These combinations are considered dangerous and should be avoided.
Note: There is a high risk of serotonin syndrome from this combination. Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. MXE has a high likelihood of increasing DPH's deliriant effects at higher dosages and can greatly increase the risk of injury, mania, and psychosis. Medical dosages are unlikely to be of concern.
Substances in these categories
Diphenhydramine
MXE
Sources
- Diphenhydramine: It is time to say a final goodbye. World Allergy Organization Journal, 18(2), 101027. — Clark, J. H., Meltzer, E. O., & Naclerio, R. M. (2025)
- Serotonin Syndrome and Other Serotonergic Disorders: Table 1. Pain Medicine, 4(1), 63–74. — Ener, R. A., Meglathery, S. B., Decker, W. A. V., & Gallagher, R. M. (2003)
- New insights into methoxetamine mechanisms of action: Focus on serotonergic 5-HT2 receptors in pharmacological and behavioral effects in the rat. Experimental Neurology, 345, 113836. — Marti, M., Talani, G., Miliano, C., Bilel, S., Biggio, F., Bratzu, J., Diana, M., De Luca, M. A., & Fattore, L. (2021)
- The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor. PLoS ONE, 8(3), e59334. — Roth, B. L., Gibbons, S., Arunotayanun, W., Huang, X.-P., Setola, V., Treble, R., & Iversen, L. (2013)
- Characterization of Diphenhydramine-Related Accidental Overdose Deaths. Academic Forensic Pathology, 5(1), 105–115. — Varghese, E., Abate, M. A., Hu, L., Kaplan, J., Kraner, J., Long, D. L., Sorg, M., Mock, A., Greenwald, M., & Andrew, T. (2015)
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.