I am an insomniac and all the sleep medications that I've been prescribed have eventually had no effect on me -- I built a tolerance to them. It's a dangerous thing because I don't want to take lots and lots of all sorts of sleeping pills to get to sleep -- that's unsafe.

I heard that Benadryl might be a good alternative. It currently has an impact on me, but will I eventually build a tolerance to it?


up vote 11 down vote accepted

First generation H1-antihistamines (such as diphenhydramine = Benadryl) are well known for their sedative effects explaining their limited use in patients with allergic rhinitis. Several pharmacological studies have shown that diphenhydramine crosses the blood brain barrier and produces CNS sedation.

Two studies have (partly) addressed your question regarding the loss in sedation efficacy over time. Both studies focused on daytime sleepiness (as this one of the side effects which prevents prescription of diphenhydramine in patients with allergic rhinitis) but the mechanisms of tolerance can probably be extended to diphenhydramine use against insomnia.

  • In the first study, participants receiving dimenhydrinate (an ethanolamine antihistamine that is metabolized to diphenhydramine and chlorotheophylline) were asked to assess their sleepiness while in parallel, psychomotor performance tests where conducted. Results showed a modest attenuation of subjective sedation and performance impairment after successive doses during a single day of drug exposure.
  • In the second study authors conducted a randomised double blind placebo controlled crossover study in 15 individuals. Here again, a tolerance to the drug was observed: sedative effects which were evident on the first day became indistinguishable from placebo by the end of 3 days of treatment.

Three possible mechanisms for the tolerance to diphenhydramine were suggested in the literature: behavioural adaptation (only if diphenhydramine was taken during the day for allergic rhinitis); (2) altered drug metabolism, e.g., increased clearance; or (3) altered neuropharmacological effect.

So according to current knowledge, there is evidence for tolerance of diphenhydramine over time.


  • Richardson G et al. Tolerance to Daytime Sedative Effects of H1 Antihistamines. Journal of Clinical Psychopharmacology. 22(5):511-515, October 2002.
  • Manning C et al. Central nervous system effects of meclizine and dimenhydrinate: evidence of acute tolerance to antihistamines. J Clin Pharmacol 1992; 32:996–1002.
  • Thank you very much! Do you know if it would help to take it in cycles? Like take it for two days and stop for a week, and take it for two days, and stop for a week? Would that work? Or would the tolerance still be there? Thanks again for such a thorough answer! Unfortunately, I don't have enough "reputation points" to vote up your answer, but I do so in spirit. haha. – Pills N Pillows Aug 20 '16 at 19:33
  • 2
    Hi! No problem. Well, I found the literature regarding diphenhydramine relatively sparse so it's difficult to say as nobody has tested the "cyclic administration" before (to my knowledge). I was wondering whether you have already seen a sleep specialist? This might also be a solution. Good luck, Best regards. M. Arrowsmith – M. Arrowsmith Aug 20 '16 at 19:52

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