Insomnia Abstracts 4 Tryptophan


            (1998) Download
5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of the amino acid L-tryptophan (LT) in the serotonin pathway. Therapeutic use of 5-HTP bypasses the conversion of LT into 5-HTP by the enzyme tryptophan hydrolase, which is the rate- limiting step in the synthesis of serotonin. Tryptophan hydrolase can be inhibited by numerous factors, including stress, insulin resistance, vitamin B6 deficiency, and insufficient magnesium. In addition, these same factors can increase the conversion of LT to kynurenine via tryptophan oxygenase, making LT unavailable for serotonin production.

L-Tryptophan. Monograph.
            (2006) Download
L-tryptophan (tryptophan; Trp) is a large neutral amino acid essential to human metabolism because it is the metabolic precursor of serotonin (a neurotransmitter), melatonin (a neurohormone), and niacin (vitamin B3). Approximately 300 mg Trp is available in three ounces of turkey, lamb, beef, tuna, or peanuts. Trp is the least abundant amino acid in the diet. Evening oral doses of tryptophan as low as 250 mg have been shown to improve sleep quality, although the typical dosage range for sleep disorders and depression is 1-3 g daily. Safe and effective dos- ages for other disorders range from 0.5-4 g daily, while potentially higher doses (50 mg/kg/day) have been used short term as a smoking cessation intervention.

Mid-morning tryptophan depletion delays REM sleep onset in healthy subjects.
            (Arnulf et al., 2002) Download
Because serotonin is involved in the diachronic regulation of sleep, we tested the effect of a midmorning rapid deficiency in the serotonin precursor tryptophan on the next night's sleep. After a 48-h low-protein diet, 17 healthy volunteers received either a tryptophan-free mixture of amino acids or a placebo at 10:30 A.M., in a randomized double-blind cross-over design, resulting in a 77% decrease and 41% decrease of serum tryptophan at 3:30 P.M. and 9:30 P.M., respectively. Urinary sulfatoxy-melatonin excretion and mood were unaffected by the rapid tryptophan depletion (RTD), but rapid eye movement (REM) sleep latency increased by 21 min (from 91.5 +/- 4.5 min to 112.2 +/- 6.9 min), sleep fragmentation 58%, and REM density of the first REM sleep period doubled. The results show that midmorning RTD delays REM sleep latency during following night-time sleep, whereas evening RTD shortens REM sleep latency in previous studies, and suggest that the serotonin control of REM sleep latency is upregulated.

5-Hydroxytryptophan: a clinically-effective serotonin precursor
            (Birdsall, 1998) Download
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.

Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans.
            (Bravo et al., 2013) Download
Melatonin and serotonin rhythms, which exhibit a close association with the endogenous circadian component of sleep, are attenuated with increasing age. This decrease seems to be linked to sleep alterations in the elderly. Chrononutrition is a field of chronobiology that establishes the principle of consuming foodstuffs at times of the day when they are more useful for health, improving, therefore, biorhythms and physical performance. Our aim was to analyze whether the consumption of cereals enriched with tryptophan, the precursor of both serotonin and melatonin, may help in the reconsolidation of the sleep/wake cycle and counteract depression and anxiety in 35 middle-aged/elderly (aged 55-75 year) volunteers in a simple blind assay. Data were collected for 3 weeks according to the following schedule: The control week participants consumed standard cereals (22.5 mg tryptophan in 30 g cereals per dose) at breakfast and dinner; for the treatment week, cereals enriched with a higher dose of tryptophan (60 mg tryptophan in 30 g cereals per dose) were eaten at both breakfast and dinner; the posttreatment week volunteers consumed their usual diet. Each participant wore a wrist actimeter that logged activity during the whole experiment. Urine was collected to analyze melatonin and serotonin urinary metabolites and to measure total antioxidant capacity. The consumption of cereals containing the higher dose in tryptophan increased sleep efficiency, actual sleep time, immobile time, and decreased total nocturnal activity, sleep fragmentation index, and sleep latency. Urinary 6-sulfatoxymelatonin, 5-hydroxyindoleacetic acid levels, and urinary total antioxidant capacity also increased respectively after tryptophan-enriched cereal ingestion as well as improving anxiety and depression symptoms. Cereals enriched with tryptophan may be useful as a chrononutrition tool for alterations in the sleep/wake cycle due to age.

L -5-Hydroxytryptophan treatment of sleep terrors in children.
            (Bruni et al., 2004) Download
UNLABELLED:  To test the hypothesis that the administration of L -5-hydroxytryptophan (L -5-HTP) might exert beneficial effects on sleep terrors, we carried out an open pharmacological trial in a group of children with sleep terrors compared to a group of children with the same disorder but without L -5-HTP treatment. Participants in the trial were 45 children (34 males and 11 females; age range 3.2-10.6 years), referred to the Sleep Centre of the Department of Developmental Neurology and Psychiatry of the University of Rome "La Sapienza", affected by sleep terrors. All subjects underwent: (1) complete medical and sleep history; (2) complete neurological examination and EEG recording whilst awake and sleeping, (3) a structured sleep diary for 2 months, (4) after 1 month, all subjects were examined again from the clinical and EEG points of view and (5) after 6 months, a structured interview in order to evaluate the clinical outcome. After the first visit, L -5-HTP was administered (2 mg/kg per day) at bedtime to 31 randomly selected patients for a single period of 20 consecutive days. After 1 month of treatment, 29/31 (93.5%) of patients showed a positive response. In the comparison group without drug therapy, after 1 month, the episodes disappeared only in four children (28.6%) while ten children (71.4%) showed the persistence of episodes with the same frequency as before. After 6 months, 26/31 (83.9%) of children treated with L -5HTP were sleep terror-free, while in five children (16.1%) sleep terror episodes persisted. Of the children in the comparison group, ten (71.4%) continued to show sleep terrors at 6-month follow-up. CONCLUSION:  to our knowledge, this is the first study demonstrating the efficacy of a new drug treatment for sleep terrors. These results confirm our initial hypothesis and represent evidence that treatment with L -5-hydroxytryptophan is able to modulate the arousal level in children and to induce a long-term improvement of sleep terrors.


Treatment of severe chronic insomnia with L-tryptophan and varying sleeping times.
            (Demisch et al., 1987) Download
Twenty-five subjects suffering from severe chronic insomnia were treated for four weeks with 2 g of L-tryptophan in combination with a schedule of varying sleeping times which caused a sleep deficiency at the beginning of treatment. A second four-week period without L-tryptophan was used as a control. Nineteen subjects (76%) experienced a markedly improved sleeping pattern after four weeks; the sleeping behavior of ten of these subjects, however, deteriorated again after the control period. Daily self-rating protocols revealed that the subjects' sleep improved significantly between the 10th and 15th day after starting treatment. Further sleep-related items such as "activity", "mood", "nervous tension", "contentment", and "quality of the preceding day" were also evaluated. This treatment schedule can thus be recommended for the treatment of severe chronic insomnia.

Protein source tryptophan versus pharmaceutical grade tryptophan as an efficacious treatment for chronic insomnia.
            (Hudson et al., 2005) Download
BACKGROUND:  Intact protein rich in tryptophan was not seen as an alternative to pharmaceutical grade tryptophan since protein also contains large neutral amino acids (LNAAs) that compete for transport sites across the blood-brain barrier (BBB). Deoiled gourd seed (an extremely rich source of tryptophan-22 mg tryptophan/1 g protein) was combined with glucose, a carbohydrate that reduces serum levels of competing LNAAs which was then compared to pharmaceutical grade tryptophan with carbohydrate as well as carbohydrate alone. METHOD:  Objective and subjective measures of sleep were employed to measure changes in sleep as part of a double blind placebo controlled study where subjects were randomly assigned to one of three conditions: (1) Protein source tryptophan (deoiled gourd seed) in combination with carbohydrate; (2) pharmaceutical grade tryptophan in combination with carbohydrate; (3) carbohydrate alone. SUBJECTS:  Out of 57 subjects 49 of those who began the study completed the three week protocol. RESULTS:  Protein source tryptophan with carbohydrate and pharmaceutical grade tryptophan, but not carbohydrate alone, resulted in significant improvement on subjective and objective measures of insomnia. Protein source tryptophan with carbohydrate alone proved effective in significantly reducing time awake during the night. CONCLUSION:  Protein source tryptophan is comparable to pharmaceutical grade tryptophan for the treatment of insomnia.


The tryptophan depletion test: impact on sleep in primary insomnia - a pilot study
            (Riemann et al., 2002) Download
The application of the tryptophan depletion test is based on the assumption that the decrease of plasma or serum tryptophan concentration following the ingestion of a tryptophan-free amino acid drink reflects a central nervous effect on serotonin metabolism. In the present study the impact of tryptophan depletion on polysomnographically recorded sleep in patients with primary insomnia was studied. Fifteen patients with primary insomnia slept for four nights in the sleep laboratory. Prior to the fourth night the tryptophan depletion test was applied. Sleep EEG variables served as outcome parameters. Patients with primary insomnia, compared to baseline values showed a highly significant decrease of serum tryptophan concentrations after the amino acid drink. Concerning sleep parameters, stage 1 (% sleep period time=SPT) was increased, whereas stage 2 (% SPT) was decreased. Indices of phasic activity of rapid eye movement (REM) sleep (REM density) were increased after the tryptophan depletion compared to baseline. The results suggest a negative impact of tryptophan depletion on sleep continuity and a stimulating effect on phasic measures of REM sleep in patients with primary insomnia.

Effects of L-tryptophan (a natural sedative) on human sleep.
            (Wyatt et al., 1970) Download
Five healthy volunteers given L-tryptophan for ten consecutive nights had an increase in non-rapied eye-movement sleep (non-R.E.M.) and delta wave sleep while they manifested a decrease in R.E.M. sleep. Seven patients with insomnia receiving L-tryptophan for either 5 or 10 consecutive nights had increases in total sleep and non-R.E.M. sleep when compared with placebo control periods. Since reducing brain serotonin by synthesis inhibition reduces R.E.M. sleep and increasing brain serotonin by 5-hydroxytryptophan administration increases R.E.M. sleep, it seems likely that L-tryptophan produces its sleep effects through a non-serotonin mechanism. Further evidence for this hypothesis derives from the finding that L-tryptophan produced significant in- creases in non-R.E.M. and decreases in R.E.M. sleep when given in the presence of p-chlorophenylalanine, a drug which blocks the metabolism of tryptophan to serotonin.

Effects of 5-hydroxytryptophan on the sleep of normal human subjects.
            (Wyatt et al., 1971) Download
In our present study, 600 mg of D, L- 5-HTP monohydrate was administered orally to eight normal subjects over a 5 night period. In addition, 200 mg doses were administered on 4 consecutive nights to two subjects and on 1 night to two other subjects. This study showed that both the duration of REM sleep and the amount of rapid eye movement activity increased when 5-HTP was administered to normal subjects. Since there was no change in total sleep, the trend toward a decrease in NREM sleep was apparently a compensation for the increased REM sleep.



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Arnulf, I, et al. (2002), ‘Mid-morning tryptophan depletion delays REM sleep onset in healthy subjects.’, Neuropsychopharmacology, 27 (5), 843-51. PubMed: 12431858
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Demisch, K, J Bauer, and K Georgi (1987), ‘Treatment of severe chronic insomnia with L-tryptophan and varying sleeping times.’, Pharmacopsychiatry, 20 (6), 245-48. PubMed: 3432358
Hudson, C, et al. (2005), ‘Protein source tryptophan versus pharmaceutical grade tryptophan as an efficacious treatment for chronic insomnia.’, Nutr Neurosci, 8 (2), 121-27. PubMed: 16053244
(2006), ‘L-Tryptophan. Monograph.’, Altern Med Rev, 11 (1), 52-56. PubMed: 16597195
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