Measurement of stable isotope ratios in methylamphetamine: a link to its precursor source

The illicit drug methylamphetamine is often prepared from the precursor ephedrine or pseudoephedrine, which in turn are obtained by three processes: extraction from the Ephedra plant ("natural"), via fermentation of sugars ("semi-synthetic"), and by a "fully synthetic" route from propiophenone. We report the first method to differentiate between the three industrial routes used to produce the precursors ephedrine and pseudoephedrine by measurement of stable isotope ratios of nitrogen (δ(15)N), hydrogen (δ(2)H), and carbon (δ(13)C). Analysis of 782 samples of seized methylamphetamine allowed classification into three groups using k-means clustering or the expectation-maximization algorithm applied to a Gaussian mixture model. By preparation of 30 samples of ephedrine by the "fully synthetic" industrial process and measuring their δ(15)N, δ(2)H, and δ(13)C values, we observed that (15)N becomes significantly depleted compared to the methylamine starting material. Conversion of ten ephedrine samples to methylamphetamine showed that this depletion is maintained in the final drug product, of which the δ(15)N, δ(13)C, and δ(2)H values were distinct from those of ephedrine and methylamphetamine samples of a semi-synthetic (fermentation pathway) origin. Combining modeling analysis with the new experiments and published information on the values of δ(2)H gave a definitive assignment of the three model groups, and equations to obtain probabilities for the precursor origin of any new sample. A simple rule of thumb is also presented. Making an assignment using delta values is particularly useful when no other chemical profiling information is available.