Dosage of Stimulants for ADHD

Completely revised 09/2026

We consider the approach described below to be fundamentally sound. However, these are merely considerations from a scientific perspective and cannot serve as therapeutic recommendations for individual cases.

In any case, a personalized treatment plan must be developed by a doctor or psychotherapist.

This information is not intended to encourage self-medication, but rather to help people with ADHD and their families better understand medical recommendations and to enable them to discuss the options described with their treating physician and therapist.

Each specific treatment must follow the instructions of the attending physician for that particular case.

What This Page Is About

An ADHD medication can only be effective if the dose is right. The appropriate dose varies from person to person. It cannot be calculated based on body weight, age, or the severity of symptoms. You have to find it. This process is called dose titration. This page describes how it works and what to keep in mind during the process.

The basic idea: start small, build up gradually

You start with a very low dose and increase it gradually. Each increment is maintained for a few days so that you can assess its effect. We recommend smaller increments and more persistence than is customary in many places. The reason: For some people with ADHD, the range within which ADHD medications work optimally is very narrow. Those who increase the dose in large increments may inadvertently skip over this range without realizing it.

More isn’t better

The effects of stimulants do not follow a linear pattern. They increase up to a certain point and then begin to decline, while side effects increase at the same time. Experts refer to this as an inverted U-curve. Therefore, the best dose is not the highest one you can tolerate, but the lowest one that produces a truly beneficial effect.

A particularly important warning: The first noticeable improvement does not yet indicate the correct dose. Many people with ADHD—and even some healthcare providers—stop increasing the dose at this point, thereby forfeiting a significant portion of the potential benefit.

Two things must be right: the size of the single dose and the coverage for the day

The single dose determines how strong a medication’s effect is. The number of single doses determines how long it remains effective throughout the day. Both must be adjusted separately. A common mistake is trying to compensate for a short duration of action by taking a higher dose. This leads to an overdose in the morning and does nothing to change the fact that the effect wears off in the afternoon. The correct approach in this case is to take an additional dose, not a higher one.

The goal is to provide coverage for the entire day, typically 12 to 16 hours. ADHD does not end with the school or workday. Homework, family life, and leisure time are also affected, and the risk of accidents is higher during the parts of the day when medication is not taken.

The manufacturer’s claims regarding duration of action are often inaccurate

How long a single dose lasts depends on how quickly the body metabolizes the active ingredient. This varies from person to person. About 15 to 20% of people with ADHD metabolize stimulants so quickly that a single dose lasts only about half as long as indicated. According to our surveys, about half of those taking lisdexamfetamine (Vyvanse) report that the effects last significantly shorter than the stated 12 hours. Those who are unaware of this may interpret the waning of the effect in the afternoon as a failure of the medication or as a personal failure. Every person with ADHD should therefore know how long their medication typically lasts and that this duration may vary for them.

Observe and write down

During the titration phase, you should keep a brief daily journal: symptoms, dose, times of administration, meals, sleep, and stress levels. It is important never to assess the effect based on individual days, but always on the average over three to four days. Individual days vary too much.

It’s also helpful to get a second opinion from an outside source. People with ADHD don’t always reliably notice changes in themselves. Feedback from people who don’t know about the medication is particularly insightful, because they don’t have any preconceived expectations.

Avoid caffeine and alcohol

This is the most important practical tip on this page. Caffeine and stimulants amplify each other’s side effects. An amount of coffee that was previously tolerated without any problems can trigger heart palpitations, tremors, and restlessness during the titration phase, which are then mistakenly attributed to the medication. In our experience, this repeatedly leads to an effective medication being discontinued unnecessarily. Caffeine must therefore be strictly avoided during the titration phase, including cola, black tea, energy drinks, and dark chocolate. Anyone who has consumed a lot of caffeine should expect withdrawal symptoms.

Alcohol significantly increases blood levels of methylphenidate and should also be avoided.

However, you should not quit smoking during the titration phase. Simultaneous nicotine withdrawal distorts the results and can cause withdrawal symptoms.

If it doesn’t fit

Not every medication works for everyone. About 30% do not respond to methylphenidate, and for about 20%, amphetamine-based medications are ineffective (“nonresponders”). Only a small minority does not respond to either active ingredient. If a medication isn’t effective, it’s worth first trying a different formulation of the same active ingredient and then switching to a different active ingredient. The same applies to side effects: Which medication a person tolerates well varies remarkably from person to person and is unpredictable.

Side effects are usually manageable

Most side effects occur during the first few weeks and then go away. When the dose is tailored to the individual, very few people with ADHD experience lasting symptoms. This page describes specific remedies for the most common symptoms: Headaches are often caused by low blood sugar and improve after eating. Difficulty falling asleep can usually be resolved by taking the last dose earlier. A feeling of emotional numbness (“zombie mode”) is generally a sign of an overdose and only rarely an unavoidable side effect of a medication—in any case, it is not a condition that one should simply put up with.

In women, the effect can vary throughout the menstrual cycle because estrogen influences dopamine breakdown. In the days leading up to menstruation, the need is often greater.

What You Can Expect from This Page

This page is very detailed and contains study data and figures in many places. It is primarily intended for healthcare providers. For people with ADHD, a brief summary can be found at the beginning of each major section under the heading “ : What This Means for People with ADHD” ( Bedeutung für Personen mit ADHD) and “What This Means for People with ADHD” (). More technically detailed passages are moved to expandable sections that begin with “ ” (Scientific) and “ ” (Scientific). Those who simply want to know what matters in practical terms can skip these sections.

A purely standardized medication regimen is not possible for ADHD. How the dosage is adjusted also depends on which medication is used. Stimulants, atomoxetine, and guanfacine each follow their own guidelines.

Initial efforts to use artificial intelligence to assist with medication dosing for ADHD are currently being researched. (E 2b)¹

1. Medication selection¶

For more information, see Choosing a Medication for ADHD or ADHD with Comorbidities

2. Dosage of Stimulants¶

2.1. Basics of stimulant dosage¶

(E 1a): In general, up-dosing that begins with low doses and increases them flexibly and individually offers a clear advantage over the administration of fixed doses.(E 4)² This has been known since the 1970s (E 4)³ and is confirmed by a new, comprehensive meta-analysis (E 1a)⁴. Studies also use a gradual titration to avoid side effects. (E 1b)⁵

(E 1a): With both MPH and AMP, as the dose increases, both efficacy and the likelihood of discontinuation due to side effects increase. In fixed-dose studies in children and adolescents, the additional benefit in efficacy decreased above approximately 30 mg of MPH or approximately 20 mg of AMP per day (converted to immediate release MPH hydrochloride or mixed amphetamine salts).(E 1a)⁴ In adults, this threshold is slightly higher: with MPH, the gains become smaller above about 35 to 40 mg/day; with AMP, the curve flattens out to a plateau starting at about 30 to 35 mg/day. (E 1a)⁶

A recent dose-response network meta-analysis found that in children and adolescents, plateaus occur at approximately 45 mg/day of MPH and approximately 25 mg/day of AMP. (E 1a)⁷

More is not necessarily better. For each person with ADHD, the appropriate individual dose—one that provides optimal symptom relief with minimal side effects—must be determined through trial and error. (E 4)⁸

(ADxS experience): Based on our experience, we recommend a approach that proceeds even more slowly than what is outlined in the guidelines.

See also the summary of various international guidelines on MPH dosing, which consistently recommend starting with a low dose and, in most cases, weekly titration based on the individual’s response.

2.1.1. Guidelines¶

2.1.1.1. European Guideline¶

The European guidelines group notes that the response to ADHD medications varies greatly from person to person and that, to date, no characteristics have been identified that can reliably predict this variability. Selecting the appropriate medication therefore remains a process of trial and error—which makes careful, gradual dose adjustment the actual diagnostic tool.¹²

The EMA recommends careful dose titration at the start of treatment with MPH. Dose titration should begin with the lowest possible dose. (E 4)¹³

The guidelines in Germany and the United States do not specify fixed doses but instead call for up-dosing.

2.1.1.2. German S3 Guidelines¶

The 2018 German S3 guideline states:

“The goal is to use the lowest possible dose. This will also reduce or prevent the problem of adverse effects (…). Under these conditions, starting with a low initial dose, the dose can be gradually increased until no further clinically significant improvement in symptoms (e.g., in terms of core symptoms, but also in terms of a change in problem behavior) can be achieved, and the adverse effects remain tolerable.” (E 4)¹⁴

The 2009 guideline stated: “For stimulants: There is no strict correlation between body weight and the required dose! (E 2a). Always titrate individually. The mg/kg body weight values listed are averages and may be lower or higher depending on the individual.” (E 4)¹⁵

MPH:

While the guidelines for MPH recommend titrating the dose in 10-mg increments using half-day-release MPH, we, along with Kühle, consider titration increments half that size to be appropriate—even if this tests the persistence of some people with ADHD. For this purpose, immediate release MPH (2.5 mg per dose) or sustained release MPH (5 mg per dose, which—due to its twice-as-long duration of action—is equivalent to two consecutive doses of 2.5 mg of immediate release MPH) can be used.

AMP:

For lisdexamfetamine (Vyvanse), which is frequently prescribed to adults in Germany, the lowest dose for children is 20 mg and—until 2023—for adults is 30 mg; starting in 2023, the lowest dose for adults will also be 20 mg. Here, even more frequently than with MPH, we found that this lowest capsule dose was already too high for a significant proportion of people with ADHD. We are aware of a significant number of adults who require—in some cases significantly—less than 20 mg per dose. For some people with ADHD, doses of 2.5 mg were appropriate and higher doses were too much; one person with ADHD reported a suitable dose of 0.5 mg. A significant proportion of people with ADHD require doses that fall between the 10 mg increments of the capsules, meaning they are underdosed with the lower-dose capsule and overdosed with the higher-dose capsule. Contrary to the manufacturer’s instructions in the package insert, these patients rely on splitting the capsules to achieve the appropriate dosage. No adverse experiences regarding capsule splitting were reported. Splitting was reported to be done mechanically by eye, using a precision scale, or by dissolving the capsule in water (the active ingredient is water-soluble; only some additives are insoluble) and measuring the dose with a syringe. Divided doses were stored for several days. When dissolved in water, they were usually stored in the refrigerator. No adverse effects resulting from the storage of divided doses were reported.

The fact that, in 2023, the manufacturer supplemented the 30, 50, and 70 mg—previously available only for adults—with 20, 40, and 60 mg options in 2023 is consistent with our experience and has reduced the number of people with ADHD who must split capsules in a manner not approved by regulatory authorities in order to achieve their optimal dose.

Doctors may deviate from the manufacturers’ instructions when conducting individualized therapeutic trials.

For people with ADHD, the instructions for use prescribed by their physician are explicitly the most important.

The experiences described here are provided for informational purposes and for discussion with the prescribing physician.

2.1.1.3. U.S. Guidelines¶

The American “Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents” From the American Academy of Pediatrics from 2019 recommends that MPH treatment should be started at a low dose, especially in children, as they metabolize the medication more slowly and respond to it differently. The dose should then be gradually increased in 7-day increments (or in 3-day increments in urgent cases) to reach a target dose that provides optimal efficacy and minimal side effects. (E 4)¹⁶ This guideline does not specify dosage increments.

(E 3): As early as 2000 (E 4), the Texas Children’s Medication Algorithm Project recommended¹⁷ (E 3)¹⁸ (E 4)¹⁹

• for MPH (immediate release)

  • to start with 5 mg of MPH per day

  • to increase the dose at weekly intervals during the first four weeks to up to 60 mg of MPH per day

• for dextroamphetamine or mixed amphetamine salts (immediate release)

  • Start with 2.5 mg per day

  • to increase the dose at weekly intervals during the first four weeks to up to 30 mg per day.

• Each dose increase is supported by a weekly assessment of symptoms by teachers and parents, who report their findings to the treating physician

• After the fourth week, a doctor’s visit is recommended to review the symptom assessments and decide on further titration of the stimulant dose.

The revised algorithm from the Texas Children’s Medication Algorithm Project recommended an individualized titration regimen based on milligrams per day, adjusted to each patient’s individual response curve. (E 4)²⁰

2.1.1.3.1. Amphetamine-based medications according to U.S. prescribing information¶

A review (Patel et al. 2025, StatPearls) summarizes the U.S. prescribing information for amphetamine medications as follows: (E 4)²¹

• 3 years old or younger: Dextroamphetamine is not recommended.

• 3 to 5 years:

  • immediate release AMP

  • Starting dose: 2.5 mg (immediate release) once daily in the morning after waking up

  • Additional doses may be given at intervals of 4 to 6 hours

  • Increase the dose by 2.5 mg each week until the optimal effect is achieved

  • Total daily dose between 2.5 and 40 mg, divided into 1 to 3 equal doses.

• Ages 6 and up:

  • immediate release or extended-release amphetamine

  • Immediate release AMP:

    • The recommended starting dose is 5 mg once or twice daily

    • first dose after waking up

    • Additional doses may be given at intervals of 4 to 6 hours

    • Increase the daily dose by 5 mg each week until the optimal effect is achieved

    • Total daily dose of 5 to 40 mg, administered in 1 to 3 evenly spaced doses.

  • Extended-release capsules

    • Recommended starting dose: 5 to 10 mg once daily in the morning

    • Increase the daily dose by 5 to 10 mg each week until the optimal effect is achieved

    • Recommended maximum daily dose: 30 mg

• Adolescents:

  • immediate release tablets or extended-release formulations

  • immediate release tablets

    • Recommended starting dose: 5 mg once or twice daily

    • Take the dose after waking up

    • The following doses may be given at intervals of 4 to 6 hours

    • Increase the daily dose by 5 mg each week until the optimal effect is achieved

    • Total daily dose between 5 and 40 mg, divided into 1 to 3 doses.

  • prolongs the effectiveness of medications

    • Recommended starting dose: 10 mg once daily in the morning

    • Increase to 20 mg daily after one week, if necessary

    • there is insufficient evidence that higher doses offer additional benefits (Note from ADxS.org: This is consistent neither with the existing research nor with empirical experience)

• Adults

  • immediate release tablets or extended-release formulations

  • immediate release tablets:

    • The starting dose is 5 mg once or twice daily

    • Increase the daily dose by 5 mg each week until the optimal effect is achieved

    • Typical dosage range is between 5 and 40 mg per day, divided into 1 to 3 doses

    • Subsequent doses may be administered at intervals of 4 to 6 hours

  • prolongs the effectiveness of medications

    • Starting dose: 20 mg once daily in the morning

    • Higher doses (up to 60 mg/day) are not believed to offer any additional benefit (Note from ADxS: This is consistent neither with the studies we are aware of nor with empirical experience)

2.1.1.3.2. Methylphenidate Recommendations for the U.S. Market¶

A publication on methylphenidate summarizes recommendations for the U.S. market: (E 4)²⁴
Unless otherwise specified, the information is based on this publication.

• Adults: (E 4)²⁴

  • Adhansia XR Capsules:

    • Starting dose: 25 mg orally once daily in the morning

    • Increase: in increments of 10 to 15 mg at intervals of at least 5 days

    • Maximum dose: 100 mg/day (increased side effects at doses of 85 mg/day or higher)

  • Aptensio XR capsules:

    • Starting dose: 10 mg orally once daily in the morning

    • Increase: 10 mg increments at intervals of at least 7 days

    • Maximum dose: 60 mg/day

  • Concerta / Relexxii tablets:

    • Starting dose: 18 to 36 mg once daily in the morning

    • Increase: 18 mg increments at intervals of at least 7 days

      • (E 2a): Warning: The Concerta package insert recommends increments of 9 or 18 mg (E 4)²⁵ (E 2a)²⁶

    • Maximum dose: 72 mg/day

  • Jornay PM Capsules:

    • Starting dose: 20 mg once daily in the evening, within 3 hours before bedtime

    • Increase: 20 mg increments at intervals of at least 7 days

    • Maximum dose: 100 mg/day

  • Metadate CD capsules, QuilliChew ER chewable tablets, and Quillivant XR oral suspension

    • Starting dose: 20 mg once daily in the morning

    • Increase: in increments of 10 to 20 mg at intervals of at least 7 days

    • Maximum dose: 60 mg/day

• Children: (E 4)²⁴

  • Immediate-release (short-acting) (chewable tablets, Ritalin tablets, and Methylin oral solution):

    • Starting dose: 5 mg by mouth twice daily, in the morning and at noon

    • Increase: in increments of 5 to 10 mg at intervals of at least 7 days

    • Maximum dose: 60 mg/day

  • Half-day-release formulations (AB-rated generics of Metadate ER or Methylin ER): ’

    • Starting dose: 10 mg by mouth twice daily, in the morning and at noon

    • Increase: 10 mg increments at intervals of at least 7 days

    • Maximum dose: 60 mg/day (two 30-mg doses)

  • All-day extended-release tablets

    • Adhansia XR capsules:

      • Starting dose: 25 mg orally in the morning

      • Increase: in increments of 10 mg to 15 mg at intervals of at least 5 days

      • Maximum dose: 100 mg/day (increased side effects at doses of 85 mg/day or higher)

    • Aptensio XR capsules:

      • Starting dose: 10 mg orally once daily in the morning

      • Increase: 10 mg increments at intervals of at least 7 days

      • Maximum dose: 60 mg/day

    • Concerta / Relexxii tablets:

      • Initial dose: 18 mg once daily in the morning (E 4)²⁵ (E 2a)²⁶

      • Increase: in increments of 9 to 18 mg at intervals of at least 7 days (E 4)²⁵ (E 2a)²⁶

      • Maximum dose: 72 mg/day

      • (E 2b): In the U.S., treatment is more often initiated at a higher daily dose and dose escalation is less common than in Japan, for example. In Japan, 91.9% of children and 77.9% of adolescents began treatment with OROS-MPH at the lowest dose of 18 mg/day, whereas starting doses in the U.S. were more widely distributed (18 to 54 mg/day) and daily doses were higher overall. In both countries, only a minority of patients—less than 40%—underwent dose titration at all. (E 2b)²⁷ (ADxS strongly recommends slow dose titration)

    • Jornay PM Capsules:

      • Starting dose: 20 mg once daily in the evening, within 3 hours before bedtime

      • Increase: 20-mg increments at intervals of at least 7 days

      • Maximum dose: 100 mg/day

    • Metadate CD capsules, QuilliChew ER chewable tablets, and Quillivant XR oral suspension

      • Starting dose: 20 mg once daily in the morning

      • Increase: in increments of 10 to 20 mg at intervals of at least 7 days

      • Maximum dose: 60 mg per day

    • Transdermal (long-acting)

      • Daytrana²⁸²⁹

        • Starting dose: 10 mg patch once daily in the morning, 2 hours before the desired onset of action

        • Increase: The prescribing information specifies a fixed titration regimen.

          • Week 1: a 12.5 cm² patch (10 mg every 9 hours, 1.1 mg/h)
          • Week 2: 18.75 cm² (15 mg, 1.6 mg/h)
          • Week 3: 25 cm² (20 mg, 2.2 mg/h)
          • Week 4: 37.5 cm² (30 mg, 3.3 mg/h)

        • Maximum dose: 30 mg/day

          • Up to 60 mg in individual cases
          • According to the clinical trials, increasing the dose from 20 mg to 30 mg every 9 hours generally did not provide any additional benefit

        • The patches must not be cut; fine-tuning between the four increments is not possible

        • Remove the patch before 9 hours have elapsed if a shorter duration of action is desired, or leave it on for up to 16 hours if a longer duration of action is required. In addition to the dose, this also allows you to adjust the duration of use.

        • Absorption through the skin continues after the patch is removed; therefore, the effect does not end when the patch is removed and lasts for several more hours

        • The size of the patch and the duration of wear determine the amount released. The concentration per unit area is the same for all thicknesses.

        • With daily use, the area under the concentration-time curve increased by 13 to 14% after 7 days and by 64 to 76% after 28 days compared to the value expected from a single dose. The peak concentration increased by approximately 69% (children) and 100% (adolescents), respectively, within four weeks. Neither accumulation nor altered excretion explains this; skin absorption apparently increases with repeated use. A patch dose that is initially appropriate may therefore become too high after a few weeks. Over time, a reduction rather than an increase in the required patch amount should be considered. We do not know whether this applies only to application at the same site or also when the application site is changed.

        • Application errors can cause variations in effectiveness.

          • Apply the patch to a clean, dry area of skin on the hip, avoiding the waistband, as clothing may cause it to come off; apply it to the opposite side the following day.
          • Press down with the palm of your hand for about 30 seconds, especially along the edges.
          • Contact with water while bathing, swimming, or showering reduces adhesion. Bandages, tape, or other adhesives are not permitted.
          • If the liner comes off with adhesive residue, discard the patch. If the patch’s effectiveness appears to be inconsistent, check first to see if it adhered evenly across its entire surface for the full nine hours.
          • When applied to inflamed skin, the rate and extent of absorption increase. Therefore, if you apply the patch to a reddened, irritated, or chafed area, you’ll absorb more of the active ingredient than intended. Since repeated application to the same spot can cause skin irritation, this can set off a self-perpetuating cycle.

        • Transdermal absorption largely bypasses the first-pass effect. A lower patch dose relative to body weight can therefore produce higher concentrations of the active d-methylphenidate than oral administration. With oral administration, barely any l-methylphenidate enters the bloodstream; after transdermal administration, it accumulates to levels nearly as high as those of the d-enantiomer. The half-life of d-methylphenidate after patch removal is 4 to 5 hours. In adolescents, peak concentrations and total exposure were approximately 50% lower than in children; therefore, they tend to require higher patch strengths.

        • The peak concentration and area under the curve for d-MPH increased proportionally with patch thickness in 34 children; the patch can therefore be dosed linearly

        • The dose titration, final dose, and duration of use should be determined individually based on the patient’s needs and response

        • A milligram-for-milligram conversion to oral formulations is not possible; when switching, treatment begins with 10 mg

        • The advantages of patches include, in particular,

          • the ability to adjust the duration of effect based on how long it is worn
          • visual monitoring of medication intake
          • suitability for people with ADHD who cannot or will not swallow tablets (children or those with ASA-related comorbidities)

      • Xelstrym (U.S., since March 2022)³⁰

        • Dexamfetamine patch
        • Approved for ages 6 and up, including adults
        • Initial dose
          • For children and adolescents: 4.5 mg every 9 hours
          • 9 mg every 9 hours for adults
        • Increase
          • Weekly increments of 4.5 mg
        • Maximum dose
          • 18 mg/9 hours
            • Following a single dose of 18 mg administered over 9 hours, the peak concentration in adults was 44.6 ng/ml, compared with 67.6 ng/ml after a 70 mg dose of lisdexamfetamine.
          • max 1 bandage per day
        • Apply two hours before the desired onset of action
        • Removal within nine hours
        • Installation
          • on the hip, upper arm, chest, upper back, or side
          • The position should be changed each time

In a survey conducted as early as 2004, most pediatricians (81.3%) and family physicians (81.7%) in the U.S. reported titrating stimulant medications for children with ADHD.(E 3)³¹ An analysis of U.S. claims data from 2000 to 2004 for children aged 6 to 12 found that, depending on the medication, 51.8% (sustained release mixed amphetamine salts) to 61.6% (immediate release MPH) of children received dose titration. For OROS-MPH, the figure was 52.7%, and for immediate release amphetamine salts, 59.5%. (E 3)¹⁸ The average initial daily dose was 23.8 mg/day for OROS-MPH, 14.8 mg/day for immediate release MPH, 12.7 mg/day for sustained release mixed amphetamine salts, and 11.2 mg/day for immediate release mixed amphetamine salts. The average maximum doses were 33.4 / 21.8 / 17.4 / 16.5 mg/day. Depending on the formulation, titration resulted in final doses that were 26 to 44% higher than (OROS-MPH: 39.1 versus 27.1 mg/day; immediate release MPH: 23.6 versus 18.8 mg/day). Lisdexamfetamine was not yet on the market at that time.

2.1.2. Dosage Forms: Immediate release or sustained release stimulants¶

The dosage form affects how precisely the dose can be adjusted. Sustained-release MPH suspensions and sustained-release chewable tablets are available in the U.S. (but not in Germany) and allow for a level of dose precision that capsules do not: With the suspension, the amount is measured using a dosing syringe; with the chewable tablets, the 20- and 30-mg tablets can be split. This is particularly relevant for people with ADHD whose optimal dose falls between the available capsule strengths, as well as for anyone who cannot swallow capsules. When switching from another MPH medication, a milligram-for-milligram conversion is not recommended; instead, the dose is titrated anew.³²

The choice of stimulant active ingredient is limited to methylphenidate or amphetamine. The number of dosage forms, on the other hand, is large, and each has its own advantages and limitations. Advances in delivery systems have led, among other things, to a faster onset of action, a longer duration of action, better tolerability due to reduced fluctuations in blood levels, greater flexibility in dose adjustment, non-oral alternatives, and less variability in response. If the active ingredient and dose are correct but the outcome is unsatisfactory, the delivery system is the next point of focus for fine-tuning the medication.³³

The choice of preparation can be based on the desired characteristics:

• rapid onset of action
• Long-lasting and consistent effects
• minimal interactions with other medications and with food
• low potential for misuse
• a smooth concentration curve without a sharp peak or an abrupt end

The delivery technology influences both the timing of the active ingredient’s release and the blood levels achieved throughout the day, and thus the onset of action, duration of action, and tolerability. In addition to the ratio of immediate-release to sustained-release components, the type of release is also crucial. Discrete bursts or a continuous flow result in different concentration profiles and, consequently, different levels of symptom control throughout the day.
Release mechanisms that depend on specific conditions—such as a certain pH level—can be disrupted by external factors, such as other medications or diet. Anyone experiencing inconsistent effects from such a medication should first check for the use of proton pump inhibitors and review their dietary habits before adjusting the dose. ³³

The prodrug principle is not limited to amphetamine. In the U.S., Azstarys—a combination drug consisting of serdex methylphenidate, a prodrug of dexmethylphenidate, and immediate release dexmethylphenidate in a fixed molar ratio of 70 to 30—is approved. The prodrug is primarily metabolized in the lower gastrointestinal tract. The half-life is 5.7 hours for the prodrug and 11.7 hours for the released active ingredient. The initial dose is 39.2/7.8 mg, with weekly adjustments upward to 52.3/10.4 mg or downward to 26.1/5.2 mg. As with all prodrugs and sustained release formulations, a milligram-for-milligram conversion to other methylphenidate formulations is not permitted. The prescribing information specifies a one-month trial period; if no improvement is observed within one month after appropriate dose adjustment, the medication should be discontinued.³⁴

A single dose of MPH may be administered using either immediate release MPH or sustained release active ingredients.

(E 4): A single dose of immediate release MPH is common. A single dose of sustained release MPH is also recommended. (E 4)³⁵ (E 4)³⁶ The physician will have to weigh the disadvantage of more frequent dosing with immediate-release MPH—since only regular dosing ensures a consistent effect without rebound—against the advantage of more precise dosing when patients are sufficiently responsible. This issue generally does not arise in school-age children.

(ADxS assessment): Given the positive experiences of adults with ADHD, the decision to now also approve lisdexamfetamine in Europe for initial dosing in adults was the right one.

(No reference): In the U.S., once-daily dosing with long-acting amphetamine salts is common (Adderall XR).

2.2. Titration¶

The dosage of stimulants is not determined by age or weight. These factors may influence the starting dose, but the individual response is the decisive factor.

In a Danish observational study of 207 newly diagnosed children aged 7 to 12 years, MPH was titrated based on weekly assessments of symptoms and side effects. 90.8% reached a mean final dose of 1.0 mg/kg/day. In 81.2%, scores normalized on at least one subscale. 15.0% were nonresponders.³⁷
Among 148 children from the same cohort who were followed up after three years, the long-term outcome was associated with early response, defined as at least a 20% reduction in symptoms after three weeks or at least a 40% reduction after twelve weeks.³⁸The mean age at follow-up was 12.4 years; 77% were boys. The symptom score decreased from 41.9 to 27.5, and the impairment score from 41.6 to 35.6. The prediction applies only to symptoms, not to impairment in daily life. Neither week 3 nor week 12 reached the significance threshold in this regard; only the baseline value was significant. Data on adherence and treatment after week 12 are missing.

2.2.1. Initial Dose Amount¶

In general, the appropriate dose must be determined individually for each person with ADHD.

2.2.1.1. Starting dose for MPH¶

For preschool children aged 3 to 5.5 years, the mean optimal daily dose of MPH was 14.2 ± 8.1 mg, corresponding to 0.7 ± 0.4 mg/kg/day. A dose of 1.25 mg three times daily did not yet have a significant effect, whereas 2.5 mg three times daily did. The effect sizes (0.4 to 0.8) were lower than in school-aged children, and the rate of side effects was higher. 11% discontinued treatment due to side effects. The younger the child, the lower the starting dose and the more frequent the monitoring.³⁹ In a randomized, double-blind study with flexible titration, children aged 4 to under 6 years received sustained-release methylphenidate (Aptensio XR), starting at 10 mg once daily, with weekly adjustments up to a maximum of 40 mg daily. The mean optimized dose was 27.5 mg. With the exception of one case of severe insomnia, the side effect profile was mild to moderate.⁴⁰

Therefore, studies that statistically determine the “optimal” dose of stimulants are of limited use for individual treatment.

In general, stimulants are prescribed at the lowest available doses. Currently, these are 2.5 mg of immediate release MPH by splitting higher-dose tablets, 5 mg for MPH half-day extended-release formulations, 18 mg for Concerta, 5 mg for Adderall XR capsules, etc. The dose is then increased in equal increments until the optimal benefit is achieved. At the dose that provides optimal symptom improvement, most adults with ADHD report only a few side effects other than a mild and temporary loss of appetite. (E 4)⁸

In 2002, the American Academy of Child and Adolescent Psychiatry (AACAP) recommended an initial dose of 5 mg for MPH and 2.5 mg for dextroamphetamine or mixed amphetamine salts, in each case in immediate release form, administered in 2 to 3 daily doses.(E 4)¹⁹

The EMA recommends starting treatment with MPH at the lowest possible dose. (E 4)¹³

• (E 4): low starting dose (2.5 mg of immediate release MPH per single dose or the equivalent in other medications) (E 4)⁴¹ (E 4)⁴² or 5 mg of half-day-release MPH (E 4)⁴³

• at least 5 days per dose level

• Dose adjustment increments: max. 2.5 mg of unret. MPH per single dose

• (E 4): The optimal dose varies greatly from person to person (E 4)⁴¹ (E 4)⁴²

• Effect of slow dosing:

  • reduces side effects

  • (E 4): prevents skipping the appropriate dose due to the sometimes very narrow therapeutic range (E 4)⁴¹ (E 4)⁴²

In Germany, a single dose of 5 mg of immediate-release MPH was recommended for school-age children in 2004. (E 4)⁴⁴ At that time, this was the lowest available dose of MPH. It was not until two years later that the first 5-mg half-day sustained-release formulation (Medikinet retard 5 mg) was approved, which corresponds to two sequentially released doses of 2.5 mg of immediate-release MPH.

(E 4): The equivalent of 5 mg of immediate release MPH in Vyvanse is 10 mg. When titrating in 2.5 mg increments of immediate release MPH or 5 mg increments of sustained release MPH, the corresponding equivalent is 5 mg increments of Vyvanse.(E 4)⁴⁵ (E 4)⁴⁶ Another conversion table, particularly for U.S. formulations, can be found in Stutzman et al. (E 4)⁴⁷

2.2.1.2. Starting dose for lisexamfetamine (LDX)¶

The manufacturer-recommended starting dose of 30 mg for lisdexamfetamine was not determined in clinical trials. The manufacturer has not conducted any studies with starting doses lower than 30 mg. The setting of the starting dose at 30 mg is therefore based solely on regulatory considerations. It is not supported by any pharmacological studies.

(ADxS experience): There are reports from people with ADHD of side effects associated with a single dose, even at low starting doses of lisdexamfetamine. The frequency of these side effects is unknown, as is whether they would not have occurred (or, indeed, would have occurred even more frequently) with a single dose at higher starting doses.

Side effects from taking the correct dose are generally less dangerous than the consequences of an overdose when it comes to stimulants, and they can improve with a controlled increase in dosage; however, we still consider a lower initial dose to be more sensible.

People with ADHD who generally tolerate medications well may also be able to tolerate higher starting doses (such as the 30 mg of lisdexamfetamine for adults or 10 mg of Medikinet Retard recommended in the prescribing information). However, you should bear in mind that even 30 mg of Vyvanse may already exceed the optimal target dose, and consider a lower dosage if appropriate signs are present.

In an open-label, manufacturer-sponsored 7-week study involving n = 316 children aged 6 to 12 years, virtually all participants began treatment with 20 mg/day of lisdexamfetamine. Those who did not respond adequately had their dose increased weekly in 10-mg increments up to a maximum of 70 mg/day. Among the target doses offered (20, 30, 40, 50, 60, and 70 mg of LDX), the optimal doses were: (E 2b)⁴⁸

(ADxS experience): In the drug duration of action survey by ADxS (as of Dec. 19, 23), 13% of 223 Vyvanse users reported an optimal dose below 30 mg, and 11.7% reported an optimal dose of 20 mg or less. 1.8% reported a dose of 10 mg or less. The 11.7% taking 20 mg or less had an average weight of 71 kg and an average age of 40 years.

People with ADHD who have a known hypersensitivity to medications should start with low doses. However, it is important that they be aware that

• A steady and consistent up-dosing every 5 to 7 days up to the target dose prescribed by the doctor is absolutely necessary in order to assess the benefits of stimulants (and discontinuing treatment prematurely often indicates not so much a drug intolerance as the person with ADHD’s impatience) and

• any side effects associated with the initial dose may be reduced at higher dosage levels.

For people with ADHD who are particularly anxious about medication, it is worth considering whether it might be better to start directly at the target dose, because the renewed concerns about possible side effects that arise with each dose increase could raise the risk of placebo-related side effects.

Ultimately, it’s like the question of whether to go around a tree on the left or the right when walking through a forest. Both paths can lead to the destination, but you should be aware of the pitfalls of each path.

A collection of single-dose standards for various American ADHD medications by Lurie A, Lurie RH, Children’s Hospital of Chicago (2024) can be found in Romba et al. (E 4)⁴⁹

2.2.2. Dosing Increments: Small Increments Are Better Than Large Ones¶

Treatment for ADHD in children begins with a low dose, which is then gradually increased.

(ADxS Assessment): In our view, smaller increment up-dosing offers a clear advantage over the currently standard up-dosing in 10 mg/half-day sustained-release MPH increments, which is the basis for the following dosing recommendations. The typically recommended duration of each step—7 days—can thus be shortened to 4 to 5 days, so that the overall rate of up-dosing changes only slightly.

The following titration steps were listed for sustained-release formulations: (E 4)³⁶

• Concerta: Start with 18 mg, increase by 18 mg weekly

• Medikinet Retard: Start at 10 mg, increase by 10 mg weekly

Mutschler also recommends starting with a low dose and increasing it gradually. (E 4)⁵¹

“Undesirable side effects are to be expected, especially at the start of treatment, which is why the dosage should be increased gradually.” (E 4)⁵²

In the Italian ADHD registry, about three-quarters of the children and adolescents treated with MPH reported no side effects: 25.9% experienced at least one mild side effect, and 4.5% experienced at least one severe side effect.(E 2b)⁵³ In the interest of the remaining quarter as well, side effects should be minimized through slow titration.

Slow titration of ADHD medications in small dose increments serves several purposes.

2.2.2.1. Low doses have different effects and affect different regions of the brain¶

Low doses of stimulants have a different effect and act on different regions of the brain than higher doses. (E 4)⁵⁵

• Low-dose MPH

  • (approx. 0.75–3.0 mg/kg orally in rats) increased extracellular norepinephrine in the hippocampus, but not dopamine in the nucleus accumbens. Only a higher dose of MPH (5.0 mg/kg orally) also produced a dopaminergic effect in the nucleus accumbens. (E 2b)⁵⁸

  • (0.25 mg i.p. / kg) selectively activate norepinephrine and dopamine neurotransmission in the PFC (working memory, executive functions, inhibition, emotion regulation), but barely affect other brain regions (E 2b)⁵⁹

  • For more information, see How Methylphenidate Works in the article MPH Part 1: Active Ingredients, Effects, and Response.

• Higher doses increase the efflux of dopamine and norepinephrine throughout the brain, thereby also affecting the striatum (drive, motivation). Attention problems in ADHD arise primarily from a lack of self-motivation (which is why attention works for intrinsically interesting things but not for intrinsically uninteresting ones). Since stimulants at higher doses also increase dopamine and norepinephrine in the striatum, they consequently boost drive and attention. Atomoxetine, which increases dopamine only in the PFC, has barely any such effect.

• Low doses of D-amphetamine (ranging from 0.5 to 1 mg/kg in rats, which corresponds to approximately 0.08 to 0.16 mg/kg in humans, which amounts to 5.7 to 11.4 mg for a 70-kg individual) reduces (hyper)activity, while higher doses increase drive (E 4)⁶⁰ Low doses increased baseline dopamine levels and thereby reduced the stimulus-related rise in dopamine. This resulted in flatter signal peaks without reducing the amount of dopamine released in response to stimuli.

• Norepinephrine and dopamine play very closely related roles in improving ADHD symptoms. What works best for a person with ADHD must be determined on an individual basis.

• (E 1b): Even in cases of severe symptoms, a very low dose may be appropriate on an individual basis. (E 4)⁶¹ Huberman reports a single case in which an optimal daily dose of 2.5 mg of Adderall was found (a woman weighing 150 kg).(E 4)⁶² In a classic study of 20 hyperkinetic children who received, in sequence, a placebo, 0.3 mg/kg, and 1.0 mg/kg of MPH, the optimal dose varied depending on the target symptom: Learning performance was best at 0.3 mg/kg and actually fell slightly below the placebo level at 1.0 mg/kg, while teachers’ assessment of social behavior was best at 1.0 mg/kg, and restlessness while seated decreased steadily as the dose increased. In the learning task, 10% of the children on placebo, 65% at 0.3 mg/kg, and 25% at 1.0 mg/kg reached their personal optimum—whereas in the teacher assessment, the figures were 0%, 28%, and 72%, respectively.(E 1b)⁶³ We know of several people with ADHD for whom a single dose of 1.25 mg of immediate-release MPH is optimal.

2.2.2.2. Preventing Side Effects Through Careful Dosage¶

• (E 4): Gradually acclimating the body to the active ingredient to avoid side effects that could lead to an avoidable discontinuation of ADHD medication. (E 4)⁶⁴ (E 4)⁶⁵

• Predictable side effects such as loss of appetite and insomnia can be minimized by starting with a low dose and gradually increasing it⁶⁶

• A dosage that is too high leads to a recurrence of the ADHD symptoms that were prevented at the appropriate dosage (inverted-U curve). (E 2b)⁶⁷

• Adverse side effects increase significantly when the dose exceeds the optimal level. (E 4)⁶⁸

• In a dose-effect network meta-analysis, the risk of discontinuation due to side effects with MPH in adults rose to 7.3% at the maximum approved dose of 60 mg/day and to 10% at 90 mg/day, while efficacy increased only marginally in this range.⁶⁹

• In children, the risk of discontinuation while taking amphetamines decreased once the dose reached the efficacy plateau of 25 mg/day.⁶⁹

• For neither MPH nor amphetamine-based medications did exceeding the maximum approved dose improve the average efficacy in children or adults. These are population-level values, not thresholds for individual cases.⁶⁹

• In a network meta-analysis of k = 48 studies involving N = 4,964 children and adolescents, efficacy followed an inverted U-shaped curve, peaking at approximately 45 mg of MPH or 25 mg of amphetamine-based medications, while the probability of discontinuation due to side effects increased steadily with dose. Above the plateau, only the side effects continued to increase.⁷⁰Studies using weight-based dosing achieved significantly larger effect sizes than those with fixed dose levels (coefficient 0.24; 95% credibility interval 0.06 to 0.41). Teacher assessments yielded larger treatment effects than assessments by clinicians (coefficient 0.26), and with each additional week of study duration, the SMD decreased by 0.05. Short studies therefore systematically overestimate the effect.

(ADxS experience): These reports refer to group values. We also have individual reports from people with ADHD in whom low doses caused severe side effects that disappeared at higher doses. However, we do not know whether the side effects resulted from the low dose or from the initial administration itself.

2.2.2.3. Particularly precise dosing using suspensions¶

For Dyanavel XR, the dosage is adjusted in finer increments than with most amphetamine preparations. Treatment begins with 2.5 or 5 mg once in the morning. The dose is increased by 2.5 to 10 mg every 4 to 7 days up to a maximum of 20 mg/day. This is made possible by the formulation as a suspension containing 2.5 mg of amphetamine base per milliliter, which is measured using a dosing syringe, allowing for precise dosing in 2.5-mg increments without splitting capsules. In the registration study involving 108 children aged 6 to 12 years, the mean optimized dose was 15.4 mg or 0.47 mg/kg, with individual optimized doses ranging from 10 to 20 mg/day. No child discontinued treatment due to side effects. The medication is not recommended for children under 6 years of age because, at the same dose, higher plasma levels and more side effects were observed in this age group.⁷¹

2.2.2.4. Special Case: Titration of Extended-Release MPH Taken in the Evening (DR/ER-MPH, Jornay PM)¶

With extended-release MPH (DR/ER-MPH, Jornay PM) taken in the evening, not only the dose but also the time of administration is titrated. In a Phase 3 study, an open-label optimization of dose (20, 40, 60, 80, or 100 mg/day) and time of administration (8:00 p.m. ± 1.5 hours) was conducted over six weeks. The mean optimized dose was 66.2 mg, and the most common time of administration was 8:00 p.m. Compared to placebo, functional performance improved in the early morning, throughout the school day, and in the late afternoon or evening.⁷²

When switching to DR/ER-MPH, conversion to milligrams is not possible because the active ingredient is primarily absorbed in the large intestine. The dose must therefore be retitrated. ⁷²After a six-week open-label dose-optimization study in children aged 6 to 12 years, the required dose was 1.8 to 4.3 times that of a sustained release formulation and 4.7 to 6.0 times that of an immediate release formulation, with these figures representing the upper limits for D-enantiomer formulations. The mean optimized dose was 68.6 mg daily. These ratios are well above what would be expected based on a bioavailability of 73.9% (approximately 1.3 for the racemic mixture, 2.7 for the D-enantiomer). The cause is a dose-dependent duration of action. As the dose increases, absorption in the large intestine is prolonged, while the peak concentration rises less sharply. The higher dose provides a longer duration of action, not greater potency. These ratios estimate the expected final dose, not the starting dose or titration profile. Only children aged 6 to 12 years without significant comorbidities and with at least a partial response to methylphenidate were included; extrapolation to other groups is not guaranteed. If participants were underdosed during pretreatment, the ratios are overestimated. Three of the five authors are employed by Highland Therapeutics and Ironshore.

2.2.2.5. Gradual Dosage Escalation for Other Classes of Medications¶

2.2.3. Duration of each dosing increment: 5 to 7 days per increment¶

From a purely pharmacological standpoint, the dose could be increased rapidly, since stimulants take effect immediately upon reaching the brain. From a clinical perspective, the dose could be increased daily, since all effects and side effects of an immediate release dose become apparent 1 hour after ingestion. Once the dose wears off, there is no further or cumulative benefit. (E 4)⁸

(ADxS assessment): In our view, however, there are several strong arguments against up-dosing:

• It’s not just about the (desired) effect, but also about the body’s adaptation to the new phase (avoiding side effects)

• The effects of sustained-release medications must be monitored throughout the day

• It is not the doctor who assesses the effect, but the people with ADHD themselves

• People with ADHD have no experience and therefore don’t know what to look out for

• People with ADHD may experience placebo effects, which depend heavily on their subjective attitude toward the medication and can only be distinguished from the actual effect after several days

• Individual daily factors can skew the results

  • Rule of thumb: monitor daily, but evaluate only the 3-day average

• For women, the current stage of the menstrual cycle must be taken into account

• The longer a drug’s effect lasts (extended-release, prodrug), the longer the increments should be. Due to its long half-life, dextroamphetamine reaches a steady state. In a multiple-dose study of healthy adults, steady state was reached around the fifth day.(E 2b)¹⁰⁵ In slow metabolizers, the period is significantly longer. The consequences are that, when titrating the dose of lisdexamfetamine, dose adjustments should not be made more frequently than once a week.

• However, increasing the dose in increments of several weeks does not improve titration (especially not with methylphenidate) and merely prolongs the time it takes to reach the appropriate dose. More often than not, this simply places an unnecessary strain on the already limited persistence of people with ADHD.

Therefore, 1-day dose increments are not recommended for MPH either.
This applies even in the case of single-dose administration during hospitalization, although the duration of the increments can be reduced in that case as well.
For MPH, the duration should be at least 4 days, but it should not be unnecessarily extended.

We recommend that people with ADHD keep daily records of their medication intake, symptoms, and side effects (e.g., using the dosage guide from the ADHD forum at AdxS.org), but never to evaluate them on a daily basis—instead, always calculate a 3-day average. It follows that an increment of Level 3 to 4 (E 4)⁴⁴ (we mean: more like 5 to 7) days are needed to allow for an assessment.

(ADxS Assessment): We consider the 1-month duration of each dose adjustment phase, as practiced by some physicians, to be of little value. It offers no benefits and may be necessary solely to compensate for dosing increments that are too large.

A German dosing regimen for schoolchildren using immediate-release MPH called for: (E 4)⁴⁴ However, this recommendation dates back to 2004, when 5 mg of immediate release MPH was the lowest available dose and the extended-release formulations used today had not yet been developed. It was not until two years later that the first 5-mg half-day sustained-release formulation was approved (Medikinet retard 5 mg, 2006).)

(No evidence): Most children need 10–20 mg in the morning and 5 to 10 mg in the early afternoon.

If necessary, take 3 doses: in the morning, late morning, and afternoon.

2.2.4. Target dose¶

The optimal dosage of an active ingredient and medication that is suitable for a person with ADHD must be determined individually based on two factors: (E 4)¹⁰⁶

• Single-dose amount

• Number of daily doses

2.2.4.1. Target Factor 1: Single-Dose Amount¶

(E 2b): In our view, the “optimal dose” should be the lowest dose that produces an optimal therapeutic effect. Some guidelines instead recommend the dose at which no further improvement is observed. (E 4)⁶⁸ In our view, the latter approach overlooks the fact that two doses can have equally good effects. Given that treatment adherence for ADHD is generally poor—in a meta-analysis, the average duration of treatment within a one-year observation period was only 136 days for children and adolescents and 230 days for adults, with medication available only 70% of the time, (meta-analysis, n = 127) (E 2b)¹⁰⁷, with similarly high discontinuation rates in other studies (E 2b)¹⁰⁸ (E 2b)¹⁰⁹ — priority should be given to minimizing side effects as much as possible. Side effects were the most frequently cited reason for discontinuation in this review. (E 2b)¹⁰⁷

Since there are marked individual differences in dose-response patterns, the optimal dose must be determined on an individual basis. In this regard, the art of treating patients with MPH (and stimulants in general) goes well beyond simply “fine-tuning the dosage.” (E 4)⁶⁸

2.2.4.1.1. Dosage should not be determined on a blanket basis or based on body weight¶

The optimal target dose for ADHD varies greatly from person to person and cannot be determined on a blanket basis.

Fortunately, the misconception that stimulants should be dosed in relation to body weight is now less common.

(E 4): The amount of methylphenidate that is absorbed (and actually enters the bloodstream) varies considerably from person to person.

• The bioavailability of methylphenidate in children ranges from 11% to 53%, with an average of about 30%. This is due to pronounced first-pass metabolism by carboxylesterase 1. Despite the low and highly variable bioavailability, therapeutic levels can be achieved through titration; thus, up-dosing compensates for this variability, which cannot be calculated in advance.¹¹⁰
• An older study reported values ranging from 11% to 43% for the right-rotating MPH isomer, which is effective on its own. (E 4)⁸
• Differences of up to 30-fold in plasma concentration one hour after administration and up to 7-fold differences in peak concentration have been reported, even at the same dose. In our own study of 28 adults with ADHD and a substance use disorder, at daily doses ranging from 30 to 600 mg (median 160 mg), the ratio of d-MPH plasma concentration to dose varied by a factor of 25 among individuals. Dosage based on body weight was inappropriate; once a dose was determined through individual titration, it remained largely stable.¹¹¹
• The resorption rate remained largely constant over time for the same individual, but varied significantly from person to person. For this reason alone, applying a flat rate based on body weight is not appropriate. (E 4)²¹¹¹

There may be a statistical average that indicates which dosage is most likely to be appropriate for a given body weight. However, because individual variations are so great, determining the correct dosage is a matter that must be addressed on a case-by-case basis. Relying solely on a statistical average would constitute medical malpractice.

However, it has been reported that in cases of obesity, the maximum dose of 1 mg/kg is required more frequently. (E 4)¹¹²

Individualized dosing is also advisable in cases of intellectual disability (RCT involving 122 treatment-naive children aged 7 to 15 with hyperkinetic Disorder and an IQ between 30 and 69).¹¹³24 out of 60 showed improvement or marked improvement while taking MPH.

It is strongly advised not to mistake the first signs of improvement as an indication of an appropriate dose or to treat arbitrary doses as target doses.

Attempts to predict response based on pre-treatment data have not yet proven practical. In a study of 83 young people with ADHD, parent questionnaires, sustained attention and Stroop tests, functional MRI scans, four genetic variants, as well as blood lead levels and urinary cotinine, and the response to an eight-week course of methylphenidate treatment was subsequently calculated. The accuracy rate rose from 64.1% when using only demographic data to 84.6% when genetic, environmental, and imaging data were included. The strongest predictors were age, weight, two variants of the alpha-2A-adrenoceptor gene, blood lead levels, Stroop performance, and oppositional symptoms.¹¹⁵ Given the costs of imaging and genetic testing, and in light of the comparatively low risk associated with methylphenidate treatment, the authors currently consider their method to be of no clinically significant use.

2.2.4.1.2. The dosing regimen influences the optimal dose and response¶

For adults, there are two studies with contrasting titration regimens. A single-dose regimen that began with a low dose and was increased based on efficacy and tolerability resulted in lower optimal doses than a fixed weight-based dosing regimen, while yielding the same response rate. Since the goal is to find the lowest dose that achieves an optimal effect, this clearly argues against weight-based dosing.

• In a 24-week randomized, double-blind study involving 359 adults, treatment with sustained-release MPH was initiated at a dose of 10 mg/day and titrated up to 60 mg/day based on efficacy and tolerability. The mean optimal daily dose was 0.55 mg/kg. 61% (a reduction of more than 30% on the Wender-Reimherr Scale) and 55% (based on the physician’s overall assessment) of MPH recipients were responders. This demonstrates that low-dose, individually titrated up-dosing in adults over a period of half a year is effective and well tolerated.¹¹⁹
• An eight-week study by the same research group involving 162 adults used a weight-based dosage of up to 1 mg/kg/day, divided into two doses taken after breakfast and lunch, 6 to 8 hours apart. Fixed daily doses were assigned based on weight category: 40 mg for those weighing less than 55 kg, 60 mg for those weighing 55 to 69 kg, 80 mg for those weighing 70 to 104 kg, and 120 mg for those weighing 105 to 130 kg. The response rate was 50% (according to the Wender-Reimherr improvement scale as well as the physician’s overall assessment), compared with 18% in the placebo group.¹²⁰
• Weight-based dosing results in significantly higher final doses but noticeably lower response rates.

2.2.4.1.3. The optimal single dose may be lower than the lowest standard dose or higher than the upper limit of the standard dose range.¶

Certain groups often require a lower target dose than usual. However, this does not rule out the possibility that some people with ADHD in these groups may require very high doses. The following are frequently mentioned in this context:

• Adults

  • often require lower doses than adolescents or children.

• inattentive presentation type (ADHD-I)

  • In a placebo-controlled crossover study with forced titration across three dose levels involving n = 47 children aged 5 to 16 years, 60% of those with ADHD-I showed improvement at doses of 36 mg or less; higher doses provided little additional benefit. For ADHD-C, two-thirds to three-quarters of patients achieved a clinically relevant reduction in symptoms only at 36 or 54 mg of OROS-MPH. ¹²¹ Side effects occurred at all dose levels and with placebo. Only insomnia and decreased appetite increased with dose.

• concomitant ASA

  • Start with a very low dose and increase it very gradually¹²²¹²³
  • In patients with comorbid ASD, only 49% responded in the largest stimulant study to date on ASD (n = 72, ages 5 to 14, MPH in three dose levels). 19% discontinued treatment due to side effects. The effect sizes were lower than those observed in ADHD without ASD. Therefore, treatment for ASD should begin at a particularly low dose and be titrated upward very gradually.¹²²
  • In a pilot study involving 27 young children with ASD and ADHD, a long-acting liquid MPH formulation was administered according to various titration regimens. Low- to moderate-dose treatments effectively improved ADHD symptoms and were well tolerated. In the first stimulant study involving adults with high-functioning ASD and ADHD, a liquid formulation was deliberately chosen because it allows for a very gradual increase starting at 5 mg per day. Precise dosing is of particular importance for this group.¹²³ Tolerability and adherence were better than expected based on earlier studies, presumably because the investigators were allowed to adjust the dose proactively at their own discretion, rather than having to increase it to the prescribed maximum dose for each group. At the low dose ranges used and with this cautious approach, there were no dose-dependent increases in insomnia or other side effects. No participants withdrew from the study due to intolerance. The liquid formulation also allows for precise dosing and is suitable for children who cannot swallow tablets. This was a pilot study without a placebo control.

In some cases, the optimal dose of MPH or AMP may be less than 5 mg/day. On the ADHD-Forum.adxs.org website, one person with ADHD reports that a single dose of 0.5 mg of Vyvanse provides the optimal effect. (ADxS experience)¹²⁴

Huberman reports a single case in which an optimal daily dose of 2.5 mg of Adderall was observed in a woman weighing 150 kg, and daily doses of 180 and 210 mg of Adderall, respectively, were required for two sisters weighing 60 and 70 kg.(E 4)⁶² We, too, are aware of individual cases in which only extremely high doses of Vyvanse (several hundred mg/day and 50 mg as necessary sleep medication at night) produced an adequate effect and significant improvement. One of these cases later turned out to be chronic poisoning from nitrogen oxides in the air or a particular sensitivity to them. Such high doses may only be administered under the close supervision of a highly experienced physician. We strongly caution against self-experimentation.

(ADxS experience): In the drug duration-of-action survey conducted by ADxS (as of Dec. 19, 2023), out of 223 adult Vyvanse users, 13% reported an optimal dose below 30 mg, and 11.7% reported an optimal dose of 20 mg or less. 1.8% reported a dose of 10 mg or less. The 11.7% taking 20 mg or less had an average weight of 71 kg and an average age of 40 years.

The optimal dose may exceed the standard maximum dose (especially in rapid metabolizers). This applies to methylphenidate as well as to amphetamine-based medications. (E 4)¹⁰⁶

For MPH, the standard maximum dose is 60 mg/day for children and adolescents and 80 mg/day for adults. However, these values are not uniform; they depend on the specific medication and the country (in Germany, for example, 54 mg/day for Concerta in children and 72 mg/day in adults). For details, see the tables below.

A maximum dose of 1 mg/kg of MPH is generally a good guideline for avoiding increased side effects. In some cases, however (when metabolism is correspondingly rapid), significantly higher doses are required and well tolerated.

European treatment guidelines specify an effective dose range for immediate release MPH in adults of typically 10 to 20 mg three to five times daily and explicitly note that higher or lower doses may be necessary in individual cases. The guidelines recommend a maximum single dose of 30 mg.(E 4)³⁶

There are also groups for whom the optimal dose is often above the usual upper limit.

Higher doses are often required in cases of comorbid substance use disorder. In a 13-week randomized trial involving 126 adults with ADHD and cocaine use disorder, 75.0% (at 60 mg) and 58.1% (at 80 mg) achieved at least a 30% reduction in symptoms, compared with 39.5% in the placebo group. Only the difference in the 60-mg group was statistically significant (OR 5.23; 95% CI 1.98–13.85); the difference in the 80-mg group was not significant (OR 2.27; 95% CI 0.94–5.49). Conversely, cocaine abstinence increased with dose (30.2% versus 17.5% and 7.0% with placebo). ¹²⁵While the higher dose did not provide any additional benefit for ADHD symptoms, it did lead to reduced substance use. The recommended maximum dose of sustained-release amphetamine salts (Adderall XR) for adults is 20 mg/day.
The same pattern is observed with methylphenidate. In a 24-week randomized, double-blind, placebo-controlled study of 54 incarcerated men with ADHD and amphetamine dependence (mean age 42 years), OROS-MPH was titrated up to 180 mg/day. The active-treatment group showed a greater reduction in ADHD symptoms, more amphetamine-negative urine samples, and better treatment retention.¹²⁶

(E 4)¹²⁷ The dose should be persistently increased until two consecutive doses result in a worsening of symptoms. It is not uncommon for a higher dose to be less effective than the next lower dose, while the dose one increment higher again produces a significant improvement.

2.2.4.1.4. Maximum dose¶

A maximum dose of 1 mg/kg of body weight, or 60 mg/day for children and 80 mg/day for adults, is often cited.

A dose-response network meta-analysis of 113 double-blind RCTs involving over 25,000 participants identified varying patterns depending on age group and drug class. In children and adolescents, the mean efficacy increased up to 45 mg/day of MPH (SMD −0.89; 95% CI −1.18 to −0.60), up to 25 mg/day of amphetamines, and up to 4 mg/day of guanfacine. Beyond these doses, no additional benefit was observed. In adults, amphetamines reached a plateau above approximately 50 mg/day, while the discontinuation rate due to side effects continued to rise. For MPH, no plateau was detectable in the high-dose range due to limited data. The doses were converted to a common scale: amphetamines as dextroamphetamine equivalents, and MPH as equivalents of immediate-release MPH hydrochloride. No benefit from increasing doses beyond the maximum approved doses was observed at the group level. Findings based on group means do not apply to individual cases.¹²⁸

A systematic review of 11 randomized trials and 38 cohort studies concluded that, while the literature recommends a wide range of maximum doses (0.8 to 1.8 mg/kg/day), it provides no clear scientific rationale for any of these individual limits. The authors call for studies on purely clinically guided titration without a fixed upper limit. (Meta-analysis, k = 11 RCTs with n = 1,304, N = 2,191, and k = 38 cohort studies, N = 5,524) (E 1a)¹⁰³ The standard values are derived primarily from manufacturers’ marketing authorization documents, in which the limitation of liability risks also plays a role.

(E 4): The professional literature recommends not exceeding MPH doses of more than 150 mg/day. (E 4)¹²⁹ (E 4)¹³⁰ European treatment guidelines consider doses of up to 2 mg/kg/day or up to 108 mg/day—whichever is lower—and are thus significantly higher than the maximum approved dose of 54 mg/day.(E 4)³⁶

A placebo-controlled study of 103 adults with ADHD reported a titration up to 1.3 mg/kg/day for OROS-MPH, a mean daily dose of 72 mg, and a maximum dose of 108 mg/day. (E 1b)¹³¹

(ADxS Assessment): It is evident that some people with ADHD require daily doses significantly higher than 60 or 80 mg. It is true that, in these cases, more frequent monitoring is advisable. In any case, a blanket rejection of a dosage of up to 150 mg/day—which is necessary to achieve an adequate effect—is not justified.

Maximum Daily Doses for ADHD Medications by Age and Formulation, According to the FDA

• Methylphenidate

  • Children (ages 6–12)

    • Immediate release: 60 mg/day (E 4)¹³⁵

    • Sustained release: 54 mg/day (E 4)¹³⁶

  • Teens (ages 13–17)

    • Immediate release:

    • Sustained release: 72 mg/day, max. 2 mg/kg/day (E 4)¹³⁶

  • Adults (ages 18–65)

    • Immediate release:

    • Sustained release: 72 mg/day (E 4)¹³⁶

• Amphetamine-based medications

  • mixed amphetamine salts

    • Children ages 6 and up and teenagers

      • ADHD: 40 mg/day (E 4)¹³⁷
      • (E 4): Narcolepsy: 60 mg/day in divided doses (E 4)¹³⁸ (E 4)¹³⁷

    • Adults

      • immediate release:

        • (E 1a): ADHD: 40 mg/day (E 4)¹³⁷ (E 1a)¹³⁹
        • (E 4): Narcolepsy: 5–60 mg/day in divided doses (E 4)¹³⁸ (E 4)¹³⁷

      • Sustained release (e.g., MYDAYIS): 50 mg/day (E 4)¹⁴⁰

      • Lisdexamfetamine:

(E 1a): The FDA emphasizes that these maximum doses are based on limited clinical studies. Some clinical guidelines recommend higher doses than those approved by the FDA, particularly for adults, where guidelines sometimes recommend up to 100 mg/day of methylphenidate.(E 1a)⁶ The dosage should be titrated individually to achieve optimal therapeutic effects with minimal side effects. (E 1a)¹⁴¹ (E 1a)¹⁴²

For more information, please contact the health authorities in the respective regions:

• Europe: EMA: ema.europa.eu

  • United Kingdom: MHRA/BNF: bnf.nice.org.uk

• Australia: TGA: tga.gov.au

• Canada: Health Canada: canada.ca/en/health-canada → Drug Product Database

• Germany: Red List (Bertelsmann): fachinfo.de

• Austria: ages.at

• Switzerland: swissmedicinfo.ch

2.2.4.1.5. Maximum dose of methylphenidate¶

- Metadate CD capsules, QuilliChew-ER chewable tablets, and Quillivant-XR oral suspension: Maximum dose: 60 mg/day

- Transdermal (long-acting, Daytrana): Maximum dose: 30 mg/day (up to 60 mg in individual cases)

2.2.4.1.6. Maximum dose of amphetamine medications¶

2.2.4.1.7. Maximum dose of atomoxetine¶

2.2.4.1.8. Maximum dose of guanfacine¶

2.2.4.1.9. Maximum dose of clonidine¶

2.2.4.1.10. Maximum dose of bupropion¶

2.2.4.2. Target Factor 2: Full-Day Coverage / Number of Individual Doses¶

2.2.4.2.1. Full-Day Care as a Goal¶

(E 4): The goal should be full-day coverage (E 4)¹⁷⁰ (E 4)¹⁸⁴ (E 4)¹⁸⁵ (E 4)¹⁸⁶ (E 4)¹⁸⁷, that is, coverage from 12 to 16 hours. (E 4)¹⁸⁸ (E 4)¹⁸⁷

In a cross-sectional survey of 616 adults with ADHD receiving medication and 200 control subjects, those receiving treatment reported significant impairments throughout the day—particularly in the afternoon and evening—despite their medication. Symptoms emerged as the medication’s effects wore off, negatively impacting homework, work tasks, household chores, emotional regulation, mood, and relationships. The most frequently cited unmet need concerned the duration of action. Participants on long-acting medication, in particular, reported significantly more often that the evening was problematic; thus, a longer duration of action alone does not solve the problem.¹⁸⁹The survey was conducted online in December 2016. Participants were divided into those taking long-acting once-daily medication (n = 201), short-acting medication up to twice daily (n = 166), and those who increased their dosage (n = 249; long-acting more than once, short-acting more than twice, or a combination of both). The fact that 40% used supplemental doses is a finding in itself. For many, the basic regimen is not sufficient. The authors conclude that healthcare providers should specifically ask about functional levels at certain times of day and for specific activities in order to adjust coverage throughout the day and into the evening. The study was funded by Shire, with the funder’s involvement in planning, analysis, and manuscript approval. Two authors are former Shire employees and Takeda shareholders. Diagnoses were not verified; the online survey relied on self-selection.

Optimizing treatment for adults with ADHD requires taking into account individual coverage needs at different times of the day and adjusting the dose accordingly. Differences among medications in terms of onset of action and duration of effect must be taken into account to ensure coverage for activities that extend over significant portions of the day, particularly into the afternoon and evening.¹⁹⁰

The duration of medication coverage required throughout the day is influenced by various factors. (E 4)⁸

(No evidence): A distinction must be made here:

• Symptoms related to attention and organization (medication as needed is acceptable, provided the person with ADHD prefers it)

  • Length of the school or work day

  • Demanding situations outside of work (events, social gatherings)

• Impulsivity and emotional dysregulation (requires round-the-clock coverage; may be combined with ATX or guanfacine as needed)

  • The need for medication to make social life manageable

In any case, ADHD doesn’t end when school is over.

• Treatment should not be aimed solely at ensuring school readiness

• ADHD has a significant negative impact on homework, social life, and family life

• Untreated ADHD is associated with a significantly increased risk of accidents, and a significantly reduced life expectancy has been reported for ADHD overall (for more on this, see: Life expectancy reduced by 8 to 11 years in the chapter “ : Consequences of ADHD”). Medication measurably reduces these risks. With stimulants, overall mortality decreased by about 20%, mortality from unnatural causes by about 22%, and the risk of suicide attempts by 12% to 72%, depending on the study (with the reduction increasing with the duration of use). For more on this, see: Reduced premature mortality, fewer suicides in the chapter “ Consequences of ADHD”). Against this backdrop, it is difficult to objectively justify treating existing ADHD not at all or only for part of the day.

  An accident during the part of the day when medication is not administered carries the risk of a liability claim.

2.2.4.2.2. Number of single doses required for full-day coverage¶

(E 4): The number of individual doses of a suitable active ingredient and formulation required to provide 24-hour coverage must be determined on an individual basis.(E 4)¹⁰⁶ With MPH, the single-dose amount does not affect the duration of action of the single dose, whereas with lisdexamfetamine, a higher single dose also prolongs the duration of action of the single dose. (E 4)¹⁹⁴

If the daily intake is not achieved with a single dose of a medication:

• Multiple doses throughout the day (up to 3 doses of a half-day-release formulation)

• Sustained-release formulations can also be supplemented with immediate-release formulations

• Full-day coverage may require a combination of sustained-release and immediate-release stimulants. (E 4)¹⁹⁵

• Dyanavel XR, an amphetamine preparation with a particularly long duration of action (not approved in Germany), is associated with a reduced need for additional doses of stimulants in immediate release (E 2b)¹⁹⁶

(E 1b): According to Dodson, concerns that stimulant medications might impair sleep are often unfounded. (E 4)⁸ As a rule, stimulants improve sleep quality in people with ADHD. A placebo-controlled crossover study of adults with ADHD found that methylphenidate was associated with shorter sleep duration but improved sleep quality.(E 1b)⁵

Therefore, it is especially important to ensure that you stop taking the medication in a timely manner in the late afternoon. For more information, see Treatment of Sleep Problems in ADHD

2.2.4.2.3. The duration of action of a single dose may be significantly shorter or longer¶

2.2.4.2.4. Manufacturer’s Specifications¶

(E 4): Manufacturer’s specifications regarding duration of action (rarely achieved in practice) (E 4)⁴¹ (E 4)⁴²

• Immediate-release MPH is effective for 2.5–3.5 hours per single dose

  • 4 to 5 single doses are required for daily coverage

  • barely feasible in the long run, especially for children

  • For dosing, immediate-release MPH is still preferable because it allows for the most precise control

• Half-day-release MPH is effective for an average of 4.5 to 6 hours per single dose

  • 2 doses + immediate-release MPH, if necessary, to cover the remainder (E 4)¹⁸⁷

  • The second dose is usually 50% to 75% of the first dose

• Sustained-release MPH taken once daily is effective for an average of 10 to 12 hours

• Attentin (immediate release AMP) is effective for an average of 4.5 hours per single dose. (E 4)⁴⁹

  • 2 doses and, if necessary, immediate-release MPH to cover the remainder

  • The second dose is usually 50% to 75% of the first dose

• Lisdexamfetamine (Vyvanse) lasts for up to about 10–12 hours (Note: In practice, the duration is much shorter in more than 50% of people with ADHD!)

  • Amphetamine medications take 3 to 5 days to reach steady state

  • 1 dose and, if necessary, immediate-release MPH to cover the remainder

  • For people with a fast metabolism (more than 50%—a second dose may be necessary)

  • For people with a very fast metabolism, a third or fourth dose should also be considered

• Guanfacine

  • Mirror medication, once a day

• Atomoxetine

  • Mirror medication, once a day

2.2.4.2.5. Prolonged effect (rather rare)¶

(ADxS experience): It is quite rare for us to encounter people with ADHD who experience a significantly longer duration of effect from a single dose of an ADHD medication than indicated by the manufacturer.

This is sometimes evident in the adequate effect of a given dose on the first day and, in some cases, even on the second day of administration. On subsequent days, symptoms of overdose occur even with the same dosage. When amphetamine-based medications are involved, the steady state should also be taken into account in this context due to their relatively long half-life.

2.2.4.2.6. Shortened duration of effect (quite common)¶

(ADxS experience): In contrast, it is more common for people with ADHD to experience a single dose that lasts significantly shorter than the manufacturer specifies.

In our experience, about 15 to 20 percent of the people with ADHD are pronounced fast metabolizers, for whom a single dose lasts only about half as long as indicated by the manufacturer. A moderately shortened duration of action is significantly more common.

• People with fast metabolisms often need several doses a day instead of higher single doses

• According to our survey data, about half of the people with ADHD report that the duration of action—particularly for lisdexamfetamine—is significantly shorter than the manufacturer’s stated duration

• typically ultra-rapid metabolizers (e.g., acidic pH or a rapid-metabolizing CYP or CES1 gene variant)

• Multiple doses per day, including of extended-release formulations intended for once-daily use

• Combination therapy for fine-tuning / in difficult cases

  • For more information, see Combination Therapy for ADHD

• in particular:

  • 50% ATX for full-day treatment of emotional dysregulation

  • 50% MPH or AMP, as they generally have a better effect on motivation and concentration

• Rebound treatment

• Rebound is particularly common with MPH

• Solution:

  • Take the second dose in time so that its effects begin before the first dose wears off during the rebound phase

  • immediate release MPH shortly before the end of the last dose

    • 1/4 to 1/3 of what would be equivalent to a single daily treatment dose

    • Example: 20 mg of semi-daily-release MPH is equivalent to 2 x 10 mg of immediate release MPH. In this case, take 2.5 to 3.5 mg of immediate release MPH 30 minutes before the last sustained-release dose wears off.

The phenomenon of a shortened duration of action per single dose is significantly more common with Vyvanse than with MPH:

• Unlike with MPH, a significantly higher number of people with ADHD taking Vyvanse reported a significantly shorter duration of action than the 12 to 14 hours specified by the manufacturer. Many of them were able to achieve optimal daily coverage by taking several single doses. For more on this, see Amphetamine-Based Medications for ADHD: Effect Profile (Over Time) / Duration of Action

• Some people with ADHD report that intense sports can shorten the duration of action of stimulants by up to 40%. (ADxS experience)¹⁹⁹

  • For more information, see Physical Activity / Sports in the article “ : Efficacy and Duration of Action of ADHD Medications”

• In an individual, higher doses of amphetamine have a longer-lasting effect (E 4)⁸

  • Since amphetamine is primarily excreted by the kidneys, the duration of action is influenced not only by the total dose but also by kidney function and, above all, by the pH of the urine

  • Another consequence of this is that blood levels of amphetamine change more slowly and are less prone to rebound than with methylphenidate

2.2.4.2.7. Information on the duration of action of the prescribed doses¶

When administering a single dose, people with ADHD must be explicitly informed of the typical duration of action of a single dose of the respective medication. This is not only ethically required, but also medically and therapeutically necessary.

We repeatedly receive reports from people with ADHD who were led to believe that a single dose of immediate release or half-day extended-release MPH (e.g., Ritalin Adult) would last all day, rather than informing them of the usual duration of action of 2.5 to 3 hours (immediate release) or 5 to 6 hours (half-day extended-release). This naturally leads to inaccurate feedback to the doctor when patients report that their symptoms remain unchanged, because—unaware of the limited duration of action—they mistakenly describe periods in the afternoon or evening when the medication is no longer effective.

2.2.5. Dosage Adjustments¶

A study conducted over 14 months examined how well the initial dose predicts the subsequent maintenance dose. The study began with a placebo-controlled, double-blind titration involving daily dose adjustments. The results were compared with the subsequent maintenance therapy. The dose determined during the titration did not remain constant; adjustments were necessary over time. Once an optimal dose has been found, it is therefore not a permanent value but must be reviewed regularly.²⁰⁰Of 230 children for whom an optimal dose was determined, only 39 (17%) remained on the same treatment and dose throughout the maintenance phase, which lasted an average of 11.8 months. For 186 (81%), at least one change occurred; 20 of these returned to the original regimen by the end, so that ultimately 59 children (25%) were back on the titration dose. On average, 2.8 adjustments per child were necessary, with the first occurring after 4.7 months. The correlation between the titration dose and the final dose ranged from 0.52 to 0.68. Children receiving additional behavioral therapy required only 31.1 mg, compared to 38.1 mg for those on medication alone. Under the titration protocol used, a change of up to 10 mg from the current dose was permitted. Each change was typically tested for one month. Further increases required the approval of an expert committee. A dose reduction was permitted only in cases of moderate to severe side effects; a scheduled reduction for evaluation purposes was not provided for.

A comparison of the MTA treatment arms showed that the quality of treatment is influenced by the dose level. The mean daily dose of MPH was significantly lower among children in standard care (18.7 mg/day) than among those treated by study physicians (32.8 mg/day). The latter group had better outcomes. A systematic review concluded that the apparent ineffectiveness of stimulants may be due to overly cautious titration or simply to underdosing. This underdosing can occur at the start of treatment or months to years later, when a previously effective regimen loses its efficacy, e.g., because the child has grown. Within the first six months of treatment, mild tolerance may develop, requiring a one-time dose increase of 20 to 30%. Predictable side effects such as loss of appetite and insomnia can be minimized by starting with a low dose and increasing it gradually. Unusual side effects that cannot be attributed to the properties of the active ingredient generally necessitate discontinuation of treatment. The authors include tics and mood changes among these.⁶⁶

The goal is for the symptoms to no longer cause significant impairment.

The perception that a very positive effect subsides a few days or weeks after the initial adjustment is often not due to a change in the drug’s effect, but rather to a change in the perception of the people with ADHD. During the so-called “honeymoon phase” immediately after reaching an effective dose, the contrast with the previous state of deficiency is perceived as a particularly positive experience. Such a feeling of significant improvement is, by its very nature, fleeting—just as the euphoria a soccer fan feels after winning a championship returns to normal within days, even though they’ve been on the edge of their seat all season. In such cases, it’s important to carefully assess whether a higher dose is truly necessary. External assessments can be helpful in this regard.

• It is possible that a one-time readjustment may be necessary after a few months. This is not a “habituation effect” that recurs regularly.

• A trial withdrawal should be conducted once a year to determine whether ADHD symptoms persist without medication.

• People with ADHD frequently exhibit 75% of the possible ADHD symptoms, while persons without ADHD exhibit 12 to 25%. The goal of optimal dosing is therefore not complete freedom from symptoms, but rather a reduction of symptoms to a healthy level. Attempting to increase the dosage until all symptoms are completely eliminated would inevitably result in an overdose.

2.2.6. No admissions in the afternoons, on weekends, and during school breaks¶

In a 28-day double-blind study, 40 boys with ADHD received either MPH seven days a week or MPH on weekdays and a placebo on weekends. Both groups showed significant improvement in symptoms as the dose was increased. Compared with the seven-day regimen, the five-day regimen with a weekend break resulted in significantly less insomnia (p = 0.05) and, at trend level, a slight reduction in appetite loss (p = 0.08). Parents’ assessment of efficacy over the weekend did not deteriorate significantly, and teachers’ assessment of ADHD symptoms on the Monday following the weekend was not elevated. The authors explicitly note that this contradicts the widespread assumption that even a single placebo day leads to a return of symptoms. (Results and Discussion)²⁰¹

A review of 22 studies from 1972 to 2013 notes that medication breaks occur in 25 to 70 percent of families, predominantly during school vacations. A beneficial effect of longer breaks on growth was observed. Shorter breaks were found to reduce sleep disturbances and improve appetite. In practice, these breaks served three purposes: to assess whether the medication was still necessary, to reduce side effects, and to counteract tolerance. Ibrahim K, Donyai P (2015): Drug Holidays From ADHD Medication: International Experience Over the Past Four Decades. J Atten Disord. 2015;19(7):551-568. doi: 10.1177/1087054714548035²⁰²

(ADxS Assessment): Since ADHD is not a disorder that is limited to the morning school hours, we would be more inclined to consider slightly reducing the dosage during periods of lower demands (to 2/3 or 3/4). This depends heavily on the individual needs of the people with ADHD. All dosage changes must be coordinated with the doctor. However, an experienced doctor will grant a trusted patient considerable leeway.

2.2.7. Intake Based on Need¶

The greater a person with ADHD’s ability to self-regulate, the more likely they are to take stimulants as needed. While a rigid dosing schedule is generally the safer approach for children, adults—once the initial titration is complete—are more likely to decide on a day-to-day basis whether and at what dose to take their prescribed stimulants (within the dosing range agreed upon with their doctor). Some people with ADHD are able to manage this well when specific tasks (e.g., evening events) require an additional evening dose or a single dose on an otherwise medication-free (because it is a low-demand) weekend day (such as shopping on Saturday afternoon or while on vacation). The guiding principle is: “I manage my ADHD; my ADHD does not manage me.” (E 4)¹¹²

(ADxS experience): During the titration phase, adults must not deviate from the prescribed regimen. We repeatedly observe that the impulsivity and impatience of people with ADHD lead them to change the dose or the timing of administration within 2 or 3 days. However, this is primarily a symptom of the disorder. Stimulants require several days at a consistent dose to enable a stable sense of self.

For women, the days leading up to menstruation are often associated with an increased need for stimulants. For more information, see the section below at Cycle-Related Symptom Fluctuations in Women.

2.2.8. Metabolism of Drugs and Active Ingredients¶

A change in medication or active ingredient may be necessary or helpful due to adverse side effects or lack of response (no effect).

If a medication does not produce the desired effect (non-response), the first step—especially with MPH—should be to switch to a different MPH formulation. Surprisingly often, people with ADHD react negatively to one MPH medication or experience severe side effects from it, yet respond positively to another MPH medication, while others may experience the exact opposite. A nationwide Korean study of 132,017 people with ADHD who were receiving medication found that 85% switched between different MPH formulations during the course of treatment. (E 3)²⁰³

If an active ingredient shows no effect overall (regardless of the formulation) (non-responsive), another active ingredient should be tried first.

(E 1a): About 40% of all people with ADHD do not respond to MPH, and about 30% do not respond to AMP (nonresponders). 87% of people with ADHD responded to one of the two types of active ingredients. (E 4)²⁰⁴ A meta-analysis of 32 studies reached the same conclusion (significantly better response rates to amphetamine medications than to MPH). (E 1a)²⁰⁵

Switching between classes of active ingredients is also worthwhile if the first active ingredient was effective but not sufficiently so. In two randomized, double-blind, placebo-controlled comparative studies in adolescents, lisdexamfetamine and sustained-release methylphenidate were directly compared. Both were superior to placebo but differed in response rates and side effect profiles.²⁰⁶

However, nonresponse rarely involves both active ingredients at the same time, so that approximately 85% to 90% of people with ADHD respond to either MPH or AMP. Approximately 40% of people with ADHD who do not respond to MPH respond to atomoxetine. (E 4)³⁶

Response rates vary widely among the different classes of active ingredients. In a six-week, placebo-controlled comparative study involving children and adolescents, OROS methylphenidate achieved a response rate of 56%, atomoxetine 45%, and placebo 24%. In the subsequent blinded crossover phase, one-third of the people with ADHD responded to only one of the two medications. A lack of response to one active ingredient therefore says little about the other, making the switch a viable treatment option in its own right rather than a stopgap measure.²⁰⁷

In the six most informative crossover studies, involving a total of 174 people with ADHD, 48 responded better to amphetamine, 27 to methylphenidate, and at least 72 to both—resulting in an overall response rate of at least 87% when both active ingredients are tested. The authors conclude that people with ADHD for whom one stimulant fails should try the other. Pharmacologically, this is because methylphenidate is a pure reuptake inhibitor, whereas amphetamine additionally releases catecholamines.²⁰⁸ Excluding the two studies from a full-day behavioral therapy summer program, which normalized the baseline values, the rate was 92%. Due to the evaluation methods used in some studies, double responders went undetected; the 87% figure is therefore a lower bound. No crossover study showed consistency in response at the individual level. In every study, there were participants who responded to one treatment but not the other, in both directions.

In a study of 49 previously untreated adults, 41% had to switch from the initially prescribed class of medication to another within 90 days due to poor tolerability. Methylphenidate was the initial prescription for 67% of the participants, while 33% were initially prescribed an amphetamine-based medication. The switch rate was significantly higher among those initially prescribed methylphenidate. Among those on amphetamine, however, changes in formulation or additional medication were more frequently necessary. More patients on amphetamine remained within the same class of medication but required a different dosage form or additional anxiolytic or antidepressant treatment. No characteristics were identified that could predict who would need to switch.²⁰⁹
When switching between methylphenidate and amphetamine-based medications, no medication-free interval is required due to their short half-lives. Similarly, no adverse effects have been reported when switching promptly to ADHD medications such as guanfacine or atomoxetine. When switching from MAO inhibitors to stimulants or atomoxetine, or from stimulants or atomoxetine to an MAO inhibitor, a 14-day waiting period must be observed—and, of course, concurrent use is not permitted.

It has been reported that the optimal dose of stimulants—which is often highly individualized—may vary between MPH and AMP. A person with ADHD may require a relatively high dose of MPH or a relatively low dose of AMP to achieve an adequate effect. Therefore, when switching active ingredients, a new individual titration is necessary. (E 4)¹¹² Consequently, the standard conversion tables should be viewed with caution when switching active ingredients.

2.2.8.1. Non-responders: Drug Metabolism¶

• MPH: 30% non-responders

  • If MPH is ineffective:

    • Check stomach acid levels

    • Change the active ingredient

• AMP: 20% non-responders

  • If AMP is ineffective:

    • Check the pH level of the urine at the time of ingestion

For more than 40% of people with ADHD who do not respond to treatment, switching medications within the first 3 months is helpful. (E 2b)²¹⁰

(E 4): When MPH and AMP are substituted due to non-response, only about 10% (E 4)⁴⁹ to 15% remain who are non-responders to both types of stimulants.(E 4)⁴¹ (E 4)⁴² This is, after all, 1.6 to 2.5 times the rate of purely random double non-responsiveness (30% × 20% = 6%), which suggests that there are indeed common factors influencing responsiveness, even if they are few in number.

REVIEW of Treatment Options for Treatment-Resistant ADHD: Cortese et al. (E 4)²¹¹

• Optimize stimulants

• Try alternative monotherapies

• Try non-stimulants

• combination drug therapy

  • A combination of stimulants and non-stimulants is superior to monotherapy with only one class of active ingredients

• Use off-label medications that have been shown to help with ADHD

• Treat comorbid conditions

2.2.8.2. Side Effects: Drug-Drug or Drug-Active Ingredient Interactions¶

To avoid side effects, see the section below titled “Avoiding Side Effects.”

• MPH

  • in the event of severe side effects:

    • Check: Have the recommendations under “Avoiding Side Effects” been followed, particularly regarding the complete elimination of caffeine?

    • Overdose?

    • Do you need a very low dosage?

    • when MPH generally responds:

      • Change the product first

        • surprisingly varied side effects

          • Person A cannot tolerate medication A but tolerates B just fine; Person B is exactly the opposite: it’s unpredictable

        • Alternative products, e.g.:

          • immediate release

          • Medikinet Retard / Adult

          • Ritalin LA / Adult

          • Concerta

          • Kinecteen

      • then switch to a different active ingredient

        • For recommended order of use, see above under “Medication Selection”

• AMP

  • in case of severe side effects:

    • Check: Have the recommendations under “Avoiding Side Effects” been followed, especially regarding the complete elimination of caffeine?

    • Overdose?

    • Do you need a very low dosage?

    • when AMP responds in general:

      • Change the product first

        • surprisingly varied side effects

          • Person A cannot tolerate medication A but tolerates B just fine; Person B is exactly the opposite: it’s unpredictable

        • Alternative products, e.g.:

          • Lisdexamfetamine (Vyvanse)

          • immediate release (Attentin)

          • Amphetamine solution (to be prepared by a pharmacy)

          • United States: a large number of additional approved drugs

      • then switch to a different active ingredient

        • For recommended order of use, see above under “Medication Selection”

2.2.8.3. Conversion Tables for Switching Between Stimulants¶

In addition to medication changes due to non-response, supply issues are another reason to consider dosage conversions. Since October 2022, mixed amphetamine salts have been on the FDA’s shortage list in the U.S., and since July 2023, lisdexamfetamine and methylphenidate have also been added to the list. In the United Kingdom, a shortage of sustained-release methylphenidate, lisdexamfetamine, and sustained-release guanfacine was reported in September 2023.

A conversion table from dexamfetamine to Vyvanse can be found on ADHSpedia. (E 4)²¹²

When switching medications or active ingredients due to side effects, the conversion table by Kühle is very helpful (in German). It provides a guide to which dose of a different type of stimulant corresponds to the dose of the previously taken medication. The UpToDate conversion table (in English) is also helpful.(E 4)²¹³

A comprehensive conversion table for American stimulant preparations, including recommendations for the transition process, can be found in Stutzman et al. (E 4)⁴⁷

According to the prescribing information, a fixed ratio of 2 to 1 applies when switching between racemic methylphenidate and dexmethylphenidate. The daily dose of dexmethylphenidate is half the previous daily dose of methylphenidate, because only the d-enantiomer is active. A 1-to-1 conversion will result in underdosing. For immediate release dexmethylphenidate, treatment begins with 2.5 mg once or twice daily and is increased by 2.5 to 5 mg weekly. The maximum daily dose is 20 mg. In contrast, a 1:1 switch is expressly prohibited for Onyda XR, DR/ER-MPH, and sustained-release clonidine; these formulations must be retitrated.²¹⁴

A 2026 review article presents a systematic framework, including a dose equivalence table and conversion formulas. The principles outlined in the article are as follows:²¹⁵

• Start by switching within the same class of active ingredients
  • Switching between methylphenidate formulations helps maintain symptom control
  • The isomer composition must be taken into account, as dexmethylphenidate is approximately twice as potent as racemic methylphenidate and requires a 50 percent reduction in dose when switching.
  • Release mechanisms must be taken into account, as OROS technology and bead-based systems differ significantly.
• Only after alternatives within the same class have been exhausted should switching between amphetamine and methylphenidate be considered.

2.2.9. Development of Tolerance to Stimulants / Habituation Effects¶

For more details, see ⇒ Medications: Development of Tolerance

2.2.10. Withdrawal from Stimulants¶

(ADxS experience): Stimulants such as methylphenidate or amphetamine-based medications have an immediate effect that is dose-dependent. As a general rule, they can be discontinued immediately and without side effects. Compared to the—sometimes very severe—side effects that people with ADHD repeatedly report from discontinuing antidepressants—especially when done too quickly (for context: Dreher (2026) (E 4)⁹), it can generally be said that stimulants do not pose any withdrawal issues. However, people with ADHD then suffer from the recurrence of ADHD symptoms, which can subjectively be misinterpreted as a withdrawal side effect.

(ADxS experience): However, there are reports from affected individuals of withdrawal symptoms associated with amphetamine medications; in isolated cases, these have even lasted up to 14 days. For a minority of people with ADHD, these symptoms appear to go beyond the unpleasant experience of the recurrence of ADHD symptoms. It is not known whether this is related to a previous overdose. It is noteworthy that these reports originate primarily from the United States. In one individual case known to us, withdrawal symptoms were reported upon discontinuation of a 10-fold overdose of Vyvanse (50 mg, while the patient required only 5 mg).

If necessary, withdrawal symptoms upon discontinuation should be managed by gradually reducing the dose.

A systematic review of 35 studies on the planned discontinuation of stimulants in children and adolescents found no significant problems with discontinuation. Two specific findings emerged: ²¹⁷

• There was a distinct group of people with ADHD who, upon discontinuation, experienced neither a relapse nor a worsening of their condition, which justified regular attempts to discontinue treatment to assess whether treatment was still necessary.
• Caution is advised when administering antipsychotics (risperidone, aripiprazole) concomitantly. In several case reports, dystonia occurred within 33 hours to 10 days after abrupt discontinuation of the stimulant. In this scenario, a gradual tapering-off under close observation for movement disorders is recommended.
  • Four studies describe seven children with acute dystonia following discontinuation of a stimulant (MPH, such as AMP, in combination with risperidone or aripiprazole). In five cases, it occurred within 33 hours; in two cases, within ten days.
  • With the stimulant, the increased dopamine levels that counteract dopamine blockade are no longer present, which enhances the antipsychotic’s binding in the striatum.
  • The disorders resolved while the patient was taking anticholinergic medications or after the medication was resumed.
  • Conversely, withdrawal dyskinesias may occur when the antipsychotic is discontinued while stimulant treatment is ongoing; this has been described in three case reports following both sudden and gradual discontinuation. In some cases, they persist for several weeks after the stimulant has been discontinued. It is recommended to taper off the antipsychotic over a period of weeks and to discontinue the stimulant immediately as soon as involuntary movements occur.
  • Another case report involves a 13-year-old girl who experienced painful calf cramps after discontinuing immediate release methylphenidate for the summer break.

2.2.11. Medication Adherence¶

Although ADHD medications do not cure the condition, most people with ADHD do not take medication for the rest of their lives or take breaks from medication lasting more than 12 months.

This may indicate fluctuating ADHD. For more information, see Fluctuating ADHD in the article “ : ADHD in Adults”.

In the largest study on medication adherence, which included 1,229,972 new patients from 9 countries between 2010 and 2020, 65% of children, 47% of adolescents, 39% of young adults, and 48% of adults were still taking their medication one year after treatment began. After five years, the figures were 24% of children, 9% of adolescents, 10% of young adults, and 15% of adults. Including cases where treatment was resumed after interruptions, 30 to 60% remained in treatment for five years. Treatment continuity among adolescents and young adults was lower than would have been expected given the known persistence of symptoms in these age groups.²¹⁸

Among n = 43,825 children and adolescents aged 6 to 18, only 43% took the medication consistently. The strongest influencing factor was age at the start of treatment. Those who started between the ages of 6 and 12 were more than four times as likely to continue taking it as those who started between the ages of 17 and 18 (OR 4.29; 95% CI 3.93–4.69). The longer the interval between diagnosis and the start of medication, the lower the adherence (OR 0.80 per year). As a first-line medication, lisdexamfetamine was associated with the highest adherence (OR 2.2; 95% CI 1.86–2.59) and was the only active ingredient to show consistent adherence rates across all age groups. However, the sample size was small (n = 654). Male gender (OR 1.47) and lower socioeconomic status were also associated with higher medication adherence.²¹⁹ The study measured continued prescription filling, not treatment success.

A systematic review of k = 91 original studies showed that part of the apparent lower adherence to immediate release stimulants compared with sustained release stimulants is attributable to the titration process itself. Immediate release formulations are often used for the initial titration and are subsequently switched to sustained release formulations as scheduled. For studies that rely on medication databases, this routine switch in formulations appears to be a discontinuation.²²⁰
The reported continuation rates ranged from 0.1% to 89.9%, depending on the permitted gap between prescriptions and the observation period. Most studies found adherence rates below 80%, which is generally considered low for ADHD treatment. Long-acting medications consistently had a higher continuation rate than short-acting stimulants. Adherence rates for ADHD are comparable to those for schizophrenia, bipolar disorder, dyslipidemia, diabetes, and hypertension; thus, the problem is not specific to ADHD. Side effects were consistently the most common reason for discontinuation, regardless of the drug class. Careful monitoring of dosage titration—including consideration of tolerability—therefore helps prevent the most common reason for discontinuation (“start low, go slow” avoids unnecessary side effects). Children and adolescents demonstrated higher adherence to non-stimulant medications than to stimulants. Among adults, adherence tended to be higher with amphetamine-based medications than with methylphenidate.

2.3. Single dose of immediate release MPH¶

Immediate-release MPH, on the one hand, allows for better monitoring of symptom improvement; on the other hand, it requires more reliable patient compliance due to the higher number of doses per day. Therefore, a single daily dose of sustained-release medication may be recommended for children, and especially for younger children.

According to the 2018 German S3 guideline, immediate-release MPH may be considered, for example, for the following reasons: (E 4)²²⁴

• More precise dose adjustment during the initial titration phase of the medication

• the need for greater flexibility in dosing regimens

Based on our experience, we recommend the following:

• Start with a single, very low dose (2.5 mg of immediate release MPH) and, for the time being, make a conscious effort not to expect any effects at all.

  • Since half-day-release MPH is available in doses starting at 5 mg, a 5-mg dose of sustained-release MPH can be taken instead of two doses of immediate-release MPH (typical duration of action: approx. 5–6 hours)

• After 4 to 7 days, 2.5 mg of immediate release medication taken twice daily

• Continue to increase the number of single doses every 4 to 7 days until the entire day is covered.

  Immediate-release MPH lasts only 2.5 to 3 hours, 3 to 5 single doses are required for full-day coverage. With only two doses, almost the entire day would go without medication. This could completely distort the assessment by people with ADHD or by third parties, especially if they have not been informed about the limited duration of action (and the expected rebound effect). Above all, however, it would not sufficiently alleviate the symptoms and thus the burden on the person with ADHD.

• Increase single doses to 5 mg (sustained release to 10 mg per single dose)

  • When doing so, increase only a single dose at a time for each dose adjustment, starting with the first dose (e.g., 2.5 / 2.5 / 2.5 to 5 / 2.5 / 2.5 to 5 / 5 / 2.5, etc.)

• After that, increase the dose by a maximum of 2.5 mg per single dose of immediate release MPH every 4 to 7 days.

  We consider dose increments of 5 mg of immediate release MPH per single dose (or 10 mg per single dose of half-day extended-release MPH, as recommended, for example, in the Medikinet prescribing information) to be detrimental.

  • Purpose: Gradually increasing the dose prevents the optimal dose from being skipped.

    • In our experience, while not many, a significant proportion of people with ADHD have a very narrow window for optimal dosing—well below 5 mg—such that 2.5 mg less per single dose is insufficient, and 2.5 mg more can already trigger the first signs of an overdose. Similarly: Dreher. (E 4)⁶⁴ It is likely that cases of intolerance have frequently been assumed in the past when, in reality, they were due to inappropriate dosages.
    • (E 1a): Since such small dosing increments do not harm other people with ADHD (but, on the contrary, help prevent dose-related side effects), (E 4)²²⁵ dosage adjustments in 2.5-mg increments (based on a single immediate-release dose of MPH) should be the gold standard. Kühle concurs. (E 4)²²⁶ A large meta-analysis points in the same direction. (E 1a)¹⁰²
    • Other sources recommend starting with 1–2 single doses of 5 mg and increasing the single dose weekly in 5-mg increments. (E 4)²²⁷ For the reasons mentioned, we consider these dose increments to be too large.
    • For people with ADHD, for whom even extremely small differences in dosage are critical, a pharmacy in Switzerland offers MPH drops. One drop contains 0.35 mg of MPH. It is manufactured in batches and preserved with E216 and E218.(E 4)²²⁸ One person with ADHD reports that dissolving immediate release MPH in alcohol in such precise quantities that they could be measured drop by drop yielded a comparable result. The typical amount of alcohol—20 drops = 1 ml of 50% alcohol—corresponds to 1/40 of 0.2 l of wine or 0.5 l of beer.

• Inform people with ADHD and (informed) third-party observers about

  • the typical duration of action of the respective medication

  • the option of a shorter or longer duration of action, depending on individual needs

  • about the expected rebound

    • Knowing the typical duration of action—and that it can vary from person to person—is just as important for monitoring the effect and its end as it is for ensuring that the last dose is taken well in advance of bedtime so that the effect has worn off at least one hour beforehand. For some people with ADHD (we suspect this is more common in ADHD-I than in ADHD-HI), a reduced dose (1/5 to 1/2 of an optimized single dose) in an immediate release form may help with falling asleep. The same principle applies here: Test very low doses (1/10 of the single daily dose) when using the medication as a sleep aid. When doing so, convert sustained-release daily doses to the duration of action of the immediate release form. (Example: 20 mg of a sustained-release formulation with a 5–6-hour duration of action corresponds to 10 mg of an immediate release formulation with a 2.5–3-hour duration of action.)

• Increase the dosage until a very satisfactory effect is achieved.

  • At the group level, symptoms decrease linearly as the dose increases—however, this does not apply equally to every child, and the side effects reported by parents also increase linearly with the dose. (E 1b)²²⁹

• When the daily dose of MPH is 20, 40, or 60 mg, a follow-up consultation with the treating physician should take place in each case.

• It is also recommended that you keep a diary (see below). Some doctors expect you to submit your diary weekly, for example, by email. This can help identify any adverse developments early on.

• After reaching the supposedly optimal dose, increase it two more times to determine whether any adverse symptoms now appear.

  Purpose:

  This ensures that not only are symptoms improved, but the optimal dose is also determined. Furthermore, the person with ADHD learns what it feels like when the dosage is slightly too high. This is important so that the person with ADHD can develop a sense of what the optimal dosage is and, if necessary, suggest further dose reductions.

• It is possible that side effects may occur at certain dosage levels below the optimal dose, which then disappear again at higher dosage levels. In particular, internal tremors (like having one too many cups of coffee) may subside within 2 to 3 days after a dose increase. This may be due to the noradrenergic system adjusting. Several people with ADHD have reported to us that this internal trembling no longer occurred at the next or subsequent dosage level. If it becomes more pronounced or persists, it is a sign of overdose.

• “Zombie” symptoms often indicate either an overdose or depression that has come to the surface.

  • A meta-analysis of studies on mood- and emotion-related side effects in children and adolescents showed that, compared to placebo, MPH increased the risk of irritability, anxiety, and euphoria, but increased the risk of apathy and reduced speech. Amphetamines increased the risk of emotional lability. Relevant factors influencing the risk included dose and dosage form. Particularly high doses of immediate-release MPH in younger children and girls were associated with an increased risk of affective flattening (“zombie mode”), which supports the interpretation of apathy and emotional flattening as dose-dependent phenomena rather than an unavoidable property of the drug.²³⁰

• Stimulants block sensory filters: This is likely one of the reasons why students may “try out” stimulants during stressful exam periods (which we strongly advise against), but then stop taking them on their own initiative afterward. In fact, students who misuse stimulants during exam periods exhibit an above-average number of ADHD symptoms. (E 3)²³¹

• People (other than people with ADHD) who do not have a stimulus filter that is too open experience a reduced quality of life as a result. We are aware of barely any reports of students who voluntarily take MPH outside of highly stressful exam periods (unless they have severe ADHD symptoms (E 2b)²³² )

• Stimulants inhibit the limbic system. An overdose can therefore diminish emotional sensitivity. (E 4)²³³

• The manufacturer’s information regarding the typical duration of action applies only to individuals with standard variants of the metabolism-related genes. However, many people with ADHD have variations in the relevant metabolism gene (MPH: CES1 gene; AMP / atomoxetine / bupropion: CYP2D6 gene; guanfacine: CYP3A4 gene). In addition to CYP 450 enzymes, there are genetic variants of the POR gene that, in turn, influence the efficacy of the CYP enzymes; therefore, the CYP genetic variant alone is not sufficient to draw conclusions. For more information, see CYP2D6 Metabolizing Enzyme, CYP3A4 Metabolizing Enzyme, CES1 Metabolizing Enzyme. In addition, there are other pharmacological factors that influence the duration of action. For more information, see Effects and Duration of Action of ADHD Medications

• Variations are so common that the typical duration of action cannot be assumed. It must be assessed individually for each person with ADHD.

  • According to our survey, a single dose of Vyvanse lasts for only 5 to 7 hours at most in two-thirds of people with ADHD. The typical duration of 12 hours specified by the manufacturer is therefore far from being achieved by the majority of people with ADHD.

  • In fast metabolizers (approximately 15 to 20 percent of people with ADHD), immediate-release MPH lasts only about 1 to 1.25 hours instead of the usual 2.5 to 3 hours, Medikinet or Ritalin for adults lasts only about 3 hours instead of the usual 5 to 6 hours, and Vyvanse lasts 5 to 7 hours instead of the usual 10 to 12 hours. The rapid metabolizers known to us reported that they tolerated the correspondingly more frequent dosing and higher daily doses well, without any side effects. Nevertheless, given the required increase in the number of doses per day and the resulting potential for exceeding the general maximum dosage recommendations, closer monitoring is certainly necessary.

  • (E 4): Amphetamines are only partially metabolized in the liver (via CYP2D6, among other enzymes). A significant proportion is excreted unchanged via the kidneys. This excretion depends heavily on the pH of the urine: acidic urine (low pH) significantly accelerates excretion, thereby shortening the potency and duration of action, while alkaline urine slows it down. If the effect of amphetamine medications is too weak or too short-lived, measuring the urine pH at the time of administration and, if necessary, adjusting the urine pH through diet (keyword: PRAL value) may be helpful. Conversely, deliberately alkalizing the urine increases the risk of an overdose. It should therefore only be done after consulting a physician. (E 4)²³⁴ (E 4)²³⁵

• Excessively rapid metabolism may, in some cases, be countered by cross-inhibition with inhibitors of the relevant metabolic enzyme. For example, several people with ADHD for whom LDX (whose active ingredient, dAMP, is also metabolized to a lesser extent via CYP2D6) had a much too short duration of action or no effect at all reported a satisfactory effect and duration of action after combining it with bupropion (which inhibits CYP2D6). Since both substances can lower the seizure threshold, such a combination should only be considered after a physician has weighed the benefits against the risks.

2.4. Transition to sustained-release MPH / AMP¶

(E 3): Once treatment with immediate release MPH has been initiated, the number of daily doses should be reduced by using extended-release formulations, since administering the 4 to 6 daily doses of immediate release MPH that would otherwise be required (E 4)²³⁶ is barely possible for children and adolescents to maintain. Medication adherence decreases in proportion to the required frequency of administration. (E 3)²³⁷ Since people with ADHD are notoriously disorganized and forgetful, each additional dose presents another opportunity to forget to take the medication. Furthermore, the embarrassment and teasing that adolescents experience when they have to pick up their medication from the school nurse are among the most common reasons for discontinuing medication treatment. (E 4)⁸ A single daily dose improves compliance. (E 4)²³⁸

Immediate release MPH is not approved for adults in Germany and can only be prescribed off-label.

Whether immediate release or sustained-release MPH works better varies from person to person. In a 1-year study, about half of the people with ADHD preferred immediate release MPH, while the other half preferred OROS MPH. (E 2b)²³⁹ As a rule, people with ADHD are better able to assess which type of medication they cope with better than the doctor. Therefore, the person with ADHD’s experience should be taken into account.

With sustained-release MPH, pharmacological methods are used to release several doses in succession.

Due to significant individual differences in the duration of action, it is possible (albeit rare) that the first dose is metabolized so quickly that a gap in efficacy occurs before the second dose takes effect. This can be avoided by taking several (possibly reduced) doses at staggered intervals. For example, if 20 mg of sustained-release MPH has an action profile of 2 hours of effect + a 30-minute gap in effect + 2 hours of effect, one option would be to administer two 10-mg sustained-release doses 30 minutes apart.

For people who have difficulty eating in the morning, Medikinet Adult and Medikinet Retard are not suitable, as these medications only provide their sustained release effect when taken with food. In such cases, Ritalin Adult, Ritalin LA, or an OROS formulation such as Concerta should be considered.

2.5. AMP Dosage¶

In addition to the general information provided above regarding the dosing of stimulants and determining the appropriate starting dose, the following applies:

2.5.2. Lisdexamfetamine (Vyvanse, Tyvanse)¶

The manufacturer-recommended starting dose of 30 mg for lisdexamfetamine was not determined in clinical trials. The manufacturer has not conducted any studies using starting doses lower than 30 mg. The establishment of the 30-mg starting dose is therefore based solely on regulatory considerations. It is not supported by any pharmacological studies.

• Since amphetamine-based medications are the first choice of medication for adults (offering the greatest effect size and fewest side effects among all ADHD medications), it would make sense to start treatment directly with these medications.

• Vyvanse/Tyvanse/Tyvanse contains lisdexamfetamine dimesylate. Lisdexamfetamine dimesylate is dextroamphetamine base bound to lysine. The lysine bond results in a slower and more steady release of dextroamphetamine into the bloodstream, thereby providing a longer-lasting effect compared to dextroamphetamine sulfate medications.

  The following are available in the U.S.:

  Capsules: 10, 20, 30, 40, 50, 60, 70 mg

  Chewable tablets: 10, 20, 30, 40, 50, 60 mg

• In our experience, the 30 mg dose recommended as the standard initial dose carries a significant risk of overdose and increases the risk of side effects associated with the initial dose.

  • We know of quite a few adults with ADHD for whom the optimal dosage range for Vyvanse falls below a margin of 5 mg per single dose. 5 mg less is too little; 5 mg more is an overdose. We also know of individual people with ADHD for whom 3 mg of Vyvanse per day is the optimal dose. Therefore—contrary to the majority opinion—we would consider dosing increments of 5 mg of LDX dimethylate to be more appropriate than the officially recommended 10 mg increments. See also the section above on titration of immediate release MPH.

  • There are also people with ADHD who experience LDX side effects at lower doses, which disappear at higher doses. It is unknown whether these are general side effects associated with the dose—which would have occurred for a limited time even at higher doses—or side effects specific to low doses.

  • Starting with lower doses therefore has both advantages and disadvantages.

    • It requires more persistence when dispensing

    • It reduces the risk of side effects from an overdose

    • It increases the risk of side effects associated with underdosing

    • With sufficient perseverance and persistence, it increases the likelihood of finding the right dose for each individual

    • For people with anxiety, it is often difficult to muster this kind of perseverance and persistence. In such cases, it is recommended to start with the standard initial dose of 30 mg.

    • In any case, the treating physician’s decision is final

  • In 2002, the American Academy of Child and Adolescent Psychiatry (AACAP) recommended a starting dose of 2.5 mg of dextroamphetamine or mixed amphetamine salts—in each case, immediate release—administered in 2 to 3 daily doses. (E 4)¹⁹

• The maximum daily dose of dextroamphetamine sulfate from lisdexamfetamine recommended by the FDA (28 mg of dextroamphetamine sulfate, derived from 70 mg of lisdexamfetamine) is lower than the maximum recommended daily dose of dextroamphetamine sulfate from immediate release dextroamphetamine preparations (40 mg).

• In a study of 4- to 5-year-old children with ADHD, in which treatment began with a dose of 5 mg of LDX and was increased by 5 mg of LDX each week, 19 out of 24 children reached an optimal dose: (E 2b)²⁴²

  • 10 mg at 10.5% (2/19)

  • 15 mg in 31.6% (6/19)

  • 20 mg at 10.5% (2/19)

  • 30 mg in 47.4% (9/19)

  • 5 out of 24 discontinued treatment

  • The mean daily dose of LDX in Week 8 was 22.9 mg/day (SD 7.25 mg).

• In a subsequent Phase III study involving N = 199 preschool children treated with fixed doses of lisdexamfetamine dimesilate ranging from 5 to 30 mg, there was also no evidence of disadvantages associated with a low dose or advantages associated with a higher dose. Rather, the dose-response relationship was highly individualized. (E 1b)²⁴³

• Although the Vyvanse package insert does not permit dividing the capsule contents, based on many years of experience among a large number of people with ADHD, this is a practical approach for both administering the medication and determining the optimal dose. We are not aware of any reports of fluctuations in efficacy due to uneven distribution of the active ingredient. Precise dosing can be achieved—to within a milligram—by dissolving the capsule contents in water and dividing the solution using a syringe. This is also noted by Kühle in the equivalence table (E 4):⁴⁵ A somewhat less precise method involves dividing the capsules into equally sized piles using a razor blade on a glass surface.

• Vyvanse dissolved in water will keep in the refrigerator for a few days. Small mounds of Vyvanse spread out on a dry glass plate will keep at room temperature for several days. You can further extend the shelf life by covering them airtight with food-grade plastic wrap. However, this is generally not necessary. Always keep the product out of the reach of children.

• Due to its long half-life, Vyvanse can take up to 5 days to reach steady state. (E 2b)¹⁰⁵ After a break in taking the medication, unpleasant side effects may occur during the first few days, but these subside quickly.

This video explains how to split Vyvanse capsules into smaller doses (German).

2.5.3. Adderall (immediate release and sustained release)¶

(E 4): The FDA recommends the following single dose of immediate release amphetamine salts (Adderall) for ADHD: (E 4)²⁴⁴ (E 4)²⁴⁵

• Children under 3 years of age: Amphetamine is not recommended

• Children ages 3 to 5:

• immediate release AMP

• Starting dose of 2.5 mg once daily in the morning after waking up

• Subsequent doses at 4- to 6-hour intervals

• weekly increase in 2.5 mg increments until the optimal response is achieved

• Dosage range between 2.5 and 40 mg per day, divided into 1 to 3 doses

• Children ages 6 and older

• immediate release AMP

• Initial dose of 5 mg once or twice daily at 4- to 6-hour intervals

• Weekly increases in 5-mg increments until the optimal response is achieved

• Dosage range of 5 to 40 mg per day, divided into 1 to 3 doses

• sustained release AMP

• Starting dose of 5 to 10 mg once daily in the morning

• Weekly increases in increments of 5 to 10 mg until the optimal response is achieved

• Maximum daily dose: 30 mg per day

• Teens

• immediate release AMP

• Initial dose of 5 mg once or twice daily at 4- to 6-hour intervals

• weekly increase in 5-mg increments until the optimal response is achieved

• Dosage range between 5 and 40 mg per day, divided into 1 to 3 doses

• sustained release AMP

• Starting dose of 10 mg once daily in the morning

• weekly increase in 10-mg increments until the optimal response is achieved

• Insufficient evidence of better results at doses higher than 20 mg per day

  • Note: This does not correspond to the experiences with Vyvanse in Europe

• Adults

• immediate release AMP

• Initial dose of 5 mg once or twice daily at 4- to 6-hour intervals

• Weekly increase in 5-mg increments until the optimal response is achieved

• Dosage range of 5 to 40 mg per day, divided into 1 to 3 doses

• sustained release AMP

• Initial dose of 20 mg once daily in the morning

• Insufficient evidence of better results at doses higher than 20 mg per day