Dr. Weeks’ Comment: Melatonin, a naturally occurring hormone with receptors in all human cells, is far more beneficial than simply a sleep aid, especially in higher dosages. Typically taken in low dosages (3-10mg a day) many doctors today, following the scientific discoveries of Dr. Russ Reiter offer doses between 60 and 180mg a day.  Side-effects of excessive melatonin are minor and self-limiting and these side-effects include:

• Feeling sleepy or tired in the daytime
• Headache
• Stomach ache
• Feeling sick (nausea)
• Feeling dizzy
• Feeling irritable or restless
• Dry mouth
• Dry or itchy skin
• Pains in your arms or legs
• Strange dreams or night sweats
• Depressed mood

So, what is to be gained by adding melatonin to your daily supplements?

As Dr. Reiter explains Melatonin is functionally like a Swiss Army Knife.

Like the multi-tooled device bearing the Swiss coat of arms, melatonin has a bewildering array of functions and employs a variety of means to carry them out. These actions likely impact every cell in every organism throughout the plant and animal kingdoms. As a consequence, the physiological and pathophysiological actions of melatonin are numerous.

So… how is your heart? your memory? your energy? your vitality?

Read the snippets below and get your melatonin!

 

HEART Benefits

Melatonin protects the heart and endothelium against high fructose corn syrup consumption–induced cardiovascular toxicity via SIRT-1 signaling

M Savran  First published online June 30, 2019

https://doi.org/10.1177/0960327119860188

Abstract

High fructose corn syrup (HFCS) has been shown to cause cardiovascular toxicity via oxidative stress and inflammation. The aim of this study is to demonstrate the protective effects of melatonin (MLT) against HFCS-induced endothelial and cardiac dysfunction via oxidative stress and inflammation. Thirty-two Sprague Dawley male rats were distributed into three groups as control, HFCS, and HFCS + MLT. HFCS form F55 was prepared as 20% fructose syrup solution and given to the rats through drinking water for 10 weeks, and MLT administrated 10 mg/kg/day orally for last 6 weeks in addition to F55. After decapitation, blood and half of the heart samples were collected for biochemical analysis and other half of the tissues for histopathological and immunohistochemical analysis. Aspartate transaminase, creatine kinase MB, lactate dehydrogenase, total oxidant status and oxidative stress index, and caspase-3 levels increased and total antioxidant status levels decreased significantly in HFCS group. MLT treatment reversed all these parameters. Histopathologically, hyperemia, endothelial cell damage and increased levels of angiogenin, C-reactive protein, inducible nitric oxide synthase, myeloperoxidase and decreased sirtuin-1 (SIRT-1) expressions were observed in HFCS group. MLT ameliorated all these changes. MLT has an anti-inflammatory, antioxidant, antiapoptotic effects on HFCS-induced cardiovascular toxicity through enhancing the expression of SIRT-1.

 

 

CANCER Benefits

Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis

Russel J Reiter ¹,  DOI: 10.3390/ijms18040843 Int J Mol Sci. 2017 Apr 17;18(4):843.

Abstract

There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin’s co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients.

 

Protection against NEURODEGENERATIVE Diseases

 

MULTIPLE SCLEROSIS. MS

Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells

George Anderson ¹, Moses Rodriguez ², Russel J Reiter ³

 

Int J Mol Sci. 2019 Nov 5;20(21):5500. DOI: 10.3390/ijms20215500

Abstract

Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1. LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide. Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate. Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide. Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin. Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA). Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function. Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology. Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS). The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology. NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology. This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate.

 

PARKINSON’S DISEASE

Melatonin and Parkinson Disease: Current Status and Future Perspectives for Molecular Mechanisms

Omid Reza Tamtaji ¹, Russel J Reiter ², DOI: 10.1007/s10571-019-00720-5

Cell Mol Neurobiol. 2020 Jan;40(1):15-23.

doi: 10.1007/s10571-019-00720-5. Epub 2019 Aug 6.

 

Abstract

Parkinson disease (PD) is a chronic and neurodegenerative disease with motor and nonmotor symptoms. Multiple pathways are involved in the pathophysiology of PD, including apoptosis, autophagy, oxidative stress, inflammation, α-synuclein aggregation, and changes in the neurotransmitters. Preclinical and clinical studies have shown that melatonin supplementation is an appropriate therapy for PD. Administration of melatonin leads to inhibition of some pathways related to apoptosis, autophagy, oxidative stress, inflammation, α-synuclein aggregation, and dopamine loss in PD. In addition, melatonin improves some nonmotor symptom in patients with PD. Limited studies, however, have evaluated the role of melatonin on molecular mechanisms and clinical symptoms in PD. This review summarizes what is known regarding the impact of melatonin on PD in preclinical and clinical studies.

And

Melatonin and Parkinson’s disease

Juan C Mayo ¹, Rosa M Sainz, Dun-Xian Tan, Isaac Antolín, Carmen Rodríguez, Russel J Reiter

 

DOI: 10.1385/ENDO:27:2:169  Endocrine. 2005 Jul;27(2):169-78.

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. It is characterized by a progressive loss of dopamine in the substantia nigra and striatum. However, over 70% of dopaminergic neuronal death occurs before the first symptoms appear, which makes either early diagnosis or effective treatments extremely difficult. Only symptomatic therapies have been used, including levodopa (l-dopa), to restore dopamine content; however, the use of l-dopa leads to some long-term pro-oxidant damage. In addition to a few specific mutations, oxidative stress and generation of free radicals from both mitochondrial impairment and dopamine metabolism are considered to play critical roles in PD etiology. Thus, the use of antioxidants as an important co-treatment with traditional therapies for PD has been suggested. Melatonin, or N-acetyl-5-methoxy-tryptamine, an indole mainly produced in the pineal gland, has been shown to have potent endogenous antioxidant actions. Because neurodegenerative disorders are mainly caused by oxidative damage, melatonin has been tested successfully in both in vivo and in vitro models of PD. The present review provides an up-to-date account of the findings and mechanisms involved in neuroprotection of melatonin in PD.

 

BRAIN Benefits

DEMENTIA

Mechanisms of Melatonin in Alleviating Alzheimer’s Disease

Mayuri Shukla ¹, Piyarat Govitrapong ², Parichart Boontem ¹, Russel J Reiter ³,

 

DOI: 10.2174/1570159X15666170313123454 Curr Neuropharmacol. 2017;15(7):1010-1031.

Abstract

Alzheimer’s disease (AD) is a chronic, progressive and prevalent neurodegenerative disease characterized by the loss of higher cognitive functions and an associated loss of memory. The thus far “incurable” stigma for AD prevails because of variations in the success rates of different treatment protocols in animal and human studies. Among the classical hypotheses explaining AD pathogenesis, the amyloid hypothesis is currently being targeted for drug development. The underlying concept is to prevent the formation of these neurotoxic peptides which play a central role in AD pathology and trigger a multispectral cascade of neurodegenerative processes post-aggregation. This could possibly be achieved by pharmacological inhibition of β- or γ-secretase or stimulating the nonamyloidogenic α-secretase. Melatonin the pineal hormone is a multifunctioning indoleamine. Production of this amphiphilic molecule diminishes with advancing age and this decrease runs parallel with the progression of AD which itself explains the potential benefits of melatonin in line of development and devastating consequences of the disease progression. Our recent studies have revealed a novel mechanism by which melatonin stimulates the nonamyloidogenic processing and inhibits the amyloidogenic processing of β-amyloid precursor protein (βAPP) by stimulating α -secretases and consequently down regulating both β- and γ-secretases at the transcriptional level. In this review, we discuss and evaluate the neuroprotective functions of melatonin in AD pathogenesis, including its role in the classical hypotheses in cellular and animal models and clinical interventions in AD patients, and suggest that with early detection, melatonin treatment is qualified to be an anti-AD therapy.

 

ENERGY Benefits

Clinical uses of melatonin: evaluation of human trials

E J Sánchez-Barceló ¹, M D Mediavilla, D X Tan, R J Reiter

 

DOI: 10.2174/092986710791233689  Curr Med Chem. 2010;17(19):2070-95.

Abstract

During the last 20 years, numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. The objective of this article is to review, in depth, the science regarding clinical trials performed to date. The efficacy of melatonin has been assessed as a treatment of ocular diseases, blood diseases, gastrointestinal tract diseases, cardiovascular diseases, diabetes, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, infectious diseases, neurological diseases, sleep disturbances, aging and depression. Melatonin has been also used as a complementary treatment in anaesthesia, hemodialysis, in vitro fertilization and neonatal care. The conclusion of the current review is that the use of melatonin as an adjuvant therapy seems to be well funded for macular degeneration, glaucoma, protection of the gastric mucosa, irritable bowel syndrome, arterial hypertension, diabetes, side effects of chemotherapy and radiation in cancer patients or hemodialysis in patients with renal insufficiency and, especially, for sleep disorders of circadian etiology (jet lag, delayed sleep phase syndrome, sleep deterioration associated with aging, etc.) as well as in those related with neurological degenerative diseases (Alzheimer, etc.,) or Smith-Magenis syndrome. The utility of melatonin in anesthetic procedures has been also confirmed. More clinical studies are required to clarify whether, as the preliminary data suggest, melatonin is useful for treatment of fibromyalgia, chronic fatigue syndrome, infectious diseases, neoplasias or neonatal care. Preliminary data regarding the utility of melatonin in the treatment of ulcerative colitis, Crohn’s disease, rheumatoid arthritis are either ambiguous or negative. Although in a few cases melatonin seems to aggravate some conditions, the vast majority of studies document the very low toxicity of melatonin over a wide range of doses.

 

ANTI-AGING Benefits

 

Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin

Russel J. Reiter

https://www.tandfonline.com/doi/abs/10.1080/10409230903044914

ABSTRACT

ABSTRACT

The discovery of melatonin and its derivatives as antioxidants has stimulated a very large number of studies which have, virtually uniformly, documented the ability of these molecules to detoxify harmful reactants and reduce molecular damage. These observations have clear clinical implications given that numerous age-related diseases in humans have an important free radical component. Moreover, a major theory to explain the processes of aging invokes radicals and their derivatives as causative agents. These conditions, coupled with the loss of melatonin as organisms age, suggest that some diseases and some aspects of aging may be aggravated by the diminished melatonin levels in advanced age. Another corollary of this is that the administration of melatonin, which has an uncommonly low toxicity profile, could theoretically defer the progression of some diseases and possibly forestall signs of aging. Certainly, research in the next decade will help to define the role of melatonin in age-related diseases and in determining successful aging. While increasing life span will not necessarily be a goal of these investigative efforts, improving health and the quality of life in the aged should be an aim of this research.

 

And…  for WHATEVER AILS YOU

 

Clinical Uses of Melatonin: Evaluation of Human Trials

 

Authors: Sanchez-Barcelo, E.J.; Mediavilla, M.D.; Tan, D.X.; Reiter, R.J.

Source: Current Medicinal Chemistry, Volume 17, Number 19, 2010, pp. 2070-2095(26)

DOI: https://doi.org/10.2174/092986710791233689

 

ABSTRACT

During the last 20 years, numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. The objective of this article is to review, in depth, the science regarding clinical trials performed to date. The efficacy of melatonin has been assessed as a treatment of ocular diseases, blood diseases, gastrointestinal tract diseases, cardiovascular diseases, diabetes, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, infectious diseases, neurological diseases, sleep disturbances, aging and depression. Melatonin has been also used as a complementary treatment in anaesthesia, hemodialysis, in vitro fertilization and neonatal care. The conclusion of the current review is that the use of melatonin as an adjuvant therapy seems to be well founded for macular degeneration, glaucoma, protection of the gastric mucosa, irritable bowel syndrome, arterial hypertension, diabetes, side effects of chemotherapy and radiation in cancer patients or hemodialysis in patients with renal insufficiency and, especially, for sleep disorders of circadian etiology (jet lag, delayed sleep phase syndrome, sleep deterioration associated with aging, etc.) as well as in those related with neurological degenerative diseases (Alzheimer, etc.,) or Smith-Magenis syndrome. The utility of melatonin in anesthetic procedures has been also confirmed. More clinical studies are required to clarify whether, as the preliminary data suggest, melatonin is useful for treatment of fibromyalgia, chronic fatigue syndrome, infectious diseases, neoplasias or neonatal care. Preliminary data regarding the utility of melatonin in the treatment of ulcerative colitis, Crohn’s disease, rheumatoid arthritis are either ambiguous or negative. Although in a few cases melatonin seems to aggravate some conditions, the vast majority of studies document the very low toxicity of melatonin over a wide range of doses.

Dr Weeks’ Comment:  Yes. You are correct. I cited that article twice as it is well worth reviewing!

 

ERECTILE DYSFUNCTION

 

BONUS: How are your erections (or those of your loved one?)

Melatonin and tadalafil treatment improves erectile dysfunction after spinal cord injury in rats

Hasan Hüseyin Tavukçu ¹, Russel J Reiter, Clin Exp Pharmacol Physiol. 2014 Apr;41(4):309-16.

PMID: 24552354

 

Abstract

Oxidative stress plays an important role both in spinal cord injury (SCI) and erectile dysfunction (ED). The present study investigated the effects of melatonin and tadalafil treatment alone or in combination on SCI-induced ED. Male Wistar albino rats (n = 40) were divided into five groups: sham-operated control and SCI-injured rats given either vehicle, melatonin (10 mg/kg, i.p.), tadalafil (10 mg/kg, p.o.) or a combination of melatonin and tadalafil. Spinal cord injury was induced using a standard weight-drop method. On Day 7 after SCI, intracavernosal pressure (ICP) was measured and all rats were decapitated. Cavernosal tissues were obtained to examine caspase 3, nitric oxide synthase (NOS), myeloperoxidase (MPO) and superoxide dismutase (SOD) activities, as well as cGMP, nerve growth factor (NGF), malondialdehyde (MDA) and glutathione (GSH) levels. Spinal cord injury caused oxidative damage, as evidenced by increases in MDA and cGMP levels. In addition, MPO and caspase 3 activites were increased after SCI, whereas GSH and NGF levels and SOD activity were reduced. Melatonin effectively reversed these oxidative changes. Furthermore, in rats treated with both melatonin and tadalafil, the recoveries were more pronounced than in rats given either melatonin or tadalafil alone. The ICP/mean arterial pressure value in vehicle-treated SCI rats was significantly higher than in the control group, whereas in the tadalafil- and tadalafil + melatonin-treated groups have returned this value had returned to control levels. As an individual treatment, and especially when combined with tadalafil, a well-known agent in the treatment of ED, melatonin prevented SCI-induced oxidative damage to cavernosal tissues and restored ED, most likely due to its anti-oxidant effects.