Serotonin a la carte: Supplementation with the serotonin precursor 5-hydroxytryptophan

Mood Disorders Center, Portland VA Medical Center, Portland, OR 97239, USA.
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 04/2006; 109(3):325-38. DOI: 10.1016/j.pharmthera.2005.06.004
Source: PubMed


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.

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    • "We also decided against the addition of carbidopa, which is known to prevent peripheral conversion of 5-HTP to 5-HT. As previously reported, the average systemic availability of oral 5-HTP was approximately 70% (Turner et al., 2006), and there is no consensus as to whether the addition of carbidopa increases the efficacy of 5-HTP (Zmilacher et al., 1988). "
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    ABSTRACT: The objective of this study was to test the hypothesis that serotonin O-sulphate (5-HT-SO4) could be quantified in human plasma using modern liquid chromatography-mass spectrometry (LC-MS) method as well as develop and validate that method. First, a suitable LC-MS method for detection of 5-HT-SO4 in human plasma samples was developed and validated. Second, a Pilot phase involving four healthy volunteers was executed, where a basal plasma level of 5-HT-SO4 was measured for all subjects and for one after the intake of 100 mg of a 5-hydroxytryptophan (5-HTP) -containing food supplement used to promote serotonergic stimulation of the central nervous system. The basal level of 0.9-2.8 ng/mL of 5-HT-SO4 was observed. The changes of plasma 5HT-O-SO4 showed 1.2 ng/mL before and 22.6 ng/mL 1 h after stimulation. Finally, nine healthy volunteers were selected for the Study phase, where a basal plasma level of 5-HT-SO4 was measured before and after the intake of 5-HTP. One hour after stimulation, six study subjects showed a decrease in 5-HT-SO4 levels while three subjects showed an increase. The changes of plasma 5HT-O-SO4 from the Study phase showed an average 5-HT-SO4 level of 19.2 ng/mL before and 15.7 ng/mL 1 h after stimulation indicating ability of method to emphasize quantitative changes. This was the first study in which naturally occurring 5-HT-SO4 was detected in the samples of human plasma obtained from healthy volunteers. The method developed herein is specific to the measurement of 5-HT-SO4, sensitive enough to quantify intra-individual changes in the samples of plasma and opens up new possibilities to evaluate pathways of serotonin metabolism by minimally invasive methods. The discovery of novel biomarkers using such approaches is increasingly required to expedite development of mechanism-based therapeutics and patient stratification.
    Frontiers in Pharmacology 04/2014; 5:62. DOI:10.3389/fphar.2014.00062 · 3.80 Impact Factor
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    • "This view was supported by injection of carbidopa, an inhibitor of the decarboxylation of the tyrosine oxidation product DOPA into the dopamine, which induced a phenotype on egg maturation very similar to that observed in PAH-silenced mosquitoes. Carbidopa can also inhibit the biosynthesis of serotonin from 5-Hydroxy-L-tryptophan [39] and we cannot exclude the possibility that the small but significant decrease in oviposition rate is also a behavioural effect due to serotonin imbalance. Concomitant to the egg development defects in PAH-silenced mosquitoes we observed an impaired ability of the mosquito to melanize Plasmodium berghei ookinetes upon the ingestion of an infected blood meal. "
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    ABSTRACT: The blood meal of the female malaria mosquito is a pre-requisite to egg production and also represents the transmission route for the malaria parasite. The proper and rapid assimilation of proteins and nutrients in the blood meal creates a significant metabolic challenge for the mosquito. To better understand this process we generated a global profile of metabolite changes in response to blood meal of Anopheles gambiae, using Gas Chromatography-Mass Spectrometry (GC-MS). To disrupt a key pathway of amino acid metabolism we silenced the gene phenylalanine hydroxylase (PAH) involved in the conversion of the amino acid phenylalanine into tyrosine. We observed increased levels of phenylalanine and the potentially toxic metabolites phenylpyruvate and phenyllactate as well as a reduction in the amount of tyrosine available for melanin synthesis. This in turn resulted in a significant impairment of the melanotic encapsulation response against the rodent malaria parasite Plasmodium berghei. Furthermore silencing of PAH resulted in a significant impairment of mosquito fertility associated with reduction of laid eggs, retarded vitellogenesis and impaired melanisation of the chorion. Carbidopa, an inhibitor of the downstream enzyme DOPA decarboxylase that coverts DOPA into dopamine, produced similar effects on egg melanization and hatching rate suggesting that egg chorion maturation is mainly regulated via dopamine. This study sheds new light on the role of amino acid metabolism in regulating reproduction and immunity.
    PLoS ONE 01/2014; 9(1):e84865. DOI:10.1371/journal.pone.0084865 · 3.23 Impact Factor
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    • "in the brain, whereas TPH1 is predominantly expressed in the pineal gland (Walther et al. 2003; Abumaria et al. 2008) and in the peripheral tissues (Malek et al. 2005; Turner et al. 2006; Nakamura and Hasegawa 2007). Genetic or epigenetic factors affecting TPH2 gene expression or catalytic properties may alter 5-HT neurotransmission and thereby modify behavioral traits, drug responses, and disease susceptibility. "
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    ABSTRACT: Serotonin (5-HT) is a neurotransmitter involved in many aspects of the neuronal function. The synthesis of 5-HT is initiated by the hydroxylation of tryptophan, catalyzed by tryptophan hydroxylase (TPH). Two isoforms of TPH (TPH1 and TPH2) have been identified, with TPH2 almost exclusively expressed in the brain. Following TPH2 discovery, it was reported that polymorphisms of both gene and non-coding regions are associated with a spectrum of psychiatric disorders. Thus, insights into the mechanisms that specifically regulate TPH2 expression and its modulation by exogenous stimuli may represent a new therapeutic approach to modify serotonergic neurotransmission. To this aim, a CNS-originated cell line expressing TPH2 endogenously represents a valid model system. In this study, we report that TPH2 transcript and protein are modulated by neuronal differentiation in the cell line A1 mes-c-myc (A1). Moreover, we show luciferase activity driven by the human TPH2 promoter region and demonstrate that upon mutation of the NRSF/REST responsive element, the promoter activity strongly increases with cell differentiation. Our data suggest that A1 cells could represent a model system, allowing an insight into the mechanisms of regulation of TPH2 and to identify novel therapeutic targets in the development of drugs for the management of psychiatric disorders.
    Journal of Neurochemistry 12/2012; 123(6):963-970. DOI:10.1111/jnc.12004 · 4.28 Impact Factor
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