NSTK · 01.2026Independent supplement reference
NutriStack
Edition 1.0Reviewed May 26, 2026

Doxepin

Prescription ·Strong evidence ·Reviewed May 2026

Doxepin is a tricyclic antidepressant used at higher doses for depression and anxiety and at very low doses for sleep-maintenance insomnia. Its pharmacology includes norepinephrine and serotonin reuptake inhibition plus strong histamine H1 antagonism, explaining sedation and anticholinergic adverse effects. Antidepressant-dose labeling carries the boxed warning for suicidal thoughts and behaviors in younger patients.

Evidence tier
Strong
Indexed sources
3 2013–2025
Interactions
4
Category
Prescription
Read the sources → Compare profiles
What it's good for
  • Treatment of major depressive disorder or anxiety at antidepressant doses2
  • Treatment of sleep-maintenance insomnia at low doses1,3
  • Reduction in nocturnal awakenings
What to watch for
  • Sedation
  • Somnolence
  • Dry mouth
  • Hypersensitivity to doxepin or other dibenzoxepines1,2
  • Concurrent use with an MAOI, linezolid, or intravenous methylene blue2

The bottom line

Evidence rating strong. Most-documented uses: treatment of major depressive disorder or anxiety at antidepressant doses, treatment of sleep-maintenance insomnia at low doses, reduction in nocturnal awakenings. 3 sources indexed (2013–2025), with 4 interaction records on file.

The science

How it works, mechanistically.

Core mechanism

At antidepressant doses, doxepin inhibits norepinephrine and serotonin reuptake and blocks muscarinic, histamine H1, and alpha-1 adrenergic receptors. At low insomnia doses, clinically relevant activity is primarily histamine H1 receptor antagonism, which promotes sleep maintenance. Tricyclic sodium-channel and anticholinergic effects are most concerning at higher doses, in overdose, and in patients with glaucoma, urinary retention, cardiac conduction disease, or interacting sedatives.1,2

Class
Tricyclic antidepressant and histamine H1 antagonist
Absorption
Best on an empty stomach
Dosing

Dosing & protocol.

Common range
Depression or anxiety: common target 75-150 mg/day orally, with individualized range up to 300 mg/day in selected patients. Insomnia: 3-6 mg orally within 30 minutes of bedtime, not within 3 hours of a meal.
Recommended form
Oral capsule or solution for depression/anxiety; low-dose tablet for insomnia

For insomnia dosing, avoid taking within 3 hours of a meal because food can delay absorption and increase next-day effects. Antidepressant doses may be taken with food if needed for tolerability.1,3

Safety

Full safety detail.

Side effects

  • Sedation
  • Somnolence
  • Dry mouth
  • Constipation
  • Blurred vision
  • Urinary retention
  • Weight gain
  • Orthostatic hypotension
  • QT prolongation or conduction effects in susceptible patients
  • Complex sleep behaviors with hypnotic use
  • Activation of mania or hypomania
  • Withdrawal symptoms if stopped abruptly

Contraindications

  • Hypersensitivity to doxepin or other dibenzoxepines1,2
  • Concurrent use with an MAOI, linezolid, or intravenous methylene blue2
  • Untreated narrow-angle glaucoma3
  • Severe urinary retention3
  • Avoid alcohol and other sedative-hypnotics with low-dose doxepin unless supervised
Interactions

Interaction records.

ModerateCaution

Melatonin

Melatonin can add to doxepin-related sedation and next-day impairment.

Recommendation: Use the lowest effective doses only with prescriber awareness; avoid alcohol and driving if impaired.

ModerateCaution

L-Theanine

L-Theanine may have calming or sedating effects that can add to doxepin.

Recommendation: Use cautiously and avoid combining before driving, working at heights, or using other sedatives.

SeriousCaution

5-HTP

At antidepressant doses, doxepin has serotonin reuptake effects; 5-HTP can increase serotonin synthesis.

Recommendation: Avoid 5-HTP with antidepressant-dose doxepin; discuss any use with the prescriber.

SeriousConflict

St. John's Wort

St. John's Wort can add serotonergic effects and alter metabolism of many drugs.

Recommendation: Avoid combining with doxepin unless directed by the prescriber.

Search all 4 interaction records for Doxepin →

Sources

Sources, by evidence tier.

Numbered references. Citations throughout the page link here.

Reviews & position papers

1
  • 1Doxepin for insomniaNeeds reviewNo linkKrystal AD et al. · Sleep Medicine Reviews · 2013

    Review summarizes low-dose doxepin efficacy for sleep maintenance and its histamine-mediated mechanism.

Reference material

2
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This page is educational. Do not start, stop, or change a supplement or medication based on it without checking with a qualified healthcare professional.

Use this with your stack

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NutriStack is an informational and organizational tool, not a medical service, and not a substitute for professional advice. Always consult a qualified healthcare professional before starting, stopping, or changing any supplement or medication.