Acute tryptophan depletion. Part I: rationale and methodology Sean D. Hood, Caroline J. Bell, David J. Nutt Objective: Acute tryptophan depletion (ATD) is an experimental technique that has been widely used over the last decade to investigate the role of serotonin (5-HT) in a variety of disorders. This review, the first of two articles, describes the rationale behind this technique and provides detail on how it is applied in research settings. Method: The authors outline the development of this technique with reference to the sem- inal literature and more recent findings from neuroimaging and neuroendocrine studies. This is supplemented by the authors’ clinical experience of over 5 years of continuous experimental work with this paradigm in over 50 subjects. Results: Acute tryptophan depletion is a method that significantly reduces central 5-HT in human subjects. Non-serotonergic explanations of the effects of ATD have not been confirmed, supporting the specificity of this method. Conclusions: The ATD technique is a valid method of manipulating central 5-HT levels. The second article in this series will review the application of ATD in depression, anxiety and other psychiatric conditions. Key words: methodology, psychopharmacology, serotonin, tryptophan. Australian and New Zealand Journal of Psychiatry 2005; 39:558–564 Acute tryptophan depletion (ATD) is an experimental procedure that has been widely used over the last decade to investigate the role of serotonin (5-HT) in a variety of disorders and in the effects of treatment. The following two articles provide an update of this technique; the first part examines the pharmacology of 5-HT synthesis and outlines the reasoning behind the development of the ATD method; the second part reviews the clinical application of ATD to the field of psychiatry. David J. Nutt, Professor (Correspondence) Psychopharmacology Unit, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, England, UK. Email: david. j.nutt@bristol.ac.uk Sean D. Hood, Senior Lecturer School of Psychiatry and Clinical Neurosciences, University of Western Australia, Australia Caroline J. Bell, Senior Lecturer Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, New Zealand Revised 25 January 2005; accepted 7 February 2005. Tryptophan and serotonin synthesis The technique of ATD examines the behavioural and cognitive consequences of acute reductions in plasma tryptophan (TRP) levels. It is based on the premise that depletion of TRP, the precursor of 5-HT, leads to deple- tion of brain 5-HT. Tryptophan is an essential amino acid that mammals acquire from dietary sources [1]. Plasma TRP levels are determined by the balance between the dietary intake of TRP and its removal from the plasma by protein synthesis. Most of the TRP in plasma is bound to albumin, with 5% being left free and available for transport into the central nervous system (CNS) [2] – thus central brain TRP lev- els are more accurately predicted by free TRP than total (free + protein bound) TRP plasma levels [3]. Tryptophan is transported across the blood-brain barrier (BBB) by a specific carrier for which TRP and all other large neutral amino acids (LNAAs) (valine, leucine, isoleucine, me- thionine, phenylalanine and tyrosine) also compete [4]. The ratio of plasma TRP/plasma LNAAs has been noted