Liposomal Delivery as a Strategy to Improve Berberine Bioavailability: A Double-Blind, Crossover, Randomized Pilot Study in Healthy Males

Purpose: Berberine, despite broad therapeutic potential, exhibits poor intestinal absorption and can cause gastrointestinal discomfort at higher doses. This pilot study compared the absorption, metabolic responses, and safety of a liposomal berberine formulation against standard unformulated berberine powder. Patients and Methods: In a randomized, double-blind, crossover design, six healthy males (n = 6; age: 37.8 ± 3.3 years; height: 174.8 ± 5.0 cm; weight: 74.6 ± 2.9 kg) ingested a single 400 mg dose of berberine, either as unformulated or liposomal berberine (Specnova LLC, Tysons Corner, VA, USA). Venous blood samples were collected at 0, 0.33-, 0.67-, 1-, 1.5-, 2-, 4-, 6-, 8-, 12-, and 24-hours post-ingestion and analyzed for plasma berberine concentrations. Metabolic and safety markers were assessed over 24 hours. Results: Liposomal berberine produced significantly higher pharmacokinetic responses compared with unformulated berberine, including a 70.1% increase in Cmax ( p = 0.03) and a 42.8% increase in AUC 0 – 2 4 ( p = 0.03). No significant differences were observed between conditions in 24-hour changes in metabolic or safety markers. Conclusion: Liposomal delivery substantially enhances berberine absorption without negatively affecting metabolic or safety parameters in healthy male subjects. These findings support liposomal formulation as a promising strategy for improving berberine’s bioavailability and potential clinical utility. Given the small sample size and the inclusion of males only, these findings should be interpreted as exploratory and may not be generalizable to females or broader populations. Keywords: liposomal delivery, pharmacokinetics, bioavailability, herbal alkaloids, nutraceuticals