In four studies, all carried out more than 20 years ago, the combination of tryptophan plus a monoamine oxidase inhibitor was significantly better than tryptophan plus placebo in the treatment of depression. However, there is no evidence that tryptophan has any clinically significant effect on other treatments such as tricyclic antidepressants and ECT. Side effects of the combination of tryptophan and a monoamine oxidase inhibitors have limited the use of this combination. The risk of the serotonin syndrome is small, but it can occur. However, rapid cessation of tryptophan seems to avoid any long lasting adverse effects of the serotonin syndrome. In situations where enhancement of the therapeutic effect of monamine oxidase inhibitors outweighs the risk of adverse effects, the combination of tryptophan and a monoamine oxidase inhibitor is clinically useful. As the studies to date have looked at regular depressed patients, what is needed now is studies of this combination in therapy resistant depression.