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Dosing of medication for ADHD

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Dosing of medication for ADHD

Like all presentations on medication at ADxS.org, this information has been compiled solely from a scientific perspective. It is not intended for self-medication, but to enable you to have a well-informed discussion with your doctor and understand their instructions.
Each specific treatment must comply with the instructions of the attending physician for each individual case.

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

1. Choice of active ingredient

See under Choice of medication for ADHD or ADHD with comorbidity

2. Dosing of stimulants

2.1. Basics of dosing stimulants

In principle, a dosage regimen that starts with low doses and increases them flexibly and individually has a clear advantage over the administration of fixed doses. This has been known since the 1970s1 and has been confirmed by a new, comprehensive meta-study2. Studies also use slow dosing to avoid side effects.3
With both MPH and AMP, the effectiveness increases with the dose level on the one hand and the probability of discontinuation due to side effects on the other. In studies with fixed doses, the additional efficacy benefit decreased from 30 mg MPH or 20 mg AMP.

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

The fact that the fixed-dose approach, which is much less suitable in practice, is still used in some cases seems to be due to the fact that the FDA requires studies with fixed doses for drug approval. However, these approval studies are not aimed at clinical practice.

The guidelines in Germany and the USA do not work with fixed doses, but provide for an increased dosage.
In our experience, it is advisable to proceed a little more slowly than is envisaged there.

Guideline recommendations for dosing

The German S3 guideline 2018 states:
“The aim is to implement the lowest possible dosage. This will also reduce or avoid the problem of adverse effects (…). Under these conditions, starting from a low initial dose, the dose can be gradually increased until no further clinically significant improvement in symptoms (e.g. at the level of core symptoms, but also in terms of a change in problem behavior) can be achieved and the adverse effects remain tolerable.”5

The 2009 guideline stated:“For stimulants: No strict correlation between body weight and necessary dose!(evidence level IIa). Always individual titration. The stated mg/kg bw are average values and can be individually under- or exceeded.”6

MPH:
While the guidelines for MPH stipulate a dosage in 10 mg titration steps of half-day-retained MPH, we consider half as fast titration to be sensible with Kühle - even if this challenges the patience of some patients. For this purpose, unretarded MPH (2.5 mg / single dose) or retarded MPH (5 mg / single dose, which corresponds to 2 successive doses of 2.5 mg unretarded MPH due to the double duration of action) can be used.

AMP:
The lowest dose of Elvanse, which is frequently prescribed for adults in Germany, is 20 mg for children and - until 2023 - 30 mg for adults, and 20 mg from 2023 onwards. Here we encountered even more frequently than with MPH that this smallest capsule dose was already too much for a relevant proportion of those affected. We know of a significant number of adults who require - in some cases significantly - less than 20 mg / dose and another significant number whose required dose is between these 10 mg increments and who are underdosed with the lower capsule and overdosed with the higher capsule. Many of them have found the right dosage by dividing the capsules - contrary to the manufacturer’s information in the package leaflet. The fact that the manufacturer has added 20, 40 and 60 mg to the doses of 30, 50 and 70 mg previously offered for adults in 2023 is in line with our experience and could make the need for non-approved capsule splitting obsolete for some - but hardly all - of those affected.

Doctors may deviate from the manufacturer’s instructions in the course of individual treatment trials.
For those affected, the method of application prescribed by the respective doctor is decisive.
The experiences reported here are for information purposes and for discussion with the prescribing doctor.

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

Package inserts for OROS-MPH (Concerta, an all-day retard MPH) in the USA and Japan recommend a starting dose of 18 mg/day for children and adolescents with ADHD and a top-up dose in increments of 9 or 18 mg. These recommendations are primarily based on clinical studies.89
In the USA, starting with a higher daily dose is more common and up-dosing is rarer than in Japan, for example, but such a procedure is by no means the clinical standard in the USA.10

2.1.1. Unretarded or retarded stimulants

MPH dosing can be carried out with unretarded MPH or retarded active substances.
Dosing with unretarded MPH is common. Dosing with sustained-release MPH is also advocated11
In view of the positive experiences of adults with ADHD, we expect that Elvanse will also become established in Europe in the medium term for dosing adults. In the USA, dosing with long-acting amphetamine salts is common (Adderall XR).

2.1.2. Amount of the initial dose

In principle, the appropriate dose must be determined individually for each person affected. Therefore, studies that statistically determine the “optimal” dose of stimulants are only of limited use for individual treatment.
Stimulants have a dose-dependent effect.12

  • low doses selectively activate noradrenaline and dopamine neurotransmission in the PFC (working memory, executive functions, inhibition, emotion regulation)
  • higher doses increase the efflux of dopamine and noradrenaline throughout the brain and thus also address the striatum (drive, motivation). Attention problems in ADHD are mainly caused by a lack of self-motivation (which is why attention works for intrinsically interesting things, but not for intrinsically uninteresting things). As stimulants in higher doses also increase dopamine and noradrenaline in the striatum, they also increase drive and attention. Atomoxetine, which only increases dopamine in the PFC, does not have this effect.

In general, stimulants 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.). The dose is then increased in equal increments until the optimum benefit is achieved. At the dose with the optimal symptom improvement, most adult ADHD sufferers report few side effects other than a mild and temporary loss of appetite.4

  • low starting dose (2.5 mg unretarded MPH / single dose or equivalent for other medications)1314
  • at least 5 days / dose level
  • Dosage increments max. 2.5 mg unret. MPH / single dose
  • optimal dose is very individual1314
  • Effect of slow dosing:
    • reduces side effects
    • prevents skipping the appropriate dose due to the sometimes very narrow therapeutic range1314
      In Germany, a single dose of 5 mg unretarded MPH was recommended for schoolchildren in 2004. 15 This was the smallest MPH dose available at the time. It was not until two years later that a 5 mg half-day retard preparation (Medikinet retard 5 mg) was approved for the first time.

The equivalent of 5 mg unretarded MPH in Elvanse is 10 mg. When dosed in 2.5 mg unretarded or 5 mg retarded increments, the equivalent is 5 mg Elvanse increments.1617

There are reports from patients about side effects even with low starting doses. The frequency is unknown, as is whether these would not also (or even more so) have occurred with dosing at higher starting doses.
In principle, the side effects of stimulants are less dangerous than the consequences of overdosing and can improve with controlled dosing, which is why we nevertheless consider a lower initial dose to be more sensible.
Patients who are generally resistant to medication may be able to cope with higher starting doses (such as the 30 mg Elvanse for adults or 10 mg Medikinet retard recommended in the prescribing information). However, you should bear in mind that even 30 mg Elvanse may already be above the optimal target dose and consider a lower dose if there are signs of a reaction.
In the Medication duration survey by ADxS (as of 12/19/2013), 13% of 223 Elvanse users indicated an optimal dose below 30 mg and 11.7% indicated an optimal dose of 20 mg or less. 1.8% stated 10 mg or less. The 11.7 % with 20 mg or less had an average weight of 71 kg and an average age of 40 years.

People with a known increased sensitivity to medication should start with low doses. However, it is important that they are aware that

  • a constant and consistent increase in dosage every 5 to 7 days up to the target dose specified by the doctor is absolutely necessary in order to be able to assess the benefit of stimulants (and a previous “withdrawal” often documents less a drug intolerance than the impatience of the person concerned) and
  • side effects may be reduced at higher dosage levels.

For particularly (drug-)anxious patients, it should be considered whether jumping into the target dose is not preferable, because the new concerns about possible side effects that arise with each increase in the dose could increase the risk of placebo side effects.

Ultimately, it’s like the question of whether to go left or right around a tree on a path through a dense forest. Sometimes there is a thorn bush to the left, sometimes a ditch to the right - and sometimes both. Both paths can lead you to your destination, but you should be aware of the pitfalls of each path.

2.1.3. Dosing levels: Small stages better than large stages

The treatment of ADHD in children starts from a low dose with a slow dose increase

In our opinion, a more gradual dosing is clearly advantageous compared to the currently usual dosing in 10 mg / half-day Retard MPH dose increments, from which the following 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 speed of dosing changes only slightly.

Mutschler also recommends starting with a low dose and slowly increasing the dose.18
“Undesirable side effects are particularly to be expected at the start of treatment, which is why the dosage should be increased gradually.”19

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

  • low doses of stimulants have a different effect and on different regions of the brain than high doses
    • low-dose MPH only has a noradrenergic effect; only higher-dose MPH also has a dopaminergic effect. More on this under Mode of action of methylphenidate in the article MPH Part 1: Active ingredients, effect, responding.
    • low-dose D-amphetamine (from 0.5 to 1 mg / kg in rats, which corresponds to approx. 0.2 to 0.6 mg / kg in humans), reduces (hyper)activity, while higher doses increase drive20
    • Noradrenaline and dopamine have very closely related roles in improving ADHD symptoms. What works better for a person affected must be tested individually
    • Even with severe symptoms, a very low dose may be appropriate for the individual.21 Huberman reports a single case of an optimal daily dose of 2.5 mg Adderall (woman weighing 150 kg).22 0.3 mg/kg showed a greater improvement in performance in learning tasks in children with ADHD than 1 mg/kg, 1 mg/kg showed better social evaluation by teachers and less restlessness in hyperactive children, but poorer learning performance than placebo.23
  • carefully acclimatizing the body to the active substance to avoid side effects that could lead to avoidable discontinuation of ADHD medication 2425
  • Too high a dosage leads to a recurrence of the ADHD symptoms avoided with the appropriate dosage (Inverted-U).26

However, we have also received individual reports from patients in whom low doses caused severe side effects that disappeared with higher doses. However, we do not know whether the side effects resulted from the low dose or from the initial dose itself.

Slow dosing with other medication classes and with ADHD medication

Slow dosing is helpful for many (other) drug classes,2728293031323334353637383940414243444546474849 while an equivalence of fast to slow dosing or disadvantages of slower dosing beyond the later onset of the full effect are much less frequently reported in studies.50515253
It is striking that slow dosing seems to be particularly important for geriatric medication. It is possible that the experience of clinical practice with stimulants is still influenced by the time when mainly children were treated. In any case, our experience with adults, which is predominantly characterized by adult patients, shows that slow dosing of stimulants is advantageous.

Surprisingly, we were unable to find any studies on stimulants in ADHD on the effect of a smaller dosage of stimulants on side effects or the determination of the optimal dose, although our experience as well as that of other2425 21 is quite clear on this.
A study on the use of MPH for age-related depression reports benefits of slow dosing54
There are studies on ADHD in which MPH was titrated.2 However, these appear to have focused on maximum efficacy rather than avoiding side effects. In addition, not all studies report on the dosage steps55
Studies on slow or fast dosing of ADHD drugs only concerned atomoxetine, with slower titration reducing side effects56
It is possible that the ADHD-phenotypical impatience of those affected is perceived as an obstacle to slow dosing.
Since no disadvantages of a slow increase in the dosage of ADHD medication have been reported, we believe that the risk of an ADHD medication being wrongly discontinued due to a supposed intolerance should be avoided above all, because this would massively affect the life of a person affected.

2.1.4. Speed of the dosing stages: 5 to 7 days / stage

From a purely technical point of view, titration could be rapid, as 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. Once the dose tapers off, there is no further or accumulated benefit4
In our opinion, however, there are a number of arguments against daily dosing:

  • The effect of slow-release medication must be monitored over the course of the day
  • The effect is not perceived by the doctor, but by the patients themselves
  • Those affected have no experience and therefore do not know what to look out for
  • Those affected may experience placebo effects that depend heavily on their subjective attitude towards the medication and which can only be distinguished from the actual effect after several days
  • Individual daily influences can distort the results
  • For women, the current cycle status must be taken into account

We therefore strongly advise against 1-day dose increments. This also applies to inpatient dosing, even if the duration of the steps can be reduced there.

We recommend that those affected keep daily records of their intake, symptoms and side effects (e.g. using the Dosage aid table from the ADHD forum at AdxS.org), but never evaluate these on a daily basis, but always form a 3-day average. It follows that a level requires 3 to 415 (we mean; or 5 to 7 days) to allow an assessment.
We do not consider the step duration of 1 month practiced by some doctors to be very useful. It is of no benefit whatsoever and may only be necessary to compensate for excessive dosage levels.

A German dosing regimen for schoolchildren using unretarded MPH provided for this:15 However, this recommendation dates back to 2004, when 5 mg unretarded MPH was the smallest MPH dose available and today’s proven retard preparations did not yet exist. It was not until two years later that the first approval of a 5 mg half-day sustained-release preparation was granted (Medikinet retard 5 mg, 2006)

Duration In the morning At lunchtime
3 days 5 mg -
4 days 10 mg -
Medical consultation for assessment
5 - 8 days 10 mg 5 mg
further individual dose titration in 5 - 8 day increments

Most children need 10 - 20 mg in the morning and 5 to 10 mg in the early afternoon.
If required, 3 doses in the morning / late morning / afternoon.

2.1.5. Target dosage

The optimal dosage of a suitable active ingredient and preparation for a patient must be determined individually in two dimensions:57

  • Single dose level
  • Number of daily doses
2.1.5.1. Target factor 1: Single dose level
2.1.5.1.1. Dosage not across the board or according to body weight

The optimal target dose for ADHD is very individual and cannot be determined across the board.

Fortunately, the misconception that stimulants should be dosed in relation to body weight is now less widespread.
Since between 11% and 43% of the methylphenidate ingested is absorbed into the blood, a generalization by weight makes no sense4
There may be a statistical average of which dosage could be more suitable for which body weight. However, as the individual fluctuations are so great, each dosage is an individual matter. A blanket reference to a statistical mean would be a treatment error.

Nevertheless, it is reported that the maximum dose of 1 mg/kg is more frequently required in obesity58

2.1.5.1.2. Optimal single dose can be below the lowest standard dose or above the standard upper limit

Certain groups often need a lower target dose than usual. Frequently mentioned here are

  • inattentive subtype
  • comorbid ASD
  • Adults often require lower dosages than adolescents or children.

However, this does not exclude the possibility that patients from these groups may require very high doses.
In individual cases, the optimal MPH or AMP dose may be less than 5 mg/day.

The optimum dose level may exceed the standard maximum dose (especially rapid metabolizers). This applies accordingly to amphetamine drugs.57
For MPH, the standard maximum dose is 60 mg / children or adolescents / day and 80 mg / adults / day
An upper dosage limit of 1 mg / kg MPH is generally a good guideline for avoiding increased side effects. In individual cases (with correspondingly rapid metabolism), however, significantly higher dosages are also required and tolerated.

Huberman reports an individual case of an optimal daily dose of 2.5 mg Adderall in a woman with 150 kg body weight and required daily doses of 180 and 210 mg Adderall in two sisters with 60 and 70 kg body weight.22 We are also aware of individual cases in which only extremely high doses of Elvanse (several hundred mg/day and 50 mg as required sleep medication at night) achieved an appropriate effect and considerable improvement. One of these cases was later explained to us as chronic poisoning with nitrogen oxides in the air. Such high doses should only be used under the close supervision of an experienced doctor. We must urgently warn against self-experimentation.

In the Medication duration survey by ADxS (as of 12/19/2013), 13% of 223 adult Elvanse users reported an optimal dose below 30 mg and 11.7% reported an optimal dose of 20 mg or less. 1.8% reported 10 mg or less. The 11.7% with 20 mg or less had an average weight of 71 kg and an average age of 40 years.

2.1.5.2. Target factor 2: All-day coverage / number of individual doses

The number of individual doses of a suitable active ingredient and preparation must be determined individually {Weiss MD, Surman CBH, Elbe D (2018): Stimulant ‘rapid metabolizers’: wrong label, real phenomena. Atten Defic Hyperact Disord. 2018 Jun;10(2):113-118. doi: 10.1007/s12402-017-0242-9. PMID: 29103196. REVIEW}}

There is also no direct correlation between the dose level and the duration of action of a single dose.

2.1.5.2.1. Ensure all-day coverage
  • When dosing, those affected should be expressly informed of the typical duration of action of a single dose of the respective preparation. We repeatedly receive reports from patients who were led to believe that a single dose of unretarded or half-day retarded MPH (e.g. Ritalin adult) would work throughout the day, instead of pointing out the usual duration of action of 2.5 - 3 hours (unretarded) or 5-6 hours (half-day retard). This naturally leads to erroneous feedback to the doctor if it is reported that the symptoms are unchanged because the period in the afternoon or evening is erroneously reported as being outside the effect in ignorance of the limited duration of action.
  • ADHD doesn’t end after school: ensuring all-day coverage
    • treatment should not only establish school readiness
    • Homework, social life and family life suffer considerably with ADHD
    • unmedicated ADHD is associated with a significantly increased risk of accidents, which is reflected in a 9-year reduction in life expectancy. Not treating this is not objectively justifiable. See the chapter Consequences of ADHD.
      The required duration of medication coverage throughout the day is influenced by various factors4
      A distinction must be made here:
  • Attention and organization symptoms (medication justifiable as required)
    • Length of the school or working day
    • Challenging situations outside of work (events, social events)
  • Impulsivity and emotional dysregulation (all-day coverage required 24/7; combination with ATX / guanfacine if necessary)
    • Need for medication to make social life bearable

If daily coverage is not achieved with a single dose of a preparation:

  • Multiple doses throughout the day (up to 3 all-day retard doses)
  • Retarded preparations can also be supplemented with unretarded preparations
  • All-day coverage may require a combination of sustained-release and non-released stimulants.59

The fear that stimulant medication would impair sleep is rarely justified.4 As a rule, stimulants improve the sleep quality of ADHD sufferers. More on this under Treatment of sleep problems with ADHD

2.1.5.2.2. Individual duration of action of a single dose can be greatly shortened / prolonged

Manufacturer’s information on duration of action (rarely achieved in practice)1314

  • unretarded MPH works for 2.5 - 3.5 hours / single dose
    • 4 to 5 single doses
    • hard to implement in the long term, especially with children
    • unretarded MPH is nevertheless advantageous for dosing, as it is the most finely adjustable
  • half-day-retarded MPH works for 5 - 6 hours / single dose
    • 2 doses + unretarded MPH for residual coverage if necessary
    • Second dose usually 50 % to 75 % of the first dose
  • all-day-retarded MPH works for 10 - 12 hours
  • Attentin (unretarded AMP) is effective for 5 - 6 hours
    • 2 doses and, if necessary, unretarded MPH for residual coverage
    • Second dose usually 50 % to 75 % of the first dose
  • Lisdexamfetamine (Elvanse) works for up to approx. 10 - 12 hours (note: often much shorter in practice!)
    • 1 dose and, if necessary, unretarded MPH for residual coverage
  • Guanfacine
    • Mirror medication, 1 x daily
  • Atomoxetine
    • Mirror medication, 1 x daily

Very rarely do we encounter patients who have a significantly longer effect from a single dose of an ADHD medication than the manufacturer claims.
This is sometimes reflected in an adequate effect of a dose level on the first and possibly second day of intake. On subsequent days, overdose symptoms occur if the dosage remains the same. If amphetamine drugs are involved, the steady state should also be taken into account in this context due to the rather long half-life.

More frequently, on the other hand, patients are affected for whom a single dose has a significantly shorter effect than specified by the manufacturer.
In our experience, around 15 - 20 % of those affected are rapid metabolizers with a shortened single dose duration of action

  • Fast metabolizers often need several doses/day instead of higher single doses
  • in about 50% of those affected, the duration of action of stimulants is only 50% of the manufacturer’s instructions
  • mostly super fast metabolizers (fast-metabolizing CYP or CES1 gene variant)
  • multiple doses per day, even of whole gestretards
  • Combination medication for fine adjustment / for difficult cases
  • in particular:
    • 50 % ATX for all-day treatment of emotional dysregulation
    • 50 % MPH or AMP, as usually better effect on drive / concentration
  • Rebound treatment
  • Rebound particularly common with MPH
  • Remedy:
    • Take the second dose in good time so that it starts before the first dose runs out in rebound
    • unretarded MPH shortly before the end of the last dose
      • 1/4 to 1/3 of what would correspond to a daily treatment dose
      • Example: 20 mg half-day delayed MPH corresponds to 2 x 10 mg unretarded MPH. In this case, 2.5 to 3.5 mg unretarded MPH 30 min before the end of the last retarded dose.

The phenomenon of shortened single-dose duration of action is much more common with Elvanse than with MPH:

  • In contrast to MPH, a significantly higher number of people affected by Elvanse reported a much shorter duration of action than the 12 to 14 hours specified by the manufacturer. Many of them were able to achieve optimum daily coverage with several single doses. More on this at Amphetamine medication for ADHD: Effect profile (temporal) / duration of action
  • Individual sufferers report that intensive sport can shorten the duration of effect of stimulants by up to 40 %.60
  • Higher doses of amphetamine last longer within a person4
    • Since amphetamine is excreted via the kidneys, the renal blood flow plays a minor but measurable role in the duration of effect in addition to the total dose
    • Another consequence of this is that amphetamine blood levels change more slowly and are less susceptible to rebound than with methylphenidate

2.1.6. Demand-based intake

The greater the self-control ability, the easier it is for those affected to take stimulants as needed. While a rigid intake schedule is generally safer for children, adults can decide on a daily basis whether and at what dose they take their prescribed stimulants (within the intake corridor agreed with their doctor). Some sufferers are able to regulate well when special tasks (e.g. evening events) require an additional evening dose or the only dose of an otherwise drug-free (because it is free of demands) weekend day (shopping on Saturday afternoon or on vacation). The guiding principle is “I control my ADHD, not my ADHD controls me”. 58
During dosing, adults must not deviate from the prescribed schedule. We experience time and again that the impulsiveness and impatience of those affected leads to changes in dose or intake within 2 or 3 days. However, this is primarily a sign of the disorder. Stimulants require several days of the same dose to enable a stable self-perception.
In women, the days before menstruation are often associated with an increased need for stimulants. See below at Cycle-dependent symptom fluctuations in women.

2.1.7. Change of preparation and active ingredient

It may be necessary or helpful to change preparations or active substances due to unfavorable side effects or non-response (lack of effect).

If a medication has no effect (non-responding), another MPH preparation should be used first, particularly in the case of MPH. Surprisingly often those affected react negatively or with excessive side effects to one MPH preparation and positively to another MPH preparation, while the opposite can be the case for others. A large study found that 85% of methylphenidate recipients changed their medication.61

If an active substance shows no overall effect (non-responding) (regardless of the preparation), another active substance should be tried first.
Around 30% of all those affected do not respond to MPH, and around 20% do not respond to AMP (non-responders). However, non-responding rarely affects both active substances at the same time, so that 90% of those affected react to either MPH or AMP. 40 % to 50 % of MPH non-responders react to atomoxetine.

It is reported that the optimal stimulant dose for MPH and AMP, which is often highly individualized, may differ. An affected person may require a relatively high dose of MPH or a relatively low dose of AMP to achieve an adequate effect. Therefore, a new individual titration is required when changing the active substance.58 As a result, the known conversion tables should be viewed with caution when changing the active substance.

2.1.7.1. Nonresponding: Change of active substance
  • MPH: 30 % non-responders
    • if MPH is not effective:
      • Check stomach acid
      • Change active ingredient
  • AMP: 20 % non-responders

Over 40% of those affected by non-responding are helped by a change of preparation in the first 3 months62
When switching between MPH and AMP due to non-responding, only approx. 10 to 15 % remain who are non-responders for both types of stimulants1314

REVIEW on treatment options for treatment-resistant ADHD: Cortese et al.63

  • Optimize stimulants
  • try alternative monotherapies
  • Try non-stimulants
  • combined pharmacotherapy
    • A combination of stimulants with non-stimulants is superior to monotherapy with only one group of active ingredients
  • Use off-label medications that have been proven to help with ADHD
  • treat comorbid diseases
2.1.7.2. Side effects: Change of preparation or active substance

To avoid side effects, see “Avoiding side effects” below.

  • MPH
    • in case of inappropriate side effects:
      • check: have the recommendations under “Avoid side effects” been followed, in particular caffeine completely omitted?
      • Overdose?
      • Need very low dosage?
      • with basic responding of MPH;
        • change preparation first
          • surprisingly individual side effect reactions
            • Person A does not tolerate preparation A and B fine, person B exactly the opposite: unpredictable
          • Preparation alternatives e.g:
            • unretarded
            • Medikinet retard / Adult
            • Ritalin LA / Adult
            • Concerta
            • Kinecteen
        • then change active ingredient
          • For recommended sequence, see above under choice of active substance
  • AMP
    • in case of inappropriate side effects:
      • check: have the recommendations under “Avoid side effects” been followed, in particular caffeine completely omitted?
      • Overdose?
      • Need very low dosage?
      • with basic responding of AMP:
        • change preparation first
          • surprisingly individual side effect reactions
            • Person A does not tolerate preparation A and B fine, person B exactly the opposite: unpredictable
          • Preparation alternatives e.g:
            • Lsdexamfetamine (Elvanse)
            • unretarded (Attentin)
            • Amphetamine juice (to be prepared by a pharmacy)
            • USA: high number of further approved preparations
        • then change active ingredient
          • For recommended sequence, see above under choice of active substance

In the event of a change of preparation or active ingredient due to side effects, the Conversion table from Kühle is very helpful (German). 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 helpful.64

2.1.8. Development of tolerance to stimulants / habituation effects

See in detail at Medication: Development of tolerance

2.1.9. Discontinuation of stimulants

Stimulants such as methylphenidate or amphetamine drugs have an immediate and dose-dependent effect. As a rule, they can be discontinued immediately and without side effects. In comparison to the - sometimes very severe - side effects that sufferers repeatedly report from discontinuing antidepressants - especially too quickly - it can be said across the board that there are no discontinuation problems with stimulants. However, those affected then suffer from the recurrence of ADHD symptoms, which can also be subjectively misinterpreted as a discontinuation side effect.
However, there are reports from those affected of discontinuation symptoms with amphetamine medication, in individual cases even lasting up to 14 days. In a minority of those affected, these actually seem to go beyond the unpleasant experience of the recurrence of ADHD symptoms. If necessary, this could be countered by slowly tapering off the medication.
Withdrawal symptoms were reported to us in a single case when discontinuing a 10-fold overdose of Elvanse (50 mg; patient only needed 5 mg).

2.2. Dosing with unretarded MPH

On the one hand, unretarded MPH allows better control over symptom improvement, but on the other hand, it requires more reliable patient compliance due to the higher number of single doses/day. For this reason, a single dose of sustained-release medication may be recommended for children and especially for younger children.

According to the German S3 guideline 2018, unretarded MPH can be considered for the following reasons, for example:5

  • more precise dose adjustment during the initial titration phase of the medication
  • Greater flexibility required in the dosing regimens

In our experience we recommend:

  • Start with a one-off very low dosage (2.5 mg unretarded MPH) and deliberately expect no effect at all.
    • As half-day sustained-release MPH is available from 5 mg, a 5 mg dose of sustained-release MPH can be taken instead of 2 doses of untreated MPH (usual duration of action approx. 5-6 hours)
  • After 4 to 7 days 2.5 mg unretarded twice a day
  • Further increase the number of single doses every 4 to 7 days until the day is covered.
    As unretarded MPH only works for 2.5 to 3 hours, 3 to 5 single doses are required to cover the entire day. With only two doses, almost the entire day would remain unmedicated. This could completely distort the assessment by patients or third parties, especially if they have not been informed about the limited window of action (and the expected rebound). Above all, however, it would not sufficiently reduce the symptoms and thus the burden on the patient.
  • Increase single doses to 5 mg (retarded to 10 mg/single dose)
    • Always increase only one single dose per dosage step and proceed from the first dose (e.g.: 2.5 / 2.5 / 2.5 to 5 / 2.5 / 2.5 to 5 / 5 / 2.5 etc.)
  • Then increase the dosage every 4 to 7 days 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 in the Medikinet technical information, for example) to be disadvantageous
    • Purpose: Slowly increasing the dose prevents the optimum dose from being skipped.
      Not many, but in our experience a significant proportion of those affected have 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. The same applies to leno.24 Up to now, intolerance has probably been assumed quite frequently, which in reality was due to inappropriate dosages.
      Since such small dosage steps do not harm other patients (on the contrary, they help to avoid side effects),65 dosage steps in 2.5 mg increments (based on an unretarded single MPH dose) should be the gold standard. So does Kühle.66 A large meta-study points in the same direction2
      Other sources recommend starting with 1-2 single doses of 5 mg and increasing the single dose weekly in 5 mg increments.67 For the reasons mentioned, we consider these dose increments to be too large.
      A pharmacy in Switzerland offers MPH drops for sufferers for whom even extremely small differences in dose are crucial. One drop contains 0.35 mg MPH. It is produced in batches and preserved using E216 and E218.68 One patient reported that dissolving unretarded MPH in alcohol in such exact quantities that they could be measured out per drop showed a comparable result.
  • Informing affected persons 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
      Knowledge of the usual duration of action, which can vary from person to person, is just as important for observing the effect and its end as it is for ensuring that the last dose can be taken in good time before going to bed so that the effect has worn off at least one hour beforehand. In some patients (we suspect ADHD-I rather than ADHD-HI), a reduced dose (1/5 to 1/2 of an optimized single dose) in unretarded form can help them fall asleep. Here, too, the following applies: test administration as a sleep aid with very low doses (1/10 of the single daily dose). In this case, the retarded daily doses should be converted to the unretarded duration of action. (Example: 20 mg retarded for 5-6 hours of action corresponds to 10 mg unretarded for 2.5-3 hours of action).
  • Increase the dosage until a very satisfactory effect is achieved.
    • For the majority of patients, but not all, a higher dose results in better symptom reduction69
  • With a daily dose of 20, 40, 60 mg MPH, a feedback discussion should be held with the attending physician.
  • It is also advisable to keep a diary (see below). Some doctors expect the diary to be sent weekly, e.g. by e-mail. This can help to recognize undesirable developments at an early stage.
  • After reaching the supposedly optimal dose, make 2 more increases in order to determine that a negative symptomatology has now been added.
    Purpose:
    It is ensured that not only an improvement in symptoms but also the optimum dose is determined. Furthermore, the patient experiences how it feels when the dosage is slightly too high. This is important so that the person concerned develops a feeling for what the optimum dosage is in order to be able to suggest further dosage reductions if necessary.
  • It is possible that side effects may occur at certain dosage levels below the optimum dose, which disappear again at higher dosage levels. In particular, internal shakiness (like one cup of coffee too many) may disappear within 2 to 3 days after a dose increase. This may be an adaptation of the noradrenergic system. Several patients have told us that this internal tremor no longer occurs at the next dose level or the one after that. If it becomes more pronounced or persists, it is a sign of overdose
  • A “zombie” symptomatology indicates either an overdose or unmasked depression.
  • The manufacturer’s information on the typical duration of action only applies to people with standard gene variants of the metabolization genes. However, many affected persons 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. More on this under CYP2D6 metabolizing enzyme, CYP3A4 metabolizing enzyme, CES1 metabolizing enzyme. There are also other pharmacological influences that affect the duration of action. More on this under Effect and duration of action of ADHD medication
  • The deviations are so frequent that the typical duration of action cannot 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 those affected. The typical value of 12 hours stated by the manufacturer is therefore far from being achieved in the majority of those affected.
    • In rapid metabolizers (approx. 15 - 20 % of those affected), unretarded MPH only works for approx. 1 to 1.25 hours instead of the usual 2.5 - 3 hours, Medikinet or Ritalin adult only for around 3 hours instead of the usual 5-6 hours and Elvanse for 5-7 hours instead of the usual 10-12 hours. The fast metabolizers known to us reported that they tolerated correspondingly more frequent doses and correspondingly higher daily doses well without any side effects. Nevertheless, with the required increase in the number of doses/day and the resulting possible exceeding of the general maximum dose recommendations, closer monitoring is certainly required.
    • Too rapid metabolism can be counteracted by cross-effects with inhibitors of the respective metabolizing enzyme. For example, several patients in whom Elvanse (which is metabolized via CYP2D6) had a much too short effect or no effect at all reported a satisfactory effect and duration of action after a combination with bupropion, which reduces CYP2D6 expression.

2.3. Transition to retarded MPH / AMP

After discontinuation with unretarded MPH, the number of single doses/day should be reduced by using sustained-release preparations.
Medication compliance decreases in proportion to the required frequency of intake. Since 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.4 Taking a single dose a day improves compliance.72

With sustained-release MPH, several doses are released in succession using pharmacological methods. Due to the considerable individual differences in duration of action, it is possible (albeit rare) that the first dose is metabolized so quickly that there is a gap in action before the second dose takes effect. This can be avoided by staggering the intake of several (possibly reduced) doses.

Medikinet adult and Medikinet retard are unsuitable for people who find it difficult to eat in the morning, as they only have a delayed effect if they eat beforehand.

2.4. Dosing of AMP

In addition to the above-mentioned general information on dosing stimulants and finding the appropriate starting dose, the following also applies:

2.4.1. Elvanse, Tyvanse (lisdexamfetamine)

  • Since amphetamine medication is the drug of first choice for adults (highest effect strength and lowest side effects of all ADHD drugs), direct dosing with these would make sense.
  • Elvanse / Tyvense contains lisdexamfetamine. Lisdexamfetamine is dextroamphetamine bound to lysine. The lysine binding causes a very slow and even release of dextroamphetamine in the blood and thus a prolonged effect.
    Available in the USA:
    Capsules: 10, 20, 30, 40, 50, 60, 70 mg
    Chewable tablets: 10, 20, 30, 40, 50, 60 mg
  • In our experience, the 30 mg recommended as standard as the first dosing step involves a considerable risk of overdosing and increases the risk of side effects.
    We know a number of patients 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 too much. We also know individual patients who are optimally dosed with 3 mg Elvanse / day. We therefore consider dosage levels of 5 mg to be more sensible than the officially stated 10 mg increments. See also above under dosage of unretarded MPH.
  • Although the package leaflet for Elvanse does not allow the capsule contents to be divided up, many years of experience with a large number of patients have shown that this is a good way of dosing and finding the optimum dose, even if 10 mg increments are not sufficient. We are not aware of any reports of fluctuations in effect due to uneven distribution of the active ingredient. A finely divided dosage can be achieved by dissolving the contents of the capsule in water and dividing it up using a syringe with almost milligram precision. This is also the method used by Kühle in the equivalence table.16 A somewhat coarser method is to divide capsules into equal-sized heaps using a razor blade on a glass surface.
  • The dissolved Elvanse / Tyvanse will keep for a few days in the fridge.

This This video explains the division of Elvanse capsules into small dosage steps.

2.4.2. Aderall N (unretarded)

The FDA recommends the use of unretarded amphetamine salts (Adderall) for ADHD:7374
- Children up to 3 years: Amphetamine is not recommended
- Children from 3 to 5 years:
- unretarded AMP
- Starting dose of 2.5 mg once a day in the morning after waking up
- Subsequent doses at intervals of 4 to 6 hours
- weekly increase in steps of 2.5 mg until optimal response is achieved
- Dosage range between 2.5 and 40 mg per day, divided into 1 to 3 divided doses
- Children from 6 years and older
- unretarded AMP
- Starting dose of 5 mg once or twice daily at intervals of 4 to 6 hours
- weekly increase in steps of 5 mg until optimal response
- Dosage range between 5 and 40 mg per day, divided into 1 to 3 divided doses
- retarded AMP
- Starting dose of 5 to 10 mg once a day in the morning
- weekly increase in steps of 5 to 10 mg until optimal response is achieved
- Maximum daily dose 30 mg per day
- Teenagers
- unretarded AMP
- Starting dose of 5 mg once or twice daily at intervals of 4 to 6 hours
- weekly increase in steps of 5 mg until optimal response
- Dosage range between 5 and 40 mg per day, divided into 1 to 3 divided doses
- retarded AMP
- Starting dose of 10 mg once a day in the morning
- weekly increase in steps of 10 mg until optimal response
- No sufficient evidence for better results with more than 20 mg per day
- Note: this is not the same as the experience with Elvanse in Europe
- Adults
- unretarded AMP
- Starting dose of 5 mg once or twice daily at intervals of 4 to 6 hours
- weekly increase in steps of 5 mg until optimal response
- Dosage range between 5 and 40 mg per day, divided into 1 to 3 divided doses
- retarded AMP
- Starting dose of 20 mg once a day in the morning
- No sufficient evidence for better results with more than 20 mg per day

3. Dosing of non-stimulants

Non-stimulants are the third choice for the treatment of ADHD after the stimulants AMP and MPH.
Clinicians report that non-stimulants sometimes lose their effect after 9 to 18 months and then a change to another non-stimulant becomes necessary.4 There are no studies with such long observation periods.

3.1. Dosing of atomoxetine

According to the study situation56 as well as our experience, slow dosing also has the advantage of a lower development of side effects with atomoxetine. While a study supported by the manufacturer does not show a clear picture75, other studies report less frequent discontinuation due to side effects with slow dosing, although the rate of side effects was comparable.76
Instead of 40 mg/day, it is sometimes recommended to start with a dose of 10 mg for women or 18 mg for men and to increase the dose every 14 days.58 or with 18 to 25 mg initially19
Atomoxetine is available as non-divisible capsules and as divisible tablets.

For long-term use, the recommended daily dose is 1.2 mg/kg, the maximum daily dose is 100 mg58
ATX is usually taken in the morning. If fatigue is a side effect, ATX can also be taken in the evening19
If patients experience side effects with a daily dose of atomoxetine, it is possible to split the dose into two halved doses in the morning and evening, according to the information for healthcare professionals for Strattera77

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

Unlike stimulants, it is important to take atomoxetine continuously.58

In our opinion - as with all antidepressant-like medications - a slow approach is highly recommended when discontinuing. Different opinion: Prasad et. al.56 However, we have received several reports of depression as a side effect of rapid discontinuation of atomoxetine.

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

3.2. Dosing of guanfacine

Guanfacine appears to reduce noradrenaline in the first 2 weeks of intake. Only afterwards does it appear to increase noradrenaline through downregulation of receptors.
It should follow from this that, as with antidepressants, it takes several weeks before an effect occurs.78

3.3. Dosing of further 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

When dosing drugs containing THC, a starting dose of 1 to 2.5 mg THC/day is recommended. The dose should be increased slowly, by 1 to 2.5 mg every 3 to 5 days. The average daily dose is 10 to 20 mg THC.79

3.4. Serotonin reuptake inhibitors

The use of serotonin reuptake inhibitors should always be individually agreed with the doctor. Serotonin reuptake inhibitors are suitable for the treatment of (comorbid) depression.
With regard to ADHD, treatment of impulsivity in ADHD-HI with minimal doses (e.g. 2 to 5 mg escitalopram) could be useful at best, which in our experience seems to have an immediate effect and is apparently not mediated via receptor down- or upregulation.
Incidentally, serotonergic medications are not useful in relation to ADHD itself and especially ADHD-I.

3.5. Slowly taper off level medication

Level medications must be dosed in slowly and phased out slowly.
In the case of serotonin reuptake inhibitors, this can take up to six months to avoid side effects.

4. Observe and document dosing

4.1. Self-monitoring: keep a dosing diary (e.g. ADxS dosing aid table)

Download ADxS dosing aid table: Dosing aid table in the ADHS forum of ADxS.org

During the dosing period, a diary should be kept that records the patient’s condition every day. This should contain

  • Daily assessment for each relevant symptom
  • Preparation
    • Not only active ingredient
    • For generics also manufacturer
  • Dose
  • Time(s) of ingestion
  • Other medication taken (type, dose, time(s))
  • Food and fluid intake (type, quantity)
  • Nicotine consumption (always cut out coffee completely when taking ADHD medication)
  • Menstrual cycle in girls / women
    Find out more at Gender differences in ADHD
  • Sport
  • Special stresses (emotional and physical, e.g. arguments, illnesses, allergies, etc.)

Important: the effect of the medication and the dosage should never be evaluated on the basis of individual days, but always retrospectively on the basis of an average of 3 to 4 days. Otherwise, irrelevant and random correlations will be overestimated.

4.2. External observation

Since not all those affected perceive an actual positive effect themselves in a timely manner (comorbid autistic traits in particular can make this more difficult), additional external observation is advisable.

Third-party observation should be carried out by an informed family member or partner and should also be documented using a dosing diary such as the ADxS dosing aid table.

It is also helpful to inconspicuously ask third parties who are not involved in the medication intake about any changes they have noticed.
Such feedback is particularly valuable and meaningful if these third parties do not know that medication is being taken. Otherwise, the attitude towards and expectations of these third parties regarding medication would always be subconsciously incorporated into the assessment and change the result.
In order to avoid a bias in the assessment of the effect by teachers or other caregivers, it is therefore advantageous not to initially inform them about the intake. If they then report a significant change in behavior within the first few weeks, this unbiased observation is much more meaningful.

The combination of continuous external observation by an informed family member (who, if possible, only knows about the medication itself, but nothing about dose changes, changes of active ingredient or omissions) and unbiased third parties, who also do not know the fact of the medication as a whole, can provide very valuable information about the effect.

Reports only make sense if the duration of action of the medication is long enough. A single unretarded MPH tablet in the morning cannot bring about any changes beyond the 2.5 to 4 hours duration of action.

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

5. Avoid side effects

At the optimum individual dose to improve symptoms (which can be considerably lower than the typical doses!), very few patients experience side effects. The most common side effects are

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

Rare, more serious side effects (high blood pressure, aggressiveness or other) should be discussed with the doctor immediately.

5.1. No caffeine when dosing stimulants (IMPORTANT!)

Caffeine should be completely omitted without compromise when taking stimulants.
Since the side effects of caffeine and stimulants can add up, side effects can occur when consumed together that do not occur when taking caffeine alone or stimulants alone.
For this reason, caffeine should be completely and consistently omitted when dosing stimulants. This may be subjectively difficult for sufferers who have previously combated their ADHD symptoms with high caffeine consumption. However, the function of symptom reduction is now taken over (much better) by the stimulants.
In addition to the above-mentioned overdose side effects, other symptoms have sometimes been reported during the administration of stimulants, which disappeared abruptly when caffeine was discontinued, such as nausea, marble skin or Raynaud’s syndrome.
In addition to a high level of shakiness, other side effects will also be drastically increased.
However, other symptoms have also been reported, such as palpitations, circulatory problems, nausea, marble skin and Raynaud’s syndrome, which disappeared abruptly when caffeine was discontinued.
If caffeine consumption was previously high, withdrawal symptoms (especially headaches) may occur for 2 to 3 days if the drug is stopped abruptly. These should not be confused with side effects of the medication.

Around 50% of those affected experience symptoms typical of an overdose (including severe overdose) when stimulants are added to a previously well-tolerated caffeine intake. We know many sufferers who did not take this into account and therefore mistakenly believed that they could not tolerate stimulants. However, a new attempt without caffeine and with a slow dosage was often successful.

Previously high caffeine consumption can lead to caffeine withdrawal symptoms for 2 to 3 days after discontinuation. These often include headaches, exhaustion and loss of energy, restlessness, insomnia, circulatory problems and nausea, constipation, lethargy, irritability and lack of concentration. These should also not be misunderstood as side effects of newly taken stimulants.

After successfully taking stimulants, caffeine can be carefully added again. The difference is that those affected then know that any side effects that occur are not the result of the stimulants
We have also heard reports of individual sufferers who - after years of taking stimulants - still react to decaffeinated coffee with a slight shakiness.
Some sufferers report that they can prolong a waning stimulant effect in the afternoon with caffeine.

5.2. No simultaneous nicotine withdrawal

Nicotine is a stimulant and increases dopamine and noradrenaline. As a result, heavy smokers have experienced a profound adaptation of these neurotransmitter balances in the brain. Quitting smoking, especially overnight, leads to strong adaptation reactions and withdrawal symptoms. When dosed at the same time, a previously heavy smoker reported very massive and intolerable side effects, which disappeared when he resumed smoking.
Even if smoking is harmful to health, it should therefore not be stopped at the same time as dosing.
It is also helpful for observing the effect of the medication during dosing if it is not distorted by extraneous factors.
In contrast to caffeine, there are far fewer reports of cross-effects with nicotine.

Those affected often lose their desire for nicotine during or after dosing. In isolated cases, an increased desire for nicotine has also been reported.

5.3. Signs of overdose

Signs of overdose usually correspond to those of excessive caffeine consumption4

  • Tremulousness
  • mild dysphoria
  • Nervousness
  • Palpitations
  • Palpitations
  • Headache
  • Irritability
  • Circulatory problems

Loss of emotion (“zombie mode”) can be a sign of overdose. For more on this, see below in this section.

5.4. Headache

This description is based on Simchen80 and is in line with our experience.

5.4.1. Hypoglycemia

Headaches as a side effect of taking stimulants are often the result of a glucose deficiency.
Stimulants increase the activity of the PFC, which increases glucose consumption and lowers blood sugar levels.
Symptoms of hypoglycemia are

  • Headache
  • Tiredness (yawning)
  • Pallor
  • Dizziness
  • Tremors (tremors can also be caused by overdose or cross-effects with caffeine).

Remedy:

  • have a good breakfast / eat before each dose
  • Snacks for in between
  • eat quickly digestible carbohydrates immediately if you get a headache
    • Dextrose
    • Bananas
    • Fruit juices (without sweetener)

During prolonged hypoglycemia, the brain forms acidic metabolic intermediates via the lactic acid metabolism, which lead to headaches that last longer and are more difficult to eliminate.
Those affected often report that a quick intake of food can restore concentration when the stimulant effect wears off.

5.4.2. Lack of fluids

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

5.4.3. Histamine intolerance

A third possible cause is histamine hypersensitivity or histamine intolerance, as all ADHD medications (with the exception of viloxazine) have a histamine-increasing effect. In this case, however, the headaches occur together with other typical symptoms of histamine intolerance.
More on the symptoms of histamine intolerance at Histamine intolerance, histamine intolerance In the article Differential diagnosis for ADHD

5.5. Gastrointestinal complaints

Stimulants can increase gastrointestinal motility, which can be perceived as painful in sensitive patients (if so, then more in children).80(

Especially higher doses on an empty stomach can cause a strange cramp-like feeling under the right costal arch about 30 minutes after ingestion. This is probably caused by a spasm of the smooth muscles of the duodenum due to the sudden increase in stimulant levels 4

Remedy:804
Adequate food intake before taking medication.
A longer time interval before taking the medication (one hour) can work even better than no time interval (15 minutes).

5.6. Problems falling asleep

Many sufferers report that they can fall asleep better and have a more restful sleep since taking stimulants.
However, some patients may experience problems falling asleep as a side effect of taking the drug. These usually disappear within the first few weeks.

Remedy:

  • take the last dose in time for its effect to end at least one hour before bedtime
    • this requires knowledge of the typical duration of action of the respective medication. See under Effect and duration of action of ADHD medication
    • increase the time interval if necessary
    • if necessary, initially omit the afternoon dose for 1 to 2 weeks, work with only one dose of half-day-retained MPH in the morning
  • Consider the possibility of slower metabolism (longer duration of action)
  • For some sufferers (we suspect ADHD-I rather than ADHD-HI), a reduced dose (1/5 to 1/2 of an optimized single dose) in unretarded form can help them fall asleep
    • Test administration as a sleep aid with very low doses (1/10 of the single daily dose)
    • the daily doses of retarded active substances should be converted to the shorter duration of action of the unretarded active substance (example: 20 mg retarded for 5-6 hours duration of action corresponds to 10 mg unretarded for 2.5-3 hours duration of action).

5.7. Tachycardia (increased heart rate), increase in blood pressure

This description is based on Simchen80 and is in line with our experience.

Stimulants stimulate the sympathetic nervous system.
MPH does not change the heart rate and increases blood pressure by 0.25. AMP and ATX increase the heart rate slightly. Any cardiovascular effects subside spontaneously in most patients. 2 % of those affected discontinued their drug treatment due to cardiovascular effects.81 Once the body has become accustomed to the drug, these effects do not recur even if the drug is taken again after longer breaks in treatment.
Since the studies did not look at caffeine cross-effects, some of the dropouts could be due to caffeine.
According to the American Heart Association, fine-tuned stimulants for ADHD are cardiac neutral and do not require special monitoring of children and adolescents82

People with high blood pressure in particular appear to suffer a further increase in blood pressure as a result of stimulants, even with a finely tuned dosage. 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 examination4

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

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

5.8. Rebound

The rebound is a short-term increase in symptoms immediately after the end of the stimulant’s effect. It is unpleasant but harmless and does not indicate any problems with the medication.4 Nevertheless, in individual cases it can be so severe that those affected consider discontinuing the medication.
Our impression is that rebound occurs primarily with unretarded and half-day-retarded MPH. The rebound lasts about half an hour.
All-day retard preparations show a lower rebound.
Amphetamines have a lower rebound risk than methylphenidate.4 In our experience, the slow-release Elvanse has (almost) no rebound. When a rebound is reported with Elvanse, our impression is that this particularly affects patients in whom a single dose of Elvanse has a shorter effect (7 hours or less, instead of the 12 to 14 hours specified by the manufacturer).

Remedy:

  • Timely intake of the follow-up dose so that it begins to take effect at the time when the rebound is 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 single daily dose (this must be converted from slow-release medication, see above under problems falling asleep)
    • approx. 15 minutes before the expected rebound time

5.9. Loss of appetite / weight loss

Stimulants and desipramine are often associated with the side effect of reduced appetite and consequent weight loss.
In most cases, this is merely a side effect of the dosage and disappears over the course of a few weeks or months.

More food should be offered outside of the medication’s active times. As many people find it difficult to eat in the morning (Medikinet adult or Medikinet retard is unsuitable for them), attention should be paid to eating plenty of food in the evening.

Nortryptiline is said to be associated with weight gain as a side effect83

Augmentative administration of low doses of antipsychotics could help prevent weight loss triggered by stimulants.
While MPH was often associated with a lack of appetite, thioridazine showed an increase in appetite as a side effect.84 Atypical antipsychotics are said to have an even stronger effect in terms of increased appetite and metabolic syndrome.85
Combination treatment with psychostimulants and antipsychotics is being used more and more frequently.86 An improved effect compared to stimulant monotherapy has also been reported in isolated cases.85 A registry study found that 3.9% of children and adolescents with ADHD who received stimulants were medicated with atypical antipsychotics.87
This opens up the option of using a combination medication to counteract excessive weight loss with stimulants.

5.10. Emotion loss / zombie mode: overdose or intolerance

Sensitive sufferers, especially those with ADHD-HI and ADHD-C4, may experience a slowing of thinking and a flattened affect (emotional depletion) (“zombie syndrome”). Avoiding an overdose or reducing the stimulant dose under combination medication with non-stimulants can help here. More on this under Combination medication for ADHD

There is no need to accept a restriction of emotionality through ADHD medication. ADHD medication works properly when the person affected feels more like themselves. Any form of perceiving oneself as a stranger or perceiving oneself less is an indication of inappropriate medication.
Stimulants dampen the limbic system. A few sufferers are particularly sensitive in this respect. In most cases, patient testing of various preparations and active ingredients helps.
It is our impression that an emotional restriction is more often the result of an overdose. In this case, a restart of the dosage in the smallest possible dosage steps should be considered. Some (albeit very few) sufferers only need a few mg of a stimulant throughout the day.

The following options should only be considered if it is certain that a reduction in dosage, which just about eliminates the emotional impairment, will not sufficiently improve the ADHD symptoms:

  • Atomoxetine or guanfacine instead of stimulants
    • Non-stimulants
      • Do not inhibit the limbic system
      • Do not improve drive
  • Stimulant dose reduction with comedication of non-stimulants (advantage: drive from stimulants remains, emotional dysregulation is improved throughout the day)
    • Adults: stimulants and atomoxetine
    • Children: stimulants and guanfacine or stimulants and atomoxetine

5.11. Cycle-dependent symptom fluctuations in women

The dopamine balance is shaped by COMT, among other things. COMT is the most important degradation mechanism in the PFC, while degradation in the striatum is primarily controlled by DAT.
The degradation is strongly influenced by the COMT gene variant.
A relevant proportion of women with ADHD report more severe symptoms in the premenstrual phase. In the case of stimulant administration, this can be improved with a temporary increase in the stimulant dose during this phase.88

5.11. Fluctuating effect

Occasionally those affected report fluctuations in effect, even after a longer, more stable effect.
There are many possible causes. More on this under Effect and duration of action of ADHD medication
Examples:

  • other medications that have been added or discontinued
    • for ADHD medications in particular:
      • Anticides
  • Cross-effects with food
    • there are many options here. Keep a food diary
    • in particular
      • Grapefruit
      • Vitamin C
        • If necessary, postpone intake to one or more hours after taking the medication
  • Changes in stomach acid
    • Both MPH and AMP are sensitive to changes in stomach acidity
    • measure the acidity of the urine if necessary
  • Faulty batches of medication
    • rare, but we have actually experienced it several times
    • did the effect change when the new pack was opened?
  • Medication stored too hot
  • Adaptation reactions

6. Dosage adjustments

  • The feeling that a very good effect wears off after a few days to weeks after the first cessation is often not due to a change in the effect, but rather to a change in the perception of those affected. In the so-called honeymoon phase immediately after reaching an effective dose, the difference to the deficient state before is perceived as a particularly positive experience. Such a feeling of particular improvement is naturally fleeting, just as the elation of a soccer fan after winning the championship normalizes within days, even though the whole season has been trembling along. It is important to check carefully whether a higher dosage is really needed. External assessments can be helpful here.
  • It may be necessary to make a one-off readjustment after a few months. This does not constitute a habituation effect.
  • An omission test should be carried out once a year to check whether 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 aim of the optimal dosage is therefore not to be completely symptom-free, but to reduce the symptoms to a healthy level. An attempt to increase the dosage until all symptoms have been completely eliminated would inevitably result in an overdose.

7. Measurement of the medication effect

Various attempts to control the dosage of medication for ADHD on the basis of blood values have so far shown little success.
With regard to ATX, it was reported that blood level measurements did not show any helpful values.
Since it is well known that stimulants cannot be dosed according to weight, and very different doses are required for an appropriate effect, it is not entirely plausible to us what benefit a blood level measurement can have.

Some doctors use sustained attention tests to determine intra-individual differences without medication and with different doses of medication and to monitor responding and the effect of stimulants. Since attention tests depend heavily on the motivation of the individual test person and can falsely convey the image of a non-affected person even with pronounced ADHD if there is a high intrinsic motivation to participate, such tests should not be used as the sole criterion. However, it can be helpful to use them as an additional evaluation tool, especially in a trained and consistent (boring) test environment.

A meta-study reports useful results of the Qb test for measuring medication success in ADHD.89
The Qb test measures the subject’s facial expressions while they complete a Go/NoGo test. Whether the results are consistent enough to be able to assess individual cases remains to be seen. In addition, the time required is likely to prevent wider use in medical practice.

8. General information

  • Unretarded MPH should be used for dosing in the first week or so. The shorter duration of action and the more linear dose-effect correlation (without a second high at the onset of action of the retarded portion) makes it easier to find the appropriate dose, especially for inexperienced observers (patients and third parties).
  • It should be noted that retarded Medikinet must be taken with food, as otherwise the entire dose will be released unretarded. Other preparations generally do not require food intake, although this must always be checked in the package leaflet. All long-acting ADHD medications should be taken with food.
  • Caffeine (coffee, cola, black tea, some green teas, mate, energy drinks), dark chocolate / cocoa (theobromine) must be completely omitted during dosing. Many people who take stimulants can no longer tolerate caffeine or other stimulants that were previously consumed without problems or even in larger quantities. Caffeine (tea) and theobromine are stimulants that also increase noradrenaline and dopamine levels. They can add up with ADHD medications. This can quickly be confused with an overdose (inner fidgetiness, inner restlessness, shakiness).
    After dosing, caffeine can be consumed again, although it is advisable to test it carefully first. If caffeine now triggers shakiness, it is clear that this is due to the caffeine and not the medication.
  • Alcohol increases the MPH blood level and must be completely avoided when dosing with MPH.
  • Avoid citrus fruits during dosing. Some patients react to citrus fruits with varying drug effects. Grapefruit should be avoided when taking any medication.
  • Use in the afternoons, at weekends and during vacations
    • As 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 strongly recommended. Whether medication should only be administered in the mornings during school hours depends on whether those affected are still able to concentrate on their homework and manage 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, the symptoms are not very disciplined when it comes to school times and, on the other hand, a longer break from taking the medication may require that the dosage is slowly increased again in order to avoid side effects.
    • However, it is conceivable to reduce the dosage slightly (to 2/3 or 3/4) in times of lower demand. This depends very much on the individual needs of the person concerned. All dosage changes must be agreed with the doctor. However, an experienced doctor will allow a trustworthy patient considerable leeway.
  • Mixing stimulants
    • Stimulants can be combined. In particular, sustained-release and non-released drugs can be taken on the same day. A combination of AMP and MPH does not cause any particular problems either.
      As a rule, a sustained-release form of medication is taken during the day, which ideally covers the whole day. Responsible and trustworthy patients can cover isolated special stresses, e.g. a particularly long evening, with unretarded MPH as a supplement.
      The instructions of the attending physician are decisive!
  • Menstrual cycle can strongly influence the effect of medication.
    • In the case of fluctuations in the effect of medication in women, the possible significant influence of oestrogen in certain COMT gene variants should be taken into account. A dosing aid table that helps to map menstruation and its effects can be found at ADHS-Forum.ADxS.org.

  1. Oettinger L Jr, Majovski LV. Methylphenidate: a review. South Med J. 1976 Feb;69(2):161-3. doi: 10.1097/00007611-197602000-00010. PMID: 1251235. REVIEW

  2. Farhat LC, Flores JM, Behling E, Avila-Quintero VJ, Lombroso A, Cortese S, Polanczyk GV, Bloch MH (2022): The effects of stimulant dose and dosing strategy on treatment outcomes in attention-deficit/hyperactivity disorder in children and adolescents: a meta-analysis. Mol Psychiatry. 2022 Mar;27(3):1562-1572. doi: 10.1038/s41380-021-01391-9. PMID: 35027679. METASTUDIE

  3. Boonstra AM, Kooij JJ, Oosterlaan J, Sergeant JA, Buitelaar JK, Van Someren EJ (2007): Hyperactive night and day? Actigraphy studies in adult ADHD: a baseline comparison and the effect of methylphenidate. Sleep. 2007 Apr;30(4):433-42. doi: 10.1093/sleep/30.4.433. PMID: 17520787.

  4. Dodson WW (2005): Pharmacotherapy of adult ADHD. J Clin Psychol. 2005 May;61(5):589-606. doi: 10.1002/jclp.20122. PMID: 15723384. REVIEW

  5. Langfassung der interdisziplinären evidenz- und konsensbasierten (S3) Leitlinie„Aufmerksamkeitsdefizit- / Hyperaktivitätsstörung (ADHS) im Kindes-, Jugend und Erwachsenenalter“AWMF-Registernummer 028-045 S. 75

  6. Leitlinie der Arbeitsgemeinschaft ADHS der Kinder- und Jugendärzte e.V., Stand 2009, ADHS bei Kindern und Jugendlichen, Seite 10

  7. Wolraich ML, Hagan JF Jr, Allan C, Chan E, Davison D, Earls M, Evans SW, Flinn SK, Froehlich T, Frost J, Holbrook JR, Lehmann CU, Lessin HR, Okechukwu K, Pierce KL, Winner JD, Zurhellen W (2019): SUBCOMMITTEE ON CHILDREN AND ADOLESCENTS WITH ATTENTION-DEFICIT/HYPERACTIVE DISORDER. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics. 2019 Oct;144(4):e20192528. doi: 10.1542/peds.2019-2528. Erratum in: Pediatrics. 2020 Mar;145(3): PMID: 31570648; PMCID: PMC7067282.

  8. Brinkman WB, Epstein JN (2011): Promoting productive interactions between parents and physicians in the treatment of children with attention-deficit/hyperactivity disorder. Expert Rev Neurother. 2011 Apr;11(4):579-88. doi: 10.1586/ern.10.151. PMID: 21469930; PMCID: PMC3146016.

  9. Epstein JN, Rabiner D, Johnson DE, Fitzgerald DP, Chrisman A, Erkanli A, Sullivan KK, March JS, Margolis P, Norton EC, Conners CK (2007): Improving attention-deficit/hyperactivity disorder treatment outcomes through use of a collaborative consultation treatment service by community-based pediatricians: a cluster randomized trial. Arch Pediatr Adolesc Med. 2007 Sep;161(9):835-40. doi: 10.1001/archpedi.161.9.835. PMID: 17768282.

  10. Xu Y, Chung H, Shu M, Liu Y, Zhang Y, Qiu H (2023): Dose titration of osmotic release oral system methylphenidate in children and adolescents with attention-deficit hyperactivity disorder: a retrospective cohort study. BMC Pediatr. 2023 Jan 23;23(1):38. doi: 10.1186/s12887-023-03850-4. PMID: 36683085; PMCID: PMC9869580.

  11. Schneider, Folmert (2023): Pharmakotherapie und Psychotherapie der ADHS im Erwachsenenalter. Schweizer Zeitschrift für Psychiatrie & Neurologie 01/2023,, deutsch

  12. Brennan, Arnsten (2008): Neuronal mechanisms underlying attention deficit hyperactivity disorder: the influence of arousal on prefrontal cortical function. Ann N Y Acad Sci. 2008;1129:236-45. doi: 10.1196/annals.1417.007. REVIEW

  13. Ryffel (2008): Vortrag beim Rheinfelder Herbstsymposium 6. November 2008

  14. Ryffel (2003): Langzeiterfahrungen mit Stimulanzien bei ADHS: Empfehlungen für die Praxis. Forum der Kinder- und Jugendpsychiatrie und Psychotherapie, 13. J. Heft 1, S. 27 - 47, 2003

  15. Warnke, Walitza (2004): Methylphenidat in der Behandlung der Aufmerksamkeits-/Hyperaktivitätsstörung (ADHS), S. 14, 22, in: Schulte-Markwort, Warnke (2004): Methylphenidat.

  16. Kühle: Äquivalenztabelle

  17. adhspedia: Unrechnungstabele Stimulanzien

  18. Geisslinger G, Menzel S, Gudermann T, Hinz B, Ruth P: Mutschler Arzneimittelwirkungen. Pharmakologie – Klinische Pharmakologie – Toxikologie. Begründet von Ernst Mutschler, 11. Auflage. Wissenschaftliche Verlagsgesellschaft, Stuttgart 2020, ISBN 978-3-8047-3663-4. S. 246.

  19. Rösler, Retz (2020): Medikamentöse Therapie der ADHS bei Erwachsenen; Psychiatrie up2date 2020; 14: 59–75

  20. Seeman P, Madras BK (1998): Anti-hyperactivity medication: methylphenidate and amphetamine. Mol Psychiatry. 1998 Sep;3(5):386-96. doi: 10.1038/sj.mp.4000421. PMID: 9774771. REVIEW

  21. Krause, Krause (2014): ADHS im Erwachsenenalter: Symptome – Differenzialdiagnose – Therapie, Seite 254, mwN

  22. Huberman (2023): Adderall, Stimulants & Modafinil for ADHD: Short- & Long-Term Effects | Huberman Lab Podcast, english

  23. Sprague RL, Sleator EK (1977): Methylphenidate in hyperkinetic children: differences in dose effects on learning and social behavior. Science. 1977 Dec 23;198(4323):1274-6. doi: 10.1126/science.337493. PMID: 337493. n = 20

  24. Dreher (2019): ADHS im Erwachsenenalter. Anleitung zur Diagnostik und erste Therapieschritte, Seite 31. Download 06.01.2020

  25. http://www.ads-hyperaktivitaet.de/FAQ/Infos/Medis/medis.html#1

  26. Arnsten AF, Dudley AG (2005). Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder. Behav Brain Funct. 2005 Apr 22;1(1):2. doi: 10.1186/1744-9081-1-2. PMID: 15916700; PMCID: PMC1143775.

  27. Torta RG (2012): Antidepressant up-titration: pharmacological and psychological considerations. Expert Opin Drug Saf. 2012 Sep;11(5):685-8. doi: 10.1517/14740338.2012.712683. PMID: 22862155.

  28. Nakamura T, Tomita M, Hirota S, Matsunaga T, Uchimura N (2022): Impact of Selected Initial Titration Schedules on Safety and Long-Term Effectiveness of Lamotrigine for the Treatment of Mood Disorders. J Clin Psychopharmacol. 2022 Jul-Aug 01;42(4):350-356. doi: 10.1097/JCP.0000000000001557. PMID: 35506599; PMCID: PMC9257060.

  29. Seiden LG, Connor GS (2022): The importance of drug titration in the management of patients with epilepsy. Epilepsy Behav. 2022 Mar;128:108517. doi: 10.1016/j.yebeh.2021.108517. PMID: 35066388.

  30. Trinka E, Steinhoff BJ, Nikanorova M, Brodie MJ (2016): Perampanel for focal epilepsy: insights from early clinical experience. Acta Neurol Scand. 2016 Mar;133(3):160-72. doi: 10.1111/ane.12529. PMID: 26506904; PMCID: PMC4738453.

  31. Basheikh M, Sadler RM (2021): Retention Rate and Efficacy of Perampanel with a Slow Titration Schedule in Adults. Can J Neurol Sci. 2021 Jan;48(1):105-111. doi: 10.1017/cjn.2020.174. PMID: 32799941.

  32. D’Onofrio G, Kuchenbuch M, Hachon-Le Camus C, Desnous B, Staath V, Napuri S, Ville D, Pedespan JM, Lépine A, Cances C, de Saint-Martin A, Teng T, Chemaly N, Milh M, Villeneuve N, Nabbout R (2020): Slow Titration of Cannabidiol Add-On in Drug-Resistant Epilepsies Can Improve Safety With Maintained Efficacy in an Open-Label Study. Front Neurol. 2020 Aug 12;11:829. doi: 10.3389/fneur.2020.00829. PMID: 32903409; PMCID: PMC7434926.

  33. Ielmini M, Poloni N, Caselli I, Bianchi L, Diurni M, Vender S, Callegari C (2018): Efficacy and Tolerability of Two Different Kinds of Titration of Paroxetine Hydrocloride Solution: an Observational Study. Psychopharmacol Bull. 2018 Mar 13;48(3):33-41. PMID: 29713104; PMCID: PMC5875366.

  34. Basile JN (2003): Titration of beta-blockers in heart failure. How to maximize benefit while minimizing adverse events. Postgrad Med. 2003 Mar;113(3):63-70; quiz 3. doi: 10.3810/pgm.2003.03.1389. PMID: 12647475.

  35. Biton V, Gil-Nagel A, Brodie MJ, Derossett SE, Nohria V (2013): Safety and tolerability of different titration rates of retigabine (ezogabine) in patients with partial-onset seizures. Epilepsy Res. 2013 Nov;107(1-2):138-45. doi: 10.1016/j.eplepsyres.2013.08.021. PMID: 24094693.

  36. Lochhead JD, Nelson MA, Schneider AL (2016): Risks and Benefits of Rapid Clozapine Titration. Ment Illn. 2016 May 18;8(1):6457. doi: 10.4081/mi.2016.6457. PMID: 27403276; PMCID: PMC4926035.

  37. Vigevano F (2005): Levetiracetam in pediatrics. J Child Neurol. 2005 Feb;20(2):87-93. doi: 10.1177/08830738050200020101. PMID: 15794171.

  38. Korian Topiramate Study Group (2002): Low dose and slow titration of topiramate as adjunctive therapy in refractory partial epilepsies: a multicentre open clinical trial. Seizure. 2002 Jun;11(4):255-60. doi: 10.1053/seiz.2001.0605. PMID: 12027573.

  39. Wroe SJ (2005): Effects of dose titration on tolerability and efficacy of interferon beta-1b in people with multiple sclerosis. J Int Med Res. 2005 May-Jun;33(3):309-18. doi: 10.1177/147323000503300306. PMID: 15938592.

  40. McIntyre RS (2002): Psychotropic drugs and adverse events in the treatment of bipolar disorders revisited. J Clin Psychiatry. 2002;63 Suppl 3:15-20. PMID: 11908917.

  41. Haanpää ML, Gourlay GK, Kent JL, Miaskowski C, Raja SN, Schmader KE, Wells CD (2010): Treatment considerations for patients with neuropathic pain and other medical comorbidities. Mayo Clin Proc. 2010 Mar;85(3 Suppl):S15-25. doi: 10.4065/mcp.2009.0645. PMID: 20194144; PMCID: PMC2844009.

  42. Libianto R, Davis TM, Ekinci EI (2020): Advances in type 2 diabetes therapy: a focus on cardiovascular and renal outcomes. Med J Aust. 2020 Feb;212(3):133-139. doi: 10.5694/mja2.50472. PMID: 31910303.

  43. Costa AC, Joaquim HPG, Pedrazzi JFC, Pain AO, Duque G, Aprahamian I (2022): Cannabinoids in Late Life Parkinson’s Disease and Dementia: Biological Pathways and Clinical Challenges. Brain Sci. 2022 Nov 22;12(12):1596. doi: 10.3390/brainsci12121596. PMID: 36552056; PMCID: PMC9775654.

  44. Baghdady NT, Banik S, Swartz SA, McIntyre RS (2009): Psychotropic drugs and renal failure: translating the evidence for clinical practice. Adv Ther. 2009 Apr;26(4):404-24. doi: 10.1007/s12325-009-0021-x. PMID: 19444657.

  45. Rizzoli PB (2012): Acute and preventive treatment of migraine. Continuum (Minneap Minn). 2012 Aug;18(4):764-82. doi: 10.1212/01.CON.0000418641.45522.3b. PMID: 22868540.

  46. Ruoff GE (1999): Slowing the initial titration rate of tramadol improves tolerability. Pharmacotherapy. 1999 Jan;19(1):88-93. doi: 10.1592/phco.19.1.88.30515. PMID: 9917081.

  47. Robert S, Hamner MB, Durkalski VL, Brown MW, Ulmer HG (2009): An open-label assessment of aripiprazole in the treatment of PTSD. Psychopharmacol Bull. 2009;42(1):69-80. PMID: 19204652.

  48. Reid AM, McNamara JP, Murphy TK, Guzick AG, Storch EA, Goodman WK, Geffken GR, Bussing R (2015): Side-effects of SSRIs disrupt multimodal treatment for pediatric OCD in a randomized-controlled trial. J Psychiatr Res. 2015 Dec;71:140-7. doi: 10.1016/j.jpsychires.2015.10.006. Erratum in: J Psychiatr Res. 2016 Mar;74:94. Goodman, Wayne K [added]. PMID: 26495770; PMCID: PMC4653063.

  49. Rauck RL, Wallace MS, Leong MS, Minehart M, Webster LR, Charapata SG, Abraham JE, Buffington DE, Ellis D, Kartzinel R (2006): Ziconotide 301 Study Group. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. 2006 May;31(5):393-406. doi: 10.1016/j.jpainsymman.2005.10.003. PMID: 16716870.

  50. Bogetto F, Albert U, Maina G (2002): Sertraline treatment of obsessive-compulsive disorder: efficacy and tolerability of a rapid titration regimen. Eur Neuropsychopharmacol. 2002 Jun;12(3):181-6. doi: 10.1016/s0924-977x(02)00012-3. PMID: 12007668.

  51. Youn SE, Kim SH, Ko A, Lee SH, Lee YM, Kang HC, Lee JS, Kim HD (2018): Adverse Events During Perampanel Adjunctive Therapy in Intractable Epilepsy. J Clin Neurol. 2018 Jul;14(3):296-302. doi: 10.3988/jcn.2018.14.3.296. PMID: 29971974; PMCID: PMC6031997.

  52. Babic T, Boothmann B, Polivka J, Rektor I, Boroojerdi B, Häck HJ, Randerath O (2006): Rotigotine transdermal patch enables rapid titration to effective doses in advanced-stage idiopathic Parkinson disease: subanalysis of a parallel group, open-label, dose-escalation study. Clin Neuropharmacol. 2006 Jul-Aug;29(4):238-42. doi: 10.1097/01.WNF.0000228179.83335.65. PMID: 16855426.

  53. Goetz CG, Blasucci L, Stebbins GT (1999): Switching dopamine agonists in advanced Parkinson’s disease: is rapid titration preferable to slow? Neurology. 1999 Apr 12;52(6):1227-9. doi: 10.1212/wnl.52.6.1227. PMID: 10214748.

  54. Smith KR, Kahlon CH, Brown JN, Britt RB (2021): Methylphenidate use in geriatric depression: A systematic review. Int J Geriatr Psychiatry. 2021 Sep;36(9):1304-1312. doi: 10.1002/gps.5536. PMID: 33829530.

  55. Ching C, Eslick GD, Poulton AS (2019): Evaluation of Methylphenidate Safety and Maximum-Dose Titration Rationale in Attention-Deficit/Hyperactivity Disorder: A Meta-analysis. JAMA Pediatr. 2019 Jul 1;173(7):630-639. doi: 10.1001/jamapediatrics.2019.0905. PMID: 31135892; PMCID: PMC6547117.

  56. Prasad S, Steer C (2008): Switching from neurostimulant therapy to atomoxetine in children and adolescents with attention-deficit hyperactivity disorder : clinical approaches and review of current available evidence. Paediatr Drugs. 2008;10(1):39-47. doi: 10.2165/00148581-200810010-00005. PMID: 18162007. REVIEW

  57. Weiss MD, Surman CBH, Elbe D (2018): Stimulant ‘rapid metabolizers’: wrong label, real phenomena. Atten Defic Hyperact Disord. 2018 Jun;10(2):113-118. doi: 10.1007/s12402-017-0242-9. PMID: 29103196. REVIEW

  58. Endrass, G (2024): ADHS aktuell – Mythen und Bedenken versus Fakten; NeuroTransmitter 2024; 35 (1-2)

  59. Banaschewski T, Coghill D, Santosh P, Zuddas A, Asherson P, Buitelaar J, Danckaerts M, Döpfner M, Faraone SV, Rothenberger A, Sergeant J, Steinhausen HC, Sonuga-Barke EJ, Taylor E (2006): Long-acting medications for the hyperkinetic disorders. A systematic review and European treatment guideline. Eur Child Adolesc Psychiatry. 2006 Dec;15(8):476-95. doi: 10.1007/s00787-006-0549-0. PMID: 16680409. REVIEW

  60. https://adhs-forum.adxs.org/t/medi-wirkdauer-bei-sport/11700

  61. Cho Y, Kim AY, Lee S, Lee H (2024): Recent updates on treatment patterns in patients with treated attention-deficit/hyperactivity disorders from a nationwide real-world database in South Korea. Int Clin Psychopharmacol. 2024 Mar 11. doi: 10.1097/YIC.0000000000000549. PMID: 38477521.

  62. Biederman J, DiSalvo M, Green A, Woodworth KY, Law C, Gabrieli JDE, Faraone SV (2021): How Frequent Is Switching From an Initial Stimulant Family to the Alternative One in the Clinical Setting?: A Pilot Study of 49 Consecutively Referred Medication-Naive Adults With Attention-Deficit/Hyperactivity Disorder. J Clin Psychopharmacol. 2021 May-Jun 01;41(3):310-314. doi: 10.1097/JCP.0000000000001374. PMID: 33657069.

  63. Cortese S, Newcorn JH, Coghill D (2021): A Practical, Evidence-informed Approach to Managing Stimulant-Refractory Attention Deficit Hyperactivity Disorder (ADHD). CNS Drugs. 2021 Oct;35(10):1035-1051. doi: 10.1007/s40263-021-00848-3. PMID: 34403134.

  64. UpToDate: Dosing guidelines when switching from one stimulant to another in the treatment of attention deficit hyperactivity disorder in children and adolescents

  65. Tan, King (2022): Finding the “Sweet Spot”: Sharing the decision-making in ADHD treatment selection. Ann Gen Psychiatry. 2022 May 27;21(1):14. doi: 10.1186/s12991-022-00394-2. PMID: 35624455; PMCID: PMC9145110.

  66. Kühle: Wie die richtige Dosis genau bestimmt wird

  67. praxis-suchtmedizin.ch: Dosierungs- und Aequivalenz-Tabelle Methylphenidat Präparate – Schweiz –

  68. Dorfplatzapotheke, CH-3110 Münsingen. Eine Flasche mit 50 Gramm kostet SFR 50,50.

  69. Vertessen K, Luman M, Swanson JM, Bottelier M, Stoffelsen R, Bet P, Wisse A, Twisk JWR, Oosterlaan J )2023): Methylphenidate dose-response in children with ADHD: evidence from a double-blind, randomized placebo-controlled titration trial. Eur Child Adolesc Psychiatry. 2023 Mar 2. doi: 10.1007/s00787-023-02176-x. PMID: 36862163. n = 45

  70. Jean FAM, Moulin F, Schwartz AN, Castel L, Montagni I, Macalli M, Notredame CE, Côté SM, Galéra C (2023): Association between ADHD symptoms and illicit stimulants use following 1 year among French university students of the i-Share cohort. Soc Psychiatry Psychiatr Epidemiol. 2023 Jun 2. doi: 10.1007/s00127-023-02499-9. PMID: 37268785.

  71. Barkley (2014): The Importance of Emotion in ADHD; https://drive.google.com/file/d/0B885LHMHOu5BWmR1YlNoOElCLTg/view?resourcekey=0-lBjUELS_pba99fW5nP5vng

  72. Soutullo CA, Are F, Schield-Grant S (2023):Factores asociados a la adherencia al tratamiento farmacológico del trastorno por déficit de atención e hiperactividad (TDAH): revisión preliminar [Factors associated with adherence to pharmacological treatment of attention deficit hyperactivity disorder (ADHD): preliminary review]. Medicina (B Aires). 2023 Mar;83 Suppl 2:27-31. Spanish. PMID: 36820479. REVIEW

  73. Sharbaf Shoar N, Marwaha R, Molla M (2023): Dextroamphetamine-Amphetamine. 2023 May 23. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 29939585.

  74. Adderall N; Barr Laboratories

  75. Wietecha LA, Ruff DD, Allen AJ, Greenhill LL, Newcorn JH (2013): Atomoxetine tolerability in pediatric and adult patients receiving different dosing strategies. J Clin Psychiatry. 2013 Mar 29;74(12):1217-23. doi: 10.4088/JCP.12m07991. PMID: 24434090.

  76. Young JL, Sarkis E, Qiao M, Wietecha L. Once-daily treatment with atomoxetine in adults with attention-deficit/hyperactivity disorder: a 24-week, randomized, double-blind, placebo-controlled trial. Clin Neuropharmacol. 2011 Mar-Apr;34(2):51-60. doi: 10.1097/WNF.0b013e31820c00eb. PMID: 21406998.

  77. Fachinformation Strattera, Stand Juni 2015

  78. Fukuyama, Nakano, Shiroyama, Okada (2021): Chronic Administrations of Guanfacine on Mesocortical Catecholaminergic and Thalamocortical Glutamatergic Transmissions. Int J Mol Sci. 2021 Apr 16;22(8):4122. doi: 10.3390/ijms22084122. PMID: 33923533.

  79. Müller-Vahl KR (2024): Cannabinoids in the Treatment of Selected Mental Illnesses: Practical Approach and Overview of the Literature. Pharmacopsychiatry. 2024 Mar 1. doi: 10.1055/a-2256-0098. PMID: 38428836.

  80. Simchen: Anleitung zur Reduzierung der Nebenwirkungen von Methylphenidat (Ritalin, Medikinet usw.) bei der Therapie des ADHS, ADS Mainz e.V., abgerufen 07.09.23, deutsch

  81. Hennissen L, Bakker MJ, Banaschewski T, Carucci S, Coghill D, Danckaerts M, Dittmann RW, Hollis C, Kovshoff H, McCarthy S, Nagy P, Sonuga-Barke E, Wong IC, Zuddas A, Rosenthal E, Buitelaar JK (2017): ADDUCE consortium. Cardiovascular Effects of Stimulant and Non-Stimulant Medication for Children and Adolescents with ADHD: A Systematic Review and Meta-Analysis of Trials of Methylphenidate, Amphetamines and Atomoxetine. CNS Drugs. 2017 Mar;31(3):199-215. doi: 10.1007/s40263-017-0410-7. PMID: 28236285; PMCID: PMC5336546. METASTUDY

  82. Gutgesell H, Atkins D, Barst R, Buck M, Franklin W, Humes R, Ringel R, Shaddy R, Taubert KA (1999): Cardiovascular monitoring of children and adolescents receiving psychotropic drugs: A statement for healthcare professionals from the Committee on Congenital Cardiac Defects, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 1999 Feb 23;99(7):979-82. doi: 10.1161/01.cir.99.7.979. PMID: 10027824.

  83. Otasowie, Castells, Ehimare, Smith (2014): Tricyclic antidepressants for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database Syst Rev. 2014 Sep 19;(9):CD006997. doi: 10.1002/14651858.CD006997.pub2. PMID: 25238582., METASTUDIE

  84. Gittelman-Klein R, Klein DF, Katz S, Saraf K, Pollack E (1976): Comparative effects of methylphenidate and thioridazine in hyperkinetic children. I. Clinical results. Arch Gen Psychiatry. 1976 Oct;33(10):1217-31. doi: 10.1001/archpsyc.1976.01770100079008. PMID: 971031.

  85. Elbe D, Barr AM, Honer WG, Procyshyn RM (2014): Managing ADHD and disruptive behaviour disorders with combination psychostimulant and antipsychotic treatment. J Psychiatry Neurosci. 2014 May;39(3):E32-3. doi: 10.1503/jpn.130288. PMID: 24758945; PMCID: PMC3997610.

  86. Linton D, Barr AM, Honer WG, Procyshyn RM (2013): Antipsychotic and psychostimulant drug combination therapy in attention deficit/hyperactivity and disruptive behavior disorders: a systematic review of efficacy and tolerability. Curr Psychiatry Rep. 2013 May;15(5):355. doi: 10.1007/s11920-013-0355-6. PMID: 23539465. REVIEW

  87. Bali V, Kamble PS, Aparasu RR (2015): Predictors of concomitant use of antipsychotics and stimulants and its impact on stimulant persistence in pediatric attention deficit hyperactivity disorder. J Manag Care Spec Pharm. 2015 Jun;21(6):486-98. doi: 10.18553/jmcp.2015.21.6.486. PMID: 26011550.

  88. de Jong M, Wynchank DSMR, van Andel E, Beekman ATF, Kooij JJS (2023): Female-specific pharmacotherapy in ADHD: premenstrual adjustment of psychostimulant dosage. Front Psychiatry. 2023 Dec 13;14:1306194. doi: 10.3389/fpsyt.2023.1306194. PMID: 38152361; PMCID: PMC10751335.

  89. Gustafsson U, Hansen M (2023): QbTest for Monitoring Medication Treatment Response in ADHD: A Systematic Review. Clin Pract Epidemiol Ment Health. 2023 Nov 1;19:e17450179276630. doi: 10.2174/0117450179276630231030093814. PMID: 38164455; PMCID: PMC10758132.

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