Dosing of Medications for ADHD

Completely revised 08/2026

 

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 in 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.

Optimal medication for ADHD often requires a highly individualized and finely tuned dosing regimen and adjustments. A purely formulaic approach to medication is not possible for ADHD.
Determining the optimal dosage of medication for ADHD depends on the type of medication.

The first clinical trials for dosing in ADHD are currently underway.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¶

In general, up-dosing that starts with low doses and increases them flexibly and individually offers a clear advantage over the administration of fixed doses.² This has been known since the 1970s³ and is confirmed by a new, comprehensive meta-analysis⁴. Studies also use a gradual up-dosing to avoid side effects.⁵
With both MPH and AMP, as the dose increases, both efficacy and the likelihood of discontinuation due to side effects rise. In fixed-dose studies in children and adolescents, the additional therapeutic benefit declined above approximately 30 mg of MPH or approximately 20 mg of AMP per day (converted to immediate release MPH hydrochloride or mixed amphetamine salts).⁴ In adults, this threshold is slightly higher: for MPH, the benefits diminish above approximately 35 to 40 mg/day, while for AMP, the curve flattens out to a plateau starting at approximately 30 to 35 mg/day.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.⁷

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

The fact that the approach of using fixed doses—which is significantly less suitable in practice—is still sometimes encountered appears to stem in part from the fact that the FDA requires studies using fixed doses for drug approval. Dreher makes a similar point regarding receptor-targeted medications⁹, even though this is not directly applicable to ADHD medications, which primarily act on transporters. The fact remains, however, that approval studies are not designed with individual clinical use in mind.
To determine the lower limit of the therapeutic range, it is more useful to employ study designs in which different patient groups each receive doses that result in a predefined blood concentration range of the drug.¹⁰ The clozapine study by VanderZwaag et al. was cited as a positive example.¹¹ Due to the logistical effort and the resulting costs, fixed-dose studies are preferred for determining the lower limit of the therapeutic reference range.

The guidelines in Germany and the U.S. do not specify fixed doses, but rather call for up-dosing.
In our experience, it is best to take a more gradual approach than the one outlined there.

2.1.1. Immediate release or sustained release stimulants¶

A single dose of MPH can be administered using either immediate release MPH or sustained release active ingredients.
A single dose of immediate release MPH is common. A single dose of sustained release MPH is also recommended.^{26 27} The physician will need to weigh the disadvantage of more frequent dosing with immediate release MPH—since only regular dosing ensures a consistent effect without rebound effects—against the advantage of more precise dosing when patients are sufficiently responsible. This issue generally does not arise in school-age children.

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.

In the U.S., once-daily dosing with long-acting amphetamine salts is common (Adderall XR).

2.1.2. Initial dose¶

In general, the appropriate dose must be determined individually for each person with ADHD. Therefore, studies that statistically determine the “optimal” dose of stimulants are of limited use for individual treatment.

In general, stimulants are administered 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.⁸
In 2002, the American Academy of Child and Adolescent Psychiatry (AACAP) recommended a starting dose of 5 mg for MPH and 2.5 mg for dextroamphetamine or mixed amphetamine salts, both in immediate release form, taken in 2 to 3 daily doses.¹⁸

The EMA recommends starting treatment with MPH at the lowest possible dose.¹²

• low starting dose (2.5 mg immediate release MPH/single dose or the equivalent in other medications)²⁸²⁹ , or 5 mg half-day immediate release MPH³⁰
• at least 5 days per dose level
• Dosage increments: max. 2.5 mg unret. MPH per single dose
• The optimal dose varies greatly from person to person²⁸²⁹
• Effect of slow dosing:
  • reduces side effects
  • prevents patients from skipping the correct dose due to the sometimes very narrow therapeutic range²⁸²⁹

In Germany, a single dose of 5 mg of immediate release MPH was recommended for school-age children in 2004. ³¹ 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.

The equivalent of 5 mg of immediate release MPH in Vyvanse is 10 mg. When titrating in 2.5 mg increments of immediate release or 5 mg increments of sustained release, the corresponding equivalent is 5 mg increments of Vyvanse.³²³³ Another conversion table, specifically for U.S. formulations, can be found in Stutzman et al.³⁴
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.

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.³⁶

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

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

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 up-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: ²⁷

• Concerta: Start with 18 mg, increase by 18 mg weekly
• Medikinet retard: Start with 10 mg, then increase by 10 mg weekly

Mutschler also recommends starting with a low dose and increasing it gradually.³⁷
“Undesirable side effects are most likely to occur at the start of treatment, which is why the dosage should be increased gradually.”³⁸
In the Italian ADHD registry, approximately three-quarters of 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.³⁹ In the interest of the remaining quarter as well, side effects should be minimized through slow titration.
Of n = 1,350 children and adolescents (ages 6 to 18) treated with MPH, 369 (25.9%) experienced at least one mild adverse event and 64 (4.5%) experienced at least one severe adverse event. The rate of severe adverse effects with MPH was higher than with atomoxetine (4.5% versus 3.1%), while MPH performed better in terms of mild adverse effects. Overall, MPH had the more favorable safety profile based on incidence rates per 100 person-years. Since this is a spontaneous reporting system, underreporting is to be expected.³⁹

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

Low doses of stimulants have a different effect and act on different regions of the brain than higher doses.⁴⁰

• Low-dose MPH

  • It increases norepinephrine in the hippocampus, but not dopamine in the nucleus accumbens. Only higher doses of MPH also have a dopaminergic effect here.⁴¹
  • Low doses of MPH (0.25 mg i.p. / kg) selectively activate norepinephrine and dopamine neurotransmission in the PFC (working memory, executive functions, inhibition, emotion regulation), but barely have an effect in other brain regions⁴²
  • 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—or 5.7 to 11.4 mg for a 70-kg individual) reduce (hyper)activity, while higher doses increase drive⁴³ Low doses increased resting dopamine levels and thereby reduced the impulse-related rise in dopamine. This flattened the 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.

• Even in cases of severe symptoms, a very low dose may be appropriate for some individuals.⁴⁴ Huberman reports a single case in which the optimal daily dose was 2.5 mg of Adderall (a woman weighing 150 kg).⁴⁵ In a classic study of 20 hyperactive children who were sequentially administered 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 teacher ratings of social behavior were 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—in contrast, for teacher assessment, the figures were 0%, 28%, and 72%.⁴⁶ We know several people with ADHD for whom a single dose of 1.25 mg of immediate-release MPH is optimal.

• gradually acclimating the body to the active ingredient to avoid side effects that could lead to an unnecessary discontinuation of ADHD medication.⁴⁷⁴⁸

• A dosage that is too high leads to a recurrence of the ADHD symptoms that were prevented at the appropriate dosage (inverted-U curve).⁴⁹

• Undesirable side effects increase significantly when the dose exceeds the optimal level.⁵⁰

However, we have also received isolated reports from people with ADHD in whom low doses caused severe side effects that disappeared at higher doses. We do not know, however, whether the side effects resulted from the low dose or from the initial administration itself.

2.1.4. 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.⁸
In our view, however, there are a number of clear arguments against up-dosing:

• 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 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 effects 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 duration of action (sustained-release, prodrug), the longer the increments should be. Due to its long half-life, dextroamphetamine reaches steady state; in a multiple-dose study in healthy adults, steady state was reached around the fifth day.⁸² 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 with once-daily dosing, although the duration of the increments can be reduced in that case.
For MPH, the duration should be at least 4 days, but 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 4³¹ (we mean: more like 5 to 7) days are needed to allow for an assessment.
We do not consider the 1-month duration of each dose adjustment step, as practiced by some doctors, to be very sensible. It offers no benefits and may be necessary only to compensate for dosing increments that are too large.

A German dosing regimen for school-age children using immediate-release MPH was as follows:³¹ However, this recommendation dates from 2004, when 5 mg of immediate-release MPH was the smallest 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).)

Duration	; Mornings	; Afternoon
3 days	5 mg	-
4 days	10 mg	-
Medical Consultation for Evaluation
5–8 days	10 mg	5 mg
Further individualized dose titration in 5- to 8-day increments

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.

2.1.5. Target dose¶

The optimal dosage of an active ingredient and medication that is appropriate for a person with ADHD must be determined on an individual basis in two dimensions:⁸³

• Single-dose amount
• Number of daily doses

2.1.5.1. Target Factor 1: Single-Dose Amount¶

In our view, the “optimal dose” should be the lowest dose that produces an optimal therapeutic effect. Some guidelines, however, recommend the dose at which no further improvement is observed.⁵⁰ In our opinion, this 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 being available only 70% of the time— (meta-analysis, n = 127) ⁸⁴, with similarly high discontinuation rates in other studies⁸⁵⁸⁶ — priority should be given to minimizing side effects. Side effects were the most frequently cited reason for discontinuation in this review.⁸⁴

Since there are marked individual differences in dose-response patterns, the optimal dose must be determined on a case-by-case basis. In this regard, the art of treating patients with MPH (and stimulants in general) goes well beyond simply “fine-tuning the dosage.”⁵⁰

2.1.5.1.1. Dosage should not be determined on a one-size-fits-all 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.
The amount of methylphenidate that is absorbed (actually enters the bloodstream) varies considerably from person to person: For the dextro-rotating MPH isomer, which is the only active form, values ranging from 11% to 43% have been reported.⁸ This percentage remains largely constant over time for a given individual but varies greatly from person to person. For this reason alone, using a flat-rate calculation based on body weight is not appropriate.²

There may be a statistical average indicating 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 case-by-case matter. Relying solely on a statistical average would constitute medical malpractice.

However, it is reported that in cases of obesity, the maximum dose of 1 mg/kg is required more frequently.⁸⁷

2.1.5.1.2. 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. The following are frequently mentioned in this context:

• inattentive subtype
• concomitant ASA
• Adults often require lower doses than adolescents or children.

However, this does not rule out the possibility that people with ADHD in these groups may require very high doses.
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 0.5 mg of Vyvanse per dose provides optimal results.⁸⁸
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.⁴⁵ 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) achieved 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.

In the ADxS Drug Duration of Action Survey conducted by ADxS (as of Dec. 19, 23), 13% of 223 adult 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.

The optimal dose may exceed the standard maximum dose (especially in rapid metabolizers). This applies to methylphenidate as well as to amphetamine-based medications.⁸³
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 required in individual cases. The guidelines recommend 30 mg as the maximum dose per single administration.²⁷

It is strongly advised not to mistake the first sign of improvement as an indication of an appropriate dose level, nor to treat arbitrary doses as target doses.⁸⁹ The dose should be persistently increased until two consecutive doses have resulted 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.

2.1.5.1.3. Maximum dose¶

A maximum dose of 1 mg/kg body weight or 60 mg/day for children and 80 mg/day for adults is often cited. A systematic review of 11 randomized trials and 38 cohort studies concludes that, while the literature recommends a wide range of maximum doses (0.8 to 1.8 mg/kg/day), it provides no discernible scientific justification 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)⁸⁰ The standard values are derived primarily from the manufacturers’ marketing authorization documents, in which the limitation of liability risks also plays a role.

The professional literature recommends not exceeding MPH doses of more than 150 mg/day.⁹⁰⁹¹ European treatment guidelines consider doses of up to 2 mg/kg/day or up to 108 mg/day—whichever is lower—to be acceptable and indicated for OROS-MPH in individual cases —whichever is lower—and are thus significantly higher than the maximum approved dose of 54 mg/day.²⁷

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.⁹²

 

The Dutch Poison Control Center has raised its threshold—the level at which it recommends hospitalization for accidental or intentional MPH overdose—to 3 mg/kg based on an analysis of 364 poisoning cases involving children and adults (previously 2 mg/kg). Regardless of the dose, hospitalization is still recommended if symptoms warrant it.⁹³

For therapeutic drug monitoring, the AGNP consensus guidelines for methylphenidate specify a laboratory warning level (at which the treating physician must be notified) of 50 ng/ml. The therapeutic reference range is 6 to 26 ng/ml for children and adolescents and 12 to 79 ng/ml for adults, measured 2 hours after an immediate release dose of 20 mg or 4 to 6 hours after a sustained release dose of 40 mg.⁹⁴

It is clear 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.

A meta-analysis of k = 47 studies involving n = 7,714 adults found that dosages exceeding the maximum daily doses recommended by the FDA⁶

• For MPH, there is evidence of minor further improvements in symptoms (SMD -0.23; 95% CI, -0.44 to -0.02; very low certainty of the results)
• No additional reduction in symptoms with AMP (SMD -0.08; 95% CI, -0.24 to 0.08; very low certainty of the results)
• MPH was also associated with significantly poorer tolerability: Discontinuation due to side effects was twice as common at off-label doses (OR 2.02; 95% CI, 1.19 to 3.43; moderate certainty of results)
• For AMP, however, the difference in discontinuation due to side effects between approved and unapproved doses was not significant (OR 1.19; 95% CI, 0.71 to 2.02); However, the dose-response curve showed a continuously increasing risk of discontinuation across the entire range studied

The results are averages and cannot be generalized to every patient. The authors conclude: “Clinicians may try doses above the recommended maximum doses if necessary and if tolerated, but should keep in mind that there may be no significant gains in response to the medication with these further dose increases.”

When AMP is administered multiple times a day, the maximum single dose for children and adolescents is 25 mg. ¹⁸

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

2.1.5.1.3.1. Maximum dose of methylphenidate¶

2.1.5.1.3.2. Maximum dose of amphetamine medications¶

2.1.5.1.3.3. Maximum dose of atomoxetine¶

2.1.5.1.3.4. Maximum dose of guanfacine¶

2.1.5.1.3.5. Maximum dose of clonidine¶

2.1.5.1.3.6. Maximum dose of bupropion¶

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

2.1.5.2.1. Full-Day Coverage as a Goal¶

The goal should be full-day coverage^{130144 145 146 147} — that is, coverage from 12 to 16 hours.¹⁴⁸¹⁴⁷
The amount of time medication coverage is needed throughout the day depends on various factors.⁸
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 workday
  • Demanding situations outside of work (events, social gatherings)
• Impulsivity and emotional dysregulation (requires 24/7 coverage; may be combined with ATX / guanfacine)
  • 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 stimulant medication, 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 treatment (more on this at: Reduced premature mortality, fewer suicides in the chapter “ : Consequences of ADHD”). Against this backdrop, it is objectively difficult to justify not treating existing ADHD at all or treating it only for part of the day.
  An accident that occurs during the part of the day when medication is not administered carries the risk of a liability claim.

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

The number of single doses of a suitable active ingredient and formulation required to cover a full day must be determined on an individual basis.⁸³ With MPH, the single-dose amount does not affect the duration of action of that dose, whereas with lisdexamfetamine, a higher single dose also prolongs the duration of action of that dose. ¹⁴⁹

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

• Multiple doses spread throughout the day (up to 3 half-day sustained-release doses)
• 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.¹⁵⁰
• Dyanavel XR, a particularly long-acting amphetamine preparation (not approved in Germany), is associated with a reduced need for additional doses of stimulants in immediate release form¹⁵¹

According to Dodson, the concern that stimulant medications might interfere with sleep is often unfounded.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.⁵
In children and adolescents, a meta-analysis of objectively measured sleep parameters found that stimulants were associated, on average, with a longer time to fall asleep, poorer sleep efficiency, and shorter sleep duration. (Effect size for sleep duration: -0.59). (Meta-analysis, k = 9, n = 246)¹⁵²
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

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

2.1.5.2.3.1. Manufacturer’s Specifications¶

Manufacturer’s specifications regarding duration of action (rarely achieved in practice)²⁸²⁹

• Immediate release MPH lasts 2.5–3.5 hours per single dose
  • 4 to 5 single doses are required for daily coverage
  • barely possible to implement in the long run, especially with children
  • For dosing, immediate-release MPH is still preferable, as it allows for the most precise control
• Half-day-release MPH is effective for an average of 4.5–6 hours per single dose
  • 2 doses + immediate-release MPH, if necessary, to cover the remainder¹⁴⁷
  • The second dose is usually 50% to 75% of the first dose
• Sustained-release, once-daily MPH 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.³⁶
  • 2 doses and, if necessary, immediate-release MPH for residual coverage
  • 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 any remaining needs
  • For people with a fast metabolism (more than 50%—a second dose may be necessary)
  • For patients with a very fast metabolism, a third or fourth dose should also be considered
• Guanfacine
  • Mirror medication, once daily
• Atomoxetine
  • Mirror medication, once daily

2.1.5.2.3.2. Prolonged effect (rather rare)¶

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

2.1.5.2.3.3. Shortened duration of effect (fairly common)¶

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 rapid metabolizers, for whom a single dose lasts only about half as long as indicated by the manufacturer. A moderately shortened duration of action is much more common.

• Fast metabolizers often need several doses per day instead of higher single doses
• According to our survey data, about half of the people with ADHD—particularly in the case of lisdexamfetamine—report that the duration of action is significantly shorter than the manufacturer’s specification.
• usually ultra-rapid metabolizers (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
• in particular:
  • 50% ATX for full-day treatment of emotional dysregulation
  • 50% MPH or AMP, as they generally have a better effect on energy 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 due to rebound
  • immediate release MPH shortly before the end of the last dose
    • 1/4 to 1/3 of what would be equivalent to a daily treatment dose
    • Example: 20 mg of half-day-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 end of the last sustained-release dose.

The phenomenon of a shortened duration of action per single dose occurs significantly more frequently 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 information, see Amphetamine Medications for ADHD: Effect Profile (Over Time) / Duration of Action
• Some people with ADHD report that intense sports can shorten the duration of stimulants by up to 40 percent.¹⁵⁴
• Higher doses of amphetamine have a longer-lasting effect in a person⁸
  • 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 the blood level of amphetamine changes more slowly and is less prone to rebound than with methylphenidate

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

People with ADHD must be explicitly informed of the typical duration of action of a single dose of the respective medication when administering a single dose. 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 pointing out the usual duration of action of 2.5–3 hours (immediate release) or 5–6 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.

2.1.6. Dosage Adjustments¶

• The perception that a very positive effect experienced after the initial adjustment wears off after a few days or weeks is often not due to a change in the effect itself, 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 evaluations 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 result of the body getting used to the device.
• A trial of discontinuing medication 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 the condition 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.

2.1.7. Intake Based on Need¶

The greater a person with ADHD’s ability to self-manage, the more likely they are to be able to take stimulants as needed. While a rigid dosing schedule is generally the safer approach for children, once the titration phase is complete, adults 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 can 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’s 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 doesn’t manage me.” ⁸⁷
During the titration phase, adults must not deviate from the prescribed regimen. We repeatedly see 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 of consistent dosing 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 Fluctuations in Symptoms in Women”.

2.1.8. Metabolism of Drugs and Active Ingredients¶

A change in medication or active ingredient may be necessary or helpful due to adverse side effects or because the patient is not responding to treatment (lack of effect).

If a medication has no effect (non-response), the first step—especially with MPH—should be to switch to a different MPH formulation. Surprisingly often, people with ADHD respond 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.¹⁵⁵

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

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 would have responded to one of the two types of active ingredients.¹⁵⁶ A meta-analysis of 32 studies reached the same conclusion (significantly better response rates to amphetamine medications than to MPH).¹⁵⁷

However, nonresponse rarely affects 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 who do not respond to MPH respond to atomoxetine.²⁷

When switching between methylphenidate and amphetamine-based medications, no medication break is required due to their short half-life. 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.⁸⁷ As a consequence, the standard conversion tables should be viewed with caution when switching active ingredients.

2.1.8.1. Non-responders: Drug Metabolism¶

• MPH: 30% non-responders
  • if MPH is ineffective:
    • Check stomach acid levels
    • Change the active ingredient
• AMP: 20% nonresponders
  • If AMP is ineffective:
    • Check the pH level of the urine at the time of administration

For more than 40% of people with ADHD who do not respond to treatment, switching medications within the first 3 months is helpful.¹⁵⁸
When there is a switch in active ingredient between MPH and AMP due to nonresponse, only about 10%³⁶ to 15% remain who are nonresponders to both types of stimulants.²⁸²⁹ This is, after all, 1.6 to 2.5 times the rate of purely random double non-response (30% × 20% = 6%), which suggests that there are indeed common response factors, albeit few.

REVIEW of Treatment Options for Treatment-Resistant ADHD: Cortese et al.¹⁵⁹

• 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

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

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

• MPH
  • in case of inappropriate 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?
    • in cases where 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 / Adults
          • 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 completely avoiding 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)
          • U.S.: A large number of additional approved drugs
      • then switch to a different active ingredient
        • For recommended order of use, see above under “Medication Selection”

2.1.8.3. Conversion Tables for Switching Between Stimulants¶

A conversion table from dexamphetamine to Vyvanse can be found on ADHSpedia.¹⁶⁰

When switching medications or active ingredients due to side effects, the conversion table by Kühle is very helpful (in German). It provides a guideline for determining which dose of a different type of stimulant corresponds to the dose of the medication previously taken. The UpToDate conversion table (in English) is also helpful.¹⁶¹

A comprehensive conversion table for American stimulant formulations, including recommendations for the transition process, can be found in Stutzman et al.³⁴

2.1.9. Development of Tolerance to Stimulants / Habituation Effects¶

For more details, see ⇒ Medications: Development of Tolerance

2.1.10. Withdrawal from Stimulants¶

Stimulants such as methylphenidate or amphetamine-based medications have an immediate, dose-dependent effect. 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 further understanding, see Dreher (2026)⁹), it can generally be said that stimulants do not pose any discontinuation issues. However, people with ADHD then suffer from a recurrence of ADHD symptoms, which can subjectively be misinterpreted as a withdrawal side effect.
However, there are reports from people with ADHD who have experienced withdrawal symptoms associated with amphetamine-based medications, in some cases lasting up to 14 days. For a small number of people with ADHD, these symptoms appear to go beyond the unpleasant experience of a recurrence of ADHD symptoms. If necessary, this could be addressed by tapering the dosage gradually.
We have received a report of withdrawal symptoms in a single case following discontinuation of a 10-fold overdose of Vyvanse (50 mg; the patient required only 5 mg).

2.1.11. 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”.

Of n = 198 children and adolescents between the ages of 6 and 18 (mean age 10.4 years), 66.1% to 75.4% were classified as fully compliant, depending on the time of assessment; thus, one-quarter to one-third did not take their medication as prescribed. Older age and a lower IQ were correlated with nonadherence. Neither monotherapy nor polypharmacy, nor the distinction between stimulants and non-stimulants, predicted (partial) discontinuation of medication or interrupted use.¹⁶²
Among Finnish children and adolescents with ADHD, the median duration of medication use (until they had stopped taking medication for at least 12 months) was 3.2 years. Boys had a longer duration of treatment than girls, and the younger the participants were, the longer the duration of treatment. Boys aged 6 to 8 had the longest duration of treatment, with a median of 6.3 years.¹⁶³
Of n = 7,661 people with ADHD, with an average age of 21.8 years, only 55.4% were prescribed medication. Of the n = 4,011 people with ADHD for whom information on medication adherence was available, the average adherence rate was 56%. 27.5% took their medication on at least 80% of the days over a 2-year period.¹⁶⁴

2.2. 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:¹⁶⁵
• 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, deliberately not expect any effects from it.

  • 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: approximately 5–6 hours)

• After 4 to 7 days, 2.5 mg (immediate release) 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 to cover the entire day. With only two doses, nearly the entire day would be 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 dose)

  • When doing so, increase only a single dose at a time for each dosage step, 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 missed.
    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. See also: Dreher.⁴⁷ It is likely that cases have frequently been attributed to intolerance when, in reality, they were due to inappropriate dosages.
    Since such fine-grained dosing increments do not harm other people with ADHD (but, on the contrary, help prevent dosing-related side effects),¹⁶⁶ dosing increments of 2.5 mg (based on a single immediate-release dose of MPH) should be the gold standard. Kühle agrees.¹⁶⁷ A large meta-analysis points in the same direction.⁷⁹
    Other sources recommend starting with 1–2 single doses of 5 mg and increasing the single dose weekly in 5-mg increments.¹⁶⁸ 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 E218.¹⁶⁹ One person with ADHD reports that dissolving immediate-release MPH in alcohol in such precise amounts 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
  • on 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 enough in advance of bedtime so that the effect has worn off at least one hour beforehand. For some people with ADHD (we suspect this applies more to ADHD-I than to ADHD-HI), a reduced dose (1/5 to 1/2 of an optimized single dose) in an immediate release form may help them fall 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. In doing so, sustained-release daily doses should be converted to their immediate release duration of action. (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.¹⁷⁰

• When the daily dose of MPH is 20, 40, or 60 mg, a follow-up consultation with the treating physician should be scheduled for each of these doses.

• 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 the dose two more times to determine whether any adverse symptoms now appear.
  Purpose:
  This ensures that not only are symptoms alleviated, 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 reductions in dosage.

• It is possible that side effects may occur at certain dosage levels below the optimal dose, which then subside 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 may indicate either an overdose or an underlying depression that has come to the surface.

  • Stimulants block sensory filters: This is likely one of the reasons why students “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.¹⁷¹

  • People (other than people with ADHD) whose stimulus filters are not overly 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 very stressful exam periods (unless they have severe ADHD symptoms¹⁷² )

  • Stimulants inhibit the limbic system. An overdose can therefore diminish emotional sensitivity.¹⁷³

• The manufacturer’s information on the typical duration of action applies only to individuals with the standard genetic variants of the metabolizing 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 effectiveness of the CYP enzymes, meaning that the CYP gene 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 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% 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 for only about 3 hours instead of the usual 5 to 6 hours, and Vyvanse for 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 necessary increase in the number of doses per day and the resulting potential for exceeding the general maximum dosage recommendations, closer monitoring is certainly required.
  • Amphetamines are only partially metabolized in the liver (including via CYP2D6). 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; therefore, this should only be done after consulting a doctor.¹⁷⁴¹⁷⁵
  • Excessively rapid metabolism can, in some cases, be counteracted by cross-inhibition with inhibitors of the respective 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.

2.3. Transition to sustained-release MPH / AMP¶

Once treatment with immediate release MPH has been initiated, the number of single doses per day should be reduced by using extended-release formulations, since the 4 to 6 single doses of immediate release MPH that would otherwise be required per day¹⁷⁶ are barely possible for children and adolescents to maintain. Medication adherence decreases in proportion to the required frequency of dosing.¹⁷⁷ 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.⁸ A single daily dose improves compliance.¹⁷⁸
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.¹⁷⁹ As a rule, people with ADHD are better able to assess which type of medication works best for them than their 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 duration of action, it is possible (albeit rare) that the first dose will be 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 + 30 minutes of treatment gap + 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 Sustained Release are not suitable, as these medications only take effect in a sustained release manner if taken with food. In such cases, Ritalin Adult, Ritalin LA, or an OROS formulation such as Concerta should be considered.

2.4. AMP Dosage¶

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

2.4.1. 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 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.

• Since amphetamine-based medications are the first-line 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 contains lisdexamfetamine dimesylate. Lisdexamfetamine dimesylate is dextroamphetamine base bound to lysine. The lysine bond results in a slower and more gradual release of dextroamphetamine into the bloodstream, leading to a prolonged 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 standard for the first 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 within a margin of less than 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 dimesylate 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 chances of finding the right dose for each individual
    • For people with anxiety, it is often difficult to muster this level of perseverance and persistence. In such cases, it is recommended to start with the standard initial dose of 30 mg.
    • In any case, the attending 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 immediate release form, administered in 2 to 3 daily doses.¹⁸

Lisdexamfetamine dimesylate (capsule, e.g., Vyvanse)	Dextroamphetamine sulfate (tablet, e.g., Attentin)	Dextroamphetamine base (pharmacologically active)	Lisdexamfetamine base (irrelevant)
10 mg		2.95 mg	5.78 mg
	5 mg	3.67 mg
20 mg	8.04 mg	5.90 mg	11.56 mg
	10 mg	7.39 mg
30 mg	12.06 mg	8.85 mg	17.34 mg
40 mg	16.08 mg	11.80 mg	23.12 mg
	20 mg	14.68 mg
50 mg	20.10 mg	14.75 mg	28.90 mg
60 mg	24.12 mg	17.70 mg	34.68 mg
70 mg	28.14 mg	20.65 mg	40.46 mg
	30 mg	22.01 mg
	40 mg	29.35 mg

The conversion ratio of lisdexamfetamine disilicate (LDX capsules) to pharmacologically active dextroamphetamine base is 0.2948.¹⁸⁰
The conversion factor for dextroamphetamine sulfate (Attentin tablets) to dextroamphetamine base can be set at 0.7338.¹⁸¹
Lisdexamfetamine base is listed for informational purposes only.

• In a study of 4- to 5-year-old children with ADHD, in which treatment began with a 5 mg dose of LDX and was increased by 5 mg weekly, 19 out of 24 children found their optimal dose:¹⁸²
  • 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-aged children receiving 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.¹⁸³
• 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 initial dosing 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.³² A slightly less precise method involves dividing the capsules into equal-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 usually 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.⁸² After a break in dosing, unpleasant side effects may occur during the first few days, but they subside quickly.

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

2.4.2. Adderall (immediate release and sustained release)¶

The FDA recommends the following single dose of immediate release amphetamine salts (Adderall) for ADHD:¹⁸⁴¹⁸⁵

• 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 6 years of age and older
• 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
• 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 of 5 to 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 experience 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
• Starting dose of 20 mg once daily in the morning
• Insufficient evidence of better results at doses higher than 20 mg per day

3. Dosage of Non-Stimulants¶

Non-stimulants are the third-line treatment for ADHD, after the stimulants AMP and MPH.
Clinicians report that non-stimulants sometimes lose their effectiveness after 9 to 18 months, at which point a switch to another non-stimulant is necessary.⁸ This is explicitly a clinical observation; published research consists almost exclusively of short-term studies on efficacy.

3.1. Dosage of Atomoxetine¶

According to the research⁸¹ as well as our own experience, gradual up-dosing also offers the advantage of reducing the incidence of side effects with atomoxetine. While a study supported by the manufacturer does not provide a clear picture¹⁸⁶, other studies report that patients are less likely to discontinue treatment due to side effects when the dosage is increased gradually, even though the incidence of side effects was comparable.¹⁸⁷
In some cases, it is recommended to start with a dose of 10 mg for women or 18 mg for men—⁸⁷ ly increasing the dose every 14 days—or to begin with a dose of 18 to 25 mg, rather than 40 mg per day.³⁸
Atomoxetine is available as non-divisible capsules and as divisible tablets.

For long-term use, the recommended daily dose is 1.2 mg/kg, and the maximum daily dose is 100 mg.⁸⁷ European treatment guidelines recommend starting with approximately 0.5 mg/kg/day for children and adolescents weighing up to 70 kg and increasing to the target dose of about 1.2 mg/kg/day no sooner than 7 days later; neither 1.8 mg/kg/day nor 100 mg/day should be exceeded.²⁷

ATX is usually taken in the morning. If fatigue is a side effect, ATX can also be taken in the evening.³⁸ A single evening dose of ATX is associated with reduced effectiveness but also with fewer side effects¹⁸⁸

According to the prescribing information for Strattera, if people with ADHD experience side effects with a single daily dose of atomoxetine, the dose may be split into two equal doses, one in the morning and one in the evening.¹⁸⁹

The first effects may become apparent after a few days; however, it takes several weeks for atomoxetine to reach its full effect. Estimates vary: Dodson cites 8 to 10 weeks⁸, while European treatment guidelines recommend 6 to 8 weeks or longer, although those who respond typically show initial improvement starting in week 4.²⁷

Unlike with stimulants, it is important to take atomoxetine consistently.⁸⁷

In our opinion, when titrating the dose—as with all antidepressant-like medications—a gradual approach is highly recommended. A different view is presented by Prasad et al.⁸¹ However, we have received several reports of depression as a side effect of rapid discontinuation of atomoxetine.

Since atomoxetine can increase blood pressure and heart rate, these should be monitored.⁸

3.2. Dosage of Guanfacine¶

Guanfacine appears to reduce norepinephrine levels during the first 2 weeks of treatment. Only after that does norepinephrine appear to increase due to receptor downregulation.
The consequences are that it may take several weeks for the full effect to set in—similar to antidepressants.¹⁹⁰ Regardless, the typical side effects of guanfacine—fatigue, a drop in blood pressure, and a slowed heart rate—occur especially during the first few weeks of treatment.¹⁹¹¹⁹² People with ADHD should therefore not assume that nothing is happening during this time.

Because guanfacine lowers blood pressure, it must be tapered off gradually to avoid blood pressure problems.⁸⁹

3.3. Adding Other Non-Stimulant Substances¶

With other non-stimulant medications, such as bupropion, imipramine, or desipramine, it can also take 8 to 10 weeks for the full effect to set in.⁸

When starting treatment with THC-containing medications, an initial dose of 1 to 2.5 mg of THC per day is recommended. The dose should be increased gradually, by 1 to 2.5 mg every 3 to 5 days. The average daily dose is 10 to 20 mg of THC.¹⁹³

3.4. Serotonin reuptake inhibitors¶

The use of serotonin reuptake inhibitors should always be discussed with a doctor on an individual basis. Serotonin reuptake inhibitors are suitable for the treatment of (comorbid) depression.
With regard to ADHD, treatment of impulsivity in ADHD-HI using minimal doses (e.g., 2 to 5 mg of escitalopram) might be beneficial; in our experience, this appears to have an immediate effect and is apparently not mediated by receptor downregulation or upregulation.
Furthermore, serotonergic medications are not appropriate for ADHD itself, and particularly not for ADHD-I.

3.5. Taper Off Blood Pressure Medications Gradually¶

Medications used to regulate fluid levels must be introduced gradually and tapered off gradually.
With serotonin reuptake inhibitors, this can take more than half a year to avoid side effects.

4. Monitor and document dosing¶

4.1. Self-monitoring: Keep a dosage log (e.g., ADxS dosage guide)¶

Download the ADxS Dosage Guide: ⇒ Dosage Guide in the ADHD Forum on ADxS.org

During the initial dosing period, you should keep a diary that records how you feel each day. It should include:

• Daily assessment of each relevant symptom

  • Identify individual symptoms based on the comprehensive list of symptoms: ⇒ Complete list of ADHD symptoms by presentation

• Preparation

  • not just the active ingredient
  • For generic drugs, include the manufacturer as well

• Dose

• Time(s) to take it

• other medications taken (type, dose, time(s))

• Food and fluid intake (type, amount)

• Caffeine intake (Always completely avoid caffeine when titrating ADHD medications)

• Nicotine use and the menstrual cycle in girls and women
  For more information, visit ⇒ Gender Differences in ADHD

• sports

• Specific sources of stress (both emotional and physical, e.g., arguments, illnesses, allergies, etc.)

Important: The effectiveness of the medication and the dosage should never be assessed on a day-by-day basis, but always retrospectively, based on an average of 3 to 4 days. Otherwise, irrelevant and random correlations will be overemphasized.

4.2. Observation by Others¶

Since not all people with ADHD immediately notice the positive effects that are actually occurring (particularly when comorbid autistic traits are present, which can make this difficult), supplementary observation by others is advisable.

Observation by a third party should be conducted by a family member or partner who is familiar with the situation and should also be documented using a dosing log, such as the ADxS dosing guide.

In addition, it is helpful to discreetly ask third parties who are not aware of the medication regimen about any changes they may have noticed.
Such feedback is particularly valuable and meaningful when these third parties are unaware that medication is being taken. Otherwise, these third parties’ attitudes toward and expectations of medication would always subconsciously influence their assessment and alter the result.
To avoid bias in the assessment of the drug’s effects by teachers or other caregivers, it is therefore advisable not to inform them of the medication use at first. If they nevertheless report a significant change in behavior within the first few weeks, this unbiased observation is much more meaningful.

The combination of ongoing observation by a family member in the know (who, ideally, knows only about the medication itself but nothing about dose changes, changes in active ingredients, or missed doses) and unbiased third parties who are completely unaware that the person is taking medication at all can provide very valuable insights into the medication’s effects.

Reports are only meaningful if the medication’s duration of action is long enough. A single immediate-release MPH tablet taken in the morning cannot produce changes that last beyond its 2.5- to 4-hour duration of action.

With younger children, it can be very helpful not to tell them directly that they are now taking medication, but rather to refer to it as vitamins during the initial dosing phase. After a few weeks, it can be helpful to talk to the teachers—who are also unaware of the situation—to see if they’ve noticed any changes. With older children, such deception would be ethically unacceptable.

4.3. Measuring the Effectiveness of Medication¶

Various attempts to adjust medication dosages for ADHD based on blood test results have so far shown little success.
With regard to ATX, it was reported that blood level measurements did not yield any useful values.
Since stimulants are known not to be dosed based on body weight, and since the doses required to achieve an appropriate effect vary greatly from person to person, we do not fully understand what benefit measuring blood levels could have.

Some physicians use sustained attention tests to identify intra-individual differences without medication and at various medication doses, and to monitor the response to and effects of stimulants. Since attention tests depend heavily on the individual subject’s motivation and, in cases of high intrinsic motivation to participate, can falsely convey the impression that the person is unaffected even in cases of severe ADHD, such tests should not be used as the sole criterion. However, using them as a supplementary assessment tool—particularly in a controlled and consistently stable (boring) testing environment—can be helpful.

A meta-analysis reports promising results from the Qb-Test for measuring the effectiveness of ADHD medication.¹⁹⁴
The Qb test measures physical restlessness while the subject completes a Go/NoGo test: An infrared camera tracks a reflective marker on the forehead, thereby recording head movements. It remains to be seen whether the results are consistent enough to assess individual cases. Furthermore, the time required to perform the test is likely to prevent its widespread use in medical practice.

4.4. Monitoring Medication Adherence¶

It is a common misconception that ADHD medications, especially stimulants, can be addictive. When taken orally as directed, they do not cause dependence in people with ADHD. ¹³⁰ A practical indication of this is that, on the contrary, the more common problem is forgetting to take the medication.
The use of a medication reminder app significantly improved medication adherence and reduced the time between prescription refills from 46 to 34 days.¹⁹⁵ This was a small study without a control group; its statistical significance is therefore limited.

5. Avoiding Side Effects¶

At the dose that provides optimal symptom relief for each individual (which may be significantly lower than typical doses!), very few people with ADHD experience side effects. The most common side effects are

• Dry mouth (a few days)
• mild, temporary loss of appetite

Side effects and effect size must be weighed against one another.
To achieve a 1 percentage point lower risk of side effects, adults with ADHD were willing to forgo percentage points of improvement in ADHD symptoms:¹⁹⁶
0.59 Insomnia (a one-percentage-point reduction in the risk of insomnia was equivalent to a 0.59-percentage-point reduction in symptom improvement)
0.57 Nausea
0.49 Anxiety
0.32 Nervousness or tremors
0.17 Dry mouth

Rare, more serious side effects (high blood pressure, aggression, or others) should be discussed with your doctor immediately.

5.1. A particular challenge: Dosing in cases of comorbid anxiety¶

In our experience, people with ADHD or high anxiety scores often experience more severe side effects.
For more information, see Treatment Guidelines for Specific Comorbidities: ADHD and Anxiety in the article “Guidelines for ADHD Treatment.”

5.2. No caffeine when taking stimulants (IMPORTANT!)¶

When titrating the dosage of stimulants, caffeine should be completely omitted without exception.
Since the side effects of caffeine and stimulants can be cumulative¹⁹⁷, consuming them together may cause side effects that do not occur when caffeine or stimulants are taken alone.
Therefore, when dosing stimulants, caffeine must be completely and consistently omitted. This may be subjectively difficult for people with ADHD who previously managed their symptoms with high caffeine intake. However, the role of reducing symptoms is now (and much more effectively) fulfilled by the stimulants.
In addition to the overdose side effects mentioned above, other symptoms have occasionally been reported during the use of stimulants, which disappeared abruptly when caffeine was discontinued, such as tremors, rapid heartbeat, circulatory problems, high blood pressure, nausea, mottled skin, or Raynaud’s syndrome.

Based on our observations, a significant proportion of people with ADHD—we estimate about half—experience symptoms typical of an overdose (up to a severe overdose), even though the same amount of caffeine had previously been tolerated without any problems. We are not aware of any controlled studies on this interaction. We know many people with ADHD who did not take this into account and therefore mistakenly believed they could not tolerate stimulants. A new attempt without caffeine and with a slow titration of the stimulant dose, on the other hand, was often successful.

If you have been consuming large amounts of caffeine, you may experience caffeine withdrawal symptoms for 2 to 3 days after stopping. These symptoms often include headaches, exhaustion and loss of energy, restlessness, insomnia, circulatory problems, nausea, constipation, lethargy, irritability, and difficulty concentrating. These symptoms should not be mistaken for side effects of newly taken stimulants.

Once stimulants have been successfully tapered off, caffeine can be reintroduced cautiously. The difference is that people with ADHD then know that any side effects that occur at this point are not caused by the stimulants.
We are also aware of reports from some people with ADHD who—after years of taking stimulants—still experience mild tremors even when drinking decaffeinated coffee.
Some people with ADHD report that they can use caffeine to prolong the stimulating effects that begin to wear off in the afternoon.

5.3. No concurrent nicotine withdrawal¶

Nicotine is a stimulant that increases dopamine and norepinephrine levels. Heavy smokers have therefore experienced a profound change in the balance of these neurotransmitters in the brain. Quitting smoking—especially cold turkey—leads to severe adjustment reactions and withdrawal symptoms. When we had him taper off his nicotine intake, a former heavy smoker reported very severe and intolerable side effects, which disappeared when he started smoking again.
Even though smoking is harmful to one’s health, it should not be stopped at the same time as starting a new medication.
In addition, when monitoring the effects of medication at a single dose, it is helpful to avoid any distortion caused by external factors.
Unlike with caffeine, we have received reports of interactions involving nicotine much less frequently.

Often, people with ADHD lose their craving for nicotine during or after the titration period. In isolated cases, an increased craving for nicotine has also been reported.

5.4. Signs of an overdose¶

Symptoms of an overdose are usually the same as those of excessive caffeine consumption:⁸

• Tremors
• mild dysphoria
• Nervousness
• Heart palpitations
• Rapid heartbeat
• Headaches
• Irritability
• Circulatory problems

A loss of emotion (“zombie mode”) can be a sign of an overdose. For more information, see below in this section.

It is difficult to distinguish between symptoms of overdose and those of underdose. If symptoms occur during titration at very low doses, an attempt to increase the dose should initially be made at regular intervals, while closely monitoring the patient for further symptoms. In the event of severe side effects or cardiac symptoms (rapid heartbeat, palpitations, chest pain, circulatory problems), seek medical advice immediately.

5.5. Headaches¶

This description is based on Simchen’s *¹⁹⁸ * And is consistent with our experience.

5.5.1. Hypoglycemia¶

Headaches as a side effect of taking stimulants are often consequences of low blood sugar.
Stimulants increase activity in the PFC, which boosts glucose consumption and lowers blood sugar levels.
Symptoms of hypoglycemia include

• Headaches
• Fatigue (yawning)
• Pallor
• Dizziness
• Tremors (though these may also result from an overdose or an interaction with caffeine).

Solution:

• Eat a good breakfast or meal before taking each dose
• Snacks for in between meals
• If you get a headache, eat easily digestible carbohydrates right away
  • glucose
  • Bananas
  • Fruit juices (without sweeteners)

During prolonged hypoglycemia, the brain produces acidic metabolic byproducts through lactic acid metabolism, which lead to headaches that last longer and are more difficult to relieve.
People with ADHD often report that, as the effects of stimulants wear off, eating quickly can help them regain their concentration.

5.5.2. Dehydration¶

Another common cause of headaches when taking stimulants is insufficient fluid intake.

5.5.3. Histamine Intolerance¶

A third possible cause is histamine hypersensitivity or histamine intolerance, since all ADHD medications (with the possible exception of viloxazine) increase histamine levels. In such cases, however, the headaches occur alongside other typical symptoms of histamine intolerance.
Learn more about the symptoms of histamine intolerance at Histamine Intolerance, Histamine Sensitivity in the article Differential Diagnosis of ADHD

5.6. Gastrointestinal symptoms¶

Stimulants can increase gastrointestinal motility, which may be perceived as painful by people with ADHD (especially children).¹⁹⁸

Higher doses taken on an empty stomach, in particular, can cause a strange, cramp-like sensation under the right rib cage about 30 minutes after ingestion. This is thought to be triggered by a spasm of the smooth muscle in the duodenum due to the sudden rise in stimulant levels.⁸

Solution:¹⁹⁸⁸
Eat a sufficient meal before taking the medication.
A longer interval before taking the medication (one hour) may be even more effective than a shorter interval (15 minutes).

5.7. Trouble falling asleep¶

Many people with ADHD report that since taking stimulants, they have been able to fall asleep more easily and enjoy more restful sleep.
However, some people with ADHD may experience difficulty falling asleep as a side effect of the initial dose. These symptoms usually subside within the first few weeks.

Solution:

• Take the last dose early enough so that its effects wear off at least one hour before bedtime
  • This requires knowledge of the typical duration of action of the respective medication. See the section on Effects and Duration of Action of ADHD Medications
  • Increase the time interval if necessary
  • If necessary, skip the afternoon dose for the first 1 to 2 weeks and use only one dose of half-day-release MPH in the morning
• Consider the possibility of slowed metabolism (prolonged duration of action)
  • For more information, see Effects and Duration of ADHD Medications
• 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 them fall asleep
  • Try administering it as a sleep aid in very small doses (1/10 of the single daily dose)
  • Sustained-release daily doses must be converted to the equivalent dose of the immediate release form based on its shorter duration of action (for example, 20 mg of a sustained-release formulation with a 5- to 6-hour duration of action is equivalent to 10 mg of the immediate release form with a 2.5- to 3-hour duration of action).
• Avoid OROS-MPH (Concerta)
  • In two separate open-label one-year studies, a higher rate of difficulty falling asleep was reported with OROS-MPH than with long-acting MPH of the Ritalin-LA type.¹⁹⁹²⁰⁰ Since this was not a direct comparison within a single study, no conclusive difference between the formulations can be inferred from these findings.

5.8. Tachycardia (increased heart rate), elevated blood pressure, tremors¶

If these symptoms occur after taking stimulants, you should first make sure that you have completely avoided caffeine.

Stimulants stimulate the sympathetic nervous system.¹⁹⁸
A meta-analysis of k = 18 studies involving n = 5,837 children and adolescents found a small but statistically significant increase in systolic blood pressure for all three active ingredients (MPH: SMD 0.25; AMP: SMD 0.09; ATX: SMD 0.16). MPH had no significant effect on diastolic blood pressure or heart rate, whereas AMP and ATX increased both (diastolic: AMP SMD 0.16, ATX SMD 0.22; heart rate: AMP SMD 0.37, ATX SMD 0.43). A direct comparison of the three active ingredients revealed no significant differences. Any cardiovascular effects resolved spontaneously in most people with ADHD. 2% of people with ADHD discontinued their medication due to cardiovascular effects. There were no reports of heart attack, stroke, or sudden cardiac death.²⁰¹ Once the body has adjusted, these effects do not recur even when the medication is resumed after prolonged treatment breaks.
Since the studies did not take caffeine interactions into account, some of the dropouts may have been due to caffeine.
The American Heart Association (AHA) recommends taking a personal and family medical history regarding cardiac abnormalities before starting stimulant therapy, as well as monitoring blood pressure and pulse during follow-up visits. A routine ECG is not required for children with healthy hearts.²⁰²²⁰³

In particular, people with ADHD appear to experience a further increase in blood pressure when taking stimulants, even at carefully adjusted doses. If high blood pressure is under control before ADHD treatment begins, stimulants may be used, but blood pressure should be monitored at every follow-up visit.⁸

In people with ADHD, a greater increase in heart rate may occur when the dose is adjusted. This should always be discussed with the doctor immediately.
Solution:

• slower dispensing
• lower dosage
• Testing for cross-reactions
• Check to see if caffeine has been completely eliminated

5.9. Rebound¶

A rebound is a temporary increase in symptoms immediately after the effects of stimulants wear off. It is unpleasant but harmless and does not indicate any problems with the medication.⁸ However, in some cases, it can be so severe that people with ADHD may consider discontinuing the medication.
Based on our observations, rebound occurs primarily with immediate release and half-day extended-release MPH. The rebound lasts about half an hour.
Full-day sustained-release formulations show less of a rebound effect.
Amphetamines have a lower risk of rebound than methylphenidate.⁸ In our experience, the extended-release formulation of Vyvanse causes (almost) no rebound. When rebound is reported with Vyvanse, our impression is that it particularly affects people with ADHD for whom a single dose of Vyvanse has a shorter duration of action (7 hours or less, instead of the 12 to 14 hours specified by the manufacturer).

Solution:

• Taking the next dose on time so that its effects begin just as the rebound is expected to occur
• A rebound effect after the last daily dose can be prevented by taking a small amount of immediate release MPH
  • approximately 1/5 to 1/2 of the amount that would correspond to an optimal single daily dose (for medications with sustained release, this must be adjusted; see above under “Difficulty Falling Asleep”)
  • About 15 minutes before the expected rebound

5.10. Gaps in coverage¶

With sustained-release MPH formulations, some people with ADHD experience gaps in effectiveness between the first and second releases. This is a clear indication of rapid metabolism.
Sustained-release MPH formulations release multiple doses of MPH over time. If the first release is metabolized too quickly, its effects may already begin to wear off before the second release takes effect. In cases of such problems with fluctuations in active ingredient levels in MPH, it may be advisable to switch, within the range of available MPH formulations, to full-day-acting MPH formulations such as Concerta, Kinecteen, or (the bioidentical alternative to Concerta) Neuraxpharm methylphenidate hydrochloride—which also provide 12-hour coverage—within the range of available MPH formulations. Alternatively, a switch to amphetamine-based medications should be considered, as these are metabolized differently, thereby increasing the likelihood of normal metabolism.

5.11. Loss of appetite / Weight loss¶

Stimulants and desipramine are often associated with the side effect of a decreased appetite and, consequently, weight loss. In most cases, this is merely a side effect related to the initial dosage and resolves on its own over the course of a few weeks or months.

In cases of clinically significant weight loss, the following is recommended:¹³⁰

• Take medication not before, but during or after meals
• additional meals or snacks in the early morning or late evening (outside the times when the medication is effective)
• Nutrition Counseling
• High-calorie foods with high nutritional value
• planned break in treatment
• Change in medication

Since many people have trouble eating in the morning (for whom Medikinet Adult or Medikinet Retard is not suitable), care should be taken to eat a substantial meal in the evening.

It has been reported that loss of appetite may be less severe with Concerta than with other MPH medications.

Atomoxetine is also frequently associated with a loss of appetite. No significant difference was found between stimulants and non-stimulants (RR 0.82; 95% CI 0.53 to 1.26; meta-analysis, k = 8, n = 1,463).²⁰⁴ Atomoxetine resulted in a weight loss of 0.6 kg, Concerta in a loss of 0.9 kg, and the placebo in a gain of 1.1 kg.²⁰⁵
The risk associated with methylphenidate and amphetamine medications was identical (RR 1.01; meta-analysis, k = 3, n = 414).²⁰⁴
A survey conducted on the ADxS forum revealed (113 participants, as of April 2026):

• Lisdexamfetamine (LDX) was 44% more effective at suppressing appetite than methylphenidate (MPH)
• LDX and MPH were equally effective at suppressing appetite (30%)
• MPH was 26% more effective at suppressing appetite than LDX

Nortriptyline is said to be associated with weight gain as a side effect.²⁰⁶

In isolated cases, the use of low-dose antipsychotics to counteract weight loss caused by stimulants is being considered. This is expressly not a recommended course of action: Antipsychotics are not approved for this purpose and carry significant risks of their own (metabolic syndrome, movement disorders, and, in children and adolescents, elevated prolactin levels).
While MPH was often associated with a loss of appetite, the typical antipsychotic thioridazine (which has since been withdrawn from the market worldwide or its use severely restricted due to QT prolongation and torsade de pointes) caused an increase in appetite as a side effect.²⁰⁷ Atypical antipsychotics are said to have an even stronger effect in terms of increasing appetite, but also in terms of metabolic syndrome.²⁰⁸
Combination therapy with psychostimulants and antipsychotics is being used more and more frequently.²⁰⁹ In isolated cases, improved efficacy compared to stimulant monotherapy has also been reported.²⁰⁸ A registry study found that 3.9% of children and adolescents with ADHD who were receiving stimulants were also being treated with atypical antipsychotics.²¹⁰ This opens up the option of using combination therapy to counteract excessive weight loss associated with stimulants.

Another option is to administer cyproheptadine.³⁴
For more information, see Cyproheptadine for ADHD

If necessary, medication breaks may be required to help the patient regain weight.

5.12. Loss of Emotion / Zombie Mode: Overdose or Intolerance¶

In people with ADHD, particularly those with ADHD-HI and ADHD-C⁸, a slowing of thought processes and blunted affect (emotional poverty) may occur (“zombie syndrome”). In such cases, avoiding an overdose or reducing the stimulant dose as part of a combination treatment with non-stimulants can help. For more information, see Combination Therapy for ADHD

There is absolutely no need to accept a reduction in emotionality as a side effect of ADHD medication. ADHD medication works properly when the person with ADHD feels more like themselves. Any sense of feeling like a stranger to oneself—or feeling less like oneself—is a sign that the medication is not the right fit.
Stimulants suppress the limbic system. A few people with ADHD are particularly sensitive in this regard. In most cases, persistent trying out different medications and active ingredients helps.
In our experience, the consequences of an overdose are often emotional blunting. In such cases, one should consider restarting the dosage in as small increments as possible. Some (albeit very few) people with ADHD require only a few milligrams of a stimulant throughout the entire day.

The following options should be considered only after it has been determined that a reduced dose—at which emotional impairment is just barely avoided—does not sufficiently improve ADHD symptoms:

• Atomoxetine or guanfacine instead of stimulants
  • Non-stimulants
    • do not inhibit the limbic system
    • Do not improve the drive
• Reducing the dose of stimulants when taken in combination with non-stimulants (benefit: the motivation provided by stimulants is maintained, and emotional dysregulation is improved throughout the day)
  • Adults: Stimulants and atomoxetine
  • Children: Stimulants and guanfacine, or stimulants and atomoxetine

5.13. Cycle-Related Fluctuations in Symptoms in Women¶

Dopamine homeostasis is influenced, among other factors, by COMT. COMT is the primary degradation mechanism in the PFC, whereas degradation in the striatum is primarily regulated by DAT.
Degradation is strongly influenced by the COMT gene variant. Estrogen inhibits COMT activity and, consequently, dopamine degradation in the PFC in a cycle-dependent manner.²¹¹

A significant proportion of women with ADHD report more severe symptoms during the premenstrual phase. When stimulants are prescribed, symptoms can be alleviated by temporarily increasing the stimulant dose during this phase. A case series from a specialized outpatient clinic in the Netherlands reports positive results from increasing the stimulant dose during the premenstrual week: For nine women, the dose was increased by 30 to 50% (average 41%); all reported improved ADHD and mood symptoms with minimal side effects, and all decided to continue the increased premenstrual dosage.²¹² Controlled studies on this topic are currently lacking.

5.14. Variable Effect¶

Occasionally, people with ADHD report fluctuations in the drug’s effectiveness, even after a prolonged period of stable response.
There are many possible causes. For more information, see Effects and Duration of ADHD Medications
Examples:

• other medications that have been added or discontinued
  • In particular, for ADHD medications:
    • Antacids
• Interactions with food
  • There are many options here. Keep a food diary
  • in particular
    • Grapefruit
    • Vitamin C
      • If necessary, take the medication one or more hours after taking your other medication
• Changes in stomach acid
  • MPH and AMP are both sensitive to changes in stomach acid
  • Measure the urine’s acidity, if necessary
• Defective drug batches
  • rare, but we’ve actually experienced it several times
  • Did the effect change when you started a new package?
• Medications stored in too hot a place
• Adaptive responses
  • rare after prolonged use with consistent results
  • For more information, see Medications: Development of Tolerance

5.15. Symptoms of Overexertion¶

After starting medication, many people with ADHD become highly active as they tackle their problems and tasks.
For some people with ADHD, this can lead to symptoms of stress overload and, in some cases, even to a breakdown.

We do not consider this to be a pharmacological consequence of the medication, but rather a psychological one. In particular, it is not a manifestation of hyperactivity or inner restlessness; on the contrary, it is a marked increase in effectiveness and work intensity compared to the period before the medication was started.

Many people with ADHD now find it easier to motivate themselves thanks to the medication and therefore think they can now accomplish everything they want, should, or feel they have to do.
But there’s a difference between being able to do “more” and being able to do “everything.”

While medication does allow you to get more done now, it doesn’t restore your full capacity. Although it often enables people to reach the same level of performance as those without the condition, this isn’t always the case, nor does it apply to everyone. Medication also doesn’t give you superpowers that would suddenly let you accomplish everything you’ve always wanted to do.
Subjectively, however, this isn’t perceptible. From the inside, you just feel that you’re doing better now. You can’t sense that this still isn’t the whole picture, because you’ve never known anything else and don’t know what it would be like to no longer have ADHD. This is also where a conflict with an inner, dysfunctional perfectionism might come to light.

Therefore, shortly after taking the medication, people with ADHD should be especially careful not to overexert themselves.
When taking medication, you first have to get to know your new limits—what’s possible now and what you can reasonably expect of yourself.
Medications can shift these limits, but they cannot eliminate them.

5.16. Raynaud’s (Circulatory Disorder Affecting the Fingers)¶

ADHD medications can trigger or worsen Raynaud’s phenomenon. Raynaud’s phenomenon has been observed less frequently with atomoxetine than with stimulants.²¹³ Reports indicate that reducing the dose, discontinuing the medication, or switching to a different active ingredient may alleviate the symptoms. Very rare cases of severe progression have also been described.
We are aware of cases in which Raynaud’s syndrome was triggered by caffeine consumption while taking ADHD medication and resolved after caffeine was eliminated from the diet.

6. General Information¶

• For titration, immediate release MPH should be used during the first week or so. The shorter duration of action and the more linear dose-response relationship (without a second peak when the portion with sustained release takes effect) make it easier to determine the appropriate dose, especially for inexperienced observers (both people with ADHD and third parties).
• With sustained-release Medikinet, it is important to note that it must be taken with food; otherwise, the entire dose will be released in immediate release form. Other formulations generally do not require food, although this should always be verified in the package insert. For all long-acting ADHD medications, it is recommended to take them with food.
• Caffeine (coffee, cola, black tea, some green teas, mate, energy drinks) and dark chocolate/cocoa (theobromine) must be completely avoided during the titration phase. Many people with ADHD can no longer tolerate caffeine or other stimulants while taking stimulant medications, even though they previously consumed them without any problems or even in larger quantities. Caffeine (theine) and theobromine are stimulants that also increase levels of norepinephrine and dopamine. They can have additive effects when combined with ADHD medications. This can easily be mistaken for an overdose (internal restlessness, agitation, trembling).
  After the dose has been administered, caffeine can be consumed again, though it is recommended to test it cautiously at first. If caffeine causes tremors at this point, it is clear that this is due to the caffeine and not the medication.

Alcohol significantly increases blood levels of MPH and must be completely avoided when taking a single dose of MPH. This is because the enzyme carboxylesterase 1 (CES1), which breaks down MPH, converts l-MPH to ethylphenidate in the presence of alcohol; as a result, less of the active d-MPH is broken down, and blood levels rise. ²¹⁴
In 24 healthy subjects, d-MPH plasma levels increased by 44 to 99% (p < 0.005) during the absorption phase following concurrent administration of alcohol (0.6 g/kg).²¹⁵
In light of this, pure dexmethylphenidate (Focalin, Focalin XR) should be considered for people with ADHD who have an acute, unresolvable alcohol problem.²¹⁶

 

• Avoid citrus fruits while taking medication. Some people with ADHD experience changes in how their medication works when they consume citrus fruits. Grapefruit should be avoided whenever taking medication.
• Taken in the afternoons, on weekends, and during school breaks
  • Since ADHD is not purely a school-related issue—even though it manifests particularly clearly in that setting due to extrinsic demands and learning difficulties caused by a lack of neurotrophic factors—continuous medication is strongly recommended. Whether medication should be taken only in the mornings during school hours depends on whether the people with ADHD are still able, with this medication, to concentrate on their homework and manage their social interactions without emotional dysregulation until early evening without experiencing symptoms.
  • You should avoid stopping medication on weekends or during school breaks. For one thing, symptoms don’t strictly follow the school schedule, and for another, a prolonged break in treatment may require gradually reintroducing the medication to avoid side effects.
  • It is, however, conceivable to reduce the dosage slightly during periods of lower demand (to 2/3 or 3/4). This depends heavily on the individual needs of the people with ADHD. Any changes to the dosage must be coordinated with the doctor. An experienced doctor, however, will grant a trusted patient considerable leeway.
• Mixing stimulants
  • Stimulants can be combined. In particular, sustained-release and immediate-release medications can be taken on the same day. A combination of AMP and MPH also does not cause any particular problems.
    As a general rule, a sustained-release form of the medication is taken during the day, which ideally provides coverage for the entire day. Responsible and trustworthy patients can supplement their treatment with immediate release MPH to manage occasional special circumstances, such as a particularly long evening.
    The instructions of the attending physician are authoritative!
• The menstrual cycle can significantly affect how medications work.
  • When considering fluctuations in the effects of medication in women, the significant influence of estrogen—which is possible with certain COMT gene variants—should be taken into account. A dosage guide that helps track menstruation and its effects can be found at ADHD-Forum.ADxS.org.