Caffeine + Diphenhydramine: Caution

Caffeine+Diphenhydramine

Caution

These combinations are not usually physically harmful, but may produce undesirable effects. Use caution.

Note: Caffeine as a stimulant may mask some negative side effects of DPH, leading to delusions of sobriety, which has additional concerns 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 cardiovascular issues such as complex tachycardia. The combination may increase anxiety levels and risks of thought loops at higher dosages, in addition to increasing each other's negative side effects. Medical dosages are reported to not be a concern.

Substances in these categories

Caffeine

Diphenhydramine

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)
Caffeine. In StatPearls. StatPearls Publishing. — Evans, J.; Richards, J. R.; Battisti, A. S. (2025)
Wide complex tachycardia secondary to massive diphenhydramine overdose: a case report. Journal of Emergency and Critical Care Medicine, 6(0). — McAtee, K. J.; Brillhart, D.; Barbuto, A. F.; Hiller, H. M. (2022)
Caffeine Toxicity. In StatPearls. StatPearls Publishing. — Murray, A.; Traylor, J. (2025)
Pharmacology of Caffeine. In Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations. National Academies Press (US). — Institute of Medicine (US) Committee on Military Nutrition Research (2001)
Diphenhydramine. In StatPearls. StatPearls Publishing. — Sicari, V.; Patel, P.; Zabbo, C. P. (2025)
Effects of caffeine and diphenhydramine on auditory evoked cortical potentials. Perceptual and Motor Skills, 76(3 Pt 1), 707–715. — Tharion, W. J.; Kobrick, J. L.; Lieberman, H. R.; Fine, B. J. (1993)

Interaction Matrix

Tap or hover on any cell to see the interaction. Click to view details.

✓+Synergy

✓Low Risk

↓Decrease

!Caution

⚠Unsafe

☠Dangerous


	!	!	↓	⚠	☠	↓	✓	!	⚠	⚠	?	✓+	!	↓	✓+	☠	✓+	!	!	?	!	✓+	!	!	✓+	✓	☠	?	↓	⚠
!		!	↓	!	☠	↓	✓	!	!	✓+	?	✓+	!	↓	✓+	☠	✓+	!	✓+	?	!	✓+	✓+	!	✓+	✓	✓+	✓+	↓	⚠
!	!		↓	⚠	☠	↓	✓	!	⚠	⚠	?	✓+	!	↓	✓+	?	✓+	☠	!	?	!	✓+	✓+	!	✓+	✓	☠	!	↓	⚠
↓	↓	↓		!	!	☠	✓	✓+	⚠	☠	☠	↓	↓	☠	☠	?	↓	⚠	!	?	↓	↓	☠	↓	!	☠	⚠	?	!	☠
⚠	!	⚠	!		☠	↓	!	!	!	⚠	!	!	⚠	!	!	✓	!	☠	!	?	!	!	!	⚠	✓+	!	⚠	⚠	✓	☠
☠	☠	☠	!	☠		↓	!	!	☠	☠	?	✓+	☠	↓	✓+	?	✓+	☠	☠	?	☠	✓+	☠	☠	✓+	✓	☠	?	☠	☠
↓	↓	↓	☠	↓	↓		↓	↓	↓	!	⚠	↓	↓	☠	!	?	↓	✓+	↓	?	↓	↓	!	↓	↓	☠	⚠	?	✓	☠
✓	✓	✓	✓	!	!	↓		✓	!	!	!	✓	!	✓	✓	?	✓	✓	!	!	✓	✓	✓	!	✓	✓	!	⚠	✓	✓
!	!	!	✓+	!	!	↓	✓		!	✓+	?	!	!	✓+	✓+	?	!	✓+	✓+	?	!	!	✓+	!	✓+	✓+	✓+	✓+	✓	✓+
⚠	!	⚠	⚠	!	☠	↓	!	!		⚠	!	!	⚠	!	!	↓	!	☠	!	?	!	!	!	⚠	✓+	☠	⚠	⚠	✓	☠
⚠	✓+	⚠	☠	⚠	☠	!	!	✓+	⚠		⚠	✓+	⚠	☠	✓+	☠	✓+	☠	☠	☠	✓+	✓+	⚠	⚠	✓+	☠	☠	⚠	☠	☠
?	?	?	☠	!	?	⚠	!	?	!	⚠		!	!	☠	☠	!	!	⚠	?	☠	!	!	☠	!	?	⚠	?	⚠	☠	☠
✓+	✓+	✓+	↓	!	✓+	↓	✓	!	!	✓+	!		✓+	↓	✓+	☠	✓+	✓+	✓+	✓+	✓+	✓+	✓+	✓+	✓+	✓	✓+	✓+	↓	⚠
!	!	!	↓	⚠	☠	↓	!	!	⚠	⚠	!	✓+		↓	✓+	☠	✓+	!	!	!	!	✓+	!	!	✓+	✓	⚠	!	↓	⚠
↓	↓	↓	☠	!	↓	☠	✓	✓+	!	☠	☠	↓	↓		☠	?	↓	✓+	!	!	↓	↓	☠	↓	!	☠	☠	☠	✓	☠
✓+	✓+	✓+	☠	!	✓+	!	✓	✓+	!	✓+	☠	✓+	✓+	☠		✓	✓+	!	✓+	?	✓+	✓+	✓+	✓+	✓+	☠	✓+	!	✓	☠
☠	☠	?	?	✓	?	?	?	?	↓	☠	!	☠	☠	?	✓		☠	?	☠	?	☠	☠	☠	☠	✓	?	?	?	✓	☠
✓+	✓+	✓+	↓	!	✓+	↓	✓	!	!	✓+	!	✓+	✓+	↓	✓+	☠		↓	✓+	!	✓+	✓+	✓+	✓+	✓+	✓	✓+	!	↓	⚠
!	!	☠	⚠	☠	☠	✓+	✓	✓+	☠	☠	⚠	✓+	!	✓+	!	?	↓		☠	?	!	✓+	⚠	!	✓	!	☠	?	☠	☠
!	✓+	!	!	!	☠	↓	!	✓+	!	☠	?	✓+	!	!	✓+	☠	✓+	☠		☠	✓+	✓+	!	!	✓+	✓	⚠	⚠	↓	☠
?	?	?	?	?	?	?	!	?	?	☠	☠	✓+	!	!	?	?	!	?	☠		?	✓+	?	?	?	!	?	⚠	?	☠
!	!	!	↓	!	☠	↓	✓	!	!	✓+	!	✓+	!	↓	✓+	☠	✓+	!	✓+	?		✓+	✓+	!	✓+	✓	✓+	!	↓	⚠
✓+	✓+	✓+	↓	!	✓+	↓	✓	!	!	✓+	!	✓+	✓+	↓	✓+	☠	✓+	✓+	✓+	✓+	✓+		✓+	✓+	✓+	✓	✓+	✓+	↓	⚠
!	✓+	✓+	☠	!	☠	!	✓	✓+	!	⚠	☠	✓+	!	☠	✓+	☠	✓+	⚠	!	?	✓+	✓+		!	✓+	☠	!	!	!	☠
!	!	!	↓	⚠	☠	↓	!	!	⚠	⚠	!	✓+	!	↓	✓+	☠	✓+	!	!	?	!	✓+	!		✓+	✓	✓+	☠	↓	⚠
✓+	✓+	✓+	!	✓+	✓+	↓	✓	✓+	✓+	✓+	?	✓+	✓+	!	✓+	✓	✓+	✓	✓+	?	✓+	✓+	✓+	✓+		!	✓+	!	✓	!
✓	✓	✓	☠	!	✓	☠	✓	✓+	☠	☠	⚠	✓	✓	☠	☠	?	✓	!	✓	!	✓	✓	☠	✓	!		!	☠	✓	☠
☠	✓+	☠	⚠	⚠	☠	⚠	!	✓+	⚠	☠	?	✓+	⚠	☠	✓+	?	✓+	☠	⚠	?	✓+	✓+	!	✓+	✓+	!		?	⚠	☠
?	✓+	!	?	⚠	?	?	⚠	✓+	⚠	⚠	⚠	✓+	!	☠	!	?	!	?	⚠	⚠	!	✓+	!	☠	!	☠	?		?	⚠
↓	↓	↓	!	✓	☠	✓	✓	✓	✓	☠	☠	↓	↓	✓	✓	✓	↓	☠	↓	?	↓	↓	!	↓	✓	✓	⚠	?		☠
⚠	⚠	⚠	☠	☠	☠	☠	✓	✓+	☠	☠	☠	⚠	⚠	☠	☠	☠	⚠	☠	☠	☠	⚠	⚠	☠	⚠	!	☠	☠	⚠	☠

Low Risk & Synergy

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.

Low Risk & No Synergy

Effects are additive. The combination is unlikely to cause any adverse or undesirable reaction beyond those that might ordinarily be expected from these drugs.

Low Risk & Decrease

One substance may reduce or counteract some of the effects of the other.

Caution

These combinations are not usually physically harmful, but may produce undesirable effects. Use caution.

Unsafe

There is considerable risk of physical harm when combining these substances. Use extreme caution.

Dangerous

These combinations are considered dangerous and should be avoided.

Unknown

The interactions between these substances are not well documented.