Doxepin

Doxepin’s sedative effect is very pronounced. This can be helpful for patients struggling with sleep, but it also increases risks of drowsiness, falls, and confusion, especially in older adults (29, 30, 9). In addition to blocking histamine receptors, doxepin also:

• Inhibits the reuptake of serotonin and noradrenaline

• Blocks adrenergic, muscarinic, and histamine receptors (9, 29)

• Has emerging evidence of anti-inflammatory effects, which are being explored in pain and other conditions (16, 1)

This wide-ranging activity explains both its potential benefits and its diverse side effects.

Anticholinergic Burden

Doxepin has mild anticholinergic side effects, less than amitriptyline but still relevant. These can affect brain function, leading to:

• Memory loss

• Confusion or delirium

• Increased risk of falls

• Higher risk of dementia with long-term use

This contributes to the overall anticholinergic burden—the cumulative effect of medicines that reduce acetylcholine, a key neurotransmitter for memory and learning (11, 12, 13).

Older adults are especially vulnerable, as many already take other medicines that add to this burden (e.g., drugs for urinary incontinence or IBS).

Serotonin Syndrome

Because doxepin increases serotonin, combining it with other serotonin-boosting medicines (SSRIs, MAO inhibitors, tramadol, opioids) or supplements (tryptophan, St John’s Wort) can trigger serotonin syndrome—a rapid and sometimes life-threatening reaction (17). Symptoms may include agitation, tremors, sweating, diarrhoea, fever, or seizures.

Prolonged QT Interval

Like other TCAs, doxepin can prolong the QT interval, disrupting the heart’s rhythm and increasing risk of arrhythmias (7).

Symptoms may include (15): palpitations, dizziness, fainting, weakness, or seizures.
Risk factors include (15): older age, female sex, electrolyte imbalances, pre-existing heart disease, or use of other QT-prolonging drugs.

Overdose and Toxicity

Doxepin overdose is dangerous and estimated to be 2–3 times more toxic than amitriptyline (29). Symptoms include:

• Dry mouth

• Low blood pressure

• Convulsions

• Heart arrhythmias

• Coma

• Urinary retention

Doxepin vs Other TCAs

• More sedating: The strongest H1 receptor blocker in the TCA family.

• Mild anticholinergic burden: Less than amitriptyline, but still relevant.

• Toxicity risk: Considered more toxic in overdose than most other TCAs.

Doxepin Side Effects

Doxepin can cause side effects, just like other tricyclic antidepressants (TCAs). Compared with medicines such as amitriptyline or imipramine, doxepin is especially known for causing strong drowsiness and sedation. This makes it useful when sleep problems are part of depression or anxiety, but it also means there’s a higher risk of daytime sleepiness, confusion, and falls—particularly in older adults. Other side effects, like dry mouth or constipation, are generally milder than with amitriptyline, but still possible.

Most Common Side Effects

• Weight gain

• Constipation

• Dry mouth

• Dizziness

• Headache

• Drowsiness (somnolence)
  
  

Alpha-Adrenergic Blockade

• Low blood pressure on standing (orthostatic hypotension)

• Dizziness

• Sedation
  
  

Anticholinergic Effects

• Blurred vision

• Dry mouth

• Difficulty passing urine (urinary retention)

• Fast heart rate (tachycardia)

• Confusion or delirium
  
  

Histamine Blockade (very pronounced)

• Strong sedation — particularly risky for older people

• Increased appetite

• Weight gain

• Confusion or delirium
  
  

Other Reported Effects

• Suicidal thoughts

• Seizures

• Abnormal liver function

Genetic variants in CYP2C19 and CYP2D6 can change how your body processes doxepin:

• Poor metabolisers (CYP2C19 or CYP2D6):
  Higher drug levels → more side effects (e.g., dizziness, drowsiness, heart rhythm changes).
  → Recommendation: Start at 50% of the usual dose and monitor closely.

• Ultrarapid metabolisers (especially CYP2D6):
  Break the drug down too quickly → reduced effectiveness.
  → Recommendation: Consider an alternative antidepressant not dependent on CYP2D6.

• Normal metabolisers:
  Standard dosing usually applies, adjusted by clinical response.

Pharmacogenomic testing can help predict your likely response, though in practice doctors usually adjust based on side effects and effectiveness.

Related Medications:

Other TCAs with similar genetic considerations include:

• Imipramine

• Amitriptyline

• Nortriptyline

• Clomipramine

• Trimipramine