity than chemical odorants. Functional screening identified 34 odorant-OR activation pairs for herb odorants (23 novel) and 11 pairs for chemical odorants (10 novel). Integrated analysis revealed that herb odorants collectively activated all 17 hOR families, whereas chemical odorants engaged only 8 families. Molecular simulations further elucidated the multi-receptor recognition mechanism of (-)-Borneol.

TCM-OT is a promising multi-target approach for OD. The broad activation of all OR families by herb odorants - contrasting with the limited engagement of conventional chemical odorants - provides a molecular rationale for the efficacy of TCM-OT and guidance for the selection of olfactory agents used in OT.

This study was retrospectively registered with the Eye Hospital of China Academy of Chinese Medical Sciences (YKEC-KT-2025-057-P002).