Estimated Therapeutic and Loael Doses of Melatonin

Melatonin is characterized in this book as an immune stimulant (see Table 1.2), but in addition to immune effects it may also have direct cytotoxic effects against

TABLE 22.11 ESTIMATED THERAPEUTIC AND LOAEL DOSES FOR MELATONIN*

DESCRIPTION

DOSE (mg/day)

Required dose as scaled from animal antitumor studies

commonly 10 to 50

Doses used in human anticancer studies

10 to 50 (commonly 10 to 20)

Required cytotoxic dose as determined from pharmacokinetic calculations

0 to 10

Target dose based on human studies and pharmacokinetic calculations

0 to 20

Minimum required antitumor dose assuming 15-fold synergistic benefits

0.67 to 1.3

Commonly prescribed human dose in noncancerous conditions

3

Estimated LOAEL dose

10 to 50

Tentative dose recommendation for further research

3 to 20

Minimum degree of synergism required

none

See Appendix J for details.

cancer cells. Therefore, it is interesting to compare doses scaled from animal and human experiments to those calculated from pharmacokinetic and in-vitro data. These doses are in agreement. The required mela-tonin dose from the animal experiments is 10 to 50 milligrams per day, the same as the range used in human studies; most of these used 10 to 20 milligrams. The anticancer dose based on pharmacokinetic calculations is similar. As discussed, a 10-milligram dose will produce an average nighttime melatonin concentration of about 14 nM, which is reasonably close to the 1-nM optimal concentration. Under normal circumstances, this 1-nM concentration can be reached in vivo with no external administration of melatonin. Thus pharmacoki-netic calculations suggest that doses of 0 to 10 milligrams may be adequate and may produce both direct and immune-stimulating effects. We use a range of 0 to 20 milligrams per day as our target human dose.

The commonly prescribed dose in noncancerous conditions (insomnia and jet lag) is 3 milligrams. The LOAEL dose is uncertain but likely to be between 10 and 50 milligrams per day (see Appendix J). Severe drowsiness can occur at doses of 3 milligrams or less, however.

Therapeutic dose estimates for melatonin are summarized in Table 22.11, with a tentative recommended dose range of 3 to 20 milligrams daily. The 3-milligram value is based on the commonly prescribed dose, and the 20-milligram value on the highest common dose in human studies.

Because the target dose is achievable, synergistic interactions may not be required for melatonin to produce an anticancer effect in humans. Nevertheless, melatonin may greatly benefit from synergism, and it makes sense to continue testing it in combination with other compounds.

It is important to note that melatonin is best taken at night. Morning administration was reported to stimulate growth of two different cancer cell lines in rodents, whereas taken in the afternoon it inhibited growth.239'240'241 Furthermore, melatonin induces drowsiness, which may be unwanted during the day.

As discussed above, normal levels of melatonin may impede tumor progression. Therefore, even without external melatonin, it may be worthwhile to maximize natural production. This can be done in at least two ways. First, the body's levels of melatonin can be maximized by reducing exposure to artificial light during the dark hours. Even short periods of light at night can dramatically reduce melatonin production for the remainder of the night.242 Second, at least two studies indicate that meditation practices can increase melatonin concentrations.243,244 In addition to an effect on mela-tonin, meditation may have other beneficial effects, not the least being increased peace of mind. Several preliminary studies have in fact reported that deep meditation may prolong the lives of some cancer patients.245-248

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