I've been reading the British National Formulary 65 (BNF-65) and it mentioned that in some, especially at higher dosages, sedating (first-generation) antihistamines, can produce paradoxical excitatory (or stimulating) effects and so I felt like asking the age-old question, "Why?" because as I hope is obvious by my questions I am fascinated by drug action and I felt there was no better place to ask this question than here on biology stackexchange.

  • $\begingroup$ A reference is needed for the paradoxical effects exhibited by certain H1-antagonists. I found only one which says: We describe three CYP2D6 UMs who reported paradoxical excitation on diphenhydramine. These cases suggest that in CYP2D6 UMs, diphenhydramine may be converted to a compound that causes excitation due to the abnormally high CYP2D6 activity... Although these are only three anecdotal cases of paradoxical excitation from three CYP2D6 UMs, the reports illustrate the need for larger, more formal studies .... Not a strong evidence. $\endgroup$ – WYSIWYG Dec 9 '14 at 6:59