Deuterium-labelled 4-hydroxy-3-methoxyphenylglycol (MHPG), when administered intravenously, is rapidly converted to 4-hydroxy-3-methoxymandelic acid (or vanillylmandelic acid [VMA]) or conjugates of MHPG. Since over half of either racemic D,L-MHPG or the natural D-MHPG is converted to VMA and since about half of urinary VMA is derived from MHPG, estimates of the proportion of urinary MHPG derived from the brain must be revised. The results indicate that only about one fifth of urinary MHPG is derived from the brain, and clearly urinary MHPG cannot be used as a valid index of brain norepinephrine metabolism. While these observations do not alter the value of urinary MHPG as a predictor of therapeutic response or in subclassifying affective disorders, it is clear that new research questions must be formulated and appropriate investigations completed before the relationship of urinary MHPG to affective disorders is understood.