Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements
Abstract
:1. Introduction
2. Scientific Mechanisms
2.1. Mechanisms Related to Aging and Disease: Antioxidant Defense, Oxidative Stress Reduction, and Anti-Inflammatory Properties
2.2. The Central Role of the Mitochondria
2.3. Gut-Synthesized Melatonin the Gut Microbiome
Gut Health, Dietary Polyphenols Melatonin
2.4. Kynurenine Pathway, Energy Regulation Stress Response
3. Clinical Uses
3.1. Central Nervous System
3.1.1. Circadian Rhythm Modulation
Circadian Rhythm Sleep-Wake Disorders
Jet Lag
Sleep Dysfunction
- Insomnia: Immediate release 1–3 mg, 30 min before bed; slow-release can be used for sleep maintenance problems
- Regulating sleep in blind individuals who often experience non-24 h sleep-wake rhythm disorder;
- Replicating the normal endogenous pattern;
- Delayed sleep phase.
3.1.2. Eye Health
3.1.3. Cognitive Conditions (Dementia)
3.1.4. Migraines and Headaches
3.1.5. Tinnitus
3.1.6. Attention-Deficit Hyperactivity Disorder (ADHD) and Autism
3.2. Cardiometabolic Health
3.3. Reproductive Health
3.3.1. Pregnancy and Fertility
3.3.2. Endometriosis
3.3.3. Polycystic Ovarian Syndrome (PCOS)
3.4. Gastrointestinal Health
3.5. (Auto)Immunity
3.5.1. Oxidative Stress and Inflammatory States
3.5.2. Cancer Prevention and Treatment
3.6. Bone Health
4. Therapeutic Considerations
4.1. Dietary Sources of Melatonin
4.1.1. Plant Sources
4.1.2. Animal Sources
4.2. Dietary Supplements
4.2.1. Chemically Synthesized Melatonin
- 5-methoxy-3-indolylacetonitrile
- 5-methoxy-3-(2-nitroethyl)-indole
- 5-methoxytryptamine
- Phthalimide (1,3-dihydro-1,3-dioxoisonidole)
- 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
- 3-(phenylamino)-alanine;
- 1,1′-ethylidene bis-(tryptophan) (‘peak E’, one of the contaminants related to EMS);
- 2-(3-indolylmethyl)-tryptophan;
- Formaldehyde-melatonin;
- Formaldehyde-melatonin condensation products;
- Hydroxymelatonin isomers;
- 5-hydroxy-tryptamine derivatives;
- 5-methoxy-tryptamine derivatives;
- N-acetyl-and diacetyl-indole derivatives;
- 1,3-diphthalimidopropane;
- Hydroxy-bromo-propylphthalimide;
- Chloropropylphthalimde.
4.2.2. Phytomelatonin
Feature | Phytomelatonin * | Synthetic Melatonin |
---|---|---|
Origin | Plants | Chemicals |
Processing | Customized cultivation technique of selecting the ideal location, soil, climate and optimal method/time to harvest based on the plant’s cycles to optimize melatonin levels | Chemical synthesis |
Constituents | Bioidentical melatonin plus other plant actives; no excipients, fillers, or binding agents | Bioidentical melatonin and possibly contaminants from the chemical synthesis; depending on the dietary supplement, it may contain excipients, fillers, or binding agents |
Environmentally safe? | Yes | No, uses toxic solvents and generates pollution |
Other nutritionally active compounds included | (Essential) Fatty acids, amino acids, vitamins (vitamin K, riboflavin (vitamin B2), choline, vitamin E, thiamin (vitamin B1), pyridoxine (vitamin B6), biotin), minerals (trace amounts of calcium, magnesium, zinc, iron, manganese, selenium, copper, potassium, sodium, phosphorus, chloride, iodine), phytonutrients (beta-carotene, xanthophyll, zeaxanthin, lutein, chlorophyll, violaxanthin); Concentration of these adjunctive compounds depend on growing and seasonal changes. | None |
Anti-inflammatory activity | Yes, more effective in inhibiting COX-2 in a cellular assay compared with synthetic melatonin [34] | Yes, although not more effective than phytomelatonin * [34] |
Antiradical scavenging activity | Yes, it possesses significantly stronger free radical scavenging capacity as compared to synthetic melatonin using a cellular assay to assess Free Radical Scavenging Percentage (DPPH%) [34]. | Yes, it has antiradical scavenging activity, although less than phytomelatonin * [34]. |
Oxygen Radical Absorbance Capacity (ORAC) (see Figure 8) | 17,200–18,500 [270] | 1932, 4492 [271] 4830 [272] |
4.3. Dosing
4.4. Timing
4.5. Bioavailability
4.6. Contraindications and Combinations
4.6.1. Contraindications
4.6.2. Combinations
Vitamin C
Vitamin B12
Myo-Inositol, Folic Acid Vitamin D
Glutathione
4.7. Lifestyle Aspects
Blue-Light-Blocking Glasses
4.8. A Comprehensive Clinical Approach to Melatonin
Laboratory Testing
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Feature | Vitamin D | Melatonin |
---|---|---|
Basic functions | Considered to act as a hormone; Antioxidant; Anti-inflammatory compound; Mitochondrial regulator | Hormone; Antioxidant; Anti-inflammatory compound; Mitochondrial regulator |
Bodily systems | All | All |
Relationship with light | Light (UV) is needed for synthesis. | Darkness is needed for synthesis. |
Synthesis | Synthesized in the skin, activated by liver and kidney | Synthesized in the skin and many other tissues; Produced by pineal gland and gut (enterochromaffin cells) |
Seasonal variation | Yes | Yes [28] |
Chemical nature | Lipid-soluble | Amphiphilic |
Transport | Crosses blood–brain barrier | Crosses blood–brain barrier |
Nutritional status | Greater risk of insufficiency and/or deficiency with increasing age | Greater risk of insufficiency and/or deficiency with increasing age |
Obtained from dietary sources | Yes | Yes |
Biological need may change depending on lifestyle | Yes | Yes |
Body System | Possible Clinical Uses |
---|---|
Central Nervous System | Circadian rhythm modulation Sleep-wake disorders Sleep disturbance Cognitive conditions such as dementia Migraines and headache Tinnitus Attention-Deficit Hyperactivity Disorder (ADHD) Autism Eye disorders (e.g., glaucoma) |
Cardiovascular System | Hypercholesterolemia Hypertension/high systolic blood pressure Metabolic syndrome Endothelial dysfunction Glycemic balance (varying effects due to differing response in MTNR1B G-risk allele carriers) |
Reproductive System | Preeclampsia Fertility As an adjunct to care for endometriosis Polycystic Ovarian Syndrome (PCOS) |
Gastrointestinal System | Gastroesophageal Reflux Disease (GERD) Ulcers Irritable Bowel Syndrome (IBS) |
Immune System | Autoimmune conditions (Multiple sclerosis, Hashimoto’s thyroiditis) Coronavirus Disease (COVID-19) Oxidative stress from athletic performance stress Oxidative stress from excessive environmental toxin load Cancer; chemopreventive and as an adjunct to treatment depending on the cancer type and individual |
Musculoskeletal System | Osteopenia |
Category | Select Types (Listed in Alphabetical Order) | References |
---|---|---|
Vegetables | Several types: Asparagus, beetroot, cabbage, carrot, corn, ginger root, purslane, spinach, taro | [209,211,220,221,222,223,224,225] |
Fruits | Several types: Apple, banana, cherries (sweet, tart), cucumber, grapes, kiwifruit, peppers, pineapple, pomegranate, strawberries, tomatoes | [220,221,222,225,226,227,228,229,230,231] |
Nuts | Almonds, pistachios, walnuts | [224,225,226,232,233,234] |
Seeds | Anise, celery, coriander, fennel, fenugreek, flax, green cardamom, mustard (black, white), poppy, sunflower; Raw and germinated seeds of alfalfa, broccoli, lentil, mung bean, onion, red cabbage, and radish | [209,225,235,236] |
Grains | Barley, oat, rice, wheat | [221,222,224,225] |
Beans Legumes | Kidney beans (sprouts), soybeans | [237,238] |
Herbs Spices | Black pepper, feverfew, sage, St. John’s wort, select Chinese medicinal herbs | [239,240,241,242] |
Oils | Argan oil, extra virgin olive oil, grapeseed oil, linseed oil, primrose oil, sesame oil, soybean oil, sunflower oil, walnut oil, wheat germ oil | [243] |
Beverages | Beer, coffee, grape juice, orange juice, wine | [226,231,244,245,246] |
Factor | Details | General Comments |
---|---|---|
Source | Animal (pineal gland) Chemical synthesis Phytomelatonin Microbial fermentation products (bioengineered) | Synthetic melatonin is the most common form of melatonin on the market but can result in the use of potentially unwanted solvents and substrates in addition to it being environmentally undesirable [210]. Plant-based melatonin presents challenges in concentrating to a viable dose of melatonin. Animal-based melatonin can involve the risk of viral infections. Microbial fermentation products are under development. |
Route | Oral intake Oral, immediate release Oral, sustained, time-release Sublingual Intravenous Intramuscular Intranasal Transdermal Anal/Suppository Vaginal delivery | There are a variety of formats available, and each needs to be individualized to the person’s needs. Several newer formats are being developed for optimizing delivery, although only oral administration is considered a dietary supplement in the U.S. [260,261]. |
Delivery | Capsule Tablet Chewable Gummies | A trending format is that of gummies, which is a sweetened gelatinous-type delivery for greater palatability. While it may be the desired delivery form for consumers, there are concerns about the stability of melatonin in such a hygroscopic matrix, the resulting sugar content, the addition of dyes or flavoring agents, and the potential for an overdose of melatonin, especially in the case of children. |
Actives | As an isolated compound In combination with other actives In a plant matrix with other phytonutrients | Often, dietary supplements of melatonin will include other nutritional or herbal actives with the intention of synergy or improved efficacy, although, on the whole, these types of preparations have not been effectively studied for interactions. |
Quality | Certified Good Manufacturing Practices (cGMP) Third-party testing for heavy metals, and contaminants Packaging integrity to ensure shelf-life and stability. | Not all dietary supplements have the same quality. cGMP and third-party testing can be markers of objective quality measures. Melatonin can degrade in the presence of air and light, so minimizing exposure [262] in oxygen-barrier blister packs would be preferential over open bottle format. |
Dose | Physiological dose (0.3–1.0 mg) Supraphysiological dose for occasional use (≥3 mg) Therapeutic dose prescribed by a qualified healthcare practitioner | There is much debate about proper dose levels. Consider safety in addition to efficacy for the clinical condition it is being used for in a patient, as well as the duration of use, whether low dose, short term or high dose, long term. |
Category | Website |
---|---|
Clinical dosing recommendation and contraindications | Natural Medicines Comprehensive Database: https://naturalmedicines.therapeuticresearch.com/ accessed on 27 July 2022 |
Research sites | Melatonin database of studies including phytomelatonin: https://www.phytomelatonin.com accessed on 27 July 2022 Melatonin Research: https://www.melatonin-research.net/index.php/MR accessed on 27 July 2022 National Center of Complementary and Integrative Health: https://www.nccih.nih.gov/ accessed on 27 July 2022 |
Professional Organizations | American Association of Naturopathic Physicians: https://naturopathic.org/ accessed on 27 July 2022 American Nutrition Association: https://www.theana.org accessed on 27 July 2022 Institute for Functional Medicine: https://www.ifm.org/ accessed on 27 July 2022 |
Clinical Aspect | Considerations |
---|---|
Constitution | |
Genes, Early Life Epigenetics | Gene variants related to receptor activity, early life exposure to melatonin through breast milk |
Conditional Influences | |
Acute and/or Chronic Triggers | Stressful events, bouts of poor-quality sleep, travel across time zones, jet lag, inflammatory cytokines from injury or illness, oxidative stress from toxic exposures, shift work, dysregulated appetite, dysbiosis, artificial, blue light at night, insufficient darkness at night, insufficient morning light, highly processed, inflammatory diet |
Body Systems | |
Bone Health | Melatonin may help in the balance of osteoblasts and osteoclasts for better bone mineral density and overall structure. |
Brain Mood | Melatonin can influence cognition and mood. High levels of kynurenine are present in the brain in depression. |
Cardiovascular Transport | Melatonin can be produced in multiple body parts, circulate to tissues, and cross the blood–brain barrier. |
Detoxification | Preliminary research suggests that melatonin may be helpful with the elimination of toxins in the brain (e.g., amyloid) through the glymphatic fluid. |
Endocrine System | Melatonin is a hormone produced by the pineal gland (and gastrointestinal tract), communicating with other hormones. It is biochemically interrelated with its precursor, serotonin, and plays a key role in circadian rhythm and sleep cycles in conjunction with other hormones (e.g., cortisol, insulin) and neurotransmitters (e.g., serotonin). Higher amounts are found in children with lower nocturnal levels in puberty. |
Gastrointestinal Tract | Melatonin is found in the gut mucosa at levels that exceed that of the pineal gland. It is produced by enterochromaffin cells, with altering responses postprandially. Furthermore, initial studies suggest it may influence the gut microbiome. |
Immunity | Based on historical data, melatonin is most known as a potent antioxidant and anti-inflammatory agent. Research suggests it has chemopreventive and tumor-suppressing activity. |
Metabolism | Melatonin can protect the mitochondria from oxidative stress due to its ability to cross the mitochondrial membrane. |
Lifestyle Factors | |
Sleep Relaxation | Aligning day-night rhythms will help to ensure healthy melatonin levels. Ensuring sleep hygiene is practiced, particularly maintaining a dark, cool room for sleeping. Wearing blue-light-blocking glasses before bedtime may help to establish better rhythm tone, enhanced sleep, and less reduction in nocturnal melatonin. |
Physical Activity | Exercise may help increase serotonin and melatonin and result in less shunting through the kynurenine pathway. |
Nutrition | Melatonin is found in both animal and plant dietary sources. Foods containing tryptophan may modulate melatonin levels due to the conversion of tryptophan to melatonin. Dietary supplementation could also be implemented either acutely, such as in jet lag, or more chronically at lower doses for those who do shift work. |
Stress Regulation Resilience | Cortisol is inversely related to melatonin. Upregulation in the kynurenine pathway can be seen in stressful events. The use of meditation, calming activities, bodywork, and creative arts may help cultivate improved stress response and, ultimately, resilience. |
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Minich, D.M.; Henning, M.; Darley, C.; Fahoum, M.; Schuler, C.B.; Frame, J. Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients 2022, 14, 3934. https://doi.org/10.3390/nu14193934
Minich DM, Henning M, Darley C, Fahoum M, Schuler CB, Frame J. Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients. 2022; 14(19):3934. https://doi.org/10.3390/nu14193934
Chicago/Turabian StyleMinich, Deanna M., Melanie Henning, Catherine Darley, Mona Fahoum, Corey B. Schuler, and James Frame. 2022. "Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements" Nutrients 14, no. 19: 3934. https://doi.org/10.3390/nu14193934