L-tryptophan is one of eight essential amino acids in the human diet. It is the metabolic precursor of serotonin, melatonin and niacin. It was discovered in 1901 by Sir Frederick Gowland Hopkins who also demonstrated its vital importance to human health. L-tryptophan is used for treating depression, promoting sleep and as an aid to weight loss.
Now re-approved for use in nutritional supplements
In 1989, the United States banned imports of tryptophan and its use in nutritional supplements, with Europe taking the same action a year later. These bans were the result of an outbreak of an autoimmune disease, in some cases fatal, which was linked to a single batch of incorrectly-produced tryptophan. So the product was subject to a blanket ban, despite acknowledgement that the ‘rogue’ batch came from one Japanese factory which had allowed a toxic bacterial metabolite to contaminate the purification process.
For more than 10 years, the use of tryptophan was restricted to prescription drugs, powdered baby milk and parenteral nutrition products.
In 1994, 5-HTP emerged as an alternative to tryptophan supplements, tryptophan being naturally converted in the body into 5-HTP.
Much more recently, tryptophan has again been made available as a nutritional supplement in the United States and in certain European countries.
An essential amino acid provided by the diet
Tryptophan is obtained from protein-based foods - meat, fish, eggs, dairy products as well as starchy foods and dried fruits are all notable sources. However, it is easily destroyed by lengthy or high temperature cooking.
Of all the amino acids, tryptophan is the least abundant; a typical diet provides just 0.25g-1.5g a day. In addition, the liver has very low reserves of tryptophan and so with daily intake often barely meeting requirements, sub-clinical deficiency in this essential amino acid is by no means infrequent.
Furthermore, tryptophan needs to be consumed six to eight hours before going to bed in order that digestion of proteins is complete and that the tryptophan is stored in the liver and released gradually into the blood stream.
In addition, depending on the food source, its absorption and use by the brain can be poor - the brain normally receives less than 1% of any tryptophan ingested. Recovering even this tiny percentage is particularly difficult because of the blood-brain barrier, the function of which is to prevent toxins and even excess levels of nutrients from entering the brain. This transit can sometimes be very difficult even for essential nutrients. Serotonin is unable to cross the blood-brain barrier whereas its precursor, tryptophan, can. However, nutrients have to be transported by carrier molecules and tryptophan has to share these carriers with five other amino acids - tyrosine, phenylalanine, valine, leucine and isoleucine. An excess or shortage of tyrosine, for example, will inhibit the transport of tryptophan across the blood-brain barrier.
Moreover, the body uses tryptophan to make various proteins, as well as melatonin, serotonin and the B vitamins (niacin). In people with low to moderate intake of vitamin B3, as much as 60mg of tryptophan may be converted by the liver to produce just 1 to 2 mg of vitamin B3. In those who are even slightly deficient in vitamin B6, tryptophan can be rapidly broken down into mildly toxic metabolites.
Tryptophan’s best-known and most important role is that of metabolic precursor of the neurotransmitter serotonin. A number of studies have shown that an increase in tryptophan concentration in the brain results in greater release of serotonin which plays an essential role in regulating mood, anxiety, appetite and sleep.
Oral supplementation with tryptophan also produces an increase in levels of other neurotransmitters and chemicals in the central nervous system such as melatonin, dopamine, norepinephrine and beta-endorphin.
There is little data linking tryptophan to modulation of the endocrine system and evidence of its effects on cortisol levels is uneven.
Intravenous administration of tryptophan stimulates secretion of prolactin and growth hormone although no such association has been tested with oral supplementation.
Mechanism of conversion into serotonin
Serotonin - or 5-hydroxytryptamine (5-HT) - was first identified more than 50 years ago, since when scientists have continued to discover new benefits and roles for it within the body.
Studies show that serotonin plays a central role in depression, mood, anxiety, sleep, appetite control, memory, learning, temperature regulation, sexual behaviour, hallucinations, cardiovascular function, skeletal muscle contractions, hormone regulation, blood coagulation and motility of the gastrointestinal system2
It was in the 1970s that serotonin’s critical role in depression was discovered. Low levels of a serotonin metabolite, 5-hydroxyindolacetic acid (5-HIAA), were observed in the fluid surrounding the brain and spinal cord of numerous people suffering from depression. This indicated that their brains were not producing or metabolising normal levels of serotonin. 3
Researchers also noted that suicidal individuals had abnormally low levels of 5-HIAA suggesting that serotonin deficiency could actually predispose certain people to attempt to take their own lives. 4
It was also demonstrated that serotonin plays an important role in aggressive behaviour.
Tryptophan, carbohydrates and obesity
Eating a protein-rich diet in order to boost your tryptophan intake actually only serves to complicate matters because you are simultaneously increasing your consumption of the five other amino acids competing with tryptophan to cross the blood-brain barrier. In fact, the only way to increase the supply of tryptophan to the brain is to eat a carbohydrate-rich diet. This is because such a diet causes the body to secrete large amounts of insulin in order to reduce the consequent rise in glucose. The insulin also removes most of the five competing amino acids from the blood, enabling the tryptophan to ‘go it alone’ and thus more of it reaches the brain.
This strategy is actually one practised instinctively by many people who, when they feel depressed, anxious or stressed, turn to high carbohydrate foods such as bread, cakes, chips, pizza or ice cream.
The resulting increase in serotonin in the brain reduces anxiety and agitation, promoting a (temporary) sense of well-being and security. However, it comes at a price. The same insulin that boosts serotonin in the brain also increases the conversion of fats, carbohydrates and amino acids removed from the bloodstream, into stored body fat - hence the link between carbohydrate dependence, obesity and serotonin.
Taking a tryptophan supplement is the most natural way of combatting the problems of serotonin production in the brain. Unlike a high-protein diet, tryptophan supplements will not increase blood levels of the five competing amino acids. Since a typical diet provides just 1-1.5g a day, even modest supplementation (500-3000mg) will have a significant effect on boosting blood and brain levels of tryptophan.
Under normal circumstances, the cerebral enzyme tryptophan hydroxylase (TH) is only half saturated with tryptophan, so the means for producing serotonin remains 50% under-exploited. Thus any increase in the raw material (tryptophan) will tend to automatically increase the introduction of cerebral serotonin. TH converts tryptophan into 5-hydroxytryptophan (5-HTP). A vitamin B6-dependent enzyme then converts 5-HTP into serotonin; more serotonin means improved activation of the serotonin neural circuits controlling calm, mood elevation, nerve impulses and appetite.
Scientists have shown that in bulimic females, a tryptophan-depleted diet results in a significant rise in fatigue and a tendency towards anxiety and indecision 5, as well as increased calorie consumption and irritable mood. These results suggest that women with bulimia nervosa have a pathological or exaggerated response to temporary changes in serotonin activity. 6
L-tryptophan, a natural anti-depressant
Among the many clinical studies published since the 1970s on the use of tryptophan in depression, those using moderate doses (1-3g a day) have often produced better results than those using larger doses (6-9g a day). This is due to a liver enzyme called tryptophan pyrrolase (TP) which plays a key role in the normal pathways of hepatic degradation of tryptophan.
TP is activated by at least two factors.
The first is the stress hormone cortisol, produced by the adrenal glands in response to persistent, chronic, inescapable stress. Cortisol is often elevated in depression, insomnia and obesity for which tryptophan and serotonin can prove beneficial. Taking tryptophan in conditions of stress-induced raised cortisol may only provide the brain with a small amount of extra serotonin due to cortisol’s activation of TP.
The second factor is the increase in tryptophan consumption. TP uses the main, kynurenine pathway of tryptophan degradation. Significantly higher consumption of tryptophan automatically raises TP activity and again, because this hepatic TP activity is considerably increased, a higher dose of tryptophan does not automatically translate into an increase in cerebral serotonin.
Therefore, the lowest dose of tryptophan that can successfully relieve symptoms of serotonin deficiency is also the most effective. Clinical studies show that a dose of 500-1500mg of tryptophan, taken regularly at bedtime, is often sufficient to relieve problems associated with serotonin deficiency.
In the period before and after the winter solstice, days are shorter and the sun is conspicuous by its absence. For some people, this grey, dreary phase results in a genuine case of the winter blues or seasonal depression. The result of a lack of sunlight, it can normally be treated by light therapy.
Placebo-controlled and other studies on individuals suffering from seasonal depression have shown that during periods of remission (over the summer or following phototherapy), their symptoms were reactivated when tryptophan was removed from their diet. A small study subsequently indicated that daily supplementation with 4-6g of L-tryptophan spread over several doses was as effective as phototherapy9 and more effective than placebo in treating seasonal depression10.
Four-week treatment with tryptophan (2g twice a day, increasing to 2g three times a day in the case of no response) was compared with light therapy (10,000-lux for 30 minutes every morning). After seven weeks, an identical response was observed in both groups of patients. However, when the light therapy was stopped, patients rapidly relapsed into depression, while those taking tryptophan took longer to do so. Similar results were obtained from light therapy and tryptophan in 14 patients with seasonal depression11. They were given 1000mg of tryptophan three times a day in addition to 30 minutes exposure every morning to a full-spectrum lamp providing an intense light of 10,000 lux. A significant improvement was observed in nine patients.
Tryptophan promotes sleep
Tryptophan’s ability to promote sleep was first reported in 1962 12 and it has since been widely used as a treatment for those experiencing difficulties in falling asleep.
Almost 50 studies have investigated tryptophan’s efficacy as a sleeping aid. While results are variable, the consensus is that tryptophan may be an effective sleeping aid in certain circumstances. While ineffective as a sleeping pill in cases of severe insomnia, for mild insomniacs it can almost halve the time it takes to fall asleep, even at low doses (250mg).
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