Research Update:5-HTP:5-Hydroxytryptophan.:Introduction and Its Benefit Applications.,Brain serotonin precursor,antidepressant,appetite suppressant,sleep aid.Serie No.:Pure10.Pure Phytochemical Series.MDidea Extracts Professional.

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Research Update:5-HTP:5-Hydroxytryptophan.

An HPLC method for the direct assay of the serotonin precursor, 5-hydroxytrophan, in seeds of Griffonia simplicifolia.:Phytochem Anal. 2002 Nov-Dec;13(6):333-7.Lemaire PA, Adosraku RK.Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, USA. Peter.Lemaire@uconn.edu

5-Hydroxytryptophan (1) is a naturally occurring amino acid found in significant levels in seeds of Griffonia simplicifolia and used in the treatment of the numerous effects of serotonin deficiency syndrome. An HPLC method has been developed for the direct assay of 1 in seeds of G. simplicifolia which overcomes the problems associated with previous techniques. By optimising the solvent extraction procedures and the HPLC conditions, levels of 1 could be estimated following a single-step seed extraction. The chromatographic conditions, solvent system and the extraction technique developed make this method relatively simple, fast and efficient. Using the described methods, the highest ever levels of 1 (namely, 20.83% on a fresh weight basis) have been determined in seeds of G. simplicifolia obtained in Ghana.

Further characterization of the combining sites of Bandeiraea (Griffonia) simplicifolia lectin-I, isolectin A(4).:Glycobiology. 1999 Nov;9(11):1161-70.Wu AM, Wu JH, Chen YY, Song SC, Kabat EA.Glyco-Immunochemistry Research Lab, Institute of Molecular and Cellular Biology, Chang-Gung University, Taiwan.

Bandeiraea (Griffonia) simplicifolia lectin-I, isolectin A(4)(GS I-A(4)), which is cytotoxic to the human colon cancer cell lines, is one of two lectin families derived from its seed extract. It contains only a homo-oligomer of subunit A, and is most specific for GalNAcalpha1-->. In order to elucidate the GS I-A(4)-glycoconjugate interactions in greater detail, the combining site of this lectin was further characterized by enzyme linked lectino-sorbent assay (ELLSA) and by inhibition of lectin-glycoprotein interactions. This study has demonstrated that the Tn-containing glycoproteins tested, consisting of mammalian salivary glycoproteins (armadillo, asialo-hamster sublingual, asialo-ovine, -bovine, and -porcine submandibular), are bound strongly by GS I-A(4.)Among monovalent inhibitors so far tested, p-NO2-phenylalphaGalNAc is the most potent, suggesting that hydrophobic forces are important in the interaction of this lectin. GS I-A(4)is able to accommodate the monosaccharide GalNAc at the nonreducing end of oligosaccharides. This suggests that the combining site of the lectin is a shallow cavity. Among oligosaccharides and monosaccharides tested as inhibitors of the binding of GS I-A(4), the hierarchy of potencies are: GalNAcalpha1-->3GalNAcbeta1-->3Galalpha1-->4Galbeta 1-->4Glc (Forssman pentasaccharide) > GalNAcalpha1-->3(LFucalpha1-->2)Gal (blood group A)()> GalNAc > Galalpha1-->4Gal > Galalpha1-->3Gal (blood group B-like)> Gal.

An insecticidal N-acetylglucosamine-specific lectin gene from Griffonia simplicifolia (Leguminosae).:Plant Physiol. 1996 Jan;110(1):195-202.Zhu K, Huesing JE, Shade RE, Bressan RA, Hasegawa PM, Murdock LL.Department of Entomology, Purdue University, West Lafayette, Indiana 47907, USA.

Griffonia simplicifolia II, an N-acetylglucosamine-specific legume lectin, has insecticidal activity when fed to the cowpea weevil, Callosobruchus maculatus (F.). A cDNA clone encoding G. simplicifolia II was isolated from a leaf cDNA library, sequenced, and expressed in a bacterial expression system. The recombinant protein exhibited N-acetylglucosamine-binding and insecticidal activity against cowpea weevil, indicating that glycosylation and multimeric structure are not required for these properties. These results support the hypothesis that genes of the legume lectin gene family encode proteins that function in plant defense against herbivores.

Separable anti-T and anti-Tk lectins from the seeds of Vicia hyrcanica.:Vox Sang. 1988;54(4):226-7.Liew YW, Bird GW.Blood Group Reference Laboratory, Oxford, UK.

Separable anti-T and anti-Tk lectins can be extracted from the seeds of Vicia hyrcanica. The anti-T lectin is similar to that of the peanut, Arachis hypogaea; the anti-Tk lectin compares favourably with that of Griffonia simplicifolia II.

Griffonia simplicifolia I-A4 staining of mice glomerular tufts and its alteration in diabetic mice.:Acta Pathol Jpn. 1986 Nov;36(11):1653-8.Yonezawa S, Shibata M, Shimizu T, Nakamura T, Sato E.

An isolectin from Griffonia simplicifolia (GS) seed--GSI-A4--stained the outer aspect of glomerular tuft (GT) intensely in the kidneys of ICR, C57BL/6J, BALB/c and NSY mice. Loss of the GSI-A4 staining was observed in the sclerotic areas of glomeruli in diabetic mice (NSY mice). This interesting staining will be useful for the analysis of the constitutions of GT in various experimental models of renal glomerular diseases in mice.

Binding of N-acetylgalactosamine-specific lectins to spin-labeled galactosamine derivatives.:Biochemistry. 1986 Jul 29;25(15):4457-61.Berliner LJ, Musci G, Maliarik M, Plessas NR, Goldstein IJ.

Legume seed lectins specific for N-acetyl-alpha-D-galactosaminyl end groups from Amphicarpaea bracteata, lima bean, Griffonia simplicifolia, Dolichos biflorus, and soybean were compared with respect to binding of several spin-labeled derivatives of D-galactosamine by electron spin resonance and precipitin inhibition analysis. Spin-label II [methyl 2-[[(2,2,5,5-tetramethyl-1-oxopyrrolidin-3-yl) carbonyl]amino]-2-deoxy-alpha-D-galactopyranoside], spin-label III [1-(methyl 2-deoxy-alpha-D-galactopyranosid-2-yl)-3-(2,2,6, 6-tetramethyl-1-oxypiperidin-4-yl)-2-thiourea], and spin-label IV [1-[4-[[(methyl 2-deoxy-alpha-D-galactopyranosid-2-yl)amino]carbonyl]phenyl]-3-(2, 2,6-tetramethyl-1-oxypiperidin-4-yl)-2-thiourea] contain 2-N-(oxypiperidinyl) or 2-N-(oxypyrrolidinyl) substituents varying in length and polarity of the linker arm between the glycoside and nitroxide ring. Spin-labels II and III were found to bind very weakly to all the lectins tested (Kd greater than or equal to 1.0 mM). Spin-label IV, containing a planar, nonpolar 2-N-phenyl group, was bound very strongly (Kd = 0.1-0.4 mM) and was moderately immobilized (2T parallel = 48-56 G) by all lectins except that from D. biflorus. Notably, the affinity of spin-label IV to lima bean lectin was 18-fold greater than that for methyl N-acetyl-alpha-galactosaminide. These results suggest that when the bulky oxypiperidinyl moiety lies in a position close to the sugar ring, it interferes with binding; in the cases where a phenyl group spacer exists, the aromatic ring in some cases actually enhances binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Contribution of alpha-D-galactopyranosyl end groups to attachment of highly and low metastatic murine fibrosarcoma cells to various substrates.:Exp Cell Res. 1984 Dec;155(2):345-58.Grimstad IA, Varani J, McCoy JP.

There are much greater numbers of cell surface terminal, non-reducing alpha-D-galactorpyranosyl groups in highly malignant (metastatic) cells than are found in low malignant cells derived from the same murine fibrosarcoma. We have examined the contribution of these residues to attachment of the cells to various collagens and to plastic. Removal of these carbohydrate groups with alpha-galactosidase or blocking them with lectins from Griffonia simplicifolia seeds or with anti-blood group B antiserum all dramatically inhibited the attachment of both the highly malignant and the low malignant cells. Following removal with the enzyme, the alpha-D-galactopyranosyl end groups were rapidly resynthesized. This resynthesis was inhibited by tunicamycin, an inhibitor of de novo glycoprotein synthesis. This antibiotic also impaired cell attachment and, when used in addition to treatment with alpha-galactosidase, it inhibited cell attachment more than did treatment with the enzyme alone. The effects of all treatments on cell attachment were greater for the highly malignant than for the low malignant cells. With the latter cells, inhibition by lectin was seen only in the absence of serum, whereas the adhesion of highly malignant cells was affected in both the presence and the absence of serum. On their surface membrane the highly malignant cells express much more than do the low malignant cells of a glycoprotein that cross-reacts immunologically with laminin. The basement membrane glycoprotein laminin promotes cell attachment to collagen, and both glycoproteins contain terminal, non-reducing alpha-D-galactopyranosyl groups. Attachment of cells is a requirement for the formation of a metastasis, and thus the laminin-like molecule and the alpha-D-galactopyranosyl end groups (whether on the laminin-related moiety or on other cell surface molecules) may both be important for expression of the most malignant phenotype.

Purification and Characterization of Griffonia simplicifolia Leaf Lectins.:Plant Physiol. 1983 Apr;71(4):879-887. Lamb JE, Shibata S, Goldstein IJ.Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109.

Leaves from mature Griffonia simplicifolia plants were examined for the presence of leaf lectins possessing sugar binding specificities similar to the four known seed lectins (GS-I, GS-II, GS-III, GS-IV). Three (GS-I, -II, -IV) of the four known G. simplicifolia seed lectins were present in the leaves. Leaf G. simplicifolia lectins I and IV were similar to the respective seed lectins. Leaf GS-II, however, was composed of two types of subunits (M(r) = 33,000 and 19,000), whereas the seed lectin consists of only one type of subunit (M(r) 32,500). Seed and leaf GS-II lectins also had different isoelectric points. All leaf and seed lectins were similar with respect to their hemagglutination and glycoconjugate precipitation properties and all subunits contained covalently bound carbohydrate. Leaf GS-IV appeared slightly under-glycosylated compared to seed GS-IV.The fate of GS-I and GS-II seed lectins in aging cotyledons was investigated. GS-I isolectins usually contain isolectin subtypes associated with each main isolectin. Upon inbibition and germination, these GS-I isolectin subtypes disappeared. Over time, GS-II lectin did not change its disc gel electrophoretic properties.

Isolation and characterization of a Lewis b-active lectin from Griffonia simplicifolia seeds.:J Biol Chem. 1982 Aug 25;257(16):9324-9.Shibata S, Goldstein IJ, Baker DA.

A fourth lectin (GS IV), a serologically Lewis b (Leb)-active binding lectin, was isolated from Griffonia simplicifolia seeds by affinity chromatography on an Leb (alpha-L-fucose-(1 leads to 2)-beta-D-Gal-(1 leads to 3)-[alpha-L-fucose-(1 leads to 4)]-beta-D-GlcNAc)-active fragment coupled to Synsorb, followed by elution with 0.1 N acetic acid. The purified lectin was shown to be homogeneous by polyacrylamide gel electrophoresis and analytical gel column chromatography on Sephadex G-200. A glycoprotein containing mannose, N-acetylglucosamine, fucose, and xylose (4:2:1:1), the lectin is a dimer composed of subunits of Mr = 29,000 and 27,000 with an aggregate Mr = 56,000. The GS IV lectin precipitate equally with blood group Leb fragment-bovine serum albumin (BSA) and H-active fragment (alpha-L-fucose-(1 leads to 2)-beta-D-Gal-(1 leads to 4)-[alpha-L-fucose-(1 leads to 3)]-beta-D-GlcNAc)-BSA conjugates but only poorly with a Lewis a fragment-BSA conjugate. Inhibition of precipitation with various mono- and oligosaccharides indicated that the lectin is specific for type 1 or 2 chains containing two alpha-L-fucosyl groups on C-2 of the D-galactosyl residue and C-3 or C-4 of the D-GlcNAc unit. One alpha-L-fucosyl residue on C-3 or C-4 of the D-GlcNAc residue of type 1 or 2 chains inhibited the reaction, although these oligosaccharides were less active than the oligosaccharides containing 2 alpha-L-fucosyl units. L-Fucose, methyl alpha- or beta-fucoside, and p-nitrophenyl alpha- or beta-L-fucoside did not inhibit the lectin. GSIV did not display mitogenic activity against mouse spleen cells or human peripheral lymphocytes.

Inhibition of Ehrlich ascites tumor cell growth by Griffonia simplicifolia I lectin in vivo.:Cancer Res. 1982 Aug;42(8):2977-9.Eckhardt AE, Malone BN, Goldstein IJ.

Griffonia (Bandeiraea) simplicifolia I (GS I) seeds contain a family of alpha-D-galactopyranosyl-binding isolectins which strongly agglutinate Ehrlich ascites tumor cells due to the presence of this determinant sugar on their cell surface glycoproteins. Administration of GS I lectin (100 micrograms/day or 300 micrograms on alternate days, i.p.) inhibits the growth of Ehrlich tumor cells in vivo. Mice given injections of only Ehrlich cells lived an average of 36 +/- 13 (S.E.) days with no mouse surviving longer than 53 days. Mice given injections of Ehrlich cells and 100 micrograms GS I lectin daily or 300 micrograms GS I lectin on alternate days showed 75 and 62% survival, respectively, after 60 days. Lectin-dependent, macrophage-mediated tumor cell lysis may be the mechanism whereby the GS I lectin exerts its cytotoxic effect.

In the search for a novel class of antipsychotic drugs: preclinical pharmacology of FG5803, a 1-piperazinecarboxamide derivative.:J Pharmacol Exp Ther. 1994 Dec;271(3):1338-47.Bj?rk A, Christensson E, Albinsson A, Gustafsson B, Pettersson E, Pettersson G, Svartengren J, Andersson G.Department of CNS Research and Development, Kabi Pharmacia Therapeutics, Malm?, Sweden.

Comparative studies of the 1-piperazinecarboxamide derivative 4-[3-(4-fluorobenzoyl)propyl]-N-cyclohexyl-1-piperazinecarboxamide hydrochloride (FG5803) were made with clozapine and haloperidol. Receptor studies revealed that FG5803 potently and selectively bound to the serotonin type 2A receptors (Ki = 13 nM). FG5803 inhibited 5-hydroxytrophan- and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-induced head twitches, which indicated potent in vivo serotonin type 2A receptor antagonism. FG5803 caused an acute activation of the tuberoinfundibular dopamine neurons and produced only a transient rise in plasma prolactin. In behavioral studies in rats, FG5803 showed strong antagonistic action on presynaptic dopaminergic autoreceptors but only weak postsynaptic dopamine D2 blockade. FG5803 was not cataleptogenic and did not antagonize amphetamine-induced stereotypies. FG5803 was active in the reduction of aggressive behavior and spontaneous exploratory behavior in mice and rats. Therefore, FG5803 is expected to constitute a promising approach in the search for a novel class of antipsychotic drugs that have a broader spectrum of activity and fewer adverse effects than the conventional, antidopaminergic antipsychotics.

Brain neurons partly expressing monoaminergic phenotype: distribution, development, and functional significance.:Ugriumov MV.

Besides the monoaminergic neurons possessing the whole set of the enzymes of monoamine synthesis from the precursor amino acid and the monoamine membrane transporter, the neurons partly expressing monoaminergic phenotype, one of the enzymes of monoamine synthesis and/or monoamine membrane transporter, have been discovered. The monoenzymatic neurons are widely distributed through the brain being even more numerous than monoaminergic neurons suggesting their important functional role. Most numerous monoenzymatic neurons express individual enzymes of dopamine (DA), tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). TH is enzymatically active in most monoenzymatic neurons converting L-tyrosine to L-DOPA. AADC is enzymatically active in all studied monoenzymatic neurons converting extracellular L-dihydroxyphenylalanine (L-DOPA) or 5-hydroxytryptophan captured from the extracellular space, to DA or serotonin, respectively. Monoenzymatic neurons expressing complementary enzymes of the DA synthetic pathway synthesize this neurotransmitter in cooperation. The cooperative synthesis of monoamines by non-monoaminergic neurons is believed to be a compensatory reaction under the functional insufficiency of monoaminergic neurons. In addition to monoenzymatic neurons, less numerous non-monoaminergic neurons expressing the serotonin membrane transporter but lacking all the enzymes or only rate-limiting enzymes of monoamine synthesis have been discovered. Although the functional significance of these neurons remains uncertain, they most probably represent a temporal store of serotonin captured within the brain either from the intercellular space or the cerebrospinal fluid. Thus, a substantial number of the brain neurons express partly the monoaminergic phenotype, probably, serving to compensate the functional deficiency of monoaminergic neurons.

Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence.:Meolie AL, Rosen C, Kristo D, Kohrman M, Gooneratne N, Aguillard RN, Fayle R, Troell R, Townsend D, Claman D, Hoban T, Mahowald M; Clinical Practice Review Committee; American Academy of Sleep Medicine.St. John's Regional Medical Center, Joplin, MO 64804, USA. meoli@pol.net

PURPOSE: To evaluate the level of evidence regarding the safety and efficacy of nonprescription therapies used for insomnia. REVIEWERS: Members of the American Academy of Sleep Medicine's Clinical Practice Review Committee. METHODS: A search of the World Wide Web was conducted using the terms insomnia, herbal remedies, and alternative treatments to develop a list of therapies. Therapies in this review include passionflower, valerian, Jamaican dogwood, hops, California poppy, chamomile, lemon balm, St. John's wort, kava kava, wild lettuce, scullcap, Patrinia root, first-generation histamine-1-receptor antagonists, alcohol, calcium, vitamin A, nicotinamide, magnesium, vitamin B12, I-tryptophan, 5-hydroxytryptophan, dietary changes, Natrum muriaticum, and Yoku-kan-san-ka-chimpi-hange. A search of the PubMed database was conducted in October 2002 using MeSH terms insomnia and each product listed in this paper, including only articles published in English between 1980 and 2002. Additional relevant articles from reference lists were also reviewed. Given the paucity of pediatric publications, this age group was excluded from this review. RESULTS AND CONCLUSIONS: Although randomized, placebo-controlled studies were available for a few compounds, rigorous scientific data supporting a beneficial effect were not found for the majority of herbal supplements, dietary changes, and other nutritional supplements popularly used for treating insomnia symptoms. Nevertheless, such treatments are described as alternative remedies for insomnia. Studies are limited by small numbers of participants and, in some instances, inadequate design, lack of statistical analysis, and sparse use of objective measurements. Sparse or no scientific data were found to support the efficacy of most products as hypnotics, including chamomile and St. John's wort. There is preliminary but conflicting evidence suggesting Valerian officinalis L. and first-generation histamine-1-receptor antagonists have efficacy as mild hypnotics over short-term use. There are significant potential risks associated with the use of Jamaican dogwood, kava kava, alcohol, and I-tryptophan. Physicians may find this information useful in counseling their patients.

Serotonin (5-HT) drugs: effects on appetite expression and use for the treatment of obesity.:Curr Drug Targets. 2005 Mar;6(2):201-13.Halford JC, Harrold JA, Lawton CL, Blundell JE.School of Psychology, University of Liverpool, Liverpool L69 7ZA, UK. j.c.g.halford@liverpool.ac.uk

The pivotal role of 5-HT in the control of appetite was formally proposed nearly 30 years ago. In particular endogenous hypothalamic 5-HT has been implicated in the processes of within meal satiation and the end state of post meal satiety. Of the numerous 5-HT receptor subtypes currently identified, 5-HT(1B) and 5-HT(2C) receptors are believed to mediate the 5-HT induced satiety. 5-HT drugs such as d-fenfluramine, selective serotoninergic reuptake inhibitor (SSRIs) and 5-HT(2C) receptor agonists have all been shown to significantly attenuate rodent body weight gain, an effect strongly associated with marked hypophagia. D-Fenfluramine, sibutramine, fluoxetine and the 5-HT(2C) receptor agonist mCPP have also all been shown to reduce caloric intake by modifying appetite in both lean and obese humans. Specifically, 5-HT drugs reduce appetite prior to and after the consumption of fixed caloric loads, and reduce pre meal appetite and caloric intake at ad libitum meals. Clinically significant weight loss over a year or more can be produced by both d-fenfluramine and sibutramine treatment, but apparently not by the SSRI fluoxetine. Treatment with the preferential 5-HT(2C) receptor agonist mCPP and the serotonin precursor 5-HTP has also been shown to produce weight loss in the obese. Issues around the actual and possible side effects of these compounds, and in the case of d-fenfluramine toxicity, have led to a search for drugs that act selectively on the CNS 5-HT receptors critical to the satiety response. Currently, a new generation of 5-HT(2C) selective agonists have been developed (including Ro 60-0175, Org 12962, VER-3323, BVT-933 and YM348) and at least one, ADP356, is currently undergoing clinical trials. Hopefully, such drugs will be as or even more effective at regulating appetite and controlling body weight, and will also be free of their predecessors' side effect.

A functional food product for the management of weight.:Crit Rev Food Sci Nutr. 2002 Mar;42(2):163-78.Bell SJ, Goodrick GK.Functional Foods, Inc., Belmont, MA 02478, USA. staceyjbell@yahoo.com

More than half of Americans have a body mass index of 25 kg/m2 or more, which classifies them as overweight or obese. Overweight or obesity is strongly associated with comorbidities such as type 2 diabetes mellitus, hypertension, heart disease, gall bladder disease, and sleep apnea. Clearly, this is a national health concern, and although about 30 to 40% of the obese claim that they are trying to lose weight or maintain weight after weight loss, current therapies appear to have little effect. None of the current popular diets are working, and there is room for innovation. With the advancing science of nutrition, several nutrients - low-glycemic-index carbohydrates, 5-hydroxytryptophan, green tea extract, and chromium - have been identified that may promote weight loss. The first two nutrients decrease appetite, green tea increases the 24-h energy expenditure, and chromium promotes the composition of the weight lost to be fat rather than lean tissue. These have been assembled in efficacious doses into a new functional food product and described in this review. The product is undergoing clinical testing; each component has already been shown to promote weight loss in clinical trials.

Effects of oral 5-hydroxy-tryptophan on energy intake and macronutrient selection in non-insulin dependent diabetic patients.:Int J Obes Relat Metab Disord. 1998 Jul;22(7):648-54.Cangiano C, Laviano A, Del Ben M, Preziosa I, Angelico F, Cascino A, Rossi-Fanelli F.Department of Clinical Medicine, University of Rome La Sapienza, Italy.

OBJECTIVE: In obese patients, brain serotonergic stimulation via orally administered 5-hydroxy-tryptophan (5-HTP), the precursor of serotonin, causes decreased carbohydrate intake and weight loss. Since diabetes mellitus is associated with depressed brain serotonin, hyperphagia and carbohydrate craving, we hypothesized that in diabetic patients, orally administered 5-HTP stimulates brain serotonergic activity and thus normalizes eating behaviour. To test this hypothesis, we investigated whether in diabetic patients: 1) predicted brain serotonin concentrations are depressed as a result of decreased availability of the precursor, tryptophan; and 2) oral 5-HTP is effective in reducing energy and carbohydrate intake. SUBJECTS AND METHODS: 25 overweight non-insulin dependent diabetic outpatients were enrolled in a double-blind, placebo-controlled study, and randomized to receive either 5-HTP (750 mg/d) or placebo for two consecutive weeks, during which no dietary restriction was prescribed. Energy intake and eating behaviour, as expressed by macronutrient selection, were evaluated using a daily diet diary. Plasma amino acid concentrations and body weight, as well as serum glucose, insulin and glycosylated haemoglobin were assessed. RESULTS: 20 patients (nine from the 5-HTP group and 11 from the Placebo group) completed the study. Brain tryptophan availability in diabetic patients was significantly reduced when compared to a group of healthy controls. Patients receiving 5-HTP significantly decreased their daily energy intake, by reducing carbohydrate and fat intake, and reduced their body weight. CONCLUSIONS: These data confirm the role of the serotonergic system in reducing energy intake, by predominantly inhibiting carbohydrate intake, and suggest that 5-HTP may be safely utilized to improve the compliance to dietary prescriptions in non-insulin dependent diabetes mellitus.

Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydroxytryptophan.:Am J Clin Nutr. 1992 Nov;56(5):863-7.Cangiano C, Ceci F, Cascino A, Del Ben M, Laviano A, Muscaritoli M, Antonucci F, Rossi-Fanelli F.3rd Department of Internal Medicine, University of Rome, La Sapienza, Italy.

Previous observations have shown that oral administration of 5-hydroxytryptophan (5-HTP) without dietary prescriptions causes anorexia, decreased food intake, and weight loss in obese subjects. To confirm these data over a longer period of observation and to verify whether adherence to dietary restriction could be improved by 5-HTP, 20 obese patients were randomly assigned to receive either 5-HTP (900 mg/d) or a placebo. The study was double-blinded and was for two consecutive 6-wk periods. No diet was prescribed during the first period, a 5040-kJ/d diet was recommended for the second. Significant weight loss was observed in 5-HTP-treated patients during both periods. A reduction in carbohydrate intake and a consistent presence of early satiety were also found. These findings together with the good tolerance observed suggest that 5-HTP may be safely used to treat obesity.

Differential effects of the novel antidepressant tianeptine on L-5-hydroxytryptophan (5-HTP)-elicited corticosterone release and body weight loss.:Eur Neuropsychopharmacol. 1992 Jun;2(2):115-20.Broqua P, Baudrie V, Chaouloff F.Laboratoire de Pharmacologie, Groupe de Neuropharmacologie, CNRS, CHU Necker-EM, Paris, France.

Biochemical and behavioural experiments have indicated that the novel antidepressant tianeptine stimulates 5-hydroxytryptamine (5-HT) reuptake. The present study has explored the influence of acute tianeptine pretreatment upon corticosterone release and body weight loss following L-5-hydroxytryptophan (5-HTP) administration in conscious rats. Administration of 5-HTP (20 mg/kg i.v.) increased plasma corticosterone levels to a similar extent in rats pretreated either with saline or tianeptine (10 mg/kg i.p., 60 min beforehand). Besides, prior administration of benserazide (50 mg/kg i.p., 30 min beforehand), an inhibitor of peripheral aromatic L-amino acid decarboxylase, prevented 5-HTP-induced corticosterone release in both saline- and tianeptine-pretreated rats. However, combined administration of benserazide and 5-HTP decreased overnight body weight in saline-, but not in tianeptine-pretreated rats. These results suggest that tianeptine preferentially activates 5-HT reuptake in central serotonergic neurones.

5-Hydroxytryptophan and carbidopa in spontaneously hypertensive rats.:J Hypertens. 1989 Apr;7(4):311-5.Itskovitz HD, Werber JL, Sheridan AM, Brewer TF, Stier CT.Department of Medicine, New York Medical College, Valhalla 10595.

Serial measurements of blood pressure, body weight, food and water intake, and salt and water excretion were compared in two groups of spontaneously hypertensive rats (SHR) over a 12-day period: control SHR (n = 11) and a group (n = 9) which received supplementary 5-hydroxytryptophan (5-HTP; 2 mg/ml) in its drinking water. During the final 4 days of study, both groups received additional oral carbidopa (50 mg/kg twice a day) to inhibit peripheral, but not brain aromatic L-amino-acid decarboxylase (LAAD), an enzyme necessary to the formation of 5-hydroxytryptamine (5-HT, serotonin) from 5-HTP. 5-Hydroxytryptophan increased urinary 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) markedly; following carbidopa, urinary 5-HT, and to a lesser degree urinary 5-HIAA, decreased, whereas brain 5-HT and 5-HIAA increased. Spontaneously hypertensive rats treated with 5-HTP plus carbidopa had significantly lower blood pressure levels, lower pulse rates, reductions in food and water intake, salt and water excretion, and a loss of body weight, when compared with the control SHR. These data indicate that enhanced brain formation of 5-HT can give rise to metabolic and circulatory responses with a resultant lowering of blood pressure.

The effects of oral 5-hydroxytryptophan administration on feeding behavior in obese adult female subjects.:J Neural Transm. 1989;76(2):109-17.Ceci F, Cangiano C, Cairella M, Cascino A, Del Ben M, Muscaritoli M, Sibilia L, Rossi Fanelli F.Department of Internal Medicine, University of Rome La Sapienza, Italy.

Nineteen obese female subjects with body mass index ranging between 30 and 40 were included in a double-blind crossover study aimed at evaluating the effects of oral 5-hydroxytryptophan administration on feeding behavior, mood state and weight loss. Either 5-hydroxytryptophan (8 mg/kg/day) or placebo was administered for five weeks during which patients were not prescribed any dietary restrictions. Feeding behavior was investigated by means of a questionnaire designed to establish the onset of anorexia and related symptoms. Food intake was evaluated using a three-day diet diary. BDI, SI, STAI-T, and STAI-S were used to assess mood state. The administration of 5-hydroxytryptophan resulted in no changes in mood state but promoted typical anorexia-related symptoms, decreased food intake and weight loss during the period of observation.

Modulation of serotonergic projection from dorsal raphe nucleus to basolateral amygdala on sleep-waking cycle of rats.:Brain Res. 2002 Jul 26;945(1):60-70.Gao J, Zhang JX, Xu TL.Laboratory of Receptor Pharmacology, Department of Neurobiology and Biophysics, University of Science and Technology of China, P.O. Box 4, Hefei 230027, PR China.

Putative serotonergic dorsal raphe nucleus (DRN) neurons display a dramatic role in the modulation of behavior. However, it is not clear how this modulation is mediated. The present study investigated the modulatory effects of serotonergic projection of the DRN to the basolateral amygdala (BLA) on the sleep-waking cycle using polysomnograph (PSG) in rats. DRN microinjection of kainic acid (KA) caused insomnia immediately. From the third day, however, slow wave sleep (SWS) and paradoxical sleep (PS) increased markedly. DRN microinjection of p-chlorophenylalanine (PCPA, once a day for 2 days), which inhibits the synthesis of serotonin (5-HT), led to similar effect to KA administration. The percent of sleep-wakefulness began to change on the third day after PCPA microinjection into the DRN, and the effect was most significant on the sixth day. The percent of sleep-wakefulness started to resume on the seventh day. SWS and PS were reduced after excitation of DRN neurons by microinjection of L-glutamate (L-Glu) into the DRN. Preapplication of the nonselective 5-HT receptor antagonist methysergide (MS) into bilateral BLA blocked the effect of DRN microinjection of L-Glu. Furthermore, bilateral BLA microinjection of 5-hydroxytryptophan (5-HTP), the precursor of 5-HT, on the sixth day after microinjection of PCPA into the DRN, could reverse the effect of PCPA microinjection. These results indicate that the modulation of the DRN on sleep is partially mediated by the serotonergic projection of the DRN to the BLA. Copyright 2002 Elsevier Science B.V.

Eosinophilia-myalgia syndrome case-associated contaminants in commercially available 5-hydroxytryptophan.:Adv Exp Med Biol. 1999;467:461-8.Klarskov K, Johnson KL, Benson LM, Gleich GJ, Naylor S.Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.

Recently, 5-hydroxy-L-tryptophan (5-OHTrp) has been promoted as an alternative to banned L-tryptophan as a dietary supplement. It has been claimed to help alleviate obesity, insomnia, depression, and headaches. However, eosinophilia-myalgia syndrome (EMS)-like symptoms have also been associated with ingestion or exposure to 5-OHTrp. HPLC-UV analysis of EMS-implicated 5-OHTrp revealed the presence of peak X, described as case-implicated. We show that peak X is actually a family of contaminants with the same molecular weight (234 Da) and similar HPLC retention times. We also demonstrate that all eight samples of commercially available 5-OHTrp analyzed by HPLC-MS contained three or more contaminants of the peak X family. The significance of these findings is discussed.

Fibromyalgia and the serotonin pathway.:Altern Med Rev. 1998 Oct;3(5):367-75.Juhl JH.

Fibromyalgia syndrome is a musculoskeletal pain and fatigue disorder manifested by diffuse myalgia, localized areas of tenderness, fatigue, lowered pain thresholds, and nonrestorative sleep. Evidence from multiple sources support the concept of decreased flux through the serotonin pathway in fibromyalgia patients. Serotonin substrate supplementation, via L-tryptophan or 5-hydroxytryptophan (5-HTP), has been shown to improve symptoms of depression, anxiety, insomnia and somatic pains in a variety of patient cohorts. Identification of low serum tryptophan and serotonin levels may be a simple way to identify persons who will respond well to this approach.

5-Hydroxytryptophan: a clinically-effective serotonin precursor.:Altern Med Rev. 1998 Aug;3(4):271-80.Birdsall TC.73541.2166@compuserve.com

5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. Unlike LT, 5-HTP cannot be shunted into niacin or protein production. Therapeutic use of 5-HTP bypasses the conversion of LT into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. 5-HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. It easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. In the CNS, serotonin levels have been implicated in the regulation of sleep, depression, anxiety, aggression, appetite, temperature, sexual behaviour, and pain sensation. Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia.

Promotion of sleep by prostaglandin D2 in rats made insomniac by pretreatment with para-chlorophenylalanine.:Neurosci Res. 1994 Nov;21(1):41-50.

The correlation between the somnogenic effect of prostaglandin (PG) D2 and the serotoninergic system was examined in freely-moving rats (n = 64) by use of a continuous infusion method. Rats pretreated with para-chlorophenylalanine (PCPA: 450 mg/kg body weight, i.p.) or non-PCPA-pretreated rats received infusion of PGD2, serotonin, or its direct precursor, 5-hydroxytryptophan (5HTP), into their third cerebral ventricle at a rate of 100 pmol/0.2 microliter/min between 11:00 and 17:00 h. In the PCPA-pretreated insomniac rats, PGD2 infusion resulted in an immediate increase in slow-wave sleep (SWS) and an increase with a 2-h latency in paradoxical sleep (PS). The total amounts of SWS and PS during the PGD2-infusion period were 151% and 154% of the respective control values. These results indicate that inhibition of the biosynthesis of serotonin and 5HTP by PCPA marginally affects the sleep-promoting effect of PGD2. The transient sleep restoration produced by 5HTP infusion into PCPA-pretreated rats was hardly affected by the simultaneous infusion (200 pmol/0.2 microliter/min; 07:00-17:00 h) of diclofenac sodium, an inhibitor of cyclo-oxygenase, suggesting that PGD2 production is not critically involved in the sleep restoration by 5HTP. The sleep-promoting property of PGD2 is thus probably independent of the serotoninergic modulation of sleep-wake activity.

The role of 5-hydroxytryptophan (5-HTP) in the regulation of the sleep/wake cycle in parachlorophenylalanine (p-CPA) pretreated rat: a multiple approach study.:Exp Brain Res. 1991;86(1):117-24.Touret M, Sarda N, Gharib A, Geffard M, Jouvet M.D¨¦partement de M¨¦decine Exp¨¦rimentale, INSERM U 52, CNRS, URA 1195, Universit¨¦ Claude Bernard, Lyon, France.

In the rat, the insomnia which follows the administration of parachlorophenylalanine (p-CPA), a serotonin synthesis inhibitor, is transiently reversed either by intra-cisternal injection of L-5-HTP or by an associated injection of 5-HTP and an L-aromatic-acid-decarboxylase inhibitor (benserazide). Histochemical, immunohistochemical and chemical investigations showed that 5-HTP administration does not lead to a detectable increase in cerebral 5-HT. These findings suggest that the restoration of sleep after p-CPA treatment could be mediated by the central action of 5-HTP.

Reversibility of para-chlorophenylalanine-induced insomnia by intrahypothalamic microinjection of L-5-hydroxytryptophan.:Neuroscience. 1989;28(1):83-94.Denoyer M, Sallanon M, Kitahama K, Aubert C, Jouvet M.D¨¦partement de M¨¦decine Exp¨¦rimentale, INSERM U52, CNRS UA1195, Facult¨¦ de M¨¦decine, Universit¨¦ Claude Bernard, Lyon, France.

Para-chlorophenylalanine, a blocker of serotonin biosynthesis by inhibiting tryptophan hydroxylase, induced total insomnia which was accompanied in cat by a permanent discharge of ponto-geniculo-occipital activity. L-5-Hydroxytryptophan microinjection (1-4 micrograms/0.5 microliters) in the anterior hypothalamus 72 h after para-chlorophenylalanine administration, restored both slow wave sleep and paradoxical sleep with variable latencies for each state of sleep. On the contrary, ponto-geniculo-occipital activity was never suppressed. The hypnogenic effects of L-5-hydroxytryptophan were always followed by a return of the para-chlorophenylalanine-induced insomnia. On the other hand, the temperature recording did not show any alteration of the cerebral temperature after para-chlorophenylalanine treatment but the subsequent L-5-hydroxytryptophan microinjection was followed by hyperthermia. Using immunohistochemistry for serotonin after intrahypothalamic L-5-hydroxytryptophan microinjection in parachlorophenylalanine-pretreated cat, we defined a restricted region of the anterior hypothalamus possibly responsible for the hypnogenic effect. This region included the lateral hypothalamus and the anterior hypothalamic area. It is suggested that the reversible hypersomnia after L-5-hydroxytryptophan microinjection in the anterior hypothalamus in para-chlorophenylalanine-pretreated cat is due to a neurohormonal action of serotonin: serotonin could act upon the anterior hypothalamus which secondarily inhibits a waking system located in the ventrolateral hypothalamus leading to the appearance of paradoxical sleep.

Insomnia caused by administration of para-chlorophenylalanine: reversibility by peripheral or central injection of 5-hydroxytryptophan and serotonin.:Sleep. 1985;8(1):56-67.Petitjean F, Buda C, Janin M, Sallanon M, Jouvet M.

Parachlorophenylalanine (PCPA) produces a total insomnia with a permanent discharge of pontogeniculooccipital (PGO) activity. We studied the reversibility of this insomnia in physiological slow-wave sleep (SWS) and paradoxical sleep (PS) after 5-hydroxytryptophan (5HTP) and serotonin (5HT) administration. Whereas D-5HTP (5 mg/kg) had no effect, parenteral injection of L-5HTP (2.5 mg/kg) or DL-5HTP (5 mg/kg) immediately suppressed PGO activity, then gave rise to the return of SWS and PS with delays of 26 and 60 min, respectively. Intraventricular or intracisternal administration of 5HTP (250 to 1500 micrograms) or 5HT produced physiological sleep with variable delays. If chloramphenicol (which selectively suppresses PS in normal cat) is administered in a PCPA-pretreated cat, 5HTP still suppressed PGO activity and gave rise to a lower amount of SWS but did not restore PS. The results suggest that 5HTP is rapidly decarboxylated into 5HT in restoring the PGO gating effect. Thus, 5HT would seem to act as a classic neurotransmitter. The long latency for PS (and its suppression by chloramphenicol) suggests that 5HT would appear to be a neurohormone controlling another sleep-inducing factor.

Sleep disturbances in a case of brain-stem lesions; pharmacological study.:Electroencephalogr Clin Neurophysiol. 1984 Jan;57(1):32-4.Laffont F, Cathala HP, Ernst A, Bormer M, Schneider-Helmert D, Schoenenberger GA.

A pharmacological study was carried out of a case of severe insomnia following brain-stem lesions; several polygraphic controls were used. Initially total duration of sleep was brief (less than 4 h) with a high REM/NREM ratio and a short paradoxical sleep (PS) latency. In addition, periodic breathing and tremor were observed. Slow injection of delta-sleep-inducing peptide (DSIP) improved sleep both quantitatively and qualitatively, although PS latency remained short. These effects were reversible. The effects of 5-HTP + benzerazide, of L-DOPA + benzerazide (Modopar) and of clonazepam (Rivotril) were compared.

Implication of hypothalamic structures in indolaminergic mechanisms of paradoxical sleep.:C R Seances Acad Sci III. 1983;297(11):531-4.Sallanon M, Petitjean F, Buda C, Janin M, Jouvet M.

Intratissue injection of 1 to 20 micrograms of L-5 HTP in numerous areas of the cat brainstem failed to reverse P-chlorophenylalanine induced insomnia. On the other hand, injection of 2 to 7 micrograms of L-5 HTP in the ventrolateral hypothalamus induced both slow wave sleep and paradoxical sleep after 36 and 76 min.

Restoration of paradoxical sleep by cerebrospinal fluid transfer to PCPA pretreated insomniac cats.:Brain Res. 1982 Nov 11;251(1):137-47.Sallanon M, Buda C, Janin M, Jouvet M.

In p-chlorophenylalanine (PCPA) pretreated insomniac cats, the intraventricular (i.v.t.) injection of artificial cerebrospinal fluid (CSF) did not impair the insomnia. CSF transfer from normal cats was followed in 4 out of 9 cats by the restoration of paradoxical sleep (PS). However, CSF transfer from paradoxical sleep deprived cats did result in 12 out of 13 experiments in a significant increase in slow wave sleep (SWS) and the induction of PS. Biochemical analysis of the CSF from normal or PS deprived cat has shown that the highest quantity of indolamines was at least 1000 times smaller than the threshold dose of 5-HTP (200 microgram) which has been shown to be able to restore sleep by i.v.t. injection in PCPA pretreated insomniac cats. These experiments provide evidence that the transfer of a small quantity of CSF (250 microliter) from a previously paradoxical sleep deprived cat can restore paradoxical sleep in an insomniac PCPA pretreated cat in bypassing the biosynthesis of serotonin (5-HT). These results suggest that a 'paradoxical sleep inducing factor' may be stored in the central nervous system during sleep deprivation.

5-HT antagonists suppress sleep and delay its restoration after 5-HTP in p-chlorophenylalanine-pretreated cats.:Eur J Pharmacol. 1982 Aug 13;82(1-2):29-35.Sallanon M, Buda C, Janin M, Jouvet M.

When injected intraperitoneally (i.p.) into normal cats, methiothepin (1-7.5 mg/kg) or metergoline (0.5-8 mg/kg) induced total insomnia. The duration of suppression of deep slow-wave sleep (SWS2) and paradoxical sleep (PS) was dose-related for methiothepin (10-30 h), but was shorter and not dose-related for metergoline (3-5 h). When injected into the fourth ventricle, methiothepin (20 microgram) induced a selective suppression of PS for 6-7 h). In rho-chlorophenyl-alanine (PCPA)-pretreated, insomniac cats, i.p. injection of 5 mg/kg of DL-5-hydroxytryptophan(5-HTP) was followed by SWS and PS after latencies of 25 and 62 min. When methiothepin (2.5 mg/kg) or metergoline (4 mg/kg) were given before 5-HTP, the latency for the first PS episode increased dramatically to 7 h. Thereafter PS occurred periodically for 10 h but no SWS appeared. These results suggest that a 'PS factor' induced by 5-HTP and different from indolamines is preserved during the antagonistic effect of methiothepin or metergoline until it can act upon the executive mechanisms of PS. Our data also suggest that metergoline and methiothepin suppress but do not delay the mechanism responsible for SWS2 in the PCPA-5-HTP paradigm.

Effects of serotonin synthesis inhibition on sleep in hippocampectomized rats.:Brain Res. 1982 May 20;240(1):175-7.Laguzzi RF.

In adult rats an anterodorsal bilateral hippocampectomy produced an increase in motor activity without modification of the amount of the different sleep stages. In hippocampectomized rats p-chlorophenylalanine produced an insomnia which can be reversed by 5-HTP. These results show that the insomnia produced by brain serotonin depletion is not a result of the hyperactivity produced by the treatments which cause such depletion.

Insomnia induced by P-chlorophenylalanine in cats. Its reversibility by intraventricular injections of indolamines.:C R Seances Acad Sci D. 1980 Dec 15;291(13):1063-6.Petitjean F, Buda C, Janin M, Sallanon M, Jouvet M.

Intraventricular injection of 250 microgram of 5 HTP induces both slow wave and paradoxical sleep, after 20-60 min. latencies, in insomniac Cats pretreated with P-chlorophenylalanine. Direct injections of 5 HTP in several brain stem structures do not induce sleep. The long latency or paradoxical sleep induction and its suppression with chloramphenicol suggest that indolamines are not directly responsible for paradoxical sleep, but that they act by controlling the synthesis and/or the liberation in the periventricular system of some specific paradoxical sleep inducing factor.

Effects of p-chlorophenylalanine (p-CPA) on sleep in olfactory bulb lesioned rats.:Jpn J Pharmacol. 1977 Jun;27(3):389-95.

The effect of p-CPA and 5-HTP followed by p-CPA on sleep was studied in rats with olfactory bulb lesions (O.B. lesioned rats). In these rats, electrodes were chronically implanted to record the EEG (frontal cortex and dorsal hippocampus), the cervical electromyogram and eye movements. The REM sleep stage was selectively decreased from 24 to 32 hours after 200 mg/kg of p-CPA in the sham lesioned rats, whereas both the slow wave sleep and REM sleep stages were markedly decreased by the same dose of p-CPA in the O.B. lesioned rats. In both sham and O.B. lesioned groups, the slow wave sleep and REM sleep stages decreased from 24 to 32 hours after 400 mg/kg of p-CPA and the percentage of decrease in the slow wave sleep stage was much larger with 400 mg/kg of p-CPA than with 200 mg/kg and 400 mg/kg of p-CPA. In the O.B. lesioned rats, the insomnia produced by 200 mg/kg and 400 mg/kg of p-CPA disappeared with 5-HTP (5 mg/kg). On the other hand, the insomnia produced by 200 mg/kg of p-CPA did not recur with 5-HTP in the sham lesioned rats, but with 400 mg/kg there was a recurrence. These results suggest that the enhanced effect of p-CPA and 5-HTP followed by p-CPA in the O.B. lesioned rats is due to changes in the sensitivity of the serotonergic system in the brain.

Neuroendocrine response to 5-hydroxy-L-tryptophan in prepubertal children at high risk of major depressive disorder.:Arch Gen Psychiatry. 1997 Dec;54(12):1113-9.Birmaher B, Kaufman J, Brent DA, Dahl RE, Perel JM, al-Shabbout M, Nelson B, Stull S, Rao U, Waterman GS, Williamson DE, Ryan ND.University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Pa., USA.

BACKGROUND: Altered serotonergic function has been observed in prepubertal children and adults with an acute episode of major depressive disorder (MDD). However, it is not known whether these alterations are present prior to the onset of MDD. METHODS: A serotonergic precursor, 5-hydroxy-L-tryptophan (L-5HTP) (oxitriptan) (0.8 mg/kg), was administered through an indwelling catheter to 36 children at high risk of MDD (with high family loading for MDD), 31 children with MDD, and 23 low-risk normal controls (with low family loading for mood disorders and no history of psychopathology). Blood samples for cortisol, prolactin (PRL), and growth hormone were obtained every 15 minutes for 180 minutes, beginning 30 minutes before L-5HTP infusion. RESULTS: Children at high risk of MDD and children with MDD had similar hormonal responses following L-5HTP infusion. After controlling for baseline values, both groups secreted significantly less cortisol and more PRL than did the low-risk normal controls, with the PRL finding being limited to girls. There were no between-group differences in baseline cortisol, PRL, or growth hormone secretion measures. CONCLUSIONS: Before the onset of affective illness, high-risk children had the same pattern of neuroendocrine response to the L-5HTP challenge as did children with MDD. These results extend earlier findings of altered serotonergic regulation in association with early-onset depression and indicate that these alterations may represent a trait marker for depression in children.

Behavioral, neuroendocrine and biochemical effects of different doses of 5-HTP in panic disorder.:Eur Neuropsychopharmacol. 1996 May;6(2):103-10.van Vliet IM, Slaap BR, Westenberg HG, Den Boer JA.Department of Psychiatry, Academic Hospital Utrecht, The Netherlands.

To investigate the role of serotonin (5-HT) in the pathophysiology of panic disorder (PD) a challenge test with L-5-hydroxytryptophan (5-HTP) was conducted. Seven patients suffering from PD and seven healthy controls received an i.v. challenge with 10 mg, 20 mg and 40 mg 5-HTP and placebo in random order on four different occasions. Before, during and until 2 h after 5-HTP administration anxious and depressive symptomatology was assessed. In addition, plasma levels of 5-HTP, cortisol, and 5-HIAA were measured at several timepoints. During and after infusion of placebo or any of the different dosages of 5-HTP, none of the patients or controls experienced a panic attack or showed an increase in anxiety or depressive symptoms. There was a dose-related increase in side effects, like nausea, dizziness and fatigue. Only infusion with 40 mg 5-HTP led to an increase in plasma cortisol in both patients and controls. The observed increase in plasma cortisol level was higher for patients compared to controls only at 30 min after infusion. In conclusion, stimulation of the serotonergic neuronal system by three different dosages of 5-HTP did not induce panic or anxiety in PD patients and healthy controls. The 5-HT hypersensitivity hypothesis of PD could not be confirmed in the present study.

Multiple sclerosis and major depression resistant to treatment. Case of a patient with antidepressive therapy-induced mood disorder, associated with manic features.:Clin Ter. 1995 Jun-Jul;146(6-7):449-52.Pariante CM, Orr¨´ MG, Carpiniello B, Rudas N.Istituto di Clinica Psichiatrica, Universit¨¤ degli Studi di Cagliari.

Patients with multiple sclerosis show higher prevalence of psychiatric disorders compared to general population, that are hardly managed by pharmacotherapy. In the present report a female patient, 44 years old, with diagnosis (according to DSM-IV) of 340 multiple sclerosis, 296.32 major depressive disorder, recurrent, moderate, 292.84 antidepressant-induced mood disorder, with manic features, is described. In this patient depressive symptoms did not respond to a number of drugs, including tricyclic antidepressants, selective serotonine re-uptake inhibitors hand lithium. Moreover, she had hypomanic and manic episodes induced by two different antidepressant, hydroxy-tryptophan and clorimipramine. Until today, only amisulpride (50 mg/die for four months, then 50 mg every two days for two months) has shown a significant effect on depressive symptomatology, moreover, this drug has not induced the occurrence of manic symptoms.

Behavioral, neuroendocrine, and biochemical effects of 5-hydroxytryptophan administration in panic disorder.:Psychiatry Res. 1990 Mar;31(3):267-78.den Boer JA, Westenberg HG.Department of Biological Psychiatry, University Hospital, Utrecht, The Netherlands.

L-5-Hydroxytryptophan (5HTP) was administered to 20 patients suffering from panic disorder and to 20 healthy controls. Subjects received 60 mg 5HTP in 300 ml saline solution. Before, during, and up to 2 hours after 5HTP administration, symptoms of anxiety and depression were assessed. In addition, plasma 5HTP, 3-methoxy-4-hydroxyethylglycol (MHPG), cortisol, beta-endorphin, and melatonin levels were measured at several time points, and the kinetics of 5-hydroxytryptamine (5HT) in blood platelets were measured. During and after the infusion of 5HTP, none of the patients showed an increase in anxiety or depressive symptoms, despite the presence of severe side effects. Some patients even experienced the 5HTP infusion as a relief. In contrast to the patients, nine control subjects reported depressed mood, although no increases in anxiety were noted. In both patients and controls, the 5HTP infusion led to substantial increases in plasma cortisol and beta-endorphin levels, while the plasma MHPG level was unchanged. Plasma melatonin increased significantly after 5HTP administration, suggesting that increasing 5HT availability in man might affect melatonin synthesis. The results of this study are at odds with the hypothesis that there is a supersensitivity of 5HT2 receptors in panic disorder.

Good and bad therapeutic combinations in the treatment of resistant depressions.:Encephale. 1986 Oct;12 Spec No:225-30.Poirier MF, Benkelfat C.

The definition of resistant depression is imprecise and variable according to the different authors. In most cases, the definition concerns depressed patients who have received well managed treatment with optimal doses of a thymoanaleptic over a sufficiently long period of time. The distinction of manic-depressive psychoses (MDP) with a rapid cycle also raises the problem of resistance to the prophylactic effect of mood regulators in MDP. The inefficacy of treatment in at least 20% of cases of depression has led a number of authors to propose original drug combinations with the aim of potentiating the action of previous treatments. Most of the studies published report isolated cases in which the therapeutic approach is often empirical and rarely explained. The most frequently reported combination is that of 2 drugs, generally including one antidepressant. Such combinations can induce pharmacodynamic or pharmacokinetic interactions resulting in either a potentiation or a reduction of the effects of one of the 2 drugs or to the induction of toxicity. These last two possibilities illustrate what the authors describe as "bad combinations". Various drug combinations are reviewed and critically analysed. The most interesting and best documented combinations involve the addition of lithium, MAOI and thyroid hormones to tricyclic treatment in non-responding patients. Other combinations with tricyclics have been reported less frequently: ECT, neuroleptics, reserpine, carbamazepine, 5 HTP, tryptophan, amphetamines, oestrogens, sleep deprivations.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment for therapy-resistant depression.:Psychopathology. 1986;19 Suppl 2:194-200.Kielholz P.

Thanks to progress in the diagnosis and treatment of depression it is now possible for most cases to be treated on an out-patient basis. Only 15-20% of patients require hospitalisation, most of them because their depression has proved resistant to therapy. To overcome therapy-resistance, the following methods of treatment are available: In therapy-resistant endogenous and psychogenic depressions, mono-infusion therapy is the treatment of choice; it can also be administered on an out-patient basis. In extremely intractable cases, it is advisable to resort to combined infusion therapy, preceded by five days of relaxation therapy with oral doses of a neuroleptic, and possibly reinforced by medication with 5-hydroxytryptophan (the precursor of serotonin) or by sleep deprival. In therapy-resistant cases of so-called masked depression, marked by overtones of anxiety and hypochondriasis, infusions of maprotiline are indicated, because this anti-depressant exerts a relaxing and mildly anxiolytic action, has a stabilising influence on the autonomic nervous system, and produces a mood-brightening effect. In patients who are apathetic and devoid of drive and suffering from involutional depression or depression of old age, infusion therapy plus administration of an MAO inhibitor can be recommended. Combination of an antidepressant with a neuroleptic agent also displaying certain antidepressive properties is really indicated only in the rare cases of schizo-affective psychosis. Electroconvulsive therapy should be employed only as a last resort in extremely retarded and apathetic patients with strong suicidal tendencies, and the indication for ECT should be established with the utmost reserve.

Affective disorders and aggression disorders: evidence for a common biological mechanism.:Suicide Life Threat Behav. 1986 Summer;16(2):103-32.van Praag HM.

Ever since the discovery that the classical antidepressants--tricyclics and MA oxidase inhibitors--exert an influence on central 5-HT, this neurotransmitter has been studied in depression, particularly in those forms responsive to this type of treatment. This chapter reviews the evidence in favor of a relationship between depression and central 5-HT dysfunctions. Most of the findings have been derived from patients with depression as the principal diagnosis. Some data have originated from patients suffering from a somatic illness and from depression as well. Both peripheral and central data are discussed. Although no single 5-HT-related finding in depression has so far been unequivocally established, the available evidence, in balance, justifies the tentative conclusion that disturbances in 5-HT metabolism can occur in depression. Lowered CSF 5-HIAA, the major indicator of disturbed central 5-HT metabolism in depression, has also been reported in aggression disorders, both in patients who had committed suicidal acts and in those with outward-directed aggression. The finding can not be explained by a concomitant state of depression. Rather than to discard the classical 5-HT-depression hypothesis, in favor of a 5-HT-aggression hypothesis, the hypothesis is launched that disturbances in serotonergic regulation can give rise to both mood and aggression disorders. This would provide a biological explanation for the clinical observation that those disorders frequently go hand in hand.

Serotonin precursors in chronic primary headache. A double-blind cross-over study with L-5-hydroxytryptophan vs. placebo.:J Neurosurg Sci. 1985 Jul-Sep;29(3):239-48.De Benedittis G, Massei R.

Serotonin (5-HT) plays a crucial role in mediating the descending pain inhibitory systems and in the pathophysiology of migraine. Previous studies regarding the use of 5-Hydroxytryptophan (5-HTP), the active precursor of 5-HT, in the treatment of Chronic Primary Headache (CPH) have been inconclusive so far. In order to assess the efficacy of the serotonin active precursor in chronic headache prophylaxis, a double-blind cross-over study has been carried out in 31 patients with CPH, comparing L-5-HTP to placebo. Clinical syndromes included: (a) migraine (16 patients); (b) mixed headache (6 patients); (c) psychogenic headache (5 patients); (d) muscle contraction headache (4 patients). L-5-HTP was administered for two months at daily doses of 400 mg p.o. The reduction in severity and frequency of headache in patients taking the active drug and placebo was noted. Mood patterns were also taken into consideration. L-5-HTP proved to be more effective than placebo in reducing both headache frequency and severity, but the difference was not statistically significant. Favourable responses (greater than 50% average reduction in headache symptoms) were obtained in 48% of the cases after the second month of treatment. No significant difference in therapeutic response was observed as related to different clinical syndromes, except for psychogenic headache patients, who responded poorly to the active drug. Side effects, experienced in 19% of the cases, were generally mild and transient. We conclude that L-5-HTP is a medication of moderate efficacy and remarkable safety, providing us with another alternative approach to CPH prophylaxis.

L-5HTP treatment in primary headaches: an attempt at clinical identification of responsive patients.:Cephalalgia. 1984 Sep;4(3):159-65.Bono G, Micieli G, Sances G, Calvani M, Nappi G.

The therapeutic response to L-5HTP, a serotonin precursor, was studied in an attempt to identify clinical subgroups of primary headache patients. The results at the 4th month control in 100 patients under L-5HTP treatment at the dose of 300 mg/day confirm previous observations on the activity profile of the drug, the effects of which are equally distributed between recurrent and daily forms as well as among clinical subtypes. The emerging profile of the responsive patients is characterized by such peculiar traits as prevalence of previous major mood disturbances and minor frequency of anxiety, longer duration of the illness and higher occurrence of some associated symptoms, lower incidence of exogenous and hormonal trigger factors, and previously positive response to pizotifen treatment.

Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. II. Relation to suicide, psychosis, and depressive symptoms.:Arch Gen Psychiatry. 1984 Apr;41(4):379-87.Meltzer HY, Perline R, Tricou BJ, Lowy M, Robertson A.

Serum cortisol levels were significantly higher after administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, in unmedicated patients with affective disorders than in controls. The magnitude of the serum cortisol increase correlated positively with the Schedule for Affective Disorders and Schizophrenia-Change (SADS-C) depression syndrome ratings and correlated negatively with psychotic symptoms in 26 patients with major depression. The serum cortisol response was greater in four depressed and three manic patients who made suicide attempts than in 33 patients who were not suicidal or only had suicidal thoughts. The cortisol response was also greater in patients with bipolar depression than in those with unipolar depression and those with a first-degree relative with an affective disorder. Absence of psychotic symptoms and commission of suicidal acts were associated with an increased cortisol response to 5-HTP in the depressed patients. The cortisol response to 5-HTP in the manic patients also tended to correlate with the SADS-C manic syndrome score.

Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. III. Effect of antidepressants and lithium carbonate.:Arch Gen Psychiatry. 1984 Apr;41(4):391-7.Meltzer HY, Lowy M, Robertson A, Goodnick P, Perline R.

Serum cortisol levels were significantly increased following administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, to patients with affective disorders. A three- to five-week period of treatment with lithium carbonate or monoamine oxidase (MAO) inhibitor augmented the mean 5-HTP-induced increase in serum cortisol concentration in manic or depressed patients, respectively: tricyclic antidepressant (TCA) and second-generation antidepressant treatment diminished the mean serum cortisol response in patients with major depression. These results are consistent with the hypothesis that lithium carbonate may enhance serotonin (5-HT) receptor sensitivity, whereas TCA and second-generation antidepressants diminish 5-HT receptor sensitivity. The enhancement of the cortisol response to 5-HTP by MAO inhibitors may be due to decreased metabolism of 5-HT. It is important to assess the effect of thymoleptic drug treatment on various responses to biogenic amine precursors or agonists in patients rather than laboratory animals.

Treatment of depression with L-5-hydroxytryptophan combined with chlorimipramine, a double-blind study.:Int J Clin Pharmacol Res. 1983;3(4):239-50.Nardini M, De Stefano R, Iannuccelli M, Borghesi R, Battistini N.

A double-blind clinical trial was carried out involving 26 hospitalized, depressed patients who were randomized into two groups. Patients in each group received chlorimipramine (50 mg/day), combined with L-5-HTP (300 mg/day) in Group A, and with placebo in Group B. The trial lasted 28 days. Two Group B patients dropped out. All the patients were evaluated by HRSD each week, and by ZDSI and CGI at the beginning and end of treatment. Several statistical analyses of the mean HRSD scores of each item presenting initial positive response and of ZDSI scores for both reactive and endogenous depression were performed, using Student's t-test. To evaluate the efficacy of the chlorimipramine +L-5-HTP combination versus control therapy the Mann-Whitney test was applied to the reduction in HRSD scores, showing 0.05 significance. The results for both types of pathology were quantitatively and qualitatively more positive for Group A than for Group B. Cluster analysis of HRSD item scores alone and between this scale and ZDSI, according to Carrol's correlation method for the symptoms of the cluster (mood, anxiety and somatic symptoms), was carried out to confirm the above results.

The effect of intravenous L-tryptophan on prolactin and growth hormone and mood in healthy subjects.:Psychopharmacology (Berl). 1982;77(3):217-22.Charney DS, Heninger GR, Reinhard JF, Sternberg DE, Hafstead KM.

In order to assess the effects of increased central nervous system serotonergic function in humans on prolactin (PRL), growth hormone (GH) and mood, intravenous L-tryptophan (TRP) was administered to ten healthy subjects. The TRP infusion induced robust increases in PRL in all ten subjects. A significant increase in GH concentration was also observed, although the response was more variable. The subjects reported feeling significantly more high, mellow, and drowsy following the TRP infusion in comparison to placebo. These findings indicate an important role for serotonin in PRL and GH secretion, as well as in mood regulation. The intravenous TRP challenge may be of use in the study of serotonergic function in a variety of neurologic and psychiatric diseases.

Antidepressant potentiation of 5-hydroxytryptophan by L-deprenil in affective illness.:J Affect Disord. 1980 Jun;2(2):137-46.Mendlewicz J, Youdim MB.

In an open trial study, L-Deprenil, an irreversible selective MAO-B inhibitor without 'chesse effect' was given to 14 patients with unipolar and bipolar depression receiving L-5-Hydroxytryptophan (L-5-HTP) and benzerazide. Ten out of 14 patients showed a good response to the combination of drugs and a correlation was found between the degree of platelet MAO inhibition and clinical response. In a double-blind controlled study, 18 affectively ill patients were randomly allocated to L-Deprenil plus L-5-HTP and benzerazide, 21 patients were treated with L-5-HTP and benzerazide and 19 patients with placebo only. Patients treated with the combination of L-Deprenil and L-5-HTP showed a significantly greater clinical improvement than placebo patients but this was not the case for patients treated with 5-HTP alone. A positive relationship was demonstrated between mood improvement and degree of platelet MAO inhibition in patients treated with L-Deprenil.

Simultaneous improvement of mood and release of growth hormone by L-5-hydroxytryptophan (Ro 3-5940) in normal subjects (author's transl).:Arzneimittelforschung. 1978;28(8):1291-2.Wirz-Justice A, Feer H, P¨¹hringer W, Graw P, Lacoste V, Gastpar M.

Infusion of a new soluble ester of L-5-hydroxytryptophan produced euphoria in 34/35 experiments in healthy subjects. Parallel measurements of growth hormone and mood changes showed a similar rise and fall of these two parameters in 8/11 subjects. These results indicate that central stimulatory serotoninergic mechanisms (in addition to the well-known dopaminergic and alpha-adrenergic stimulation) play a role in the control of growth hormone release.

Pharmacology of a new phthalane (Lu 10-171), with specific 5-HT uptake inhibiting properties.:Eur J Pharmacol. 1977 Jan 21;41(2):153-62.Christensen AV, Fjalland B, Pedersen V, Danneskiold-Samsoe P, Svendsen O.

The pharmacological profile of a new bicyclic substance, Lu 10-171 (1-(3-(dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalancarbonitril), is described and compared with that of existing tricyclic thymoleptics. In mice and rats the compound exhibited marked 5-HT potentiating properties both in vivo and in vitro, being 5-10 times as active as chlorimipramine. The tests included 5-HT-, 5-HTP- and tryptophan-potentiation. In monoamine oxidase inhibitor treated dogs and rabbits the compound caused a marked hyperthermia. In rabbits this effect was completely blocked by pretreatment with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine. Hyperthermia induced by the central catecholamine displacing substance H 77/77 in rats was not affected by Lu 10-171, whereas the substance abolished the temperature rise induced by H 75/12. Reserpine- and tetrabenazine-induced ptosis and tetrabenazine-induced immobility in mice were antagonized by relatively low doses of existing tricyclic thymoleptics, whereas Lu 10-171 was very weak in this respect. Very weak in vitro anticholinergic and antihistaminergic properties were also registered for Lu 10-171. It is concluded that Lu 10-171 is a very potent and highly specific potentiator of 5-HT both in vivo and in vitro probably due to inhibition of 5-HT uptake. Thus this compound might be a useful agent in studying the role of 5-HT neurone systems in the control of mood. The substance does not possess the NA potentiating and anticholinergic and antihistaminergic properties characteristic of the tricyclic antidepressants.

Theoretical and therapeutic potential of indolamine precursors in affective disorders.:Neuropsychobiology. 1977;3(4):199-233.Wirz-Justice A.

The strategy of loading with precursor amino acids of the monoamines postulated to be involved in the affective disorders is reviewed. Phenylalanine, tyrosine, L-dopa, L-tryptophan and L-5-hydroxytryptophan (L-5HTP) have been found to induce differential behavioral and biochemical effects in both healthy subjects and endogenous depressives. Indoleamine precursors predominantly cause mood changes. However, the efficacy of these amino acids as antidepressants has been neither clearly established nor refuted, probably due to insufficient consideration of the following criteria; sufficiently high plasma levels to be taken up into the brain, effective stimulation of serotoninergic systems, and selective increase of serotonin turnover with minimal interaction with other neurotransmitters. The use of intravenous L-5HTP as a provocative test in depressive patients, with concomitant neuroendocrinological and psychometric measurements, may be a method adequately fulfilling these requirements.

Intravenous L-5-hydroxytryptophan in normal subjects: an interdisciplinary precursor loading study. Part IV: Effects on body temperature and cardiovascular functions.:Pharmakopsychiatr Neuropsychopharmakol. 1976 Nov;9(6):289-94.Lacoste V, Wirz-Justice A, Graw P, P¨¹hringer W, Gastpar M.

In 14 healthy subjects the effect of a new soluble 1-5HTP ester (Ro 3-5940) in combination with a peripheral decarboxylase inhibitor on circulatory variables and body temperature was studied. The orthostatic adaptative functions were impaired while no consistent changes were observed in resting parameters. With the exception of an initial rise during infusion, measurements of oral temperature in the group as a whole showed no significant changes. However, if gender was considered, a long-lasting fall of temperature in males (N = 7) and rise in females (n = 6) was observed. The greatest difference between the hypothermic reaction in men and the hyperthermic reaction in women occured two hours after the end of infusion, at the same time where mood effects were most intense. The temperature findings support a modulatory function of central serotoninergic mechanisms in thermoregulation in man and emphasize the importance of sex specific factors in pharmacological studies.

Intravenous L-5-hydroxytryptophan in normal subjects: an interdisciplinary precursor loading study. Part III: Neuroendocrinological and biochemical changes.:Pharmakopsychiatr Neuropsychopharmakol. 1976 Nov;9(6):277-88.Wirz-Justice A, P¨¹hringer W, Lacoste V, Graw P, Gastpar M.

In a precursor study with i.v. 1-5HTP (Ro 3-5940) after peripheral decarboxylase inhibition with benserazide (Ro 4-4602) in healthy human subjects the following biochemical changes were found: 1. Prolactin release was stimulated by benserazide alone, and further stimulated by 1-5HTP (more in women than in men). 2. Basal growth hormone secretion was not affected by benserazide, but was significantly stimulated by 1-5HTP, often to extremely high values. The time course of growth hormone release followed that of mood elevation in 8/11 subjects (and was even correlated in 3), providing data for speculation as to the interrelationships between affective state and neuroendocrinological function. 3. Cortisol levels were higher than normal throughout the experiment, but followed the diurnal decline. A late stimulation of cortisol release after 1-5HTP was observed. 4. The lack of increased platelet serotonin after 1-5HTP indicated efficacious peripheral decarboxylase inhibition by benserazide. 5. Benserazide treatment inhibited platelet MAO activity in certain subjects. Short-term increases in MAO activity after 1-5HTP were observed. 6. 1-5HTP displaced albumin-bound tryptophan by 20%.

Intravenous L-5-hydroxytryptophan in normal subjects: an interdisciplinary precursor loading study. Part II: profile of psychotropic effects derived from protocols and psychometric investigations.:Pharmakopsychiatr Neuropsychopharmakol. 1976 Nov;9(6):269-76.Graw P, P¨¹hringer W, Lacoste V, Gastpar M, Wirz-Justice A.

L-5HTP was found to act primarily on mood, and unequivocally in the direction of elation. The subjective, protocols, psychometric results, and a double-blind study demonstrated convincingly and intra-individually consistent course of action of the substance under the chosen conditions of application. This course of effects can be described in three phases: In a first phase (about 0 to 1 1/2 hours after end of infusion) an intensive mood elevation (mostly experienced as a disharmonious feeling), psychomotoric activity, changed perception, as well as somatic side effects were observed. A second phase (about 1 1/2 to 3 1/2 hours after end of infusion) was characterized by elevated mood (feeling of well-being) together with a tendency to inactivity, whereas other phenomena were less often reported. A third phase (about 3 1/2 to 6 hours after end of infusion) was characterized by mood decline and the feeling of having again reached "normality". Side effects again tended to occur. It is shown that neither placebo nor situative effects greatly influenced elevation of mood or other substance effects. This is demonstrated by the homogenous time course and the blind studies.

Intravenous L-5-hydroxytryptophan in normal subjects: an interdisciplinary precursor loading study. Part 1: Implications of reproducible mood elevation.:Pharmakopsychiatr Neuropsychopharmakol. 1976 Nov;9(6):260-8.P¨¹hringer W, Wirz-Justice A, Graw P, Lacoste V, Gastpar M.

L-5-hydroxytryptophan ethylester (Ro 3-5940), a new soluble form of this serotonin precursor, was administered to 26 healthy, non-depressed subjects after premedication with the peripheral decarboxylase inhibitor benserazide (Ro 4-6402) in a total of 51 infusions. Those conditions were chosen for the main trial which in a pre-trial investigation had proved to combine minimal side effects with clear central effects in particular the observed marked mood elevation after 1-5HTP. Using these standardized conditions of application, an interindividually similar pattern of the time course of substance effects could be shown, and convincing evidence was deducible for an objective mood elevating effect of 1-5HTP infusion. Amongst the most impressive results was the parallelity of the time course of mood changes and concomitant changes in serum growth hormone levels. Especially emphasized are the important questions of effectivity, specificity and clinical practicability or safety, which are essential for any precursor study. Arguments are presented supporting the assumption that primarily serotoninergic changes underlie these mood effects. In our opinion this mode of i.v. application of 1-5HTP represents a practicable strategy for investigating biochemical hypotheses as to serotonin mediated normal and deviant human behaviour, especially in affective disorders.

Double-blind clinical trial of 5-hydroxytryptophan in a case of Lesch-Nyhan syndrome.:J Neurol Neurosurg Psychiatry. 1976 Jul;39(7):656-62.Frith CD, Johnston EC, Joseph MH, Powell RJ, Watts RW.

5-Hydroxytryptophan (5-HTP) treatment of a single case of Lesch-Nyhan syndrome showing compulsive self-mutilation, athetoid movements, and characteristic clinical biochemical picture was studied on a double-blind basis. 5-HTP or placebo was administered for seven fortnightly treatment blocks. 5-HTP produced a significant reduction of athetoid movement and a sedative effect but did not improve the patient's mood or reduce self-mutilation.

  Scientific References:

  1.Research Update:5-HTP:5-Hydroxytryptophan.:Introduction and Its Benefit Applications.
  2.Research Update:Griffonia Seed and 5-hydroxy tryptophan.

Claims & Warning:

Claims: Information this web site presented is meant for Nutritional Benefit and as an educational starting point only, for use in maintenance and promotion good health in cooperation with a common knowledge base reference...Furthermore,it based solely on the traditional and historic use or legend of a given herb from the garden of Adonis. Although every effort has been made to ensure its accurate, please note that some info may be outdated by more recent scientific developments......

Pharmakon Warning: The order of knowledge is not the transparent order of forms and ideas,as one might be tempted retrospectively to interpret it; it is the antidote....(Dissemination,Plato's Pharmacy,II.The Ingredients:Phantasms,Festivals,and Paints;138cf. Jacques Derrida.).

And as it happens,the technique of imitation,along with the production of the simulacrum,has always been in Plato's eyes manifestly magical,thaumaturgical:......and the same things appear bent and straight to those who view them in water and out,or concave and convex,owing to similar errors of vision about colors, and there is obviously every confusion of this sort in our souls.And so scene painting (skiagraphia) in its exploitation of this weakness of four nature falls nothing short of witchcraft (thaumatopoia), and so do jugglery and many other such contrivances.(Republic X,602c-d;cf.also 607c).