Meletonin/Autism

[JoAnn Dunk]

I have an 8 year old son who was diagnosed at three with Autism.  He has always had problems sleeping since he was an infant.  Although he should be tired, he would stay up till 12 or 1 am, and he would not be able to fall asleep.  He would yawn, but would lie awake with his bervous system and brain not cooperating to let him sleep.  He is not particularly hyper during the day.  I have tried altering his diet, no sugar caffiene msg etc.  I have tried routine and discipline, and have been firm and consistant with everything I tried.  Several years ago I decided to try him on meletonin.  He is now taking 1\2 of a 2.5 mg sublingual half an hour before bedtime.  This has worked for years very effectively, and also seems to improve his behavior the next day at school.  In all my reading there is no information about it's use in children.  The only thing I could find at all was a comment against it's use in children, but it did not list any reason or concern for that. During our history of using it I have tried on three occasions to stop using it.  Within days he was back to the same problem, and poor behaviors increased at school.  Please comment on what you know about it's usage with children.  Thank you.  JoAnn

[Kevin Kennedy, Ph.D.]

Dear JoAnn,

Many medications, both over-the-counter and prescription, are not exposed to clinical studies with children. Nonetheless, medications are used in clinical practice with children and, on the basis of clinical experience, some medications gain widespread use and are quite effective.

Unless clinical trials have been conducted with children, the FDA will always caution against use of a medication because, in a strict research sense, the safety and effectiveness have not been determined. Prescribing physicians employ their judgement, in addition to what they know via clinical trials, in their prescribing practices. And, in many instances, the applied clinical field is 'ahead' of the research field in the use of medications.

The use of melatonin is further complicated by the reality that it is not regulated in the sense that prescription medications are. As you know, it is available over the counter, and has been useful to both adults and children as an aide to sleep. However, you should be careful to discuss its use with your doctor(s) and see if they offer any reason why you should refrain from its use. Be sure to be forthcoming about your use of the medication and how successful you have found it.

[Jeff Luper]

CAUTIONS
          ADVERSE REACTIONS
               ADVERSE REACTIONS, CARDIOVASCULAR
                    A. CARDIOVASCULAR EFFECTS
                         1. TACHYCARDIA has been reported rarely after
                         melatonin administration (Claustrat et al, 1992); a
                         cause-effect relationship is doubtful.
               3.3.3 CENTRAL NERVOUS SYSTEM
                    A. CENTRAL NERVOUS SYSTEM EFFECTS
                         1. Four of 6 neurologically impaired children (ages
                         9 months to 18 years) who were given oral
                         melatonin 5 milligrams/night at bedtime for chronic
                         sleep complaints developed new or increased
                         seizure activity. In all cases, seizure activity returned
                         to pre-treatment levels after discontinuing melatonin.
                         Melatonin alleviated sleep disorders in 5 of the 6
                         children (Sheldon et al, 1998).
                         2. A 73-year-old woman with no history of
                         psychotic behavior was hospitalized for an ACUTE
                         PSYCHOTIC EPISODE after taking ten
                         3-milligram tablets of melatonin one morning after a
                         sleepless night. Her other regular medications were
                         thought not to be responsible for the episode. She
                         slept through the night of admission and had normal
                         mental status the next morning (Force et al, 1997).
                         3. ALTERED SLEEP PATTERNS have been
                         reported after the administration of melatonin
                         (Middleton et al, 1996).
                         4. Discontinuation of melatonin after 1 year of
                         nightly treatment (5 milligrams/night) resulted in
                         WITHDRAWAL-EMERGENT DYSKINESIA
                         and AKATHISIA in a 22-year-old woman who
                         suffered from spastic diplegia (from cerebral palsy)
                         and severe mental retardation. Melatonin treatment
                         was terminated because of repeated vomiting. One
                         week later, the woman began to develop
                         involuntary lip- smacking movements and tongue
                         protrusion, with moaning, shouting, and
                         restlessness. Reintroduction of melatonin in
                         gradually increasing doses caused disappearance of
                         the involuntary motions and improvement of
                         agitation and insomnia. A month later, another
                         episode of abdominal pain resulted in termination of
                         melatonin, with the same consequences. When
                         melatonin 5 milligrams per night was reinstituted, all
                         symptoms disappeared the next day. Melatonin was
                         then stopped gradually over a 2-month period
                         without any movement abnormalities. The authors
                         cautioned against the use of melatonin in patients
                         with organic brain damage (Giladi § Shabtai,
                         1999).
                         5. SEDATION or DROWSINESS and FATIGUE
                         can occur with melatonin administration, although
                         the incidence of these effects has varied
                         considerably (0 to 100%), related to the small
                         numbers of patients/subjects treated in individual
                         studies (Dollins et al, 1994; Dollins et al, 1993;
                         Petrie et al, 1993; Tzischinsky § Lavie, 1994;
                         Cavallo, 1993; Claustrat et al, 1992; Lissoni et al,
                         1991; Petrie et al, 1989; Nordlund § Lerner,
                         1977).
                         6. Drowsiness was described by one of 18
                         international flight crew receiving oral melatonin 5
                         mg daily (after arrival) for jet lag in a controlled
                         study (Petrie et al, 1993).
                         7. HEADACHE and CONFUSION may occur
                         occasionally after oral doses of melatonin (Claustrat
                         et al, 1992; Petrie et al, 1993; Dollins et al, 1993;
                         Dahlitz et al, 1991).
                         8. In patients with major depression, melatonin
                         therapy has worsened DYSPHORIA and sleep
                         loss (Carman et al, 1976).
               3.3.4 ENDOCRINE/METABOLIC
                    A. ENDOCRINE EFFECTS
                         1. A 56-year-old man with amyotrophic lateral
                         sclerosis (ALS) of 3 years duration developed
                         painful, asymmetric gynecomastia over 3 months.
                         He had been treated with riluzole 50 milligrams
                         (mg) twice daily for 2 years, vitamin E 400 mg
                         daily, and citalopram 20 mg daily. In addition he
                         had been taking over-the-counter melatonin for a
                         year and a half: 1 mg per day for the first year and
                         then 2 mg per day. Discontinuation of the melatonin
                         without any changes in other drug regimens resulted
                         in complete regression of the gynecomastia within a
                         few weeks. Impurities in the melatonin cannot be
                         ruled out as causal (De Bleecker et al, 1999).
               3.3.7 LIVER
                    A. HEPATITIS
                         1. A woman developed AUTOIMMUNE
                         HEPATITIS after taking melatonin 3 milligrams/day
                         for insomnia for 2 weeks. Because of other reports
                         of the immunomodulatory effects of melatonin and
                         the timing of the melatonin use in relation to the
                         development of hepatitis, the authors speculated
                         that melatonin may have initiated the autoimmune
                         response or precipitated the clinical manifestation of
                         an already existing, asymptomatic disorder (Hong
                         § Riegler, 1997).
               3.3.10 SKIN
                    A. DERMATOLOGIC EFFECTS
                         1. PRURITUS was reported in 1 of 12 elderly
                         subject with insomnia during therapy with
                         sustained-release melatonin in one study (Garfinkel
                         et al, 1995). A causal relationship is uncertain.
               3.3.12 OTHER
                    A. OVERDOSE See POISINDEX(R) Management
                    "MELATONIN"
                    B. ADVERSE EFFECTS - GENERAL
                         1. Statistically significant reductions in body
                         temperature (0.5 to 1.5 degree Fahrenheit) have
                         been reported during oral melatonin administration
                         (Dollins et al, 1993; Deacon et al, 1994), and are
                         considered an integral part of the ability of the
                         hormone to facilitate phase-shifts in circadian
                         rhythm (Deacon et al, 1994). Severe decreases in
                         temperature have not been reported.
                         2. Numerous adverse effects have been reported
                         during combined melatonin/interleukin-2 therapy of
                         cancer, including fever, vomiting, and rash;
                         however, virtually all effects could be attributed to
                         interleukin-2 administration (Lissoni et al, 1992;
                         Lissoni et al, 1995; Lissoni et al, 1994). Melatonin
                         has abrogated falls in blood pressure induced by
                         interleukin-2 (Lissoni et al, 1990).
     4.0 CLINICAL APPLICATIONS
          4.1 MONITORING PARAMETERS
               4.1.1 THERAPEUTIC
                    A. LABORATORY PARAMETERS
                    B. Plasma levels
                         1. Assessment of nocturnal melatonin plasma levels
                         may be useful in the diagnostic workup of certain
                         patients, although variability is large (0 to 250
                         pg/mL; average, 90 pg/mL).
                         2. Therapeutic melatonin plasma levels (increases
                         over normal) have not been established. Plasma
                         level monitoring of treatment is impractical in most
                         instances due to the great intersubject variability in
                         levels achieved.
                    C. Urinary 6-hydroxymelatonin sulfate
                         1. Urine concentrations of this metabolite have been
                         used as an indirect marker of plasma melatonin
                         levels as its excretion is relatively consistent (normal
                         young or elderly subjects, 4 to 5 mcg/hour). Urinary
                         levels have been reduced in elderly subjects with
                         chronic insomnia (Garfinkel et al, 1995).
                    D. PHYSICAL EXAMINATION
                         1. Improvement of sleep in insomnia (eg, reduced
                         sleep latency, longer sleep duration, improved
                         quality of sleep)
                         2. Alleviation of symptoms in jet lag (eg, correction
                         of disturbed sleep, reduced daytime tiredness)
               4.1.2 TOXIC
                    A. PHYSICAL EXAMINATION
                         1. Signs of excessive sedation/fatigue warranting
                         dose reduction
          4.3 PLACE IN THERAPY
               A. Melatonin has shown variable degrees of efficacy in jet lag
               syndrome and sleep disorders, and has been used for its
               immunostimulant actions in patients with solid tumors. There is no
               evidence that melatonin can prevent cancer. It is also being
               investigated as an oral contraceptive. At present, however, data
               are too limited and/or inconsistent to recommend melatonin for
               any specific indication. For one of its widest uses, jet lag
               (promulgated in part by the media), benefits achieved with
               melatonin may simply be a placebo effect; a large,
               rigidly-controlled study is needed to detect significant benefits of
               the hormone.
               B. Clinical and sleep laboratory data suggest that improvements
               seen with melatonin in some conditions may be attributed to an
               hypnotic effect, similar to the benzodiazepines, as opposed to
               phase-shifting activity. Additional studies to delineate the
               mechanism of action of melatonin are needed in order to optimize
               its use; comparisons with benzodiazepines are needed for most
               potential sleep-disorder indications.
          4.4 MECHANISM OF ACTION/PHARMACOLOGY
               A. MECHANISM OF ACTION
                    1. Melatonin (N-acetyl-5-methoxytryptamine) is a
                    neurohormone produced by pinealocytes in the pineal
                    gland during the dark hours (night) of the day-night cycle.
                    Serum levels of melatonin are very low during most of the
                    day, and it has been labeled the "hormone of darkness".
                    Melatonin is involved in the induction of sleep, and may
                    play a role in the internal synchronization of the mammalian
                    circadian system and serve as a marker of the "biologic
                    clock" (Dollins et al, 1994; Tzischinsky § Lavie, 1994;
                    Garfinkel et al, 1995; Cavallo, 1993; Haimov § Lavie,
                    1995; Jan et al, 1994; Short, 1993).
                    2. In general, the pineal gland (projecting from
                    diencephalon into third ventricle) is a neuroendocrine
                    transducer, related to its secretion of melatonin. The
                    hormone serves as a messenger to the neuroendocrine
                    system regarding environmental conditions (especially the
                    photoperiod). Putative functions of endogenous melatonin
                    in this regard include regulation of sleep cycles, hormonal
                    rhythms, and body temperature (Dollins et al, 1993;
                    Deacon et al, 1994; Cavallo, 1993). Melatonin may also
                    have a role in influencing the maturation and function of the
                    hypothalamic-pituitary-gonadal axis and in determining the
                    onset of puberty (Cavallo, 1993).
                    3. Production of melatonin is regulated by postsynaptic
                    receptors originating in the superior cervical ganglion,
                    which innervate the pineal gland. The suprachiasmatic
                    nucleus of the hypothalamus (entrained by the light-dark
                    cycle and considered the anatomic site for the biologic
                    clock) receives stimuli from the retina (retinohypothalamic
                    tract), and during dark hours the suprachiasmatic nuclei
                    forward a stimulus to the superior cervical ganglion and
                    pineal gland, resulting in melatonin secretion (Cavallo,
                    1993; Haimov § Lavie, 1995). This stimulatory activity is
                    suppressed by light, especially bright light (Cavallo, 1993;
                    Thalen et al, 1995; Strassman et al, 1987). Melatonin
                    synthesis in the pinealocyte is dependent upon
                    noradrenergic stimulation (Cavallo, 1993). The normal
                    endogenous production rate is 28 to 30 mcg/day (Short,
                    1993; Lane § Moss, 1985). Production of the hormone is
                    reduced in cirrhotic patients (12 mcg/day) (Lane § Moss,
                    1985) and in the elderly (Garfinkel et al, 1995).
                    4. Continuous abolition of melatonin secretion has been
                    achieved in normal sleep-deprived men exposed to
                    constant nocturnal bright light, this procedure essentially
                    constituting a "functional pinealectomy" (Strassman et al,
                    1987).
               B. ACUTE EXOGENOUS EFFECTS
                    1. Acute oral daytime doses of melatonin (0.1 to 80 mg)
                    have produced sedative effects, fatigue, increased sleep
                    propensity, decrements in performance and self-reported
                    vigor, confusion, and a reduction in body temperature in
                    healthy subjects. A tendency for dose-related behavioral
                    changes was seen with lower doses (0.1 to 10 mg) but
                    was less clear in higher doses ranges (Dollins et al, 1993;
                    Dollins et al, 1994). In another study, daytime and
                    nighttime doses of melatonin 5 mg (12 noon, 5 pm, 7 pm,
                    and 9 pm) were also associated with reduced body
                    temperature, as well as time-dependent increases in
                    sleepiness, sleep propensity, and the spectral power in
                    theta, delta, and spindles bands on the
                    electroencephalogram; latency to maximal effects varied
                    linearly from 3.6 hours at noon to 1 hour at 9 pm
                    (Tzischinsky § Lavie, 1994). Decreases in body
                    temperature are considered an integral part of the ability of
                    the hormone to facilitate phase-shifts in circadian rhythm
                    (Deacon et al, 1994). However, one study using daytime
                    administration showed no reduction in rectal temperature
                    during diurnal sleep after melatonin, in comparison to
                    placebo (Matsumoto, 1999).
                    2. These data clearly indicate a hypnotic effect of
                    melatonin. However, results of these and other studies
                    (Deacon et al, 1994; Dahlitz et al, 1991; MacFarlane et
                    al, 1991; Cavallo, 1993) raise the question as to whether
                    this action represents a direct effect of the hormone, phase
                    shifts in circadian rhythms of sleep, or both. Some
                    investigators suggest that effects of melatonin are similar to
                    those of benzodiazepines (Dollins et al, 1994). Additional
                    studies are needed to distinguish the hypnotic mechanism.
                    3. Hormonal effects observed after acute doses of
                    melatonin include increases in serum prolactin in adults
                    (morning doses) and pubertal and prepubertal children
                    (afternoon doses), and increases in basal growth hormone
                    release and growth hormone responses to GHRH
                    stimulation (possibly via inhibiting endogenous
                    somatostatin release) (Valcavi et al 1993; Cavallo, 1993).
                    In most studies, no significant effect of acute doses has
                    been observed on baseline luteinizing hormone (LH)
                    concentrations (children or adolescents), the LH response
                    to luteinizing hormone-releasing hormone (LHRH)
                    stimulation (adults), or the amplitude and frequency of LH
                    pulses (adults) (Weinberg et al, 1980; Cavallo, 1993).
               C. CHRONIC EXOGENOUS EFFECTS
                    1. Prolonged administration of oral melatonin has
                    reportedly induced phase-setting effects on circadian
                    rhythms, such as the sleep-wake cycle and rest-activity.
                    The hormone has been reported to produce reentrainment
                    of circadian rhythms after time zone shifts, and entrainment
                    of previously free-running rhythms in the blind (Dollins et
                    al, 1993; Arendt et al, 1988; Dahlitz et al, 1991; Cavallo,
                    1993; Arendt et al, 1986).
                    2. A significant decrease in LH secretion in women has
                    been observed during long-term administration of
                    melatonin, and the hormone is being evaluated as a
                    contraceptive (Voordouw et al, 1992; Cavallo, 1993). In
                    men, no significant alteration of growth hormone, LH,
                    testosterone, prolactin, or thyroxine has been observed
                    with chronic dosing (Cavallo, 1993). No significant effect
                    on hypothalamic-pituitary-adrenal function was reported in
                    parkinsonian patients treated with melatonin for one month
                    (Shaw, 1977).
               D. ANTITUMOR ACTIVITY
                    1. In vitro and animal studies have reported that melatonin
                    is capable of inducing 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). Melatonin has
                    been used alone and in combination with interleukin-2 as
                    an immunotherapeutic regimen in the treatment of cancer
                    (Lissoni et al, 1994; Lissoni et al, 1995).
               E. REVIEWS
                    1. The use of melatonin in sleep-wake cycle disorders of
                    children has been reviewed (Jan et al, 1999).
                    2. The pharmacology and functions of melatonin in humans
                    have been reviewed (Brzezinski, 1997).
                    3. Experimental and pre-clinical findings relating to the use
                    of melatonin in malignancy are summarized in a German
                    language article (Bartsch § Bartsch, 1997).
                    4. Nighttime hypnogenic effects of melatonin are reviewed
                    in German (Saletu, 1997).
                    5. A German language review of the effects of melatonin in
                    humans is available (Langer et al, 1997).
          4.5 THERAPEUTIC USES
               A. CANCER
                    1. OVERVIEW:

                             FDA APPROVAL: Adult, no; pediatric, no
                             EFFICACY: Adult, possibly effective
                             DOCUMENTATION: Adult, fair

                    2. SUMMARY:

                              - Complete or partial responses minimal with
                                melatonin in patients with solid tumors

                              - Stable disease achieved in one-third of
                                patients

                              - More effective in combination with other agents

                    3. ADULT:
                         a. Addition of melatonin to chemotherapy regimens
                         treating metastatic solid tumors reduced the toxicity
                         of the chemotherapy and enhanced tumor
                         regression and survival time. Two hundred fifty
                         patients with metastatic solid tumors (non-small cell
                         lung cancer, breast cancer, gastro-intestinal tract
                         tumors, or head and neck cancers) were
                         randomized to receive either chemotherapy alone or
                         chemotherapy with oral melatonin 20 milligrams
                         each evening, beginning 7 days prior to
                         chemotherapy and continuing after chemotherapy
                         interruption, until disease progression. No patient
                         treated with chemotherapy alone (0 of 126)
                         achieved a complete response (CR, defined as
                         complete regression of neoplastic lesions for at least
                         1 month), whereas 6 of 124 patients in the
                         melatonin group experienced CR (p less than 0.02).
                         Partial responses (PR) were attained by 15% of
                         those in the chemotherapy-only group and 29% in
                         the melatonin group (p less than 0.01). Median and
                         mean times to progression were greater in the
                         melatonin group (means: 8.9 months vs 4.2 months,
                         p less than 0.05). One-year survival was higher in
                         the melatonin group (p less than 0.001). There was
                         no toxicity associated with melatonin. Frequency of
                         chemotherapy-induced toxicities was significantly
                         reduced by melatonin in comparison to
                         chemotherapy alone: myelosuppression (p less than
                         0.001), thrombocytopenia (p less than 0.05),
                         neurotoxicity (p less than 0.05), cardiotoxicity (p
                         less than 0.05), stomatitis (p less than 0.05),
                         asthenia (p less than 0.001) (Lissoni et al, 1999).
                         b. Single-agent therapy with melatonin 20 milligrams
                         (mg) intramuscularly daily for 2 months followed by
                         oral doses (10 mg daily) was associated with a
                         partial response in only one patient (pancreatic
                         carcinoma) of 54 (1.8%) with a variety of solid
                         tumors, primarily non-small cell lung cancer and
                         colorectal carcinoma, in an open study. Stable
                         disease, which was considered evidence of efficacy,
                         was observed in 39% of patients (median duration,
                         4 months). An improvement in performance status
                         was seen in 33% of patients (Lissoni et al, 1991).
                         This study enrolled patients who had failed prior
                         chemotherapy or for whom there was "lack of an
                         effective treatment"; however, the number of
                         patients in each category was not specified and it is
                         unclear whether all patients had been pretreated.
                         The uncontrolled design limits adequate efficacy
                         evaluation.
                         c. Other studies have reported significantly
                         prolonged survival and greater improvement in
                         performance status with oral melatonin plus
                         supportive care compared to supportive care alone
                         in patients with NON-SMALL CELL LUNG
                         CANCER (n=63) (Lissoni et al, 1992a) and brain
                         metastases of solid tumors (n=50) (Lissoni et al,
                         1994a). In the non-small cell lung cancer patients, a
                         dose of 10 milligrams (mg) daily for 21 of 28 days
                         was administered; no complete or partial responses
                         were observed, although stable disease was
                         achieved in significantly more patients treated with
                         melatonin (32% versus 9%). A dose of 20 mg daily
                         until progression was given to patients with brain
                         metastases; the period of
                         free-from-brain-progression was greater and the
                         frequency of steroid-induced metabolic and
                         infective complications were significantly lower with
                         melatonin therapy relative to supportive care alone
                         in this study. In both studies, patients had failed or
                         progressed on prior chemotherapy, although details
                         of previous therapy or criteria for failure were not
                         provided. Methods of randomization and
                         pretreatment clinical status of patients (eg,
                         underlying conditions) in each group, which could
                         affect outcome, were also not specified, and the
                         numbers of patients may have been too small for
                         adequate statistical analysis. All studies were
                         conducted by the same group of investigators.
                         d. Patients with GLIOBLASTOMA who were
                         treated with melatonin 20 milligrams (mg)/day and
                         radiotherapy (RT) (n=16) experienced prolonged
                         overall survival time compared to patients given RT
                         alone (n=14). Both groups were given steroids and
                         anticonvulsants. The melatonin-treated group had a
                         higher rate of survival at 1 year than did the
                         RT-only group (p less than 0.02). Patients with RT
                         alone experienced a significantly higher number of
                         infections compared to melatonin plus RT group (p
                         less than 0.025) (Lissoni et al, 1996).
                         e. In one small randomized trial, oral melatonin 40
                         milligrams daily plus low-dose subcutaneous
                         recombinant interleukin-2 (3 million units/day for 6
                         days/week for 4 weeks) was superior to supportive
                         care alone in metastatic COLORECTAL
                         CARCINOMA patients unresponsive to or
                         progressing on first-line 5-fluorouracil/folate
                         chemotherapy. Partial responses occurred in 12%
                         and 0% of patients receiving immunotherapy and
                         supportive care alone, respectively, and patient
                         survival at one year was significantly higher in the
                         immunotherapy group (Barni et al, 1995). Another
                         randomized study (n=80) employing the same dose
                         regimen reported that oral melatonin plus
                         recombinant interleukin-2 produced higher
                         response rates (26% versus 3%) and more

[Jeff Luper]

CAUTIONS
          ADVERSE REACTIONS
               ADVERSE REACTIONS, CARDIOVASCULAR
                    A. CARDIOVASCULAR EFFECTS
                         1. TACHYCARDIA has been reported rarely after
                         melatonin administration (Claustrat et al, 1992); a
                         cause-effect relationship is doubtful.
               3.3.3 CENTRAL NERVOUS SYSTEM
                    A. CENTRAL NERVOUS SYSTEM EFFECTS
                         1. Four of 6 neurologically impaired children (ages
                         9 months to 18 years) who were given oral
                         melatonin 5 milligrams/night at bedtime for chronic
                         sleep complaints developed new or increased
                         seizure activity. In all cases, seizure activity returned
                         to pre-treatment levels after discontinuing melatonin.
                         Melatonin alleviated sleep disorders in 5 of the 6
                         children (Sheldon et al, 1998).
                         2. A 73-year-old woman with no history of
                         psychotic behavior was hospitalized for an ACUTE
                         PSYCHOTIC EPISODE after taking ten
                         3-milligram tablets of melatonin one morning after a
                         sleepless night. Her other regular medications were
                         thought not to be responsible for the episode. She
                         slept through the night of admission and had normal
                         mental status the next morning (Force et al, 1997).
                         3. ALTERED SLEEP PATTERNS have been
                         reported after the administration of melatonin
                         (Middleton et al, 1996).
                         4. Discontinuation of melatonin after 1 year of
                         nightly treatment (5 milligrams/night) resulted in
                         WITHDRAWAL-EMERGENT DYSKINESIA
                         and AKATHISIA in a 22-year-old woman who
                         suffered from spastic diplegia (from cerebral palsy)
                         and severe mental retardation. Melatonin treatment
                         was terminated because of repeated vomiting. One
                         week later, the woman began to develop
                         involuntary lip- smacking movements and tongue
                         protrusion, with moaning, shouting, and
                         restlessness. Reintroduction of melatonin in
                         gradually increasing doses caused disappearance of
                         the involuntary motions and improvement of
                         agitation and insomnia. A month later, another
                         episode of abdominal pain resulted in termination of
                         melatonin, with the same consequences. When
                         melatonin 5 milligrams per night was reinstituted, all
                         symptoms disappeared the next day. Melatonin was
                         then stopped gradually over a 2-month period
                         without any movement abnormalities. The authors
                         cautioned against the use of melatonin in patients
                         with organic brain damage (Giladi § Shabtai,
                         1999).
                         5. SEDATION or DROWSINESS and FATIGUE
                         can occur with melatonin administration, although
                         the incidence of these effects has varied
                         considerably (0 to 100%), related to the small
                         numbers of patients/subjects treated in individual
                         studies (Dollins et al, 1994; Dollins et al, 1993;
                         Petrie et al, 1993; Tzischinsky § Lavie, 1994;
                         Cavallo, 1993; Claustrat et al, 1992; Lissoni et al,
                         1991; Petrie et al, 1989; Nordlund § Lerner,
                         1977).
                         6. Drowsiness was described by one of 18
                         international flight crew receiving oral melatonin 5
                         mg daily (after arrival) for jet lag in a controlled
                         study (Petrie et al, 1993).
                         7. HEADACHE and CONFUSION may occur
                         occasionally after oral doses of melatonin (Claustrat
                         et al, 1992; Petrie et al, 1993; Dollins et al, 1993;
                         Dahlitz et al, 1991).
                         8. In patients with major depression, melatonin
                         therapy has worsened DYSPHORIA and sleep
                         loss (Carman et al, 1976).
               3.3.4 ENDOCRINE/METABOLIC
                    A. ENDOCRINE EFFECTS
                         1. A 56-year-old man with amyotrophic lateral
                         sclerosis (ALS) of 3 years duration developed
                         painful, asymmetric gynecomastia over 3 months.
                         He had been treated with riluzole 50 milligrams
                         (mg) twice daily for 2 years, vitamin E 400 mg
                         daily, and citalopram 20 mg daily. In addition he
                         had been taking over-the-counter melatonin for a
                         year and a half: 1 mg per day for the first year and
                         then 2 mg per day. Discontinuation of the melatonin
                         without any changes in other drug regimens resulted
                         in complete regression of the gynecomastia within a
                         few weeks. Impurities in the melatonin cannot be
                         ruled out as causal (De Bleecker et al, 1999).
               3.3.7 LIVER
                    A. HEPATITIS
                         1. A woman developed AUTOIMMUNE
                         HEPATITIS after taking melatonin 3 milligrams/day
                         for insomnia for 2 weeks. Because of other reports
                         of the immunomodulatory effects of melatonin and
                         the timing of the melatonin use in relation to the
                         development of hepatitis, the authors speculated
                         that melatonin may have initiated the autoimmune
                         response or precipitated the clinical manifestation of
                         an already existing, asymptomatic disorder (Hong
                         § Riegler, 1997).
               3.3.10 SKIN
                    A. DERMATOLOGIC EFFECTS
                         1. PRURITUS was reported in 1 of 12 elderly
                         subject with insomnia during therapy with
                         sustained-release melatonin in one study (Garfinkel
                         et al, 1995). A causal relationship is uncertain.
               3.3.12 OTHER
                    A. OVERDOSE See POISINDEX(R) Management
                    "MELATONIN"
                    B. ADVERSE EFFECTS - GENERAL
                         1. Statistically significant reductions in body
                         temperature (0.5 to 1.5 degree Fahrenheit) have
                         been reported during oral melatonin administration
                         (Dollins et al, 1993; Deacon et al, 1994), and are
                         considered an integral part of the ability of the
                         hormone to facilitate phase-shifts in circadian
                         rhythm (Deacon et al, 1994). Severe decreases in
                         temperature have not been reported.
                         2. Numerous adverse effects have been reported
                         during combined melatonin/interleukin-2 therapy of
                         cancer, including fever, vomiting, and rash;
                         however, virtually all effects could be attributed to
                         interleukin-2 administration (Lissoni et al, 1992;
                         Lissoni et al, 1995; Lissoni et al, 1994). Melatonin
                         has abrogated falls in blood pressure induced by
                         interleukin-2 (Lissoni et al, 1990).
     4.0 CLINICAL APPLICATIONS
          4.1 MONITORING PARAMETERS
               4.1.1 THERAPEUTIC
                    A. LABORATORY PARAMETERS
                    B. Plasma levels
                         1. Assessment of nocturnal melatonin plasma levels
                         may be useful in the diagnostic workup of certain
                         patients, although variability is large (0 to 250
                         pg/mL; average, 90 pg/mL).
                         2. Therapeutic melatonin plasma levels (increases
                         over normal) have not been established. Plasma
                         level monitoring of treatment is impractical in most
                         instances due to the great intersubject variability in
                         levels achieved.
                    C. Urinary 6-hydroxymelatonin sulfate
                         1. Urine concentrations of this metabolite have been
                         used as an indirect marker of plasma melatonin
                         levels as its excretion is relatively consistent (normal
                         young or elderly subjects, 4 to 5 mcg/hour). Urinary
                         levels have been reduced in elderly subjects with
                         chronic insomnia (Garfinkel et al, 1995).
                    D. PHYSICAL EXAMINATION
                         1. Improvement of sleep in insomnia (eg, reduced
                         sleep latency, longer sleep duration, improved
                         quality of sleep)
                         2. Alleviation of symptoms in jet lag (eg, correction
                         of disturbed sleep, reduced daytime tiredness)
               4.1.2 TOXIC
                    A. PHYSICAL EXAMINATION
                         1. Signs of excessive sedation/fatigue warranting
                         dose reduction
          4.3 PLACE IN THERAPY
               A. Melatonin has shown variable degrees of efficacy in jet lag
               syndrome and sleep disorders, and has been used for its
               immunostimulant actions in patients with solid tumors. There is no
               evidence that melatonin can prevent cancer. It is also being
               investigated as an oral contraceptive. At present, however, data
               are too limited and/or inconsistent to recommend melatonin for
               any specific indication. For one of its widest uses, jet lag
               (promulgated in part by the media), benefits achieved with
               melatonin may simply be a placebo effect; a large,
               rigidly-controlled study is needed to detect significant benefits of
               the hormone.
               B. Clinical and sleep laboratory data suggest that improvements
               seen with melatonin in some conditions may be attributed to an
               hypnotic effect, similar to the benzodiazepines, as opposed to
               phase-shifting activity. Additional studies to delineate the
               mechanism of action of melatonin are needed in order to optimize
               its use; comparisons with benzodiazepines are needed for most
               potential sleep-disorder indications.
          4.4 MECHANISM OF ACTION/PHARMACOLOGY
               A. MECHANISM OF ACTION
                    1. Melatonin (N-acetyl-5-methoxytryptamine) is a
                    neurohormone produced by pinealocytes in the pineal
                    gland during the dark hours (night) of the day-night cycle.
                    Serum levels of melatonin are very low during most of the
                    day, and it has been labeled the "hormone of darkness".
                    Melatonin is involved in the induction of sleep, and may
                    play a role in the internal synchronization of the mammalian
                    circadian system and serve as a marker of the "biologic
                    clock" (Dollins et al, 1994; Tzischinsky § Lavie, 1994;
                    Garfinkel et al, 1995; Cavallo, 1993; Haimov § Lavie,
                    1995; Jan et al, 1994; Short, 1993).
                    2. In general, the pineal gland (projecting from
                    diencephalon into third ventricle) is a neuroendocrine
                    transducer, related to its secretion of melatonin. The
                    hormone serves as a messenger to the neuroendocrine
                    system regarding environmental conditions (especially the
                    photoperiod). Putative functions of endogenous melatonin
                    in this regard include regulation of sleep cycles, hormonal
                    rhythms, and body temperature (Dollins et al, 1993;
                    Deacon et al, 1994; Cavallo, 1993). Melatonin may also
                    have a role in influencing the maturation and function of the
                    hypothalamic-pituitary-gonadal axis and in determining the
                    onset of puberty (Cavallo, 1993).
                    3. Production of melatonin is regulated by postsynaptic
                    receptors originating in the superior cervical ganglion,
                    which innervate the pineal gland. The suprachiasmatic
                    nucleus of the hypothalamus (entrained by the light-dark
                    cycle and considered the anatomic site for the biologic
                    clock) receives stimuli from the retina (retinohypothalamic
                    tract), and during dark hours the suprachiasmatic nuclei
                    forward a stimulus to the superior cervical ganglion and
                    pineal gland, resulting in melatonin secretion (Cavallo,
                    1993; Haimov § Lavie, 1995). This stimulatory activity is
                    suppressed by light, especially bright light (Cavallo, 1993;
                    Thalen et al, 1995; Strassman et al, 1987). Melatonin
                    synthesis in the pinealocyte is dependent upon
                    noradrenergic stimulation (Cavallo, 1993). The normal
                    endogenous production rate is 28 to 30 mcg/day (Short,
                    1993; Lane § Moss, 1985). Production of the hormone is
                    reduced in cirrhotic patients (12 mcg/day) (Lane § Moss,
                    1985) and in the elderly (Garfinkel et al, 1995).
                    4. Continuous abolition of melatonin secretion has been
                    achieved in normal sleep-deprived men exposed to
                    constant nocturnal bright light, this procedure essentially
                    constituting a "functional pinealectomy" (Strassman et al,
                    1987).
               B. ACUTE EXOGENOUS EFFECTS
                    1. Acute oral daytime doses of melatonin (0.1 to 80 mg)
                    have produced sedative effects, fatigue, increased sleep
                    propensity, decrements in performance and self-reported
                    vigor, confusion, and a reduction in body temperature in
                    healthy subjects. A tendency for dose-related behavioral
                    changes was seen with lower doses (0.1 to 10 mg) but
                    was less clear in higher doses ranges (Dollins et al, 1993;
                    Dollins et al, 1994). In another study, daytime and
                    nighttime doses of melatonin 5 mg (12 noon, 5 pm, 7 pm,
                    and 9 pm) were also associated with reduced body
                    temperature, as well as time-dependent increases in
                    sleepiness, sleep propensity, and the spectral power in
                    theta, delta, and spindles bands on the
                    electroencephalogram; latency to maximal effects varied
                    linearly from 3.6 hours at noon to 1 hour at 9 pm
                    (Tzischinsky § Lavie, 1994). Decreases in body
                    temperature are considered an integral part of the ability of
                    the hormone to facilitate phase-shifts in circadian rhythm
                    (Deacon et al, 1994). However, one study using daytime
                    administration showed no reduction in rectal temperature
                    during diurnal sleep after melatonin, in comparison to
                    placebo (Matsumoto, 1999).
                    2. These data clearly indicate a hypnotic effect of
                    melatonin. However, results of these and other studies
                    (Deacon et al, 1994; Dahlitz et al, 1991; MacFarlane et
                    al, 1991; Cavallo, 1993) raise the question as to whether
                    this action represents a direct effect of the hormone, phase
                    shifts in circadian rhythms of sleep, or both. Some
                    investigators suggest that effects of melatonin are similar to
                    those of benzodiazepines (Dollins et al, 1994). Additional
                    studies are needed to distinguish the hypnotic mechanism.
                    3. Hormonal effects observed after acute doses of
                    melatonin include increases in serum prolactin in adults
                    (morning doses) and pubertal and prepubertal children
                    (afternoon doses), and increases in basal growth hormone
                    release and growth hormone responses to GHRH
                    stimulation (possibly via inhibiting endogenous
                    somatostatin release) (Valcavi et al 1993; Cavallo, 1993).
                    In most studies, no significant effect of acute doses has
                    been observed on baseline luteinizing hormone (LH)
                    concentrations (children or adolescents), the LH response
                    to luteinizing hormone-releasing hormone (LHRH)
                    stimulation (adults), or the amplitude and frequency of LH
                    pulses (adults) (Weinberg et al, 1980; Cavallo, 1993).
               C. CHRONIC EXOGENOUS EFFECTS
                    1. Prolonged administration of oral melatonin has
                    reportedly induced phase-setting effects on circadian
                    rhythms, such as the sleep-wake cycle and rest-activity.
                    The hormone has been reported to produce reentrainment
                    of circadian rhythms after time zone shifts, and entrainment
                    of previously free-running rhythms in the blind (Dollins et
                    al, 1993; Arendt et al, 1988; Dahlitz et al, 1991; Cavallo,
                    1993; Arendt et al, 1986).
                    2. A significant decrease in LH secretion in women has
                    been observed during long-term administration of
                    melatonin, and the hormone is being evaluated as a
                    contraceptive (Voordouw et al, 1992; Cavallo, 1993). In
                    men, no significant alteration of growth hormone, LH,
                    testosterone, prolactin, or thyroxine has been observed
                    with chronic dosing (Cavallo, 1993). No significant effect
                    on hypothalamic-pituitary-adrenal function was reported in
                    parkinsonian patients treated with melatonin for one month
                    (Shaw, 1977).
               D. ANTITUMOR ACTIVITY
                    1. In vitro and animal studies have reported that melatonin
                    is capable of inducing 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). Melatonin has
                    been used alone and in combination with interleukin-2 as
                    an immunotherapeutic regimen in the treatment of cancer
                    (Lissoni et al, 1994; Lissoni et al, 1995).
               E. REVIEWS
                    1. The use of melatonin in sleep-wake cycle disorders of
                    children has been reviewed (Jan et al, 1999).
                    2. The pharmacology and functions of melatonin in humans
                    have been reviewed (Brzezinski, 1997).
                    3. Experimental and pre-clinical findings relating to the use
                    of melatonin in malignancy are summarized in a German
                    language article (Bartsch § Bartsch, 1997).
                    4. Nighttime hypnogenic effects of melatonin are reviewed
                    in German (Saletu, 1997).
                    5. A German language review of the effects of melatonin in
                    humans is available (Langer et al, 1997).
          4.5 THERAPEUTIC USES
               A. CANCER
                    1. OVERVIEW:

                             FDA APPROVAL: Adult, no; pediatric, no
                             EFFICACY: Adult, possibly effective
                             DOCUMENTATION: Adult, fair

                    2. SUMMARY:

                              - Complete or partial responses minimal with
                                melatonin in patients with solid tumors

                              - Stable disease achieved in one-third of
                                patients

                              - More effective in combination with other agents

                    3. ADULT:
                         a. Addition of melatonin to chemotherapy regimens
                         treating metastatic solid tumors reduced the toxicity
                         of the chemotherapy and enhanced tumor
                         regression and survival time. Two hundred fifty
                         patients with metastatic solid tumors (non-small cell
                         lung cancer, breast cancer, gastro-intestinal tract
                         tumors, or head and neck cancers) were
                         randomized to receive either chemotherapy alone or
                         chemotherapy with oral melatonin 20 milligrams
                         each evening, beginning 7 days prior to
                         chemotherapy and continuing after chemotherapy
                         interruption, until disease progression. No patient
                         treated with chemotherapy alone (0 of 126)
                         achieved a complete response (CR, defined as
                         complete regression of neoplastic lesions for at least
                         1 month), whereas 6 of 124 patients in the
                         melatonin group experienced CR (p less than 0.02).
                         Partial responses (PR) were attained by 15% of
                         those in the chemotherapy-only group and 29% in
                         the melatonin group (p less than 0.01). Median and
                         mean times to progression were greater in the
                         melatonin group (means: 8.9 months vs 4.2 months,
                         p less than 0.05). One-year survival was higher in
                         the melatonin group (p less than 0.001). There was
                         no toxicity associated with melatonin. Frequency of
                         chemotherapy-induced toxicities was significantly
                         reduced by melatonin in comparison to
                         chemotherapy alone: myelosuppression (p less than
                         0.001), thrombocytopenia (p less than 0.05),
                         neurotoxicity (p less than 0.05), cardiotoxicity (p
                         less than 0.05), stomatitis (p less than 0.05),
                         asthenia (p less than 0.001) (Lissoni et al, 1999).
                         b. Single-agent therapy with melatonin 20 milligrams
                         (mg) intramuscularly daily for 2 months followed by
                         oral doses (10 mg daily) was associated with a
                         partial response in only one patient (pancreatic
                         carcinoma) of 54 (1.8%) with a variety of solid
                         tumors, primarily non-small cell lung cancer and
                         colorectal carcinoma, in an open study. Stable
                         disease, which was considered evidence of efficacy,
                         was observed in 39% of patients (median duration,
                         4 months). An improvement in performance status
                         was seen in 33% of patients (Lissoni et al, 1991).
                         This study enrolled patients who had failed prior
                         chemotherapy or for whom there was "lack of an
                         effective treatment"; however, the number of
                         patients in each category was not specified and it is
                         unclear whether all patients had been pretreated.
                         The uncontrolled design limits adequate efficacy
                         evaluation.
                         c. Other studies have reported significantly
                         prolonged survival and greater improvement in
                         performance status with oral melatonin plus
                         supportive care compared to supportive care alone
                         in patients with NON-SMALL CELL LUNG
                         CANCER (n=63) (Lissoni et al, 1992a) and brain
                         metastases of solid tumors (n=50) (Lissoni et al,
                         1994a). In the non-small cell lung cancer patients, a
                         dose of 10 milligrams (mg) daily for 21 of 28 days
                         was administered; no complete or partial responses
                         were observed, although stable disease was
                         achieved in significantly more patients treated with
                         melatonin (32% versus 9%). A dose of 20 mg daily
                         until progression was given to patients with brain
                         metastases; the period of
                         free-from-brain-progression was greater and the
                         frequency of steroid-induced metabolic and
                         infective complications were significantly lower with
                         melatonin therapy relative to supportive care alone
                         in this study. In both studies, patients had failed or
                         progressed on prior chemotherapy, although details
                         of previous therapy or criteria for failure were not
                         provided. Methods of randomization and
                         pretreatment clinical status of patients (eg,
                         underlying conditions) in each group, which could
                         affect outcome, were also not specified, and the
                         numbers of patients may have been too small for
                         adequate statistical analysis. All studies were
                         conducted by the same group of investigators.
                         d. Patients with GLIOBLASTOMA who were
                         treated with melatonin 20 milligrams (mg)/day and
                         radiotherapy (RT) (n=16) experienced prolonged
                         overall survival time compared to patients given RT
                         alone (n=14). Both groups were given steroids and
                         anticonvulsants. The melatonin-treated group had a
                         higher rate of survival at 1 year than did the
                         RT-only group (p less than 0.02). Patients with RT
                         alone experienced a significantly higher number of
                         infections compared to melatonin plus RT group (p
                         less than 0.025) (Lissoni et al, 1996).
                         e. In one small randomized trial, oral melatonin 40
                         milligrams daily plus low-dose subcutaneous
                         recombinant interleukin-2 (3 million units/day for 6
                         days/week for 4 weeks) was superior to supportive
                         care alone in metastatic COLORECTAL
                         CARCINOMA patients unresponsive to or
                         progressing on first-line 5-fluorouracil/folate
                         chemotherapy. Partial responses occurred in 12%
                         and 0% of patients receiving immunotherapy and
                         supportive care alone, respectively, and patient
                         survival at one year was significantly higher in the
                         immunotherapy group (Barni et al, 1995). Another
                         randomized study (n=80) employing the same dose
                         regimen reported that oral melatonin plus
                         recombinant interleukin-2 produced higher
                         response rates (26% versus 3%) and more