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TRYPTOPHAN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tryptophan is an essential amino acid in the human diet.

Specific Substances

    1) L-2-amino-3-(indol-3-yl) propionic acid
    2) L-tryp (IUPAC abbreviation)
    3) L-tryptophan
    4) CAS 73-22-3

Available Forms Sources

    A) FORMS
    1) RECENT PRODUCT AVAILABILITY
    a) As of 2005, tryptophan products were reintroduced to the US market (Howland, 2012). L-trypotphan is currently available for purchase by mail order and over the internet.
    2) PRIOR PRODUCT WITHDRAWAL
    a) PRODUCT CONTAMINATION: In 1989, the FDA recalled all commercial forms of L-tryptophan after the eosinophilia-myalgia syndrome (EMS) outbreak was associated with its use.
    1) A single company in Japan had produced most of the available L-tryptophan (Amor et al, 1990).
    2) As of August 1998, impurities were confirmed by the US Food and Drug Administration in some dietary supplements of 5-hydroxy-L-tryptophan (5HTP) that were marketed and promoted at that time ((Anon, 1998)). One impurity was known as "peak X". Although its significance is not known, it has been associated with EMS in the past.
    B) SOURCES
    1) TryptoPure L-Tryptophan from Swanson Ultra contains 500 mg capsules in a vegetable capsule in bottles of 90. The recommended dose is 1 capsule 30 to 60 minutes prior to bedtime. It is available for purchase over the internet (www.swansonvitamins.com).
    C) USES
    1) SUMMARY: Tryptophan is an essential amino acid in the human diet. In the US, the typical Recommended Daily Allowance (RDA) is 5 mg/kg/day (or .35 g for a 70 kg individual). The most common uses for tryptophan supplementation is to improve mood and aid in sleep (Fernstrom, 2012).
    2) INSOMNIA: L-tryptophan is metabolized to 5-hydroxytryptophan that is then converted to the neurotransmitter serotonin. Melatonin, a hormone important for sleep regulation, is synthesized from serotonin. It is thought that based on this pathway, it can induce sleep and is beneficial in the treatment of insomnia (Fernstrom, 2012; Howland, 2012). However, in clinical studies, its effectiveness has not been proven. For sleep, L-trypotophan is usually taken alone (Howland, 2012).
    3) DEPRESSION: It has been shown that L-tryptophan has a beneficial effect on individuals with unipolar depression (Sarris et al, 2011). In patients with depression, L-trypotophan is usually taken along with an antidepressant. In clinical studies, its effectiveness has not been proven (Howland, 2012).
    4) RELAXATION DRINKS: In the US, there are more than 300 different beverages that are marketed as "relaxation drinks" that are purportedly sold to produce calmness and decrease stress. The ingredients in these beverages often include herbs, amino acids and chemicals that are thought to produce sleep and sedation. The drinks usually contain one or more of the following herbal products: kava, valerian root and melatonin. Other ingredients often include tryptophan, 5-hydroxytroptophan, passion flower, rose hip and lavender. Some manufacturers have encouraged the use of these products along with alcohol to enhance the feelings of relaxation resulting in further sedation and possible impaired concentration and cognition (Stacy, 2011).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Tryptophan, an essential amino acid, is available as a dietary supplement and has typically been used to improve mood and treat insomnia and depression with mixed results. Dietary sources of tryptophan include egg whites, cheese, cod, soybeans and pumpkin seeds. In the US, there are more than 300 different beverages that are marketed as relaxation drinks which are sold to produce calmness and decrease stress. The ingredients in these beverages often include herbs, amino acids (including tryptophan and 5-hydroxytryptophan) and other chemicals that are thought to produce sleep and sedation.
    B) PHARMACOLOGY: Tryptophan is a precursor of 5-hydroxytryptophan. L-tryptophan is metabolized to 5-hydroxytryptophan that is then converted to the neurotransmitter serotonin. Based on this pathway, L-tryptophan and 5-hydroxytryptophan have been studied in the treatment of insomnia and depression.
    C) EPIDEMIOLOGY: Exposure can occur, but serious events have not been reported with acute ingestion. Cases of Eosinophilia-Myalgia syndrome were reported in the late 1980s following isolated contamination of L-tryptophan by a single manufacturer.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Adverse reactions have been reported with therapeutic use of 5 to 12 g of tryptophan for the treatment of insomnia, depression or chronic pain. The most common adverse events included headache, nausea, diarrhea, muscle tenderness and sedation. Other events reported with doses as high as 15 g/day included euphoria, lightheadedness, dry mouth, blurred vision and nystagmus; the effects appeared to be dose related.
    2) SEROTONIN SYNDROME: L- tryptophan increases the availability of serotonin in the CNS and may produce "serotonin syndrome" when taken alone (rare) or more commonly in combination with MAOI or serotonergic agents (eg, fluoxetine). Symptoms are characterized by myoclonus, resting tremor, restlessness, unsteady gait, hyperreflexia, diaphoresis and hyperthermia.
    3) EOSINOPHILIA-MYALGIA SYNDROME: In the late 1980s, Eosinophilia-Myalgia syndrome (EMS) occurred in over 1,500 patients taking L-tryptophan supplements. Characteristics included severe, incapacitating myalgia and eosinophilia. It was suspected to have originated in one manufacturer, the exact causative agent of EMS remains unknown but a contaminant(s) was suspected. As of 2005, tryptophan dietary supplements were reintroduced to the US market. Since that time there have been rare reports of 2 possible cases of EMS and one recent documented case following tryptophan use; impurities could not be completely ruled out in this latest case.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdose has not been reported. Events are likely similar to those reported with dietary use.
    0.2.3) VITAL SIGNS
    A) Hyperthermia may accompany serotonin syndrome or EMS. Tachycardia occurs commonly with EMS.
    0.2.20) REPRODUCTIVE
    A) Because L-tryptophan is more lethal to neonates, due to a deficiency of adrenal steroids and tryptophan pyrrolase, administration to pregnant women may be hazardous to the fetus.
    0.2.21) CARCINOGENICITY
    A) Tryptophan has not been shown to be carcinogenic, but was found to be a promoter of carcinogenicity in some studies. The positive studies have generally been with the DL isomer while negative studies have been with the L-isomer.

Laboratory Monitoring

    A) Monitor CNS function; drowsiness is an anticipated event with exposure.
    B) Monitor fluid status, electrolytes if significant vomiting develops.
    C) No other specific laboratory tests are necessary unless otherwise clinically indicated. Obtain an eosinophil count and liver enzymes tests in patients with signs or symptoms of eosinophilia myalgia syndrome.
    D) Plasma concentrations of tryptophan are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Minor adverse events (ie, drowsiness, nausea, headache, lightheadedness) have been reported with dietary supplement use.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. SEROTONIN SYNDROME: L-tryptophan increases the availability of serotonin in the CNS, and has been associated with myoclonus, restlessness, unsteady gait, rigidity, hyperreflexia, diaphoresis, and hyperthermia, especially when given in combination with MAO inhibitors or possible combination with a serotonin reuptake inhibitor (ie, fluoxetine). Discontinue L-tryptophan; initially treat with benzodiazepines.
    C) DECONTAMINATION
    1) PREHOSPITAL: Acute toxicity is limited, GI decontamination is generally not necessary.
    2) HOSPITAL: Acute toxicity is limited, GI decontamination is generally not necessary.
    D) SEROTONIN SYNDROME
    1) Serotonin syndrome is infrequent. Primary treatment is sedation with IV benzodiazepines and cooling measures. CYPROHEPTADINE: A serotonin antagonist with high affinity for the 5-HT2 receptors; effective for mild to moderate cases of serotonin syndrome. DOSE: ADULT: 12 mg orally or nasogastric tube, followed by 4 to 8 mg every 4 to 6 hours. CHILD: 0.25 mg/kg/day orally or nasogastric tube divided every 6 hours, maximum dose 12 mg/day. CHLORPROMAZINE: A phenothiazine antipsychotic with 5-HT2 antagonist activity; indicated in severe serotonin syndrome cases. DOSE: 12.5 to 50 mg IV, followed by 25 to 50 mg every 6 hours. It is NOT generally recommended because it may cause severe hypotension. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with nondepolarizing agents.
    E) EOSINOPHILIA-MYALGIA SYNDROME
    1) Cases of Eosinophilia-Myalgia (EMS) syndrome were reported in the late 1980s following isolated contamination of L-tryptophan by a single manufacturer. Since that time there have been rare reports of possible EMS following L-tryptophan use. In a recent confirmed case of EMS, empiric treatment with prednisone and mycophenolate mofetil produced some improvement. However, the addition of methotrexate and anakinra did not completely resolve symptoms of myalgia, neuropathy or skin induration.
    F) ENHANCED ELIMINATION
    1) There is no information to suggest that hemodialysis or hemoperfusion would be beneficial.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A minor (1 to 2 dietary supplements) inadvertent dose in an asymptomatic patient or a patient with mild drowsiness that is currently taking L-tryptophan can likely be managed at home. An asymptomatic child or a child with mild drowsiness that is easily arousable following an inadvertent exposure (1 to 2 dietary supplements) can likely be monitored at home, if a responsible adult is present.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions or with more than mild symptoms should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic (more than mild drowsiness) should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients with evidence of significant CNS events (ie, agitation, seizures, serotonin syndrome) should be admitted with ongoing treatment and monitoring.
    4) CONSULT CRITERIA: Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom the diagnosis is unclear.
    H) PITFALLS
    1) Ingestion of other agents that may place the patient at risk for serotonin syndrome (ie, MAO inhibitors or SSRI therapy). Acute toxicity is limited, do not overtreat.
    I) PHARMACOKINETICS
    1) L-tryptophan is 65 to 78% bound to plasma albumin. The volume of distribution for free tryptophan is 1 to 3 L/kg and total tryptophan is 0.34 to 0.7 L/kg. The plasma half-life ranges from 1.14 to 2.85 hours.

Range Of Toxicity

    A) TOXIC DOSE: A toxic dose has not been established. Oral doses as high as 15 g/day have been reported to treat depression with minimal or no adverse events. Healthy volunteers given 7.5 to 12 g/night reported nausea, dizziness, headache and drowsiness.
    B) THERAPEUTIC DOSE: Varies by indication. Doses of 1 to 10 g/day have been used for sleep.

Clinical Effects

Summary Of Exposure

    A) USES: Tryptophan, an essential amino acid, is available as a dietary supplement and has typically been used to improve mood and treat insomnia and depression with mixed results. Dietary sources of tryptophan include egg whites, cheese, cod, soybeans and pumpkin seeds. In the US, there are more than 300 different beverages that are marketed as relaxation drinks which are sold to produce calmness and decrease stress. The ingredients in these beverages often include herbs, amino acids (including tryptophan and 5-hydroxytryptophan) and other chemicals that are thought to produce sleep and sedation.
    B) PHARMACOLOGY: Tryptophan is a precursor of 5-hydroxytryptophan. L-tryptophan is metabolized to 5-hydroxytryptophan that is then converted to the neurotransmitter serotonin. Based on this pathway, L-tryptophan and 5-hydroxytryptophan have been studied in the treatment of insomnia and depression.
    C) EPIDEMIOLOGY: Exposure can occur, but serious events have not been reported with acute ingestion. Cases of Eosinophilia-Myalgia syndrome were reported in the late 1980s following isolated contamination of L-tryptophan by a single manufacturer.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Adverse reactions have been reported with therapeutic use of 5 to 12 g of tryptophan for the treatment of insomnia, depression or chronic pain. The most common adverse events included headache, nausea, diarrhea, muscle tenderness and sedation. Other events reported with doses as high as 15 g/day included euphoria, lightheadedness, dry mouth, blurred vision and nystagmus; the effects appeared to be dose related.
    2) SEROTONIN SYNDROME: L- tryptophan increases the availability of serotonin in the CNS and may produce "serotonin syndrome" when taken alone (rare) or more commonly in combination with MAOI or serotonergic agents (eg, fluoxetine). Symptoms are characterized by myoclonus, resting tremor, restlessness, unsteady gait, hyperreflexia, diaphoresis and hyperthermia.
    3) EOSINOPHILIA-MYALGIA SYNDROME: In the late 1980s, Eosinophilia-Myalgia syndrome (EMS) occurred in over 1,500 patients taking L-tryptophan supplements. Characteristics included severe, incapacitating myalgia and eosinophilia. It was suspected to have originated in one manufacturer, the exact causative agent of EMS remains unknown but a contaminant(s) was suspected. As of 2005, tryptophan dietary supplements were reintroduced to the US market. Since that time there have been rare reports of 2 possible cases of EMS and one recent documented case following tryptophan use; impurities could not be completely ruled out in this latest case.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Overdose has not been reported. Events are likely similar to those reported with dietary use.

Vital Signs

    3.3.1) SUMMARY
    A) Hyperthermia may accompany serotonin syndrome or EMS. Tachycardia occurs commonly with EMS.
    3.3.3) TEMPERATURE
    A) Hyperthermia may occur as a result of interaction of L-tryptophan with MAO inhibitors (Kline et al, 1989).
    B) Fever was reported in 47% of patients with EMS in a series of 210 cases (CDC, 1990a).

Heent

    3.4.2) HEAD
    A) TEETH CHATTERING along with jaw quivering may be a manifestation of the serotonin syndrome, secondary to combinations of L-tryptophan with MAO inhibitors (Levy et al, 1985).
    3.4.3) EYES
    A) OCULAR OSCILLATIONS: Ocular oscillations are associated with tryptophan given in combination with a MAO inhibitor such as tranylcypromine (Baloh et al, 1982) or phenelzine (Thomas & Rubin, 1984).
    B) NYSTAGMUS: Nystagmus was reported in 7 subjects given oral doses of 70 to 90 mg/kg L-tryptophan (Smith & Prockop, 1962). It has also been reported in individuals taking up to 15 g/day; the effects appeared to be dose related (Kimura et al, 2012).
    C) BLURRED VISION: Blurred vision has been reported in individuals taking up to 15 g/day; the effects appeared to be dose related (Kimura et al, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) EOSINOPHILIA-MYALGIA SYNDROME
    1) Eosinophilia-Myalgia Syndrome (EMS): Tachycardia is a common symptom associated with EMS (Philen et al, 1991).
    B) MYOCARDITIS
    1) WITH THERAPEUTIC USE
    a) EOSINOPHILIA-MYALGIA SYNDROME
    1) Eosinophilia-Myalgia Syndrome (EMS): Acute congestive heart failure with myocarditis, pulmonary artery hypertension, pericardial effusion, and atrial fibrillation occur rarely as complications of EMS (CDC, 1990a).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) EOSINOPHILIA-MYALGIA SYNDROME
    1) Dyspnea is a common feature of EMS, occurring in about 64% of cases (CDC, 1990a). The chest roentgenogram may be normal or demonstrate pulmonary infiltrates (16%) or pleural effusions (15%) (CDC, 1990a).
    2) Pulmonary function tests have demonstrated restrictive disease consistent with neuromuscular dysfunction (Clauw & Katz, 1990).
    3) Lung biopsy has shown vasculitis and perivasculitis, with evidence of chronic interstitial pneumonia (Strumpf et al, 1991; Tazelaar et al, 1990).
    B) PULMONARY HYPERTENSION
    1) WITH THERAPEUTIC USE
    a) Pulmonary hypertension may occur (Tazelaar et al, 1990; Catton et al, 1991; Yakovlevitch et al, 1991).
    C) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Interstitial pneumonitis was reported in a 65-year-old man who had been taking 6 g L-tryptophan daily for 5 months (Bogaerts et al, 1991). Hypersensitivity pneumonitis may occur (Travis et al, 1990)
    D) VASCULITIS
    1) WITH THERAPEUTIC USE
    a) Pulmonary vasculitis has been reported (Travis et al, 1990; Bogaerts et al, 1991).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) WITH THERAPEUTIC USE
    a) Drowsiness and sedation are likely to develop and can be desirable (Howland, 2012; Kimura et al, 2012). The degree of drowsiness appears to be dose-related (Kimura et al, 2012).
    b) CASE SERIES: Drowsiness is the most consistent effect observed after administration of large doses of L-tryptophan, occurring in 5 of 7 patients within 1 to 2 hours after receiving oral doses of 30 to 70 mg/kg. Drowsiness was reported in all subjects given 90 mg/kg (Smith & Prockop, 1962).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been rarely reported. Contributing factors have included underlying seizure disorders or vitamin B6 deficiency (Coursin, 1971).
    C) SEROTONIN SYNDROME
    1) WITH THERAPEUTIC USE
    a) Serotonin syndrome, a result of precipitously increased CNS serotonin concentrations, has been well defined in animal models. The manifestations include resting tremor, rigidity, generalized seizures, and hyperthermia (Grahame-Smith, 1971).
    b) L-tryptophan increases the availability of serotonin in the CNS, and has been associated with myoclonus, restlessness, unsteady gait, rigidity, hyperreflexia, diaphoresis, and hyperthermia, especially when given in combination with MAO inhibitors (Pope et al, 1985; Price et al, 1986; Thomas & Rubin, 1984; Levy et al, 1985; Kline et al, 1989; Kim & Mueller, 1989).
    c) Combination therapy with L-tryptophan and fluoxetine, a serotonin reuptake inhibitor, has also resulted in this syndrome, usually without hyperthermia (Steiner & Fontaine, 1986).
    d) Combination with monoamine oxidase inhibitors is a common cause, since the breakdown of serotonin is catalyzed by monoamine oxidase.
    e) It may be difficult to distinguish between the "serotonin syndrome" and neuroleptic malignant syndrome in patients receiving neuroleptic agents.
    1) In general, hyperreflexia, myoclonus, and restlessness are more characteristic of the serotonin syndrome, and autonomic dysfunction is more characteristic of NMS (Kline et al, 1989).
    2) The onset of the serotonin syndrome is typically within 1 to 3 hours after combination therapy, which is shorter than that seen with NMS, and spontaneous resolution normally occurs within 12 hours; (Levy et al, 1985); however fatalities have been reported (Kline et al, 1989).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported with the use of L-tryptophan dietary supplements (Howland, 2012; Smith & Prockop, 1962).
    E) EUPHORIA
    1) WITH THERAPEUTIC USE
    a) Euphoria and light-headedness have been reported with tryptophan doses as high as 15 g/day. The effects appeared to be dose related (Kimura et al, 2012).
    F) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) EOSINOPHILIA-MYALGIA SYNDROME
    1) CASE REPORT: Progressive ascending axonal polyneuropathy was reported in a fatal case of eosinophilia-myalgia syndrome (CDC, 1989c; Smith & Dyck, 1990).
    G) NEURITIS
    1) WITH THERAPEUTIC USE
    a) EOSINOPHILIA-MYALGIA SYNDROME
    1) CASE REPORT: Hyperesthesias and extreme muscle tenderness in all 4 extremities was a prominent aspect of EMS in a 48-year-old woman (Dicker et al, 1990; Turi et al, 1990).
    H) ALTERED MENTAL STATUS
    1) WITH THERAPEUTIC USE
    a) EOSINOPHILIA-MYALGIA SYNDROME
    1) A high prevalence of mental status changes was self-reported by 139 EMS patients (Auerbach & Falk, 1991).
    2) Complaints noted included difficulty concentrating (63%), difficulty remembering words or names (52%), difficulty thinking logically (52%), difficulty conversing (43%), and impairment of short-term memory (42%).
    3) The presence of psychiatric problems prior to developing EMS was admitted by 41% of patients.
    I) CEREBROVASCULAR DISEASE
    1) WITH THERAPEUTIC USE
    a) EOSINOPHILIA-MYALGIA SYNDROME
    1) CASE REPORT: Multiple central nervous system lesions were reported following MRI scanning in a 46-year-old woman with EMS (Tolander et al, 1991). No cause and effect relationship could be established. Neurologic findings resembled a stroke.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea is a common side effect (Kimura et al, 2012; Howland, 2012). It was reported in at least 50% of subjects receiving a 5 g oral dose.
    b) Nausea and vomiting occur within 10 to 30 minutes postingestion, and are probably due to a peripheral mechanism, either unpleasant taste or gastric irritation.
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported with the use of L-tryptophan dietary supplements (Howland, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) EOSINOPHILIA-MYALGIA SYNDROME
    1) CASE SERIES: Mild liver function abnormalities were noted in 14 of 16 patients with EMS that occurred in New Mexico between May 1 and November 17, 1989 (Philen et al, 1991).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LIVER FATTY
    a) Animals given high doses of L-tryptophan (250 mg/kg) for several days developed small droplet fatty metamorphosis of the liver, and enlarged canaliculi and sinusoids which persisted at least 2 weeks after discontinuation (Trulson & Sampson, 1987).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) MICTURITION FINDING
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Urinary hesitancy occurred on the day following administration of L-tryptophan 4 g at bedtime (Rubin, 1981). No cause and effect relationship could be established.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) EOSINOPHIL COUNT RAISED
    1) WITH THERAPEUTIC USE
    a) EOSINOPHILIA-MYALGIA SYNDROME
    1) SUMMARY: As of June 1, 1991, the United States Centers for Disease Control had received reports of 1543 cases of this syndrome, and 28 deaths (Auerbach & Falk, 1991; Auerbach & Falk, 1991).
    a) Virtually all patients were receiving L-tryptophan as a sole or major-ingredient tablet or capsule, with the bulk material manufactured by Showa Denko in Japan (Slutsker et al, 1990). None of the minor ingredient food products were implicated.
    b) Daily doses have ranged from 10 to 15000 mg/day (median: 1500 mg/day) (CDC, 1989b; CDC, 1990; Swygert et al, 1990).
    c) Duration of exposure to L-tryptophan prior to onset of illness ranged from 2 weeks to 15 years in a series of 20 patients (Martin et al, 1990) and 0 to 3668 days in a series of 12 patients (Swygert et al, 1990).
    d) Cases of EMS have been reported outside the United States (Belgium, Canada, France, Israel, Japan, United Kingdom, and West Germany) (Hertzman & Brown, 1991; CDC, 1990f).
    e) As of August 1998, impurities were confirmed by the US Food and Drug Administration in some dietary supplements of 5-hydroxy-L-tryptophan (5HTP) products currently being marketed ((Anon, 1998)). One impurity is known as "peak X". Although its significance is not known, it has been associated with EMS in the past.
    b) POST-EPIDEMIC EOSINOPHILIA-MYALGIA SYNDROME
    1) CASE REPORT: A 44-year-old healthy woman started using L-tryptophan 1500 mg/day for insomnia and 3 weeks later developed swelling in the upper and lower extremities followed by severe myalgia and weakness. This was followed by progressive skin induration in all extremities, excluding her fingers and toes. Laboratory analysis included an elevated white blood cell count with 24% eosinophils. Biopsies of the skin and muscle were consistent with Eosinophilia-myalgia syndrome (EMS). The patient was treated with prednisone and mycophenolate mofetil with resolution of eosinophilia and ground-glass opacifications on chest CT with modest improvement in muscle strength and myalgia. However, there was minimal improvement in skin induration and polyneuropathy even with the addition of methotrexate and anakinra. Analysis of L-tryptophan supplements from the same batch taken by the patient (the exact product was no longer available) found no impurities at greater than 10 ppm in any of the samples (Allen et al, 2011).
    c) SIGNS/SYMPTOMS
    1) The characteristics of this syndrome include severe myalgia, often interfering with the ability to pursue normal daily activities, intense eosinophilia, ranging from 2,000 to 30,000 eosinophils/cubic millimeter, subjective weakness, fever, and arthralgia.
    2) The most frequently reported features of EMS include arthralgia (73%), rash (60%), peripheral edema (59%), cough or dyspnea (59%), elevated aldolase level (46%), and elevations in the results of liver function tests (43%) (Swygert et al, 1990).
    3) Less frequently noted manifestations include a respiratory prodrome (cough, dyspnea, pulmonary infiltrates), limb edema, scleroderma, mononeuritis (peripheral neuropathy) evanescent skin rash, vasculitis, joint contractures, mild LFT elevations, and leukocytosis (CDC, 1989; CDC, 1989a; CDC, 1989c).
    4) Heart failure and arrhythmias (arterial fibrillation, second degree heart block) have been reported in some patients (Kilbourne et al, 1990).
    5) Eosinophilic fasciitis, pneumonitis and myocarditis, neuropathy culminating in respiratory failure, encephalopathy, conjunctivitis, xerostomia fibrosis about the common bile duct, and pancreatitis have also been reported in some patients (Martin et al, 1990; Chiba et al, 1990; Golden, 1990).
    6) Mental status changes including difficulty concentrating (63%), difficulty remembering words or names (52%), difficulty thinking logically (52%), difficulty conversing (43%), and impairment of short-term memory (42%) were reported by 139 patients in a survey of self-reported symptoms (Auerbach & Falk, 1991). The presence of psychiatric
    7) There are reports of 3 patients with an illness that resembles EMS. In 2 patients myalgia was absent (Adamson & Legge, 1991) and in one case the patient had mild myalgia (Groves et al, 1992).
    d) DIAGNOSTIC CRITERIA
    1) Preliminary diagnostic criteria established for CDC surveillance include the following (CDC, 1989c):
    a) Eosinophil count >/=1000 cells/mm(3)
    b) Severe generalized myalgia interfering with daily activities
    c) Absence of infection or neoplasm
    2) The failure to meet the above criteria specified in the surveillance definition does not preclude a clinical diagnosis of EMS (CDC, 1990c). The appropriate weighing of all available information and clinical judgment are important in the clinical diagnosis of EMS (CDC, 1990c).
    3) REPORTING/CASE REGISTRY: Possible cases should be reported to state health departments.
    4) EOSINOPHILIC FASCIITIS: EMS is closely related to previous reports of eosinophilic fasciitis.
    a) It is noteworthy that the first description of this disease coincided with the introduction of L-tryptophan supplements to the United States in 1974 (Medsger, 1990).
    b) Investigation of reports has documented L-tryptophan usage in some cases (Clauw & Katz, 1990; Gorn, 1990; Medsger, 1990; Hamilton, 1991).
    c) Onset of tryptophan-associated cutaneous disease (eosinophilic fasciitis) preceded the availability of contaminated tryptophan in seven of 13 patients (Blauvelt & Falanga, 1991).
    e) LABORATORY
    1) It is suggested that EMS may be related to abnormal accumulation of tryptophan metabolites through the kynurenine pathway in selected individuals, possibly due to increased activity of the enzyme indoleamine-2,3-dioxygenase (Silver et al, 1990).
    a) Patients with active EMS have been shown to have elevated plasma levels of L-kynurenine and quinolinic acid. Quinolines, breakdown products of tryptophan and kynurenine, have been associated with the toxic oil syndrome, secondary to contamination of rapeseed oil. This syndrome has many features in common with EMS.
    2) CASE REPORT: Absent stainable neutrophil alkaline phosphatase was reported in a 30-year-old woman with EMS (Jaffe et al, 1991).
    f) ETIOLOGY
    1) Attempts are being made to identify the contaminant in the L-tryptophan product that may be responsible for EMS.
    a) One group has identified a bacitracin-like peptide (Barnhart et al, 1990) and another group identified the peak E component (Belgonia et al, 1990) of tryptophan (Sakimoto & Denko, 1990).
    b) The peak E component of L-tryptophan decomposes in an acid solution to L-tryptophan and 1-methyl-1,2,3,4- tetrahydrobeta-carboline-3-carboxylic acid (MTCA) (Sakimoto & Denko, 1990).
    c) The CDC identified peak 97 by HPLC which was the single most predictive peak (P<0.0001), based on Wilcoxon rank-sum test, of case-associated L-tryptophan lots (CDC, 1990d). It is likely that peak 97 described by CDC is the same as peak E described by the Mayo Clinic (CDC, 1990d).
    d) Another implicated compound Di-L-tryptophan aminal of acetaldehyde (DTAA) could breakdown to produce MTCA (CDC, 1990d; CDC, 1990e). Studies of biologic effects of synthesized DTAA in a rat model for EMS are in progress.
    e) ABNORMAL METABOLISM: Mainetti et al (1991) demonstrated abnormal metabolism of L-tryptophan in one patient with EMS when compared to a control (Mainetti et al, 1991a):
    1) Basal plasma tryptophan concentration was elevated
    2) Urinary kynurenine was elevated
    3) Plasma serotonin was elevated
    4) Basal urinary 5-HIAA excretion was lower
    g) RISK FACTORS
    1) Patients with conditions associated with abnormal tryptophan metabolism, such as those taking serotonin uptake inhibitor antidepressants (ie, fluoxetine) and those with alcohol-related pyridoxine deficiency, may be at greater risk (Clauw & Katz, 1990).
    a) Other drugs or conditions that result in impairment of the hypothalamic-pituitary-adrenal axis, such as Addison's disease or concurrent benzodiazepine ingestion, may increase susceptibility (Silver et al, 1990).
    b) In another study of 418 L-tryptophan users, the two factors that were definite risks for eosinophilia/myalgia syndrome were dose of a certain brand of L-tryptophan and age (risk increased with both) (Kamb et al, 1992).
    h) DIFFERENTIAL DIAGNOSIS
    1) One should attempt to rule out the spectrum of eosinophilic muscle diseases including eosinophilic fasciitis, eosinophilic perimyositis, eosinophilic polymyositis, and focal eosinophilic myositis. In addition, trichinosis and polyarteritis nodosa should also be ruled out (Golden, 1990).
    a) Varga et al (1991) identified clinical and laboratory test differences between patients with eosinophilic fasciitis and eosinophilia-myalgia syndrome.
    2) CASE SERIES: In a retrospective cohort study of 418 psychiatric patients, 47 (11%) were definite cases of eosinophilia/myalgia syndrome and another 68 (16%) were possible cases (Kamb et al, 1992).
    a) Risk factor analysis indicated that one retail brand of L-tryptophan was more involved than others; among the 157 users of this brand, 45 (29%) had definite eosinophilia/myalgia and another 36 (23%) were possible cases.
    b) Among the 157 users of the implicated brand, 19 out of 38 (50%) using more than 4000 mg/day developed definite eosinophilia/myalgia, illustrating an increased risk as dosage increased.
    c) Sex, race, and use of other medications were not found to be risk factors; age and dose of L-tryptophan were the only significant risk factors identified in this population.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Diaphoresis is a common manifestation of the serotonin syndrome (Levy et al, 1985).
    B) SYSTEMIC SCLEROSIS
    1) WITH THERAPEUTIC USE
    a) SCLERODERMA-LIKE SYNDROME
    1) The characteristics of this syndrome include swelling of the extremities, skin rash, myalgia, and elevation of the peripheral blood eosinophil count (Varga et al, 1990; Lacour et al, 1991).
    a) Histopathologic examination revealed thickening of the fascia, deep dermal fibrosis, and accumulation of mononuclear cells and abundant eosinophils (Varga et al, 1991). Dermal mucinosis may also be present (Winkelmann et al, 1991; Dubin et al, 1990; Farmer et al, 1990).
    2) Enhanced expression of the collagen gene was indicated by increased hybridization signal detection in the deep dermis and fascia.
    3) No cause and effect relationship could be established. Prednisone (30 mg/day) and colchicine (1 mg/day) had no apparent effect on the patient's skin lesions (Lacour et al, 1991).
    b) POST-EPIDEMIC EOSINOPHILIA-MYALGIA SYNDROME
    1) CASE REPORT: A 44-year-old healthy woman started using L-tryptophan 1500 mg/day for insomnia and 3 weeks later developed swelling in the upper and lower extremities followed by severe myalgia and weakness. This was followed by progressive skin induration in all extremities, excluding her fingers and toes. Laboratory analysis included an elevated white blood cell count with 24% eosinophils. Biopsies of the skin and muscle were consistent with Eosinophilia-myalgia syndrome (EMS). The patient was treated with prednisone and mycophenolate mofetil with resolution of eosinophilia and ground-glass opacifications on chest CT with modest improvement in muscle strength and myalgia. However, there was minimal improvement in skin induration and polyneuropathy even with the addition of methotrexate and anakinra. Analysis of L-tryptophan supplements from the same batch taken by the patient (the exact product was no longer available) found no impurities at greater than 10 ppm in any of the samples (Allen et al, 2011).
    C) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Eosinophilia-Myalgia Syndrome (EMS): Alopecia was noted in 18% of patients with EMS in one series (CDC, 1990a; Farmer et al, 1990a).
    D) DISORDER OF SKIN
    1) PSEUDOXANTHOMA ELASTICUM: Two patients who fulfilled the criteria for L-tryptophan-induced eosinophilia-myalgia syndrome had skin changes that clinically mimicked pseudoxanthoma elasticum as well as morphea-like and fasciitis-like sclerotic skin changes (Mainetti et al, 1991a).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) POST-EPIDEMIC EOSINOPHILIA-MYALGIA SYNDROME
    1) CASE REPORT: A 44-year-old healthy woman started using L-tryptophan 1500 mg/day for insomnia and 3 weeks later developed swelling in the upper and lower extremities followed by severe myalgia and weakness. This was followed by progressive skin induration in all extremities, excluding her fingers and toes. Laboratory analysis included an elevated white blood cell count with 24% eosinophils. Biopsies of the skin and muscle were consistent with Eosinophilia-myalgia syndrome (EMS). The patient was treated with prednisone and mycophenolate mofetil with resolution of eosinophilia and ground-glass opacifications on chest CT with modest improvement in muscle strength and myalgia. However, there was minimal improvement in skin induration and polyneuropathy even with the addition of methotrexate and anakinra. Analysis of L-tryptophan supplements from the same batch taken by the patient (the exact product was no longer available) found no impurities at greater than 10 ppm in any of the samples (Allen et al, 2011).
    b) EOSINOPHILIA-MYALGIA SYNDROME
    1) Severe, incapacitating myalgia has been the hallmark of the eosinophilia-myalgia syndrome associated with chronic L-typtophan use (CDC, 1989).
    2) Tanhehco et al (1992) reported electrodiagnostic findings in 2 patients with EMS, indicating myopathy with low amplitude, short duration, and polyphasic motor unit action potentials. Fiber density and jitter were moderately increased, with normal nerve conduction velocities throughout the clinical course.
    B) DISORDER OF TENDON
    1) WITH THERAPEUTIC USE
    a) EOSINOPHILIA-MYALGIA SYNDROME
    1) Patients with the Eosinophilia-Myalgia syndrome may present with features consistent with eosinophilic fasciitis (Silver et al, 1990).
    2) INITIAL SIGNS/SYMPTOMS include skin swelling, pitting edema, weight gain, urticaria, pain, and paresthesia, beginning with the extremities.
    3) LATER SIGNS/SYMPTOMS include compression neuropathy and peripheral sensorimotor neuropathy. Mild to severe inflammatory infiltrates of the superficial fascia have been reported.
    C) TOXIC MYOPATHY
    1) WITH THERAPEUTIC USE
    a) EOSINOPHILIA-MYALGIA SYNDROME
    1) Abnormal skin (6/6) and facia (9/9) and positive muscle acid phosphatase activity (11/11) were consistently noted (Verity et al, 1991).
    2) Type II muscle atrophy (13/14), perimysiitis (12/14), denervation muscle atrophy (12/14), and epimysitis (11/13) were additional pathologic changes noted in a study of 14 patients fulfilling the CDC diagnostic criteria for L-tryptophan-associated eosinophilia-myalgia syndrome (Verity et al, 1991).

Endocrine

    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOGLYCEMIA
    a) RATS: Hypoglycemia has been reported following oral administration of 800 mg/kg to rats (McMenany & Oncley, 1958).

Reproductive

    3.20.1) SUMMARY
    A) Because L-tryptophan is more lethal to neonates, due to a deficiency of adrenal steroids and tryptophan pyrrolase, administration to pregnant women may be hazardous to the fetus.
    3.20.3) EFFECTS IN PREGNANCY
    A) PERINATAL DISORDER
    1) Because L-tryptophan is more lethal to neonates, due to a deficiency of adrenal steroids and tryptophan pyrrolase, administration to pregnant women may be hazardous to the fetus (Trulson & Ulissey, 1987).
    2) CASE REPORT: Eosinophilia, rash, fever, vomiting, and diarrhea were reported in a neonate whose mother took tryptophan during the last 4 months of pregnancy (CDC, 1990a; Hatch et al, 1991). Of note, the neonate did not meet the case definition for Eosinophilia-Myalgia Syndrome (EMS) because myalgias are difficult to diagnose in a neonate (Hatch et al, 1991).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Tryptophan has not been shown to be carcinogenic, but was found to be a promoter of carcinogenicity in some studies. The positive studies have generally been with the DL isomer while negative studies have been with the L-isomer.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) Tryptophan has not been shown to be carcinogenic, but was found to be a promoter of carcinogenicity in some studies.
    a) The positive studies have generally been with the DL isomer (Cohen et al, 1979) while negative studies have been with the L-isomer (Ito et al, 1983; Kakizoe et al, 1985).
    2) In a study in rats, bladder cancers were increased in animals receiving large doses of L-tryptophan and a vitamin B6 deficient diet (Birt et al, 1987).
    3) Carcinogenicity has been attributed to several metabolites of the major metabolic pathway for L-tryptophan, the kynurenine pathway, particularly 3-hydroxyanthranilic acid and 3-hydroxykynurenine (Boyland et al, 1955).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CNS function; drowsiness is an anticipated event with exposure.
    B) Monitor fluid status, electrolytes if significant vomiting develops.
    C) No other specific laboratory tests are necessary unless otherwise clinically indicated. Obtain an eosinophil count and liver enzymes tests in patients with signs or symptoms of eosinophilia myalgia syndrome.
    D) Plasma concentrations of tryptophan are not readily available or clinically useful in the management of overdose.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) EOSINOPHILIA-MYALGIA SYNDROME: patients with signs or symptoms of eosinophilia myalgia syndrome should have an eosinophil count measured. The normal eosinophil count ranges from 50 to 350/mm(3).
    2) Other laboratory abnormalities that have been noted in patients with EMS include mild to moderate elevations in LDH, serum aspartate aminotransferase, alanine aminotransferase, and erythrocyte sedimentation rate (Clauw & Katz, 1990). Elevated LDH was reported in 51% of patients in a series of 210 cases (CDC, 1990a).
    3) A statistically significant elevation of eosinophil toxic granule proteins, major basic protein, and eosinophil-derived neurotoxin were noted in the serum and urine of patients with EMS when compared to normal control subjects (Martin et al, 1990).
    4) Gibbons & Metzger (1990) reported two patients with classic EMS that had normal creatine kinase concentrations, negative electromyograms, and normal erythrocyte sedimentation rates.
    B) OTHER
    1) The liver changes seen in animals did not result in any biochemical abnormality and could only be detected by liver biopsy (Trulson & Sampson, 1987).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with evidence of significant CNS events (ie, agitation, seizures, serotonin syndrome) should be admitted with ongoing treatment and monitoring.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A minor (1 to 2 dietary supplements) inadvertent dose in an asymptomatic patient or a patient with mild drowsiness that is currently taking L-tryptophan can likely be managed at home. An asymptomatic child or a child with mild drowsiness that is easily arousable following an inadvertent exposure (1 to 2 dietary supplements) can likely be monitored at home, if a responsible adult is present.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions or with more than mild symptoms should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic (more than mild drowsiness) should be observed in a healthcare facility.

Monitoring

    A) Monitor CNS function; drowsiness is an anticipated event with exposure.
    B) Monitor fluid status, electrolytes if significant vomiting develops.
    C) No other specific laboratory tests are necessary unless otherwise clinically indicated. Obtain an eosinophil count and liver enzymes tests in patients with signs or symptoms of eosinophilia myalgia syndrome.
    D) Plasma concentrations of tryptophan are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Acute toxicity is limited, GI decontamination is generally not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) Acute toxicity is limited, GI decontamination is generally not necessary.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor CNS function; drowsiness is an anticipated event with exposure.
    2) Monitor fluid status and electrolytes if significant vomiting or diarrhea develop.
    3) No other specific laboratory tests are necessary unless otherwise clinically indicated.
    4) Obtain an eosinophil count and liver function tests in a symptomatic patient with suspected Eosinophilia-myalgia syndrome.
    5) Plasma concentrations of tryptophan are not readily available or clinically useful in the management of overdose.
    C) SEROTONIN SYNDROME
    1) L-tryptophan increases the availability of serotonin in the CNS, and has been associated with myoclonus, restlessness, unsteady gait, rigidity, hyperreflexia, diaphoresis, and hyperthermia, especially when given in combination with MAO inhibitors (Pope et al, 1985; Price et al, 1986; Thomas & Rubin, 1984; Kim & Mueller, 1989), and is possible when combined with a serotonin reuptake inhibitor (eg, fluoxetine) (Steiner & Fontaine, 1986).
    2) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    3) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    4) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    5) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    6) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    7) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2010; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    8) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    9) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989a).
    D) EOSINOPHILIA MYALGIA SYNDROME
    1) SUMMARY
    a) Cases of Eosinophilia-Myalgia syndrome were reported in the late 1980s following isolated contamination of L-tryptophan by a single manufacturer. Since that time there have been rare reports of possible EMS following L-tryptophan use. In a recent case of confirmed EMS, a healthy woman taking L-tryptophan for 3 weeks was treated with prednisone and mycophenolate with modest improvement in myalgia, muscle strength and resolution of eosinophilia. However, the addition of methotrexate and anakinra did not completely resolve symptoms of myalgia, neuropathy and skin induration (Allen et al, 2011).
    b) The cause of this syndrome was never fully elucidated and definitive treatment cannot be recommended.
    2) GLUCOCORTICOIDS
    a) Empiric treatment has included glucocorticoids, which have generally been beneficial without dramatic results. More potent immunosuppressant treatment might be considered in patients with particularly severe manifestations (CDC, 1989).
    1) Administration of prednisone 15 to 60 mg/day resulted in substantial relief of myalgias and cutaneous symptoms, but did not enhance recovery of muscle weakness, which was still present more than one year after discontinuation of L-tryptophan (Clauw & Katz, 1990).
    2) Culpepper et al (1991) found no benefit of prednisone therapy in the reduction of long-term symptom severity or duration in a study of 45 EMS patients (28 treated vs 17 no treatment).
    3) High-dose corticosteroids produce a rapid decrease in the eosinophil count (Hertzman et al, 1990).
    3) CYPROHEPTADINE
    a) CYPROHEPTADINE: Four mg twice a day was effective in alleviating muscle spasms and cramps in one case (Hertzman et al, 1990).
    4) PYRIDOXINE
    a) Administration of pyridoxine for eosinophilia-myalgia syndrome is NOT recommended. Additional studies are needed to demonstrate the safety and efficacy of pyridoxine.
    b) Mainetti et al (1991) noted partial correction of abnormal tryptophan metabolism by administration of 100 mg pyridoxine concomitantly with L-tryptophan 2.25 g every night for 5 nights.
    5) OCTREOTIDE
    a) Octreotide is a somatostatin analogue that effectively inhibits the function of eosinophils in animals. Treatment of EMS with octreotide is NOT recommended.
    b) LACK OF EFFECT: Administration of 50 mcg of octreotide subcutaneously daily increased to 100 mcg subQ twice daily within 3 weeks did not result in improvement of myalgia, skin rash, muscle strength, or serum lactate dehydrogenase or aldose values (Clauw & Katz, 1990).

Enhanced Elimination

    A) LACK OF INFORMATION
    1) There is no information to suggest that hemodialysis or hemoperfusion would be beneficial.

Abstracts

Case Reports

    A) ADULT
    1) A 58-year-old woman developed myalgia, fatigue, and weakness after taking L-tryptophan 5 to 6 g/day. She had leukocytosis and 18% eosinophils, along with axonal neuropathy. Progressive ascending polyneuropathy ensued, with quadriplegia and bifacial hemiparesis. She died following cardiorespiratory arrest (CDC, 1989c).
    2) A previously healthy 47-year-old woman presented with a 2-week history of worsening malaise and diffuse myalgias that made her unable to work or pursue her daily activities. She was taking L-tryptophan 500 mg 3 times daily for insomnia for the past 3 years and propranolol 80 mg 3 times daily for mitral valve prolapse for the past one year. She had leukocytosis and 82% eosinophils. While in the hospital she did not receive any L-tryptophan. The patient resumed taking L-tryptophan. One week later she continued to complain of severe myalgias with mild arthralgias involving both shoulders and the right elbow (Flannery et al, 1990).

Range Of Toxicity

Summary

    A) TOXIC DOSE: A toxic dose has not been established. Oral doses as high as 15 g/day have been reported to treat depression with minimal or no adverse events. Healthy volunteers given 7.5 to 12 g/night reported nausea, dizziness, headache and drowsiness.
    B) THERAPEUTIC DOSE: Varies by indication. Doses of 1 to 10 g/day have been used for sleep.

Therapeutic Dose

    7.2.1) ADULT
    A) INSOMNIA: A dose of 150 to 300 mg daily has been used to treat insomnia (Howland, 2012).
    B) HYPNOTIC DOSE: The usual hypnotic dose is 1 to 2 g at bedtime. This is equivalent to 15 to 30 mg/kg for a 70 kg male and 17 to 34 mg/kg for a 60 kg female (Hartmann, 1987).
    C) ANTIDEPRESSANT: L-tryptophan has been used as an antidepressant in doses of up to 6 to 9 g/day (Hartmann, 1987). Historically, oral doses as high as 15 g/day (200 mg/kg/day for a 70 kg individual ) were used to treat depression; adverse events were absent or minimal when they occurred (Hiratsuka et al, 2013).

Minimum Lethal Exposure

    A) SUMMARY
    1) A minimum lethal dose has not been established.

Maximum Tolerated Exposure

    A) SUMMARY
    1) Oral doses as high as 15 g/day (200 mg/kg/day) for a 70 kg individual have been reported for the treatment of depression. Typical doses of 5 to 8 g/day (70 to 100 mg/kg/day) were administered. Side effects were generally mild or absent. Symptoms have included euphoria, drowsiness, lightheadedness, dry mouth, nausea, blurred vision and nystagmus. Of the symptoms reported, the events were dose related (Kimura et al, 2012).
    2) LACK OF EFFECT: In a randomized, double-blind, placebo-controlled crossover intervention study, no adverse events were reported in Japanese women taking up to 5 g/day L-tryptophan for 21 days (Hiratsuka et al, 2013).
    B) CASE REPORTS
    1) Healthy volunteers given 7.5 to 12 g at night reported side effects of nausea, dizziness, headache and drowsiness (Wyatt, 1970; Griffiths, 1972).
    2) SEROTONIN SYNDROME: A 35-year-old woman developed severe serotonin syndrome after a single 2 g dose of L-tryptophan. She had also been taking phenelzine (15 mg daily) for depression (Kim & Mueller, 1989).
    C) EOSINOPHILIA/MYALGIA SYNDROME
    1) In a retrospective cohort study of 418 psychiatric patients, 47 (11%) were definite cases of eosinophilia/myalgia syndrome and another 68 (16%) were possible cases (Kamb et al, 1992):
    a) Risk factor analysis indicated that one retail brand of L-tryptophan was more involved than others; among the 157 users of this brand, 45 (29%) had definite eosinophilia/myalgia and another 36 (23%) were possible cases.
    b) Among the 157 users of the implicated brand, 19 out of 38 (50%) using more than 4000 mg/day developed definite eosinophilia/myalgia, illustrating an increased risk as dosage increased.
    c) Sex, race, and use of other medications were not found to be risk factors; age and dose of L-tryptophan were the only significant risk factors identified.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 1600 mg/kg (Gullino et al, 1956)
    2) 11.6 mg/kg (Trulson & Ulissey, 1987)

Pharmacology Toxicology

Toxicologic Mechanism

    A) EOSINOPHILIA-MYALGIA SYNDROME
    1) Tryptophan may become antigenic in some patients. The receptors of the stimulated T-cell clones could recognize tryptophan-rich peptides on myelin basic protein and a wide spectrum of serotonin-binding sites in neuromuscular tissues. Lymphocyte attack on these sites could result in secondary inflammation, eosinophilia, and acute myositis (Sale, 1990).
    2) Hertzman & Brown (1991) suggest that excess interferon gamma may be an important factor in the pathogenesis of EMS. No one has measured interferon gamma in patients with EMS.
    3) Peak E contaminated L-tryptophan did not directly provide an immune activation trigger comparable to endotoxin (Werner-Felmayer et al, 1991).
    4) Other authors have suggested an interleukin-5 mediated mechanism (Yamaoka et al, 1991).
    B) HUNTINGTON'S DISEASE
    1) HUNTINGTON'S DISEASE/EXACERBATION: Increased quinolinic acid in the striatum has been implicated in exacerbations of chorea in patients with Huntington's disease following administration of tryptophan (Belendiuk et al, 1980).

Physicochemical

Physical Characteristics

    A) L-tryptophan has an unpleasant, bitter, nauseating taste (Wyatt, 1970).

Ph

    A) 5.5 to 7.0 (1% aqueous solution)

Molecular Weight

    A) 204.2

Animal Toxicology

Clinical Effects

    11.1.5) EQUINE/HORSE
    A) HEMOLYSIS: Four of 5 ponies given 0.6 g tryptophan/kg of body weight by stomach tube had evidence of severe hemolysis at necropsy (Paradis et al, 1991).

References

General Bibliography

    1) Adamson DJA & Legge JS: L-tryptophan-induced eosinophilia without myalgia (letter). Lancet 1991; 337:1474-1475.
    2) Allen JA, Peterson A, Sufit R, et al: Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan. Arthritis Rheum 2011; 63(11):3633-3639.
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