Esmirtazapine
S-enantiomer of mirtazapine, an H1 antihistamine studied as a low-dose sleep agent.
Pharmacology
Contents
WHAT IS ESMIRTAZAPINE?
Detailed overview
Esmirtazapine (Org 50081) is the active (S)-enantiomer of the antidepressant mirtazapine, a tetracyclic compound developed mainly as a low-dose hypnotic for primary insomnia. As a potent histamine H1 inverse agonist it produces sedation, blocks serotonin 5-HT2A/2C and 5-HT3 receptors, and antagonizes alpha-2 adrenergic autoreceptors, the same action that gives mirtazapine its antidepressant component. With a shorter half-life than racemic mirtazapine, roughly 10 hours, it was designed to provide overnight sleep support with fewer next-day residual effects. Several randomized, placebo-controlled trials showed increased total sleep time and improved sleep quality, but Merck/Organon ultimately discontinued development, so esmirtazapine never reached the market.
Mechanism
H1 inverse agonist + 5-HT2/alpha-2 antagonist
Half-life
About 10 hours (shorter than racemic mirtazapine)
Legal status
Not approved (development discontinued)
Receptor profile
- Histamine H1 receptorStrong
- Alpha-2 adrenergic autoreceptorModerate
- 5-HT2A / 5-HT2C receptorsModerate
- 5-HT3 receptorModerate
Safety
Side effects, stop signs, contraindications
Side effects · 5
- Daytime somnolence and sedation, especially at higher doses, from histamine H1 blockade
- Increased appetite and weight gain, characteristic of the mirtazapine class
- Next-day residual effects: generally mild in trials but individually may appear as fatigue or reduced concentration
- Dry mouth, dizziness, headache
- Rare but serious blood-count effects (neutropenia, agranulocytosis) as reported for mirtazapine-scaffold agents
Contraindications · 5
- Pregnancy and breastfeeding: safety not established, avoid
- Contraindicated with MAO inhibitors or within 14 days of stopping them (serotonin syndrome risk)
- Additive sedation with alcohol, benzodiazepines and other CNS depressants
- Caution in patients with a history of blood dyscrasia
- Not an approved medicine: development was discontinued, not recommended without clinical supervision
Related Nootropics
Same therapeutic category
Studies
Related research and clinical findings
Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study and open-label extension
Ivgy-May N, Hajak G, van Osta G
A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia
Ruwe F, IJzerman-Boon P, Roth T
Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a randomized, 6-week sleep laboratory trial
Ivgy-May N, Ruwe F, Krystal A
Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a 2-week randomized outpatient trial
Ivgy-May N, Roth T, Ruwe F
Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype
Ramaekers JG, Conen S, de Kam PJ
FAQ
FAQ
S-enantiomer of mirtazapine, an H1 antihistamine studied as a low-dose sleep agent.
Telegram
Have a question about Esmirtazapine?
Reach out to us on Telegram for a personalized stack. We'll be happy to help.
Personalized consultation
Want a detailed conversation tailored to your data?
Fill out the prep intake form (your goals, training and health data), and the advisor prepares from it to give genuinely personalized guidance.
Fill out the form~5–7 min · prep questionnaire · confidential · GDPR-compliant
Structure & chemistry
The information here is strictly for educational and scientific purposes. It does not replace medical advice or clinical consultation, and it does not encourage illegal substance or pharmaceutical use. Data is sourced. When in doubt, consult your doctor.