Melatonin Side Effects and Safety 101

Can’t sleep and looking for a nonhabit-forming sleep aid?

It’s not unusual to deal with insomnia from time to time. You may have difficulty falling asleep. Or if you’re able to fall asleep quickly, you may wake up after two or three hours. This can cause daytime sleepiness, irritability, and decreased productivity.

One night of bad sleep might not wreak too much havoc on your body. But when the problem goes on for days, weeks, or months, supplementing with melatonin can get your sleep back on track.

Melatonin is a hormone that your body makes naturally. Your melatonin level increases a couple of hours before bedtime, which signals your body to prepare for rest. (1) It’s important to note, however, that melatonin isn’t a sleep initiator but rather a sleep regulator, explains Carolyn Dean, MD, a sleep expert and author of 365 Ways to Boost Your Brain Power: Tips, Exercise, Advice.

Some people, however, don’t produce enough melatonin. And as a result, sleep doesn’t come easily. But while melatonin is a natural hormone that can help reset your circadian clock, oral melatonin isn’t right for everyone. (2)

What Are Melatonin Side Effects?

Melatonin needs vary from person to person. On average, most people need less than 3 milligrams (mg) per night to sleep better. Yet some people take more. (3)

Melatonin is generally safe for short-term use of one to two months in most healthy adults. But some people are more sensitive to the oral hormone and experience side effects. Adverse effects tend to occur with long-term use or when a person takes too much. (2,4)

Possible side effects of oral melatonin include: (1,3,5)

• Headache A mild to moderate headache can indicate that you’ve taken too much or that your body is sensitive to oral melatonin.
• Stomach Problems Melatonin also causes stomach discomfort in some people. This may include cramps, nausea, and diarrhea.
• Dizziness Some people who take melatonin also report mild dizziness, lightheadedness, or vertigo.
• Irritability Too much melatonin can also affect mood. You may feel cranky, anxious, or have periods of depression.
• Drowsiness Even though melatonin doesn’t usually cause a “hangover effect,” some people do experience daytime drowsiness. This can reduce alertness and make it difficult to drive or operate machinery. If you take melatonin, wait at least five hours before operating machinery. Keep in mind that some medication may intensify drowsiness, such as depressants and selective serotonin reuptake inhibitors. (1)
• Low Blood Pressure Sometimes, melatonin causes abnormally low blood pressure. Melatonin side effects are usually mild. (6) However, untreated low blood pressure can lead to life-threatening complications. Low blood pressure means that your body can’t carry enough oxygen to your organs. This can affect heart and brain function. Symptoms of low blood pressure include dizziness, fainting, blurry vision, confusion, and fatigue. (7)

If you experience mild side effects of oral melatonin, reduce your dosage to see if symptoms improve. Talk with your doctor about your dosage if your symptoms persist or worsen. Everyone’s body is different. So while one person may be able to tolerate 3 mg of melatonin a night, another person may be able to tolerate only 1 mg.

Melatonin for Children

Adults aren’t the only ones with acute or chronic sleep problems. Melatonin is also safe for children who have difficulty sleeping due to insomnia, circadian rhythm disorders, attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD), autism, and other neurological disorders.

Dosing for children varies. Some children may need only 1 to 3 mg a night, whereas a child with ADHD or autism may need 3 to 6 mg per night. But because oral melatonin is a supplement and is not regulated by the U. S. Food and Drug Administration, experts caution that parents should consult with a doctor before allowing children and adolescents to try melatonin. (10,11)

Your doctor can help you understand whether melatonin is right for your child and review the risk of side effects. “Side effects reported for children include nausea, diarrhea, headaches, changes in mood, sleepiness the next day, and bed-wetting,” notes Dr. Dean.

Who Shouldn’t Take Melatonin?

Some herbal and dietary supplements can interact negatively with prescription medication, and melatonin is no exception.

Before you take this supplement to improve the quality of your sleep, speak with your doctor.

Melatonin doesn’t interact with every prescription drug, but it can make some medicines less effective, like blood pressure and seizure medication. It can also boost blood sugar and is therefore not recommended for people with diabetes, warns Dean.

The supplement can also interact with blood-thinning medication, immunosuppressants, and corticosteroids. There’s also the risk of increased drowsiness when taken with birth control pills, depressants, or selective serotonin reuptake inhibitors. (1)

If you have chronic pain due to an inflammatory disease, melatonin might seem like a safe solution for better sleep. But this supplement isn’t recommended for people who have an autoimmune disease like lupus or arthritis. (12)

Melatonin can stimulate the immune system, triggering an inflammatory response and worsening these diseases.

There is no definitive research on the safety of using melatonin during pregnancy or while breastfeeding, so experts recommend talking to your doctor if that’s something you want to consider. (13)

Melatonin is preferred by some because it’s nonhabit-forming and a natural sleep aid. But the supplement isn’t right for everyone, and side effects can occur if not taken properly.

If you experience side effects, reduce the amount you take. If symptoms continue, stop taking oral melatonin. Also, don’t forget to consult your doctor before combining melatonin with a prescription medication.

For the most part, melatonin should be used only as a short-term remedy. See your doctor or a sleep specialist if sleep problems worsen or don’t improve after a few months.

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Side effects of melatonin – NHS

Like all medicines, melatonin can cause side effects, but most people will not have any side effects.

Common side effects

Melatonin does not have many common side effects but there are things you can do to help cope with them:

Feeling sleepy or tired in the daytime

Do not drive, cycle or use tools or machinery if you’re feeling this way. Do not drink any alcohol as this will make you feel more tired.

If you’re taking more than one 2mg tablet talk to your doctor to see if you can reduce your dose. If this does not help, talk to your doctor as melatonin may not be the right medicine for you.

Headache

Make sure you rest and drink plenty of fluids. Do not drink too much alcohol as it can make your headache worse, and it affects the way that melatonin works. Ask a pharmacist to recommend a painkiller.

Talk to a doctor if headaches last longer than a week or are severe.

Stomach ache

Try putting a heat pad or covered hot water bottle on your tummy. Talk to your doctor if the pain continues or is severe.

Feeling sick (nausea)

Take melatonin tablets or liquid after food. Stick to simple meals and do not eat rich or spicy food. It can help to eat and drink slowly and have smaller and more frequent meals.

Feeling dizzy

If taking melatonin makes you feel dizzy, stop what you’re doing and sit or lie down until you feel better. Do not drive, cycle or use tools or machinery if you’re feeling dizzy. Do not drink alcohol as it will make you feel worse.

Feeling irritable or restless

If this does not get better after a few days, stop taking the medicine and talk to your doctor.

Dry mouth

Chew sugar-free gum or suck sugar-free sweets.

Dry or itchy skin

Apply a moisturiser often. Try using an oil-free face moisturiser for sensitive skin.

If this does not get better after 1 week, stop taking the medicine and talk to your doctor.

Pains in your arms or legs

If this does not get better after a few days, stop taking the medicine and talk to your doctor.

Strange dreams or night sweats

If this does not get better after a few days, stop taking the medicine and talk to your doctor.

Speak to a doctor or pharmacist if the advice on how to cope does not help and a side effect is still bothering you or does not go away.

Serious side effects

Serious side effects are rare and happen to less than 1 in 1,000 people.

Speak to your doctor if you start feeling low or sad as this could be a sign of depression.

Call your doctor or call 111 now if you:

• get changes to your eyesight, such as blurred vision
• feel faint or pass out
• start feeling confused or dizzy, or things seem to be spinning around you (vertigo)
• have any bleeding that does not stop, unexplained bruising or blood in your urine

Serious allergic reaction

In rare cases, it’s possible to have a serious allergic reaction (anaphylaxis) to melatonin.

Immediate action required: Call 999 now if:

• your lips, mouth, throat or tongue suddenly become swollen
• you’re breathing very fast or struggling to breathe (you may become very wheezy or feel like you’re choking or gasping for air)
• your throat feels tight or you’re struggling to swallow
• your skin, tongue or lips turn blue, grey or pale (if you have black or brown skin, this may be easier to see on the palms of your hands or soles of your feet)
• you suddenly become very confused, drowsy or dizzy
• someone faints and cannot be woken up
• a child is limp, floppy or not responding like they normally do (their head may fall to the side, backwards or forwards, or they may find it difficult to lift their head or focus on your face)

You or the person who’s unwell may also have a rash that’s swollen, raised, itchy, blistered or peeling.

These can be signs of a serious allergic reaction and may need immediate treatment in hospital.

Other side effects

These are not all the side effects of melatonin. For a full list, see the leaflet inside your medicine packet.

Information:

You can report any suspected side effect using the Yellow Card safety scheme.

Visit Yellow Card for further information.

Page last reviewed: 13 February 2023

Next review due: 13 February 2026

Melatonin: Here’s what you need to know

What is melatonin?

Melatonin is the hormone that controls your circadian rhythm, or the internal clock that tells you when to sleep. Your brain produces and releases melatonin depending on the time of day. As you get older, your brain produces less melatonin. Fortunately, you can also get this hormone as a supplement.

Sleep supplement

Melatonin is best known for helping with sleep problems such as jet lag, insomnia, and delayed sleep phases, a disorder that causes you to fall asleep later and wake up later. It can also treat circadian rhythm sleep disorders in the blind. Melatonin may help you fall asleep a little faster than usual, but its impact on the quality of your sleep and the amount of time you sleep is still being studied. More research is also needed on whether melatonin can help you fall asleep if you work late shifts.

Other health benefits

Melatonin can control more than just sleep. While more research is needed, early research suggests that the hormone can influence your body temperature and lower nighttime blood pressure if you have hypertension. But research on how melatonin affects blood sugar levels is conflicting. Animal studies show it may help with weight loss, but more research is needed to see if this is true in humans.

Additional benefits being explored

Early research suggests that melatonin may also be helpful for macular degeneration, gastroesophageal reflux disease (heartburn), tinnitus (tinnitus), and migraines.

Is it safe?

Think of melatonin as a sleeping pill that you take for a short period of time, but not all the time. Melatonin is generally safe for occasional use, but researchers aren’t sure about its long-term effects. Always consult your physician first regarding use and dosage, especially if you are pregnant or nursing, have dementia, epilepsy, or an autoimmune disease. Some people may have an allergic reaction to melatonin.

Potential side effects

The most common side effects of melatonin supplements are headache, dizziness, nausea, and daytime sleepiness. Rare side effects include confusion, stomach cramps, irritability or depression, tremors, and restlessness. If you have any side effects, ask your doctor if it is safe to continue taking melatonin.

Drug interactions

Melatonin is considered a dietary supplement in the US, which means it is not regulated as tightly as over-the-counter drugs. In some countries, this requires a prescription. Melatonin does not mix well with certain medications, including:
Anticonvulsants
Contraceptives
Blood thinners
Blood pressure medicines
Central nervous system depressants
Medicines for diabetes
Diazepam
Medications that lower your seizure threshold
Fluvoxamine
Immunosuppressants

Natural melatonin in food

Your body produces melatonin naturally – it is even found in breast milk. Some products also contain natural melatonin. The highest amounts are found in eggs, fish, and nuts, but you can also find it in certain types of mushrooms and grains. Tart cherries contain both melatonin and tryptophan, an amino acid used to make melatonin and serotonin. This combination can help you fall asleep faster and stay awake longer.

How much to take and why

Take just enough melatonin to get the job done, starting at 0.3-1 milligram. If that doesn’t work, talk to your doctor about increasing your dose. If you take too much melatonin, you may experience headaches, nausea, or daytime sleepiness.

Can children take Melatonin?

In general, short-term use of low doses of melatonin is safe for children and adults, but not for infants. Because it is not strictly regulated by the FDA, it is best to ask your pediatrician to recommend a safe brand and dosage for your child’s age, weight, and general health.

How to choose it

Melatonin comes in two forms: natural and synthetic. The natural version is made from animal glands and may contain viruses that make you sick. To avoid this risk, use the synthetic version instead.

When to take it

Melatonin is not a fast acting supplement. For maximum benefit, take it a few hours before bedtime. Closer to bed, set yourself up for a successful sleep by making sure your room is cool and dark. Turn off your screens and go to bed around the same time every night.

Melatonin for chronic pain syndromes

The concept of circadian rhythms was introduced by F. Halberg in 1959 and turned the understanding of researchers about many processes occurring in the human body. Circadian rhythms are associated with a number of physiological processes, such as the sleep-wake cycle, body temperature regulation, hormone secretion, cell division and proliferation, the functioning of the gastrointestinal tract, etc. It is known that disturbances in circadian rhythms can lead to a number of pathological conditions, while at the same time, the vast majority of diseases can cause their desynchronization. So, chronic pain syndromes are almost always associated with one or another degree of severity of violations of biological rhythms. The biological rhythm control center in mammals is located in the suprachiasmatic nuclei of the hypothalamus. The suprachiasmatic nuclei, unable to perceive light signals directly, receive them with the help of the optic nerve, which transmits information from the retina [1].

Another important formation involved in the regulation of biological rhythms is the pineal gland or pineal gland. The pineal gland is an endocrine gland located in the region of the diencephalon above the superior tubercles of the roof of the mesencephalon. The pineal gland synthesizes and secretes the neurohormone metalonin. It should be noted that although up to 80% of melatonin is secreted by the pineal gland, there are also extrapineal sources of melatonin synthesis – cells of the gastrointestinal tract (GIT), lungs and kidney cortex, retina, lymphocytes, platelets, mast cells, etc. Most of the functions of melatonin are well studied, while others are still the subject of study. Melatonin has chronobiological properties, is able to regulate the circadian rhythm, restore disturbed sleep, in addition, melatonin has demonstrated its antioxidant functions, which formed the basis for the idea of ​​its use in such neurodegenerative diseases as Parkinson’s disease and Alzheimer’s disease [2]. In a number of experimental and clinical studies, melatonin has demonstrated oncostatic and immunomodulatory effects, the ability to normalize mood and reduce anxiety, affect the cardiovascular system and gastrointestinal tract, participate in reproductive functions and regulate metabolism and body weight [3]. The analgesic potential of melatonin has always been of particular interest. Considering that the treatment of chronic pain syndromes is still far from perfect, the constant search for new molecules with analgesic capabilities is relevant, as well as the study in this aspect of existing substances used for other indications. In this matter, the combination of high efficacy and a good safety profile of the drug becomes decisive [4]. Melatonin has demonstrated its efficacy and safety in cases of nociceptive and neuropathic pain in a number of experimental and clinical studies.

Experimental experience with melatonin

Back in 1991, D. Golombek et al. [5], using a model of nociceptive pain, demonstrated that melatonin at a dose of 20–40 mg/kg intraperitoneally has the maximum analgesic effect when administered in the evening. This analgesic effect was significantly reduced by administration of the opiate antagonist naloxone or the central benzodiazepine antagonist flumazenil, thus indicating involvement of the central opioid and benzodiazepine (BZD) receptors.

In another work, also on the model of nociceptive pain, C. Yu et al. [6] proved the dose-dependent antinociceptive effect of melatonin in a group of rats that were intraperitoneally injected with melatonin at three different doses (30, 60, 120 mg/kg) and simultaneously performed pain stimulation. The antinociceptive effect began within 15 minutes after injection of 60-120 mg/kg, peaked after 30 minutes and lasted for 100 minutes. Intravenous administration of naloxone neutralized the analgesic effect of melatonin within 10 minutes after injection [6]. A number of subsequent works further strengthened the understanding that melatonin may be effective in relation to nociceptive pain. S. El-Shenawy et al. [7] in 2002, E. Esposito et al. [8] in 2010 and M. Mantovani et al. [9] in 2003 proved in their experiments the analgesic potential of melatonin in relation to nociceptive pain. Melatonin led to a decrease in the release of prostaglandins and suppressed the integration of polymorphonuclear leukocytes at the site of inflammation, suppressed inflammation by affecting cyclooxygenase-2 and NO-synthase.

It should be noted that melatonin has also been shown to be effective in neuropathic pain in experimental studies. Y. Tu et al. in 2004 showed [10] that the administration of melatonin led to a decrease in the intensity and duration of capsaicin-induced secondary mechanical allodynia and hyperalgesia; it was concluded that the effect of melatonin on the CNS can prevent the occurrence and generalization of central sensitization caused by injection of capsaicin.

A. Ulugol et al. [11] in 2006 demonstrated the effectiveness of melatonin in relation to neuropathic pain. In a mouse study, sciatic nerve ligation resulted in pain associated with mechanical allodynia and thermal hyperalgesia. Injections of melatonin at high doses (120 mg/kg intraperitoneally) and 0.1 nmol intravenously led to an increase in the pain threshold and a decrease in the severity of thermal hyperalgesia.

Experience with melatonin in clinical trials

Melatonin for headaches

Recently, the fact that circadian rhythm disturbance plays an important role in the pathogenesis of headaches has been increasingly discussed. The use of melatonin in such a situation, through the normalization of circadian rhythms and its own analgesic mechanisms, can reduce the frequency and severity of pain syndromes. Receptors for melatonin have been found in the ganglion and nuclei of the trigeminal nerve, suggesting that melatonin attenuates trigeminovascular nociception. A number of clinical studies have examined the relationship between nocturnal melatonin levels and migraine. A study of 146 patients with migraine showed a significantly lower level of 6-sulfatoxymelatonin (the main metabolite of melatonin) in the urine of patients with migraine than in a group of healthy volunteers [12].

Another study [13], which included 34 patients, evaluated the effectiveness of melatonin in the prevention of migraine. It has been demonstrated that melatonin at a dose of 3 mg at bedtime is able to reduce the frequency, intensity and duration of headache in patients with migraine. The melatonergic receptor agonist agomelatine has recently been shown [14] to be effective in the treatment of patients with migraine attacks. Appointment of agomelatine at a dose of 25 mg/day for 6 months led to a decrease in the frequency and duration of migraine attacks, the severity of depression significantly decreased, and sleep normalized [14].

Despite the fact that the pathophysiology of cluster headache is not fully understood, current concepts suggest an invariable involvement of circadian rhythms in the pathogenesis of this disease. Studies have shown a decrease in the level of nocturnal secretion of melatonin in patients suffering from cluster headache compared to healthy subjects, as well as a lower level of melatonin during an exacerbation of cluster headache compared to remission [15]. In one of the clinical studies in parallel groups [16], patients suffering from cluster headache received melatonin 10 mg or placebo at bedtime for 14 days. There was a statistically significant decrease in the severity of pain and a decrease in the frequency of seizures in the group taking melatonin. In addition, there was a trend towards a decrease in the consumption of analgesics in the main group, however, these results did not reach statistical significance. In another study [17], patients with cluster headache received 2 mg of melatonin, but there was no significant difference compared to the placebo group in terms of pain syndrome.

Melatonin has also been shown to be effective in tension headache [18]. When prescribing 3 mg of melatonin to children at bedtime for 3 months, 14 out of 21 patients reported that the intensity of the pain syndrome decreased by 50% or more, 4 of them did not have pain attacks at all.

Melatonin for chronic back pain

To evaluate the effectiveness of melatonin in chronic back pain, a study was conducted in 178 patients aged 40 to 65 years who suffered from low back pain lasting at least 12 weeks and intensity more than 3 points on the visual analog scale. Patients were divided into six groups and made up 3 comparison pairs. In the 1st pair, patients of the main group (31 people) received artra (a combination of glucosamine hydrochloride 500 mg and chondroitin sulfate 500 mg) 1 tablet 2 times a day for 1 month, then 1 tablet for 2 months and additionally melaxen (melatonin 3 mg 30-40 minutes before bedtime), comparison group patients (29) received only arthra. In the 2nd pair, patients of the comparison group (30) took Artra 1 tablet 2 times a day and diclofenac at a dose of 25 mg 2-3 times a day, patients of the main group (30) additionally took melaxen according to the scheme similar to that used in the 1st comparison pair. In the 3rd pair, patients of the main group (29) received diclofenac at a dose of 25 mg 3 times a day and melaxen according to the scheme described above, patients from the comparison group (29) did not receive melaxen. The results were evaluated in the 1st pair after 3 months, in the 2nd and 3rd — after 1 month. The data obtained indicated a statistically significantly more pronounced decrease in the intensity of pain during movement and at rest in all main groups than in the comparison groups. In addition, the effect of pain on daily activities, the severity of anxiety and depression decreased, and sleep normalized. It was concluded that the addition of melatonin to the standard treatment regimen increases its effectiveness in back pain [19].

Melatonin and irritable bowel syndrome

It is known that, in addition to the pineal gland, melatonin is synthesized by enterochromaffin cells of the gastrointestinal tract; it is assumed that this is important in relation to the physiology and pathology of the gastrointestinal tract. The synthesis and secretion of melatonin in the gastrointestinal tract do not have a daily rhythm. Melatonin contributes to the inhibition of macrophages and the reduction of inflammatory mediators, which prevents the formation of gastrointestinal mucosal ulcers and damage to the colon. It has been clinically proven that the level of melatonin in saliva in patients suffering from irritable bowel syndrome is significantly lower compared to healthy ones [20]. Melatonin is able to reduce abdominal pain and facilitate the act of defecation without affecting sleep and anxiety in patients with irritable bowel syndrome [21]. At the same time, there is evidence of a positive effect of melatonin on extraintestinal symptoms in irritable bowel syndrome, which is due either to its anxiolytic effect or a direct effect on the gastrointestinal tract [22].

Two randomized, placebo-controlled clinical trials investigated the analgesic effects of melatonin in patients with irritable bowel syndrome. In both studies, patients took 3 mg of melatonin. One study involved 40 patients who took melatonin or placebo for 2 weeks [23]. Another study involved 24 patients who took melatonin or placebo for 8 weeks with a 4-week washout period [24]. In both studies, patients treated with melatonin noted a significant reduction in the severity of pain compared to control groups.

C. Chojnacki et al. [25] showed that when taking melatonin for 6 months, along with a decrease in the severity of abdominal pain, there is an improvement in intestinal motility.

Melatonin for fibromyalgia

Impaired melatonin secretion is thought to be part of the pathogenesis of fibromyalgia. However, experimental data on this matter are contradictory. A number of studies have examined the features of the circadian rhythm and melatonin secretion in patients with fibromyalgia. According to the results of one study [26], there were no significant differences in the level of melatonin in patients with fibromyalgia and healthy people. According to other data [27], the concentration of nocturnal melatonin in plasma and urine was significantly lower in patients with fibromyalgia compared to the control group.

In Russia, a study was made of the effect of nightly intake of 1.5 mg of melatonin (melaxen) for 10 days on the subjective assessment of the quality of night sleep and its objective characteristics in 11 patients with fibromyalgia [28]. A polysomnographic study confirmed night sleep disturbances in the form of difficulty falling asleep, lengthening of the latent period of light and paradoxical sleep, suppression of deep sleep, a decrease in the number of completed sleep cycles, an increase in periods of wakefulness and movements in sleep, etc. before treatment. After the completion of the course of treatment, there was a subjective improvement in sleep: easier falling asleep, shorter periods of wakefulness within sleep, etc. There was also an improvement in well-being, a decrease in the level of depression, and an improvement in fine motor skills of the hands during the daytime. It was concluded that melatonin has a positive effect on the quality of sleep in case of sleep disorders. In these same patients, the level of pain decreased slightly and depression decreased.

In another open randomized trial with 21 patients [29], melatonin was taken for 4 weeks. At the end of therapy, a significant improvement in the quality of sleep and a decrease in the number of painful trigger points were noted. The authors also claimed to have received good results in terms of treatment of pain, fatigue and depressive symptoms, however, these changes were not statistically significant.

S. Hussein et al. [30] conducted a double-blind, placebo-controlled study in which 101 patients with fibromyalgia took part. The effectiveness of various doses of melatonin alone or in combination with fluoxetine was evaluated. Patients were divided into four groups: group A receiving fluoxetine 20 mg per day, group B receiving melatonin 5 mg, group C with a combination of fluoxetine 20 mg and melatonin 3 mg, and group D with a combination of fluoxetine 20 mg and melatonin 5 mg. During treatment with fluoxetine alone, a decrease in the severity of symptoms such as fatigue, morning stiffness, anxiety and depression was noted. The effect of therapy with melatonin alone was lower in relation to the listed symptoms, but still remained significant both in relation to pain and in relation to depression, anxiety and sleep disorders. The combination of melatonin and fluoxetine made it possible to reduce anxiety, fatigue and very significantly reduce the severity of depressive symptoms.

In a study by S. de Zanette et al. [31] 63 patients with fibromyalgia aged 18 to 65 years were randomized into three groups: group 1 — amitriptyline 25 mg at bedtime, group 2 — melatonin 10 mg at bedtime, and group 3 — amitriptyline 25 mg + melatonin 10 mg combined. Treatment continued for 6 weeks. It turned out that the combination of melatonin and amitriptyline and isolated melatonin are more effective than amitriptyline monotherapy in relation to pain, morning stiffness, daytime fatigue, sleep disturbances.

The pathophysiological relationship between circadian rhythm disorders and fibromyalgia has not been fully elucidated, however, the fact that melatonin is effective in treating such patients has been proven in a number of clinical studies with a high degree of certainty.

Melatonin and rheumatoid arthritis

In patients with rheumatoid arthritis, the level of melatonin secretion at night is significantly higher, in the morning the level of melatonin in blood serum is higher in patients with a shorter history of the disease [32, 33]. Inflammatory cytokines, such as interferon-gamma, interleukin-1 and interleukin-6, are secreted in human peripheral blood in response to melatonin stimulation, in addition, melatonin is found in synovial fluid in patients with rheumatoid arthritis [34]. These studies suggest that melatonin has an adverse effect on rheumatoid arthritis. At the same time, melatonin inhibits the activity of matrix metalloproteinase, which is involved in joint destruction in patients with rheumatoid arthritis [35]. Thus, further studies are designed to determine the role of melatonin in joint destruction.

Possible mechanisms of action of melatonin

Melatonin has shown itself to be a substance with a significant analgesic effect in a number of experimental and clinical studies. It is achieved due to the normalization of circadian rhythms, which are inevitably disturbed in chronic pain syndromes, there is an improvement in sleep and activation of one’s own adaptive capabilities. At the same time, there are data on the own analgesic effect of melatonin, realized through receptors and a number of neurotransmitter systems.

There are membrane melatonin receptors MT1/MT2 and nuclear receptors RZRα/RZRβ. The involvement of membrane receptors in the analgesic action of melatonin is partly confirmed by the localization of MT1 and MT2 receptors in the thalamus, hypothalamus, dorsal horns of the spinal cord, spinotrigeminal tract, trigeminal nucleus. In addition, in experimental studies with the introduction of lysindol, an antagonist to the MT1 and MT2 melatonin receptors, or substances 4-P-PODT / K-185, selective inhibitors of MT2 receptors, a decrease in the severity of the antinociceptive effect occurs. Studies have shown that melatonin has a complex analgesic effect, which, however, is mainly based on the inhibition of spinal nociception (see figure).

Activation of melatonin receptors is thought to increase cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Mediators such as Ca2+ ions, diacylglycerol, inositol phosphate, and arachidonic acid are inhibited by melatonin, at least in the rat anterior pituitary gland [37]. In one of the electrophysiological studies, it was demonstrated that melatonin activates calcium-dependent Cl ion channels through phospholipase, and this effect can be inhibited by specific MT1/MT2 melatonin receptor antagonists [38]. In addition, it has been suggested that melatonin may block the interaction of calmodulin (CaM) with its specific enzymes [39]. These data are important because CaM kinase II plays an important role in the formation of central sensitization. Melatonin can promote the release of endogenous opioids by pituitary cells, which leads to the activation of antinociception. Melatonin activates MT2 receptors, which are located in the postsynaptic membrane of second-order neurons, thus melatonin is able to reduce intracellular levels of cAMP and Ca2+. Under the influence of melatonin, potassium channels are activated and calcium channels are blocked. In addition, melatonin can activate nuclear melatonin receptors and possibly thus reduce the expression of NO synthase and phospholipase A2.

One recent experimental study [40] evaluated the efficacy of a new selective MT2 melatonin receptor agonist N-{2-([3-bromophenyl]-4-fluorophenylamino)ethyl}acetamide (UCM924) in 2 rat models of neuropathic pain and studied its supraspinal mechanism of action. In rats with L5-L6 spinal root ligation in a nerve injury model, UCM924 (20–40 mg/kg, s. c.) produced a long-lasting antinociceptive effect with the following features: dose-dependent and could be blocked by the selective MT2 melatonin receptor antagonist 4-phenyl-2-propionamidotetralin at high doses ax (150 mg/kg) was comparable to gabapentin (100 mg/kg), but without noticeable impairment of motor coordination in tests. The use of double immunohistochemical staining revealed that MT2 receptors are present in glutamatergic neurons in the rostral gray matter near the aqueduct. Using electrophysiological methods in vivo , it was possible to prove that microinjections of UCM924 into this zone reduce pain impulses, suppress the activity of ON cells and, on the contrary, activate OFF cells; All of these effects were mediated through MT2 receptors. Overall, these data indicate that selective MT2 melatonin receptor agonists have analgesic properties through modulation of the antinociceptive system, and MT2 receptors may represent a new target in the treatment of neuropathic pain.

With regard to nuclear receptors, it is known, on the one hand, that RZRβ plays a special role as a transcription factor in the sensory system, and on the other hand, that RZRα-melatonin receptors are involved in inflammatory reactions. D. Steinhilber et al. [41] reported that melatonin can reduce the expression of 5-lipoxygenase (5-LOX), an important inflammatory mediator, in B-lymphocytes via RZRα receptors.

Experimental studies have shown that the antinociceptive effects of melatonin are at least partially due to the activation of potassium channels. At the cellular level, melatonin activates the G-protein paired channels Kir3, which, in turn, inhibits a series of action potentials in neurons. In addition, in the cells of the cerebellum, the suprachiasmatic nucleus, and some other areas of the nervous system, melatonin activates the release of K+ ions [42].

Calcium channels play a critical role in the development and maintenance of central sensitization associated with inflammation and neuropathic pain, an effect mediated by gabapentin, which is widely used to treat neuropathic pain. A. Ayar et al. [43] demonstrated that melatonin inhibits Ca2+ entry into neurons of the posterior spinal ganglia. This occurs by blocking Ca2± channels and, as a result, a decrease in the intracellular concentration of free Ca2+.

There is good reason to believe that the central effects of melatonin include the facilitation of GABAergic transmission by modulating GABA receptors. It is known that the pineal gland is connected by afferent fibers with the suprachiasmatic nucleus, which, in turn, is connected with the subparaventricular zone and the dorsomedial nucleus. The neurons of the suprachiasmatic nucleus are able to simultaneously provide both excitation and inhibition of the paraventricular nucleus and the ventrolateral preoptic nucleus (these mechanisms are mediated by glutamate and GABA, respectively). As already noted, melatonin inhibits a series of action potentials in the neurons of the suprachiasmatic nucleus, which can lead either to a loss of inhibition (and, as a result, an increase in the excitation of those structures that receive innervation from the suprachiasmatic nucleus), or a loss of excitation. In addition, it is quite possible that melatonin is able to modulate the functions of GABA receptors [44]. In the experiment, it was found that melatonin enhances the affinity of GABA for receptors in the rat brain. It is also known that melatonin itself and its analogues are able to bind to GABA receptors. In addition, melatonin also increases GABA concentration by 50% [45]. Thus, the data obtained indicate that there is a significant relationship between the melatonin and GABAergic systems, and some of the neuropharmacological effects of melatonin (including its hypnotic activity) seem to be mediated through GABA receptors and can be blocked by the use of GABA antagonists.

Conclusion

The effects of melatonin are still being studied. Some of them remain the subject of controversy, while others are not in doubt. The latter include the analgesic effect of melatonin. Its effects on pain have been proven in a number of experimental animal studies and in clinical trials in patients with various pain syndromes. There is an understanding that the antinociceptive mechanisms of melatonin have a complex, complex structure. On the one hand, being a chronobiotic, melatonin restores circadian rhythms disturbed in chronic pain, thereby increasing the body’s adaptive capabilities. On the other hand, melatonin, having an anxiolytic effect, can also reduce pain by reducing the severity of anxiety and autonomic reactions. And finally, there is definitely a separate, own analgesic effect of melatonin, which is realized due to the representation of melatonin receptors in those brain structures that are responsible for the perception and control of pain, and through a number of neurotransmitter systems (GABA, opioid system, NO-arginine pathway, etc.). It should also be noted that melatonin has an extremely high safety profile. The literature describes possible side effects of melatonin, including daytime sleepiness, headaches, dizziness, abdominal discomfort, irritability, and confusion. However, in practice, in clinical studies for various chronic pain syndromes, the number of undesirable effects is extremely low.