Ambien and Bupropion Interaction: Risks, Mechanism, and Monitoring

Why these two drugs end up together

Bupropion is FDA-approved for major depressive disorder and for prevention of seasonal affective disorder in the Wellbutrin XL labeling [4], and the Zyban labeling covers its use as an aid to smoking cessation [5]. Zolpidem is a Schedule IV sedative-hypnotic approved for short-term treatment of insomnia with difficulty falling asleep [1].

Insomnia is a labeled bupropion adverse reaction. In the Contrave (naltrexone plus bupropion extended-release) trials it was reported in 9.2% of patients versus 5.9% on placebo [3].

Zolpidem is a GABA-A receptor positive modulator that slows brain activity to allow sleep [1]. Bupropion is described in the Contrave label as a dopamine and norepinephrine reuptake inhibitor [3].

Does bupropion raise zolpidem blood levels?

The Ambien label draws the boundary itself: some compounds that induce or inhibit CYP3A may affect zolpidem exposure, but the effect of drugs that induce or inhibit other P450 enzymes on zolpidem exposure is not known [1].

Bupropion's best-documented enzyme effect is on CYP2D6, which the Ambien label does not discuss as a zolpidem pathway. In one study, 13 smokers took sustained-release bupropion 150 mg twice daily for 17 days; the urinary dextromethorphan to dextrorphan ratio rose from 0.012 at baseline to 0.418, and 6 of the 13 met criteria for poor CYP2D6 metabolizer status, versus none of the 8 on placebo [2]. The Contrave label gives an exposure figure: with Contrave 32 mg/360 mg daily, metoprolol AUC rose about 4-fold and peak level about 2-fold [3].

For contrast, here are the zolpidem interactions the Ambien label does quantify. Ketoconazole, a potent CYP3A4 inhibitor, raised zolpidem AUC by 70% and peak level by 30%, and the label says to consider a lower zolpidem dose when a potent CYP3A4 inhibitor is given with it [1]. Rifampin, a CYP3A4 inducer, cut zolpidem AUC by 73%, peak level by 58% and half-life by 36%, and the label says the combination is not recommended [1].

The two labels name different partners. The Ambien drug interaction section covers alcohol, opioids and other CNS depressants, imipramine, chlorpromazine, sertraline, fluoxetine, haloperidol, and CYP3A4 inducers and inhibitors [1]. The Contrave label's interaction section covers MAO inhibitors, CYP2D6 substrates, digoxin, CYP2B6 inhibitors and inducers, drugs that lower the seizure threshold, and levodopa and amantadine [3].

Sedation and next-morning impairment

The Ambien label's additive-effect warning covers benzodiazepines, opioids, tricyclic antidepressants and alcohol, and it says doses of zolpidem or the other depressant may need adjusting [1]. Bupropion is not named in that warning.

The Ambien label does bear on next-morning impairment. It lists four things that raise the risk of impaired driving and reduced alertness the morning after a dose: taking it with less than 7 to 8 hours of sleep remaining, taking more than the recommended dose, taking it with other CNS depressants or alcohol, and taking it with other drugs that increase zolpidem blood levels [1]. FDA has also stated that patients can be impaired the morning after even when they feel fully awake, with the highest risk from extended-release zolpidem [6].

Seizure risk: what is labeled

Bupropion's seizure risk is dose-related. The Zyban label describes about 0.1% (1 in 1,000) with sustained-release bupropion up to 300 mg/day and about 0.4% with immediate-release at 300 to 450 mg/day, and says risk is lowered by gradual titration [5]. The Contrave label lists seizure disorder or a history of seizures, bulimia or anorexia nervosa, abrupt discontinuation of alcohol, benzodiazepines, barbiturates or antiepileptic drugs, and use of other bupropion-containing products among its contraindications. It also directs extreme caution, low starting doses and gradual increases when other drugs that lower the seizure threshold are used [3]. Wellbutrin XL carries the same seizure-related contraindications.

On the zolpidem side, the Ambien label warns that abrupt discontinuation can produce withdrawal symptoms ranging from mild dysphoria and insomnia to cramps, vomiting, sweating, tremors, convulsions and delirium [1]. A published case report describes a 29-year-old woman who had a generalized seizure after suddenly stopping zolpidem while dependent on 160 mg per day [7].

The Contrave contraindication for abrupt discontinuation names alcohol, benzodiazepines, barbiturates and antiepileptic drugs; zolpidem is not among the drugs it names [3].

Complex sleep behaviors

Zolpidem's boxed warning concerns behavior performed while not fully awake: sleep-walking, sleep-driving, preparing and eating food, making phone calls, having sex. Some of these events cause serious injury or death, and the label says to discontinue zolpidem immediately after one; zolpidem is contraindicated in anyone who has had such an episode [1]. The label states these behaviors can occur with zolpidem alone at recommended doses, with or without alcohol or other CNS depressants, and that patients usually do not remember them [1].

FDA added the boxed warning in 2019 after reviewing its adverse event database from December 1992 through February 2018 plus the medical literature. Sixty-six serious cases met criteria, including 20 deaths and 46 serious injuries, and 22 of those cases had an earlier episode of the same behavior on a Z-drug [8][9].

Doses and timing the labels specify

Ambien: 5 mg for women and 5 or 10 mg for men, once per night immediately before bed with at least 7 to 8 hours remaining before planned awakening. The total is capped at 10 mg, the dose is not repeated the same night, older adults and people with mild to moderate hepatic impairment have a recommended dose of 5 mg, and it is avoided in severe hepatic impairment [1]. Ambien CR: 6.25 mg for women, 6.25 or 12.5 mg for men [10]. The label says the initial doses differ because zolpidem clearance is lower in women [1], and FDA required the lower women's doses in January 2013 over next-morning driving impairment [6].

Older adults

The 2023 AGS Beers Criteria recommend avoiding zolpidem, eszopiclone and zaleplon in older adults (strong recommendation, moderate-quality evidence) because of delirium, falls, fractures and motor vehicle crashes with minimal sleep benefit [11]. The Ambien label also flags falls, particularly in the elderly, as a consequence of its sedative effect [1].

What the labels point to during treatment

The Ambien label says insomnia that does not remit after 7 to 10 days of treatment may signal an unrecognized psychiatric or medical illness, and that treatment should be as short as possible with reassessment [1]. The Ambien label's warnings center on next-morning alertness and driving [1][6], complex sleep behaviors [1], and mood, since it says depression can worsen and suicidal thinking can occur in people taking sedative-hypnotics [1].

For chronic insomnia, the American College of Physicians recommends cognitive behavioral therapy for insomnia as the initial treatment, with medication added through shared decision-making when CBT-I alone has not worked [12].