5-Hydroxytryptophan, a precursor for serotonin synthesis, reduces seizure-induced respiratory arrest.

OBJECTIVE: The DBA/1 mouse is a relevant animal model of sudden unexpected death in epilepsy (SUDEP), as it exhibits seizure-induced respiratory arrest (S-IRA) evoked by acoustic stimulation, followed by cardiac arrhythmia and death. Defects in serotonergic neurotransmission may contribute to S-IRA. The tryptophan hydroxylase-2 (TPH2) enzyme converts L-tryptophan to 5-hydroxytryptophan (5-HTP), a precursor for central nervous system (CNS) serotonin (5-HT) synthesis; and DBA/1 mice have a polymorphism that decreases TPH2 activity. We, therefore, hypothesized that supplementation with 5-HTP may bypass TPH2 and suppress S-IRA in DBA/1 mice. METHODS: TPH2 expression was examined by Western blot in the brainstem of DBA/1 and C57BL/6J mice both with and without acoustic stimulation. Changes in breathing and cardiac electrical activity in DBA/1 and C57BL/6J mice that incurred sudden death during generalized seizures evoked by pentylenetetrazole (PTZ) were studied by plethysmography and electrocardiography. The effect of 5-HTP administration on seizure-induced mortality evoked by acoustic stimulation or by PTZ was investigated in DBA/1 mice. RESULTS: Repetitive acoustic stimulation resulted in reduced TPH2 protein in the brainstem of DBA/1 mice as compared with C57BL/6J mice. S-IRA evoked by acoustic stimulation in DBA/1 mice was significantly reduced by 5-HTP. Following S-IRA, cardiac electrical activity could be detected for minutes before terminal asystole and death in both DBA/1 and C57BL/6J mice after PTZ treatment. The incidence of S-IRA by PTZ administration was greater in DBA/1 than in C57BL/6J mice, and administration of 5-HTP also significantly reduced S-IRA by PTZ in DBA/1 mice. SIGNIFICANCE: Our data suggest that S-IRA is the primary event leading to death incurred in most DBA/1 and some C57BL/6J mice during PTZ-evoked seizures. Suppression of S-IRA by 5-HTP suggests that 5-HT transmission contributes to the pathophysiology of S-IRA, and that 5-HTP, an over-the-counter supplement available for human consumption, may be clinically useful in preventing SUDEP.

Natural products of relevance in the prevention and supportive treatment of depression.

The use of herbs or their parts: leaves, roots, rhizomes, flowers, seeds, natural strains, as well as extracts or isolated metabolites is becoming more and more popular. Natural remedies not only act prophylactically, but also help to alleviate symptoms of many diseases and enhance the overall functioning of the internal organs. Many raw materials of natural origin plays a role in treatment of health problems, and also in case of serious diseases such as depression. Depression (affective disorder) now affects about 10% of the population, but in next few years due to the development of civilization and increasing pace of life, the probable number of people suffering from this disease can grow rapidly. Natural raw materials such as Bacopa monnieri, Crocus sativus, Eleutherococcus senticosus, Griffonia simplicifolia, Hypericum perforatum, Sceletium tortuosum, Piper methysticum, Rhodiola rosea, Aspalathus linearis, Camellia sinensis, Ficus carica, Lycium chinense, Cuminum cyminum, Panax Ginseng can effectively assist the prevention and treatment of depression. Daily diet may also have positive effect in prevention of this disease. It was found that 5-hydroxy-L-tryptophan, L-tryptophan (which are precursors of serotonin in the CNS), omega-3 fatty acids and anthranilic acid (vitamin L1) are able to improve mood. L-Tryptophan, 5-hydroxy-L-tryptophan are present in the largest quantities in the fruiting bodies of edible mushrooms. Omega-3 fatty acids are found in the flesh of fish, walnuts, soybeans, beans and chicken egg protein, while the anthranilic acid is commonly found in plants.

Mood disorders in youth: exercise, light therapy, and pharmacologic complementary and integrative approaches.

The therapeutic value of physical exercise, bright light therapy and dawn simulation, and several pharmacologic treatments, including hypericum (St. John's wort), S-adenosylmethionine, and 5-hydroxytryptophan, are reviewed, with a focus on their use for treating major depressive disorder in children and adolescents and also for alleviating depressed mood in the general (nonclinical) population of youth. For each treatment discussed, all published randomized, double-blind, placebo-controlled trials are summarized, along with some additional selected studies. Nutritional psychopharmacology and several other approaches to treating depression will be presented in an upcoming volume in the Child and Adolescent Psychiatric Clinics of North America.

Relationship between the absorption of 5-hydroxytryptophan from an integrated diet, by means of Griffonia simplicifolia extract, and the effect on satiety in overweight females after oral spray administration.

The management of overweight may include the use of dietary supplements targeted to counter the feeling of hunger. A randomized, double-blind, placebo-controlled trial has been performed in 20 overweight females. These subjects were randomly assigned to supplement their diet with either an extract from Griffonia Simplicifolia (10 subjects) or a placebo (10 matched subjects) for 4-weeks, in conjunction with a personalised reduced calorie diet. The main aim of this study was to evaluate the efficacy, by the assessment of 24-h urinary 5-hydroxyindoleacetic acid levels (5-HIAA), of 1-month administration of a dietary supplement containing 5-hydroxytryptophan (5-HTP) from botanical extracts in healthy, overweight females. Secondary endpoints were the assessment of sensation of appetite (by Haber score), body composition, and severity of binge eating. The supplemented group had a significant increase of 24-h urinary 5-HIAA levels (p<0.001), and a decrease in Haber score (p<0.001) while the placebo group did not show significant changes. With regard to changes in body composition, statistically significant differences between the treatment groups were found for the mean change in BMI, suprailiac skinfold thicknesses, arm circumference and hip circumference. Other parameters were found to be similar in the treated and in the placebo groups. In conclusion, this study shows that the 5-hydroxytryptophan present in the Griffonia extract, administered via spray to the oral cavity, is adequately absorbed, as confirmed by the increase in 24-h urinary 5-HIAA, and that the supplementation of the diet of overweight women with 5-hydroxytryptophan increases the feeling of satiety associated with a decrease in BMI.

Evaluation of anti-depressant-like activity of linezolid, an oxazolidinone class derivative - an investigation using behavioral tests battery of depression.

Linezolid, an oxazolidinone class derivative is a reversible and nonselective inhibitor of monoamine oxidase (MAO), predominantly for MAO-A type. MAO-A is a key enzyme regulating the catabolism of catecholamine neurotransmitters in the brain. It is well known that the catecholaminergic neuronal systems are associated with depression and inhibition of MAO-A level in the brain could be used to treat depression. Hence, the objective of this study was to evaluate the anti-depressant-like effect of linezolid, a MAO-A inhibitor in the animal models of depression. In the present study, linezolid (10 & 20mg/kg, i.p.), exhibited anti-depressant-like effects in forced swim test (FST) and tail suspension test (TST) in mice without influencing the baseline locomotion. Moreover, linezolid (10 & 20mg/kg, i.p.), potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and antagonized the reserpine-induced hypothermia in rats. In conclusion, the behavioral investigation revealed the anti-depressant-like effect of linezolid in rodent's behavioral model.

Nutraceuticals in the treatment of obsessive compulsive disorder (OCD): a review of mechanistic and clinical evidence.

Obsessive-compulsive disorder (OCD) is a debilitating mental illness which has a significant impact on quality of life. First-line SSRI treatments for OCD typically are of limited benefit to only 40-60% of patients, and are associated with a range of adverse side effects. Current preclinical research investigating nutraceuticals (natural products) for OCD, reveals encouraging novel activity in modulating key pathways suggested to be involved in the pathogenesis of OCD (glutamatergic and serotonergic pathway dysregulation). Emerging clinical evidence also appears to tentatively support certain nutrients and plant-based interventions with known active constituents which modulate these pathways: N-acetlycysteine, myo-inositol, glycine, and milk thistle (Silybum marianum). The serotonin precursor tryptophan is unlikely to be of use in treating OCD while 5-HTP may possibly be a more effective precursor strategy. However, there is currently no clinical evidence to test the efficacy of either of these substances. Currently the balance of clinical evidence does not support the use of St. John's wort (Hypericum perforatum) in OCD. While clinical research in this area is in its infancy, further research into nutraceuticals is warranted in light of the promising preclinical data regarding their mechanisms of action and their favourable side effect profiles in comparison to current SSRI treatments. It is recommended that future clinical trials of nutraceutical treatments for OCD utilize randomized placebo-controlled study designs and considerably larger sample sizes in order to properly test for efficacy.

Second-tier natural antidepressants: review and critique.

The use of Complementary and Alternative Medicine (CAM) for physical and mental problems has increased significantly in the US over the past two decades, and depression is one of the leading indications for the use of CAM. This article reviews some of the lesser-known natural products with potential psychiatric applications that are starting to emerge with some scientific and clinical evidence and may constitute a next wave of natural antidepressants: Rhodiola rosea, chromium, 5-Hydroxytryptophan (5-HTP) and inositol. Background information, efficacy data, proposed mechanisms of action, recommended doses, side effects, and precautions are reviewed. We found some encouraging data for the use of these natural products in specific populations of depressed patients. R. rosea is an adaptogen plant that can be especially helpful in treating asthenic or lethargic depression, and may be combined with conventional antidepressants to alleviate some of their common side effects. Chromium has a beneficial effect on eating-related atypical symptoms of depression, and may be a valuable agent in treating atypical depression and seasonal affective disorder. Inositol may be useful in the treatment of bipolar depression when combined with mood stabilizers. Evidence for the clinical efficacy of 5-HTP is also promising but still preliminary. Although more well-designed and larger controlled studies are needed before any substantive conclusions can be drawn, the available evidence is compelling and these natural products deserve further investigation as a possibly significant addition to the antidepressant armamentarium.

Clinical depression: an evidence-based integrative complementary medicine treatment model.

BACKGROUND: Clinical depression has a major impact on individuals and society, often presenting the clinician with a significant challenge. Recent evidence suggests that synthetic antidepressants- although effective in the treatment of severe depressed mood-may have only a weak effect against mild-moderate forms of depression. In such cases, nonpharmaceutical options may be indicated. Furthermore, research findings suggest that select natural products are effective adjuvants when combined with synthetic antidepressants. Research concerning the treatment of depression emphasizes individual monotherapies, which is often incongruent with clinical reality. In practice, clinicians often use a variety of interventions; however, this approach may not be systematic, and many interventions used may not be based on strong evidence. PRIMARY OBJECTIVE: This article proposes an evidence-based prescriptive clinical model based on the biopsychosocial model to treat unipolar depression. The "Antidepressant-Lifestyle- Psychological-Social (ALPS) depression treatment model" integrates nonpharmacological interventions (such as complementary medicines, lifestyle advice, and psychosocial techniques) for use by clinicians. RESULTS: Initially a review of nonpharmacological mood-elevating interventions was undertaken. Evidentiary support was revealed for use of psychological techniques such as cognitive and behavioral medicine and interpersonal therapy, St John's wort, S-adenosyl methionine, and aerobic and anaerobic exercise. There were inconsistent research findings for acupuncture, omega-3 fish oils, and L-tryptophan for depressed mood. From these evidencebased interventions an integrative model was formed. Clinical recommendations in addition to a practical stepped-care decision tree are outlined. CONCLUSION: The ALPS model has the potential to improve treatment outcomes and reduce relapse rates in clinical depression and warrants research using rigorous and appropriate methodology.

A randomized targeted amino acid therapy with behaviourally at-risk adopted children.

BACKGROUND: Increasing numbers of children are at-risk for behavioural and emotional disorders, a phenomenon contributing to increased use of pharmacological interventions for paediatric clients. Adverse side effects and other risks associated with pharmacological approaches have helped fuel interest in nutritional interventions for behaviourally at-risk children. METHODS: The current randomized clinical trial evaluates the efficacy of a neurochemical intervention involving the glutamine and glutamate analogue L-theanine and 5-hydroxytryptophan, the precursor for serotonin, with children adopted from traumatic backgrounds. RESULTS: Results include significant increases in urinary levels of the biomarkers for serotonin and gamma-aminobutyric acid, coupled with significant decreases in parent reports of the children's behaviour problems. CONCLUSIONS: While further research is needed, these initial findings are encouraging and are consistent with a growing number of studies indicating the efficacy of nutritional approaches to help behaviourally at-risk children.

Sleep and rhythm consequences of a genetically induced loss of serotonin.

BACKGROUND: A genetic deficiency in sepiapterin reductase leads to a combined deficit of serotonin and dopamine. The motor phenotype is characterized by a dopa-responsive fluctuating generalized dystonia-parkinsonism. The non-motor symptoms are poorly recognized. In particular, the effects of brain serotonin deficiency on sleep have not been thoroughly studied. OBJECTIVE: We examine the sleep, sleep-wake rhythms, CSF neurotransmitters, and melatonin profile in a patient with sepiapterin reductase deficiency. PATIENT: The patient was a 28-year-old man with fluctuating generalized dystonia-parkinsonism caused by sepiapterin reductase deficiency. METHODS: A sleep interview, wrist actigraphy, sleep log over 14 days, 48-h continuous sleep and core temperature monitoring, and measurement of CSF neurotransmitters and circadian serum melatonin and cortisol levels before and after treatment with 5-hydroxytryptophan (the precursor of serotonin) and levodopa were performed. RESULTS: Before treatment, the patient had mild hypersomnia with long sleep time (704 min), ultradian sleep-wake rhythm (sleep occurred every 11.8 +/- 5.3 h), organic hyperphagia, attentionlexecutive dysfunction, and no depression. The serotonin metabolism in the CSF was reduced, and the serum melatonin profile was flat, while cortisol and core temperature profiles were normal. Supplementation with 5-hydroxytryptophan, but not with levodopa, normalized serotonin metabolism in the CSF, reduced sleep time to 540 min, normalized the eating disorder and the melatonin profile, restored a circadian sleep-wake rhythm (sleep occurred every 24 +/- 1.7 h, P < 0.0001), and improved cognition. CONCLUSION: In this unique genetic paradigm, the melatonin deficiency (caused by a lack of its substrate, serotonin) may cause the ultradian sleep-wake rhythm.

Formulations of dietary supplements and herbal extracts for relaxation and anxiolytic action: Relarian.

Dietary supplements are widely used for desired effects on memory, insomnia, mood and anxiety. This review focuses on supplements which have anxiolytic or mild relaxation properties and enhance mood. For example, Kava (Piper methysticum) is reported to have anaxiolytic actions and to reduce tension through skeletal muscle relaxation. Dried passion flower (genus Passiflora) is reported to reduce insomnia and hysteria. Skullcap (genus Scutellaria), hops (Humulus lupulus), lemon balm (Melissa officinalis) and Valerian (Valeriana officinalis) root are all herbs reported as anaxiolytic calming agents. Further, extracts of Magnolia and Phellondendron bark are mild sedatives. Supplements such as gamma-aminobutyric acid (GABA), theanine, tryptophan and 5-hydroxytryptophan (5-HTP) are reported to promote relaxation. In general, these supplements appear to act as GABA receptor agonists or to boost GABA levels, although Kava inhibits both norephinephrine uptake and sodium and potassium channels and 5-HTP may act through elevation of serotonin. While questions remain in the literature regarding the medicinal value of these supplements in treating mood and anxiety disorders, based on cellular and animal studies as well as human clinical trials the literature supports a role for these preparations as useful alternatives in the management of the stress and anxiety of everyday life.

The potential of 5-hydryoxytryptophan for hot flash reduction: a hypothesis.

Hormone replacement therapy (HRT) is contraindicated in women with a history of breast cancer or a high risk of breast cancer development. Recent results from large clinical trials, such as the Women's Health Initiative, have demonstrated increased risks of thromboembolic events and a moderate increased risk of breast cancer in women using conjugated estrogens and progestogens. There is a need for viable non-hormonal alternative treatments to HRT, such as nutritional and botanical therapies, in this population of women, who tend to experience more significant vasomotor symptoms. Safe and effective therapies that do not stimulate breast cell proliferation could prove extremely useful for the management of such symptoms for women in both low- and high-risk breast cancer populations. As a non-hormonal treatment, anti-depressants, such as selective serotonin reuptake inhibitors (SSRIs), have been shown to improve hot flash symptoms in women. The proposed mechanism is related to an increase in serotonin allowing for an increase in the set point of the brain's thermoregulator. In small clinical studies, the administration of tryptophan and 5-hydroxytryptophan (5HTP), the precursors of serotonin, have been shown to reduce depressive symptoms, possibly by enhancing the synthesis of serotonin. Thus, increased serotonin levels may have the ability to decrease hot flashes in a mechanism similar to that of SSRIs without the risks of breast cell stimulation. This would be particularly desirable for menopausal women with breast cancer or with risks of breast cancer. This article discusses the background information on hot flashes, SSRIs, tryptophan, and 5HTP, and possible clinical application of 5HTP for menopausal women with breast cancer risk.

Selected integrative medicine treatments for depression: considerations for women.

This review evaluates the research published between 1966 and 2004 on several integrative treatments for depression, including omega-3 fatty acids, Hypericum perforatum (St. John's Wort), S-adenosyl-methionine, folate, 5-Hydroxytryptophan, acupuncture, exercise, and light therapy, with a particular emphasis on issues pertinent to women. Data from double-blind, placebo-controlled trials support each of these as treatment interventions for depression. We discuss both the strength of the evidence for each treatment and methodological issues related to interpretation of efficacy. Available data pertaining to considerations in women, including use during pregnancy and breastfeeding and interactions with hormonal therapies are discussed. The reviewed treatments deserve further research. Their appropriate place in the armamentarium of depression treatments for women must be defined. An evidence-based integrative medicine approach brings together treatment options with proven efficacy and the public's desire for complementary and alternative medicine treatments.

Treatment and outcome of Taiwanese patients with 6-pyruvoyltetrahydropterin synthase gene mutations.

Ten cases of tetrahydrobiopterin (BH4) deficiency were identified in 1,337,490 newborns screened in a Chinese population in Taiwan. The high incidence of BH4 deficiency in the Taiwanese population may be explained by a founder effect, since all of the patients revealed 6-pyruvoyltetrahydropterin synthase gene mutations, and grouping N52S and P87S mutations together constituted 88.9% of the disease alleles. BH4 supplementation with restriction of high-protein foods gave control of plasma phenylalanine within normal range, and levodopa itself prevented seizure. However, the average intelligence quotient (IQ) score of these patients was only 76 +/- 14 (56-98). Statistically, the age of starting medication, including 5-hydroxytryptophan (5-HTP), was inversely correlated to IQ scores of these patients. We suggest the combination of BH4, levodopa and 5-HTP as the standard protocol to commence the treatment of BH4 deficiency as early as possible, although prenatal brain damage could have existed.

Use of neurotransmitter precursors for treatment of depression.

Insufficient activity of the neurotransmitters serotonin and norepinephrine is a central element of the model of depression most widely held by neurobiologists today. In the late 1970s and 1980s, numerous studies were performed in which depressed patients were treated with the serotonin precursors L-tryptophan and 5-hydroxytryptophan (5-HTP), and the dopamine and norepinephrine precursors tyrosine and L-phenylalanine. This article briefly reviews the published research on the efficacy of neurotransmitter precursors in treating depression, highlights the findings of studies, and discusses issues regarding the interpretation of those findings. The nature of the studies makes it difficult to draw firm conclusions regarding the efficacy of neurotransmitter precursors for treating depression. While there is evidence that precursor loading may be of therapeutic value, particularly for the serotonin precursors 5-HTP and tryptophan, more studies of suitable design and size might lead to more conclusive results. However, the evidence suggests neurotransmitter precursors can be helpful in patients with mild or moderate depression.

L-5-hydroxytryptophan does not stimulate LH secretion directly from the pituitary in patients with gonadotrophin releasing hormone deficiency.

OBJECTIVE: There is abundant histological and physiological evidence that serotonin plays a role in the regulation of LH secretion in rats. Studies in human subjects have been few, but their results include the finding that pulsatile administration of L-5-hydroxytryptophan (5-HTP, the immediate precursor of serotonin) amplifies LH secretion in women in the medium-late follicular phase, and that this effect is not due to 5-HTP directly inducing LH secretion by the pituitary. We have investigated whether 5-HTP amplifies LH secretion by enhancing the response of the pituitary to GnRH. PATIENTS: Seven patients aged 20-40 years with hypogonadotrophic hypogonadism (HH) of hypothalamic origin (3 men with Kallmann's syndrome, 2 women without anosmia and with GH deficiency, and 2 women with anorexia nervosa). DESIGN: To prime the pituitary, subcutaneous pulsatile GnRH was administered for 7 days at the rate of one 5-20 micrograms pulse every 90 min. The day before the investigation, this regimen was replaced by 1.5-3 micrograms intravenous pulses at the same frequency. On the day of the investigation, 3 ml blood samples were taken every 10 min from 0850 to 19:00 hours. After the first two samples, the intravenous GnRH pulse frequency was increased to one per hour and was maintained at this level throughout the rest of the study. The first 4 h of the study acted as a control phase allowing determination of the pituitary response to GnRH. At 1300 h, 75 mg of the aromatic-L-amino-acid decarboxylase inhibitor carbidopa was administered orally; carbidopa does not cross the blood-brain barrier, and prevents peripheral conversion of 5-HTP to serotonin. At 1600 h, another 75 mg dose of carbidopa was administered, and administration of 8-20 mg pulses of 5-HTP at a rate of one pulse per hour was begun. MEASUREMENTS: LH was determined in triplicate by an immunoradiometric assay (IRMA), and LH pulses identified by means of a program developed in our laboratory. RESULTS: When pulsatile administration of GnRH was accompanied by administration of carbidopa and 5-HTP, LH pulse amplitude (2.32 +/- 0.71 IU/I) did not differ significantly from its value in either the GnRH+ carbidopa phase (2.58 +/- 1.12 IU/I) or the unaccompanied GnRH phase (2.77 +/- 1.76 IU/I). CONCLUSIONS: L-5-hydroxytryptophan-induced amplification of LH secretion in humans is not due to enhancement of the pituitary response to GnRH. The effect of L-5-hydroxytryptophan must therefore be due to its action on the hypothalamus, where it may be hypothesized that it increases GnRH release.

Fibromyalgia and the serotonin pathway.

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.

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.