What Causes Low Tryptophan Levels?

December 7, 2025 •

4 min read

According to a 2024 study in The Lancet EBioMedicine, reduced serum tryptophan levels are linked to increased inflammation across numerous chronic inflammatory disorders. This highlights that low tryptophan levels are not simply a result of diet but can stem from a variety of complex issues, including gut health, genetic factors, and underlying health conditions.

Quick Summary

Low tryptophan levels can be triggered by insufficient dietary intake, intestinal malabsorption, genetic conditions like Hartnup disease, chronic inflammation, and altered gut microbiome function.

Key Points

Diet and Competition: Insufficient protein intake or a high-protein, low-carbohydrate diet can limit tryptophan availability due to competition from other amino acids for brain entry.
Inflammation is a Major Culprit: Chronic inflammatory diseases and infections redirect tryptophan into the kynurenine pathway, reducing the amount available for serotonin production.
Gut Health is Critical: An imbalanced gut microbiome (dysbiosis) can disrupt tryptophan metabolism and the production of beneficial metabolites that regulate intestinal barrier function and immunity.
Genetic Factors Exist: Rare inherited disorders, like Hartnup disease, cause defective amino acid transport, leading to excessive loss of tryptophan and potential niacin deficiency.
Medical Conditions Play a Role: Diseases such as diabetes and cancer, along with chronic stress and excessive alcohol intake, can all contribute to altered tryptophan metabolism.
Absorption Issues Matter: Malabsorption syndromes, including fructose malabsorption and intestinal issues from conditions like IBD, can prevent proper tryptophan uptake.

The Importance of Tryptophan

Tryptophan is an essential amino acid, meaning the human body cannot produce it and must obtain it through diet. It is a precursor to several vital compounds, including the neurotransmitter serotonin, which regulates mood, sleep, and appetite. It is also converted into vitamin B3 (niacin) and various other metabolites via the kynurenine pathway, which plays a major role in regulating immune responses. A disruption in tryptophan's availability or metabolism can therefore have far-reaching effects on both physical and mental health.

Dietary and Absorption Issues

While outright dietary deficiency is rare in developed countries, factors related to diet and nutrient absorption are common causes of reduced tryptophan availability. A primary issue can arise from the competition for transport across the blood-brain barrier. Tryptophan shares a transport system with other large neutral amino acids (LNAAs), such as tyrosine and phenylalanine. A meal high in protein but low in carbohydrates may not effectively increase brain tryptophan levels because the high concentration of competing LNAAs outcompetes it. Conversely, a high-carbohydrate meal triggers insulin release, which helps shuttle other amino acids into muscle tissue, leaving more free tryptophan available to enter the brain.

Common Dietary and Absorption Inhibitors

Inadequate Protein Intake: While uncommon, a very low-protein diet can lead to insufficient intake of all essential amino acids, including tryptophan.
Excessive Alcohol: Chronic alcohol consumption has been shown to decrease the ratio of tryptophan to competing amino acids in the blood.
Vitamin B6 Deficiency: Tryptophan's metabolism requires vitamin B6 as a cofactor. A deficiency can impair its conversion into important metabolites, including niacin.
Fructose Malabsorption: This digestive disorder can lead to the improper absorption of tryptophan in the intestines, causing lower levels in the blood.
Gut Microbiome Dysbiosis: An imbalance in gut bacteria can significantly alter tryptophan metabolism, as many bacteria are involved in converting it into different derivatives.

Chronic Inflammation and the Kynurenine Pathway

One of the most significant and common causes of low tryptophan is chronic inflammation. During an inflammatory state, the body activates the kynurenine pathway, which consumes a large portion of available tryptophan, diverting it away from serotonin synthesis. This process is mediated by enzymes like indoleamine 2,3-dioxygenase (IDO1), which is upregulated by pro-inflammatory cytokines like interferon-gamma (IFN-γ).

This phenomenon has been observed in various health conditions:

Inflammatory Bowel Diseases (IBD): Patients with Crohn's disease and ulcerative colitis often have increased IDO activity, leading to reduced serum and fecal tryptophan levels.
Chronic Infections: Persistent, low-grade infections can lead to chronic inflammation that fuels the kynurenine pathway.
Diabetes Mellitus: Both type 1 and type 2 diabetes are associated with chronic, low-grade inflammation that alters tryptophan metabolism. Studies have shown increased tryptophan catabolism in T2DM patients.
Cancer: Enhanced tryptophan breakdown is frequently observed in cancer patients and is linked to inflammation, fatigue, and depression.

Genetic and Inherited Conditions

In some cases, a genetic predisposition can be the root cause of low tryptophan levels. The most classic example is Hartnup disease.

Hartnup Disease

This is a rare, autosomal recessive metabolic disorder affecting the transport of neutral amino acids, including tryptophan, in the small intestine and kidneys. The result is that tryptophan is poorly absorbed from the diet and excessively excreted in the urine, leaving the body with inadequate amounts. This can lead to a niacin deficiency and symptoms resembling pellagra, such as skin rashes, neurological disturbances, and psychiatric issues. While symptoms can vary in severity and are often triggered by stress, sunlight, or dietary deficiencies, a high-protein diet and nicotinamide supplements are used for management.

Comparison of Key Causes for Low Tryptophan Levels


Cause	Primary Mechanism	Associated Conditions	Key Biomarker or Indicator
Inadequate Diet	Insufficient protein intake or competition from other amino acids.	Rare dietary deficiencies, unbalanced high-protein meals.	Low total tryptophan, low Trp/LNAA ratio.
Chronic Inflammation	Activation of the kynurenine pathway, diverting tryptophan away from serotonin synthesis.	Inflammatory Bowel Disease (IBD), Diabetes, Chronic Infections, Cancer.	Elevated Kynurenine/Tryptophan (Kyn/Trp) ratio, high C-reactive protein (CRP).
Genetic Disorder	Defective transport system for neutral amino acids in the kidneys and intestines.	Hartnup Disease.	Excess neutral amino acids in urine.
Intestinal Malabsorption	Conditions leading to poor absorption of nutrients in the gut.	Fructose malabsorption, Celiac disease, Crohn's disease.	Poor nutrient absorption, gastrointestinal symptoms.

Other Medical and Lifestyle Triggers

Beyond the primary causes, other factors can disrupt tryptophan metabolism and contribute to low levels:

Chronic Stress: Long-term psychological stress can impact the immune system, leading to an inflammatory response that increases tryptophan metabolism down the kynurenine pathway, similar to the effect of chronic infections.
Gut Microbiome: The health of your gut microbiota is crucial. In states of dysbiosis, gut bacteria may not produce beneficial tryptophan metabolites, or inflammatory processes within the gut can increase tryptophan degradation by host enzymes.
Medications: Some drugs can interfere with tryptophan absorption or metabolism. For example, certain antidepressants (like SSRIs) and other substances that affect serotonin pathways can have complex interactions with tryptophan levels. It is crucial to consult a doctor before taking supplements alongside such medications.

Conclusion: A Multifaceted Problem

Low tryptophan levels are rarely the result of a single cause but are often a complex interplay of several factors. From the intricacies of dietary absorption and the presence of chronic inflammation to the influence of the gut microbiome and rare genetic predispositions, the causes can be highly individual. Understanding these potential root causes is the first step toward addressing the issue effectively. For persistent symptoms, consulting a healthcare professional is essential for accurate diagnosis and a comprehensive management plan. You can read more about how tryptophan depletion is used in research and its effects on the brain in this 2012 NIH article: Influence of Tryptophan and Serotonin on Mood and Cognition with and without a Genetic Vulnerability to Depression.

Frequently Asked Questions

Consuming a carbohydrate-rich, protein-containing meal can help. The insulin spike from carbohydrates helps other amino acids enter muscle tissue, leaving less competition for tryptophan to enter the brain.

Yes, chronic stress is known to increase immune activation, which diverts tryptophan away from serotonin production through the kynurenine pathway. This can lead to decreased circulating tryptophan levels.

Symptoms associated with low tryptophan often reflect low serotonin levels. These can include anxiety, depression, irritability, insomnia, poor dream recall, and increased pain and noise sensitivity.

The gut microbiota can either help or hinder tryptophan metabolism. Certain bacteria produce beneficial metabolites from tryptophan, while dysbiosis can trigger inflammatory responses that increase its breakdown and reduce its availability.

Hartnup disease is a rare genetic disorder where the body cannot properly transport certain amino acids, including tryptophan, across the small intestine and kidneys. This leads to excessive loss of tryptophan.

While an extremely low-protein diet could be a factor, it is rare. Most people in developed countries get enough protein. Issues are more likely related to absorption, inflammation, or genetic factors.

Dietary fiber, probiotics, and prebiotics can help regulate the gut microbiome. A balanced diet supports the growth of beneficial bacteria, which in turn can positively influence tryptophan metabolism and gut barrier function.