“My focus is to forget the pain of life. Forget the pain, mock the pain, reduce it. And laugh.”
– Jim Carrey

Melatonin

 Melatonin, a pineal gland neurohormone synthesized from L-tryptophan, plays an important role in the biologic regulation of circadian rhythms, sleep, mood, reproduction, tumor growth, and the protection of nerves. Recent research indicates melatonin plays a significant part in chronic pain as well.

 

It is recommended to first read the following sections to become familiarized with some of the terms and concepts related here:

 

 

See also:

 

Definitions and Terms Related to Pain

Key to Links:

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  • Red text – another page on this website
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Melatonin

Melatonin is a hormone secreted by the pineal gland in the brain. It helps regulate other hormones and maintains the body’s circadian rhythm. The circadian rhythm is an internal 24-hour “clock” that plays a critical role in when we fall asleep and when we wake up. When it is dark, our body produces more melatonin; when it is light, melatonin production drops. Being exposed to bright lights in the evening or too little light during the day can disrupt the body’s normal melatonin cycles. For example, jet lag and shift work can disrupt melatonin cycles.

 

Melatonin is commonly used as a hypnotic medication for insomnia. Other clinical uses of melatonin include menopause, anxiety, benzodiazepine withdrawal and chronic pain. A few reports have suggested that melatonin supplements may especially help with sleep and anxiety when discontinuing therapy with benzodiazepine (Xanax, Valium, Klonopin etc.).

 

 Melatonin – Chronic Pain

It has been established that the intensity of pain sensation displays distinct day and night variations. Since the intensity of pain perception tends to be lower during dark hours of the night when melatonin levels are high, melatonin has been evaluated as a pain-relieving substance. A recent study indicates that melatonin raises pressure and heat pain thresholds (the levels of stimulation needed to trigger pain) in a dose-dependent pattern. Growing evidence supports the belief that melatonin is particularly effective in hyperalgesia and allodynia (inappropriate, excessive perception of pain – see Pain Definitions), which are common complications of chronic pain syndromes, especially chronic nerve pain.

 

A number of animal studies have established the analgesic benefits of melatonin in acute, inflammatory and neuropathic pain. Human studies suggest melatonin may be helpful for the pain associated with fibromyalgia, irritable bowel syndrome (IBS) and in headaches. Melatonin has also been reported to help with the pain of endometriosis.

 

Melatonin and Oxidative Stress

Melatonin has potent antioxidant properties including scavenging of reactive oxygen (ROS) and reactive nitrogen (RNS) species, which protects against oxidative stress, a major contributor to neuroinflammation and chronic pain. Melatonin has synergistic effects with other antioxidants and helps limit free radicals overproduction in mitochondria. 

 

Melatonin – Fibromyalgia Syndrome (FMS)

Studies suggest that patients with fibromyalgia (FMS) have low melatonin secretion, which could explain the lack of restorative sleep seen with FMS.

Treatment of fibromyalgia patients with melatonin has been tested in a limited number of studies. In one study carried out on 21 female patients, melatonin was administered in doses of 3 mg for 4 weeks, 30 minutes before bed time. Improvements with respect to pain, fatigue and depressive symptoms were noted.

Melatonin in combination with antidepressants for FMS

Another study showed that melatonin caused significant improvements in pain, fatigue, sleep/rest activity, depression and morning stiffness. The combination of fluoxetine (Prozac) with melatonin caused even greater significant reductions in both anxiety and depressive symptoms, along with reduction of fatigue. The symptom improvement in this combination was greater than the improvement of either drug given individually.

In another study, melatonin (10 mg) alone or in combination with amitriptyline (Elavil – 25 mg) significantly reduced  pain. As above, the symptom improvement in this combination was greater than the improvement of either drug given individually.

Melatonin – Endometriosis

Endometriosis, a disorder in which tissue that normally lines the uterus grows outside the uterus, is associated with chronic pelvic pain. Endometriosis lesions produce pain by compressing or infiltrating the nerves near the lesions. The presence of nerve growth factors in lesions is correlated with hyperalgesia and  peripheral and central sensitization that results in an amplification of nerve impulses causing persistent, severe pelvic pain. Results of previous studies in animals have shown that melatonin caused the regression and atrophy of endometriotic lesions.

 

A recent study indicated that a 10 mg dose of melatonin at bedtime produced a large improvement in chronic pelvic pain associated with endometriosis. Melatonin treatment for eight weeks reduced daily pain scores by 39% and dysmenorrhea (menstrual pain) by 38%. Melatonin also improved sleep quality and reduced the likelihood of needing an analgesic by 80%. This study provides additional evidence regarding the analgesic effects of melatonin on chronic pain and melatonin’s ability to improve sleep, independent of it’s pain benefits.

  

 Melatonin – Headaches

Evidence suggests that melatonin is helpful for tension, cluster, and migraine headaches.

 

Migraine Headaches

Evidence suggests that melatonin is helpful for tension, cluster, and migraine headaches. An association between nocturnal melatonin secretion and symptoms of migraine has been identified in which people with abnormal melatonin secretion or disruption in normal circadian rhythms have a higher incidence of migraine headaches. Furthermore, treatment with melatonin has been shown in a number of studies to reduce the frequency and severity of migraine headaches.

Cluster Headaches

Melatonin is also involved in the cause of cluster headaches since circadian rhythm is disrupted in this disorder. A decrease in nocturnal melatonin secretion with loss of melatonin rhythm has also been identified in cluster headache patients. Based on this, melatonin was studied in the treatment of cluster headaches and it was found that melatonin treatment resulted in a significant decrease of cluster headache attacks. In one study, 9 mg dosing of melatonin not only prevented the nocturnal cluster headaches but also prevented the daytime attacks as well.

 

Melatonin – IBS

Limited studies also show potential benefit for melatonin in treating irritable bowel syndrome (IBS). This condition is associated with abdominal pain, flatulence, constipation, diarrhea and sleep disturbances. Two clinical trials administering 3 mg/day of melatonin showed reductions in abdominal and rectal pain.

Melatonin and the Gut Microbiome

Melatonin has a significant role in gut microbiota maintenance. By modulating the gut microbiota, melatonin can impact the gastrointestinal tract and prevent dysbiosis, the breakdown of a normal balanced population of the microorganisms in the gut, thus contributing to a healthy balanced microbiome.  Dysbiosis can lead to several conditions, such as neurodegenerative diseases, diabetes, obesity, cancer, metabolic syndrome, and cardiovascular diseases.

Clinical trials evaluating the role of melatonin, and that got microbiome are very limited. There is growing evidence, however, that L tryptophan and 5HTP, precursor to melatonin, do you have significant impact on the microbio in a positive manner.. One study, a single-blind, parallel randomized controlled trial,  investigated the use of melatonin (100 mg daily for 12 weeks) in adults (66 ±3 years). The composition of gut microbiota and short-chain fatty acids in stool were evaluated at weeks 0 and 12. Their results showed that using melatonin could exhibit beneficial effects on sleep quality. increased microbiota diversity and a relative abundance of beneficial short-chain fatty acid-producing bacteria in the gut.

 

Melatonin – Insomnia

Clinical studies suggest that melatonin is  effective in reducing the time it takes to fall asleep, increasing the number of sleeping hours, and boosting daytime alertness.  Melatonin has a very low risk of side effects and only limited evidence of habituation and tolerance. Research is still lacking to confirm strong sleep benefits, especially in primary insomnia, when insomnia is not associated with circadian (“body clock”) disruption or other medical conditions.

 

Studies suggest that melatonin supplements may help people to sleep better in those who have disrupted circadian rhythms (such as people with jet lag and those who alternate night/day shift work) or those with low melatonin levels (such as some seniors). A review of clinical studies found that melatonin supplements do help prevent jet lag, particularly in people who cross five or more time zones. The studies evaluating the benefit of melatonin for insomnia related to shift work remain inconclusive.

 

Several human studies have measured the effects of melatonin supplements on sleep in primary insomnia. A wide range of oral doses have been studied, taken 30 – 60 minutes prior to sleep time. Results have been mixed. Some evidence suggests that melatonin may work best for people over 55 who have insomnia. One study of people with primary insomnia aged 55 and older found that sustained-release melatonin helped people fall asleep faster, sleep better, be more alert in the morning, and improve quality of life.

 

Melatonin – Insomnia Related to Benzodiazepine Withdrawal

Growing concerns regarding the chronic use of benzodiazepines, especially when used with opioids, has led to broad recommendations for discontinuing their use. The consensus guidelines for benzodiazepine therapy recommends prescriptions for only short-term therapy of insomnia, limiting use for periods not exceeding 2 weeks, and intermittent courses only. However, development of physical and/or psychological dependencies and rebound insomnia often interfere with attempts at discontinuation chronic benzodiazepine use.

It has been reported that treatment with melatonin can help reverse the withdrawal-related insomnia associated with discontinuing benzodiazepines. It is uncertain how melatonin works in improving benzodiazepine withrawal insomnia, but it is hypothesized that long-term benzodiazepine therapy may impair the natural melatonin rhythms, which may in turn induce or aggravate sleep disturbances.

 

 In a case report of a 43 y/o woman using benzodiazepines for sleep for 11 years, treatment with 1 mg of controlled release melatonin enabled the patient to completely cease any benzodiazepine use within two days, with an improvement in sleep quality and no side effects (???) . A 12 week study evaluated the use of a 2 mg dose of controlled release melatonin in a group of patients who were encouraged to taper off benzodiazepines by 50% in the first 2 weeks, 75% over the next 2 weeks and discontinue completely by the end of week 6. Melatonin therapy was continued for another 6 weeks and by the end of the 12 week period, 24 of the 34 subjects were able to discontinue their benzodiazepines. In a 6 month follow-up, 19 of the 24 subjects reported good quality sleep and no return to the use of benzodiazepines.

The facilitation of benzodiazepine therapy discontinuation by melatonin was achieved with each of the different benzodiazepines, including those with a short half-life (alprazolam-Xanax) and long half-life (diazepam-Valium, clonazepam-Klonopin). The dose of benzodiazepine also did not seem to impact the success or failure of melatonin treatment.

 

Melatonin – Products

Melatonin is available in time-release and immediate release formulas, including sublingual versions which offer more rapid onset and possibly more effectiveness. Ramelteon (Rozerem), a prescription hypnotic medication that acts on melatonin receptors, has been shown to be helpful in insomnia.

 

Melatonin Metabolism

Melatonin is produced mainly in the pineal gland. Once formed, melatonin is not stored in the pineal gland but diffuses into the blood. But most of the melatonin from the pineal gland is also released simultaneously into the cerebrospinal fluid (CSF) that circulates throughout the brain and spinal cord. The concentration of melatonin in the CSF is 20 to 30 times higher than that found in the blood.

 

Circulating melatonin is metabolized mainly in the liver by cytochrome P450 isoenzymes CYP1A and to a lesser extent CYP1B, which are enzymes that do not appear to be commonly affected by genetic variants or drug interactions. In the brain, melatonin is metabolized to compounds that also have antioxidant and anti-inflammatory benefits.

 

Melatonin Dosing and Side Effects

There is currently no specific recommended dose for melatonin supplements. Different people will have different responses to its effects. Lower doses appear to work better in people who are especially sensitive, while higher doses may cause anxiety and irritability.

 

Melatonin can be taken sublingually or orally in adults and children. After its oral administration, a peak serum melatonin concentration is reached after approximately 60 minutes; thereafter its concentration declines over a four-hour period. In numerous long-term studies in children and adults, no significant side effects have been determined after its oral administration. 

The best approach for any condition is to begin with very low doses of melatonin. Consider starting with a low dose, close to the amount that our bodies normally produce (< 0.3 mg per day). You should always use the lowest dose possible to achieve the desired effect. Your doctor can help you determine the most appropriate dose for your situation, including how to increase the amount, if needed.

Studies indicate that patients receiving melatonin therapy do not develop tolerance to the hormone during prolonged periods of use and experience no withdrawal effects upon discontinuation.

 

Adult Dosing

Insomnia: 1 to 3 mg 1 hour before bedtime is usually effective, although doses as low as 0.1 -0.3 mg may improve sleep for some people. If 3 mg per night does not work after 3 days, try 5 – 6 mg 1 hour before bedtime. Doses up to 10 mg are generally well-tolerated. You should work with your doctor to find the safest and most effective dose for you. The right dose for you should produce restful sleep with no daytime irritability or fatigue.

Jet lag: 0.5 – 5 mg of melatonin 1 hour prior to bedtime at final destination has been used in several studies. Another approach that has been used is 1 – 5 mg, 1 hour before bedtime for 2 days prior to departure and for 2 – 3 days upon arrival at final destination.

Fibromyalgia: Studies suggest that higher doses  – up to 10mg at night – may be more effective in obtaining symptom relief with fibromyalgia.

 

Plant Sources of Melatonin

Plant generative organs (e.g., flowers, fruits), and especially seeds, have the highest melatonin concentrations, markedly higher than those found in vertebrate tissues. Obtaining melatonin from plants presents several advantages. First, plant-derived melatonin can be associated with other bioactive compounds found in plants that often have antioxidant, anti-inflammatory effects. Depending on the plant species, these may be flavonoids, vitamins, and other compound classes which also exert synergistic effects, improving bioavailability and reducing side effects.

However, melatonin bioavailability demonstrates extensive variation between individuals, including oral and intravenous administration. In addition, there is considerable variations in melatonin absorption, metabolism, and elimination between individuals. In one study, oral and intravenous melatonin elimination half-lives were 54 min and 39 min, respectively, and oral melatonin bioavailability was found to be only 3%, with considerable inter-volunteer variability.

1. Foods Naturally High in Melatonin:

  • Tart Cherries & Cherry Juice – One of the best sources, with studies showing improved sleep quality.
  • Goji Berries – Contain melatonin and antioxidants that may support sleep.
  • Grapes (especially red/purple varieties) – Naturally contain melatonin.
  • Tomatoes – Small amounts of melatonin are present.
  • Strawberries, Raspberries, & Blackberries  – Berries have trace amounts.
  • Pistachios – Among the highest melatonin content in nuts, up to 23 gms melatonin in 100 gms of pistachios.
  • Almonds – Contain melatonin and magnesium, which aids relaxation.
  • Walnuts – Provide melatonin and healthy fats for sleep support.

Some food sources, like nuts and grains, are richer in melatonin than others, while fruits and vegetables typically contain lower amounts. For example, 100 grams of pistachios may contain around 23 mg of melatonin, while 100 grams of tart cherries might have about 19.5 nanograms,

Melatonin content in some common foods:

  • Nuts:
    Pistachios, almonds, walnuts, and pecans are known to be rich sources of melatonin. Pistachios can contain around 23 mg of melatonin per 100 grams.
  • Grains:
    Cereals like wheat, oats, and barley also contain melatonin.
  • Fruits:
    Tart cherries, grapes, and bananas contain melatonin, but in lower quantities than nuts and grains.
  • Other:
    Fatty fish (like salmon), tomatoes, and even milk have been found to contain melatonin, though in smaller amounts

2. Foods Rich in Tryptophan (Melatonin Precursor):

See: L-tryptophan & 5-HTP

  • Tryptophan is an amino acid that converts to serotonin and then melatonin. Foods high in tryptophan include:
  • Turkey – Often linked to sleepiness after meals.
  • Chicken – Another good source of tryptophan.
  • Eggs– Especially the whites.
  • Milk & Dairy Products – Warm milk is a traditional sleep aid.
  • Fish (Salmon, Tuna) – Also provide vitamin B6, which aids melatonin production.
  • Pumpkin Seeds – High in tryptophan and magnesium.
  • Soy Products (Tofu, Edamame) – Plant-based tryptophan sources.

 

Other Sleep-Supportive Nutrients:

  • Magnesium (leafy greens, nuts, seeds, bananas) – Helps relax muscles.
  • Vitamin B6 (chickpeas, bananas, potatoes) – Supports melatonin synthesis.
  • Complex Carbs (oats, whole grains) – May enhance tryptophan absorption.

 

Time to Consume:

Eating melatonin-rich foods about 2 hours before bedtime may help improve sleep quality. Combining them with a balanced diet enhances their effects.

Melatonin and Possible Side Effects

In a major review published in 2007, no serious side effects from the use of melatonin were reported. The most common complaints were headache and sleepiness, with other side effects reported infrequently. Some people may have vivid dreams or nightmares when they take melatonin. Additional uncommon side effects include stomach cramps, dizziness, headache, irritability, decreased libido, breast enlargement in men (called gynecomastia), and decreased sperm count.

Taking too much melatonin may disrupt circadian rhythms (“body clock”). Melatonin can cause drowsiness, especially if taken during the day. If you are drowsy the morning after taking melatonin, try taking a lower dose.

The Neurobiology of Melatonin – How it Helps Pain 

It has been shown that melatonin provides anti-nociceptive (pain-blocking) effects by acting on both the spinal cord and the brain. The exact mechanisms are not fully understood and probably include complex combinations of mechanisms. The analgesic actions of melatonin involve multiple receptors, including opioid, NMDA, benzodiazepine, α1- and α2-adrenergic, serotonergic and cholinergic receptors. The involvement of MT1/MT2 melatonergic receptors in the spinal cord has been well documented as an anti-nociceptive mechanism in a number of studies.

Pain is a dynamic phenomenon resulting from the activity of both endogenous pain excitatory and inhibitory systems, including inhibitory conditioned pain modulation (ICPM – See descending pathways, The Neurobiology of Pain). The efficacy of ICPM in fibromyalgia has been related to sleep quality. This relationship is supported on neurobiological grounds by common neurotransmitters involved in both sleep and ICPM, including noradrenalin, serotonin and dopamine. Melatonin offers multifaceted mechanisms that may interfere in the peripheral and central pain mechanisms. Evidence suggests that in long-term chronic pain situations, there is a loss of inhibitory system function. In a recent study, it was shown that long-term musculoskeletal pain occurs with excessive cortical facilitation (a lack of inhibition), which is associated with lower pain threshold and higher levels of catastrophizing thought processing related to pain.

In addition, numerous pre-clinical studies have demonstrated that ICPM depends on the recruitment of endogenous opioids in the periaqueductal gray, which trigger the release of serotonin from neurons localized in the raphe nuclei (medulla), which, in turn, dampens nociceptive afferents at the dorsal horn of the spinal cord. Noradrenergic projections from the locus coeruleus produce similar effects.

Together, this evidence suggests exploring the effect of melatonin on the descending modulatory pain systems, alone or combined with medications such as duloxetine and amitriptyline. It has also been demonstrated that melatonin increases the pain threshold and improves sleep quality in healthy subject by modulating systems involved in pain, such as the GABAergic and opioidergic systems.

 

Melatonin’s effect on pain may be explained by multiple mechanisms, including hormonal pathways.The analgesic effect of melatonin is known to involve the activation of supraspinal sites and the inhibition of ‘‘spinal windup.’’ In addition, experimental evidence suggests that the analgesic effects of melatonin involve opioid and other receptors including NMDA and GABA systems. Moreover, melatonin produces marked anti-inflammatory effects by inhibiting the release of pro-inflammatory cytokines.

See also: Neurobiology of Pain

 

 

References:

 

Melatonin – Overviews

  1. Analgesic, Anxiolytic and Anaesthetic Effects of Melatonin – New Potential Uses in Pediatrics – 2015
  2. Melatonin from Plants- Going Beyond Traditional Central Nervous System Targeting-A Comprehensive Review of Its Unusual Health Benefits – 2025
  3. Melatonin in Medicinal and Food Plants_ Occurrence, Bioavailability, and Health Potential for Humans – 2019

 

Melatonin – Benzodiazepine Withdrawal

  1. Facilitation of Benzodiazepine Discontinuation by Melatonin – 1999
  2. Rapid reversal of tolerance to benzodiazepine hypnotics by treatment with oral melatonin: a case report. – PubMed – NCBI

 

Melatonin – Pain

  1. Melatonin in Pain Modulation – Analgesic or Proalgesic? – 2014
  2. A COMBINED EFFECT OF DEXTROMETHORPHAN AND MELATONIN ON NEUROPATHIC PAIN BEHAVIOR IN RATS – 2009
  3. Analgesic Effects of Melatonin – A Review of Current Evidence from Experimental and Clinical Studies -2011
  4. Melatonin in Antinociception – Its Therapeutic Applications – 2012
  5. Melatonin and its agonists in pain modulation and its clinical application. – PubMed – NCBI
  6. Combined neuromodulatory interventions in acute experimental pain – assessment of melatonin and non-invasive brain stimulation – 2015
  7. A Phase II, Randomized, Double-Blind, Placebo Controlled, Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects – 2013
  8. Melatonin and their analogs as a potential use in the management of Neuropathic pain – 2018
  9. Role of Melatonin in the Regulation of Pain – 2020

 

Melatonin – Endometriosis

  1. Efficacy of melatonin in the treatment of endometriosis – 2013
  2. Regression of endometrial explants in a rat model of endometriosis treated with melatonin – 2008

 

Melatonin – Fibromyalgia

  1. Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in fibromyalgia – a phase II, randomized, double-dummy, controlled trial – 2014
  2. The effect of melatonin in patients with fibromyalgia: a pilot study. – PubMed – NCBI
  3. Adjuvant use of melatonin with fluoxetine (Prozac) for treatment of fibromyalgia. – 2012
  4. Fibromyalgia–a syndrome associated with decreased nocturnal melatonin secretion. – PubMed – NCBI
  5. Abnormality of Circadian Rhythm of Serum Melatonin and Other Biochemical Parameters in Fibromyalgia Syndrome – 2011
  6. A Quest for Better Understanding of Biochemical Changes in Fibromyalgia Syndrome – 2014
  7. Is the Deficit in Pain Inhibition in Fibromyalgia Influenced by Sleep Impairments? – 2012
  8. Melatonin therapy in fibromyalgia – 2006
  9. Melatonin-Mitochondria

 

Melatonin – Insomnia

  1. The effectiveness of melatonin for promoting healthy sleep – a rapid evidence assessment of the literature – 2014
  2. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. – 2007
  3. Ramelteon: MedlinePlus Drug Information

 

Melatonin – Opioid Tolerance

  1. Melatonin prevents morphine-induced hyperalgesia and tolerance in rats -role of protein kinase C and N-methyl-D-aspartate receptors – 2015
  2. Comparative study between transdermal fentanyl and melatonin patches on postoperative pain relief after lumber laminectomy, a double-blind, placebo- controlled trial – 2015
  3. Role of endogenous melatoninergic system in development of hyperalgesia and tolerance induced by chronic morphine administration in rats. – PubMed – NCBI 2017
  4. Melatonin regulation of transcription in the reversal of morphine tolerance – Microarray analysis of differential gene expression – 2019

 

 

Melatonin – Oxidative Stress

  1. Evaluating the Oxidative Stress in Inflammation – Role of Melatonin -2015

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.

 

Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

 

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