Abstract
BACKGROUND: Chronic pain affects approximately 1.5 billion individuals worldwide, and currently available treatments often fail to provide adequate analgesia. Consequently, there is a need to explore novel analgesic compounds, including tetrodotoxin. In this study, we evaluated sensory and respiratory biomarkers of tetrodotoxin exposure in healthy volunteers. METHODS: Twenty-five healthy participants (mean age 23 years) were enrolled in a single-blind, dose escalation study conducted over two days. Participants received subcutaneous injections of tetrodotoxin at doses of 30 μg and 45 μg. Changes from baseline to 1 h post administration were assessed using quantitative sensory testing, olfactory function testing, hypoxic ventilatory response measurements and standardised neurological examinations. RESULTS: Administration of 30 μg tetrodotoxin resulted in significant alterations in mechanical detection threshold, pressure pain threshold and electrical pain tolerance. At the 45 μg dose, a modest effect on the cold pressor test was observed. No significant changes were detected in hypoxic ventilatory response or olfactory function at either dose. Tetrodotoxin was well tolerated, and no serious adverse events were reported. CONCLUSIONS: These findings suggest that subcutaneous tetrodotoxin at doses of 30 μg and 45 μg produces modest effects on specific sensory parameters in healthy individuals and demonstrates a favourable short-term safety profile. SIGNIFICANCE STATEMENT: This study provides the first comprehensive assessment of tetrodotoxin's effects on sensory and respiratory function in healthy humans. It shows that 30 μg and 45 μg doses selectively modulate mechanical detection and pressure pain thresholds without affecting olfaction, neurological performance or hypoxic ventilatory response. These findings confirm the short-term safety of tetrodotoxin and advance understanding of its human pharmacodynamics, supporting its continued evaluation as a potential analgesic for chronic or neuropathic pain.