Melatonin’s Importance Is So Much Bigger Than Sleep
- Melatonin is produced by the pineal gland, retina, GI tract, and WBCs.
- It is made from tryptophan which is also used to make serotonin.
- If melatonin goes up, serotonin goes down.
- If you eat too many high glycemic index carbohydrates you will make less melatonin (more serotonin is made instead).
- The body needs vitamin B to convert melatonin from tryptophan.
Functions of Melatonin
- Affects the release of sex hormones
- Aids the immune system
- Acts as an antioxidant
- Blocks estrogen from binding to receptor sites
- Decreases cortisol levels
- Helps balance the stress response
- Helps prevent cancer
- Improves mood
- Improves sleep quality
- Increases the action of benzodiazepines
- Stimulates the parathyroid gland
- Stimulates the production of growth hormone
- Protects against GERD
Melatonin and Sleep
- Melatonin has been shown to synchronize the circadian rhythms, and improve the onset, duration and quality of sleep.
- Exogenous melatonin supplementation is well tolerated and has no obvious short- or long term adverse effects.
Reference: Xie, Z., et al., “A review of sleep disorders and melatonin,” Neurol Res 2017; 29(6):559-565.
Auld, F., et al., “Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders,” Sleep Med Rev 2017; 34:10-22.
Melatonin and Pre-Op Anxiety
- When compared to placebo, melatonin given as premedication (tablets or sublingually) can reduce preoperative anxiety in adults. In fact, melatonin maybe equally as effective as standard treatment with midazolam in reducing preoperative anxiety in adults.
- The effect of melatonin on postoperative anxiety in adults is mixed but suggests an overall attenuation of the effect compared to preoperatively.
Reference: Hansen, M., et al., “Melatonin for pre-and postoperative anxiety in adults,” Cochrane Database Syst Rev 2015; 2015(4):CD009861.
Melatonin and GI Reflux
- The enterochromaffin cells of the gastrointestinal (GI) tract secrete 400 times as much melatonin as the pineal gland.
- A randomized, single-blind clinical trial of subjects with gastroesophageal reflux disease (GERD), the combination of melatonin with other natural supplements was found to was superior to omeprazole, a proton pump inhibitor (PPI).
- Melatonin 6 mg, 5-hydroxytryptophan 100 mg, D,Lmethionine 500 mg, betaine 100 mg, L-taurine 50 mg,riboflavin 1.7 mg, vitamin B6 0.8 mg, folic acid 400 microg, and calcium 50 mg. After 40 days, the PPI was withdrawn without a return of symptoms.
- Subsequently, an attempt to reduce melatonin to 3 mg resulted in symptoms, while all other ingredients were withdrawn with minimal symptoms during 10 months of follow-up.
Reference: Werbach, M., “Melatonin for the treatment of gastroesophageal reflux disease,” Altern Ther Health Med 2008, 14(4):54–8.
Melatonin and the Immune System
- Melatonin is a major regulator of the immune system.
- Disease states affecting a wide range of organ systems have been reported as benefitting from melatonin administration.
Reference: Csaba, G., “The pineal regulation of the immune system: 40 years since the discovery,” Acta Microbiol Immunol Hung, 2013; 60(2):77-91.
Bondy, S., et al., “Melatonin and regulation of immune function: Impact on numerous diseases,” Curr Aging Sci 2020; Jull 11. doi: 10.2174/1874609813666200711153223, online ahead of print.
Melatonin and Breast Cancer
- Many studies have shown that melatonin is an effective therapy for breast cancer as an adjunct to traditional care.
References: Barcelo, S., et al., “Breast cancer therapy based on melatonin,” Recent Pat Endocr Metab Immune Drug Discov 2012; 6(2):108-16.
Cos, S., et al., “Melatonin as a selective estrogen enzyme modulator,” Curr Cancer Drug Targets 2008; 8(8):691-702.
Sanchez-Barcelo, E., et al.,” Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation,” Expert Opin Investig Drugs 2012; 21(6):819-31.
Proietti, S., et al., Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells,” Jour Pineal Res 2011; 50(2):150-58.
Thaiz Ferraz, B., et al., “Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression,” Jour Pineal Res 2015; Aug 21.
do Nascimento Gonçalves, N., “Effect of melatonin in epithelial mesenchymal transition markers and invasive properties of breast cancer stem cells of canine and human cell lines,” PLoS One2 016;11(3):e0150407.
Melatonin and COVID-19
- Melatonin is now being used as an adjuvant treatment for COVID-19 since it has been shown to limit virus-related diseases.
- It is protective against acute lung injury and adult respiratory distress syndrome caused by viruses and other pathogens due to is anti-inflammatory and anti-oxidative effects.
Reference: Zhang, R., et al., “COVID-10: Melatonin as a potential adjuvant treatment,” Life Sci 2020; 250:117583.
Salles, C., “Correspondence COVID-19: Melatonin as a potential adjuvant treatment,” Life Sci 2020; 253:117716.
Juybari, K., et al., “Melatonin potentials against viral infections including COVID-19: Current evidence and new findings,” Virs Res 2020; 287:198108.
- Covid-19 takes a more severe course in individuals with chronic metabolic diseases such as obesity, diabetes mellitus, and hypertension.
- Since Covid-19 infection and complications involve severe inflammation and oxidative stress in people with obesity and diabetes, melaotnin is being suggested as an add-on therapy for patients that are diabetic and overweight.
Reference: El-Missiry, M., et al., “Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of Covid-19,” Eur Jour Pharmacol 2020; 882:173329.
Causes of Melatonin Deficiency
- Electromagnetic fields
- Numerous medications including benzodiazepines
Benzodiazepines and Melatonin Suppression
- Study showed that a single dose of 2 mg alprazolam at 9 pm suppressed melatonin levels all night long and even at 7 am the next morning.
Reference: McIntyre, I, et al., “Alterations to plasma melatonin and cortisol after evening alprazolam administration in humans,” Chronobiol Int 1993; 10(3):205-13.
Benzodiazepines and Melatonin and Suppression (cont).
- A medical trial showed that patients that used benzodiazepines at any time in their life had a 50% greater risk for developing dementia than people that did not use benzodiazepines.
Reference: Billioti de Gage, BB., et al., “Benzodiazepine use and risk of dementia: prospective population based study,” BMJ 2012; 345:e6231.
- Another study showed that for patients with benzodiazepine dependence, the risk of probable cognitive impairment was more than quintupled.
Reference: Potvin, O., et al., “Prevalence of psychiatric disorders in community-dwelling older men and women with cognitive impairment in dementia: results from the ESA study,” Aging Ment Health 2012; 16(2):218-27.
Symptoms of Excess Melatonin
- Daytime sleepiness/fatigue
- Increase in cortisol which can lead to fat storage
- Intense dreaming/nightmares
- Suppression of serotonin which increases carbohydrate cravings
- Transient dizziness
- Abdominal pain
Reference: Wei, S., et al., “Efficacy and safety of melatonin for sleep onset insomnia in children and adolescents: a meta-analysis of randomized controlled trials,” Sleep Med 2020; 68:1-8.
Ways to increase Melatonin production
- Sweet corn
Other ways to increase Melatonin production
- St. John’s wort
- Taking excess melatonin as a supplement
- Caution should be exercised in patients on multiple medications due to potential unknown interactions and in patients taking a medication that can inhibit cytochrome P450, since melatonin is mainly metabolized by this enzyme.
Reference: Balduini, W., et al., “Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia,” Jour Pineal Res 2019; 66(4).
Besag, F., et al., “Adverse events associated with melatonin for the treatment of primary or secondary sleep disorders: a systematic review,” CNS Drugs. 2019; 33(12):1167–186.
Who Should Not Take Melatonin?
- Use with caution in patients with an autoimmune disease since it can stimulate the immune system
- Pregnant or breast-feeding women
- Patients taking steroids
- Use with caution in patients that are depressed
- Do not use if patient has lymphoma or leukemia