IN DEPTH DESCRIPTION
Glycine is an amino acid that acts directly as an inhibitory neurotransmitter. This means that it stops your nerve cells over-firing and counteracts the action of stimulating neurotransmitters, giving a calming and balancing effect. Glycine has been shown to improve sleep. A trial carried out in Japan on volunteers experiencing unsatisfactory sleep found that taking 3 grams of glycine before bed improved subjective sleep quality and reduced sleepiness during the day. Glycine may work in this way by increasing blood flow to the surface of the skin and reducing core body temperature, which induces the onset of sleep.[2,3] According to a study on rats, glycine may also increase levels of serotonin – a neurotransmitter that contributes to feelings of well-being and is involved with regulating sleep.
As well as potentially supporting sleep, glycine is one of the amino acids that your body uses to produce glutathione, a vitally important antioxidant molecule that protects your cells against damage from free radicals. Supplementing glycine together with cysteine has been found to improve glutathione levels in patients who are deficient. In addition, glycine is a primary component of collagen, so it is needed to support strength and repair of your connective tissues including muscle, tendons and ligaments, and skin.
Glutamine is the most abundant amino acid in the body, including in muscle tissue. Glutamine levels in the muscles are depleted during exercise, which may increase the breakdown of muscle mass. For this reason, glutamine supplements may be taken to support muscle strength and recovery after exercise, preventing muscle breakdown and promoting protein synthesis. As well as providing a primary building-block of muscle protein, glutamine has been found to stimulate the release of growth hormone from the pituitary gland [7,8], which can support muscle growth and repair.
There is also good evidence that taking glutamine may help to reduce the impact on the immune system and the incidence of infections after intensive exercise.
Like glycine, glutamine is one of the three amino acids needed for the body to make glutathione, a master antioxidant that protects our cells.
The amino acid arginine is known to stimulate growth hormone release [10,11]; in fact, it’s been found that taking oral arginine alone can increase the body’s circulating GH levels by at least 100% .
There also positive links between arginine supplementation and antioxidant activity in the body, including glutathione levels. A double-blind trial on 46 patients found that supplementing 3 grams of arginine increased their serum total antioxidant capacity (the antioxidants in their blood) compared with those on placebo. A recent study on pigs found that adding more arginine to their feed reduced the effects of oxidative stress (i.e. free radicals) and increased antioxidant capacity in the liver, and specifically enhanced the activities of glutathione peroxidases and superoxide dismutases – two of the body’s most important antioxidant enzymes. Another study on carp found that arginine supplementation significantly enhanced glutathione content and the activities of antioxidant enzymes in muscle, as well as improving muscle protein levels and force.
There is some indication that arginine may improve collagen production. Arginine has been extensively tested for its potential to benefit wound healing in humans and animals [e.g. 16,17,18] and is thought to work partly by increasing collagen synthesis.
With regards to exercise performance, arginine has also been found to improve oxygen utilisation during moderate-intensity exercise and increase time to exhaustion. 
Lysine is an essential amino acid – one that the body cannot make itself and must be supplied by our diet. Lysine is another amino acid that may promote growth hormone secretion . In a study on 16 men, a combination of 1.5 grams of arginine and 1.5 grams of lysine was found to increase growth hormone secretion from baseline levels ; and an earlier study found that 1.2 grams of each stimulated GH but only when they were used together, not individually .
Lysine is also involved in collagen production: it is converted to hydroxylysine, a ‘derivative’ amino acid found mainly in collagen. However, it is not clear whether supplementing additional lysine can improve collagen production.
The amino acid tyrosine is best-known for its role in the production of thyroid hormones, which are made purely from tyrosine and the mineral iodine. The thyroid governs our metabolism, including the production of energy from the food that we eat; and it has an important role in growth too. Tyrosine is also needed for our body to make dopamine – a neurotransmitter and hormone whose roles include a feeling of reward or pleasure that motivates us to continue an activity or behaviour – for example when you’ve had a good session at the gym! And from dopamine, the body makes noradrenaline and adrenaline, hormones that give us ‘get up and go’ and get us ready for action.
As dopamine and noradrenaline/adrenaline also play a role in mood (together with serotonin), tyrosine has been studied for its potential to relieve depression. A clinical trial from 2004 found that volunteers who took an amino acid mixture that did not contain tyrosine and phenylalanine (the amino acid precursor to tyrosine) showed more behaviours consistent with low mood and depression compared to those taking a balanced amino acid mixture.. A similar effect was observed in a clinical trial from 2000 on 41 healthy women, finding vulnerability to lowered mood in the group taking a formula deficient in tyrosine and phenylalanine.
Ornithine is an amino acid that is produced from arginine in the body, and can be converted back to arginine. Arginine and ornithine are often used together in supplement form to support exercise performance, including with the aim of stimulating growth hormone production. A double-blind study on experienced strength-trained athletes found that those supplementing arginine and ornithine had higher growth hormone levels after an exercise test compared with the placebo group. This effect on growth hormone is thought to be due to conversion of ornithine to arginine.
Arginine and ornithine together in supplement form have also been found to increase lean body mass and total strength in men participating in a 5-week strength training programme; and in another trial, ornithine on its own was found to directly improve energy levels and reduce physical fatigue after exercise, in this case a cycling test.
Also like arginine, ornithine may support collagen synthesis. A study on mice found that ornithine supplementation enhanced wound healing and collagen deposition.
Ornithine alpha-ketoglutarate (OAKG)
Ornithine alpha-ketoglutarate is a compound (salt) consisting of two molecules of ornithine and one molecule of alpha-ketoglutarate. OAKG has been found to have an anti-catabolic effect on the muscles, which is thought to be through promoting the secretion of growth hormone and insulin, and acting as a precursor to arginine and glutamine. As a precursor to these amino acids, OAKG is thought to work better than either ornithine or alpha-ketoglutarate taken on their own.
Arginine pyroglutamate is a compound consisting of arginine bonded to pyroglutamic acid. There is some evidence that arginine pyroglutamate may increase the release of growth hormone when taken with lysine: one study from 1981 on 15 men found that 1200mg each of arginine pyroglutamate and lysine hydrochloride raised growth hormone by up to 8 times from the baseline levels. The same study also reported an increase in insulin-like growth factor 1 (IGF-1), another hormone that has an anabolic effect in the body. However there don’t seem to be any recent clinical trials or other studies on this form of arginine specifically.
N-Acetyl Cysteine (NAC)
N-acetyl cysteine (NAC) is a derivative of the amino acid L-cysteine. It is perhaps best known for its role as an antioxidant and for supporting the synthesis of glutathione.
NAC may act directly as an antioxidant through donating sulfhydryl groups, and has been found to be react with several different types of reactive oxygen species (free radicals).
Glutathione is synthesized from the three amino acids cysteine, glycine and glutamic acid. Cysteine is known as the ‘rate-limiting’ amino acid for glutathione synthesis, which means that it’s the one most likely to be in inadequate supply to allow optimal glutathione production. But instead of supplementing cysteine itself, it’s been found that NAC has a better effect on restoring glutathione levels. For this reason, NAC is given in hospitals as a treatment for paracetamol overdose[32,35], which depletes glutathione levels in the liver.
5-HTP (5-hydroxytryptophan) is the direct precursor to serotonin. For this reason, it is taken as a supplement with the goal of increasing serotonin levels, often to support those with mild to moderate depression or anxiety, or to support sleep.
Studies dating back to the 1970s have examined the effects of 5-HTP on mood and depression. One trial on 59 patients with depressive symptoms using a dose of 150–300mg of 5-HTP per day for three weeks found a favourable response in 68% of the patients; and another similar trial on 18 patients found that 10 were ‘much improved’ or ‘very much improved’.
Because of its role as a precursor to serotonin, 5-HTP may also support sleep (serotonin is converted to melatonin, the hormone that regulates the circadian rhythm and sleep cycles). There seems to be little in the way of clinical trials directly examining this effect, however. One double-blind trial on 18 patients with sleep disorders using an amino acid preparation containing 5-HTP and GABA (gamma-Aminobutyric acid) found that the supplement reduced the time to fall asleep, increased the duration of sleep and improved sleep quality – but didn’t examine the effects of 5-HTP on its own.
5-HTP may stimulate growth hormone release. Serotonin precursors such as 5-HTP are said to have an effect on the hypothalamus-pituitary-adrenal (HPA) axis and the hormones it produces, including growth hormone. Several studies on animals have found that giving 5-HTP can stimulate an increase in growth hormone [39,40,41]. An early human study also found this effect but there seems to be little in the way of clinical trials examining this in humans.
The mineral magnesium is used as a cofactor in over 300 enzymatic reactions in the body. It plays a critical role in energy production in the body’s cells, protein synthesis, nerve transmission, muscular contraction, DNA and RNA synthesis (for growth and repair), and glucose and insulin metabolism, amongst others.
Physical exercise may deplete magnesium, both through use consumption and also through loss in the sweat and urine. This can then impair energy metabolism and affect muscle function and exercise performance[44,45]. Intake of magnesium in the Western diet can also be below recommended levels, partly because meat, dairy foods and refined flour contain less magnesium than green vegetables and whole plant foods. This combination of factors means that supplementary magnesium could be helpful for many people, and especially for those engaged in sporting activities or exercise programmes.
Magnesium may be beneficial for sleep too. In an article from the Townsend Letter for Doctors & Patients (2004), the author discusses how depletion of magnesium may disrupt sleep cycles and affect the body’s biological clock. It’s thought that magnesium may stimulate inhibitory (i.e. calming) neurotransmitter systems such as GABA, and adequate levels may be necessary for proper function of the pineal gland, which secretes melatonin. Taking magnesium supplements in a dosage of 200–300mg in the evening is said to improve sleep quality. There seems to be little in the way of clinical trials on humans to back up this effect, but studies in mice and rats have found that higher levels of magnesium in the brain promotes sleep quality and that a magnesium-deficient diet correlated with disorganised, light sleep.
There is also a possible link between magnesium and serotonin levels. Magnesium has been investigated for its effects on mood, and as a potential treatment for those with depression and other affective disorders[e.g. 49,50]. A review from 2010 included the suggestion that inadequate brain magnesium appears to reduce serotonin levels, and so supplementing magnesium could help to normalise levels and relieve depression.
Zinc is a trace mineral that has a role in many aspects of cell metabolism. This includes over 300 different enzymes that catalyse essential chemical reactions in our bodies.
One of the primary roles of zinc is in growth and development. Zinc deficiency is known to inhibit growth , a link that’s been found especially in children and infants[53,54]. Zinc may directly affect growth hormone levels. A case study on two teenagers who were growth hormone-deficient found that GH levels returned to normal when they were given zinc supplements. Another study from 2013 on 40 children and adolescents with growth hormone deficiency found that they also had a decreased level of zinc in their blood, and the authors concluded that zinc testing and supplementation should be a priority in these cases.
Zinc also plays an important role in the body’s antioxidant defences. Zinc has a structural role in one of the superoxide dismutase (SOD) enzymes, which catalyse the breakdown of damaging superoxide radicals that are formed from oxygen metabolism in our cells. Zinc may also have other mechanisms of action as an antioxidant, which are not yet fully understood. There is also a link between zinc and glutathione: it has been found that zinc deficiency is correlated with decreased levels of glutathione and oxidative stress in different cells and tissues.
Zinc may have an effect on the sleep-wake cycle through influencing melatonin production. A study on rats found that those given zinc supplements had higher plasma melatonin levels, and those that were fed a zinc-deficient diet had a decrease in melatonin. However, there doesn’t seem to be much in the way of clinical trials directly examining the effects of zinc supplementation on sleep in humans or animals.
Lastly, zinc supplementation has been found to support the healing of wounds, and therefore may encourage collagen production. Topical zinc is known to improve wound healing; and studies in animals have suggested that oral zinc supplementation could also have this effect, and is linked with an increase in collagen fibres at the wound site.
Manganese is an essential trace mineral. One of its primary roles in the body is as a constituent of the enzyme manganese superoxide dismutase (MnSOD), the main antioxidant enzyme found in the mitochondria (the energy-producing factories) of our cells.  Because a lot of free radicals are generated through the production of energy in the mitochondria, manganese is therefore essential to protect the cell against oxidative stress.
As well as directly functioning as an antioxidant as part of MnSOD, there is some evidence from laboratory studies that manganese can increase glutathione levels in human cells.[63,64]
Manganese also has a role in collagen production and wound healing. It is needed for the action of the enzyme prolidase, which provides the amino acid proline for collagen formation.
Selenium is an essential trace mineral that we need in very small amounts. One of its most important roles in the body is as part of the glutathione peroxidase enzymes. Glutathione peroxidases have important antioxidant activity, catalysing the reduction of hydrogen peroxide radicals to harmless alcohols or water, using reduced glutathione . Selenium is also found in thioredoxin reductase enzymes, which are thought to have antioxidant activity and recycle vitamin C.
Selenium may also increase actual glutathione levels. A double-blind study on 36 adults males found that those taking a supplement of 247ųg of selenium per day showed a 32% increase in their blood glutathione levels when tested after 9 months. In a later study, the same researchers measured selenium concentrations and blood glutathione levels in a total of 372 people, finding that higher selenium correlated with higher glutathione.
Another primary role of selenium is in thyroid function. As well as glutathione peroxidases and thioredoxin reductases, it is part of another group of enzymes called iodothyronine deiodinases. These enzymes catalyse the conversion of the inactive thyroid hormone thyroxine (T4) to the active triiodothyronine (T3). The thyroid governs our metabolism, including production of energy from the food that we eat; and also has a role in growth.
Copper is part of two types of superoxide dismutase (SOD) enzymes. SOD enzymes have essential antioxidant activity, catalysing the breakdown of damaging superoxide radicals that are formed from oxygen metabolism in our cells.
Copper also has a vital role in the production of collagen. An enzyme called lysyl oxidase, which is activated by copper, modifies the amino acids lysine and hydroxylysine into pyridinoline cross-links, which increase the strength and integrity of collagen.
Inositol is often considered a B-vitamin, although it can be made in the human body from glucose. Its primary function is in the structure of the body’s cell membranes, where it is found as part of a phospholipid called phosphatidyl inositol.
Inositol has been extensively studied with regards to its effects on the brain and nervous system, including its link with serotonin. A study from 1978 found that depressed patients have low levels of inositol in the cerebrospinal fluid compared with healthy patients and this led to the study of inositol for the treatment of depression. One double-blind trial on 28 depressed patients found that those receiving 12 grams of inositol a day showed a significantly greater improvement in depressive symptoms than those in placebo after four weeks of treatment. Inositol has also been found to relieve symptoms of obsessive-compulsive disorder and panic disorder. It is thought that inositol may help in these conditions by regulating serotonin levels, including reversing desensitisation of serotonin receptors.
Taking inositol may also be beneficial for sleep. Although there don’t seem to be any clinical trials specifically examining this effect, several authors have noted that taking at least 1000 mg of inositol at night may facilitate sleep or improve sleep quality[76,77].
Inositol may have antioxidant activity too. A specific form (isomer) of inositol called myo-inositol is known to act as an antioxidant, as is myo-inositol hexaphosphate, also known as Ip6 or phytic acid[79,80]. Both of these can be made by the body from inositol.
Vitamin B12 is a water-soluble vitamin with many known roles and many uses as a supplement. Among these, vitamin B12 is thought to have a role in regulating the circadian rhythm and sleep-wake cycles. Supplemental vitamin B12 has been investigated for helping those with sleep-wake rhythm disorders, with good results in some studies [81,82]. B12 is thought to have a direct effect on melatonin levels.[83,84]
Vitamin B12 may also have an indirect role in the production of serotonin. Vitamins B12 and folate are required for a process called methylation (the donation of methyl groups), which is needed for production of serotonin as well as many other neurotransmitters. Deficiency in B12 or folate (and high homocysteine levels, related to poor methylation) are associated with mood disorders such as depression.[86,87]
Vitamin B6 (pyridoxine / pyridoxal-5-phosphate)
A primary role of vitamin B6 is in production of the neurotransmitter serotonin: it is a co-factor in the pathway for synthesis of serotonin from tryptophan. Because of this role, low levels of vitamin B6 in the blood can be linked to depression (often a symptom of low serotonin). Giving vitamin B6 supplements was found in an early study to increase serotonin levels in the blood in hyperactive children; and a later observational study – also on children – found that higher intake of vitamin B6 and tryptophan at breakfast promoted the synthesis of serotonin when the children were exposed to sunlight for at least 10 minutes.
Vitamin B6 can also be said to have a role in sleep, through its part in serotonin production. Serotonin is of course converted to melatonin, the hormone that regulates the circadian rhythm and sleep cycles. However, there don’t seem to be any clinical trials directly examining the effects of vitamin B6 supplements on sleep.
There is also some evidence that vitamin B6 may have antioxidant effects. A lab study on different forms of B6 including pyridoxine and pyridoxal-5-phosphate found that they could reduce the formation of free radicals and damage to cell membrane lipids (fats).
Folic acid (folate)
Like vitamin B12, folate may have an indirect role in the production of serotonin. Vitamins B12 and folate are required for a process called methylation (the donation of methyl groups), which is needed for production of serotonin as well as many other neurotransmitters. Deficiency in B12 or folate (and high homocysteine levels, related to poor methylation) are associated with mood disorders such as depression.[86,87]
Folate may have antioxidant activity. Folate deficiency is associated with oxidative stress, perhaps due a build-up of homocysteine as a result of poor methylation. And several human studies have found that folate supplementation can reduce markers of oxidative stress in the body – although often using high doses.[94,95]
Vitamin B3 (niacin/niacinamide)
Niacin and niacinamide (also known as nicotinamide) are two forms of vitamin B3 that are used in the body – and can be consumed in food or supplements.
Like the other B vitamins, B3 has an important role in metabolism. It is the precursor to nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), coenzymes that are required for over 400 enzymatic reactions in the body, including those involved in energy production.
Vitamin B3 is thought to have antioxidant activity. Several studies have examined this link, including a trial that found reduced DNA damage to lymphocytes (white blood cells) after 8 weeks of supplementation with 100mg of B3 (as niacin).; and a study on 127 older adults that found a link between higher dietary niacin intake and reduced oxidative stress.
There is some suggestion that vitamin B3 could also encourage growth hormone production. A laboratory study using rat pituitary cells found that vitamin B3 (as niacinamide) and its derivatives increased the synthesis of growth hormone in the cells, including in response to triiodothyronine (T3 – a thyroid hormone). While there seem to be few human studies on this, one double-blind trial on 42 adults tested a combination of glycine, glutamine and niacin for its effects on memory, growth hormone secretion and insulin-like growth factor-I (IGF-1), finding that those taking the supplement showed a 70% increase in serum growth hormone levels.
Ensuring the body has adequate levels of vitamin B3 may also support serotonin synthesis. This is because in situations of vitamin B3 deficiency, B3 can be manufactured in the body from tryptophan, the precursor to serotonin. Hence, more of the tryptophan is being used for manufacture of B3 instead of being converted to serotonin. However, again there seems to be little in the way of studies directly examining intake of vitamin B3 in diet or supplements and its effect on serotonin levels.
The primary function of vitamin E in the body is as an antioxidant. Vitamin E is a fat-soluble vitamin and is thought to protect cell membranes, which have a high content of fats. Vitamin E may also protect LDL cholesterol against oxidation, helping to protect against coronary artery disease.
Vitamin E may also directly increase glutathione levels. A double-blind trial on diabetic children found that giving 100iu per day of vitamin E for three months increased the blood glutathione levels in the supplemented group by 9%, whereas glutathione levels in the placebo group did not increase. The authors concluded that ‘glutathione level is significantly related to vitamin E level’. Another study on rats fed a high-cholesterol diet found that vitamin E supplementation increased levels of glutathione, and activities of the enzymes glutathione peroxidase and glutathione transferase.
Vitamin C is another vitamin with many known roles in the body. These include contributing to the function of the immune system, including during or after intense exercise; and contributing to energy production.
Another primary role of vitamin C is as an antioxidant – in fact, it’s said to be the most important antioxidant substance in plasma and tissues that is not an enzyme (e.g. superoxide dismutase or glutathione peroxidase that are made in the body). Vitamin C readily donates electrons to other molecules – including free radicals – and protects all types of substances in the body, including proteins, carbohydrates, fats and DNA/RNA. It also recycles vitamin E, a fat-soluble antioxidant that protects our cell membranes.  Intake of vitamin C is associated with reduced risk of chronic diseases such as cancer, cardiovascular disease and cataracts, probably due to its role as an antioxidant.
Through its role as an antioxidant, vitamin C can also ‘spare’ and regenerate glutathione. Several studies have examined this effect. A human study on nine participants consuming a vitamin C-restricted diet found that taking just 500mg vitamin C a day increased the mean glutathione levels in their red blood cells by nearly 50% after two weeks. Another study on 48 healthy adults with low vitamin C levels at baseline found that taking 500mg or 1000mg of vitamin C increased the glutathione concentration in their lymphocytes (white blood cells) by 18% compared to baseline, and this returned back to the original levels when they were put on placebo.
Another primary role of vitamin C is in the production of collagen, including in bones, cartilage and muscles. It is a cofactor for the enzymes prolyl and lysyl hydroxylase (enzymes that produce hydroxyproline and hydroxylysine, necessary for the formation and stability of collagen) and stimulates collagen gene expression.
St John’s Wort
The herb St John’s Wort has been extensively studied and used as a natural treatment for mood, including mild to moderate depression. Double-blind studies have shown its effectiveness, including a trial on 105 participants comparing St John’s Wort to placebo, which found that depressive symptoms reduced significantly in 28 of 42 patients in the active group (according to the Hamilton Depression Scale) versus just 13 out of 47 in the placebo group. Another trial on 375 patients with mild to moderate major depression found that St John’s Wort extract was safe and more effective than placebo at reducing depressive symptoms and produced a greater response rate to treatment than the placebo. It is thought that the antidepressant activity of St John’s Wort may be due to its effect on serotonin levels: a study on rats found that a St John’s Wort extract reduced reuptake of serotonin at the postsynaptic receptors by up to 50%.
St John’s Wort has also been found to improve sleep. Several studies examining the effects of St John’s Wort for depressive disorders have also found a significant improvement in sleep, including reduction in sleep disorders[113,114]. It’s thought that St John’s Wort could increase the nocturnal secretion of melatonin, the hormone that regulates the circadian rhythm and sleep cycles.
St John’s Wort extracts may also have antioxidant effects. A study from 2013 examining five different species of St John’s Wort found that all the extracts showed notable antioxidant potential. Another study comparing the antioxidant potential of various plant extracts found St John’s Wort to have a greater antioxidant effect than many other commonly used herbs such as eleutherococcus (Siberian ginseng), rhodiola, valerian and panax ginseng.