Associate editor: K.A. Neve
Serotonin a la carte: Supplementation with the serotonin precursor 5-hydroxytryptophan

https://doi.org/10.1016/j.pharmthera.2005.06.004Get rights and content

Abstract

This paper reviews the preclinical and clinical evidence regarding the use of the dietary supplement 5-hydroxytryptophan (5-HTP) for the treatment of depression. In the absence of supplementation with exogenous 5-HTP, the amount of endogenous 5-HTP available for serotonin synthesis depends on the availability of tryptophan and on the activity of various enzymes, especially tryptophan hydroxylase, indoleamine 2,3-dioxygenase, and tryptophan 2,3-dioxygenase (TDO). Factors affecting each of these are reviewed. The amount of 5-HTP reaching the central nervous system (CNS) is affected by the extent to which 5-HTP is converted to serotonin in the periphery. This conversion is controlled by the enzyme amino acid decarboxylase, which, in the periphery, can be blocked by peripheral decarboxylase inhibitors (PDIs) such as carbidopa. Preclinical and clinical evidence for the efficacy of 5-HTP for depression is reviewed, with emphasis on double-blind, placebo-controlled (DB-PC) trials. Safety issues with 5-HTP are also reviewed, with emphasis on eosinophilia myalgia syndrome (EMS) and serotonin syndrome.

Introduction

The synthesis of serotonin from tryptophan proceeds via the intermediary l-5-hydroxytryptophan (5-HTP; Fig. 1). The purpose of this paper is to review the preclinical and clinical evidence for the use of the dietary supplement 5-HTP in the treatment of depression.

5-HTP is an aromatic amino acid naturally produced by the body from the essential amino acid l-tryptophan. Produced commercially by extraction from the seeds of the African plant Griffonia simplicifolia, 5-HTP has been used clinically for over 30 years. In addition to depression, the therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including fibromyalgia, insomnia, binge eating associated with obesity, cerebellar ataxia, and chronic headaches (reviewed by Birdsall, 1998). 5-HTP easily crosses the blood–brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin (Birdsall, 1998). Supplementation with 5-HTP is hypothesized to normalize serotonin synthesis, which is putatively related to its antidepressant properties (see Section 2.1). However, most of the studies involving the use of 5-HTP for depression were conducted 20 or more years ago. At that time, there was a high level of interest in the serotonin hypothesis of depression. In December of 1987, the first selective serotonin re-uptake inhibitor (SSRI)–fluoxetine (Prozac)–was approved in the United States. Other SSRIs quickly followed. This new class of antidepressants became widely prescribed, as they were found to be both generally effective and safe. It is possible that this series of events led to a loss of interest in 5-HTP.

Section snippets

Serotonin hypothesis of depression

The serotonin hypothesis of major depression has been formulated in several different ways. One version of this hypothesis is that a deficit in serotonergic activity is related to the etiology of depression. Based on this hypothesis, the goal of antidepressant treatment is to increase synaptic serotonin levels. Serotonin re-uptake inhibitors increase synaptic serotonin levels by inhibiting re-uptake. However, many, if not most, antidepressants have serotonin re-uptake inhibition as part of

Preclinical evidence for efficacy of 5-hydroxytryptophan

5-HTP is commonly given to rats or mice to test the SSRI potency of putative antidepressants (O'Neil & Moore, 2003). This simple in vivo test measures the potency of a compound in potentiating the serotonin syndrome induced by the administration of 5-HTP (Grahame-Smith, 1971). The behavioral and physiological features of this syndrome include hypolocomotion, head twitch, forepaw treading, tremors, hindlimb abduction, flat body posture or hunched back, cyanosis, and hyperthermia. In rodents,

Brain imaging

In the early 1990s, 5-HTP labeled with [11C] became available for studies using positron emission tomography (PET) to assess serotonin-related metabolic activity in the brain (Hartvig et al., 1992, Reibring et al., 1992). In addition to studying serotonin synthesis, [11C]5-HTP has also been used to identify and detect neuroendocrine tumors. A recent review found that [11C]5-HTP PET was better than computed tomography and somatostatin receptor scintigraphy for tumor visualization, and [11C]5-HTP

Future directions

Unfortunately, because 5-HTP is a dietary supplement and not a prescription pharmaceutical, there is comparatively little financial incentive for extensive clinical research as to its efficacy and safety for depression. However, in view of (1) the clear role of serotonin in depression, (2) 5-HTP's obvious role in serotonin synthesis, and (3) the number of factors biochemically “upstream” from 5-HTP that are subject to dysregulation, we believe that 5-HTP supplementation deserves to be

Acknowledgment

The authors would like to thank Cory Stenzel for his help in creating the figures for this manuscript.

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