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Pharmacology of rising oral doses of 5-hydroxytryptophan with carbidopa

Centre for Human Drug Research and Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands

GE Jacobs

Centre for Human Drug Research and Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands, gjacobs{at}chdr.nl

DHM Hoeberechts-Lefrandt

Centre for Human Drug Research, Leiden, The Netherlands

ML de Kam

Centre for Human Drug Research, Leiden, The Netherlands

JP van der Post

Centre for Human Drug Research, Leiden, The Netherlands

R de Rijk

Department of Medical Pharmacology, LACDR, Leiden, The Netherlands

J van Pelt

Department of Clinical Chemistry, Leiden University Medical Centre, Leiden, The Netherlands

RC Schoemaker

Centre for Human Drug Research, Leiden, The Netherlands

FG Zitman

Centre for Human Drug Research and Department of Psychiatry, Leiden University Medical Centre, The Netherlands

JMA van Gerven

Centre for Human Drug Research, Leiden, The Netherlands

HJ Gijsman

Centre for Human Drug Research, Leiden, The Netherlands

5-hydroxytryptophan (5-HTP) is a direct 5-hydroxytryptamine (5-HT) precursor used to assess central serotonergic function. Its use has been limited by a narrow window between neuroendocrine changes and side effects, and variable kinetics related to inconsistent administration modes. By combining 5-HTP with carbidopa (CBD), increased bioavailability for brain penetration and decreased peripheral side effects would be expected, due to reduced peripheral decarboxylation of 5-HTP to 5-HT. A doubleblind, placebo-controlled, single rising dose, four-way crossover trial with placebo randomisation was performed in 15 healthy male volunteers to investigate the neuroendocrine dose–response relationship at various 5-HTP levels; the tolerability and subjective effects of oral 5-HTP at 100, 200 and 300mg combined with CBD and the pharmacokinetic properties of the 5-HTP/CBD-challenge. Dose-dependent increases in average cortisol concentrations were observed. Mean response (area-under-the-curve) over the first 4 hours (SD): 172.0 nmol/L (22.3) for placebo, 258.3nmol/L (72.6) for 100mg, 328.47nmol/L (84.6) for 200mg and 387.3nmol/L (82.4) for 300mg 5-HTP. Similar dose-dependent increases for prolactin were seen while adreno-corticotrophic hormone response was more variable. 5-HTP kinetics were adequately described using a one-compartment model with first-order absorption and a lag time (mean oral clearance 28 L/h interindividual coefficient of variation 31%). Nausea and vomiting occurred dose-dependently as most frequent side effects, resulting in dose-related dropout of 6.6% at 100mg and 45.5% at 300mg 5-HTP. Orally administered 5-HTP combined with CBD is an effective serotonergic challenge test, exhibiting dose-related plasma concentrations and neuroendocrine responsiveness. Frequent occurrence of nausea and vomiting limits the applicability of this challenge at 5-HTP doses above 100mg

Key Words: 5-HTP • challenge test • 5-HT • serotonergic function • pharmacokinetics • pharmacodynamics • side effects • cortisol • prolactin • HPA-axis

This version was published on June 1, 2008

Journal of Psychopharmacology, Vol. 22, No. 4, 426-433 (2008)
DOI: 10.1177/0269881107082025


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