Methamphetamine HCl was synthesized using three variations of the hydriodic acid/red phosphorus (HI/P_red) synthetic route. A Plackett-Burman experimental design was used to determine how reaction parameters affected the isotopic composition of the product. Isotope ratio mass spectrometry results showed only the source of precursor ¹³C was significant in determining product δ ¹³C; the manufacturer, reaction temperature, time, scale, and source of HI were not significant. The precursor was also the main determinant of product δ ²H, with smaller contributions from the HI source for one method. From precursor to product, large δ ²H depletion occurred for most samples. Deuterium nuclear magnetic resonance spectroscopy (²H NMR) was used to investigate the specific site of this. Significant fraction of deuterium was observed only at the benzylic position, the site of hydrogen addition during synthesis. Methamphetamine synthesized from ephedrine was shown to be depleted in this position.