Both supplements of L-tryptophan and 5-HTP have been used in the treatment of depression, but the use of 5-HTP may offer the advantage of bypassing the conversion of L-tryptophan into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. Tryptophan hydroxylase can be inhibited by numerous factors, including stress, insulin resistance, vitamin B6 deficiency, and insufficient magnesium... Moreover, 5-HTP easily crosses the blood–brain barrier, and unlike L-tryptophan, does not require a transport molecule to enter the central nervous system (Green et al., 1980; Maes et al., 1990). Besides serotonin, other neurotransmitters and hormones, such as melatonin, dopamine, norepinephrine, and beta-endorphin have also been shown to increase following oral administration of 5-HTP. All of these compounds are thought to be involved in the regulation of mood as well as sleep and may represent mechanistic pathways stimulated by 5-HTP administration.
Evidence suggests that stress and/or a dietary lack of tryptophan may make deficiencies of serotonin and melatonin common. In addition, older animals and human beings have a reduced ability to synthesize melatonin. Disorders of melatonin levels and rhythms are suggested to be a cause of affective disease, abnormal sleep, Alzheimer's disease, and some age related disorders. If these ideas prove to be true, then preventive measures are possible.
The effects of 3 g L-tryptophan on sleep, performance, arousal threshold, and brain electrical activity during sleep were assessed in 20 male, chronic sleep-onset insomniacs (mean age 20.3 +/- 2.4 years). Following a sleep laboratory screening night, all subjects received placebo for 3 consecutive nights (single-blind), ten subjects received L-tryptophan, and ten received placebo for 6 nights (double-blind). All subjects received placebo on 2 withdrawal nights (single-blind). There was no effect of L-tryptophan on sleep latency during the first 3 nights of administration. On nights 4-6 of administration, sleep latency was significantly reduced. Unlike benzodiazepine hypnotics, L-tryptophan did not alter sleep stages, impair performance, elevate arousal threshold, or alter brain electrical activity during sleep.
Over the past 20 yr, 40 controlled studies have been described concerning the effects of L-tryptophan on human sleepiness and/or sleep. The weight of evidence indicates that L-tryptophan in doses of 1 g or more produces an increase in rated subjective sleepiness and a decrease in sleep latency (time to sleep). There are less firm data suggesting that L-tryptophan may have additional effects such as decrease in total wakefulness and/or increase in sleep time. Best results (in terms of positive effects on sleep or sleepiness) have been found in subjects with mild insomnia, or in normal subjects reporting a longer-than-average sleep latency. Mixed or negative results occur in entirely normal subjects--who are not appropriate subjects since there is no room for improvement. Mixed results are also reported in severe insomniacs and in patients with serious medical or psychiatric illness.
Modulating central serotonergic function by acute tryptophan depletion (ATD) has provided the fundamental insights into which cognitive functions are influenced by serotonin. It may be expected that serotonergic stimulation by tryptophan (Trp) loading could evoke beneficial behavioural changes that mirror those of ATD. The current review examines the evidence for such effects, notably those on cognition, mood and sleep. Reports vary considerably across different cognitive domains, study designs, and populations. It is hypothesised that the effects of Trp loading on performance may be dependent on the initial state of the serotonergic system of the subject. Memory improvements following Trp loading have generally been shown in clinical and sub-clinical populations where initial serotonergic disturbances are known. Similarly, Trp loading appears to be most effective for improving mood in vulnerable subjects, and improves sleep in adults with some sleep disturbances. Research has consistently shown Trp loading impairs psychomotor and reaction time performance, however, this is likely to be attributed to its mild sedative effects. (c) 2009 Elsevier Ltd. All rights reserved.
Light suppresses melatonin while darkness stimulates its synthesis. Many people have trouble falling asleep. Delayed sleep phase syndrome results in late sleep onset, despite normal sleep architecture and total sleep duration. Melatonin has been shown to improve sleep latency (the time it takes to fall asleep) in several randomized controlled studies. Rather than immediately prior to sleeping, melatonin works best when given two hours before sleeping. Melatonin is also useful for jet lag, irregular sleep-wake rhythms, and shift work sleep disorder. Exogenously administered melatonin has phase shifting properties, and the effect follows a phase- response curve (PRC) that is about 12 h out of phase with the PRC [phase response curve] of light Melatonin administered in the afternoon or early evening will phase advance the circadian rhythm, whereas melatonin administered in the morning will phase delay the circadian rhythm (Fig. 2). The magnitude of phase shifts is time-dependent, and the maximal phase shifts result when melatonin is scheduled around dusk or dawn. The effect of exogenous melatonin is minimal when administered during the night, at least during the first-half of the night.
Nonapnea sleep disorders: Nonapnea sleep disorder In humans, melatonin secretion increases soon after the onset of darkness, peaks in the middle of the night (between 2 and 4 a.m.), and gradually falls during the second half of the night
Taurine has a variety of actions in the body such as cardiotonic, host-defensive, radioprotective and glucose-regulatory effects. However, its action in the central nervous system remains to be characterized. In the present study, we tested to see whether taurine exerts anti-anxiety effects and to explore its mechanism of anti-anxiety activity in vivo. The staircase test and elevated plus maze test were performed to test the anti-anxiety action of taurine. Convulsions induced by strychnine, picrotoxin, yohimbine and isoniazid were tested to explore the mechanism of anti-anxiety activity of taurine. The Rotarod test was performed to test muscle relaxant activity and the passive avoidance test was carried out to test memory activity in response to taurine. Taurine (200 mg/kg, p.o.) significantly reduced rearing numbers in the staircase test while it increased the time spent in the open arms as well as the number of entries to the open arms in the elevated plus maze test, suggesting that it has a significant anti-anxiety activity. Taurine's action could be due to its binding to and activating of strychnine-sensitive glycine receptor in vivo as it inhibited convulsion caused by strychnine; however, it has little effect on picrotoxin-induced convulsion, suggesting its anti-anxiety activity may not be linked to GABA receptor. It did not alter memory function and muscle activity. Taken together, these results suggest that taurine could be beneficial for the control of anxiety in the clinical situations. Copyright (c) 2007 S. Karger AG, Basel.
Excitatory amino acid stimulation of phosphatidylinositol (PI) hydrolysis has been associated with development of the CNS. Normally minimally ineffective in stimulating PI hydrolysis in the neonatal rat cerebellum, N-methyl-D-aspartate (NMDA) increased levels of PI hydrolysis 82.3 +/- 5.5% above basal values in the presence of 1 microM baclofen, a gamma-aminobutyric acidB (GABAB) receptor agonist. This effect was observed at day 7 but not in adult cerebellum. The effect of baclofen could be mimicked by low dose GABA and taurine, actions which were blocked by prior application of a specific GABAB antagonist. Therefore, the ability of NMDA to stimulate PI hydrolysis in neonatal cerebellar tissue may be regulated by the degree of GABAB receptor stimulation.
The interactions of taurine with GABAB receptors were studied in membranes from the brain of the mouse by measuring the binding of [3H]baclofen and that of [3H]GABA in the presence of isoguvacine. Taurine displaced ligand binding to GABAB receptors concentration-dependently with an IC50 in the micromolar range. The effects of baclofen on the release of taurine and GABA from slices of cerebral cortex of the mouse were assessed using a superfusion system. Potassium-stimulated release of both [3H]taurine and [3H]GABA was unaffected by baclofen but potentiated by delta-aminovalerate. The enhancement of release of [3H]taurine by delta-aminovalerate was partially antagonized by baclofen, suggesting that baclofen-sensitive receptors could modify the release.
Taurine, an inhibitory amino acid, potently acts on a subclass of gamma-aminobutyric acid type A (GABAA) receptors. Taurine competitively inhibits [3H]muscimol binding to purified GABAA receptors with an average IC50 value of 50 microM, and enhances [3H]flunitrazepam binding to GABAA-linked benzodiazepine receptors with an EC50 of about 10 microM and with maximal extent lower than that for GABA. Taurine shows variable affinities (low micromolar to near millimolar) for muscimol binding sites in different brain regions as measured by autoradiography. The taurine-sensitive GABA sites are enriched in dentate gyrus, substantia nigra, cerebellum molecular layer, median thalamic nuclei, and hippocampal field CA3; these areas are also enriched in mRNA for the GABA-binding beta 2 subunit subtype. Taurine shows differential affinities for the multiple muscimol-GABA binding polypeptides present in purified GABAA receptors, notably a higher affinity for a beta 55 than a beta 58 polypeptide; these probably represent beta 2 and beta 3 clones, respectively. This work defines a significant target of taurine's inhibitory activity as some GABAA receptor GABA sites, lending support to the hypothesis that this endogenous substance may have a physiological action.
Anxiety & Sleep: Taurine helps with both sleep and anxiety through reducing excitatory neurotransmission. It increases GABA in the brain, can bind to GABA receptors, and indirectly suppresses NMDA signaling. It also acts on glycine receptors, which contributes to its anti-anxiety effects.
Adrenal Fatigue / Hypoadrenalism - Low CoQ10 has been shown to lead to hypoadrenalism. The role of adrenal steroids in antioxidant regulation is not known. Previously, we demonstrated some Coenzyme Q(10) (CoQ(10)) alterations in pituitary diseases, which can induce complex pictures due to alterations of different endocrine axes. Therefore we determined CoQ(10) and Total Antioxidant Capacity (TAC) in pituitary-dependent adrenal diseases: 6 subjects with ACTH-dependent adrenal hyperplasia (AH); 19 with secondary isolated hypoadrenalism (IH), 19 with associated hypothyroidism (multiple pituitary deficiencies, MPH). CoQ(10) was assayed by HPLC; TAC by the system metmyoglobin-H(2)O(2), which, interacting with the chromogenous 2,2(I)-azinobis-(3-ethylbenzothiazoline-6-sulphonate), generates a spectroscopically revealed radical compound after a latency time (Lag) proportional to the antioxidant content. CoQ(10) levels were significantly lower in IH than AH and MPH, with a similar trend when adjusted for cholesterol. Also TAC was lower in IH than in AH and MPH, suggesting that adrenal hormones can influence antioxidants. However, since thyroid hormones modulate CoQ(10) levels and metabolism, when thyroid deficiency coexists it seems to play a prevalent influence.
The statins or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitors are the most effective drugs in lowering serum low density lipoprotein (LDL) concentration. They decrease cardiovascular morbidity and mortality of hypercholesterolemic patients, even in primary prevention. Large controlled prospective studies have shown that statins as a group improve the prognosis of coronary heart disease (CHD) patients. The HMG-CoA reductase inhibitors affect competitively the early key enzyme of the mevalonate pathway (Fig. 1), thus inhibiting the synthesis of cholesterol and other non-sterol end products. One of them is coenzyme Q10 (2,3-dimethoxy-5-methyl-6-decaprenyl benzoquinone), also known as ubiquinone. It may be estimated that on a normal diet, 60% of plasma ubiquinone is endogenous.
Coenzyme Q10 (ubiquinone) the essential mitochondrial redox-component and endogenous antioxidant, packaged into the LDL + VLDL fractions of cholesterol, has been suggested as an important anti-risk factor for the development of atherosclerosis as explained by the oxidative theory.
High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.
CoenzymeQ10 is a cofactor produced by the body that aids in energy production in the Krebs cycle and mitrochondrial electron transport chain. It is converted into the antioxidant ubiquinol following ingestion: Dyslipidemia, High Cholesterol, Current statin use. CoQ10 levels decrease with age and have also been observed to be low in patients with certain disorders (e.g. cardiovascular diseases, diabetes). CoQ10 supplementation has been shown to offset some negative side effects of statin medications. Statins + CoQ10 - HMG-CoA reductase inhibitors (lovastatin, pravastatin, rosuvastatin, and simvastatin) decrease the concentration of CoQ10 in the human body.
Individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to prevent fasting hyperhomocysteinemia in such persons.
MK-4 stimulates testosterone production in rats and testis-derived tumor cells via activation of PKA. MK-4 may be involved in steroidogenesis in the testis, and its supplementation could reverse the downregulation of testosterone production in elders.
It has long been known that insulin-like growth factor 1 (IGF1) causes an increase in the circulating levels of 1,25-dihydroxyvitamin D (1,25(OH)2D), the hormonally active vitamin D metabolite, by stimulating the expression and activity of the 1α-hydoxylase that produces 1,25(OH)2D in the kidney. Indeed, plasma 1,25(OH)2D is significantly higher in active than controlled acromegaly, with a tendency to hypercalcemia, hyperphosphatemia, and hypercalciuria. On the other hand, more recent data has suggested that vitamin D may contribute to determining IGF1 concentrations. Mice knockout for the vitamin D receptor (VDR) exhibit 30% lower IGF1 levels compared with WT animals and a significant increase in serum IGF1 was noted in response to vitamin D in two small cohorts of children. Furthermore, cross-sectional analyses of community-based cohorts disclosed a positive correlation between the concentrations of 25-hydroxyvitamin D (25(OH)D), the marker of vitamin D status, and IGF1. Here we first conducted an open-label, controlled study of the changes in circulating IGF1 following vitamin D supplementation in adults. Then, we asked whether the influence of vitamin D on IGF1 might be clinically relevant for the management of growth hormone deficiency (GHD), which relies on measurement of IGF1 levels.
