Aside from other health benefits of melatonin, it also has many important roles in the immune system. How melatonin affects immune cells might explain why some autoimmune diseases are more likely to flare up seasonally.

In addition, this is why we recommend all SelfHacked clients who suffer from autoimmunity and inflammation entrain their circadian rhythm – by limiting blue light at night and getting sun exposure during the day.

Read this post to learn about the effects of melatonin on the immune system, as an anti-inflammatory substance, and how it may be used to manage autoimmune disorders.

Part 2 of a 3-Part Series

  • Melatonin Part 1: 24 Surprising Health Benefits of Melatonin – Sleep, Brain, Gut Health, Antiaging, Cancer, Fertility, and more
  • Melatonin Part 2: Surprising Roles of Melatonin in Controlling Inflammation and Preventing Autoimmune Diseases
  • Melatonin Part 3: Ways to Increase and Decrease Melatonin, Food/Drug/Supplement Interactions and Side Effects of Melatonin

Melatonin Reduces Inflammation and Promotes Healthy Immune Function

Melatonin receptors are present in a wide variety of immune cells (R). Melatonin is immunomodulatory, which means that it reduces excessive immune function in inflammatory conditions and enhances immune function in immunocompromised people.


Melatonin plays an important role in the immune system. The membranes of immune cells such as CD4+ T cells, CD8+ T cells, and B cells all have melatonin receptors [R].

Melatonin can either activate and suppress immune cells [R].

In mice, melatonin treatment increases the production of T cells, natural killer cells, and monocytes. The nuclear melatonin receptor can also induce cytokine production [R].

Melatonin and Th1/Th2/Th17 Cells

Melatonin is involved in Th1/Th2 development. The balance of T helper 1 and T helper 2 cells plays a critical role in controlling cellular immune responses [R].

Th1 cells play a key role in the development of inflammatory responses. They help with the production of proinflammatory cytokines like IFN-y and IL-2 [R].

On the other hand, Th2 is anti-inflammatory. Th2 cells produce cytokines like IL-4, IL-5, IL-10 and IL-13 [R].

Depending on its concentration, melatonin can promote both Th1 and Th2 responses. In mice, low doses of melatonin increased Th1 cytokine levels. In contrast, high doses decreased the proinflammatory cytokines [R, R].

Melatonin suppresses the development of Th17 cells and increases regulatory T cells [R].

Melatonin Can Suppress Pro-Inflammatory Cytokine Production

Melatonin blocks the release of the following cytokines and inflammatory substances:

  • TNF-alpha from macrophages in responses to LPS (lipopolysaccharides, which may be present in the bloodstream in cases of leaky gut) [R].
  • Nitric oxide (which causes oxidative stress) from immune cells in response to LPS [R].
  • iNOS, COX-2, and MMPs (by blocking NF-κB) [R].
  • IL-1β and IL-6 [R].

Melatonin and Autoimmune Diseases

1) Melatonin Helps Improve Type 1 Diabetes

Autoimmune destruction of insulin-producing β cells in the pancreas causes Type 1 diabetes (insulin-dependent diabetes mellitus). Pro-inflammatory cytokines like TNF-α and IFN-γ contribute to β cell destruction [R].

In non-obese diabetic mice (an animal model of type 1 diabetes), chronic administration of melatonin increased survival and delayed the onset of diabetes [R].

Type 1 diabetes is a Th1-cell-dominant disease. Thus, when melatonin shifts the immune response towards Th2 cells, it can be beneficial [R].

By reducing TNF-α and IFN-γ production, melatonin can protect against β cell destruction [R].

Surgical transplantation of pancreatic islets grafts (cluster of cells) that produce insulin is a potential therapy for type 1 diabetes. However, the immune system might attack or reject the transplants. Melatonin might be able to prolong graft survival [R].

In diabetic mice, melatonin administration decreased Th1 cells and increased anti-inflammatory IL-1o cytokines. This inhibits the autoimmune response to the islet transplants. On average, the islet grafts survived for 17 days with melatonin treatment in comparison to 7 days in untreated mice [R].

2) Melatonin Helps Stop the Progression of Multiple Sclerosis

Multiple sclerosis (MS) is a disease that affects the central nervous system. Immune cells wrongly attack the neurons’ myelin sheaths. This causes pain, fatigue, weaknesses, and may even cause vision loss [R].

Multiple sclerosis patients excrete an abnormal amount of melatonin metabolites in the urine at night. This indicates a dysregulation of melatonin production [R].

Melatonin deficiency plays an important role in the fluctuation of multiple sclerosis symptoms, fatigue, and mood disorders in patients [R].

Th17 cells also contribute to multiple sclerosis. Melatonin suppresses Th17 cells, which can help stop the progression of the disease [R].

Experimental autoimmune encephalomyelitis (EAE) is the animal model of multiple sclerosis. Scientists use animals with EAE to test possible treatments [R].

In rats with EAE, oral melatonin administration significantly reduced paralysis severity. These effects were due to the suppression of intracellular adhesion molecule-1 production in the spinal cord [R].

However, there were conflicting results from a different study. Luzindole is a melatonin receptor antagonist, which means that it inhibits melatonin receptor activity. Luzindole-treated mice did not develop EAE while control mice did [R].

3) Melatonin Might Reduce Inflammatory Bowel Disease Symptoms

Crohn’s disease and ulcerative colitis are immune disorders. Together, they are referred to as inflammatory bowel disease (IBD). Characteristics of IBD include the accumulation of immune cells in the intestinal tissues and inflammation in the intestines [R].

The immune cells that accumulate in the intestinal tissues include B cells, T cells, neutrophils, macrophages, and dendritic cells. Activation of these cells can cause inflammation and increase proinflammatory cytokine levels [R].

Melatonin helps IBD symptoms by reducing proinflammatory markers such as TNF-α production, NF-κB activation. In addition, melatonin administration also reduces DNA damage and oxidative stress from the inflammation [R].

Short-term melatonin administration reduces inflammation in a mouse model of colitis [R].

However, the same study found that long-term administration of melatonin worsened colitis symptoms and caused intestinal cell death in mice. However, it was not a typical dose, which might have affected the results [R].

Various case studies also showed conflicting effects of melatonin in humans. While daily melatonin supplementation helped one patient reduce colitis symptoms, it worsened IBD symptoms in two others [R].

In a study (DB-RCT) of 60 ulcerative colitis patients, the combination of Mesalazine (an anti-inflammatory drug) and melatonin was tested against Mesalazine and a placebo. The melatonin group had less intestinal inflammation. The melatonin also helped the patients sustain remission (disease symptoms became less severe) [R].

4) Melatonin has Conflicting Effects on Systemic Lupus Erythematosus

An overproduction of autoantibodies causes immune cells to damage tissues, causing Systemic Lupus Erythematosus (SLE). Symptoms include rashes, arthritis, light sensitivity, and kidney inflammation [R].

Melatonin administration can help treat animal models of lupus. However, its effects can depend on the timing of administration or gender of the subject [R].

Melatonin administration reduced autoantibodies and kidney injury in a mouse model of (pristane-induced) lupus [R].

Daily melatonin injections also enhanced survival rates in female mice in the morning. However, evening treatments did not change survival rates [R].

In a different mouse model of lupus, IL-10 deficiency contributes to disease development. IL-10 deficiency reduces survival rate, increases kidney inflammation, and increased the severity of skin lesions [R].

One month of melatonin administration in female rats decreased inflammatory cytokine production. It also increased the induction of anti-inflammatory IL-10 production [R].

However, in the same study, melatonin treatment worsened lupus symptoms in male mice. It increased inflammatory cytokines and autoantibodies [R].

When melatonin reduces testosterone, it can cause immune cells to increase pro-inflammatory cytokines. This might be the cause for melatonin’s negative effects in male mice [R].

Negative Effects of Melatonin on Autoimmunity

1) Melatonin Worsens Rheumatoid Arthritis Symptoms

Rheumatoid arthritis is chronic inflammation of the joints. Rheumatoid arthritis patients have worn cartilage and bone, as well as abnormal tissue growth over joints (pannus). Inflammatory immune cells contribute to disease progression [R].

Melatonin tends to promote the development and increase the severity of rheumatoid arthritis. Rheumatoid arthritis patients have increased melatonin concentration in their blood [R].

In a study (DB-RCT), 75 patients either received 10 mg of melatonin (considered a high dose) at night or a placebo for 6 months. Melatonin increased ESR and neopterin, which are indicators of inflammation [R].

However, there was no significant difference in rheumatoid arthritis symptoms and proinflammatory cytokine levels in melatonin and control groups [R].

One animal model of rheumatoid arthritis is collagen-induced arthritis (CIA) in mice. These mice have increased levels of proinflammatory cytokines, such as IL-1β and IL-6 [R].

In one study, researchers surgically removed the pineal gland, which produces melatonin, in CIA mice. These mice had significantly reduced levels of IL-1β and IL-6 in their blood and brains compared to CIA mice that still had pineal glands [R].

In another study, researchers also removed the pineal gland in CIA mice. The mice showed reduced severity of arthritis, suggesting that melatonin can worsen disease severity [R].

Caution and Side Effects of Melatonin

Melatonin supplement is not toxic. Oral supplementation of melatonin at 240 mg and injections at 500 mg did not have any major side effects. Scientists have not yet found a lethal dose [R, R].

Some side effects include headaches, insomnia, rashes, upset stomach, abdominal pain, low blood pressure, and nightmares [R, R].

The treatment doses in some animal studies may be higher than the normal doses used in human clinical trials. So while melatonin may have positive effects in animal studies, these results might not be replicated in humans [R].

The most important thing to remember about melatonin supplementation is the timing. Inappropriate timing of melatonin administration can cause hormonal problems and desensitization of melatonin receptors [R].

Melatonin injections in the morning can increase tumor growth. Administration throughout the day can also increase bipolar and depression symptoms (R).

Additionally, melatonin activators (like Ramelteon or Agomelatine) should not be used in patients with liver failure, kidney failure, alcohol addiction, or high lipid (fat) levels (R).

Melatonin and bright light are known to improve the mood and symptoms of Alzheimer’s patients. However, without the additional bright light, it may have a negative effect on the mood of such patients. It may also lead to an increase in aggressive behavior (R).

In rats, melatonin also helps eliminates harmful oxidative molecules in the nerve cells after brain injury. However, it prolongs coma caused by the trauma (R).

Melatonin Part 2 of a 3-Part Series

  • Melatonin Part 1: 24 Surprising Health Benefits of Melatonin – Sleep, Brain, Gut Health, Antiaging, Cancer, Fertility, and more
  • Melatonin Part 2: Surprising Roles of Melatonin in Controlling Inflammation and Preventing Autoimmune Diseases
  • Melatonin Part 3: Ways to Increase and Decrease Melatonin, Food/Drug/Supplement Interactions and Side Effects of Melatonin

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