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Melatonin Has Many Health Benefits

Melatonin production tends to be reduced and/or it lacks the normal cycling pattern in old age and many diseases including dementia, HIV infection, anorexia nervosa, autism, heart attacks, heart failure, migraines, obesity, and duodenal ulcers.

Double-blind studies have found some evidence of benefit in diabetes, dyspepsia, GERD, hair loss, hemodialysis anemia, high blood pressure, infant respiratory distress syndrome, irritable bowel syndrome, metastatic cancer, nocturia from benign prostatic hypertrophy, sarcoidosis, and tardive dyskinesia.  Unfortunately, for most of these, only a single small- to moderate-sized study is available, usually with supporting animal research.

Melatonin research certainly looks very promising, especially in view of the exciting findings from the many animal studies.  At very least, melatonin looks excellent for sleep and older individuals taking it for sleep will probably reap other benefits as well.  Pregnant women should not take melatonin. I would suggest the same in couples attempting to conceive a child.  In fact, the benefits of melatonin are probably greatest in individuals over age 50 when endogenous levels are declining or in individuals with acute diseases characterized in part by oxidative damage, e.g. heart attacks and strokes.  Obviously, much more human research is needed.

Aging: Nighttime Peak Blunted; More with Dementia; Less in Centenarians: Elderly, ages 66-94, demented or not, exhibited a flattened circadian profile, because of the suppression of the nocturnal peak. This was greater in demented individuals and significantly correlated with the severity of the cognitive impairment. As in young controls, in centenarians the aMT6s excretion was significantly higher at night than during the day. In centenarians, ages 100-107, the maintenance of the circadian organization of melatonin secretion may suggest that the amplitude of the nocturnal peak and/or the persistence of a prevalent nocturnal secretion may be an important marker of biological age and of health status. Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians. Magri F, Sarra S, et al. University of Pavia, Italy. J Pineal Res. 2004 May;36(4):256-61; Melatonin in a large Chinese study began falling after age 59. Chronobiol Int. 2002 Nov;19(6):1171-82.  Another smaller Chinese study reports decreases after age 40. J Pineal Res. 2003 Jan;34(1):11-6. Supplement levels are typically far higher than endogenous levels.

AIDS: Melatonin Reduced in HIV Infected and Drops with Progression: In HIV-1 infection, an impairment of interleukin-12 (IL-12) production precedes a switch from a T-helper 1 (Th1) to a T-helper 2 (Th2) stage of cellular immunity. Melatonin, the main hormone produced by the pineal gland, seems to promote a Th1 response by increasing the production of IL-12. In a study of 77 anti-HIV-1-positive subjects and 20 healthy controls, melatonin were significantly lower in HIV-1-infected individuals in comparison with controls (p < 0.001). Within the HIV-1-seropositive group, mean melatonin and IL-12 concentrations were significantly lower in patients in CDC stage C, as compared with patients in CDC stages B and A (p < 0.01). Reduction of serum melatonin levels in HIV-1-infected individuals' parallel disease progression: correlation with serum interleukin-12 levels. Nunnari G, Nigro L, et al. Thomas Jefferson University. Infection. 2003 Dec;31(6):379-82

Alzheimer's: More Pineal Gland Calcification: CT determination of the degree of pineal calcification and the size of uncalcified pineal tissue in 279 memory clinic outpatients (AD: 155; other dementia: 25; mild cognitive impairment: 33; depression: 66) and 37 age-matched controls found the size of uncalcified pineal tissue in AD (0.15cm(2)) was significantly smaller than in patients with other types of dementia (0.26), with depression (0.28; P=0.005), or in controls (0.25; P=0.027). Additionally, the DOC in patients with AD (mean 76.2%) was significantly higher than in patients with other types of dementia (63.7; P=0.042), with depression (60.5; P=0.001), or in controls (64.5; P=0.021).

Alzheimer's Disorder: AD patients have more profound reductions in melatonin. Melatonin helps sundowning, and slows the progression of cognitive impairment in AD patients. It protects neuronal cells from Abeta-mediated toxicity via antioxidant and anti-amyloid properties and attenuates AD-like tau hyperphosphorylation and protects cholinergic neurons. Wang JZ, et al. Acta Pharmacol Sin 2006 Jan;27:41-9. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-beta toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning.

Alzheimer's: Genetic Abnormality May Reduce Serotonin for Melatonin Production: In a case-control association analysis, the risk of sleep disturbance in AD may be, at least in part, influenced by the availability of serotonin used for melatonin synthesis secondary to polymorphic variation at the enzyme monoamine oxidase A (MAO-A). Of  426 AD patients surveyed, 54% experienced sleep disturbance. A high-activity 4-repeat allele of the MAO-A VNTR promoter polymorphism confered increased susceptibility to sleep disturbance (p = .008). A quantitative sleep disturbance score was significantly higher in the patients possessing MAO-A 4-repeat allele genotypes. APOE had no influence on the development of an altered sleep phenotype.

ALS: Rectal High-Dose Melatonin Eliminated Elevated Oxidative Stress: Amyotrophic lateral sclerosis (ALS) is the collective term for a fatal motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression. Melatonin is an amphiphilic molecule with a unique spectrum of antioxidative effects. In cultured motoneuronal cells, melatonin attenuated glutamate-induced cell death of cultured motoneurons. In a genetic mouse model of ALS, high-dose oral melatonin delayed disease progression and extended survival. In a group of 31 patients with sporadic ALS, chronic high-dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment.

Anesthesia: Medication Need Reduced 40%: In a DB study of 200 surgical patients, either 0.2 mg/kg melatonin or a placebo were used for premedication. 50 min later, subgroups of 10 melatonin and 10 placebo patients were administered various doses of propofol (0.5, 1.0, 1.5, 2.0, or 2.4 mg/kg) or thiopental (2.0, 3.0, 4.0, 5.0, or 6.0 mg/kg) for anesthetic induction. The ability of each patient to respond to the command, "open your eyes," and the disappearance of the eyelash reflex were assessed 60 s after the end of the injection of propofol or thiopental. Melatonin premedication decreased thiopental ED50 values for loss of response to verbal command and eyelash reflex from 3.4 mg/kg and 3.7 mg/kg to 2.7 mg/kg  and 2.6 mg/kg (P < 0.05). Propofol ED50 values decreased from 1.5 mg/kg and 1.6 mg/kg to 0.9 mg/kg and 0.9 mg/kg  (P < 0.05).

Anorexia: Melatonin Cycle Flattened; Same in Obesity: Researchers measured the circadian rhythms of plasma melatonin, serum cortisol, growth hormone (GH) and prolactin (PRL) in 26 patients with anorexia nervosa (AN), 27 with primary obesity (OB) and 7 with bulimia nervosa (BN). They found daytime persistence of melatonin in AN and OB, and similar cortisol changes in AN and BN. Circadian neuroendocrine functions in disorders of eating behavior. Ferrari E, Magri F, et al. University of Pavia, Italy. Eat Weight Disord. 1997 Dec;2(4):196-202

Anxiety: Didn't Help Elderly Preoperative Anxiety: Melatonin has been reported to reduce preoperative anxiety. In a DB PC study of 138 patients over age 64, preoperative anxiety was not reduced by 10 mg of melatonin.

Arthritis: Rheumatoid Might Be Aggravated by Melatonin: A rat study of a model of rheumatoid arthritis showed that decreased melatonin helped and increased melatonin aggravated arthritis. Rheumatoid arthritis patients have increased nocturnal plasma levels of melatonin and that their synovial macrophages respond to melatonin with an increased cytokine production. Melatonin role in experimental arthritis. Cardinali DP, et al. Universidad de Buenos Aires. Curr Drug Targets Immune Endocr Metabol Disord. 2004 Mar;4(1):1-10

Asthma: Melatonin Lower: Lower levels of salivary melatonin were found in asthma patients compared with control subject (P<0.01). The amplitude, peak-level, and baseline of salivary melatonin were all significantly lower. Cortisol was greatly reduced. Alterations in circadian rhythms of melatonin and cortisol in patients with bronchial asthma. Fei GH, et al. Hefei, China. Acta Pharmacol Sin. 2004 May;25(5):651-6. Night time aggravation of asthma may be induced by melatonin.

Autism: Nocturnal Production Low: In a study of 49 children and adolescents with autistic disorder and 88 normal children, nocturnal production of melatonin was reduced in autism. Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder. Tordjman S, Anderson GM, et al. Universite de Rennes, France. Biol Psychiatry. 2005 Jan 15;57(2):134-8.

Blind People Helped by Melatonin: Melatonin 300 microg can entrain (synchronize) free-running circadian rhythms of 10 totally blind subjects that would otherwise drift later each day. Totally blind people will need to take melatonin daily over their entire lifetimes in order to remain entrained to the 24 h day. Left untreated, their free-running endocrine, metabolic, behavioral, and sleep/wake cycles can be almost as burdensome as not having vision.

Benign Prostatic Hypertrophy: Nocturia Reduced: In a DB PC crossover study of 20 men with BPH, those given 2 mg of melatonin-CR had a decrease in nocturia of 0.32 vs. 0.05 episodes per night (p = 0.07) and a decrease in the nocturia bother score of 0.51 vs. 0.05, respectively (p = 0.008). Daytime urinary frequency, International Prostate Symptom Score, relative nocturnal urine volume, maximum urinary flow rate and post-void residual were unaffected. Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement. Drake MJ, Mills IW, Noble JG. University of Newcastle upon Tyne, UK. J Urol. 2004 Mar;171(3):1199-202

Blood Pressure: Supplement Lowering Effect at Night in Diabetic Teens: Melatonin 5 mg taken at bedtime increases the nocturnal drop of diastolic blood pressure (BP) in adolescents with type 1 diabetes. In an open-label trial of 10 mg melatonin for 7 days with 9 normotensive adolescents with type 1 diabetes, and 8 healthy teens, for diabetic teens systolic BP decreased 4.4 mmHg and diastolic 2.2 mmHg, but no change for controls. Blood pressure-lowering effect of melatonin in type 1 diabetes. Cavallo A, Daniels SR, et al. University of Cincinnati. J Pineal Res. 2004 May;36(4):262-6

Blood Pressure: Nighttime BP Reduced in Hypertensives by Supplement: Patients with essential hypertension have disturbed autonomic cardiovascular regulation and circadian pacemaker function. The biological clock is involved in autonomic cardiovascular regulation. In a 3-week DB PC crossover study of 16 men with untreated essential hypertension, those taking melatonin 2.5 mg/night had reduced systolic and diastolic blood pressure during sleep by 6 and 4 mm Hg, respectively. The treatment did not affect heart rate. A single dose of melatonin had no effect on blood pressure or sleep. Improvements in blood pressure and sleep were statistically unrelated. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Scheer FA, Van Montfrans GA, et al. Netherlands Institute for Brain Research, Amsterdam. Hypertension. 2004 Feb;43(2):192-7. Similar findings: Am J Hypertens 2005 Dec;18:1614-8.

Cancer: Melatonin Increases Survival in Solid Tumor Cancer: In a review of 10 randomized controlled trials of melatonin in 643 solid tumor cancer patients and its effect on survival at 1 year, melatonin significantly reduced the risk of death by 34% (RR: 0.66). Effects were consistent across melatonin dose, and type of cancer. No severe adverse events were reported. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. Mills E, et al. McMaster University. J Pineal Res. 2005 Nov;39(4):360-6. A small, uncontrolled study for brain metastases did not find benefit. Int J Radiot Oncol Biol Phys 2007 Apr 5.

Cancer: Breast: Higher Melatonin Associated with Lower Cancer Risk:  Exposure to light at night suppresses melatonin production, and night-shift work has been associated with an increased risk of breast cancer. In a prospective case-control study nested within the Nurses' Health Study II cohort, researchers measured the concentration of the major melatonin metabolite, 6-sulphatoxymelatonin (aMT6s), in the first morning urine of 147 women with invasive breast cancer and 291 matched controls. The relative risk of invasive breast cancer for women in the highest quartile of urinary aMT6s compared with those in the lowest was 41% lower (OR = 0.59). This association was unchanged after adjustment for breast cancer risk factors or plasma sex hormone levels but was slightly weakened when the analysis included 43 case patients with in situ breast cancer and their 85 matched control subjects (OR = 0.70). The exclusion of women who had a history of night-shift work left the findings largely unchanged. Urinary melatonin levels and breast cancer risk. Schernhammer ES, et al. Brigham and Women's- Harvard. J Natl Cancer Inst. 2005 Jul 20;97(14):1084-7.

Cancer: Breast: Melatonin Might Be Involved: Environmental light powerfully suppresses the release of melatonin, which peaks in the middle of the night. This decreased  has been hypothesized to increase the risk of cancer. Evidence from experimental studies supports a link between melatonin and tumor growth. There is also fairly consistent indirect evidence from observational studies for an association between melatonin suppression, using night work as a surrogate, and breast cancer risk. Light at night and cancer risk. Schernhammer E, Schulmeister K. Harvard. Photochem Photobiol. 2004 Apr;79(4):316-8

Cancer: Breast: Mixed Evidence: In the prospective Guernsey III Study, the concentrations of 6-sulfatoxymelatonin, the main metabolite of melatonin in urine and a validated marker of circulating melatonin levels, were no significantly different in 127 patients diagnosed with breast cancer during follow-up vs. 353 matched controls. Melatonin and breast cancer: a prospective study. Travis RC, Allen DS, et al. University of Oxford. J Natl Cancer Inst. 2004 Mar 17;96(6):475-82; An inhibition of the pineal function with pinealectomy or a constant light regimen stimulates mammary carcinogenesis, whereas the light deprivation inhibits the carcinogenesis. Epidemiological findings of increased risk of breast cancer in night shift workers, flight attendants, radio and telegraph operators and of decreased risk in blind women are in accordance with experiments in rodents. Treatment with pineal indole hormone melatonin inhibits mammary carcinogenesis in pinealectomized rats, in animals kept at the standard light/dark regimen or at the constant illumination regimen. Anisimov. Crit Rev Oncol Hematol. 2003 Jun;46(3):221-34.

Cancer: Breast: Studies have shown that melatonin both treats and prevent breast cancer induced by DMBA in rats.  The authors speculate that it could do the same in humans who have breast cancer induced by other agents. Lenoir et al. Paris, France. Breast Cancer Res. 2005;7(4):R470-6.

Cancer: Breast: Night Work Linked to Increased Risk: Environmental light powerfully suppresses the release of melatonin, which peaks in the middle of the night. This decreased  has been hypothesized to increase the risk of cancer. Evidence from experimental studies supports a link between melatonin and tumor growth. There is also fairly consistent indirect evidence from observational studies for an association between melatonin suppression, using night work as a surrogate, and breast cancer risk. Light at night and cancer risk. Schernhammer E, Schulmeister K. Harvard. Photochem Photobiol. 2004 Apr;79(4):316-8

Cancer: Colon: Melatonin Slows Metastatic Disease:  Melatonin has been proven to enhance the anti-cancer efficacy of cisplatin, anthracyclines and 5-fluorouracil. In a randomized study of 30 metastatic colorectal cancer progressing after at least one previous chemotherapeutic line containing 5-fluorouracil, who were randomized to be treated with irinotecan (CPT-11) alone or CPT-11 plus MLT 20 mg/d, a partial response (PR) was achieved in 2 out of 16 patients treated with CPT-11 alone and in 5 out of 14 with MLT. A stable disease (SD) was obtained in 5 out of 16 patients treated with CPT-11 alone and in 7 out of 14 patients treated with CPT-11 plus MLT. Thus, some disease control was achieved by 86% with melatonin vs. 44% without, p < 0.05. Cerea G, Vaghi M, et al. Milan, Italy. Anticancer Res. 2003 Mar-Apr;23(2C):1951-4

Cancer: GI: Melatonin and Fish Oil Each Helped Advanced Cancer Some: In a randomized study of 24 patients with untreatable GI cancer and documented weight loss and/or decreased serum albumin, 38% of 13 patients given 30 cc of fish oil per day for 4 weeks and 27% of 11 given melatonin 18 mg/d had their weight stabilize or improve.  After combining the two, 63% showed stabilization. Impact of fish oil and melatonin on cachexia in patients with advanced gastrointestinal cancer: A randomized pilot study. Persson C, Glimelius B, et al. Uppsala University, Sweden. Nutrition. 2005 Feb;21(2):170-8

Cancer: Liver: Melatonin Helped Inoperably Hepatocellular Carcinoma: In a DB PC study of 100 patients with inoperable advanced primary hepatocellular carcinoma, transcatheter arterial chemoembolization (TACE) was compared to TACE+Melatonin (20 mg nightly starting 7 days before TACE). The effective rates of TACE vs. TACE+Melatonin were 16% vs. 28% (P<0.05). The resection rate at two-stage of TACE was 4% vs. 14% (P<0.01). The 0.5-, 1- and 2-year survival rates in the TACE group were 82%, 54% and 26%; in the TACE+Melatonin group did significantly better: 100%, 68% and 40%. With a definite protection and treatment effect on the liver function damage caused by TACE, Melatonin can enhance the immunological activities of patients. Patients with advanced primary hepatocellular carcinoma treated by melatonin and transcatheter arterial chemoembolization: a prospective study. Hepatobiliary Pancreat Dis Int. 2002 May;1(2):183-6.

Cancer: Lung: Helped Longevity when Added to Treatment: In a 5-year randomized study of 100 metastatic non-small cell lung cancer patients treated with cisplatin and etoposide, with or without melatonin (20 mg/day HS), overall tumor regression rate and the 5-year survival results were significantly higher in patients concomitantly treated with melatonin. Five-year survival with 0% without and 6% with melatonin. Chemotherapy was better tolerated in patients treated with melatonin. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. Lissoni P, Chilelli M, et al. Milan, Italy. J Pineal Res. 2003 Aug;35(1):12-5

Cancer: Solid Cancers Helped by Melatonin, Both Untreatable Patients and Those of Chemotherapy:  In the first DB PC study of 1,440 patients with untreatable advanced solid tumors, those who received melatonin 20 mg/day had a frequency of cachexia, asthenia, thrombocytopenia and lymphocytopenia that was significantly lower than in those who received supportive care alone. Moreover, the percentage of patients with disease stabilization and the percentage 1-year survival were both significantly higher in patients concomitantly treated with MLT than in those treated with supportive care alone. In a second DB PC study of 200 metastatic patients with chemotherapy-resistant tumor histotype, in those receiving melatonin 20 mg/day in addition to the chemotherapy the objective tumor response rate was significantly higher. Moreover, MLT induced a significant decline in the frequency of chemotherapy-induced asthenia, thrombocytopenia, stomatitis, cardiotoxicity and neurotoxicity.

Chronic Fatigue Syndrome: Melatonin, Phototherapy No Value in Study: In a randomized crossover study of 30 chronic fatigue syndrome patients, neither 12 weeks of melatonin 5 mg. at night nor 1 hour of morning phototherapy (2500 lux) reduced physical or emotional symptoms of CFS. Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy. Williams G, Waterhouse J, et al. University Hospital Aintree, Liverpool, UK. Eur J Clin Invest. 2002 Nov;32(11):831-7.

Chronic Fatigue Syndrome: Melatonin Might Help: In a report of 29 patients with chronic fatigue syndrome and Dim Light Melatonin onset later than 9:30 p.m., reflective of delayed circadian rhythmicity, patients took 5 mg of melatonin five hours before DLMO during 3 months. In a 6-week pre-treatment period the fatigue sub-score improved significantly. After treatment, the total CIS score and the sub-scores for fatigue, concentration, motivation and activity improved significantly. The sub-score fatigue normalized in two of the 29 patients in the pre-treatment period and in eight of 27 patients during treatment. This change was significant. In the patients with DLMO after 10:00 p.m. (n = 21) the total CIS score and the sub-scores for fatigue, concentration and activity improved significantly more than in the patients with DLMO earlier.

Chronic Fatigue Syndrome: Melatonin Helped Some: In a 3-month study of 29 patients with chronic fatigue syndrome (CFS) and Dim Light Melatonin onset (DLMO) later than 9:30 p.m., melatonin 5 mg, 5 h before DLMO improved fatigue, concentration, motivation and activity significantly. The sub-score fatigue normalized in two of the 29 patients in the pre-treatment period and in eight of 27 patients during treatment. This change was significant. In the patients with DLMO later than 10:00 p.m. (n = 21) the total CIS score and the sub-scores for fatigue, concentration and activity improved significantly more than in the patients (n = 8) with DLMO earlier than 10:00 p.m.

Dental: Melatonin Lower with More Severe Periodontal Disease: In a study of 37

Depression: Melatonin Levels Normal But Late in Onset and Offset: In this study of 14 major depressive inpatients, compared to 14 matched controls, the results suggest that the melatonin production is phase-shifted in major depression. Serum melatonin and urinary 6-sulfatoxymelatonin in major depression. Crasson M, Kjiri S, et al. Universite de Liege, Belgium. Psychoneuroendocrinology. 2004 Jan;29(1):1-12

Depression: Some Help for Mild Seasonal Affective Disorder: In a DB PC 3-week study of 58 adults with subsyndromal seasonal affective disorder (s-SAD) and/or the negative or positive type of weather-associated syndrome (WAS), melatonin 2 mg at night improved the quality of sleep (P=0.03) and vitality (P=0.02) in the subjects with s-SAD, but did not help individuals with WAS, positive type. Effect of controlled-release melatonin on sleep quality, mood, and quality of life in subjects with seasonal or weather-associated changes in mood and behaviour. Leppamaki S, Partonen T, et al. National Public Health Institute,  Helsinki, Finland. Eur Neuropsychopharmacol. 2003 May;13(3):137-45.

Depression: Melatonin May Have Helped Older Women in DB: Women over age 43 in Italy in a DB PC study took melatonin 3 mg at bedtime or placebo. Although the women not clinically depressed, the study found most reported a decrease in depressive symptoms while on melatonin. Exp Gerontol 2001 Feb;36(2):297-310

Depression: No Extra Benefit from Melatonin added to Fluoxetine After ECT: DB 12 weeks after ECT. 28.5% relapse in both fluoxetine and fluoxetine + melatonin groups. Coadministration of melatonin and fluoxetine does not improve the 3-month outcome following ECT. Israel: Grunhaus L, Hirschman S, et al. J ECT 2001 Jun;17(2):124-8

Diabetes: Melatonin and Zinc Reduce Harmful Effects: The inadequate responses to oral hypoglycemic agents may be attributed to inadequate postreceptor events even when insulin levels are quite sufficient, and associated with oxidative stress induced by long-term hyperglycemia. In a DB PC study of 46 type 2 diabetic patients, a single daily oral doses of both 10 mg of melatonin and 50 mg of zinc acetate alone vs. 10 mg of melatonin and 50 mg of zinc acetate in addition to the regularly used metformin or placebo, given at bedtime for 90 days found improved fasting lipid profiles and microalbuminuria with melatonin and zinc for both groups. Effects of melatonin and zinc on glycemic control in type 2 diabetic patients poorly controlled with metformin. Hussain SA, et al. University of Baghdad. . Saudi Med J 2006 Oct;27(10):1483-8.

Diabetes: Melatonin Reduced Hyperglycemic Kidney Injury in Vitro: The antioxidative effects of melatonin (Mel), 5-hydroxytryptophan (5-HTP) and taurine (TAU) on hyperglycemia-induced oxidative stress was investigated in primary cultures of kidney-cortex tubule cells. In the presence of 30 mm glucose (hyperglycemic conditions), cell viability was decreased by about 35%. Melatonin reduced protein and DNA injuries by about 50% vs. 25% for taurine and 0% for 5-HPT.

Epilepsy in Children: Possible Benefit: Two pediatric epileptic patients with intractable epilepsy of early onset had not been adequately helped by different anticonvulsive treatments for many years. However, in response to 3 mg melatonin co-medication at bedtime, suppression of seizure activity was shown on the EEG record of both children, and the number of their convulsions reduced clinically. 3 month later the melatonin co-medication was stopped. The seizures appeared again. Effect of melatonin on intractable epilepsies. Saracz J, Rosdy B. Budapest. Orv Hetil. 2004 Dec 19;145(51):2583-7.

Eye: Age-related Macular Degeneration Halted by Melatonin: Melatonin has been shown to have the capacity to control eye pigmentation and thereby regulate the amount of light reaching the photoreceptors, to scavenge hydroxyradicals and to protect retinal pigment epithelium (RPE) cells from oxidative damage. The physiological decrease of melatonin in aged people may be an important factor in RPE dysfunction, which is a well known cause for initiation of AMD. In a case-control study with a follow-up of 6-24 months, 100 patients with AMD were given 3 mg melatonin at bedtime for at least 3 months with 55 patients followed for more than 6 months. At 6 months, the visual acuity had been kept stable in general. This result is better than the otherwise estimated natural course. Only 8 eyes showed more retinal bleeding and 6 eyes more retinal exudates. The majority had reduced pathologic macular changes. We conclude that the daily use of 3 mg melatonin seems to protect the retina and to delay macular degeneration. No significant side effects were observed.

GI Tract: Melatonin an Important Role: The gastrointestinal (GI) tract presents another, many times larger, source of melatonin. It may exert a direct effect on GI tissues but its major influence on GI organs seems to occur indirectly, via the brain-gut axis including peripheral receptors, sensory afferent (vagal or sympathetic) pathways and central nervous system (CNS) acting on these organs via autonomic efferents and neuromediators. Melatonin is also discharged into the gut lumen and is implicated in the postprandial stimulation of pancreatic enzyme secretion, mediated by melatonin-induced release of cholecystokinin, acting through entero-gastro-pancreatic reflexes. It has highly protective actions against the damage of both the stomach and the pancreas and accelerates the healing of chronic gastric ulcerations by stimulating the microcirculation and cooperating with arachidonate metabolites such as prostaglandins, with nitric oxide released from vascular endothelium, and/or sensory nerves and with their neuropeptides such as calcitonin gene related peptide. The beneficial effects of melatonin results in gastro- and pancreato-protection, prevents various forms of gastritis and pancreatitis through the activation of specific MT2-receptors and scavenges reactive oxygen species (ROS). Melatonin counteracts the increase in the ROS-induced lipid peroxidation and preserves, at least in part, the activity of key anti-oxidizing enzymes such as superoxide dismutase.

GI Tract: GERD Helped by Melatonin Combination: In a DB study of 351 GERD patient comparing a dietary supplementation containing: melatonin, l-tryptophan, vitamin B6, folic acid, vitamin B12, methionine and betaine vs. 20 mg omeprazole (melatonin has known inhibitory activities on gastric acid secretion and nitric oxide biosynthesis. Nitric oxide has an important role in the transient lower esophageal sphincter relaxation (TLESR), which is a major mechanism of reflux in patients with GERD, 100% of group A reported a complete regression of symptoms after 40 days vs. 65.7% of the omeprazole group (P < 0.05).

GI Tract: Irritable Bowel Syndrome Helped: In a 2-week, DB PC study of 30 IBS patients with sleep disturbances, melatonin 3 mg/night significantly decreased abdominal pain, reduced bloating, and enhanced the rectal pain threshold. There was no difference in stool type, frequency of defecation, and anxiety and depression between the treatment groups. Melatonin did not influence total sleep time, sleep latency, sleep efficiency, sleep onset latency, number of awakenings, duration of stage 1-4, REM sleep and REM onset latency. Melatonin improves bowel symptoms in irritable bowel syndrome patients who have sleep disturbances. Gut 2004; 53 (Suppl VI) A69

GI Tract: Irritable Bowel Syndrome Pain Helped by Melatonin  In a 2-week DB PC study of 40 Irritable Bowel Syndrome adults with sleep disturbances, melatonin 3 mg at before bedtime significantly decreased mean abdominal pain score (2.35 vs 0.70, p<0.001), and increased mean rectal pain threshold (24.8 vs 33.7 mmHg, p<0.01). Bloating, stool type, stool frequency, anxiety and depression scores did not significantly differ. Melatonin did not influence sleep including total sleep time, sleep latency, sleep efficiency, sleep onset latency, arousals, duration of stage 1-4, REM sleep and REM onset latency. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised double blind placebo controlled study. Song GH, Leng PH, et al. National University of Singapore. Gut. 2005 May 24.

GI Tract: Melatonin Low in Duodenal Ulcer Patients: Strong decreases in melatonin were found in 15 ulcer patients compared to 11 controls. Neuroendocrinology Letters 2001:22:109-17.

G-I: Dyspepsia Helped in Large Majority: In a 12-week DB PC study of 60 patients ages 19-39 with the diagnosis of functional dyspepsia and no Helicobacter pylori infection, 57% of patients taking melatonin, 5 mg a night, had  dyspeptic symptoms completely subside. An additional 30%  had a partial improvement in health, especially in the frequency and intensity of nocturnal pain. After placebo, 93% of  patients did not experience any improvement (odds ratio 95.86, <0.01). H. pylori past infection decreased positive effect of melatonin in ulcerlike dyspepsia. Therapeutic effect of melatonin in patients with functional dyspepsia. Klupinska G, et al. Medical University of Lodz, Poland. J Clin Gastroenterol 2007 Mar;41(3):270-4.

G-I: Irritable Bowel Syndrome Helped: In an 8 week DB PC study of 18 IBS adults, J Clin Gastroenterol 2007 Jan;41(1):29-32.

G-I: Irritable Bowel Syndrome Pain Reduced: Melatonin, a sleep promoting agent, is also involved in the regulation of gastrointestinal motility and sensation. In a 2-week DB PC study of 40 IBS adults with sleep disturbances, melatonin 3 mg significantly decreased mean abdominal pain score (2.35 v 0.70; p<0.001) and increased mean rectal pain threshold (8.9 v -1.2 mm Hg; p<0.01). Bloating, stool type, stool frequency, and anxiety and depression scores did not significantly differ after treatment in both groups. Melatonin did not influence sleep parameters.

Hair: Melatonin Helped Female Hair Loss: Melatonin has been reported to have a beneficial effect on hair growth in animals. In a DB PC study of 40 women suffering from diffuse alopecia or androgenetic alopecia, a 0.1% melatonin solution daily for 6 months led to a significantly increased anagen hair rate in occipital hair in women with androgenetic hair loss compared with placebo (n=12; P=0.012). For frontal hair, melatonin gave a significant increase in the group with diffuse alopecia (n=28; P=0.046). Melatonin increases anagen hair rate in women with androgenetic alopecia or diffuse alopecia: results of a pilot randomized controlled trial. Fischer TW, et al. Friedrich-Schiller-University, Jena, Germany. 

Headaches: Melatonin, 3 mg Reported Effective for Migraine Prevention: Peres MF, Zukerman E, et al. Hospital Israelita Albert Einstein, Sao Paulo, Brazil. Neurology. 2004 Aug 24;63(4):757. Ed: I don’t know any details of this report.

Headaches: Migraine Victims Melatonin Falls Markedly with Nighttime Light: In a study of 12 women with familial migraines during headache-free periods vs. 12 controls, the nighttime melatonin production of the migraine sufferers was much more sensitive to light exposure (300 lx): -53.8 vs. 18.5 pg/h/ml, P<0.005; maximum of MLT suppression = -35.7 vs. - 6.7 pg/ml, P<0.05.  Melatonin secretion is supersensitive to light in migraine. Claustrat B, Brun J, et al. Institut Federatif de Neurosciences, Lyon, France. Cephalalgia. 2004 Feb;24(2):128-33

Headache: Melatonin as treatment for idiopathic stabbing headache. Rozen TD. Michigan Head-Pain and Neurological Institute, Ann Arbor. Neurology. 2003 Sep 23;61(6):865-6.

Headache: Hemicrania continua: a case in which a patient experienced complete relief on melatonin.

Heart: Heart Attack Victims Lower Nighttime Melatonin and Higher Interleukin-6: Atherosclerosis involves inflammatory cells, inflammatory proteins, and inflammatory responses from vascular cells. Cytokine activities are under neuroendocrine control, in part exerted by the pineal gland through the circadian secretion of its main product melatonin. In a study of 60 heart attack victims and 60 health adults, IL-6 was higher in the acute myocardial infarction group (101.26 vs. 52.67 pg/ml at 02:00 h,  and 41.93 vs. 22.98 pg/ml at 09:00 h, p < 0.05). Nighttime melatonin levels were high in the healthy adults (48.19 at 02:00 h, 14.51 at 09:00 h, pg/ml) vs. (25.97 at 02:00 h, 12.29 at 09:00 h, pg/ml) (p < 0.05). Melatonin seems to have an anti-inflammatory effect. Light/dark patterns of interleukin-6 in relation to the pineal hormone melatonin in patients with acute myocardial infarction. Dominguez-Rodriguez A, Abreu-Gonzalez P, et al. Hospital Universitario de Canarias, Spain. Cytokine. 2004 Apr 21;26(2):89-93; Similar melatonin findings were reported in an earlier study. Yaprak M, Altun A, et al. Int J Cardiol. 2003 May;89(1):103-7; In another study population of 60 patients with AMI and 60 control adults, heart attack victims had higher nocturnal serum oxidized LDL levels (95.47 vs. 68.35 U/l; p=0.004). Nocturnal serum levels of MEL were lower in AMI (20.97 vs. 53.19 pg/ml; p=0.009). Serum levels of total, high-density lipoprotein (HDL), and LDL cholesterol did not differ between the groups. Multiple regression analysis was performed on cases to study the association between AMI and serum levels of OxLDL and MEL (OR: 2.93; p=0.01 and OR: 0.94; p=0.02, respectively).

Heart: Heart Failure Victims Low in Melatonin: Urinary 6-sulfatoxymelatonin was much lower in 33 hospitalized patients with CHF than in 146 healthy volunteers (2.6 vs. 6.0 mcg; p<.0001). There were no significant differences in urinary 6-sulfatoxymelatonin levels between chronic and acute CHF patients. Such a decrease may precede aggravation of heart failure. Low urinary 6-sulfatoxymelatonin levels in patients with severe congestive heart failure. Girotti L, Lago M, et al. Buenos Aires, Argentina. Endocrine. 2003.  Dec;22(3):245-8; In patients with ST-segment elevation myocardial infarction, those had developed adverse events during follow-up had significantly lower nocturnal melatonin levels than patients without events. Am J Cardiol 2006 Apr 15;97(8):1162-4; The total antioxidant capacity of human serum is related to melatonin levels. Incidence of sudden cardiac death is high in the morning hours. It has been shown that melatonin levels are significantly low at these times and patients with coronary heart disease have lower than normal individuals. Melatonin would be valuable to test in clinical trials for prevention of possible ischemia-reperfusion-induced injury, especially life threatening arrhythmias and infarct size, effecting life quality, associated with thrombolysis, angioplasty, coronary artery spasm or coronary bypass surgery. 

Heart: Low Melatonin Predicts Bad Outcome in Heart Attack Victims: In patients with ST-segment elevation myocardial infarction, those who had developed adverse events during follow-up had significantly lower nocturnal melatonin levels than patients without events.

Hemodialysis Anemia Helped Dramatically by Melatonin: Treatment of anemia in hemodialysis results in high ferritin and low transferrin saturation depstie IV iron supplementation because of iron trapping in the reticulaendothelial system. Melatonin reduces sytokines and prevents oxidative stress caused by iron and erythropoietin treatment. In 10 hemodialysis patients with ferritins of 981 and TASTs of 15.6%, oral lematonin 6 mg/d for 30 days markedly raised TASTs to 35.5% (p<0.0001), decreased ferritin to 752 ng/ml (p<0.05) and dramatically increased serum iron from 42.4 to 110 mgc/dL (p<0.0001). Hemotocrit and hemoglobin increased from 28.6/9.19 to 31.9/10.04 (p<0.05). Values fell back to baseline levels within 2 weeks of stopping melatonin. Neurology 2005 Dec;10:583-7.

Hematology: Might Help ITP: Idiopathic thrombocytopenic purpura refractory to corticosteroids and splenectomy (refractory ITP) has a high morbidity from disease and a mortality rate of 16%. A patient is reported with severe bleeding symptoms related to refractory ITP successfully treated with melatonin. Todisco, Italy. Am J Ther. 2003 Mar-Apr;10(2):135-6.

Infant Respiratory Distress Syndrome: Oxidants Play Role; Melatonin Helps: Newborns with grade III or IV respiratory distress syndrome in the first 6 hours of life were given melatonin or placebo. Compared with the melatonin-treated respiratory distress syndrome newborns, in the untreated infants the concentrations of interleukin-6, interleukin-8, and tumor necrosis factor alpha were significantly higher at 24 hours, 72 hours, and at 7 days. Nitrite/nitrate levels at all time points were higher in the untreated respiratory distress syndrome newborns than in the melatonin-treated babies. Following melatonin administration, nitrite/nitrate levels decreased significantly, whereas they remained high and increased further in the respiratory distress syndrome infants not given melatonin. Oxidative and inflammatory parameters in respiratory distress syndrome of preterm newborns: beneficial effects of melatonin. Gitto E, Reiter RJ, Cordaro SP, et al. University of Messina, Italy. Am J Perinatol. 2004 May;21(4):209-16

Infant Respiratory Distress: Improved Outcome: In a DB PC study of 60 newborns with respiratory distress syndrome, those receiving melatonin had reduced cytokines and lower nitrite/nitrate levels. Eight infants not given melatonin developed chronic lung disease and two died vs. none for melatonin. Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. Gitto E, Reiter RJ, et al. University of Messina, Italy. J Pineal Res. 2004 May;36(4):250-5; Report expanded to DB PC of 110 newborns. J Pineal Res. 2005 Oct;39(3):287-93

Infertility in Males: Melatonin Levels are Reduced: In a study of 120 infetile males, serum and seminal plasma melatonin was reduced in all types of infertility. Melatonin levels correlated with sperm motility and with serum prolactin. Melatonin hormone profilel in infertile males. Awad H, et al. Int J Androl 2005 Dec 20.

Menopause: Melatonin and Soy Isoflavone No Benefit for Menopause in DB: In a 3-month DB PC study of 262 menopausal women, women received placebo or soy isoflavones 80 mg. or melatonin 3 mg/day. Neither supplement did any better than the placebo. Soy isoflavones and melatonin for the relief of climacteric symptoms: a multicenter, double-blind, randomized study. Secreto G, Chiechi LM, Amadori A, Miceli R, Venturelli E, Valerio T, Marubini E. Maturitas. 2004 Jan 20;47(1):11-20. Ed: This was a large study and thus more likely to detect any benefit.

Obesity: Smaller Pineal Glands in Obese: This study found a lower pineal width and volume in overweight individuals. Other studies find less sleep associated with more obesity and less night time melatonin in the obsess. Morphometry of the pineal gland in overweight individuals. Torres K, Staskiewicz GJ, et al. Medical University of Lublin. Ann Univ Mariae Curie Sklodowska [Med]. 2003;58(2):270-5

Obesity: Night Eaters Low in Nighttime Melatonin: Night-eating syndrome (NES) consists of morning anorexia, heavy evening eating, and insomnia. In a behavioral study, compared with 10 control subjects,10 night eaters had more eating episodes in the 24 hours (9.3 vs. 4.2; P<.001) and consumed significantly more of their daily energy intake at night than did controls (56% vs. 15%; P<.001). They averaged 3.6 awakenings per night compared with 0.3 by controls (P<.001). In night eaters, 52% of these awakenings were associated with food intake, with a mean intake per ingestion of 1134 calories. None of the controls ate during their awakenings. In the neuroendocrine study, compared with control subjects, night eaters had attenuation of the nocturnal rise in plasma melatonin and leptin levels (P<.001 for both) and higher circadian levels of plasma cortisol (P = .001). Behavioral and neuroendocrine characteristics of the night-eating syndrome. Birketvedt GS, Florholmen J, et al. University of Tromso, Norway. JAMA. 1999 Aug 18;282(7):657-63

Obesity: TV Watching Decreases Melatonin in Children: Changes in magnetic field are associated with a decrease in nocturnal urinary melatonin excretion. Using 24-hour urines from 42 boys and 32 girls ages 6-13 after one week of watching TV and after another week of abstaining, exposure to a TV screen was associated with lower urinary melatonin concentrations, affecting particularly younger children at a pubertal stage. Researchers wonder whether exposure from TV might have an effect increasing obesity apart from any decreased activity and/or other lifestyle alterations.

Pre-operative Anxiety in Children: Melatonin Better: Unlike midazolam, a minor tranquilizer and the current standard pre-operative medication for anxiety, melatonin premedication is not associated with cognitive impairment in adults despite its anti-anxiety properties. In a DB PC study comparing perioperative melatonin vs. midazolam in children, 7 groups of children (15 in each) were randomly assigned to: midazolam 0.1, 0.25 or 0.5 mg/kg orally, melatonin 0.1, 0.25 or 0.5 mg/kg orally each mixed in 15 mg/kg acetaminophen, or placebo only (15 mg/kgacetaminophen). Melatonin or midazolam each in doses of 0.25 or 0.5 mg kg(-1) were equally effective as premedicants in alleviating separation anxiety and anxiety associated with the introduction of the anaesthesia mask. Midazolam tended to prolong recovery times as the dosage increased. Melatonin had a lower incidence (P = 0.049) of excitement at 10 min postoperatively, and a lower incidence (P = 0.046) of sleep disturbance at week 2 postoperatively than that observed with midazolam and control groups. No postoperative excitement was noted in the melatonin groups at 20, 30 and 45 min. Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study. Samarkandi A, Naguib M, et al. King Saud University, Riyadh, Saudi Arabia. 

Sarcoidosis Helped by Melatonin: Chronic sarcoidosis (CS) is often unresponsive to usual treatments. Melatonin was given for 2 yr (20 mg/day in the first year, 10 mg/day in the second year) to 18 CS patients. Normalization of ACE, improvement of pulmonary parameters and resolution of skin involvement were found in the patients given melatonin. After 24 months of melatonin therapy, hylar adenopathy completely resolved in eight patients and parenchymal lesions were markedly improved in all patients; in the five patients with reduced diffusion capacity of the lung for carbon monoxide, the values normalized after 6 months of therapy and remained stable until month 24. After 24 months, Ga(67) pulmonary and extra-pulmonary uptake was totally normalized in seven patients and, at month 12 months, ACE was normalized in six patients in which the values were high at the baseline. Skin lesions, present in three patients, completely disappeared at month 24 months. No side effects were experienced and no disease relapse was observed during melatonin treatment.

Schizophrenia: Speculation That Melatonin Might Help: Neuronal shape, loss of dendrites and spines, as well as irregular distribution of neuronal elongations occur in specific brain areas of schizophrenic patients. Increase in non-phosphorylated MAP2 and MAP 1B at hippocampus has been suggested as responsible for somatodendritic and cytoarchitectural abnormalities found in schizophrenia. In addition, neurofibrillary tangles are more frequent among schizophrenic patients who received pharmacologic antipsychotic treatment. Melatonin promotes neuritogenesis through cytoskeletal rearrangements. The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. Benitez-King G, et al. Mexico, D.F., Mexico. Curr Drug Targets CNS Neurol Disord. 2004 Dec;3(6):515-33

Schizophrenia: Possible Lack of Daily Pattern or Inadequate Production: In a study of 10 male schizophrenics, 7 had low daily melatonin production or lack a normal circadian pattern. Reduction of night/day difference in melatonin blood levels as a possible disease-related index in schizophrenia. Bersani G, Mameli M, et al. University of Rome La Sapienza. Neuro Endocrinol Lett. 2003 Jun-Aug;24(3-4):181-4; Similar: Schizophr Res. 1992 Apr;7(1):77-84.

Schizophrenia: ICU Surgical Psychosis Higher with Melatonin Irregularity: Intensive care unit (ICU) psychosis is frequent complication after esophageal surgery. In 41 patients who underwent esophagectomy for esophageal cancer, 11 (26.8%) developed ICU psychosis. These patients were older (P =.01), but had no significant differences in the duration of surgery, volume of blood loss, term in the ICU, term of intubation, tumor location, disturbances of organ function, and postoperative complications. There was a significant correlation was seen between ICU psychosis and an irregular melatonin circadian rhythm (P =.0001). Authors suggest that supplementation with melatonin may protect patients from development of ICU psychosis. Correlation between serum melatonin circadian rhythm and intensive care unit psychosis after thoracic esophagectomy. Miyazaki T, Kuwano H, et al. Gunma University, Maebashi, Japan. Surgery. 2003 Jun;133(6):662-8.

Schizophrenia: Melatonin Low; Supplement Helps Sleep: In a DB PC crossover study of 19 schizophrenic adults, during 3 weeks of melatonin 2 mg at bedtime, there was improved rest-derived sleep efficiency (83.5% vs. 78.2%, p = .038). Improvement of sleep efficiency was significantly greater (p < .0014) in low-efficiency (80% vs. 67%) than high-efficiency sleepers (88% vs. 90%). There were trends toward shortened sleep latency (by 40 minutes, p < .056) and increased sleep duration (by 45 minutes, p < .078) in low- but not high-efficiency sleepers. All patients were low in melatonin. Melatonin improves sleep quality of patients with chronic schizophrenia. Shamir E, Laudon M, Tel Aviv University, Israel. J Clin Psychiatry. 2000 May;61(5):373-7.

Schizophrenia: Melatonin Low; Unaffected by Treatment: In 9 drug-free schizophrenics, the nocturnal increase in plasma melatonin levels was significantly blunted as compared to healthy subjects (p < 0.0001). Chronic treatment with antipsychotic drugs improved psychotic symptoms, but did not change the secretory pattern of melatonin. Decreased nocturnal secretion of melatonin in drug-free schizophrenics: no change after subchronic treatment with antipsychotics. Monteleone P, Natale M, et al. Second University of Naples, Italy. Neuropsychobiology. 1997;36(4):159-63. Similar: Acta Psychiatr Scand. 1991 Sep;84(3):221-4.

Schizophrenia: Hypothalamus Damage May Cause Low Melatonin: Melatonin secretion is stimulated by the paraventricular nucleus (PVN) of the hypothalamus. Lesions of the PVN mimic the endocrine effects of pinealectomy. Since the PVN lies adjacent to the third ventricle, periventricular damage may account for the third ventricular dilatation seen on computed tomographic (CT), may disrupt PVN-pineal interactions and ultimately enhance the process of pineal calcification (PC) in schizophrenia. A CT study on the relationship of PC size to third ventricular width (TVW) in 12 chronic schizophrenic patients (mean age: 34) found a significant correlation between PC size and TVW (p < .05). Habenular calcification (HAC) on CT in 23 chronic schizophrenic-patients was present in 87% vs. 15% of controls (p < .0001) in chronic schizophrenia as compared to normal controls. Pineal and habenula calcification in schizophrenia. Sandyk R. Albert Einstein. Int J Neurosci. 1992 Nov-Dec;67(1-4):19-30.

Schizophrenia: Pineal Calcification More Common in Pre-menopausal Onset Schizophrenia: In a study of 29 randomly selected chronic institutionalized female schizophrenic patients, premenopausal-onset patients were more likely to have pineal gland calcificationn (PC) on CT: 55.5% vs. 18.1%, p < .05. PC was unrelated to historical, demographic, and treatment variables. The pineal gland may exert a protective effect against its onset. Pineal calcification in relation to menopause in schizophrenia. Sandyk R. Albert Einstein. Int J Neurosci. 1992 Nov-Dec;67(1-4):1-8.

Seizures: Two Child Cases Where Possible Benefits: Two pediatric epileptic patients with intractable epilepsy of early onset with various anticonvulsive treatments having been ineffective improved on 3 mg melatonin co-medication at bedtime. Seizure activity on EEG with suppressed and the number of convulsions reduced. 3 month later the melatonin co-medication was stopped. The seizures reappeared. Effect of melatonin on intractable epilepsies. Saracz J, Rosdy B. Budapest. Orv Hetil. 2004 Dec 19;145(51):2583-7.

Surgery: Propofol Anesthesia Dose Reduced: In a DB PC study of 45 adults undergoing surgical procedures, melatonin 3 mg or 5 mg at 100 min preoperatively reduced the induction dose of propofol needed: 134 mg in the placebo group vs. 115 and 114 mg in the M3 and M5 groups (P < 0.05). The propofol dose required to achieve loss of eyelash reflex and loss of response to verbal commands was more in the placebo group. Anxiety score as assessed by visual analogue scale scored more in the placebo group. Time spent in the recovery room did not differ between the three groups.

Tardive Dyskinesia: Melatonin Helps in DB: In a DB PC crossover study of 22 patients with TD given melatonin 10 mg/day for 6 weeks, there was a decreased AIMS score of 2.45 points vs. 0.77 with placebo. Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Shamir E, Barak Y, et al. Israel. Arch Gen Psychiatry 2001 Nov;58(11):1049-52.  No benefit was found for 2 mg/day for 4 weeks on 19 patients in an earlier study by the same research team. J Clin Psychiatry. 2000 Aug;61(8):556-8. Melatonin is a very inexpensive and reasonably effective over-the-counter natural sleep remedy increasingly used by the lay public but ignored by treating physicians. Bipolars are more susceptible to TD side-effects and have been reported to have a much higher risk of pineal gland calcification than average.  Melatonin is produced in the pineal gland. Int J Neurosci. 1990 Oct;54(3-4):307-13; It helped reserpine-induced chewing movements in rats. Brain Res. 2001 Jun 15;904(1):149-52. Chronically hospitalized schizophrenic and bipolar patients are more likely to have calcified pineal glands (18% vs. 1%). Int J Neurosci. 1990 Aug;53(2-4):223-9. Schizophrenic patients with calcifications are more likely to have tardive dyskinesia. Int J Neurosci. 1990 Aug;53(2-4):217-22.  Melatonin also reduced age-related orofacial movements in rats. Psychopharmacology (Berl). 2002 Jun;161(4):340-7. 

Tardive Dyskinesia: Melatonin May Help as Anti-Oxidant: Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats, referred to as vacuous chewing movements (VCMs). VCMs in rats are widely accepted as an animal model of TD. Rats chronically treated with haloperidol develop VCMs and tongue protrusions. Melatonin dose-dependently (1, 2, and 5 mg/kg) reversed the haloperidol-induced VCM and tongue protrusions frequencies. The haloperidol treatment induced lipid peroxidation and decreased the forebrain glutathione (GSH) levels in the rats. Haldol also decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD), and catalase. Coadministration of melatonin (1, 2, and 5 mg/kg) along with haloperidol significantly reduced the lipid peroxidation and restored the decreased GSH levels by chronic haloperidol treatment, and significantly reversed the haloperidol-induced decrease in forebrain SOD and catalase levels. However, a lower dose of melatonin (1 mg/kg) failed to reverse chronic haloperidol-induced decreases in forebrain GSH, SOD, and catalase levels. Possible mechanism of action in melatonin attenuation of haloperidol-induced orofacial dyskinesia. Naidu PS, et al. Panjab University, Chandigarh, India. Pharmacol Biochem Behav. 2003 Feb;74(3):641-8.

Thomas E. Radecki, M.D., J.D.

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