Melatonin Effects on the Brain, Sleep, Mitochondria, Vision/Eyes, and Hearing (Part 1)

Melatonin is important for normal brain and eye function. While it occurs naturally in the body, people often take melatonin supplements to improve their sleep patterns. Additionally, melatonin also reduces oxidative stress, boosts the immune system, and helps with eye health.

These health benefits might explain why having a healthy circadian rhythm and sleep are crucial for health, and why poor circadian rhythm increases the risk of cancer.

Read this post to learn about its beneficial effects.

Introduction

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151498/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151498/

Melatonin is derived from the amino acid tryptophan and the neurotransmitter serotonin (R).

We know that melatonin is a very important molecule because it is present in every living organism from bacteria and plants to animals. Throughout evolution, it has acquired a lot of different functions and has become indispensable in humans (R).

Here are several of its main functions:

  • Influences the circadian rhythm
  • Aids the immune system
  • Helps eye function
  • Reduces oxidative stress
  • Promotes sleep
  • Controls many cellular events, including synthesis of important molecules
  • Protects against radiation

A part of the brain, the pineal gland, makes melatonin. The quantity of melatonin in the blood depends on the time of the day. At night there is 10 to 15 times more melatonin in the blood that in the day, which helps people sleep (R).

Melatonin is also made by many other organs in the body, especially in the stomach (R).

If sleep is interrupted by blue light exposure at night, melatonin levels decrease drastically. In addition, melatonin levels also decrease with age (R). However, darkness does not stimulate melatonin production. It simply permits melatonin production (R).

Melatonin acts through interacting with two receptor proteins, MT1 and MT2 (R).

MT1 and MT2 receptors control different stages of sleep: MT1 controls deep sleep or REM sleep, and MT2 controls the stages of sleep preceding dreaming (R).

How Melatonin Works with the Circadian Rhythm

Some scientists believe that melatonin can shift the circadian rhythm phase and entrain the circadian rhythm (R, R2). However, this property of melatonin is controversial.

In zebrafish mutants that lack melatonin, the fish sleeps less but still have normal circadian rhythm (based on per1B production). The same study found that melatonin induced sleep by increasing adenosine signaling in the fish’s brain (R). These mutant fish were equally easy to wake up and slept as deep as the control fish.

Health Benefits of Melatonin

1) Melatonin Works for Treating Sleep Disorders

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Melatonin controls the sleep-awake cycle (R).

In patients with insomnia, melatonin concentration is significantly lower compared to people with normal sleep (R).

Melatonin induces sleep through two melatonin receptors, MT1, and MT2 (R).

Melatonin helps patients to go to sleep quicker, sleep longer, and deeper (R).

Some studies suggest that melatonin itself is not effective in some types of sleep disorders, though it does improve sleep quality (R).

It helps patients discontinue therapy with benzodiazepines, a class of drugs usually prescribed for anxiety and insomnia. Benzodiazepines have potential side effects, resulting in addiction. Also, withdrawal of such therapy is hard for the patient, leading to sleep deprivation and anxiety (R).

Melatonin supplementation helps patients reduce their dependence on drugs, without major side effects (R).

Melatonin is also a safe option for children with autism disorders and ADHD. In the case of ADHD, administration of melatonin has helped children to go to sleep an hour earlier in average (R).

Why Melatonin May Not Be an Effective Sleep Aid

Nattha’s experience: Consistently, I observe that melatonin doesn’t appear to be helpful in cases of stress-related insomnia among my clients. In these cases, stress management, meditation, sleep hygiene, and other sedating substances such as theanine, passionflower and lemon balm tend to be more effective.

Exogenous (supplemental) melatonin has very subtle (2 – 3%) sleep-enhancing effects in humans comparing to prescription sleep medications (R, R2), which might explain why some people don’t find melatonin beneficial as a sleep aid.

A meta-analysis evaluating whether melatonin is effective for secondary sleep disorders found no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders that are secondary to other health problems, jet lag, and shift work (R).

2) Melatonin is an Important Antioxidant that Protects Cells and Their Mitochondria

Mitochondria are the part of the cell that generates energy. They have their own DNA. As energy factories, they are crucial for survival. The nucleus and mitochondria are the areas that have the most melatonin (R).

Energy production by mitochondria leads to the creation of harmful molecules that are referred to as “molecular terrorists.” Those terrorists are usually made from oxygen and nitrogen and are referred as reactive oxygen species (ROS) and reactive nitrogen species (RNS) (R).

The main danger of these molecules is that they damage mitochondrial DNA and proteins, rendering them unable to produce energy. Also, as the mitochondrial walls become destroyed due to harmful molecules, the molecules leak potential poisons into the cell, spreading harm more widely, and leading to cell death (R).

Melatonin is able to bind to such molecules, acting as a scavenger. It performs this task through several reactions, transforming into new molecules along the way (R).

Most of the molecules that melatonin transform into retain the ability to bind harmful oxygen and nitrogen species, which makes melatonin and its products highly effective protection (R).

A single molecule of melatonin may neutralize up to 10 toxic reactants (R).

Besides directly binding harmful substances, melatonin activates other molecules that help clean the cell and bloodstream from harmful molecules (R).

It also blocks an enzyme called nitric oxide synthase that produces reactive nitrogen species (R).

The use of synthetic melatonin analogs or melatonin-related molecules to block nitric oxide synthase are being evaluated for the treatment of neural diseases ranging from stroke to Alzheimer’s and Parkinson’s disease (R).

Melatonin increases γ-glutamylcysteine synthase (γ-GCS), an enzyme that is very important for the production of glutathione, a potent cellular antioxidant (R).

Moreover, melatonin and a molecule directly made from it, such as AMK (N1-acetyl-5-methoxykynuramine) has an activity that prevents the formation of most damaging free radicals (R).

3) Melatonin Is Good For Your Brain

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Melatonin Helps with Mitochondria Health

As nerve cells usually possess a very big quantity of mitochondria, requiring the most energy, and as melatonin is essentially a hormone for nerves, it helps the brain in many instances (R).

On mice models of stroke, melatonin was able to block the release of death-activating protein cytochrome c from mitochondria, which effectively prevented cell death as a result of the injury (R).

On another rat model of a stroke, melatonin blocks the activity of several proteins such as IL-1β, TNF-α, BAD, and BAX that initiate inflammation and death of the nerve cells after the artery leading to the brain gets blocked (R).

Melatonin increased the levels of proteins that prevent cell death (R).

Another way of preventing cell death through the influence of melatonin is its ability to repair damaged mitochondria directly, thus preventing leakage of damaging molecules (R).

Melatonin Activates BDNF

Melatonin activates brain-derived neurotrophic factor (BDNF), a protein responsible for nerve cells’ well-being and regeneration (R).

Melatonin Strengthens the Blood-Brain Barrier

It also strengthens the barrier between brain and the blood (R).

It prevents nerve cell death due to its ability to interfere with proteins that initiate the event (R).

4) Melatonin Helps with Traumatic Brain Injury

Melatonin helps with brain trauma (R).

Treatment of rats with melatonin after brain injury helps reduce the subsequent swelling of various brain regions (R).

 

5) Melatonin Helps with Neurodegenerative Diseases

Melatonin and Alzheimer’s

Melatonin helps alleviate symptoms similar to Alzheimer′s and Parkinson′s disease in mice and rats (R).

In humans, both MT1 and MT2 levels are low in elderly patients with Alzheimer’s (R).

In mouse nerve cells, melatonin prevents cell death caused by amyloid beta25-35, a substance that causes a condition similar to Alzheimer’s disease (R).

The decrease in melatonin activity and synthesis may explain in part the disruption of sleep and problems with processing information observed in Alzheimer’s patients (R).

The treatment of elderly patients with Alzheimer’s disease (AD) with bright light and melatonin improved their sleep and overall rest (R).

A similar study carried out for several years in the Netherlands showed that combined treatment of an AD patient with bright light and melatonin was beneficial both for rest and mental problems (R).

Melatonin Helps with Parkinson’s

The development of Parkinson’s disease also disrupts sleep (R).

There are several studies that show melatonin to improve sleep in patients with this condition, but it does not improve other associated problems (R, R2).

Melatonin Helps with Amyotrophic Lateral Sclerosis (ALS)

In amyotrophic lateral sclerosis (ALS), the nerve cells responsible for movement begin to die, causing this disease to be usually fatal. According to experiments on mouse models, melatonin helps relieve symptoms of ALS. It prevents the death of those cells and slows the disease progress in mice (R).

6) Melatonin Helps Against Some Poisons

Due to such diverse properties, melatonin is able to downplay the effects of several poisons that directly affect the mitochondria (R).

It is protective against rotenone – a poison that can mimic Parkinson’s disease in rats (R).

MPTP is a poison dangerous to nerve cells that deprives them of energy and leads to their death. This substance disrupts the activity of a crucial mitochondrial protein – complex I. It leads to severe neurological symptoms similar to Parkinson’s disease (R).

Melatonin prevents the damage to the cell fat molecules in many regions of the brain in mice after MPTP injection. It also makes many important proteins return to their normal state, and protects DNA in the mitochondria from damage (R).

Melatonin is also protective against 3-NPA, which is a toxin from fungi that infects sugarcane. There have been cases of children who ate contaminated sugarcane, developing a condition similar to Huntington’s disease that impairs movement (R).

In rats affected by this poison, melatonin prevents nerve cell loss, corrects damaging behavior, prevents protein and fat molecule damage, and restores levels of dopamine – a molecule responsible for controlling movement and mood (R).

Melatonin is helpful even against cyanide (R, R2).

Cyanide is a highly lethal poison that causes the massive death of nerve cells and seizures, eventually leading to death. It also damages the nerve cells’ mitochondria. In mice that received cyanide injections, previous treatment with melatonin reduced the severity of seizures caused by the poison (R).

Melatonin also protects the damage to mitochondrial DNA caused by potassium cyanide in mice and in culture (R).

7) Melatonin Helps Calm You Down

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Melatonin also has a use in the treatment of anxiety and depression.

Depression and other mood disorders are often coupled with sleep disturbances, requiring agents that have both a sedating and calming effect. Drugs that activate and bind MT2 receptors are potential therapeutic agents for such conditions (R).

Changes in day-and-night concentrations of melatonin are markers of severe depression (R).

Melatonin helps with sleep regulation and depression in patients with delayed sleep phase syndrome (R).

In rats, melatonin alleviates depression induced by chronic stress and significantly changes the dynamics of several parameters in the brain of these animals (R).

Treatment with melatonin in breast cancer patients reduces the risk of development of depression (R).

Melatonin synthesis is also disrupted in in patients with bipolar disorder. Melatonin and drug agents interacting with MT receptors, like ramelteon and tasimelteon, are a beneficial therapy for bipolar disorder as well (R).

As bipolar disorder is also associated with sleep and mood deregulation, melatonin improves the condition in patients with this problem (R).

8) Melatonin Is Important For The Eyes

The cells of the eye, especially the retina, make melatonin (R).

Light influences its production, and the cells that react to light produce it. The more light there is, the less melatonin the cells in the eye produce (R).

Disruption of MT receptors leads to the death of cones – cells in the eye that help the eye to discern color (R).

Melatonin is also important for normal eye development. For example, mice that lacked one of the melatonin receptors – MT1 – had a decrease in specific nerve cells content crucial for vision (R).

Additionally, it decreases elevated pressure in the eye in humans. Moreover, removal of MT1 in mice results in an increase in the pressure inside the eye and death of nerve cells (R).

The disturbances in melatonin functioning may be one of the causes of glaucoma (R).

Melatonin and 5-MCA-NAT are promising agents for treating glaucoma, which is an eye condition caused by elevated pressure (R).

It was also shown to protect human cells that make eye pigment from cell death (R).

Melatonin also prevents the death of nerve cells in an experimental model of optic neuritis in rats. Optic neuritis is a disease that causes the death of optic nerve cells responsible for vision (R).

Also, it is beneficial in refractory central serous chorioretinopathy, a condition that affects the eyes of diabetic patients (R).

A supplementation with melatonin drops in infancy and in the elderly is potentially beneficial for eye protection (R).

9) Melatonin Relieves Noises in the Ear (Tinnitus)

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Tinnitus is the unexplained noise in the ears that affects many people: the elderly, those with a hearing disability, or those affected as a result of certain drugs (R, R2).

Melatonin was 150 times more effective compared with other drugs that treat tinnitus. It decreased the symptoms of the condition (R).

In elderly patients with tinnitus, melatonin levels are very low. This may indicate that its levels are connected with normal ear activity (R).

Melatonin Part 2

Technical

  • There is about 100 times more MT in the stomach than blood (R).
  • Mice that had their MT1 receptors knocked out not only had severe sleep disturbances, they also had melancholic-like behavior similar to depression in humans (R).
  • In mouse mitochondria, directly incubating mitochondria with MT improves various parameters of their activity; it also improves production of the main energy molecule – ATP (R).
  • There are a lot of cells that have suprachiasmatic nucleus, or SCN receptors, in an area of the brain called that is responsible for controlling day-night cycles and sleep (R).
  • The MT2 receptor is lower in the eyes of Alzheimer’s patients (R).
  • Agomelatine is an MT analogue that is able to activate both MT receptors in the same time block where the 5-HT2c receptor binds with serotonin (R).
  • Melatonin prevents cell death more effectively than other antioxidants, like vitamin E, glutathione, mannitol, and vitamin C (R).
  • Recently, several combination therapies containing melatonin and a chemical associated with the MT3 receptor, 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT), decreased eye pressure in rabbits (R).

Caution

Melatonin and bright light is 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).

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