Melatonin - The Swiss Army Knife Among Antioxidants

David Quig PhD | April 28, 2021

Melatonin, a tryptophan-derived hormone mainly produced by the pineal gland, is well known for receptor mediated regulation of circadian rhythm in vertebrates. However, melatonin (MLT) is now known to be ubiquitous across the animal and plant kingdoms, where it has autacoid non-receptor mediated protective effects in many tissues, cells and subcellular organelles. Most recently, the extraordinary antioxidant properties of MLT have gained research interest with respect to mitochondrial dysfunction, environmental medicine, male fertility, and age-related neurodegenerative diseases. There is much to learn about optimal, harmonic dosing of MLT for condition specific antioxidant interventions, and general preventive medicine.

The orbit of influence of MLT against oxidative stress is anomalistic among antioxidants. The protective effects of MLT and its metabolites against reactive oxygen and nitrogen species (ROS/RNS) include direct scavenging of free radicals, and upregulation of the biosynthesis of glutathione and antioxidant enzymes (superoxide dismutase, glutathione peroxidase and glutathione reductase). Unique to amphiphilic MLT is the capacity to scavenge and limit formation of the peroxynitrite anion (oxidant), and the very short-lived and destructive hydroxyl radical (OH). Mitochondria are a major site of inherently high production of ROS (e.g. superoxide radical). However, mitochondria are normally protected from oxidative damage as a result of its synthesis and active transport of MLT. Those processes facilitate high concentrations of mitochondrial MLT that are essential for the organelle’s integrity and functions.

Outside of the mitochondria, MLT reportedly “chelates” transition metals (e.g. copper, iron, cobalt, nickel). Those free metal ions spark production of  •OH via Fenton/Haber–Weiss reactions, and may perpetuate a destructive cascade of radical and non-radical ROS/RNS that are also associated with inappropriate inflammation. MLT has also been reported to bind pro-oxidative free ions of aluminum, cadmium, lead and zinc in a concentration dependent manor. Such metal binding may neutralize the metal ions, but evidence has not been presented to indicate that MLT enhances the irreversible excretion of excess free metal ions from cells.

The collective literature indicates that exogenous MLT supports male fertility and testicular health. The protective effects of MLT have been demonstrated in a murine model of extreme cadmium-induced oxidative stress. Treatment with MLT ameliorated cadmium-induced disruption of the activities of antioxidant enzymes and GSH levels, increased TNF-α, altered levels of sex hormones, diminished sperm mobility and apoptosis, and oxidative damage to testicular DNA (8-OHdG). Elevated urinary 8-OHdG is a favored indicator of oxidative damage to mitochondrial and nuclear DNA, and provides non-invasive assessment of intracellular oxidative stress. The short-term study provides thorough proof of concept, and exogenous MLT might be considered for patients presenting with infertility issues that may be associated with exposures to environmental toxicants.

Oxidative stress, mitochondrial dysfunction, and cell death are common pathophysiological mechanisms associated with aging and neurodegenerative diseases such AD, HD, ALS and PD. Neuroprotective effects of MLT have been demonstrated in numerous preliminary studies, and it has been suggested that clinical trials employing pharmacological doses of MLT (50–100 mg/day) are warranted.

For general preventive antioxidant/anti-inflammatory support consider that many plant foods, especially pistachio nuts and tart cherries, can provide bioavailable MLT throughout the day. For higher dosing consider that MLT has a very low toxicity profile, a half-life of only 45-90 minutes, and it is catabolized primarily by hepatic microsomal CYP1A2. To maintain effective therapeutic levels for antioxidant/anti-inflammatory/neuroprotective applications, such a short half-life would typically dictate relatively frequent dosing over the course of the day. However, considering the important role of MLT in receptor mediated regulation of circadian rhythms, it could be argued that dosing be restrictively aligned with an individual’s dark cycle. That may be a reasonable compromise since appropriate support of circadian rhythms is likely associated with less oxidative stress, since chronodisruption may increase production of ROS/RNS.



Reiter RJ et al. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res (2016)61:253-78.

Luo F et al. Melatonin and autophagy in aging-related neurodegenerative diseases. Int J Molec Sci (2020)21, 7174

Sun T-C et al. Protective effects of melatonin on male fertility preservation and reproductive system. Cryobiol (2020)

Li RY et al. The protective effects of melatonin against oxidative stress and inflammation induced by acute cadmium exposure in mice testis. Cryobiol (2016)

Meng X et al. Dietary sources and bioactivities of melatonin. Nutrients (2017)9:367


Wellness Wednesday Webinar

Comprehensive Hormone Health for Men

Heather Hydzik, ND

May 5, 2021 at 9:30 AM and 12 PM Pacific

Each session is approximately 60 minutes with Q&A

  1. Understand the role of testosterone in men's health
  2. Understand andropause and the health impacts of "Low T"
  3. Review the roles of estrogen and progesterone in men's health
  4. Review the research on prostate cancer and cardiovascular health in regards to testosterone replacement
  5. Explore therapies to address hormonal changes in men
  6. Discuss risks and benefits of testosterone replacement therapy (TRT)

The Epigenetics of Pain and Inflammation - Natural Methods of Reversing:

How stress, depression, nutrition, and inflammation increase nociceptive sensitivity in the brain and body

Brandon Lundell, DC

May 19, 2021 | 11 AM Pacific

Pain causes chromatin-structure epigenetic changes. Learn how to reverse these changes with nutrition and functional medicine treatments to aid in pain reduction and healing.

Addiction induces epigenetic changes that can be altered in recover from substance abuse and behavioral issues. Learn how to support patients with addictions using NT testing and inflammatory assessments.

The gut and immune system may be the source of chronic pain in extra-intestinal organs and tissues. Learn how evaluating neurotransmitter, hormonal, GI, and nutritional testing can aid in the management and resolution of pain.

Chronic pain causes epigenetic changes in glial cells that can be addressed with natural medicine.

Balancing neurotransmitters may help patients with chronic pain not only experience less nociception, but actually recover from chronic illness.


Disclaimer: All information given about health conditions, treatment, products, and dosages are for educational purposes only and do not constitute medical advice.



800.323.2784 (US and Canada)

+1.630.377.8139 (Global)