These combinations are not usually physically harmful, but may produce undesirable effects. Use caution.
Note: There is a concern of serotonin syndrome at higher dosages of this combination. Caution is recommended in restricting diphenhydramine to medical dosages (25-50mg). Lithium and diphenhydramine both have concerns of QT prolongation which may be increased when taken in combination; risks increase due to a variety of factors such as the health of the user and drug dosages. Additionally, the combination may increase each drug's side effects, such as dizziness and loss of consciousness.
Substances in these categories
Diphenhydramine
Lithium
Sources
- Diphenhydramine: It is time to say a final goodbye. World Allergy Organization Journal, 18(2), 101027. (2025) — Clark, J. H., Meltzer, E. O., & Naclerio, R. M.
- Clinical Relevance and Management of Drug‐Related QT Interval Prolongation. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 23(7), 881–908. (2003) — Crouch, M. A., Limon, L., & Cassano, A. T.
- QT Prolonging Drugs. In StatPearls. StatPearls Publishing. (2025) — Farzam, K., & Tivakaran, V. S.
- Drug Interactions with Lithium: An Update. Clinical Pharmacokinetics, 55(8), 925–941. (2016) — Finley, P. R.
- Efficacy, safety and tolerability of combined administration of lithium and selective serotonin reuptake inhibitors: a review of the current evidence. International Clinical Psychopharmacology, 15(4), 197–206. (2000) — Hawley, C. J., Loughlin, P. J., Quick, S. J., Gale, T. M., Sivakumaran, T., Hayes, J., & McPhee, S.
- Diphenhydramine induced QT prolongation and torsade de pointes: An uncommon effect of a common drug. Cardiology Journal, 17(5), 509–511. (2010) — Husain, Z., Hussain, K., Nair, R., & Steinman, R.
- Serotonin Syndrome Presenting with Concomitant Tramadol and Diphenhydramine Use: A Case Report of an Unlikely Side-Effect. Cureus. (2018) — Khan, S., Saud, S., Khan, I., Asif, M., Ismail, O., Salam, A., Yang, T. J., & Norville, K. J.
- 5-HT1B Receptors: A Novel Target for Lithium: Possible Involvement in Mood Disorders. Neuropsychopharmacology, 21(4), 530–541. (1999) — Massot, O., Rousselle, J.-C., Fillion, M.-P., Januel, D., Plantefol, M., & Fillion, G.
- Lithium‐induced electrocardiographic changes: A complete review. Clinical Cardiology, 40(12), 1363–1367. (2017) — Mehta, N., & Vannozzi, R.
- Drug Interactions with Lithium: A Guide for Clinicians. CNS Drugs, 11(1), 41–48. (1999) — Müller-Oerlinghausen, B.
- Serotonin Syndrome Associated With High-dose Diphenhydramine Use Complicating Abdominoplasty and Mastopexy. Plastic and Reconstructive Surgery - Global Open, 13(3), e6634. (2025) — Rosenberg, A. E., Wang, R., & Rosenberg, M. H.
- Effects of Toxic Lithium Levels on ECG—Findings from the LiSIE Retrospective Cohort Study. Journal of Clinical Medicine, 11(19), 5941. (2022) — Truedson, P., Ott, M., Lindmark, K., Ström, M., Maripuu, M., Lundqvist, R., & Werneke, U.
Interaction Matrix
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These drugs work together to cause an effect greater than the sum of its parts. They aren't likely to cause an adverse or undesirable reaction when used carefully.
Effects are additive. The combination is unlikely to cause any adverse or undesirable reaction beyond those that might ordinarily be expected from these drugs.
One substance may reduce or counteract some of the effects of the other.
These combinations are not usually physically harmful, but may produce undesirable effects. Use caution.
There is considerable risk of physical harm when combining these substances. Use extreme caution.
These combinations are considered dangerous and should be avoided.
The interactions between these substances are not well documented.