Drug & supplement interaction

Adrafinil + Methotrexate

Methotrexate brand names: Rheumatrex, Otrexup, Rasuvo, Reditrex.

No Known Interaction
Medically reviewed by · Updated July 2026 · Pair last verified Sep 13, 2026
The bottom line No known interaction

We found no known interaction between Adrafinil and Methotrexate in our sources. Absence of a documented interaction is not the same as proven safety, and does not guarantee one does not exist. Do not start, stop, or change a medication or supplement based on this page; confirm with your pharmacist or doctor first. Additionally, although there is no interaction, the two are separately associated with some of the same side effects, which would make a new symptom harder to attribute to one or the other.

Know someone taking this? Share
Facebook Post Reddit Email
On this page
Interaction report

Adrafinil and Methotrexate

We checked these two against our interaction database. Here is what we found.

No Known Interaction Found

We did not find a documented interaction between Methotrexate and Adrafinil in our sources. This does not guarantee that the combination is completely free of risk — there is often limited research on supplements and herbal products, especially around drug interactions.

If you decide to take both, the practical routine is simple: add one new thing at a time and note the date you started it. If the combination is going to disagree with you, it usually shows in the first days to a couple of weeks — and a start date turns “I’ve been feeling off” into something a pharmacist can actually work with. Do not stop a prescribed medicine on your own.

Always talk with your pharmacist or doctor before making changes to your medications or supplements, particularly if you take several medications or have an ongoing health condition.

Adrafinil safety at a glance

Adrafinil overall Use caution It converts to a prescription stimulant-like drug and may stress the liver, so it should not be used casually.
Pregnancy Possibly Unsafe When used orally. Adrafinil is a precursor to the stimulant prescription drug modafinil. Modafinil has been associated with reports of intrauterine growth restr... Read the full pregnancy detail
Breastfeeding Possibly Unsafe When used orally. Adrafinil is a precursor to the stimulant prescription drug modafinil. Modafinil has been associated with reports of intrauterine growth restr... Read the full breastfeeding detail

Pregnancy & breastfeeding ratings are from Natural Medicines (Therapeutic Research Center) — the full detail is in the Special populations card below. Safety guidance is general; always confirm with your pharmacist or doctor for your situation.

Still wondering about combining Methotrexate and Adrafinil? Ask Dr. Brian Staiger, PharmD, BCPS directly ›
How we checked

Why No Interaction Is Listed for Methotrexate

Interactions in our licensed database are recorded against drug classes, not just single drug names. Methotrexate is filed under 6 classifications — including organic anion-transporting polypeptide substrates (oatp), organic anion transporter 3 (oat3) substrates, hepatotoxic drugs. Adrafinil has documented interactions with 11 drug classes — the most serious being modafinil (provigil) (major), antihypertensive drugs (moderate) and cytochrome p450 1a2 (cyp1a2) substrates (moderate) — and none of Methotrexate’s classifications are among them.

Classification data comes from our licensed Natural Medicines dataset. A medication can belong to classes beyond those recorded there, so this describes how the check was run — it is not a safety guarantee.

Keep it in perspective

Adrafinil Does Interact With Other Medications

Adrafinil has 1 major, 1,056 moderate known drug interactions in our database — Methotrexate isn’t one of them. If you take anything else, check it against the full list below.

Major 1 Moderate 1,056 No known interaction 1,773 (incl. Methotrexate)
Taking anything else?

Check Another of Your Medications Against Adrafinil

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

What to actually watch for

No Interaction Found — But Data Suggests Adrafinil and Methotrexate May Share Several of the Same Side Effects

This is not an interaction. Neither one changes how your body handles the other, and nothing here says they react together. What our sources do show is that each has separately been linked to the effects below — so taking both can make those effects more likely to turn up, and harder to pin on one or the other if they do. One of them is worth acting on rather than waiting out — marked below.

  • A severe skin reaction Worth acting on Additional detail

    Adrafinil

    “Adrafinil is a precursor to the stimulant prescription drug modafinil. Serious drug rashes, including erythema multiforme/Stevens Johnson syndrome (EM/SJS), have been reported following the use of modafinil.”

    Adrafinil · Natural Medicines adverse-effect record, reported in erythema.

    2 sources cited
    1. 104950. Urban AE, Cubala WJ. The role of eugeroics in the treatment of affective disorders. Psychiatr Pol. 2020;54(1):21-33. PubMed
    2. 109229. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68(13):1803-39. PubMed

    Methotrexate

    Listed in the ADVERSE REACTIONS section of the FDA label for Methotrexate. Read the label on DailyMed ›

  • Drowsiness Additional detail

    Adrafinil

    “Anecdotally, headache, poor concentration, irritability, sedation, disturbed sleep, unpleasant stimulation, and anxiety have been reported following intake of adrafinil. It is unknown if individuals reporting these symptoms were also taking other substances.

    Adrafinil is a precursor to the stimulant prescription drug modafinil. Insomnia, headache, and nervousness are common adverse effects of modafinil.”

    Adrafinil · Natural Medicines adverse-effect record, reported in anxiety.

    4 sources cited
    1. 109225. Lowe DW, Dobson E, Jewett AG, Whisler EE. Adrafinil: Psychostimulant and purported nootropic? Am J Psych Res J. 2021;17(1):7-9. DOI
    2. 104950. Urban AE, Cubala WJ. The role of eugeroics in the treatment of affective disorders. Psychiatr Pol. 2020;54(1):21-33. PubMed
    3. 109229. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68(13):1803-39. PubMed
    4. 109226. Thobois S, Xie J, Mollion H, Benatru I, Broussolle E. Adrafinil-induced orofacial dyskinesia. Mov Disord 2004;19(8):965-6. PubMed

    Methotrexate

    Listed in the ADVERSE REACTIONS section of the FDA label for Methotrexate. Read the label on DailyMed ›

  • Reduced appetite / Nausea reported in 5.9% of FDA reports for Methotrexate Additional detail

    Adrafinil

    “Adrafinil is a precursor to the stimulant prescription drug modafinil. Nausea is a common adverse effect of modafinil. Decreased appetite is common in children and adolescents and may be related to weight loss.”

    Adrafinil · Natural Medicines adverse-effect record, reported in nausea and vomiting.

    2 sources cited
    1. 104950. Urban AE, Cubala WJ. The role of eugeroics in the treatment of affective disorders. Psychiatr Pol. 2020;54(1):21-33. PubMed
    2. 109229. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68(13):1803-39. PubMed

    Methotrexate

    Listed in the ADVERSE REACTIONS section of the FDA label for Methotrexate, and in voluntary FDA adverse-event reports. Read the label on DailyMed ›

  • Tiredness reported in 6.7% of FDA reports for Methotrexate Additional detail

    Adrafinil

    “Anecdotally, feelings of withdrawal have been reported following cessation of adrafinil. Symptoms included fatigue, irritability, lack of focus, headache, and gastrointestinal symptoms. It is unknown if individuals reporting these symptoms were also taking other substances.

    Adrafinil is a precursor to the stimulant prescription drug modafinil.”

    Adrafinil · Natural Medicines adverse-effect record, reported in cluster headache.

    3 sources cited
    1. 109225. Lowe DW, Dobson E, Jewett AG, Whisler EE. Adrafinil: Psychostimulant and purported nootropic? Am J Psych Res J. 2021;17(1):7-9. DOI
    2. 104950. Urban AE, Cubala WJ. The role of eugeroics in the treatment of affective disorders. Psychiatr Pol. 2020;54(1):21-33. PubMed
    3. 109229. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68(13):1803-39. PubMed

    Methotrexate

    Listed in the ADVERSE REACTIONS section of the FDA label for Methotrexate, and in voluntary FDA adverse-event reports. Read the label on DailyMed ›

  • Headache Additional detail

    Adrafinil

    “There is limited reliable information available about the safe use of adrafinil. However, adrafinil is a precursor to the stimulant prescription drug modafinil and may cause similar adverse effects.

    Most Common Adverse Effects:

    Orally: Disturbed sleep, headache, malodorous urine, and unpleasant stimulation.

    Serious Adverse Effects (Rare):

    Orally: Orofacial dyskinesia.”

    Adrafinil · Natural Medicines adverse-effect record, reported in cluster headache.

    Methotrexate

    Listed in the ADVERSE REACTIONS section of the FDA label for Methotrexate. Read the label on DailyMed ›

Reported for Adrafinil but not commonly for Methotrexate: mood changes or irritability, raised blood pressure, anxiety or restlessness and a fast or pounding heartbeat.

Effects for Methotrexate come from the ADVERSE REACTIONS section of its FDA label; effects for Adrafinil come from the Natural Medicines adverse-effect record, quoted above. Where a percentage is shown, it is the share of 489,806 voluntary FDA FAERS reports for Methotrexate that mention that effect — a reporting proportion, not an incidence rate and not evidence the drug caused it. Wording is matched across sources by our own clinical vocabulary, so treat this as a prompt to pay attention, not a diagnosis.

Special populations

Adrafinil in Pregnancy & Breastfeeding

Pregnancy And Lactation Possibly Unsafe

When used orally. Adrafinil is a precursor to the stimulant prescription drug modafinil. Modafinil has been associated with reports of intrauterine growth restriction and spontaneous abortion. Also, animal studies show that developmental toxicity occurs with use of modafinil during pregnancy. Although modafinil, and possibly adrafinil, might have addictive potential, the potential for abuse is low. However, there have been anecdotal reports of withdrawal symptoms following use of adrafinil, alone or in combination with other products. Avoid using.

DISCLAIMER: This tool is intended for informational purposes only, and should not be interpreted as specific medical advice. Patients should consult with a qualified healthcare provider before making decisions about therapies and/or health conditions.© 2026 Therapeutic Research Center

From our Q&A

Questions About Adrafinil or Methotrexate

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Adrafinil or Methotrexate, 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 Methotrexate

This page covers Adrafinil only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Methotrexate page lists 82 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), Apple (major), Beer (major), Grapefruit (major) and Siberian Cocklebur (major).

By severity: 7 major · 60 moderate · 15 minor.

From our pharmacist’s overview on the Methotrexate page

“The liver is where methotrexate and supplements clash most. Methotrexate (Rheumatrex, Otrexup, Rasuvo), used for rheumatoid arthritis, psoriasis, and certain cancers, can strain the liver on its own, and 38 of the 82 interacting ingredients on this list add liver risk of their own, alcohol included, which makes this a list to approach…”

Reviewed by 2 · Jul 18, 2026

Open the Methotrexate interaction page

One more smart check

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

We hold 7 real supplement products containing Adrafinil, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Adrafinil. Even though Adrafinil itself has no known interaction with Methotrexate, another ingredient on your label might. Find your product and we’ll check every ingredient on its label:

How much people look this up

Where Adrafinil and Methotrexate 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 Adrafinil
Top half

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

29 days ago today
Medication Methotrexate
Top 5%

#49 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.

Where does our data come from?
  • Source: the Natural Medicines (TRC Healthcare) clinical database — the evidence-graded professional reference for herb & supplement interactions.
  • Citation library: 103,510 references behind our interaction content, 65,311 of them resolved to verified PubMed/DOI sources. See every Adrafinil reference on this page ↓
  • Freshness: we automatically re-check this combination every week — this pair was last verified September 13, 2026. The Adrafinil and Methotrexate records this page draws on were last updated July 10, 2026.
  • What “no known interaction” means: no documented interaction in the sources above — not a guarantee of safety. Supplements are studied far less than prescription drugs, so we say exactly what the evidence supports, and nothing more.
Data structure & sourcing designed and verified by .
Supplement

About Adrafinil

What is Adrafinil?

Adrafinil
  • Wakefulness and alertness
  • Fatigue
  • Focus and concentration
  • Cognitive enhancement (nootropic)
  • Daytime sleepiness

Adrafinil is a synthetic compound that the body converts into modafinil, a prescription wakefulness-promoting drug. It is sometimes sold as a nootropic supplement, but it is unregulated, carries real risks (especially to the liver), and is banned in some sports and countries. Talk with a doctor or pharmacist before using it.

Synthetic compound (not from a plant) · Capsules, tablets, powder

An interaction check asks whether these two react with each other — it does not ask whether Adrafinil is a good idea for someone in your situation. Here is what our Adrafinil record says about it on its own.

Adrafinil: dosing

There is no officially established or standardized supplement dose for adrafinil, and it is not approved as a dietary supplement by health authorities. Doses used historically as a prescription medicine were determined by doctors and are not the same as casual self-dosing.If a product is used, follow the directions on the label and do not exceed them. Because of the liver risk, it is generally not recommended for daily or long-term use, and periodic liver function testing may be wise.

From our Adrafinil monograph — the full record covers uses, side effects and every documented interaction.

Read the full Adrafinil monograph & all interactions
Medication

About Methotrexate

What Is Methotrexate Used For?

Brand names: Rheumatrex, Otrexup, Rasuvo, Reditrex

Methotrexate treats a wide range of serious conditions. In cancer care, it is used for acute lymphoblastic leukemia, non-Hodgkin lymphoma, osteosarcoma, breast cancer, head and neck cancer, and gestational trophoblastic neoplasia (a rare tumor related to pregnancy). It is also used to prevent and treat meningeal leukemia (cancer affecting the lining of the brain and spinal cord).

Outside of cancer, methotrexate is prescribed for adults with rheumatoid arthritis (RA), children with polyarticular juvenile idiopathic arthritis (a form of childhood arthritis), and adults with severe psoriasis that hasn't responded well to other treatments.

Most-Reported Side Effects for Methotrexate

From FAERS, the FDA’s public side-effect reporting system (489,806 reports, all brands). Reports are voluntary and are not proof the drug caused the effect.

Rheumatoid arthritis 42,798 reports
Arthralgia 40,830 reports
Fatigue 33,049 reports
Nausea 28,999 reports
Joint swelling 25,026 reports
See full Methotrexate drug information
Keep checking

Other Drugs & Adrafinil

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

1Major
1,056Moderate
0Minor
1,772No known interaction
1 Major 1,056 Moderate 1,772 No interaction
Major

1 interaction

Moderate

1,056 interactions

Showing 60 of 1,056 moderate interactions — see all 1,056 on the Adrafinil page.

No interaction 1,772 drugs checked — show the list

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

Showing the 60 most looked-up of 1,772 medications checked with no known interaction — see the full Adrafinil list.

See the full Adrafinil interactions page
See every supplement checked against Methotrexate, ranked by severity
Evidence & sources

Adrafinil References

The 7 references that drive our Adrafinil monograph and interaction data, from the evidence-graded Natural Medicines (TRC Healthcare) database. Citations with a link open the study on PubMed or the publisher’s site.

  1. Urban AE, Cubala WJ. The role of eugeroics in the treatment of affective disorders. Psychiatr Pol. 2020;54(1):21-33. PubMed
  2. Lowe DW, Dobson E, Jewett AG, Whisler EE. Adrafinil: Psychostimulant and purported nootropic? Am J Psych Res J. 2021;17(1):7-9. DOI
  3. Thobois S, Xie J, Mollion H, Benatru I, Broussolle E. Adrafinil-induced orofacial dyskinesia. Mov Disord 2004;19(8):965-6. PubMed
  4. Chariot J, Appia F, Vaille C, Rozé C. Effect of modafinil on pancreatic exocrine secretion in rats. A comparison with adrafinil and related drugs. Fundam Clin Pharmacol 1987;1(4):243-52. PubMed
  5. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68(13):1803-39. PubMed
  6. Provigil (modafinil) [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc. Published: January 2015. Accessed on: Nov 11, 2022.
  7. Kinslow, CJ, Shapiro SD, Grunebaum MF, Miller EC. Acute hypertensive crisis and severe headache after concurrent use of armodafinil and tranylcypromine: Case report and review of the literature. Clinical Short Communication. October 2018; 393:1-3. PubMed

Medication overviews come from MedlinePlus (NIH); supplement label data from the NIH Dietary Supplement Label Database. Content is written and reviewed by licensed HelloPharmacist pharmacists — see our data sources and editorial standards.

Pharmacist Counseling Corner

Taking Adrafinil and Methotrexate Together: Common Questions

Is it safe to take Adrafinil with Methotrexate?
We do not list a known interaction between Adrafinil and Methotrexate. That does not guarantee the combination is risk-free, so confirm with your pharmacist or doctor — especially if you take other medications or have a health condition.
Do Adrafinil and Methotrexate have any of the same side effects?
Yes — our sources link each of them separately to 6 of the same effects. That is not an interaction: neither changes how your body handles the other. It does mean that if one of those effects turns up, it can be harder to tell which one is behind it. They are listed on this page with the source behind each.
How was the Adrafinil and Methotrexate combination checked?
Interactions in our licensed database are recorded against drug classes. Methotrexate is filed under 6 classifications, and Adrafinil has documented interactions with 11 drug classes — none of Methotrexate's classifications are among them. A medication can belong to classes beyond those recorded in our dataset, so this describes how the check was run rather than guaranteeing safety.
Does Adrafinil interact with any other medications?
Yes. Adrafinil has 1,057 documented drug interactions in our database — Methotrexate is simply not one of them. If you take anything else, it is worth checking each one; they are all listed on this page.
Does Methotrexate interact with any supplements?
Yes. Methotrexate has documented interactions with 82 supplements in our database — Adrafinil is not one of them. The Methotrexate interaction page linked on this page lists every one, ranked by severity.

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

Where next

Keep Exploring

Adrafinil monograph Uses, safety profile, and every drug interaction in one place Methotrexate drug information The full plain-English guide to this medication Methotrexate supplement interactions Every supplement checked against Methotrexate, ranked by severity Supplement interaction checker Check any supplement or product against your medications Browse medications A–Z Every drug we’ve checked against herbs & supplements References The 7 citations behind this page Ask a pharmacist Free, personal answer from our licensed team

Still Have a Question About Methotrexate and Adrafinil?

Our pharmacists answer your medication & supplement questions — free.

Ask a pharmacist

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.