Medication dosage for ADHD

Like all presentations on medications at ADxS.org, this information is compiled solely from a scientific perspective. It is not intended for self-medication, but to enable well-informed discussion with the treating physician and to understand his instructions.
Each specific treatment must be based on the instructions of the attending physician for the individual case.

Setting the optimal dosage of medication for ADHD depends on the type of medication.

• 1. Medication adjustment of stimulants
  • 1.1. Choice of the active substance
    • 1.1.1. Order of the means of choice
      • 1.1.1.1. Means of choice for children
      • 1.1.1.2. Means of choice for adolescents
      • 1.1.1.3. Means of choice for adults
    • 1.1.2. Other factors for the choice of active ingredient
    • 1.1.3. Try and Error: Finding the right active ingredient takes patience
  • 1.2. Stimulant dosage
    • 1.2.1. Basics of the dosage of stimulants
      • 1.2.1.1. Amount of the first dose
      • 1.2.1.2. Dosage levels: Small stages better than large stages
      • 1.2.1.3. Speed of dosing levels: 5 to 7 days / level
    • 1.2.2. Dosing with unretarded MPH
    • 1.2.3. Transition to sustained release MPH / AMP
    • 1.2.4. AMP dosing
      • 1.2.4.1. Elvanse (Lisdexamfetamine)
      • 1.2.4.2. Aderall N (unretarded)
    • 1.2.5. Duration of action of individual doses and daily coverage
    • 1.2.6. Dosage not all-inclusive or according to body weight
  • 1.3. Dosing of non-stimulants
    • 1.3.1. Atomoxetine dosage
    • 1.3.2. Serotonin reuptake inhibitor
    • 1.3.3. Dosing of other non-stimulants
    • 1.3.4. Slowly taper off level medications
  • 1.4. Avoid side effects
    • 1.4.1. Overdose and caffeine cross effects
    • 1.4.2. Headache
    • 1.4.3. Gastrointestinal complaints
    • 1.4.4. Problems falling asleep
    • 1.4.5. Tachycardia (increased heart rate), blood pressure increase
    • 1.4.6. Rebound
  • 1.5. Change of preparation and active ingredient
  • 1.6. Dosage adjustments
  • 1.7. General notes
  • 1.8. Stimulant discontinuation
• 2. Diary documentation and external observation

1. Medication adjustment of stimulants¶

Stimulants such as methylphenidate or amphetamine drugs have an immediate and dose-dependent effect. They can be discontinued immediately without side effects. Withdrawal symptoms were reported to us in a single case of a 10-fold overdose of Elvanse (50 mg; patient required only 5 mg).

1.1. Choice of the active substance¶

1.1.1. Order of the means of choice¶

1.1.1.1. Means of choice for children¶

• First choice is methylphenidate
• Second choice is amphetamine drugs
• Third choice, in our view, is guanfacine (especially for generic or MPH- or AMP-induced hypertension or comorbid tics), which has statistically significantly better effect size with fewer side effects than atomoxetine
• Fourth choice is atomoxetine. It may be first choice for comorbid SCT or severe ADHD-I.
  • Among children with ADHD, 8.4% switched from a first-line MPH medication to atomoxetine, 31.3% switched from a first-line ATX medication to MPH¹
  • Approximately 50% of MPH nonresponders respond to atomoxetine, and approximately 75% of MPH responders also respond to atomoxetine. Atomoxetine can be co-administered with MPH during the conversion period without undue concern for adverse events, such as cardiovascular effects (although monitoring of blood pressure and heart rate is required)²
• For other possible medications, see related articles

1.1.1.2. Means of choice for adolescents¶

• First choice continues to be methylphenidate
• Second choice is amphetamine drugs
• Third choice, in our opinion, is guanfacine (especially for hypertensive reactions to MPH and AMP or comorbid tics), which statistically has a much better effect size with fewer side effects than atomoxetine.
• Fourth choice is atomoxetine. It may be first choice for SCT or severe ADHD-I.
• For other possible medications, see related articles

1.1.1.3. Means of choice for adults¶

• First choice is amphetamine drugs
• Second choice is methylphenidate
• Third choice is atomoxetine. It may be first choice for SCT or severe ADHD-I.
• Fourth choice, in our opinion, is guanfacine, as the positive efficacy reports of guanfacine are primarily for children
• For other possible medications, see related articles

1.1.2. Other factors for the choice of active ingredient¶

Further consideration should be given to the choice of active ingredient:

• Comorbidities
• Metabolizing enzyme gene variants that accelerate or slow degradation
• other medications taken
• Stomach acid

More about this under

• Choice of medication for ADHD
• Medication duration for ADHD
• Combination medication for ADHD

1.1.3. Try and Error: Finding the right active ingredient takes patience¶

Psychiatric disorders and other CNS conditions present unique challenges in finding an appropriate medication.
ADHD has a special position within the psychiatric disorders³, because the responder rates of 70% (MPH) to 80% (AMP) are much higher than in other disorders. Likewise, the effect strength of ADHD medications is enormously high compared to other disorders.
Nevertheless, it is not possible to predict which drug will work for a particular ADHD sufferer. Even within a drug class (MPH), one drug may have intolerable side effects in one sufferer, while the other works excellently - while the next sufferer reacts to the two drugs in exactly the opposite way. The different reactions are presumably due to the different initiation and degradation profiles of the active ingredient, which can differ considerably between the individual preparations.
Therefore, patient and fine-tuned medication adjustment is also the decisive factor for improving symptoms and quality of life in ADHD. We would like to encourage all those affected to “keep at it” if the results are not satisfactory, and to always try out new preparations and active substances together with your doctor.

“In controlled trials, the drug is selected before subjects are recruited, and the dosage is determined by a protocol. In clinical practice, the dosage is determined by the individual response of the subjects. In fact, there is no identified parameter that predicts the molecule, dose, timing of intake, and frequency of intake at which an individual will derive optimal benefit from the medication. … In clinical practice, medications in the stimulant class are tailored to the needs and responses of the individual patient in at least five ways: Active ingredient, delivery system, dose, duration, and frequency.”⁴

1.2. Stimulant dosage¶

1.2.1. Basics of the dosage of stimulants¶

In principle, an up-dosing regimen that starts with low doses and increases them flexibly and individually is clearly advantageous over the administration of fixed doses. This has been known since the 1970s⁵ and is confirmed by a new, extensive metastudy⁶. Studies also use slow dosing to avoid side effects.⁷
With MPH, as with AMP, efficacy increases along with dose level on the one hand and the likelihood of discontinuation due to side effects on the other. In fixed-dose studies, the additional efficacy benefit decreased from 30 mg MPH or 20 mg AMP.

More is not better. For each affected person, the individually appropriate dose with optimal symptom improvement and low side effects must be sought through trial and error⁴

The fact that the fixed-dose approach, which is significantly less suitable in practice, is still encountered in some cases seems to result from the fact that the FDA requires fixed-dose studies for drug approval. However, these approval studies are not aimed at clinical practice application.

The guidelines in Germany and the USA do not work with fixed doses, but provide for up-dosing.
In our experience, it is recommended to proceed even a little slower than what is provided there.

MPH dosage can be given with unretarded MPH or retarded agents.

1.2.1.1. Amount of the first dose¶

Generally, drugs are dosed at the lowest available doses (now 5 mg for MPH half-day retard preparations, 18 mg for Concerta, 5 mg for Adderall XR capsules, etc.). Subsequently, the dose is increased in equal increments until the optimal benefit is achieved. At the dose with the optimal symptom improvement, most adult ADHD sufferers report few side effects other than mild and transient loss of appetite.⁴

1.2.1.2. Dosage levels: Small stages better than large stages¶

In our view, a smaller-step up-dosing regimen is clearly advantageous compared to the current standard up-dosing regimen of 10 mg / half-day retard MPH dose increments, from which the following up-dosing recommendations are derived. The usually recommended step length of 7 days can thus be shortened to 4 to 5 days, so that the overall rate of up-dosing changes only slightly.

Slow titration of ADHD medications in small dose increments has several purposes:

• low doses of stimulants act differently and on different brain regions than high doses
  • low-dose MPH only has a noradrenergic effect, only higher-dose MPH also has a dopaminergic effect. For more information see Mode of action of methylphenidate in the article MPH part 1: active ingredients, effect, responding.
  • Norepinephrine and dopamine have very closely related roles in improving ADHD symptoms. What works better for a person must be tested on an individual basis
  • Even when symptoms are severe, a very low dose may be appropriate on an individual basis.¹⁴ Huberman reports a single case of an optimal daily dose of 2.5 mg Adderall (150 kg female).¹⁵ 0.3 mg/kg showed greater performance improvement in learning tasks than 1 mg/kg in children with ADHD, 1 mg/kg showed better social evaluation by teachers and less sitting restlessness in hyperactive children, but poorer learning performance than placebo.¹⁶
• carefully acclimating the body to the drug to avoid side effects that could lead to avoidable discontinuation of ADHD medications ¹⁷¹⁸
• Too high a dosage will result in a recurrence of ADHD symptoms avoided at the appropriate dosage (inverted-U).¹⁹

1.2.1.3. Speed of dosing levels: 5 to 7 days / level¶

From a purely efficacious point of view, titration could be rapid, since stimulants are effective as soon as they reach the brain. Clinically, the dose could be increased daily, as all effects and side effects of an unretarded dose become apparent 1 hour after ingestion. If the dose subsides, there is no further or accumulated benefit⁴
In our opinion, however, several arguments clearly speak against daily dosing:

• The effect of sustained-release drugs must be monitored over the course of the day
• The perception of the effect is not made by the doctor, but by the affected persons themselves
• Affected people have no experience and therefore do not know what to look for
• Affected individuals may experience placebo effects that are strongly dependent on subjective attitudes toward the drug, and that can only be distinguished from the actual effect after several days
• Individual daily influences can falsify the results
• For women, the current cycle status must be taken into account

Therefore, we strongly advise against 1-day dose increments. This also applies to inpatient dosing, although the duration of the steps can be reduced there.

We recommend that sufferers keep daily records of intake, symptoms, and side effects (e.g., using the Dosing chart from the ADHD forum of AdxS.org), but never evaluate these on a daily basis, always taking a 3-day average. It follows that an assessment of one level requires 5 to 7 days.
We consider the step duration of 1 month practiced by some physicians to be of little use. It does not bring any advantage and is possibly the necessary consequence to compensate for too large-step dosing levels.

1.2.2. Dosing with unretarded MPH¶

Unretarded MPH allows better control of symptom improvement on the one hand, but on the other hand requires more reliable patient compliance due to the higher number of single doses / day. Therefore, in children and especially in younger children, single dosing with sustained-release medication may be recommended.

According to the 2018 German S3 guideline, unretarded MPH may be considered for the following reasons, for example:⁸

• More accurate dose adjustment during the initial titration phase of medication
• Higher flexibility in dosing regimens required

In our experience, it is recommended that:

• Start with a one-time very low dosage (2.5 mg unretarded MPH) and deliberately expect no effect at all.
  • Since half-day sustained-release MPH is available starting at 5 mg, a 5 mg dose of sustained-release MPH can be taken instead of 2 doses of unretained MPH (usual duration of action approximately 5-6 hours)
• After 4 to 7 days 2.5 mg unretarded twice a day
• Further increase in the number of single doses every 4 to 7 days until the day’s coverage.
  Since unretarded MPH is effective for only 2.5 to 3 hours, 3 to 5 single doses are required for daily coverage. With only two doses, almost the entire day would remain unmedicated. This could completely distort the assessment by affected individuals or third parties, especially if they have not been educated about the limited effective time window (and the expected rebound). Most importantly, it would not sufficiently reduce the symptomatology and thus the burden on the affected person.
• Increase single doses to 5 mg (sustained release to 10 mg/single dose)
  • Always increase only one single dose per dosing step, starting from the first dose (e.g.: 2.5 / 2.5 / 2.5 to 5 / 2.5 / 2.5 to 5 / 5 / 2.5 etc.)
• Thereafter, every 4 to 7 days, increase the dosage by a maximum of 2.5 mg / single dose of unretarded MPH.
  We consider dose jumps of 5 mg unretarded MPH / single dose (or 10 mg / single dose half-day retard, as recommended, for example, by the Medikinet technical information) to be disadvantageous
  • Purpose: Slow up-dosing avoids skipping the optimal dose.
    Not many, but a quite considerable part of the affected persons have, according to our experience, a very narrow window for an optimal dosage of significantly less than 5 mg, so that 2.5 mg less / single dose is not sufficient and 2.5 mg more can already trigger the first overdose phenomena. Likewise, leno.¹⁷ It may have been quite often assumed so far an intolerance, which in reality was due to inappropriate dosages.
    Since such small-dose increments do not harm other sufferers (but, on the contrary, help avoid single-dose side effects),⁴⁹ dosing increments in 2.5-mg increments (relative to an unretarded single MPH dose) should be the gold standard. So, too, does Kühle.⁵⁰ A large metastudy points in the same direction⁶
    Other sources recommend a start with 1-2 single doses of 5 mg and a weekly increase of the single dose in 5 mg steps.⁵¹ For the reasons mentioned, we consider these dose jumps already too large.
    For sufferers for whom even extremely small differences in dose are crucial, a pharmacy in Switzerland offers MPH drops. One drop contains 0.35 mg of MPH. It is produced in batches and preserved using E216 and E218.⁵² One affected person reported that dissolving unretarded MPH in alcohol in such exact amounts that they could be measured by drop showed a comparable result.
• Educate affected and (initiated) observing third parties about
  • The usual duration of action of the respective preparation
  • The possibility of an individually shorter or longer duration of action
  • About the expected rebound
    Knowing the usual duration of action, that it may vary from individual to individual, is as important for observing the effect and its end as it is for ensuring that the last dose can be taken in time before going to bed so that the effect has worn off at least an hour before. In some sufferers (we suspect more in ADHD-I than ADHD-HI), a reduced dose (1/5 to 1/2 of an optimized single dose) in unretarded form may help them fall asleep. Again, test administration as a sleep aid with very low doses (1/10 of the single daily dose). Retarded daily doses are to be converted to the unretarded effective time. (Example: 20 mg sustained release for a 5-6 hour action time corresponds to 10 mg sustained release for a 2.5-3 hour action time).
• Increase the dosage until a very satisfactory effect is achieved.
  • For the majority, but not all, of sufferers, a higher dose produces better symptom reduction⁵³
• At a daily dose of 20, 40, 60 mg MPH, a feedback discussion should be held with the treating physician in each case.
• In addition, it is recommended to keep a diary (see below). Some physicians expect a weekly transmission of the diary, e.g. by mail. This can help to detect undesirable developments at an early stage.
• After reaching the supposed optimal dose, make 2 more increases to find that negative symptomatology is now added.
  Purpose:
  It is ensured that not only an improvement of the symptomatology but also the optimal dose is determined. Furthermore, the affected person learns how it feels when there is a slightly too high dosage. This is important so that the affected person develops a feeling for what the optimal dosage is, in order to be able to stimulate further dosage reductions if necessary.
• It is possible that side effects may occur at certain dosage levels below the optimal dose that disappear at higher dosage levels. In particular, internal shakiness (like one too many cups of coffee) may resolve within 2 to 3 days after a dose increase. It is possible that this is an adjustment of the noradrenergic system. Several sufferers have reported to us that at the next dose level or the one after that, this internal tremor no longer occurred. If it becomes more pronounced or persists, it is a sign of overdose
• “Zombie” symptomatology indicates either overdose or unmasked depression.
  • Stimulants close stimulus filters: This is probably the reason why students “try out” stimulants for stressful exam times (which we strongly advise against), but do not continue to take them afterwards of their own accord
  • Those who (unlike ADHD sufferers) do not have a stimulus filter that is too wide open will lose quality of life. There are no reports of students taking MPH voluntarily outside of very stressful exam periods (unless they have severe ADHD symptoms⁵⁴ )
  • Stimulants inhibit the limbic system. An overdose can therefore lower the emotional sensation.⁵⁵
• The manufacturer’s data on the typical duration of action only apply to individuals with standard gene variants of the metabolization genes. However, many affected individuals have deviations in the relevant metabolization gene (MPH: CES1 gene; AMP, atomoxetine, bupropion: CYP2D6 gene; guanfacine: CYP3A4 gene.) In the case of CYP 450 enzymes, gene variants of the POR gene are added, which in turn influence the efficacy of the CYP enzymes, so that the CYP gene variant alone is not yet meaningful. For more information see CYP2D6 metabolizing enzyme, CYP3A4 metabolizing enzyme, CES1 Metabolizing enzyme. In addition, there are other pharmacological influences that affect the duration of action. For more information see Effect and duration of action of ADHD drugs
• The deviations are so frequent that the typical duration of action must not be assumed. It must be checked individually for each affected person.
  • A single dose of Elvanse only works for a maximum of 5 to 7 hours in 2/3 of sufferers. The typical value of 12 hours stated by the manufacturer is therefore by far not achieved in the majority of sufferers.
  • In rapid metabolizers (about 15-20% of those affected), unretarded MPH is effective for only about 1 to 1.25 hours instead of the usual 2.5-3 hours, Medikinet or Ritalin adult for only about 3 hours instead of the usual 5-6 hours, and Elvanse for 5-7 hours instead of the usual 10-12 hours. The rapid metabolizers we knew reported that they tolerated appropriately more frequent doses and appropriately higher daily doses well without any side effects. Nevertheless, with the increase in the number of doses/day required here and the consequent possible exceeding of the general maximum dose recommendations, closer monitoring is certainly required.
  • If necessary, excessively rapid metabolization can be countered by cross-treatment with inhibitors of the respective metabolizing enzyme. For example, several sufferers in whom Elvanse (which is metabolized via CYP2D6) had a much too short or no effect reported a satisfactory effect and duration of action after combination with bupropion, which reduces CYP2D6 expression.

1.2.3. Transition to sustained release MPH / AMP¶

Once discontinuation with unretarded MPH has occurred, the number of single doses/day should be reduced by using sustained-release preparations.
Medication compliance decreases proportionally to the required frequency of intake. Because ADHD sufferers are notoriously disorganized and forgetful, each additional dose represents another opportunity to forget to take it. In addition, 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 treatment⁴

1.2.4. AMP dosing¶

1.2.4.1. Elvanse (Lisdexamfetamine)¶

• Since Elvanse is the drug of choice in adults (highest effect size and lowest side effects among all ADHD drugs), direct dosing with Elvanse would be reasonable.
• Elvanse adult is available in capsules of 30, 50 and 70 mg (20, 40 and 60 mg will also be available from the end of 2023), Elvanse (without “adult”), which is fully bioidentical, is available in sizes of 20, 30, 40, 50, 60 and 70 mg.
• 30 mg for single-dose administration, in our experience, involve a significant risk of overdose and increase the risk of single-dose side effects.
  We know quite a few sufferers for whom the optimal dosage range of Elvanse is below a margin of 5 mg / single dose. 5 mg less is too little, 5 mg more is overdosed. We also know individual sufferers who are optimally dosed with 3 mg Elvanse / day. Therefore, we consider dosage levels of 5 mg to be optimal. See also above under dosage of unretarded MPH.
• Although the package insert of Elvanse does not allow the contents of the capsules to be divided up, this is, according to the many years of experience of a large number of patients, a viable method for dosing as well as for finding the optimal dose. We do not know of any reports of fluctuations in effect due to uneven distribution of the active ingredient. A fine dosage can be achieved by dissolving the contents of the capsule in water and dividing it by means of a syringe with almost milligram precision. This is also the case with Kühle in the equivalence table.⁵⁶ A somewhat coarser method is to divide capsules into equal-sized heaps using a razor blade on a glass surface.
• The dissolved Elvanse keeps in the refrigerator for a few days.

This Video explains how to divide Elvanse capsules into small dosing increments.

1.2.4.2. Aderall N (unretarded)¶

The FDA recommends as a single dose of unretarded amphetamine salts (Adderall) for ADHD:⁵⁷⁵⁸
- Children up to 3 years: amphetamine is not recommended
- Children from 3 to 5 years:
- unretarded AMP
- Initial dose of 2.5 mg once daily in the morning after waking up
- Subsequent doses at intervals of 4 to 6 hours
- weekly increase in increments of 2.5 mg until optimal response is achieved
- Dosage range between 2.5 to 40 mg per day, divided into 1 to 3 divided doses
- Children from 6 years and older
- unretarded AMP
- Initial dose of 5 mg once or twice daily at 4 to 6 hour intervals
- weekly increase in increments of 5 mg until optimal response is achieved
- Dosage range between 5 and 40 mg per day, divided into 1 to 3 divided doses
- retarded AMP
- Initial dose of 5 to 10 mg once daily in the morning
- weekly increase in increments of 5 to 10 mg until optimal response is achieved
- Maximum daily dose 30 mg per day
- Teenagers
- unretarded AMP
- Initial dose of 5 mg once or twice daily at 4 to 6 hour intervals
- weekly increase in increments of 5 mg until optimal response is achieved
- Dosage range between 5 and 40 mg per day, divided into 1 to 3 divided doses
- retarded AMP
- Initial dose of 10 mg once daily in the morning
- weekly increase in increments of 10 mg until optimal response is achieved
- No sufficient evidence for better results with more than 20 mg per day
- Note: this does not coincide with the experience on Elvanse in Europe
- Adults
- unretarded AMP
- Initial dose of 5 mg once or twice daily at 4 to 6 hour intervals
- weekly increase in increments of 5 mg until optimal response is achieved
- Dosage range between 5 and 40 mg per day, divided into 1 to 3 divided doses
- retarded AMP
- Initial dose of 20 mg once daily in the morning
- No sufficient evidence for better results with more than 20 mg per day

1.2.5. Duration of action of individual doses and daily coverage¶

• Affected persons should be explicitly informed about the typical duration of action of a single dose of the respective preparation during dosing. We repeatedly receive reports from affected persons who were led to believe that a single dose of unretarded or half-day-retarded MPH (e.g. Ritalin adult) would take effect over the whole day, instead of pointing out the usual duration of action of 2.5 - 3 or 5-6 hours. This naturally leads to erroneous feedback to the physician when it is reported that the symptomatology is unchanged because, in ignorance of the duration of action, it was set to the afternoon or evening.
• Unretarded MPH is effective for about 2.5 to 3 hours, the “normal” half-day retarded MPH preparations (Medikinet, Ritalin adult) for about 5 to 6 hours, and some MPH full-day retard preparations (Concerta, Kinecteen) and Elvanse for up to about 10 to 12 hours. Daytime coverage requires medication for about 14 to 15 hours, which is difficult to achieve with a single dose.
• All-day coverage may require the combination of sustained-release and unreleased stimulants.⁵⁹
• Approximately 15-20% of patients are fast metabolizers, in whom the duration of action of a single dose is shorter, so that more daily doses may be required. For more information, see above.
• A notable number of sufferers report significantly shorter duration of action with Elvanse than the 12 to 14 hours stated by the manufacturer. Many of them were able to achieve optimal daily coverage by taking several single doses. For more on this topic, see Amphetamine medication for ADHD: effect profile (temporal) / duration of action
• Individuals report that intense exercise can shorten the duration of action of stimulants by up to 40%.⁶⁰
• Within a person, higher doses of amphetamine have a longer effect⁴
  • Because amphetamine is excreted by the kidneys, renal blood flow plays a small but measurable role in duration of action in addition to total dose
  • Another consequence of this is that amphetamine blood levels change more slowly and are less prone to rebound than with methylphenidate

The required duration of drug coverage throughout the day is influenced by several factors⁴
A distinction must be made here:

• Attention and organization symptoms (medication as needed justifiable)
  • Length of the school or work day
  • Challenging situations outside of work (events, social events)
• Impulsivity and Emotional Dysregulation (all-day coverage 24/7 required; may be combined with ATX / Guanfacine)
  • Need for medication to make social life tolerable

The fear that stimulant medications would impair sleep is rarely well-founded.⁴ As a rule, stimulants improve the quality of sleep in ADHD sufferers. For more information, see Treatment of sleep problems in ADHD

1.2.6. Dosage not all-inclusive or according to body weight¶

The misconception that stimulants should be dosed in proportion to body weight is still widespread.
Since individually varying between 11% and 43% of the ingested methylphenidate arrives in the blood, a lump sum according to weight does not make sense⁴
There may be a statistical mean of which dosage might be more often appropriate at which body weight. However, since the individual variations are so great, each dosage is an individual matter. A blanket reliance on a statistical mean would be a treatment error.
An upper dosage limit of 1 mg / kg MPH is usually a good guide to avoid increased side effects. However, in individual cases (with correspondingly rapid metabolism), significantly higher dosages have also been required and tolerated. Adults often require lower dosages than adolescents or children. In individual cases, the optimal MPH or AMP dose may be below 5 mg / day.
Huberman reports a single case of an optimal daily dose of 2.5 mg Adderall in a woman weighing 150 kg and required daily doses of 180 and 210 mg Adderall in two sisters weighing 60 and 70 kg, respectively.(lHuberman (2023): Adderall, Stimulants & Modafinil for ADHD: Short- & Long-Term Effects | Huberman Lab Podcast, english)) We also know of individual cases where only extremely high doses of Elvanse (several hundred mg / day and 50 mg as required sleep medication at night) achieved an adequate effect and significant improvement. Such high doses may only be used with close supervision by an experienced physician. Self-testing must be warned very strongly.

1.3. Dosing of non-stimulants¶

Non-stimulants are third choice after stimulants AMP and MPH in the treatment of ADHD.
Clinicians report that nonstimulants sometimes lose their effect after 9 to 18 months, at which point a switch to another nonstimulant becomes necessary.⁴ Studies with such long observation periods do not exist.

1.3.1. Atomoxetine dosage¶

According to the study situation² as well as in our experience, a slow up-dosing also has the advantage of a lower side effect development with atomoxetine. Another study supported by the manufacturer does not show a clear picture ⁶¹, while a third showed a less frequent discontinuation of use due to side effects with slow dosing, although the side effect rate was comparable.⁶²
Atomoxetine is available as non-divisible capsules and divisible tablets.

According to the Strattera package insert, if patients experience side effects with one daily dose of atomoxetine, it is possible to divide the dose into two halved doses in the morning and evening.⁶³

The first effects may be seen after 2 to 3 days. Atomoxetine takes 8 to 10 weeks to take full effect⁴

When dosing out, in our opinion - as with all antidepressant-like drugs - a slow approach is highly recommended. Other view: Prasad et. al.² However, we have several reports of depression as a side effect of rapid discontinuation of atomoxetine.

Since atomoxetine can also increase blood pressure and heart rate, these should be monitored⁴

1.3.2. Serotonin reuptake inhibitor¶

The use of serotonin reuptake inhibitors must always be coordinated individually with the physician. Serotonin reuptake inhibitors are suitable for the treatment of (comorbid) depression.
Regarding ADHD, treatment of impulsivity in ADHD-HI by minimal doses might be useful at best (e.g., 2 to 5 mg escitalopram), which in our experience seems to act immediately and does not appear to be mediated by receptor downregulation or upregulation.
Incidentally, serotonergic medications are not useful with respect to ADHD itself and especially ADHD-I.

1.3.3. Dosing of other non-stimulants¶

It can also take 8 to 10 weeks for other non-stimulants such as bupropion, imipramine, or desimipramine to take full effect.⁴

1.3.4. Slowly taper off level medications¶

Level medications must be dosed slowly and phased out slowly.
For serotonin reuptake inhibitors, this can take up to more than half a year to avoid side effects.

1.4. Avoid side effects¶

At the individually optimal symptom-improving dose (which can be considerably lower than typical doses!), few sufferers experience side effects. The most common side effects are

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

Rare more serious side effects (hypertension, aggressiveness or other) discuss immediately with doctor.

Sensitive individuals, especially ADHD-HI and ADHD-C⁴, may experience slowing of thinking and flattened affect (emotion depletion) (“zombie syndrome”). Here, avoiding an overdose or reducing the stimulant dose under combination medication with non-stimulants can be helpful. More about this under Combination medication for ADHD

1.4.1. Overdose and caffeine cross effects¶

Overdose signs usually correspond to those of excessive caffeine consumption⁴

• Tremors
• mild dysphoria
• Nervousness
• Palpitations
• Headache
• Irritability

Since the side effects of caffeine and stimulants can add up, side effects can occur when they are consumed together that do not occur when caffeine alone or stimulants alone are taken. Based on our observation, this affects about half of all sufferers. We know many sufferers who did not pay attention to this and therefore mistakenly believed that they could not tolerate stimulants. A new attempt without caffeine and with slow dosing, on the other hand, was often successful.
Therefore, when dosing stimulants, caffeine should be completely and consistently omitted. This may be subjectively difficult for sufferers who previously combated their ADHD symptoms with high caffeine consumption. However, the function of symptom reduction is now taken over (us much better) by the stimulants. With previously high caffeine consumption, caffeine withdrawal symptoms may occur for 3 days. Again, these should not be confused with dosing side effects.

1.4.2. Headache¶

This presentation is based on Simchen⁶⁴ and is in line with our experience.

Headache as a side effect of stimulant use is often a result of glucose deficiency.
Stimulants increase the activity of the PFC, which increases glucose consumption and lowers blood glucose levels.
Symptoms of hypoglycemia are

• Headache
• Tiredness (yawning)
• Paleness
• Dizziness
• Shakiness (but shakiness may also be from overdose or cross-effects with caffeine).

Remedy:

• eat a good breakfast / meal before each dose intake
• Snacks for in between
• at the onset of a headache immediately eat quickly digestible carbohydrates
  • Dextrose
  • Bananas
  • Fruit juices (without sweetener)

During prolonged hypoglycemia, the brain forms acidic metabolic intermediates via lactic acid metabolism, which lead to headaches that last longer and are more difficult to eliminate.

Another common cause of headache when dosing stimulants is inadequate fluid intake.

Sufferers report that when the stimulant effect wears off, a quick intake of food can restore concentration.

1.4.3. Gastrointestinal complaints¶

Stimulants can increase gastrointestinal motor activity, which may be perceived as painful in sensitive sufferers (if, more so in children).⁶⁴(

Especially higher doses on an empty stomach can cause a strange cramping sensation under the right costal arch about 30 minutes after ingestion. This is thought to be caused by a spasm of the duodenal smooth muscle due to the sudden increase in stimulant levels.⁴

Remedy:⁶⁴⁴
Adequate food intake prior to medication.
A larger time interval before taking the medication (one hour) can again work better than no small time interval (15 minutes).

1.4.4. Problems falling asleep¶

Many sufferers report that since taking stimulants they are able to fall asleep better and have more restful sleep.
Some patients may nevertheless experience problems falling asleep as a side effect of the dosage. These usually disappear within the first few weeks.

Remedy:

• take last dose in time that its effect ends at least one hour before bedtime
  • this requires knowledge of the typical duration of action of the drug in question. For more information, see Effect and duration of action of ADHD drugs
  • increase time interval if necessary
  • if necessary, initially omit afternoon dose for 1 to 2 weeks, work with only one dose of half-day-retarded MPH in the morning
• Consider possibility of slowed metabolism (prolonged duration of action)
  • more about this under Effect and duration of action of ADHD drugs
• In some sufferers (we suspect more in ADHD-I than ADHD-HI), a reduced dose (1/5 to 1/2 of an optimized single dose) in unretarded form may help them fall asleep
  • Test administration as a sleep aid with very low doses (1/10 of the daily single dose)
  • retarded daily doses must be converted to the shorter duration of action of unretarded active substance (example: 20 mg retarded with 5-6 hours duration of action corresponds to 10 mg unretarded with 2.5-3 hours duration of action).

1.4.5. Tachycardia (increased heart rate), blood pressure increase¶

This presentation is based on Simchen⁶⁴ and is in line with our experience.

Stimulants stimulate the sympathetic nervous system.
MPH does not alter heart rate and increases blood pressure by 0.25. AMP and ATX slightly increase heart rate. Any cardiovascular effects resolve spontaneously in most sufferers. 2% of sufferers discontinued their drug treatment due to cardiovascular effects.⁶⁵ Once the body has become accustomed to these effects, they do not reoccur even when they are taken again after longer breaks in therapy.
Because the studies did not look for caffeine cross-effects, some of the discontinuations may have been due to such.
According to the American Heart Association, finely tuned stimulants are cardiac neutral in ADHD and do not require special monitoring of children and adolescents⁶⁶

In particular, sufferers with high blood pressure appear to suffer a further increase in blood pressure from stimulants even when the dosage is finely tuned. If high blood pressure is under control before starting ADHD treatment, stimulants can be used, although blood pressure should be monitored at each follow-up visit⁴

Particularly sensitive sufferers may experience a higher increase in heart rate during dosing. This should always be discussed immediately with the doctor.
Remedy:

• slower dosing up
• lower dosage
• Testing for cross effects
• Check whether caffeine has been completely omitted

1.4.6. Rebound¶

Rebound is a brief increase in symptoms immediately after the end of the active period of stimulants. It is unpleasant but harmless and is not an indication of problems with the drug.⁴ Nevertheless, in individual cases, it may be severe enough that individuals consider discontinuing medication.
According to our impression, rebound occurs mainly with unretarded and half-day retarded MPH. The rebound lasts about half an hour.
All-day retard preparations show less rebound.
Amphetamines have a lower rebound risk than methylphenidate.⁴ In our experience, the slow-release Elvanse has (almost) no rebound.

Remedy:

• Timely intake of the follow-up dose, so that its onset of action already occurs at the time when the rebound is to be expected.
• Rebound after the last daily dose can be avoided by a small amount of unretarded MPH
  • approx. 1/5 to 1/2 of the amount that would correspond to an optimal daily single dose (of retarded drugs this has to be converted, see above under problems falling asleep)
  • approx. 15 minutes before expected rebound entry

1.5. Change of preparation and active ingredient¶

Changes in preparation or drug may be necessary or helpful due to unfavorable side effect reactions or nonresponding.

If a medication does not show any effect (nonresponding), the first step should be to switch to another MPH preparation, especially in the case of MPH. Surprisingly often, patients react negatively or with too strong side effects to one MPH preparation and positively to another MPH preparation, while it can happen the other way around.

If an active ingredient shows no effect overall (regardless of the preparation) (nonresponding), another active ingredient should be tried first.
Around 30 % of all sufferers do not respond to MPH, and around 20 % do not respond to AMP (nonresponders). However, nonresponding rarely involves both agents at the same time, so 90% of those affected respond to either MPH or AMP. 40% to 50% of MPH nonresponders respond to atomoxetine.

In the event of a change of preparation or active ingredient due to side effects, the Conversion table from Kühle is very helpful. This provides an indication of which dose of another type of stimulant corresponds to the dose of a drug previously taken. The conversion table from UpToDate is also helpful⁶⁷

1.6. Dosage adjustments¶

• The perception that a very good effect after the first setting wears off after a few days to weeks is often not due to a change in the effect, but to a change in the way the person feels. In the so-called honeymoon phase immediately after reaching an effective dose, the difference from the deficit state before is perceived as a particularly positive experience. Such a feeling of special improvement is naturally transient, just as the elation of a soccer fan after winning the championship returns to normal within days, even though the whole season was trembling along. In this case, it must be carefully examined whether there is really a need for a higher dosage. External assessments can be helpful here.
• It may happen that a readjustment is required once after a few months. This does not represent a habituation effect.
• An omission test should be done once a year to check if the behavior continues to show ADHD symptoms without medication.
• ADHD sufferers frequently show 75% of the possible ADHD symptoms, non-affected people 12 to 25%. The goal of optimal dosing is therefore not complete freedom from symptoms, but a reduction of symptoms to a healthy level. An attempt to increase the dosage until all symptoms are completely eliminated would inevitably end in an overdose.

1.7. General notes¶

• For dosing, unretarded MPH should be used for approximately the first week. The shorter duration of action and the more linear dose-response correlation (without a second high at the onset of action of the retarded portion) facilitate finding the appropriate dose, especially for untrained observers (affected persons as well as third parties).
• In the case of retarded medikinet, it must be noted that this must be taken together with food, as otherwise the entire dose is delivered unretarded. Other preparations usually do not require food intake, although this must be checked in the package insert in each case. For all long-acting ADHD medications, it is recommended to take them together with food.
• Caffeine (coffee, cola, black tea, some green teas), dark chocolate / cocoa (theobromine) must be completely omitted during the dosage. Many affected persons can no longer tolerate caffeine or other stimulants that were previously consumed without problems or even in larger quantities when taking stimulants. Caffeine (teein) and theobromine are stimulants. They can add up with ADHD medications. This can quickly be mistaken for an overdose (internal jitteriness, inner restlessness, shakiness).
  After dosing, caffeine can be consumed again, although it is recommended to test it carefully at first. If caffeine now triggers shakiness, it is transparent that this is due to the caffeine and not the medication.
• Alcohol increases MPH blood levels and must be avoided completely when taking MPH.
• Avoid citrus fruits during dosing. Some affected individuals react to citrus fruits with varying drug effects. Grapefruit should be avoided during any medication dosing.
• Taking in the afternoons, weekends and vacations
  • Since ADHD is not a purely school-related problem, even if it is particularly evident there due to the extrinsic demands and the learning problems caused by the lack of neurotrophic substances, continuous medication is urgently recommended. Whether medication should only be given in the mornings during school hours depends on whether those affected are still able to manage their homework in a concentrated manner and their social contacts without emotional dysregulation until the early evening without symptoms.
  • Stopping the medication at weekends or during vacations should be avoided. On the one hand, symptoms do not adhere to school hours in a very disciplined manner and, on the other hand, a longer break in taking the medication may require that it be dosed again slowly in order to avoid side effects.
  • However, it is conceivable to reduce the dosage somewhat (to 2/3 or 3/4) in times of lower demands. Here it depends very much on the individual needs of the person concerned. All dosage changes must be coordinated with the physician. However, an experienced physician will allow a trustworthy patient considerable room for maneuver.
• Mixing stimulants
  • Stimulants can be combined. In particular, sustained-release and unreleased drugs can be taken on the same day. Also a combination of AMP and MPH does not cause any particular problems.
    As a rule, a sustained-release form of medication will be taken during the day, optimally covering the entire day. Responsible and trustworthy patients can cover isolated special stresses, e.g. a particularly long evening, using unretarded MPH as a supplement.
    The instructions of the attending physician are authoritative!
• Menstrual cycle can strongly influence drug effect.
  • Variations in drug effects in women should take into account the significant influence of estrogen that is possible with certain COMT gene variants. A dosing aid chart to assist in mapping menstruation and its effects can be found at ADHD-Forum.ADxS.org.

1.8. Stimulant discontinuation¶

From a medical point of view, stimulants can be discontinued quite easily from one day to the next. Apart from the recurrence of symptoms and the reappearance of side effects when dosing again after a longer break from medication, we are not aware of any typical disadvantages, especially withdrawal symptoms.
Nevertheless, always consult the attending physician.

We have observed isolated cases of genuine withdrawal symptoms from stimulants. These were cases in which individuals overdosed 5 to 10 times and were discontinued overnight. One specific case reported 50 mg of Elvanse, while 5 to 10 mg later proved to be the appropriate dosage.
Compared to the - sometimes very severe - side effects that patients repeatedly report from discontinuing antidepressants (especially too quickly), it can be generally said that there are no discontinuation problems with stimulants.

2. Diary documentation and external observation¶

During the dosing period, a diary should be kept to record how the patient is feeling each day. This should contain:

• Present symptoms (identify using overall symptom list: ⇒ Overall list of symptoms of ADHD by manifestations)
• Note change for each symptom
  optimal, but hardly feasible, would be a quotation with 24 hours to 48 intervals to avoid overvaluation of individual moments
• Dose
• Intake date(s)
• Other medications taken (type, dose, time(s))
• Food intake (type, quantity)
• Menstrual cycle in girls / women
  See more at ⇒ Sex differences in ADHD
• Sports
• Special stresses (emotional as well as physical, e.g. quarrels, illnesses, allergies, etc.)
• Important: the evaluation of the effect of the drug and the dosage is not done on the basis of individual days, but always in retrospect on the basis of an average of 3 to 4 days. Otherwise, irrelevant and random correlations are overestimated.

It is also helpful to unobtrusively ask uninitiated third parties about changes they have noticed. It must be expressly warned against informing these third parties that medication is being taken, as this would always have the effect that their attitude towards medication would be subconsciously included in the assessment and change the result. In order to avoid a bias in the assessment of the effect by teachers or other reference persons, it is therefore advantageous not to inform them initially about the intake. If they nevertheless report a significant change in behavior within the first few weeks, this unbiased observation is much more meaningful.
Reports only make sense if the duration of action of the medication is long enough. An unretarded MPH tablet in the morning cannot cause any changes beyond the 2.5 to 4 hour duration of action.

With children, it can be very helpful not to tell them themselves that they are now receiving medication, but to refer to it as vitamins during the dosing phase. After a few weeks, discussions with the teachers, who are also not in the loop, can be informative as to whether they have noticed any changes.