Medications for ADHD - Overview

Completely revised 09/2026

 

All of the medications described here should always be prescribed only by experienced physicians. Our comments are intended solely to serve as a starting point for a personal consultation with your doctor.

This article provides an overview of the classes of active ingredients used to treat ADHD. Each active ingredient is discussed on its own page.

(E 4): Since ADHD symptoms originate almost exclusively from the dopaminergic and noradrenergic systems, a combination of dopaminergic and noradrenergic medications is recommended. (E 4)¹(E 4)²(E 4)³(E 4)⁴(E 4)⁵
Stimulants—specifically methylphenidate and amphetamine-based medications—are the most effective. They increase the availability of dopamine and norepinephrine. Non-stimulants, such as atomoxetine and guanfacine, are the next most effective. They have a weaker effect but provide a more consistent level of relief throughout the day. Serotonergic medications (SSRIs) do not improve the core symptoms of ADHD, but they may be useful when depression is also present. Tricyclic antidepressants are considered a fifth-line treatment. Antipsychotics are indicated for ADHD only in exceptional cases. MAO inhibitors play barely any role in ADHD treatment.

Since ADHD symptoms primarily stem from the dopaminergic and noradrenergic systems, a combination of both types of medication is often used. Dopaminergic medications tend to target attention and motivation, while noradrenergic medications tend to target outbursts of anger, emotional impulse control, alertness, and sustained attention.

The short-term benefits are well documented. In children and adolescents, all approved active ingredients significantly improved symptoms, with amphetamine-based medications and methylphenidate showing the greatest effect. In adults, stimulants and atomoxetine were effective. There are barely any studies covering a period longer than six months, but clinical practice indicates long-term efficacy.

In addition to alleviating core symptoms, ADHD medications also improve the impact of the disorder on daily life. In large registry studies, suicide attempts, substance abuse, traffic accidents, and criminal offenses occurred less frequently among those on medication; academic performance was better; and mortality rates were lower. The effects are small to moderate in each case and do not eliminate the disadvantages compared to those without ADHD.

Medications do not cure ADHD. They compensate for the underlying dysfunction as long as they are taken, much like a pair of glasses that corrects an existing vision problem as long as they are worn.

Tolerability varies between the groups. Stimulants are more likely to cause a loss of appetite and difficulty falling asleep, while non-stimulants are more likely to cause fatigue. Blood pressure and heart rate rise slightly with both groups and should be monitored. Guanfacine lowers them. No link to cardiovascular disease could be established. Tics and anxiety do not increase with stimulants. High doses of amphetamine-based medications increase the otherwise rare risk of psychosis and mania, which is not the case with methylphenidate.

Increasing the dose beyond the maximum approved levels does not improve the average effect but does reduce tolerability. The values listed are group averages; individual people with ADHD may require and tolerate higher doses.

Adherence to medication is low. One year after starting treatment, only about two-thirds of children and just under half of adolescents and adults are still taking their medication; after five years, the number is significantly lower. Educating patients about the medication and keeping a record of their intake improve adherence, whereas simple reminder systems do not. Accompanying psychotherapy reduces the dropout rate.

When titrating stimulants, caffeine should be completely avoided, because otherwise cross-reactions may be mistakenly interpreted as an intolerance to the stimulants.

A significant proportion of the people with ADHD who were actually treated would not have been eligible for the clinical trials—about three-quarters of the adults. The study results can therefore be applied to real-world clinical practice only to a limited extent.

Of 4,948 students aged 7 to 17 who had received an administrative ADHD diagnosis in 2020 (average age 12.4 years, 74.9% boys), 40.3% were currently receiving psychological, psychotherapeutic, or psychiatric treatment for ADHD. The parents of these 1,994 children and adolescents receiving treatment reported (E 3)⁶

• 76% satisfaction with treatment
• 36.8% said the treatment was very effective
• 49.6% said the treatment was somewhat effective
• 11.3%, saying the treatment was barely effective
• 2.3%, the treatment is not effective at all
• Children with more severe ADHD symptoms were nearly three times more likely to receive treatment (OR 2.82).
• Children and adolescents from immigrant backgrounds were less likely to receive treatment (OR 0.64).

1. Medications That Affect the Stress Response¶

By “influencing the stress response,” we do not mean sedative or other general effects, but rather the effects of medications on the response of stress regulation systems.

1.1. Anxiolytics¶

Anxiolytics (anti-anxiety medications) generally reduce the reactivity of stress systems even with a single dose. (E 4)⁷

1.2. Antidepressants¶

Single doses of antidepressants have effects on the stress systems that are partly inhibitory and partly stimulating. (E 4)⁷

1.3. Stimulants¶

A stimulant effect alone is not sufficient for the drug to be effective in treating ADHD. According to Dodson, pseudoephedrine and ephedrine have the same stimulant mechanism of action but no measurable effect on ADHD symptoms. Dodson further states that L-methylphenidate is about six times as stimulating as D-methylphenidate, but that only the D-enantiomer is effective for ADHD. (E 4)⁸

Dodson does not cite a source for the 6-fold figure. Primary studies do not support this claim. L-threo-methylphenidate bound predominantly nonspecifically in human and baboon brains and did not increase dopamine levels in the rat striatum, whereas D-threo-methylphenidate increased them by 650%.(E 2b⁹ D-methylphenidate is approximately 10 times more potent than the L-enantiomer. (E 4)¹⁰¹¹

A network meta-analysis of double-blind randomized trials compared amphetamine medications, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil. In children and adolescents, after 12 weeks, all active ingredients studied were superior to placebo according to clinician assessment: amphetamine medications with an SMD of 1.02 (95% CI 1.19 to 0.85), methylphenidate at 0.78 (0.93 to 0.62), and atomoxetine at 0.56 (0.66 to 0.45). According to teacher assessments, only methylphenidate (0.82) and modafinil (0.76) were more effective than placebo. In adults, amphetamine medications (0.79), methylphenidate (0.49), bupropion (0.46), and atomoxetine (0.45) were more effective than placebo; modafinil was not. Amphetamine medications were less well tolerated than placebo (OR 2.30 in children and adolescents, 3.26 in adults). (Network meta-analysis, k = 133, N = 18,199, E 1a)¹²
In adults, after 12 weeks, stimulants alone (clinician-rated SMD 0.61, self-report SMD 0.39) and atomoxetine (0.51 and 0.38, respectively) consistently improved core ADHD symptoms in both assessment methods after 12 weeks. Atomoxetine was less well tolerated than placebo (OR 1.43), whereas stimulants were not. Psychological and neurostimulation interventions were effective only in clinician-rated assessments, not in self-rated assessments. (Component network meta-analysis, k = 113, N = 14,887, E 1a)¹³
A meta-analysis on quality of life found that amphetamine medications were superior to placebo (Hedges g = 0.51, 95% CI 0.08 to 0.94), methylphenidate (0.38, 0.23 to 0.54), and atomoxetine (0.30, 0.19 to 0.40). The effect sizes were significantly lower than those for core symptoms (meta-analysis, k = 17, N = 5,388, E 1a)¹⁴

A network meta-analysis compared pharmacological and nonpharmacological interventions in children and adolescents at the classroom level. Behavioral therapy, stimulants, and nonstimulants were more effective than placebo. Behavioral therapy combined with stimulants was more effective than stimulants or non-stimulants alone. Stimulants were more effective than behavioral therapy, cognitive training, and non-stimulants. The effective medications were associated with reduced appetite, weight loss, and difficulty falling asleep, but not with an increased risk of serious adverse events (network meta-analysis, k = 190, N = 26,114, E 1a)¹⁵
ADHD symptoms also improved significantly with placebo, with an SMD ranging from 0.36 to 0.75 depending on the assessor. The placebo response was greatest as assessed by clinicians and correlated positively with the efficacy of the active treatment. Side effects also occurred with the placebo (nocebo response). Effect sizes relative to the placebo therefore do not reflect the full extent of improvement achieved with medication. (Meta-analysis, k = 128, N = 19,753, E 1a)¹⁶

Over a treatment period of at least one week, methylphenidate improved all cognitive domains examined (attention, inhibition, reaction time, working memory) compared to placebo, with Hedges’ g values ranging from 0.34 to 0.59. Atomoxetine improved all domains except working memory (g = 0.36 to 0.64). No difference was observed between stimulants and non-stimulants (meta-analysis, k = 25, N = 2,496, E 1a).¹⁷
Of the 189,699 people with ADHD in Sweden who began taking medication, 53% would have been excluded from the clinical trials, including 74% of adults, 35% of adolescents, and 21% of children. This subgroup of people with ADHD changed medications more frequently (HR 1.14, 95% CI 1.12 to 1.16), discontinued medication slightly less often (0.96, 0.94 to 0.98), and had significantly higher rates of psychiatric hospitalizations (IRR 9.68), specialist consultations for substance use disorders (14.78), depression (6.00), and anxiety disorders (11.63). This limits the generalizability of the study results to clinical practice. (Registry study, N = 189,699, E 2b)¹⁸

 In children and adolescents, the mean efficacy increased up to 45 mg/day of methylphenidate, 25 mg/day of amphetamine-based medications, and 4 mg/day of guanfacine; beyond these doses, no additional benefit was observed. In adults, amphetamine medications reached a plateau at doses above approximately 50 mg/day, while methylphenidate did not reach a plateau at that level. The probability of discontinuation due to side effects increased in a dose-dependent manner for amphetamine-based medications (above 25 mg/day in children, 50 mg/day in adults) and for methylphenidate in adults (above 50 mg/day). No dose-response pattern was found for atomoxetine and modafinil. The figures represent group averages; people with ADHD may require and tolerate higher doses (dose-response network meta-analysis, k = 113, N = 25,154, E 1a).¹⁹
In preschool-aged children, stimulants improved ADHD symptoms compared with placebo (SMD 0.59, 95% CI 0.77 to 0.41). The discontinuation rate did not differ from that of placebo (meta-analysis, k = 5, N = 489, E 1a)²⁰

In 87 randomized, placebo-controlled trials involving 18,924 participants and lasting 3 to 28 weeks, medication treatment improved ADHD symptoms by 7.35 scale points compared with placebo (95% CI 6.64 to 8.06). The duration of treatment did not affect efficacy (meta-analysis with meta-regression, k = 87, N = 18,924, E 1a)²¹

In adults, medication improved ADHD symptoms with an SMD of 0.45 (95% CI 0.37 to 0.52). Stimulants were more effective than nonstimulants (difference in SMD 0.18). Clinicians rated the effect as significantly greater than patients did (difference in SMD 0.44), and the effect was greater in shorter studies than in longer ones. Adverse effects occurred more frequently than with placebo (OR 2.29, 95% CI 1.97 to 2.66). Slightly more people with ADHD discontinued treatment than with placebo (OR 1.18, 95% CI 1.02 to 1.36). In studies with concomitant psychotherapy, discontinuation rates did not differ from those of placebo (OR 0.91); in studies without psychotherapy, they were higher (OR 1.27) (meta-analysis with meta-regression, k = 44, N = 9,952, E 1a)²²

 

In an analysis of treatment records for 113 people with ADHD aged 55 to 79, 65% responded positively to stimulant medication. 42% discontinued the medication due to side effects or lack of response. Weight and heart rate changed slightly but significantly (weight loss, increased heart rate). Monitoring of cardiovascular parameters before and during treatment is necessary in older adults (retrospective medical record analysis, N = 113). (E 3)²³

Between 2015 and 2019, the use of ADHD medications increased by 9.72% annually (95% CI 6.25 to 13.31) in 64 countries, from 1.19 to 1.43 defined daily doses per 1,000 inhabitants per day. The increase was limited to high-income countries. In 2019, consumption in these countries stood at 6.39, while in upper-middle-income countries it was 0.37 and in lower-middle-income countries 0.02 daily doses per 1,000 inhabitants per day. In most middle-income countries, consumption is thus well below compared to The epidemiological prevalence of ADHD (longitudinal study, 64 countries, E 2b)²⁴

1.3.1. Stimulants and Stress Resistance¶

Stimulants increase the reactivity of stress systems. (E 4)⁷
In an fMRI study, children with ADHD showed an elevated motivational threshold at which task-relevant stimuli deactivate the DMN. Under methylphenidate, this threshold normalized, and the task-related DMN deactivation was then indistinguishable from that of typically developing children.(E 2b)²⁵ This could (partly) explain why stimulants are just as helpful for ADHD-HI and ADHD-C as they are for ADHD-I. For more information on the altered function of the DMN in ADHD and its normalization through stimulants, along with additional references, see ⇒ DMN (Default Mode Network) In the article ⇒ Neurophysiological Correlates of Hyperactivity.

1.3.2. Stimulants and Emotions¶

Barkley (E 4)²⁶ explained in a lecture that stimulants can dampen emotions by inhibiting the limbic system. The higher the dosage, the more strongly the limbic system (including the amygdala) is inhibited. This naturally reduces emotional responses.
Taking too high a dose of stimulants therefore leads to a narrowing of emotions.
He goes on to report that, for this reason, combination therapies consisting of lower doses of both stimulants and non-stimulants are being used more and more frequently. We believe this is a sensible approach to preserve the major benefit of stimulants (stimulation), limit their drawbacks or side effects, and add the benefits of non-stimulants (full-day coverage).

Stimulants and atomoxetine improved emotional lability in adults, with an SMD of 0.41 (95% CI 0.57 to 0.25). The same studies showed improvements in core ADHD symptoms with an SMD of 0.80 (1.07 to 0.53), representing an effect approximately twice as large (meta-analysis, k = 9, E 1a)²⁷

1.3.3. Long-term compliance (phases of medication use)¶

In an Australian longitudinal cohort, 166 of 4,634 children (3.6%) had ever filled a prescription for ADHD medication. The mean medication coverage between the first and last filled prescription was 59.8%. It was highest in the first year of treatment, then declined steadily, and did not rise again until after 5 to 6 years of treatment. (E 2b)²⁸

Our hypothesis is that this return to increased intake could possibly be mediated, among other things, by the following mechanism:

Stimulants have been shown to increase neuroplasticity by raising levels of dopamine and other neurotrophic factors. This enables better learning (i.e. knowledge acquisition) and better adaptation to experiences in the sense of internalizing and automating functional behaviors as an adjustment process to environmental experiences. More on this at ⇒ Neurophysiological Correlates of Learning Problems in ADHD.
Taking stimulants now makes it possible to adapt functional behaviors to current demands.
If this adaptation has occurred sufficiently after a few years, a short-term discontinuation of stimulants will not lead to immediate behavioral deficits, since the currently stored behavioral patterns are now adapted to the current environment and therefore continue to function at the moment even without medication.
However, if medication is not taken consistently, the ongoing need to adapt behaviors to new environmental demands goes unmet. As environmental demands gradually change, the stored behaviors—which were optimized for earlier environmental demands—become increasingly dysfunctional. Once the difficulties have reached a certain level again, the psychological distress serves as a reminder that the medication was very effective in alleviating these difficulties at the outset, leading to a resumption of medication use.

Parents of children with ADHD cited concerns about side effects, weight loss, and a feared developmental delay as the main reasons for opposing medication. The adolescents predominantly cited a different reason: the desire to develop freely without medication. (Qualitative focus group study, 3 groups with 23 parents, 2 groups with 11 adolescents, E 3)²⁹

A multinational analysis of prescription registries found that one year after the start of treatment, 65% of children, 47% of adolescents, 39% of young adults, and 48% of adults were still taking ADHD medications. After five years, these figures were 24%, 9%, 10%, and 15%. Resumption of treatment after a break was common (registry study, multinational, E 2b)³⁰

 

In randomized trials, interventions to improve medication adherence increased adherence (OR 2.39, 95% CI 1.19 to 4.79) and reduced ADHD symptoms (Hedges’ g = -0.96, 95% CI -1.38 to -0.54). Education about the medication and medication logging were effective, whereas simple reminder systems were not (meta-analysis, k = 6, E 1a)³¹

Medication breaks are practiced by 25% to 70% of families, primarily during school vacations. They serve to assess the ongoing need for treatment as well as to manage side effects and the development of tolerance. Longer breaks had a beneficial effect on physical growth, while shorter breaks reduced difficulty falling asleep and improved appetite (Systematic Review, k = 22, E 4)³²

2. Dopaminergic medications¶

Dopaminergic medications play a leading role in the treatment of ADHD, as most symptoms are caused by a dopamine (or dopamine receptor) deficiency in the dlPFC and striatum.

In addition to psychotherapeutic interventions, dopaminergic medications have the added benefit of increasing the brain’s neuroplasticity, thereby supporting the effectiveness of therapy or facilitating a state conducive to therapy. (E 4)³³
(E 2b): About 5% of dopamine is metabolized into norepinephrine, so dopaminergic medications always have a (albeit minor) noradrenergic effect as well. (E 4)³³(E 2b)³⁴

Dopaminergic medications target the anterior attention center.
⇒ The dopaminergic and noradrenergic attention centers.

3. Noradrenergic medications¶

Norepinephrine is produced in the nucleus coeruleus and, among other things, regulates the posterior attentional center in the parietal cortex.
⇒ The dopaminergic and noradrenergic attention centers.

3.1. Medications that increase norepinephrine levels¶

Norepinephrine reuptake inhibitors inhibit the norepinephrine transporter (NET). Although the NET generally reabsorbs primarily norepinephrine—thereby increasing the amount of norepinephrine available in the synaptic cleft— In the PFC, however, it reabsorbs more dopamine than norepinephrine, so norepinephrine reuptake inhibitors primarily exert dopaminergic effects in the PFC in the context of ADHD.

Pure norepinephrine reuptake inhibitors are the “second-line” treatment alongside stimulants with dopaminergic and noradrenergic effects. However, they may supplement treatment with MPH when appropriate.
MPH, amphetamine-based medications, and atomoxetine each exert dopaminergic and noradrenergic effects; however, atomoxetine exerts noradrenergic and dopaminergic effects only in the PFC, whereas MPH also exerts dopaminergic effects in the striatum.
⇒ Atomoxetine works differently than MPH

3.2. Effects of Noradrenergic Medications¶

People with ADHD subjectively describe the effect of noradrenergic medications as widening the “green zone” between being underchallenged (which causes the person with ADHD to mentally tune out) and being overwhelmed (which drives the person with ADHD into a state of stress). A sense of balance increases. Emotional outbursts (rages, emotional overreactions) decrease.

Noradrenergic medications improve ADHD symptoms

• Emotional outbursts (outbursts of anger)
• emotional impulse control
• Alertness
• Vigilance

Dopaminergic medications cannot directly affect these symptoms (if at all, it is through norepinephrine, which is produced when dopamine is broken down).
Amphetamine-based medications are also said to be helpful in this context. (E 4)³⁵

An augmentative, optimally adjusted regimen with noradrenergic medications can subjectively double the benefits provided by methylphenidate. (Some) people with ADHD report that an optimally adjusted dosage, in combination with stimulants, completely eliminated their ADHD symptoms. Unfortunately, this effect was temporary, suggesting receptor up- or downregulation (see 2.4.).

When used as monotherapy, alpha-2 agonists improved overall ADHD symptoms (SMD 0.59), hyperactivity and impulsivity (0.56), inattention (0.57), and oppositional symptoms (0.44). When used as an adjunct to stimulants, the effects were smaller (0.36, 0.33, and 0.34). When used as monotherapy, they were discontinued less frequently due to lack of efficacy than placebo (RR 0.39). Fatigue, sedation, and drowsiness occurred more frequently, as did blood pressure-lowering and heart rate-lowering effects. When used as an adjunct to stimulants, discontinuation rates were similar to those of placebo, but drowsiness occurred more frequently. Eight of the 12 included studies were industry-funded. (Meta-analysis, k = 12, N = 2,276, E 1a)³⁶

3.3. Onset of action of noradrenergic medications¶

Primarily noradrenergic medications generally need to be administered for 2 to 3 weeks before they take effect.
Noradrenergic medications should be tapered off gradually over the same period of time to prevent depression.
Because of the slow response to a new dosage, noradrenergic medications should not be increased, skipped, or discontinued on short notice.
The onset of action is similar to that of medications that inhibit serotonin reuptake.

3.4. The Long-Term Effects of Noradrenergic Medications Are Problematic¶

The effects of noradrenergic medications may diminish somewhat over time (unlike those of stimulants).

We suspect that most noradrenergic medications have a tonic effect, i.e., they cause a long-term increase in NE levels. However, ADHD symptoms improve only with a transient increase in norepinephrine levels. A tonically elevated NE level is actually counterproductive. (E 4)³⁷
Many people with ADHD have reported a short-term positive effect from noradrenergic medications (e.g., nortriptyline), which took effect after just a few doses but wore off after a few days. Some individuals have also reported this as an individual reaction to atomoxetine.

This is followed by Scheidtmann’s observation that noradrenergic medications (e.g., antidepressants) do not help with motor rehabilitation when used as long-term treatment, since tricyclic antidepressants permanently stimulate the noradrenergic receptors, causing the receptors to lose their sensitivity (particularly with regard to learning processes). (E 4)³⁸
This is consistent with the experience regarding the use of noradrenergic tricyclic antidepressants for ADHD. It is often reported that patients initially respond very well to these medications, but that this response diminishes with continued treatment.

While dopaminergic medications can be safely discontinued for hours or days at a time, or increased for a short period, as needed, this is not recommended for noradrenergic medications. Noradrenergic medications carry a risk of depression if taken in excessive doses or if the dosage fluctuates erratically.

A clearly structured daily routine, with a balanced alternation of activity and breaks, is intended to train the noradrenergic system and help restore normal norepinephrine production. (E 4)³⁹

3.5. Contraindications¶

Benzodiazepines reduce activity in the locus coeruleus ** , thereby decreasing the production and transport of norepinephrine to other parts of the brain. For this reason, they should generally be contraindicated for ADHD. Nevertheless, they are helpful in the short term. Their potential for dependence is significant and can develop within just a few weeks of regular use, which is why they should not be prescribed for ADHD. MPH and amphetamine-based medications have no significant potential for dependence when taken orally as directed at therapeutic doses.

In addition, there are other secondary and interactive effects.

4. Serotonergic medications¶

A review identified 24 active ingredients with a serotonergic mechanism of action that were investigated for ADHD. Sixteen of these failed in clinical trials or were not further developed. None of them were approved for ADHD. (E 4)⁴⁰

 

4.1. General Information About SSRIs¶

4.1.1. Onset of Action of Serotonergic Medications¶

Although serotonergic medications alter serotonin levels very rapidly, they generally need to be taken for 2 to 3 weeks before they take effect. It can therefore be assumed that serotonin levels themselves do not mediate the actual effect.

Serotonergic medications should be tapered off gradually over at least the same period of time to avoid side effects. According to other reports, tapering off serotonergic medications can take more than half a year. We have now received numerous reports from people with ADHD who derived little benefit from antidepressant medication but who suffered severe side effects—particularly when discontinuing antidepressants—that were many times more severe than the side effects of ADHD medications.

Because of the slow response to changes in dosage, serotonergic medications should not be increased, skipped, or discontinued on short notice.

4.1.2. SSRIs and σ-Receptors¶

4.1.3. Single doses of SSRIs prolong anxiety¶

A single dose of escitalopram (10 or 20 mg) did not alter anxiety before or during a simulated public speaking task in 43 healthy men, but it prolonged the anxiety that followed the task.(E 1b)⁴⁵ Anxiety and tension were also increased by a single dose of chlorimipramine (clomipramine), a tricyclic antidepressant that acts primarily as a serotonin reuptake inhibitor (E 2b)⁴⁶, but also acts as an antagonist of the histamine H1 receptor, the muscarinic acetylcholine receptor, and the α1-adrenergic receptor. (E 4)⁴⁷

4.1.4. SSRIs increase oxytocin levels¶

4.1.5. SSRIs require histamine¶

4.1.6. Antidepressants work via PPARα¶

4.2. Notes on Selective Serotonin Reuptake Inhibitors (SSRIs) for ADHD¶

SSRIs (selective serotonin reuptake inhibitors) should be used with caution in cases of ADHD.
Clinical experience does not support the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating the core symptoms of ADHD. (E 4)⁵³

4.2.1. The Difference Between Dysphoria as a Common Symptom of ADHD and Depression That Requires Treatment¶

Many clinicians do not recognize dysphoria associated with inactivity as a primary symptom of ADHD; instead, they confuse it with dysthymia or depression and therefore treat people with ADHD inappropriately, as if they had true depression.
However, dysphoria during inactivity is a functional stress symptom (the drop in mood during inactivity is intended to encourage the person with ADHD to remain active until the stressor is overcome) and is typical of ADHD. It is not a symptom of dysthymia or depression.
Differential Diagnosis of Depression and Dysphoria Associated with Inactivity ⇒ Depression and Dysphoria in ADHD.

In practice, it has been shown that treatment with a significantly reduced dose of escitalopram (compared to its use as an antidepressant) can improve dysphoric mood. In this context, doses of 2 to 5 mg per day may already be sufficient (instead of 10 to 20 mg when used as an antidepressant).
However, simply switching ADHD treatment from methylphenidate to amphetamine-based medications (Vyvanse) often provides a fully adequate improvement, and this approach is therefore strongly preferred.
Unlike in ADHD-HI, treatment of dysphoria with SSRIs should be avoided in ADHD-I. In ADHD-I, SSRIs should only be considered in cases of severe depression.

4.2.2. SSRIs Do Not Improve Attention¶

Unlike stimulants, selective serotonin reuptake inhibitors do not improve the core symptoms of ADHD. In an open-label case series of 11 people with ADHD and comorbid depression (7 children and adolescents aged 10 to 16, 4 adults aged 38 to 44), monotherapy with fluoxetine or sertraline improved depression in all people with ADHD but did not improve ADHD symptoms in any of them. Only the addition of a stimulant had an effect on ADHD symptoms. (E 4)⁵⁴
A Swedish registry study compared the results of the Swedish university entrance exam among 930 people with ADHD during periods when they were taking ADHD medication and when they were not. During periods of medication, scores were, on average, 4.80 points higher after adjusting for age and practice effects (95% CI 2.26 to 7.34, p < 0.001, scale 1 to 200). The same study found no corresponding effect for SSRIs. Among people with ADHD who had taken SSRIs, the difference between SSRI-use periods and SSRI-free periods was 2.37 points and was not statistically significant. (95% CI -0.88 to 5.63, E 4)⁵⁵

A Scottish cohort study of 766,244 schoolchildren found that children treated for ADHD were more likely than their peers to have special educational needs, poorer test scores, more unexcused absences, more school expulsions, and higher rates of unemployment after leaving school. No comparison was made between people with ADHD who were on medication and those who were not. (E 2b)⁵⁶

4.2.3. SSRIs increase the availability of DAT¶

In 17 healthy subjects, citalopram (40 mg/day) increased striatal DAT binding by 15% to 17% after 8 and 16 days.(E 2b)⁵⁷ Escitalopram increased striatal DAT availability by 20% in 19 people with ADHD, with a greater increase observed in younger people with ADHD than in older ones.(E 2b)⁵⁸ (E 1b): DAT binding also increased with escitalopram in patients with social anxiety disorder. (E 2b)⁵⁹(E 1b)⁶⁰ (E 4): Increased DAT availability would be detrimental in ADHD. (E 4)⁶¹(E 4)⁶²

A comparable increase was observed in 10 people with ADHD treated with paroxetine (20 mg/day) over a 6-week period. (E 2b)⁵⁷ Paroxetine also influenced measurements of striatal DAT binding in healthy individuals. (E 1b)⁶³
Venlafaxine (150 mg/day) increased striatal DAT binding by 10.1% in 8 healthy subjects after 5 days. (E 2b)⁶⁴
No change in DAT binding was observed with bupropion, either alone or as an augmentation to citalopram. (E 2b)⁵⁷

If sleep problems are also present (as is often the case with ADHD), medications that increase serotonin levels are also believed to be harmful. (E 4)⁶⁵

4.2.4. SSRIs increase the cortisol stress response: beneficial in ADHD-HI, detrimental in ADHD-I¶

In 43 healthy men, a single 20-mg dose of escitalopram—but not a 10-mg dose—increased cortisol and prolactin release immediately after a simulated public speaking test. The test alone did not significantly alter cortisol and prolactin levels. (E 1b)⁴⁵ A single dose of escitalopram triggered a cortisol response even in the absence of a stressor, which was used as a measure of central serotonin availability.(E 2b)⁶⁶ A single dose of the 5-HT1A agonist ipsapirone (0.3 mg/kg) increased cortisol release in 8 patients with bipolar depression as well as in 26 controls, with no difference between the groups.(E 2b)⁶⁷ An infusion of the serotonin precursor tryptophan (50 mg/kg i.v.) triggered a cortisol release in 14 controls, but not in 11 euthymic patients with bipolar disorder. (E 2b)⁶⁸

At both 10 and 20 mg, escitalopram did not increase anxiety either before or during a stress test, but it did prolong it afterward. (E 1b)⁴⁵

When treating comorbid depression in ADHD, it is essential to be aware that an increased cortisol response to stress in people with ADHD-HI (who often have a flattened cortisol response, preventing the HPA axis from shutting down) can be beneficial, but may be detrimental from this perspective in people with ADHD-I (who very often have an excessive cortisol response).

Nevertheless, it is unclear whether the long-term effects of SSRIs (escitalopram)—which normalize HPA axis activity in approximately 50% of people with ADHD—are also effective for the ADHD-I subtype.

• The Depression League recommends SSRIs, particularly for atypical depression (E 4)⁷⁰, which, like the ADHD-HI subtype, represents an externalizing form of stress expression and correlates with a blunted cortisol stress response.
• (E 1a): The Handbook of Psychopharmacotherapy (E 4)⁷¹ points out that in cases of severe (here: melancholic) depression (which, like the ADHD-I subtype, exhibits an internalizing stress phenotype with an excessive cortisol response to an acute stressor) treatment with tricyclic antidepressants (primarily amitriptyline and clomipramine) or SNRIs (here, duloxetine and venlafaxine) is superior to treatment with SSRIs. (E 4)⁷²(E 1a)⁷³
• The suboptimal efficacy of SSRIs is further discussed in the section on the SSRI sertraline, which is said to be more effective than other SSRIs in treating severe melancholic depression. (E 4)⁷⁴
• Ritzmann also expresses criticism of SSRIs for treating melancholic depression in Schweizerische pharma-Kritik (E 4).⁷⁵

4.2.5. SSRIs for Impulsivity Issues in ADHD-HI¶

In one specific case, we observed a positive effect on impulsivity issues, such as those typically seen in ADHD-HI. Neurophysiologically, impulsivity correlates with low serotonin levels. Even a very low dose of escitalopram (2 to 5 mg, compared to the 10 to 20 mg/day used as an antidepressant (E 1b)⁷⁶) help reduce impulsivity, which may allow for a reduction in the dosage of concomitantly administered stimulants.

Impulse purchases, as seen primarily in ADHD-I, could, in our view, be attributed more to the urge for immediate reward and to spontaneous gratification of needs (as in addiction) rather than to externalizing impulsivity induced by low serotonin levels.

4.2.6. SSRIs Do Not Improve ADHD Symptoms¶

(E 4): SSRIs were ineffective for ADHD. (E 4)⁸(E 4)⁵⁴
A randomized, double-blind study of the multimodal serotonergic antidepressant vortioxetine (10 or 20 mg/day, n = 227) found no improvement in ADHD symptoms compared with placebo after 6 weeks. Symptoms improved by approximately 8 points on the AISRS in all groups; the primary endpoint was not met. However, both dosages improved functional status (Sheehan Disability Scale) compared with placebo. (E 1b)⁷⁷

The updated European consensus on the diagnosis and treatment of ADHD in adults logically concludes that SSRIs are not effective in treating ADHD. (E 4)⁷⁸

We are aware of reports from numerous people with ADHD who have taken SSRIs. None of them experienced a positive effect on their ADHD. Overall negative effects were frequently reported.
Particularly problematic are the several weeks it takes for any (antidepressant) effects to set in, and even more so the sometimes significant side effects associated with tapering off the medication, which in some cases require a very gradual tapering process (especially with venlafaxine).

One hypothesis is that the use of SSRIs for ADHD could be enhanced by combining them with 5-HT1A antagonists. The authors explain that the inhibitory somatodendritic 5-HT1A autoreceptors, which reduce the firing rate of 5-HT neurons, are desensitized only after long-term SSRI treatment. The authors speculate that previous studies did not observe medication use over a sufficiently long period and point to pharmacological studies in animal models in which the effect of SSRIs was successfully enhanced by antagonizing the inhibitory 5-HT1A autoreceptors prior to the administration of the SSRI fluoxetine.(E 4)⁷⁹
This hypothesis is contradicted by the fact that even cohort studies involving long-term medication use found no improvement in attention resulting from SSRIs.

4.2.7. SSRIs and Stimulants: Risk of Serotonin Syndrome¶

A combination of SSRIs and stimulants should be used with caution due to the risk of serotonin syndrome. (E 4)⁸⁰
At normal dosages, however, the serotonergic effect of stimulants is limited.

Serotonergic Mechanisms: (E 4)⁸¹

• Increases serotonin synthesis
  L-tryptophan
• Increases serotonin release
  • Amphetamines
    • only slightly effective for medication dosing
  • Cocaine
  • Methadone
  • Mirtazapine
• Serotonin reuptake inhibition
  • SSRI
  • SNRI
  • TZA
    • clomipramine, in particular
  • St. John’s Wort
  • Methadone
  • Pethidine
  • Tramadol
  • Fentanyl
  • Dextromethorphan
  • Buprenorphine
  • Tilidine
• Inhibition of serotonin breakdown
  • MAO inhibitors
  • Linezolid
  • Methylene blue
  • Procarbazine
• Direct serotonin agonists
  • Buspirone
  • Triptans
  • Ergotamines
  • LSD
• Increased serotonin receptor sensitivity
  • Lithium

Serotonin syndrome can result from an overdose of serotonergic medications, from a combination of multiple serotonergic medications, from metabolic interactions, or from interactions with opioids. It usually becomes apparent within 24 hours and typically subsides within 24 hours after discontinuing the triggering medication.
The severity of symptoms can vary greatly.
(E 4): Possible symptoms: (E 4)⁸²(E 4)⁸³(E 4)⁸¹

• Central nervous system symptoms
  • Agitation, restlessness, nervousness
  • Confusion
  • Hypomania
  • Impaired consciousness
  • Coma
  • Anxiety
  • Startle response
  • Delirium with confusion
  • drowsiness
• Autonomic-vegetative symptoms
  • rapid heartbeat
  • High blood pressure
  • high body temperature, fever
  • Sweating
  • Chills
  • Nausea, vomiting
  • Diarrhea
  • Abdominal pain
  • Pupil dilation
• Neuromuscular symptoms
  • Improved reflexes
  • Tremor
  • Ataxia
  • Tremors
  • Myoclonus (muscle twitching)
  • Muscle spasms
  • Muscle stiffness / Seizures
  • Clonus (a series of reflex muscle contractions following a stretch stimulus)

5. The Effectiveness of Antidepressants in Treating Depression¶

For general information on this topic, see the article Depression and Dysphoria in ADHD and, more specifically, under

• Effect of SNRIs on Depression via Corticosteroid Receptors *
• (Some) antidepressants work by inhibiting S-ASM (FIASMA)

6. Notes on Tricyclic Antidepressants for ADHD¶

Tricyclic antidepressants are considered the fifth-line choice of medication for ADHD. Tricyclic antidepressants have a very broad spectrum of action. They typically also

• noradrenergic
  • as a norepinephrine reuptake inhibitor (fairly potent) (E 4)⁸⁴
• dopaminergic
  • as a dopamine reuptake inhibitor (E 4)⁸⁵

(E 4): In double-blind, placebo-controlled studies, tricyclic antidepressants improved core ADHD symptoms in children and adults in the short term. (E 4)⁸⁶(E 4)³(E 4)⁸⁷(E 4)⁸⁸ There is no direct evidence of equivalence with stimulants. Combination therapy with stimulants and tricyclic antidepressants may be more effective than monotherapy, particularly for hyperactivity, inattention, and oppositional symptoms; however, regular cardiac examinations must be ensured.(E 4)⁸⁹

A Cochrane review identified 6 randomized, double-blind studies involving a total of 216 participants—primarily on desipramine—for children and adolescents. In these studies, tricyclic antidepressants were more likely to achieve a predefined improvement in core ADHD symptoms than placebo (OR 18.50, 95% CI 6.29 to 54.39; 3 studies, 125 participants). The quality of evidence was low to very low; no study was free of risk of bias. Only one of the 6 studies included methylphenidate as a comparator arm; a comparison of efficacy against stimulants was not calculated. (E 1a)⁹⁰

TZA should be administered in the event of nonresponse from

• both types of stimulants (methylphenidate and amphetamine-based medications)
• Guanfacine
• Atomoxetine

be a last choice of medication.

Tricyclic antidepressants are traditionally effective for comorbid anxiety, depression, and dysphoria. Imipramine is recommended for comorbid bedwetting (enuresis). (E 4)⁹¹

Another brief summary of studies on tricyclic antidepressants and other non-stimulant medications for ADHD-HI can be found in Budur et al. 2005. (E 4)⁹²

During treatment with tricyclic antidepressants, regular monitoring of the ECG, blood pressure, and heart rate is required. (E 4)³

Certain tricyclic antidepressants (trimipramine) and similar antidepressants (trazodone) have proven to be highly effective for treating sleep problems associated with ADHD. Unlike conventional sleep aids, they do not carry a risk of dependence.

7. General Information on Antipsychotics for ADHD¶

7.1. Dopaminergic Effects of Antipsychotics¶

Neuroleptics / antipsychotics act as D2 receptor antagonists, meaning they block the D2 receptor. However, they are not able to normalize the presynaptic increase in dopamine release that occurs in psychosis and schizophrenia; rather, they block the postsynaptic D2 receptor. This blockade is reversible—that is, it has a certain half-life—so the medication must be taken at regular intervals. A meta-analysis of raw data from SPECT and PET studies involving 139 people with ADHD found that both typical and atypical antipsychotics achieve high occupancy of D2 and D3 receptors in the temporal cortex, whereas only typical antipsychotics achieve high occupancy in the striatum. The clinically effective dose correlated with the dose producing maximum receptor occupancy in the temporal cortex (meta-analysis of individual patient data, N = 139, E 2b).⁹³(E 4)⁹⁴

(E 4): However, antipsychotics also appear to secondarily target D2 autoreceptors, thereby stimulating dopamine release (E 4)⁹⁵(E 4)⁹⁶
This is considered an adverse side effect in the treatment of psychosis with antipsychotics; therefore, it can likely be assumed to be a secondary effect.

In addition to blocking D2 receptors in the limbic system, atypical antipsychotics are also thought to stimulate D1 receptors in the prefrontal cortex (PFC), which is why they can be effective as ADHD medications in exceptional cases. (E 4)⁹⁷

At first glance, antipsychotics/neuroleptics are likely to be of little help in treating ADHD—from a dopaminergic perspective—since they primarily aim to reduce dopamine activity, whereas ADHD is characterized precisely by a dopamine deficit. The benefit for ADHD would likely stem from a side effect that occurs as an undesirable side effect during the treatment of psychoses.
An analysis of claims data found that antipsychotics were prescribed off-label for ADHD primarily in relation to comorbid behavioral disorders, but barely in relation to ADHD itself. (E 2b)⁹⁸
The mechanisms of action of stimulants and antipsychotics are potentially contradictory. A review study concluded that concerns regarding their concurrent use were justified and relevant, based on an examination of dopamine pathways and dopamine receptors. It reviewed the efficacy of concurrent use for several indications, with a focus on comorbid ADHD and aggression, and proposed a model of complex dopamine mechanisms to resolve the dilemma. (E 4)⁹⁹

7.2. α-Adrenergic effects of antipsychotics¶

Antipsychotics (D2 antagonists) are nevertheless believed to have a positive effect on ADHD at low doses, even though they reduce dopamine uptake. Antipsychotics are overwhelmingly prescribed off-label for children and adolescents. In a Dutch review of 436 initial prescriptions, only 5.5% had an indication approved by the EMA. (E 3)¹⁰⁰ (E 2b): However, the effect (at low doses) on ADHD is attributed not to a dopaminergic effect but to the blockade of the α-adrenergic receptor (antagonism), which positively stimulates the release of dopamine in the nucleus accumbens as well as dopamine uptake.(E 4)¹⁰¹(E 2b)¹⁰²(E 2b)¹⁰³

“The most common off-label use of antipsychotics (25%) is for ADHD.” (E 2b)⁹⁸

8. Monoamine oxidase inhibitors (MAO inhibitors)¶

Monoamine oxidase (MAO) catalyzes the breakdown of monoamines through deamination.
Monoamine oxidase inhibitors reduce the breakdown of monoamines, thereby increasing their availability.

MAO-A breaks down norepinephrine and serotonin in the brain and intestines. MAO-B breaks down dopamine in the brain and liver. MAO-A catalyzes the breakdown of tyramine ingested with food in peripheral tissues, primarily in the intestinal wall, while MAO-B performs a complementary role in the liver. Together, they prevent dietary tyramine from entering the bloodstream in significant amounts. (E 4)¹⁰⁸
Tyrosine is a precursor for the biosynthesis of DOPA, dopamine, catecholamines, melanin, thyroxine, and tyramine.
When taking irreversible MAO inhibitors, a low-tyramine diet is required (e.g., no aged cheese, no red wine). Without peripheral tyramine breakdown, dietary tyramine enters the bloodstream, where it releases norepinephrine. This can lead to hypertensive crises.

MAO inhibitors:

• Selegiline
  • irreversible MAO-B inhibitor.
    “Irreversible” means that MAO must first be resynthesized before it can become active again.
• Moclobemide
  • reversible selective MAO-A inhibitor.
    “Reversible” means that the effect is not permanent.
• Tranylcypromine
  • irreversible inhibitor of MAO-A and MAO-B
    Greek mountain tea (Sideritis scardica) is not an MAO inhibitor. In vitro, extracts inhibited the reuptake of serotonin, norepinephrine, and dopamine by their respective transporters in synaptosomes from rat brains (EC50 30 to 40 µg/ml), with alcoholic extracts showing greater inhibitory activity than the water extract. (E 2b)¹⁰⁹

9. Drug Tolerability in ADHD¶

Based on our observations and the data from the ADxS symptom test, ADHD always involves high sensitivity, which can sometimes be very pronounced. ASD is one of the most common comorbidities of ADHD. Highly sensitive people (even those without ADHD) and people with ADHD are more likely to have sensitive reactions to medications, and these reactions can sometimes be paradoxical.

Examples:

• Pain relievers can
  • have no effect at all
  • effective even at the lowest doses
• Sedatives can cause agitation
• Anesthetics can have unexpected effects
  We have heard of cases in which anesthetics are said to be effective at significantly lower doses. There is therefore a risk of overdose. We would appreciate it if anesthesiologists could share their relevant experiences with us.
• Caffeine has a more intense effect (even independent of any interactions with stimulants, which should, however, be avoided even more strictly in this context).
• Nicotine can make you feel tired instead of energized
  One person with ADHD reported that his bedtime ritual consists of two cigarettes or a cigarillo. Afterward, he has 20 to 30 minutes during which the nicotine makes him drowsy and allows him to fall asleep easily.
• A low dose of stimulants (1/3 to 1/2 of a single daytime dose) helps many people with ADHD fall asleep by counteracting racing thoughts

10. Drug Interactions with ADHD Medications¶

With ADHD medications (especially tricyclic antidepressants, MAO inhibitors, and medications that target the alpha-2 adrenoceptor), drug interactions are unfortunately common and must be taken into account.

One cross-reaction involving stimulants that receives far too little attention involves caffeine. In our experience, about half of all people with ADHD who are experiencing cross-effects when titrating stimulants due to caffeine may experience symptoms that feel like a stimulant overdose or significant stimulant side effects, even if they had previously tolerated caffeine on its own without any problems. Therefore, caffeine should be consistently avoided during the titration process for stimulants. Once titration is complete, caffeine is less dangerous even if the same cross-reactions occur, because the cross-reactions can then be easily attributed to the caffeine. People with ADHD who report “not tolerating” stimulants and who did not consistently avoid caffeine during the titration process should consider a new, slow titration without caffeine.

A fairly comprehensive overview of drug interactions involving ADHD medications, as well as precautions to take when prescribing and taking these medications, can be found in Steinhausen et al. (E 4)¹¹⁰