Meta Information
ID:microdose-time-release-melatonin
Name:
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-05-21T22:30:00Z
Model
phase-a-upgrade-claude-sonnet-4.6
Interactions
Target id:
/circadian/sleep
Target name:
Going to Sleep
Severity:
major
Interaction type:
requirement
Nature:
temporal
Temporal spacing:
Hours before target:
1
Hours after target:
null
Description:
Melatonin is a chronobiotic hormone that signals the brain to prepare for sleep. Its effectiveness is entirely dependent on being taken at the correct time relative to your desired sleep onset.
Actionable advice:
It should be taken 1 hour before the intended bedtime to align with the sleep-wake cycle.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Chronotherapy aims to restore the proper circadian pattern of the sleep-wake cycle, through adequate sleep hygiene, timed light exposure, and the use of chronobiotic medications, such as melatonin, that affect the output phase of circadian rhythms, thus controlling the clock.
Label source:
PubMed: Chronotherapy. (PMID 34225975)
Action type:
separate
Target id:
/circadian/wake
Target name:
Daytime Wakefulness
Severity:
major
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
8
Hours after target:
null
Description:
Taking melatonin during the day or too close to your wake-up time can cause significant circadian rhythm disruption, leading to daytime drowsiness, impaired performance, and sleep-wake cycle confusion.
Actionable advice:
Melatonin should never be taken during the day or within 8 hours of the planned wake time.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Melatonin, a pineal hormone that modulates circadian rhythms, sleep, and neurotransmitters, is widely used to treat sleep disorders.
Label source:
PubMed: Investigating the safety profiles of exogenous melatonin and associated adverse events: A pharmacovigilance study using WHO-VigiBase. (PMID 38528668)
Action type:
separate
Target id:
/dietary/alcohol-acute
Target name:
Alcohol (Acute Consumption)
Severity:
major
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
4
Hours after target:
8
Description:
Alcohol is a central nervous system depressant that has an additive effect with melatonin, potentially causing excessive drowsiness, dizziness, and impaired coordination. It also disrupts sleep architecture in the second half of the night.
Actionable advice:
Alcohol should not be consumed for at least 4 hours before taking melatonin.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
studies found that in nonalcoholics who occasionally use alcohol, both high and low doses of alcohol initially improve sleep, although high alcohol doses can result in sleep disturbances during the second half of the nocturnal sleep period.
Label source:
PubMed: Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism (2001)
Source url:
Exact phrase from label:
As a rhythm regulator, melatonin exerts a wide range of different effects: circadian rhythm regulation, thermoregulation, sleep induction, antioxidant, immunomodulatory, and anti-stress ones. This review presents from a chronobiological perspective the impact of melatonin on alcohol intoxication in terms of mental disorders, sleep and inflammation, hepatic injury, and mitochondrial function.
Label source:
PubMed: Chronobiology international (2021)
Source url:
Exact phrase from label:
At 140 and 190 min after alcohol administration, melatonin level was reduced by 15% and 19%, respectively, in comparison to placebo. The findings indicate that a moderate dose of alcohol in the evening suppressed melatonin in young adults.
Label source:
PubMed: Chronobiology international (2007)
Action type:
separate
Target id:
/class/cns-depressants
Target name:
Sedatives and CNS Depressants (Pharmacologic)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Combining melatonin with other sedating substances (e.g., benzodiazepines, Z-drugs like zolpidem, opioids, certain antihistamines) can lead to excessive sedation, impaired motor function, and potentially dangerous respiratory depression.
Actionable advice:
This should not be combined with other sedating medications unless explicitly approved by a physician.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Among all the reports, 5,147 involved respiratory depression. After adjustments for sex, age, reporting year, concomitant medications, and medical history the associations with non-benzodiazepines (adjusted ROR=1.06; 95% CI=0.92-1.23) and DORAs (adjusted ROR=0.94; 95% CI=0.70-1.27) were not significant. In contrast, significant associations remained for BZRAs (adjusted ROR=1.34; 95% CI=1.20-1.49) and MRAs (adjusted ROR=2.03; 95% CI=1.56-2.64).
Label source:
PubMed: In vivo (Athens, Greece) (2026)
Source url:
Exact phrase from label:
Fourteen studies evaluated sedation and generally found that benzodiazepine caused the highest degree of sedation, but melatonin also showed sedative properties compared to placebo.
Label source:
PubMed: The Cochrane database of systematic reviews (2020)
Source url:
Exact phrase from label:
Their side effects are either associated with the direct sedating effects of the drugs, doses greater than clinical doses, or a combination with alcohol or other sedating drugs.
Label source:
PubMed: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (2012)
Action type:
avoid
Target id:
/class/cyp1a2-inhibitors
Target name:
CYP1A2 Inhibitors (e.g., Fluvoxamine, Ciprofloxacin)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
These drugs strongly inhibit the primary enzyme (CYP1A2) responsible for metabolizing melatonin. This can cause melatonin levels in the blood to increase dramatically, elevating the risk of side effects like next-day drowsiness.
Actionable advice:
This combination should be avoided, and it is important to consult a doctor for alternatives as dose adjustments are critical.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Coadministration of fluvoxamine, on average, led to an 17-fold higher (P < .05) area under concentration-time curve (AUC) and a 12-fold higher (P < .01) serum peak concentration (Cmax) of melatonin.
Label source:
PubMed: Clinical pharmacology and therapeutics (2000)
Source url:
Exact phrase from label:
Melatonin was found to be almost exclusively metabolized by CYP1A2 to 6-hydroxymelatonin and N-acetylserotonin with a minimal contribution of CYP2C19. Both reactions were potently inhibited by fluvoxamine, with a Ki of 0.02 microM for the formation of 6-hydroxymelatonin and 0.05 microM for the formation of N-acetylserotonin.
Label source:
PubMed: Journal of clinical psychopharmacology (2001)
Source url:
Exact phrase from label:
Pharmacokinetics was affected by age, caffeine, smoking, oral contraceptives, feeding status, and fluvoxamine.
Label source:
PubMed: European journal of clinical pharmacology (2015)
Action type:
avoid
Target id:
/condition/pregnancy
Target name:
Pregnancy
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Melatonin is a hormone that crosses the placenta and plays a role in fetal development. The effects of exogenous supplementation on the fetus are not well-established, and it is therefore contraindicated.
Actionable advice:
This should be strictly avoided during pregnancy.
Validation status:
anecdotal
Evidence tier:
tier_d
Evidence basis:
anecdotal_summary
Evidence anchors:
Exact phrase from label:
Taking melatonin supplements during pregnancy has not been well studied.
Label source:
Anecdotal: NIH
Action type:
avoid
Target id:
/condition/lactation
Target name:
Breastfeeding (Lactation)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Melatonin is known to pass into breast milk. The effects of supplemental melatonin on a nursing infant's developing circadian system are unknown and potentially harmful.
Actionable advice:
It should be avoided completely while breastfeeding.
Validation status:
anecdotal
Evidence tier:
tier_d
Evidence basis:
anecdotal_summary
Evidence anchors:
Exact phrase from label:
And while melatonin supplements seem to be safe for short-term use in the general adult population, we just don’t know for sure how safe they are if you’re breastfeeding.
Label source:
Anecdotal: Healthline
Action type:
avoid
Target id:
/environment/blue-light-exposure
Target name:
Blue Light Exposure (Screens, Bright Lights)
Severity:
moderate
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
0
Hours after target:
2
Description:
Exposure to blue-spectrum light, particularly from electronic screens and bright indoor lighting, sends a strong wakefulness signal to the brain that directly suppresses and counteracts the sleep-promoting effects of both endogenous and supplemental melatonin.
Actionable advice:
Cease use of all screens and dim household lights at least 1-2 hours before bed.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
room light exerts a profound suppressive effect on melatonin levels and shortens the body's internal representation of night duration
Label source:
Primary literature: https://pmc.ncbi.nlm.nih.gov/articles/PMC3047226/
Action type:
separate
Target id:
/class/cyp1a2-inducers
Target name:
CYP1A2 Inducers (e.g., Smoking, Carbamazepine)
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
These substances, particularly compounds in tobacco smoke, accelerate the activity of the CYP1A2 enzyme, causing melatonin to be broken down and cleared from the body much faster, thereby reducing its effectiveness.
Actionable advice:
It is worth being aware that smoking or taking these specific drugs may render melatonin supplements ineffective.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The parameters of CSE production were optimized for a 2.5-min cigarette burning and a cell culture medium as CSE solvent. A reliable, concentration-dependent induction of CYP1A1 and CYP1A2 by CSE across different donors and cigarettes was verified based on an enzyme activity (LC-MS/MS) and mRNA expression levels (qRT-PCR).
Label source:
Action type:
informational_none
Target id:
/class/anticoagulants-antiplatelets
Target name:
Anticoagulants and Antiplatelets (e.g., Warfarin, Aspirin)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Melatonin may inhibit platelet aggregation. When combined with medications that thin the blood or prevent clotting, there is a theoretical increased risk of bruising and bleeding.
Actionable advice:
This is best used with caution, and it is important to talk to a doctor before combining it with blood-thinning medications.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of COUMADIN therapy.
Label source:
Action type:
informational_none
Target id:
/class/antidiabetic-medications
Target name:
Diabetes Medications
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Melatonin can influence glucose metabolism and insulin sensitivity, particularly when taken at night. This may alter blood sugar levels and interfere with the intended action of medications for diabetes.
Actionable advice:
Blood glucose levels are best monitored closely for those with diabetes, especially when starting or stopping melatonin.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Label source:
Action type:
monitor
Target id:
/condition/autoimmune-disease
Target name:
Autoimmune Conditions (e.g., Rheumatoid Arthritis, Lupus)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Melatonin has immune-modulating effects, including the potential to stimulate certain immune cells (like T-helper cells). This could theoretically exacerbate conditions where the immune system is already overactive.
Actionable advice:
It is important to talk to a specialist before using melatonin with a diagnosed autoimmune condition.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
Melatonin seems to modulate the immune system in multiple and complex ways, but we can generally think of it as immune-stimulating
Label source:
Primary literature: https://www.sciencedirect.com/science/article/abs/pii/S1359610119300449
Action type:
informational_none
Target id:
/condition/seizure-disorder
Target name:
Seizure Disorder / Epilepsy
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
There are conflicting reports, but some evidence suggests melatonin may alter brain electrical activity and potentially lower the seizure threshold in individuals with epilepsy.
Actionable advice:
Melatonin is best not used with a seizure disorder without consulting a neurologist.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The pineal gland and melatonin exert a major influence in the control of brain electrical activity and have been shown to be involved in seizure and sleep mechanisms. Since pinealectomy has been reported to result in seizures in experimental animals, it is assumed that melatonin has anticonvulsant properties. Indeed, limited studies in humans with temporal lobe epilepsy indicate that melatonin attenuates seizure activity. In the present communication we present evidence, based on magnetoencephalographic (MEG) brain measurements, that melatonin may exert proconvulsive activity in humans as well.
Label source:
PubMed: The International journal of neuroscience (1992)
Source url:
Exact phrase from label:
On the other hand, melatonin has been shown to induce electroencephalographic abnormalities in patients with temporal lobe epilepsy and increase seizure activity in neurologically disabled children.
Label source:
PubMed: Pharmacological reports : PR (2011)
Source url:
Exact phrase from label:
Experimental studies point to a possibility that endogenous melatonin may possess proconvulsive activity. Moreover, some scarce clinical data seem to express this view; however, a limited number of patients were included.
Label source:
PubMed: International journal of molecular sciences (2024)
Action type:
avoid
Target id:
/intervention/caffeine
Target name:
Caffeine
Severity:
moderate
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
8
Hours after target:
null
Description:
Caffeine is a potent adenosine receptor antagonist, a mechanism that promotes wakefulness and directly opposes the sleep-promoting actions of melatonin. Its long half-life means afternoon consumption can still interfere with nighttime sleep.
Actionable advice:
All sources of caffeine are best avoided for at least 8 hours before taking melatonin.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Caffeine, an adenosine receptor antagonist, is a potent central nervous system stimulant that also impairs insulin signaling.
Label source:
PubMed: Caffeine Inhibits Both Basal and Insulin-Activated Urate Transport. (PMID 38932509)
Action type:
separate
Target id:
/class/immunosuppressants
Target name:
Immunosuppressant Medications
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The immune-stimulating properties of melatonin may counteract the intended effects of medications designed to suppress the immune system, such as those used after organ transplantation (e.g., cyclosporine, tacrolimus).
Actionable advice:
Melatonin is best avoided by those taking immunosuppressive therapy.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The simultaneous Mel-CsA administration prevented the involution of the thymic medulla and the reduction of the number of macrophages. These findings suggested that Mel probably antagonized the immunosuppressive CsA effects.
Label source:
PubMed: International immunopharmacology (2001)
Source url:
Exact phrase from label:
While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation.
Label source:
PubMed: International journal of molecular sciences (2013)
Source url:
Exact phrase from label:
Melatonin administration in experimental models decreased rejection and improved transplant success.
Label source:
PubMed: Revista da Associacao Medica Brasileira (1992) (2020)
Action type:
avoid
Target id:
/class/beta-blockers
Target name:
Beta-Blocker Medications
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Certain beta-blockers (e.g., propranolol, atenolol) are known to suppress the body's natural nighttime synthesis and release of melatonin from the pineal gland, which can contribute to sleep disturbances.
Actionable advice:
This medication may be the cause of sleep issues; discussing melatonin supplementation with a doctor may help.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
(7.2)
• TOPROL-XL Extended-Release Tablets (metoprolol succinate): 25 mg, • Beta-blockers including metoprolol, may exacerbate the rebound
50 mg, 100 mg, and 200 mg.
Label source:
Action type:
informational_none
Target id:
/class/calcium-channel-blockers
Target name:
Calcium Channel Blockers
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Both melatonin and certain calcium channel blockers (e.g., nifedipine) can lower blood pressure. Their combined use may have a small additive hypotensive effect.
Actionable advice:
This is best used with caution, and it is worth monitoring blood pressure when taking these medications.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or
pacing) in patients with normal ventricular function treated with NORVASC have generally demonstrated a small increase in
cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume.
Label source:
Action type:
monitor
Target id:
/class/nsaids
Target name:
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
NSAIDs inhibit prostaglandin synthesis. Since prostaglandins are involved in the body's natural production of melatonin, chronic or evening use of NSAIDs may slightly reduce endogenous melatonin levels.
Actionable advice:
Regular evening use of NSAIDs might slightly blunt natural melatonin production.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
In animal studies,
NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and
increase the incidence of stillbirth.
Label source:
Action type:
informational_none
Target id:
/class/estrogens
Target name:
Estrogens and Progestins (Hormonal Therapy & Contraceptives)
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Oral contraceptives and hormonal therapies containing estrogen may alter the metabolism of melatonin, potentially leading to higher-than-expected levels.
Actionable advice:
Hormonal medications may increase melatonin levels; a lower dose may be needed.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Transdermal versus Oral Contraceptives The norelgestromin and ethinyl estradiol transdermal system delivers EE and NGMN over a 7-day period while oral contraceptives (containing NGM 250 mcg / EE 35 mcg) are administered on a daily basis.
Label source:
Action type:
informational_none
Target id:
/class/herbal-sedatives
Target name:
Sedating Herbal Supplements (e.g., Valerian, Kava, Chamomile) (Herbal Additive)
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Combining melatonin with other supplements known to cause drowsiness can result in an additive sedative effect, potentially leading to excessive sleepiness or grogginess.
Actionable advice:
Caution may help when combining with other sleep-promoting supplements, and a low starting dose is generally best.
Validation status:
validated_via_clinical_guidance
Evidence tier:
tier_b
Evidence basis:
clinical_guidance_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
the NIH also cautions against taking valerian root alongside St. John's wort, kava and melatonin
Label source:
Clinical guidance: NIH/AARP — Sleep supplements and drug interactions
Action type:
informational_none