© International Psychogeriatric Association 2016.Background: Studies using acute tryptophan depletion (ATD) to examine the effects of a rapid reduction in serotonin function have shown a reduction in global cognitive status during ATD in Alzheimer's disease (AD) and Parkinson's disease (PD). Based on the severe cholinergic loss evident in dementia with Lewy bodies (DLB) and Parkinson's disease and dementia (PDD), we predicted that a reduction of global cognitive status during ATD would be greater in these conditions than in AD. Methods: Patients having DLB or PDD underwent ATD in a double-blind, placebo-controlled, randomized, counterbalanced, crossover design. Results: While the study intended to test 20 patients, the protocol was poorly tolerated and terminated after six patients attempted, but only four patients - three with DLB and one with PDD - completed the protocol. The Modified Mini-Mental State Examination (3MSE) score was reduced in all three DLB patients and unchanged in the PDD and dementia patient during ATD compared with placebo. Conclusions: This reduction in global cognitive function and the poor tolerability may fit with the hypothesis that people with dementia with Lewy bodies have sensitivity to the effects of reduced serotonin function.