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MELATONIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Melatonin is a natural physiologic neural transducer, an endogenous hormone, produced in the pineal gland from tryptophan and secreted rhythmically, usually at night. Exogenous formulations are used for treatment of sleep disorders, for control of the sleep-wake cycle, and as experimental concomitant therapy in cancers.

Specific Substances

    1) N-acetyl-5-methoxytryptamine
    2) N-(2-(5-methoxyindol-3-yl)ethyl) acetamide
    3) CAS 73-31-4

Available Forms Sources

    A) FORMS
    1) Various formulations are available through health food outlets and retail pharmacies as capsule and tablet formulations containing between 0.5 mg and 10 mg melatonin. The most common strengths available include 0.5 mg, 1.8 mg, 3 mg, 6 mg and 10 mg. Sustained release formulations are also available Prod Info, Melatonin (1996).
    a) Melatonin is marketed over-the-counter in accordance with the Dietary Supplement Health Education Act of 1994, thus it does not require, nor has, FDA evaluation or approval, except as an orphan product (Turow, 1996).
    B) USES
    1) Over-the-counter preparations are most commonly used for treatment of sleep disorders, including jet lag following long flights, delayed sleep phase syndrome, and various forms of insomnia, especially in the elderly (Arendt, 1986; Petrie, 1989; Dahlitz, 1991; Haimov & Lavie, 1995).
    a) Wright et al (1998) compared melatonin to placebo in 15 emergency room physicians on 3 consecutive nights after night-shift duty, with cross-over to the opposite agent after a subsequent block of night shifts. No difference was found in sleep quality, tiredness, or cognitive function between melatonin and placebo (Wright et al, 1998).
    2) Melatonin has also been used as an experimental therapy in combination with chemotherapy or radiotherapy in patients with solid tumors. In one study, the addition of melatonin to chemotherapy or radiotherapy compared with chemotherapy or radiotherapy alone significantly improved overall remission rates (32.6% vs 16.5%) and 1-year survival rates (52.2% vs 28.4%) and significantly reduced thrombocytopenia, neurotoxicity, and fatigue in a systematic review of 8 randomized, open-label studies involving 761 patients (Wang et al, 2012).
    3) Other uses of melatonin include regulation of sleep in depressive illnesses (Brown, 1995), adjunct to interleukin-2 therapy for malignant neoplasms (Lissoni et al, 1993; Lissoni et al, 1994), and as a contraceptive aid with a reported associated reduced risk of breast cancer (Short, 1993; Cohen, 1995).

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: Melatonin is commonly used for treatment of sleep disorders, including jet lag following long flights, delayed sleep phase syndrome, and various forms of insomnia. Melatonin has also been used as an experimental therapy in combination with chemotherapy or radiotherapy in patients with solid tumors.
    B) PHARMACOLOGY: Melatonin (N-acetyl-5-methoxytryptamine) is a natural physiologic neural transducer, an endogenous hormone, produced in the pineal gland from tryptophan and secreted rhythmically, usually at night. Melatonin is involved in the induction of sleep, and may play a role in the internal synchronization of the mammalian circadian system.
    C) EPIDEMIOLOGY: Overdose is not common and severe toxicity has not been reported.
    D) WITH THERAPEUTIC USE
    1) Therapeutically, melatonin has a very wide margin of safety. Presenting adverse effects are expected to be those of CNS depression, including lethargy, confusion, fatigue, headache, pruritus, and vasodilation. Tachycardia and hypothermia have been reported. Respiratory depression may occur. A case of autoimmune hepatitis was reported following onset of melatonin use.
    E) WITH POISONING/EXPOSURE
    1) Acute overdose is not expected to result in any significant clinical toxicity. Lethargy, asthenia, disorientation, confusion, drowsiness, lethargy, agitation/irritability, ataxia, vertigo/dizziness, headache, slurred speech, tremors, and possibly psychotic effects, such as hallucinations and nightmares have been reported.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Hypothermia may occur.
    2) Increased pulse has been reported.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vitals signs and mental status.
    C) Routine laboratory studies are not necessary unless otherwise clinically indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Insulating blankets, heating lamps, hot water bottles or heating pads may be used to increase the patient's core temperature in cases of significant hypothermia.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not necessary.
    2) HOSPITAL: Aggressive decontamination is generally not necessary. Consider activated charcoal if a more toxic coingestant is involved.
    D) ANTIDOTE
    1) None.
    E) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is unlikely to be of value because of the large volume of distribution.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Most inadvertent ingestions can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of mental status. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with persistent CNS depression or hypothermia should be admitted for observation and treatment.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    G) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    H) PHARMACOKINETICS
    1) Absorption is rapid, with peak serum levels occurring within one hour. Absorption is slower following sustained-release preparations, with peak levels occurring in approximately 4 hours. Oral bioavailability is poor (mean 33%) and variable (10% to 56%) as a consequence of hepatic first-pass extraction. Vd: 35 L after an intravenous dose. Excretion: Up to 85% of a given dose is excreted in the urine as 6-hydroxymelatonin sulfate. Elimination half-life: from 30 to 50 minutes following oral doses.
    I) DIFFERENTIAL DIAGNOSIS
    1) Other chemicals or drugs that cause CNS depression (eg, toxic alcohols, benzodiazepines, opiates/opioids, antipsychotic medications).

Range Of Toxicity

    A) TOXICITY: ADULTS: In one study, melatonin 1 g/day for 25 to 30 days was well tolerated; CHILDREN: Ingestions of 3 to 80 mg have resulted in minimal toxicity.

Clinical Effects

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) In a retrospective study of 394 melatonin exposures reported to Texas poison centers during 2000-2003, it was found that agitation/irritability, ataxia, vertigo/dizziness, headache, slurred speech, and tremors occurred rarely (in less than 4 cases) (Forrester, 2004).
    B) DROWSY
    1) WITH THERAPEUTIC USE
    a) Sedation or drowsiness and fatigue have occurred with therapeutic doses of melatonin, with a variable incidence rate (0% up to 100%), related to the number of patients in the individual studies (Dollins et al, 1994; Dollins et al, 1993; Petrie et al, 1993; Tzischinsky & Lavie, 1994; Cavallo, 1993; Claustrat et al, 1992; Petrie, 1989; Nordlund & Lerner, 1977). In a randomized, double-blind clinical trial, volunteers given melatonin 10 mg/day for 40 days experienced somnolence and headache as the most relevant adverse effects (Seabra et al, 2000).
    b) Petrie et al (1993) reported lethargy in 1 of 18 international flight crew members after taking 5 mg melatonin daily for jet lag in a controlled study(Petrie et al, 1993a).
    2) WITH POISONING/EXPOSURE
    a) In a retrospective series of 394 cases of melatonin exposures reported to a poison center network during 200-2003, drowsiness or lethargy developed in 58 (14.7%) of patients (Forrester, 2004).
    C) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) Confusion and headache have been reported occasionally following therapeutic melatonin doses (Shannon, 1999; Petrie et al, 1993; Dollins et al, 1993; Claustrat et al, 1992; Dahlitz, 1991).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 66-year-old man became lethargic and disoriented after taking 8 tablets (24 mg) of melatonin. The patient underwent elective prostate surgery under spinal anesthesia without complications approximately 12 hours after the dose. The patient resumed his usual dose of 2 tablets daily at 48 hours (Holliman & Chyka, 1997).
    D) DEPRESSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Carman et al (1976) report worsened dysphoria and sleep loss in patients with underlying major depression taking therapeutic doses(Carman et al, 1976).
    E) PSYCHOTIC DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 40-year-old woman with a pre-existing manic-depressive disorder was treated with 1600 mg/day in a clinical trial for depressive disorders. At that high dose she exhibited signs of inappropriate behavior, including delusions, looseness of associations, and auditory hallucinations (Carman et al, 1976a).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 73-year-old white woman developed psychosis with paranoid and delusional ideation following ingestion of 10 melatonin tablets. Symptoms resolved within 24 hours (Force, 1997).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) COORDINATION ABNORMAL
    a) Doses greater than 200 mg/kg IP in mice produced motor incoordination as shown by the rotorod test. Doses greater than 400 mg/kg resulted in decreased flexor reflexes (Sugden, 1983).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Chronic ingestion has been associated with abdominal cramps (Shannon, 1999).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) A case of biopsy-proven autoimmune hepatitis developed in a patient following onset of melatonin use for insomnia (Hong & Reigler, 1997).
    B) ALKALINE PHOSPHATASE RAISED
    1) WITH THERAPEUTIC USE
    a) In a clinical trial of 8 men taking melatonin, 5 mg daily, one was reported to have increased plasma alkaline phosphatase levels (650 IU/L) which decreased to 360 IU/L after 20 weeks of continued therapy (Dahlitz, 1991).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Garfinkel et al (1995) reports 1 out of 12 elderly subjects experiencing pruritus following therapy with sustained-release melatonin(Garfinkel et al, 1995a).
    B) VASODILATATION
    1) WITH THERAPEUTIC USE
    a) Occasional vasodilation has been reported in Parkinson patients treated with a maximum of 1000 mg/day (Shaw, 1977).
    C) FIXED DRUG ERUPTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: Fixed drug eruptions on the glans was described as burning, itching and sharply marginated, erythemato-vesicular plaques and well-demarcated erosions on the shaft in 2 adult males, occurring within 6 to 8 hours after taking melatonin for jet lag. Lesions dissipated within 10 days (Bardazzi et al, 1997).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) VASODILATATION
    a) Rats and mice administered 400 mg/kg exhibited vasodilation of the extremities as revealed by reddening of ears and feet (Sugden, 1983).

Musculoskeletal

    3.15.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ATAXIA
    a) Muscle relaxation, as shown by a marked decrease in motor activity and ataxia, occurred in rats and mice given 400 mg/kg (Sugden, 1983).

Summary Of Exposure

    A) USES: Melatonin is commonly used for treatment of sleep disorders, including jet lag following long flights, delayed sleep phase syndrome, and various forms of insomnia. Melatonin has also been used as an experimental therapy in combination with chemotherapy or radiotherapy in patients with solid tumors.
    B) PHARMACOLOGY: Melatonin (N-acetyl-5-methoxytryptamine) is a natural physiologic neural transducer, an endogenous hormone, produced in the pineal gland from tryptophan and secreted rhythmically, usually at night. Melatonin is involved in the induction of sleep, and may play a role in the internal synchronization of the mammalian circadian system.
    C) EPIDEMIOLOGY: Overdose is not common and severe toxicity has not been reported.
    D) WITH THERAPEUTIC USE
    1) Therapeutically, melatonin has a very wide margin of safety. Presenting adverse effects are expected to be those of CNS depression, including lethargy, confusion, fatigue, headache, pruritus, and vasodilation. Tachycardia and hypothermia have been reported. Respiratory depression may occur. A case of autoimmune hepatitis was reported following onset of melatonin use.
    E) WITH POISONING/EXPOSURE
    1) Acute overdose is not expected to result in any significant clinical toxicity. Lethargy, asthenia, disorientation, confusion, drowsiness, lethargy, agitation/irritability, ataxia, vertigo/dizziness, headache, slurred speech, tremors, and possibly psychotic effects, such as hallucinations and nightmares have been reported.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hypothermia may occur.
    2) Increased pulse has been reported.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) HYPOTHERMIA: Decreases in body temperature of 0.5 to 1.5 degrees Fahrenheit have been reported during therapeutic melatonin use, and are considered an integral part of the drug's mechanism to facilitate phase-shifts in circadian rhythm (Dollins et al, 1994; Deacon et al, 1994).
    2) ANIMAL STUDIES: Marked reductions in body temperature occurred in rats and mice given doses greater than 400 mg/kg (Sugden, 1983).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) TACHYCARDIA: Increased pulse rate has been reported as an occasional adverse effect (Claustrat et al, 1992).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has occasionally been reported following therapeutic doses of melatonin (Claustrat et al, 1992).

Respiratory

    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOVENTILATION
    a) Slow, labored respirations preceded death in rats and mice given doses greater than 400 mg/kg (Sugden, 1983).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) DISORDER OF ENDOCRINE SYSTEM
    1) WITH THERAPEUTIC USE
    a) Chronic ingestion of 1 gram per day in humans resulted in depression of serum luteinizing hormone (LH) (Nordlund & Lerner, 1977). Chronic ingestion has also been associated with loss of libido, gynecomastia, and reduced sperm count (Shannon, 1999).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) ANIMAL STUDIES
    a) RATS - In a developmental toxicity study, pregnant rats were administered melatonin orally in doses ranging from 1- to 200-mg/kg body weight per day on days 6 through 19 of gestation. No effect was seen on prenatal survival, fetal body weight, or incidences of fetal malformations or variations (Jahnke et al, 1999).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vitals signs and mental status.
    C) Routine laboratory studies are not necessary unless otherwise clinically indicated.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Therapeutic plasma melatonin levels have not been established. Serum levels following overdoses may not be clinically useful, particularly because of the large interpatient variability in exogenous and physiologic melatonin levels (Aldhous et al, 1985).

Methods

    A) CHROMATOGRAPHY
    1) Melatonin and hydroxymelatonin may be measured by high performance liquid chromatography (HPLC) methods (Prod Info Melatone(R), melatonin, 1996; Raynaud et al, 1993; Drijfhout et al, 1996).
    B) IMMUNOASSAY
    1) Serum melatonin concentrations have been measured by a radioimmunoassay (RIA) technique. A limit of detection was reported as 0.5 pg/mL (Seabra et al, 2000).

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 persistent CNS depression or hypothermia should be admitted for observation and treatment.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Most inadvertent ingestions can be managed at home.
    B) Most pediatric ingestions and inadvertent overdoses in adults can be managed at home (Forrester, 2004; Herrington et al, 1996). In a series of 16 cases of melatonin overdose (10 children and 6 adults ingesting 2 to 80 milligrams) all patients developed no or minimal effects (Herrington et al, 1996). Fifteen of the patients were managed at home without decontamination and one was treated in a health care facility with ipecac.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of mental status. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vitals signs and mental status.
    C) Routine laboratory studies are not necessary unless otherwise clinically indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) GI decontamination is generally not necessary. Consider activated charcoal if a more toxic coingestant is involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Routine laboratory studies are not needed unless otherwise clinically indicated.
    2) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    3) Monitor vitals signs and mental status.
    B) HYPOTHERMIA
    1) Insulating blankets, heating lamps, hot water bottles or heating pads may be used to increase the patient's core temperature in cases of significant hypothermia.

Enhanced Elimination

    A) EFFICACY
    1) Hemodialysis is unlikely to be of value because of the large volume of distribution.

Range Of Toxicity

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) In a series of 16 cases of melatonin overdose (10 children and 6 adults ingesting 2 to 80 mg), all patients developed no or minimal effects (Herrington et al, 1996). In one study, 5 patients with hyperpigmented skin from various causes received melatonin 1 g/day for 25 to 30 days, and developed only drowsiness (Nordlund & Lerner, 1977).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) GENERAL
    a) Plasma melatonin levels greater than 100 picograms/milliliter were produced following a single intravenous dose of 5 or 10 micrograms intravenously in healthy subjects. A constant intravenous infusion of 4 micrograms/hour for 5 hours produced mean steady-state melatonin plasma levels of 72 picograms/ milliliter achieved in 1 to 2 hours (Mallo et al, 1990).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CHRONIC
    a) Serum melatonin concentrations were measured during a 28-day treatment period in volunteers given 10 milligrams/day and in controls given no melatonin. From visit 2 through 4, melatonin serum concentrations ranged from 5.3 to 9.7 and from 30 to 56 picomoles/milliliter, respectively, in controls and volunteers given melatonin (Seabra et al, 2000).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 1168 mg/kg (Sugden, 1983)
    2) LD50- (ORAL)MOUSE:
    a) 1250 mg/kg (RTECS , 2002)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) >1600 mg/kg (RTECS , 2002)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 1131 mg/kg (RTECS , 2002)
    5) LD50- (ORAL)RAT:
    a) >3200 mg/kg (RTECS , 2002)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) >1600 mg/kg (RTECS , 2002)

Summary

    A) TOXICITY: ADULTS: In one study, melatonin 1 g/day for 25 to 30 days was well tolerated; CHILDREN: Ingestions of 3 to 80 mg have resulted in minimal toxicity.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) SLEEP DISORDERS OF THE BLIND -
    a) Oral doses of 5 milligrams at bedtime have been used for treatment of blind persons with desynchronized sleep-wake cycles (Arendt et al, 1988).
    2) CHRONIC INSOMNIA -
    a) Oral doses of 75 milligrams have been used in chronic insomnia (MacFarlane et al, 1991).
    3) DELAYED SLEEP PHASE SYNDROME -
    a) Oral melatonin in doses of 5 milligrams has been given daily at 10 PM in patients with delayed phase sleep syndrome (Dahlitz, 1991).
    4) JET LAG -
    a) Usual oral doses of 5 milligrams daily for 3 days prior to airline departure (between 10 AM and 6 PM local time), then 5 milligrams daily (between 10 PM and midnight local time) for 4 days, beginning the day of the flight have been recommended (Arendt, 1986; Petrie, 1989).
    5) NORMALIZATION OF NOCTURNAL LEVELS -
    a) Oral doses of 0.1 and 0.3 milligrams, given in the AM, have produced peak plasma levels within the normal range of nocturnal levels reported in controls (Dollins et al, 1994).
    6) CANCER THERAPY -
    a) Doses of 20 milligrams intramuscularly daily for 2 months followed by 10 milligrams orally daily until progression have been given for treatment of solid tumors (Lissoni et al, 1991).
    b) Combination low-dose interleukin-2 therapy with daily oral doses of 40 to 50 milligrams melatonin have been used for treatment of a variety of tumor types (Lissoni et al, 1995; Lissoni et al, 1993; Lissoni et al, 1994; Barni et al, 1995).
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) SEVERE SLEEP DISTURBANCES -
    a) Children 3 to 14 years of age with severe sleep disturbances due to neurologic defects have been given oral melatonin 0.5 to 10 milligrams daily at bedtime (Jan et al, 1994).
    b) A 6-month-old infant was administered oral melatonin 2.5 milligrams daily at bedtime for a congenital sleep disorder (Jan et al, 1994).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) PYRIDOXAL-KINASE ENHANCER -
    1) Melatonin is a pineal gland hormonal agent which may increase the concentration of aminobutyric acid and serotonin in the midbrain and hypothalamus. It enhances the activity of pyridoxal-kinase, an enzyme necessary for the synthesis of aminobutyric acid, dopamine, and serotonin. Valvevski et al (1995) have demonstrated that melatonin inhibits serotonin uptake by serum platelets at very high concentrations only, not at physiologic levels.
    2) Sugden (1983) has demonstrated in animal studies that whole brain 5-hydroxytryptamine or 5-hydroxyindole acetic acid concentrations were not altered with sedative doses of melatonin (20 mg/kg IP). This would suggest that the sedative action is not due to an interaction with serotoninergic neurons.
    3) No significant effect on hypothalamic-pituitary-adrenal function was reported in parkinsonian patients treated with melatonin (Shaw, 1977).
    4) Exogenously administered melatonin has been shown to double glutathione peroxidase activity in rat brains, which may partially account for the neuroprotective effect of melatonin (Barlow-Walden et al, 1995).
    B) PUBERTY - Melatonin plays a role in the inhibition of gonadal development and in the control of estrus. It may influence the maturation and function of the hypothalamic-pituitary-gonadal axis and in turn determine the onset of puberty (Cavallo, 1993). Melatonin has been shown to stimulate growth hormone secretion, but the site of its action is not yet clear (Valcavi et al, 1993).
    C) SLEEP PATTERNS -
    1) The diurnal rhythm of melatonin secretion, occurring at night time and influencing circadian rhythm, appears to affect sleep patterns. Serum levels of endogenous melatonin are very low during most of the day. It has been labeled as the "hormone of darkness". It appears to be involved in the induction of sleep and serve as a marker of the "biologic clock" (Dollins et al, 1994; Cavallo, 1993; Tzischinsky & Lavie, 1994; Garfinkel et al, 1995; Haimov & Lavie, 1995; Jan et al, 1994; Short, 1993).
    a) Production of lowered body temperature is considered an important part of the melatonin-facilitated phase-shifts of circadian rhythm (Deacon et al, 1994).
    D) CONTRACEPTIVE ACTIVITY - Melatonin has reportedly induced a significant decrease in LH secretion in women during long-term administration, and thus may have potential as a contraceptive (Voordouw et al, 1992; Cavallo, 1993; Cohen, 1995).
    E) ANTITUMOR ACTIVITY -
    1) In vitro and animal studies have demonstrated a capability of melatonin to induce direct cytostatic actions on some human cancer cell lines, stimulating host immune responses, and inhibiting release of somatomedin-C (Lissoni et al, 1991; Lissoni et al, 1995).
    2) Melatonin has been shown to act as a free radical scavenger, an antioxidant, both in vitro and in vivo. When administered to rats prior to safrole, an agent known to produce hepatic DNA damage, melatonin was protective of the DNA as it was exposed to oxidative radical attack. These findings are suggestive of an anti-cancer role for melatonin, although clinical studies will need to validate this function (Reiter et al, 1994).

References

General Bibliography

    1) Aldhous M, Franey C, & Wright J: Plasma concentrations of melatonin in man following oral absorption of different preparations. Br J Clin Pharmacol 1985; 19:517-521.
    2) Arendt J, Aldhous M, & Wright J: Synchronisation of a disturbed sleep-wake cycle in a blind man by melatonin treatment. Lancet 1988; 772-73.
    3) Arendt J: Alleviation of jet lag by melatonin: preliminary results of controlled double blind trial. Br Med J 1986; 292:1170.
    4) Bardazzi F, Placucci F, & Neri I: Fixed drug eruption due to melatonin (letter). Acta Derm Venereol (Stockh) 1997; 78:69.
    5) Barlow-Walden LR, Reiter RJ, & Abe M: Melatonin stimulates brain glutathione peroxidase activity. Neurochem Internat 1995; 26:497-502.
    6) Barni S, Lissoni P, & Cazzaniga M: A randomized study of low-dose subcutaneous interleukin-2 plus melatonin versus supportive care alone in metastatic colorectal cancer patients progressing under 5-fluorouracil and folates. Oncology 1995; 52:243-245.
    7) Brown GM: Melatonin in psychiatric and sleep disorders: therapeutic implications. CNS Drugs 1995; 3:209-226.
    8) Carman JS, Post RM, & Buswell R: Negative effects of melatonin on depression. Am J Psychiatry 1976a; 133:1181-1186.
    9) Carman JS, Post RM, Buswell R, et al: Negative effects of melatonin on depression. Am J Psychiatry 1976; 133:1181-1186.
    10) Cavallo A: The pineal gland in human beings: relevance to pediatrics. J Pediatr 1993; 123:843-851.
    11) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    12) Claustrat B, Brun J, & David M: Melatonin and jet lag: confirmatory result using a simplified protocol. Biol Psychiatry 1992; 32:705-711.
    13) Cohen M: Hypotheses: melatonin/steroid combination contraceptives will prevent breast cancer. Breast Cancer Res Treat 1995; 33:257-264.
    14) Dahlitz M: Delayed sleep phase syndrome response to melatonin. Lancet 1991; 337:1121-1124.
    15) Deacon S, English J, & Arendt J: Acute phase-shifting effects of melatonin associated with suppression of core body temperature in humans. Neuroscience 1994; 178:32-34.
    16) Dollins AB, Lunch HJ, & Wurtman RJ: Effect of pharmacological daytime doses of melatonin on human mood and performance. Psychopharmacology 1993; 112:490-496.
    17) Dollins AB, Zhdanova IV, & Wurtman RJ: Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci 1994; 91:1824-1828.
    18) Drijfhout WJ, Grol CJ, & Westerink BHC: Parasympathetic inhibition of pineal indole metabolism by prejunctional modulation of noradrenaline release. Eur J Pharmacol 1996; 308:117-124.
    19) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    20) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    21) Force RW: Psychotic episode after melatonin (letter). Ann Pharmacother 1997; 31:1408.
    22) Forrester MB: Melatonin exposures reported to Texas poison centers in 1998-2003. Vet Human Toxicol 2004; 46(6):345-346.
    23) Garfinkel D, Laudon M, & Nof D: Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995; 346:541-544.
    24) Garfinkel D, Laudon M, Nof D, et al: Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995a; 346:541-544.
    25) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    26) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    27) Haimov I & Lavie P: Potential of melatonin replacement therapy in older patients with sleep disorders. Drugs Aging 1995; 7:75-78.
    28) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    29) Herrington LF, Gorman SE, & Geller RJ: Melatonin: the next gamma hydroxybutyrate (GHB)? (abstract). J Toxicol Clin Toxicol 1996; 34:595.
    30) Holliman BJ & Chyka PA: Problems in assessment of acute melatonin overdose. South Med J 1997; 90:451-453.
    31) Hong YG & Reigler JL: Is melatonin associated with the development of autoimmune hepatitis?. J Clin Gastroenterol 1997; 25:376-378.
    32) Jahnke G, Marr M, & Myers C: Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Toxicol Sci 1999; 50:271-279.
    33) Jan JE, Espezel H, & Appleton RE: The treatment of sleep disorders with melatonin. Dev Med Child Neurol 1994; 36:97-107.
    34) Lane EA & Moss HB: Pharmacokinetics of melatonin in man: first pass hepatic metabolism. J Clin Endocrinol Metab 1985; 61:1214-1216.
    35) Le Bars D, Thivolle P, & Vitte PA: PET and plasma pharmacokinetic studies after bolus intravenous administration of (11C) melatonin in humans. Int J Rad Appl Instrument 1991; 18:357-362.
    36) Lissoni P, Barni S, & Cattaneo G: Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 1991; 48:448-450.
    37) Lissoni P, Barni S, & Tancini G: A randomized study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma. Br J Cancer 1994; 69:196-199.
    38) Lissoni P, Barni S, & Tancini G: Immunoendocrine therapy with low-dose subcutaneous interleukin-2 plus melatonin of locally advanced or metastatic endocrine tumors. Oncology 1995; 52:163-166.
    39) Lissoni P, Barni S, & Tancini G: Immunotherapy with subcutaneous low- dose interleukin-2 and the pineal indole melatonin as a new effective therapy in advanced cancers of the digestive tract. Br J Cancer 1993; 67:1404-1407.
    40) MacFarlane JG, Cleghorn JM, & Brown GM: The effects of exogenous melatonin on the total sleep time and daytime alertness of chronic insomniacs: a preliminary study. Biol Psychiatry 1991; 30:371-376.
    41) Mallo C, Zaidan R, & Galy G: Pharmacokinetics of melatonin in man after intravenous infusion and bolus injection. Eur J Clin Pharmacol 1990; 38:297-301.
    42) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    43) Nordlund JJ & Lerner AB: The effect of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab 1977; 45:768-774.
    44) Nordlund JJ & Lerner AB: The effect of oral melatonin on skin color and on the release of pituitary hormones. J Clin Endocrinol Metab 1977a; 45:768-774.
    45) Petrie K, Dawson AG, & Thompson L: A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biol Psychiatry 1993; 33:526-530.
    46) Petrie K, Dawson AG, Thompson L, et al: A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biol Psychiatry 1993a; 33:526-530.
    47) Petrie K: Effect of melatonin on jet lag after long haul flights. Br Med J 1989; 298:705-77.
    48) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    49) Product Information: Melatone(R), melatonin. Cardiovascular Research, Ltd, Concord, CA, 1996.
    50) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    51) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    52) Raynaud F, Mauviard F, & Geoffriau M: Plasma 6-hydroxymelatonin, 6-sulfatoxymelatonin and melatonin kinetics after melatonin administration to rats. Biological Signals 1993; 2:358-366.
    53) Reiter RJ, Tan DX, & Poeggeler B: Melatonin as a free radical scavenger: implications for aging and age-related diseases. Ann Acad Sci 1994; 719:1-12.
    54) Seabra MLV, Bignotto M, & Pinto LR Jr: Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 2000; 29:193-200.
    55) Shannon M: Alternative medicines toxicology: a review of selected agents (review). Clin Toxicol 1999; 37:709-713.
    56) Shaw KM: Hypothalamo-pituitary-adrenal function in Parkinsonian patients treated with melatonin. Curr Med Res Opin 1977; 4:743-746.
    57) Short RV: Melatonin. Br Med J 1993; 307:952-953.
    58) Sugden D: Psychopharmacological effects of melatonin in mouse and rat. J Pharmacol Exp Ther 1983; 227:587-591.
    59) Turow V: Melatonin for insomnia and jet lag (letter). Pediatrics 1996; 97(3):439.
    60) Tzischinsky O & Lavie P: Melatonin possesses time-dependent hypnotic effects. Sleep 1994; 17:638-645.
    61) Valcavi R, Zini M, & Maestroni GJ: Melatonin stimulates growth hormone secretion through pathways other than the growth hormone-releasing hormone. Clin Endocrin 1993; 39:193-199.
    62) Voordouw BCG, Euser R, & Verdonk RER: Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation. J Clin Endocrinol Metab 1992; 74:108-117.
    63) Waldhauser F, Waldhauser M, & Lieberman HR: Bioavailability of oral melatonin in humans. Neuroendocrinology 1984; 39:307-313.
    64) Wang YM, Jin BZ, Ai F, et al: The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol 2012; 69(5):1213-1220.
    65) Wright SW, Lawrence LM, & Wrenn KD: Randomized clinical trial of melatonin after night-shift work: efficacy and neuropsychologic effects. Ann Emerg Med 1998; 32:334-339.
    66) Yeleswaram K, McLaughlin LG, & Knipe JO: Pharmacokinetics and bioavailability of exogenous melatonin in preclinical animal models and clinical implications. J Pineal Res 1997; 22:45-51.
    67) Young IM, Lione RM, & Francis P: Melatonin is metabolized to N-acetyl serotonin and 6-hydroxymelatonin in man. J Clin Endocrinol 1985; 60:114-119.