Cox et al ^{Reference Cox, Benkelfat, Dagher, Delaney, Durand and Kolivakis1} address an issue that has long been assumed to be a central aspect of brain function – the interplay of different neurotransmitters – but for which we have very little evidence so far. The 5-hydroxtryptamine (5-HT) system is perhaps the easiest to manipulate in that many studies have shown that simply by reducing the access of the 5-HT precursor L-tryptophan to the brain using a dietary manipulation (the tryptophan depletion technique) 5-HT function falls. This results in major alterations in brain function such as the loss of the antidepressant and anxiolytic effect of selective serotonin reuptake inhibitors (SSRIs) ^{Reference Bell, Abrams and Nutt2} and the shortening of rapid eye movement (REM) sleep latency. ^{Reference Evans, Golshan, Kelsoe, Rapaport, Resovsky and Sutton3} However, by and large, such changes in 5-HT function have not revealed much evidence of significant interactions with other neurotransmitters. In particular, when the tryptophan depletion approach was used to test a 5-HT link in the action of noradrenaline-acting antidepressants no measureable interaction was detected. ^{Reference Delgado, Miller, Salomon, Licinio, Krystal and Moreno4}

So is dopamine different? It seems that this might be the case as in Cox et al’s ^{Reference Cox, Benkelfat, Dagher, Delaney, Durand and Kolivakis1} study lowering 5-HT function by tryptophan depletion led to a reduction in the actions of cocaine to release dopamine that was to some extent paralleled by a reduction in cocaine craving. This finding fits with some preclinical literature that suggests 5-HT restrains dopamine neuronal function, which is sometimes seen clinically when elevating 5-HT by SSRIs causes symptoms attributable to low dopamine function such as akathisia and dystonias.

Low brain 5-HT function has long been associated with impulsive and aggressive traits ^{Reference Virkkunen, Rawlings, Tokola, Poland, Guidotti and Nemeroff5} that themselves may be predictors of stimulant misuse. The possibility that cocaine users might exacerbate their addiction by being in a state of relative L-tryptophan deficiency from poor diet and reduced appetite should also be considered.