Can tolerance develop to Benadryl (diphenhydramine)?

Medical Advisory BoardAll articles are reviewed for accuracy by our Medical Advisory Board
Educational purpose only • Exercise caution as content is pending human review
Article Review Status
Submitted
Under Review
Approved

Last updated: June 7, 2025View editorial policy

Personalize

Help us tailor your experience

Which best describes you? Your choice helps us use language that's most understandable for you.

From the Research

Yes, tolerance can develop to Benadryl (diphenhydramine) with regular use, particularly affecting its sedative properties. People who take this antihistamine frequently may notice diminished effects over time, requiring higher doses to achieve the same effect. This occurs because the body adapts to the drug's presence, with brain receptors becoming less responsive to its effects. The development of tolerance is most noticeable with diphenhydramine's sedative effects rather than its antihistamine properties. For this reason, diphenhydramine is not recommended for long-term use as a sleep aid, and most healthcare providers suggest limiting its use to short periods (generally less than two weeks) 1.

Key Points to Consider

  • Tolerance to diphenhydramine can lead to reduced efficacy, necessitating higher doses or alternative treatments.
  • The sedative effects of diphenhydramine are more prone to tolerance development compared to its antihistamine properties.
  • Regular use of diphenhydramine for sleep or allergies may result in diminished effectiveness over time.
  • Alternative medications, such as second-generation antihistamines, may be more suitable for long-term management due to their favorable side-effect profiles and efficacy, as suggested by recent studies 2.

Recommendations for Clinical Practice

  • Limit the use of diphenhydramine to short periods (less than two weeks) to minimize the risk of tolerance development.
  • Consider alternative antihistamines or treatments for long-term management of allergies or sleep disorders.
  • Be aware of the potential for rebound effects when stopping diphenhydramine after regular use, particularly if it was used as a sleep aid.

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

Have a follow-up question?

Our Medical A.I. is used by practicing medical doctors at top research institutions around the world. Ask any follow up question and get world-class guideline-backed answers instantly.