What is Doxepin?
Doxepin is a tricyclic compound that, at ultra-low doses (3-6 mg), functions as a highly selective histamine H1-receptor antagonist specifically FDA-approved for treating sleep maintenance insomnia in adults. 1
Mechanism of Action
At low doses (3-6 mg), doxepin works fundamentally differently than at antidepressant doses:
Selective H1-receptor antagonism: Doxepin binds with subnanomolar affinity to histamine H1 receptors, which promotes sleep initiation and maintenance without the broader tricyclic antidepressant effects seen at higher doses (25-50 mg). 2, 3
Dose-dependent receptor selectivity: The 3-6 mg dosing range provides selective antihistamine activity, while doses ≥20 mg shift toward broader tricyclic effects with increased adverse effects including anticholinergic burden. 1
Clinical Efficacy for Insomnia
Sleep Maintenance (Primary Indication)
Wake after sleep onset (WASO): Reduces WASO by 22-23 minutes compared to placebo (95% CI: 14-30 minutes), meeting clinical significance thresholds. 4, 1
Total sleep time (TST): Increases TST by 26-32 minutes compared to placebo (95% CI: 18-40 minutes) at both 3 mg and 6 mg doses. 4, 1
Sleep efficiency: Demonstrates clinically significant improvements in sleep efficiency at both dosing levels. 4, 1
Duration of effect: Sleep benefits extend into the last third of the night, addressing early morning awakening without next-day residual effects. 5
Sleep Onset (Limited Effect)
Latency to persistent sleep: Shows minimal effect on sleep onset, with only a 2.30-minute reduction at 3 mg (not clinically significant) and 5.29-minute reduction at 6 mg. 4
Recent pooled analysis: A 2025 study confirmed only a 22% improvement in sleep latency after a single dose, which was statistically but not clinically significant. 6
Guideline Recommendations and Place in Therapy
Treatment Algorithm Position
Second-line pharmacotherapy: The American Academy of Sleep Medicine recommends low-dose doxepin (3-6 mg) as a second-line option when Cognitive Behavioral Therapy for Insomnia (CBT-I) is insufficient, unavailable, or the patient is unable/unwilling to receive it. 1
Preferred for sleep maintenance: Specifically recommended for patients with predominant sleep maintenance insomnia rather than sleep onset difficulties. 1, 7
Comparative Effectiveness
Superior to zolpidem for maintenance: A head-to-head trial found doxepin 6 mg superior to zolpidem 5-10 mg for wake after sleep onset, total sleep time, and sleep efficiency. 1
Alternative first-line options: Eszopiclone 2-3 mg, temazepam 15 mg, suvorexant 10-20 mg, and zolpidem 10 mg are alternative first-line options depending on the specific insomnia phenotype. 1
Safety Profile
Adverse Effects
Comparable to placebo: The safety profile at 3-6 mg doses is comparable to placebo in clinical trials. 1, 7
Somnolence: Mild increase in somnolence at 6 mg dose (the most common adverse effect). 4, 1
No next-day impairment: Unlike higher antidepressant doses, low-dose doxepin produces minimal next-day sedation, cognitive impairment, or psychomotor effects. 5, 3
Dependence and Withdrawal
No physical dependence: Studies up to 12 weeks showed no evidence of tolerance, physical dependence, or rebound insomnia after withdrawal. 2, 3
Non-controlled substance: Unlike benzodiazepines and Z-drugs, doxepin at these doses has no addiction potential. 1
Special Populations
Elderly Patients (≥65 years)
Preferred agent: Doxepin 3 mg is one of the safest choices for elderly patients due to minimal fall risk and cognitive impairment compared to benzodiazepines. 1, 5
Three studies in elderly: Of five major trials, three (n=571) were conducted specifically in older adults, demonstrating sustained efficacy and safety. 5
Patients on Corticosteroids (Context-Specific)
For patients on dexamethasone or other corticosteroids experiencing insomnia:
Addresses corticosteroid-induced insomnia: The sleep maintenance benefits make doxepin particularly suitable for corticosteroid-induced insomnia, which typically manifests as difficulty staying asleep and early morning awakening. 1, 7
Dosing: Start with 3 mg taken 30 minutes before bedtime; may increase to 6 mg if insufficient response after 1-2 weeks. 1, 7
Duration: Use the lowest effective dose for the shortest duration possible, with regular follow-up to assess continued need. 1, 7
Important Clinical Caveats
When NOT to Use Doxepin
Primary sleep onset insomnia: Doxepin has minimal effect on sleep latency; consider ramelteon 8 mg or zaleplon instead. 4, 1
Patients with depression and insomnia: A 2014 retrospective analysis found low-dose doxepin did NOT improve sleep onset or maintenance in patients with major depressive disorder, contrasting with results in primary insomnia. 8
Avoid higher doses: Doses ≥20 mg represent a shift away from selective H1 antagonism and are NOT recommended for insomnia due to increased adverse effects. 1