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POSSIBLY INEFFECTIVE

• Depression. Although it is unclear if oral L-tryptophan is beneficial in patients with depression, there is a lack of supporting evidence and a rare risk of adverse effects such as serotonin syndrome. Details: Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that L-tryptophan is not currently recommended for adjunctive or monotherapy use for major depressive disorder. The available small and low-quality studies have not supported L-tryptophan for this use (110318). Some older research suggests that taking L-tryptophan with clomipramine might improve the effectiveness of clomipramine (10856). However, it is not clear whether L-tryptophan is beneficial when taken along with newer classes of antidepressants. Also, the CANMAT Taskforce cautions the co-use of L-tryptophan with serotonergic antidepressants due to the rare risk of serotonin syndrome (110318).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. Although there is interest in using oral L-tryptophan for anxiety, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Athletic performance. It is unclear if oral L-tryptophan is beneficial for improving athletic performance. Details: Some clinical research shows that taking L-tryptophan 300 mg orally along with a sugar and electrolyte drink twice daily for 3 days prior to exercise and on the day of exercise improves power output during the last 20 minutes of exercise when compared with taking a sugar and electrolyte drink without L-tryptophan. The improvement in power output increases distance covered by about 5% without increasing perceived exhaustion (91462). However, other clinical research shows that taking L-tryptophan 12 mg/kg after 5 minutes of warm-up and then 6 mg/kg orally every 15 minutes during exercise does not improve time to exhaustion in endurance-trained male athletes (1135). Reasons for the discrepancy are not clear. It is possible that L-tryptophan benefits some measures of athletic performance, but not others.
• Bruxism. It is unclear if oral L-tryptophan is beneficial for bruxism. Details: A very small clinical trial in adults with nocturnal bruxism shows that taking L-tryptophan 50 mg/kg daily orally for 8 days does not improve levels of teeth grinding when compared with placebo (1139).
• Cognitive impairment. It is unclear if oral L-tryptophan is beneficial in patients with cognitive impairment. Details: Clinical research in elderly individuals with mild cognitive impairment shows that taking L-tryptophan 95 mg orally with docosahexaenoic acid (DHA) 720 mg, eicosapentaenoic acid (EPA) 286 mg, vitamin E 16 mg, soy phospholipids 160 mg, and melatonin 5 mg (IBSA Farmaceutici Italia) nightly for 12 weeks improves cognitive function and sensitivity to smells by a small amount when compared with placebo. Patients treated with the combination showed a 1-point improvement in cognitive function based on the mini-mental state examination (MMSE) scale, while patients in the placebo group showed a 2-point decline (62847). However, these results might not be clinically significant. Also, it is not known if any potential benefit is due to L-tryptophan, other ingredients, or the combination.
• Fibromyalgia. It is unclear if oral L-tryptophan is beneficial in patients with fibromyalgia. Details: Preliminary clinical research in females with fibromyalgia shows that eating a standardized Mediterranean diet supplemented with walnuts, to supply L-tryptophan 60 mg daily and magnesium 60 mg daily for 16 weeks, modestly reduces anxiety, mood disturbance, eating disorders, and dissatisfaction with body image, but does not affect sleep, when compared with the Mediterranean diet alone. It is unclear if these effects are due to L-tryptophan, magnesium, other components of the added foods, or the combination (103172).
• Gout. Oral L-tryptophan has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with mild hyperuricemia shows that taking a powder containing L-tryptophan 0.2 grams and glycine 3 grams nightly for 6 weeks decreases serum uric acid levels by 0.3 mg/dL when compared with placebo. Improvements also occurred in the subgroup of patients with uric acid levels greater than 7 mg/dL, the point at which symptoms of gout can occur (99883). However, the effect of this combination for gout-related pain is unknown. Also, it is not clear if this effect is due to L-tryptophan, glycine, or the combination.
• Helicobacter pylori. A small clinical study suggests that adding L-tryptophan to treatment with omeprazole increases ulcer healing. Details: Clinical research shows that taking L-tryptophan (Ardeydorm, Ardeypharm GmbH) 250 mg twice daily in combination with omeprazole 20 mg twice daily for 21 days improves ulcer healing rates when compared with omeprazole alone in individuals with H. pylori-associated gastroduodenal ulcers (62803).
• Insomnia. Small clinical studies suggest that oral or intravenous L-tryptophan may modestly improve symptoms, particularly sleep latency, in patients with insomnia. Details: Clinical research shows that taking L-tryptophan 500 mg twice daily for 2 weeks improves insomnia in patients undergoing detoxification from methamphetamine or ketamine when compared with placebo. However, it does not seem to improve psychological symptoms in these patients (97242). One small clinical study shows that taking L-tryptophan orally, 1 gram 20 minutes before bed, might decrease sleep latency and improve mood when compared with placebo in healthy people with insomnia. Smaller doses of 250 mg and 500 mg did not demonstrate benefit (1146). Other clinical research shows that a single 5 gram intravenous infusion of L-tryptophan decreases sleep latency and increases total sleep time when compared with baseline in patients with insomnia (14896).
• Migraine headache. The incidence of migraine headaches may decrease with increased dietary L-tryptophan intake. Details: Preliminary clinical research shows that a dietary L-tryptophan intake of 0.84-1.06 grams per day reduces the odds of experiencing a migraine of any type by 54% to 60% when compared with an intake of 0.56 grams per day or less (103171).
• Myofascial pain syndrome. It is unclear if oral L-tryptophan is beneficial in patients with myofascial pain syndrome. Details: Some clinical research in adults with chronic maxillofacial pain shows that taking L-tryptophan orally 3 grams daily for 4 weeks is associated with a greater reduction in pain score and an increase in pain tolerance when compared with placebo (1145). However, other clinical research shows that L-tryptophan does not reduce pain when compared with placebo (1140).
• Obesity. Although there is interest in using oral L-tryptophan for obesity, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Premenstrual dysphoric disorder (PMDD). Limited clinical research suggests that L-tryptophan may reduce symptoms of PMDD. Details: A small clinical study in adults with PMDD shows that taking L-tryptophan orally 6 grams daily for approximately 17 days, from the time of ovulation to the third day of menstruation, for three consecutive cycles reduces mood swings, tension, and irritability when compared with placebo (6246).
• Premenstrual syndrome (PMS). Although there is interest in using oral L-tryptophan for premenstrual syndrome, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Seasonal affective disorder (SAD). It is unclear if oral L-tryptophan is beneficial in patients with SAD. Details: One very small clinical crossover study shows that taking L-tryptophan 4-6 grams orally daily in divided doses for 4 weeks improves seasonal affective disorder to a similar degree as receiving light therapy for 2 weeks (6247). However, this study was not powered to detect a difference between groups.
• Sleep apnea. Although there is interest in using oral L-tryptophan for sleep apnea, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition.
• Smoking cessation. It is unclear if oral L-tryptophan is beneficial for smoking cessation. Details: A small clinical study in adults attempting to quit smoking shows that taking L-tryptophan 50 mg/kg daily orally for 2 weeks in conjunction with standard smoking cessation treatments results in fewer daily cigarettes smoked when compared with placebo. Reported anxiety and other withdrawal symptoms were also lower in the L-tryptophan group (1138). However, the study was not powered to detect a statistically significant difference in these outcomes between groups.
• Tourette syndrome. Although there is interest in using oral L-tryptophan for Tourette syndrome, there is insufficient reliable information available about the clinical effects of L-tryptophan for this condition. More evidence is needed to rate L-tryptophan for these uses.

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POSSIBLY EFFECTIVE

• Vitiligo. Small clinical studies suggest that oral or topical L-phenylalanine, when used in combination with UVA light, might modestly improve symptoms in adults and children with vitiligo. Details: Taking L-phenylalanine, as 50 mg/kg two to three times weekly or up to 100 mg/kg once daily orally for up to 3 months, or applying L-phenylalanine 10% cream topically, both in combination with UVA light exposure, seem to be effective for treating vitiligo in adults (2461,2463,2464,2466) and in children (2467).

POSSIBLY INEFFECTIVE

• Attention deficit-hyperactivity disorder (ADHD). Taking phenylalanine orally does not seem to be beneficial for ADHD. Details: Some research suggests that patients with ADHD have lower levels of amino acids such as phenylalanine (9948), but neither D-phenylalanine nor DL-phenylalanine appear to have any sustained effect on ADHD symptoms (9950,9951).
• Pain (chronic). Taking D-phenylalanine orally does not seem to be beneficial for chronic pain. Details: A small clinical study in patients with chronic pain of various etiologies shows that taking D-phenylalanine 250 mg four times daily for 4 weeks does not reduce pain when compared with placebo (2459). Additionally, a small clinical study in adults with chronic low back pain shows that taking D-phenylalanine 4 grams orally as a single dose prior to acupuncture does not enhance analgesic effects when compared with acupuncture alone (2456).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if topical undecylenoyl phenylalanine is beneficial for age spots. Details: Preliminary clinical research shows that applying undecylenoyl phenylalanine 2% cream to age spots, also known as solar lentigines, twice daily for 12 weeks significantly reduces the number of spots or their pigmentation when compared with controls (92704).
• Alcohol use disorder. Oral DL-phenylalanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients experiencing alcohol withdrawal symptoms shows that taking a combination of DL-phenylalanine 300 mg, L-glutamine 150 mg, and 5-HTP 5 mg orally daily for 40 days improves depression, hostility, and physical symptoms caused by psychological distress, when compared with placebo (30100).
• Depression. It is unclear if oral phenylalanine is beneficial in patients with depression. Details: Older clinical research conducted prior to 1985 suggests that taking L-phenylalanine 250 mg orally or intravenously daily for 14-96 days in combination with selegiline, or DL-phenylalanine 50-200 mg orally daily for 15-30 days, might improve symptoms of depression (2468,2469,68795,68825). However, taking D-phenylalanine, 50-100 mg daily for 15 days, does not seem to provide any benefit (68795,68830).
• Multiple sclerosis (MS). Oral L-phenylalanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that treatment with Cari Loder's regimen, which includes oral L-phenylalanine and lofepramine, plus intramuscular (IM) vitamin B12 for 24 weeks, does not improve disability in patients with MS when compared with placebo plus IM vitamin B12 (68796).
• Obesity. It is unclear if oral L-phenylalanine is beneficial in obese or overweight patients. Details: Preliminary clinical research in females with overweight or obesity shows that taking L-phenylalanine 5 grams or 10 grams orally 20 minutes before meals twice daily does not reduce energy intake or improve satiety when compared with placebo (92705).
• Osteoarthritis. Although there is interest in using oral phenylalanine for osteoarthritis, there is insufficient reliable information about the clinical effects of phenylalanine for this condition.
• Pain (acute). It is unclear if oral D-phenylalanine is beneficial for acute pain. Details: Preliminary clinical research shows that taking D-phenylalanine 2-4 grams orally as a single dose 30 minutes prior to tooth extraction modestly enhances the analgesic effects of acupuncture when compared with acupuncture alone (2456).
• Parkinson disease. Although there is interest in using oral phenylalanine for Parkinson disease, there is insufficient reliable information about the clinical effects of phenylalanine for this condition.
• Rheumatoid arthritis (RA). Although there is interest in using oral phenylalanine for RA, there is insufficient reliable information about the clinical effects of phenylalanine for this condition. More evidence is needed to rate phenylalanine for these uses.

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LIKELY SAFE ...when used orally in the amounts commonly found in foods. L-tryptophan is an essential amino acid that must be obtained from the diet. A typical diet in the United States supplies 0.5-2 grams of L-tryptophan daily (1146).

POSSIBLY SAFE ...when used orally in medicinal amounts, short-term. L-tryptophan 5 grams daily for 21 days has been used with apparent safety (91460,97243). In 1989, L-tryptophan was linked to over 1500 reports of eosinophilia-myalgia syndrome (EMS) and several deaths (7067,8053,10085,11474,11478), leading to its removal from the U.S. market in 1990 (7067). The exact cause of EMS in patients taking L-tryptophan is unknown, but some evidence suggests that nearly all cases were due to contaminated L-tryptophan products from a single manufacturer (8050,8051,11477,11478). Under the Dietary Supplement Health and Education Act (DSHEA) of 1994, L-tryptophan is currently available and marketed as a dietary supplement. There is insufficient reliable information available about the safety of L-tryptophan when used orally, long-term.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods.

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts because it may cause respiratory depression in utero (1142). Avoid using in amounts greater than those found in foods.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. There is insufficient reliable information available about the safety of larger medicinal amounts; avoid using.

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LIKELY SAFE ...when L-phenylalanine is consumed in amounts typically found in foods (11120).

POSSIBLY SAFE ...when L-phenylalanine is used orally in doses up to 100 mg/kg daily for up to 3 months (2463,2464,2466,2467,2469). ...when D-phenylalanine is used orally in doses up to 1 gram daily for up to 4 weeks, or as a single dose of 4-10 grams (2455,2456,2459,68795,104792). ...when DL-phenylalanine is used orally in doses up to 200 mg daily for up to 4 weeks (2468,68795,68825). ...when phenylalanine cream is applied topically, short-term (2461,92704).

PREGNANCY: LIKELY SAFE
when L-phenylalanine is consumed in amounts typically found in foods by pregnant patients with normal phenylalanine metabolism (2020,11120).

PREGNANCY: UNSAFE
when L-phenylalanine is consumed in amounts typically found in foods by pregnant patients with high serum phenylalanine concentrations, such as those with phenylketonuria (PKU). Serum levels of phenylalanine greater than 360 micromol/L increase the risk of birth defects (1402,11468). Experts recommend that patients with high phenylalanine serum concentrations follow a low phenylalanine diet for at least 20 weeks prior to conception to decrease the risk for birth defects (1402). There is insufficient reliable information available about the safety of L-phenylalanine when taken by mouth in large doses during pregnancy; avoid using. There is insufficient reliable information available about the safety of oral D-phenylalanine during pregnancy; avoid using.

LACTATION: LIKELY SAFE
when L-phenylalanine is consumed in amounts typically found in foods by breast-feeding patients with normal phenylalanine metabolism (2020,11120). There is insufficient reliable information available about the safety of L-phenylalanine when taken by mouth in medicinal amounts during lactation; avoid using. There is insufficient reliable information available about the safety of oral D-phenylalanine during lactation; avoid using.

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CNS DEPRESSANTS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use of L-tryptophan with CNS depressants might cause additive sedative effects.  Details Clinical research shows that L-tryptophan can cause fatigue and drowsiness (1143).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining L-tryptophan with serotonergic drugs might cause additive serotonergic effects.  Details L-tryptophan is a precursor to serotonin (1141). Theoretically, combining serotonergic drugs with L-tryptophan might increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstrictive disorders (8056).

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BACLOFEN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant intake of phenylalanine may reduce the intestinal absorption of baclofen.  Details Phenylalanine and baclofen share the same intestinal carrier for absorption; phenylalanine competitively inhibits the absorption of baclofen, reducing its plasma levels (23788).

LEVODOPA Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Phenylalanine, especially in high doses, can reduce the effectiveness of levodopa.  Details Phenylalanine competes with levodopa for carrier-mediated transport into the brain. The resulting reduction in levels of levodopa in the brain can exacerbate tremor, rigidity, and the "on-off" phenomenon in patients with Parkinson disease (3291,3294).

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of L-phenylalanine and non-selective MAOIs might increase the risk of hypertensive crisis.  Details L-phenylalanine is metabolized to tyrosine (2052,9949). Some evidence suggests that L-phenylalanine, given with the non-selective MAOI pargyline, might prevent the elimination of tyramine, increasing the risk of hypertensive crisis (2021). However, this was not reported in a small number of patients when using L-phenylalanine with the partially selective MAO-B inhibitor, selegiline (2469).

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General ...Orally, L-tryptophan is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, diarrhea, drowsiness, dry mouth, flatulence, headache, heartburn, lightheadedness, nausea, stomach pain, visual blurring, and vomiting.
Serious Adverse Effects (Rare):
Orally: L-tryptophan has been associated with the neurological disorder eosinophilia-myalgia syndrome (EMS). However, almost all cases were traced to L-tryptophan produced by a single manufacturer in Japan and are likely related to contamination.

Cardiovascular ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include cardiovascular symptoms such as myocarditis, arrhythmias, and palpitations (8053,11477).

Dermatologic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include dermatological symptoms such as sclerodermiform skin changes, alopecia, and rash (8053,11477).

Gastrointestinal ...Orally, L-tryptophan can cause gastrointestinal side effects such as heartburn, stomach pain, belching and flatulence, nausea, vomiting, diarrhea, dry mouth, and anorexia (10853,99884).

Hematologic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include hematologic symptoms such as eosinophilia (8053,11477).

Hepatic ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include hepatic symptoms such as hepatomegaly (8053,11477).

Musculoskeletal ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include musculoskeletal symptoms such as myalgia and inflammation of the joints and connective tissue (8053,11477).

Neurologic/CNS ...Orally, L-tryptophan can cause headache, lightheadedness, and ataxia (10853,99884).
In 1989, more than 1500 cases of the neurological disorder EMS were associated with oral L-tryptophan use in the US. About 95% of all EMS cases were traced to contaminated L-tryptophan produced by a single manufacturer in Japan (8054,10288,10289,11475,11476). In 1990, L-tryptophan was recalled in the U.S. and an FDA alert was put into force limiting the importation of all over-the-counter L-tryptophan products (7067,11477,11478). After the limitation of L-tryptophan products, the incidence of EMS dropped abruptly (11474). Symptoms of EMS associated with L-tryptophan use include intense eosinophilia; fatigue; myalgia; neuropathy; sclerodermiform skin changes; alopecia; rash; and inflammatory disorders affecting the joints, connective tissue, lungs, heart, and liver (8053,11477). Symptoms tend to improve over time, however some individuals may still experience symptoms up to 2 years after the onset of EMS and complete resolution of symptoms may not occur (8053,10287).
There is some evidence of an association between L-tryptophan-related EMS and the occurrence of chronic B-cell lymphocytic leukemia (8055).

Ocular/Otic ...Orally, L-tryptophan can cause side effects such as visual blurring (10853).

Pulmonary/Respiratory ...Orally, L-tryptophan has been associated with eosinophilia-myalgia syndrome (EMS), which can include respiratory symptoms such as dyspnea and cough (8053,11477).

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General ...Orally, L-phenylalanine and D-phenylalanine are generally well tolerated when used in typical doses.
Most Common Adverse Effects:
Orally: Anxiety, constipation, headache, heartburn, insomnia, nausea, and sedation.
Topically: Burning, erythema, and itching.

Cardiovascular ...One patient in a small case series developed extrasystoles after 10 days of treatment with DL-phenylalanine, but this resolved on the 12th day of treatment without discontinuing phenylalanine (68825).

Dermatologic ...Topically, erythema, itching, and burning have been reported in some patients using an undecylenoyl phenylalanine 2% cream for treatment of age spots (92704).

Gastrointestinal ...Orally, constipation, heartburn, and nausea has been reported in some patients taking phenylalanine (2463,68827,68829,68830).

Neurologic/CNS ...Orally, headaches, which are typically transient and do not require treatment or dosage reduction, have been reported during the first 10 days of treatment with L-, D-, and DL-phenylalanine (68795,68825,68827,68829). Transient vertigo has also been reported with D- and DL-phenylalanine (68795).
In patients with Parkinson disease, taking DL-phenylalanine, especially in high doses, interferes with levodopa transport into the brain, causing increased rigidity, tremor, and occurrence of the on-off phenomenon. Akinesia has been reported more rarely (3291,3292,3293,3294,68828). In patients with schizophrenia, taking a single dose of L-phenylalanine 100 mg/kg has been associated with worsening of medication-induced tardive dyskinesia (2457).

Psychiatric ...Orally, L-phenylalanine has been associated with anxiety, insomnia, and, more rarely, hypomania (68827,68829). DL-phenylalanine has been associated with fatigue and sedation (9951).

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