Tylenol and Supplements: Melatonin, Kava and More

Yes, you can take plain Tylenol (acetaminophen) and melatonin together at label doses. In a lab test on human liver preparations, acetaminophen did not slow melatonin's breakdown¹, and a review found no serious interactions with therapeutic acetaminophen doses confirmed in people².

Two things change the answer. Tylenol PM adds a sedating antihistamine, diphenhydramine³. And some herbs, notably kava, can injure the liver, so check before combining them with Tylenol⁴. Whatever you take, keep total acetaminophen under 4,000 mg a day from all sources⁵.

Yes, at the doses on the label. The evidence is indirect, because we found no trial that gave people both.

• Lab data: in human liver preparations, acetaminophen, diazepam and tamoxifen did not impair the conversion of melatonin to its main metabolite at concentrations reached after therapeutic doses¹.
• Review data: a pharmacology review of paracetamol (the name for acetaminophen outside the US) found few clinically significant acetaminophen interactions, and none serious at therapeutic doses confirmed in humans².
• Melatonin's own cautions: short-term use appears safe for most people, and reported side effects include headache, dizziness, nausea and sleepiness⁶.

The same review does name two interactions to ask about: enzyme-inducing drugs, which probably raise liver toxicity after an overdose, and warfarin, where the effect on blood thinning is disputed². Nothing in this data calls for spacing melatonin and acetaminophen apart. A mouse study found melatonin reduced acetaminophen liver toxicity without changing its pain or fever relief⁷. Mouse data like that does not make melatonin a liver safeguard in people.

If your pain medicine is ibuprofen instead, see Can You Take Melatonin and Ibuprofen Together?

Not by default. Tylenol PM already contains a sleep aid, so adding melatonin stacks two products that cause drowsiness. Each caplet holds 500 mg of acetaminophen and 25 mg of diphenhydramine, and the adult dose is 2 caplets at bedtime³.

The label does not name melatonin. It does say to ask a doctor or pharmacist before use if you take sedatives or tranquilizers, and it warns that drowsiness will occur³. Sleepiness is also a listed melatonin side effect⁶.

• If pain keeps you awake: choose plain acetaminophen plus melatonin rather than Tylenol PM plus melatonin.
• Other products with acetaminophen: the label says not to use Tylenol PM with any other drug containing acetaminophen, or any other product containing diphenhydramine³.
• Alcohol: the label says to avoid alcoholic drinks while using it³.
• Duration: stop and ask a doctor if sleeplessness lasts more than 2 weeks³.
• Children: the label says not to use it in children under 12 years³.
• Ask a doctor first if you have: liver disease, glaucoma, trouble urinating from an enlarged prostate, or a breathing problem such as emphysema or chronic bronchitis. Ask a doctor or pharmacist if you take warfarin³.
• Pregnancy and breastfeeding: the label says to ask a health professional first³. MedlinePlus reports a September 22, 2025 FDA safety warning that acetaminophen in pregnancy may be associated with autism or ADHD in children, although no evidence shows it causes them⁵. NCCIH says melatonin has had little safety research in pregnant or breastfeeding women⁶.

Does Tylenol PM have melatonin in it?

No. The label we read lists two active ingredients, acetaminophen and diphenhydramine, and no melatonin among its inactive ingredients³. Other products sold under similar names can differ, so check the Drug Facts panel on yours.

Cold and flu products need the same check. MedlinePlus lists a daytime product with acetaminophen, dextromethorphan and pseudoephedrine, and a night product with acetaminophen, dextromethorphan and doxylamine, another sedating antihistamine⁵.

Kava is the clearest case. Ashwagandha and turmeric also have documented liver injury, though we found no study that tested either with acetaminophen. Start with the baseline: acetaminophen itself has a ceiling.

In a randomized trial of 145 healthy adults, 31% to 44% of those taking 4 g of acetaminophen daily reached an ALT (a liver enzyme) above 3 times the upper limit of normal, against none of 39 on placebo⁸. The daily maximum is a ceiling, not a target. MedlinePlus also says not to take acetaminophen if you drink three or more alcoholic drinks every day⁵. See our liver health guide for the wider picture.

Kava: the one to avoid unless a clinician agrees

In rat liver cells, kava plus acetaminophen caused 100% loss of cell viability, against about 50% for kava alone and about 30% for acetaminophen alone, and kava deepened acetaminophen's depletion of glutathione, the liver's main antioxidant⁹. That is a cell study, not a human trial.

In people, a review gathered 78 reported cases of liver injury reputedly linked to kava. Four were probably from kava alone and 23 more possibly, with other substances involved. Eleven cases of liver failure led to transplants, four of them fatal⁴. Another review listed overdose, prolonged use and taking kava with other drugs or supplements as risk factors¹⁰. A pharmacology review suggests liver toxicity may be added when acetaminophen is used with kava or echinacea, but it rests on case reports, animal studies and lab data¹¹.

Ashwagandha: liver injury is documented

A series of 5 cases from Iceland and the US Drug-Induced Liver Injury Network found jaundice, nausea, lethargy and itching after 2 to 12 weeks on ashwagandha. Liver tests normalized within 1 to 5 months in four of the five¹².

An Indian series of 8 people with single-ingredient products found that three with chronic liver disease developed acute-on-chronic liver failure and all three died¹³. People with existing liver disease are the group to protect.

Turmeric: rare, but rising

The US network reviewed 10 cases of turmeric-associated liver injury. Median age was 56, 5 people were hospitalized, 1 died, and injury appeared 1 to 4 months after starting¹⁴. Seven of the 10 carried the HLA-B*35:01 gene variant, and 3 of the 7 products tested also contained piperine (black pepper)¹⁴.

Yellow skin or eyes, nausea or itching after starting any of these herbs is a reason to stop it and get medical care¹².

No. NAC (N-acetylcysteine) is the hospital antidote for acetaminophen overdose, and glutathione has not been shown to protect the human liver from it.

NAC works as an antidote, and timing matters

In a national study of 2,540 overdose patients, liver toxicity developed in 6.1% of at-risk patients treated within 10 hours and 26.4% of those treated 10 to 24 hours after the overdose¹⁵. A review of 34 studies in 19,580 patients found NAC cut mortality when started within 8 hours, and no later than 24 hours¹⁶.

That protocol uses weight-based doses given under medical care¹⁵. A shelf supplement is not a substitute, and it does not make an extra dose of Tylenol safe. For any overdose, get medical help or call Poison Control at 1-800-222-1222 right away, even without symptoms³.

Glutathione raises blood levels, not proven liver cover

In a 6-month trial of 54 adults, 1,000 mg a day of oral glutathione raised levels 30% to 35% in red cells, plasma and lymphocytes, and levels returned to baseline within a month of stopping¹⁷. That measures blood stores. We found no human trial showing oral glutathione prevents acetaminophen liver injury.

No interaction has been documented in people. The pharmacology review found no serious human interactions with therapeutic acetaminophen doses², and our searches found no study pairing acetaminophen with any form of magnesium, glycinate included.

A 2024 mouse study found oral magnesium prevented acetaminophen-induced acute liver failure by changing gut bacteria's metabolism, and gut microbiota from magnesium-supplemented humans protected mice¹⁸. That is early animal work. It does not support taking magnesium as cover for extra Tylenol.

If you are pairing magnesium with melatonin at night, our guide on magnesium and melatonin together covers that combination.

Few combinations are absolute, but these are the ones to raise with a pharmacist first.

• Fluvoxamine: in 7 healthy volunteers it raised 20-hour melatonin exposure by a factor of 2.8, while citalopram did not¹⁹.
• Strong CYP1A2 inhibitors: in the lab, the potent inhibitor 5-methoxypsoralen impaired melatonin breakdown at relevant concentrations¹.
• Several sedating medicines at once: a 19-year-old taking citalopram, nortriptyline and oxycodone had severe sedation after melatonin was added²⁰.
• Epilepsy and blood-thinner medicines: NCCIH says people on them need medical supervision when taking melatonin⁶.
• Alcohol and ibuprofen: see melatonin and alcohol and melatonin and ibuprofen.

Our guide to SSRIs and supplements covers antidepressant combinations in more depth.

A 2024 dose-response meta-analysis of 26 trials found the benefit peaked at 4 mg a day. It compared about 3 hours before the desired bedtime at 4 mg with the common schedule of 2 mg 30 minutes before bed. Because that combines earlier timing with a higher dose, the authors say only that it "might" optimize the effect²¹.

Melatonin is used mainly for sleep, and its effect is modest. A meta-analysis of 19 trials in 1,683 people with primary sleep disorders found it cut the time to fall asleep by 7.06 minutes and added 8.25 minutes of total sleep²². See our melatonin for insomnia page and the sleep optimization guide for the evidence behind it.

The evidence is thin for both. A meta-analysis of 4 trials in people with hypertension found that only controlled-release melatonin lowered asleep systolic blood pressure, by 3.57 mm Hg, and the 95% confidence interval (-7.88 to 0.73) included zero. Evidence quality was low to very low²³.

For anxiety, a meta-analysis of 5 trials in 441 postmenopausal women found a reduction, with a standardized mean difference of -0.806²⁴. It covers one group of women, so it does not settle the question for other adults.

Use these rules instead of a spacing schedule, because the risks here come from the liver and from stacked sedation rather than from absorption timing.

• Plain Tylenol with melatonin: fine at label doses^{1, 2}.
• Tylenol PM with melatonin: ask a pharmacist first, since the label asks you to check before combining it with sedatives³.
• Tylenol with warfarin: ask a pharmacist; the effect on blood thinning is disputed^{2, 3}.
• Tylenol with magnesium: no documented interaction².
• Tylenol with kava: avoid unless a clinician agrees, because kava has its own liver-injury record and the combined risk is plausible^{9, 4, 11}.
• Tylenol with ashwagandha or turmeric: ask a clinician first if you have liver disease, and stop either herb if jaundice or nausea appears^{12, 14}.
• NAC or glutathione as protection: do not rely on them^{15, 17}.
• Daily total: count every product containing acetaminophen toward the 4,000 mg limit⁵.

Related evidence pages: pain relief and management and insomnia.

We searched PubMed through the Firecrawl research index and read the abstracts of 21 journal papers, then read the Drug Facts label for Tylenol PM on DailyMed, MedlinePlus's acetaminophen page and NCCIH's melatonin fact sheet on 1 November 2026. We favored meta-analyses, randomized trials and case series on liver injury and interactions.

No trial tests Tylenol with these supplements. The NCBI LiverTox pages were unavailable to us, so the liver-injury statements rest on the published case series. Several findings are lab or mouse data and are labelled that way. This guide does not replace advice from your pharmacist or doctor.

1. Papagiannidou E, et al. Potential drug interactions with melatonin. Physiol Behav. 2014;131:17-24. doi:10.1016/j.physbeh.2014.04.016
2. Toes MJ, et al. Drug interactions with paracetamol. Am J Ther. 2005;12(1):56-66. doi:10.1097/00045391-200501000-00009
3. DailyMed (U.S. National Library of Medicine). Tylenol PM (acetaminophen, diphenhydramine hydrochloride) tablet, film coated: Drug Facts label, revised 5/2026. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8ed9a9f0-d37e-5c10-e053-2a95a90a559f&type=display
4. Clouatre DL. Kava kava: examining new reports of toxicity. Toxicol Lett. 2004;150(1):85-96. doi:10.1016/j.toxlet.2003.07.005
5. MedlinePlus (U.S. National Library of Medicine). Acetaminophen: MedlinePlus Drug Information. Last revised 10/15/2025. https://medlineplus.gov/druginfo/meds/a681004.html
6. National Center for Complementary and Integrative Health. Melatonin: What You Need To Know. https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know
7. Kanno S, et al. Melatonin protects on toxicity by acetaminophen but not on pharmacological effects in mice. Biol Pharm Bull. 2006;29(3):472-6. doi:10.1248/bpb.29.472
8. Watkins PB, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87-93. doi:10.1001/jama.296.1.87
9. Yang X, et al. Kava extract, an herbal alternative for anxiety relief, potentiates acetaminophen-induced cytotoxicity in rat hepatic cells. Phytomedicine. 2011;18(7):592-600. doi:10.1016/j.phymed.2011.02.006
10. Teschke R. Kava hepatotoxicity--a clinical review. Ann Hepatol. 2010;9(3):251-65. https://pubmed.ncbi.nlm.nih.gov/20720265/
11. Abebe W. Herbal medication: potential for adverse interactions with analgesic drugs. J Clin Pharm Ther. 2002;27(6):391-401. doi:10.1046/j.1365-2710.2002.00444.x
12. Björnsson HK, et al. Ashwagandha-induced liver injury: A case series from Iceland and the US Drug-Induced Liver Injury Network. Liver Int. 2020;40(4):825-829. doi:10.1111/liv.14393
13. Philips CA, et al. Ashwagandha-induced liver injury-A case series from India and literature review. Hepatol Commun. 2023;7(10). doi:10.1097/HC9.0000000000000270
14. Halegoua-DeMarzio D, et al. Liver Injury Associated with Turmeric-A Growing Problem: Ten Cases from the Drug-Induced Liver Injury Network [DILIN]. Am J Med. 2023;136(2):200-206. doi:10.1016/j.amjmed.2022.09.026 Our study summary.
15. Smilkstein MJ, et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988;319(24):1557-62. doi:10.1056/NEJM198812153192401
16. Licata A, et al. N-Acetylcysteine for Preventing Acetaminophen-Induced Liver Injury: A Comprehensive Review. Front Pharmacol. 2022;13:828565. doi:10.3389/fphar.2022.828565
17. Richie JP, et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr. 2015;54(2):251-63. doi:10.1007/s00394-014-0706-z Our study summary.
18. Li D, et al. Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism. Cell Host Microbe. 2024;32(1):48-62.e9. doi:10.1016/j.chom.2023.11.006
19. von Bahr C, et al. Fluvoxamine but not citalopram increases serum melatonin in healthy subjects-- an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin. Eur J Clin Pharmacol. 2000;56(2):123-7. doi:10.1007/s002280050729
20. Foster BC, et al. Melatonin Interaction Resulting in Severe Sedation. J Pharm Pharm Sci. 2015;18(2):124-31. doi:10.18433/j3ss35
21. Cruz-Sanabria F, et al. Optimizing the Time and Dose of Melatonin as a Sleep-Promoting Drug: A Systematic Review of Randomized Controlled Trials and Dose-Response Meta-Analysis. J Pineal Res. 2024;76(5):e12985. doi:10.1111/jpi.12985
22. Ferracioli-Oda E, et al. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013;8(5):e63773. doi:10.1371/journal.pone.0063773 Our study summary.
23. Lee EK, et al. Controlled-release oral melatonin supplementation for hypertension and nocturnal hypertension: A systematic review and meta-analysis. J Clin Hypertens (Greenwich). 2022;24(5):529-535. doi:10.1111/jch.14482
24. Demirhan Kayacik A, et al. Effects of melatonin intake on depression and anxiety in postmenopausal women: a systematic review and meta-analysis of randomised controlled trials. Arch Womens Ment Health. 2024;27(2):265-273. doi:10.1007/s00737-023-01395-0