Low-dose Doxepin for Insomnia Treatment

Doxepin is a tricyclic antidepressant drug with significant sedative effect recently studied for use as a hypnotic in the treatment of insomnia.  Doxepin has strong antagonistic effects on several neurotransmitter receptors including the histamine (one and two), serotonin (two), alpha one adrenergic and muscarinic acetylcholinergic receptors.

Juliane Weber and colleagues recently reviewed clinical trial research related to doxepin and insomnia treatment.  For depression, doxepin typically requires 150 mg to 300 mg to achieve an antidepressant.  Many individuals are unable to tolerate this type of dose due to the sedative side effects.  Much lower doses (3 mg to 6 mg) have been investigated for effects on sleep.

A summary of the key points from their review:

• Doxepin decreased time awake after onset of sleep by 40-46%
• Total sleep time increased from 40 to 50 minutes per night
• Proportion of sleep time in REM and slow wave sleep did not change
• Elderly patients had similar effects with the lower 3 mg dosage
• Effects were similar for patients with chronic or transient insomnia
• In sleep lab testing doxepin reduced time to sleep onset from 35 minutes down to 20 minutes

A more recent study from Krystal and colleagues at Duke University looked at 1 mg and 3 mg doses of doxepin in elderly patients with chronic primary insomnia.  They found the 3 mg dose was effective in reducing wake time after sleep onset, total sleep time and overall sleep efficiency (percent of time asleep).

The duration of doxepin's effect has been studied for up to 12 weeks and there does not seem to be tolerance to the hypnotic effect over this duration.  At these low doses, doxepin appeared well-tolerated.  Longer term studies are needed to determine efficacy for periods of longer than 12 weeks.  One potential concern would be weight gain as the histamine and muscarinic receptors appear to be related to increased appetite and weight gain.

The FDA has approved doxepin 3 mg and 6 mg for insomnia treatment.  Typically, the lowest generic doses for this drug are 10 mg.  Three mg and 6 mg doses are available under the brand name Silenor.

This research suggests low-dose doxepin may be an alternative to hypnotics such as Ambien (zolpidem) for primary insomnia.  This research supports further study of current drugs for novel mechanisms and new indications.


Disclosure:  The author has no financial conflict of interest and has not received funding for research of this compound.

Image of chemical structure for two isomers of doxepin courtesy of Creative Commons authored by Ju.

Weber J, Siddiqui MA, Wagstaff AJ, & McCormack PL (2010). Low-dose doxepin: in the treatment of insomnia. CNS drugs, 24 (8), 713-20 PMID: 20658801

Krystal AD, Durrence HH, Scharf M, Jochelson P, Rogowski R, Ludington E, & Roth T (2010). Efficacy and Safety of Doxepin 1 mg and 3 mg in a 12-week Sleep Laboratory and Outpatient Trial of Elderly Subjects with Chronic Primary Insomnia. Sleep, 33 (11), 1553-61 PMID: 21102997