CONTRAINDICATIONS
For all supplements, interactions with medications
should always be cross-referenced before use.
Oral melatonin is perceived as safe based on published reports, even in higher doses (1); however, specific instances may necessitate further diligence and clinical oversight.
Due to isolated reported incidents and theoretical risks, general healthcare guidance is advised around the concomitant use of melatonin with the following medication classes (1,2):
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Anticoagulant/antiplatelets
-
Anticonvulsants
-
Antidiabetes drugs
-
Anti-hypertensive drugs
-
Caffeine
-
CNS depressants
-
Cytochrome P540 substrates (i.e., caffeine, grapefruit, warfarin)
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Immunosuppressants
-
Oral contraceptives
Most of these interactions are based on a ‘safety-first model’; more research is warranted to determine the occurrence's severity and likelihood of occurrence.
Blood thinners
For example, melatonin may have a slight blood thinning effect, so it may be additive with anticoagulants (1,2) The primary study cited on this topic was done with healthy young men who were not on blood thinners. However, sixty minutes after administration of 3 mg of melatonin, lower levels of procoagulant factors were found in the bloodstream, directly correlating to the subject’s serum melatonin level (3). This finding highlights the need for additional studies in assessing whether this is a passing or sustained effect. Additionally, it would need to be considered what, if any, effect it would have on women and older populations and those taking this group of medications. Case reports have associated melatonin with increased bleeding in patients taking warfarin, possibly due to melatonin’s platelet aggregation or blood coagulation activity (4). As a result of this information, until further elucidation, caution is warranted for anyone on blood thinners, especially before surgery (4).
Anti-hypertensives
Another example is using melatonin with anti-hypertensives. Multiple studies point to reduced blood pressure in men and women diagnosed with hypertension and nocturnal hypertension when melatonin is administered (1,5,6). Therefore, clinicians should closely monitor blood pressure when administering melatonin with hypertensive medications. A study utilizing the antihypertension medication, nifedipine, showed competition between melatonin and the medication at the calcium channel, effectively making the medication less active and raising the blood pressure in these individuals (7).
Hypoglycemic agents
In animal and human studies, research has demonstrated that melatonin can reduce glucose and improve insulin sensitivity (8–10). In a 12-week study of obese individuals, 3 mg/day of melatonin significantly reduced glucose and insulin levels (p<0.05) (8). Despite the positive impact on reducing glucose and insulin, there are conflicting findings in this body of literature in which melatonin did not impact glucose levels (10). It is, therefore, clinically prudent to monitor glucose levels in patients when taking melatonin and diabetes medication to avoid hypoglycemia.
Cytochrome (CYP) substrates
Earlier research has identified that the majority of melatonin is metabolized through cytochrome (CYP) 1A2 (11,12), with lesser metabolic activity through CYP1A1, CYP1B1, and CYP2C19 (12,13). Therefore, medications that affect these enzymatic pathways will influence melatonin metabolism. Caution should be exercised when melatonin is taken with one or more medications; otherwise, adverse side effects (like extreme sedation) can result (14). For example, one of the most well-known interactions is melatonin with the anti-depressant medication, fluvoxamine. This pharmaceutical is a known inhibitor of CYP1A2 and can result in the potentiation of melatonin levels due to reducing its degradation (15). Similarly, caffeine is also metabolized through CYP1A2 and can increase melatonin levels (16).
General recommendations for interactions:
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Clinicians are advised to always check for drug-melatonin interactions before recommending this therapy.
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Given its over-arching safety profile of melatonin, rather than avoiding melatonin supplementation when its use is indicated, it is advisable to approach the implementation of melatonin conservatively and with clinical reasoning.
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Research on melatonin supports the lowest, physiological dose for the shortest period of time.
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Consider using lower doses of melatonin for individuals on medications, routinely monitor the patient, including labs, when necessary.
Possible drug-melatonin interactions
Drug Class:
Anticoagulants/
Antiplatelets
Examples of medications:
apixaban
coumadin
rivaroxaban
warfarin
Possible Mechanism of Action for Interaction:
Theoretically, melatonin has possible anticoagulant activity or platelet aggregation activity, increasing risk of bleeding. Known interactions are isolated to limited number of case reports/studies.
Citation:
(1,3,4,17)
Drug Class:
Anticonvulsants
Examples of medications:
carbamazepine
gabapentin
lamotrigine
phenytoin
valproic acid
Possible Mechanism of Action for Interaction:
Melatonin has similar hepatic clearance pathways.
May decrease the effectiveness of medication and seizure threshold.
Citation:
(18)
Drug Class:
Antidiabetics
Examples of medications:
acarbose
metformin
pioglitazone
sitagliptin
sulfonylureas
Possible Mechanism of Action for Interaction:
Reduction in inflammatory pathways and oxidative stress. Safety based interaction given findings regarding the impact melatonin may have on lowering glucose and insulin, resulting in hypoglycemia.
Citation:
(8,9)
Drug Class:
Anti-hypertensives
Examples of medications:
lisinopril
losartan
nifedipine
propranolol
Possible Mechanism of Action for Interaction:
Possible competition at calcium channel.
Citation:
(1,5–7)
Drug Class:
Caffeine
Examples of medications:
caffeine
Possible Mechanism of Action for Interaction:
Caffeine and melatonin are metabolized through CYP1A2, causing possible reduction of melatonin secretion/increase in melatonin levels in the blood.
Citation:
(19–21)
Drug Class:
CNS Depressants (sedatives, tranquilizers, and hypnotics)
Examples of medications:
alcohol
alprazolam
clonazepam
diazepam
eszopiclone
lorazepam
zolpidem
Possible Mechanism of Action for Interaction:
Theoretically, melatonin is likely additive as hypnotic.
Similar metabolism pathways in liver.
Citation:
(14)
Drug Class:
Oral Contraceptives
Examples of medications:
drospirenone/ethinyl estradiol
norethindrone/ethinyl estradiol
norgestimate/ethinyl estradiol
Possible Mechanism of Action for Interaction:
Oral contraceptives may increase melatonin levels.
Citation:
(22)
Drug Class:
CYP450/CYP1A2/
CYP2C19 substrates
Examples of medications:
Main examples:
caffeine
fluvoxamine
lidocaine
nortriptyline
SSRIs
theophylline
tizanidine
triamterene
Lesser extent: acetominophen amitriptyline cyclobenzaprine
naproxen
propranolol
warfarin
Possible Mechanism of Action for Interaction:
May decrease the metabolism of medication & melatonin resulting in higher blood levels of melatonin.
Citation:
(23–26)
Drug Class:
Immunosuppressants
Examples of medications:
drospirenone/ethinyl
estradiol
norethindrone/ethinyl
estradiol
norgestimate/ethinyl
estradiol
Possible Mechanism of Action for Interaction:
This is theoretical given melatonin’s ability to stimulate the immune system.
Citation:
(27)
In summary, while not a comprehensive listing, melatonin can interact or be influenced by pharmaceuticals, nutrients, or herbs with blood thinning, blood sugar-lowering, blood pressure reducing, anti-convulsing, sedative, anti-depressant, and/or immunosuppressive activities (28). Importantly, melatonin metabolism and activity can be potentially impacted by many dietary, supplemental, and pharmaceutical agents, all of which add to the fact that there is variability in an individual’s personalized response to this compound based on their dietary and medical context. Historically, due to the lack of safety data, melatonin supplementation was not recommended for pregnant or nursing women. However, there is some indication that melatonin supplementation may be of benefit during both these stages (29,30). Therefore, having these women consult with a health professional who understands the patient’s personalized needs is key. Similarly, people diagnosed with any disease should consult their health professionals and take it under medical supervision (28).
While there are many reasons to be concerned about interactions, there may also be a role for melatonin to offset the toxicity of certain drugs through its antioxidant activity (31,32). Thus, more research and clinical oversight into using supplemental melatonin are warranted.
Authors: Mona Fahioum, ND and Kim Ross, DCN
Reviewer: Deanna Minich, Ph.D.
Last updated: July 28, 2022
References
1. Scheer FAJL, Van Montfrans GA, Van Someren EJW, Mairuhu G, Buijs RM. Daily Nighttime Melatonin Reduces Blood Pressure in Male Patients with Essential Hypertension. Hypertension. 2004;43(2 I).
2. Cardinali DP, Golombek DA, Rosenstein RE, Brusco LI, Vigo DE. Assessing the efficacy of melatonin to curtail benzodiazepine/Z drug abuse. Vol. 109, Pharmacological Research. 2016.
3. Wirtz PH, Spillmann M, Bärtschi C, Ehlert U, Von Känel R. Oral melatonin reduces blood coagulation activity: A placebo-controlled study in healthy young men. J Pineal Res. 2008;44(2).
4. Hatfield J, Saad S, Housewright C. Dietary supplements and bleeding. Vol. 35, Baylor University Medical Center Proceedings. 2022.
5. Cagnacci A, Arangino S, Angiolucci M, Maschio E, Melis GB. Influences of melatonin administration on the circulation of women. Am J Physiol Regul Integr Comp Physiol. 1998;274(2 43-2).
6. Grossman E, Laudon M, Zisapel N. Effect of melatonin on nocturnal blood pressure: Meta-analysis of randomized controlled trials. Vasc Health Risk Manag. 2011;7(1).
7. Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: A 24-hour study. Br J Clin Pharmacol. 2000;49(5).
8. Sun H, Wang X, Chen J, Gusdon AM, Song K, Li L, et al. Melatonin treatment improves insulin resistance and pigmentation in obese patients with acanthosis nigricans. Int J Endocrinol. 2018;2018.
9. Pourhanifeh MH, Hosseinzadeh A, Dehdashtian E, Hemati K, Mehrzadi S. Melatonin: New insights on its therapeutic properties in diabetic complications. Vol. 12, Diabetology and Metabolic Syndrome. 2020.
10. Doosti-Irani A, Ostadmohammadi V, Mirhosseini N, Mansournia M, Reiter RJ, Kashanian M, et al. The Effects of Melatonin Supplementation on Glycemic Control: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Vol. 50, Hormone and Metabolic Research. 2018.
11. Facciolá G, Hidestrand M, Von Bahr C, Tybring G. Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. Eur J Clin Pharmacol. 2001;56(12).
12. Ma X, Idle JR, Krausz KW, Gonzalez FJ. Metabolism of melatonin by human cytochromes P450. Drug Metabolism and Disposition. 2005;33(4).
13. Huuhka K, Riutta A, Haataja R, Ylitalo P, Leinonen E. The effect of CYP2C19 substrate on the metabolism of melatonin in the elderly: A randomized, double-blind, placebo-controlled study. Methods Find Exp Clin Pharmacol. 2006;28(7).
14. Foster BC, Cvijovic K, Boon HS, Tam TW, Liu R, Murty M, et al. Melatonin interaction resulting in severe sedation. Journal of Pharmacy and Pharmaceutical Sciences. 2015;18(2).
15. Härtter S, Wang X, Weigmann H, Friedberg T, Arand M, Oesch F, et al. Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin. J Clin Psychopharmacol. 2001;21(2).
16. Ursing C, Wikner J, Brismar K, Röjdmark S. Caffeine raises the serum melatonin level in healthy subjects: An indication of melatonin metabolism by cytochrome P450(CYP)1A2. J Endocrinol Invest. 2003;26(5).
17. Cardinali DP. Melatonin: Clinical perspectives in neurodegeneration. Vol. 10, Frontiers in Endocrinology. 2019.
18. Wurtman RJ, Zhdanova II. Oral melatonin in neurologically disabled children. The Lancet. 1998;351(9120).
19. Härtter S, Nordmark A, Rose DM, Bertilsson L, Tybring G, Laine K. Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYPIA2 activity. Br J Clin Pharmacol. 2003;56(6).
20. Peuhkuri K, Sihvola N, Korpela R. Dietary factors and fluctuating levels of melatonin. Food Nutr Res. 2012;56(1).
21. Minich DM, Henning M, Darley C, Fahoum M, Schuler CB, Frame J. Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients [Internet]. 2022;14(19). Available from: https://www.mdpi.com/2072-6643/14/19/3934/htm
22. Cipolla-Neto J, Amaral FG, Soares JM, Gallo CC, Furtado A, Cavaco JE, et al. The Crosstalk between Melatonin and Sex Steroid Hormones. Neuroendocrinology. 2022;112(2).
23. Yeleswaram K, Vachharajani N, Santone K. Involvement of cytochrome P-450 isozymes in melatonin metabolism and clinical implications. Vol. 26, Journal of Pineal Research. 1999.
24. Faber MS, Jetter A, Fuhr U. Assessment of CYP1A2 activity in clinical practice: Why, how, and when? Vol. 97, Basic and Clinical Pharmacology and Toxicology. 2005.
25. Härtter S, Grözinger M, Weigmann H, Röschke J, Hiemke C. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin Pharmacol Ther. 2000;67(1).
26. von Bahr C, Ursing C, Yasui N, Tybring G, Bertilsson L, Röjdmark S. Fluvoxamine but not citalopram increases serum melatonin in healthy subjects - an indication that cytochrome P 450 CYP1A2 and CYP2C19 hydroxylate melatonin. Eur J Clin Pharmacol. 2000 May 17;56(2):123–7.
27. Lissoni P, Barni S, Mandalà M, Ardizzoia A, Paolorossi F, Vaghi M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer. 1999;35(12).
28. Therapeutic Research [Internet]. [cited 2022 Jul 30]. Melatonin. Available from: https://naturalmedicines.therapeuticresearch.com/
29. Vine T, Brown GM, Frey BN. Melatonin use during pregnancy and lactation: A scoping review of human studies. Vol. 44, Brazilian Journal of Psychiatry. 2022.
30. Verteramo R, Pierdomenico M, Greco P, Milano C. The Role of Melatonin in Pregnancy and the Health Benefits for the Newborn. Biomedicines. 2022 Dec 14;10(12):3252.
31. Raza Z, Naureen Z. Melatonin ameliorates the drug induced nephrotoxicity: Molecular insights. Vol. 40, Nefrologia. 2020.
32. Shaki F, Ashari S, Ahangar N. Melatonin can attenuate ciprofloxacin induced nephrotoxicity: Involvement of nitric oxide and TNF-α. Biomedicine and Pharmacotherapy. 2016;84.