Which is a better sleep aid, trazodone or mirtazapine?

October 8, 2025 •

4 min read

According to a 2023 study published in Sleep Medicine, trazodone is one of the most commonly prescribed off-label medications for insomnia, but its use is inconsistent with some expert recommendations citing insufficient evidence for efficacy in many cases. When considering which is a better sleep aid, trazodone or mirtazapine, it is important to weigh each drug's specific mechanism, side effect profile, and patient-specific factors in consultation with a healthcare provider.

Quick Summary

This article compares the effectiveness, side effects, and ideal use cases for the antidepressant medications trazodone and mirtazapine when prescribed for insomnia. It explores the different mechanisms that induce sedation, contrasts their side effect profiles, and provides guidance for patients discussing options with a doctor.

Key Points

Differentiating Mechanisms: Trazodone primarily blocks serotonin and histamine receptors, while mirtazapine is a potent H1 antagonist that also modulates other neurotransmitters, contributing to their sedative effects.
Effectiveness Varies: Both can be effective sleep aids, but individual responses differ based on body chemistry and co-existing conditions.
Side Effect Contrast: A key distinction is their side effect profile: mirtazapine has a high potential for weight gain and significant daytime sedation, while trazodone carries risks of orthostatic hypotension and, rarely, priapism.
Consider Co-morbidities: Mirtazapine is often favored for patients with depression and appetite loss, where its side effects are advantageous. Trazodone is often chosen when weight gain is a concern.
Dosage Differences: At lower levels of administration, mirtazapine is more sedating than at higher levels, while trazodone's optimal hypnotic effect for sleep is at lower levels of administration.
Long-term Safety and Dependence: Neither medication has the same risk of dependence as controlled sleeping pills like benzodiazepines. Trazodone has a low risk of habit formation.
Consult a Professional: The choice should always be made in consultation with a healthcare provider who can evaluate the patient's complete medical history and needs.

Comparing Trazodone and Mirtazapine for Insomnia

While both trazodone and mirtazapine are antidepressant medications, they are frequently prescribed off-label for insomnia due to their sedative properties. The choice between them is not universal; rather, it depends heavily on the individual's specific health needs, including any co-occurring conditions like depression or appetite loss, as well as the patient's sensitivity to potential side effects. Understanding the pharmacological differences is key to determining which might be the more suitable option.

How They Work: Different Paths to Sleepiness

The sedative effects of trazodone and mirtazapine result from distinct mechanisms of action involving different neurotransmitter pathways in the brain.

Trazodone (Desyrel)

Blocks Serotonin Receptors (5-HT2A): At certain administration levels, trazodone acts as a serotonin antagonist, specifically blocking 5-HT2A receptors, which are associated with wakefulness and agitation. This action quiets the brain, making it easier to fall asleep.
Blocks Histamine Receptors (H1): Similar to over-the-counter antihistamines, trazodone's ability to block H1 histamine receptors also contributes to its drowsy, calming effect.
Blocks Alpha-1 Adrenergic Receptors: By blocking these receptors, trazodone can cause a drop in blood pressure and a reduction in the body's "fight or flight" response, promoting a more relaxed state.

Mirtazapine (Remeron)

Blocks Histamine Receptors (H1): Mirtazapine is a potent antagonist of H1 receptors. This antihistaminergic effect is a primary driver of its sedative properties, especially at certain administration levels.
Blocks Serotonin Receptors (5-HT2 and 5-HT3): By blocking certain serotonin receptors, mirtazapine influences sleep continuity and quality. Importantly, it does not block the 5-HT1A receptor, allowing for enhanced serotonergic activity at that site.
Blocks Alpha-2 Adrenergic Receptors: Mirtazapine's action as an alpha-2 antagonist increases the release of both norepinephrine and serotonin, which contributes to its antidepressant effects. However, the sedative effect from H1 blockade is most pronounced at certain administration levels, and this effect may diminish at higher administration levels as the noradrenergic activity becomes more prominent.

Side Effect Profiles: A Tale of Two Medicines

The side effect profiles are a major differentiating factor when choosing between these two medications for sleep. While both can cause drowsiness, their other common and rare side effects are notably different.

Mirtazapine's Key Side Effects

Weight gain and increased appetite: Mirtazapine is well-known for significantly increasing appetite and often leading to weight gain. This can be beneficial for individuals with depression-related appetite loss but is a major concern for others.
Morning drowsiness: Its longer half-life (around 20-40 hours) can lead to next-day grogginess or "hangover" effects, particularly at initiation.
Dry mouth: Another frequently reported side effect.

Trazodone's Key Side Effects

Orthostatic Hypotension: The blocking of alpha-1 adrenergic receptors can cause a sudden drop in blood pressure upon standing, leading to dizziness or fainting. This is an important consideration, especially for older adults.
Gastrointestinal Issues: Nausea and vomiting can occur, though they are typically mild.
Less Next-Day Sedation: Trazodone has a shorter half-life (5-9 hours) than mirtazapine, meaning it is less likely to cause lingering daytime drowsiness for many people.
Rare, but Serious Risks: A rare but serious risk is priapism (a prolonged and painful erection), though this is uncommon. Serotonin syndrome is also a rare possibility, particularly when combined with other serotonergic agents.

A Comparative Look


Feature	Trazodone (Desyrel)	Mirtazapine (Remeron)
Mechanism	Serotonin Antagonist & Reuptake Inhibitor (SARI)	Noradrenergic and Specific Serotonergic Antidepressant (NaSSA)
Primary Sedative Action	H1 and 5-HT2A receptor antagonism	Potent H1 receptor antagonism, especially at low levels of administration
FDA Approval for Sleep	No (off-label use)	No (off-label use, standard for depression)
Effect on Appetite/Weight	Can cause minor weight or appetite changes	Strong potential for increased appetite and significant weight gain
Half-Life	Shorter (5–9 hours)	Longer (20–40 hours)
Next-Day Sedation	Generally lower risk	Higher risk, especially at low administration levels
Ideal for Patients with...	Insomnia alone, or with anxiety/depression but desiring less weight gain	Insomnia paired with depression and/or low appetite/weight loss

Who is the Ideal Candidate for Each?

The decision of which medication is superior is highly personalized and should be made in conjunction with a healthcare professional, factoring in all health conditions and preferences. Here are some general considerations:

Consider Trazodone if...
- Your primary concern is help with sleep onset, not necessarily maintenance.
- You are concerned about weight gain, as it is a less common side effect than with mirtazapine.
- You are prone to next-day drowsiness and a shorter-acting medication is preferred.
- You are trying to avoid a controlled substance.
Consider Mirtazapine if...
- You have co-occurring depression and poor appetite or weight loss, for which mirtazapine's side effects are beneficial.
- You need help staying asleep throughout the night.
- You can tolerate the potential for greater daytime sedation and appetite increase.

Conclusion

Neither trazodone nor mirtazapine is definitively "better" than the other for all patients seeking a sleep aid. While clinical guidelines often caution against the first-line use of trazodone for insomnia due to a weaker evidence base compared to newer agents, it remains a very common off-label choice for its low potential for abuse and low cost. Mirtazapine is more effective for some, particularly those with comorbid depression, but carries a higher risk of weight gain and pronounced morning grogginess. A detailed discussion with a doctor is necessary to weigh the benefits against the risks and personal circumstances to find the most appropriate and safest treatment option for your sleep needs.

Talk to a healthcare provider for medical advice and to determine the best medication for you.

Frequently Asked Questions

No, it is generally not advised to take trazodone and mirtazapine together due to the increased risk of serotonin syndrome, a potentially life-threatening condition caused by excess serotonin.

Mirtazapine may be the better choice for patients with both insomnia and depression, especially if they also experience poor appetite or weight loss, as its side effects of increased appetite can be beneficial.

Mirtazapine is significantly more likely to cause increased appetite and weight gain compared to trazodone.

Both can produce sedative effects relatively quickly, often within 30 to 60 minutes. However, individual response times can vary.

Compared to traditional sleep aids and controlled substances, both trazodone and mirtazapine have a low risk of dependence and habit formation.

Trazodone is generally less likely to cause next-day drowsiness due to its shorter half-life. Mirtazapine, with its longer half-life, has a higher risk of lingering sedation.

No, you should not stop either medication abruptly without consulting your doctor. A healthcare provider will recommend a tapering schedule to minimize potential withdrawal symptoms and side effects.