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.

Neuroprotection:  Other benefits of melatonin include general neuroprotective effects, as melatonin is a powerful antioxidant. Melatonin also has several anti-cancer properties, and is currently being investigated for its role in fighting breast cancer.  “Both in vitro studies and in vivo studies have shown that melatonin is a potent scavenger of the highly toxic hydroxyl radical and other oxygen- centered radicals, suggesting that it has actions not mediated by receptors.31 In one study, melatonin seemed to be more effective than other known anti- oxidants (e.g., mannitol, glutathione, and vitamin E) in protecting against oxidative damage. There- fore, melatonin may provide protection against dis- eases that cause degenerative or proliferative changes by shielding macromolecules, particularly DNA, from such injuries. However, these antioxidant effects require concentrations of melatonin that are much higher than peak nighttime serum concentrations. Thus, the antioxidant effects of melatonin in humans probably occur only at pharmacologic concentrations….The decrease in nighttime serum melatonin concentrations that occurs with aging, together with its multiple biologic effects, has led several investigators to suggest that melatonin has a role in aging and age-related diseases. Studies in rats and mice suggest that diminished melatonin secretion may be associated with an acceleration of the aging process. Melatonin may provide protection against aging through attenuation of the effects of cell damage induced by free radicals or through immunoenhancement. However, the age-related reduction in nighttime melatonin secretion could well be a consequence of the aging process rather than its cause, and there are no data supporting an antiaging effect of melatonin in humans.”

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

In young adults, with neuroticism scores above rather than below the median, the taking of 300mg PS each day for a month was associated with feeling less stressed and having a better mood. The study for the first time reports an improvement in mood following PS supplementation in a sub-group of young healthy adults.

Breast Chemoprotection - DIM exert a variety of biochemical effects including the induction of phase I and phase II enzymes that detoxify carcinogenic estrogens.  Administration of either I3C or DIM results in increased 2-hydroxylation of estrogens.

The endogenous estrogen 17beta-estradiol can be metabolized to 16alpha-hydroxyestrone (16alpha OHE1) or 2-hydroxyestrone (2OHE1). In contrast to 2OHE1, 16alpha OHE1 is highly estrogenic and has been found to enhance the proliferation of estrogen-sensitive breast cancer cells in culture. It has been hypothesized that shifting the metabolism of 17beta-estradiol toward 2OHE1 and away from 16alphaOHE1 could decrease the risk of estrogen-sensitive cancers, such as breast cancer. In a small clinical trial, increasing cruciferous vegetable intake of healthy postmenopausal women for four weeks increased urinary 2OHE1:16alpha OHE1ratios, suggesting that high intakes of cruciferous vegetables can shift estrogen metabolism.

DIM inhibited endogenous PSA transcription and reduced DHT-induced intracellular and secreted PSA protein levels in LNCaP human androgen-dependent prostate cancer cells.

Lipid Lowering Effects: In this a randomized double-blind placebo-controlled trial of 64 type two diabetic patients, CoQ10 improved glycemic control, total and LDL cholesterol.

LDL to CoQ10 Ratio and Atheroschlerosis - Research suggests ubiquinone may be involved in atherosclerosis prevention and the ratio of LDL cholesterol to ubiquinone may be an indicator of atherosclerosis risk.

Ubiquinone is a carrier of the mitochondrial respiratory chain which regulates oxidative phosphorylation: it also acts as a membrane stabilizer preventing lipid peroxidation. In man the quinone ring originates from tyrosine, while the formation of the polyisoprenoid lateral chain starts from acetyl CoA and proceeds through mevalonate and isopentenylpyrophosphate; this biosynthetic pathway is the same as the cholesterol one. We therefore performed this study to evaluate whether statins (hypocholesterolemic drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase) modify blood levels of ubiquinone. Thirty unrelated outpatients with primary hypercholesterolemia (IIa phenotype) were treated with 20 mg of simvastatin for a 3-month period (group S) or with 20 mg of simvastatin plus 100 mg CoQ10 (group US). The following parameters were evaluated at time 0, and at 45 and 90 days: total plasma cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, Apo A1, Apo B and CoQ10 in plasma and in platelets. In the S group, there was a marked decrease in total cholesterol low-density lipoprotein-cholesterol and in plasma CoQ10 levels from 1.08 mg/dl to 0.80 mg/dl. In contrast, in the US group we observed a significant increase of plasma CoQ10 (from 1.20 to 1.48 mg/dl) while the hypocholesterolemic effect was similar to that observed in the S group. Platelet CoQ10 also decreased in the S group (from 104 to 90 ng/mg) and increased in the US group (from 95 to 145 ng/mg).(ABSTRACT TRUNCATED AT 250 WORDS)

The biosynthetic pathway of the CoQ polyisoprenoid side chain, starting from acetyl-CoA and proceeding through mevalonate and isopentenylpyrophosphate, is the same as that of cholesterol. We performed this study to evaluate whether vastatins (hypocholesterolemic drugs that inhibit HMG-CoA reductase) modify blood levels of ubiquinone. Thirty-four unrelated outpatients with hypercholesterolemia (IIa phenotype) were treated with 20 mg of simvastatin for a 6-month period (group S) or with 20 mg of simvastatin plus 100 mg CoQ10 (group US). The following parameters were evaluated at time 0, 45, 90, 135 and 180 days: total plasma cholesterol (TC), HDL-cholesterol, LDL-cholesterol (LDL-C), triglycerides (TG), apo A1, apo B and CoQ10 in plasma and platelets. In the S group, there was a marked decrease in TC and LDL-C (from 290.3 mg/dl to 228.7 mg/dl for TC and from 228.7 mg/dl to 167.6 mg/dl for LDL-C) and in plasma CoQ10 levels from 1.08 mg/dl to 0.80 mg/dl. In contrast, in the US group we observed a significant increase of CoQ10 in plasma (from 1.20 to 1.48 mg/dl) while the hypocholesterolemic effect was similar to that observed in the S group. Platelet CoQ10 also decreased in the S group (from 104 to 90 ng/mg) and increased in the US group (from 95 to 145 ng/mg). This study demonstrates that simvastatin lowers both LDL-C and apo B plasma levels together with the plasma and platelet levels of CoQ10, and that CoQ10 therapy prevents both plasma and platelet CoQ10 decrease, without affecting the cholesterol lowering effect of simvastatin.

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.

Inhibitors of HMG-CoA reductase are new safe and effective cholesterol-lowering agents. Elevation of alanine-amino transferase (ALT) and aspartate-amino transferase (AST) has been described in a few cases and a myopathy with elevation of creatinine kinase (CK) has been reported rarely. The inhibition of HMG-CoA reductase affects also the biosynthesis of ubiquinone (CoQ10).

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.

Ratio of low-density lipoprotein cholesterol to ubiquinone as a coronary risk factor.

A meta-analysis of 12 randomized trials of vitamin supplements to lower homocysteine levels was carried out to determine the optimal dose of folic acid required to lower homocysteine levels and to assess whether vitamin B12 or vitamin B6 had additive effects. This meta-analysis demonstrated that reductions in blood homocysteine levels were greater at higher pretreatment blood homocysteine levels and at lower pretreatment folate concentrations. After standardization for a pretreatment homocysteine concentration of 12 micromol/L and folate concentration of 12 nmol/L (approximate average concentrations for western populations), dietary folic acid reduced homocysteine levels by 25% (95% confidence interval [CI]: 23 to 28%) with similar effects in a daily dosage range of 0.5 to 5 mg… Large-scale randomized trials of such regimens are now required to determine whether lowering homocysteine levels by folic acid and vitamin B12, with or without added vitamin B6, reduces the risk of vascular disease

Folic acid deficiency has been found in people with depression and has been linked to poor response to antidepressant treatment. Homocysteine is considered a significant risk factor for cardiovascular disease and may be modified by B vitamins, including folate or derivatives. Daily doses of > or =0.8 mg folic acid are typically required to achieve the maximal reduction in plasma homocysteine concentrations produced by folic acid supplementation. Doses of 0.2 and 0.4 mg are associated with 60% and 90%, respectively, of this maximal effect. Homocysteine Lowering Trialists’ Collaboration. 

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.

Methylenetetrahydrofolate reductase (MTFHR) is an enzyme involved in the processing of amino acids using folic acid, specifically the conversion of homocysteine to methionine. Patients with C677T polymorphism may see increased levels of blood homocysteine when folate levels are low, which may lead to a need for folate supplementation. Various mutations to the MTFHR enzyme may result in altered need and response to folate supplementation.

L-Methylfolate is the centrally active derivative of the vitamin folate and is used for both neurotransmitter synthesis, and vital methylation reactions in all cells. It regulates BH4 (or tetrahydrobiopterin) a critical enzyme cofactor required for serotonin, dopamine and norepinephrine synthesis. Some forms of depression resistant to antidepressant treatment may respond to folate or l-methylfolate. Synthesis of the monoamine neurotransmitters serotonin, dopamine, and norepinephrine is regulated by L-methylfolate, a derivate of the vitamin folate. Copyright 2008 Physicians Postgraduate Press, Inc.

Pyridoxine (B6) nutritional status has a significant and selective modulatory impact on central production of both serotonin and GABA - neurotransmitters which control depression, pain perception, and anxiety.

Vitamin B6-dependent enzymes play a role in the biosynthesis of five neurotransmitters: serotonin, norepinephrine, epinephrine, dopamine and GABA. Vitamin B-6, comprised of pyridoxal, pyridoxamine, and pyridoxine, is one alternative treatment that may be a mitigating factor in hormone related depression, via its role in the proper metabolism of various neurotransmitters considered relevant in the manifestation of depression.