Does Bupropion Cause Increased Alertness or Insomnia?
Yes, bupropion commonly causes insomnia and increased alertness due to its activating properties as a norepinephrine-dopamine reuptake inhibitor, which is why the second daily dose must be taken before 3 PM to minimize sleep disturbances. 1
Mechanism Behind Alertness and Insomnia
Bupropion's activating effects stem from its dual inhibition of norepinephrine and dopamine reuptake, with no clinically significant serotonergic activity. 2 This mechanism produces mild central nervous system stimulation through weak dopaminergic effects and predominantly noradrenergic activity. 3 The drug has been shown to reverse sleepiness and improve alertness in narcoleptic patients, demonstrating its wake-promoting properties. 4
Clinical Evidence of Insomnia Risk
Insomnia is one of the most common side effects of bupropion across all formulations and indications:
- In major depressive disorder trials, insomnia occurred in 11-16% of patients on bupropion sustained-release compared to 6% on placebo. 5
- In seasonal affective disorder trials, 20% of patients on bupropion extended-release experienced insomnia versus 13% on placebo. 5
- Insomnia was the leading cause of discontinuation in SAD trials, affecting 2% of bupropion patients versus <1% on placebo. 5
- Common neurological side effects include nervousness, agitation, anxiety, and feeling jittery—all reflecting the drug's activating properties. 6, 5
Practical Dosing Strategies to Minimize Insomnia
The timing of bupropion administration is critical to managing its alertness-promoting effects:
- Morning dosing is essential: The first dose should always be taken in the morning to leverage bupropion's activating properties during waking hours. 1
- Second dose timing: For sustained-release formulations requiring twice-daily dosing (150 mg BID), the second dose must be administered before 3 PM to prevent sleep disturbances. 1
- Extended-release advantage: Bupropion XL (300 mg once daily in the morning) may reduce insomnia risk compared to twice-daily formulations by avoiding afternoon dosing. 1
- Combination therapy caution: When using naltrexone-bupropion ER for weight management (2 tablets twice daily at maintenance), the second dose should not be taken late in the day specifically to minimize insomnia risk. 7, 1
Special Population Considerations
For older adults, the gradual titration starting at 37.5 mg every morning with increases every 3 days helps assess tolerability of the activating effects, with strict adherence to the before-3-PM rule for the second dose. 1
Clinical Pearls
The activating properties that cause insomnia can be therapeutically beneficial for patients with depression characterized by low energy, apathy, or hypersomnia. 1 However, patients with pre-existing insomnia or anxiety may experience worsening symptoms. 6, 5 Unlike SSRIs, bupropion does not cause sedation or weight gain, making its alertness-promoting effects part of its distinct clinical profile. 8, 2