Melatonin Tolerance: No Evidence It Exists?

Melatonin is a hormone endogenously secreted by the pineal gland at night/evening and regulates one’s circadian rhythm (i.e. sleep-wake cycle) via interaction with melatonin receptors in the brain.

Melatonin also: regulates blood pressure; interacts with the immune system; and acts as a potent antioxidant (scavenging free radicals).

It has been thought that melatonin production decreases with age – such that older adults generally benefit from supplementation in terms of sleep quality and circadian regulation.

Dr. Richard Wurtman (emeritus MIT professor who studies melatonin and the pineal gland) believes we shouldn’t take more than 300 mcg of melatonin per night (due to higher doses causing desensitization of melatonin receptors). (R)

Based on Wurtman’s hypothesis, the ideal melatonin supplement for older adults is something like: Melatonin 300 mcg (XR).

(Note: Affiliate link used – I earn commission. Price is the same regardless of whether buy through me.)

Melatonin can be administered intermittently or regularly to potentially improve or prevent various health conditions:

  • Insomnia (may help treat insomnia)
  • Jet-lag (reestablish circadian rhythm after long flights with time zone change)
  • Shift work (might improve sleep and circadian rhythms in shift workers)
  • Tinnitus (may reduce tinnitus perception at night)
  • Bipolar mania (as an adjunct with Ramelton)
  • Depression (may exert an antidepressant effect at certain dosages in certain people)
  • Headaches (cluster & hypnic)
  • Radiation protection (broad protection of cells from radiation-induced oxidative stress)
  • Cancer (inconclusive)
  • GERD (relieves pain and heartburn)

Although some experts (like Dr. Wurtman) hypothesize that chronic melatonin supplementation above 300 mcg can desensitize melatonin receptors and cause tolerance – current scientific evidence does not support this notion.

Table of Contents

According to melatonin experts, how would melatonin tolerance develop? (Hypothetical)

Dr. Wurtman hypothesizes that supplementing with exogenous melatonin above 300 mcg (micrograms) stimulates melatonin receptors excessively which inevitably results in receptor desensitization.

Dr. Wurtman is not alone in this hypothesis – melatonin researcher Zhadanova (2005) noted that “too high” of melatonin doses may “desensitize melatonin receptors.” (R)

Russcher et al. stated: “A possible explanation for the decline in hypnotic effects after 3 months may be altered melatonin receptor sensitivity or decreased receptor density.” (R)

In other words, consistently administering melatonin (i.e. nightly) for a sustained duration (e.g. weeks, months, etc.) at a dosage above 300 mcg – might cause melatonin receptors to become desensitized or less responsive to melatonin’s effect.

Why? Above 300 mcg shifts melatonin receptor activation and feedback loops out of homeostasis.

The receptors receive so much more melatonin than is naturally generated within the body – that the sensitivity of each melatonin receptor is diminished.

In other words, the melatonin receptors “adjust” (over time) to receiving such a large amount (i.e. a supraphysiologic dose) of melatonin (binding as a ligand) that they stop reacting as significantly as in the first few days or weeks of supplementation.

If an extremely small amount of melatonin is administered (e.g. 300 mcg per night), no such desensitization of melatonin receptors occurs – and thus there’s no major neurochemical adjustments that ensue to cause tolerance.

This might be especially true in older adults that may not produce as much endogenous melatonin as when younger – such that the 300 mcg per night increases melatonin concentrations to a normative, healthier level (perhaps from a mildly or moderately deficient level).

It should be mentioned that while many believe melatonin production does decrease, on average, in older age – not all evidence backs this up and there’s likely significant inter-individual variability.

Logically, it makes sense to assume that administering a high-dose of melatonin would result in melatonin tolerance (possibly evidenced by: receptor desensitization, alterations in receptor densities in certain brain regions, change in metabolism rate of melatonin, reduced endogenous melatonin production, etc.).

Could low melatonin dosages of 300 mcg cause subtle (albeit a lower magnitude of tolerance)?

Possibly but unlikely.

Why? A study by Dollins et al. (1994) compared the effects of a wide range of melatonin dosages (0.1 mg to 10 mg) and reported that low (0.1 to 0.3 mg) dosages keep melatonin within physiologically normal “nocturnal ranges.” (R)

Worth noting is that the low doses (0.1 to 0.3 mg) did NOT significantly differ from the efficacy of higher doses (1-10 mg) in promoting sleep when administered to 20 young, healthy subjects.

Melatonin tolerance onset (Scientific Research)

Despite the fact that melatonin tolerance is hypothesized to occur following the regular administration of dosages above 300 mcg – this does NOT mean that tolerance actually occurs.

At this time, there is zero strong scientific evidence suggesting that melatonin users become “tolerant” to high-doses as a result of nightly, long-term administration.

To be fair though, I’m not aware of any large-scale RCT that has examined melatonin receptor sensitivity following chronic (i.e. nightly) melatonin administration for ~2-5 years (this isn’t even feasible for a trial).

Included below are brief overviews of studies that examined the effect of long-term melatonin administration – and respective notes as to whether tolerance occurred (evidenced by diminished efficacy, dosage increases, rebound effects following cessation, and/or withdrawal symptoms).

Melatonin (StatPearls) (R)

StatPearls is essentially a high-quality overview of evidence that’s frequently updated.

  • Date: 2021
  • Authors: Savage et al.

Tolerance? No. “No evidence suggests that people develop tolerance to melatonin.”

Sleep, Growth, and Puberty After 2 Years of Prolonged-Release Melatonin in Children with Autism Spectrum Disorder (R)

  • Date: 2020
  • Authors: Malow et al.
  • Design: Open-label, prospective
  • Methods: Track safety, efficacy, and puberty among children using melatonin for an extended duration (104 weeks).
  • Participants: 80 children (2-17.5 years old) with autism spectrum disorder who completed a double-blind, placebo-controlled trial.
  • Limitations: Small sample; long-term phase not randomized/controlled; atypical sample
  • Results: Melatonin was safe and effective for long-term use in children with ASD and insomnia. No effect seen on pubertal development.

Tolerance? No. Effectiveness of nightly prolonged-release melatonin (2 mg, 5 mg, 10 mg) was maintained over a long-term (2-year) duration (as evidenced by improvement in sleep and quality of life symptoms relative to baseline).

There were no safety issues nor signs of withdrawal upon discontinuation of the drug.

The fact that there were no withdrawal symptoms after 2 years means melatonin treatment probably doesn’t cause tolerance.

Long-Term Melatonin Treatment for Sleep Problems & Aberrant Behaviors of Children with NDDs (R)

  • Date: 2020
  • Authors: Yuge et al.
  • Design: Open-label
  • Methods: Evaluate the effectiveness of melatonin granules (1 mg, 2 mg, 4 mg) in children with NDDs – over a 26-week period
  • Measures: Sleep onset latency & aberrant behaviors
  • Participants: 99 children with NDDs (93 completed all 3 phases)
  • Limitations: Small sample, atypical sample, length (26 weeks may not be sufficient for tolerance, no randomization/controlling, sleep hygiene interventions (confound)
  • Results: Long-term melatonin treatment (26 weeks) significantly improved sleep quality, aberrant behaviors, and quality of life in the 93 children.

Tolerance? No. Melatonin appeared to provide benefit over the course of 26 weeks.

Long-Term Melatonin Therapy for Adolescents and Young Adults with Chronic Sleep Onset Insomnia (R)

  • Date: 2018
  • Authors: Zwart et al.
  • Design: Epidemiological
  • Methods: Compare the effect of long-term melatonin therapy in adolescents and young adults to age-matched controls.
  • Participants: 33 adolescents & young adults vs. age-matched controls (154 individuals ages 10-20). Details about participants such as: gender, age, weight, height, offspring, educational attainment, chronotype, and lifestyle factors were documented – in addition to details about melatonin use.
  • Measures: Online survey & questionnaire (Pittsburgh Sleep Quality Index; Insomnia Severity Index; Morningness-Eveningness Questionnaire; Munich Chronotype Questionnaire)
  • Limitations: Small sample size (low statistical power); epidemiological (difficult to know causality – many confounds); questionnaire data (notoriously inaccurate due to recall bias/errors)
  • Results: Most children with sleep onset problems related to delayed nocturnal melatonin secretion end up normalized by adulthood – whereas ~27% continue melatonin therapy into adulthood.

Tolerance? No. In this long-term study (melatonin administration from childhood to adulthood) there was zero evidence of tolerance development.

Researchers noted that “long-term melatonin therapy appeared to be safe after an average of 7.1 years” (based on data from the limited study population).

Those taking melatonin consistently for a long-term did NOT differ from age-related controls in regard to sleep quality – supporting the idea that tolerance to melatonin does not develop.

9 of 33 (27.3%) respondents still used melatonin after an average duration of 10.8 years – whereas 24 of 33 (72.7%) discontinued melatonin therapy (at some point between childhood and adulthood).

Among the 24 participants that discontinued melatonin – sleep onset latency did not differ from controls (suggesting that sleep onset latency eventually normalized since being initially prolonged in childhood).

Interesting: Those who administered melatonin from childhood into adulthood perceived pubertal timing as being late relative to age-related controls.

Although there was no evidence of melatonin tolerance or melatonin withdrawal symptoms associated with long-term administration (in adolescents and young adults) – it’s important to underscore the study’s limitations (sample size; epidemiology; questionnaire data; etc.).

Researchers acknowledged the possibility that they may be underestimating the number of children that are “unable to stop using melatonin” (such as due to rebound effects or withdrawal symptoms).

Also worth noting: (A) 4 participants temporarily discontinued melatonin then restarted; (B) 5 participants stopped melatonin during holidays; and (C) 3 skipped melatonin during weekends.

(It’s possible that stopping and starting melatonin and/or taking mini-breaks would prevent or limit tolerance onset – assuming tolerance can be developed).

Average melatonin dosage ranged from 0.5 mg to 5 mg per night – with average times of administration between 19:00 (7 PM) and 23:00 (11 PM).

Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children with Autism Spectrum Disorder (R)

  • Date: 2018
  • Authors: Maras et al.
  • Design: RCT followed by prospective, open-label phase
  • Participants: 95 children (2-17.5 years old) with insomnia & ASD
  • Methods: 13-week RCT followed by 39-week open label trial to evaluate the safety and efficacy of nightly pediatric-appropriate prolonged-release melatonin (2 mg, 5 mg, 10 mg)
  • Measures: Caregiver-reported Sleep & Nap Diary; Composite Sleep Disturbance Index (CSDI); Pittsburgh Sleep Quality Index (PSQI); Epworth Sleepiness Scale; Quality of Life (WHO-5 Well-Being Index)
  • Limitations: Small sample, atypical sample (ASD + insomnia + pediatrics), caregiver reporting, long-term phase wasn’t randomized or controlled
  • Results: Pediatric-appropriate prolonged-release melatonin (2-10 mg) was effective and safe for long-term treatment (up to 52 weeks) in children with ASD with insomnia

Tolerance? No. It was noted that there was no evidence of decreased efficacy of melatonin with long-term treatment (1 year).

After 52 weeks of continued melatonin treatment, patients: (1) slept longer; (2) fell asleep faster; (3) had more uninterrupted sleep; (4) fewer nighttime awakenings; and (5) better sleep quality – relative to baseline.

Also worth noting is that melatonin provided significant benefit in improving sleep and quality of life (relative to the placebo) in the initial 13-week randomized, placebo-controlled, double-blind phase.

The Effect of Long-Term Melatonin Supplementation on Psychosomatic Disorders in Postmenopausal Women (R)

  • Date: 2018
  • Authors: Chojnacki et al.
  • Design: RCT
  • Participants: 60 postmenopausal women (51-64 years old)
  • Methods: 60 women were randomly assigned to receive: (1) placebo (2 x 1 tablet) OR (2) melatonin (3 mg in morning, 5 mg at bedtime) – for 12 months
  • Limitations: Homogenous cohort (postmenopausal women); sample size (small); dosages standardized (not adjusted based on individual responses, etc.)
  • Results: Melatonin supplementation (12 months) exerted a positive effect on psychosomatic symptoms in postmenopausal women

Tolerance? No. Authors noted that, based on the study results, “melatonin can be safely and permanently used in complex treatment of psychosomatic disorders in postmenopausal women.”

Researchers noted that melatonin synthesis is reduced in postmenopausal women in the pineal gland and peripheral organs (including those in the GI tract). (This was the rationale behind supplementation in the morning and night).

Because we know that melatonin synthesis and concentrations are already low in postmenopausal women, we must acknowledge the possibility that supplementation (with exogenous melatonin) is bringing melatonin status up to a physiologically normative level (as opposed to remaining deficient).

Assuming melatonin supplementation merely increases intraneural melatonin to a physiologically normative concentration (as opposed to a supraphysiologic concentration) – this would be incapable of causing alterations in receptor sensitivity/density (and thus would not cause tolerance).

Meta-analysis: Melatonin for the Treatment of Primary Sleep Disorders (R)

  • Date: 2013
  • Authors: Ferracioli-Oda et al.
  • Design: Meta-analysis
  • Methods: Evaluate data from RCTs assessing melatonin vs. placebo for the treatment of primary sleep disorders
  • Studies: 19 studies with 1683 participants were included in the meta-analysis
  • Results: Melatonin significantly decreased sleep latency and increased total sleep time. Higher doses of melatonin exhibited greater effects on sleep latency (decreasing) and total sleep time (increasing). Sleep quality improved with melatonin relative to placebo.

Tolerance? No. “The effects of melatonin on sleep are modest but do NOT appear to dissipate with continued use.” (Furthermore: “No significant effects of trial duration and melatonin dose were observed on sleep quality.”)

Long-term effects of melatonin on quality of life and sleep in hemodialysis patients (R)

  • Date: 2013
  • Authors: Russcher et al.
  • Design: Double-blind, RCT
  • Methods: 67 hemodialysis patients randomized to receive melatonin (3 mg/night) or a placebo (nightly). 42 patients completed the trial.
  • Measures: Quality of life; sleep parameters; salivary melatonin concentrations
  • Limitations: Small sample (underpowered), hemodialysis (confound), dosage probably NOT optimized for each patient, high dropout rate

Tolerance? Possibly. Short-term melatonin administration improved sleep quality and melatonin rhythm. Long-term (6-12 months) melatonin administration resulted in a loss of therapeutic effect (relative to placebo).

Why didn’t melatonin show sustained benefit in hemodialysis patients when administered over a long-term?

Perhaps solely due to such a small sample size and high dropout rate (underpowering).

Another possibility is that hemodialysis patients fail to excrete melatonin and its metabolites as efficiently as healthy individuals – resulting in excessive melatonin (and/or melatonin metabolite) accumulation and subsequent dysregulation of the circadian rhythm (with predictably diminished efficacy in long-term use).

Authors hypothesized that melatonin (3 mg/night) might have induced tolerance by altering “melatonin receptor sensitivity” and/or “receptor density” – explaining the diminished long-term efficacy. (However, this might be more likely to occur as a result of accumulation from inefficient excretion).

Researchers also hypothesized that accumulation of highly-liposoluble melatonin in fatty tissues and subsequent redistribution from these tissues may have impaired its long-term efficacy in the hemodialysis cohort. (R)

It was noted that salivary melatonin concentrations in the melatonin group were “higher than in the placebo group at all time points, including the early evening and morning samples” which (authors noted) were “higher than desirable daytime melatonin concentrations.”

To me, this is evidence of melatonin accumulation and suggests that dosage was not optimized by researchers in accordance with best practices.

Proper dosage optimization would’ve involved administering 100-300 mcg to the hemodialysis patients (lower is better when melatonin isn’t efficiently excreted such as in persons with impaired kidney function).

Authors also admitted that the timing of melatonin administration may have been suboptimal (this would have major impact on whether melatonin continues providing benefit).

Overall, there are too many issues with this study to draw any firm conclusions as to whether long-term melatonin administration yields “tolerance.”

Prolonged-release melatonin for insomnia (R)

  • Date: 2011
  • Authors: Lemoine et al.
  • Design: Open-label, prospective
  • Aim: Determine efficacy, safety, and withdrawal phenomena associated with 6-12 months of prolonged-release melatonin treatment at a dosage of 2 mg/night.
  • Participants: 112 (6 months) & 96 (12 months) adults with primary insomnia
  • Methods: Participants received prolonged-release melatonin (PRM) nightly for 6-12 months followed by a 2-week withdrawal period.
  • Measures: Patient-reported sleep quality ratings (diary), adverse events, vital signs, lab tests at each visit, and withdrawal symptoms. Nocturnal urinary melatonin (6-sulfatoxymelatonin) excretion was assessed upon discontinuation (this measures endogenous melatonin production).

What were the results? (Takeaways)

The average number of nights by which patients reported sleep quality as “good” or “very good” was significantly higher during the prolonged-release melatonin therapy (than pre-treatment).

There was no evidence of tolerance or withdrawal symptoms (e.g. rebound insomnia) to prolonged-release melatonin.

In actuality, residual benefit was observed following melatonin cessation (relative to pre-treatment) and there was zero suppression of endogenous melatonin production.

Tolerance? No. In this study there were no signs of tolerance to prolonged-release melatonin in 208 adults with primary insomnia over spans of 6 months (112 adults) and 12 months (96 adults).

It’s possible that 2 mg is still such a relatively low dose that it won’t cause tolerance in most adults.

Furthermore, perhaps the “prolonged-release” format ensures that melatonin concentrations within the brain never exceed a certain threshold such as would be needed desensitize melatonin receptors.

Still, it’s pretty reasonable to suspect that if melatonin tolerance was a legitimate phenomenon – we’d see some evidence of it within 12 months.

Nightly treatment of primary insomnia with prolonged-release melatonin for 6 months (R1, R2)

  • Date: 2010
  • Authors: Wade et al.
  • Design: Randomized, placebo-controlled, double-blind
  • Participants: 791 adults with primary insomnia (18-80 years old)
  • Methods: Adults treated with placebo (2 weeks) then randomized to receive 3 weeks of prolonged-release melatonin (2 mg) or a placebo control. Melatonin recipients continued and placebo completers were re-randomized 1:1 (melatonin or placebo) for 26 weeks with 2 weeks of a single-blind placebo run-out.
  • Measures: Sleep latency (sleep diary); Pittsburgh Sleep Quality Index (PSQI); CGI-I (Clinical Global Impression of Improvement); and adverse effects plus vital signs at each visit.

What were the results?

Effects of PRM (2 mg/night) for 3 weeks in patients with low endogenous melatonin (6-sulphatoxymelatonin concentrations under 8 mcg/night) did NOT differ from the placebo with regard to sleep latency.

PRM (2 mg/night) significantly reduced sleep latency relative to the placebo in elderly patients (65+ years of age) regardless of melatonin levels.

Effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over 6 months with no signs of tolerance.

Researchers concluded that PRM (2 mg/night) is effective and safe among elderly insomnia patients.

Low melatonin production is not useful in predicting responses to melatonin therapy in insomnia (regardless of age).

Tolerance? No. This study found zero signs of tolerance following 6 months of prolonged-release melatonin (2 mg/night).

It’s possible that 2 mg is too low of a dosage to cause tolerance, particularly in older adults – a cohort that may exhibit suboptimal: (A) melatonin production and/or (B) intraneural concentrations to begin with.

Assuming, on average, that many older adults exhibit suboptimal endogenous melatonin production and/or intraneural concentrations – then one might infer that their melatonin receptors may become slightly sensitized.

Not only was just 2 mg of melatonin administered, but it was a prolonged-release format – which may prevent melatonin concentrations from exceeding an intraneural threshold that could potentially desensitize receptors (and thus lead to tolerance).

Loss of response to melatonin treatment is associated with slow melatonin metabolism (R)

  • Date: 2010
  • Authors: Braam et al.
  • Design: Double-blind, placebo-controlled, parallel
  • Participants: 6 patients (3 with loss of melatonin response – following initial good response vs. 3 with no loss of response after 6 months)
  • Methods: Measure rate of melatonin metabolism via saliva samples to optimize melatonin dosing.
  • Limitations: Small study, extreme ages (pediatrics/older adult), concomitant medications (may impact melatonin’s pharmacokinetics)
  • Conclusion: Loss of response to melatonin is hypothesized to stem from decreased activity/inducibility of CYP1A2 enzymes in the liver. In patients with “loss of response” to melatonin, a clearance test is recommended along with significant dosage reduction.

After 4 weeks of melatonin administration to patients with intellectual disability (5 mg/night for those 6+ years old; 2.5 mg/night for those under 6) – some parents reported loss of response to melatonin.

Researchers measured evening salivary melatonin levels at baseline and after 4 weeks of treatment on a day that no study medication was given.

Melatonin concentrations in 3 of 4 patients who received melatonin were extremely high (over 50 mg/mL) after 4 weeks of treatment – yet the levels had been low at baseline.

As a result of the high concentrations, researchers reduced melatonin dosages to 0.1 mg which substantially improved the sleep of these children.

Researchers believed that loss of therapeutic response to melatonin was attributable to being CYP1A2 poor metabolizers.

Case #1

61-year-old woman with mild ID with sleep onset problems

Took melatonin (5 mg/night) with initial favorable response. Thereafter, beneficial effect ceased.

Woman exhibited salivary melatonin concentrations over 50 pg/mL ~6 hours after melatonin administration.

Researchers believed she was a CYP1A2 poor metabolizer.

They then lowered her melatonin dose to 0.5 mg and her sleep onset problems disappeared. 6+ months after this dose adjustment, the positive effect of melatonin was still present (indicating that it’ll probably work indefinitely).

Case #2

6-year-old girl with sleep onset and maintenance problems (ongoing for years)

Took melatonin (2.5 mg/night) for 2 weeks with beneficial response.

One month later, beneficial effects ceased and sleep-maintenance issues returned.

Additionally, her sleep patterns became worse relative to pre-melatonin.

The mother doubled the melatonin dose on her own accord (suspecting tolerance) but this didn’t improve her daughter’s sleep.

Salivary melatonin concentrations during the day and night exceeded 50 pg/mL on a day when zero melatonin was administered.

After a 2-week “washout” period, melatonin was administered and salivary still exceeded 50 pg/mL ~6 hours post-administration.  Researchers concluded she was a CYP1A2 poor metabolizer.

The dosage was shifted to 0.5 mg per night and her sleep dramatically improved. This improvement was maintained 6 months later – and is suspected to be indefinite.

Case #3

3-year-old boy with Down’s syndrome (sleep maintenance problems)

Took melatonin (1 mg/night) with initial therapeutic response.

Frequent nighttime awakenings returned after ~4 weeks of treatment and melatonin treatment was discontinued by parents.

Melatonin treatment was reinstated but sleep maintenance worsened.

Melatonin treatment was discontinued again and salivary melatonin levels were determined (levels exceeded 50 pg/mL 2 days post-melatonin cessation).

The boy’s sleep improved without melatonin over a 2-week period (fewer nighttime awakenings).

A melatonin clearance test performed after the 2-week washout found that melatonin concentrations exceeded 50 pg/mL ~6 hours after 0.1 mg was administered.

Researchers concluded that the boy was a CYP1A2 poor metabolizer.

Melatonin dosage was adjusted to 0.1 mg and sleep improvement was maintained for 6 months.

Control group

3 patients (ages 40, 12, 8) with zero loss of response to melatonin treatment after 6 months served as controls.

Melatonin clearance tests (salivary measurements) indicated normal clearance profiles (~83% decline in melatonin levels).

Respective half-lives exhibited by control patients were: 44, 46, and less than 50 minutes.

Tolerance? No. Loss of therapeutic response? Yes – but limited to inefficient clearance (likely resulting from slow CYP1A2 metabolism).

Melatonin is metabolized in the liver almost entirely by cytochrome P450 enzyme CYP1A2 (melatonin is broken down into 6-hydroxy-melatonin then conjugated to sulfate and excreted in urine).

In most people, supplemental (i.e. exogenous) melatonin has a half-life of 35-45 minutes (meaning it’s fully eliminated from your system in ~4.13 hours).

There are large inter-individual differences in: (1) plasma levels of melatonin following oral administration (up to 37-fold) AND (2) bioavailability (up to 2.5-fold) – all of which are attributed to variation in metabolism (via CYP enzyme activity in the liver).

According to Braam et al., reports on “loss of response” after initial good response to melatonin treatment are scarce – but a few reports suggest possible development of tolerance.

To be clear – loss of “response” (i.e. therapeutic effect) is NOT the same thing as tolerance – although tolerance often does explain loss of response (to a drug/supplement).

In this case, what’s likely happening is melatonin concentrations are accumulating to such a high level (as a result of inefficient CYP1A2 metabolism) – that they’re dysregulating circadian rhythms and sleep cycles.

In this case, reducing melatonin dosage to 300 mcg or less seems to provide benefit without systemic accumulation in CYP1A2 poor metabolizers.

Long-term effectiveness outcome of melatonin therapy in children with treatment-resistant circadian rhythm sleep disorders (R)

  • Date: 2007
  • Authors: Carr et al.
  • Participants: 44 children with neurodevelopmental disabilities
  • Melatonin formats: Sustained-release melatonin (1 mg fast, 4 mg controlled-release) & Fast-release melatonin (5 mg)
  • Methods: Caregivers administered melatonin to their children and adjusted the dosage as they saw fit. Professionals assessed the children physically and neurologically. Caregivers were given telephone guidance and interviewed every 3 months. Caregivers’ impressions of melatonin therapy were recorded via interviews.

Details worth noting:

Melatonin dosages at beginning of effectiveness study: 5 mg (19 patients); 10 mg (21 patients); 15 (4 patients).

It was noted that the sustained-release version was more effective than fast-release version for sleep-maintenance.

Dosage adjustments were made when the format switched (halfway through the study) from sustained-release to fast-release.

At this point, dosages were: 5 mg (13 patients); 10 mg (21 patients); 15 mg (10 patients).

Prior to the cross-over trial, 11 children were on melatonin therapy from 5 months to 9.6 years (mean = 5.1 years) and were followed by an investigator.

The 33 children who did not take melatonin prior to the trial were on treatment from 9 months to 3.8 years (mean = 2.5 years).

The final dosage between the melatonin experienced and naïve groups was not significantly different – indicating that tolerance in the melatonin-experienced patients did NOT develop with long-term administration.

All caregivers (41/41) reported therapeutic benefit to their children as a result of melatonin therapy.

Researchers further noted that magnitude of effect on sleep and health persisted for as long as melatonin was administered (short-term and long-term) suggesting lack of tolerance over time.

Tolerance? No. There were zero data from this study suggesting that melatonin causes tolerance with long-term administration (5 months to 9+ years) in children at dosages of 5 mg, 10 mg, and 15 mg per night (sustained-release and immediate-release formats).

Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances (R)

  • Date: 1997
  • Authors: Palm et al.
  • Design: Open-label
  • Participants: 8 blind children
  • Method: Melatonin (0.5-2 mg) was taken 30-60 minutes before desired bedtime (at the same time every evening) & dosages were adjusted (up to 4 mg) after 6 weeks if effect was insufficient.
  • Limitations: Small sample; no controlling; no randomization; atypical sample (blind individuals)
  • Results: Melatonin given in the evening significantly improved sleep-wake patterns in all 8 patients. Effect was maintained over a long-term without side effects.

Tolerance? No. The beneficial effect was “maintained during long-term therapy for between 1 and 6 years in 6 patients.”

Specifically, patients in this study had been using continuous melatonin therapy for: 6 years (1 patient); 4 years (1 patient); 2-3 years (2 patients); and 1-2 years (2 patients).

Although one patient fell back into the earlier sleep pattern after 6-8 months and another developed sleep disturbance (due to esophagitis) – circadian rhythm improvement remained (relative to pre-melatonin).

At the time, these were the longest durations of melatonin therapy reported in scientific literature.

No side effects were noted and no changes in hormones, growth rate, or skeletal muscle were noted (relative to pre-melatonin).

In sum, does the scientific literature suggest melatonin causes tolerance?

NoHowever, it does suggest that taking too high of a dose is detrimental for some individuals (e.g. slow CYP1A2 metabolizers) when administered nightly for an extended term (e.g. 6-12 months).

It is unclear as to whether slow CYP1A2 metabolizers develop “tolerance” though.

It is known that slow metabolizers end up with an accumulation of melatonin so significant – that it dysregulates their circadian rhythm and thus negatively impacts sleep.

For these individuals – a 2-week “washout phase” (i.e. no melatonin) followed by dosage reduction (300 mcg per night) is usually optimal such that sleep improves and the smaller dose can be administered indefinitely without loss of effect.

Interestingly, in one case series, some patients with slow CYP1A2 metabolism actually had their dosages increased following loss of effect – and this exacerbated sleep problems (failing to improve symptoms).

Dosage reduction providing benefit isn’t commonly observed with substances that cause “tolerance.”

Additionally, substances that induce tolerance tend to have noticeable “withdrawal symptoms” or “rebound effects” following cessation (melatonin seemingly has none).

Although I cannot be certain, it appears as though a similar phenomenon wherein melatonin loses its efficacy occurs in hemodialysis patients – such that benefits are nonexistent 6-12 months after treatment initiation (despite there being significant initial benefit relative to placebo).

My guess here is that melatonin is accumulating systemically (similar to poor CYP1A2 metabolizers) in hemodialysis patients as a result of impaired kidney function.

Accumulation & circadian dysregulation?

Some researchers note that highly-liposoluble melatonin may accumulate in fatty tissues followed by subsequent redistribution in those tissues – which could disrupt circadian rhythms and/or impact both peripheral and central receptor activation/expression – particularly in persons with suboptimal clearance (e.g. hemodialysis patients). (R)

Perhaps these patients would benefit from measuring salivary melatonin concentrations and lowering dosage if salivary levels are beyond a certain threshold.

Then again, they could just drop to a lower dose (e.g. 300 mcg).

Similar to those with kidney (i.e. renal) impairment, I’d guess that those with liver (i.e. hepatic) impairment accumulate melatonin as well (such that lower doses than average are more beneficial than higher ones).

Someone who’s a slow CYP1A2 metabolizer and has both kidney and renal impairment may need an even smaller dose than 300 mcg.

In a case like this, salivary concentrations should be measured and dosage optimized accordingly.

To play devil’s advocate and suggest that tolerance might actually occur with melatonin (despite zero strong evidence that it does), I might speculate that it occurs in an unconventional sense wherein melatonin excessively taxes CYP1A2 enzymes such that enzyme expression changes with ongoing administration.

Additionally, accumulation of intraneural melatonin could desensitize melatonin receptors in the brain and subsequently alter how they respond or are expressed (i.e. regional densities).

If tolerance exists – withdrawal then reinstatement at 300 mcg should be fine…

If tolerance is a genuine phenomenon (and some people really experience it), a 2-4 week melatonin hiatus (i.e. break) followed by reinstatement of treatment at 300 mcg/night or less should probably prevent fading efficacy and tolerance in the future.

Why? 300 mcg melatonin (or less) keeps melatonin concentrations within a physiologically-normative range and thus will not dysregulate the circadian rhythm or desensitize receptors.

That said, some might argue that the reason 300 mcg doesn’t induce tolerance is because only 15% of the 300 mcg makes it to the brain (as a result of poor melatonin bioavailability).

Some would argue that melatonin doesn’t “do much of anything” – and they may be correct (especially for certain supplements).

Why? Supplements are not regulated by the FDA and therefore the listings may not accurately reflect the contents.

Problems with melatonin supplements

A study of 31 melatonin supplements found that 71% of the supplements weren’t even within 10% of the listed melatonin content – and many had additional ingredients like serotonin. (R)

Therefore, many people may be using nothing more than a placebo – or might be taking some melatonin/serotonin hybrid (perhaps serotonin is the therapeutic component).

Even in melatonin trials, it’s possible that a subset of trials didn’t use chromatography/spectrometry to verify the contents of the melatonin supplements administered to participants (and thus dosages didn’t reflect the actual content).

Perhaps a true assessment of melatonin tolerance would require: (1) GC/MS-verified melatonin; (2) much larger doses; (3) individually-calibrated dosing regimens (to ensure high systemic concentrations following first-pass metabolism) – over a long-term (e.g. 12-36 months).

For example: Getting everyone in a cohort to exhibit salivary melatonin concentrations within a certain range to ensure that concentrations are not way different from one person to another (this would be much better than standardizing the dose).

What if melatonin were highly bioavailable, administered to persons with normal levels of melatonin at baseline, and dosages listed in melatonin supplements were accurate?

In this case, we would be more likely to see tolerance (assuming it could occur).

However, there’s still no good evidence to suggest that melatonin causes tolerance.

Perhaps beyond a certain dose threshold (e.g. above 20 mg per night) would cause tolerance with repeated administration. (But maybe not…)

Tolerance with other melatonin receptor agonists?

Let’s assess various medications that act similarly to melatonin, including (A) Ramelteon (Rozerem) and (B) Agomelatine (Valdoxan) – melatonin receptor agonists.

  • Ramelteon: Not been shown to produce dependence, no potential for abuse, no withdrawal or rebound insomnia with long-term administration. (6 months) (R)
  • Agomelatine: No dosage tapering is needed on treatment discontinuation. (This suggests it doesn’t significantly alter physiology enough to cause tolerance with relatively long-term use) It may actually help reverse opioid tolerance via its actions on metabotropic glutamate receptors. (R)

Note: I would argue that 6 months isn’t always sufficient enough of a duration to determine whether someone will develop tolerance to a medication.

Why doesn’t melatonin supplementation cause tolerance?

I have many hypotheses and they include (but are not limited to) the following:

Poor oral bioavailability

I’m not in total agreement with melatonin researchers who claim 300 mcg dose is best. Why? Melatonin supplements have horrendous bioavailability (on average).

DeMuro et al. (2000): “Both 2 mg and 4 mg oral dosages showed an absolute bioavailability of ~15%” (inter-individual bioavailability ranged from 3% to 76%). (R)

If we do some basic math, we’d know that 15% of 300 mcg leaves just 45 mcg (0.045 mg) for systemic circulation and subsequent activity. (15% of 5 mg = 0.75 mg; 15% of 10 mg = 1.5 mg).

If you are a slow CYP1A2 metabolizer – you’ll end up with more melatonin in systemic circulation from your dose (due to inefficient metabolism).

If you’re a rapid CYP1A2 metabolizer like me – you may need a higher dose because less melatonin will enter systemic circulation (I respond to doses of ~10 mg or more per night).

Low baseline melatonin levels

Many people taking melatonin (such as older adults) may be doing so because they have slight or significant deficiencies in endogenous melatonin production.

Many drugs, lifestyle factors, and age can decrease melatonin synthesis and action.

  • What decreases melatonin? Beta blockers; NSAIDs; blue light exposure at night (e.g. from screens); aging; fasting (or lack of calories); nutrient deficiencies; circadian rhythm abnormalities; caffeine; various stimulants.
  • Most people are unaware that basic things like caffeine and blue light exposure interfere with melatonin production and signaling.
  • Supplementation may be bringing most people up to a normative range (offsetting lifestyle factors that interfere with/suppress melatonin production).
  • If supplementation helps normalize melatonin concentrations in the brain (physiologically normal level from a low/suboptimal level) – then supplementing shouldn’t cause tolerance (as receptors are expecting this amount).

Melatonin content in supplements

Melatonin supplements are not regulated by the FDA and contents may not accurately reflect the ingredients listed.

Perhaps melatonin isn’t causing tolerance because the supplements barely contain any melatonin.

(This, coupled with low bioavailability is a recipe for placebo).

Erland & Saxena (2017): In an analysis of 31 supplements (via ultra-performance liquid chromatography): melatonin did NOT meet label within 10% margin of the label claim in more than 71% of supplements and an additional 26% were found to contain serotonin. (R)

Complex mechanisms of action

Melatonin exerts a variety of effects throughout the body, including (not limited to) (R):

  • CNS & Brain
  • Cardiovascular system
  • Glucose metabolism
  • Immune function
  • Detoxification & antioxidant systems

It’s complex actions and/or a specific isolated action/subset of actions may be reason for lack of tolerance development.

Some of its actions actually reverse tolerance to opioids in animal models (e.g. via modulation of: protein kinase C, NMDA pathways, GLT-1, BDNF, CREB, NF-kB, microglia, etc.). (R1, R2, R3)

Neurobiological evolution

Another reason melatonin might not induce tolerance is related to evolution.

Perhaps the brain/nervous system of modern humans evolved to handle excessive or high amounts of melatonin without much consequence.

It may be that humans efficiently utilize and excrete melatonin without change in neurochemical architecture – even over a long-term.

Interesting fact: There are zero confirmed cases of death attributable solely to melatonin overdose in humans. (Read: Melatonin Overdose)

In no way is this fact endorsing taking more than an amount recommended by your doctor – but it does show that humans aren’t negatively by melatonin overdose (in most cases).

Why is this? Melatonin isn’t inherently toxic to the cells in your body and doesn’t affect any neurons responsible for keeping you alive (e.g. those that regulate breathing).

Issues (some might have) with assuming “no tolerance” based on current data…

Although I personally do NOT think that melatonin causes tolerance (based on what I’ve read), it would be relatively easy to argue that the current data are insufficient for ruling out tolerance. Why?

  • Dosing & bioavailability (low): Most of the melatonin dosages administered are small (1-10 mg) when considering bioavailability of just 15%. Perhaps a supraphysiologic concentration (such as from a way higher dose) is needed to induce tolerance. Chronic dosing with 10-50 mg might help us better understand whether tolerance occurs.
  • Inter-individual variability (high): In both (1) bioavailability (up to 2.5-fold) and (2) plasma concentrations of melatonin following oral administration (up to 37-fold).
  • Designs & durations: Most of the extremely long-term trials are merely follow-up tracking (rather than randomized controlled trials). Many of the long-term RCTs are only for ~6 months (which probably isn’t sufficient for tolerance).
  • Samples (size & specifics): Much data on melatonin were from studies with small samples and atypical populations (e.g. blind persons, neurodevelopmental disorders, older adults (60+ years old), etc.).
  • Ingredients in melatonin supplements: It’s unclear as to whether the melatonin issued to study participants was chemically analyzed (to verify ingredient accuracy) or whether participants bought their own melatonin (which isn’t regulated and actual contents & other ingredients may vary).
  • Extended release vs. immediate-release: In many long-term melatonin studies, prolonged-release melatonin (PRM) was administered. Perhaps extended-release formats are less likely to induce tolerance than standard, immediate-release. (Perhaps they’re also more likely to cause tolerance – or perhaps there’s no difference). One study that switched from prolonged-release to immediate noted that patients required higher dosages of immediate-release for the same benefit. Extended-release may ensure a more even delivery of melatonin to the brain such that receptors are less likely to become desensitized – particularly if a lower dose is administered.  On the other hand, immediate-release may give receptors more time to recover between doses (rather than being activated for ~6 hours by an extended-release format).
  • Older adults: Most studies showing that long-term melatonin doesn’t induce tolerance have older adults (~65 years old). It is possible that endogenous melatonin production for these individuals is significantly lower (on average) than younger adults – such that they’d be significantly less likely to develop tolerance to melatonin (particularly to a low-dose, extended-release format).
  • Consumer dosing (?): Because melatonin varies among supplements in actual content, we can’t be sure whether retail supplement consumers are getting: (1) expected melatonin (amount listed on package); (2) excessive melatonin (way more than listed); (3) insufficient melatonin (way less than expected). (R) Perhaps the consumers who are getting insufficient melatonin never develop tolerance and the ones who get way more than is actually listed on their product (e.g. listing of 5 mg – actual contents: 30 mg) go on to develop tolerance.
  • Dose vs. format (interaction): There may be some important interaction between dosing and format. For example: Perhaps 10 mg delivered as an extended-release keeps melatonin concentrations within a normal synaptic range (due to the even-keel delivery over ~6 hours) whereas 10 mg as an immediate-release might overwhelm receptors and increase risk of tolerance. (Perhaps the opposite applies).

How might melatonin lose its therapeutic effect over time?

Understand: Loss of therapeutic effect with long-term melatonin administration is not always due to “tolerance.”

It seems as though the reason melatonin ends up losing effectiveness (in some individuals) after regular administration is (according to Braam et al.) due to poor metabolism via CYP1A2 enzymes. (R)

Keep in mind that CYP1A2 metabolism is largely determined by genetics. (R)

Major CYP1A2 SNPs of interest include:

  • RS762551 (AA; CC; AC) – (AA = fast metabolizers; AC & CC = slow metabolizers)
  • RS11854147 (CC; CT; TT) – (CC = rapid metabolizers; CT & TT = slow metabolizers)

Repeated administration of high-dose melatonin in slow CYP1A2 metabolizers causes melatonin to accumulate to abnormally high concentrations within the body – ultimately disrupting the circadian rhythm and worsening sleep.

Why does sleep improve initially for the first few weeks for these individuals?

Because concentrations of melatonin haven’t peaked and CYP1A2 activation may change with repeated administration.

Therefore, if you’re a slow CYP1A2 metabolizer – you should probably steer clear of nightly, high-dose melatonin administration (as it will likely worsen your sleep) – and instead use a lower-dose melatonin (e.g. 0.1-0.3 mg per night).

In those who aren’t slow CYP1A2 metabolizers, various health conditions (e.g. liver/kidney problems) and/or medications taken along with melatonin may alter its metabolism and increase accumulation followed by circadian dysregulation (not the same as tolerance).

What about in otherwise healthy individuals with normal or fast CYP1A2 metabolism?

In these individuals, perhaps a genuine “tolerance” could occur following nightly administration of a high-dose for an extended duration – but no scientific evidence (currently) supports its development.

Administering melatonin at a suboptimal time, developing a health problem, starting a new medication or supplement, switching to a different brand of melatonin supplement (with different melatonin content relative to dosage listing and/or bioavailability), and/or being extremely stressed may diminish the effect of melatonin and/or cause you to think you’ve developed melatonin tolerance (even if you haven’t).

Melatonin tolerance (Potential mechanisms)

Because melatonin tolerance is not scientifically-validated, below are potential mechanisms by which melatonin tolerance might occur (such as in a subset of the populace).

Alteration in CYP1A2 metabolism

Chronic administration of a substance that’s metabolized by a specific enzyme (in this case CYP1A2) might alter its activity and/or expression over a long-term – such that metabolism efficiency may change (which could result in tolerance to a specific dose).

Accumulation of melatonin

This isn’t necessarily “tolerance” but could be a reason for tolerance development (e.g. melatonin accumulates > reaches supraphysiologic concentration > this concentration maintained for extended duration > alters receptor activation/expression, etc.).

Desensitization of melatonin receptors

Receptors become less responsive or “sensitive” to melatonin as a result of supraphysiologic concentrations.

Altered melatonin receptor densities

Such as upregulation or downregulation as a byproduct of receptor desensitization.

Reduced endogenous melatonin production

Endogenous melatonin production might decrease as a result of excessive exogenous melatonin supplements.

(One study I found examined whether melatonin supplements altered endogenous melatonin secretion – and there was no evidence of a change).

Note: There are peripheral melatonin receptors (in addition to those in the CNS/brain) and melatonin administration does influence these. (The same effects of receptor desensitization and density alteration may apply).

Do I think melatonin supplementation can cause tolerance?

Logically it would make sense (in theory) that it could.

However, there are various supplements that don’t cause tolerance such that they stop working after a sustained duration of chronic (i.e. daily) administration.

Perhaps as long as certain conditions are met: (1) dose doesn’t spike intraneural melatonin to a supraphysiologic concentration and/or (2) baseline melatonin synthesis/secretion are suboptimal – then tolerance is less likely.

The most surefire way to know whether melatonin causes tolerance would be to design a large-scale study with:

  • A large sample (randomized to receive melatonin or a placebo)
  • A long-term timeframe (e.g. 1-5 years) of nightly melatonin use
  • Brain scans (MRI, PET, etc. – to analyze melatonin receptor activity/expression at baseline, during treatment, and after a long-term of chronic supplementation)
  • Bioavailable melatonin or high-dose melatonin (to ensure a legitimate physiologic effect)
  • Dosage adjustments (based on individual bioavailability, CYP1A2 metabolism, age) with pharmacokinetic analyses (ensure concentrations are within specific ranges for all participants)
  • Circadian rhythm & sleep architecture analyses (to determine whether any measures change over time in the melatonin group)

And while melatonin content listed on a supplement container doesn’t always accurately reflect its contents (due to lack of regulation/standardization), my guess is that supplement companies aren’t putting excessive amounts of melatonin in products.

Instead, I suspect that (if anything) they’re skimping on adding melatonin to save money – and thus (after considering poor bioavailability of just 15% orally) coupled with potentially lower melatonin than listed – most people won’t develop tolerance to the melatonin (at least within 6 months).

Right now, I’m going to defer to the best evidence from long-term studies.

Therefore I do NOT believe melatonin supplementation causes tolerance in healthy users.

Tolerance is even more unlikely in those who use melatonin: (1) intermittently or “as-needed” (rather than nightly); (2) at low doses (1 mg or less); (3) at an appropriate time; (4) for less than 6 months.

It is possible that high-dose use beyond 6-12 months might cause tolerance in some people – but given the current data, I wouldn’t bet on it at this time.

Melatonin tolerance may vary among individuals (Variables to consider)

I want to emphasize the importance to NOT confuse tolerance with “loss of effect.”

Loss of effect (particularly after 4-8 weeks) may be solely attributable to poor CYP1A2 metabolism.

In the event of “effect loss” due to poor CYP1A2 metabolism, lowering the dosage (rather than increasing it) should bring back the same therapeutic effect.

Assuming “tolerance” can occur from melatonin, below are various variables that may play a role in determining: (1) who experiences tolerance AND (2) to what extent.

  • Age: Older adults are probably less likely to develop tolerance to melatonin supplementation than younger persons.
  • Body size & composition (height, weight, fat, lean mass): Body size/composition might have some effect on how you respond to melatonin – particularly if your body changes significantly relative to the dosage you’ve been taking (e.g. you gain a lot of weight).
  • Circadian rhythm & chronotype: Natural circadian rhythm or chronotype may impact how melatonin works initially – and over a long-term (and could determine whether tolerance can occur).
  • Dosage & bioavailability of melatonin: The dosage and bioavailability of melatonin will determine how well it works. Perhaps a high dosage would increase risk of tolerance in some users.
  • Duration & frequency of use: Long-term, nightly melatonin administration might increase risk of tolerance (assuming it can occur) relative to short-term and/or intermittent use.
  • Drugs, medications, supplements: Using various substances with or on the same day as melatonin might determine whether it works well or doesn’t work at all. (Don’t assume tolerance if you’re using other substances and it stops working).
  • Genetics: May influence expression of melatonin receptors in the brain, peripheral production of melatonin, circadian biology, and melatonin metabolism rate (via CYP1A2 enzymes) – all of which could impact its efficacy.
  • Habits: It’s possible that certain lifestyle habits influence whether you develop tolerance to melatonin (e.g. cardio exercise might decrease risk).
  • Health status: Are you healthy? Or are you currently in poor health? This may influence how well melatonin works.
  • Medical conditions: Having certain medical conditions might influence how well melatonin works.
  • Organ function: Suboptimal liver and/or kidney function may cause melatonin to accumulate such that a lower dose will work better.
  • Time of melatonin administration: Administering melatonin at a suboptimal time may be reason as to why melatonin stops working (as opposed to a true “tolerance”).
  • Sex: Perhaps males respond better/worse than females and are more or less likely to develop tolerance.

My personal experience with melatonin supplementation (5-10 mg/night)

Growing up: Never took melatonin supplements. No issues with sleep.

(Maybe this was a good decision: Melatonin Shrinks Testicles?)

In young adulthood, I knew others that used them either regularly or intermittently – but they never managed to convince me to try.

Occasionally I’d take magnesium citrate (learned this from Dave Asprey) to recover from exercise, relax, and get better sleep (subjectively it did improve my sleep – but I didn’t take it every night).

On a single occasion, I did a self-experiment wherein I read an article about “hacking sleep” and melatonin was recommended – so I ordered some and gave it a try.

Subjectively, I felt as though my sleep quality improved – but I experienced significant “brain fog” and mild depression the next day (which I disliked enough to discontinue melatonin permanently).

Additionally, at the time, I’d listened to a podcast with Dr. Richard Wurtman who suggested that high doses (above 300 mcg) will lead to tolerance – so this was another reason to avoid.

Fast-forward 5+ years and my interest in melatonin reemerges when I get a gene analysis and sleep report (suggesting that I’m a good candidate for melatonin supplementation to enhance sleep quality).

I bought various brands, formats (immediate-release & extended-release), and dosages (300 mcg, 1 mg, 5 mg, 10 mg) and experimented.

Initial 3-6 months of supplementation

Melatonin administered ~30-90 minutes before sleep seemed to significantly decrease sleep onset latency, increase total sleep time, and made me wake up feeling extremely refreshed with mild brain fog but no depression.

Worth noting: Melatonin seemed to help override caffeine to some extent (if I drank too much earlier in the day) AND the morning grogginess/brain fog after waking up in the morning could be completely overridden by caffeine).

Although melatonin did cause me to have some extremely vivid and bizarre dreams (relative to sleeping sans-melatonin), I didn’t mind the dreams (and actually thought the dreams made my sleep more interesting).

All-in-all, my sleep quality subjectively improved with melatonin supplementation (particularly within the first few months of its administration).

6+ months of supplementation

As I continued supplementing (~6 months of nightly administration), I noticed zero significant change in its effect and ended up Googling whether regular melatonin administration caused tolerance.

However, just because I failed to “subjectively” notice tolerance does NOT mean that some degree of tolerance hadn’t occurred (e.g. change in melatonin receptor sensitivity/expression).

I’m not sure of the highest melatonin dosage I’ve taken – but I believe it was 40-50 mg over a 12-hour span when dealing with extreme stress.

It made me feel a bit spaced out and slightly sleepy – but nothing excessive.

Update: Have taken melatonin nightly for ~2+ years and have noticed zero change in its effect.

What I’ve noticed about melatonin (in my experience)

None of these are scientifically factual – I’m just sharing my perceptions based on using melatonin.

  • High stress diminishes melatonin effect: Hyperarousal (such as from PTSD or extreme anxiety) significantly diminishes the effect of melatonin. You may think that the melatonin is no longer working – but in reality the stress response is overriding it. If I calm down, I “feel” the melatonin working again.
  • Working with melatonin is best: Rather than relying solely on melatonin to induce sleep, working with it such as by avoiding caffeine, avoiding bright light at night, exercising during the day, etc. seems to be best.
  • Next-day-depression or brain fog? Caffeine, morning sunlight, and exercise generally fixes this. Really just drinking more caffeine pulls me out of a melatonin twilight-zone-esque haze very quickly.
  • Caffeine causing insomnia? Melatonin helps with this. I used to drink a lot of caffeine (don’t anymore) and if I didn’t take melatonin, I’d fall asleep WAY later than without melatonin.
  • Synergistic with other things (?): Magnesium (threonate, glycinate, citrate), B-vitamins, taurine, glycine, morning/afternoon cardio exercise, and pre-sleep relaxation (e.g. headspace). (Keep in mind this is just my subjective experience).
  • May cause maintenance insomnia or premature waking: Although I’m not sure whether this was due to melatonin or my stress – it’s possible that melatonin was causing me to experience maintenance insomnia and “wake up too early.” Perhaps it was synergistic with the stress in causing this.
  • Optimal administration timing: Seems to be ~45-90 minutes before going to sleep (sweet spot ~60 minutes).

Melatonin withdrawal symptoms nonexistent

I thought I’d experience melatonin withdrawal symptoms when stopping melatonin “cold turkey” (i.e. abruptly) after daily supplementation (5-10 mg) for 6+ months.

Interestingly there was no noticeable “withdrawal” from melatonin (in my experience).

After melatonin discontinuation…

  • Delayed sleep onset: I didn’t fall asleep quite as quickly as with melatonin, but I really didn’t notice much of a change. (I simply reverted back to my pre-melatonin baseline sleep onset).
  • Less noticeable dreams: Dreams may have been less vivid and/or memorable upon waking. (I’m fine with more dreams and am fine with no dreams).
  • More alert after waking: Wasn’t quite as mentally foggy or hazy upon waking without melatonin.
  • More difficult to sleep if caffeinated: If I drink a lot of caffeine (such as an energy drink), it’s more difficult to fall asleep without melatonin (this makes sense – as caffeine delays the body clock by ~40 minutes).

Note: I didn’t really sense any “withdrawal” symptoms or rebound effects after stopping melatonin. Instead, it [subjectively] seemed like a reversion to pre-melatonin homeostasis.

I should note that: (1) I was NOT taking any other supplements after stopping melatonin AND (2) I actually expected to experience withdrawal symptoms (e.g. inability to fall asleep, poorer sleep quality, etc.).

Despite serious potential for a “nocebo” effect (expecting negative effects) – I didn’t experience any…

A couple of nights after stopping melatonin after long-term use, I actually felt as though my sleep was just as good as it was with the melatonin (go figure).

Perhaps longer-term or higher-dose melatonin administration may have resulted in more pronounced symptoms, but I’d been taking 5 mg per night (immediate-release) for ~3 months and 10 mg per night (immediate-release and extended-release) for another ~3 months.

Why did I jump from 5 mg to 10 mg? Mostly out of curiosity and the fact that I’d read that 10 mg was completely safe (even for long-term administration).

Is melatonin tolerance the same thing as loss of therapeutic effect?

Tolerance is generally defined as decreased reaction to a substance following its regular use.

In the case of melatonin, we should be careful to avoid automatically assuming that “loss of therapeutic effect” means “tolerance.”

In the case of poor CYP1A2 metabolizers who experience “loss of therapeutic effect” following 4+ weeks of nightly melatonin administration (2.5-5 mg) – it is because melatonin is accumulating in the body throughout the ~4-week period (due to inefficient hepatic metabolism).

As such, melatonin concentrations stay high and end up dysregulating the circadian rhythm (which negatively impacts subsequent sleep).

This doesn’t mean that melatonin is losing its biochemical effect – but it does mean that it’s lost its therapeutic effect.

Its biochemical effect may be more pronounced than ever such that users are overreacting to its effect (the opposite of tolerance) – but more is not always better. (That said, its biochemical effect may be reduced – nobody is sure here).

It remains unknown as to whether the abnormally high accumulation of melatonin desensitizes melatonin receptors and/or hepatic receptors (involved in its metabolism) such as to create a conventional state of “tolerance.”

Some would argue that this might not be the case – given that melatonin has a “sweet spot” (too much and too little are deleterious) – and perhaps there’s just too much in circulation.

However, to play devil’s advocate, I’ve yet to see a study wherein patients with “loss of therapeutic effect” (to melatonin) receive an increased dosage of melatonin to assess whether the initial therapeutic effect returns.

If the beneficial effect returned in the patients with initial loss of therapeutic effect, then it would be pretty obvious that a legitimate tolerance has occurred.

How will you know if you’ve developed melatonin tolerance?

True melatonin tolerance would mean that you continually need to increase the dosage of melatonin to achieve the same beneficial effect that you derived from melatonin when you first started taking it (e.g. the initial days or weeks).

For example, you start taking melatonin at 5 mg per night and it works great (you fall asleep faster, sleep deeper, and sleep longer).

After 1-4 months, the 5 mg melatonin is no longer helping you fall asleep, so you increase to 10 mg per night and you experience the same beneficial effect as before the 5 mg “wore off.”

After 1-4 more months, the 10 mg melatonin is no longer helping – and you bump up the dose to 15 mg per night and it works well again.

The above scenario is one that would indicate tolerance to melatonin.

Another sign of tolerance would be that you stop taking melatonin (e.g. 10 mg) after prolonged usage and suddenly you experience harsh “rebound” symptoms that were worse than the original condition for which you decided to use melatonin.

For example: You struggle with insomnia that keeps you up 2 hours longer than you’d like. You take melatonin 5 mg per night for 3 months with good effect and it stops working.  You bump up the dosage to 10 mg and it works again, but eventually stops working 3 months later. You stop melatonin completely and experience insomnia that keeps you up for 4 hours longer than you’d like.

This would indicate that you’ve developed tolerance to exogenous melatonin supplementation – and that you should probably avoid melatonin beyond the normative physiologic level (300 mcg).

All that said, I’ve yet to find any cases reports or research that suggest melatonin tolerance can occur.

But high-dose melatonin isn’t working, therefore “tolerance”?

Not necessarily. Melatonin is a hormone that has significant effect within the brain and body on a variety of neurobiological systems/feedback loops.

Some experts believe that melatonin dosing has more to do with finding a “sweet spot” for your particular biology and administering it at the right time.

For example: Taking too little melatonin won’t have a noticeable effect – whereas taking way too much may actually WORSEN your sleep and dysregulate your circadian rhythm.

In other words, more melatonin will not only NOT enhance your sleep to a greater extent than a lower dose – but it might significantly WORSEN your sleep.

Moreover, taking melatonin at a suboptimal time might be reason as to why some people aren’t responding well to their current dose (e.g. taking melatonin 5 minutes before bed).

Melatonin tolerance (Anecdotes & Analysis)

Keep in mind that these are merely self-reports and are not necessarily accurate.

What I believe many people believe to be “melatonin tolerance” is actually a combination of: (1) health, lifestyle, environment changes and/or (2) tolerance to other substances (mistakenly attributed to melatonin) and/or (3) use of other substances (e.g. stimulants).

Anecdote #1

Believed his melatonin receptors were “pretty shot.”

Has used melatonin ~80% of nights for ~7 years fluctuating between 3 mg and 15 mg.

What he also mentions is that he uses Benadryl and Doxylamine (antihistamines).

My thoughts:

  • Tolerance to antihistamines and the outcome is worsening of sleep. (Antihistamine tolerance onset is rapid).
  • May also be a poor CYP1A2 metabolizer and thus would benefit from a much lower dose (300 mcg) melatonin per night.
  • Melatonin at a high dose may be the reason he’s experienced insomnia for so long.

Anecdote #2

13-year melatonin user for Shift Work Disorder.

Claims it works great to help him fall asleep and suspects he’s become “dependent” on it.

Also claims that his “tolerance” went up over the 13-year period and that he adjusted his dosage from 300 mcg to 20 mg (present).

At his 20 mg dosage, he has trouble “staying asleep” and wakes up frequently and tosses/turns all night.

(He also has MS which may play a role in his sleep maintenance issues).

My thoughts:

  • May have developed tolerance to melatonin – but it remains unknown as to why he increased his dosage all the way to 20 mg.
  • He read that melatonin is “good for MS” which may have been a reason for him wanting to take more.
  • His current sleep problems may be due to taking too high of a dosage.
  • Melatonin abstinence for 2 weeks followed by reinstatement at 300 mcg would be smart.

Anecdote #3

Tolerance after one night? This person claims he feels like he builds up a tolerance to melatonin after 1 night – so he waits to take it again.

(2 others reacting to this anecdote claim they have the same experience.)

My thoughts:

  • Seems unlikely, but I’m not going to argue with their subjective experience.
  • Perhaps they do notice a decrease in melatonin effect after one night.
  • Might be due to some placebo-esque effect wherein they’re hype to take melatonin for “lucid dreaming” (this was on a lucid dreaming type post) and the hype isn’t as strong on a subsequent night.

Medical doctors (MD) discuss

A medical doctor asked for feedback about prescribing melatonin to patients – and asked whether tolerance (upregulation of melatonin receptors) was likely to occur.

Many replies suggested that lower dose melatonin (e.g. 0.3 mg) is as effective as 3 mg with fewer adverse events.

Some replies claimed that higher doses might interfere with sleep. Why? According to “u/herman_gill” (MD) – breakdown products of melatonin are supposed to promote wakefulness.

My thoughts:

  • I’m not sure where u/herman_gill (MD) read about melatonin metabolites promoting wakefulness.
  • I think it’s possible the body is sensitive to fluctuations in melatonin levels and that this could be disrupted by high-dose supplements.

Anecdote #4

Asked whether they may have developed tolerance to diphenhydramine and melatonin (12 mg/night).

Individual also administered calcium, magnesium, and valerian.

Sleep has been “abbreviated” (i.e. suboptimal).

My thoughts:

  • Probably developed tolerance to diphenhydramine.
  • May have developed tolerance to valerian.
  • May benefit from stopping all supplements/drugs and reinstating melatonin at 300 mcg at a circadian-appropriate time.

Anecdote #5

Individual claims that melatonin ruined their sleep.

They’d been using 5 mg melatonin extended-release for 2 nights and woke up at 3 AM.

Stopped taking melatonin for 6 days and apparently is still waking up in the middle of the night.

My thoughts:

  • I’d stop melatonin altogether for a while and consider reinstating at 300 mcg to determine whether it provides benefit.
  • It’s unlikely that 2 nights of melatonin would still be negatively affecting this indivdiual’s sleep ~6 days post-discontinuation.

Note: It should be noted that many people have used melatonin at high doses for years without any decline in perceived beneficial effect. I did not document these anecdotes.

Loss of therapeutic response to melatonin in CYP1A2 poor metabolizers… (Presentation)

Clinical documentation suggests that a subset of the populace will respond well to melatonin at conventionally-prescribed dosages (e.g. 2.5 mg to 5 mg).

Melatonin will provide therapeutic benefit in terms of regulating the circadian rhythm, reducing sleep onset latency, and enhancing overall sleep quality – for ~4 weeks – followed by deterioration of therapeutic effect thereafter.

If the melatonin is continued at the conventional dose following ~4+ weeks of use, not only does the therapeutic effect disappear, but sleep actually gets WORSE than pre-melatonin baseline.

The one way to determine whether you’re one of these individuals is to have a doctor measure concentrations of melatonin in saliva ~6 hours after melatonin administration (after a ~2 week washout).

(If levels remain above 50 pg/mL, you aren’t metabolizing melatonin efficiently and need a lower dose).

Another thing you could do is have your genes analyzed and check whether you’re a slow CYP1A2 metabolizer (this is pretty easy to do).

Overall, the best course of action for most people who want to take melatonin is to try it for ~4 weeks (with a high-quality supplement).

If the benefits are fading between 4-8 weeks and/or your sleep actually worsens, stop taking it for ~2 weeks then reinstate at a tiny dose (300 mcg).

If you respond to this low dose (i.e. notice benefit) – you should be able to take it indefinitely without tolerance.

What if you’ve developed melatonin tolerance? (How to Overcome It)

The only individuals who are likley to develop “loss of therapeutic effect” to melatonin are slow CYP1A2 metabolizers.

Stop melatonin supplementation (2-4 weeks)

This is pretty simple and straightforward. This will give your body a chance to: (1) eliminate any exogenous melatonin that accumulated; (2) alter receptor sensitivity/expression in the brain and liver.

Use lower-dose melatonin (300 mcg or less)

If you like using melatonin and are a slow CYP1A2 metabolizer – take a lower dose (such as 300 mcg or less).

This is generally considered a physiologically normal level (such that tolerance won’t occur).

Use different melatonin format

I’d recommend extended-release melatonin instead of immediate-release because, in theory, it seems as though this would be less likely to overwhelm melatonin receptors (via a more controlled delivery). You could experiment with both versions though.

Circadian reset

Outdoor light exposure for 30-60 minutes first thing in the morning; high-protein breakfast; zero or less caffeine (limited to morning); exercise throughout the day; block blue/green-wavelength light at night (i.e. after sunset); meditate before bed.

How to prevent melatonin tolerance?

This assumes that melatonin tolerance is a legitimate phenomenon (it currently hasn’t been proven).

Do NOT take more than 300 mcg melatonin

Pretty simple and straightforward. Unfortunately, most melatonin manufacturers sell doses 10-100x this amount.

However, you can find this low dose on Amazon. (I suspect most people will be completely safe with 1 mg melatonin as well).

Consider extended-release melatonin

Sometimes called “sustained-release” or “prolonged-release” or “extended-release” – these formats should ensure that smaller amounts of melatonin are delivered to receptors over a longer duration.

This might keep melatonin levels within or closer to a physiologically normative range relative to immediate-release versions.

Immediate-release melatonin delivers a “bolus” all at once and  spikes melatonin concentrations to a supraphysiological level – which could desensitize melatonin receptors.

Use “as needed”

If you aren’t someone that administers melatonin nightly – you don’t really need to worry about taking too high of a dose.

For example: If you take melatonin once a week or so, I wouldn’t worry.

Most people don’t even need melatonin supplements – particularly if they exercise during the day, abstain from caffeine, and get outdoor light in the morning.

Self-experiment & self-audit

If you want to use higher doses of melatonin (5, 10, 15, 20 mg) – give it a try and assess your sleep.

If your sleep subjectively worsens after ~4-12 weeks, just stop the melatonin altogether and then go back to 300 mcg.

If melatonin keeps “working” for whatever reason you’re using it – no need to stop it.

Note: It is important to mention that many people who notice “melatonin stops working” probably are just taking too high of a dose (rather than developing tolerance).

These individuals should stop melatonin for 2-4 weeks, then restart at 300 mcg or less – as they probably have slow CYP1A2 metabolism.

Self-experiment protocol

  • Keep a sleep journal, logs of sleep onset latency; sleep duration; subjective sleep quality.
  • Have a partner (or someone you trust) dissolve a melatonin capsule in a beverage or protein shake at night (on random nights).
  • After 1 month, determine whether you slept better on nights the melatonin was added.

Melatonin Supplements I Recommend

Below are some melatonin supplements that I’ve personally used and found beneficial – you’re mileage may vary.

Note: Confirm safety with a medical doctor and/or pharmacist before taking any supplement.

Note: These are affiliate links – meaning I earn commission if you buy through me. The cost is the exact same. Support is appreciated.

Life Extension (300 mcg)

This is probably good if you’re just starting out.

The scientifically “optimal” dose according to Dr. Wurtman in an extended-release (6-hour) format.

Nobody should develop tolerance to this dose – but it may be possible to still dysregulate your circadian rhythm if administered at an inappropriate time.

Life Extension or Pure Encapsulations (1-3 mg)

Both are good brands as far as I’m concerned.

Have personally used both and responded equally well.

Some individuals think that using a dose of melatonin at 1 mg is unlikely to cause tolerance because it’s still within a physiologic “range.”

NOW Melatonin (5 mg or 10 mg)

This was the first melatonin product I tried (Now Melatonin 5 mg) and it worked well.

I randomly increased the dosage to 10 mg to determine whether there would be any additional effect – and subjectively I got even better sleep.

Beyond 10 mg I didn’t notice any additional benefit.

NOW Melatonin has a “B+” score on Labdoor (and are #3 overall in quality rankings).

Natrol (time-release melatonin) (5 mg or 10 mg)

I have used both and don’t notice a significant difference between the dosages – other than the 10 mg seems to be optimal for me.

Sometimes I’ll combine these with the NOW (immediate-release) such as by taking 5 mg NOW and 5 mg or 10 mg or Natrol.

(They also have a good Labdoor quality score). Beware if you’re using these as an experiment – they contain a high dose of vitamin B6 (confound).

Some people may be energized by B6 – I’m sedated by it.

Pure Encapsulations (Melatonin 20 mg)

This is a high-dose melatonin supplement that only contains melatonin – no additives (which is why I like pure encapsulations).

I’ve used 20 mg melatonin as a self-experiment and it certainly helps me fall asleep quickly, but didn’t notice much of any subjective difference relative to 10 mg.

I should state that I’ve personally used all of these brands with success.

Note: I’ve also used Nature Made Melatonin (10 mg) – which is what I’m currently taking and find it works as well as any other brand. (Seems pretty difficult to find a brand that doesn’t work…)

Additional notes:

  1. Administer melatonin at the right time. There’s some controversy regarding optimal time of administration before bed (30 minutes, 30-60 minutes, 1-2 hours, 2-4 hours, 4-6 hours). I typically take ~1 hour before I plan on sleeping.
  2. Know your CYP1A2 status. I’m also a CYP1A2 rapid metabolizer (genetically) so likely don’t accumulate melatonin long-term (perhaps why I haven’t noticed any loss of effect despite months of administration).
  3. Stick with one brand if possible. You may find that melatonin “stops working” after you try a different “brand” or switch brands. (Amount of melatonin – and other ingredients – varies so significantly between brands – that switching is almost guaranteed to provide a drastically different “dose” even if it lists the same dose as your old brand).

Have you experienced melatonin tolerance?

If you believe you’ve developed a tolerance to melatonin, provide some details and discuss your experience.

Things that may help include:

  • CYP1A2 metabolism status (you’d need a genetic analysis)
  • Melatonin dosage (e.g. 5 mg)
  • Duration used (e.g. months, years, etc.)
  • Frequency of use (nightly, randomly, etc.)
  • Age (older individuals may be less likely to develop tolerance)
  • Medical conditions
  • Drugs, medications, supplements (including caffeine & alcohol)
  • Recent withdrawal from a drug or medication

When you noticed melatonin tolerance, how did you manage it? Did you stop taking melatonin or did you increase the dosage? (If a dosage increase, what happened thereafter?)

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