These combinations are considered dangerous and should be avoided.
Note: Both drugs increase the risk of serotonin syndrome. While at medical dosages, this is unlikely to be of concern, recreational doses should be avoided. Diphenhydramine may increase tramadol’s seizure risk.
Substances in these categories
Diphenhydramine
Tramadol
Sources
- Diphenhydramine dose–response: a novel approach to determine triage thresholds. Clinical Toxicology, 48(8), 820–831. — Benson, B. E., Farooqi, M. F., Klein-Schwartz, W., Litovitz, T., Webb, A. N., Borys, D. J., Lung, D., Rutherfoord Rose, S., Aleguas, A., Sollee, D. R., & Seifert, S. A. (2010)
- Tramadol. In StatPearls. StatPearls Publishing. — Dhesi, M., Maldonado, K. A., Patel, P., & Maani, C. V. (2025)
- Clinical and patient characteristics associated with severe outcome in diphenhydramine toxicity. Clinical Toxicology, 59(10), 918–925. — Hughes, A. R., Lin, A., Hendrickson, R. G., & on behalf of Toxicology Investigator’s Consortium (ToxIC). (2021)
- Serotonin Syndrome Presenting with Concomitant Tramadol and Diphenhydramine Use: A Case Report of an Unlikely Side-Effect. Cureus. — Khan, S., Saud, S., Khan, I., Asif, M., Ismail, O., Salam, A., Yang, T. J., & Norville, K. J. (2018)
- Antihistamines as a common cause of new-onset seizures: a single-center observational study. Neurological Sciences: Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 42(6), 2505–2508. — Kim, H., Kim, S. H., & Kim, J. B. (2021)
- Inherent seizure susceptibility in patients with antihistamine-induced acute symptomatic seizure: a resting-state EEG analysis. Scientific Reports, 13(1), 9146. — Kim, H., Wang, I.-N., Park, J.-S., Kim, K.-T., Kong, J., Kim, J. B., & Kim, D.-J. (2023)
- Diphenhydramine overdose and serotonin syndrome. Psychiatry and Clinical Neurosciences, 66(3), 244–245. — Sanaei-Zadeh, H. (2012)
- Diphenhydramine. In StatPearls. StatPearls Publishing. — Sicari, V., Patel, P., & Zabbo, C. P. (2025)
Interaction Matrix
Tap or hover on any cell to see the interaction. Click to view details.
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.