Are quetiapine and promethazine safe for treating insomnia in a patient with chronic alcohol use disorder?

Safety of Quetiapine and Promethazine for Insomnia in Patients with Alcohol Use Disorder

Neither quetiapine nor promethazine should be used for insomnia in a patient with chronic alcohol use disorder. Both medications carry unacceptable risks in this population and lack evidence supporting their use for sleep disturbance.

Why Quetiapine Should Be Avoided

The American Academy of Sleep Medicine explicitly warns against off-label use of quetiapine for insomnia due to weak efficacy evidence and significant adverse effects including neurological complications, weight gain, and metabolic dysregulation. 1

Specific Risks in Alcohol Use Disorder

• Quetiapine potentiates the cognitive and motor effects of alcohol according to FDA labeling, creating dangerous additive CNS depression when combined with alcohol or during early recovery 2
• A 2025 retrospective cohort study of 375 older adults found that low-dose quetiapine for insomnia was associated with significantly increased mortality (HR 3.1,95% CI 1.2-8.1), dementia (HR 8.1,95% CI 4.1-15.8), and falls (HR 2.8,95% CI 1.4-5.3) compared to trazodone 3
• While one 2004 retrospective study suggested quetiapine (25-200 mg nightly) improved abstinence rates in 30 alcohol-dependent veterans, this was a small, uncontrolled study with multiple confounders 4
• A larger 2008 VA database study found quetiapine monotherapy was associated with significantly higher risk of rehospitalization for alcohol dependence (HR 1.22,95% CI 1.06-1.41) compared to trazodone combination therapy 5

Guideline Position

• The American Academy of Sleep Medicine recommends quetiapine only as a fifth-line option, and only when patients have comorbid psychiatric conditions that would benefit from its primary antipsychotic action 6
• The 2025 Treatment of Insomnia During Alcohol Withdrawal guideline states quetiapine has only moderate evidence for insomnia in alcohol use disorder and should be reserved for cases with insufficient response to safer alternatives 7

Why Promethazine Should Be Avoided

The 2005 NIH State-of-Science Conference on Insomnia concluded there is no systematic evidence supporting antihistamine effectiveness for off-label insomnia treatment, and potential risks outweigh any presumed benefits. 6

Specific Concerns

• Promethazine has strong anticholinergic properties that cause confusion, urinary retention, and fall risk—particularly dangerous in patients with alcohol-related cognitive impairment 8
• FDA labeling explicitly warns that promethazine may increase, prolong, or intensify sedative effects of alcohol and other CNS depressants, requiring dose reduction of concurrent sedatives 8
• A 2025 BJPsych Bulletin article argues promethazine has no good evidence base for sleep, impedes cognitive-behavioral techniques that actually improve sleep, has underappreciated addictive potential, and an unacceptable side-effect profile 9
• The American Academy of Sleep Medicine explicitly recommends against over-the-counter antihistamines due to lack of efficacy data, anticholinergic effects, and tolerance development after only 3-4 days 1, 6

Recommended Treatment Algorithm for Insomnia in Alcohol Use Disorder

Step 1: First-Line Non-Pharmacologic Treatment

• Initiate Cognitive Behavioral Therapy for Insomnia (CBT-I) immediately as the standard of care before any medication. CBT-I demonstrates superior long-term outcomes with sustained benefits after discontinuation 6, 7
• CBT-I includes stimulus control therapy, sleep restriction therapy, relaxation techniques, and cognitive restructuring 6

Step 2: If Pharmacotherapy Is Necessary

The American Academy of Sleep Medicine recommends avoiding benzodiazepines and benzodiazepine receptor agonists (BzRAs) in alcohol use disorder due to cross-tolerance with alcohol and significant risks of dependence and relapse. 7

Safest Pharmacologic Options:

• Ramelteon 8 mg at bedtime is the preferred first-line agent because it has zero addiction potential, no cross-tolerance with alcohol, and is not a DEA-scheduled medication 6, 7
• Low-dose doxepin 3-6 mg is an alternative for sleep maintenance insomnia, with moderate-quality evidence showing 22-23 minute reduction in wake after sleep onset, minimal anticholinergic effects at hypnotic doses, and no abuse potential 6

Medications to Explicitly Avoid:

• Benzodiazepines (lorazepam, clonazepam, temazepam) are cross-tolerant with alcohol and carry high risk of dependence and relapse 7
• Z-drugs (zolpidem, eszopiclone, zaleplon) are also cross-tolerant with alcohol 7
• Antihistamines (diphenhydramine, promethazine) lack efficacy data and have problematic anticholinergic effects 7
• Trazodone has low-level evidence in alcohol use disorder and is not recommended by general insomnia guidelines 7
• Alcohol itself worsens insomnia and increases relapse risk 1, 7

Step 3: Implementation Strategy

• Use the lowest effective dose for the shortest duration possible 6
• Reassess after 1-2 weeks to evaluate efficacy on sleep parameters and daytime functioning 6
• Monitor for complex sleep behaviors and discontinue immediately if they occur 6
• Combine any pharmacotherapy with ongoing CBT-I, as medication should supplement—not replace—behavioral interventions 6, 7

Critical Safety Warnings

• The combination of quetiapine or promethazine with alcohol creates dangerous additive CNS depression, respiratory depression, cognitive impairment, and fall risk 8, 2
• Both medications lack evidence supporting their use specifically for insomnia in alcohol use disorder 7, 9
• The 2025 study showing increased mortality, dementia, and falls with low-dose quetiapine in older adults represents the highest-quality recent evidence against its use for insomnia 3