These combinations are not usually physically harmful, but may produce undesirable effects. Use caution.
Note: Amphetamines as a stimulant may mask some of the negative side effects of DPH, leading to delusions of sobriety which has additional concern in states of delirium. The combination of stimulants will increase strain on the heart and may cause some physical discomfort, and has the chance to cause life-threatening cardiovascular issues. The combination may also increase each other's neurotoxicity at higher dosages. The combination may increase anxiety levels and risks of thought loops on higher dosages, in addition to increasing each others negative side effects. Medical and common dosages of each substances are reported to not be a concern. Additionally, it is suggested that DPH potentiates amphetamine psychomotor activation, in addition to other interactions such as potentiation through inhibition of CYP2D6 and histamine H1 and H2 receptors, among other alterations.
Substances in these categories
Amphetamines
Diphenhydramine
Sources
- Potential adverse effects of amphetamine treatment on brain and behavior: a review. Molecular Psychiatry, 14(2), 123–142 (2009) — Berman, S. M.; Kuczenski, R.; McCracken, J. T.; London, E. D.
- 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.
- Amphetamine. In StatPearls. StatPearls Publishing (2025) — Martin, D.; Le, J. K.
- Wide complex tachycardia secondary to massive diphenhydramine overdose: a case report. Journal of Emergency and Critical Care Medicine, 6 (2022) — McAtee, K. J.; Brillhart, D.; Barbuto, A. F.; Hiller, H. M.
- Methamphetamine and diphenhydramine effects on the rate of cognitive processing. Psychopharmacology (1978) — Mohs, R. C.; Tinklenberg, J. R.; Roth, W. T.; Kopell, B. S.
- Drug interaction between methamphetamine and antihistamines: behavioral changes and tissue concentrations of methamphetamine in rats. European Journal of Pharmacology, 505(1), 135–144 (2004) — Okuda, T.; Ito, Y.; Nakagawa, N.; Hishinuma, T.; Tsukamoto, H.; Iwabuchi, K.; Watanabe, T.; Kitaichi, K.; Goto, J.; Yanai, K.
- Diphenhydramine. In StatPearls. StatPearls Publishing (2025) — Sicari, V.; Patel, P.; Zabbo, C. P.
- The ugly side of amphetamines: short- and long-term toxicity of MDMA, methamphetamine and d-amphetamine. Biological Chemistry, 392(0) (2011) — Steinkellner, T.; Freissmuth, M.; Sitte, H. H.; Montgomery, T.
- Amphetamine Toxicity. In StatPearls. StatPearls Publishing (2025) — Vasan, S.; Murray, B. P.; Olango, G. J.
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.