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Bupropion for ADHD

Bupropion for ADHD

Completely revised 08/2026

Trade names: (E 4)1

  • extended-release (XR), once daily:

    • Elontril®

    • Wellbutrin XL®

    • Budep® (150 mg and 300 mg)

    • Weldep XR® (150 mg and 300 mg)

    • Bupropion XR Adco® (150 mg)

  • slow-release (SR), 2 doses per day:

    • Voxra XL® SR (150 mg and 300 mg)
    • Zyban

XR has a longer-acting effect than SR.

Active ingredient name prior to 2000: Amfebutamon

Introduction:
(E 1a): Bupropion is an antidepressant that is occasionally used to treat ADHD. It is not approved for the treatment of ADHD. Therefore, when prescribed for ADHD, it is always considered “off-label use,” meaning it is used outside the approved indications.

(E 2b): Bupropion works differently from standard ADHD medications. It prevents the neurotransmitters dopamine and norepinephrine from being reabsorbed too quickly from the synaptic cleft. As a result, they remain available for a longer period of time. In a test tube (“in vitro”), this effect is more pronounced for dopamine than for norepinephrine.
In living humans (“in vivo”), the situation is different: Imaging studies show that bupropion, at standard doses, occupies only a small portion of the dopamine transporters (about 14 to 26 percent). At standard doses, methylphenidate occupies more than 50 percent. This is likely a major reason why bupropion is less effective than stimulants in treating ADHD.

(E 2b): Bupropion is metabolized in the body into three metabolites, each of which is active. One of these, hydroxybupropion, reaches levels in the blood many times higher than those of bupropion itself. A significant portion of the overall effect is therefore likely attributable not to bupropion itself, but to this metabolite. The amount produced depends heavily on an individual’s genes and varies considerably from person to person.

(E 1a): Bupropion is more effective than a placebo, but less effective than stimulants and very likely less effective than atomoxetine as well. The studies on this topic are small, methodologically weak, and in some cases contradictory. It is striking that in several studies, doctors and teachers observed an improvement, but the people with ADHD themselves or their parents did not. Useful results were usually seen only at fairly high doses of 400 to 450 mg per day. Experts therefore unanimously recommend bupropion only after the first through third choices of medication have failed or were not tolerated. It may be particularly useful when depression is also present.

(E 4): In terms of side effects, bupropion has several advantages over other antidepressants. It does not cause more drowsiness than a placebo, it tends to result in slight weight loss rather than weight gain, and it has barely any effect on sexual function. This distinguishes it clearly from SSRIs. On the other hand, dry mouth, nausea, and sleep disturbances are common. The most important safety concern is the risk of seizures. This risk depends on the blood concentration and, with the sustained-release formulations commonly used today, occurs in about 1 in 1,000 patients. With non-sustained-release bupropion and at high doses, the risk is significantly higher.

(E 1b): Particular attention should be paid to drug interactions. Bupropion strongly inhibits the CYP2D6 metabolic enzyme in the liver, and this effect persists for at least one week after the last dose. Medications metabolized by this enzyme are therefore more potent and have a longer duration of action. Among ADHD medications, this primarily affects atomoxetine and, to a lesser extent, amphetamine-based medications. Such a combination should be managed by a physician, in part because both bupropion and stimulants can lower the seizure threshold.

(E 4): Bupropion must not be used in cases involving, among other things, a history of seizures, eating disorders such as bulimia or anorexia, severe liver cirrhosis, or alcohol or benzodiazepine withdrawal. A gradual tapering off is recommended when discontinuing treatment.

(E 2b): Bupropion is not traditionally classified as a stimulant, even though it has a stimulating effect (like nicotine and caffeine). Therefore, bupropion does not require a prescription for controlled substances. In a rapid urine drug test, it can falsely trigger a positive result for amphetamines. This is due to a cross-reaction between bupropion and its metabolites and the test antibody, not an actual detection of amphetamines. A confirmatory test using mass spectrometry (GC-MS or LC-MS/MS) reliably clarifies the issue. Anyone taking bupropion who anticipates having to undergo a drug test—for example, during a traffic stop in countries with zero-tolerance policies, such as the Czech Republic—should be able to provide proof of a doctor’s prescription and, if in doubt, insist on a confirmatory analysis. (E 2b)2(E 2b)3

(E 2b): During treatment, a rapid urine drug test (immunoassay) may yield a false-positive result for amphetamine and methamphetamine

(E 4): The active ingredient bupropion is a β-ketoamphetamine derivative. Chemically, bupropion is an aminoketone and is structurally related to cathinone: it has an additional ketone group compared to amphetamine. However, this structural similarity to amphetamine says little about its effects, which differ significantly from those of amphetamine-based medications.(E 4)4

The structural—but not neurochemical—similarity between bupropion and amphetamines was the reason bupropion was tested for ADHD. (E 4)5

1. How Bupropion Works

Implications for People with ADHD

(E 4): Bupropion ensures that the neurotransmitters dopamine and norepinephrine remain available longer in the synapse between two nerve cells. In other words, it inhibits their reuptake. This is the same basic mechanism as that of methylphenidate, although it is significantly less pronounced.

(E 2b): Bupropion is metabolized in the body into three metabolites that are active in their own right. The most important of these, hydroxybupropion, reaches levels in the blood that are about 14 times higher than those of bupropion itself. Therefore, when bupropion is taken, it is primarily not the active ingredient itself that produces the effect, but rather what is formed from it in the body. How much of this is produced depends on a person’s genes.

(E 2b): In humans, bupropion at the usual dosage occupies only about 14% to 26% of the dopamine transporters. Methylphenidate accounts for over 50%. In animal studies, bupropion has a stronger effect on the dopamine system, but only at doses far higher than those taken by humans. The results of animal studies on bupropion are therefore only partially applicable to humans.

(E 4): In addition, bupropion blocks certain nicotine binding sites in the brain. This may explain why it helps with smoking cessation. No link to its effect on ADHD has been demonstrated to date.

(E 4): The half-life of bupropion is approximately 21 hours, while that of its metabolites is up to 37 hours. Bupropion therefore has a long duration of action. In cases of severe liver disease or severe renal impairment, the active ingredient and its metabolites accumulate in the body. In such cases, a lower dose is necessary.

Bupropion is effective as an active ingredient in its own right and is metabolized into hydroxybupropion, threohydrobupropion, and erythrohydrobupropion.(E 4)6 All three metabolites are also effective norepinephrine reuptake inhibitors, albeit weaker than bupropion itself.

(E 2b): A significant portion of the overall effect is likely attributable not to bupropion itself, but to hydroxybupropion.(E 2b)7 In animal models, hydroxybupropion achieves 50 to 100% of the potency of bupropion, while threo- and erythrohydrobupropion each achieve approximately 20%.(E 2b)7 At the same time, hydroxybupropion achieves by far the highest plasma levels. In a study of 42 healthy adults who took 150 mg of Bupropion XL daily for 7 days, its total exposure (AUC) at steady state averaged 14 times that of bupropion (95% confidence interval 12.6 to 16.2), the peak concentration was approximately 8 times higher, and the AUC was approximately 17 times higher.(E 4)8 In addition, a larger proportion of hydroxybupropion is present in the unbound and thus active form (approximately 23%) than is the case for bupropion (approximately 16%). (E 2b)7

The plasma half-life of bupropion is approximately 21 hours, and that of hydroxybupropion is approximately 20 hours. In patients with severe liver cirrhosis, bupropion exposure increases threefold and the half-life increases by about 10 hours. In end-stage renal failure, the exposure and half-life of hydroxybupropion increase by 136% and 73%, respectively. In six elderly patients, the mean half-life of both substances was 34.2 hours. (E 4)9

Bupropion is almost completely absorbed. Bioavailability is greatly reduced by first-pass metabolism. However, the commonly cited range of 5 to 20% is based on estimates from animal models rather than on measurements in humans. The bioavailability of sustained-release (SR) bupropion is similar to that of immediate-release (IR) bupropion, while that of extended-release (XR, ER) bupropion is slightly lower. Bupropion SR and bupropion XR have higher tmax values. (E 4)6

A narrative review from 2025 summarizes the mechanism of action, efficacy, and side effects of bupropion in ADHD. It does not reach any conclusions beyond those already mentioned in the studies cited here. (E 4)10
(ADxS Assessment): The review is not useful as evidence. It lists three databases and six search terms; the selection was based on “relevance.” There are no inclusion or exclusion criteria, no quality assessment, and no quantitative summary. In addition, there are technical errors. The source is cited here solely for the sake of completeness.

1.1. Dopamine and norepinephrine reuptake inhibition

Bupropion acts as a dopamine and norepinephrine reuptake inhibitor. DAT inhibition is more pronounced in vitro. (E 4)11
Bupropion and its three major metabolites cross the blood-brain barrier and bind to the dopamine transporter there. The mean volume of distribution is approximately 19 L/kg, which is attributed to the active ingredient’s high fat solubility. (E 4)6

(E 2b): In humans, however, bupropion binds only to a small extent to dopamine transporters. Two imaging studies found values of approximately 14% and 26%. (E 2b)12(E 2b)13(E 4)9 MPH achieves more than 50% at standard therapeutic doses.(E 2b)14 It is therefore questionable whether bupropion acts as a relevant dopamine reuptake inhibitor in humans at standard therapeutic doses.

(ADxS assessment): Since dopamine in the PFC is also taken up by the norepinephrine transporter (NET) (even slightly more than norepinephrine), our hypothesis suggests that bupropion (similar to atomoxetine) could also increase dopamine levels in the PFC in humans through this mechanism.
These findings could provide a compelling explanation for why, in practice, bupropion is less effective as an ADHD medication compared to stimulants, which also target the DAT in humans—a system found primarily in the striatum, the brain’s motivational center, where, in contrast, few NETs are found.

Method , DAT (µM) , NET (µM) , Ratio
³H-Dopamine uptake, COS-7 cells with human transporter (E 4)15 0.95 ± 0.25 4.63 ± 0.5 4.9 : 1
³H-Nisoxetine displacement, COS-7(E 4)15 1.51 ± 0.32 3.42 ± 0.4 2.3 : 1
Rat synaptosomes (striatum vs. hypothalamus) (E 4)15 2.0 ± 0.6 5 ± 1 2.5 : 1
Mouse synaptosomes (E 4)15 2.0 ± 0.8 4 ± 1 2 : 1
³H-monoamine uptake, rat cortical synaptosomes (E 2b)16 0.55 ± 0.065 1.9 ± 0.012 3.5 : 1

The “Ratio” column is calculated based on the values from the respective original work.

In animal studies, bupropion increases dopamine levels in the nucleus accumbens: In rats, a single dose of 30 mg/kg (i.p., well above the doses used therapeutically in humans) increased both locomotor activity—which remained elevated for up to two hours—and dopamine release in the nucleus accumbens.(E 2b)17

(E 2b): In living humans, however, DAT occupancy is low. A PET study of eight adults with depression receiving titrated doses (100, 200, 300 mg/day for one week each) found DAT occupancy of 14%. The authors concluded that less than 22% of the DAT is occupied during clinical treatment.(E 2b)12
A second PET study involving six healthy men (bupropion SR 150 mg daily for three days, followed by 150 mg every 12 hours for eight days) also found a low value of approximately 26%. (E 2b)13(E 4)9 In rats, the binding of the tracer [¹¹C]raclopride to dopamine D2/D3 receptors decreased significantly, indicating an increase in dopamine concentration in the tissue. In healthy human volunteers, however, a single dose of 150 mg of bupropion showed no detectable increase. Marker binding actually increased slightly.(E 2b)18

(E 2b): For comparison: In a PET study involving seven healthy adults, oral MPH occupied 12% of the DAT 120 minutes after administration at a dose of 5 mg, 40% at 10 mg, 54% at 20 mg, 72% at 40 mg, and 74% at 60 mg. The dose required for 50% occupancy was 0.25 mg/kg. At the usual therapeutic dose of 0.3 to 0.6 mg/kg, more than 50% of the DAT is thus occupied.(E 2b)14 However, a DAT occupancy of 85% (E 2b)19 has been reported in rhesus monkeys following intravenous administration, and 35% (E 2b)18 in rats following intraperitoneal (i.p.) administration.(E 4)9 However, this is not attributable to the slower onset of action following oral administration, nor is it applicable to humans.

In animal studies, bupropion reduced the activity of noradrenergic neurons in the locus coeruleus, which influence sleep and arousal. (E 4)6

1.2. VMAT2 via D2

(E 2b): Bupropion also affects dopamine homeostasis via the vesicular monoamine transporter 2 (VMAT-2), which takes up dopamine from the cell interior into the storage vesicles of the nerve terminal, from which it is later released. In rats, bupropion increased dopamine uptake into the vesicles rapidly, in a dose-dependent and reversible manner, thereby shifting the VMAT-2 protein within the nerve terminal. The same effect is known to occur with methylphenidate. The effect was dependent on dopamine D2 receptors. Pretreatment with the D2 blocker eticloprid prevented this effect, whereas pretreatment with the D1 blocker SCH23390 did not. Bupropion therefore does not act directly on the VMAT-2 transporter but rather via a feedback loop in the dopamine system through D2R.20 While methylphenidate was able to prevent permanent dopamine damage following repeated methamphetamine administration in earlier studies, bupropion was not. It attenuated the acute reduction in VMAT-2 activity but did not prevent long-term damage to dopamine neurons.

1.3. Dopamine and norepinephrine release?

In addition, bupropion may also have a mild effect on dopamine and norepinephrine release. (E 4)15 The available data on this are inconsistent. The neurochemical properties of bupropion in humans are considered complex and not yet fully understood. (E 4)15

In contrast, a study of healthy men found no evidence that bupropion inhibits the reuptake of norepinephrine or serotonin. The authors considered it possible that bupropion instead increases the available amount of norepinephrine through increased release. An older animal study, however, found no release of biogenic amines and no MAO inhibition, but did find a weak inhibition of monoamine uptake in vitro. (E 2b)21

A study using isolated transporters rules out a releasing effect. The researchers gradually broke down the bupropion molecule and compared the fragments with cathinone, a chemically simpler analog that acts as a releaser at the same transporters. Bupropion itself showed no release-promoting effect at the DAT, NET, or SERT. The reason identified was a bulky side group on the nitrogen atom, which prevents bupropion itself from being transported through the transporter—a prerequisite for release. In contrast, fragments with a smaller side group acted as releasers at dopamine and norepinephrine transporters. (E 2b)22
(ADxS assessment): If the size of the nitrogen-containing side group alone determines whether a substance inhibits reuptake or releases neurotransmitters, this could explain bupropion’s low risk of abuse.

1.4. Inhibition of nicotinic acetylcholine receptors (nAChR, nicotinic receptors)

Bupropion is a noncompetitive antagonist of several nicotinic acetylcholine receptors (nAChR). (E 4)23 At therapeutic doses, α3-containing receptors are likely to be primarily affected. This receptor inhibition is considered the most likely mechanism underlying bupropion’s efficacy in smoking cessation.

No link has yet been established between this effect and an improvement in ADHD symptoms.

Sensitivity varies greatly depending on the receptor subtype and has the following order of priority: α3-containing > α4-containing ≈ α1-containing > α7-containing receptors. A half-maximal inhibitory concentration (IC₅₀) of 0.82 µM was measured for the human α3β4 receptor. This is on the order of magnitude of blood levels following administration of bupropion (approximately 0.5 to 1 µM), whereas inhibition of the other receptor types is unlikely at therapeutic doses. Hydroxybupropion inhibits the α4β2 receptor with approximately the same potency as bupropion itself, while achieving blood levels that are about ten times higher. Therefore, α4β2 receptors may also contribute to the clinical effect. (E 4)23

The inhibitory mechanism is two-stage: Bupropion first binds to the receptor in its resting state, thereby reducing the likelihood that the ion channel will open. The remaining open channels then desensitize more rapidly. However, there is no simple closure of the open channel. The binding site is located within the channel pore and is shared with tricyclic antidepressants and phencyclidine. (E 4)23

1.5. TNF-alpha levels decreased

(E 2b): In animal models, bupropion reduces TNF-alpha levels. It remains unclear whether this also occurs in humans during therapeutic use. (E 2b)24(E 4)25

1.6. No / minimal serotonergic effect

(E 4): According to the prevailing view, bupropion does not have serotonergic effects. (E 4)6(E 4)26 According to another view, bupropion has a slight serotonergic effect. (E 4)15 This contradiction is largely resolved when direct and indirect effects are distinguished: No direct inhibition of serotonin reuptake can be detected. In animal studies, however, the firing rate of serotonergic neurons increases significantly under bupropion, which is attributed to an indirect, norepinephrine-mediated pathway. (E 4)15

1.7. OCT2 inhibitor

Of the three organic cation transporters, bupropion is most likely to inhibit OCT2. (E 2b)27

In cell culture experiments, however, inhibition at the upper therapeutic plasma concentration was only about 18%. OCT1 and OCT3 were virtually uninhibited. (E 2b)27 The clinical significance of this weak inhibition has not yet been established.

For a description of OCT, see *Dopamine degradation by organic cation transporters (OCT) *in the article Dopamine reuptake, dopamine degradation

2. Onset and Duration of Action

Bupropion is available on the market in various extended-release formulations. While Wellbutrin XR (Elontril) has such a long duration of action that a single daily dose is sufficient, Bupropion SR (Zyban), with a shorter sustained-release profile, is intended to be taken twice daily. In comparison, the immediate-release (IR) form had to be taken three times a day.

Graph showing the different steady-state plasma concentration profiles of bupropion IR, SR, and XR.

3. Efficacy of Bupropion for ADHD

Implications for People with ADHD

Bupropion is more effective for ADHD than a placebo, but less effective than stimulants. Experts agree that it should only be considered if first- through third-choice medications have been ineffective, were not tolerated, or cannot be prescribed. (E 1a)

The body of research is limited and inconsistent. Most studies include only 15 to 160 participants. A few small studies found no difference compared to methylphenidate. However, this does not prove equivalence; it merely indicates that the studies were too small to detect a difference. In cases where a direct comparison was made, methylphenidate performed better. (E 1a)

Often, only doctors and teachers noticed an improvement, while the people with ADHD themselves and their parents either did not notice it or did not notice it until much later. In everyday life, this is a sobering finding, because an improvement that one does not feel oneself is of little help. (E 1a)

In studies, the effect was usually not observed until fairly high doses of 400 to 450 mg per day were administered. However, this also increases the risk of seizures. (E 4)

Bupropion may be particularly useful when depression is also present. In a study that explicitly excluded people with ADHD, the effect was weaker. Based on clinical experience, bupropion tends to have a stimulating effect. In ADHD without hyperactivity (ADHD-I), this could be helpful; in ADHD with hyperactivity, however, it could increase restlessness and irritability. There is a lack of robust studies on this topic. (E 1b)

Although bupropion is considered a safe alternative for those at risk of addiction, a closer look reveals that the body of research is limited, and there are also reports of abuse of bupropion itself. (E 4)

3.1. Bupropion and Forms of ADHD

(ADxS experience): Based on clinical experience, bupropion has a more stimulating effect and boosts motivation more than nortriptyline, making it a better option for patients with pronounced ADHD-I symptoms (without hyperactivity). People with ADHD-HI or ADHD-C (with hyperactivity) may experience increased restlessness, irritability, or aggression. However, there are no robust studies supporting such a distinction based on the presentation form of ADHD. An experienced specialist in neurology and psychotherapy known to us preferred to use bupropion for ADHD-I and was very cautious about using it for ADHD-C or ADHD-HI.

3.2. Bupropion for Children and Adolescents with ADHD

In children, a multicenter RCT involving N = 109 children aged 6 to 12 years (n = 72 receiving bupropion at 3 to 6 mg/kg/day, 37 on placebo) over four weeks of treatment, bupropion improved ADHD symptoms. Teacher ratings of hyperactivity and social behavior showed significant improvement as early as the third day of treatment. Parent ratings were less pronounced and did not become significant until day 28. In contrast, the Clinician Global Impression (CGI) score did not differ significantly from placebo across the four centers. The changes on the teacher rating scale corresponded to approximately half a standard deviation, whereas meta-analyses for stimulants report effect sizes of 0.8 to 0.9. Skin reactions occurred twice as frequently with bupropion as with placebo (16.7% versus 8.1%); four children had to discontinue treatment due to a rash with hives. (E 1b)28

A small double-blind crossover study without a placebo group compared individually titrated methylphenidate (mean 0.7 mg/kg/day, range 0.4 to 1.3 mg/kg/day) and bupropion (mean 3.3 mg/kg/day, range 1.4 to 5.7 mg/kg/day, corresponding to 50 to 200 mg/day) for six weeks each. Both active ingredients significantly improved symptoms (p < 0.001) and did not differ from one another in the overall assessment. In parental assessments, MPH was significantly superior in terms of attention. Nearly all scales showed a trend in favor of methylphenidate. Side effects were reported by 9 of the 15 participants on bupropion, compared to 5 of the 15 on methylphenidate. At the end of the study, 10 of the 15 participants chose to continue with MPH.(E 2a)29 In the absence of a placebo group, it remains unclear what proportion of the improvement is actually attributable to the medications. The study was too small to demonstrate equivalence; approximately 49 participants per group would have been necessary for this.

A non-placebo-controlled, double-blind study compared bupropion with MPH over a six-week period in 44 children and adolescents. Bupropion was dosed according to body weight (100 mg daily for those under 30 kg, 150 mg daily for those over 30 kg), and MPH was dosed at 20 to 30 mg daily. Based on the ADHD assessment scale completed by teachers and parents at baseline and after three and six weeks, both active ingredients showed a comparable efficacy and safety profile. MPH was associated with more frequent headaches; there was no difference in anxiety.(E 1b)30Forty children had at least one assessment after the start of treatment; 38 completed the study. There was no significant difference between the groups on either the parent or teacher scales. After six weeks, 18 children (90%) in each group showed a response according to parental assessment. According to the teachers’ assessment, 8 children (40%) responded to bupropion compared with 12 children (60%) on methylphenidate, which was not statistically significant (p = 0.206).
(ADxS assessment): The bupropion dose used—100 to 150 mg daily—is below the level at which usable results were first observed in adults (400 to 450 mg daily). For a child weighing 30 kg, 150 mg does correspond to approximately 5 mg/kg, which is within the range of older pediatric studies. However, this does not provide evidence of the efficacy of low doses of bupropion.

A double-blind, randomized study compared bupropion with methylphenidate in 40 children aged 6 to 12 years over a period of eight weeks. The primary outcome measures were the ADHD rating scales for parents and teachers, as well as the Clinician Global Impression (CGI) score, assessed at baseline and after four and eight weeks. Side effects were recorded after four and eight weeks. Both active ingredients significantly reduced ADHD symptoms as assessed by parents and teachers (p < 0.001). In the parental assessment, treatment outcomes were better with MPH than with bupropion (p = 0.014). (E 2b)31

The earliest studies on bupropion for ADHD date back to the 1980s.
The very first study was conducted in 1986. It was an open-label study—that is, without blinding and without a control group—and examined 17 boys aged 7 to 13.4 years (average 10.4 years) with an attention disorder and/or a social behavior disorder. A four-week placebo period was followed by eight weeks of bupropion and two weeks of placebo. Fifteen of the 17 children received a maximum of 150 mg daily, one received 100 mg, and one received 50 mg. The physician’s global impression improved significantly in 5 children, moderately in 7, slightly in 2, and not at all in 3. According to the parent questionnaires, disorder of social behavior, anxiety, hyperactivity, muscle tension, and physical complaints improved significantly. None of the nine cognitive tests showed a significant improvement, but all nine showed a positive trend. Side effects were rare, temporary, and mild; laboratory values and vital signs remained normal. Two weeks after discontinuation, the improvement persisted in 8 children; 7 relapsed, and 2 showed no improvement. (E 4)32 We were unable to locate or access two studies.3334 Another study from this early phase examined the clinical and neuropsychological effects of bupropion. It is listed in the 2017 Cochrane review as one of the studies evaluated.(E 2b)35 Three of these four studies were published as brief reports, just a few pages long, in the Psychopharmacology Bulletin, a now-defunct journal of the U.S. National Institute of Mental Health. Their methodology is barely possible to verify today. None of them has ever been replicated. However, these four studies are repeatedly cited in the scientific literature as evidence of bupropion’s efficacy for ADHD. By today’s standards, three of them would no longer be considered full-fledged publications.

(ADxS assessment): This does not mean that bupropion is ineffective for ADHD, but only that the body of research should not rely on these older studies.

3.3. Bupropion in Adults with ADHD

3.3.1. Meta-analyses

According to a 2018 meta-analysis, bupropion was superior to placebo in terms of physicians’ assessment of ADHD symptoms in adults, but not in terms of self-assessment by people with ADHD or parental assessment. The confidence interval was wide. (E 1a)36

(ADxS assessment): An improvement that the doctor observes but that people with ADHD do not feel is of little value in everyday life.

A Cochrane review (k = 6 RCTs, N = 438 adults) from 207 found that bupropion is effective for ADHD: (E 1a)37

  • Severity of ADHD symptoms: SMD 0.50 (k = 3, N = 129)

  • Proportion showing clinically significant improvement: risk ratio 1.50 (k = 4, N = 315)

  • Improvement in CGI-I: risk ratio 1.78 (k = 5, N = 337)

  • Discontinuation due to side effects: risk ratio 1.20 (k = 3 studies, N = 253), i.e., no discernible difference from placebo

The analysis included six studies with a total of 438 participants, five of which were from the United States and one from Iran. All studies used extended-release formulations in doses ranging from 150 to 450 mg daily, and the duration of treatment ranged from six to ten weeks. Four of the six studies were funded by the pharmaceutical industry. Four of the six studies explicitly excluded people with comorbid psychiatric disorders. Another study examined only individuals with opioid dependence.

(ADxS Assessment): Bupropion is typically recommended when ADHD is accompanied by depression, an anxiety disorder, or a substance use disorder. However, the studies on which the evidence of efficacy is based largely excluded people with ADHD, meaning that the evidence comes from a group that does not meet these criteria. The few studies that included people with ADHD were either open-label and uncontrolled or found no benefit over placebo.

An older meta-analysis from 2011 (k = 5, N = 349 adults, n = 175 on extended-release bupropion) reached similar conclusions. On the ADHD Symptom Scale (ADHD-RS), the improvement with bupropion was 5.08 points greater than with placebo (95% confidence interval 3.13 to 7.03). The response rate was 1.67 times higher with bupropion (1.23 to 2.26).(E 1a)38 Neither the overall discontinuation rate (risk ratio 1.11, 0.71 to 1.72) nor the discontinuation rate due to side effects (0.87, 0.08 to 9.79) differed from that of placebo.

(ADxS assessment): The two meta-analyses (Cochrane 2017 and Maneeton et al., 2011) are largely based on the same few studies.

3.3.2. Individual studies

(E 4): An older, small, open-label study without a placebo group treated 19 adults—who had previously received stimulants or MAO inhibitors for an average of 3.7 years—with an average of about 360 mg of bupropion daily, along with MAO inhibitors. Fourteen of the 19 reported moderate to marked improvement. Ten participants continued treatment with bupropion after the trial. (E 4)39 Due to the lack of a placebo group and blinding, the study’s validity is limited. In 2005, bupropion was reported to be helpful for approximately half of adolescents and adults with ADHD.(E 4)5 Since then, however, stimulants have undergone significant further development (extended-release formulations, new active ingredients such as lisdexamfetamine), so that bupropion is now considered even more of a second-line option.

A study of 30 adults with ADHD found responder rates of 64% for bupropion SR at doses up to 300 mg/day over 7 weeks, 50% for methylphenidate, and 27% for placebo. The difference between the active ingredient and placebo was not significant (p = 0.14). (E 1b)40

A study of 47 adults with ADHD found that bupropion SR, titrated to a maximum of 400 mg/day (average 298 mg/day) over six weeks, was statistically significant only for one analysis measure that was defined retrospectively. 39% of those treated, compared with 11% on placebo, showed at least a 50% improvement on the symptom scale. The physician’s global impression (41% vs. 22%) and the mean scale score did not reach statistical significance. Responders received, on average, a slightly lower dose than nonresponders (287 vs. 306 mg/day). (E 1b)41 In this study, all people with ADHD were excluded.

An RCT involving 40 adults treated with up to 2 x 200 mg/day of bupropion SR found a 42% reduction in ADHD symptoms after 6 weeks, compared with 24% in the placebo group. 76% of those treated with bupropion were responders (at least a 30% reduction in symptoms) compared with 37% in the placebo group. (E 1b)42

A multicenter, placebo-controlled, 8-week study of n = 162 adults with ADHD (combined and inattentive subtypes) treated with bupropion XL at doses up to 450 mg/day found a responder rate (at least a 30% reduction on the ADHD Rating Scale) of 53% compared with 31% in the placebo group. (E 1b)43

A placebo-controlled study of 42 adults with ADHD found a significant improvement on the self-report questionnaire (CAARS) after six weeks of treatment with a low daily dose of 150 mg of bupropion. (E 1b)44(Einschätzung ADxS): Unlike many other studies, which showed improvement only at doses of 400 to 450 mg daily, one-third of that dose was sufficient in this study. Furthermore, the effect was observed in the self-reports of the people with ADHD, whereas other studies did not find any superiority in this regard. Given the small sample size, these findings are not yet conclusive.

3.4. Bupropion for ADHD and Comorbid Depression

Bupropion may be helpful for ADHD with comorbid depression. In the U.S., depression is the most common diagnosis for which bupropion is prescribed (57% in children, 47% in young adults, and 36% in adults). ADHD is the second most common diagnosis in children (25%) and young adults (12%). The most common initial dose was 150 mg of Bupropion XL (62%). 22% were taking an SSRI at the same time. 39 to 45% remained on bupropion treatment for at least six months. (E 2b)45

A 2026 review article examined the use of bupropion for ADHD and comorbid depression. (E 4)46

An open-label study involving 24 adolescents aged 11 to 16 years with ADHD and a comorbid depressive episode or persistent depressive mood examined, following a two-week single-blind placebo run-in phase, the effect of sustained-release bupropion, titrated to 3 mg/kg twice daily, over a period of at least eight weeks. The mean final dose was 2.2 mg/kg in the morning and 1.7 mg/kg in the evening. Twenty-one of the 24 participants completed the study. Both ADHD and depressive symptoms improved. (E 4)47

3.5. Bupropion for ADHD and Comorbid Bipolar Disorder

Bupropion may be an alternative to stimulants for ADHD with comorbid bipolar disorder, as there is concern that stimulants could trigger a manic episode. A single prospective study has been conducted on this topic. It was an open-label study—that is, without a placebo group and without blinding—and treated 36 adults with ADHD (DSM-IV) and a history of bipolar disorder (90% Bipolar II, 10% Bipolar I) with sustained-release bupropion SR at doses up to 200 mg twice daily, averaging 370 mg daily. Of the 36 participants, 94% had at least one other lifetime diagnosis, and 69% had a substance use disorder. Thirty of the 36 completed the study (83%). The ADHD Symptom Checklist score decreased by 55% (from 34.5 to 15.6; p < 0.001), and 82% showed an improvement of at least 30%. The CGI severity score for ADHD decreased by 40% (p < 0.001), and 70% were considered to have improved significantly or very significantly. The Mania Rating Scale (YMRS) decreased by 58%, indicating that, on average, there was no manic activation. However, one participant developed hypomania requiring treatment in week 2 and was withdrawn from the study. Only 4 of the 36 participants (11%) were concurrently receiving a mood-stabilizing medication. Response to treatment depended on mood status: 83% of those who were not depressed at the end of the study responded to treatment, compared with only 50% of those who were depressed (p < 0.05). The most common side effects were headache (36%), insomnia (31%), dry mouth (25%), and nausea and muscle pain (14% each). (E 4)48

(ADxS Assessment): The validity of this study is limited. Without a placebo group, it is impossible to determine what proportion of the improvement is attributable to the medication. The group consisted almost exclusively of people with bipolar II disorder who exhibited only mild manic symptoms at the time of the study. The study provides no insights regarding bipolar I disorder or an acute manic phase. Bupropion is an antidepressant, and antidepressants can trigger a phase shift in bipolar disorder. Bupropion is considered to carry a comparatively low risk in this regard, but the risk is not zero. If bupropion is being considered for ADHD in patients with bipolar disorder, this should be managed by a specialist.

3.6. Bupropion for ADHD and comorbid ODD/CD

(E 3): A very large analysis of treatment data from an international medical records network compared how often people with ADHD were subsequently diagnosed with oppositional defiant disorder or conduct disorder. The study compared 372,330 individuals taking stimulants with 132,457 individuals taking bupropion. Individuals with a pre-existing diagnosis or who used tobacco were excluded. Both diagnoses occurred less frequently among those taking bupropion than among those taking stimulants, even in a survival analysis. 49
(ADxS assessment): This is a retrospective analysis of billing and medical record data without random assignment. Patients receiving bupropion differ systematically from those treated with stimulants, including in terms of severity and comorbidities. Pronounced behavioral problems, in particular, are more likely to lead to a prescription for stimulants, so the observed difference could also be explained by this factor. The size of the sample does not change this; it merely makes random findings less likely, but does not reduce the bias. The study does not provide evidence that bupropion protects against these Disorders. Furthermore, it was published in a questionable open-access journal with inadequate quality control.

3.7. Bupropion for ADHD and Co-occurring Addiction

Bupropion is often presented as a safe alternative for individuals at risk of addiction. However, there are also reports of abuse of bupropion itself. (E 4)6

A randomized, placebo-controlled trial of bupropion in combination with behavioral therapy in n = 105 adolescents with ADHD and substance use disorder was completed in 2013; the results were submitted to the U.S. clinical trials registry in 2015. Treatment lasted 16 weeks with a target dose of 300 mg of bupropion daily; both groups also received weekly behavioral therapy. The primary endpoints were ADHD symptoms and the number of days spent smoking:(E 1b)50

  • ADHD symptoms on the ADHD Assessment Scale (range 0 to 54, assessed by a physician):
    • Bupropion: - 14.2 points (95% confidence interval 11.4 to 17.1)
    • Placebo: - 13.8 points (11.1 to 16.6)
  • Days of smoking in the past 28 days:
    • Bupropion: - 4.1 days (1.5 to 6.7)
    • Placebo: - 2.7 days (0.1 to 5.3)
  • Days of cannabis use in the past 28 days (secondary outcome measure):
    • Bupropion: - 4.7 days (1.8 to 7.6)
    • Placebo: - 6.5 days (3.6 to 9.4)

(ADxS assessment): Bupropion was no more effective than a placebo, although both groups showed significant improvement. The significant reduction of about 14 points is roughly equivalent to what drug trials typically report as treatment success. ADHD symptoms therefore improved significantly even without an effective medication, as long as weekly behavioral therapy was provided.

Bupropion did not result in more side effects than placebo, with the exception of migraine: (E 1b)50

  • Sleep disturbances: 13.2% with bupropion vs. 19.2% with placebo
  • Weight gain: 26.4% vs. 36.5%
  • Slowed heart rate: 5.7% vs. 9.6%
  • Migraine: 7.6% vs. 3.8%

(ADxS assessment): The study apparently was never published in a peer-reviewed journal and is missing from the 2017 Cochrane review, the 2018 network meta-analysis, and the principal investigator’s list of publications. As the largest controlled study on bupropion for ADHD with substance use disorder, it is largely unknown to the scientific community, whereas the open-label preliminary study involving 13 boys by Riggs et al. (1998) continues to be cited as evidence to this day. Consequently, the published literature appears more favorable than the actual evidence suggests.
The study used strict inclusion and exclusion criteria. Excluded were, among others, participants with bipolar disorder, those with a first-degree relative with bipolar I disorder, a history of seizures, a history of an eating disorder, opiate dependence, and anyone taking other psychotropic medications during the study period.

A large controlled study contradicts the assumption that bupropion is the better choice for ADHD with co-occurring substance use disorder. In a 12-week double-blind comparison of sustained-release MPH, sustained-release bupropion, and placebo in 98 adults with ADHD who were enrolled in a methadone program, 70% completed the study. ADHD symptoms improved in all three groups, though there was no significant difference between the groups. Neither MPH nor bupropion reduced additional cocaine use. 46% of the placebo group reported a significant improvement on their own (at least a 30% reduction in symptoms on the ADHD scale). For the remaining outcome measures, both the placebo and drug responses were significantly lower. For methylphenidate, there was no evidence of misuse of the study medication or an increase in cocaine use. (E 1b)51
(ADxS assessment): The high placebo response explains some of the conflicting results. When nearly half of the untreated control group reports significant improvement, it is barely possible to demonstrate efficacy with just under 100 participants. The study therefore does not prove that bupropion is ineffective in this context.

(E 4): Several small, uncontrolled studies found bupropion to be helpful in cases of comorbid addiction. Taken together, these four open-label studies included fewer participants than the controlled study by Levin et al. (2006)51, which found no advantage over placebo:

  • Among 13 non-depressed boys receiving inpatient addiction treatment who also had ADHD and a conduct disorder, daily doses of up to 300 mg of bupropion over five weeks improved ADHD symptoms.(E 4)52 (ADxS Assessment): With no control group, no blinding, and 13 participants in an inpatient setting—where the treatment environment alone could produce an improvement—this study does not allow for a reliable conclusion regarding the drug’s efficacy.
  • Eleven adults with cocaine dependence and ADHD received bupropion in doses spread throughout the day in a single-blind study over 12 weeks, supported by weekly relapse prevention therapy. Adherence to treatment and retention in the study were good; participants reported significant reductions in attention problems, hyperactivity, and impulsivity. (E 4)53
  • An open-label study treated 14 outpatients with ADHD who also had both a substance use disorder and a mood disorder with sustained-release bupropion. Thirteen participants completed the study and, while taking an average of 315 mg of bupropion SR, showed clinically significant reductions in DUSI scores (-39%; p < 0.05), the ADHD Symptom Checklist (-43%; p < 0.001), the HAM-D (-76%; p ≤ 0.001), and the CGIs for ADHD (p ≤ 0.001), depression (p ≤ 0.001), and substance abuse (p < 0.05). No significant adverse events were observed during the follow-up period. (E 4)54
  • A six-week open-label study of sustained-release bupropion in 32 adults aged 18 to 55 with ADHD and concurrent, active substance use disorder began with a dose of 100 mg and was increased weekly to 200 mg twice daily. 19 (59%) completed the study. ADHD symptoms improved significantly, with the scale score decreasing from 34.1 to 19.4—a 43% reduction (p < 0.0001). In contrast, self-reported substance use remained virtually unchanged. (E 4)55(Einschätzung ADxS): The dropout rate of 41% is high, although not unusual in cases of active substance use disorder.

A 2025 review considers bupropion a promising option for ADHD patients with a history of substance abuse, as it helps prevent the risk of addiction and may reduce the use of other substances. However, its effectiveness has not yet been conclusively demonstratedt, as the body of research is limited and, in some cases, biased, and long-term data are lacking. Bupropion is considered an alternative when stimulants cannot be used or are not tolerated. (E 4)56

Among 16 adolescents taking bupropion SR 150 mg twice daily, 31.2% achieved complete nicotine abstinence after 4 weeks. (E 4)57

In a study examining whether bupropion reduces substance use itself, adults with moderate-to-severe methamphetamine dependence received 380 mg of naltrexone as a depot injection every three weeks, along with 450 mg of extended-release bupropion daily, in a two-stage, double-blind, placebo-controlled multicenter study; they received a 380-mg naltrexone depot injection every three weeks along with 450 mg of sustained-release bupropion daily. In the first increment, 403 participants were treated; in the second, 225. A response was defined as a specified number of methamphetamine-free urine samples. Averaged across both increments, 13.6% of patients on naltrexone and bupropion responded, compared with 2.5% on placebo—a difference of 11.1 percentage points (p < 0.001). Side effects included gastrointestinal complaints, tremors, malaise, increased sweating, and loss of appetite. Serious adverse events occurred in 8 of 223 treated patients (3.6%). The authors describe the response rate itself as low, although higher than with placebo. (E 1b)58
(ADxS assessment): This study did not focus on ADHD and did not use bupropion alone, but rather in combination with naltrexone. It is not possible to determine from this study what proportion of the effect is attributable to bupropion. The findings temper the widespread expectation that bupropion also reduces substance use as a side effect in individuals with ADHD and substance use disorder.

4. Bupropion Compared to MPH, LDX, and ATX

A systematic review directly compared bupropion with MPH based on RCTs conducted between 1991 and 2014. The response rate, overall discontinuation rate, and discontinuation rate due to side effects did not differ significantly between the two active ingredients, although the number of studies was limited. (Meta-analysis, k = 4, n = 146) (E 1a)59

A double-blind, randomized study compared bupropion with methylphenidate in 40 children aged 6 to 12 years over a period of eight weeks. Both active ingredients significantly reduced ADHD symptoms as assessed by parents and teachers (p < 0.001). According to parental assessments, treatment outcomes were better with methylphenidate than with bupropion (p = 0.014). (E 1b)31

A meta-analysis of RCTs compared bupropion, atomoxetine, lisdexamfetamine, and methylphenidate with placebo in children and adolescents and found a small, statistically nonsignificant effect of bupropion on ADHD symptoms (SMD -0.32, 95% confidence interval: –0.69 to +0.05). Atomoxetine (SMD –0.68; –0.76 to +0.59) was more effective, but the effect was also not statistically significant. MPH (-0.75; -0.98 to -0.52) and lisdexamfetamine (-1.28; -1.84 to -0.71) were significantly more effective. (E 1a)60
Regarding tolerability: There were fewer treatment discontinuations with MPH than with placebo (odds ratio 0.35; 0.24 to 0.52), while there were more with bupropion (OR 1.64; 0.5 to 5.43).

(ADxS assessment): This shows that bupropion is not comparable to MPH for the treatment of ADHD. The evidence base for bupropion is weaker in children and adolescents than in adults. Particularly in children and adolescents, bupropion should be used only after the first through third choices of medication have failed.

(E 1a): According to three studies, bupropion is said to have a comparable effect size with respect to ADHD as methylphenidate; another study found a weaker effect. (E 1a)61 However, the absence of a significant difference in three small studies does not prove equivalence. The sample sizes are too small for that. A systematic review on children and adolescents identified only six clinical trials in total. In the three direct comparison studies, the effect of bupropion did not differ significantly from that of methylphenidate (p > 0.05). However, a large multicenter RCT found that bupropion had smaller effect sizes in teacher and parent assessments than methylphenidate (MPH). (E 1a)61

According to a meta-analysis, bupropion, dasotraline, venlafaxine, and viloxazine were not statistically significantly less effective than MPH in treating ADHD.62 (ADxS assessment): This finding would contradict the other findings on this page. We were unable to access the full text.

5. Dosage of Bupropion for ADHD

(E 4): Studies have shown that usable results when used alone for ADHD were only observed at relatively high doses of 400 to 450 mg/day. The updated European consensus on the diagnosis and treatment of ADHD in adults describes the evidence regarding bupropion as contradictory and, due to the limited evidence, recommends restricting the use of bupropion to people with ADHD who cannot tolerate other ADHD medications.(E 4)63 A 2023 review article reaches the same conclusion and attributes the inconsistent findings to methodologically weak randomized trials, small sample sizes, and a lack of long-term studies. (E 4)6

(ADxS Assessment): Bupropion may be effective for ADHD at higher doses; however, it should only be used as monotherapy if all stimulants have proven ineffective. A potential secondary benefit could be the prolongation of the short duration of action of single doses of amphetamine medications, since amphetamines are also metabolized to a lesser extent via CYP2D6.

(E 2b): For use as an antidepressant, a therapeutic reference range of 850 to 1,500 ng/mL of hydroxybupropion is specified. In an analysis of 52 adults, a better antidepressant response was expected at levels above approximately 860 ng/mL. However, earlier studies reported the exact opposite—a better response at trough levels below 100 ng/ml of bupropion and below 1,200 ng/ml of hydroxybupropion—so the available data are contradictory. (E 2b)64(E 4)9 In adolescents with depression aged 11 to 17 years, levels measured 7.5 hours after the morning dose distinguished responders from nonresponders based on the following thresholds: bupropion ≥ 37 ng/mL (p = 0.001), hydroxybupropion ≥ 575 ng/mL (p = 0.003), threohydrobupropion ≥ 240 ng/mL (p = 0.009), erythrohydrobupropion ≥ 45 ng/mL (p = 0.009). These preliminary findings suggest that plasma levels of bupropion and its metabolites, particularly hydroxybupropion, may predict the acute response in adolescents with depression treated with bupropion SR. (E 2b)65

(No evidence): These values apply to the treatment of depression. There are no established target levels for the treatment of ADHD.

6. Metabolism and Drug Interactions of Bupropion

Implications for People with ADHD

(E 1b): Bupropion strongly inhibits a liver enzyme called CYP2D6. As a result, other medications that are metabolized by this enzyme remain in the body longer and in higher concentrations, and their effects are correspondingly stronger. Their dosage must therefore be reduced.

(ADxS experience): For people with ADHD, this primarily applies to atomoxetine and, to a lesser extent, to amphetamine-based medications. Some people with ADHD deliberately use this to extend the duration of action of their amphetamine-based medication, which is otherwise too short. There are no studies on this. Important: Both bupropion and stimulants can lower the (epileptic) seizure threshold. Such a combination should therefore be supported by a doctor.

(E 4): It is particularly important to note that this inhibition persists for at least one week after discontinuing bupropion. If a medication metabolized by CYP2D6 is taken at the same time as bupropion is discontinued, the effect of that medication may suddenly diminish about one week after discontinuing bupropion.

(E 4): Conversely, other medications also affect bupropion levels. For example, carbamazepine drastically lowers them, while the blood thinners clopidogrel and ticlopidine significantly increase them.

(E 2b): The amount of the active metabolite hydroxybupropion your body produces depends heavily on your genes. About half of people of European descent have a gene variant that leads to lower blood levels. However, because there is significant variation even within the same gene variant, measuring blood levels is more informative than a genetic test.

The half-lives are: (E 4)6

  • Bupropion: 21 hours

  • Hydroxybupropion: 20 hours

  • Erythrohydrobupropion: 33 hours

  • Threohydrobupropion: 37 hours

Excretion occurs primarily in the urine and, to a lesser extent, in the feces. (E 4)6

When taking bupropion, caution is advised when administering other medications that affect CYP2B6. Concomitant administration of CYP2B6 inhibitors such as clopidogrel or ticlopidine increased the AUC of bupropion by 60% and 90%, respectively. Concomitant administration of carbamazepine (an inducer of CYP2B6 and CYP3A4) reduced the AUC of bupropion by 90% and increased the AUC of hydroxybupropion by 50%. (E 4)9

Although bupropion itself has little or no serotonergic effect, serotonin syndrome may occur when it is administered concomitantly with serotonergic medications, as well as in cases of bupropion overdose alone. (E 4)6

Bupropion is also a potent inhibitor of CYP2D6. This inhibition results partly from direct blockade of the enzyme and partly from downregulation of its expression. A significant portion of the inhibitory effect is attributable to bupropion metabolites. (E 2b)66

(E 1b): CYP2D6 inhibition caused by bupropion persists for at least seven days after the last dose, which should be taken into account when switching to or discontinuing CYP2D6-dependent medications.(E 1b)67 This CYP2D6 inhibition is dose-dependent. (E 2b)68

(ADxS assessment): Active ingredients metabolized via CYP2D6 must therefore be administered at lower doses when given concurrently. Among ADHD medications, this primarily applies to atomoxetine and, to a lesser extent, to amphetamine-based medications.

(ADxS experience): Several people with ADHD who found that the effects of amphetamine medications wore off too quickly reported that taking bupropion at the same time successfully prolonged the effects. No studies are available on this topic.

(ADxS Assessment): It is important to note that both bupropion and stimulants can lower the central seizure threshold, so such a combination should be used with medical support.

(E 2b): Hydroxybupropion is formed from bupropion primarily via CYP2B6. Quantitatively, however, this is not the main metabolic pathway: the majority is reduced to threohydrobupropion by carbonyl reductases. CYP2B6 is nevertheless clinically significant because hydroxybupropion reaches very high levels and has its own effects. CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 contribute only minimally to the metabolism. Bupropion is metabolized by carbonyl reductases to the active metabolites threohydrobupropion and erythrohydrobupropion.(E 4)6 Hydroxybupropion and threohydrobupropion reach plasma levels that are significantly higher than those of bupropion itself: hydroxybupropion is more than ten times higher at steady state, threohydrobupropion lies in between, and erythrohydrobupropion is roughly on par with bupropion. It is assumed that they have therapeutic benefits. (E 2b)7

Bupropion also has the metabolites 4′-hydroxybupropion and the corresponding erythro- and threo-4′-hydroxyhydrobupropion. (E 2b)69

The CYP2B6 genotype significantly influences hydroxybupropion levels. In a study of 42 healthy adults taking 150 mg of Bupropion XL daily, hydroxybupropion levels were approximately one-third lower in carriers of the CYP2B6*6 or CYP2B6*18 were about one-third lower, while levels in individuals with two *6 variants were about half as high. Bupropion levels themselves, however, remained unchanged because bupropion is also metabolized through other pathways. Approximately 25% of people of Asian descent, 45% of European descent, and 50% of African American descent carry at least one *6 variant. Genotype and sex together accounted for about half of the differences between individuals. Women had higher hydroxybupropion levels than men. Since there is considerable variation even within the same genotype, the authors consider measuring levels to be more informative than genotyping. (E 2b)7

Mathematically, direct inhibition alone accounts for only about 43% of the loss of activity. Only when combined with reduced enzyme synthesis does this result in the predicted value of approximately 82%, which is close to the approximately 90% decline observed in humans.(E 2b)66 The largest single contribution to direct inhibition comes not from bupropion itself, but from the metabolite R,R-hydroxybupropion. Mathematically, it accounts for approximately 65% of the direct inhibition. Downregulation of CYP2D6 expression alone: predicted 68% decrease in CYP2D6 mRNA at steady state at 300 mg/day.

7. Side Effects

Implications for People with ADHD

Bupropion has several advantages over other antidepressants. It does not cause more drowsiness than a placebo. It tends to result in a slight weight loss of about 1.5 kg rather than weight gain. And it has barely any effect on sexual function. With SSRIs or venlafaxine, the likelihood of sexual dysfunction is four to six times higher. For many people, these are the reasons why they stop taking an antidepressant.(E 4)

The most common side effects are dry mouth, nausea, and sleep disturbances. Sleep disturbances occur in 11 to 20% of patients. They are related to the blood level in the evening, which is why the sustained-release formulation XR is preferable here to the less sustained-release bupropion SR. (E 4)

The most important safety concern is generalized (epileptic) seizures. The risk depends on the peak concentration in the blood. With the sustained-release formulations commonly used today, the risk is about 1 in 1,000 patients treated, which is comparable to that of SSRIs. With non-sustained-release bupropion and at doses above 450 mg per day, the risk increases significantly. (E 4)

A total of 7% of the patients in the treatment group discontinued treatment due to side effects, compared with 4% in the placebo group. The side effects decreased over the course of treatment. (E 4)

Overdoses can cause severe cardiac arrhythmias. Of the intentional overdoses reported in the United States between 2000 and 2013, 45% involved adolescents and young adults between the ages of 13 and 19. (E 4)

In placebo-controlled studies of bupropion SR, the following adverse reactions occurred in more than 5% of treated patients and more frequently than with placebo: headache, dry mouth, nausea, sleep disturbances, constipation, and dizziness. Of these, only dry mouth, nausea, and sleep disturbances occurred at a statistically significantly higher rate than with placebo. (E 4)26

Reported side effects of bupropion include: (E 4)26

  • Headaches

  • Dry mouth

  • Sleep Disorders

  • Blood levels at bedtime are lower with Bupropion XR than with Bupropion SR. Sleep disturbances occur in 11 to 20% of patients taking bupropion, compared with 4 to 7% of those taking a placebo and 10 to 19% of those taking SSRIs. (E 4)26

  • Nausea

  • Loss of appetite

  • slight weight loss averaging about 1.5 kg at the start of treatment

  • Unlike SSRIs, bupropion is not associated with weight gain (E 4)26

  • States of arousal

  • Anxiety

  • Constipation

  • allergic reactions (anaphylactoid or delayed reactions, e.g., joint symptoms)

  • Increased blood pressure (clinical reports, not from clinical trials)

  • Tinnitus

  • Dizziness

  • Vision problems

  • psychotic reactions

  • Skin rash

  • Nausea

  • Restlessness

  • Migraine

In the event of an overdose, severe cardiac arrhythmias—such as QT prolongation and QRS widening—may occur. Between 2000 and 2013, 975 intentional overdoses involving bupropion as the sole substance were reported to U.S. poison control centers. Of these, 45.4% involved adolescents and young adults between the ages of 13 and 19. (E 4)6

Treatment discontinuation due to side effects occurred in 7% of patients taking bupropion SR across all dose groups, in 9% of those taking 300 mg/day, and in 11% of those taking 400 mg/day, compared with 4% in the placebo group. (E 4)26

Side effects decreased with continued treatment. In the 52-week relapse prevention study, they occurred less frequently in the randomized arm than at the start of the study. (E 4)26

Among the newer antidepressants, bupropion has one of the lowest rates of sexual dysfunction. In a pooled analysis of comparative studies against SSRIs, the risk of sexual dysfunction with bupropion was nearly identical to that with placebo. In an observational study of 6,297 individuals, bupropion had the lowest rate among the newer antidepressants available at the time. For people without any other cause of sexual dysfunction, the likelihood of experiencing sexual dysfunction was four to six times higher with SSRIs or venlafaxine XR than with bupropion. (E 4)26

Bupropion SR is not associated with an increased risk of daytime sleepiness. The incidence of daytime sleepiness was similar with bupropion to that with placebo and was lower than with SSRIs such as sertraline or fluoxetine, as well as lower than with tricyclic antidepressants and trazodone. (E 4)26

7.1. Bupropion and Central Seizures

(E 2b): The increased risk of central (epileptic) seizures at higher doses of bupropion should be taken into account.(E 4)70 Due to the risk of seizures, immediate release (IR) bupropion was temporarily withdrawn from the market following its initial U.S. approval in 1985 and reintroduced in 1989 with lower maximum dose recommendations.(E 2b)45 Today, however, sustained release bupropion is used.

The risk of seizures associated with bupropion use appears to depend on the maximum plasma concentration and is therefore higher with IR than with SR and presumably lowest with XR. (E 4)26

  • Bupropion IR:

    • 0.4% (4/1,000) at 300 to 450 mg/day

    • a significant increase in risk at even higher doses

  • Bupropion SR:

    • 0.1% (1/1,000) at 300 mg/day.

  • Bupropion XR:

    • 0.1% (1/1000) for up to 450 mg/day (E 4)71

  • SSRI:

    • 0.1% (1/1,000)

7.2. Bupropion for Comorbid Tourette Syndrome

(E 4): Bupropion may exacerbate tics in patients with comorbid Tourette syndrome. In a review of treatment cases, four children were described who had Tourette syndrome in addition to ADHD and experienced an increase in their tics while taking bupropion.72

(E 4): A similar case has also been reported in adults. A tic disorder that had already subsided recurred while the patient was taking bupropion.73

7.3. Bupropion During Pregnancyt

(E 3): An analysis of billing data from 38,074 families examined whether children whose mothers had taken antidepressants during pregnancy were more likely to receive an ADHD diagnosis by age five. The analysis found an increased likelihood for bupropion, but not for SSRIs. A causal relationship has therefore not been established and should be investigated further.74

(E 1a): The association between antidepressant use during pregnancy and ADHD in children has since been systematically investigated on multiple occasions. A 2018 systematic review of seven studies involving approximately 2.77 million people found a 38% increased risk of ADHD (adjusted risk ratio with random effects [RaRR]: 1.38; 95% confidence interval 1.13 to 1.69). When the comparison was restricted to women who also had a mood disorder but did not take antidepressants, the association was no longer significant (1.18; 0.91 to 1.52), nor was it significant in sibling studies (0.96; 0.65 to 1.42). The RaRR for ASA was 1.53 (1.31 to 1.78).(E 1a) 75 The most comprehensive systematic review to date, published in 2026, analyzed k = 37 studies with N = nearly 25 million pregnancies and n = 648,626 women taking antidepressants and confirmed this pattern. Unadjusted, the risk of ADHD was elevated (RR 1.35; 1.24 to 1.47), but it weakened or disappeared when maternal mental health conditions as well as familial and genetic influences were taken into account. The father’s use of antidepressants during pregnancy was also associated with an increased risk of ADHD in the child (1.46; 1.38 to 1.56).76
(ADxS Assessment): Since the father does not carry the child to term, this argues against the drug having an effect in utero. The apparent association is likely due in large part to the fact that parental depression itself is associated with an increased risk of ADHD in the child, which is partly genetically mediated. No separate analyses are available for bupropion itself. Untreated moderate-to-severe depression during pregnancy carries its own significant risks for both mother and child. The study does not have any consequences for discontinuing necessary treatment with bupropion during pregnancy. However, this issue should be discussed with the treating physician.

8. Contraindications

Implications for People with ADHD

(E 4): Bupropion must not be taken if a patient has certain pre-existing medical conditions. Most of these contraindications are related to the risk of seizures.

(E 4): Bupropion must not be taken if the patient has current or past bulimia or anorexia. Eating disorders are more common among people with ADHD than in the general population. The doctor should also be informed of any eating disorders that occurred long ago.

(E 4): Bupropion must not be taken by patients with a history of central (epileptic) seizures, a brain tumor, severe liver cirrhosis, or during withdrawal from alcohol or benzodiazepine-type sedatives. After taking certain older antidepressants (MAO inhibitors), a waiting period must be observed.

(E 4): Bupropion is contraindicated in the following cases: (E 4)71(E 4)77

  • Hypersensitivity to bupropion or any of the excipients

  • Taking other medications containing bupropion

  • current seizure disorder or a history of seizures.

  • a known tumor of the central nervous system.

  • during abrupt withdrawal from

  • Alcohol

  • Medications, if they increase the risk of seizures, e.g.,

  • Benzodiazepines

  • Benzodiazepine-like medications

  • severe cirrhosis of the liver

  • current or past bulimia or anorexia nervosa

    • Eating disorders are extremely common in ADHD. (E 2a)78 (E 2a)78

  • if irreversible monoamine oxidase inhibitors have been used within the past 14 days

  • if reversible monoamine oxidase inhibitors have been taken within the last 24 hours

9. Discontinuation of Bupropion

Implications for People with ADHD

(E 4): Bupropion should not be stopped abruptly; instead, it should be tapered off gradually. Discontinuation and the appropriate tapering schedule should be discussed with the doctor beforehand.

A gradual reduction in dosage is recommended. (E 4)71

(E 4): When discontinuing the medication, it is important to note that inhibition of the CYP2D6 metabolizing enzyme persists for at least one week after the last dose. If, for example, atomoxetine or an amphetamine-based medication is taken at the same time, their effects may be enhanced during this period and then subside afterward.

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