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Tryptophan - Bioavailability & Mood Disorders

Updated: Oct 15, 2021


Tryptophan is an essential amino acid required for normal growth and serves as a precursor to many bioactive compounds including nicotinamide (vitamin B6), serotonin, melatonin, tryptamine, quinurenine, 3-hydroxyquinine and 3-hydroxyquinurine and

(Friedman, 2018; Gibson, 2020).


Rich source of tryptophan: milk (α-lactalbumin) & fatty fish (fat content over 5%) (Naufel et al., No date).

(Layman, Lo and Fernstrom, 2018)


Tryptophan is a precursor of serotonin - increased levels of TRP in the brain induce the synthesis of serotonin. Cross of dietary TRP via the blood-brain barrier is favored by a higher plasma TRP concentration compared to other competing major neutral amino acids (LNAAs). Plasma TRP / LNAA ratio is known to be affected by both dietary carbohydrates and dietary proteins. Proteins rich in TRP, such as α-galactoalbumin, increase the plasma TRP / LNAA ratio by up to 130% and therefore favor the increase of serotonin in the brain. However, if the diet contains many other LNAAs, TRP transport across the blood-brain barrier is reduced. (Peuhkuri, Sihvola and Korpela, 2012).

In addition to protein, carbohydrates from the diet also play a role. A high postprandial insulin level after a carbohydrate load favors the transport of TRP to the brain because, insulin either inhibits the release of peripheral amino acids or promotes the peripheral uptake of other LNAAs. Thus, in response to an increasing plasma glucose concentration, insulin mediates LNAA uptake into muscle but not TRP. TRP is highly bound to plasma albumin. As a result, the TRP / LNAA ratio remains high and the concentration of other competing LNAAs decreases. In addition to protein and carbohydrates, there are certain vitamins that promote the availability of tryptophan to be converted to serotonin such as vitamins B3 and B6 (Peuhkuri, Sihvola and Korpela, 2012).

Tryptophan hydroxylase is the enzyme involved in the synthesis of serotonin. Approximately ≈6g of tryptophan leads to enzyme saturation and up to 2-fold increase in the rate of serotonin synthesis (Young and Leyton, 2002).

In a study to investigate the effects of different forms of dietary tryptophan, Markus et al examined whether hydrolyzed protein had a greater effect on Trp / LNAA ratio and therefore mood, compared to intact protein in healthy volunteers (n = 18). They observed significantly faster increases and a longer duration of the ratio with the hydrolyzed source of tryptophan than with intact tryptophan. In a related study, Markus et al found that the consumption of egg protein rich in hydrolyzed tryptophan by 17 participants with high and 18 with low chronic stress, led to increased tryptophan intake in plasma, brain and thus improved mood and performance under acute stress exposure, suggesting a positive effect and greater availability of hydrolyzed compared to intact tryptophan (Friedman, 2018).

(Peuhkuri, Sihvola and Korpela, 2012)


Trp supplements are largely safe (limited evidence)

Symptom reports: nausea, tremor or dizziness in high doses (common symptoms also reported in people taking placebo).

Increased risk of side effects when TRP is combined with other drugs that improve the availability of serotonin-5-HT (antidepressants or MAO-monoamine oxidase inhibitors). Risk of toxic "serotonin syndrome" that may cause hyperthermia or coma

(Gibson, 2020).

Tryptophan and mood disorders-depression

Mental disorders, including depression, have a major impact on people's lives and are estimated to affect about 1/10 of the world's population. It cannot be diagnosed early due to a lack of biomarkers and often antidepressant treatment is not effective. It is worth noting that such mental disorders are associated with the development of cardiovascular disease, osteoporosis, diabetes and cerebral ischemia. Studies have linked mood disorders with decreased HDL cholesterol levels and elevated triglyceride levels (Wigner et al., 2018).

Data from the US National Health and Nutrition Examination Survey for approximately 30,000 adults have shown that dietary tryptophan is associated with improvement in depressive states and improved sleep duration (Gibson, 2020).

Early studies examining tryptophan on mood--> tryptophan was administered to patients with depression for several days or weeks, alone and in combination with an antidepressant. Tryptophan has been found to have antidepressant activity on its own and to enhance the antidepressant effectiveness of monoamine oxidase inhibitors and another antidepressant, chlorimipramine (Layman, Lo and Fernstrom, 2018).

The acute effect of tryptophan when administered in doses of 0.5-7 g in healthy subjects was a feeling of euphoria. However, it is emphasized that such an effect does not affect the whole population and is related to the individual himself (Young and Leyton, 2002).

In a study by Wenefrida et al, 35 middle-aged / elderly people typically ate tryptophan 22.5 mg / 30 g cereals at breakfast and dinner during the control week and tryptophan 60 mg / 30 g cereals during the intervention week. The results show that consuming higher-grade tryptophan cereals increased the quality and duration of sleep and improved symptoms of anxiety and depression (Friedman, 2018).

Research with ATD (acute tryptophan depletion) has shown that changes in tryptophan levels can affect mood as well as behavior associated with aggression and irritability. ATD: a method in which a person is given a mixture of amino acids that does not contain tryptophan. The mixture promotes protein synthesis resulting in the necessary tryptophan being given by the body and reducing its levels in the blood and tissues. The result is a reduction in the synthesis of serotonin in the brains of both animals and humans. Generally, decreased serotonin levels lead to a more negative mood and behavior while elevated levels have the opposite effect. Of course, some people are more sensitive to such effects than others, and here the article also raises the question of whether these people generally have reduced serotonin levels. Mood and behavior are also affected by various neurotransmitters, not just serotonin (Young and Leyton, 2002; Gibson, 2020).

Studies confirm that doses of the amino acid Trp administered orally, intraperitoneally or subcutaneously lead to an increase in serotonin in different areas of the brain at different intensities. However, further studies are needed to assess the dose-response of Trp administration to serotonin-5-HT levels in the brain (Braga et al., 2018).

Serotonin is involved in regulating sleep, appetite, metabolism, mood and libido and inhibits aggressive behavior in mammals (Carlos et al., 2017). One of the most powerful ways that serotonin regulates sleep is through changes in melatonin concentration because serotonin is an intermediate in its production (Peuhkuri, Sihvola and Korpela, 2012).

However, things are not so simple since the breakdown of tryptophan on the quinurenine axis not only will not reduce depression levels but may increase them. The breakdown of tryptophan on the quinurenine axis is accelerated in conditions associated with inflammatory disorders. Chronic inflammatory disorders are often accompanied by decreased quality of life, decreased mood and depression, as well as neurocognitive symptoms. In addition, pro-inflammatory mechanisms contribute to the pathophysiology of major depression. The highest percentage of dietary tryptophan (> 95%) ends up in the quinurenine pathway. If for some reason the immune system is activated first, outside the brain, then the availability of tryptophan (some tryptophan metabolites are involved in the immune system-quinurene) will be reduced for serotonin synthesis, thus reducing mood (Gostner and Stonig 2020).

(Wigner et al., 2018)

In addition, tryptophan as a precursor to serotonin and melatonin ultimately affects sleep. Approximately 80% of depressed patients develop various sleep disorders (Wigner et al., 2018).

One type of depression is winter depression, which seems to be related to melatonin, serotonin, and their amino acid precursor, tryptophan. Winter depression as the name suggests is depression with flares in the winter and autumn period and is probably associated with longer nights and therefore increased melatonin production especially in countries with reduced light period. Melatonin is synthesized from tryptophan, outside the blood-brain barrier. Overproduction of melatonin can lead to increased ¨consumption” of tryptophan, from which serotonin is synthesized. When tryptophan is used excessively to synthesize melatonin, its levels in the blood can be reduced. Therefore, it is more difficult for tryptophan to cross the blood-brain barrier and reach serotonergic neurons as the ratio of tryptophan to other amino acids competing for the same transporter decreases. Therefore, less tryptophan is available for serotonin synthesis (Carlos et al., 2017).

In conclusion

• The main source of Trp is milk

• Role in bioavailability: dietary proteins, carbohydrates, vitamins & type of protein

• Supplements --> generally safe

• The authors suggest that tryptophan could be a promising tool for shaping social behavior (Friedman, 2018)

• Tryptophan deficiency can lead to mood and sleep disorders & depression

• Such effects do not affect the whole population


Braga, I. et al. (2018) ‘administration and increase in cerebral serotonin levels : Systematic review L -tryptophan’, 836(August), pp. 129–135. doi: 10.1016/j.ejphar.2018.08.009.

Carlos, J. et al. (2017) ‘Secondary to excessive melatonin synthesis , the consumption of tryptophan from outside the blood-brain barrier and melatonin over- signaling in the pars tuberalis may be central to the pathophysiology of winter depression’, 98, pp. 69–75. doi: 10.1016/j.mehy.2016.11.020.

Friedman, M. (2018) ‘Analysis , Nutrition , and Health Benefits of Tryptophan’. doi: 10.1177/1178646918802282.

Gibson, E. L. (2020) ‘Conference on “ Diet , nutrition and mental health and wellbeing ” Symposium 4 : Public health and nutrition strategies to promote good mental health Tryptophan supplementation and serotonin function : genetic variations in behavioural effects Proceedings of the Nutrition Society Proceedings of the Nutrition Society’, (December 2016), pp. 174–188. doi: 10.1017/S0029665117004451.

Gostner, J. M. and Stonig, M. (2020) ‘Tryptophan Metabolism and Related Pathways in Psychoneuroimmunology : The Impact of Nutrition and Lifestyle’, pp. 89–99. doi: 10.1159/000496293.

Layman, D. K., Lo, B. and Fernstrom, J. D. (2018) ‘Applications for a -lactalbumin in human nutrition’, 76(6), pp. 444–460. doi: 10.1093/nutrit/nuy004.

Naufel, M. F. et al. (no date) ‘Influence of Dietary Sources of Melatonin on Sleep Quality : A Review’. doi: 10.1111/1750-3841.14952.

Peuhkuri, K., Sihvola, N. and Korpela, R. (2012) ‘Diet promotes sleep duration and quality’, Nutrition Research. Elsevier Inc., 32(5), pp. 309–319. doi: 10.1016/j.nutres.2012.03.009.

Porter, R. J. et al. (2008) ‘Tryptophan hydroxylase gene ( TPH1 ) and peripheral tryptophan levels in depression’, 109, pp. 209–212. doi: 10.1016/j.jad.2007.11.010.

Wigner, P. et al. (2018) ‘The molecular aspects of oxidative & nitrosative stress and the tryptophan catabolites pathway ( TRYCATs ) as potential causes of depression’, Psychiatry Research. Elsevier Ireland Ltd, 262(April 2017), pp. 566–574. doi: 10.1016/j.psychres.2017.09.045.

Young, S. N. and Leyton, M. (2002) ‘The role of serotonin in human mood and social interaction Insight from altered tryptophan levels’, 71, pp. 857–865.

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