Drug & supplement interaction

Melatonin + Progesterone (prescription drug)

Progesterone (prescription drug) brand names: Prometrium, Endometrin, Utrogestan.

Moderate Interaction
Medically reviewed by · Updated October 2026
The bottom line Moderate

Progesterone (prescription drug) falls into 2 drug categories that Melatonin can interact with; the most serious is rated moderate. Theoretically, melatonin might increase levels of drugs metabolized by CYP2C19.

Read the full interaction report
SeverityModerate
LikelihoodProbable
Interactions2
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Melatonin and Progesterone (prescription drug)

These two interact in 2 distinct ways. Each one is explained separately below.

Why Are There 2 Interactions?

Melatonin interacts with whole categories of medication. Progesterone (prescription drug) falls into 2 of those categories, so it can interact with Melatonin in 2 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES

1 of 2

Why this applies to Progesterone (prescription drug)

Progesterone (prescription drug) falls under CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES — the group Melatonin interacts with.

Theoretically, melatonin might increase levels of drugs metabolized by CYP2C19. Also, other CYP2C19 substrates might decrease the metabolism of melatonin, increasing melatonin levels.
Melatonin is metabolized in the liver primarily by the CYP2C19 and CYP1A2 enzymes. Theoretically, combined administration of melatonin with certain drugs metabolized by the CYP2C19 enzyme may reduce the metabolism of these drugs, resulting in increased serum levels. Conversely, some drugs metabolized by CYP2C19 may inhibit the metabolism of melatonin, resulting in increased serum levels of melatonin. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
Severity Moderate Likelihood Probable Evidence D

Interaction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports..

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the gist with melatonin and your prescription progesterone. Your liver uses an enzyme called CYP2C19 to help clear progesterone out of your body. The theory is that melatonin might slow that enzyme down a touch, which could let a little more progesterone hang around. If that happened, you might feel its usual effects more strongly, things like drowsiness, dizziness, breast tenderness, bloating, or mood changes.

I want to be honest though: this is only a theoretical concern based on how these chemicals behave in the lab, not something proven to cause real problems in people. For most folks, an occasional dose of melatonin alongside progesterone isn't a big deal. Since both can make you sleepy, just be aware of that combined drowsiness, and check with your pharmacist or doctor before starting melatonin regularly.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Yeleswaram, K., Vachharajani, N., and Santone, K. Involvement of cytochrome P-450 isozymes in melatonin metabolism and clinical implications. J Pineal Res 1999;26(3):190-191. PubMed
  2. Faber, M. S., Jetter, A., and Fuhr, U. Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic Clin Pharmacol Toxicol. 2005;97(3):125-134. PubMed
Minor

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

2 of 2

Progesterone (prescription drug) also falls under CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES.

Theoretically, melatonin might increase levels of drugs metabolized by CYP3A4.
Laboratory research shows that certain lots of melatonin inhibit CYP3A4. Theoretically, combined administration of melatonin with certain drugs metabolized by CYP3A4 may reduce the metabolism of these drugs, resulting in increased serum levels. Until more is known, use melatonin cautiously in patients taking drugs metabolized by these enzymes.
Severity Minor Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the gist for taking melatonin alongside your prescription progesterone (Prometrium and similar). Your liver uses an enzyme called CYP3A4 to break progesterone down. Some lab studies suggest melatonin might slow that enzyme a little, which could in theory let progesterone build up slightly and make its usual effects more noticeable, things like drowsiness, dizziness, breast tenderness, or bloating.

I want to be honest with you, though: this is a minor, theoretical concern based only on test-tube research, not on real patients. For most people using both, it's unlikely to cause a real problem. Since progesterone itself can already make you sleepy, taking it with melatonin at night may simply feel a bit more sedating. If you notice that, just mention it to your pharmacist or doctor before changing anything.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Foster BC, Cvijovic K, Boon HS, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci 2015;18(2):124-31. PubMed

What These Ratings Mean

Every interaction above is graded three ways — here’s the key to each label.

Severity how clinically significant the interaction is
Major

Clinically significant. Avoid the combination, or use only under close professional supervision.

Moderate

Usually worth avoiding or managing — may need monitoring, a dose change, or timing apart.

Minor

Generally not serious. Be aware of it and mention it to your pharmacist.

Likelihood how strong the evidence is that the interaction actually happens in people
  • LikelyWell-controlled human studies have demonstrated the likely existence of this interaction.
  • ProbableInteraction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
  • PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.
  • UnlikelyInteraction has been demonstrated in animal or in lab research but has been shown not to occur in humans.
Evidence the quality of the studies behind the rating (graded A–D)
  • AHigh-quality meta-analysis (quantitative systematic review).
  • BCase-control study.
  • CConsensus.
  • DAnecdotal evidence.

These ratings are for information only. Never start, stop, or otherwise change your therapy before speaking with your provider.

Keep it in perspective

Melatonin Also Interacts With Other Medications

Melatonin has 1,116 moderate, 346 minor known drug interactions in our database — the Progesterone (prescription drug) one above is among them. If you take anything else, check it against the full list below.

Moderate 1,116 Minor 346 No known interaction 1,368 (incl. Progesterone (prescription drug))
Taking anything else?

Check Another of Your Medications Against Melatonin

Covers the 2,830 medications we’ve checked against Melatonin. Pick one to open its full report.

From our Q&A

Questions About Melatonin or Progesterone (prescription drug)

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Melatonin or Progesterone (prescription drug), not necessarily both, but if one is close to what you were about to ask it will usually go further than a database entry can:

Not quite your question? Ask our pharmacists directly — it is free, there is no account required, and answers usually come back within 24 hours.

Everything else you take

See Every Supplement That Interacts With Progesterone (prescription drug)

This page covers Melatonin only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Progesterone (prescription drug) page lists 148 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), Grapefruit (major), St. John's Wort (major), Acacia Rigidula (moderate) and Adrafinil (moderate).

By severity: 3 major · 104 moderate · 41 minor.

From our pharmacist’s overview on the Progesterone (prescription drug) page

“Prescription progesterone (Prometrium, Endometrin) supports pregnancy, regulates cycles, and protects the uterine lining during estrogen therapy, and because a steady hormone level is the whole point of taking it, its 148 documented supplement interactions warrant genuine vigilance. Most of them act on CYP3A4, the liver enzyme that cle…”

Reviewed by 2 · Jul 18, 2026

Open the Progesterone (prescription drug) interaction page

One more smart check

Taking Melatonin as Part of a Dietary Supplement Product? Check It for Interactions

We hold 2,885 real supplement products containing Melatonin, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Melatonin. Your product may carry other ingredients that interact with Progesterone (prescription drug) too, on top of Melatonin — and those would not show on this page. Find your product and we’ll check every ingredient on its label:

How much people look this up

Where Melatonin and Progesterone (prescription drug) Sit Against Everything Else

Out of every supplement and medication people look up on HelloPharmacist, here is where these two land this week — and which way each has been moving.

Supplement Melatonin
Top 5%

#57 of 1,452 supplements looked up here in the last 7 days

29 days ago today
Medication Progesterone (prescription drug)
Top 10%

#267 of 2,830 medications looked up here in the last 7 days

29 days ago today

Position among everything looked up on this site, not a measure of how commonly either one is used or how important it is. A supplement can climb this list because of a news story. It counts every request to the page, automated ones included, and nothing here identifies anyone.

Supplement

About Melatonin

What is Melatonin?

Melatonin
  • Trouble falling asleep (insomnia)
  • Jet lag
  • Delayed sleep phase syndrome
  • Non-24-hour sleep-wake disorder
  • Shift-work sleep problems
  • Sleep problems in some children with conditions like autism or ADHD

Melatonin is a hormone your body makes naturally to help control your sleep-wake cycle, and the supplement form is widely used to help with sleep timing problems and jet lag. The evidence is strongest for certain circadian (body-clock) disorders and is more mixed for everyday insomnia. It is generally well tolerated for short-term use, but talk with your pharmacist or doctor before starting, especially for children or during pregnancy.

Read the full Melatonin monograph & all interactions
Medication

About Progesterone Vaginal

What Is Progesterone Vaginal Used For?

Brand names: Prometrium, Endometrin, Utrogestan

Progesterone vaginal products are used as part of fertility treatment. Endometrin, a vaginal insert, is used in an Assisted Reproductive Technology (ART) program to support embryo implantation in infertile women under 35. It also helps maintain pregnancy after implantation, up to 10 weeks.

Crinone, a vaginal gel, is also used in ART for women who need progesterone supplementation or replacement. Crinone 4% (and Crinone 8% if needed) is also used for secondary amenorrhea, meaning periods have stopped in a woman who previously had them.

See full Progesterone Vaginal drug information
Keep checking

Other Drugs & Melatonin

Browse every other medication we’ve checked against Melatonin — both the ones with a known interaction and the ones without. Select any drug for the full detail.

0Major
1,116Moderate
346Minor
1,367No known interaction
1,116 Moderate 346 Minor 1,367 No interaction
Moderate

1,116 interactions

Showing 60 of 1,116 moderate interactions — see all 1,116 on the Melatonin page.

Minor

346 interactions

Showing 60 of 346 minor interactions — see all 346 on the Melatonin page.

No interaction 1,367 drugs checked — show the list

We also checked Melatonin against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 1,367 medications checked with no known interaction — see the full Melatonin list.

See the full Melatonin interactions page
See every supplement checked against Progesterone (prescription drug), ranked by severity
Sources

Sources & How We Checked

Interaction details are evidence-graded and sourced from the Natural Medicines database. The medication overview comes from MedlinePlus.

Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.

Parts of this content are provided by the Therapeutic Research Center, LLC.

DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.

© 2021 Therapeutic Research Center, LLC

Keep exploring
Melatonin monograph › Uses, safety, and every drug interaction in one place Progesterone (prescription drug) supplement interactions › Every supplement checked against Progesterone (prescription drug), ranked by severity Progesterone Vaginal drug information › The full plain-English guide to this medication Supplement interaction checker › Check any supplement or product against your medications Browse medications A–Z › Every drug we've checked against herbs & supplements Ask a pharmacist › Free, personal answer from our licensed team
Pharmacist Counseling Corner

Taking Melatonin and Progesterone (prescription drug) Together: Common Questions

Can you take Melatonin with Progesterone (prescription drug)?
There is a moderate interaction, so it may be acceptable with monitoring or timing changes — but check with your pharmacist first. Read the full details on this page and confirm with your pharmacist before combining them.
Why are there 2 interactions listed for Melatonin and Progesterone (prescription drug)?
Progesterone (prescription drug) belongs to more than one drug category, and Melatonin interacts with each of those categories a little differently. We list every one so nothing is missed — your overall risk is driven by the most serious of them.
How serious is the Melatonin and Progesterone (prescription drug) interaction?
We rate it Moderate. This combination may require monitoring, a dose adjustment, or separating the times you take each one. Consult your pharmacist before using them together.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Still Have a Question About Progesterone (prescription drug) and Melatonin?

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This information is for education only and is not a substitute for professional medical advice. Always check with your pharmacist or doctor before starting, stopping, or combining supplements and medications.