2.3.4. Supplementing C: From Formulation to Dose

Vitamin C formulations are as diverse as the recommendations and health claims made in support various marketed supplements. However, there is no data to suggest that any formulation containing ascorbate, alone or in combination with bioflavonoids, liposomes, vitamin C breakdown products, or minerals, has any measurable effect on vitamin C bioavailability in humans. While there are claims that vitamin C from natural *versus* synthetic sources, there is little evidence to support this in human subjects [128].

Pharmacokinetic studies suggest the consumption of at least 200 mg/day of vitamin C in healthy young men and women results in plasma concentrations greater than 50 μM [105,106]. At this dose, nearly complete oral bioavailability is obtained, leukocyte saturation is achieved, and urinary excretion is minimized, suggesting a saturation point has been reached for vitamin C transport. A dose of 200 mg/day can be achieved through a diet rich in fresh fruit and vegetables. Although the limitations of extrapolating this data have been discussed, it has been suggested that 200 mg/day of vitamin C should be set as an optimal intake level for the general population [1]. As mentioned above, it is possible that increased intake of vitamin C is necessary for plasma saturation in some individuals, such as the elderly [101] or individuals with various genetic polymorphisms [103], which would likely necessitate the use of supplements.

Can a case be made for "megadose" levels of vitamin C, or those in excess of 1 g/day? As much as different authors have put forth their own perspectives on the subject, there are few RCTs examining the effect of large daily oral doses of vitamin C. Thus, it is difficult to speculate on the beneficial effect of such doses. Pharmacokinetic data show that daily oral doses of vitamin C up to 2.5 g/day result in higher plasma ascorbate levels than a 200 mg/day dose, despite decreased bioavailability and increased urinary excretion of vitamin C [105,106]; however, the differences are small and biologically most likely of little consequence. It has been speculated that high plasma ascorbate levels can be maintained by frequent dosing with ascorbic acid [129], but it unclear what health effect would be achieved by this regimen. To date, no papers have shown a benefit of achieving greater-than-saturation plasma levels in the long term, and this mechanism would need to be delineated before a recommendation could be made.

One possible effect of megadose levels of vitamin C may be in the gastrointestinal tract, where it may prevent the formation of carcinogenic *N*-nitroso compounds [130] and highly reactive electrophilic compounds from the diet, such as acrolein [131] or lipid peroxidation products [132]. An intriguing idea for a biological role of vitamin C in the digestive tract is an exploration of beneficial changes to microbiota populations in the gut. However, in all of these cases, studies have yet to be performed, currently making it premature to draw any conclusions about the beneficial effects of oral supplementation with high-dose vitamin C. Large doses of intravenous ascorbate are associated with anti-cancer effects [133] and represent a promising area of research in the future that should be a subject of future review.
