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. While there are several guidelines to follow, there are no biomarkers that can predict a response to ADHD medications.¹ Furthermore, the unique characteristics of each person with ADHD often put all empirical knowledge 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 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 with few side effects. There is no other class of medications in psychiatry with such a high effect size.^{23 4} They take effect from the first day of use and can be discontinued at any time without withdrawal symptoms. However, stimulants can impair emotional functioning if taken in excessive doses and are controlled substances. Non-stimulants such as atomoxetine and guanfacine do have the advantage of a longer duration of action, are more effective at addressing the subjectively most distressing ADHD symptom—emotional dysregulation—and do not have a dampening effect on emotional experience. However, their effect size is significantly lower, and they have noticeably more side effects. Furthermore, 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 distress 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 simultaneously 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.

In the United States, children with ADHD who were receiving medication were most commonly prescribed 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%).⁵

When determining the dosage, it is important to take into account the fact that people with ADHD are often highly sensitive to even slight differences in dosage or to variations in the effects of different formulations containing the same active ingredient. This goes so far 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-stimulants. 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.

Information provided without guarantee. This information is not intended for self-medication. Always consult 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 hold a unique position among all psychiatric medications: no other class of drugs has such a high effect size while causing so few side effects.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 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 a combination therapy of atomoxetine and MPH or AMP (at lower doses than those used in monotherapy)
  • Subject to narcotics control laws due to the theoretical possibility of abuse
    • No risk of abuse when taken as directed (orally in medicinal doses)
    • At every train station and in every nightclub bathroom, there are better “spinning” things for less money and with less effort
    • Nevertheless, it may still be a potential trigger for 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
    • Stimulants reduce the likelihood of developing an addiction;⁶⁷ they certainly do not increase it.⁸⁹
      Treating ADHD with stimulants as early as possible reduced the risk of developing addiction in adulthood. For every year that stimulant treatment was delayed, the risk of developing addiction in adulthood increased by a factor of 1.46.¹⁰
• Methylphenidate (MPH)
  • Advantages:
    • A particularly significant increase in power
    • Immediate release (2.5–3 hours)
  • Disadvantages:
    • Non-response rate: approximately 30%
      • “MPH non-responders” are not the same as “AMP non-responders”
• Amphetamine 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-responders are not the same as MPH non-responders

1.2. Non-stimulants¶

• Atomoxetine (ATX)
  • Advantages
    • Mirror 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
    • The margin between underdosing and overdosing is sometimes very narrow
    • Significantly more side effects than stimulants
    • Less effective than stimulants
    • Should be administered in small, gradual doses
  • More about atomoxetine at Atomoxetine for ADHD
• Guanfacine
  • Advantages
    • Effective treatment for comorbid tic disorders
    • 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

• Of people with ADHD—for whom medication would be helpful—only about 20 to 25% receive medication. Less than 1% of people who are not affected receive medication they do not need.²¹
• Before starting treatment with stimulants, it is recommended that
  • A cardiovascular examination.²² to screen for cardiovascular abnormalities such as:²³
    • High blood pressure
    • Heart murmurs
    • Syncope during physical exertion
    • An ECG is optional
• Contraindications for stimulants (most of which are uncommon in childhood):²³
  • Schizophrenia
    • On the other hand, a large long-term study from 2025²⁰
  • Severe depression
  • Hyperthyroidism
  • Heart Rhythm Disorders
  • Moderate to severe high blood pressure
  • Angina pectoris
  • Glaucoma
  • Monoamine oxidase (MAO) inhibitors
    • Previous hypersensitivity
    • Concurrent use
    • Use within the last 2 weeks
• Caution is advised in patients with²³
  • Motor tics
  • Known drug addiction
  • History of Drug Addiction, Alcoholism, and Caffeine Addiction
    • But:
      • Stimulants for ADHD can significantly reduce the urge to use substances
      • Alcohol and MPH do not mix at all
      • Combining alcohol and AMP isn’t a good idea, but it’s far less dangerous than combining alcohol and MPH
    • No Caffeine When Taking Stimulants—Risk of Interactions
  • 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.

2.1.1. The choice of medication for children and adolescents¶

For adults, the most scientifically sound* Approach to prioritizing medications is:
* Health insurance coverage may vary

• The first-line treatment is methylphenidate²⁴
• Amphetamine-based medications are the second choice²⁵²⁶
• The third-line treatment is atomoxetine. It may be the first-line treatment in cases of comorbid anxiety disorder²⁷, comorbid CDS (SCT), or severe ADHD-I.
  • Among children with ADHD, 8.4% switched from an initial MPH treatment to atomoxetine, and 31.3% switched from an initial ATX treatment to MPH²⁸
  • Approximately 40%²⁹ to 50% of MPH nonresponders respond to atomoxetine, and approximately 75% of MPH responders also respond to atomoxetine. Atomoxetine can be administered alongside 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).³⁰
• In our opinion, the fourth-line treatment is guanfacine (particularly for generic hypertension or hypertension caused by MPH or AMP, or in cases of comorbid tics), which, statistically speaking, has a greater effect size and fewer side effects than atomoxetine
• For more information on other possible medications, see the related articles

2.1.2. The choice of medication for adults¶

For adults, the most helpful approach from a scientific perspective is* Prioritizing medications:²⁵²⁶
* 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.³¹
    • 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 lisdexamfetamine³²

• The second-best option is methylphenidate

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

• In our opinion, the fourth choice is guanfacine, since the reports of its positive effects primarily concern children

  • Guanfacine is used off-label in adults
  • In old age, exercise caution 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: approx. 20%
  • About 30% of adults who switch from MPH to Vyvanse switch back³³
    • Increasing the dose too quickly in too large increments increases the discontinuation 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 ineffective: 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
  • Nonresponders: approx. 30%
    • Increasing the dose too quickly in too large increments increases the discontinuation rate due to side effects or overdose

2.1.2. The choice of medication for seniors¶

In Switzerland, lisdexamfetamine and methylphenidate are approved for use in adults with no age restriction.¹⁵¹⁶
Stimulants are listed as a contraindication for benign prostatic hyperplasia with residual urine.³⁴ The professional literature mentions this in reference to stimulants as drugs. So far, we have not been able to find any reports of adverse effects associated with their use in medication dosing devices.

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 metabolism-related genes 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 taken 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 the people with ADHD
  • Treatment that was in line with the preferences of people with ADHD was
    • Discontinuation was less common by 38% (meta-analysis, k = 34)³⁵ to 41% (meta-analysis, k = 35)³⁶
    • showed a greater effect size ranging from SMD 0.18 (meta-analysis, k = 27)³⁷ to SMD 0.31 (meta-analysis, k = 35)³⁶..

See also:

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

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

Psychiatric disorders and other central nervous system (CNS) conditions pose particular challenges when it comes to finding the right medication.
ADHD occupies a special position among psychiatric disorders³, as the response rates—ranging from 70% (MPH) to 80% (AMP)—are far higher than for other disorders. Similarly, the effect size of ADHD medications is enormously high compared to that of medications for other disorders.
Nevertheless, it is impossible to predict which active ingredient will be effective for a particular person with ADHD. Even within a single class of active ingredients (MPH), one formulation may cause intolerable side effects in one person, while another works exceptionally well—and yet another person may react to the two formulations in exactly the opposite way. These differing reactions are likely due to the varying absorption and metabolism profiles of the active ingredient, which can differ significantly among individual formulations.
That is why, even with ADHD, persistent adjustment of medication in small increments is the key to improving symptoms and quality of life. We would like to encourage people with ADHD to “stick with it” if results are unsatisfactory and to keep trying new medications and active ingredients together with your doctor.

“In controlled trials, the drug is selected before subjects are recruited, and the dosage is determined by a protocol. In clinical practice, the dosage is determined by the individual response of the participants. In fact, there is no identified parameter that predicts the molecule, the dose, the timing of administration, and the frequency of administration at which an individual will derive optimal benefit from the medication. … In clinical practice, drugs in the stimulant class are tailored to the needs and responses of individual patients in at least five ways: active ingredient, delivery system, dose, duration, and frequency.”³⁸

3. Choosing Medications for Specific Cases¶

3.1. Responding¶

According to a meta-analysis, children with ADHD showed the greatest improvement in symptoms with:³⁹

• 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¶

The ADHD symptom of impaired inhibition of executive functions is caused by dopaminergic mechanisms in the basal ganglia (striatum, putamen).⁴⁰ Impaired inhibition of emotional regulation is caused by noradrenergic mechanisms in the hippocampus.⁴⁰
Therefore, the former is likely to respond better to dopaminergic treatment, while emotion regulation and affect control are likely to respond better to noradrenergic treatment.

Impulsivity is also mediated by serotonin.
If severe impulsivity is a prominent symptom in people with ADHD, it would be negligent to prescribe stimulants at such a high dose—without further consideration—that this symptom is adequately alleviated, as this would result in an overdose with regard to the other symptoms. In cases of particularly high impulsivity, treatment with low-dose SSRIs may be helpful.

• Serotonin reuptake inhibitors
  • At a significantly lower dose than when used as antidepressants
  • For example:
    • (Es)Citalopram 2–4 mg/day
    • Imipramine 10 mg/day

3.2.2. Inattention / ADHD-I¶

In a small placebo-controlled study, selegiline improved inattention but not hyperactivity/impulsivity.⁴¹

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, on the other hand, has a stronger stimulating/motivation-boosting effect and is therefore considered more suitable for treating ADHD-I (without hyperactivity [children] / inner restlessness [adults]).⁴² However, we know of quite a few people with ADHD-HI who find that amphetamine medications help them significantly more than MPH.

For people with the ADHD-I subtype—a significant proportion of whom are believed to be nonresponders to MPH⁴³ —D-amphetamine may therefore be an effective alternative to MPH.

3.2.3. Emotional Dysregulation¶

Emotional dysregulation in ADHD can be treated with stimulants or atomoxetine.⁴⁴

In our experience, atomoxetine and guanfacine have advantages over stimulants in the treatment of emotional dysregulation. Atomoxetine and guanfacine are effective throughout the day. In particular, the highly socially debilitating symptom of rejection sensitivity—which can place a significant strain on social relationships and romantic partnerships, especially when stimulants are no longer active—can be significantly improved by non-stimulant medications that provide all-day relief.
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 more side effects. In particular, the control of 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 a finely adjusted dosage regimen, this will often be the optimal approach.

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.

Methylphenidate significantly reduces feelings of distrust in people with ADHD.⁴⁵

3.2.4.2. Guanfacine and Clonidine¶

According to a single case report by an American physician (Dodson), a combination of the alpha-2-adrenoreceptor 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, overall, this treatment has a greater positive impact on quality of life than treatment with stimulants.⁴⁶

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.

Guanfacine is more effective than atomoxetine as a treatment for ADHD.

Alpha-2-adrenoreceptors (adrenoceptors) are activated by the neurotransmitters epinephrine and norepinephrine. They are therefore responsible for the effects mediated by epinephrine and norepinephrine.⁴⁷
Agonists enhance the effect of the receptors. Guanfacine and clonidine therefore have a noradrenergic effect and reduce the adrenergic effect.

3.2.4.3. MAO-A reuptake inhibitors¶

Dodson⁴⁶ goes on to describe 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 said to be more effective (than valproate) in combating rejection sensitivity.⁴⁸.

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.⁴⁹

3.2.5. Lack of drive¶

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

In addition:

• Bupropion

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-boosting effect and is therefore considered more suitable for treating ADHD-I (without hyperactivity [children] / inner restlessness [adults]).⁴²
However, we know of quite a few people with ADHD-HI for whom amphetamine medications are significantly more effective than MPH.

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¶

If symptoms are severe in the early morning or in the evening (before stimulants take effect and/or after their effects wear off), supplemental use of non-stimulant medications may be helpful, as these provide coverage throughout the day.⁵⁰

3.3. Preventing Specific Side Effects of ADHD Medications¶

For more information, see Dosage of Medications for ADHD

3.4. Choosing Medications for ADHD with Comorbidities¶

3.4.1. Anxiety Disorder Comorbid with ADHD¶

3.4.1.1. Anxiety Disorders Are Generally Comorbid with ADHD¶

3.4.1.1.1. 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, and UpToDate are listed as common side effects of stimulants.⁵¹.

However, most people with ADHD also benefit from stimulant treatment when it comes to comorbid anxiety symptoms.⁵¹
A meta-analysis of k = 23 studies involving n = 2,959 children with ADHD found a significant reduction in anxiety symptoms among those taking stimulants compared to those taking a placebo.⁵²
Immediate release methylphenidate derivatives reduced anxiety more effectively than placebo. Sustained-release MPH and amphetamine derivatives had no effect on the risk.
In a minority of people with ADHD, stimulants can worsen anxiety, although this occurs more frequently with amphetamine-based medications than with methylphenidate. High doses, especially those above the recommended maximum daily doses, increase the risk. ⁵² Anxiety disorders can 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.⁵³
We have seen reports on the forum of symptoms of depression or anxiety as side effects when starting treatment with amphetamine-based medications. Although 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 stimulant medication.⁵¹

An analysis of the proteins targeted by Vyvanse showed evidence that Vyvanse might also be effective in treating anxiety.⁵⁴

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, while MPH is contraindicated for severe anxiety and states of tension.¹⁵¹⁶

3.4.1.1.2. Non-stimulants¶

Atomoxetine can help reduce comorbid anxiety symptoms in children and adolescents.^55565758
Positive effects of atomoxetine on comorbid anxiety disorders have been reported.⁵⁹ Atomoxetine is said to have an effect size of 0.5 with regard to anxiety.²⁹
The reduction in anxiety symptoms with atomoxetine was slightly greater than that with MPH.⁶⁰⁶¹

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. This information presumably refers to the legal situation in Switzerland.¹⁵¹⁶

3.4.1.1.3. Combination therapy¶

A study examined the combination treatment of atomoxetine with SNRIs and SSRIs in adults with ADHD and comorbid generalized anxiety disorder. In all participants, SNRI or SSRI monotherapy failed to improve anxiety symptoms. Combination therapy with an SNRI or SSRI and atomoxetine showed significant improvements in anxiety symptoms compared to the previous monotherapy with an SNRI or SSRI.⁶²

A review identified comorbid anxiety disorder as an indication for the co-administration of stimulants with guanfacine (extended-release).⁵⁰

Positive experiences with ADHD and mild to moderate comorbid anxiety disorders have been reported by:

• Stimulants plus venlafaxine 18.75 to 150 mg/day⁶³
• Stimulants plus duloxetine 30 mg/day⁶³
• Stimulants plus fluoxetine 10 to 20 mg per day⁶³

A case report noted that, in a 15-year-old girl with ADHD who did not respond to atomoxetine, reacted with dysphoria to MPH, and could not tolerate clonidine as an adjunct, a combination of vortioxetine (10 mg/day) and MPH on stimulant-induced anxiety and ADHD symptoms. This was achieved with high tolerability.⁶⁴

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

3.4.1.2. Comorbid Social Anxiety Disorder in ADHD¶

Positive effects of atomoxetine on comorbid social anxiety have been reported.⁵⁹

3.4.2. 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).
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.¹⁷ Other studies report a reduction in suicide risk with long-term MPH use.⁶⁵

Dysthymia/dysphoria, defined as a persistent (for years) mild depression (low mood, especially during periods of inactivity), is rarely a comorbid depression but is typically an intrinsic symptom of ADHD. In our view, ADHD-specific medication—particularly stimulants (bupropion, amphetamine-based medications)—is indicated for dysthymia/dysphoria.
In cases of comorbid mild-to-moderate depression (and, in our opinion, possibly also in cases of 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 removes 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 it can often take months to fine-tune the dosage of ADHD stimulants
• MPH does not reach a steady state; lisdexamfetamine reaches a steady state after 3 days (and 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, medications 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 (especially 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).

3.4.2.1. 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 decreased by 43%.⁶⁶
Treatment of adults with ADHD using MPH also improved existing depressive symptoms, although not to the same extent as in healthy controls.⁶⁷
Amphetamine-based medications are (even) more suitable than MPH for the adjunctive treatment of comorbid dysphoria or depression⁶⁸⁶⁹ , possibly due to their noticeable serotonergic effect⁷⁰, and are often more effective than MPH.
In online forums, many people with ADHD report that amphetamine medications have a significant antidepressant effect that they do not experience with MPH.⁷¹ D-amphetamine 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.⁷²
In our experience as well, lisdexamfetamine (Vyvanse) has been shown to result in greater improvement in depressive symptoms than methylphenidate as part of ADHD treatment.
An analysis of the proteins targeted by Vyvanse showed evidence that Vyvanse might also play a positive role in the treatment of depression.⁵⁴

Moderate or severe depression can be exacerbated by stimulants, since anxiety and mood are regulated by dopaminergic activity in the ventromedial prefrontal cortex (PFC) in conjunction with the limbic system.⁵³
We have seen reports on the forum of symptoms of depression or anxiety as side effects when starting treatment with amphetamine-based medications. Although 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. Dextroamphetamine and MPH remain contraindicated in Switzerland for severe depression.¹⁵¹⁶ It is unclear whether this applies only to Switzerland or also to Germany.

Neither stimulants nor non-stimulants increased the risk of suicide to a statistically significant degree. However, there was an increased trend among non-stimulants, while there was no such trend among stimulants.⁷³

3.4.2.2. Atomoxetine as monotherapy¶

Whether atomoxetine is effective for depression is a matter of debate. While the majority of opinions say it is not^{2374 75} , one study found that atomoxetine improved depression symptoms to an extent comparable to that of paroxetine and venlafaxine.⁷⁶
Among 27 adolescents with non-suicidal self-injurious behavior and clinical or subclinical ADHD, atomoxetine improved both the self-injurious behavior and depression scores.⁷⁷

Atomoxetine is contraindicated in Switzerland for patients with severe depression (it is unclear whether this applies only to those at risk for suicidal behavior).¹⁵¹⁶

One study found that atomoxetine increased the risk of suicidal and self-harming behavior in children and adolescents with ADHD, whereas monotherapy with stimulants and combination therapy with atomoxetine and stimulants did not.⁷⁸ According to another study, neither stimulants nor non-stimulants statistically significantly increased the risk of suicide. However, the risk was higher with non-stimulants, while this was not the case with stimulants.⁷³ Another study found that atomoxetine reduced the risk of suicidal behavior in children and adolescents compared to stimulants, regardless of whether ATX was used as a first-line or second-line medication.⁷⁹

3.4.2.3. Guanfacine for ADHD with comorbid depression¶

Guanfacine is not contraindicated in Switzerland for patients with comorbid depression.¹⁵¹⁶

3.4.2.4. Bupropion¶

Bupropion has antidepressant effects, is a fifth-line treatment for ADHD, and is used to help people quit smoking.

In participants with a high polygenic risk score (PGS) for ADHD, the risk of suicidal thoughts associated with SSRIs was 66% higher than with bupropion. SNRIs and SSRIs increased the risk to the same extent. Among participants with a low PGS, SSRIs increased the risk of suicidal thoughts by only 6% more than bupropion (6%).⁸⁰
The antidepressant effect of SSRIs and SNRIs was much stronger in women than in men.⁸⁰

3.4.2.5. Combination Therapy for Comorbid Depression and ADHD¶

3.4.2.5.1. Atomoxetine and Fluoxetine¶

A double-blind, placebo-controlled study examined combination therapy with atomoxetine and fluoxetine (an SSRI) compared to monotherapy with atomoxetine in children and adolescents with ADHD and comorbid symptoms of depression or anxiety. The study found no significant improvements in ADHD symptoms with combination therapy. There were small improvements in symptoms of comorbid depression with combination therapy compared to monotherapy with atomoxetine, although the latter already improved symptoms of depression and anxiety in addition to ADHD symptoms. Combination therapy did not result in an increase in side effects. Blood pressure was slightly higher with combination therapy than with monotherapy.⁵⁸

3.4.2.5.2. Atomoxetine and Sertraline¶

A study found evidence of a benefit from atomoxetine combined with sertraline in individuals with the HTTLPR (SERT) s/s genotype compared to sertraline monotherapy.⁸¹

3.4.2.5.3. SSRIs and MPH for ADHD with comorbid depression¶

A study raises concerns that SSRIs (such as fluoxetine) may enhance moderate addiction-related gene regulation of MPH in the striatum of rats, thereby potentially increasing dependence on methylphenidate. This effect is less pronounced with vilazodone.⁸²

3.4.2.5.4. Escitalopram and MPH for comorbid depression and ADHD¶

A study found no increased risk associated with the adjunctive use of escitalopram with MPH for ADHD, except in cases of additional comorbid TIC disorders.⁸³

3.4.2.5.5. 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 depression⁶³

A study of people with ADHD and comorbid depression who did not show sufficient improvement in ADHD symptoms with MPH alone found that the addition of fluoxetine resulted in 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. No increase in side effects was observed.⁸⁴ Another study found no increased side effects with fluoxetine when used in combination with MPH for ADHD and a significantly lower risk compared to escitalopram in cases of comorbid TIC disorders.⁸³
In rats, the combined administration of MPH and fluoxetine reduced anxiety and depression-like behaviors to a significantly greater extent than either drug alone.⁸⁵

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

Co-administration of MPH and fluoxetine to adolescent rats resulted in increased sensitivity to rewarding stimuli (which is likely to be beneficial in ADHD) and increased anxiety and stress sensitivity (which would be detrimental in ADHD) in adult animals.⁸⁶ However, the study tested healthy animals, not ADHD model animals.

A combination of MPH and fluoxetine reduced D2R binding in rats, an effect that neither MPH nor fluoxetine alone produced, in:⁸⁷

• dorsal caudate 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. A reduction in overall D2R levels was observed in people with ADHD.⁸⁸

3.4.2.5.6. Selegiline and Lisdexamfetamine for Comorbid Depression¶

A study reports successful co-administration of selegiline and lisdexamfetamine (Vyvanse) in patients with ADHD and comorbid depression.⁸⁹ Another study on the co-administration of stimulants and MAO inhibitors for depression found no associated problems.⁹⁰
Therefore, a combination therapy of selegiline and stimulants may also be considered for ADHD.

3.4.2.5.7. Duloxetine and Stimulants for Comorbid Depression¶

Positive results have been reported with stimulants plus duloxetine 30 mg/day for mild to moderate depression⁶³

3.4.2.5.8. 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 depression⁶³

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.

3.4.2.5.9. MAO Inhibitors and Stimulants for Comorbid Depression¶

A study on the co-administration of stimulants and MAO inhibitors for depression found no associated problems,⁹⁰ contrary to the commonly held belief that it could lead to blood pressure crises.
The safety requirement is that MAO inhibitors must be discontinued 14 days before taking a stimulant.

3.4.2.5.10. Lamotrigine for ADHD with comorbid depression¶

See the section on Lamotrigine for ADHD

3.4.2.5.11. Comorbid Depression with Specific Features¶

3.4.2.5.11.1. 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 difficulties concentrating and a lack of motivation:

• Nortriptyline⁹¹
• Milnacipran 25 to 100 mg⁹¹

3.4.2.5.11.2. 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 mg⁹¹

3.4.2.5.11.3. Depression with Comorbid Obsessive-Compulsive Symptoms¶

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

• Sertraline 50 to 100 mg⁹¹

3.4.2.5.11.4. Depression with Irritability¶

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

• Moclobemide 75 to 100 mg⁹¹

3.4.2.5.11.5. Comorbid depression with irritability¶

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

• Amisulpride 25 to 100 mg per day⁶³⁹¹

3.4.4. Bipolar disorder with ADHD as a comorbid condition¶

Methylphenidates and mixed amphetamine salts are considered the most promising options for treating 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 have a favorable safety profile without an increased risk of manic episodes, particularly when combined with mood stabilizers.⁹²

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.⁵⁶

Stimulants can be safely used in children and adolescents with comorbid bipolar disorder if their manic/hypomanic symptoms are effectively treated with a mood stabilizer.⁵¹

A meta-analysis of k = 5 studies with n = 1,653 data points found no increase in scores on the Young Mania Rating Scale for patients with bipolar disorder who were in a euthymic or depressive state when treated with stimulants compared to placebo (SMD minus 0.17). The study results were highly heterogeneous, and a qualitative synthesis of the studies indicated a limited risk of medication-induced manic symptoms.⁹³

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

• Lamotrigine⁹¹
  • For more information, see Lamotrigine for ADHD
• carbamazepine or valproate, if necessary

In cases of comorbid bipolar disorder with irritable depression, positive results have been reported from
- Aripiprazole 5 to 15 mg/day⁶³
- Lamotrigine (important: increase the dose gradually)⁶³

An analysis of the proteins targeted by Vyvanse showed evidence that Vyvanse might also play a positive role in the treatment of bipolar disorder.⁵⁴

Stimulants should be used with caution even in cases of well-controlled bipolar disorder:¹⁵¹⁶
Lisdexamfetamine (Vyvanse) and MPH are contraindicated in Switzerland for (acute) mania.
Dexamfetamine is contraindicated in patients with severe or episodic (Type I) bipolar affective disorder (that is not well controlled).
Guanfacine and atomoxetine are not contraindicated in bipolar disorder.

3.4.5. Mood Swings Comorbid with ADHD¶

Severe and frequent mood swings are said to be helpful:

• Venlafaxine extended-release 18.75 to 150 mg⁹¹
• Carbamazepine
• Valproate
• Lamotrigine
  • For more information, see Lamotrigine for ADHD

3.4.6. Borderline Personality Disorder Comorbid with ADHD¶

A comparative efficacy study involving N = 22,601 people with emotionally unstable personality disorder and comorbid ADHD showed that ADHD medications were the only class of drugs that significantly reduced the risk of suicidality.⁹⁴

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

• Venlafaxine extended-release 37.5 to 75 mg⁹¹
• Venlafaxine extended-release 18.75 to 150 mg⁶³

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.⁴⁹

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

DMDD is characterized by persistent, severe irritability and high impulsivity. ADHD is often comorbid with it.

A study found that combination therapy with aripiprazole and methylphenidate had a positive effect on children with comorbid DMDD and ADHD. No increase in side effects was observed.⁹⁵

3.4.8. Irritability in ADHD¶

A study reports a significant reduction in irritability with dextromethorphan, which was administered in addition to MPH, in children and adolescents with ADHD.⁹⁶

3.4.9. Aggression as a Comorbid Condition of ADHD¶

A review cited comorbid aggression or oppositional behavior as an indication for the co-prescription of stimulants and non-stimulants (alpha-2 agonists or atomoxetine).⁵⁰

Several atypical antipsychotics, particularly risperidone, effectively reduced aggression. Some studies showed (contrary to the FDA’s warning that stimulants could worsen aggression) that stimulants, just like antipsychotics, effectively reduced aggression, especially in hyperactive children.⁹⁷

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.⁵¹ In a study involving rapid titration of MPH in n = 155 boys aged 6 to 12 with ADHD and comorbid CD, two-thirds of the participants showed remission of aggression symptoms (R-MOAS score <18) after an average of 75 days of stimulant treatment.

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 have been insufficient to treat aggression.⁹⁸ Various expert panels have concluded that if aggression comorbid with ADHD (not: aggression resulting from stimulants) is not sufficiently improved by the prescription of stimulants, the concurrent use of atypical antipsychotics is indicated, provided the dosage is carefully titrated.⁹⁹¹⁰⁰

Molindone with extended-release formulation (SPN-810) is being tested for comorbid oppositional defiant disorder.^{101102 103 104 105 106 107} SPN-810M is a potent antagonist of the dopamine receptors D2S and D2L and the serotonin receptor 5-HT2B.¹⁰⁸¹⁰⁹
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).
Side effects included headaches, sedation, and increased appetite.¹⁰¹

For information on the co-administration 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.⁵¹

3.4.10. Oppositional defiant behavior comorbid with ADHD¶

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).⁵⁰

A meta-analysis of k = 28 studies found that stimulants were just as effective at improving aggressive behaviors in ADHD as they were at improving the core symptoms of ADHD themselves. For aggressive behaviors without comorbid ADHD, the effect of stimulants was somewhat less pronounced.¹¹⁰ In this context, MPH¹¹¹¹¹² was just as effective as AMP²⁹.

Atomoxetine is thought to be helpful for comorbid oppositional defiant disorder.⁵⁶¹¹³ However, one study found an effect size of only 0.39 for oppositional defiant disorder, with higher doses being more effective than for ADHD without comorbidity¹¹⁴; two studies found no efficacy.¹¹⁵²⁹

Guanfacine showed positive effects on oppositional behavior in children with ADHD, both as monotherapy¹¹⁶ and in combination with MPH¹¹⁷.

In cases of comorbid ODD and ADHD, combination therapy with risperidone and MPH proved to be helpful¹¹⁸, as it did in cases of comorbid conduct disorder (CD).¹¹⁹

Effect sizes of various medications on ODD compared to placebo:¹²⁰

• 0.85 Stimulants (k = 6, n = 545)
• 0.43 Guanfacine (k = 2, n = 678)
• 0.33 Atomoxetine (k = 15, n = 1,907)
• 0.27 Clonidine (k = 3, n = 283)

3.4.11. Conduct Disorder (CD) Comorbid with ADHD¶

Atomoxetine is said to be helpful in cases of comorbid conduct disorder.⁵⁶¹²¹

Conduct disorder is also frequently treated with:¹²¹

• 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%)
• Pipamperon (15%)
• Tiaprid (8%)

One-quarter of the users of combination therapy with MPH and antipsychotics were prescribed it only once.
The use of combinations of MPH with risperidone and tiaprid was often appropriate (> 72%), whereas the use of the MPH-pipamperone combination was rarely appropriate (< 15%).¹²²

3.4.12. ASD comorbid with ADHD¶

Up to 70% of people with ASD also have ADHD.¹²³

Medication for Autism Disorder and Comorbid ADHD:

• There are frequent reports of increased sensitivity to medications in general—including ADHD medications—or a reduced need for dosage. In some cases, the required doses are extremely low.⁵¹ Other sources report that the same doses of ADHD medications are used for patients with comorbid ASD (though they cite Hyman et al. (2020), whose findings do not align with the studies cited there; see below), while also noting an increased risk of side effects¹²³
• Stimulants
  • Children with ASD and comorbid ADHD reported the following (as a percentage of patients):¹²⁴
    • Restlessness:
      • 47.4% improvement (particularly among children diagnosed at a later stage)
      • 28.1% worse (particularly due to sustained release MPH)
    • Concentration
      • Improved by 56.1%
      • 15.8 worsened
    • Sleep
      • Improved by 8.8%
      • 17.5% decline
    • Language
      • 86% unchanged
      • Decreased by 12.25%
      • Improved by 1.75%
    • Other behavioral changes
      • 50.9%, unchanged
      • 45.6% negative changes
      • 3.5% positive changes
• MPH:
  • 49% responders among n = 72 children aged 5 to 14¹²⁵
  • The starting dose should be very low, e.g., 2.5 mg of immediate release MPH per dose; followed by 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 days¹²⁶
    • This study even reports cases involving a daily dose of 2.5 mg of sustained-release MPH
    • Another study of preschool-aged children with ADHD and comorbid ASD or other developmental disorders started with 1.25 mg of MPH twice daily and allowed a maximum dose of 10 mg twice daily.¹²⁷
  • Low initial dose under careful monitoring (e.g., 0.3 mg/kg/day) with low target doses (e.g., 0.5 mg/kg/day)¹²⁸
    • The claim in the text that the dosage is the same as for children with ADHD who are not taking ASA is not found in the source cited for this. The studies cited there indicate strikingly low dosages.
  • More severe side effects from stimulants are possible, particularly loss of appetite and insomnia¹²⁸
  • Effective for symptoms of hyperactivity, inattention, and irritability; fewer side effects than ATX¹²⁹
  • Less effective and associated with more side effects than ADHD without SSRIs¹³⁰
  • Less effective in treating hyperactivity in cases of intellectual disability¹³¹
• Lisdexamfetamine:
  • Second-line choice of medication if MPH is ineffective or causes unacceptable side effects. Again, start with a low dose and aim for a lower target dose (half or less).⁵¹¹²⁸
  • Recommended daily doses are reported to range from 10 to 70 mg¹²⁶
• Amphetamine salts:
  • Appropriate daily doses are reported¹²⁶
    • 2.5 mg to 40 mg, immediate release
    • 5 mg to 60 mg, sustained release
• Atomoxetine:
  • Less effective in treating ADHD symptoms while maintaining the same level of tolerability¹³¹¹³⁰
  • Modest effect on hyperactivity and inattention symptoms with a relatively mild side effect profile; more frequent discontinuation of treatment due to more severe side effects than with MPH¹²⁹
• Guanfacine:
  • Initial dose (immediate release): 0.5 mg/day, titrated in 0.5-mg increments¹²⁶
  • Starting dose: 1 mg/day (sustained release), 1-mg titration increments¹²⁶
  • Same effect on hyperactivity in ASD as in TD¹³⁰
  • Same effect on hyperactivity in cases of intellectual disability, with poorer tolerability¹³¹
• Amitriptyline:
  • At a dosage of approximately 1 mg/kg/day, when used with caution, it is effective for¹³⁰
    • Sleep, anxiety, impulsivity, and ADHD, repetitive behaviors, and enuresis

In cases of autistic traits (subclinical ASD)

• Fluoxetine 10 to 20 mg⁹¹
• Fluoxetine 5 to 20 mg⁶³
• Aripiprazole
  • 2.5 mg (starting dose) to 5 mg, rarely up to 10 mg⁹¹
  • 2.5 to 7.5 mg⁶³

Pure ASA medication:
In the U.S., only risperidone and aripiprazole are approved by the FDA for the treatment of SAD¹³⁰

• Risperidone
  • Hyperactivity and impulsivity associated with autism or intellectual disability can be improved with stimulants or 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.²³
  • For schizophrenia: 2 mg recommended starting dose, 2 mg lowest effective dose, 8 mg recommended maximum dose, 20 mg approved maximum dose.¹³² 6 mg already occupies 75% to 80% of the D2 receptors.¹³³¹³⁴ 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 hypersensitivity develops.¹³² EPS and hypersensitivity are common side effect risks and are therefore likely to apply to ASA as well.
• Citalopram and Fluoxetine (SSRIs):
  • Poor tolerance and lack of effectiveness in repetitive behaviors¹³⁰
• Oxytocin:
  • Showed no efficacy¹³⁰
• Amitriptyline and Loxapine:
  • Promising¹³⁰
• Loxapine:
  • At a dosage of 5 to 10 mg daily in PET, similar to an atypical antipsychotic, possibly without side effects related to weight gain¹³⁰

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

3.4.13. Co-occurring high irritability / 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 mg⁹¹

A study reports a reduction in sensory over-responsivity (SOR) following high-dose vitamin B6 (100 mg/day).¹³⁵
100 mg/day is the maximum safe dose. Given the risk of serious side effects, taking this medication without medical supervision is not recommended.
At the same time, it is important to note that vitamin B6 toxicity can lead to neuropathies, which may be accompanied by impaired sensory perception.¹³⁶

3.4.14. Tic Disorders Comorbid with ADHD¶

A review identified comorbid tic disorders as an indication for the co-administration of stimulants and alpha-2 agonists.⁵⁰

Tourette syndrome has an estimated prevalence of 0.52% and is four times more common in boys than in girls. One in two adolescents with Tourette syndrome has ADHD.¹³⁷

For children and adolescents with ADHD and tic disorders or Tourette syndrome, stimulants can be an effective treatment. Generally, they do not worsen tics or Tourette syndrome, although there are isolated cases where this is not the case.¹³⁸⁵¹

Since dextroamphetamine can (initially) worsen tics in some children when taken in high doses, methylphenidate should be the drug of choice.⁵¹ As always, a slow and gradual titration of the dose is recommended, even if this requires more persistence.
According to a Cochrane review, MPHs such as dextroamphetamine are effective for children and adolescents with ADHD who also have tics. MPHs also improved the tics. However, dose increases were limited due to concerns about an increased risk of tics.¹³⁸ Krause reports that comorbid tics may initially worsen with stimulant monotherapy. However, this usually resolves within about 4 weeks. In addition, gradual up-dosing and a low dosage may be helpful.¹⁸ 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.¹³⁹

In the past, stimulants were not recommended for adolescents with Tourette syndrome or chronic tic disorders,¹⁴⁰ because case reports from the 1970s described children who were being treated with a stimulant for ADHD tics had been reported (particularly motor tics, such as eye blinking, nose wrinkling, and lip licking).¹⁴⁰
However, a meta-analysis of k = 22 studies involving n = 2,385 children with ADHD found no evidence that stimulants caused tics in adolescents without pre-existing tic disorders, compared with placebo.¹³⁹

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

• Guanfacine¹⁴¹¹⁴²
• Atomoxetine¹⁴¹¹⁹
• Selegiline
  • 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 minimal.¹⁴³
  • Another study of 24 children with ADHD and comorbid Tourette syndrome found only minor improvements in ADHD symptoms, along with a high dropout rate among participants.¹⁴⁴
• Clonidine
  • Was more effective in children with ADHD and comorbid tic disorders than methylphenidate combined with haloperidol.¹⁴⁵

An analysis of the proteins targeted by Vyvanse showed evidence that Vyvanse might also be effective in treating tic disorders.⁵⁴

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.¹⁴⁶

For tic disorders without ADHD, antipsychotics appear to have a greater effect size.¹⁴²

3.4.15. Obsessive-Compulsive Disorder Comorbid with ADHD¶

Atomoxetine had positive effects on compulsive behaviors.¹⁴⁷
A report on two children with compulsions and ADHD (ages 9 and 10) suggested a positive effect from a combination of behavioral therapy, sertraline, and guanfacine.¹⁴⁸
Positive results have been reported with sertraline 50 to 100 mg/day in patients with comorbid obsessive-compulsive disorder.⁶³

3.4.16. Schizophrenia and Psychosis Comorbid with ADHD¶

Taking stimulants or atomoxetine reduced the risk of hospitalization due to psychosis by two-thirds (HR = 0.36) in the 12 months following the initiation of these medications, when taken in combination with antipsychotics.¹⁴⁹
A Swedish cohort study found that among adolescents with no history of psychosis (average age 17 years), there was a very slight 4% increase in the risk of psychosis in the 12 weeks following the start of MPH treatment compared with the 12 weeks prior to the start of treatment.¹⁵⁰

A large long-term study (n = 131,476) examined the total number of hospitalizations, deaths, and hospitalizations due to psychosis, somatic diseases, and cardiovascular diseases among people with schizophrenia who were taking ADHD medications. The use of ADHD medications (particularly lisdexamfetamine at all dosages and long-acting methylphenidate at low to moderate dosages) was safer than generally assumed:²⁰

• Lisdexamfetamine
  • reduced risk of hospitalizations and all-cause mortality (11% reduction; aHR = 0.89, 95% CI = 0.84–0.94)
  • reduced risk of somatic hospitalizations (30% lower; aHR = 0.70 [0.58–0.84])
  • Evidence of U-shaped relationships between the doses used and the risk of hospitalizations, all-cause mortality, and psychosis
• Methylphenidate
  • slightly increased risk (+4%; aHR = 1.04 [1.01–1.08])
  • Increased risk of hospitalizations and all-cause mortality with methylphenidate only at doses of ≥ 95 mg/day (+8%; aHR 1.08 [1.03–1.14])
  • increased risk of hospitalization/mortality when not taking an antipsychotic concurrently (+6%; aHR = 1.06 [1.01–1.12])
  • Evidence of U-shaped relationships between the doses used and the risk of hospitalizations, all-cause mortality, and psychosis
• Atomoxetine
  • reduced risk (only) of hospitalizations due to psychosis (13% lower; aHR = 0.87 [0.78–0.98])
• ADHD combination therapy
  • increased risk (only) for somatic hospitalizations (+37%; aHR = 1.37 [1.07–1.74])
• all ADHD medications
  • no other statistically significant correlations
  • No effect on cardiovascular hospitalizations

Older sources, on the other hand, identified the following as risk factors for stimulant-induced psychosis:⁵¹

• Schizophrenia
• 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.¹⁵¹

A study of stable schizophrenia patients with ADHD found no psychotic symptoms or other serious side effects at doses of up to 250 mg of lisdexamfetamine per day (3.5 times the recommended maximum daily dose).¹⁵²

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 dosage⁹¹
• Quetiapine, Aripiprazole, Amisulpride⁶³ e

3.4.17. Substance Abuse / Addiction Comorbid with ADHD¶

Stimulants do not increase the risk of addiction in people with ADHD,¹⁵³ —neither for non-medical stimulants¹⁵⁴ nor for stimulant medications. People with ADHD often forget to take their medication, which would not happen if they were experiencing cravings.
In ADHD, stimulants significantly reduce the risk of addiction and relapse while they are being taken.⁷⁴ Substance use was about 35% lower during stimulant treatment than during periods without medication.¹⁵⁵ MPH significantly reduced the incidence of subsequent substance use disorders (meta-analysis, k = 6, n = 1,014).¹⁵⁶ The risk of subsequent substance use disorders—whether involving alcohol or other substances—was reduced by a factor of 1.9.¹⁵⁷
Methylphenidate is now considered a treatment option for substance use disorders.¹⁵⁸ A case report illustrates the effects of lisdexamfetamine in a former addict.¹⁵⁹ In one study, lisdexamfetamine reduced drug use among methamphetamine-dependent individuals.¹⁶⁰ Methylphenidate significantly reduced the risk of relapse among former cocaine-dependent individuals (OR 5.85 to 11.87).¹⁶¹
The risk of developing an addiction later in life—whether to alcohol or other substances—is reduced by a factor of 1.9 (nearly halved).¹⁶² A case report provides an example.¹⁵⁹
One year of MPH treatment resulted in:¹⁶³

• Reduced internet addiction
• Reduced shopping addiction
• Reduces food cravings
• Reduces sex addiction
• Gambling addiction remains unchanged

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.¹⁶⁴
Treatment with extended-release mixed amphetamine salts in people with ADHD and comorbid cannabis dependence resulted in 15% of patients discontinuing cannabis use, compared with 0% in the placebo group.¹⁶⁵

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 to be a sign of self-medication among people with ADHD.
It should also be noted that there are substances available in every nightclub restroom and behind every train station that are cheaper and easier to obtain, and that produce a significantly more intense 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 these restrictions make sense from a sociopolitical perspective when weighing the overall benefits and costs.

The Joint Addiction Commission of the German Society for Child and Adolescent Psychiatry and Related Associations summarizes its 2024 recommendations: “Despite these concerns, the use of stimulants in patients with comorbid ADHD and SUD is generally recommended, although 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.”¹⁶⁶
While atomoxetine is considered beneficial in cases of acute comorbid amphetamine substance abuse due to its lower risk of abuse⁵⁶, people with ADHD and opioid addiction currently undergoing treatment (opioids are dopaminergic drugs) showed greater adherence to opioid substitution therapy (buprenorphine). Among those who received stimulants, 33% were less likely to discontinue buprenorphine treatment. This supports the use of stimulant treatment even in cases of a history of addiction to dopaminergic drugs.¹⁶⁷
A history of substance abuse is not usually a contraindication for stimulants.¹⁶⁸

Amphetamine-based medications are now available as a prodrug (lisdexamfetamine). This means that they are available in a form that is simply ineffective when misused (abuse involving massive overdoses administered nasally or intravenously), because they are present 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.
In this paper, Daberkow et al.¹⁶⁹ show that graph , under “D,” the slow rise in dopamine (medication) at 1 mg/kg AMP and the rapid rise (drug) at 10 mg/kg AMP. The concentration profile at 1 mg/kg AMP corresponds to the curves typically observed with amphetamine medications.
Lisdexamfetamine (Vyvanse) produces similar D-Amp levels when taken intranasally (snorted)¹⁷⁰ or intravenously (injected)¹⁷¹ —even when used off-label—as it does when taken orally. The effects were roughly the same, with slightly increased side effects. No euphoric effect was observed. This shows that the risk of abuse of lisdexamfetamine is very low.

A study compared the abuse potential of single oral doses of lisdexamfetamine (LDX) at 50, 100 (equivalent to 40 mg DAmp), and 150 mg, 40 mg of d-amphetamine and 200 mg of diethylpropion in 36 individuals with a history of stimulant abuse. When assessing abuse potential using the Drug Rating Questionnaire-Subject Liking Scale, lisdexamfetamine at 50 mg and 100 mg showed no significant increase compared to placebo (2.1), but at 150 mg it showed a significant increase (6.1). Dextroamphetamine (DAmp) and diethylpropion showed significantly higher scores of 4.0 and 4.5, respectively. The subjects preferred 40 mg of DAmp over 100 mg of LDX, while 150 mg of LDX and 40 mg of DAmp were equally preferred.¹⁷² The maximum regular daily dose of lisdexamfetamine is 70 mg.

In cases of acute THC or alcohol 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, the administration of stimulants can help alleviate withdrawal symptoms and prevent relapse.

Lisdexamfetamine (Vyvanse), guanfacine, and atomoxetine are not contraindicated in Switzerland for acute alcohol or drug abuse.^173174175
Dexamphetamine and methylphenidate are contraindicated in Switzerland in cases of acute alcohol or drug abuse.¹⁵¹⁶

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.¹⁷⁶ It should be noted, however, 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 study’s findings can be applied to conditions outside the U.S., and particularly in Europe.

3.4.18. Emotional Disorders Comorbid with ADHD¶

3.4.18.1. Binge Eating as a Comorbid Condition of ADHD¶

An analysis of the proteins targeted by Vyvanse showed evidence that Vyvanse might also play a positive role in the treatment of binge eating.⁵⁴
In the U.S., Vyvanse is approved for the treatment of binge eating in adults. At a dose of 50 to 70 mg daily for 11 weeks, it reduced the severity and frequency of binge eating episodes.⁵¹

Although lisdexamfetamine has not been systematically studied in children and adolescents with BED, a retrospective review (N = 25; ages 12–19) suggests some benefit regarding self-reported binge-eating symptoms.30 Current guidelines for the treatment of eating disorders do not include specific recommendations for the use of lisdexamfetamine in children and adolescents with BED, as there is a lack of robust data. Based on clinical practice, lisdexamfetamine may be considered for adolescents with moderate-to-severe BED and comorbid ADHD who have no clinically significant cardiac history, in combination with other supportive ED treatment (e.g., cognitive behavioral therapy).3,31

3.4.18.2. Bulimia nervosa comorbid with ADHD¶

A meta-analysis reported that nearly all studies found that stimulants had a positive effect on eating behavior in bulimia.²¹⁵ However, safety concerns remain due to a lack of data on their use in children and adolescents with bulimia.⁵¹
With regard to stimulants, the following has been reported among 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:⁵¹

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

3.4.18.3. Anorexia nervosa comorbid with ADHD¶

Stimulants should be avoided in children and adolescents with anorexia nervosa. There are various risks:²¹⁶

• additional appetite suppression
• additional weight loss
• Worsening of restrictive eating behaviors
• Increased cardiovascular risks, including cardiomyopathy (e.g., hypertrophy), in severely malnourished children

Once anorexia has subsided, treatment of ADHD symptoms with stimulants may be considered, provided that appetite, weight, and eating habits are closely monitored.⁵¹
A case study reports successful treatment with amphetamine-based medications without affecting body weight.²¹⁷

3.4.19. Obesity¶

Stimulants are known to reduce appetite.
Atomoxetine is approved by the FDA for the treatment of obesity.¹⁴⁷

²¹⁸ decreased two years after starting treatment for ADHD with lisdexamfetamine

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

3.4.20. Chronic pain comorbid with ADHD¶

Chronic pain is a common comorbidity associated with ADHD
Stimulants, as well as atomoxetine²¹⁹, can also reduce chronic pain in people with ADHD.

3.4.21. Enuresis Comorbid with ADHD¶

Duloxetine alleviates comorbid enuresis (bedwetting) and stimulant-induced dysphoria in ADHD. A case report documented relief of comorbid enuresis (bedwetting) and stimulant-induced dysphoria, as well as an improvement in cognitive abilities, in an adolescent with ADHD.²²⁰
Atomoxetine increased the number of dry nights by half.²²¹
Imipramine was also recommended for comorbid bedwetting (enuresis).²²²

3.4.22. Sleep Problems and ADHD¶

People with ADHD often suffer from sleep problems. 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 initial dosage, which 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 ADHD Medications

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

3.4.22.1. Melatonin and Stimulants¶

A Swedish cohort study found that two-thirds of the boys and half of the girls who received melatonin were also taking ADHD medication²²³, suggesting that melatonin is highly effective for ADHD-related sleep problems.
Learn more about melatonin as a medication for treating sleep problems associated with ADHD at Melatonin for ADHD

3.4.22.2. Guanfacine (especially in the evening)¶

One person with ADHD told us she had good results taking guanfacine about 5 hours before bedtime. Fatigue is a common side effect of guanfacine. Guanfacine is a sustained-release medication that works for almost the entire day, so it should continue to have a positive effect on ADHD symptoms the next day as well.

3.4.22.3. Amitriptyline¶

Amitriptyline, at a dosage of approximately 1 mg/kg/day and when used with caution, showed improvement in sleep, anxiety, impulsivity, ADHD, repetitive behaviors, and enuresis.¹³⁰

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

3.4.22.4. Trazodone¶

Experience has shown that the following can be helpful in cases of comorbid sleep disorders, particularly when they are accompanied by comorbid anxiety disorders and depression:

• Trazodone; starting dose 25 mg, rarely more than 100 mg⁶³⁹¹

3.4.23. Bruxism (Teeth Grinding) in ADHD¶

A case study reports a positive effect of buspirone on bruxism caused by atomoxetine.²²⁴
ADHD medications can exacerbate bruxism.

3.4.24. 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 children with CDS/SCT. The improvement in SCT symptoms was completely independent of ADHD symptoms.²²⁵

People with SCT are also particularly likely to be MPH nonresponders. In contrast, the ADHD-HI and ADHD-I subtypes do not differ in terms of their MPH response rates.²²⁶

3.4.25. 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 acts peripherally in the gut rather than centrally).
An experienced ADHD physician reported that, among a four-digit number of ADHD patients, he had never observed any histamine-related problems caused by ADHD medications.
Several cases of (possibly histaminergic) allergic reactions caused by ADHD medications have been reported 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 common ADHD medications appear to increase histamine levels only in the brain.

• Atomoxetine increased extracellular histamine in the PFC of rats²²⁷²²⁸  
• Methylphenidate increased extracellular histamine levels in the PFC of rats²²⁸
• Amphetamine increased histamine levels in the hypothalamus of rats²²⁹²³⁰
• Modafinil
  • Modafiil released histamine in the hypothalamus of rats²³¹

In contrast, stimulants appear to promote histamine breakdown peripherally by increasing DAO:

• MPH induces diamine oxidase, which increases peripheral histamine degradation²³²
• Lisdexamfetamine caused a marked upregulation of DAO mRNA levels in Caco-2 cells, which increases peripheral histamine degradation²³²
  Viloxazine appears to exert no competitive inhibition—or, at most, only weak competitive inhibition (< 25%)—at the H1 and H2 histamine receptors.²³³²³⁴

Regardless of this, excipients can also have a peripheral histamine-elevating effect. Winkler reported the following regarding excipients:²³⁵

• Among AMP medications, Attentin is said to have fewer side effects than Vyvanse in cases of histamine intolerance
• Among MPH medications, Medikinet (immediate release) and Kinecteen are said to be less problematic for people with 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).

3.4.26. Gluten Intolerance¶

Excipients in medications may contain gluten.
Winkler reports that, with regard to the active ingredients, Medikinet (immediate release), Medikinet Retard, 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.²³⁵

3.4.27. Lactose Intolerance¶

Excipients in medications may contain lactose.
Winkler reports that, with regard to the following medications— , Medikinet retard, Medikinet adult, Ritalin LA, and Ritalin adult— Vyvanse, Attentin, Strattera, and Agakalin are safe, while immediate-release Ritalin, immediate-release Medikinet, Concerta, and Kinecteen can cause problems for people with lactose intolerance.²³⁵

3.4.28. Fructose Intolerance¶

Excipients in medications may contain fructose.
Winkler reports that, with regard to these medications, Ritalin (immediate release), Medikinet (immediate release), Vyvanse, Strattera, and Agakalin are safe, while Medikinet (extended-release), Medikinet Adult, Ritalin LA, Ritalin Adult, Concerta, Kinecteen, and Attentin can be problematic for people with fructose intolerance.²³⁵ Concerta and Kinecteen are now said to be sucrose- and fructose-free (May 2025).

3.4.29. Sorbitol Intolerance¶

Excipients in medications may contain sorbitol.
Winkler reports that, with regard to the active ingredients, 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.²³⁵

3.4.30. Down Syndrome¶

Down syndrome is associated with a significantly higher prevalence of ADHD.
A study of n = 21 people with Down syndrome and ADHD reported a 48% response rate to guanfacine. 43% reported side effects, most commonly daytime sleepiness (33%) and constipation (10%).²³⁶

In cases of Down syndrome and comorbid ADHD, we consider screening for sleep-related breathing disorders to be helpful, 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

3.4.31. Emotional Dysregulation¶

ADHD medications also help normalize the emotional dysregulation associated with ADHD in adolescents.²³⁷

Atomoxetine is well-suited as monotherapy for emotional instability.^{238168 239}

Experience has shown that stimulants, such as methylphenidate²⁴⁰, 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.^{241242 243 240}
A study found that stimulants did not improve emotional regulation.²⁴⁴
Among n = 30 participants, methylphenidate improved emotional dysregulation in 73.3% (Hegdes’ g = 2.62). Among the non-responders, an additional 16.6% responded to aripiprazole (Hegdes’ g = 1.30).²⁴⁵

A study found that, in adult inpatients with ADHD and significant 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.²³⁸

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 life 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 therapies will become standard treatments in the future, even if this requires even more persistence and sensitivity when titrating the doses.

3.4.32. High Blood Pressure as a Comorbidity 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.²⁴⁶
Guanfacine-XR prolonged the QTc interval.²⁴⁶

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.²⁴⁷
• Systolic blood pressure increases by an average of 3.7 with atomoxetine, by 2.4 with Concerta, and by 1.3 with placebo.²⁴⁷
• Diastolic blood pressure increases by an average of 3.8 with atomoxetine, by 3.1 with Concerta, and by 0.4 with placebo.²⁴⁷

A Swedish long-term study spanning 14 years with n = 62,060 participants on the risks of certain cardiovascular diseases associated with long-term use of ADHD medication found the following, in each case compared to no medication use:²⁴⁸

• for high blood pressure
  • a 72% increased risk when taken for 3 to 5 years
  • an 80% increased risk when taken for more than 5 years
• for arterial diseases
  • a 65% increased risk when taken for 3 to 5 years
  • a 49% increased risk when taken for more than 5 years

Amphetamines, atomoxetine, lisdexamfetamine, methylphenidate, and viloxazine increase hemodynamic parameters in children, adolescents, and adults. The mean increase compared to 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)²⁴⁹

• 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

3.4.33. Heart Problems as a Comorbid Condition of ADHD¶

A Swedish long-term study spanning 14 years with n = 62,060 participants on the risks of certain cardiovascular diseases associated with long-term use of ADHD medication found the following, compared to no medication use:²⁴⁸

• No increased risk of cardiac arrhythmias, heart failure, ischemic heart disease, thromboembolic diseases, or cerebrovascular diseases
• 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 during the first year

A Swedish long-term study spanning 15 years with n = 112,605 participants and n = 563.024 matched controls aged 5 to 30 years (median age 20 years) found that ADHD medications increased the risk of cardiac events:²⁵⁰

• by 63% for cardiac events overall
• 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 ADHD itself and to what extent ADHD medication contributed to the findings.

ADHD itself increases the risk factors for cardiovascular problems.²⁵¹

3.4.34. Epilepsy Comorbid with ADHD¶

Methylphenidate appears to be the best option for treating ADHD in patients with epilepsy and is associated with a low risk of worsening seizures.²⁵²²⁵³ In addition to MPH, AMP or atomoxetine can also be administered with a low risk.²⁵⁴
Any tendency toward seizures should be properly treated before administering stimulants.⁵¹

Anti-epileptic medications themselves can either worsen or improve the symptoms of ADHD.
A worsening of ADHD symptoms has been reported with the following epilepsy medications:⁵¹

• Valproate (strong evidence of impaired attention)²⁵⁵²⁵⁶
• Phenobarbital
• Phenytoin
• Topiramate
• Zonisamide
• Perampanel
• Ethosuximide

An improvement in ADHD symptoms has been reported for the following epilepsy medications:⁵¹

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

Whether ADHD symptoms improve or worsen depends on:⁵¹

• Levetiracetam²⁵⁵

3.4.35. Dissociative Disorders Comorbid with ADHD¶

Positive effects of sustained-release MPH on dissociative states in patients with comorbid ADHD have been reported in several individual cases.²⁵⁷ A case study reports a beneficial effect of mixed amphetamine salts.²⁵⁸

3.4.36. Raynaud¶

ADHD medications can trigger or worsen Raynaud’s.²⁵⁹ Amphetamine-based medications appear to be more commonly associated with this condition than methylphenidate and atomoxetine; guanfacine was not mentioned.²⁶⁰ 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 has been observed less frequently with atomoxetine than with stimulants.
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.

3.4.37. Intellectual Disability¶

In cases of intellectual disability, a lower medication dosage is often required, or there may be a higher sensitivity to side effects.²⁶¹⁵¹ In addition, people with ADHD often have more difficulty communicating side effects.

4. Choosing Medications Under Other Conditions¶

4.1. Giftedness¶

Highly gifted individuals are said to respond better to amphetamine-based medications than to MPH.²⁶²
Giftedness is not a comorbidity.

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

• Atomoxetine is not suitable

A study examined the EEG patterns of atomoxetine responders and nonresponders. According to the study, atomoxetine is more effective in individuals who have increased alpha and delta power in the frontal and temporal regions and who, at the same time, show no abnormalities in the beta and theta bands. Atomoxetine non-responders, on the other hand, exhibit reduced absolute power across all EEG frequencies or increased alpha power accompanied by increased beta power. Over the long term, atomoxetine led to a normalization of the elevated alpha and delta values, whereas these remained unchanged in non-responders. In cases where alpha, beta, and theta values were all elevated simultaneously, atomoxetine appeared to be unsuitable.²⁶³
If there is increased alpha and delta power in the frontal and temporal regions and unchanged power in the beta and theta bands, atomoxetine is not considered unsuitable. This does not address whether amphetamine-based medications, MPH, and guanfacine are not preferable due to their greater effect size.

4.3. COMT Met-158-Met¶

If a person has the COMT Met-158-met polymorphism, amphetamine-based medications are considered unsuitable.
In individuals with the COMT Val-158-Met gene polymorphism, amphetamine increased the efficiency of prefrontal cortex function in subjects with presumed low dopamine levels in the PFC. In contrast, in individuals with the COMT Met-158-Met polymorphism, amphetamine had no effect on cortical efficiency under low- to moderate-level working memory load and caused a decline under high working memory load. Individuals with the Met-158-Met polymorphism appear to have an increased risk of an adverse reaction to amphetamine.²⁶⁴

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

4.4. Pregnancy¶

Human studies have shown that taking ADHD medications during pregnancy does not increase the risk of birth complications, developmental disorders, or neurological developmental disorders in the child.²⁶⁵²⁶⁶
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.²⁶⁷

However, it was found that when taking pregnancy medications

• for MPH
  • a slight increase in congenital heart defects²⁶⁸
• an increased risk of²⁶⁹ for AMP
  • Premature births
  • low birth weight

AMP, amphetamine-based medications, and atomoxetine cross the placenta.^{270271 272 273 274} The prescribing information for Vyvanse advises breastfeeding women not to take amphetamine-based medications.²⁷⁵

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.²⁷⁶²⁷⁰
MPH increased the risk of cardiovascular problems in children from 1.07% to 1.7% (+59% at a low absolute risk).²⁷⁰
There is very little data available on atomoxetine and guanfacine during pregnancy.²⁷⁶
Clonidine, when used as a blood pressure medication during pregnancy, did not cause any serious side effects.²⁷⁶²⁷⁰
Most 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.²⁷⁶

Methylphenidate and atomoxetine did not alter the already elevated risk of spontaneous miscarriage associated with ADHD.²⁷⁷ (meta-analysis, n = 30,830).²⁷⁸ Likewise, they did not significantly increase the risk of congenital malformations (+14%) (meta-analysis, n = 30,830).²⁷⁸
MPH and ATX increased the risk of an Apgar score below 10 by 106% (aRR 2.06), whereas children of women with ADHD who did not take these medications during pregnancy did not have an increased risk (aRR 0.99).²⁷⁹
Methylphenidate is considered relatively safe during pregnancy.²⁸⁰

4.5. Breastfeeding¶

Amphetamines pass into breast milk.²⁸¹
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. High doses of amphetamines can impair milk production.²⁸²²⁸³ Since it cannot be ruled out that amphetamines are also metabolized via CYP2D6, and since newborns barely have any CYP2D6 activity during the first 3 months of life, amphetamine medications should not be used during pregnancy or during the first 3 months of a newborn’s life while the infant is being breastfed. The American Academy of Pediatrics (AAP) advises against the use of amphetamine medications while breastfeeding.²⁸⁴
While methylphenidate is considered relatively safe during breastfeeding, amphetamines and lisdexamfetamine are contraindicated due to the potential for accumulation in the infant during breastfeeding.²⁸⁰

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 that stimulants used to treat ADHD were associated with a short-term increase in cardiovascular problems; however, long-term use was possible without any issues.²⁸⁵
Another study found (on average) an increase in heart rate but no increase in blood pressure and, otherwise, no adverse effects associated with the use of stimulants in older adults. AMP clearance was slightly reduced²⁸⁶, so a lower and slower dose is recommended.

4.7. Heat Stress¶

In cases of passive heat stress (high ambient temperature), MPH is less effective or has no effect.²⁸⁷

5. Different Mechanisms of Action of ADHD Medications¶

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

The active ingredients methylphenidate (MPH), d-amphetamine (d-AMP), l-amphetamine (l-AMP), and atomoxetine (ATX) bind with varying affinities to dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT). This binding inhibits the activity of the respective transporters.²⁸⁸

Binding affinity: higher for smaller numbers (KD = Ki)	DAT	NET	SERT
MPH	34 - 200	339	> 10,000
d-AMP (Vyvanse, Attentin)	34–41	23.3–38.9	3,830–11,000
l-AMP	138	30.1	57,000
ATX	1451–1600	2.6–5	48–77

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 modified from Madras,²⁸⁸.

	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.

See the section on 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