Combination Therapy for ADHD

Some people with ADHD do well on a single medication. For many, however, one medication alone is not enough. In such cases, it may be helpful to combine two or more medications. Experts refer to this as combination therapy, augmentation, or polypharmacy.

In adults, treatment with stimulants alone is insufficient in about 30 to 50 percent of cases.¹ In children, stimulants are ineffective in about 25 to 35 percent of cases, are not well tolerated, or are not an option for other reasons.²
Combinations are more common than many people think. Contrary to a common assumption, there are many ways to combine ADHD medications.³ In the U.S., privately insured patients were prescribed multiple ADHD active ingredients simultaneously in about one out of every ten months of treatment, while Medicaid enrollees were prescribed multiple ADHD active ingredients in about one out of every four months.⁴ About one-quarter of children and adolescents who received stimulants were also prescribed another psychiatric medication—most commonly an antidepressant—during the same year.⁵

The added benefit is usually small. For most combinations, there is currently little reliable evidence. The benefits of the combination are generally much smaller than the effect of the first drug. The combination is most likely to be worthwhile when a single drug has provided only partial relief.

Side effects can add up—but sometimes they can also cancel each other out. When a stimulant is taken in combination with atomoxetine, sleep disturbances and loss of appetite occur significantly more frequently. Conversely, a stimulant significantly reduces the drowsiness associated with guanfacine, clonidine, or viloxazine, and stimulants and guanfacine partially counteract each other’s effects on heart rate and blood pressure.
Combining stimulants with MAO inhibitors is dangerous. This combination is strictly prohibited and can be life-threatening. See Section 8 for more information.

Many studies are conducted by manufacturers. A large portion of the research on atomoxetine, guanfacine, and viloxazine was funded or co-authored by the respective manufacturers. This does not automatically mean the results are incorrect, but it is important to keep this in mind when reading the studies. The article points this out in the relevant sections.

What the Guidelines Say

The combination of multiple active ingredients is being used with increasing frequency.⁶ Several treatment guidelines mention this as an option, particularly in cases of comorbidities and when a single medication is not sufficient.^{78 9 10} However, the British guideline classifies the evidence for this approach at the lowest level (Evidence Level IV).⁷ In general, there is currently little evidence to support better treatment outcomes with combination therapies, and safety concerns must be taken into account.⁶
It’s important to distinguish between two very different things here: You can combine two ADHD medications to better manage ADHD symptoms. Or you can combine an ADHD medication with a medication for a comorbid condition.⁸ Incidentally, the most common treatment regimen for ADHD is not the combination of two ADHD medications, but rather a stimulant combined with an antidepressant.⁶

When is a combination a viable option?

A review article for pediatricians lists the following situations:¹¹
• The stimulant only partially alleviates the symptoms.
• The dose cannot be increased any further due to side effects, even though the symptoms are still bothersome.
• The symptoms are particularly severe early in the morning or in the evening—that is, outside the stimulant’s effective period.
• There are additional conditions present: tics or Tourette syndrome, defiant or aggressive behavior, or an anxiety disorder.

A thought on this: The various ADHD medications

Although they largely affect the same areas of the brain, they do not do so entirely. Barkley estimates the overlap to be about 70% and therefore recommends combinations to achieve a broader effect with fewer side effects.¹² Similar considerations can also be found in the work of other authors.¹³

An analysis of U.S. health insurance data (N = 211,226 privately insured individuals and N = 125,104 Medicaid enrollees, all aged 6 and older) found that in 10.3% of 1,125,119 treatment months for privately insured individuals and in 24.0% of 721,986 treatment months for Medicaid enrollees, multiple ADHD active ingredients were prescribed simultaneously.⁴
Conversely, when looking at the individual classes of active ingredients, these were most frequently combined with another ADHD medication in the Medicaid group (percentage of treatment months for each class):⁴

• immediate release stimulants: 70.0%
• α2-adrenergic agonists (guanfacine, clonidine): 63.8%
• Half-day-release stimulants: 51.8%

Among privately insured patients, the highest rates of combination therapy were observed with immediate-release stimulants (45.3%) and α2-agonists (54.0%). This analysis was funded by Eli Lilly, the manufacturer of atomoxetine. The first author and co-authors were Lilly employees.⁴

Another analysis of U.S. insurance data (2011–2014, ranging from 133,354 to 157,303 children and 95,632 to 111,280 adolescents per year) found that about one-quarter of children and adolescents with ADHD who were prescribed stimulants also received another psychotropic medication in the same year:⁵

• Children (ages 6 to 12): 22.9% to 25.0%

• Adolescents (ages 13 to 17): 25.2 to 28.2%
  The most common additional medications prescribed were (from 2011 to 2014):⁵

• SSRI

  • Children: 6.8 to 7.9%
  • Adolescents: 12.7 to 14.9%

• Atypical antipsychotics

  • Children: 4.2 to 5.4%
  • Adolescents: 5.3 to 6.3%

• Guanfacine Extended-Release (XR)

  • Children: 5.1 to 7.0%
  • Adolescents: 2.3 to 3.6%

• Immediate release guanfacine

  • Children: 1.2 to 2.2%

During the study period, the use of SSRIs and Guanfacine XR increased, while the use of atypical antipsychotics decreased. The study was funded by Shire, the manufacturer of Vyvanse and Intuniv at the time.
For information on medication selection for comorbid conditions, see Choice of medication for ADHD or ADHD with comorbidities

For a general assessment of risks associated with drug interactions, the epa.health’s AI is available.
All combinations or dosing options described below are based on studies or reports from people with ADHD who consulted with their treating physician. We strongly advise against changing the dosage or administration schedule on your own!

1. Comparison of Methylphenidate Preparations¶

It is perfectly possible to combine different methylphenidate formulations, particularly sustained-release and immediate-release ones.¹⁴
Immediate-release MPH plays a particularly important role in balancing the duration of action and adapting to specific stressful situations. Immediate-release MPH can prolong the duration of action in the afternoon or early evening, or bridge the gap in the morning until the extended-release formulation reaches its full therapeutic effect. A European treatment guideline states that, due to the wide variations among individual children, some who take a sustained-release formulation may benefit from an additional dose of immediate-release MPH, starting at 5 mg, either in the morning to cover the start of the day or in the evening to prevent a restless tapering off of the effect, which can manifest as disruptive behavior or difficulty falling asleep.¹⁵ The same guideline points out that achieving sufficient morning efficacy with Concerta comes at the cost of a higher methylphenidate load later in the day. An alternative is to combine Concerta with a morning dose of immediate-release MPH. Whether an additional dose of immediate-release MPH is appropriate for adults, or whether atomoxetine is a better option, depends on when symptoms recur and how the respective medication is absorbed and eliminated from the body.¹⁵

Similarly, the British NICE guidelines for sleep disturbances caused by stimulants recommend determining the underlying cause and, in cases of rebound effects (an abrupt decline in the drug’s effect accompanied by increased restlessness), adding small doses of short-acting stimulants in the evening.¹⁶

In a clinical survey, up to 40% of adults enrolled in an ADHD treatment program were prescribed combinations of short- and long-acting stimulants to prolong the duration of action of the long-acting ones.¹⁷

Occasionally, (experienced) people with ADHD report that they manage better with two different half-day sustained-release MPH formulations—one in the morning and one in the early afternoon—than with taking the same sustained-release formulation a second time. These people with ADHD also often use immediate-release MPH to extend their daily coverage.
It should be noted that the fine-tuning of such combinations is usually carried out primarily by the person with ADHD themselves, and requires that the attending physician recognize that the person with ADHD has the necessary sense of responsibility to guide them in making appropriate adjustments to their medication. In the case of children, this is likely to be difficult, especially if they already have difficulty taking their medications at scheduled times throughout the day.

2. Amphetamine-based medications compared to one another¶

Combining different amphetamine medications is usually not intended to improve symptoms or reduce side effects, but rather to ensure better coverage throughout the day.

Some people with ADHD report positive experiences with a combination of Attentin (immediate release D-amphetamine) and sustained-release amphetamine (Vyvanse). While Vyvanse releases the lysine-bound amphetamine very slowly through the intestines and into the bloodstream—a process that can take up to 2 hours for the full effect to set in—Attentin is reported to produce a noticeable onset of action after about 15 minutes, which is consistent with immediate release MPH.

While Vyvanse is effective for 10 to 11 hours after taking it for most people with ADHD (a few people report that it is metabolized within 6 hours, and in isolated cases even much faster), Attentin is effective for about 5 hours.

Some people with ADHD find that taking a low dose of Attentin in the morning, followed by Vyvanse either at the same time or a few hours later, works well for them.¹⁸ Others report that taking Attentin in the afternoon or early evening helps them get through a long day. As a general rule, the Vyvanse dose is reduced slightly after a prior dose of Attentin.
In addition, many people with ADHD report that they cope best with two smaller doses of Vyvanse taken at different times.

While many people with ADHD taking Vyvanse report reduced evening drowsiness and, as a result, improved ability to fall asleep, if difficulty falling asleep persists even after several weeks, you should consider changing the dosage schedule to ensure the drug’s effects wear off earlier.

3. Amphetamine-based medications and methylphenidate¶

Many people with ADHD report taking amphetamine-based medications and (especially immediate-release) MPH at different times on the same day, in consultation with their doctor. There are barely any systematic studies on this combination. We are not aware of any adverse outcomes based on user reports; however, this does not constitute proof of efficacy or safety.

Here, too, the primary significance of (immediate release) MPH lies in its role as a time-delayed supplement to the duration of action of the long-acting amphetamine medication (lisdexamfetamine as a prodrug) early in the morning or in the evening.

In the (rather rare) cases where MPH or AMP alone does not produce a sufficient effect at the usual acceptable daily doses, concurrent administration of MPH and AMP is also possible.
At the group level, amphetamine medications are more effective than methylphenidate. In crossover studies, approximately 41% of participants responded equally well to amphetamines and methylphenidate, 28% responded better to amphetamine medications, and 16% responded better to MPH. The remaining 15% did not respond to either medication. To this day, the most appropriate medication for each individual must still be determined through trial and error. The current understanding of the neurobiology of ADHD is not yet sufficient to guide an informed preliminary selection.¹⁶

In addition, there are a number of medications that can enhance the effects of other medications used to treat ADHD.

4. Guanfacine/Clonidine and Stimulants¶

Guanfacine—like clonidine—is an α₂-adrenoceptor agonist. In the U.S., extended-release guanfacine (Intuniv) and extended-release clonidine (Kapvay) are specifically approved for children and adolescents aged 6 to 17 years, both as monotherapy and as adjunctive therapy to stimulants.^19202122
In Germany and the EU, by contrast, Intuniv is approved only for children and adolescents aged 6 to 17 for whom stimulants are not an option, are not tolerated, or have proven ineffective. There is no explicit approval for its use as a combination therapy in those regions. In children who do not respond adequately to stimulants alone, the addition of guanfacine improves symptoms more effectively than the stimulant alone.¹¹

Interaction studies have shown that the concomitant administration of guanfacine extended-release with long-acting methylphenidate or with lisdexamfetamine does not result in clinically significant changes in blood levels.²³²⁴

If symptoms are severe in the early morning or in the evening (before the onset and/or after the end of the stimulant’s effect), supplemental administration of non-stimulants may be helpful, as these provide coverage throughout the day.¹¹

Meta-analyses
A systematic review with a meta-analysis conducted by the U.S. agency AHRQ found the following effect sizes for ADHD symptoms overall when alpha-2 agonists (guanfacine, clonidine) were added to stimulant medication in children and adolescents:²⁵

• A pooled 0.36 additional effect size compared with stimulants alone (SMD −0.36; 95% confidence interval −0.52 to −0.19; k = 5 studies, N = 724; low evidence)
• The two studies found values of 0.64 and 0.34 for Guanfacin XR (both statistically significant)
• The three studies found values of 0.34, 0.30, and 0.16 for clonidine (only one of which was statistically significant).

A review article evaluated 39 studies and 17 randomized controlled trials on combination therapy for ADHD, 16 of which combined a stimulant with an alpha-2 agonist. The combination was consistently more effective than an alpha-2 agonist alone, but not always more effective than a stimulant alone. It was superior to the stimulant in partial responders (SMD 0.40 for residual ADHD symptoms). The added benefit was generally smaller than the effect of the initial medication. However, combination therapy was more frequently associated with a slowed heart rate, sedation, drowsiness, and low blood pressure. Side effects may be more severe with combination therapy. The duration of follow-up in the evaluated studies did not allow for conclusions regarding long-term side effects.²⁶

When used as adjunctive therapy with stimulants, alpha-2 agonists reduced ADHD symptoms overall with an effect size of 0.36 SMD. When administered in addition to stimulants, discontinuation rates were comparable to those with placebo; however, drowsiness occurred more frequently (in one out of every ten patients treated). Blood pressure-lowering and heart rate-slowing effects were more pronounced with extended-release clonidine and extended-release guanfacine. (Meta-analysis, k = 3, N = 726, p < 0.0001)²⁷

Studies
A large, randomized, double-blind, placebo-controlled study conducted over 9 weeks in 461 children and adolescents aged 6 to 17 who had only partially responded to a long-acting stimulant alone evaluated the addition of extended-release guanfacine (up to 4 mg/day) in the morning or evening. Both guanfacine groups showed greater improvement on the ADHD Rating Scale (ADHD-RS-IV) than the group receiving a stimulant plus placebo. No serious treatment-related adverse events occurred. However, mild to moderate side effects occurred more frequently than with the stimulant plus placebo, particularly drowsiness, fatigue, insomnia, dizziness, and abdominal pain. 3% of the guanfacine patients discontinued treatment for this reason, compared with 1% in the placebo group. Apparently, several publications are based on the same study.²⁸²⁹³⁰
An analysis of the same study showed that the additional administration of guanfacine—regardless of whether it was given in the morning or in the evening—also improved the child’s functional level in the early morning, as assessed by the parents (p < 0.01 in each case). Most side effects were mild or moderate.³⁰

Among the children and adolescents, the following achieved a reduction in symptoms of at least 40%: ²⁹

• 69.8% while taking guanfacine in the morning
• 70.3% taking guanfacine in the evening
• 57.9% lower than stimulant plus placebo

Among children and adolescents, the following groups achieved a reduction of at least 50%:

• 63.1% taking guanfacine in the morning
• 64.9% taking guanfacine in the evening
• 43.4% lower than stimulant plus placebo

Symptomatic remission (ADHD-RS-IV total score of 18 points or less) was achieved by:

• 61.1% on guanfacine in the morning
• 62.2% taking guanfacine in the evening
• 46.1% lower than stimulant plus placebo

The most common side effects of the combination were headaches (21.2%) and drowsiness (13.6%).²⁹

At the end of the study, the effect size was 0.377 SMD (guanfacine in the morning) and 0.447 (guanfacine in the evening), placing it in the small-to-moderate range—comparable to the 0.36 reported in the meta-analysis mentioned above.²⁸

An open-label study without a control group involving n = 75 children and adolescents aged 6 to 17 years who had been taking methylphenidate or amphetamine for at least one month and whose symptoms were not adequately controlled supplemented their treatment with gradually increasing doses of extended-release guanfacine over 9 weeks (1 to 4 mg per day, with a mean of 3.1 mg). 63 of the 75 participants (84.0%) completed the study. The ADHD-RS-IV total score decreased by an average of 16.1 points, corresponding to a reduction of 56.0% (p < 0.0001). The improvement was greater among participants previously treated with MPH (17.8 points) than among those previously treated with amphetamine (13.8 points). According to the physicians’ overall assessment, 73.0% of the participants showed improvement; according to the parents’ assessment, 84.1% did. The most common treatment-related side effects were upper abdominal pain (25.3%), fatigue (24.0%), irritability (22.7%), headache (20.0%), and drowsiness (18.7%). Most side effects were mild to moderate. The authors assessed the combination as safe overall.³¹
An analysis of billing data also found that children and adolescents who had previously taken their stimulant irregularly adhered to their medication more consistently after receiving an additional dose of extended-release guanfacine. The medication adherence rate rose from 0.68 to 0.87. However, only the 165 patients with the poorest baseline values were included in the analysis. With such a selection, an improvement is to be expected for statistical reasons alone. Among the 1,209 patients who had previously adhered to their treatment, the rate, by contrast, fell slightly from 0.95 to 0.92.³²

A double-blind, placebo-controlled crossover study of 50 children aged 6 to 12 with ADHD who were already receiving a stimulant found that the additional administration of extended-release guanfacine improved executive functions (BRIEF-P parent questionnaire, p = 0.04), ADHD symptoms (ADHD-RS-IV, p < 0.001), and the overall clinical impression (p = 0.0007 and p = 0.003, respectively). No serious side effects occurred, and no participant discontinued treatment with guanfacine due to side effects. However, certain side effects were significantly more common than with placebo, particularly fatigue (23% vs. 2%), abdominal pain (30% vs. 10%), and mood swings (13% vs. 2%).³³ Interestingly, drowsiness occurred in only 11% of participants here, whereas it was reported in approximately 44% in studies of guanfacine as monotherapy. The authors attribute this to the interaction between the stimulant and guanfacine.³³ An analysis from another study examined how guanfacine, d-methylphenidate, and their combination affect the resting EEG and found a distinct pattern of effect on brain activity for each of the three treatments.³⁴

A randomized, double-blind, 8-week comparative study involving 207 children aged 7 to 14 years compared monotherapy with d-MPH extended-release (5–20 mg/day) or immediate-release guanfacine (1–3 mg/day) with the combination of both. It found a small but consistent benefit of combination therapy in terms of reducing the inattentive subscale scores on the ADHD-RS-IV, as well as a higher response rate than with monotherapy. No serious adverse events occurred in any of the three study arms. Sedation, somnolence, lethargy, and fatigue were more pronounced with monotherapy using guanfacine than with combination therapy. All treatments were well tolerated. The response rates (as assessed by the physician as “very much” or “much” improved) were as follows:³⁵

• Guanfacine alone: 69%
• d-methylphenidate alone: 81%
• Combination of d-methylphenidate and guanfacine: 91%

When a more stringent criterion is applied (physician assessment plus the ADHD-RS-IV score at the end of the study), the rates drop to 63% (guanfacine), 62% (d-methylphenidate), and 75% (combination therapy).³⁵

A follow-up analysis of the same study found that higher levels of hyperactivity and impulsivity, as well as oppositional behavior, combined with lower levels of anxiety, predicted greater improvement in all three treatment groups.²

An analysis of the same study involving 182 children aged 7 to 14 examined four cognitive domains: working memory, inhibitory control, reaction time, and reaction time variability. Differences between the treatments were observed only in working memory. The combination treatment with d-MPH and guanfacine improved working memory more than guanfacine alone, but was not superior to d-MPH alone. The working memory deficit observed at baseline in the ADHD group compared with a non-ADHD control group (SMD 0.53) was not fully compensated for by any of the treatments.³⁶

In the same study group, the cardiovascular effects were evaluated separately: Guanfacine alone reduced heart rate as well as systolic and diastolic blood pressure, while d-MPH alone increased heart rate, both blood pressure readings, and the QTc interval. The combination increased only diastolic blood pressure and had no effect on heart rate, systolic blood pressure, or QTc interval. The combination thus had, overall, fewer cardiovascular effects than monotherapy with d-MPH.³⁷

A single-center RCT studied 26 adults aged 19 to 62 with ADHD who had an unsatisfactory response to a stimulant alone. Over a 10-week period, they additionally received either extended-release guanfacine at an individually adjusted dose of 1 to 6 mg or a placebo. Both groups showed significant improvement. However, the guanfacine group was not superior to the placebo group in terms of either efficacy or tolerability. No increase in side effects was observed.³⁸ For adults, the evidence regarding the adjunctive use of guanfacine is thus significantly weaker than for children and adolescents. Guanfacine is not approved for adults in either Germany or the United States. Two drug interaction studies in healthy adults found that blood levels do not change in a clinically significant way when guanfacine sustained-release is taken concomitantly with lisdexamfetamine (Vyvanse) or with sustained-release MPH, and that the combination does not cause any new side effects.²³²⁴ In the LDX study, one participant had to discontinue the study because he could not tolerate the combination. In the methylphenidate study, 16 of the 38 participants (42.1%) experienced at least one side effect, most commonly headaches and dizziness; two participants developed notable ECG findings two hours after taking the combination; these were mild and resolved on the same day. It was also notable that the effects on heart rate and blood pressure partially counteracted each other when the drugs were administered concurrently—the same finding as in the aforementioned study of children.²⁴ In one case, it was reported that clonidine, administered as an adjunct, was able to eliminate MPH-induced nighttime teeth grinding.³⁹ One person with ADHD reported to us that clonidine alleviated their muscle tension.

It would be interesting to see whether guanfacine/clonidine might also be able to reduce tension-relieving behaviors (such as nail-biting or lip-biting) that sometimes occur as side effects of stimulants. A single case report is not sufficient evidence for this.
A review article describes clonidine as an additional treatment option to stimulants for ADHD. According to the article, up to 30% of children and adolescents do not respond adequately to stimulants. For these individuals, the additional administration of an α2-adrenoceptor agonist may further reduce symptoms. The two classes of medications may complement each other by jointly improving the regulatory function of the prefrontal cortex. The older studies were conducted using immediate release clonidine, which must be taken several times a day and reaches high blood levels more rapidly than the newer extended-release formulation.⁴⁰ Nevertheless, guanfacine is likely the preferred choice today: Guanfacine acts much more selectively on the α2A receptor, whereas clonidine also acts on the α2B and α2C receptors, which explains the greater sedation and more pronounced blood pressure reduction observed with clonidine.

In a 5-week RCT, the ADHD-RS-IV total score improved more significantly with clonidine extended-release plus a stimulant than with placebo plus a stimulant (95% confidence interval −7.83 to −1.13; p = 0.009). The same was true for the subscales of hyperactivity (p = 0.014) and inattention (p = 0.017), as well as the global clinical impression (p = 0.021 and p = 0.006) and the parental rating (p = 0.001). Side effects and cardiovascular changes were predominantly mild.⁴¹ This is one of the five studies that are likely to have been included in the AHRQ meta-analysis ²⁵.

A small Japanese retrospective analysis of treatment courses suggests that concomitant administration of methylphenidate or atomoxetine may reduce the risk of discontinuing guanfacine due to drowsiness.⁴² The same analysis also shows how often drowsiness actually leads to discontinuation: 44% of discontinuations occurring within 70 days were due to drowsiness, compared with 8.3% of later discontinuations (p = 0.008). Among patients not taking a concomitant ADHD medication, the difference was 55.0% versus 7.1% (p = 0.009). No difference was observed among patients taking a concomitant ADHD medication.⁴²

5. Atomoxetine in combination with other ADHD medications¶

5.1. Atomoxetine and Stimulants¶

In Germany, a combination of atomoxetine and other ADHD medications is not approved.

In the U.S., a data analysis⁴ found such a combination in

• 36.1% of the months of atomoxetine treatment among people with ADHD who are Medicaid-insured (all age groups)
• 22.2% of the treatment months with atomoxetine for privately insured people with ADHD aged 6 to 17
• 9.8% of the treatment months for people with ADHD who are privately insured and aged 18 or older

The prevalence of co-occurrence decreased significantly with age. Compared to 6- to 12-year-olds, the adjusted odds ratio for those over 45 was 0.40. Girls and women were less likely to have a co-occurrence than boys and men (0.74). Comorbidities were significantly more common in ADHD with hyperactivity (1.81) and in cases accompanied by tics or Tourette syndrome (2.33).⁴

Reviews and recent studies report that the combined administration of atomoxetine and stimulants is generally well tolerated and can be effective.^{4344 11} This also applies during a medication-switching phase, in which case blood pressure and pulse should be monitored.⁴⁵ For the switch itself, a gradual approach with slow up-dosing in small increments is recommended, as this mitigates side effects during the first few weeks; atomoxetine can then be discontinued abruptly without the expectation of rebound or withdrawal symptoms. At least 6 to 8 weeks should elapse before evaluating efficacy and tolerability.⁴⁵ A Turkish review of clinical records identified 12 out of 824 ADHD patients treated over four years who received combination therapy with atomoxetine and methylphenidate. The 12 people with ADHD were between 7 and 17 years old; the clinical severity score decreased on average from 5.08 to 3.08 points (p = 0.03), and 75% experienced a significant improvement in symptoms. The most common side effects were irritability (5 out of 12), decreased appetite (3), palpitations (2), and headaches (1).⁴⁶ A review article found mixed results.²⁶ Another systematic review included six retrospective studies, three of which contained efficacy data. Two of these found a significant improvement in symptoms in patients who did not respond to monotherapy after switching to the combination therapy, while one found no difference.⁴⁷ One of these studies, conducted in South Korea, analyzed the treatment records of 96 children aged 6 to 12 years. Thirty-four received methylphenidate and atomoxetine together, 32 received only methylphenidate, and 30 received only atomoxetine. The combination was prescribed when monotherapy was not sufficiently effective (44%), had a too-short duration of action (30%), or could not be increased in dose due to side effects (27%). After switching to the combination, the overall clinical impression improved significantly (p < 0.001). Twenty-three of the 34 children (68%) achieved the remission threshold typically used in studies. Thirty-two percent of the 34 children developed new side effects, most commonly loss of appetite, which led 2 of them to discontinue treatment.⁴⁴

Of the four studies in the same review that examined treatment adherence, three found better adherence with the combination therapy than with monotherapy. One study, however, found that the additional prescription of atomoxetine facilitated the discontinuation of methylphenidate. The authors rate the evidence from these studies as low.⁴⁷

Ryffel-Rawak cites a personal communication from J. Krause stating that atomoxetine is particularly effective when used in combination with stimulants.⁴⁸ Brown presents four case studies intended to demonstrate how atomoxetine and stimulants can be used together either to prolong the duration of action without causing intolerable side effects or to address a broader range of distressing symptoms than any of the active ingredients can address on their own.⁴⁹ Mason⁵⁰ reports that in 2003, when atomoxetine was introduced to the market, he switched 35 children with ADHD from stimulants to atomoxetine. To ensure as smooth a transition as possible, the previous stimulant dose was first halved in the first step and supplemented with half the target dose of atomoxetine. After 14 days, in the second step, the patients were fully transitioned to the target dose of atomoxetine. Surprisingly, about half of the people with ADHD asked to continue the combination of reduced stimulants and half the atomoxetine dose. This combination therapy proved to be very successful. Most people with ADHD significantly reduced their previous stimulant dose. Side effects were less severe than in people with ADHD who received stimulants alone. In particular, people with ADHD who were undergoing combination therapy reported that their family life had improved because the meltdowns—which many families had come to regard as normal outside the stimulants’ active period—had decreased. This seems to us to be a plausible consequence of the fact that atomoxetine, as a maintenance medication, remains effective for almost the entire day, whereas stimulants have only a limited duration of action during the day.

Mason—a physician who describes his clinical experience in a magazine for people with ADHD and, according to the list of authors of a manufacturer-sponsored study published in 2015 (⁵¹ ), served on a medical advisory board for Eli Lilly—also recounts a personal conversation he had with Timothy Wilens in 2006.⁵⁰At the time, Wilens had conducted a study at Harvard in which high doses of atomoxetine and sustained-release MPH (Concerta) were combined to determine the maximum possible reduction in symptoms. The patients who completed the study reportedly showed symptom reductions of more than 90%. However, the crucial point is the sentence that follows immediately: The dosages required for this caused intolerable side effects in many participants. Mason himself points out that this is common in dose-optimization studies because participants are expected to tolerate side effects in order to measure the technically best possible improvement. In practice, however, care is taken to keep side effects within acceptable limits. He treats his own patients with significantly lower doses. Since this is a transcript of a conversation and not a published article, this claim cannot be verified.
A systematic review evaluated 16 publications. It showed that combination therapy with atomoxetine and stimulants was usually prescribed due to an unsatisfactory response to monotherapy. Most of the participants were male children and adolescents with ADHD-C. The most commonly reported combination was atomoxetine with methylphenidate. In some, but not all, of the people with ADHD, the combination therapy improved symptoms. No serious adverse events were reported. According to the authors, their analysis suggests that this combination of active ingredients benefits some people with ADHD who have tried multiple ADHD medications without success. (Meta-analysis, n = 16)⁵²
When evaluating this section, it is important to note that a large portion of the literature on the combination with atomoxetine was funded or co-authored by the manufacturer of the active ingredient—this applies to the review article cited here⁵² as well as to the prescription data cited above⁴ and the information on the transition phase.⁴⁵

An open-label study without a control group involving children and adolescents aged 6 to 17 years examined what happens when people with ADHD who only partially respond to atomoxetine are given sustained-release MPH (OROS, up to 54 mg) as an adjunct. Initially, all participants received atomoxetine alone for at least 4 weeks. The partial responders then received MPH in addition for 3 weeks. Fifty people with ADHD received the combination; 41 completed the study. The ADHD rating scale score decreased by 40% with the combination, and executive functions improved. The overall clinical impression also improved significantly (p < 0.0001).⁵³ However, the additional administration of MPH led to an accumulation of side effects. Insomnia rose from 14% to 52%, loss of appetite from 14% to 44%, and irritability from 16% to 32%. Loss of appetite and insomnia were thus approximately twice as high as in short-term studies with sustained-release MPH alone. Fatigue, on the other hand, decreased from 34% to 10%. Diastolic blood pressure rose slightly but significantly. No significant changes were observed in the ECG, liver function tests, or atomoxetine blood levels. Most side effects occurred after the first week of combination therapy, which is why the authors recommend paying particular attention during this period.⁵⁴ The authors themselves emphasize that, before making specific recommendations, a repeat study under controlled conditions with an appropriate control group is necessary.

Another study also reports significant improvements in symptoms with combination therapy using atomoxetine and methylphenidate compared to monotherapy.⁴⁶

Mason⁵⁰ reports from his own medical practice that most of his adult ADHD patients take sustained-release stimulants, which typically last 8 to 10 hours, which is why most of them also need immediate-release medications to get through the day.

In contrast, patients in his practice who take a combination of atomoxetine and stimulants use low- to moderate-dose stimulants and report that the effects last for more than 12 hours.
Mason reports on individual cases:

• In one case, the previous dose of 72 mg of MPH per day (which had resulted in an unsatisfactory 25% reduction in symptoms) was changed to 27 mg of MPH and 60 mg of atomoxetine per day. This resulted in an 80% reduction in symptoms, which persisted for many years without any signs of tolerance.
• In another individual case, reducing the dose of an amphetamine-based medication (Adderall) from 50 to 30 mg/day while simultaneously administering 40 mg/day of atomoxetine led to an improvement in symptom reduction to 67%.
• A further improvement, with symptom reduction now at 74%, was achieved by switching from 50 mg of Adderall to 50 mg of Vyvanse (known as Elvanse in the EU), which is equivalent to 20 mg of Adderall, while continuing the 40 mg dose of atomoxetine.

Mason himself points out that not every person with ADHD experienced such improvements by switching to a combination therapy of atomoxetine and stimulants. Mason also refers to the experiences of other physicians who achieved similarly positive effects by supplementing stimulants with guanfacine, bupropion, or antidepressants.⁵⁰ A neurologist known to us frequently used a combination of stimulants and bupropion (due to bupropion’s stimulating effect, usually for ADHD-I, not for ADHD-HI or ADHD-C).

One review cites an inadequate response to stimulants alone as an indication for the co-administration of stimulants with atomoxetine as an adjunct.¹¹
A retrospective analysis of treatment records from a Korean university outpatient clinic from 2009 to 2019 compared four groups formed based on the physicians’ decisions: atomoxetine alone, methylphenidate alone, both active ingredients sequentially, and both active ingredients simultaneously. The two groups receiving monotherapy discontinued treatment significantly more often than the groups receiving both active ingredients. For patients aged 18 and older, the risk of discontinuation was additionally increased by a factor of 1.21.⁵⁵

In a lecture, Barkley discusses the benefits of combining stimulants with atomoxetine to counteract the suppression of the limbic system caused by stimulants and the resulting reduction in emotional perception.⁵⁶

A study (funded, however, by Lilly, the manufacturer of atomoxetine) found no advantage in symptom improvement with combination therapy using atomoxetine and other ADHD medications compared to monotherapy (possibly because prescribing was based on the individual needs of the people with ADHD by the treating physicians and was not uniform across all participants in a group), but it also did not result in more side effects than with monotherapy with atomoxetine. At the final follow-up, the combination group actually experienced side effects significantly less frequently than the monotherapy group (35.8% versus 54.9%; p = 0.012). No serious side effects occurred in either group. However, the authors do not attribute the difference to the combination itself, but rather to the fact that participants in the combination group had more frequently taken ADHD medications previously and that treatment in both groups was often administered at doses below the recommended levels.⁵¹ The study included 191 patients (82 in the monotherapy group, 109 in the combination group), with an average treatment duration of 264 days. Two-thirds of the combination treatments were initiated because monotherapy had been ineffective. There was no significant difference in treatment discontinuation rates (35.4% versus 29.4%).
Atomoxetine alone has significantly more side effects than stimulants alone.

Methylphenidate and atomoxetine both increase the efficiency of prefrontal pyramidal neurons, though through different mechanisms:⁵⁷¹³⁵⁸

• Methylphenidate reduced nonspecific signals—that is, neural noise—via D1 receptors
• Atomoxetine increased the strength of specific signals related to the activation of alpha-2 receptors.

This is one possible reason why a combination of these active ingredients may be beneficial for patients with ADHD who do not respond optimally to monotherapy.

Based on our observations, a combination of atomoxetine and stimulants is an appropriate method for treating ADHD. It combines the benefits of atomoxetine (all-day efficacy, particularly for symptoms of emotional dysregulation) and stimulants (increased daytime drive). When combining atomoxetine with amphetamine-based medications, it is important to note that both active ingredients are metabolized by the CYP2D6 enzyme (primarily for atomoxetine, secondarily for amphetamine) and may therefore mutually enhance each other’s effects and side effects. In individuals with naturally low CYP2D6 activity (“poor metabolizers,” approximately 7% of the Central European population), this can cause blood levels of both active ingredients to rise significantly, so lower doses may be necessary.⁶

5.2. Atomoxetine and hopantenic acid¶

Hopantonic acid (N-pantoyl-GABA) is more commonly used in Russia to treat ADHD. It is not approved in the U.S. or the EU.
The evidence regarding hopantenic acid is too inconclusive to recommend treatment with it.
A randomized, double-blind, placebo-controlled, multicenter study of hopantenic acid for ADHD enrolled children aged 6 to 12 years receiving outpatient treatment at four centers, of whom 45 received hopantenic acid (30 mg/kg/day, in two doses, over four months) and 44 received a placebo. After three and four months, respectively, 66.7% and 68.9% of those receiving hopanthenic acid achieved a symptom reduction of more than 25%, compared with 52.3% and 61.4% of those receiving placebo. The advantage of the active drug group was thus only about 8 to 14 percentage points.⁵⁹
The CGI severity score decreased significantly. Significant improvements were observed in four of the six WFIRS-P domains. The incidence of adverse events did not differ from that of placebo.

An open-label, non-randomized pilot study examined 24 children aged 6 to 11 (16 boys, 8 girls, mean age 9.2 years) with hyperkinetic disorder of social behavior (ICD-10 F90.1), in whom treatment with atomoxetine at an adequate dose for at least 3 months had not been sufficiently effective. In addition, they received hopanthenic acid (Pantogam) at a dose of 500 to 1,250 mg per day, depending on their age and response to treatment. The severity of ADHD symptoms decreased from 24 to 18 points after one month and to 15 points after two months. The social functioning score (CGAS) rose from 41.2 to 50.5 to 54.7 points, and the Clinical Global Impression (CGI) improved from 3.8 to 2.5 to 1.9. Just under 70% of the children showed significant improvement, 25% showed minor improvement, and 5% (primarily older children receiving inpatient treatment with severe comorbid conditions) showed no change. The areas showing the greatest improvement on the CHIP-CE quality-of-life scale were academic performance (from 23.6 to 34.7) and risk avoidance (from 26.8 to 37.8).⁶⁰ A case report by the same lead author describes a 9-year-old boy in whom atomoxetine improved hyperactivity and distractibility, but behavioral problems persisted. It was only the additional administration of up to 750 mg of Pantogam daily that led to an improvement starting in the second week, which continued to increase over two months and remained stable after three months.⁶¹

In a mouse model of attention deficit disorder, hopanthenic acid reduced the density of dopamine D2 receptors in the prefrontal cortex by 22%, which was slightly greater than the reduction observed with atomoxetine (14%). In addition, it increased the density of GABA-B receptors by 44%. However, both active ingredients improved attentional behavior only in those mice that had previously exhibited a marked attention deficit.⁶²

6. Viloxazine and Stimulants¶

Viloxazine can be combined with:

• Methylphenidate⁶³
• Lisdexamfetamine⁶⁴

An open-label study without a control group (Phase 4) involving 56 children and adolescents aged 6 to 17 who did not respond adequately to a psychostimulant alone supplemented their treatment with Viloxazin retard over 8 weeks—in the morning for the first 4 weeks, and in the evening thereafter. The ADHD score (ADHD-RS-5) decreased from an average of 37.2 points by 13.5 points after 4 weeks and by 18.2 points after 8 weeks (p < 0.0001 in both cases). The overall clinical impression improved accordingly. Improvements in morning and evening behavior, as well as in sleep, occurred regardless of whether Viloxazine was taken in the morning or in the evening. The most common side effects were headaches (17.9%), decreased appetite (12.5%), and respiratory tract infections (10.7%). It is noteworthy that drowsiness—the most common side effect at approximately 16% when viloxazine was used as monotherapy—practically did not occur here (1.8%), while insomnia, at 8.9%, was more common than when viloxazine was used alone. This is the same pattern observed with guanfacine and is consistent with what would be expected with concomitant stimulant use.⁶⁵
All of the studies on viloxazine cited here were conducted by the manufacturer, Supernus.⁶³⁶⁴⁶⁵

7. Bupropion and Stimulants¶

A neurologist we know often used a combination of stimulants and bupropion (due to bupropion’s stimulating effect, usually for ADHD-I, not for ADHD-HI or ADHD-C).
When combining bupropion with amphetamine-based medications, it is important to note that bupropion is a potent inhibitor of the CYP2D6 enzyme and can therefore slow the breakdown of amphetamine. This can cause amphetamine levels to rise, which is equivalent to an increase in dose, so correspondingly lower doses of amphetamine may be required.⁶ Bupropion increases the risk of epileptic seizures in the brain.⁶⁶⁶⁷
Several people with ADHD reported to us that co-administration of bupropion extended the duration of action of amphetamine-based medications—which had previously been too short—to an appropriate level. Pharmacologically, this is plausible, as bupropion inhibits CYP2D6. However, the targeted use of this interaction has not been studied and must under no circumstances be attempted on one’s own initiative.

8. MAO inhibitors and stimulants¶

According to the prescribing information for all commonly used stimulants, the concurrent use of stimulants and MAO inhibitors is contraindicated. It can trigger a hypertensive crisis—that is, a life-threatening rise in blood pressure. This risk arises not from altered metabolism in the liver, but from the cumulative effects on the norepinephrine system.
Even after discontinuing an irreversible MAO inhibitor, a safety interval of at least 14 days must be observed.
Reports of successful combinations come from specialized centers that closely monitor blood pressure. Such a combination should be initiated only by experienced specialists and never on one’s own initiative.

A review article on the co-administration of stimulants and MAO inhibitors for depression reports that experienced clinicians use this combination—despite the risk of a hypertensive crisis or other serious complications—when other treatment options have been exhausted.⁶⁸ A case report describes the successful co-administration of low-dose transdermal selegiline and lisdexamfetamine (Vyvanse) for ADHD and comorbid depression.⁶⁹ Low-dose transdermal selegiline primarily inhibits monoamine oxidase B and has barely any effect on the gut. It therefore carries a lower risk of drug interactions than classic, non-selective MAO inhibitors. The case report does not apply to these agents.⁶⁹

9. MPH and Tipepidine¶

Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) is a synthetic, non-opioid cough suppressant (antitussive). By inhibiting GIRK channels, tipepidine increases dopamine levels in the nucleus accumbens without, however, increasing motor activity or producing methamphetamine-like behavioral sensitization.
It has been used in Japan since 1959 and, due to its lack of stimulant properties, could be an interesting alternative to MPH and AMP.⁷⁰
A small, open-label pilot study without a control group involving 10 children (average age 9.9 years) found a significant improvement in all scores on the ADHD rating scale after 4 weeks of daily treatment with 30 mg of tipepidine (p < 0.001). Cognitive performance showed only a trend toward improvement (p = 0.093). Tipepidine was well tolerated. No participant discontinued treatment due to side effects.⁷¹
A randomized, double-blind, placebo-controlled study conducted over 8 weeks in 53 children compared methylphenidate plus tipepidine with methylphenidate plus placebo. The addition of tipepidine was superior to the placebo; both treatments were similarly well tolerated.⁷² However, a crucial factor for everyday clinical practice in Germany is that tipepidine is commercially available exclusively in Japan and is neither approved nor available in Germany.

10. Desipramine and Stimulants¶

A retrospective analysis of treatment records for 142 children and adolescents aged 6 to 17 (113 on desipramine alone, 29 on desipramine plus a stimulant, for a total of 401 blood level measurements) found no difference in desipramine blood levels between the two groups. Pharmacokinetic interactions are therefore not to be expected with this combination.⁷³
Desipramine is the active metabolite of imipramine. Desipramine medications are now largely no longer available on the market. One reason for this is reports of sudden deaths in children taking tricyclic antidepressants.⁷⁴ ECG monitoring is required before and during treatment.

11. Antipsychotics Along with Stimulants¶

The review article mentioned earlier found that the adjunctive use of risperidone or divalproex improves the response to stimulant monotherapy in cases of comorbid aggression and social disorder. The evidence is strongest for risperidone. Adverse effects include a significant increase in prolactin levels and weight gain, despite short study durations and low doses of risperidone (less than 2 mg per day).²⁶

In clinical practice, stimulants and antipsychotics are often prescribed together without this being viewed as problematic—even though their mechanisms of action are contradictory (see below). A review article on this topic concludes that, upon closer examination of dopamine pathways and receptors, the concerns regarding this combination are justified and significant, and calls for a careful benefit-risk assessment. At the same time, the author discusses a concept he calls the “Complex Dopamine Theory”: According to this theory, low doses of both classes of drugs could reduce the risk of developing tolerance and experiencing side effects.⁷⁵ An analysis of health insurance data found that among 39,981 children and adolescents aged 6 to 16 who newly initiated treatment with a long-acting stimulant, 1,560 (3.9%) were also prescribed an atypical antipsychotic for at least 14 days.⁷⁶ The same analysis found that children who also received an atypical antipsychotic took their stimulant for an average of 71 days longer than children on stimulants alone (approximately 200 days versus 143 days).⁷⁶ However, these children were significantly more severely affected and received more intensive treatment overall: A diagnosis of psychosis or profound developmental disorders was present in 22.3% of them, compared with 2.9% of the others; 47.2% received antidepressants, compared with 13.6%, and 28.2% received alpha-2 agonists, compared with 7.6%. Therefore, no conclusion regarding the efficacy advantage of the combination can be drawn from these findings.⁷⁶
Even a low-dose neuroleptic augmentation improved symptoms: In a double-blind crossover study, 14 children who responded only partially to a stimulant were additionally given either periciazine (max. 0.2 mg/kg) or a placebo for 2 weeks. According to teacher ratings (Conners Scale), the combination was superior to the higher dose of stimulant plus placebo. In contrast, parent ratings showed no difference between the active ingredient and the placebo.⁷⁷ The active ingredient used, periciazine, is a classic phenothiazine and is no longer commercially available in Germany. In two children, the symptoms disappeared completely as soon as they received any supplemental medication—regardless of whether it was the active ingredient or a placebo. The authors suspect that the parents administered the MPH more carefully during the study.⁷⁷

The European ADHD Guidelines Group cites a specific application: If tics occur while taking stimulants, their progression should first be monitored for three months. If the tics are found to be stimulant-induced, options to consider include reducing the dose, switching to guanfacine, atomoxetine, or clonidine, adding an antipsychotic, or discontinuing the medication. If psychotic symptoms occur at therapeutic doses, the NICE guidelines recommend reducing the dose or discontinuing the medication. Once the symptoms have subsided, a renewed attempt at treatment may be considered.¹⁶

An older study compared four treatments for hyperactive children: MPH alone, thioridazine alone, a combination of the two, and a placebo. The active treatment lasted 12 weeks, and the placebo period lasted 4 weeks. All three active treatments were superior to the placebo. The combination tended to be more effective than MPH alone at the beginning, but this was no longer the case after 12 weeks. MPH alone and the combination were more effective than thioridazine alone. The most common side effects of MPH were decreased appetite, difficulty falling asleep, and increased mood sensitivity, whereas the most common side effects of thioridazine were increased appetite and bedwetting.⁷⁸ Thioridazine has since been withdrawn from the market due to serious cardiac arrhythmias and is no longer considered a treatment option.

A Turkish cross-sectional study of 547 children aged 6 to 12 (152 people with ADHD who are untreated, 156 on stimulants, 53 on stimulants plus an antipsychotic, and 186 healthy control children) found the following obesity rates:

• 13.8% of people with ADHD who are not receiving treatment
• 4.5% of people with ADHD are on stimulants alone
• 7.5% of people with ADHD on combination therapy
• 8.6% healthy controls

Both people with ADHD and the combination therapy group exhibited behavior more focused on eating, with the combination therapy group also showing increased eating driven by emotional factors.⁷⁹ Atypical antipsychotics are said to have an even stronger effect in terms of weight gain and metabolic syndrome.⁸⁰

The idea that stimulants significantly alleviate the metabolism-related side effects of antipsychotics (weight gain, metabolic syndrome) has not been confirmed.⁸¹ Nor has there been any evidence to date of a consistent advantage of combination therapy with antipsychotics and stimulants over stimulant monotherapy. Some treatment guidelines recommend a combination of an antipsychotic and a stimulant for aggressive behavior—though explicitly only as a third-line treatment, that is, after stimulant monotherapy and a combination of stimulants with behavioral therapy interventions have proven insufficient. To date, this combination has been examined in only a few studies; the authors believe that further research on efficacy and tolerability is necessary.⁸²
There is no evidence of the overall superiority of combination therapy for ADHD. In the specific case of comorbid aggression, there is limited evidence of its benefit as a third-line treatment.
A retrospective analysis of 44 treatment cases in French child psychiatry examined the combination of MPH and risperidone. Twenty-eight children had initially received MPH, and 16 had initially received risperidone. Almost all had been diagnosed with ADHD. In over 60% of the children, the dual treatment—regardless of which medication had been started first—reduced symptoms of ADHD and conduct disorder, as well as sleep disturbances and anxiety.⁸³

While stimulants increase dopamine levels and dopamine activity—that is, they act as agonists—antipsychotics act as dopamine antagonists. At first glance, this makes their co-administration seem contradictory and illogical. However, they act on different receptor subtypes and brain regions: The primary effect of antipsychotics is to block mesolimbic D2 receptors, while stimulants increase synaptic dopamine in the mesocortical system. The authors speculate that the interaction between antipsychotics and stimulants is far more complex, as both agents also exert effects outside the brain regions mentioned.⁸⁰

12. Combination Medication with Other Substances¶

The active ingredients listed below are not prescription medications. They can support the treatment of ADHD, as can the additional intake of vitamins, minerals, or polyunsaturated fatty acids.
The following section presents studies that were specifically designed to examine combination therapy with stimulants. However, the administration of vitamins, minerals, or polyunsaturated fatty acids alongside stimulants does not raise any particular concerns; it should, however, only be done after prior testing of blood levels, as an overdose of vitamins or minerals can have significant adverse effects. A large portion of the studies listed below come from the same research group and follow the same study design. Independent replication studies are largely lacking to date.

⇒ Vitamins, Minerals, and Dietary Supplements for ADHD

12.1. Resveratrol in Combination with MPH¶

Resveratrol is an antioxidant.
A randomized, double-blind, placebo-controlled study conducted over 8 weeks in 66 children with ADHD evaluated 500 mg of resveratrol daily in addition to their regular MPH treatment. In the parent assessment (ADHD-RS), all three subscales showed greater improvement than with placebo (overall p-value = 0.015). No difference was observed in the teacher assessment. It should be noted that the placebo group also showed a very significant improvement—the parent rating score decreased from 34.1 to 10.9 points in that group, compared to a decrease from 33.9 to 8.5 points in the resveratrol group. The difference between the two groups was therefore small. Side effects occurred with similar frequency in both groups, with loss of appetite and headaches being the most common.⁸⁴ The fact that an effect is evident only in the parental assessment and not in the teacher assessment is a well-known warning sign of a nonspecific effect, since blinding is practically never complete among parents.

12.2. L-Carnosine Alongside MPH¶

L-carnosine is a bioactive dipeptide consisting of the amino acids β-alanine and histidine.
A randomized, double-blind, placebo-controlled study conducted over 8 weeks in 56 previously untreated children and adolescents aged 6 to 17 years evaluated 800 mg of L-carnosine daily (divided into two doses) in addition to the MPH they were already receiving (0.5 to 1.5 mg/kg). Fifty participants completed the study. Positive effects were observed only in the parental assessments, but not in the teacher assessments.⁸⁵ An effect observed solely in the parental assessments is more likely to reflect a placebo effect than a specific therapeutic effect.

12.3. Zinc sulfate in combination with MPH¶

A randomized, double-blind, placebo-controlled study conducted over 6 weeks in 44 children aged 5 to 11 years (mean age 7.9 years) evaluated 55 mg of zinc sulfate daily —equivalent to approximately 15 mg of elemental zinc—in addition to the standard dose of MPH (1 mg/kg). According to both parental and teacher assessments, the children’s scores improved more significantly with zinc sulfate than with placebo.⁸⁶ The study was conducted in a region with widespread zinc deficiency (Tehran, Iran). It remains unclear whether these findings can be generalized to well-nourished populations. Zinc supplementation should therefore only be administered after determining zinc levels, especially since a chronic excess of zinc impairs copper absorption.

12.4. L-methylfolate in addition to MPH¶

A 12-week randomized, double-blind, placebo-controlled study involving 44 adults with ADHD evaluated the addition of 15 mg of L-methylfolate to optimally titrated MPH (OROS methylphenidate). The study found no improvement. On the contrary, participants in the L-methylfolate group required higher doses of MPH over the course of the study (p = 0.007).⁸⁷

13. Combination Therapy with ADHD Medications for Comorbid Conditions¶

To avoid duplication, see Medication Selection for ADHD or ADHD with Comorbidities

13.1. Combination Medication and Risk of Psychosis¶

A retrospective cohort study examined the risk of psychosis among patients receiving monotherapy and combination therapy for ADHD. The study analyzed the treatment histories of 5,171 children and adolescents aged 6 to 18 with ADHD who had not previously been diagnosed with psychosis. Psychotic symptoms were diagnosed for the first time in 134 of them (2.6%) during the course of the study. An increased risk was found for amphetamine (hazard ratio 1.41) and for atomoxetine (HR 2.01), in each case compared to not using the respective active ingredient.⁸⁸
The following table lists the incidence of psychotic symptoms by combination of active ingredients. Please note: These are raw figures without statistical adjustment, some of which are based on very small subgroups. They do not allow us to conclude that the medications caused the psychosis. Atomoxetine and alpha-2 agonists are primarily used in more complex cases, and ADHD itself is associated with an increased risk of psychosis even without medication.

Combination therapy	Cases / People with ADHD	Proportion with psychotic symptoms	Odds ratio (95% CI)	Proportion relative to the overall average (100% = overall average)	Proportion relative to atomoxetine monotherapy (100%)
Amphetamine + α-2 agonist	1 / 90	1.11%	not reported	34%	66%
Atomoxetine monotherapy	2 / 119	1.68%	1.22 (0.28–5.24)	51%	100%
α-2 agonist monotherapy	2 / 96	2.08%	not reported	63%	124%
Methylphenidate monotherapy	42 / 1,869	2.25%	1.64 (0.97–2.76)	68%	134%
Methylphenidate + Amphetamine + α-2 Agonist	7 / 271	2.58%	1.89 (0.80–4.47)	78%	154%
Amphetamine monotherapy	14 / 501	2.79%	2.05 (1.04–4.04)	84%	166%
Methylphenidate + Amphetamine	25 / 690	3.62%	2.68 (1.50–4.79)	109%	215%
Atomoxetine + α-2 agonist	1 / 26	3.85%	not reported	116%	229%
Methylphenidate + α-2 agonist	17 / 397	4.28%	3.20 (1.68–6.06)	129%	255%
Atomoxetine + methylphenidate + amphetamine + α-2 agonist	5 / 109	4.59%	3.43 (1.27–9.23)	139%	273%
Atomoxetine + methylphenidate + amphetamine	10 / 140	7.14%	5.48 (2.54–11.82)	216%	425%
Atomoxetine + Methylphenidate	12 / 156	7.69%	5.93 (2.88–12.25)	232%	458%
Atomoxetine + Amphetamine + α-2 agonist	3 / 34	8.82%	6.90 (1.96–24.26)	266%	525%
Atomoxetine + Methylphenidate + α-2 agonist	5 / 53	9.43%	7.42 (2.70–20.44)	285%	561%
Atomoxetine + Amphetamine	6 / 48	12.50%	10.18 (3.92–26.41)	378%	744%
Overall average	152 / 4,599	3.31%	–	100%	197%