Tryptophan depletion in addictive behaviours.

We read with interest the article by Cox et al 1 and the insightful editorial by Nutt 2 and applaud both the research staff and the patients involved in this important study in view of the ethical issues and challenges in their work. They provide supportive evidence that low serotonin activity can increase dopaminergic responses to cocaine in humans, suggesting a possible mechanism specific to 'a low-serotonin state' in causing addictive behaviours. Although illuminating, the results of the study should be interpreted with caution. First, Cox et al use acute tryptophan depletion producing a reduction in plasma tryptophan, assumed to represent low levels of serotonin in the brain. The primary neuropharmacological effect of cocaine is to block the uptake of monoamines released into synapses, thereby increasing synaptic monoamine availability. It has been shown that cocaine can increase extracellular levels of serotonin in the nucleus accumbens of rats. 3 Notably, in Cox et al's study, plasma concentrations of tryptophan did not significantly differ between cocaine and placebo, which appears to be an unexpected finding. This should be left open to discussion. Second, the interplay between serotonin and cocaine may be altered after repeated cocaine administration, 4 a common manifestation in 'real-world' cocaine users. In this context, a study using an acute tryptophan depletion method plus repeated cocaine administration for patients with or without cocaine dependence, although ethically challenging, may obviously be of great clinical significance. Third, using repeated measures ANOVAs, it was assumed that the effects of cocaine did not carry over across conditions. Thus, it would have been clearer if the intervals between each condition were defined. In addition to the issues raised by Nutt, 2 as to the differences in response to various drugs of addiction, we would like to suggest that future research in the field of addiction focuses on using the tryptophan depletion test. For example, we now know that in pathological gamblers, dopamine release in ventral striatum correlates with excitement levels during the Iowa Gambling Task. 5 However, tryptophan depletion significantly decreased, rather than increased, the number of decisions made to chase losses and the number of consecutive decisions to chase, independent of changes in mood. 6 These findings, indubitably, did not support the hypothesis that low serotonin transmission may predispose to increased susceptibility to impulsive behaviours. It would be of interest to investigate the extent to which tryptophan depletion regulates dopamine release in patients who …