Can You Take Addyi and Trazodone Together?
No, you should not take Addyi (flibanserin) and trazodone together due to significant safety concerns, particularly the risk of severe hypotension, syncope, and excessive sedation from additive central nervous system (CNS) depression.
Why This Combination Is Dangerous
Additive CNS Depression and Hypotension Risk
Both flibanserin and trazodone are sedating agents that depress the central nervous system; their combined use produces additive CNS depression, markedly increasing the risk of hypotension, syncope, respiratory depression, cognitive impairment, falls, and complex sleep behaviors. 1
Flibanserin already carries FDA warnings for hypotension and syncope, especially when combined with other CNS depressants or alcohol; adding trazodone—which itself causes orthostatic hypotension and dizziness—compounds these risks. 2, 3, 4
The American Academy of Sleep Medicine explicitly warns that combining multiple sedating agents creates dangerous polypharmacy with additive psychomotor impairment, increased fall risk, and potentially life-threatening respiratory depression. 1
Evidence Against Trazodone for Insomnia
Trazodone Is Not Recommended for Primary Insomnia
The American Academy of Sleep Medicine issues a weak recommendation against using trazodone for sleep onset or sleep maintenance insomnia because clinical trials showed only modest improvements (≈10 min reduction in sleep latency, ≈8 min reduction in wake after sleep onset) with no improvement in subjective sleep quality, and harms outweigh benefits. 5, 6
The U.S. Department of Veterans Affairs/Department of Defense guidelines explicitly advise against trazodone for chronic insomnia disorder, citing low-quality evidence and an adverse-effect profile (daytime drowsiness, dizziness, psychomotor impairment) that outweighs any modest benefit. 5
Trazodone is considered a third-line agent only after benzodiazepine receptor agonists and ramelteon have failed, and is more appropriate when comorbid depression or anxiety is present—not for primary insomnia. 5, 6
Safer Alternatives for Insomnia Management
First-Line Non-Pharmacologic Therapy
The American Academy of Sleep Medicine and the American College of Physicians issue a strong recommendation that all adults with chronic insomnia receive Cognitive Behavioral Therapy for Insomnia (CBT-I) as the initial treatment before any medication, because CBT-I provides superior long-term efficacy with sustained benefits after discontinuation. 1, 5, 6
Core CBT-I components include stimulus control (use bed only for sleep, leave bed if unable to fall asleep within ≈20 minutes), sleep restriction (limit time in bed to actual sleep time + 30 minutes), relaxation techniques, and cognitive restructuring of maladaptive sleep beliefs. 1
First-Line Pharmacologic Options (After CBT-I)
For sleep-maintenance insomnia (the most common complaint):
Low-dose doxepin 3–6 mg at bedtime is the preferred first-line hypnotic, reducing wake after sleep onset by 22–23 minutes with minimal anticholinergic effects and no abuse potential. 1, 5, 6
Suvorexant 10 mg (orexin-receptor antagonist) reduces wake after sleep onset by 16–28 minutes with a lower risk of cognitive and psychomotor impairment than benzodiazepine-type agents. 1
For sleep-onset insomnia:
Ramelteon 8 mg (melatonin-receptor agonist) is preferred for patients with substance-use history because it has no abuse potential, is not DEA-scheduled, and causes no withdrawal symptoms. 1, 5, 6
Zaleplon 10 mg (5 mg if age ≥65 years) has an ultrashort half-life (≈1 hour) providing rapid sleep initiation with minimal next-day sedation. 1, 5, 6
For combined sleep-onset and maintenance insomnia:
Eszopiclone 2–3 mg (1 mg if age ≥65 years) increases total sleep time by 28–57 minutes and improves both sleep onset and maintenance with moderate-to-large gains in subjective sleep quality. 1, 5, 6
Zolpidem 10 mg (5 mg if age ≥65 years) shortens sleep-onset latency by ≈25 minutes and adds ≈29 minutes to total sleep time. 1, 5, 6
Flibanserin Safety Profile
General Safety in Premenopausal Women
In a randomized, placebo-controlled trial of 111 premenopausal women taking SSRIs or SNRIs for depression, flibanserin 100 mg at bedtime was generally safe and well tolerated, with the most common adverse events being dry mouth (5.5%), insomnia (5.5%), back pain (4.1%), and dizziness (4.1%). 7
No serious adverse events, suicidal ideation, or behavior occurred; depression symptom worsening was lower in the flibanserin group (6.9%) compared to placebo (21.6%). 7
Alcohol Interaction Warning
Flibanserin carries an FDA contraindication for alcohol use due to increased risk of hypotension and syncope; a phase 1 study showed that co-administration of flibanserin with alcohol increased the incidence of hypotension and syncope, with sedation increasing 20–27% from baseline at 4 hours post-dose. 3, 4
In a subsequent study of 96 premenopausal women, co-administration of flibanserin 100 mg with varying doses of alcohol (0.2–0.6 g/kg) resulted in dizziness rates of 27.4–39.8% compared to 31.1% for flibanserin alone, though no syncope was observed. 3
Clinical Decision Algorithm
Step 1: Discontinue Trazodone
- Stop trazodone immediately because it is not evidence-based for primary insomnia and creates dangerous polypharmacy when combined with flibanserin. 1, 5, 6
Step 2: Initiate or Optimize CBT-I
- Start CBT-I immediately as the standard of care, incorporating stimulus control, sleep restriction, relaxation techniques, and cognitive restructuring; this is mandatory before or alongside any pharmacotherapy. 1, 5, 6
Step 3: Add First-Line Pharmacotherapy If CBT-I Is Insufficient
For sleep-maintenance insomnia: Start low-dose doxepin 3 mg at bedtime; if insufficient after 1–2 weeks, increase to 6 mg. 1, 5, 6
For sleep-onset insomnia: Start ramelteon 8 mg at bedtime (preferred for zero addiction potential) or zaleplon 10 mg (5 mg if age ≥65 years). 1, 5, 6
For combined sleep-onset and maintenance insomnia: Start eszopiclone 2 mg at bedtime (1 mg if age ≥65 years); if tolerated but insufficient after 1–2 weeks, increase to 3 mg (maximum 2 mg for age ≥65 years). 1, 5, 6
Step 4: Monitor and Reassess
Reassess sleep parameters (sleep-onset latency, total sleep time, nocturnal awakenings, daytime functioning) and adverse effects after 1–2 weeks; adjust dose or switch agents if response is inadequate. 1
Screen for complex sleep behaviors (sleep-driving, sleep-walking, sleep-eating) at every visit; discontinue the hypnotic immediately if such behaviors occur. 1
FDA labeling limits hypnotic use to ≤4 weeks for acute insomnia; continuation beyond this period requires documented rationale and periodic reassessment. 1
Common Pitfalls to Avoid
Do not combine flibanserin with trazodone or any other sedating agent (benzodiazepines, Z-drugs, antihistamines, antipsychotics) because this creates dangerous polypharmacy with additive CNS depression, respiratory compromise, falls, and cognitive impairment. 1, 5, 6
Do not prescribe trazodone for primary insomnia; this contravenes explicit guideline recommendations and exposes patients to adverse effects without proven benefit. 5, 6
Do not initiate pharmacotherapy without concurrent CBT-I; behavioral therapy yields more durable improvements than medication alone and is mandated as first-line treatment by guideline societies. 1, 5, 6
Do not use over-the-counter antihistamines (diphenhydramine, doxylamine) for insomnia; they lack efficacy data, cause strong anticholinergic effects (confusion, urinary retention, falls, daytime sedation, delirium), and develop tolerance within 3–4 days. 1, 5, 6
Do not use antipsychotics (quetiapine, olanzapine) for insomnia; evidence of benefit is weak and they carry significant risks including weight gain, metabolic syndrome, extrapyramidal symptoms, and increased mortality in the elderly. 1
Do not consume alcohol while taking flibanserin; this is an FDA contraindication due to increased risk of hypotension and syncope. 3, 4