Venlafaxine Diphenhydramine

CYP2D6 is the major enzyme involved in the metabolism of venlafaxine, and diphenhydramine alters the disposition of venlafaxine, increasing plasma concentrations and predisposing to cardiovascular adverse effects (16). 

Lessard E, Yessine MA, Hamelin BA, Gauvin C, Labbe L, O Hara G, LeBlanc J, Turgeon J. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol 2001 21(2) 175-84. 

This drug significantly increases the plasma concentration of venlafaxine. The oral clearance of diphenhydramine, in both extensive and reduced metabolizers, is reduced by 6% and 18%, respectively. 

Theoretically the metabolism of venlafaxine may be inhibited by CYP2D6 inhibitors or substrates such as diphenhydramine, melperone, quinidine or thioridazine. CYP3A4 inhibitors such as ketoconazole may also have some effect. An isolated case describes a hypertensive crisis associated with venlafaxine and di-sulfiram. The manufacturers predict that the use of triptans with venlafaxine may have additive effects on serotonin, which could lead to the serotonin syndrome. 

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