There is considerable risk of physical harm when combining these substances. Use extreme caution.
Note: The combination is reported to reduce the side effects of each drug and potentiate many of the recreational effects. There is a significant risk of serotonin syndrome, increased delirium, CNS depression, cognitive inhibition, risk of physical injury, hyperthermia, mania, paranoia, and psychosis, especially at higher dosages. There is an additional concern of tachycardia, hypertension, and in extreme cases, heart failure. Diphenhydramine is reported to inhibit the CYP2D6 enzyme which can increase levels of DXM. Medical dosages are not reported to be a concern. Caution is strongly recommended with this combination.
Substances in these categories
Dextromethorphan
Diphenhydramine
Sources
- The antitussive effect of dextromethorphan in relation to CYP2D6 activity. British Journal of Clinical Pharmacology, 48(3), 382–387. — Abdul Manap, Wright, Gregory, Rostami‐Hodjegan, Meller, Kelm, Lennard, Tucker, & Morice. (1999)
- Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 35(1), 72–78. — Akutsu, T., Kobayashi, K., Sakurada, K., Ikegaya, H., Furihata, T., & Chiba, K. (2007)
- 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)
- Mind Expansion: An Experience with DXM & Diphenhydramine (exp33999). Erowid.org. — Crazy Steve. (2004)
- Paradoxical Excitation on Diphenhydramine May Be Associated with Being a CYP2D6 Ultrarapid Metabolizer: Three Case Reports. CNS Spectrums, 13(2), 133–135. — De Leon, J., & Nikoloff, D. M. (2008)
- Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clinical Pharmacology & Therapeutics, 67(5), 466–477. — Hamelin, B. (2000a)
- First Overdose: An Experience with DXM & Diphenhydramine (exp116238). Erowid.org. — HANS. (2022)
- Abuse liability and stimulant properties of dextromethorphan and diphenhydramine combinations in rats. Psychopharmacology, 172(3), 277–282. — Jun, J. H., Thorndike, E. B., & Schindler, C. W. (2004a)
- The DXM and DPH combination, broken down and described — Josie Kins
- Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. Journal of Clinical Psychopharmacology, 21(2), 175–184. — Lessard, E., Yessine, M. A., Hamelin, B. A., Gauvin, C., Labbé, L., O’Hara, G., LeBlanc, J., & Turgeon, J. (2001)
- DXM & DPH — Psychonaut Wiki
- Dextromethorphan abuse: Clinical effects and management. Journal of the American Pharmacists Association, 49(2), e20–e27. — Romanelli, F., & Smith, K. M. (2009)
- Dextromethorphan-induced serotonin syndrome. Clinical Toxicology, 46(8), 771–773. — Schwartz, A. R., Pizon, A. F., & Brooks, D. E. (2008)
- Delirium Visions and Teleportation: An Experience with DXM & Diphenhydramine (exp113902). Erowid.org. — The Salvia Shaman. (2025)
- The "right way" to do DXM + DPH combo, from an experienced user — u/syrup_ben_goed (n.d.)
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.