Dosing of medication for ADHD

Like all presentations on medications 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.

Optimal medication for ADHD often requires a very individual and fine-tuned dosage and adjustment. A purely schematic medication is not possible with ADHD.
Setting the optimal dosage of medication for ADHD depends on the type of medication.

• 1. Medication selection
• 2. Dosing of stimulants
  • 2.1. Basics of stimulant dosage
    • 2.1.1. Immediate release or sustained release stimulants
    • 2.1.2. Amount of the initial dose
    • 2.1.3. Dosing increments: Small increments better than large increments
    • 2.1.4. Speed of dosing increments: 5 to 7 days / increment
    • 2.1.5. Target dosage
      • 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
        • 2.1.5.1.2. Optimal single dose can be below the lowest standard dose or above the standard upper limit
        • 2.1.5.1.3. Maximum dose
      • 2.1.5.2. Target factor 2: All-day coverage / number of individual doses
        • 2.1.5.2.1. Aiming for all-day coverage
        • 2.1.5.2.2. Number of individual doses required for all-day coverage
        • 2.1.5.2.3. Individual duration of action of a single dose can be greatly shortened / prolonged
        • 2.1.5.2.3.1. Manufacturer information
        • 2.1.5.2.3.2. Prolonged effect (rather rare)
        • 2.1.5.2.3.3. Shortened effect (quite common)
        • 2.1.5.2.4. Information on the duration of action of the prescribed doses
    • 2.1.6. Dosage adjustments
    • 2.1.7. Demand-based intake
    • 2.1.8. Change of preparation and active ingredient
      • 2.1.8.1. Nonresponding: Change of active substance
      • 2.1.8.2. Side effects: Change of preparation or active substance
      • 2.1.8.3. Conversion tables for switching between stimulants
    • 2.1.9. Development of tolerance to stimulants / habituation effects
    • 2.1.10. Discontinuation of stimulants
  • 2.2. Dosing with immediate release MPH
  • 2.3. Transition to sustained release MPH / AMP
  • 2.4. Dosing of AMP
    • 2.4.1. Vyvanse, Tyvanse (lisdexamfetamine)
    • 2.4.2. Aderall N (immediate release)
• 3. Dosing of non-stimulants
  • 3.1. Dosing of atomoxetine
  • 3.2. Dosing of guanfacine
  • 3.3. Dosing of further non-stimulants
  • 3.4. Serotonin reuptake inhibitors
  • 3.5. Slowly taper off level medication
• 4. Observe and document dosing
  • 4.1. Self-monitoring: keep a dosing diary (e.g. ADxS dosing aid table)
  • 4.2. External observation
  • 4.3. Measurement of the medication effect
• 5. Avoid side effects
  • 5.1. Particular challenge: dosing for comorbid anxiety
  • 5.2. No caffeine when dosing stimulants (IMPORTANT!)
  • 5.3. No simultaneous nicotine withdrawal
  • 5.4. Signs of overdose
  • 5.5. Headache
    • 5.5.1. Hypoglycemia
    • 5.5.2. Lack of fluids
    • 5.5.3. Histamine intolerance
  • 5.6. Gastrointestinal complaints
  • 5.7. Problems falling asleep
  • 5.8. Tachycardia (increased heart rate), increase in blood pressure
  • 5.9. Rebound
  • 5.10. Effect holes
  • 5.11. Loss of appetite / weight loss
  • 5.12. Emotion loss / zombie mode: overdose or intolerance
  • 5.13. Cycle-dependent symptom fluctuations in women
  • 5.14. Fluctuating effect
  • 5.15. Symptoms of overload
• 6. General information

1. Medication selection¶

See under Choice of medication for ADHD or ADHD with comorbidity

2. Dosing of stimulants¶

2.1. Basics of stimulant dosage¶

In principle, up-dosing, which starts with low doses and increases them flexibly and individually, has a clear advantage over the administration of fixed doses.¹ This has been known since the 1970s² and has been confirmed by a new, extensive meta-analysis³. Studies also use slow dosing to avoid side effects.⁴
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 with ADHD, the individually appropriate dose with optimal symptom improvement and minimal side effects must be sought through trial and error⁵

The fact that the fixed-dose approach, which is much less suitable in practice, is still used in some cases also appears 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.
To determine the lower limit of the therapeutic range, study designs in which different patient groups each receive doses that lead to a previously defined blood concentration range of the drug are more useful.⁶ The clozapine study by VanderZwaag et al was cited as a positive example.⁷ Due to the logistical effort and the resulting costs, studies with a fixed dose are preferred to determine the lower limit of the therapeutic reference range.

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

2.1.1. Immediate release or sustained release stimulants¶

MPH dosing can be carried out with immediate release MPH or sustained release active ingredients.
Dosing with immediate release MPH is common. Dosing with sustained release MPH is also advocated¹⁴
In view of the positive experiences of adults with ADHD, we expect that Vyvanse 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 with ADHD. Therefore, studies that statistically determine the “optimal” dose of stimulants are only of limited use for individual treatment.
Stimulants have a dose-dependent effect.¹⁵

• 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 (2.5 mg of immediate release MPH udrch telung of higher tablets, 5 mg for MPH half-day retard preparations, 18 mg for Concerta, 5 mg for Adderall XR capsules etc.). Consequences: the dose is increased in equal increments until the optimal benefit is achieved. At the dose with the optimal symptom improvement, most adult persons with ADHD report few side effects other than a mild and temporary loss of appetite.⁵

• low starting dose (2.5 mg immediate release MPH / single dose or equivalent for other medications)¹⁶¹⁷ or 5 mg half-day sustained release MPH¹⁸
• at least 5 days / dose level
• Dosage increments max. 2.5 mg unret. MPH / single dose
• optimal dose is very individual¹⁶¹⁷
• Effect of slow dosing:
  • reduces side effects
  • prevents skipping the appropriate dose due to the sometimes very narrow therapeutic range¹⁶¹⁷
    In Germany, a single dose of 5 mg of immediate release MPH was recommended for schoolchildren in 2004. ¹⁹ 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 immediate release MPH in Vyvanse is 10 mg. When dosed in 2.5 mg immediate release or 5 mg sustained release increments, the equivalent is 5 mg Vyvanse increments.²⁰²¹ A further conversion table, particularly for American preparations, can be found in Stutzman et al.²²

2.1.3. Dosing increments: Small increments better than large increments¶

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

In our opinion, a smaller increment up-dosing is clearly advantageous compared to the currently usual up-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 up-dosing changes only slightly.

Mutschler also recommends starting with a low dose and increasing the dose slightly.²³
“Undesirable side effects are particularly to be expected at the start of treatment, which is why the dosage should be increased gradually.”²⁴
Although around three quarters of the people with ADHD dosed with MPH did not suffer any side effects²⁵ - this rate should nevertheless be reduced by slow titration.

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 has a noradrenergic effect only; dopaminergic effects are attained only with higher-dose MPH. 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 drive²⁶
  • Noradrenaline and dopamine have very closely related roles in improving ADHD symptoms. Which works better for a person with ADHD must be tested individually
  • Even with severe symptoms, a very low dose may be appropriate for the individual.²⁷ Huberman reports a single case of an optimal daily dose of 2.5 mg Adderall (woman weighing 150 kg).²⁸ 0.3 mg/kg showed greater performance improvement in learning tasks than 1 mg/kg in children with ADHD, 1 mg/kg showed better social evaluation by teachers and less sitting restlessness in hyperactive children, but poorer learning performance than placebo.²⁹ We know of several people with ADHD for whom a single dose of 1.25 mg of immediate release MPH is optimal.
• carefully acclimatizing the body to the active ingredient to avoid side effects that could lead to avoidable discontinuation of ADHD medication ³⁰³¹
• Too high a dosage leads to a recurrence of the ADHD symptoms that were avoided with the appropriate dosage (Inverted-U).³²
• Undesirable side effects increase significantly beyond the optimal dose.³³

However, we have also received individual reports from people with ADHD in which 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.

2.1.4. Speed of dosing increments: 5 to 7 days / increment¶

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 immediate release dose become apparent 1 hour after ingestion. Once the dose tapers off, there is no further or accumulated benefit⁵
In our opinion, however, there are a number of arguments against daily up-dosing:

• The effect of sustained release medication must be observed over the course of the day
• The effect is not perceived by the doctor, but by the people with ADHD themselves
• People with ADHD have no experience and therefore do not know what to look out for
• People with ADHD can experience placebo effects, which depend heavily on the 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
• the longer a drug is effective (prolonged release, prodrug), the longer the increments should be. In the case of lisdexamfetamine, the steady state is apparently reached on day 5.⁶⁵ Consequences of this are that when dosing lisdexamfetamine (Vyvanse), dose titrations should not be made below a weekly rhythm.
• However, dose increments of several weeks do not improve the dosage and only prolong the time until the appropriate dosage is reached. They usually only unnecessarily overtax the already limited persistence of people with ADHD.

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

We recommend that people with ADHD keep daily records of their intake, symptoms and side effects (e.g. using the Dosing aid table from the ADHD forum at AdxS.org), but never evaluate these on a daily basis, but always form a 3-day average. Consequences are that an increment requires 3 to 4¹⁹ (we mean; or 5 to 7 days) to allow for an assessment.
We do not consider the step duration of 1 month practiced by some doctors to be very useful. It brings no advantage whatsoever and may only be necessary to compensate for dosing increments that are too large.

A German dosing regimen for schoolchildren using immediate release MPH was recommended:¹⁹ However, this recommendation dates back to 2004, when 5 mg immediate release MPH was the smallest MPH dose available and today’s proven sustained-release 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 person with ADHD must be determined individually in two dimensions:⁶⁶

• Single dose level
• Number of daily doses

2.1.5.1. Target factor 1: Single dose level¶

In our opinion, the “optimal dose” should be the lowest dose that produces an optimal therapeutic effect. Instead, some guidelines recommend the dose above which there is no further improvement.³³ In our opinion, the latter overlooks the fact that two doses can have an equally good effect. In view of the fact that around 30 % of people with ADHD discontinue their medication within 12 months and around 50 % within 2 to 3 years⁶⁷, and even more in children and adolescents,⁶⁸⁶⁹ , the lowest possible side effects should be emphasized.

Since there are pronounced individual differences in terms of the dose-response pattern, the optimal dose must be determined individually. The art of treatment with MPH (and stimulants in general) goes far beyond simply “fine-tuning the dosage”.³³

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 reaches the bloodstream, a generalization by weight makes no sense⁵
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 obesity⁷⁰

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 rule out the possibility that people with ADHD from these groups may require very high doses.
In individual cases, the optimal MPH or AMP dose may be less than 5 mg/day.
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.²⁸ We also know of individual cases in which only extremely high doses of Vyvanse (several hundred mg / day and 50 mg as required sleep medication at night) achieved an adequate effect and considerable improvement. One of these cases later turned out to be chronic poisoning with nitrogen oxides in the air or a particular sensitivity to this. 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 Vyvanse 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.

The optimal dose level may exceed the standard maximum dose (especially rapid metabolizers). This applies to methylphenidate as well as amphetamine medication.⁶⁶
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.
Faraone and Biederman reported 3 to 5 doses of 10 to 20 mg each as the empirical value for immediate release MPH in adults. They cited 30 mg as the maximum dose for a single dose of MPH IR.⁷¹

It is important to warn against misinterpreting the first improvement as a marker for a suitable dose level or arbitrary doses as target doses.⁷² Doses should be persistently increased until two consecutive doses have shown deterioration. It is not unusual for a higher dose to have a worse effect than the next lower dose, while the next increment up again shows a significant improvement.

2.1.5.1.3. Maximum dose¶

A maximum dose of 1 mg/kg body weight or 60 mg/day for children and 80 mg/day for adults is often mentioned. However, there is no scientific evidence for these maximum doses. These values are mainly stated by the manufacturers, who naturally want to avoid contingent risks in order to reduce liability risks.

As a rule of thumb, patients should not receive MPH doses of more than 150 mg/day ⁷³⁷⁴

Hospitalization due to a possible overdose in children is indicated from 3 mg/kg,⁷⁵ The laboratory warning value is 50 ng/ml.⁷⁶

It is obvious that some people with ADHD require significantly higher daily doses than 60 or 80 mg. It is true that in these cases closer monitoring is advisable. A blanket rejection of a dosage of up to 150 mg/day required for an appropriate effect is not justified in any case.

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

2.1.5.2.1. Aiming for all-day coverage¶

The aim should be all-day coverage^{7778 79 80 81} , i.e. coverage for 12 to 16 hours.⁸²⁸¹
The required duration of medication coverage throughout the day is influenced by various factors⁵
A distinction must be made here:

• Attention and organization symptoms (medication as required, if preferred by the person with ADHD)
  • 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

In any case, ADHD does not end after school.

• 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 reduced life expectancy of 9 years. Not treating this is not objectively justifiable. See the chapter Consequences of ADHD.

2.1.5.2.2. Number of individual doses required for all-day coverage¶

The number of single doses of a suitable active ingredient and preparation required for daily coverage must be determined individually.⁶⁶ With MPH, there is no correlation between the dose level and the duration of action of a single dose⁸³, while with lisdexamfetamine a higher single dose also extends the duration of action of the single dose.

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

• Multiple doses throughout the day (up to 3 half-day doses of Retard preparation)
• Sustained release preparations can also be supplemented with immediate release preparations
• All-day coverage may require the combination of sustained release and immediate release stimulants.⁸⁴

The fear that stimulant medication would impair sleep is rarely justified.⁵ As a rule, stimulants improve the quality of sleep of people with ADHD. More on this under Treatment of sleep problems with ADHD

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

2.1.5.2.3.1. Manufacturer information¶

Manufacturer’s information on duration of action (rarely achieved in practice)¹⁶¹⁷

• immediate release MPH works for 2.5 - 3.5 hours / single dose
  • 4 to 5 single doses
  • barely feasible in the long term and especially for children
  • however, immediate release MPH is advantageous for dosing, as it is the most finely adjustable
• half-day sustained release MPH works on average 5 - 6 hours / single dose
  • 2 doses + immediate release MPH for residual coverage if necessary⁸¹
  • Second dose usually 50 % to 75 % of the first dose
• all-day sustained release MPH works on average 10 - 12 hours
• Attentin (immediate release AMP) is effective for an average of 5 - 6 hours
  • 2 doses and, if necessary, immediate release MPH for residual coverage
  • Second dose usually 50 % to 75 % of the first dose
• Lisdexamfetamine (Vyvanse) works for up to approx. 10 - 12 hours (note: often much shorter in practice!)
  • 1 dose and, if necessary, immediate release MPH for residual coverage
  • Amphetamine drugs require 3 to 5 days to reach a steady state
• Guanfacine
  • Mirror medication, 1 x daily
• Atomoxetine
  • Mirror medication, 1 x daily

2.1.5.2.3.2. Prolonged effect (rather rare)¶

Rather rarely do we encounter people with ADHD who have a significantly longer effect of a single dose of an ADHD medication than stated by the manufacturer.
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.

2.1.5.2.3.3. Shortened effect (quite common)¶

More frequently, however, people with ADHD are affected by a single dose having a significantly shorter effect than specified by the manufacturer.
In our experience, around 15 - 20 % of people with ADHD 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 persons with ADHD, the duration of action of stimulants is only 50% of the manufacturer’s indication
• 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
  • immediate release of 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 sustained release MPH corresponds to 2 x 10 mg immediate release MPH. In this case, 2.5 to 3.5 mg of immediate release MPH 30 minutes before the end of the last sustained release dose.

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

• In contrast to MPH, a significantly higher number of people with ADHD 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 persons with ADHD report that intensive sports can shorten the duration of effect of stimulants by up to 40 %.⁸⁵
• Higher doses of amphetamine last longer within a person⁵
  • 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

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

People with ADHD must be expressly informed of the typical duration of action of a single dose of the respective preparation. This is not only ethically required, but also medically and therapeutically necessary.
We repeatedly receive reports from people with ADHD who were led to believe that a single dose of immediate-release or half-day-release MPH (e.g. Ritalin adult) would work throughout the day, instead of referring to the usual duration of action of 2.5 - 3 hours (immediate-release) or 5-6 hours (half-day-release). 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.

2.1.6. Dosage adjustments¶

• The perception 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 to a change in the perception of the person with ADHD. 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 trial should be done once a year to check whether the behavior continues to show ADHD symptoms without medication.
• Persons with ADHD frequently show 75% of the possible ADHD symptoms, people without ADHD 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 end in an overdose.

2.1.7. Demand-based intake¶

The greater the self-control ability, the easier it is for people with ADHD 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 people with ADHD are thus 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 requirement-free) weekend day (shopping on Saturday afternoon or on vacation). The guiding principle is “I control my ADHD, not my ADHD controls me”. ⁷⁰
During dosing, adults must not deviate from the prescribed schedule. We experience time and again that the impulsiveness and impatience of people with ADHD 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.

2.1.8. 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, especially in the case of MPH. Surprisingly often, people with ADHD react negatively or with excessive side effects to one MPH preparation and positively to another MPH preparation, while the opposite can be true for others. A large study found that 85% of methylphenidate recipients changed their medication.⁸⁶

If an active ingredient shows no overall effect (non-responding) (regardless of the preparation), another active ingredient should be tried first.
Around 30 % of all people with ADHD do not respond to MPH, and around 20 % do not respond to AMP (non-responders). However, non-responding rarely affects both active ingredients at the same time, so that 90% of people with ADHD 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. A person with ADHD may require a relatively high dose of MPH or a relatively low dose of AMP for an adequate effect. Therefore, if the active ingredient is changed, a new individual titration is required.⁷⁰ Consequences: The known conversion tables should be viewed with caution when changing the active substance.

2.1.8.1. Nonresponding: Change of active substance¶

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

In over 40% of persons with ADHD, a change of preparation in the first 3 months helps with non-responding⁸⁷
When switching between MPH and AMP due to non-responding, only approx. 10 to 15 % remain who are non-responders for both types of stimulants¹⁶¹⁷

REVIEW on treatment options for treatment-resistant ADHD: Cortese et al.⁸⁸

• 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

2.1.8.2. 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:
          • immediate release
          • Medikinet retard / Adult
          • Ritalin LA / Adult
          • Concerta
          • Kinecteen
      • then change active ingredient
        • For recommended sequence, see above under medication selection
• 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 from 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 (Vyvanse)
          • immediate release (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 medication selection

2.1.8.3. Conversion tables for switching between stimulants¶

A conversion table from dexamphetamine to Vyvanse can be found on ADHSpedia⁸⁹

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.⁹⁰

A comprehensive conversion table for American stimulant preparations, including recommendations for the conversion process, can be found in Stutzman et al.²²

2.1.9. Development of tolerance to stimulants / habituation effects¶

See in detail at ⇒ Medication: Development of tolerance

2.1.10. 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 people with ADHD repeatedly report from discontinuing antidepressants - especially too quickly - it can be said across the board that there are no discontinuation problems with stimulants. However, the people with ADHD 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. For a minority of people with ADHD, 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 on discontinuation of a 10-fold overdose of Vyvanse (50 mg; patient required only 5 mg).

2.2. Dosing with immediate release MPH¶

On the one hand, immediate release 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. Therefore, a single dose of sustained release medication may be recommended for children and especially for younger children.

According to the German S3 guideline 2018, immediate release MPH can be considered for the following reasons, for example:⁸

• 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-time very low dosage (2.5 mg of immediate release MPH) and do not expect any 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 immediate release MPH (usual duration of action approx. 5-6 hours)
• After 4 to 7 days 2.5 mg immediate release twice a day
• Continue to increase the number of single doses every 4 to 7 days until the day is covered.
  As immediate release MPH only works for 2.5 to 3 hours, 3 to 5 single doses are required to cover the day. With only two doses, almost the entire day would remain unmedicated. This could completely distort the assessment by people with ADHD 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 person with ADHD.
• Increase single doses to 5 mg (sustained release 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 immediate release MPH.
  We consider dose jumps of 5 mg immediate release MPH / single dose (or 10 mg / single dose half-day sustained release, 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 people with ADHD have a very narrow window for an optimal dosage of well below 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.³⁰ Up to now, intolerance has probably been assumed quite frequently, which in reality was due to inappropriate dosages.
    Since such small dosing increments do not harm other people with ADHD (on the contrary, they help to avoid dosing side effects),⁹¹ the gold standard should be dosing increments in 2.5 mg steps (based on an immediate release single dose of MPH). So does Kühle.⁹² A large meta-analysis points in the same direction⁶²
    Other sources recommend starting with 1-2 single doses of 5 mg and increasing the single dose weekly in 5 mg increments.⁹³ For the reasons mentioned, we consider these dose increments to be too large.
    For people with ADHD for whom even extremely small differences in dose are crucial, a pharmacy in Switzerland offers MPH drops. One drop contains 0.35 mg MPH. It is produced in batches and preserved using E216 and E218.⁹⁴ A person with ADHD reported that dissolving immediate release MPH in alcohol in such exact quantities that they could be measured out per drop showed a comparable result.
• Informing people with ADHD and third parties (involved) 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. For some people with ADHD (we suspect ADHD-I rather than ADHD-HI), a reduced dose (1/5 to 1/2 of an optimized single dose) in immediate release 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). Sustained release daily doses should be converted to the immediate release. (Example: 20 mg sustained release with an active time of 5-6 hours corresponds to 10 mg immediate release with an active time of 2.5-3 hours).
• Increase the dosage until a very satisfactory effect is achieved.
  • For the majority, but not all people with ADHD, a higher dose results in better symptom reduction⁹⁵
• 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, carry out 2 further increases in order to establish that negative symptoms have now been added.
  Purpose:
  It is ensured that not only an improvement in symptoms but also the optimum dose is determined. Furthermore, the person with ADHD experiences what it feels like when the dosage is slightly too high. This is important so that the person with ADHD develops a feeling for what the optimal dosage is in order to be able to suggest further dose 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. It is possible that this is an adaptation of the noradrenergic system. Several people with ADHD have reported to 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.
  • Stimulants close stimulus filters: This is probably one of the reasons why students “try out” stimulants for stressful exam periods (which we strongly advise against), but then stop taking them of their own accord. (In fact, students who abuse stimulants for exam periods have higher than average ADHD symptoms{{Caron C, Dondaine T, Bastien A, Chérot N, Deheul S, Gautier S, Cottencin O, Moreau-Crépeaux S, Bordet R, Carton L (2023): Could psychostimulant drug use among university students be related to ADHD symptoms? A preliminary study. Psychiatry Res. 2023 Nov 25;331:115630. doi: 10.1016/j.psychres.2023.115630. PMID: 38043409. n = 4.431}})
  • Those who (unlike persons with ADHD) do not have a stimulus filter that is too wide open lose quality of life. There are no reports of students voluntarily taking MPH outside of very stressful exam periods (unless they have severe ADHD symptoms⁹⁶ )
  • Stimulants inhibit the limbic system. An overdose can therefore reduce emotional perception.⁹⁷
• The manufacturer’s information on the typical duration of action only applies to people with standard gene variants of the metabolization genes. However, many people with ADHD 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 effectiveness 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 person with ADHD.
  • A single dose of Vyvanse only works for a maximum of 5 to 7 hours in 2/3 of people with ADHD. The typical value of 12 hours stated by the manufacturer is therefore far from being achieved in the majority of people with ADHD.
  • In rapid metabolizers (approx. 15 - 20 % of persons with ADHD), immediate release 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 Vyvanse 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 necessary.
  • Too rapid metabolism can be counteracted by cross-effects with inhibitors of the respective metabolizing enzyme. For example, several people with ADHD in whom Vyvanse (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 sustained release MPH / AMP¶

Once discontinued with immediate-release MPH, the number of single doses/day should be reduced by using sustained-release preparations, as administration of the otherwise required 4 to 6 single doses of immediate-release MPH per day⁹⁸ is barely sustainable for children and adolescents. Medication compliance decreases in proportion to the required frequency of administration. Because people with ADHD 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.⁵ Taking a single dose a day improves compliance.⁹⁹
For adults, immediate release MPH is not approved in Germany and can only be prescribed off-label.

Whether immediate release or sustained release MPH works better varies from person to person. In a 1-year study, about half of the people with ADHD preferred immediate release MPH, the other half preferred OROS-MPH.¹⁰⁰ As a rule, people with ADHD are better able to judge which type of medication they cope better with than the doctor. Therefore, the experience of the person with ADHD should be taken into account.

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 effect before the second dose takes effect. This can be avoided by staggering the intake of several (possibly reduced) doses. For example, if 20 mg sustained release MPH shows an effect profile of 2 hours effect + 30 minutes effect gap + 2 hours effect, one option would be to give two sustained release doses of 10 mg offset by 30 minutes.

Medikinet adult and Medikinet sustained release are unsuitable for people who have difficulty eating in the morning, as they only develop their sustained release effect if food is eaten beforehand. In this case, Ritalin adult, Ritalin LA or an OROS preparation such as Concerta should be considered.

2.4. Dosing of AMP¶

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

2.4.1. Vyvanse, Tyvanse (lisdexamfetamine)¶

• Since amphetamine medication is the first choice of medication for adults (highest Effect size and lowest side effects of all ADHD medications), direct dosing with this medication would make sense.
• Vyvanse / 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 relevant risk of overdose and increases the risk of side effects.
  We know quite a few people with ADHD for whom the optimal dosage range of Vyvanse 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 people with ADHD who are optimally dosed with 3 mg Vyvanse / day. We therefore consider dosing increments of 5 mg to be more sensible than the officially stated 10 mg increments. See also above under dosing of immediate release MPH.
• Although the Vyvanse package leaflet does not allow the capsule contents to be divided up, the many years of experience of a large number of people with ADHD 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.²⁰ A somewhat coarser method is to divide capsules into equal-sized heaps using a razor blade on a glass surface.
• The dissolved Vyvanse / Tyvanse will keep for a few days in the fridge.

This Video explaining the division of Vyvanse capsules into small dosage steps.

2.4.2. Aderall N (immediate release)¶

The FDA recommends immediate release amphetamine salts (Adderall) for ADHD:¹⁰¹¹⁰²
- Children up to 3 years: Amphetamine is not recommended
- Children from 3 to 5 years:
- immediate release 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 increments 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
- immediate release AMP
- Starting dose of 5 mg once or twice daily at intervals of 4 to 6 hours
- weekly increase in increments of 5 mg until optimal response is achieved
- Dosage range between 5 and 40 mg per day, divided into 1 to 3 divided doses
- sustained release AMP
- Starting dose of 5 to 10 mg once a day in the morning
- weekly increase in increments of 5 to 10 mg until optimal response is achieved
- Maximum daily dose 30 mg per day
- Young people
- immediate release AMP
- Starting dose of 5 mg once or twice daily at intervals of 4 to 6 hours
- weekly increase in increments of 5 mg until optimal response is achieved
- Dosage range between 5 and 40 mg per day, divided into 1 to 3 divided doses
- sustained release AMP
- Starting dose of 10 mg once a day in the morning
- weekly increase in increments of 10 mg until optimal response is achieved
- No sufficient evidence for better results with more than 20 mg per day
- Note: this is not the same as the experience with Vyvanse in Europe
- Adults
- immediate release AMP
- Starting dose of 5 mg once or twice daily at intervals of 4 to 6 hours
- weekly increase in increments of 5 mg until optimal response is achieved
- Dosage range between 5 and 40 mg per day, divided into 1 to 3 divided doses
- sustained release 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 in 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.⁵ There are no studies with such long observation periods.

3.1. Dosing of atomoxetine¶

According to the study situation⁶⁴ as well as our experience, slow up-dosing also has the advantage of fewer side effects with atomoxetine. While a study supported by the manufacturer does not show a clear picture¹⁰³, other studies report less frequent discontinuation due to side effects with slow dosing, although the rate of side effects was comparable.¹⁰⁴
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.⁷⁰ or with 18 to 25 mg initially²⁴
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 mg⁷⁰
ATX is usually taken in the morning. If fatigue is a side effect, ATX can also be taken in the evening²⁴
If people with ADHD experience side effects with a daily dose of atomoxetine, the information leaflet for Strattera states that it is possible to split the dose into two halved doses in the morning and evening¹⁰⁵

The first effects may become visible after 2 to 3 days. Atomoxetine takes 8 to 10 weeks to take full effect⁵

Unlike stimulants, it is important to take atomoxetine continuously.⁷⁰

In our opinion - as with all antidepressant-like medications - a slow approach is highly recommended when discontinuing. Different opinion: Prasad et. al.⁶⁴ However, we have received several reports of depression as a side effect of rapid discontinuation of atomoxetine.

Since atomoxetine can increase blood pressure and heart rate, these should be monitored⁵

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.
Consequences of this should be that, as with antidepressants, it takes several weeks before an effect occurs.¹⁰⁶

Due to the antihypertensive effect of guanfacine, it must be slowly phased out when dosing in order to avoid blood pressure problems.⁷²

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.⁵

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.¹⁰⁷

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 ADHD 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
  • Determine individual symptoms using the overall symptom list: ⇒ Overall list of symptoms of ADHD according to manifestations
• 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, amount)
• Nicotine consumption (always cut out coffee completely when taking ADHD medication)
• Menstrual cycle in girls / women
  Find out more at ⇒ Gender differences in ADHD
• Sports
• 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 people with ADHD perceive an actual positive effect themselves in a timely manner (comorbid autistic traits in particular can make this more difficult), supplementary external observation is advisable.

External observation should be carried out by an authorized 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 this third party with regard to medication would always be subconsciously included in the assessment and change the result.
In order to avoid a bias in the assessment of the effect by teachers or other 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 in the active substance 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 immediate release MPH tablet in the morning cannot cause 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.

4.3. 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. As attention tests depend heavily on the motivation of the individual subject 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-analysis reports useful results of the Qb test for measuring medication success in ADHD.¹⁰⁸
The Qb test measures the subject’s facial expressions while they complete a Go/NoGo test. It remains to be seen whether the results are consistent enough to assess individual cases. In addition, the time required is likely to prevent wider use in medical practice.

5. Avoid side effects¶

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

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

Side effects and Effect size must be weighed against each other differently.
To achieve a 1% point lower risk of side effects, adults with ADHD were willing to give up percentage points of ADHD symptom improvement:¹⁰⁹
0.59 nausea (1 percentage point less nausea was worth 0.59 percentage points ADHD symptom worsening)
0.57 Insomnia
0.49 Anxiety
0.32 Nervousness
0.17 Dry mouth

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

5.1. Particular challenge: dosing for comorbid anxiety¶

In our experience, people with ADHD who have a comorbid anxiety disorder or high anxiety levels often experience more severe side effects.
More on this at Treatment guidelines for specific comorbidities: ADHD and anxiety In the article ADHD treatment guidelines.

5.2. 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.
Therefore, caffeine should be completely and consistently omitted when dosing stimulants. This may be subjectively difficult for people with ADHD 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 people with ADHD experience symptoms typical of an overdose (including severe overdose) when stimulants are added to a previously well-tolerated caffeine intake. We know many people with ADHD 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. This often includes 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 the person with ADHD then knows that any side effects that occur are not the result of the stimulants
We are also aware of reports from individual people with ADHD who - after years of taking stimulants - still react to decaffeinated coffee with a slight shakiness.
Some people with ADHD report that they can prolong a waning stimulant effect in the afternoon with caffeine.

5.3. No simultaneous nicotine withdrawal¶

Nicotine is a stimulant and increases dopamine and noradrenaline. As a result, heavy smokers have experienced a profound adjustment 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.

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

5.4. Signs of overdose¶

Signs of overdose usually correspond to those of excessive caffeine consumption⁵

• 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.

Overdose symptoms are difficult to distinguish from underdose symptoms. If the symptoms occur during dosing at very low doses, an increase in the dose should always be tried first, with special observation of the further symptoms. If the symptoms tend to become weaker or change completely, they may be symptoms of underdosing.

5.5. Headache¶

This description is based on Simchen¹¹⁰ and is in line with our experience.

5.5.1. 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.
People with ADHD often report that when the stimulant effect wears off, a quick intake of food can restore concentration.

5.5.2. Lack of fluids¶

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

5.5.3. Histamine intolerance¶

A third possible cause is histamine hypersensitivity or histamine intolerance, 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 of ADHD

5.6. Gastrointestinal complaints¶

Stimulants can increase gastrointestinal motility, which can be perceived as painful in sensitive persons with ADHD (if so, then more in children).¹¹⁰(

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 ⁵

Remedy:¹¹⁰⁵
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).

5.7. Problems falling asleep¶

Many people with ADHD report that they can fall asleep better and have a more restful sleep since taking stimulants.
Nevertheless, some people with ADHD 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 early enough so that its effect ends 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)
  • more on this under Effect and duration of action of ADHD medication
• For some people with ADHD (we suspect ADHD-I rather than ADHD-HI), a reduced dose (1/5 to 1/2 of an optimized single dose) in immediate release form can help them fall asleep
  • Test administration as a sleep aid with very low doses (1/10 of the single daily dose)
  • sustained release daily doses should be converted to the shorter duration of action of the immediate release active ingredient (example: 20 mg sustained release for 5-6 hours duration of action corresponds to 10 mg immediate release for 2.5-3 hours duration of action).
• Avoid OROS-MPH (Concerta)
  • A comparison between two studies showed a higher rate of problems falling asleep with OROS-MPH compared to Ritalin-LA.¹¹¹¹¹²

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

This description is based on Simchen¹¹⁰ 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 resolve spontaneously in most people with ADHD. 2 % of people with ADHD discontinued their drug treatment due to cardiovascular effects.¹¹³ 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 adolescents¹¹⁴

In particular, people with ADHD who have high blood pressure appear to suffer a further increase in blood pressure as a result of stimulants, even with finely tuned doses. If high blood pressure is under control before starting ADHD treatment, stimulants can be used, although blood pressure should be monitored at each follow-up⁵

In particularly sensitive persons with ADHD, a higher increase in heart rate may occur 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

5.9. 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.⁵ Nevertheless, in individual cases it can be so severe that people with ADHD consider discontinuing the medication.
According to our impression, rebound occurs primarily with sustained release and half-day sustained release MPH. The rebound lasts about half an hour.
All-day retard preparations show a lower rebound.
Amphetamines have a lower rebound risk than methylphenidate.⁵ In our experience, the slow-release Vyvanse has (almost) no rebound. When a rebound is reported with Vyvanse, our impression is that this particularly affects people with ADHD in whom a single dose of Vyvanse 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 with a small amount of immediate release MPH
  • approx. 1/5 to 1/2 of the amount that would correspond to an optimal single daily dose (this must be converted from sustained release medication, see above under problems falling asleep)
  • approx. 15 minutes before the expected rebound time

5.10. Effect holes¶

With sustained release MPH preparations, some people with ADHD perceive gaps in the effect between the first and second release. This is a clear indication of rapid metabolization.
Sustained release MPH preparations release several doses of MPH at different times. If the first release is metabolized too quickly, its effect may subside before the second release begins. In the event of such problems with fluctuations in the active ingredient of MPH, it is possible to switch to MPH preparations with an all-day effect such as Concerta, Kinecteen or methylphenidate hydrochloride Neuraxpharm (which is bioidentical to Concerta), which also have a 12-hour effect. Alternatively, a switch to amphetamine medication should be considered, as these are metabolized in a different way, so that there is a chance of normal metabolism.

5.11. Loss of appetite / weight loss¶

Stimulants and desipramine are often associated with the side effect of reduced appetite and consequent weight loss.
This is usually only a side effect of the dosage and disappears after 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.

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

Atomoxetine is also frequently associated with a loss of appetite, but the risk is slightly lower (by 12%) than with MPH (RR 0.82; meta-analysis, k = 8, n = 1,463)¹¹⁵ Atomoxetine caused a weight loss of 0.6, Concerta of 0.9, placebo of 1.1 (placebo thus caused a greater weight loss than ATX and MPH).¹¹⁶
The risk of methylphenidate and amphetamine medication was identical (RR 1.01; meta-analysis, k = 3, n = 414)¹¹⁵

Nortryptiline is said to be associated with weight gain as a side effect¹¹⁷

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.¹¹⁸ Atypical antipsychotics are said to have an even stronger effect in terms of increased appetite and metabolic syndrome.¹¹⁹
Combination treatment with psychostimulants and antipsychotics is being used more and more frequently.¹²⁰ An improved effect compared to stimulant monotherapy has also been reported in isolated cases.¹¹⁹ A registry study found that 3.9% of children and adolescents with ADHD who received stimulants were comedicated with atypical antipsychotics.¹²¹
This opens up the option of using a combination medication to counteract excessive weight loss with stimulants.

Another option is the administration of cyproheptadine.²²
More on this at Cyproheptadine for ADHD

If necessary, medication breaks are required to increase the weight again.

5.12. Emotion loss / zombie mode: overdose or intolerance¶

Sensitive people with ADHD, especially those with ADHD-HI and ADHD-C⁵, 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 with ADHD feels more like themselves. Any form of perceiving oneself as alien or perceiving oneself less is an indication of inappropriate medication.
Stimulants dampen the limbic system. A few people with ADHD are particularly sensitive in this respect. In most cases, persistent testing of various preparations and active ingredients helps.
In our opinion, a restriction of emotions is more often the consequence of an overdose. In this case, a restart of the dosage in the smallest possible dosage steps should be considered. Some (albeit very few) people with ADHD only need a few mg of a stimulant throughout the day.

The following options should only be considered when it is certain that a reduction in dosage that just about eliminates emotional impairment will not sufficiently improve 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

5.13. 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 in this phase. One study reports good experiences with increasing the stimulant dose by an average of 41% in the premenstrual week.¹²²

5.14. Fluctuating effect¶

Sometimes people with ADHD report fluctuations in effect, even after a longer period of stable use.
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
  • rarely after prolonged use with a constant effect
  • more on this under Medication: Tolerance development

5.15. Symptoms of overload¶

After starting medication, many people with ADHD develop a high level of activity with which they tackle their problems and tasks.
For some people with ADHD, this can lead to symptoms of overload and sometimes even to a breakdown.

We do not consider this to be a pharmacological, but a psychological consequence of the medication. In particular, it is not an expression of hyperactivity or inner restlessness, but on the contrary a significantly increased effectiveness and work intensity compared to the time before the medication.

Many people with ADHD can now motivate themselves better thanks to the medication and therefore think that they can now do everything they want, should or have to do.
But there is a difference between being able to do “more” and being able to do “everything”.

Although medication means that you can now do more, it does not restore full performance. Although the performance of people who are not affected is often achieved, this is not always the case and not for everyone. Medication does not give you superpowers that allow you to do everything you have always wanted to do.
Subjectively, however, this is not perceptible. All you feel from the inside is that you’re better now. You can’t feel that this is still not everything, because you never knew it and don’t know what it would be like if you no longer had ADHD. A conflict with an inner dysfunctional perfectionism could also come to light here.

Especially shortly after dosing, people with ADHD should therefore take particular care not to overload themselves.
With medication, you first have to get to know your new limits, what is now possible and what you can demand of yourself.
Medication can shift these boundaries, but it cannot remove them.

6. General information¶

• Immediate release 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 sustained release portion) makes it easier to find the appropriate dose, especially for inexperienced observers (people with ADHD and third parties).
• In the case of sustained release Medikinet, it must be noted that this must be taken with food, as otherwise the entire dose will be delivered in an immediate release. Other preparations generally do not require food intake, although this must always be checked in the package leaflet. It is recommended that all long-acting ADHD medications are 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 with ADHD no longer tolerate caffeine or other stimulants when taking stimulants, which were previously consumed without any 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 mistaken for an overdose (inner fidgetiness, 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 people with ADHD 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 given in the mornings during school hours depends on whether the person with ADHD is 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 with ADHD. 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 immediate release 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 occasional special stresses, e.g. a particularly long evening, with immediate release MPH.
    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 ADHD-Forum.ADxS.org.