What are the effects of taking Benadryl (diphenhydramine) and hydroxyzine together?

Taking Benadryl and Hydroxyzine Together: Risks and Concerns

Taking diphenhydramine (Benadryl) and hydroxyzine together is not recommended due to the significant risk of additive sedation, anticholinergic effects, and cognitive impairment that could lead to dangerous outcomes including respiratory depression and falls.

Understanding the Medications

Both medications are first-generation antihistamines with similar mechanisms of action:

• Diphenhydramine (Benadryl):

  • First-generation H1-receptor antagonist
  • Significant sedative potential (50% of users) 1
  • Strong anticholinergic effects
  • Crosses blood-brain barrier readily

• Hydroxyzine (Atarax/Vistaril):

  • First-generation H1-receptor antagonist
  • Very high sedative potential (80% of users) 1
  • Strong anticholinergic effects
  • Crosses blood-brain barrier readily

Risks of Combination Use

1. Additive Sedation and CNS Depression

• Both medications cause significant sedation individually
• Combined use dramatically increases sedation risk 2
• Potential for dangerous levels of central nervous system depression

2. Enhanced Anticholinergic Effects

• Combined anticholinergic burden increases risk of:
  • Dry mouth
  • Blurred vision
  • Urinary retention (especially in males with prostatic hypertrophy) 1
  • Constipation
  • Cognitive impairment
  • Delirium (particularly in elderly patients) 3

3. Cognitive and Performance Impairment

• Both medications individually impair cognitive processing 2
• Combined use would significantly worsen:
  • Reaction time
  • Decision-making ability
  • Coordination
  • Driving performance (1.5× higher risk of accidents) 1

4. Respiratory Concerns

• Risk of respiratory depression, particularly when combined with:
  • Other sedating medications
  • Opioids
  • Benzodiazepines
  • Alcohol 3

High-Risk Populations

The combination is particularly dangerous for:

1. Elderly patients:

   • More sensitive to anticholinergic effects
   • Higher risk of falls and cognitive impairment
   • Explicitly advised against by American Geriatrics Society 1

2. Patients with comorbidities:

   • Prostatic hypertrophy (increased urinary retention risk)
   • Glaucoma (risk of increased intraocular pressure)
   • Cognitive impairment (worsening confusion)
   • Cardiovascular disease (risk of tachycardia) 1

3. Those taking other CNS depressants:

   • Opioids
   • Benzodiazepines
   • Alcohol
   • Gabapentinoids 3

Alternative Approaches

If antihistamine therapy is needed:

• Use a single second-generation antihistamine instead (fexofenadine, loratadine, etc.) 4, 5

• Second-generation options have:

  • Similar efficacy for allergic symptoms
  • Minimal sedation (1-8% vs. 50-80%)
  • Minimal anticholinergic effects
  • Better safety profile 1

• If stronger antipruritic effect is needed: Hydroxyzine alone is significantly more potent (750-fold increase in histamine threshold) than diphenhydramine (10-fold increase) 6

If Already Combined

If someone has already taken both medications together:

• Monitor for excessive sedation and respiratory depression
• Avoid driving or operating machinery
• Avoid additional CNS depressants
• Seek medical attention if experiencing severe drowsiness, confusion, or difficulty breathing

Bottom Line

The combination of diphenhydramine and hydroxyzine represents redundant therapy with significantly increased risk. Modern antihistamine therapy strongly favors second-generation options that provide similar efficacy with dramatically improved safety profiles 4, 5.