Trazodone Does NOT Become Less Sedating at Higher Doses
The claim that trazodone becomes less sedating at higher doses is a myth—sedation remains a prominent side effect across the entire dosing range, though the mechanism of action does shift from primarily serotonin antagonism at low doses to serotonin agonism at higher doses. 1
Dose-Dependent Pharmacology
At low doses (25-100 mg), trazodone acts primarily as a serotonin antagonist with prominent sedative, hypnotic, and anxiolytic effects through antagonism of alpha2-adrenergic receptors and 5-HT2/1C receptors 2, 1
At higher doses (150-600 mg), trazodone shifts to act as a serotonin agonist, providing antidepressant effects, but sedation persists as a major side effect throughout the entire therapeutic range 1, 3
The therapeutic antidepressant dose range is 150-400 mg daily, with sedation (drowsiness/somnolence) remaining the most commonly reported adverse effect even at these higher doses 4, 5
Clinical Evidence on Sedation Across Doses
In a study of 60 veterans prescribed trazodone for nightmares, doses ranged from 25-600 mg (mean 212 mg), and 60% of patients who tolerated the medication complained of daytime sedation, with 19% discontinuing due to side effects including excessive daytime sedation 6
When comparing single nighttime dosing to multiple daily dosing, single nighttime administration at treatment onset produces more sleep with less daytime drowsiness, but these differences disappear with continued administration—indicating tolerance to timing effects but not elimination of sedation 4
The prolonged-release formulation was developed specifically to improve tolerability, acknowledging that drowsiness/sedation remains problematic across the dosing spectrum 5
Dosing Strategy to Minimize Daytime Sedation
The optimal strategy is to administer trazodone predominantly or entirely at bedtime (150 mg initially, increased to 200-300 mg as needed for antidepressant efficacy), which concentrates sedative effects during sleep hours rather than eliminating them 4
This bedtime-weighted dosing leverages the 3-9 hour half-life and produces equal antidepressant efficacy compared to divided daytime dosing, while reducing daytime drowsiness 4
Important Clinical Caveats
Elderly patients and those with hepatic impairment require lower starting doses due to increased sensitivity to sedative effects, with maximum tolerated doses of 300-400 mg/day in elderly patients versus up to 600 mg/day in younger patients 7, 8
Other dose-related adverse effects include orthostatic hypotension (particularly concerning in elderly patients), dizziness, and increased fall risk—all of which persist or worsen at higher doses 3, 7
The American Academy of Sleep Medicine explicitly recommends against using trazodone for insomnia (even at the 50 mg dose studied), as benefits do not outweigh harms, and it should only be considered as a third-line agent after benzodiazepine receptor agonists and ramelteon have failed 8