Tryptophan: Effects, Dosage and Use

Tryptophan, more precisely L-tryptophan, is an essential amino acid. The body cannot produce it on its own but must obtain it through food. Tryptophan is especially abundant in protein sources such as turkey meat, eggs, hard cheese, soy, oats, pumpkin seeds, cashews and bananas. Tryptophan has become known primarily as a biochemical precursor to serotonin and melatonin, two neurotransmitters that regulate mood, motivation and the sleep-wake cycle.

In Germany, L-tryptophan is approved as a prescription medication (for example Ardeydorm, Kalma) for sleep disorders. Additionally, over-the-counter dietary supplements are available. The evidence for clinical efficacy is mixed: there are indications of an effect in mild sleep-onset disorders and premenstrual mood worsening, but for moderate to severe depression the evidence for monotherapy is insufficient. It is important not to understand tryptophan as a replacement for specialist medical diagnosis or established antidepressant therapy.

Mechanism of Action

Ingested tryptophan enters the blood stream and reaches the blood-brain barrier, where it competes with other large neutral amino acids such as leucine, isoleucine, valine, phenylalanine and tyrosine for entry into the brain via an active transporter (LAT1). A carbohydrate-rich meal partially lifts this competition because insulin increases muscle uptake of competing amino acids, allowing tryptophan to enter the brain more easily.

In the central nervous system, tryptophan is converted to serotonin (5-hydroxytryptamine) in two steps: first via tryptophan hydroxylase to 5-hydroxytryptophan (5-HTP), then via aromatic L-amino acid decarboxylase to serotonin. In the pineal gland, serotonin is time-dependently converted to melatonin, which regulates the day-night rhythm. Only a small proportion of tryptophan, approximately one to two percent, is actually converted to serotonin. The vastly larger portion (approximately 95 percent) undergoes the kynurenine metabolic pathway, at the end of which niacin (vitamin B3) and energy-rich compounds such as NAD are produced.

During inflammation or chronic stress, the enzyme indoleamine 2,3-dioxygenase (IDO) is activated. It directs more tryptophan into the kynurenine pathway and can in this way reduce serotonin formation. This mechanism is discussed as a link between inflammatory processes and depressive mood, but it is not evidence that tryptophan supplementation reliably corrects these effects.

Uses

• Mild sleep disorders, particularly sleep-onset difficulties, short-term and in combination with sleep hygiene
• Adjunctive treatment in premenstrual syndrome with irritability or depressed mood, supplementing lifestyle and possibly hormonal therapy
• Adjuvant for seasonal affective disorder, supplementing light therapy and medical supervision
• Supportive for carbohydrate cravings, for example within weight reduction diets, low evidence
• Dietary use as an amino acid preparation for special nutritional needs, for example in parenteral amino acid solutions

In the treatment of moderate to severe depression, anxiety disorders, obsessive-compulsive disorder or bipolar disorder, tryptophan is not a substitute for standard therapies such as SSRI, SNRI, lithium or psychotherapy. Self-medication for suspected depression should be avoided, as untreated depression increases the risk of health complications and suicidality.

Dosage and Administration

Standard dose for sleep disorders: usually 500 to 1000 mg L-tryptophan approximately half to one hour before bedtime. Administration should be with a small carbohydrate-containing meal or a glass of juice, because insulin promotes absorption into the brain.

Higher dosages up to 3 g per day are described in individual studies, but are not appropriate for every patient and increase the risk of side effects and pharmacological interactions. Duration of use: Treatment should be time-limited, generally for a few weeks, followed by re-evaluation. Long-term self-medication is not recommended.

Administration note: do not take together with protein-rich meals, because other amino acids compete with tryptophan for transport into the brain. Water is sufficient as a beverage, large amounts of alcohol should be avoided.

Side Effects

Common: next-day drowsiness, mild sleepiness, headache, dizziness, nausea, heartburn, dry mouth.

Occasional: gastrointestinal complaints, decreased appetite, concentration difficulties, mild mood fluctuations, increased sweating.

Rare but relevant: serotonin syndrome in combination with serotonergic medications (see Interactions). Symptoms include restlessness, tremor, muscle twitching, dilated pupils, sweating, fever, confusion. In severe cases, seizures and circulatory collapse. Immediate medical attention required.

Historical note: In the late 1980s, cases of eosinophilia-myalgia syndrome (EMS) occurred in the United States, which were traced to contamination in a single batch from one manufacturer. Currently approved medications and quality-tested dietary supplements are subject to strict purity requirements, and the risk is considered very low. A residual risk remains with products of unclear origin.

Interactions

• SSRI (for example sertraline, citalopram, escitalopram, paroxetine, fluoxetine), SNRI (venlafaxine, duloxetine), tricyclics and MAO inhibitors (tranylcypromine, moclobemide): increased risk of serotonin syndrome. Combination only under medical supervision and with caution.
• Triptans for migraine (sumatriptan, zolmitriptan, rizatriptan): additive serotonergic effect, cautious combination.
• Lithium, tramadol, pethidine, linezolid, methylene blue: serotonergic potential, caution or avoid combination.
• Herbal preparations containing St. John's wort or Griffonia (5-HTP): additive effects with tryptophan, serotonin syndrome risk.
• Sedatives, benzodiazepines, alcohol, first-generation antihistamines: enhanced drowsiness and fall risk, especially in elderly people.
• Levodopa in Parkinson's disease: theoretically competing amino acid transport, clinical relevance low, in practice consult physician.

Special Precautions

Pregnancy and breastfeeding: Data are limited. Routine use without medical indication is not recommended. For acute sleep problems, sleep hygiene, cognitive behavioral therapy and possibly established pregnancy-compatible therapies are preferable.

Children and adolescents: no broad approval for self-medication, use only under medical supervision.

Pre-existing conditions: Caution is advised in liver disease, renal insufficiency, carcinoid syndrome or known metabolic disorders such as vitamin B6 deficiency. Vitamin B6 is a cofactor for several tryptophan-degrading enzymes. Deficiency can shift metabolism.

Fitness to drive: Tryptophan can cause daytime drowsiness. Before activities requiring increased alertness (driving, operating machinery), individual reaction capacity should be checked.

Diagnostic note: Tryptophan can falsify laboratory values for 5-hydroxyindoleacetic acid (5-HIAA) in 24-hour urine collection, which is relevant for carcinoid diagnostics. Discontinue in advance of such tests.

You might also be interested in

• Zolpidem, classical Z-substance sleeping medication for short-term sleep-onset difficulties
• Paroxetine, SSRI for depression and anxiety disorder with serotonergic effect
• Agomelatin, melatonergic antidepressant with sleep-normalizing profile
• Donepezil, cholinesterase inhibitor in dementia therapy
• Trazodon, sedating antidepressant for depression with sleep disorder

Frequently Asked Questions

Sources

• Gelbe Liste, L-tryptophan active ingredient profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines for sleep disorders and non-restorative sleep
• DGE, Recommendations for amino acid supply and nutrition