Actions and Uses of Melatonin & Melatonin with Accessory Factors: Part


Melatonin is a pineal hormone that is secreted at night. It sets and maintains the internal clocks governing the natural rhythms of the body. Experimentally, melatonin modifies immunity, the stress response, and some aspects of the aging process. Clinically, melatonin has been used in rhythm disturbances, sleep disorders, and cancer. Given its multifaceted and far-reaching biological effects, the clinical and wellness-enhancing potential of melatonin has barely begun to be realized.

Melatonin Biosynthesis and General Physiology

Melatonin is derived from serotonin, which in turn, is derived from tryptophan. Melatonin -- N-acetyl-5-methoxyserotonin -- is simply a methylated arid acetylated version of serotonin. Serotonin is first acetylated by N-acetyltransferase (probably the rate-limiting step), then methylated by hydroxyindole orthomethyltransferase (HIOMT) to form the hormone.(1) The practical significance of its biochemistry is that melatonin, in contrast to serotonin, is lipid-soluble - enabling it to readily traverse membranes and enter the brain.

Melatonin synthesis depends on intact beta adrenergic receptor function. Specifically, this refers to the action of norepinephrine (the prototypical beta-agonist),(2) that activates N-acetyltransferase. Predictably, beta receptor-blockers depress melatonin secretion.(3)

Melatonin is made in the pineal gland by enzymes that are activated and depressed, respectively, by darkness and light. Release of the hormone follows a circadian rhythm. It rises and falls in a 24-hour pattern which is to some extent controlled by light. The phases of light and darkness act as synchronizers of the pattern, determining the timing of the rise and fall.(4) Thus, during the night (or in darkness) pineal activity and melatonin synthesis and release are increased,(2) and during the day (or upon exposure to bright light) they are depressed and sometimes barely measurable(1); thus melatonin has been described as the "Hormone of darkness."(5)

The degree of rise and fall of melatonin (and other rhythmic hormones and processes) is referred to as amplitude. Low valleys and high peaks make for high amplitude, while a flattened curve is low amplitude. The significance of amplitude will become clear in forthcoming sections. Apart from being influenced by circadian environmental changes (light/darkness), the pineal, through melatonin, conditions the internal environment by setting and maintaining the internal clocks governing the natural rhythms of body function. This apparent clock-setting property of melatonin has led to the suggestion that it be called a "chronobiotic" -- a substance that alters and normalizes biological rhythms. The influence of melatonin on biochemical and physiological processes is so broad that it seems unlikely that it is exerting direct effects. Rather, it appears that melatonin manages and adjusts the timing of other critical processes and biomolecules (hormones, neuro-transmitters, etc.), that in turn exert numerous peripheral actions.(6)

Rhythm, Sleep and Sleep Disturbances

Several lines of evidence suggest a relation between sleep and pineal function and melatonin levels. Nocturnal melatonin levels and the quality of sleep both decline at puberty.(7) In the elderly, melatonin levels decline and sleep tends to be shorter and poorer.

Feeding trials have shown that melatonin corrects the sleep disturbances, mental inefficiency, and daytime fatigue (cumulatively known as "jet lag") that occurs after plane flights over several time zones.(8,9) The biological rhythm disorganization caused by the sudden change of environment (and associated light/dark cues) can apparently be corrected by melatonin. However, melatonin taken before travel can actually worsen symptoms, in contrast to the benefit of melatonin feeding initiated immediately upon arrival.(9)

Supplemental melatonin has been used successfully in delayed sleep phase syndrome (a type of insomnia), characterized by wakefulness past conventional bedtime and inability to fall asleep before 2-3 a.m.. Small doses (5 mg) of melatonin given at 10 p.m. resulted in advance of the sleep phase (shortening of time to sleep) by about 1.5 hours.(10,11) In one of these studies melatonin was shown to reduce sleep duration by about 30 minutes,(10) suggesting a decreased sleep requirement consequent on improved sleep quality.

Delayed sleep phase syndrome is considered an unusual (low-incidence) form of insomnia. However, it is possible that many "night people" -- individuals who favor activity late into the evening, with a correspondingly sluggish start the next morning -- are afflicted with a subtle variety of this phase-delayed condition. These individuals might wish to attempt an experimental lifestyle alteration with well-timed supplementary melatonin.

Melatonin has also been used to alter sleep architecture in narcolepsy -- a disorder of disturbed circadian sleep/wake rhythm. The pathology of narcolepsy involves REM sleep deficit. Changes in REM sleep patterns suggestive of narcolepsy(12) also occur in animals and humans after removal of the pineal gland. Pharmacologic doses of melatonin (50 mg) dramatically increased REM (rapid eye movement) sleep time in both narcoleptics and normals, and was associated with much intensified subjective dream phenomena.(12)

Several studies have demonstrated sedative and sleep-inducing effects of supplementary melatonin.(2) High-dose (80 mg) melatonin given to healthy subjects "exerts a-hypnotic effect by accelerating sleep initiation, improving sleep maintenance and altering sleep architecture in a similar manner to anxiolytic sedatives;......[the results] indicate good tolerance of one dose of melatonin without hangover problems on the following morning.(13)" Ultra high-dose melatonin (240 mg/day) caused sedation and slowed reaction time without significantly impairing memory.(14) This is in contrast to the effects of benzodiazepines. Melatonin is also reported to have anti-anxiety effects and in vitro benzodiazepine-like actions.(14) Low-dose (1.7 mg) melatonin given as a nasal spray at 9-10 a.m. induced sleep within 1-2 hours in 70% of recipients(15) All subjects reported feelings of well-being and emotional balance after the sleep period. The effectiveness of the very low dose intranasal delivery system used in this study, might be due to avoidance of the (otherwise rapid) hepatic metabolism of oral melatonin.

Low-dose (2 mg) oral melatonin given at 5 p.m. can increase subjective sensations o£ fatigue. This is followed the next morning by decreased fatigue,(16) suggesting phase advance of a subjective energy rhythm and possibly improved sleep quality. Low-dose (<5 mg) oral melatonin probably cannot be relied upon for acute hypnotic effects, but if used persistently may be useful for entrainment of sleep, activity and other rhythms.(7)

Sleep-disordered breathing and snoring, characteristics of the sleep apnea syndrome, have recently been found to affect 9% of women and 24% of men in the general population,(17) Sleep-disordered breathing and sleep apnea are associated with daytime hypersomnolence and cardiovascular disease. It is possible that melatonin supplementation, improving the quality of nighttime sleep, could play a role in the management of this very common and sometimes disabling condition.

Endocrine Function and Immunity

There is a close reciprocal relation between the pineal and the pituitary/adrenal axis. Melatonin modulates the activity of this axis as well as the peripheral actions of corticoids. Pinealectomy causes adrenal hypertrophy which is reversed by melatonin administration, and melatonin itself induces adrenal hypotrophy.(18) There is controversy as to whether this represents a direct effect on the adrenals, an inhibition of the release of corticotropin releasing hormone (CRF), or other actions.(2) Effects on hypothalamo/pituitary mechanisms are most likely, since inhibition of adrenal function by melatonin does not occur in hypophysectomized animals.(2) It has been proposed that melatonin acts as a CRF-inhibiting factor and that low melatonin levels, as occur in major depression,(19) are due to a lack of the modulating influence on the pituitary/adrenal axis by the pineal.(20) Melatonin levels are low in patients with Cushing's disease, a pathological variety of hyperadrenocorticism,(19) Presumably, this is because melatonin releases vasotocin, which lowers corticoid levels.(21)

Melatonin antagonizes the immunologic depression(22) catabolic acceleration, thymic involution, and adrenal-suppressive effects(33) of exogenous corticoids. This leads to the suggestion that the hormone "might be working as an anti-adrenocortical or anti-stress factor in human physiology."(23) The relation is reciprocal, since nighttime stress or corticoid administration depresses pineal melatonin levels and the rate-limiting enzyme (N-acetyltransferase) of melatonin synthesis.(24) Modification of the stress response by melatonin is abolished by adrenalectomy, confirming its mediating role on corticoids. This melatonin/corticoid relation has great significance since chronic hypercortisolemia has been associated with age-related deterioration of the brain, glucose intolerance, atherogenesis, impaired immune function and cancer.(25) In sum, melatonin appears to mediate the entire aging process.

Furthermore, it is not only high absolute levels of corticoids that are pathogenic, but disorganization of the normal rhythm of corticoid release. This is normally high in the early morning, through the daytime and low at night. Disorganized circadian cortisol rhythm (i.e. loss of amplitude of the day/night, low/high pattern) and other phenomena indicative of dysfunctional pituitary/adrenal function are characteristic of aging and have been described in subjects with senile dementia.(25) Properly-timed exogenous melatonin may entrain (reorganize) this critical endocrine rhythm, resulting in profound long-term systemic benefit. Indeed, the immune-enhancing and anti-corticoid effects of melatonin -- or putative mediators of melatonin action -- appear to depend on nocturnal administration.(22,27) It has been suggested that this represents an integral immune recovery mechanism: "the normal circadian release of melatonin may be seen as a kind of buffer device, quenching the adverse effects of stressful events on immune homeostasis."(22)

Beta-blocker drugs, which depress melatonin secretion, have immunosuppressive effects, only when given in the evening.(28) This is when blood melatonin (and the immuno-enhancing effect of melatonin) is highest. Exogenous melatonin reverses beta blocker-induced immunosuppression and enhances immune parameters (e.g. T helper/suppressor ratio) in non-immunosuppressed animals.(28)

There is very little literature on the use of melatonin in immunocompromised states apart from cancer. A preliminary report on melatonin (20 mg/day, in the evening) in AIDS patients revealed uneven but generally beneficial effects on immune parameters.(28) It was noted that not only is melatonin best given during the night time period, but periodically within a month: Treatment periods of 3-4 weeks are recommended, followed by a week-long "vashout" period.

Predictably, melatonin-induced corticoid antagonism and immune enhancement may not always be desirable. Melatonin exacerbated the pathology in one arthritic animal model.(28) Melatonin should be used cautiously, if at all, in autoimmune conditions.


It has been suggested that the steady increase in the incidence of cancer in developed countries over the last 100 years, is due to artificially extended photoperiods made routine by electric lights -- "light pollution."(29) A long photoperiod results in depressed melatonin during times (night) when historically, it would have been high. Whether or not "light pollution" is a factor in cancer epidemiology, there is an intriguing relation between the pineal gland, melatonin and the development, and potentially, the control of malignancy.

Melatonin inhibits the incidence of chemically-induced (DMBA) tumors, which are increased by pineal suppression (long light phase) or pinealectomy.(30) Pinealectomy stimulates and conversely, melatonin inhibits, the growth and sometimes the metastasis of lung, liver, ovary, pituitary, prostate, melanoma and leukemia tumors in experimental models.(31)

Melatonin may have special roles in breast and prostate cancer. The circadian amplitude of melatonin was reduced by over half in patients with breast cancer versus patients with nonmalignant breast disease.(32) High urinary melatonin has been found in breast cancer patients in the morning,(33) suggesting circadian disorganization. Circadian amplitude of melatonin was reduced by two-thirds in patients with prostate cancer versus patients with benign prostate disease, and similar phenomena were observed in colorectal cancer patients.(32) A possibility that the lower nocturnal melatonin levels were due to enhanced hepatic metabolism (rather than reduced secretion) was ruled out by urinary metabolite analysis.

Melatonin downregulates estrogen receptors, inhibits estrogen-stimulated breast cancer growth, and complements the oncostatic action of anti-estrogen drugs (tamoxifen).(34) The suggestion is that "melatonin may be the pineal gland's, and thus the body's own `natural antiestrogen."(34)' This may have implications for non-malignant conditions associated with estrogen excess such as uterine fibroids, endometriosis, and premenstrual syndrome.

Melatonin, 10-50 mg/day - given at 8 p.m., potentiates interleukin-2 immunotherapy in pulmonary metastases.(28) As with melatonin therapy in AIDS, treatment periods of 3-4 weeks with a 1-week washout were encouraged. Intramuscular melatonin, 20 mg/day given at 3 p.m. for two months, then reduced to 10 mg/day for two months, was given to 54 patients with metastatic solid tumors, mostly lung and colorectal. The results were stabilized disease and improved quality of life for about 40% of the recipients.(35)

Melatonin injections given in the morning stimulate tumor growth. In mid-afternoon, they have no effect, and in the evening have a retarding effect.(33,34) This is consistent with the findings that the melatonin rhythm found in (tumor-free) youth and in health is the one most conducive to those conditions.

Brain Function, Neuropsychiatry and Behavior

Melatonin stabilizes the electrical activity of the central nervous system and causes rapid synchronization of the electroencephalogram. Removal of the pineal predisposes animals to seizures. It has been proposed that the pineal, acting mostly, but not exclusively through melatonin, is a "tranquilizing organ on behalf of homeostatic equilibrium," and that it "acts as a general synchronizing, stabilizing and moderating organ."(2) Melatonin may thus have many neuropsychiatric applications.

The relation of melatonin to depression has attracted great interest in psychiatry. Nocturnal melatonin levels are low in subjects with major depressive disorder and panic disorder.(36,37) This is particularly true for those with abnormal pituitary-adrenal responses to exogenous corticoids (abnormal dexamethasone suppression),(20) who also have disturbed corticoid secretion patterns. Normal individuals with a dysthymic disposition (mild or episodic depression) also had lower than normal nocturnal melatonin levels(20) -- as did subjects with melancholic depression.(38) In contrast, higher than normal melatonin levels have been observed in manic subjects during the manic phase.(38)

The linkage of melatonin levels and pineal function with mood disorders is strengthened by epidemiologic and chronobiologic evidence. Both Seasonal Affective Disorder (SAD) and "nonseasonal" depressions have a marked seasonal incidence with peaks in the fall and spring, respectively.(39,40) This coincides with the troughs of the circannual melatonin rhythm.(41) One critical enzyme in melatonin synthesis (hydroxyindole orthomethyltransferase, HIOMT) rises and falls in an annual rhythm. Troughs occur in March and October and peaks occur in January and July.(42)

The authors of seminal studies on melatonin in depression have proposed the existence of a "low melatonin syndrome." This is characterized by low nocturnal melatonin, disturbed corticoid rhythms, pituitary/adrenal axis disinhibition (abnormal dexamethasone suppression), and little daily and annual cyclic variation in symptoms of depression.(20) Interestingly, depressed individuals who had lost a parent before the age of 17 (an apparent conditioning factor for depression) had lower nocturnal melatonin levels than those who had not had a loss.(20) This suggests correctly-timed melatonin supplementation as an experimental treatment for depressed people who had lost parents or suffered other adolescent trauma.

The requirement of intact beta receptor function for melatonin synthesis and the stimulatory effect of norepinephrine on melatonin synthesis and release,(2) joins up a theoretic relation of melatonin to depression. A substantial body of evidence suggests that suboptimal activity of norepinephrine is involved in at least some depressions(43,44) and it was even proposed that depression is a "norepinephrine-deficiency disease." Many of the tricyclic antidepressants and all the monoamine oxidase inhibitors enhance effective norepinephrine activity. (45) Tricyclics also dramatically increase melatonin synthesis in humans.(46) Thus it is possible that the relation of norepinephrine action to affective disorders is mediated in part by effects on melatonin synthesis. Tricyclic drugs often have sedative effects (melatonin enhancement?) and for this reason are often administered at night -- an appropriate time for enhancement of melatonin rhythm amplitude.

Beta receptor-blockers depress melatonin secretion(3) and can cause neuropsychiatric problems such as nightmares, insomnia, lassitude, dizziness and depression.(47) Treatment with beta-blockers often results in nightmares and disturbing nocturnal hallucinations.(48) The linkage of beta receptor blockade to psychiatric disorders via melatonin is illustrated by the observation that beta blocker recipients with nightmares and other sleep disorders had markedly lower melatonin levels than drug-treated individuals without such symptoms.(48) Apparently, too, there is considerable interindividual variation in the sensitivity of the pineal to beta blockers.

One study that purported to test the melatonin hypothesis of Seasonal Affective Disorder (i.e. that light therapy used in treatment acts by suppressing melatonin) used the beta-blocker atenolol, which did suppress melatonin production but did not attenuate the depression.(3) This is not surprising, in light of the neuropsychiatric side effects of beta-blockers. Three of the 19 in the treatment group did, however, improve markedly. Atenolol, being a long-acting beta-blocker,(3) depressed melatonin secretion continuously, thus having no effect (or a negative effect) on circadian melatonin amplitude. Also, the atenolol was given at 4 p.m., one of the worst possible times from the standpoint of melatonin rhythm normalization (i.e. atenolol would tend to be most active during the normally high-melatonin period). Properly-timed light therapy with or without melatonin supplementation, so as to enhance amplitude, may be a more rational approach. Beta-blockers with short-term effects, given early in the morning, might also be useful.

Brain serotonin levels are increased by melatonin administration(49) -- a potentially significant finding since serotonin has been linked to an array of neuropsychiatric phenomena. Diminished central serotonin, as indicated by low levels of the serotonin marker 5-HIAA in cerebrospinal fluid, are associated with impulsiveness, aggression and autoaggression.(50-52) Serotonin inadequacy may predispose to many "disorders of constraint" including impulsive violence, alcoholism, compulsive gambling, overeating and other obsessive-compulsive behaviors.(53,54) Support of the serotonin system with serotonergic nutrients or drugs can elevate mood, reduce aggression, increase the pain threshold, (55) reduce anxiety, (54) relieve insomnia, (56) improve impulse control, and ameliorate obsessive-compulsive syndromes.(54) Melatonin might thus influence sleep, mood, eating, addictive and related disorders by virtue of its effects on brain serotonin.

In spite of a rich theoretical basis, there have been no systematic studies on the potential of melatonin supplementation in the treatment of depression. Inference can be drawn from the finding that the drug psoralen, which exaggerates nocturnal melatonin release, has anti-depressant effects.(57) The potential of melatonin in depression will probably be realized, if at all, as part of a multifaceted therapy involving properly-timed bright light exposure and other techniques.

The interrelated subjects of circadian endocrine rhythms, mood, sleep and the biological effects of light are very complex and not easily reduced to simple conclusions,(40,58) much less prescriptions. Nevertheless, a few general statements can be made, representing probabilities but not certainties in the named populations.

Seasonal Affective Disorder (SAD; "atypical depression") is characterized by late sleep, morning hypersomnia, increased appetite and retarded onset of nocturnal melatonin release; these subjects are probably phase-delayed ("night people").(58,69) SAD typically begins in the fall and persists through the winter(40) -- the period of light phase shortening. SAD sufferers may benefit from induced phase advance (and light phase lengthening) effected by bright light exposure in the morning (especially pre-dawn), early rising (to the point of partial morning sleep deprivation, e.g. rising at 3-4 a.m.), and melatonin administration before bed, which should be early in the evening. If naps are needed it is important that they not be taken before mid-afternoon.(60) Classic endogenous or "non-seasonal" depression is characterized by insomnia (especially early morning awakening), appetite depression and weight loss, and advanced onset of nocturnal melatonin release; these subjects are probably phase-advanced ("morning people", though not very effective ones).(59) Classic depression typically begins in the spring and persists through the summer(40) -- the period of light phase lengthening. This group may benefit from induced phase delay (and light phase shortening) effected by bright light exposure in the evening,(58) later rising with avoidance of bright light in the morning, and melatonin (especially delayed-release melatonin) in the late evening or immediately before bed.

A warning is in order. Melatonin administration that prolongs the nocturnal melatonin rise may exacerbate SAD(61) and bipolar and classic depression.(62) In the latter study, very large doses (>1 gram/day) were given, divided through the day, thus effectively abolishing the normal daily melatonin rhythm. (This represents exceedingly poor design for a study of melatonin in depression.) Melatonin should be used only with caution in depression, and always in conjunction with appropriately-timed light therapy and sleep phase change.

Melatonin secretion declines with age, and melatonin may help prevent age-related and free radical-mediated brain damage.

Part 2

Actions and Uses of Melatonin & Melatonin with Accessory Factors: Part 2

Longevity and Age-Related Parameters

Melatonin levels decline with age in humans,( 63) and the nocturnal melatonin peak is almost completely abolished.( 64) This near-total loss of melatonin rhythmicity, because of the close reciprocal relation of melatonin and corticoids, probably results in the pituitary/adrenal axis disinhibition that has been described as a characteristic of aging.( 25) The adrenals of elderly humans are apparently hypersensitive to ACTH, and midnight corticoid levels (low in youth) are markedly elevated.( 65) The effects of melatonin on both corticoid release and peripheral effects, the pathogenic conditioning influence of corticoid excess, and the phasic inhibitory influence of melatonin on the pituitary/adrenal axis were each discussed previously. Melatonin modification of corticoid-related phenomena could explain much of the hormone's apparent anti-aging and other beneficial actions.

Blindness increases the life span of rats,( 66) probably owing to the pineal (melatonin) stimulation of the effective constant darkness.

Melatonin may induce slow-wave sleep( 67) - a deeply restful type of sleep during which restoration of damaged tissue takes place, and which declines with age. It has also been suggested that melatonin stimulates DNA repair mechanisms.( 67) Neurochemical and neuropsychological features of dementia resemble some effects of melatonin deficiency, and nightly supplementary melatonin has been suggested for prevention of senile dementia.( 68)

The relation of age-related phenomena to melatonin loss, and the case for melatonin as a potential anti-aging hormone, has been presented at length.( 6)( 25)( 67) A representative of this hypothesis suggests that "the Melatonin Deficiency Syndrome" is perhaps the basic mechanism through which aging changes can be explained in terms of a single causative lesion, a lesion that would cause the progressive patterns of change seen in the older population".( 67)

Exogenous melatonin may have potential for long-term preventive and age-retarding application. In young, healthy individuals, reaction to the classic environmental cue (light/dark cycle) is robust and sufficient to produce a high-amplitude circadian pattern of melatonin levels. This in turn modulates many cyclic functions, especially the activity of the pituitary/adrenal axis -- allowing the organism to recover from the day's (high-corticoid) stresses. With age, endogenous melatonin declines, especially the nighttime peaks. Exogenous melatonin given in the late evening or before bed might act as chronobiotic replacement therapy, depressing cortisol release and action at precisely the time that they should be lowest, and otherwise simulating the high-amplitude rhythm characteristic of youth -- with all that implies.

This suggestion is illustrated by observations in tumor-bearing animals given melatonin as an experimental oncostatic: "To our surprise chronic, circadian, night administration of melatonin resulted in a progressive, striking improvement of the general state of the mice and, most important, in a remarkable prolongation of life...astonishing differences in the fur and in the general condition of the [melatonin vs. control] groups (vigor, activity, posture) became increasingly evident."( 21)

Melatonin and Pyridoxine as Mutual Complements

Brain serotonin concentrations are increased by melatonin administration, and this has been attributed to the hormone's ability to stimulate markedly the activity of brain pyridoxal kinase.( 49) The product of pyridoxal kinase - the active pyridoxine metabolite pyridoxal-5-phosphate (P5P) - is a cofactor for many enzymes including the decarboxylases that are involved in the biosynthesis of serotonin and GABA.

Pineal melatonin and its precursor serotonin are reduced in pyridoxine-deficient animals.( 69) Pyridoxine deficiency also induces a marked (55%) reduction in serum melatonin at night along with a slight increase in the day, with the result that the night:day ratio decreased from 6:1 to about 2:1. Pineal melatonin levels were affected similarly, the night:day ratio decreasing from 46:1 to 19:1.( 69) Thus, pyridoxine deficiency reduces not only absolute nighttime levels of melatonin but dramatically reduces the amplitude of the circadian melatonin rhythm.

The relationship of pyridoxine and melatonin is strengthened by the clear effects of supplementary pyridoxine on relevant amine acid metabolism. The liver catabolizes the serotonin/melatonin precursor tryptophan via the enzyme tryptophan pyrrolase (TP; also known as tryptophan oxygenase). TP converts tryptophan into derivatives that are inactive as serotonin/melatonin precursors. Experimentally, rather large doses of pyridoxine (10 mg/kg, equivalent to about 6-800 mg in humans) reduce urinary excretion of TP products (suggesting enzyme inhibition) while increasing brain tryptophan, brain uptake of supplemental tryptophan, and brain serotonin synthesis.( 70) Much smaller doses of pyridoxine (.5 mg/kg, about 30-40 mg) attenuate the rise in urinary TP products in humans given moderately-large tryptophan loads,( 71) indicating modification of TP activity at near-physiologic levels of pyridoxine intake.

All of this suggests a mutual complementarity of melatonin and pyridoxine in neuropsychiatric applications, where the supplementary vitamin is intended to induce neurotransmitter synthesis or other CNS effects. It also suggests that some of the reported neuropsychiatric benefits of supplementation with tryptophan( 55) and perhaps pyridoxine( 72) are due to melatonin enhancement. This idea has in fact been discussed at some length.( 21, 73)

It is germane to add detail here on pyridoxine forms for supplementary use. The active pyridoxine metabolite pyridoxal-5-phosphate (P5P) is in vogue in high-tech nutritional supplements, which appears at first to be a good idea. P5P would bypass pyridoxal kinase by supplying the preformed enzymic cofactor. Unfortunately, most P5P given orally is split by intestinal phosphatases into its constituents pyridoxal and phosphate.( 74)( 75) Further, only non-phosphorylated B6 vitamers - not P5P itself - are taken up by the brain,( 76) and are generally more able to cross membranes than is P5P.( 75) Even if P5P were absorbed intact, it would have to be reduced to non-phosphorylated forms before it would become available to the CNS and to most other tissues of the body. P5P is also very expensive. Coadministration of a simple, cheap form of pyridoxine (e.g. HCl) along with melatonin would be more cost-effective as well as useful for a broader range of effects. Lastly, additional coadminist ration of riboflavin may be advisable since P5P synthesis depends on this vitamin.( 77)

Pharmacokinetics and Safety; Mode and Time of Administration

The toxicity of melatonin is extremely low. In animals an LD50 could not be established; even 800 mg/kg - a fantastically high dose - was not lethal.( 13) Huge doses (up to 6.6 grams/day for 35 days) have been given to humans without incident except for abdominal cramps.( 78) One subject was given 200 mg intravenously daily for five days with no immediate or delayed toxicity even as much as 18 years later. Many investigators have used doses of 100 mg to 1.2 grams daily for days or weeks with few or no side effects.( 78)

Orally-administered melatonin is absorbed readily and causes rapid serum melatonin increments with a high plateau for an hour or two thereafter.( 79) Nasal delivery of melatonin may be more effective than the oral route, judging from the results of one trial in which small doses (1.7 mg) were used in this manner.( 15) The authors speculate that "the short way between the nasal cavities and the brain" might explain the high efficacy of such low doses. Avoidance of the high first-pass hepatic metabolism (below) of oral melatonin must also be a factor.

The importance of periodic (nighttime) administration of melatenin has been emphasized throughout this paper. To review the effects of circadian, nighttime melatonin administration, it reconstitutes immunity in animals( 22); restores normal circadian patterns of pituitary and adrenal hormones, improves sleep quality and mood, retards tumor growth,( 33)( 34) in the absence of a pineal.( 80)

In contrast, daytime melatonin administration may: disorder circadian rhythms, stimulate tumor growth, and exacerbate depression, induce fatigue, drowsiness, and slowed reaction time - with implications for drivers and others for whom mental acuity and physical coordination is important for safety.

Even low-dose oral melatonin, given at the appropriate times, can produce marked changes of the internal clocks. For example, oral melatonin (2 mg), given to volunteers at 6 p.m., phase advances the circadian rhythm of (endogenous) melatonin, testosterone, and probably corticoids.( 81) A minute dose (20 mcg) given by infusion over a 3-hour period starting at 4 p.m. or 8 p.m. likewise markedly phase-advanced the melatenin circadian rhythm.( 82)

Further, since melatonin naturally peaks for several hours during the night, and since orally-administered melatonin is subject to rapid hepatic metabolism( 83) (i.e. has short-lived effects on blood levels), a sustained-release preparation - capable of elevating blood levels for several hours - would be ideal.

Melatonin/Nutrient Supplements: Tools for Rhythm, Synchronization, Lucid Dreaming and Self-Discovery?

A combination of melatonin with vitamins and accessory factors may constitute a useful experimental tool for circadian rhythm synchronization, lucid dreaming, oneiric analysis, visualization and meditation. (Lucid dreaming is characterized by consciousness of the dream state and conscious control of the course or content of the dream.)( 84) The stabilizing and synchronizing effect of melatonin on brain electrical activity was mentioned above. During periods of deep relaxation, such as Transcendental Meditation, blood levels of pineal indoles are increased.( 2) Current research on the pineal and on melatonin has provided some preliminary support for the romantic conception of the pineal as "the morphological substrate of the seventh `Chakra', being the gateway to perfect rest and harmony".( 2)

The traditional yogic practice of "amaroli" consists of rising very early in the morning (4 a.m.) and drinking one's own mid-stream urine. Urinary melatonin levels are high at this time. It has been suggested that amaroli provides a melatonin supplement that enhances the user's subsequent meditation and visualization practice, which is traditionally performed early in the morning ( 4-6a.m.).( 85) The urine of prepubescents is considered superior for this purpose, which is interesting, since melatonin levels decline precipitously during puberty. At any rate, synthetic melatonin certainly represents a more acceptable experimental tool for such purposes. Current or prospective practitioners of amaroli may be pleased to learn of this.

Pharmacologic doses of melatonin (50 mg) dramatically increased REM (rapid eye movement) sleep time and dream activity in both narcoleptics and normals. "The narcoleptics reported intense colored dreams, completely devoid of their usual nightmare-like elements...[normal subjects reported] dreams with intense colored visual imagery".( 12) Volunteers receiving high-dose melatonin (about 80-100 mgs) experienced increased alpha brain wave activity and a feeling of well-being and elation which persisted for several hours.( 2)( 86) Melatonin also increased REM sleep time and resulted in "abundant and vivid" dream episodes. Most recallable dreams occur during REM sleep, and REM sleep deprivation is characterized by anxiety, overeating, behavioral disturbances, and decreased concentration and learning.( 87) REM sleep seems to enhance memory and the resolve of emotional events, and it is decreased in the mentally retarded.( 88) Most REM sleep occurs in the two hours before awakening - the per iod of most vivid dreams.

Many psychotropic drugs such as LSD and cocaine increase melatonin synthesis.( 62) It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs (e.g. LSD) emulate melatonin activity in the awakened state,( 21) and that both act on the same areas of the brain.( 89) While melatonin is clearly not a wake-state hallucinogen as is LSD, it may have mild homologous effects during sleep by virtue of lengthening REM periods and perhaps intensifying them.

The enhancement of CNS pyridoxine metabolism by melatonin was discussed above. Supplementary pyridoxine (without melatonin) often enhances dream recall,( 90) and sustained-release pyridoxine preparations taken before bed may be especially effective (author's personal observation). Again, coadministration of riboflavin is advisable since pyridoxine metabolism depends on this vitamin.( 77)

Dimethylaminoethanol (DMAE), a metabolic intermediate and precursor of choline, has been used to induce lucid dreaming.( 91) This observation has some biological basis since DMAE is a cholinergic compound (fosters formation of acetylcholine), and since cholinergic drugs increase REM sleep time.( 92)

Vitamin B12 is reported anecdotally to intensify dream coloration, though high doses (1 mg) must be used and tolerance develops quickly.( 93) High-dose vitamin B12 ( 3-4mg/day) has been used successfully in the treatment of rhythm disorders characterized by non-24-hour cycles of sleep and waking (e.g. 25-hour "days").( 94) Such disorder may represent a variety or a relative of the delayed sleep phase syndrome discussed previously. High-dose vitamin B12 (3 mg/day) phase-advanced by over an hour the 24-hour melatonin rhythm in human volunteers, and markedly increased their sensitivity to bright light-induced melatonin suppression,( 95) suggesting a role for the vitamin as an adjunct to bright light therapy of depression. The vitamin did not, however, affect sleep/wake cycle rhythms. The combination of melatonin and vitamin B12, along with morning bright light, would likely accentuate melatonin amplitude, and phase-advance both melatonin and sleep/wake cycle rhythms, with implications for Seasonal Affective Disorder.

Pyroglutamic acid is an amino acid derivative that occurs naturally throughout the body and is present in many common foods.( 96)( 97) It is known to accumulate in the brain when administered orally, and serves as a precursor of glutamic acid, an amino acid with cognition-enhancing properties. Pyroglutamate is in fact very similar in structure to the piracetam family of cerebroactive, cognition-enhancing compounds ("nootropics"). Both pyroglutamate and glutamic acid serve as precursors of GABA, a sedative and antidepressant neurotransmitter that may have a role in circadian timekeeping.( 98) Pyroglutamate enhances the release of acetylcholine, antagonizes drug- and shock-induced amnesia, and partially corrects memory deficits in aged humans.( 99) Glutamic acid has been suggested as a treatment for senile dementia (though pyroglutamate would be a better candidate). Pyroglutamate is also a precursor of glutamine, an amino acid with mild sedative and antidepressant properties, and whic h may also enhance dream recall.( 100)

The optimal formula for rhythm synchronization, lucid dreaming, and meditative activity might therefore include melatonin, pyridoxine, riboflavin, DMAE, vitamin B12, pyroglutamic acid, and perhaps glutamic acid or glutamine, to be taken in the evening or before bed. Sustained- or delayed-release technology will more closely mimic the natural nightly crest of melatonin, and may help deliver pyridoxine and other factors to the brain during the pre-dawn concentrated REM/dream period. Such a formula is currently in production.

Melatonin/Nutrient Supplements: Tools for Stress Recovery, Immune Enhancement and Longevity?

A combination of melatonin with vitamins and accessory factors may have a significant impact on stress recovery, immune function, and age related changes throughout the body. Some of the points to follow have already been covered, but will be reviewed here briefly with detail as to the potential role of co-administered nutrients on the processes in question.

Modulation of the pituitary/adrenal axis and modification of peripheral corticoid effects by melatonin has been discussed (see Endocrine Function and Immunity Section). The significance of this is great since chronic hypercortisolemia has been linked with glucose intolerance, atherogenesis, and impaired immune function and cancer( 25) - all of which are more or less aspects of the aging process.

Co-administered nutrients may also play a role in modifying corticoid release and/or action on target tissues. There is a large mass of evidence indicating blockade of peripheral corticoid effects by pyridoxine derivatives.( 101) These effects are mediated by the active pyridoxine metabolite pyridoxal-5phosphate (P5P). P5P alters the binding of corticoids to nuclear receptors, thus interfering with hormone action. Deficiency of the vitamin, in contrast, enhances corticoid responsiveness.( 102) In light of the positive mutual interaction of pyridoxine and melatonin, it would seem that pyridoxine/melatonin coadministration may optimize the effects of both on corticoid-related (stress) phenomena. Again, the marked synergy of riboflavin with pyridoxine calls for additional riboflavin as well. Vitamin A inhibits some peripheral effects of corticoids such as depression of collagen synthesis( 103) and cell-mediated immunity.( 104) Supplementary vitamin A ameliorates the impaired wound-heal ing, adrenal enlargement and (probably consequent) thymic and lymphoid suppression in experimental diabetes.( 105)

Zinc may modulate corticoid metabolism or action. Zinc-deficient animals have elevated levels of corticoids and associated defects of cellmediated immunity.( 106)( 107) and most of the behavioral effects of zinc deficiency in animals parallel the effects of corticoid and catecholamine excess.( 107) Corticoids themselves induce zinc wasting,( 108) which suggests a vicious cycle of zinc depletion-induced stress and stress-induced zinc depletion. Supplementary zinc with pyridoxine reduces the excretion of catecholamine metabolites( 109) -- suggesting a general sedative and anti-stress effect. Zinc promotes vitamin A nutrition by enhancing the formation of vitamin A-binding proteins needed to maintain normal blood levels of vitamin A. Zinc also acts as a membrane stabilizer( 110) and renders them more resistant to toxic and oxidative insults.( 111) Zinc also contributes indirect antioxidant activity.( 112) Because of its role in tissue healing, protein synthesis, and oxidative stress prote ction, it has been suggested that cellular zinc deficiency may be an important factor in aging.( 113)

The action of the B-complex vitamin niacinamide on cellular integrity in the face of oxidative injury may complement that of melatonin. The effect of melatonin in preventing oxidation-induced structural damage to DNA has already been mentioned. Oxidative damage causes depletion of cellular NAD (nicotinamide adenine dinucleotide) which is used in the process of DNA repair.( 114) Since NAD is also required for radical scavenging, NAD depletion has adverse effects on both processes. White blood cells are particularly sensitive to this depletion. Supplementary niacinamide, however, slows or stops NAD depletion.

Other actions of niacinamide tend to complement those of melatonin. Large doses of the vitamin have been used to reverse some parameters of age-related dysfunction. Multi-gram doses ( 1-4grams/day) produced marked enhancement of joint mobility, muscular strength and exercise tolerance, and mood in a large human population.( 115) These changes may well have been due to the indirect antioxidant effect of niacinamide, and elevation by the vitamin of cellular NAD levels required for DNA repair. Large doses of niacinamide also have sedative, hypnotic, anticonvulsant, anti-aggressive and muscle relaxant activities in both animals and humans.( 116)( 117) These actions complement the mild sedative and hypnotic effects of melatonin disussed above. The optimal formula for stress recovery, corticoid antagonism, immune enhancement, DNA repair, antioxidant activity and general anti-aging effects might therefore include melatonin, pyridoxine, riboflavin, zinc, vitamin A, and high-dose niacinamid e, to be taken in the evening or before bed. Such a formula is currently in production.

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Alan E. Lewis

Director of Research KAL, Inc.

6415 De Soto Ave, P.O. Box 4023

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Article copyright Townsend Letter for Doctors & Patients.


By Alan E. Lewis

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