Ascorbate-Mediated Attenuation of Oral Amphetamine Absorption: Beyond Gastrointestinal Acidification: A Transporter Biology Hypothesis

The co-administration of ascorbic acid (vitamin C) with oral amphetamine reliably attenuates the drug's absorption and central effects, but only when administered during the absorption phase; post-absorption administration has no appreciable effect. The conventional explanation --- gastrointestinal acidification leading to increased ionisation of the weakly basic amphetamine --- is physiologically untenable given the stomach's native acidity, the strong buffering capacity of intestinal bicarbonate, and the failure of other acids to reproduce the effect. This paper proposes that the interaction arises from a biological rather than physicochemical mechanism, centred on the electrophysiological consequences of high-capacity sodium-coupled ascorbate transport (SVCT1) at the intestinal brush-border membrane. The misconceptions surrounding this interaction exists at three levels of sophistication: that vitamin C cancels amphetamine at any time; that the acidification mechanism implies vitamin C could also accelerate systemic clearance; and that the interaction is absorption-phase specific but mediated by gut acidification. This review addresses and seeks to correct all three levels, evaluates the acidification hypothesis against physiological evidence, introduces a mechanistic framework grounded in transporter biology and enterocyte electrophysiology, and identifies testable predictions that distinguish the proposed mechanism from the conventional model.