Melatonin
The Cognitive Enhancement Research Institute
This file is the textual content of the Melatonin chapter of Smart Drugs II: The Next Generation. Graphs and charts from the book are not included.
The pineal gland, until recently, has been referred to as mystery gland, since its functions were largely unknown. The pineal is now recognized as a key element in the maintenance of the body's endocrine regulation (hormone balance), immune system integrity, and circadian rhythm (daily metabolic balance). Melatonin is the principal hormone produced by the pineal gland. Melatonin is under investigation as a treatment for a number of conditions, including jet-lag, seasonal affective disorder (SAD), depression, and cancer. Pineal polypeptide extract (which contains a broad spectrum of other, protein-based pineal hormones) has been shown to inhibit the development of atherosclerosis [Tasca, et al., 1974], reduce blood triglyceride levels [Ostroumova and Vasiljeve, 1976], improve cellular immunity [Belokrylov, et al., 1976; Dilman, 1977], and increase lifespan in animals [Dilman, et al., 1979].
The pineal gland functions as a biological clock by secreting melatonin (along with many other neuropeptides) at night. As you can see from the following illustration, melatonin levels peak at about 2 a.m. in normal, healthy young people and about 3 a.m. in elderly people. The maximum amount of melatonin released in the bloodstream of the elderly is only half of that in young adults.
Melatonin levels are low during the day. At sunset, the cessation of light triggers neural signals which stimulate the pineal gland to begin releasing melatonin. This rise continues for hours, eventually peaking around 2 a.m. (3 a.m. for the elderly) after which it steadily declines to minimal levels by morning. The delay in timing and decrease in intensity of the melatonin pulse is a manifestation of the aging process.
The melatonin pulse regulates many neuroendocrine functions. When the timing or intensity of the melatonin peak is disrupted (as in aging, stress, jet-lag, or artificial jet-lag syndromes), many physiological and mental functions are adversely affected. The ability to think clearly, remember key facts, and make sound decisions can be profoundly hampered by these upsets in the biological clock.
Melatonin for Jet-Lag
Jet-lag is a condition caused by desynchronization of the biological clock. It is usually caused by drastically changing your sleep-wake cycle, as when crossing several time zones during east-west travel, or when performing shift work. Jet-lag is characterized by fatigue, early awakening or insomnia, headache, fuzzy thinking, irritability,constipation, and reduced immunity. The symptoms are generally worse when flying in an easterly direction, and it may take as long as one day for each time zone crossed in order to fully recover. Older people have an even tougher time adjusting to these changes than younger people.
Circadian disturbances can easily result from conditions other than jet travel. We call these "artificial jet-lag syndromes" because jet-lag is universally understood. Artificial jet-lag can be induced by working night shifts, working rotating shifts (like physician-interns, management trainees for 24-hour businesses, and soldiers under battle-alert conditions), or by staying up all night. Whatever its causes, jet-lag and artificial jet-lag syndromes are seriously debilitating to cognitive function.
Melatonin taken in the evening (in the new time zone!) will rapidly reset your biological clock and almost totally alleviate (or prevent) the symptoms of jet-lag. The ability of melatonin to alleviate jet-lag was demonstrated in a study of 17 subjects flying from San Francisco to London (eight time zones away). Eight subjects took 5 mg of melatonin, while nine subjects took a placebo. Those who took melatonin had almost no symptoms of jet-lag (see illustration below) [Arendt, et al., 1986]. Six out of nine placebo subjects scored above 50 on the jet lag scale, and all of the melatonin subjects scored below 17.
Most people sleep well with melatonin, and wake up the next day refreshed with no symptoms of jet-lag [Claustrat, 1992] (although they may still have some fatigue from the wear and tear of traveling).
Many melatonin fans without any noticeable symptoms of circadian disturbance are now using melatonin to enhance their circadian rhythms. They report that it helps them get to sleep and helps them sleep more soundly. It also makes them more alert the next day and even lessens mid-afternoon tiredness (and naps).
In all cases, melatonin should be taken at night (preferably before midnight) before going to bed. That's when your pineal gland naturally releases melatonin. Taking melatonin at night (or before your normal bedtime if you are a shift worker) helps restore and maintain normal circadian metabolic rhythms. See the Precautions section in this chapter.
With circadian enhancers like melatonin, the timing is critical. When taken in opposition to the body's natural circadian rhythm, they cause cognitive deficit just like jet-lag does. But when taken in synchronization with the body's natural circadian rhythms, they enhance mental performance. By giving melatonin in the daytime, before the cognitive tests, the researchers were causing the test subjects to suffer from artificial jet-lag and then measuring the resulting cognitive impairment. Disruption of circadian rhythms produces amnesia by interfering with the circadian organization of memory processes [Sandyk, 1991].
Melatonin, by correcting circadian rhythms should, theoretically, improve mental performance. We could only find one study in which melatonin was given to rats at night. This study confirmed that next-day measures of learning ability improved [Ovanesov, 1990]. We believe that melatonin, when taken before sleep, will decrease sleep disturbances of any kind, and will, therefore, improve mental function during the following day.
Melatonin secretion naturally drops off with age (see the following graph). This decrease is so reliable that blood melatonin levels have been proposed as a measurement of biological age [Nair, et al., 1986]. This age-related reduction in melatonin levels may partially account for the reason many older people have difficulty sleeping at night, and for why they are so fatigued during the day. We believe they may be suffering from age-induced "jet-lag." Restoration of normal sleep-wake cycles in many of my [WD] elderly patients with supplemental melatonin before bedtime has dramatically improved their quality of life.
Exposure to electromagnetic fields from appliances and from powerlines may be even more significant than we think. There are reports of altered neural function from exposure to ELF (extremely low frequency) fields, as found near high-voltage powerlines, including suppressed melatonin levels [Lovely, 1988]. Supplemental melatonin may help to overcome the negative health consequences of these fields.
This observation (and others like it) demonstrate the importance of not only adjusting the dosage but also the time of the dose. Melatonin seems to be much more critical in this regard than other smart drugs. One melatonin user reports that he gave himself terrible jet-lag by absent-mindedly taking melatonin at 3 a.m. after staying up late. He recovered from this error, resetting his circadian rhythm back to normal with melatonin at 10 p.m. the following evening, but not before he had to spend an entire day in jet-lag hell for his mistake.
Belokrylov GA, Morozov VG, Khavinson VH, et al. The action of low molecular extracts from heterological thymus, pineal and hypothalamus on the immune response in mice. Biull Eksp Biol Med 81: 202-4, 1976.
Brown GM. Psychoneuroendocrinology of depression. Psychiatr J Univ Ott 14(2): 344-8; Jun 1989. Discussion follows article.
Claustrat B, Brun J, David M, Sassolas G and Chazot G. Melatonin and jet-lag: Confirmatory result using a simplified protocol. Biol Psychiatry (USA) 32(8): 705-11, 1992.
Dilman VM, Anisimov VN, and Ostroumova MN. Increase in lifespan of rats following polypeptide pineal extract treatment. Exp Pathology 17: 539-45, 1979.
Dilman VM. Improvement of cell-mediated immunity after pineal gland extract treatment. Vopr Oncol (Problems of Oncology) 7: 70-72, 1977.
Lieberman HR, Waldhauser F, Garfield G, et al. Effects of melatonin on human mood and performance. Brain Res (Netherlands) 323(2): 201-7, 1984.
Lissoni P, Barni S, Crispino S, Tancini G and Fraschini F. Endocrine and immune effects of melatonin therapy in metastatic cancer patients. Eur J Cancer Clin Oncol (United Kingdom) 25(5): 789-95, 1989.
Lovely RH. Recent studies in the behavioral toxicology of ELF electric and magnetic fields. Prog Clin Biol Res 257: 327-47, 1988.
Maestroni GJ, Conti A and Pierpaoli W. Pineal melatonin, its fundamental immunoregulatory role in aging and cancer. Ann N Y Acad Sci 521: 140-8, 1988.
Maurizi CP. The therapeutic potential for tryptophan and melatonin: possible roles in depression, sleep, Alzheimer's disease and abnormal aging. Med Hypotheses 31(3): 233-42, March 1990.
Nair NPV, Hariharasubramanian N, Pilapil C, Issac I, and Thavundayil JX. Plasma melatonin--an index of brain aging in humans? Biological Psychiatry 21: 141-50, 1986.
Neville K and McNaughton N. Anxiolytic-like action of melatonin on acquisition but not performance of DRL. Pharmacol Biochem Behav 24(6): 1497-502, June 1986.
Ostroumova MN and Vasiljeve IA. Effect or polypeptide pineal extract on fat-carbohydrate metabolism. Probl Endokrinol 22: 66-9, 1976.
Ovanesov KB. Vliianie ostrogo i khronicheskogo vvedeniia melatonina na pereobuchenie krys v U-obraznom labirinte i ikh chuvstvitel'nost' k galoperidolu [The effect of the acute and chronic administration of melatonin on the relearning of rats in a Y maze and their sensitivity to haloperidol]. Farmakol Toksikol 53(2): 15-7, Mar-Apr 1990.
Pierpaoli W, Changxian VI and Dall'aza A. Aging--Postponing effect of circadian melatonin: Experimental evidence, significance and possible mechanism. Intern J Neuroscience 51: 334-342, 1990.
Pierpaoli W and Maestroni GJM. Melatonin: A principal neuroimmunoregulatory and anti-stress hormone: Its anti-aging effects. Immunol Lett (Netherlands) 16(3-4): 355-61, 1987.
Regelson W and Pierpaoli W. Melatonin: a rediscovered antitumor hormone? Cancer Investig 5: 379-385, 1987.
Sandyk R, Anninos PA and Tsagas N. Age-related disruption of circadian rhythms: possible relationship to memory impairment and implications for therapy with magnetic fields. Int J Neurosci (England) 59(4): 259-62, Aug 1991.
Skene DJ, Vivien-Roels B, Sparks DL, Hunsaker JC, Pevet P, Ravid D and Swaab DF. Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer's disease. Brain Res 528(1): 170-4, 24 Sept 1990.
Souetre E, Salvati E, Krebs B, Belugou JL and Darcourt G. Abnormal melatonin response to 5-methoxypsoralen in dementia. Am J Psychiatry 146(8): 1037-40, Aug 1989.
Tasca C, Damian E and Stefaneanu L. Disappearance of aortic lesions in the rabbits with experimental atheromatosis after pineal extraction administration. Rev Roum d'Endocr 11: 209-13, 1974.
Tohgi H, Abe T, Takahashi S, Kimura M, Takahashi J and Kikuchi T.Concentrations of serotonin and its related substances in the cerebrospinal fluid in patients with Alzheimer-type dementia. Neurosci Lett (Ireland) 141(1): 9-12, 1992.
Tzischinsky O, Pal I, Epstein R, Dagan Y and Lavie P. The importance of timing in melatonin administration in a blind man. J Pineal Res (Denmark) 12(3): 105-8, 1992.
The pineal gland, until recently, has been referred to as mystery gland, since its functions were largely unknown. The pineal is now recognized as a key element in the maintenance of the body's endocrine regulation (hormone balance), immune system integrity, and circadian rhythm (daily metabolic balance). Melatonin is the principal hormone produced by the pineal gland. Melatonin is under investigation as a treatment for a number of conditions, including jet-lag, seasonal affective disorder (SAD), depression, and cancer. Pineal polypeptide extract (which contains a broad spectrum of other, protein-based pineal hormones) has been shown to inhibit the development of atherosclerosis [Tasca, et al., 1974], reduce blood triglyceride levels [Ostroumova and Vasiljeve, 1976], improve cellular immunity [Belokrylov, et al., 1976; Dilman, 1977], and increase lifespan in animals [Dilman, et al., 1979].
The pineal gland functions as a biological clock by secreting melatonin (along with many other neuropeptides) at night. As you can see from the following illustration, melatonin levels peak at about 2 a.m. in normal, healthy young people and about 3 a.m. in elderly people. The maximum amount of melatonin released in the bloodstream of the elderly is only half of that in young adults.
Melatonin levels are low during the day. At sunset, the cessation of light triggers neural signals which stimulate the pineal gland to begin releasing melatonin. This rise continues for hours, eventually peaking around 2 a.m. (3 a.m. for the elderly) after which it steadily declines to minimal levels by morning. The delay in timing and decrease in intensity of the melatonin pulse is a manifestation of the aging process.
The melatonin pulse regulates many neuroendocrine functions. When the timing or intensity of the melatonin peak is disrupted (as in aging, stress, jet-lag, or artificial jet-lag syndromes), many physiological and mental functions are adversely affected. The ability to think clearly, remember key facts, and make sound decisions can be profoundly hampered by these upsets in the biological clock.
Melatonin for Jet-Lag
Jet-lag is a condition caused by desynchronization of the biological clock. It is usually caused by drastically changing your sleep-wake cycle, as when crossing several time zones during east-west travel, or when performing shift work. Jet-lag is characterized by fatigue, early awakening or insomnia, headache, fuzzy thinking, irritability,constipation, and reduced immunity. The symptoms are generally worse when flying in an easterly direction, and it may take as long as one day for each time zone crossed in order to fully recover. Older people have an even tougher time adjusting to these changes than younger people.
Circadian disturbances can easily result from conditions other than jet travel. We call these "artificial jet-lag syndromes" because jet-lag is universally understood. Artificial jet-lag can be induced by working night shifts, working rotating shifts (like physician-interns, management trainees for 24-hour businesses, and soldiers under battle-alert conditions), or by staying up all night. Whatever its causes, jet-lag and artificial jet-lag syndromes are seriously debilitating to cognitive function.
Melatonin taken in the evening (in the new time zone!) will rapidly reset your biological clock and almost totally alleviate (or prevent) the symptoms of jet-lag. The ability of melatonin to alleviate jet-lag was demonstrated in a study of 17 subjects flying from San Francisco to London (eight time zones away). Eight subjects took 5 mg of melatonin, while nine subjects took a placebo. Those who took melatonin had almost no symptoms of jet-lag (see illustration below) [Arendt, et al., 1986]. Six out of nine placebo subjects scored above 50 on the jet lag scale, and all of the melatonin subjects scored below 17.
Most people sleep well with melatonin, and wake up the next day refreshed with no symptoms of jet-lag [Claustrat, 1992] (although they may still have some fatigue from the wear and tear of traveling).
Many melatonin fans without any noticeable symptoms of circadian disturbance are now using melatonin to enhance their circadian rhythms. They report that it helps them get to sleep and helps them sleep more soundly. It also makes them more alert the next day and even lessens mid-afternoon tiredness (and naps).
In all cases, melatonin should be taken at night (preferably before midnight) before going to bed. That's when your pineal gland naturally releases melatonin. Taking melatonin at night (or before your normal bedtime if you are a shift worker) helps restore and maintain normal circadian metabolic rhythms. See the Precautions section in this chapter.
Does Melatonin Improve or Impair Mental Performance?
We were initially surprised to find a number of studies which reported on adverse effects of melatonin on performance and alertness. One study [Lieberman, 1984] reported that melatonin users were less alert, more sleepy, and demonstrated slowed "choice-reaction time." Other studies also indicated that melatonin impaired memory and performance [Neville, 1986]. We found, however, that in all of these studies, melatonin was given to subjects in the daytime, before the performance tests, just the opposite of what they should have been doing!With circadian enhancers like melatonin, the timing is critical. When taken in opposition to the body's natural circadian rhythm, they cause cognitive deficit just like jet-lag does. But when taken in synchronization with the body's natural circadian rhythms, they enhance mental performance. By giving melatonin in the daytime, before the cognitive tests, the researchers were causing the test subjects to suffer from artificial jet-lag and then measuring the resulting cognitive impairment. Disruption of circadian rhythms produces amnesia by interfering with the circadian organization of memory processes [Sandyk, 1991].
Melatonin, by correcting circadian rhythms should, theoretically, improve mental performance. We could only find one study in which melatonin was given to rats at night. This study confirmed that next-day measures of learning ability improved [Ovanesov, 1990]. We believe that melatonin, when taken before sleep, will decrease sleep disturbances of any kind, and will, therefore, improve mental function during the following day.
Melatonin for SAD and Depression
Two particularly notable features of depression and SAD are diminished nighttime release of melatonin and abnormal sensitivity to melatonin suppression by light [Brown, 1989]. This has led researchers and clinicians to try melatonin as an experimental treatment for depression, with gratifying results.Melatonin Extends Lifespan
Melatonin has also been shown to improve immunity and extend lifespan in rodents [Regelson & Pierpaoli, 1987; Pierpaoli, et al., 1990]. Dr. Maestroni [1988] gave melatonin to middle-aged mice each evening. The treated mice became more healthy (better posture, increased activity levels, and thicker, more lustrous fur) and lived an average of 20% longer than control mice.Melatonin secretion naturally drops off with age (see the following graph). This decrease is so reliable that blood melatonin levels have been proposed as a measurement of biological age [Nair, et al., 1986]. This age-related reduction in melatonin levels may partially account for the reason many older people have difficulty sleeping at night, and for why they are so fatigued during the day. We believe they may be suffering from age-induced "jet-lag." Restoration of normal sleep-wake cycles in many of my [WD] elderly patients with supplemental melatonin before bedtime has dramatically improved their quality of life.
Melatonin: Anti-Stress Hormone
Nighttime administration of melatonin can also counteract the immune-suppressing effects of acute anxiety stress in mice. Measures used to confirm this were: thymus weight, antibody production, and ability to fight off a lethal viral infection [Pierpaoli and Maestroni, 1987].Melatonin for Cancer Treatment
Melatonin also appears to inhibit tumor growth. In the United Kingdom, a study was carried out on 14 cancer patients with cancers of different types. The researchers concluded that "this study would suggest that melatonin may be of value in untreatable metastatic cancer patients, particularly in improving their quality of life. Moreover, based on its effects on the immune system, melatonin could be tested in association with other anti-tumor treatments" [Lissoni, 1989].Melatonin in Alzheimer's Disease
Very recent studies have found reduced levels of melatonin in the cerebrospinal fluid of patients with Alzheimer's disease compared to age-matched control subjects [Tohgi, 1992; Skene, 1990]. Since circadian rhythms are disrupted in Alzheimer's disease, it is interesting to speculate whether restoration of melatonin to normal levels in these patients would alleviate other symptoms as well.Melatonin and Exposure to Electromagnetic Fields
Sunlight is the primary environmental influence that regulates the internal clock and the associated late-night melatonin pulse. There is some evidence that the earth's magnetic field may also be an environmental signal affecting circadian rhythms in humans. When shielded from the earth's ambient magnetic field, human circadian rhythms can become disrupted [Tohgi, 1992].Exposure to electromagnetic fields from appliances and from powerlines may be even more significant than we think. There are reports of altered neural function from exposure to ELF (extremely low frequency) fields, as found near high-voltage powerlines, including suppressed melatonin levels [Lovely, 1988]. Supplemental melatonin may help to overcome the negative health consequences of these fields.
Dosage
The appropriate dose can vary enormously from person to person. Dr. Pierpaoli, a leading melatonin researcher, has successfully used dosages ranging from 0.1 to 200 mg. That's a 2000-fold difference between the lowest dose and the highest! Several intelligent melatonin users we know started by taking 3 mg at 11 p.m., and then adjusted the dose from there. If they found that they slept well but were drowsy in the morning, they cut the dose in half. If they found the dose had little or no sleep-inducing effect, they increased the dose by 3 mg each night until they got the desired effect. We have received reports from one person who gets good results from less than one milligram, and several from people who use in the vicinity of 20 mg. Most people get good results with doses between 3 and 10 mg.Precautions
Timing may be crucial for the most effective use of melatonin. Individual differences in the absorption and metabolism of melatonin may account for the differences in size and timing of the resulting melatonin pulse. A good illustration of this effect is found in the experiences of Dr. Tzischinsky [1992] of the medical university in Haifa, Israel. Dr. Tzischinsky treated an 18-year-old blind man suffering from chronic sleep disturbances. Presumably, the young man's blindness prevented sunlight from cueing his circadian rhythm. He suffered from daytime fatigue, often falling asleep during the day, but was awake at night. After two unsuccessful treatment regimens with 5 mg and 10 mg melatonin administered at bedtime (10 - 10:30 p.m.), Dr. Tzischinsky tried a third regimen of only 5 mg administered at 8 p.m. for three weeks. This approach resulted in a successful resolution of the man's sleep disturbances.This observation (and others like it) demonstrate the importance of not only adjusting the dosage but also the time of the dose. Melatonin seems to be much more critical in this regard than other smart drugs. One melatonin user reports that he gave himself terrible jet-lag by absent-mindedly taking melatonin at 3 a.m. after staying up late. He recovered from this error, resetting his circadian rhythm back to normal with melatonin at 10 p.m. the following evening, but not before he had to spend an entire day in jet-lag hell for his mistake.
Sources
Melatonin is a non-prescription substance and can often be found where supplements are sold. For information about mail-order sources for melatonin you can send in the tearout card at the front of this book and ask for the product sources list. (See also Appendix A).References
Arendt J, Aldhous M and Marks V. Alleviation of jet-lag by melatonin: Preliminary results of controlled double-blind trial. Brit Med J 292: 1170, 1986.Belokrylov GA, Morozov VG, Khavinson VH, et al. The action of low molecular extracts from heterological thymus, pineal and hypothalamus on the immune response in mice. Biull Eksp Biol Med 81: 202-4, 1976.
Brown GM. Psychoneuroendocrinology of depression. Psychiatr J Univ Ott 14(2): 344-8; Jun 1989. Discussion follows article.
Claustrat B, Brun J, David M, Sassolas G and Chazot G. Melatonin and jet-lag: Confirmatory result using a simplified protocol. Biol Psychiatry (USA) 32(8): 705-11, 1992.
Dilman VM, Anisimov VN, and Ostroumova MN. Increase in lifespan of rats following polypeptide pineal extract treatment. Exp Pathology 17: 539-45, 1979.
Dilman VM. Improvement of cell-mediated immunity after pineal gland extract treatment. Vopr Oncol (Problems of Oncology) 7: 70-72, 1977.
Lieberman HR, Waldhauser F, Garfield G, et al. Effects of melatonin on human mood and performance. Brain Res (Netherlands) 323(2): 201-7, 1984.
Lissoni P, Barni S, Crispino S, Tancini G and Fraschini F. Endocrine and immune effects of melatonin therapy in metastatic cancer patients. Eur J Cancer Clin Oncol (United Kingdom) 25(5): 789-95, 1989.
Lovely RH. Recent studies in the behavioral toxicology of ELF electric and magnetic fields. Prog Clin Biol Res 257: 327-47, 1988.
Maestroni GJ, Conti A and Pierpaoli W. Pineal melatonin, its fundamental immunoregulatory role in aging and cancer. Ann N Y Acad Sci 521: 140-8, 1988.
Maurizi CP. The therapeutic potential for tryptophan and melatonin: possible roles in depression, sleep, Alzheimer's disease and abnormal aging. Med Hypotheses 31(3): 233-42, March 1990.
Nair NPV, Hariharasubramanian N, Pilapil C, Issac I, and Thavundayil JX. Plasma melatonin--an index of brain aging in humans? Biological Psychiatry 21: 141-50, 1986.
Neville K and McNaughton N. Anxiolytic-like action of melatonin on acquisition but not performance of DRL. Pharmacol Biochem Behav 24(6): 1497-502, June 1986.
Ostroumova MN and Vasiljeve IA. Effect or polypeptide pineal extract on fat-carbohydrate metabolism. Probl Endokrinol 22: 66-9, 1976.
Ovanesov KB. Vliianie ostrogo i khronicheskogo vvedeniia melatonina na pereobuchenie krys v U-obraznom labirinte i ikh chuvstvitel'nost' k galoperidolu [The effect of the acute and chronic administration of melatonin on the relearning of rats in a Y maze and their sensitivity to haloperidol]. Farmakol Toksikol 53(2): 15-7, Mar-Apr 1990.
Pierpaoli W, Changxian VI and Dall'aza A. Aging--Postponing effect of circadian melatonin: Experimental evidence, significance and possible mechanism. Intern J Neuroscience 51: 334-342, 1990.
Pierpaoli W and Maestroni GJM. Melatonin: A principal neuroimmunoregulatory and anti-stress hormone: Its anti-aging effects. Immunol Lett (Netherlands) 16(3-4): 355-61, 1987.
Regelson W and Pierpaoli W. Melatonin: a rediscovered antitumor hormone? Cancer Investig 5: 379-385, 1987.
Sandyk R, Anninos PA and Tsagas N. Age-related disruption of circadian rhythms: possible relationship to memory impairment and implications for therapy with magnetic fields. Int J Neurosci (England) 59(4): 259-62, Aug 1991.
Skene DJ, Vivien-Roels B, Sparks DL, Hunsaker JC, Pevet P, Ravid D and Swaab DF. Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer's disease. Brain Res 528(1): 170-4, 24 Sept 1990.
Souetre E, Salvati E, Krebs B, Belugou JL and Darcourt G. Abnormal melatonin response to 5-methoxypsoralen in dementia. Am J Psychiatry 146(8): 1037-40, Aug 1989.
Tasca C, Damian E and Stefaneanu L. Disappearance of aortic lesions in the rabbits with experimental atheromatosis after pineal extraction administration. Rev Roum d'Endocr 11: 209-13, 1974.
Tohgi H, Abe T, Takahashi S, Kimura M, Takahashi J and Kikuchi T.Concentrations of serotonin and its related substances in the cerebrospinal fluid in patients with Alzheimer-type dementia. Neurosci Lett (Ireland) 141(1): 9-12, 1992.
Tzischinsky O, Pal I, Epstein R, Dagan Y and Lavie P. The importance of timing in melatonin administration in a blind man. J Pineal Res (Denmark) 12(3): 105-8, 1992.