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Serotonin Research

Serotonin Metabolism, by Abelard Lindsay

Serotonin is a neurotransmitter responsible for mood[1], fear[2], aggression[3] and anxiety[4]. It plays a large part in the digestive process as it interacts with neurons present in the gut[5]. Healthy serotonin levels allow one to be in the moment instead of becoming drawn into negative thought patterns.

Where does serotonin come from? It starts with tryptophan. Tryptophan is an essential amino acid that is a precursor to serotonin. It is found in many foods such as egg whites, soybean and turkey and is also available as a nutritional supplement[6].

It is converted into 5-HTP by the enzyme tryptophan hydroxylase(TH). TH is a key rate limiting enzyme that controls the production of 5-HTP in the body. TH comes in two variants. TPH1, which is present in the gut and the peripheral nervous system, and TPH2, which is primarily expressed in the central nervous system[7].

Serotonin outside the CNS is not particularly interesting for cognitive enhancement. It is however suspected that a lack or excess of serotonin in the digestive tract can lead to irritable bowel syndrome. Some drugs with antidepressant effects are actually used to control certain intractable digestive problems, presumably by having an effect on the neurochemical aspects of digestion[8].

Serotonin is an agonist for many different serotonin receptors in the brain. Many antidepressant drugs developed over the past 30 years, known as SSRIs, have been developed in order to keep serotonin active in the synaptic cleft by reducing the activity of the SERT enzyme[9].

The theory behind this is that stimulating serotonin receptors via increased synaptic serotonin will improve and alleviate depression[10]. Exercise, a well studied treatment for depression[11], has been investigated as a serotonin production enhancer through various mechanisms[12].

Serotonin is broken down and then processed into melatonin via methylation[13]. Melatonin is crucial for sleep. Methylation is also active in the dopamine system and breaks down norepinephrine to epinephrine. Supplementation of melatonin has been shown to increase serotonin in animal models[14].

Seasonal affective disorder, a form of depression caused by lack of sunlight in winter months, is tied to serotonin deficiency[15]. This is possibly due to excess melatonin production from serotonin as melatonin production is controlled by light exposure and the circadian rhythms[16].

Another system that has a profound effect on serotonin metabolism is regulated by the hormone cortisol.

Cortisol pathways, which are induced by stress, cause an increase in serotonin reuptake, possibly contributing to depression[17]. Increased cortisol also may increase the production of N-formyl-L-kynurenine by increasing the activity of tryptophan 2,3-dioxygenase[18]. This pathway uses up L-Tryptophan in the eventual production of niacin instead of serotonin. Niacin is produced from tryptophan in competition with the serotonin pathway[19]. Supplementing niacin thus may free up tryptophan to be processed into serotonin.

Magnesium is important in processing serotonin[20]. A correlation has been shown between low magnesium levels and depression[21]. Experimental evidence has also shown that magnesium is needed as a cofactor of tryptophan hydroxylase, which converts tryptophan into 5-HTP, a serotonin precursor, and magnesium is also needed for binding serotonin[22]. It also increases activity at the 5-HT1A serotonin receptor.[23]

Zinc also enhances outcomes in unipolar depression[24]. The mechanism of action on serotonin is that it modulates uptake of serotonin into cells[25].

Herbs that have exhibited serotonin reuptake inhibition activity like St. John’s Wart[26] and herbs with observed MAO-A inhibition activity like resveratrol[27] are powerful increasers of serotonin and should only be used in situations where there is a significant deficiency. Berberine heavily influences the 5-HTT transporter[28] while having positive health benefits and being well tolerated over long periods of time.

Serotonin is a regular and reliable system that responds to supplementation and has positive effects on mood and energy. There’s a huge difference between low levels of serotonin and optimal levels in how you think, feel and perform.




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