Melatonin: A Review

Dr Arlene Goldman MB.BCh. M.R.C.P.(UK) M.A.C.P.

Summary

The hormone melatonin (hereinafter referred to as 'mel') is now a popular therapy for jet-lag and disturbances of sleep. Claims are made for improved sex-life, longevity and even lowering of blood pressure. Melatonin is not licensed for sale in pharmacies in the UK at the present time but can be bought over the counter in health food shops. Recent newspaper reports suggest that the Medicines Control Agency has written to the suppliers of the synthetic hormone to tell them that in future it will only be available on prescription. A survey of the medical literature reveals investigations are being done by many workers to determine the efficacy and side effects of the use of mel in a number of conditions.The main focus of attention is on sleep disturbances, seasonal affective disorder, neuroendocrine disorder and cancer therapy.

An overview of the literature is presented in order to show avenues of research into the use of melatonin.

It is not recommended that melatonin should be taken unless prescribed by a qualified medical practitioner and according to the Drug Enforcement laws of the country in which it is taken.

This review article deals with the following subjects:

What is melatonin(mel)?
Jet-lag and sleep disturbances.
Melatonin as an anti-oxidant.
Melatonin and cancer.
Melatonin and depressive disorders.
Melatonin and endocrine disorders.
Adverse effects of Melatonin.
General comments.
References.

What is Melatonin? (mel)

Melatonin is a hormone (N-acetyl-5 methoxytryptamine) produced especially at night in the pineal gland. Its secretion is stimulated by the dark and inhibited by light. Tryptophan is converted to serotonin and finally converted to melatonin which is an Indole. The suprachiasmatic nuclei (SCN) of the hypothalamus have melatonin receptors and melatonin may have a direct action on SCN to influence "circadian" rhythms. (Weaver et al., 1993). Melatonin is metabolised to 6-hydroxy-mel in the liver and the main metabolite excreted is 6-sulphatoxy-mel. Isolated measurements of mel are difficult to interpret given its circadian secretion, however urinary excretion of 6-sulphatoxy-mel may be helpful in studying pineal function especially in children.

Jet-lag and sleep disturbances.

Jet-lag is the result of long distance travel east/west crossing time zones at a rapid rate. Symptoms such as sleep disturbance, loss of appetite, reduced psychomotor efficiency and general malaise may occur.

The problem for aircrews on longhaul schedules has been coped with by alterations in sleep patterns. Short naps may alternate with intermediate and long periods of sleep.Synchronisers "zeitgebers" (time givers) are environmental factors that help to keep the organism in phase. Travel at rapid rates across time zones disturbs the normal rhythm. One adapts more easily after a flight Westward because there is a longer day and we have an endogenous clock of about 25 hours. Circadian rhythms need about one day to adapt for each time zone crossed. In other words 5 hours' time difference will require approximately 5 days adaptation.(2)

The CAA in the UK do not appear to have guide-lines for the management of jet-lag in pilots which include the use of melatonin. I understand that studies are in progress.The current recommendation is for pilots having sleep disturbance to take a benzodiazepine such as temazepam. A combination of treatment including light, mel and diazepams may be needed.(3)

The Oxford Textbook of Medicine recommends Diazepam 10mgs or Temazepam 10-20mgs for symptoms of jetlag.

An investigation was done into the efficacy of oral melatonin in alleviating jet lag in flight crew after a series of international flights. The optimal time for taking melatonin was also investigated. When melatonin 5 mgs was given on arrival for 5 days a trend showing improved recovery in jet-lag, mood and sleepiness was shown. There was also a significantly faster recovery of energy and alertness. Melatonin given for 3 days prior to arrival and 5 days after return showed a worse recovery than placebo.(4)

A study was done in shift workers. 5mgs melatonin was given at bedtime and increased alertness in waking hours was observed. Authors caution that effects on performance need careful evaluation.(5)

Nocturnal melatonin secretion may be involved in physiologic sleep onset and exogenous melatonin may be useful in treating insomnia. 0.3mgs or 1mg were given at 6 pm and 8 pm close to times of endogenous melatonin release and habitual sleep onset. No "hangover " effects were noted as assessed by mood and performance tests administered the morning after treatment. (6)

Melatonin has been found to be efficacious in delayed sleep phase syndrome. 5mgs/day was administered for one month. Mean sleep onset time was advanced 115 mins and mean final awakening hour by 106mins.(7)

15 children were treated with 2-10mgs of oral melatonin given at bedtime. Most of the children were neurologically multiply disabled. All had failed to respond to conventional management. There were no adverse side effects and behavioural and social benefits were significant. The authors concluded that mel has an important role in the treatment of certain types of chronic sleep disorders. (8)

Melatonin as an antioxidant.

Melatonin is a highly important antioxidant. Free radicals are chemical constituents that have an unpaired electron. If an electron is added to O2 then the superoxide anion radical O2- is formed. O2- is reduced by superoxide dismutase to H2O2 which is toxic at high concentrations and can be reduced to.OH. The hydroxyl radical (.OH) damages cells. Melatonin is an efficient neutraliser of.OH. (9)

Age related brain deterioration is extremely costly in terms of quality of life. One of the potential major causes of age-related destruction of neuronal tissue is toxic free radicals that are a natural result of aerobic metabolism. The brain is particularly susceptible to free radical attack.(10(

Vitamin antioxidants.vitamin E (alpha- tocopherol in particular) and vitamin C (ascorbate) aid in protecting the brain from oxidative stress by directly scavenging toxic radicals. The pineal hormone melatonin is rapidly taken up by the brain. In vitro melatonin is more effective than glutathione in scavenging the highly toxic (.OH) radical and also more efficient than vitamin E in neutralising the peroxyl radical. It also stimulates the main antioxidant enzyme of the brain, glutathione peroxidase. In vivo melatonin is a potent antioxidant.(10)

Melatonin and Cancer

Electromagnetic fields (EMF) have been linked to tumours. If the pineal gland is removed in rats the incidence of tumours is increased. EMFs may influence mel production in the pineal gland. Gliomas have been linked to EMFs. (11) Inhibition of cancer growth by mel has been observed. Melatonin is most effective when given in the evening. There are data which indicate that mel antagonises the mitogenic effects of oestrogens (Blask et al., 1991; 1992; Wilson et al., 1992). (1) Inhibition of antioxidants by reducing agents such as glutathione eliminates the oncostatic effects of mel in certain human breast cancer cell lines. (Blask et al., 1994) As stated above mel has been found to be the most effective scavenger of highly toxic free radicals (Tan et al., 1994), which induce DNA damage.(1) Melatonin may augment the anti tumour activity of IL-2 (Interleukin 2) by inhibiting tumour growth factor production. A pilot study was done using low dose IL-2 plus mel in 14 patients with untreatable endocrine tumours. The results suggest that low dose IL-2 and mel may be a well tolerated therapy for advanced endocrine tumours.(12) Melatonin was added to IL-2 therapy for advanced solid neoplasms resistant to IL-2. Melatonin may enhance IL-2 antitumour immune effect. 40mgs mel was given every day,starting 7 days prior to IL-2. Objective tumour regression was noted in 3/14. (lung,kidney and liver tumours) (13)

Melatonin and Depressive Disorders

Much has been written about Melatonin, Seasonal Affective Disorder and Endogenous Depression.Webb and Puig-Domingo have reviewed the literature and I quote from their article.(1)

"Seasonal Affective Disorder (SAD) a depression occurring in the Winter months and associated with hypersomnia,weight gain and craving for carbohydrate has been found to improve with bright light treatment (Rosenthal et al., 1984) The benefit appeared to be related to light rather than Melatonin inhibition as these workers found that pharmacological suppression of Melatonin did not improve their depression."

Changes in magnetic fields alter Melatonin secretion and affect circadian rhythms. Environmental magnetic fields (MF) have diminished strength during the Winter months and there may be desynchronisation of circadian rhythm.Both acute exposure to light and exposure to MF suppress Melatonin secretion and may be beneficial for patient's with Winter depression. It has been proposed that the synergistic effect of light and magnetic therapy in these patients may be superior to phototherapy alone.(14) Low Melatonin levels have been observed in depressed subjects, (McIntyre et al., 1986) unipolar or bipolar Affective Disorders (Beck-Friis et al.,1985) and chronic schizophrenia (Ferrier et al., 1982). Low nocturnal Melatonin has been proposed as a trait marker for major depressive disorders by Beck-Friis et al.,1985 (1) Therapy with monoamine oxidase inhibitors (MAO) increases pineal content of serotonin (Melatonin precursor),Tricyclic antidepressants reduce Melatonin production and secretion in rodents (Lewis et al., 1990) Other psychotropic drugs which interfere with monoamine pathways also affect pineal mel. Melatonin has been proposed to inhibit CRH(corticotrophin release hormone) during major depression.(1) Receptors for Benzodiazepines have been reported to exist in the pineal gland of several animal species (Lowenstein et al., 1984) In humans Alprazolam given before lights out suppressed nocturnal Melatonin and cortisol.(1) Many environmental and endogenous factors can potentially affect Melatonin secretion and thus a definite therapeutic relationship between mel and psychiatric disorders remains unproven.(1) The conventional view that the underlying abnormality in endogenous depression is due to an abnormality in the body clock has been challenged. (Healy D., Waterhouse JM, Pharm and Therapeutics 65 (2):241-63,1995 Feb). They suggest that the circadian system in endogenous depression resembles its state in healthy individuals after time-zone transitions or in shift work maladaptation syndrome and disturbances result from changes in the phasing of external time givers(zeitgebers) rather than from an abnormality in the clock itself.

Melatonin and Endocrine Disorders

External magnetic fields have been found to synchronise Melatonin secretion in experimental animals and humans and may be beneficial in the treatment of postmenopausal osteoporosis. Pineal Melatonin has been shown in animals to be involved in the regulation of calcium and phosphorus metabolism by stimulating the parathyroid glands and by inhibiting calcitonin release and prostaglandin synthesis The menopause is associated with a decline in Melatonin secretion and increased pineal calcification.(15)

The pineal gland has been linked to the immune system and immunodepression has been counteracted by Melatonin administration. The thymus is one of the main targets of mel and its immunoenhancing effects may be mediated by opioids derived from T-helper cells,lymphokines and possibly pituitary hormones. Lymphokines such as gamma-interferon and IL2 as well as thymic hormones can modulate the synthesis of mel in the pineal gland. (16)

A relation between the pineal and puberty has been speculated for many years. Normal pubertal development does not appear to be linked to alterations in mel profile. However there is some evidence that delayed puberty,precocious puberty and hypothalamic amenorrhoea may have altered mel profiles.(17)

Melatonin and Adverse Effects.

Controlled release mel effectively improved sleep quality in 12 elderly people. The subjects were treated with 2mgs per night for 3 weeks. 2 cases developed pruritis one on mel and one on placebo. Both resolved spontaneously.(18)

Advanced tumours of the digestive tract were treated with IL-2 and mel.(colorectal cancer 14, gastric cancer 8, Hepato carcinoma 6, Pancreatic adenoca 7) Toxicity was low in all patients who received the therapy at home.(19)

22 Patients with advanced renal cell carcinoma were treated for 12 months with human lymphoblastoid interferon (IFN) and melatonin 10mgs per day.General toxicity was mild. Fevers,chills, arthralgias and myalgias occurred rarely.Leukopenia and hepatic enzyme elevation were modest and always reversible.(20)

Melatonin was combined with a synthetic progestin norethisterone to study its influence on the pituitary- ovarian axis.An additive or synergistic effect between mel and norethisterone was suggested.Medications did not alter sleep/wake rhythms and were not complicated by any side effects. 300mgs mel daily (days 1-30) caused significantly decreased mean levels of LH compared to 8 non medicated controls. Present data suggest that mel and mel/net combinations inhibit ovarian function in women and the authors suggest a future effective oral contraceptive.(21)

A study was done in 1972 to assess the effects of mel in Parkinsonism giving mel alone or plus levadopa. Eleven patients were in the study. Melatonin induced some episodes of cutaneous flushing,abdominal cramps, diarrhoea,scotoma lucidum and migraine headaches.300-1000mgs / night were given for 1-4 weeks.(22)

Effects of metoprolol and atenolol on plasma mel levels revealed lower plasma mel levels in moderate hypertensives receiving betablockers than in those on diuretics alone or in combination. Authors are unsure whether findings have clinical implications.(23)

General comments

The studies done to date are either laboratory studies or have been done on small numbers of patients. Hormones are generally required in small doses and the doses of mel recommended in some of the studies are generally much greater than physiologically indicated. Not enough is known about the effects in "normal" individuals.Once mel is on prescription it will be possible to document side-effects more accurately. A major side-effect appears to be fatigue which is understandable given that one is resetting the "body-clock"

Melatonin will almost certainly have a role in the treatment of jet-lag and sleep disorder syndromes but the exact dose regime still requires to be worked out as there appears to be a variability in the recommendations.Some studies suggest taking mel 3 days prior to departure and others on arrival. Some recommend taking it at 2pm the day before travelling. Others again recommend taking it in the early am when travelling west and in the pm when travelling east. The problem with getting it wrong is you may actually make the jet-lag worse.

Some studies have been done using very large doses and these have produced adverse effects. Authors in general caution that studies need to be done to find the most efficacious physiological dose. Melatonin as sold at the present time is not a pure pineal extract and is therefore regarded by some workers to be impure. One format contains melatonin, herbs such as valerian and chamomile, together with amino- acids, calcium and magnesium.

There appears to be some consensus about its efficacy as an adjuvant therapy in advanced cancer especially when used with Interleukin-2. There may therefore be some justification for taking it in these conditions under strict medical supervision.

Anti-aging claims will require detailed investigation and are difficult to measure given the vast differences in memory recall and physical fitness that exist between individuals. The same applies to sexual potency which declines with age. There may be an end organ lack of response to low normal levels of testosterone as propounded by some workers. Whether mel administration or suppression of mel secretion can in any way improve this response has still to be shown.

The use of mel in psychiatric patients is under investigation and some guide-lines may be forthcoming given that there are pineal receptors to benzodiazepines and that there appears to be suppression of mel secretion by Alprazolam(a benzodiazepine) Suppression of mel by exposure to to bright light may alleviate symptoms in some cases and may be a helpful treatment for Winter depression but this remain unproven. It has been recommended that as fluoxetine (Prozac) and mel may interact (due to the effect on serotonin secretion by fluoxetine) that they should not be taken at the same time. An alteration in mel rhythm leading to altered sleep patterns requires further research and recommendations are needed as to how best to manipulate mel secretion to affect these rhythms and benefit depressed patients.

The studies done to date indicate the vast number of systems affected by mel or leading to changes in mel levels in the plasma. The significance of these changes is not known and must be studied before claims can be made for it as the new wonder-drug. Purified extracts of mel must be administered and not multi-complex medications. The exact role of the pineal in normal daily physiology must be more clearly defined

References

1. Susan M Webb and Manuel Puig-Domingo Role of melatonin in health and disease. Clinical Endocrinology (1995) 42, 221-234

2. Richard M Harding and F John Mills Aviation Medicine Articles from BMJ 1983

3. Redfern P Minors D Waterhouse J Chronobiology International 11(4): 253-65 1994 August

4 Petrie K. Dawson AG. Thompson L. Brook R. A double-blind trial of melatonin as a treatment in international cabin crew. Biological Psychiatry. 33 (7): 526-30, 1993 April 1

5. Folkard S Arendt J Can melatonin improve shiftworkers tolerance of the night shift? Some preliminary findings. Chronobiology International 1 (5):315-20 Oct1993

6. Zhdanova IV Wurtman RJ Lynch HJ Ives JR Dollins AB Morabito C Matheson JK Schomer DL Sleep-inducing effects of low doses of melatonin ingested in the evening. Clinical Pharmacology and Therapeutics. 57(5): 552-8, 1995 May.

7. Oldani A Ferini-Strambi L Zucconi M Stankov B Fraschini F Smirne S Melatonin and delayed sleep phase syndrome:ambulatory polygraphic evaluation. Neuroreport. 6(1):132-4 1994 Dec 30

8.Jan JE Espezel H Appleton RE The treatment of sleep disorders with melatonin. Developmental Medicine and Child Neurology. 36(2):97-107, 1994 February

9 Reiter RJ Melatoninchiorri D Sewerynek E Poeggeler B Barlow-Walden L Chuang J Ortiz GG Acuna- castroviejo D A review of the evidence supporting melatonin's role as an antioxidant. Journal of pineal research 18(1): 1-11 1995 January.

10. Reiter RJ Oxidative processes and antioxidative defence mechanisms in the aging brain. FASEB Journal. 9(7):526-33,1995 April

11. Hughes JT Teratogenesis. Carcinogenesis and Mutagenesis 14(5): 213-7 1994

12. Lissoni P Barni S Tancini G Mainini E Piglia F Maestroni GJ Lewinski A Immunoendocrine therapy with low-dose subcutaneous interleukin-2 plus melatonin of locally advanced or metastatic endocrine tumours. Oncology. 52(2): 163-6, 1995 Mar- April

13. Lissoni P Barni S Cazzaniga M Ardizzoia A Rovelli F Brivio F Tancini G Efficacy of the concomitant administration of the pineal hormone melatonin in cancer immunotherapy with low dose IL-2 in patients with advanced solid tumours who had progressed on IL-2 alone. Oncology. 51(4): 344-7, 1994 Jul-Aug

14. Sandyk R Anninos PA Tsagas N Magnetic Fields and Seasonality of Affective Illness:implications for therapy. International Journal of Neuroscience. 58(3-4):261-7,1991 June.

15. Sandyk R Anastasiadis PG Anninos PA Tsagas N Is postmenopausal osteoporosis related to pineal gland function? International Journal of Neuroscience 62(3-4):215-25,1992 February

16. Maestroni GJ The immunoendocrine role of melatonin.Journal of Pineal Research 14(1):1- 10,1993 January

17. Cavallo A Melatonin and human puberty:current perspectives Journal of Pineal Research 15(3):115-21,1993 October.

18. Garfinkel D, Laudon M,Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled release melatonin. Lancet.1995,Vol/Iss/Pg.346/89743(541-544)

19. Lissoni P Barni S Tancini G Ardizzoia A Rovelli F Cazzaniga M Brivio F Piperno A Aldeghi R Fossati D et al. Immunotherapy with subcutaneous low dose IL 2 and the pineal indole melatonin as a new effective therapy in advanced cancers of the digestive tract. Br J Cancer 1993 Jun.Vol 67(6).1404-7.

20. Neri B Fiorelli C Moroni F Nicita G Paoletti MC Ponchieatti R Raugei A Santoni G Trippitelli A Grechi G. Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma a phase 2 study. Cancer Vol/IssPg73/12(3015-3019)

21 Voordouw GC Euser R Verdonk RE Alberda BD de Jong FH Drogendijk AC Fauser BC Cohen M. Melatonin and melatonin-progestin combinations alter Pituitary -ovarian function in women and can inhibit ovulation. Journal of Clinical Endocrinology and Metabolism.74(1):108-17,1992 January

22. Papavasiliou PS Cotzias GC Duby SE Steck AJ Bell M et al. Melatonin and Parkinsonism. Journal of American Medical Association vol 221, Pg:88 July 3 1972.

23. Cowan PJ Bevan JS Gosden B Elliott SA treatment with beta-adrenoceptor blockers reduces plasma melatonin concentration.

British Journal of Clinical Pharmacology vol 19 Pg 258-260 February 1995

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