Liang & Ho raise a number of interesting points. First, participants were tested following cocaine ingestion while in a low serotonin v. control state. Investigating the effects of repeated cocaine use in these states, we agree, would be interesting. Second, cocaine ingestion did not alter plasma tryptophan levels. We consider this a strength. Although acute cocaine administration increases extracellular serotonin levels, this need not be associated with decreased tryptophan levels in the periphery. In comparison, tryptophan levels fell as expected after the acute tryptophan depletion procedure, changes that are indicative of decreased availability of the serotonin precursor in brain. Third, Liang & Ho cite recent work indicating that greater striatal dopamine release in pathological gamblers correlates with higher subjective excitement and poorer performance during the Iowa Gambling Task. ^{Reference Linnet, Peterson, Doudet, Gjedde and MoSller1,Reference Linnet, Peterson, Gjedde and Doudet2} Our own study raises the possibility that individuals exhibiting the largest dopamine responses might have lower serotonergic tone. Although Campbell-Meiklejohn et al's elegant study ^{Reference Campbell-Meiklejohn, Wakeley, Herbert, Cook, Scollo and Ray3} suggests that low serotonin increases sensitivity to punishment when healthy participants perform an unfamiliar task, other work indicates that serotonin induces the opposite effect in response to highly salient rewards. ^{Reference Abler, GroUn, Hartmann, Metzger and Walter4} Moreover, numerous impulsivity subcomponents have been proposed, and serotonin's contribution to them seems to vary. Fourth, the minimum time between cocaine test sessions was 2 days, well beyond the drug's plasma half-life of 40–60 min. Average time between test sessions 1 and 2 was 30 days (s.d. = 19), and 36 days (s.d. = 46)between sessions 2 and 3. These sessions were randomised and counterbalanced, and no order effects were observed.

Finally, as Liang & Ho note, Professor Nutt commented on the two main effects of acute tryptophan depletion. That is, acute tryptophan depletion increased the dopamine response when patients took cocaine, and decreased it when the drug was absent. These opposite effects in the presence v. absence of drug might contribute to a core feature of substance misuse: i.e. increased incentive motivational states when drugs and highly salient drug cues are present, and decreases when these stimuli are absent. ^{Reference Leyton5}