These combinations are considered dangerous and should be avoided.
Note: There is a high risk of serotonin syndrome at recreational dosages. Medical dosages are reported not to be a concern for the general population. The combination may increase each other's side effects, such as dizziness and drowsiness.
Substances in these categories
Diphenhydramine
SSRIs
Sources
- Diphenhydramine: It is time to say a final goodbye. The World Allergy Organization Journal, 18(2), 101027 (2025) — Clark, J. H., Meltzer, E. O., & Naclerio, R. M.
- Serotonin Syndrome and Other Serotonergic Disorders: Table 1. Pain Medicine, 4(1), 63-74 (2003) — Ener, R. A., Meglathery, S. B., Decker, W. A. V., & Gallagher, R. M.
- Serotonin Syndrome Presenting with Concomitant Tramadol and Diphenhydramine Use: A Case Report of an Unlikely Side-Effect. Cureus, 10(4), e2421 (2018) — Khan, S., Saud, S., Khan, I., Asif, M., Ismail, O., Salam, A., Yang, T. J., & Norville, K. J.
- The SSRIs: advantages, disadvantages and differences. Journal of Psychopharmacology, 9(2 Suppl), 163-178 (1995) — Lane, R., Baldwin, D., & Preskorn, S.
- Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence. Clinical Pharmacokinetics, 33(6), 454-471 (1997) — Sproule, B. A., Naranjo, C. A., Brenmer, K. E., & Hassan, P. C.
- Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clinical Pharmacokinetics, 24(3), 203-220 (1993) — van Harten, J.
- Characterization of Diphenhydramine-Related Accidental Overdose Deaths. Academic Forensic Pathology, 5(1), 105-115 (2015) — Varghese, E., Abate, M. A., Hu, L., Kaplan, J., Kraner, J., Long, D. L., Sorg, M., Mock, A., Greenwald, M., & Andrew, T.
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.