Choosing a Medication for ADHD or ADHD with Comorbidities

“Treating ADHD is easy. Treating ADHD effectively is very difficult.”

Selecting the medication that is most effective for each individual with ADHD and determining the optimal dosage is a challenge. Although there are a number of guidelines to follow, no clinically available factor is currently known that can reliably predict a patient’s response to ADHD medications. (E 2b)¹

Furthermore, the unique characteristics of each person with ADHD often put all established experience to the test. Since ADHD is a syndrome, its symptoms can stem from a wide variety of causes. Consequently, there is no one-size-fits-all treatment. If necessary, a wide range of different options must be tried out with great persistence for people with ADHD.

ADHD medications can be divided into two categories: stimulants and non-stimulants.

Stimulants such as methylphenidate (MPH) and amphetamine-based medications (AMP) have the advantage of having a high effect size while causing few side effects. (E 1a): There is no other class of medications in psychiatry with such a high effect size. (E 1a)²(E 4)³(E 4)⁴ Stimulants are among the medications with the highest effect sizes in psychiatry. In a cross-indication comparison of meta-analyses, they ranked among the most effective treatments overall.(E 1a)⁵ They generally take effect starting on the first day of use and can be discontinued at any time without withdrawal symptoms. In a placebo-controlled study of 146 adults, 76% responded to methylphenidate, compared to 19% on placebo. (E 1b)⁶ Similar or higher response rates are reported for amphetamine-based medications. A direct comparison of the two classes of active ingredients can be found in Arnold (2000). (E 1a)⁷However, stimulants can impair emotional perception if taken in excessive doses and are controlled substances.

Although non-stimulants such as atomoxetine and guanfacine offer the advantage of a longer duration of action, are more effective at addressing emotional dysregulation—the most subjectively distressing symptom of ADHD—and do not dampen emotional experience, However, their effect size is significantly lower, and the incidence of side effects is noticeably higher. In addition, due to the long time it takes for them to take effect and their long half-life, they are more difficult to dose than stimulants.

Furthermore, specific problem cases and comorbidities must be taken into account when selecting medication. For example, AMP, atomoxetine, or guanfacine can be used in patients who do not respond to various MPH preparations. If stimulants cause emotional disturbances despite avoiding excessively high doses, they can be replaced with atomoxetine or guanfacine, or administered at lower doses in combination with these medications.

A combination of stimulants and atomoxetine can improve motivation while reducing emotional dysregulation. Certain medications offer particular benefits for tic disorders, anxiety disorders, substance abuse, and other comorbidities.

The mechanisms of action of the various medications differ in terms of their binding affinity for transporters and their effects on dopamine and norepinephrine in different regions of the brain. It is important to tailor the medication to each individual in order to achieve the best possible effect with minimal side effects.
Among children with ADHD in the U.S. who were receiving medication and were also taking other psychiatric medications, the largest proportion was treated with stimulants alone (60% to 67%), followed by a combination of stimulants and non-stimulants (13% to 15%), a combination of stimulants and antidepressants (6% to 9%), and finally non-stimulants alone (5% to 9%). (E 3)⁸

When determining the dosage, it is important to take into account the often heightened sensitivity of people with ADHD to even slight differences in dosage or to the varying effects of different formulations containing the same active ingredient. This sensitivity is such that even switching from a generic drug to a supposedly bioequivalent formulation from another manufacturer can result in significant differences, including a loss of efficacy. This applies to both sustained-release and immediate-release stimulants, as well as non-stimulant medications. It is not the norm, but—as we know from the ADHD forum at ADxS.org—it is far more common than previously assumed. For more on this, see Dosage Adjustment for ADHD Medications.

As is the case throughout ADxS.org, all information is provided without guarantee. This information is not intended for self-medication, but rather to serve as a reference for a discussion with your doctor.

1. Advantages and Disadvantages of Various ADHD Medications¶

1.1. Stimulants¶

• Benefits (common benefits of stimulants)
  • Stimulants include methylphenidate and amphetamine-based medications.
    • See Methylphenidate (MPH) for ADHD
    • see Amphetamine-based medications for ADHD
  • Stimulants for ADHD occupy a unique position among all psychiatric medications: No other class of medications has such a high effect size combined with such few side effects. (E 1a)²
    • It is a good idea to compare the package inserts for aspirin, antidepressants, and methylphenidate
    • Stimulants have been used as ADHD medications for many decades—longer than barely any other class of drugs
  • Stimulants usually take effect starting on the first day of use
  • Stimulants can be discontinued at any time without the risk of withdrawal symptoms (unlike antidepressants, some of which can cause dependence and severe withdrawal side effects)
• Disadvantages (common disadvantages of stimulants)
  • Impaired emotional sensitivity in approximately 20% of people with ADHD due to the dampening effect of stimulants on the limbic system
    • Causes: Hypersensitivity or overdose
    • In this case, consider combination therapy with atomoxetine and MPH or AMP (at lower doses than those used in monotherapy)
  • Subject to narcotics control laws because of the theoretical possibility of abuse
  • (E 1a): Stimulants reduce the likelihood of developing an addiction. (E 4)⁹(E 1a)¹⁰ Stimulants do not increase the likelihood of developing an addiction.¹¹ Stimulant treatment during childhood did not alter the subsequent risk of substance use and substance use disorders (meta-analysis of longitudinal studies, k = 15, N = 2,565, E 2b)¹²
    • No risk of abuse when taken as directed (orally in medicinal doses)
    • At every train station and in every public restroom, there are better “spinning” options for less money and with less effort
    • However, there is a potential risk of drug use among people with ADHD who have acute or past amphetamine addiction. In such cases, it is better to try atomoxetine and guanfacine first.
    • Treating ADHD with stimulants as early as possible reduced the risk of developing addiction in adulthood: (E 2b)¹³
      • Individuals with ADHD have a 7.7-fold higher risk of substance use disorders compared to the general population (4.3 to 13.9).
      • For every additional year that stimulant treatment began later, the risk increased by a factor of 1.46 (95% CI 1.09 to 1.93). The duration of treatment, however, had no effect.
      • Women with ADHD are at a higher risk of addiction than men
      • A comorbid social behavior disorder in childhood further increased the risk by a factor of 4.77 (1.73 to 13.21).
• Methylphenidate (MPH)
  • Advantages:
    • particularly good increase in power
    • Short duration of action with immediate release (2.5 to 3 hours)
  • Disadvantages:
    • Non-responder rate: approximately 30%
      • MPH nonresponsiveness does not predict AMP nonresponsiveness
• Amphetamine-based medications (AMP)
  • Advantages
    • More effective at stabilizing mood than MPH
    • slightly greater effect size and slightly fewer side effects than MPH, especially in adults
  • Disadvantages:
    • Non-response rate: approximately 20%
      • AMP non-responsiveness does not predict MPH non-responsiveness

1.2. Non-stimulants¶

• Atomoxetine (ATX)
  • Benefits
    • Extended-release medication (works (almost) all day long)
    • No impairment of emotional perception, as there is no inhibitory effect on the limbic system
  • Disadvantages
    • difficult to measure out
    • Full effect is not achieved until 4 to 8 weeks later
    • sometimes a very narrow range between underdosing and overdosing
    • significantly more side effects than stimulants
      • in rare cases, irritability, outbursts of anger, or aggression ¹⁴
      • rare but severe idiosyncratic liver damage¹⁴
    • weaker effect size than stimulants
    • should be administered in small, gradual doses
  • Learn more about atomoxetine at Atomoxetine for ADHD
• Guanfacine
  • Benefits
    • helpful for comorbid tic disorders (see below)
    • blood pressure-lowering (helpful for high blood pressure)
• Disadvantages
  • is less common in adults
  • Not approved for adults in Germany (off-label)
  • less effective than stimulants
  • More side effects than stimulants
• More about guanfacine at Guanfacine for ADHD

1.3. Suitability Presented in Table Form¶

2. Choosing Medications Without Specific Problems¶

⇒ Medications for ADHD (Overview)

The following information is based on the 2006/2008 European treatment guidelines.²⁶¹⁴ For cardiovascular screening, the most recent version of the European ADHD Guidelines Group is authoritative.²⁷

• Of the children and adolescents diagnosed with ADHD, only about 19% receive medication for ADHD (95% CI 11.5 to 29.9%). Among those without an ADHD diagnosis, 0.9% (95% CI 0.5 to 1.7%) receive such medication. For every person in the U.S. taking ADHD medication without a formal diagnosis, there are, statistically, three diagnosed individuals who could benefit from medication but are not receiving it. (E 1a)²⁸
• Before undergoing treatment with stimulants, it is recommended that
  • (E 1a): a cardiovascular examination (E 4)²⁹ to detect cardiovascular abnormalities such as: (E 1a)²⁶¹⁴
    • high blood pressure
    • Heart murmurs
    • Syncope during physical exertion
    • An ECG is optional
  • Contraindications for stimulants (most of which are uncommon in childhood): (E 1a)²⁶¹⁴
    • Schizophrenia
      • otherwise, a large long-term study from 2025 (E 2b)²⁵
    • severe depression
    • Hyperthyroidism
    • Arrhythmias
    • moderate to severe high blood pressure
    • Angina pectoris
    • Glaucoma
    • Monoamine oxidase (MAO) inhibitors
      • previous hypersensitivity
      • simultaneous use
      • Use within the last 2 weeks
  • Caution is advised in patients with (E 1a)²⁶¹⁴
    • motor tics
    • known drug addiction
    • History of drug addiction, alcoholism, or caffeine addiction
      • Stimulants for ADHD can significantly reduce the urge to use drugs
    • Alcohol and MPH do not mix at all
      • Combining alcohol and AMP isn’t a good idea, but it’s far less harmful than combining alcohol and MPH - Avoid caffeine when taking stimulants
      • Risk of cross-reactions
    • Pregnancy
    • Breastfeeding
    • Anorexia nervosa
    • History of suicidal behavior

2.1. Order of priority for the choice of medication¶

The following statements are based solely on our scientific opinion. Regulatory restrictions have not been taken into account.

This order of priority is based on a network meta-analysis of 133 double-blind randomized trials involving 14,346 children and adolescents and 10,296 adults. It should be noted that the analysis explicitly refers to short-term treatment and that studies involving people with ADHD were excluded (it is therefore only of limited applicability to the conditions discussed on this page).³⁰ In short-term studies, inattention and hyperactivity improve to a greater extent than the measured quality of life.³¹

2.1.1. The choice of medication for children and adolescents¶

For children and adolescents, the most scientifically sound* Approach to prioritizing medications is:

* Health insurance coverage may vary

• (E 1a): The first-line treatment is methylphenidate (E 1a)³⁰ (E 1a)³² (E 4)³³
• (E 1a): The second-line treatment is amphetamine-based medications (E 4)³⁴(E 1a)³⁰
• Atomoxetine is the third-line treatment. It may be the first-line treatment in cases of comorbid anxiety disorder (E 2a)³⁵, comorbid SCT, or severe ADHD-I. For more information, see the sections on the respective comorbidities.
• In a Taiwanese registry study (256,882 diagnosed patients, of whom 147,210 were on medication; 98.2% received methylphenidate), 8.4% of those who had started on MPH later switched to atomoxetine; conversely, 31.3% of the n = 2,716 children who had started on atomoxetine later switched to MPH (E 3)³⁶ Atomoxetine was not covered by health insurance in Taiwan until 2007 and was barely prescribed prior to that.
• Approximately 40% (E 1a)¹⁴ to 50% of MPH nonresponders respond to atomoxetine, and approximately 75% of MPH responders also respond to atomoxetine. Atomoxetine can be administered together with MPH during the transition phase without excessive concern regarding adverse events, such as cardiovascular effects (although monitoring of blood pressure and heart rate is necessary).(E 4)³⁷ Before evaluating atomoxetine, a treatment trial of at least 6 to 8 weeks—preferably longer—is recommended. The figures of 50% and 75% are based on a single study.
• In our opinion, the fourth-line treatment is guanfacine (particularly for hypertension caused by generic medications, MPH, or AMP, or in cases of comorbid tics), which, statistically speaking, has a greater effect size and fewer side effects than atomoxetine
• Other possible medications: see related posts

2.1.2. The choice of medication for adults¶

(E 1a): In adults, the most scientifically useful* Approach to prioritizing medications is: (E 4)³⁴(E 1a)³⁰
* Health insurance coverage may vary

• Amphetamine-based medications are the first choice

  • Since March 2024, Vyvanse has been indicated in Germany as a first-line treatment for adults; for children, however, it remains indicated only when MPH has been ineffective. (E 4)³⁸
    • Doctors (in Germany) must continue to adhere to the principle of cost-effectiveness. Since lisdexamfetamine is not the least expensive medication, it can only be prescribed on a health insurance prescription if less expensive medications have not been sufficiently effective or have caused unacceptable side effects.
    • NICE: Dextroamphetamine is the second-line treatment after lisdexamfetamine (E 4)³¹

• The second-best option is methylphenidate

• Atomoxetine is the third-line treatment. It may be the first-line treatment for SCT or severe ADHD-I.

• In our opinion, the fourth option is guanfacine (off-label). Reports of guanfacine’s positive effects primarily involve children.

  • Guanfacine is used off-label in adults
  • In older adults, caution is advised due to an increased risk of falls when blood pressure drops rapidly

• Other possible medications: See the articles on specific active ingredients

• Amphetamine-based medications (e.g., lisdexamfetamine (Vyvanse/Elvanse), amphetamine salts (Adderall), immediate release (Attentin))

  • are generally more effective in adults and are better tolerated

  • Nonresponders: about 20%

  • About 30% of adults who switch from MPH to Vyvanse switch back (E 2b)³⁹

  • Increasing the dose too quickly in too large increments raises the dropout rate due to side effects or overdose

  • Lisdexamfetamine: Generic versions may have different effects, even though there is currently no pharmacological explanation for this

• Methylphenidate:

  • If it is not effective: try several other MPH medications
  • Different MPH medications can have very different effects
  • Differences in efficacy tend to be individual rather than specific to a particular medication
  • Non-responders: approximately 30%
  • Increasing the dose too quickly in too large increments raises the dropout rate due to side effects or overdose

2.1.3. Choice of medication for Seniors¶

(E 4): In Switzerland, lisdexamfetamine and methylphenidate are approved for use in adults with no age restriction. (E 4)²⁰(E 4)²¹
Prostate hyperplasia with residual urine is cited as a contraindication for stimulants. (E 4)⁴⁰ The professional literature refers to stimulants as drugs in this context. To date, we have not been able to find any reports of adverse effects associated with their use at therapeutic doses.

2.2. Additional Factors in the Selection of Active Ingredients¶

When performing medication selection, the following should also be taken into account:

• Comorbidities

• Variants in genes encoding metabolic enzymes that accelerate or slow down metabolism

• other medications taken

• Stomach acid

• Possible premenstrual worsening of ADHD symptoms

  • People with ADHD should primarily use stimulants, as these can be administered at a higher dose—even for a short period—during those days. See the section below on side effects when adjusting the dosage.

• Preference of people with ADHD (In studies on medical and psychotherapeutic treatments in general—not specifically regarding ADHD medication—treatment that aligned with the preferences of people with ADHD was discontinued 38% (k = 34, n = 5,294) to 41% (k = 35) less likely to be discontinued. Treatment outcomes improved only slightly (effect size 0.18 to 0.31). In the largest of the three studies, no effect was observed on any outcome measures other than dropout rates and the therapeutic relationship.⁴¹⁴² [^37]

  • (E 1a): showed a higher effect size ranging from SMD 0.18 (meta-analysis, k = 27) (E 1a)⁴³ to SMD 0.31 (meta-analysis, k = 35) (E 1a)⁴².

See also:

• Duration of Medication Effectiveness for ADHD
• Combination Therapy for ADHD

2.3. Trial and Error: Finding the Right Active Ingredient Takes Persistence¶

3. Choosing Medications for Specific Clinical Cases¶

3.1. Responding¶

According to a comparative review, children with ADHD showed the greatest improvement in symptoms with: (E 1a)⁷

• Dextroamphetamine: 35.5%

• Methylphenidate: 26.2%

• Equally effective with both active ingredients: 38.3%

• Dextroamphetamine: 35.5%

• Methylphenidate: 26.2%

• Equally effective with both active ingredients: 38.3%

3.1.1. MPH non-responders¶

• Adults: AMP, then atomoxetine, then guanfacine, then bupropion.
• Children: AMP, then guanfacine, then atomoxetine, then bupropion.

3.1.2. Patients Who Do Not Respond to Amphetamine Medications¶

• Adults: MPH, then atomoxetine, then guanfacine, then bupropion.
• Children: MPH, then guanfacine, then atomoxetine, then bupropion.

3.2. Treatment of Specific ADHD Symptoms¶

3.2.1. Inhibition / Impulse Control¶

Impulsivity is also serotonergically mediated. If severe impulsivity is a prominent symptom in a person with ADHD, it would be negligent to indiscriminately prescribe stimulants at doses high enough to adequately alleviate this symptom, as this would result in an overdose with regard to the other symptoms. In cases of strikingly high impulsivity, treatment with low-dose SSRIs may be helpful.

• Serotonin reuptake inhibitors
  • administered in significantly lower doses than when used as antidepressants
  • e.g.:
    • Escitalopram 2 to 4 mg/day
    • Imipramine 10 mg/day

3.2.2. Inattention / ADHD-I¶

Amphetamine-based medications appear to have a more stimulating effect than methylphenidate. Therefore, amphetamine-based medications are more appropriate than methylphenidate for ADHD-I.
It has also been reported that people with ADHD-I are more likely to be nonresponders to MPH.
While MPH tends to have an inhibitory effect and is therefore particularly suitable for treating ADHD-HI (with hyperactivity [children] / inner restlessness [adults]), D-amphetamine has a stronger stimulating/motivation-enhancing effect and is therefore considered more suitable for treating ADHD-I (without hyperactivity [children] / inner restlessness [adults]). (E 4)⁴⁷ The difference in suitability stems from their different sites of action. Dexamphetamine activates D2 receptors in the striatum, leading to a secondary release of norepinephrine and thereby increasing arousal, which is helpful in cases of an underactive autonomic nervous system, as is assumed in the inattentive subtype. Methylphenidate, on the other hand, increases dopamine concentration by blocking its reuptake. Amphetamines also increase vigilance and attention and improve the differentiation between sounds and noise, which is essential for perceptual filtering. Since their mechanisms of action and sites of action differ, methylphenidate and dexamphetamine are not interchangeable. (E 4)⁴⁷
Dexamfetamine is contraindicated in cases of peripheral and pulmonary arterial hypertension, as well as in patients with cardiovascular conditions. Blood pressure and pulse must be checked before the first administration. (E 4)⁴⁷

However, there are quite a few people with ADHD-HI who find that amphetamine-based medications help them significantly more than MPH.
For people with the ADHD-I subtype—a significant proportion of whom are believed to be MPH non-responders (E 4)⁴⁸ —D-amphetamine may therefore be an effective alternative to MPH.

3.2.3. Emotional Dysregulation¶

Emotional dysregulation is a dimensional trait and is not specific to ADHD (it is also common in other neurodevelopmental disorders and in early-onset mood and anxiety disorders). In the long term, it represents a risk factor for other mental disorders, such as Cluster B and C personality disorders. Among adults with ADHD, it affects up to two-thirds of the people with ADHD.⁴⁹⁵⁰ Emotional dysregulation affects up to two-thirds of adults with ADHD and is increasingly recognized as a core symptom. It is associated with greater functional impairment and more psychiatric comorbidities.⁵⁰

Emotional dysregulation in ADHD can be treated with stimulants or atomoxetine. (E 1a)⁴⁹

Experience has shown that stimulants, e.g., (E 1b): methylphenidate (E 1b)⁵¹, not only improve attention and reduce hyperactivity and impulsivity, but also enhance emotional self-regulation, which may be at least partly a consequence of reduced impulsivity.(E 2b)⁵²(E 2b)⁵³(E 2b)⁵⁴(E 1b)⁵¹ In a 24-week RCT involving n = 363 adults with ADHD, sustained-release methylphenidate (up to 60 mg/day) improved not only cognitive but also emotional symptoms more significantly than placebo. In two long-term studies, emotional dysregulation responded acutely to sustained-release methylphenidate and continued to improve over a six-month follow-up period.⁵⁴In a study of n = 1,480 pre-screened people with ADHD, adults who received psychotherapy or counseling combined witht Methylphenidate for three months achieved significantly better scores on measures of impulsivity and emotional lability than those who received psychotherapy plus placebo. An eight-week double-blind study found similar improvements in irritability, aggressive outbursts, anxiety, and hyperexcitability for lithium (up to 1,200 mg/day) and methylphenidate (up to 40 mg/day).⁴⁹
In an observational study of N = 297 adolescents (mean age 15.8 years; of whom n = 86 had ADHD), emotional dysregulation among adolescents currently taking ADHD medication did not differ from that among adolescents without ADHD. In contrast, untreated adolescents with ADHD exhibited more pronounced emotional dysregulation. Differences from the untreated group remained apparent even after medication had been discontinued. (E 2b)⁵⁵A single dose of a stimulant administered to adults with ADHD showed no improvement in emotional regulation. (E 2b)⁵⁰
In adults, the effect sizes—approximately 0.5 for MPH and approximately 0.4 for atomoxetine—are slightly lower than in children. To date, there has been no direct comparative study of the two active ingredients in adults.

The effects of alpha-2 agonists such as guanfacine and clonidine on emotional dysregulation have not been specifically studied.⁴⁹ In our experience, atomoxetine and guanfacine offer advantages over stimulants in the treatment of emotional dysregulation. Atomoxetine and guanfacine are effective throughout the day. In particular, the socially debilitating symptom of rejection sensitivity—which can place a significant strain on social relationships and romantic partnerships, especially outside the active period of stimulants—can be significantly improved by non-stimulant medications with all-day effects. However, these medications have the drawbacks of a more difficult titration process (titration medications), which can take weeks, as well as a significantly lower effect size on the remaining ADHD symptoms, coupled with higher rates of side effects. In particular, the control over drive and motivation that can be achieved with stimulants cannot be achieved with non-stimulants. Therefore, a combination of (low-dose) non-stimulants and stimulants is recommended in this case. For people with ADHD who are able to tolerate finely tuned dosing, this will often be the optimal approach.

(E 1b): Atomoxetine is well-suited as monotherapy for bipolar disorder and emotional instability. In a naturalistic study, emotional dysregulation decreased with atomoxetine without a mood stabilizer and with methylphenidate only when accompanied by a mood stabilizer. (E 2b)⁵⁶(E 4)⁵⁷(E 1b)⁵⁸
A systematic review with a meta-analysis summarizes the effects of ADHD medications on emotional dysregulation in adults.⁵⁹

A multicenter randomized trial compared atomoxetine and methylphenidate in 152 children with ADHD in terms of their effect on emotional lability. Emotional lability decreased significantly in both groups, with no significant difference between the active ingredients. This effect persisted even after adjusting for improvements in core ADHD symptoms. Thus, emotional dysregulation improves not only as a consequence of symptom improvement. Concomitant MRI scans revealed corresponding changes in the connectivity between the amygdala and the prefrontal and cingulate regions. Since the study did not include a placebo group, the proportion of nonspecific effects cannot be estimated.⁶⁰

In an open-label, three-stage study lasting 10 weeks involving n = 30 children and adolescents aged 6 to 18 with ADHD and emotional dysregulation, 22 (73.3%) responded to methylphenidate (Hedges’ g 2.62). Of the 8 nonresponders, 5 responded to aripiprazole in the second increment. The remaining participants received the combination therapy in the third increment. (E 4)⁶¹
This is an open-label study without a placebo group. The data consist of before-and-after measurements, and the effect sizes are not comparable to the typical placebo-controlled effect sizes of approximately 0.8 to 1.0.

A study found that, in adult inpatients with ADHD and corresponding severe emotional dysregulation (irritability), a combination of MPH with mood stabilizers such as lithium, valproate, a combination of lithium and valproate, or a combination of lithium and oxcarbazepine could be helpful when monotherapy with atomoxetine was insufficient. (E 2b)⁵⁶

In our experience, stimulants can bring about sufficient improvement in cases of moderate emotional dysregulation. If stimulants are not effective enough, atomoxetine (or guanfacine) can be helpful; these medications are more effective for emotional dysregulation but are less effective at managing typical ADHD symptoms.
When in doubt, a combination of atomoxetine (or guanfacine) and stimulants (each at a correspondingly lower dose) is helpful, since ATX, as a full-day medication, can then help improve social functioning even outside the stimulants’ active periods (family life in the evening), while the stimulants improve drive and attention control during the day. We suspect that these combination regimens will become established as standard treatments in the future, even if this requires even more persistence and sensitivity when titrating the doses.

3.2.4. Rejection Sensitivity¶

3.2.4.1. Methylphenidate¶

Many people with ADHD reported that stimulants had a significant and immediate effect on their rejection sensitivity. Specifically, 90% reported that MPH had a positive effect that reduced RS, while 10% reported that it tended to increase RS.

3.2.4.2. Guanfacine and Clonidine¶

According to a single case report by an American physician (Dodson), a combination of the alpha-2-adrenergic receptor agonists guanfacine and clonidine is particularly effective for rejection sensitivity. He reports that at doses ranging from 0.5 to 7 mg of guanfacine and from 0.1 mg to 0.5 mg of clonidine, one in three people with ADHD experiences a resolution of their rejection sensitivity symptoms. He further reports that this treatment ultimately has a greater impact on quality of life than treatment with stimulants. (E 4)⁶³

Dodson goes on to report on a Harvard University study indicating that increasing the dosage of guanfacine to 4 mg and that of clonidine to 7–8 mg results in a 40% higher response rate; however, these dosages exceed the recommended limits. This also results in increased side effects.
1 mg guanfacine: low. 4 mg guanfacine: upper end of the normal range. 7 mg guanfacine: upper limit of what is medically acceptable. Clonidine 0.1 mg: low, usual starting dose, usually taken in the evening. 0.4 to 0.5 mg per day: high total dose in child and adolescent psychiatry.

Guanfacine is more effective than atomoxetine as a treatment for ADHD, at least in children. It is not approved for use in adults.

3.2.4.3. MAO-A reuptake inhibitors¶

Dodson (E 4)⁶³ further describes successes with MAO-A reuptake inhibitors, particularly Parnate (tranylcypromine), which had been the standard treatment for rejection sensitivity up to that point. MAO-A reuptake inhibitors have also been used successfully to treat ADHD symptoms.

3.2.4.4. Imipramine, Phenelzine¶

Depending on the specific symptoms present, imipramine and phenelzine are each considered more suitable (than valproate) for treating rejection sensitivity. (E 2b)⁶⁴.

Imipramine is a possible adjunct medication to stimulants for ADHD. However, the synergistic effect between imipramine and methylphenidate should be taken into account.

3.2.4.5. Valproate for Borderline Personality Disorder¶

Valproate (250 mg to 500 mg) moderately improved symptoms of irritability, anger, anxiety, rejection sensitivity, and impulsivity in 50% of people with ADHD. The results varied greatly from person to person. (E 4)⁶⁵

3.2.5. Lack of drive¶

• Amphetamine-based medications
• for AMP non-responders: MPH

In addition:

• Bupropion

Bupropion can be helpful in cases of low motivation. Conversely, bupropion can lead to decompensation in ADHD-HI and ADHD-C.

3.2.6. Severe symptoms early in the morning and/or in the evening¶

For more information, see Dosage of Medications for ADHD

3.3. Choosing Medications for ADHD with Comorbidities¶

3.3.1. Anxiety Disorder Comorbid with ADHD¶

3.3.1.1. Anxiety Disorders Are Generally Comorbid with ADHD¶

3.3.1.1.1. Stimulants¶

Some doctors have reservations about treating children with ADHD and comorbid anxiety disorders with stimulants, since “anxiety and nervousness” are listed as common side effects of stimulants in major drug information databases such as Micromedex, Lexicomp (now UpToDate Lexidrug), and UpToDate as common side effects of stimulants. (E 1a)⁶⁷.

However, most people with ADHD also benefit from stimulant treatment in terms of comorbid anxiety symptoms.(E 1a)⁶⁷ People with ADHD and comorbid anxiety or impulse-control disorders respond just as well to stimulants for ADHD symptoms as people without these comorbidities. (E 1a)¹⁴
A meta-analysis of k = 23 studies involving n = 2,959 children with ADHD found a significantly lower risk of anxiety symptoms with stimulants than with placebo (relative risk 0.86; 95% CI 0.77 to 0.95).(E 1a)⁶⁸
Immediate release methylphenidate derivatives reduced anxiety more effectively than placebo (RR 0.85 for MPH derivatives, RR 0.83 for short-acting formulations). Amphetamine derivatives did not differ from placebo. (E 1a)⁶⁸
In a minority of people with ADHD, stimulants can nevertheless exacerbate anxiety. (E 1a): This occurs more frequently with amphetamine-based medications than with methylphenidate, and is most likely to happen when the recommended maximum daily doses are exceeded.(E 1a)⁶⁷ It should be noted that in the meta-analysis mentioned above, higher doses were associated with less, not more, anxiety.(E 1a)⁶⁸ Anxiety symptoms can nevertheless be exacerbated by stimulants, as anxiety and mood are regulated by the dopaminergic activity of the ventromedial prefrontal cortex in conjunction with the limbic system. (E 4)⁶⁹

We have seen reports on the forum of symptoms of depression or anxiety as side effects when titrating the dose of amphetamine medications. While such reports are relatively rare, they should be taken seriously. In these cases, the first step should be to consider switching to a different active ingredient.

Stimulants can therefore be used in children with ADHD and comorbid anxiety disorders. Even when anxiety symptoms occur, it is rarely necessary to discontinue the stimulants. (E 1a)⁶⁷

According to the prescribing information, Vyvanse is no longer contraindicated in Switzerland for patients with comorbid anxiety disorders. Dextroamphetamine (Attentin) remains contraindicated in Switzerland for anxiety disorders, and methylphenidate (MPH) is contraindicated for severe anxiety and tension states. (E 4)²⁰(E 4)²¹

3.3.1.1.2. Non-stimulants¶

Between 25 and 35 percent of children with ADHD have a comorbid anxiety disorder. (E 1b)⁷¹

(E 1a): Atomoxetine may help reduce comorbid anxiety symptoms in children and adolescents. (E 1a)⁷²(E 1b)⁷¹(E 1b)⁷³ The strongest evidence comes from a double-blind, placebo-controlled study involving 176 children aged 8 to 17 with ADHD and an anxiety disorder: Over 12 weeks, atomoxetine significantly reduced both ADHD and anxiety symptoms. (E 1b)⁷¹ A systematic review reached the same conclusion but is based on only four studies. (E 1a)⁷² (E 1b)⁷³ The anxiety-reducing effect was greater in cases where an anxiety disorder was actually present than in cases of ADHD alone. The mean atomoxetine dose in the included studies ranged from 1.3 to 1.5 mg/kg/day. (E 1a)⁷²
(E 1a): Positive effects of atomoxetine on comorbid anxiety disorders have been reported. (E 4)⁷⁴ Atomoxetine is reported to have an effect size of 0.5 with regard to anxiety. (E 1a)¹⁴
(E 1b): The improvement in anxiety symptoms with atomoxetine was slightly greater than that with MPH, but only beginning in the fourth week of treatment. No difference was observed in the first few weeks. (E 1b)⁷⁵(E 4)⁷⁶A direct comparison with methylphenidate in an open-label study involving n = 60 children also showed a benefit for atomoxetine in treating anxiety.³⁵
(E4): Guanfacine is not contraindicated in Switzerland for patients with comorbid anxiety disorders. Atomoxetine is contraindicated in Switzerland for patients with severe anxiety who are at risk for suicidal behavior. (E 4): This information presumably refers to the legal situation in Switzerland. (E 4)²⁰(E 4)²¹

3.3.1.1.3. Combination Therapy¶

An open-label study without a control group examined the addition of atomoxetine to an SSRI or SNRI in 29 adults with ADHD and comorbid generalized anxiety disorder. All participants had responded only partially to eight-week treatment trials with SSRIs or SNRIs. With the combination therapy, both ADHD and anxiety symptoms improved. (E 4)⁷⁷

A review identified comorbid anxiety disorder as an indication for the co-administration of stimulants with guanfacine (extended-release). (E 4)⁶⁶

Krause & Krause reported favorable clinical results for ADHD and mild-to-moderate comorbid anxiety disorders:

• Stimulants plus venlafaxine 18.75 to 150 mg/day (E 4)⁷⁸
• Stimulants plus duloxetine 30 mg/day (E 4)⁷⁸
• Stimulants plus fluoxetine 10 to 20 mg/day (E 4)⁷⁸

A case report describes a 15-year-old girl with ADHD for whom atomoxetine (up to 60 mg/day for 2 months) had no effect whatsoever and methylphenidate (up to 72 mg/day) had only a moderate effect, but which triggered pronounced dysphoria and anxiety that did not improve even after reducing the dose. An attempt to treat her with supplemental clonidine had to be discontinued due to symptomatic bradycardia and presyncope. The addition of vortioxetine (10 mg/day) significantly reduced anxiety (HAM-A score decreased from 38 to 14) and also improved cognitive performance. The combination was well tolerated and was still being used after 10 months. (E 4)⁷⁹

It has been reported that CBD helped people with anxiety reduce their dosage of anti-anxiety medications.

3.3.1.2. Comorbid Social Anxiety Disorder in ADHD¶

Positive effects of atomoxetine on comorbid social anxiety have been reported. (E 4)⁷⁴

3.3.2. Depression Comorbid with ADHD¶

Because stimulants increase energy levels, they can trigger existing suicidal tendencies that had not previously been acted upon due to depression. Stimulants should therefore be used with extreme caution in cases of severe depression (including undiagnosed depression).
(E 2b): One study found no increased risk of suicide associated with MPH when comparing periods of use and non-use within the group of people with ADHD who were treated with MPH.(E 2b)²² Other studies report a reduction in suicide risk with long-term MPH use. (E 3)⁸⁰
Dysthymia/dysphoria, defined as a persistent (for years) mild depression (low mood, particularly during periods of inactivity), is rarely a comorbid depression but is typically a primary symptom of ADHD. In our view, ADHD-targeted medication—specifically stimulants (bupropion, amphetamine-based medications)—is indicated for dysthymia/dysphoria.In cases of comorbid mild to moderate depression (and, in our view, possibly even severe depression provided the risk of suicidal tendencies has been ruled out), ADHD should be treated first. Given the rapid onset of action of stimulants, it is then possible to observe whether eliminating the ADHD symptoms also eliminates the stressor driving the depression. This is quite often the case.

• Comorbid depression is often a consequence of untreated ADHD. In about one-third of all cases of treatment-resistant depression, previously undiagnosed ADHD is present. ADHD medications take effect much more quickly (15 minutes to 1 hour) than antidepressants (2 weeks or more), even though properly fine-tuning ADHD stimulants can often take months
• MPH does not reach a steady state; lisdexamfetamine reaches a steady state in 5 days (even longer in slow metabolizers)
• Stimulants have significantly fewer side effects than antidepressants. Stimulants do not need to be tapered off; they can be discontinued immediately.
  As a consequence, formulations and active ingredients can be changed immediately
• Stimulants cause withdrawal side effects only in very rare, exceptional cases, whereas antidepressants are much more likely to cause withdrawal side effects, which in some cases can become very severe (particularly with venlafaxine, to the point of requiring hospitalization)
• Stimulants have a much greater effect size (MPH 0.9 to 1.1, lisdexamfetamine up to 1.5, in each case for ADHD) than antidepressants (on average 0.3, with venlafaxine having the best effect size of 0.49 for depression).

3.3.2.1. Stimulant monotherapy as a first step in treating comorbid depression and ADHD¶

Among people with ADHD and comorbid depression, the risk of depression was 20% lower during the period of ADHD medication than during the period without medication. The 3-year long-term risk of depression was reduced by 43%. (E 2b)⁸¹

Treatment of adults with ADHD using MPH also improved existing depressive symptoms, although not completely to the level seen in healthy controls. (E 4)⁸²
(E 1b): Amphetamine-based medications are ((even) more suitable than MPH) for the adjunctive treatment of comorbid dysphoria or depression (E 4)⁸³(E 1b)⁸⁴. This could possibly be due to their noticeable serotonergic effect. (E 4)⁸⁵

There is evidence supporting the use of lisdexamfetamine as an adjunct to an antidepressant in cases of mild residual depression with persistent impairment of executive functions. However, larger Phase 3 studies have not been able to confirm these findings.⁸⁴ Amphetamine salts also exert serotonergic effects through MAO inhibition and neurotransmitter release. This same property increases the risk of serotonin syndrome when multiple serotonergic medications are administered concurrently.⁸⁵ To date, comparative studies have not demonstrated an advantage of amphetamine-based medications over methylphenidate in cases of comorbid depression.

A small pharmacological study found that atomoxetine inhibits the norepinephrine transporter to a degree similar to that of venlafaxine at higher doses. Some participants also showed improvement in their depression. The study was not designed to compare efficacy.⁸⁶

(E 4): In online forums, many people with ADHD report a significant antidepressant effect from amphetamine medications that they do not experience with MPH.(E 4)⁸⁷ dAMP is said to be more stimulating than MPH and is therefore the preferred recommendation for ADHD-I, which should be particularly helpful here given the often internalizing nature of depression. (E 4)⁸⁸

Moderate or severe depression can be exacerbated by stimulants, as anxiety and mood are regulated by dopaminergic activity in the ventromedial prefrontal cortex (PFC) in conjunction with the limbic system. (E 4)⁶⁹
We have seen reports on the forum of symptoms of depression or anxiety as side effects when starting treatment with amphetamine-based medications. While such reports are relatively rare, they should be taken seriously. In these cases, the first step should be to consider switching to a different active ingredient.

Lisdexamfetamine (Vyvanse) is no longer contraindicated in Switzerland for patients with comorbid severe depression. (E 4): Dextroamphetamine and MPH remain contraindicated in Switzerland for severe depression. (E 4)²⁰(E 4)²¹ It is unclear whether this applies only to Switzerland or also to Germany.

Neither stimulants nor non-stimulants were associated with an increased risk of completed suicide. This held true for the overall group as well as separately for the age groups 12 to 24 and 25 to 49 years, and for people with ADHD who have been diagnosed with the condition. The duration of use also played no role. Compared with stimulant use alone, non-stimulants alone resulted in an odds ratio of 1.27 (95% CI 0.62 to 2.63), for the combination of both, 1.01 (0.33 to 3.08), and for an ADHD consultation without medication, 0.94 (0.69 to 1.28) (all not significant).(E 3)⁸⁹ A cohort study by the same research group found that treatment periods with stimulants were associated with lower overall mortality and fewer unintentional injuries. Non-stimulants reduced injuries but did not reduce mortality.⁹⁰

3.3.2.2. Atomoxetine as monotherapy¶

Whether atomoxetine is effective for depression is a matter of debate. (E 1a): While the majority of experts disagree (E 1a)²⁶(E 4)⁹¹(E 1b)⁹², one study found that atomoxetine improved depressive symptoms to an extent comparable to that of paroxetine and venlafaxine (E 1a)⁸⁶.
In a placebo-controlled study of 142 adolescents with ADHD and major depression, ADHD symptoms improved significantly more than with placebo, whereas depression scores did not. Atomoxetine was thus effective for ADHD but not for depression.⁹²

In an open-label pilot study of adolescents with non-suicidal self-injurious behavior and clinical or subclinical ADHD, adjunctive atomoxetine treatment improved both self-injurious behavior (p = 0.007) and depression scores (CDRS p < 0.001; CDI p = 0.031). Of the 27 adolescents enrolled, 23 completed treatment (22 girls, 1 boy. Mean final dose: 58.3 ± 13.7 mg). (E 1a)⁹³In the subgroup with full-blown ADHD, both depression scores (p = 0.017) and self-injurious behavior (p = 0.034) improved. In the subclinical ADHD group, only depression scores improved (p = 0.006), while self-harm showed only a trend toward improvement (p = 0.083).⁹³

(E 4): Atomoxetine is contraindicated in Switzerland for patients with severe depression (it is unclear whether this applies only to those at risk for suicidal behavior). (E 4)²⁰(E 4)²¹

An analysis of spontaneous reports submitted to the U.S. Food and Drug Administration (FDA) found a notable reporting signal for atomoxetine regarding suicidal and self-harming behavior in children and adolescents with ADHD, whereas methylphenidate showed the opposite trend. (E 3)⁹⁴ Such reporting analyses cannot estimate risk due to the lack of a denominator. The warning label for atomoxetine, which has been in place since 2005, increases the likelihood of reports being filed.
According to another study, neither stimulants nor non-stimulants statistically significantly increased the risk of suicide. (E 2b): However, the risk was higher among non-stimulants, while it was not higher among stimulants. (E 3)⁸⁹
In contrast, a cohort study of n = 279,315 children and adolescents found no increased risk of suicide or suicide attempts among those taking atomoxetine compared with those taking stimulants, regardless of whether ATX was used as a first-line or second-line medication. (E 2b)⁹⁵

Other studies report a reduction in the risk of suicide with long-term methylphenidate use.²²⁹⁶

3.3.2.3. Guanfacine for ADHD with comorbid depression¶

(E 4): Guanfacine is not contraindicated in Switzerland for patients with comorbid depression. (E 4)²⁰(E 4)²¹

3.3.2.4. Bupropion¶

Bupropion has antidepressant effects and is used to help people quit smoking. In our assessment, bupropion is a reserve treatment (approximately the fifth choice) for ADHD. Bupropion is not approved for ADHD in Germany (off-label use). It should be noted that bupropion lowers the seizure threshold and is contraindicated in patients with current or past history of seizures, bulimia, or anorexia nervosa (including a history of these conditions), as well as in those with a history of bipolar disorder.[NEW1]

Among participants with a high polygenic risk score (PGS) for ADHD, the risk of suicidal thoughts was 66% higher with SSRIs than with bupropion; SNRIs and SSRIs increased the risk to the same extent. For those with a low PGS, the difference between SSRIs and bupropion was only 6%. This is a preprint (medRxiv) that has not yet undergone peer review. The results are therefore preliminary. (E 2b)⁹⁷
A comparison of SSRIs and SNRIs revealed a gender difference: Among men, the risk of suicidal thoughts was 31% higher with SSRIs than with SNRIs (hazard ratio 1.31; 95% CI 1.04 to 1.65), but this was not the case for the other genders (0.86; 0.70 to 1.05; p for interaction 0.01). (E 2b)⁹⁷

3.3.2.5. Combination Therapy for Comorbid Depression and ADHD¶

3.3.2.5.1. Atomoxetine and Fluoxetine¶

A double-blind study involving 173 children and adolescents with ADHD and comorbid symptoms of depression or anxiety compared the combination treatment of atomoxetine plus fluoxetine with atomoxetine plus placebo. In both groups, ADHD, depression, and anxiety symptoms improved significantly. The combination did not provide any additional benefit compared to atomoxetine monotherapy and was well tolerated. Blood pressure was slightly higher with combination therapy than with monotherapy. Since all participants received atomoxetine and there was no placebo-only arm, this study does not allow us to conclude whether the improvement in anxiety and depression was due to atomoxetine. (E 1b)⁷³

3.3.2.5.2. Atomoxetine and Sertraline¶

A post-hoc genotype analysis of adults with depression (but not ADHD) found evidence of a specific effect of atomoxetine in combination with sertraline in the 5-HTTLPR s/s genotype. With the combination therapy, 81.8% of s/s carriers achieved remission, compared with 32.7% of those with other genotypes. Sertraline alone showed no genotype-related differences. The authors themselves describe their conclusions as speculative. (E 1b)⁹⁸

3.3.2.5.3. SSRIs and MPH for ADHD with Comorbid Depression¶

A study raises concerns that SSRIs (such as fluoxetine) may amplify the moderate addiction-related gene regulation of MPH in the striatum of rats, thereby potentially increasing dependence on methylphenidate. (E 2b): This effect is less pronounced with vilazodone. (E 2b)⁹⁹Vilazodone increased the motor activity in the animals induced by MPH. The attenuating effect was reversed by blocking 5-HT1A receptors. (E 2b)⁹⁹

3.3.2.5.4. Escitalopram and MPH for Depression Comorbid with ADHD¶

No clinical data are available on the risk of addiction associated with the use of SSRIs plus methylphenidate in humans. A cohort study in adolescents found no increased risk for the combination of methylphenidate and an SSRI across the 13 endpoints examined. (E 2b)¹⁰⁰

When comparing the active ingredients, the risk of developing a tic disorder was significantly lower with fluoxetine than with escitalopram (hazard ratio 0.43; 95% CI 0.25 to 0.71); for all other endpoints, there was no difference between the two. (E 2b)¹⁰⁰
Therefore, when an SSRI is added to methylphenidate for ADHD with depression, fluoxetine is preferable to escitalopram if the risk of tics is a concern.

3.3.2.5.5. Fluoxetine and MPH for Comorbid Depression and ADHD¶

Positive results have been reported with stimulants plus fluoxetine 10 to 20 mg/day in patients with comorbid mild to moderate depression (E 4)⁷⁸

An open-label study without a control group involving n = 32 children and adolescents with ADHD and comorbid depression—in whom MPH alone did not result in sufficient improvement in ADHD symptoms—found that the addition of fluoxetine led to significant improvements in ADHD symptoms in nearly all participants. For 40% of the participants, an additional dose of less than 20 mg of fluoxetine was sufficient to achieve this improvement. No increase in side effects was observed during up-dosing with fluoxetine. One participant’s condition worsened after 12 weeks.(E 2b)¹⁰¹ Another study found no increased side effects with fluoxetine when used as an adjunct to MPH treatment for ADHD and a significantly lower risk compared to escitalopram in cases of comorbid TIC disorders. (E 2b)¹⁰⁰
Combined administration of MPH and fluoxetine in drinking water for four weeks significantly reduced anxiety- and depression-like behaviors in adolescent rats to a much greater extent than either drug alone, while also increasing overall activity. Fluoxetine alone showed no effect in these tests. Both with fluoxetine alone and with the combination, food intake and body weight decreased. (E 2b)¹⁰²

This does not contradict the findings in¹⁰³. In that study, measurements were taken at the end of the four-week treatment period, whereas in this study, they were taken 24 hours and two months after the end of treatment.¹⁰²¹⁰³

Fluoxetine is said to be the only SSRI with a mood-boosting effect. As a monotherapy, it does not appear to be suitable for treating ADHD. *⇒ [Fluoxetine for ADHD](/de/page/220/fluoxetin-bei-adhs

Co-administration of MPH and fluoxetine to adolescent rats over 15 days resulted, even two months later in adulthood, in increased sensitivity to rewarding stimuli (both sugar and cocaine) and, at the same time, increased anxiety and stress sensitivity. The authors identified a long-term alteration in the ERK signaling pathway in the VTA as the cause. When this signaling pathway was specifically blocked, the effect disappeared in the behavioral test. (E 2b)¹⁰³ However, the study tested healthy male animals and not ADHD model animals.

A combined oral administration of MPH and fluoxetine over four weeks to adolescent rats reduced D2R binding by approximately 45 to 52 percent, an effect that neither MPH nor fluoxetine alone produced; D1R binding remained unchanged. The following were affected: (E 2b)¹⁰⁴

• dorsal caudate nucleus and putamen (51.5%)
• dorsolateral caudate-putamen (50.4%)
• Nucleus accumbens core (44.8%)
• ventral caudate-putamen (47.7%)
• ventromedial caudate-putamen (49.1%)

D2R activity, particularly in the affected regions, plays a key role in learning and memory, as well as in the development of addictive behavior. In individuals with cocaine dependence, D2 receptor availability in the striatum was reduced by 15 to 17% compared with healthy control subjects, with this reduction being uniform across all subregions (limbic 15.2%, associative 15.0%, sensorimotor 17.1%; PET study involving 17 participants in each group). However, this study was unable to demonstrate a correlation between D2 availability and actual cocaine use behavior. (E 2b)¹⁰⁵

3.3.2.5.6. Selegiline and Lisdexamfetamine for Comorbid Depression¶

(E 4): A case report describes the successful co-administration of transdermal selegiline and lisdexamfetamine (Vyvanse) in a patient with major depression and comorbid ADHD; the authors emphasize that this combination should be used only with caution and under ongoing monitoring of heart rate and blood pressure.(E 4)¹⁰⁶ A review of the co-administration of stimulants and MAO inhibitors found no documented cases of hypertensive crises when the stimulant was added cautiously. (E 4)¹⁰⁷

Therefore, a combination therapy of selegiline and stimulants may also be considered for ADHD.

3.3.2.5.7. Duloxetine and Stimulants for Comorbid Depression¶

Positive results have been reported with stimulants plus duloxetine 30 mg/day for mild to moderate depression (E 4)⁷⁸

3.3.2.5.8. Venlafaxine and Stimulants for Comorbid Depression¶

Positive results have been reported with stimulants plus venlafaxine at doses ranging from 18.75 to 150 mg/day for mild to moderate depression (E 4)⁷⁸

We are aware of many reports of severe withdrawal symptoms associated with venlafaxine. In some cases, discontinuation was not possible at all or took half a year, accompanied by severe side effects. Given this, venlafaxine should be considered one of the very last antidepressants to be used.

3.3.2.5.9. MAO Inhibitors and Stimulants in Cases of Comorbid Depression¶

Stimulants are combined with MAO inhibitors by experienced clinicians on a case-by-case basis. A systematic review found no documented cases of hypertensive crises or deaths in the literature from 1962 to 2003 when the stimulant was cautiously added to an already existing MAO inhibitor. It should be noted, however, that the prescribing information continues to list this combination as a contraindication, and an older case report in the literature¹⁰⁸describes one fatality. The combination should therefore be administered only by experienced practitioners and requires close monitoring of blood pressure and pulse. (E 4)¹⁰⁷

The safety requirement is that MAO inhibitors must be discontinued 14 days before taking any stimulants.

3.3.2.5.10. Lamotrigine for ADHD with comorbid depression¶

For more information, see Lamotrigine for ADHD

3.3.2.5.11. Comorbid depression with specific manifestations¶

3.3.2.5.12. Comorbid depression with difficulties concentrating and a lack of motivation¶

Experience has shown that the following can be helpful in cases of comorbid depression with concentration and motivation difficulties:

• Nortriptyline (E 4)¹⁰⁹
• Milnacipran 25 to 100 mg (E 4)¹⁰⁹

3.3.2.5.13. Comorbid depression with severe loss of motivation¶

Experience has shown that the following can be helpful in cases of comorbid depression with pronounced loss of motivation:

• Bupropion 150 to 300 mg (E 4)¹⁰⁹

3.3.2.5.14. Comorbid depression with obsessive-compulsive features¶

Experience has shown that the following can be helpful in cases of comorbid depression with a compulsive personality structure:

• Sertraline 50 to 100 mg (E 4)¹⁰⁹

3.3.2.5.15. Depression with Irritability as a Comorbid Condition¶

Experience has shown that the following can be helpful in cases of comorbid irritable depression:

• Moclobemide 75 to 150 mg (E 4)¹⁰⁹

3.3.2.5.16. Comorbid depression with irritability¶

Experience has shown that the following can be helpful in cases of comorbid depression with severe irritability:

• (E 4): Amisulpride 25 to 100 mg/day (E 4)⁷⁸(E 4)¹⁰⁹

3.3.3. Bipolar disorder with ADHD as a comorbid condition¶

Methylphenidates and mixed amphetamine salts are considered the most promising options for the treatment of bipolar disorder, particularly in children and adolescents. The available data on atomoxetine, viloxazine, modafinil, and armodafinil are limited. The same applies to lisdexamfetamine (the only stimulant marketed for the treatment of ADHD that has also been studied as an add-on strategy for treatment-resistant bipolar depression). The use of these active ingredients should therefore be evaluated with caution and on an individualized basis. ADHD medications exhibit a favorable safety profile without an increased risk of manic episodes, particularly when combined with mood stabilizers. (E 4)¹¹¹
The discussion also addressed the significance of variants in the DAT and COMT genes for the interaction between ADHD and bipolar disorder.¹¹¹ For more information, see COMT gene polymorphism In Section 4.3.

MPH, when used in combination with a mood stabilizer, does not increase the risk of a manic episode or psychotic symptoms. If stimulants are ineffective or poorly tolerated, atomoxetine appears to be an option. (E 1a)¹¹⁰
Treatment-induced mania occurred in 0.0% of adolescents treated with atomoxetine and in 1.5% of those treated with placebo.⁹²

Stimulants can be safely used in children and adolescents with comorbid bipolar disorder if the manic/hypomanic symptoms are effectively treated with a mood stabilizer. (E 1a)⁶⁷

In bipolar disorder, mood stabilization does not treat ADHD. Of 32 children and adolescents aged 6 to 17 whose mania score was at least halved during eight weeks of open-label divalproex treatment, only three also experienced an improvement in their ADHD symptoms. In the subsequent four-week randomized, double-blind, placebo-controlled crossover study involving 30 people with ADHD who continued taking divalproex, amphetamine mixed salts were significantly more effective than placebo in reducing ADHD symptoms, without significant side effects and without worsening manic symptoms. The study thus supports the approach of first stabilizing mood and then administering the stimulant. Of 40 participants, 77.5% had bipolar I disorder and 22.5% had bipolar II disorder.¹¹²

In a Swedish registry analysis of 2,307 adults with bipolar disorder who began treatment with MPH, the risk of manic episodes was significantly increased during the first three months when MPH was administered without a mood stabilizer (HR 6.7; 95% CI 2.0 to 22.4), with similar results for the following three months. In contrast, when administered concurrently with a mood stabilizer, the risk of mania after treatment initiation was actually lower than before (HR 0.6; 0.4 to 0.9). The authors conclude that concerns about mania are not a reason to withhold MPH if adequate mood stabilization is achieved. However, before initiating stimulant monotherapy, a careful evaluation to determine whether a bipolar disorder is present is warranted.¹¹⁴

For bipolar disorder and severe mood swings, the following is said to be helpful:

• Lamotrigine (E 4)¹⁰⁹
  • For more information, see Lamotrigine for ADHD
• carbamazepine or valproic acid, if necessary

In cases of comorbid bipolar disorder with irritable depression, positive results have been reported from

• Aripiprazole 5 to 15 mg/day (E 4)⁷⁸
• Lamotrigine (important: increase the dose gradually) (E 4)⁷⁸

(E 4): Stimulants should be used with caution even in patients with well-controlled bipolar disorder:(E 4)²⁰(E 4)²¹
Lisdexamfetamine (Vyvanse) and MPH are contraindicated in Switzerland for (acute) mania.
Dexamfetamine is contraindicated in severe or episodic (Type I) bipolar affective disorders (that are not well controlled). Guanfacine and atomoxetine are not contraindicated in bipolar disorders.

3.3.4. Mood Swings Associated with ADHD¶

The following are said to be helpful for severe and frequent mood swings:

• Venlafaxine extended-release 18.75 to 150 mg (E 4)¹⁰⁹
• Carbamazepine
• Valproate
• Lamotrigine
  • For more information, see Lamotrigine for ADHD

3.3.5. Borderline Personality Disorder Comorbid with ADHD¶

The analysis was conducted as a within-individual analysis, in which each person served as their own control. The follow-up period spanned 16 years, with an average of 6.9 years per person.¹¹⁵

The authors conclude that ADHD medications should be the treatment of choice for people with borderline personality disorder who also have ADHD symptoms and suicidal behavior.¹¹⁵

The following are said to be helpful for borderline personality disorder with comorbid conditions:

• Venlafaxine extended-release 37.5 to 75 mg (E 4)¹⁰⁹
• Venlafaxine extended-release 18.75 to 150 mg (E 4)⁷⁸

Valproate (250 mg to 500 mg) moderately improved symptoms of irritability, anger, anxiety, rejection sensitivity, and impulsivity in 50% of people with ADHD. The results varied greatly from person to person. (E 4)⁶⁵

3.3.6. Disruptive Mood Dysregulation Disorder (DMDD) Comorbid with ADHD¶

DMDD is characterized by persistent, severe irritability and high impulsivity. ADHD often occurs as a comorbid condition.

An open-label study involving n = 24 children and adolescents aged 7 to 17 with comorbid disorder of mood regulation (DMDD) and ADHD found that, over a 6-week period, combination therapy with aripiprazole and methylphenidate had a positive effect on irritability, externalizing symptoms, depression, anxiety, attention, social problems, and reaction time variability. The effect sizes for irritability, oppositional symptoms, and inattention were similarly high (Cohen’s d = 1.26, 1.11, and 1.40). The combination was well tolerated. (E 4)¹¹⁶

Children with DMDD and comorbid ADHD exhibit greater irritability, more disruptive behavior, more anxiety and depressive symptoms, and more social problems than children with ADHD alone.¹¹⁶

3.3.7. Irritability in ADHD¶

An RCT involving n = 19 children and adolescents aged 7 to 17 with ADHD and irritability found that dextromethorphan administered in addition to methylphenidate (30 mg/day for the first 2 weeks, then 60 mg/day) administered in addition to methylphenidate reduced irritability more effectively than placebo. The benefit was greatest in week 2 (difference of −5.50 points on the Affective Reactivity Index; 95% CI −8.13 to −2.87) and decreased by week 8 (−2.77; −5.29 to −0.24).(E 1b)¹¹⁷Dextromethorphan is a cough suppressant and is not approved for this use. No treatment recommendation can be derived from a study involving 19 children.

In cases of irritability and mood dysregulation, most people with ADHD do not require a second medication. In a three-stage, 10-week trial involving 30 children aged 6 to 18 with ADHD and emotional regulation disorders, 22 (73.3%) responded to methylphenidate alone. Of the remaining 8, 5 responded to aripiprazole alone. Only 2 received the combination therapy. Those who responded to methylphenidate or aripiprazole showed significant improvement in emotional regulation (Hedges’ g = 2.62 and 1.30, respectively) and in school adjustment. The severity of the emotion regulation disorder was associated with oppositional symptoms, not with core ADHD symptoms.¹¹⁸The 2025 study provides no information regarding the response of the two children who received the combination treatment.
In 24 people with ADHD aged 7 to 17 who have an affect regulation disorder with dysphoria, the combination of aripiprazole and methylphenidate improved irritability, externalizing symptoms, depression, anxiety, attention, social difficulties, and variability in reaction time over a 6-week period. The effect sizes for parent-rated irritability, oppositional symptoms, and inattention were 1.26, 1.11, and 1.40, respectively. The 2018 study was open-label and lacked a control group, so the effect sizes above 1.0 should be interpreted with caution.¹¹⁹

In cases of severe non-episodic irritability, 45% of people with ADHD aged 7 to 17 were not randomized at all because they showed significant improvement during a two-week, single-blind placebo run-in phase. No significant differences were found between the groups randomized to lithium (14) or placebo (11) in either clinical or MRI spectroscopic endpoints.¹²⁰
Anyone who adds a second medication in this situation without allowing time to pass will mistakenly attribute the improvement to the medication. In cases of irritability and aggression, the majority of patients improve without a second medication if the initial treatment is carefully adjusted and the patient is given time to respond.

3.3.8. Aggression Comorbid with ADHD¶

A review identified comorbid aggression or oppositional behavior as an indication for the combined use of stimulants and non-stimulants (alpha-2 agonists or atomoxetine). (E 4)⁶⁶

Several atypical antipsychotics, particularly risperidone, effectively reduced aggression. Some studies showed (contrary to the FDA’s warning that stimulants could exacerbate aggression) that stimulants, like antipsychotics, effectively reduced aggression, particularly in hyperactive children.(E 4)¹²¹ For the treatment of ADHD, there is no evidence from randomized controlled trials regarding risperidone in people with intellectual disabilities. A Cochrane review examined eleven studies, none of which met the inclusion criteria. Prescribing in this group is based on open-label studies or on extrapolating findings from research on people with autism and behavioral disorders.¹²²

However, the underlying review notes that stimulants and antipsychotics have opposing mechanisms of action and that interactions between these two classes of drugs must be taken seriously.¹²¹

Stimulants that improve ADHD symptoms often also improve aggression and disruptive behavior associated with comorbid oppositional defiant disorder, conduct disorder, mood regulation disorder, or ASD.(E 1a)⁶⁷ In a randomized controlled trial with rapid titration of stimulants involving n = 175 children aged 6 to 12 years with ADHD and a comorbid conduct disorder, just under 64% of participants achieved remission of aggressive symptoms (R-MOAS score < 18) after an average of 75 days. The mean dose was 42 mg/day (in immediate release methylphenidate equivalents) or approximately 1.2 mg/kg/day.(E 1a)¹²³

(E 1a): Combination therapy with (low-dose) antipsychotics and psychostimulants may be particularly helpful in cases of comorbid aggression when monotherapy with stimulants and a combination of stimulants with behavioral therapy interventions for treating aggression have been insufficient.(E 1a)¹²⁴ Superiority over monotherapy with antipsychotics or stimulants has not been demonstrated. The underlying studies were short, partly open-label, rarely placebo-controlled, and did not include comparisons with behavioral therapy interventions. The hope that a stimulant might mitigate weight gain and other metabolic effects of antipsychotics is unfounded. Stimulants did not significantly reduce the metabolic side effects of antipsychotics. (E 1a)¹²⁴

Various expert panels concluded that, in cases of aggression comorbid with ADHD (not: aggression resulting from stimulants) that is not sufficiently alleviated by stimulants, the concurrent use of carefully dosed atypical antipsychotics is indicated. (E 4)¹²⁵(E 4)¹²⁶ The earlier consensus conference was convened specifically at the request of Johnson & Johnson, the sponsor.

Molindon is an atypical/conventional antipsychotic that is approved in the United States as an immediate-release (IR) formulation for the treatment of schizophrenia (brand name: Moban).
Molindon with prolonged-release formulation (SPN-810) was evaluated for comorbid oppositional aggression. (E 1b): In a placebo-controlled Phase 2b study involving 121 children aged 6 to 12 years, aggression improved with low and moderate doses but not with high doses. (E 1b)¹²⁷ Side effects included headaches (10.0%), sedation (8.9%), and increased appetite (7.8%). (E 1b)¹²⁷ An open-label pilot study in 78 children primarily assessed tolerability. (E 1b)¹²⁸
(E 4): The development program was discontinued following the Phase III trials due to a lack of efficacy. (E 4)¹²⁹(E 4)¹³⁰

(E 2b): Regarding the reproductive toxicology assessment: A manufacturer’s study concluded that molindon is safe.(E 2b)¹³¹ An expert commentary contradicted this conclusion, (E 4)¹³² whereupon the authors acknowledged a small but statistically significant decrease in the postnatal survival rate of the offspring. (E 4)¹³³
(E 2b): In in vitro studies, SPN-810M is a potent antagonist of the dopamine receptors D2S and D2L and the serotonin receptor 5-HT2B. (E 2b)¹³⁴(E 4)¹³⁵

For information on the concomitant use of antipsychotics and psychostimulants, see also the section on weight loss above.
Bipolar disorders, intermittent explosive disorder, and early-onset psychoses without comorbid ADHD are more likely to result in treatment-induced mania or psychosis when treated with stimulants, or their explosive behavior may become more aggressive. Stimulants are therefore only helpful in reducing aggression in cases of existing ADHD. (E 1a)⁶⁷

3.3.9. Oppositional defiant behavior comorbid with ADHD¶

 

A meta-analysis of k = 28 studies found that stimulants improved aggressive behavior in ADHD just as effectively as they did the core ADHD symptoms themselves (mean effect size 0.84 for overt aggression and 0.69 for covert aggression). When accompanied by a co-occurring social behavior disorder, the effect on overt aggression was smaller. (E 1a): Girls responded just as well as boys. The dose was not associated with the Effect size, but the duration of treatment was. (E 1a)¹³⁶

The following were helpful in cases of comorbid ODD

• MPH⁶¹³⁷
• A randomized controlled trial (RCT) involving 282 children aged 6 to 12 years over a 28-day period found that OROS methylphenidate administered once daily was just as effective at reducing core ADHD symptoms as immediate release methylphenidate administered three times daily (both significantly more effective than placebo).¹³⁷
• AMP¹⁴
• Concomitant use of stimulants and non-stimulants (alpha-2 agonists or atomoxetine)
  • A review cited comorbid aggression or oppositional behavior as an indication for the combined use of stimulants and non-stimulants (alpha-2 agonists or atomoxetine). (E 4)⁶⁶
• Atomoxetine
  • (E 1a): Atomoxetine reliably improves ADHD symptoms in cases of comorbid oppositional defiant disorder (ODD) (just as effectively as in ADHD without ODD). (E 1a)¹³⁸ However, it has barely any effect on the oppositional symptoms themselves: One study found an effect size of only 0.39, although higher doses were required than for ADHD without comorbidity (E 1b)¹³⁹; two other studies found no significant effect on ODD symptoms. (E 1b)¹⁴⁰(E 1a)¹⁴
  • In a study of ADHD with ODD, improvement was not observed until a dose of 1.8 mg/kg/day was reached, whereas in cases without ODD, a dose of 1.2 mg/kg/day was sufficient.¹³⁹
  • In contrast, a meta-analysis found no difference in response between children with and without ODD.¹³⁸ In our view, however, it is still worthwhile to attempt treatment because oppositional symptoms often subside as ADHD symptoms improve.
  • Another study found that atomoxetine had an effect on oppositional symptoms in weeks 2 and 5, but no longer in week 8, as well as a sustained improvement in ADHD symptoms.¹⁴¹
  • Conversely, comorbid ODD does not worsen the prognosis for ADHD relapse: Of 416 children and adolescents whose ADHD symptoms had remitted under open-label atomoxetine treatment, 17% of those with ODD experienced a relapse, compared with 26% of those without ODD (relative risk 0.67; 95% CI 0.42 to 1.06).¹⁴²
• Guanfacine
  • (E 1b): Guanfacine demonstrated a positive effect on oppositional behavior in children with ADHD as monotherapy (E 1b)¹⁴³ as well as when used in combination with a stimulant (E 1b)¹⁴⁴. The study specifically examined sustained-release guanfacine (1 to 4 mg/day) in children and adolescents aged 6 to 17 years for whom the stimulant alone was not sufficiently effective. Oppositional symptoms improved significantly compared to placebo.¹⁴⁴
  • In a double-blind RCT involving 217 children aged 6 to 12 years (138 receiving guanfacine, 79 on placebo) over 9 weeks, the score on the Conners “Oppositional” subscale decreased by 10.9 points with sustained-release guanfacine (1 to 4 mg/day) compared with 6.8 points with placebo (p < 0.001; Effect size 0.59).¹⁴³ It is noteworthy that approximately 62% of the improvement also occurred with placebo. The placebo effect is substantial for parent-rated behavioral symptoms. Results from studies without a control group should therefore be interpreted with caution.¹⁴³

(E 1b): In cases of comorbid ODD and ADHD, combination therapy with risperidone and MPH proved helpful (E 1b)¹⁴⁵; the same was true for comorbid conduct disorder (CD) (E 3)¹⁴⁶ However, in the same study, weight, waist circumference, and prolactin levels increased with risperidone, which represents alarming side effects. (E 1b)¹⁴⁵ Elevated prolactin levels can lead to breast development, lactation, and amenorrhea in children and adolescents. This can be particularly distressing during adolescence, as body image and self-esteem are closely linked.¹⁴⁵

This is a retrospective analysis of 44 cases. In over 60% of cases, the combination reduced symptoms of ADHD, disorder of behavior, sleep disturbances, and anxiety. In 70% of cases, there was a stabilizing effect on weight gain, and in 50% of cases, on appetite. Tachycardia occurred in 3 cases, and dyskinesia in one case, which resolved after discontinuation. (E 3)¹⁴⁶
In contrast, a systematic review found that a stimulant does not significantly reduce the metabolic effects of antipsychotics.¹²⁴

Effect sizes of various medications on ODD compared to placebo: (E 1a)¹⁴⁷

• 0.84 stimulants in the teacher’s assessment (k = 8, high evidence)
• 0.55 stimulants in parental judgment (k = 9, high evidence)
• 0.43 Guanfacine sustained release (k = 2, n = 678, moderate evidence)
• 0.33 Atomoxetine (k = 15, n = 1,907, high evidence)
  • Effect on ODD regardless of whether ODD had been diagnosed
• 0.27 Clonidine (k = 3, n = 283, very low evidence)

3.3.10. Conduct Disorder (CD) Comorbid with ADHD¶

(E 1b): According to a systematic review, atomoxetine may be helpful in cases of comorbid conduct disorder.(E 4)¹⁴⁸ (E 1b): However, placebo-controlled studies found that atomoxetine had no effect on the oppositional symptoms themselves in cases of comorbid oppositional defiant disorder. (E 1b)¹³⁹(E 1b)¹⁴⁰ No corresponding studies are available for conduct disorder.

Conduct disorder is also frequently treated with: (E 4)¹⁴⁸

• Antipsychotics
• Antidepressants such as imipramine, desipramine, and SSRIs
• Lithium

A study found that, among children and adolescents who began taking methylphenidate between 2005 and 2013, 67,595 received combination therapy with MPH and antipsychotics. Among them was a combination with

• Risperidone (72%)
• Pipamperone (15%)
• Tiaprid (8%)

One-quarter of the users of a combination therapy of MPH and antipsychotics were prescribed it only once.
In a German analysis of claims data for 67,595 children and adolescents with ADHD who began treatment with MPH, more than 6% were also prescribed an antipsychotic within 9 years. MPH was most commonly combined with risperidone (72%), pipamperone (15%), and tiaprid (8%). The use of MPH in combination with risperidone and tiaprid was often appropriate (over 72%), whereas the combination of MPH with pipamperone was rarely appropriate (15%).(E 3)¹⁴⁹ A combination was considered appropriate if a suitable approved indication or a guideline recommendation for the antipsychotic was documented. This says nothing about suitability in individual cases.¹⁴⁹
In the year prior to the first combination therapy, 33% (risperidone), 43% (pipamperone), and 19% (Tiaprid) of the children had been hospitalized for psychiatric treatment. Social behavior disorders were common with the risperidone combination, while tic disorders were common with the tiaprid combination. The authors call for ADHD guidelines to establish algorithms for the use of antipsychotics.¹⁴⁹

In children with ADHD and oppositional disorder, atomoxetine levels did not predict treatment response. After eight weeks on 1.2 mg/kg daily, non-responders with levels below 800 ng/ml were randomized to receive either 1.2 or 2.4 mg/kg for four weeks. Symptom improvement was numerically greater at the 2.4 mg/kg dose. After 12 weeks, the concentration was not a meaningful predictor of improvement. Therefore, if oppositional symptoms persist, doubling the atomoxetine dose should be considered before initiating combination therapy. Measuring the concentration does not aid in this decision.¹⁵⁰

3.3.11. ASD with ADHD¶

Estimates of the prevalence of comorbid ADHD in people with SAD vary considerably (24 to 83 percent). On average, about half of the people with ADHD are affected. (E 1a)⁶⁷

Medication for Autism Disorder and Comorbid ADHD:

• There are frequent reports of increased sensitivity to medications in general, including ADHD medications, or a reduced dosage requirement. In some cases, the required doses are extremely low. (E 1a)⁶⁷ Other sources report that the same doses of ADHD medications are used for comorbid ASD (E 4)¹⁵², citing Hyman et al. (2020 ¹⁵³, the American Academy of Pediatrics’ clinical report on ASD, whose conclusions, however, do not align with the studies cited therein. The studies mentioned there report strikingly low dosages, accompanied by an increased risk of side effects).

• Stimulants

  • Stimulants do not appear to worsen oppositional or repetitive behavior in children with ASD and are more effective in children without intellectual disabilities. The most common side effects are loss of appetite and sleep disturbances. Irritability, social withdrawal, and depressive mood are also reported.⁶⁷

  • In a cross-sectional survey of n = 68 children with ASD who were receiving stimulants, the people with ADHD or their parents reported the following (as a percentage of patients): (E 3)¹⁵⁴

    • Restlessness:

      • 47.4% improvement (particularly among children diagnosed at a later stage)
      • 28.1% decline (primarily due to sustained release MPH)

    • Concentration:

      • Improved by 56.1%
      • 15.8, a decline

    • Sleep

      • Improved by 8.8%
      • 17.5% decline

    • Language

      • 86% unchanged
      • 12.25% decline
      • Improved by 1.75%

    • other behavioral changes

      • 50.9% unchanged
      • 45.6% negative changes
      • 3.5% positive changes
      • Female gender was significantly correlated with other negative behavioral changes
      • A longer duration of treatment was associated with a higher likelihood of improvement in restlessness, concentration, and other behavioral symptoms, which argues against discontinuing treatment early

• MPH:

  • 49% responders among n = 72 children aged 5 to 14
    • Effect sizes ranging from 0.20 to 0.54, depending on the dose and the rater
    • 18% of patients discontinued treatment due to side effects (in the MTA study of children with ADHD who were not taking ASA, the rate was only 1.4%, with a response rate of 69%). (E 1b)¹⁵⁵
  • The starting dose should be very low, e.g., 2.5 mg of immediate release MPH per dose; the next step is 2.5 mg of immediate release MPH twice daily; then slowly increase the dose in 2.5 mg to 5 mg increments every 5 to 7 days. (Guideline recommendation from clinicians at a single specialized center, developed through expert consensus. Not an official guideline.) (E 4)¹⁵⁶
    • This study even reports cases involving a daily dose of 2.5 mg of sustained-release MPH
  • A systematic review with meta-analysis of 25 randomized controlled trials involving individuals under 25 years of age taking ASA confirms that methylphenidate is a first-line treatment option: It significantly reduced hyperactivity (SMD 0.63 as assessed by parents, 0.81 as assessed by teachers) and, to a lesser extent, inattention (SMD 0.36 as assessed by parents, 0.30 as assessed by teachers).¹⁵⁷

• For some people with ADHD and ASD, alpha-2 agonists are considered more appropriate than stimulants. For comorbid anxiety, buspirone and mirtazapine were recommended over SSRIs; for comorbid depression, duloxetine, mirtazapine, bupropion, and vortioxetine were recommended over SSRIs; and for irritability, depending on the severity, guanfacine, risperidone, or aripiprazole were recommended. (E 4)¹⁵⁶

  • Another study involving n = 14 preschoolers with ADHD and comorbid ASD or other developmental disorders began with 1.25 mg of MPH twice daily and allowed for a maximum dose of 10 mg twice daily.(E 1b)¹⁵⁸ Half of them experienced side effects, including increased stereotypical behaviors, abdominal pain, sleep problems, and emotional instability.
  • Low initial dose administered under careful monitoring (e.g., 0.3 mg/kg/day) with low target doses (e.g., 0.5 mg/kg/day) (E 4)¹⁵³
    • The claim in the text that the dosage is the same as for children with ADHD who do not take ASA is not found in the source cited for this. The studies cited there indicate notably lower dosages.
  • More severe side effects from stimulants are possible, particularly loss of appetite and insomnia (E 4)¹⁵³
  • effective in treating symptoms of hyperactivity, inattention, and irritability; fewer side effects than ATX(E 1a)¹⁵⁹
  • Less effective and associated with more side effects than in children with ADHD who do not take ASA. ASA has the same effect on hyperactivity in children with ADHD as in children without ADHD. This assessment is based on a review of the literature by an author who served as an investigator for several manufacturers. (E 4)¹⁶⁰
  • A systematic review with a meta-analysis of k = 25 randomized controlled trials involving individuals under 25 years of age taking ASA found small to large effects for guanfacine, with low to very low levels of evidence.¹⁵⁷

• Less effective in treating hyperactivity in cases of intellectual disability (E 4)¹⁵¹

• Of the three substances, guanfacine is the only one that shows barely any loss of efficacy when used with ASA, although it is less well tolerated¹⁶⁰¹⁵¹

• Lisdexamfetamine:

  • Second-line treatment if MPH is ineffective or causes unacceptable side effects. (E 1a): Again, start with a low dose and expect a lower target dose (half or less). (E 1a)⁶⁷(E 4)¹⁵³
  • Recommended daily doses range from 10 mg to 70 mg (E 4)¹⁵⁶

• Amphetamine salts:

  • Appropriate daily doses are reported (E 4)¹⁵⁶
    • 2.5 mg to 40 mg, immediate release
    • 5 mg to 60 mg, sustained release

• Atomoxetine:

  • A systematic review with meta-analysis of k = 25 randomized controlled trials involving individuals under 25 years of age taking ASA found that atomoxetine improved inattention (SMD 0.54 as rated by parents, 95% CI = -0.98, -0.09, and SMD 0.38 on the teacher assessment, 95% CI = -0.75, -0.01) and hyperactivity (SMD 0.49 on the parent assessment, 95% CI = −0.76, −0.23, and SMD 0.43 as assessed by teachers, 95% CI = −0.92, 0.06), although the evidence to date is only low to very low.¹⁵⁷

• (E 4): Less effective for ADHD symptoms with the same level of tolerability (E 4)¹⁵¹(E 4)¹⁶⁰

• modest effect on symptoms of hyperactivity and inattention with a relatively benign side-effect profile; more frequent treatment discontinuations due to more severe side effects than with MPH (E 1a)¹⁵⁹

• Guanfacine:

  • Initial dose (immediate release): 0.5 mg/day, titrated in 0.5-mg increments (E 4)¹⁵⁶
  • Initial dose: sustained release 1 mg/day, 1-mg titration increments (E 4)¹⁵⁶
  • The same effect on hyperactivity was observed in the ASS group as in the control group (E 4)¹⁶⁰
  • Same effect on hyperactivity in cases of intellectual disability, with poorer tolerability (E 4)¹⁵¹

• Amitriptyline:

  • Effective at a dosage of approximately 1 mg/kg/day when used with caution (E 4)¹⁶⁰
    • Sleep, anxiety, impulsivity, and ADHD, repetitive behaviors, and enuresis

In cases of autistic traits (subclinical ASD)

• Fluoxetine 10 to 20 mg (E 4)¹⁰⁹
• Fluoxetine 5 to 20 mg (E 4)⁷⁸
• Aripiprazole
  • 2.5 mg (starting dose) to 5 mg, rarely up to 10 mg (E 4)¹⁰⁹
  • 2.5 to 7.5 mg (E 4)⁷⁸

Pure ASA medication:
In the U.S., only risperidone and aripiprazole are approved by the FDA for the treatment of SAD (E 4)¹⁶⁰

• Risperidone
  • Hyperactivity/impulsivity associated with autism or intellectual disability can be improved by stimulants as well as by risperidone. Risperidone is not generally approved for the treatment of ADHD, but it could be considered in cases of comorbid autism. Due to the potential for increased side effects, careful dosing is required for these combinations of symptoms. (E 1a)²⁶
  • (E 2b): For schizophrenia: 2 mg recommended starting dose, 2 mg lowest effective dose, 8 mg recommended maximum dose, 20 mg approved maximum dose.(E 4)¹⁶¹, 6 mg already occupied 75% to 80% of the D2 receptors. (E 2b)¹⁶²(E 2b)¹⁶³ In sensitive patients (CYP23D6 poor metabolizers), even lower doses are sufficient to achieve this. A receptor occupancy of 60 to 70% is the target in drug therapy. Higher doses primarily increase side effects. At 80% or higher, extrapyramidal symptoms occur and supersensitivity develops. (E 4)¹⁶¹ EPS and supersensitivity are common risks of side effects and are therefore likely to apply to ASA as well.
• Citalopram and fluoxetine (SSRIs):
  • Poor tolerability and lack of effectiveness in cases of repetitive behaviors (E 4)¹⁶⁰
• Oxytocin:
  • showed no efficacy (E 4)¹⁶⁰
• Amitriptyline and loxapine:
  • promising (E 4)¹⁶⁰
• Loxapine:
  • at a dosage of 5 to 10 mg daily in PET, similar to an atypical antipsychotic, possibly without weight-related side effects (E 4)¹⁶⁰

Memantine has proven helpful for both ASD and ADHD. For more information, see Memantine for ADHD.

3.3.12. Co-occurring high reactivity / increased sensitivity¶

Experience has shown that the following can be helpful in cases of severe sensory hypersensitivity with comorbid conditions:

• Aripiprazole (off-label): starting dose 2.5 mg, up to 10 mg (E 4)¹⁰⁹

• Vitamin B6

  • A study reports a reduction in sensory over-responsivity (SOR) following high-dose vitamin B6 (100 mg/day). (E 2b)¹⁶⁴
    • Although the 100 mg/day used in this study corresponds to the upper limit for daily intake in the United States, 100 mg/day is far above the intake level considered safe in Europe. In 2023, the EFSA lowered the Tolerable Upper Intake Level (UL) for adults from 25 mg to 12 mg/day.¹⁶⁵ The BfR adopted this assessment in 2024.¹⁶⁶ An intake of 100 mg/day should therefore, if at all, be strictly limited in duration and only taken under medical supervision. Self-medication is strongly discouraged, as vitamin B6 toxicity can lead to neuropathies, which may be accompanied by impaired sensory perception.(E 4)¹⁶⁷ In our view, further studies should first be conducted to ensure that the study did not merely measure side effects of neuropathy.

3.3.13. Tic Disorders Comorbid with ADHD¶

Tourette syndrome has an estimated prevalence of 0.52% and is four times more common in boys than in girls. (E 4)¹⁶⁸ One in two adolescents with Tourette syndrome also has ADHD. (E 3)¹⁶⁹

The following medications have been reported to have beneficial effects on tics and Tourette’s syndrome:

• Stimulants
  • For children and adolescents with ADHD and tic disorders or Tourette syndrome, stimulants can be an effective treatment. (E 1a): As a rule, they do not worsen tics or Tourette syndrome, although there are isolated cases where this is not the case. (E 1a)¹⁷⁰(E 1a)⁶⁷
  • In practice, concerns about tics lead to underdosing, even though the available data do not support this. Caution is warranted only with high-dose amphetamine medications. (Cochrane Review)¹⁷¹
  • Methylphenidate (Evidence: low) (E 1a)¹⁷⁰
    • MPH showed the strongest and most rapid improvement in ADHD symptoms and a trend toward improvement in tics (SMD 0.28; 95% CI -0.03 to 0.58; p = 0.07). (Meta-analysis, k = 9 double-blind studies, N = 477 children)¹⁷²
    • Improved tics (Cochrane Review) ¹⁷¹
    • In children with ADHD and tic disorder, a two-year course of MPH treatment did not worsen the frequency or severity of motor and vocal tics. The study included 34 prepubertal children who were assessed every six months through behavioral observation in a simulated classroom setting, as well as through parent and physician questionnaires. The behavioral improvements observed during the acute phase of the study were sustained. No clinically significant effects on cardiovascular function or growth were observed.¹⁷³
  • Dextroamphetamine (E 1a)¹⁷⁰
    • Since dextroamphetamine in high doses can (initially) worsen tics in some children¹⁷¹, methylphenidate should be preferred. (E 1a)⁶⁷ (E 1a) Dextroamphetamine doses above the therapeutic range were associated with a worsening of tics. (Meta-analysis, k = 9 double-blind studies, N = 477 children)¹⁷²
    • A computer simulation of the proteins affected by lisdexamfetamine (co-authored by the manufacturer) predicted a beneficial effect even in tic disorders. No clinical data are available on this. (E 2b) ⁷⁰
    • The once-widespread belief that stimulants trigger or worsen tics does not hold up to scrutiny. A meta-analysis of randomized, placebo-controlled trials found no increased risk of new-onset or worsening tics with stimulants compared to placebo (RR 0.99; 95% CI 0.78–1.27). There were no differences between MPH, mixed amphetamine salts, and dexmethylphenidate. A suspected tic therefore does not justify either discontinuing the medication or avoiding stimulants.¹⁷⁴
• Guanfacine (E 4)¹⁷⁵(E 1a)¹⁷⁶
  • effective
    • SMD 0.72 for ADHD (E 1a)¹⁷⁷
    • on Tics SMD 0.70 (E 1a)¹⁷⁷to 0.68 (E 1a)¹⁷⁶
  • improves tics (Cochrane Review) ¹⁷¹
  • Evidence: very low (E 1a)¹⁷⁰
  • For tic disorders without comorbid ADHD, alpha-2 agonists such as guanfacine and clonidine had only a weak and non-significant effect on tics (SMD 0.15; 95% CI −0.06 to 0.36); in contrast, for tic disorders with comorbid ADHD, the effect was significant (SMD 0.68; 95% CI 0.36 to 1.01; p < 0.001)
  • Effective for comorbid tic disorders (E 1a)¹⁷⁰
  • Alpha-2 agonists such as guanfacine improve ADHD symptoms and tics.¹⁷²
  • In the first placebo-controlled guanfacine study conducted in 2001 on children with ADHD and tic disorder, teacher-rated ADHD symptoms improved by 37% compared with 8% in the placebo group (with stimulants, 50 to 60% would be typical), and tic severity improved by 31% compared to 0%. In contrast, parent-rated hyperactivity improved only non-significantly by 27% compared to 21% with placebo. The authors hypothesize that a combination of guanfacine with a stimulant in Tourette syndrome and ADHD could allow for lower stimulant doses while also protecting against an increase in tics.¹⁷⁸
• Clonidine
  • In a study of 154 children with tic disorder and comorbid ADHD (77 in each group), it was more effective than MPH plus haloperidol (in terms of clinical efficacy, motor and vocal tics, and the YGTSS total score (all p < 0.05), as well as the safety profile). (E 1b)¹⁷⁹ Haloperidol is a highly potent typical antipsychotic that is no longer the first-line treatment for tics. A comparison with guanfacine or with methylphenidate alone would be more meaningful.
  • Low evidence. (E 1a)¹⁷⁰
  • Alpha-2 agonists such as clonidine improve ADHD symptoms and tics.¹⁷²(Cochrane-Review)¹⁷¹
  • In a Chinese study of 154 children with ADHD and comorbid tic disorder, clonidine alone was superior to the combination of MPH and haloperidol in terms of motor and vocal tics as well as the total tic score (p < 0.05 in each case), as well as for behavioral problems, learning difficulties, psychosomatic disorders, hyperactivity, and impulsivity, and the anxiety and hyperactivity indices. Side effects occurred less frequently with clonidine (p < 0.05).¹⁷⁹ Since the older antipsychotic haloperidol has significant side effects, clonidine’s advantage in terms of side effects was to be expected.
• Combination of stimulants and guanfacine
  • A review identified comorbid tic disorders as an indication for the concurrent use of stimulants and alpha-2 agonists. (E 4)⁶⁶
  • In a lecture, Barkley discusses the benefits of combining stimulants with guanfacine (which is helpful for comorbid tics) to counteract the suppression of the limbic system caused by stimulants and the resulting reduced perception of emotions. (E 4)¹⁸⁰
• Atomoxetine (E 4)¹⁷⁵(E 1b)²⁴
  • (Evidence: low) (E 1a)¹⁷⁰
  • In an RCT involving n = 117 children and adolescents aged 7 to 17 with ADHD and Tourette’s syndrome, atomoxetine (0.5 to 1.5 mg/kg/day) significantly reduced tic severity over 18 weeks to a greater extent than placebo (Yale Global Tic Severity Scale). ADHD symptoms also improved. However, the difference was not statistically significant based on the children’s self-reports. Decreased appetite, nausea, increased heart rate, and weight loss were more common. Several authors are employed by the manufacturer of atomoxetine.²⁴
  • In the overarching study of children with ADHD and chronic tic disorders in general, the effect on tics fell just short of statistical significance (YGTSS −5.5 ± 6.9 with atomoxetine versus −3.0 ± 8.7 with placebo; p = 0.063). This confirms, above all, that atomoxetine does not worsen the tics.¹⁸¹
  • Did not worsen tics. (Cochrane Review)¹⁷¹
• Selegiline (Deprenyl)
  • A study found that selegiline significantly improved ADHD symptoms in children with ADHD and comorbid tic disorder over a trial period of more than 6 months. Only 2 of the 29 participants reported a worsening of their tics. Side effects were mild. (E 4)¹⁸²
    An open-label study without a control group involving 29 children with ADHD and comorbid tic disorder who had ceased to respond to conventional treatments found, over an average of 6.7 months, that 26 of 29 (90%) showed a clinically significant improvement in ADHD symptoms at a mean daily dose of 8.1 mg. Only 2 of the 29 participants reported a worsening of their tics. (E 4)¹⁸² A later double-blind, placebo-controlled cross-over-over study involving 24 children with ADHD and comorbid Tourette syndrome, however, found no statistically significant benefit regarding ADHD symptoms (p = 0.50) and only a trend regarding tics (p = 0.06). Of the 24 participants, only 15 completed the study. (E 1b)¹⁸³Deprenyl (Evidence: very low) (E 1a)¹⁷⁰A Cochrane review found no improvement in ADHD symptoms with selegiline (deprenyl).¹⁷¹
• Antipsychotics had an effect on tics regardless of this (SMD 0.58; 95% CI 0.36 to 0.80). For tic disorders without ADHD, antipsychotics therefore demonstrate a greater effect size. A longer duration of treatment was associated with a greater effect size for alpha-2 agonists. (E 1a)¹⁷⁶
• A Chinese study of 154 children with ADHD and comorbid tic disorder compared MPH in combination with haloperidol to clonidine alone. Clonidine was superior in terms of clinical efficacy, motor and vocal tics, and the total tic score (p < 0.05 in each case), as well as in behavioral problems, learning difficulties, psychosomatic disorders, hyperactivity and impulsivity, and the anxiety and hyperactivity indices. Side effects occurred less frequently with clonidine (p < 0.05).¹⁷⁹ The choice of haloperidol as the comparator is unusual, as this older antipsychotic has significant side effects. The advantage of clonidine in terms of side effects is therefore to be expected. The journal’s impact factor should be taken into account in the weighting.
• Desipramine (Evidence: very low) (E 1a)¹⁷⁰

In contrast, a meta-analysis of k = 22 placebo-controlled studies involving n = 2,385 children with ADHD found no increased risk of new-onset or worsening tics associated with stimulants: Such tics were reported in 5.7% of children on stimulants and in 6.5% of children on placebo (risk ratio 0.99; 95% CI 0.78 to 1.27). Neither the type of active ingredient, nor the dose, duration of treatment, nor age influenced this result. The authors expressly recommend that children in whom a worsening of tics is reported be re-titrated on stimulants, as the temporal association is usually coincidental. (E 1a)¹⁸⁴As always, a slow and gradual titration is recommended, even if this requires more persistence.
Krause & Krause report that comorbid tics may initially worsen during monotherapy with stimulants. However, this usually resolves after about four weeks if the dosage remains constant. Anyone who notices tics after starting a new course of stimulant treatment should therefore not stop taking the medication immediately, but rather maintain the dose and wait out this period. Sometimes even a slight reduction in dosage is enough to make the tics disappear. (E 4)²³ In cases of severe ADHD and a history of tic worsening due to stimulants, it is possible that the stimulant will not worsen the tics upon re-administration.(E 1a)¹⁸⁴In the past, stimulants were not recommended for adolescents with Tourette syndrome or chronic tic disorders (E 4)¹⁶⁸, as case reports from the 1970s involving children treated with a stimulant for ADHD tics had been reported (particularly motor tics, e.g., eye blinking, nose wrinkling, lip licking). (E 4)¹⁶⁸

3.3.14. Obsessive-Compulsive Disorder Comorbid with ADHD¶

A report on two children with obsessive-compulsive disorder and ADHD (ages 9 and 10) suggested a positive effect of a combination of cognitive behavioral therapy, sertraline, and guanfacine. (E 4)¹⁸⁶ Cognitive behavioral therapy is the first-line treatment for obsessive-compulsive disorder.

Positive results have been reported with sertraline at doses of 50 to 100 mg/day in patients with comorbid obsessive-compulsive disorder. (E 4)⁷⁸

3.3.15. Schizophrenia and Psychosis Comorbid with ADHD¶

In cases of comorbid schizophrenia spectrum disorder, the dosage of methylphenidate and the combination of multiple medications—when used with caution—are the decisive factors. A large registry analysis of n = 131,476 people with ADHD examined the total number of hospitalizations, deaths, and hospitalizations due to psychosis, somatic diseases, and cardiovascular diseases among individuals with schizophrenia-spectrum disorders who were taking ADHD medications. Lisdexamfetamine was associated with a reduced risk of hospitalization or death (aHR 0.89; 95% CI 0.84 to 0.94), while methylphenidate was associated with a slightly increased risk (aHR 1.04; 1.01 to 1.08). However, the increased risk associated with methylphenidate was observed only at doses of 95 mg/day or higher (aHR 1.08) or during periods without concomitant antipsychotic use (aHR 1.06). Atomoxetine was associated with a reduced risk of psychosis hospitalization (aHR 0.87). For methylphenidate and lisdexamfetamine, a U-shaped relationship between dose and risk was observed; very low and very high doses were associated with a higher risk than moderate doses.

Hospitalization from any cause or death (aHR, 95% CI; dose in mg/day)

Dosage	, methylphenidate	, lisdexamfetamine
less than 45 mg	1.02 (0.97–1.08)	1.03 (0.90–1.17)
45 to less than 75 mg	0.91 (0.86–0.97)	0.86 (0.78–0.96)
75 to less than 95 mg	0.82 (0.75–0.88)	0.83 (0.73–0.94)
95 mg or more	1.07 (1.03–1.12)	0.86 (0.80–0.93)

Admission due to psychosis (aHR, 95% CI; dose in mg/day)

Dosage	, methylphenidate	, lisdexamfetamine
less than 45 mg	0.83 (0.73–0.95)	0.98 (0.69–1.39)
45 to less than 75 mg	0.83 (0.72–0.95)	0.71 (0.54–0.94)
75 to less than 95 mg	0.71 (0.59–0.85)	0.75 (0.54–1.04)
95 mg or more	1.04 (0.94–1.14)	0.92 (0.77–1.10)

Only those values whose confidence interval does not include 1 are significant.

• Atomoxetine¹⁸⁷
  • reduced risk (only) of hospitalizations due to psychosis (13% lower; aHR = 0.87 [0.78 to 0.98])
• ADHD polytherapy¹⁸⁷
  • increased risk (only) for somatic hospitalizations (+37%; aHR = 1.37 [1.07 to 1.74])
• all ADHD medications¹⁸⁷
  • no other statistically significant correlations
  • no effect on cardiovascular hospitalizations

The authors concluded that ADHD medications are safer for this group than is often assumed, particularly lisdexamfetamine at all dosages and long-acting methylphenidate at low to moderate doses. (E 2b)¹⁸⁷

A retrospective cohort study of n = 2,219 people with a schizophrenia-spectrum disorder who, in addition to their antipsychotic treatment, began taking methylphenidate (71.6%), amphetamines (15.3%), or atomoxetine (13.1%) in addition to their antipsychotic treatment found a two-thirds reduction In the risk of psychosis-related hospitalization in the 12 months following initiation compared to the previous year (adjusted hazard ratio 0.36; 95% CI 0.24 to 0.54; p < 0.0001).(E 2b)¹⁸⁸ The authors conclude that MPH, AMP, and atomoxetine are likely safer than generally assumed for people with ADHD, provided they are administered concurrently with an antipsychotic.

A Swedish cohort study found no evidence among adolescents and young adults that starting methylphenidate treatment increases the risk of psychotic events, even in those with a history of psychosis. The authors explicitly consider this to be a cause for reassurance and question the widespread practice of avoiding or limiting methylphenidate use in cases with a history of psychosis.(E 2b)¹⁸⁹In contrast, an older, methodologically weaker study had reported an increased risk of psychotic disorders and hallucinations with methylphenidate.¹⁹⁰

The following are cited as risk factors for stimulant-induced psychosis: (E 1a)⁶⁷

• schizophrenia that begins in childhood
• bipolar disorders
• other psychiatric disorders with psychotic features in childhood

Psychotic symptoms triggered by stimulants resolve in 92% of patients after discontinuation of the stimulant, without the need for antipsychotic treatment. (E 1a)⁶⁷In an analysis of 337,919 adolescents and young adults aged 13 to 25, a psychotic episode occurred in 0.21% of those treated with amphetamine and in 0.10% of those treated with methylphenidate (hazard ratio 1.65; 95% CI 1.31 to 2.09), with a median of 128 days after the start of treatment (a total of approximately 1 in 660 treated individuals).¹⁹¹
Psychosis associated with stimulants is rare, but it can be very distressing for people with ADHD and their families. Given the proven effectiveness of stimulants, this does not argue against their use, but rather in favor of close monitoring, especially during the first few months of treatment.¹⁹¹

Experience has shown that this can be helpful in cases of comorbid psychotic symptoms, although people with ADHD are said to develop extrapyramidal symptoms quickly:

• Quetiapine, amisulpride, even at doses below the usual dosage (E 4)¹⁰⁹
• Quetiapine, Aripiprazole, Amisulpride (E 4)⁷⁸

For people with schizophrenia spectrum disorder, monotherapy with an ADHD medication is safer than a combination of two ADHD active ingredients. Among 131,476 people with ADHD, combination therapy was associated with an increased risk of hospitalization due to physical illness (adjusted risk ratio 1.37; 95% CI 1.07 to 1.74).
The individual treatments performed better. Lisdexamfetamine reduced the risk of hospitalization or death from any cause (0.89; 95% CI 0.84 to 0.94) and of hospitalization for physical causes (0.70; 95% CI 0.58 to 0.84), while atomoxetine reduced the risk of psychosis-related hospitalizations (0.87; 95% CI 0.78 to 0.98). Methylphenidate slightly increased the risk of hospitalization or death (1.04; 95% CI 1.01 to 1.08), but only at doses of 95 mg or more per day (1.08; 95% CI 1.03 to 1.14) or during periods without concomitant antipsychotic medication (1.06; 95% CI 1.01 to 1.12). For methylphenidate and lisdexamfetamine, there was a U-shaped relationship between dose and risk.²⁵ The risk associated with methylphenidate occurred specifically when no antipsychotic was administered concurrently. Antipsychotic administration has a protective effect in this context. The U-shaped dose-risk relationship means that both very low and very high doses were associated with higher risks.

3.3.16. Substance Abuse / Addiction Co-occurring with ADHD¶

3.3.16.1. The Effect of ADHD Medications on the Risk of Addiction and Relapse¶

(E 1a): Stimulants do not increase the risk of addiction in ADHD (E 1a)¹⁹²(E 4)¹⁹³, neither with regard to the nonmedical use of stimulants (E 2b)¹⁹⁴ nor with regard to stimulant medications (E 4)¹⁹³. People with ADHD often forget to take their medication, which would not happen if they were experiencing cravings.
(E 1a): In fact, stimulants significantly reduce the risk of substance abuse and relapse in individuals with ADHD while they are taking them. (E 4)⁹¹ A large study based on U.S. insurance data from 2,993.887 adolescents and adults diagnosed with ADHD from 2005 to 2014 found that substance use while on stimulant medication was 35% lower among men and 31% lower among women compared to when they were not on medication. Two years after periods of medication, the risks of substance-use-related events were reduced by 19% in men (OR 0.81; 0.78 to 0.85) and by 14% in women (OR 0.86; 0.82 to 0.91) in women. (E 2b)⁹⁶
MPH significantly reduced the incidence of subsequent addiction (meta-analysis, k = 6, n = 1,014). (E 1a)¹⁹⁵ The risk of subsequent addiction—whether to alcohol or other substances—was reduced by a factor of 1.9.(E 4)¹⁹⁶
In humans, early stimulant use did not result in sensitization to subsequent exposure, as was the case in animal models. ¹⁹⁷

A prospective, nationally representative study of 11,905 U.S. students aged 18 and older, conducted over a six-year period, found no increase in subsequent non-medical stimulant use, either compared to people with ADHD who used only non-stimulants or compared to the general population.(E 2b)¹⁹⁴

Among pregnant women with opioid use disorder, prescribed treatment with psychostimulants was also associated with better initiation and retention in addiction treatment. ¹⁹⁸⁣While atomoxetine is considered beneficial in cases of acute comorbid amphetamine substance abuse due to its lower risk of misuse, people with ADHD and opioid dependence currently undergoing treatment (opioids are dopaminergic drugs) demonstrated greater adherence to opioid substitution therapy (buprenorphine). Those who received stimulants were 33% less likely to discontinue buprenorphine treatment. This supports the use of psychostimulants even in cases of a history of addiction to dopaminergic drugs. Psychostimulants were also associated with a lower likelihood of opioid-related hospitalizations (the more prescriptions, the fewer hospitalizations). This was also true for people with ADHD and additional substance use disorders. According to the authors, the benefits of psychostimulants in opioid use disorder and ADHD outweighed the risks. (E 2b)¹⁹⁹

3.3.16.2. Effectiveness of ADHD Medications on ADHD Symptoms in Patients with Co-occurring Substance Use Disorders¶

Stimulants can also be used in the treatment of substance use disorders. The most effective approach is a holistic one that combines medication and non-medication-based treatments. (E 4)¹⁹³

In cases of ADHD with comorbid substance use disorder, medication reduced ADHD symptoms compared with placebo (OR 1.93, SMD approx. 0.30). The effect was thus smaller than in studies without substance use disorder. Atomoxetine and methylphenidate were effective, whereas bupropion, lisdexamfetamine, and pemoline were not. When analyzed by type of dependence, an effect was observed for alcohol and nicotine dependence, but not for dependence on psychostimulants or opioids. The medication had no effect on abstinence (OR 1.09) or on treatment discontinuation (OR 1.14). The greater the effect on ADHD symptoms, the greater the effect on substance use (meta-analysis, k = 13, N = 1,271, E 1a)²⁰⁰
(E 4): Methylphenidate is being discussed as a potential treatment option for substance use disorders. It remains unclear whether all forms of addiction benefit equally. (E 4)²⁰¹ An older meta-analysis found no efficacy of ADHD medication in patients with concurrent substance use disorder when only controlled studies were considered. (E 1a)¹⁹²

3.3.16.3. Effect of ADHD Medication on Addiction Symptoms¶

In a 33-year-old man with a methamphetamine use disorder and ADHD that was diagnosed late, LDX 40 mg improved his concentration and ability to organize his thoughts, significantly reduced his craving for stimulants, and urine tests confirmed that he was drug-free. (E 4)²⁰²
A small Phase 2 study involving 16 methamphetamine-dependent individuals primarily evaluated the tolerability of lisdexamfetamine at doses up to 250 mg/day (well above a therapeutic dose).(E 4)²⁰³ The subsequent randomized, placebo-controlled study by the same research group (LiMA) showed that sustained-release amphetamine salts significantly reduced the risk of relapse among former cocaine-dependent individuals (OR 5.85 to 11.87). Continuous abstinence was achieved during the last three (of 13) weeks (with accompanying cognitive behavioral therapy): (E 1b)²⁰⁴

• 30.2% below 80 mg/day
• 17.5% below 60 mg/day
• 7.0% lower than placebo

The lower dose was more effective in treating ADHD symptoms (75.0% versus 58.1% responders), while the higher dose was more effective in promoting cocaine abstinence. Doses of 60 and 80 mg are significantly higher than those typically used for ADHD.

A one-year course of MPH treatment for n = 37 adults with ADHD resulted in the following in a naturalistic, prospective observational study without a control group: (E 2b)²⁰⁵

• Reduced Internet addiction
• Reduced shopping addiction
• Reduces food cravings
• Reduces sex addiction

The proportion of people with ADHD who have at least one comorbid behavioral addiction decreased from 51.4% to 35.1% (not statistically significant given this sample size; χ² = 3.00; p = 0.083).²⁰⁵

People with ADHD and comorbid cocaine addiction showed a significant reduction in addictive behavior when treated with stimulants, corresponding to the decline in ADHD symptoms. (E 2b)²⁰⁶ The authors attribute this to the self-medication hypothesis. In cases of untreated ADHD, cocaine use can sometimes be an attempt at self-medication, which is why effective ADHD treatment reduces its use. To date, there is no effective pharmacotherapy for cocaine use disorder itself. Stimulants are considered promising in this context.
Nevertheless, abuse and misuse of methylphenidate do occur among people with ADHD and substance use disorders. Therefore, sustained release formulations, strict prescription controls, and integration into a comprehensive treatment plan are recommended. (E 1a)²⁰⁷(E 1a)²⁰⁸

A pilot study of treatment with sustained-release mixed amphetamine salts in n = 28 people with ADHD and comorbid cannabis dependence resulted in 15% of participants discontinuing cannabis use, compared with 0% in the placebo group. (E 1b)²⁰⁹

This is consistent with the experiences shared on the ADHD forum at ADxS.org. Far more people with ADHD report that their cravings for alcohol or nicotine have decreased significantly since starting stimulant medication, while reports to the contrary tend to be isolated cases.
Nevertheless, in the case of people with ADHD who have a preexisting acute or past addiction to amphetamines or cocaine, it should be noted that receiving medications with similar effects could serve as a trigger, leading them to attempt to misuse these substances as drugs again.In the case of other acute or past addictions (alcohol, THC without amphetamine addiction), there should be barely any triggering effect.

Occasional amphetamine use (weekend use) in the past is also unlikely to pose a risk and, even if repeated, is more likely a sign of self-medication among people with ADHD.Furthermore, it should be noted that in every nightclub restroom and behind every train station, there are cheaper and more readily available substances that produce a significantly stronger intoxicating effect. In our view, the risk of abuse of ADHD medications is largely theoretical. Given their importance for the treatment of people with ADHD, we doubt that the restrictions make sense from a sociopolitical perspective when considering the overall picture.

The Joint Addiction Commission of the German Society for Child and Adolescent Psychiatry and Related Associations summarizes its best-practice recommendations for children and adolescents for 2025: “Despite these concerns, the use of stimulants in patients with comorbid ADHD and SUD is generally recommended, even though careful consideration is necessary in each individual case, as the benefits of early, concurrent treatment outweigh the risks. In addition, careful supervision and therapeutic monitoring are essential.” … * “The Commission recommends informing adolescents and their caregivers about the protective effect of stimulant treatment on the further development of addiction (and that lack of treatment itself poses a risk). The criteria cited include sustained abstinence, structural maturation, and academic, vocational, and social integration. Ongoing monitoring of abstinence through urine tests is required.”* (E 4)²¹⁰

A history of substance abuse is not usually a contraindication for stimulants. (E 4)⁵⁷

Amphetamine-based medications are now available as prodrugs (lisdexamfetamine). This means that they are in a form that is simply ineffective when misused (abuse involving massive overdoses administered nasally or intravenously), because they exist as a compound which is only very slowly metabolized into the active ingredient in the blood over many hours; as a result, they cannot induce a drug-induced “high,” but can only produce the therapeutic effect of a gradually rising and falling functional dopamine level.

For a long time, amphetamine was considered an exception among addictive substances because it was thought to disrupt normal dopamine transmission. In fact, at therapeutic doses, it enhances phasic dopamine signals (which is more consistent with its therapeutic effects). The values are based on measurements in rats. The doses used in those studies, expressed in mg/kg, are not directly transferable to humans. (E 2b)²¹¹“

 

In cases of acute THC or alcohol substance abuse without acute amphetamine addiction, we consider the risk that a person with ADHD will attempt to misuse prescribed stimulants as a drug to be very low. During withdrawal from dopaminergic drugs, administering stimulants can help alleviate withdrawal symptoms and prevent relapse.
(E 4): Lisdexamfetamine (Vyvanse), guanfacine, and atomoxetine are not contraindicated in Switzerland for acute alcohol or drug abuse. (E 4)²¹⁵(E 4)²¹⁶(E 4)²¹⁷
(E 4): Dexamphetamine and methylphenidate are contraindicated in Switzerland in cases of acute alcohol or drug abuse. (E 4)²⁰(E 4)²¹

A study reports that factors such as the start of medication and interruptions in medication use for ADHD may influence the likelihood of developing addiction later on.(E 3)²¹⁸ However, it should be noted that addiction has reached epidemic proportions in the U.S. (one in 13 Americans has been diagnosed with an addiction), which is due in particular to inappropriate prescriptions of painkillers (opioids)—a practice that has never occurred in Europe. It is unclear to what extent the findings can be generalized to conditions outside the U.S., and particularly in Europe.

In conclusion, it is important to keep in mind that it is not only substance abuse that can cause health problems—untreated ADHD can as well. ¹⁹⁷

3.3.17. Eating Disorders Comorbid with ADHD¶

3.3.17.1. Binge Eating as a Comorbidity of ADHD¶

In the United States, Vyvanse is approved for the treatment of binge eating disorder (BED) in adults.
At a dose of 50 to 70 mg daily for 11 weeks, it reduced the severity and frequency of binge eating episodes. (E 1a)⁶⁷

Lisdexamfetamine has not been systematically studied in children and adolescents with BED; however, a retrospective review (n = 25; ages 12 to 19) suggests some benefit regarding self-reported binge-eating symptoms. Current guidelines for the treatment of eating disorders do not include specific recommendations for lisdexamfetamine in children and adolescents with BED due to a lack of robust data. In clinical practice, lisdexamfetamine may be considered for adolescents with moderate-to-severe BED and comorbid ADHD who have no clinically significant cardiac history, as an adjunct to other supportive eating disorder treatments (e.g., cognitive behavioral therapy).²⁶²

3.3.17.2. Bulimia nervosa comorbid with ADHD¶

A systematic review of stimulants for bulimia and anorexia (primarily case reports and small open-label studies) reported mostly favorable effects on eating behavior. However, the evidence is insufficient. Frequent side effects are reported (weight loss, decreased appetite, tachycardia). (E 1a)²⁶³ In addition, there are safety concerns because data on use in children and adolescents with bulimia are lacking. (E 1a)⁶⁷

With regard to stimulants, the following has been reported in children and adolescents with bulimia:

• Cardiovascular complications associated with dehydration and electrolyte imbalances as consequences of purging
• self-induced vomiting and misuse of laxatives; orthostatic tachycardia and elevated blood pressure when taking stimulants

Treatment with stimulants for ADHD symptoms in cases of comorbid bulimia is a possibility if: (E 1a)⁶⁷

• Purging behavior is mild or very rare
• Laboratory test results and hydration status are stable.

3.3.17.3. Anorexia nervosa comorbid with ADHD¶

Stimulants should be avoided in children and adolescents with anorexia nervosa. There are various risks:(E 4)²⁶⁴

• additional appetite suppression

• additional weight loss

• Worsening of restrictive eating behaviors

• Increased cardiovascular risks, including cardiomyopathy (e.g., hypertrophy), in severely malnourished children

A case series involving n = 6 people with ADHD treated on an outpatient basis found that stimulants led to a decrease in appetite and weight loss, but did not result in a worsening of eating disorder symptoms. A subjective improvement in ADHD symptoms, a reduction in the negative effects of ADHD on the eating disorder, and subjective improvements in anxiety, depression, and suicidal ideation were reported. The authors consider the carefully monitored use of stimulants in this group to be justifiable until larger studies are available.²⁶⁵

Once anorexia has subsided, treatment of ADHD symptoms with stimulants may be considered, provided that appetite, weight, and eating habits are closely monitored. (E 1a)⁶⁷
A case report describes a woman with neurofibromatosis type 1 who developed anorexia nervosa in her early 30s. Following successful psychotherapy for the anorexia (current BMI 20.5 kg/m²), she was additionally diagnosed with ADHD and successfully treated with dexamfetamine. Her body weight remained unaffected. (E 4)²⁶⁶

3.3.18. Obesity¶

Stimulants are known to reduce appetite.
In a retrospective analysis of medical records from n = 330 children and adolescents under the age of 18 (mean age 10 years), two years after the start of ADHD treatment with lisdexamfetamine:(E 3)²⁶⁷

• In cases of severe obesity, the BMI Z-score decreases by -0.41, and the BMI percentile at the 95th percentile decreases by -11.2%
• for mild to moderate obesity, the BMI Z-score is -0.44 and the BMI percentage at the 95th percentile is -11.1%
• In cases of mild to moderate obesity and overweight, younger children aged 4 to 10 showed a greater reduction in their BMI

A reduction in the BMI Z-score of 0.20 to 0.25 is considered clinically significant and corresponds to approximately a 5% weight loss. The values found thus fall within the clinically relevant range.

3.3.19. Chronic Pain Comorbid with ADHD¶

Chronic pain is a common comorbidity associated with ADHD.

Learn more about chronic pain in ADHD at Chronic Pain / Muscle Tension in ADHD in the chapter “ : Symptoms” as well as at Chronic Pain and Muscle Tension in ADHD—Neurophysiological Correlates

Various medication options for chronic pain associated with ADHD are being discussed. Overall, the evidence is very weak.

31.8% of patients with various types of chronic pain who were referred to a psychiatrist at a pain clinic were diagnosed with ADHD. Twenty-one of them were prescribed ADHD medication (methylphenidate and/or atomoxetine). In 20 of the 21 (95.5%), ADHD symptoms improved. In 14 of the 21 (66.7%), their pain symptoms also improved, by an average of 4.6 points (64.7%) on the Numerical Rating Scale (NRS) for pain. Among the 7 patients on medication who had persistent chronic nonspecific lower back pain, all 7 (100%) experienced an improvement in their pain symptoms, by an average of 4.3 points (65.3%) on the NRS.²⁶⁹

• Methylphenidate
  • MPH can alleviate the increased sensitivity to pain in people with ADHD.^{270271272273274}
• Atomoxetine
  • (E 4): Several case reports mention that atomoxetine also reduced chronic pain in people with ADHD. No controlled studies on this topic are available to date. (E 4)²⁷⁵(E 4)²⁷⁶(E 4)²⁷⁷
  • Atomoxetine was able to reduce pain sensitivity in 6-OHDA mice (an animal model of ADHD) (E 4)²⁷⁸
• Guanfacine
  • Case Report on Guanfacine and MPH (E4) ²⁷⁹
  • Clonidine, like guanfacine an alpha-adrenergic receptor agonist, is said to be helpful for ADHD and chronic pain. ²⁸⁰
• Amphetamine-based medications
  • U.S. President John F. Kennedy is said to have had ADHD. (E 4)²⁸¹ Kennedy also suffered from chronic lower back pain, which he successfully treated with amphetamine-based medications. (E 4)²⁸²
• Antipsychotics
  • According to case reports, risperidone (E 4)²⁷⁶ and aripiprazole (E 4)²⁸³ may be helpful in treating chronic pain.
• Tricyclic antidepressants
  • TZA were long considered the most important medications for treating chronic neuropathic pain, but they are associated with significant side effects.²⁸⁰ TZA were also used in the past to treat ADHD (particularly imipramine).
• Antiepileptic drugs
  • Antiepileptic drugs such as gabapentin, carbamazepine, and lamotrigine are also helpful in treating chronic neuropathic pain.²⁸⁰
  • Gabapentin
    • Due to the severe withdrawal side effects—which are similar to those associated with opioid or alcohol withdrawal and often require hospitalization—gabapentin should be recommended only as a last resort and only after patients have been thoroughly informed about the associated risks.
    • The SHR animal model of ADHD exhibits a disrupted noradrenergic pain-inhibitory system. In SHR rats, gabapentin was ineffective in treating neuropathic pain caused by segmental spinal nerve ligation, whereas in Wistar rats, gabapentin alleviated neuropathic pain. ²⁸⁴
• Duloxetine
  • The SHR animal model of ADHD exhibits a disrupted noradrenergic pain-inhibitory system. In SHR and Wistar rats, duloxetine was effective in treating neuropathic pain caused by segmental spinal nerve ligation.²⁸⁴ Unlike gabapentin, duloxetine increases spinal norepinephrine independent of locus coeruleus activation. Accordingly, norepinephrine reuptake inhibitors may be helpful for chronic pain associated with ADHD.
• Baclofen
  • Baclofen is a muscle relaxant and may be helpful for certain people with ADHD.²⁸⁰
• Mexiletine
  • Mexiletine is a Class Ib antiarrhythmic drug that is currently used primarily to treat muscle stiffness (myotonia) in adults with non-dystrophic myotonic disorders.** Mexiletine may be helpful for certain people with ADHD.²⁸⁰

3.3.20. Increased muscle tension as a comorbidity of ADHD¶

According to Stray, motor disinhibition and increased muscle tone in ADHD are directly associated with dysregulation of the dopamine and norepinephrine systems.²⁸⁵
This is consistent with the fact that, in ADHD, increased muscle tone can be reduced by methylphenidate²⁸⁶and that the norepinephrine reuptake inhibitor orphenadrine (Norflex®) acts as a skeletal muscle relaxant. Norepinephrine reuptake inhibitors are also used as ADHD medications (atomoxetine, viloxazine).

Based on our observations, increased muscle tension is reported more frequently in the ADxS forum in connection with lisdexamfetamine. A person with ADHD reported severe neck stiffness caused by lisdexamfetamine, which was unbearable despite intensive psychotherapy. Switching to methylphenidate significantly improved the neck stiffness. Switching back and forth again confirmed that LDX was the trigger for the neck stiffness.

(E 1a): With regard to fibromyalgia, which is often associated with significantly increased muscle tension, very low doses of naltrexone (0.5 to 4.5 mg instead of the usual 150 mg) have been reported to be an effective treatment. The treatment is said to be virtually free of side effects.²⁸⁷ (E 1a)²⁸⁸(E 1a)²⁸⁹(E 1a)²⁹⁰(E 1a)²⁹¹ Naltrexone is a long-acting competitive opioid antagonist that is also used to treat alcohol and opioid dependence. A person with ADHD reported to us that low-dose naltrexone also helped alleviate their co-occurring ADHD symptoms.
Paracetamol was repeatedly mentioned as a treatment option.
Magnesium is also said to be helpful.
Myotonolytics (e.g., methocarbamol, tolperisone, tetrazepam, flupirtine, tizanidine, baclofen, pridinol, eperison, or methocarbamol) have a muscle-relaxing effect by inhibiting polysynaptic reflex transmission in the spinal cord and subcortical centers. However, they are less suitable for long-term use and have significant side effects. Tizanidine and cyclobenzaprine have sedative effects and can help with concurrent sleep problems.²⁹² Methocarbamol and metaxalone are somewhat less sedating, but are also likely to be less effective. Dizziness and drowsiness have been reported with all myotonolytics.

In one isolated case, it was reported that clonidine, administered as an adjunct, was able to eliminate MPH-induced nocturnal teeth grinding. (E 4)²⁹³
People with ADHD told us that clonidine relieved their muscle tension.

Learn more about increased muscle tension in ADHD at Chronic Pain / Muscle Tension in ADHD in the chapter Symptoms as well as at Chronic Pain and Muscle Tension in ADHD—Neurophysiological Correlates

3.3.21. Enuresis Comorbid with ADHD¶

In one case, duloxetine alleviated comorbid enuresis (bedwetting) and stimulant-induced dysphoria and improved cognitive function in an adolescent with ADHD. Details such as dosage or duration of observation were not reported; however, 20 to 35% of participants in clinical trials are reported to have an inadequate response, partly due to dose-limiting side effects. (E 4)²⁹⁴

In a placebo-controlled study, atomoxetine increased the number of dry nights by about one and a half times. However, this effect alone is not sufficient for the treatment of enuresis. (E 1b)²⁹⁵
Imipramine was also recommended (in 2009) for comorbid bedwetting (enuresis).(E 4)²⁹⁶ Tricyclic antidepressants such as imipramine are now considered only a secondary option for enuresis due to their pronounced cardiotoxicity in the event of an overdose (which is particularly significant in children with ADHD and increased impulsivity).

3.3.22. Sleep Problems and ADHD¶

People with ADHD often have trouble sleeping. Stimulants can help improve sleep problems. Many people with ADHD report that their sleep has improved significantly since they started taking stimulants. For some people with ADHD (we estimate about 5 to 10%), low doses (1/4 to 1/3 of a single daily dose) of immediate release MPH can also help them fall asleep.

However, stimulants can also cause sleep problems. These are usually side effects related to the dosage that disappear within the first few weeks. Sometimes they result from taking the medication too late or from the medication’s effects lasting too long due to slowed metabolism. For more on the latter, see Effects and Duration of Action of ADHD Medications

For information on treating sleep problems associated with ADHD, see the detailed article Sleep Problems in ADHD—Treatment

3.3.22.1. Melatonin for Sleep Problems¶

For more information on melatonin as a medication for treating sleep problems associated with ADHD, see Melatonin for ADHD

3.3.22.2. Guanfacine (especially in the evening)¶

People with ADHD told us they had good results taking guanfacine about 5 hours before bedtime. Fatigue is a common side effect of guanfacine. Guanfacine is a sustained-release medication and remains effective for most of the day, so it should still have a positive effect on ADHD symptoms the next day as well.

3.3.22.3. Clonidine¶

A review confirmed that clondidine has a beneficial effect on sleep problems associated with ADHD. It also has an effect on the ADHD symptoms themselves.²⁹⁷

3.3.22.4. Amitriptyline¶

Amitriptyline, at a dosage of approximately 1 mg/kg/day when used with caution, showed improvement in sleep, anxiety, impulsivity, ADHD, repetitive behaviors, and enuresis. (E 4)¹⁶⁰

As with all serotonergic antidepressants, withdrawal symptoms should be taken into account, and a gradual tapering-off is recommended.

3.3.22.5. Trazodone¶

Experience has shown that trazodone can be helpful in cases of comorbid sleep disorders, particularly when accompanied by comorbid anxiety disorders and depression.
(E 4): Trazodone has varying effects depending on the dose. At low doses (up to about 50 mg), it acts almost exclusively on 5-HT2A receptors and not on serotonin transporters. Its half-life of 5 to 9 hours at most is consistent with the nighttime sleep cycle, which is why people with ADHD feel rested in the morning. Unlike mirtazapine, trazodone neither impairs sexual function nor causes weight gain.⁷⁸ Starting dose 25 mg, rarely exceeding 100 mg (E 4)⁷⁸(E 4)¹⁰⁹

3.3.23. L-Theanine¶

L-theanine showed only a slight effect on sleep problems associated with ADHD.²⁹⁷

3.3.24. Zolpidem¶

Zolpidem is not effective for ADHD-related difficulty falling asleep and caused many side effects and the highest discontinuation rate. ²⁹⁷Over 8 weeks, children and adolescents aged 6 to 17 years received zolpidem 0.25 mg/kg up to a maximum of 10 mg daily or a placebo in a 2:1 ratio in a double-blind study, stratified by age (111 aged 6 to 11 years, 90 aged 12 to 17 years). The adjusted mean change in time to sleep onset did not differ in week 4 (−20.28 versus −21.27 minutes). Differences in favor of zolpidem were found only in the overall clinical assessment in the older age group. The most common side effects occurring in more than 5% of participants were dizziness, headache, and hallucinations. Due to side effects, 7.4% discontinued the study. No next-day effects or rebound symptoms occurred.²⁹⁸

Furthermore, contrary to earlier assumptions, Z-drugs such as zolpidem do indeed carry a risk of dependence.

3.3.25. Bruxism (Teeth Grinding) in ADHD¶

ADHD medications can exacerbate bruxism.

A case study reports a positive effect of buspirone on bruxism caused by atomoxetine. (E 4)²⁹⁹ This is only the second such case ever reported.

In one isolated case, it was reported that clonidine, administered as an adjunct, was able to eliminate MPH-induced nocturnal teeth grinding. (E 4)²⁹³

People with ADHD told us that clonidine relieved their muscle tension.

3.3.26. CDS / SCT (Cognitive Disengagement Syndrome, Sluggish Cognitive Tempo)¶

In one study, atomoxetine significantly improved 7 out of 9 symptoms of the Kiddie-Sluggish Cognitive Tempo Interview (K-SCT) in patients with CDS/SCT. However, the improvement in SCT symptoms was only partially independent of the improvement in ADHD inattention symptoms. (E 1b)³⁰⁰ Several authors were or are employed by Eli Lilly, the manufacturer of atomoxetine.
SCT symptoms may indicate a weaker response to methylphenidate. In contrast, the ADHD-HI and ADHD-I subtypes do not differ in their methylphenidate (MPH) response rates. However, this association was observed only for the “sluggish-sleepy” component of the CDS, not for daydreaming. (E 1b)³⁰¹

3.3.27. Histamine Intolerance / Mast Cell Activation Syndrome¶

Since ADHD medications—and stimulants in particular—increase histamine levels only in the brain but decrease them in the rest of the body, they should generally be beneficial for people with histamine intolerance (which affects the gut peripherally rather than centrally).
An experienced ADHD specialist reported that, among a four-digit number of ADHD patients, he had never observed any histamine-related problems caused by ADHD medications.
Cases of (possibly histaminergic) allergic reactions caused by ADHD medications have been reported repeatedly on the ADxS forum. People with ADHD and histamine intolerance reported that they could not tolerate AMP or sustained-release MPH at all, but were able to tolerate immediate-release MPH in small doses.

Another person with ADHD reported that she was able to effectively manage the histamine intolerance reactions caused by her ADHD medication by taking cetirizine in the morning.

Most commonly used ADHD medications appear to increase histamine levels only in the brain. To date, two rat studies have been conducted on methylphenidate and atomoxetine. The remaining findings pertain to methamphetamine and modafinil, which are not approved in Germany for the treatment of ADHD:

• (E 2b): Atomoxetine increased extracellular histamine in the PFC of rats (E 2b)³⁰²(E 2b)³⁰³ Histamine plays a key role in the brain in attention, learning, and memory. It is possible that increased histamine release contributes to the efficacy of methylphenidate and atomoxetine in ADHD. (E 2b)³⁰³
• Methylphenidate increased extracellular histamine in the PFC of rats (E 2b)³⁰³
• (E 2b): Methamphetamine increased histamine levels in the hypothalamus of rats (E 2b)³⁰⁴(E 2b)³⁰⁵
• Modafinil increased histamine levels in the hypothalamus of rats (E 2b)³⁰⁶

Conversely, stimulants may promote the breakdown of histamine by increasing diamine oxidase (DAO) levels.

• Methylphenidate did not inhibit diamine oxidase and, in cell culture experiments, tended to increase its activity.³⁰⁷
• Lisdexamfetamine caused a strong upregulation of DAO mRNA levels in Caco-2 cells, which increases peripheral histamine degradation (E 2b)³⁰⁷ (E 2b): Viloxazine appears to exert no or, at most, weak competitive inhibition (< 25%) at the H1 and H2 histamine receptors (E 4).³⁰⁸(E 2b)³⁰⁹ The findings regarding transmitter effects are based on rat studies.

Regardless of this, other substances may also have a peripheral histamine-elevating effect.

The following information on excipients is current as of 2021 and is taken from a blog post. Excipients are subject to change. Section 6.1 of the current prescribing information for the respective product is always authoritative.
Winkler reported the following regarding the co-substances: (E 4)³¹⁰

• Among AMP medications, Attentin is said to have fewer adverse effects than lisdexamfetamine in cases of histamine intolerance
• Among MPH medications, Medikinet (immediate release) and Kinecteen are said to have fewer adverse effects in cases of histamine intolerance than Ritalin (immediate release), Medikinet (extended-release), Medikinet (adult), Ritalin LA, Ritalin (adult), and Concerta
• Among ATX medications, Agakalin is said to have fewer side effects than Strattera in cases of histamine intolerance
  A list of other medications that increase histamine levels can be found at Histaminintioleranz.ch: List of Medications (German, English, French).

3.3.28. Gluten Intolerance¶

Excipients in medications may contain gluten.
Winkler reports that, with regard to the active ingredients, Medikinet (immediate release), Medikinet (extended-release), Medikinet Adult, Ritalin LA, Ritalin Adult, Concerta, Kinecteen, Vyvanse, Attentin, Strattera, and Agakalin are safe, while immediate-release Ritalin can be problematic for people with gluten intolerance. (E 4)³¹⁰

3.3.29. Lactose Intolerance¶

Excipients in medications may contain lactose.
Winkler reports that, with regard to the following medications—Medikinet Retard, Medikinet Adult, Ritalin LA, Ritalin Adult, Vyvanse, Attentin, Strattera, and Agakalin are safe, while immediate-release Ritalin, immediate-release Medikinet, Concerta, and Kinecteen may cause problems in cases of lactose intolerance. (E 4)³¹⁰

3.3.30. Fructose Intolerance¶

Excipients in medications may contain fructose.
Winkler reports that, with regard to these medications, immediate release Ritalin, immediate release Medikinet, Vyvanse, Strattera, and Agakalin are safe, while extended-release Medikinet, Medikinet Adult, Ritalin LA, Ritalin Adult, Concerta, Kinecteen, and Attentin can be problematic for people with fructose intolerance. (E 4)³¹⁰ Concerta and Kinecteen are now said to be sucrose- and fructose-free (May 2025).

3.3.31. Sorbitol Intolerance¶

Excipients in medications may contain sorbitol.
Winkler reports that, with regard to adjunctive medications, Ritalin (immediate release), Medikinet (immediate release), Medikinet (extended-release), Medikinet Adult, Ritalin LA, Ritalin Adult, Concerta, Kinecteen, Vyvanse, Strattera, and Agakalin are safe, while Attentin can be problematic for those with sorbitol intolerance. (E 4)³¹⁰

3.3.32. Down Syndrome¶

Down syndrome is associated with a significantly higher prevalence of ADHD.
A retrospective analysis of medical records from n = 21 children and adolescents with Down syndrome and ADHD reported a response rate of 48% for guanfacine. Side effects were documented in 43% (95% CI 24 to 63%), most commonly daytime sleepiness (7 of 21) and constipation (2 of 21).(E 3)³¹¹The side effects were documented only in the treatment notes and were not systematically elicited. The actual frequency is therefore likely to be higher.

In cases of Down syndrome and comorbid ADHD, we believe it is helpful to screen for sleep-related breathing disorders, as these can often trigger ADHD symptoms and frequently occur in individuals with Down syndrome due to reduced muscle tone. For more information, see Sleep-Related Breathing Disorders (SBAS, SDB, SRBD) in the article “ ” Diseases as ADHD Risk Factors In the section “ ” Environmental Factors as Causes of ADHD in the chapter “ ” Development

3.3.33. High Blood Pressure as a Comorbid Condition of ADHD¶

Treatment with α-2 agonists (clonidine, guanfacine) may be indicated for high blood pressure.
Clonidine-IR has an even stronger hypotensive (blood pressure-lowering) and bradycardic (heart rate-lowering) effect than Clonidine-XR and Guanfacine-XR. (E 1a)³¹²

When used as monotherapy, alpha-2 agonists reduced overall ADHD symptoms by an SMD of −0.59 compared with placebo.³¹²

Guanfacine-XR prolonged the QTc.(E 1a)³¹²

MPH raises blood pressure less than atomoxetine:

• On average, atomoxetine causes a 6.4-beat increase in heart rate, Concerta a 3-beat increase, and the placebo a 0.3-beat increase. (E 1b)³¹³
• Systolic blood pressure increases by an average of 3.7 with atomoxetine, by 2.4 with Concerta, and by 1.3 with placebo. (E 1b)³¹³ However, these differences were not statistically significant compared to placebo.
• Diastolic blood pressure increases by an average of 3.8 with atomoxetine, by 3.1 with Concerta, and by 0.4 with placebo. (E 1b)³¹³

A Swedish case-control study with 14 years of follow-up examined the risks of certain cardiovascular diseases associated with long-term use of ADHD medication. Out of 278,027 people with ADHD, 10,388 individuals with newly diagnosed cardiovascular disease and 51,672 control subjects were analyzed (combined n = 62,060). Adjusted odds ratios (aOR) are reported compared to no medication use: (E 3)³¹⁴

• for high blood pressure
  • a 72% increased risk with use for 3 to 5 years (aOR 1.72; 95% CI 1.51 to 1.97)
  • an 80% increased risk with use for more than 5 years (aOR 1.80; 95% CI 1.55 to 2.08)
• for arterial diseases
  • a 65% increased risk when taken for 3 to 5 years (aOR 1.65; 95% CI 1.11 to 2.45)
  • a 49% increased risk with use for more than 5 years (not statistically significant; aOR 1.49; 95% CI 0.96 to 2.32)

For each additional year of use, the overall risk of cardiovascular disease increased by 4% (aOR 1.04; 1.03 to 1.05). No significantly increased risk was found for arrhythmias, heart failure, ischemic heart disease, or thromboembolic and cerebrovascular events.³¹⁴“

Amphetamines, atomoxetine, lisdexamfetamine, methylphenidate, and viloxazine increase hemodynamic parameters in children, adolescents, and adults. The mean increase compared with placebo was (decrease due to guanfacine and the lowest and highest values of the increase, respectively) (meta-analysis, k = 103, n = 13,315 children and adolescents, n = 9,387 adults): (E 1a)³¹⁵

• Children and adolescents:
  • systolic blood pressure
    • Guanfacine: - 2.83
    • Atomoxetine: 1.07
    • Methylphenidate: 1.81
  • diastolic blood pressure
    • Guanfacine: - 2.08
    • Amphetamines: 1.93
    • Methylphenidate; 2.42
  • Pulse
    • Guanfacine: - 4.06
    • Viloxazine: 2.79
    • Atomoxetine: 5.58
• Adults
  • systolic blood pressure
    • Guanfacine: - 10.1
    • Methylphenidate: 1.66
    • Amphetamines; 2,3
  • diastolic blood pressure
    • Guanfacine: - 7.73
    • Methylphenidate: 1.6
    • Lisdexamfetamine: 3.07
  • Pulse
    • Guanfacine: - 6.83
    • Methylphenidate: 4.37
    • Viloxazine: 5.8

The data are from a network meta-analysis of randomized controlled trials. In some cases, individual active ingredients were compared with one another indirectly through shared control groups.

Blood pressure and pulse should be monitored during any ADHD treatment with medication, not just when using stimulants. No cardiovascular benefit of non-stimulant medications over stimulants could be demonstrated.³¹⁵

3.3.34. Heart Problems as a Comorbidity of ADHD¶

A Swedish case-control study with 14 years of follow-up examined the risks of certain cardiovascular diseases associated with long-term use of ADHD medication. Out of 278,027 people with ADHD, 10,388 individuals with newly diagnosed cardiovascular disease and 51,672 control subjects were analyzed (total N = 62,060). Adjusted odds ratios (aOR) are reported compared to no medication use: (E 3)³¹⁴

• No increased risk of cardiac arrhythmias, heart failure, ischemic heart disease, thromboembolic disease, or cerebrovascular disease
• for cardiovascular diseases
  • a 20% increased risk associated with taking methylphenidate for 3 to 5 years
  • a 19% increased risk associated with taking methylphenidate for more than 5 years
  • a 23% increased risk associated with taking lisdexamfetamine for 2 to 3 years
  • a 17% increased risk associated with taking lisdexamfetamine for more than 3 years
  • a 7% increased risk associated with taking atomoxetine in the first year

A Swedish case-control study spanning 13 years involving n = 112,605 people with ADHD (57.9% female) and n = 563.024 age-, sex-, and region-matched controls aged 5 to 30 years (median age 20 years) found that ADHD medications increased the risk of cardiac events (adjusted odds ratio for all events, aOR 1.63; 95% CI 1.47 to 1.81):(E 3)³¹⁶

• by 63% for total cardiac events
• by 166% for unspecified arrhythmias
• 10% for long-term medication compared to short-term medication

The risk of cardiac arrest and specific arrhythmias remained unchanged.

Unfortunately, the study did not include cases of ADHD in which medication was not used, so it remains unclear to what extent the influence was due to ADHD itself and to what extent it was due to ADHD medication.

A study using Mendelian randomization (a method that infers causality from genetic data) found that ADHD itself increases the risk of cardiovascular problems: body mass index, waist circumference, body fat percentage, and the risk of type 2 diabetes. (E 2b)³¹⁷ A significant portion of this association is mediated by a lower level of education. Thus, the vascular risks are not solely due to biological factors.

3.3.35. Epilepsy Comorbid with ADHD¶

(E 1a): Methylphenidate appears to be the best option for treating ADHD in patients with epilepsy. Overall, sustained-release MPH was not associated with a significant worsening of epilepsy. However, higher doses may be associated with an increased risk of seizures. The underlying evidence is of low certainty. (E 4)³¹⁸(E 1a)³¹⁹
In addition to MPH, AMP or atomoxetine may also be administered with a low risk. (E 4)³²⁰

ADHD occurs in up to 40% of people with epilepsy. (E 1a)³¹⁹ Unlike ADHD without epilepsy, boys are not affected more frequently than girls. (E 1a)³²¹ It should also be noted that nonconvulsive seizures (absences) can resemble inattention (in cases of epilepsy and attention problems, the two must be distinguished from one another). (E 4) ³²⁰

Any tendency toward seizures should be well controlled before administering stimulants. (E 1a)⁶⁷

Anti-epileptic medications themselves can either worsen or improve the symptoms of ADHD.
A worsening of ADHD symptoms has been reported for the following antiepileptic drugs: (E 1a)⁶⁷- (E 1a): valproate (high evidence of impaired attention) (E 4)³²²(E 1a)³²¹- Phenobarbital

• Phenytoin

• Topiramate - Zonisamide

• Perampanel

• Ethosuximide

An improvement in ADHD symptoms has been reported for the following epilepsy medications: (E 1a)⁶⁷

• Lacosamide
• Carbamazepine
• Lamotrigine
  • For more information, see Lamotrigine for ADHD

Whether ADHD symptoms improve or worsen remains unclear for: (E 1a)⁶⁷

• Levetiracetam (E 4)³²²

 

For treatment-resistant epilepsy, a supplementary pilot study is available that describes low doses of methylphenidate as safe and effective for treating ADHD symptoms without increasing seizure frequency or severity. Twenty-two people with ADHD (16 boys, 6 girls; mean age 11 years 2 months) from a specialized outpatient clinic for severe epilepsy received methylphenidate for three months, but only after antiepileptic treatment had been discontinued for three months. Seventeen had focal epilepsy, and five had generalized epilepsy. Seventeen experienced primary or secondary generalized seizures. ADHD symptoms, seizure severity, and side effects were assessed using standardized questionnaires. Low-dose methylphenidate significantly improved ADHD symptoms as well as seizure severity. For this group, the authors suggest that treatment should not be withheld, but rather that a particularly cautious approach using low doses should be taken. The authors point out that randomized controlled trials to confirm these findings are still lacking.³²³

In a population-based self-controlled case series of 6- to 25-year-olds without a history of seizures or epilepsy, the incidence of seizures was increased in the period immediately following the start of MPH treatment, but not thereafter (days 31 to 180: IRR 1.13; 95% CI 0.56–2.25; thereafter 1.38; 0.92–2.07). No participant died from a seizure. The authors interpret this as a safety signal at the start of treatment and recommend monitoring for neurological abnormalities, particularly during this phase.³²⁴

From a clinical perspective, the important question is whether an EEG is necessary before starting treatment. A three-year follow-up study of 517 children with ADHD aged 6 to 14 years found EEG abnormalities in 273 (52.8%) of them. Children with and without EEG abnormalities did not differ in the initial use of methylphenidate, their response to treatment, or the continuation of treatment. No child without comorbid epilepsy and no child with epilepsy that was seizure-free developed new seizures. Only three children with treatment-resistant epilepsy experienced seizures, and their frequency did not increase. The presence of EEG abnormalities, with or without patterns typical of epilepsy, was not associated with an increased risk of seizures while on methylphenidate. The available evidence does not support screening children with ADHD for EEG abnormalities before starting stimulant treatment.³²⁵

3.3.36. Dissociative Disorders Comorbid with ADHD¶

(E 4): Positive effects of sustained-release MPH on dissociative states in patients with comorbid ADHD have been reported in several individual cases. (E 4)³²⁶ A case study reports a beneficial effect of mixed amphetamine salts.(E 4)³²⁷To date, no medication has been approved or shown to be specifically effective for dissociative disorders themselves. In the cases described, ADHD medication was administered because of the co-occurring ADHD. The improvement in dissociative symptoms was an observation in individual cases and not a proven treatment option.³²⁶³²⁷ “

3.3.37. Raynaud¶

(E 3): ADHD medications can trigger or worsen Raynaud’s phenomenon. The evidence is based on only 61 reported cases. No controlled studies are available. (E 4)³²⁸ Amphetamine-based medications appear to be associated with this condition more frequently than methylphenidate and atomoxetine; Guanfacine was not mentioned. (E 3)³²⁹ It has been reported that reducing the dose or switching to a different active ingredient may help. However, there have also been (very rare) reports of serious consequences. Raynaud’s phenomenon was observed less frequently with atomoxetine than with stimulants.

Because of the potential for serious consequences (albeit rare), regular monitoring for signs of Raynaud’s syndrome is recommended, especially during exposure to cold.³²⁸

Guanfacine was not mentioned in this analysis. However, since this is a database of voluntary adverse event reports, the consequences are not that guanfacine is safer.³²⁹

We are aware of cases in which Raynaud’s phenomenon was triggered by caffeine consumption while taking ADHD medication and resolved after caffeine was eliminated from the diet.

3.3.38. Intellectual Disability¶

In children with ADHD and intellectual disability or borderline intellectual functioning, methylphenidate improved ADHD symptoms compared with placebo (Hedges’ g = 0.878). Higher doses were associated with greater improvement. The discontinuation rates did not differ from those of placebo (meta-analysis, k = 8, N = 423, E 1a)³³⁰

In cases of intellectual disability, a lower medication dose is often required, or there may be a higher sensitivity to side effects

• for stimulants⁶⁷
• for clonidine³³¹

In addition, people with ADHD often find it harder to communicate their side effects.⁶⁷

The total dose of clonidine, the degree of cognitive impairment, concomitant medications, and comorbidities predicted functional improvement after two months. The improvement persisted after one year.³³¹

4. Choosing a Medication Under Other Conditions¶

4.1. Giftedness¶

Highly gifted individuals are said to respond better to amphetamine-based medications than to MPH (Castello et al. 1992, cited in Arnold 2000). (E 4)⁷
Giftedness is not a comorbidity.

4.2. EEG: Elevated alpha, beta, and theta values¶

• Atomoxetine is not suitable

4.3. COMT Met-158-Met¶

If a COMT Met-158-met polymorphism is present, amphetamine-based medications are considered unsuitable.

As of January 2026, a genetic analysis of the COMT gene cost just over 100 EUR in Germany.

4.4. Pregnancy¶

There is no automatic requirement to discontinue ADHD medications during pregnancy and breastfeeding. The international consensus is that the extent of the documented risks is very low and that medication should not be discontinued if it is necessary for the pregnant or breastfeeding person’s daily functioning. One way to reduce overall exposure is to take stimulants as needed rather than continuously; however, this approach is pharmacologically effective only for stimulants, not for maintenance medications. There is also discussion about switching to bupropion during the perinatal period, particularly when depression requiring treatment is present. In any case, the decision should be made in consultation with the treating physician.³³⁴

(E 2b): Human studies have shown that taking ADHD medications during pregnancy does not increase the risk of developmental disorders or neurodevelopmental disorders in the offspring. (E 2b)³³⁵ For stimulants, a slightly increased risk of preeclampsia was found (adjusted risk ratio 1.29; 95% CI 1.11 to 1.49), while atomoxetine, used as a comparator, was not associated with any of the risks examined. (E 2b) ³³⁶

A 7-year population-based cohort study of n = 2,257 children exposed to ADHD medications during pregnancy found no increased risk of long-term neurodevelopmental disorders associated with AMP, MPH, or ATX.(E 2b)³³⁷ The analysis was conducted separately for methylphenidate, amphetamine-based medications, and atomoxetine. No increased risk was found for any of the active ingredients.
The study compared children of mothers who continued taking the medication during pregnancy with children of mothers who stopped taking it before pregnancy. This comparison rules out the possibility that the results are due to the mother’s ADHD rather than the medication.³³⁵³³⁷

However, it was found that when taking pregnancy medications

• for MPH

  • a slight increase in congenital heart defects (E 2b)³³⁸

• a slight increase in congenital heart defects (in absolute terms, from about 10 to about 13 per 1,000 births). The difference was not statistically significant (adjusted relative risk 1.11; 95% CI 0.91 to 1.35).

• for amphetamines

  • No increase in congenital heart defects was observed with amphetamine-based medications (E 2b)³³⁸
  • an increased risk of (E 1a) for amphetamine-type drugs³³⁹
    • Preterm births (OR 4.11; 95% CI 3.05 to 5.55)
    • low birth weight (OR 3.97; 2.45 to 6.43)
    • small for gestational age (OR 5.79; 1.39 to 24.06)

A perinatal guideline for managing ADHD during pregnancy and the postpartum period recommends individualized treatment planning, psychoeducation, self-management or coaching, and psychotherapy, as well as (if necessary) continued medication. Approximately 3% of adult women have been diagnosed with ADHD. Symptoms often worsen during the perinatal period. (E 4)³⁴⁰
There is virtually no data available on the long-term effects on child development for most of these active ingredients. Bupropion appears to be safe during pregnancy. Data on atomoxetine, guanfacine, and clonidine are sparse. Findings regarding children of women who use methamphetamine cannot be generalized to prescribed amphetamine medications. (E 4)³⁴¹
The prescribing information for Vyvanse advises breastfeeding women not to take amphetamine-based medications. (E 4)³⁴⁵

(E 4): MPH and AMP as ADHD medications, bupropion as an antidepressant, or guanfacine as a blood pressure medication during pregnancy did not increase the rate of serious congenital anomalies. (E 4)³⁴⁶(E 4)³⁴⁰
MPH increased the risk of cardiovascular problems in the child from 1.07% to 1.7% (+59% with a low absolute risk). (E 4)³⁴⁰
There is very little data available on atomoxetine and guanfacine during pregnancy. (E 4)³⁴⁶
(E 4): Clonidine, when used as an antihypertensive during pregnancy, did not cause any serious side effects. (E 4)³⁴⁶(E 4)³⁴⁰Most ADHD medications are excreted into breast milk, but the concentrations in the infant’s blood are very low, with the exception of clonidine and amphetamines.
Breastfeeding while taking clonidine and amphetamines is therefore contraindicated. (E 4)³⁴⁶
(E 1a): Methylphenidate and atomoxetine did not alter the risk of miscarriage, which is already elevated in ADHD (Danish cohort study with n = 989,932 pregnancies; the association could be explained, at least in part, by confounding by indication).(E 2b)³⁴⁷ A meta-analysis of 10 studies involving a total of 16.5 million pregnant women, including 30,830 with exposure to methylphenidate or atomoxetine, also found no significantly increased risk of congenital malformations (+14%, not significant). (E 1a)³⁴⁸

In the same Danish cohort study, taking MPH or ATX was associated with approximately twice the risk of an Apgar score below 10 (aRR 2.06; 95% CI 1.11 to 3.82), whereas children of women with ADHD who did not take these medications during pregnancy did not have an increased risk (aRR 0.99; 95% CI 0.48 to 2.05).(E 2b)³⁴⁹ This should be interpreted as follows: The study defined “low” as an Apgar score below 10, even though an Apgar score of 9 is clinically unremarkable, and the analysis was based on very few events. The practical significance of this finding is therefore minimal.

Methylphenidate is considered relatively safe during pregnancy. (E 1a)³⁵⁰

4.5. Breastfeeding¶

Amphetamines pass into breast milk. (E 4)³⁵¹
On the 10th and 42nd days after delivery, amphetamine levels in breast milk were 3 and 7 times higher, respectively, than in maternal plasma. Amphetamine was also detected in the infant’s urine. (E 4): High doses of amphetamines can impair milk production. (E 4)³⁵²(E 4)³⁵³ Since it cannot be ruled out that amphetamines are also metabolized via CYP2D6, and since newborns barely have the ability to metabolize via CYP2D6 during the first 3 months of life, amphetamine medications should not be used during pregnancy or during the first 3 months of a breastfed infant’s life. The American Academy of Pediatrics (AAP) advises against the use of amphetamine medications while breastfeeding.(E 4)³⁵⁴
Most ADHD medications are excreted into breast milk. With the exception of clonidine and amphetamines, the concentrations in the infant’s blood are very low. Breastfeeding is not recommended when taking high doses of amphetamine-based medications or in cases of active substance abuse. At therapeutic doses, however, experts consider breastfeeding while taking amphetamines to be acceptable, provided the infant is monitored for irritability, insomnia, and feeding difficulties. The effects on neurological development have not been well studied.^{346352 353} “

High doses can interfere with milk production (especially while the breastfeeding relationship is still being established).³⁵²³⁵³

While methylphenidate is considered relatively safe during breastfeeding, amphetamines and lisdexamfetamine are contraindicated due to the potential for accumulation in the infant during breastfeeding. (E 1a)³⁵⁰

4.6. Advanced age, seniors¶

Treatment with stimulants is also permitted into old age.
All clinical trials for stimulants cover only the age range up to 65 years. The absence of studies beyond a certain age limit does not automatically constitute off-label use.
Consequently, the relevant professional associations are not aware of any recourse proceedings initiated by health insurance plans regarding prescriptions issued after the age of 65.
A blanket refusal to prescribe stimulants after a certain age (particularly for those under 65) without a specific, individual reason is likely to constitute a case of medical malpractice.

A study found a short-term increase in cardiovascular problems associated with stimulants used to treat ADHD. Long-term use was possible without any problems. (E 2b)³⁵⁵There is an errata for this study, but it does not specify the corrected values.³⁵⁶

A pharmacokinetic study of 47 healthy older adults without ADHD found an increase in heart rate but no increase in blood pressure following a single dose of lisdexamfetamine. Clearance decreased only slightly with age. Nevertheless, a lower and more gradual dose escalation is recommended for older adults.³⁵⁷

Another study found (on average) an increase in heart rate, but no increase in blood pressure and no other adverse effects associated with the use of stimulants in older adults. AMP clearance was slightly reduced (E 1b),³⁵⁷ so a lower and slower dose is recommended.

4.7. Heat Stress¶

In a study of 12 healthy men without ADHD, methylphenidate was unable to compensate for the heat-induced decline in cognitive performance during passive heat stress; it merely increased the heart rate by about 5 to 15 beats per minute.(E 1b)³⁵⁸

In hot weather, the cardiovascular effects of methylphenidate and heat stress add up. The results are only partially applicable to people with ADHD, as the study involved healthy men without ADHD.<footnoteref>288

5. Different Mechanisms of Action of ADHD Medications¶

5.1. Binding Affinity of MPH, AMP, and ATX to DAT, NET, and SERT¶

Binding affinity: higher for smaller numbers (KD = Ki)	DAT	NET	SERT
MPH	34 - 200	339	> 10,000

5.2. Effects of MPH, AMP, and ATX on Dopamine and Norepinephrine by Brain Region¶

The active ingredients methylphenidate (MPH), d-amphetamine (AMP), and atomoxetine (ATX) affect extracellular dopamine (DA) and norepinephrine (NE) to varying degrees in different regions of the brain. Table based on Madras (E 4)³⁵⁹, modified.

	PFC	Striatum	Nucleus accumbens	Occipital cortex	Lateral hypothalamus	Dorsal hippocampus	Cerebellum
MPH	DA + NE (+)	DA + NE +/- 0	DA + NE +/- 0
AMP	DA + NE +	DA + NE +/- 0	DA + NE +/- 0
ATX	DA + NE +	DA +/- 0 NE +/- 0	DA +/- 0 NE +/- 0	DA +/- 0 NE + (rat)	DA +/- 0 NE + (rat)	DA +/- 0 NE + (rat)	DA +/- 0 NE + (rat)

Note: The NET binds dopamine in the PFC slightly better than norepinephrine, while the DAT binds dopamine much better than norepinephrine.
Nevertheless, atomoxetine increases dopamine levels only in the PFC and not everywhere it binds to NET, suggesting that a specific mechanism of action is at work here.

6. Duration of Action of Various ADHD Medications¶

In our experience, the actual duration of action is generally shorter than stated. This is particularly evident with Vyvanse.

For more information, see Duration of Medication Effect in ADHD

7. Approval Status of ADHD Medications¶

This section has been moved to a separate post: Approval Status of ADHD Medications