Enhanced Vitamin C Delivery: A Systematic Literature Review Assessing the Efficacy and Safety of Alternative Supplement Forms in Healthy Adults

Vitamin C is an antioxidant and is essential for immune function and infection resistance. Supplementation is necessary when a sufficient amount of vitamin C is not obtained through the diet. Alternative formulations of vitamin C may enhance its bioavailability and retention over traditional ascorbic acid. This systematic review consolidates the evidence on this and the effects on immunity and infection. A systematic literature search was conducted in October 2024 in Embase and Medline, focused on healthy adults (Population); oral forms of liposomal-encapsulated ascorbic acid, liposomal-encapsulated lipid metabolite ascorbic acid, calcium ascorbate, slow-release ascorbic acid, or lipid metabolite ascorbic acid (Intervention); compared to placebo/others (Comparison); in terms of bioavailability, absorption, vitamin C concentration in plasma, serum, and leukocytes, and impacts on tolerability, immunity, and infection (Outcome); and included randomized or non-randomized controlled trials, single-arm trials, and observational studies (Study design). Thirteen studies were included, several evaluating calcium ascorbate in combination with vitamin C metabolites, including L-threonate, referred to here as Calcium ascorbate EC (Ester C®; n = 7). No safety or tolerability concerns were noted with Calcium ascorbate EC vs. placebo or ascorbic acid. Calcium ascorbate EC showed better tolerability and fewer epigastric adverse events, improved quality of life, and induced favorable oxalate changes vs. ascorbic acid. Four studies reported leukocyte vitamin C concentration, some showing higher concentrations with Calcium ascorbate EC vs. ascorbic acid; seven reported more favorable plasma concentrations with the alternative forms over ascorbic acid or placebo; one reported higher serum vitamin C levels with vitamin C lipid metabolites than with Calcium ascorbate EC, calcium ascorbate, and ascorbic acid. No study reported retention in tissues. One study reported a favorable impact of Calcium ascorbate EC on immune parameters, and one found an association of Calcium ascorbate EC with fewer colds and a shorter duration of severe symptoms vs. placebo. Findings suggest that alternative vitamin C forms can improve leukocyte vitamin C, sometimes without affecting plasma levels. Most studies (77%) had a low risk of bias. In conclusion, the type and delivery modality of vitamin C can impact its bioavailability and functionality. Studies highlight the advantages of Calcium ascorbate