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Circadian Rhythm/Melatonin Drug Interactions

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While most medications do not impact the circadian rhythm or melatonin production directly, there are several classifications of pharmacological compounds that can impact typical results, depending on the dosage and the individual’s physiology.

General Guidance

A general guideline is to stop any medication that your patient can safely and comfortably discontinue under your care for 3-5 days before beginning the assessment.

Prescription Medications

There are two prevailing modalities among healthcare providers regarding the assessment of melatonin production levels in the context of prescription medication and supplements:

  1. Discontinue all medications and supplements (increases patient burden) to determine the baseline circadian profile to rule out physiological dysregulation first.
  2. Discontinue sleep-related medications only and determine an individual’s current circadian profile to rule out physiological dysregulation last. In the event of atypical results, you may consider discontinuing or inverting dosing schedules based on the timing of the results to observe effects on sleep behavior.

Melatonin Supplementation

While measurable levels of exogenous melatonin supplementation or melatonin-containing supplements typically persist in saliva for up to 24 hours, we frequently observe prolonged circadian dysregulation for a duration of up to 10 days or more post-supplementation. This can manifest as elevated melatonin levels, phase shifts, and oscillating profiles. This phenomenon is inter-individual dependent and influenced by the duration and dosage of routine supplementation. It is recommended to follow a discontinuation/withdrawal protocol for melatonin supplementation as outlined below:

  • 3 days (minimum) for >5 mg dosing as needed
  • 5 days (better) for >5 mg routine dosing to >3mg dosing as needed
  • 10 days (best) for >3 mg routine dosing to >5mg dosing as needed
  • 15 days (ultimate) for >5 mg routine dosing

Circadian Rhythm Drug Interaction Index

While assessing every pharmacological compound, dosage, and combination effect would be astronomical, we are working to create an index of medications that likely impact either circadian timing or melatonin production. Please note that the evidence below is anecdotal and has not been part of a formal clinical trial – however, it is still important to note in the event that atypical results are present. Although the clinical significance is typically moderate, emerging evidence suggests that certain medications elevate the probability of impact to a clinically significant level, as delineated in the table provided below:


Medication Name/Class Effect on Melatonin Impact Probability
Stimulants May Dysregulate Levels High
Sedatives May Dysregulate Levels High
Beta-blockers May Decrease Levels High
Selective Serotonin Reuptake Inhibitors (SSRIs) May Decrease Levels High/Moderate
Fluvoxamine May Decrease Levels Moderate
Benzodiazepines May Decrease Levels Moderate
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) May Decrease Levels Moderate
Proton Pump Inhibitors (PPIs) May Decrease Levels Moderate
Antipsychotics May Decrease Levels High
H2 Blockers May Decrease Levels Moderate
Corticosteroids May Decrease Levels High
H2 Blockers May Decrease Levels Moderate
Beta-agonists May Decrease Levels Moderate
Mirtazapine May Increase Levels High
Fluoxetine May Increase Levels High
Clonidine May Increase Levels High
Lithium May Increase Levels High
Topiramate May Increase Levels High
Carbamazepine May Increase Levels Moderate
Contact: Salimetrics (USA)
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