Monitor Dosage, Avoid Side Effects

Completely revised 09/2026

1. Monitor and document dosing¶

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

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

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

• Daily assessment of each relevant symptom

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

• Preparation

  • not just the active ingredient

  • For generic drugs, include the manufacturer as well

• Dose

• Time(s) to take

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

• Food and fluid intake (type, amount)

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

• Nicotine use

• Menstrual cycle in girls and women

  • For more information, visit ⇒ Gender Differences in ADHD

• sports

• Specific stressors (both emotional and physical, such as arguments, illnesses, allergies, etc.)

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

1.2. Observation by Others¶

(ADxS assessment): Since not all people with ADHD immediately notice the positive effects that are actually occurring (comorbid autistic traits, in particular, can make this difficult), supplementary observation by others is advisable.

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

In addition, it is helpful to discreetly ask third parties who are not aware of the medication regimen about any changes they may have noticed.

Such feedback is particularly valuable and meaningful when these third parties are unaware that medication is being taken. Otherwise, these third parties’ attitudes toward and expectations of medication would always subconsciously influence their assessment and alter the result.

To avoid bias in the assessment of the drug’s effects by teachers or other caregivers, it is therefore advisable not to inform them of the medication use at first. If they nevertheless report a significant change in behavior within the first few weeks, this unbiased observation is much more meaningful.

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

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

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

1.3. Measuring the Effectiveness of Medication¶

Various attempts to adjust medication dosages for ADHD based on blood test results have so far shown little success.

1.3.1. Blood level measurements¶

With regard to ATX, it was reported that blood level measurements did not yield any useful values.

Since stimulants are known not to be dosed based on body weight, and since the doses required to achieve an appropriate effect vary greatly from person to person, we do not fully understand what benefit measuring blood levels could have.

1.3.2. Sustained Attention Tests¶

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

1.3.3. QbTest¶

The Qb test measures physical restlessness while the subject completes a Go/No-Go test: An infrared camera tracks a reflective marker on the forehead, thereby recording head movements. In the Go/No-Go paradigm for children, the participant must press a button on the handheld device every time a circle appears on the screen, but must refrain from doing so if a cross appears before the circle. For adolescents and adults, a “One-Back” task is used, which includes four types of stimuli. The target stimulus is the shape and color of the preceding one. It remains to be seen whether the results are consistent enough to assess individual cases. Furthermore, the time required is likely to prevent wider use in medical practice.

A meta-analysis of k = 15 studies, 13 of which involved participants diagnosed with ADHD, reports useful results from the Qb test for measuring the effectiveness of medication in ADHD. In the majority of cases, a clinically relevant decrease in Q-values was observed when medication was administered at therapeutic doses. The test can reflect treatment effects within hours of a dose adjustment. (E 2b)¹

A randomized feasibility study (not an efficacy study) examined the usefulness of the QbTest in determining the appropriate dosage for 44 children and adolescents aged 6 to 15 who were starting treatment with stimulants. They were assigned either to a QbTest protocol (test before the start of treatment and after 2 to 4 and 8 to 10 weeks) or to standard treatment with at least two follow-up visits. Inattention scores on the SNAP-IV decreased more significantly in the QbTest group (difference -5.85; 95% CI -10.33 to -1.36). Therapists and parents rated the objectivity of the procedure positively. However, therapists noted that the additional time and resources required made its use in all cases impractical. Only 37% of the QbTests were conducted within the intended time frame.²

1.3.4. Placebo controls¶

In a titration RCT involving children aged 5 to 13 years who alternated weekly between placebo and 5, 10, 15, and 20 mg of MPH twice daily, the placebo condition contributed significantly to symptom reduction, partly due to the placebo effect and regression to the mean.³According to parental reports, in addition to the active ingredient’s effect, nonspecific effects—that is, the significant improvement observed even under placebo—contributed to the overall effect. According to teacher reports, there was no significant improvement from baseline under placebo, but there was under all methylphenidate doses. Teacher assessments are less susceptible to placebo effects than parent assessments, which is why both should be collected in parallel. Only those children who had higher symptom scores at baseline showed a significant improvement under placebo. In cases of very high baseline symptoms, these improved simply over time. Neither the parents’ agreement with the diagnosis and treatment nor their expectations regarding treatment, nor the child’s attitude toward the diagnosis and treatment or their aversion to medication predicted the magnitude of the placebo effect. The placebo effect, therefore, cannot be inferred from expectations. Across k = 128 RCTs involving 10,578 children and adolescents as well as 9,175 adults, clear and highly variable placebo effects were found for all measures of efficacy. Side effects were also reported with the placebo. Both factors must be taken into account when evaluating individual dose levels.⁴

A placebo-controlled single-dose trial (PCT), in which placebo weeks were interspersed between active-drug stages, was tested in a clinical setting. Children aged 5 to 13 years with an indication for MPH treatment were randomized to either placebo-controlled titration or standard care, with a seven-week controlled phase and a six-month open-label follow-up. The study compared weekly placebo with 5, 10, 15, and 20 mg of methylphenidate twice daily in 45 children aged 5 to 13 years. The goal was to identify placebo responders and determine the actual dose required. In the PCT group, significantly more children discontinued MPH (24.5% versus 5.9% after 7 weeks; 41.7% versus 10.4% after 6 months) and were more likely to discontinue any other medication (20.4% versus 3.9% and 20.8% versus 6.3%, respectively). The groups did not differ at any time in terms of mean MPH dose, symptom severity, or treatment satisfaction. The authors concluded that placebo-controlled titration helps identify children who do not benefit from methylphenidate and could thereby reduce overtreatment.⁵ The accompanying dose-response analysis study ⁶showed, at the group level, positively linear dose-response curves in parent- and teacher-rated symptoms as well as for parent-reported side effects. Teachers observed an improvement compared to placebo at all dose levels, while parents noted an improvement only at doses above 5 mg per dose. At the individual level, however, the picture was inconsistent.

• 73 to 88 percent of the children showed a positively increasing dose-response curve.
• For the remaining 27 to 18%, the dose increase did not result in any additional improvement or showed a negative dose-response curve (a higher dose worsened the outcome)
• Increasing the dose is more likely to be beneficial if the following characteristics are present:
  • more pronounced hyperactive-impulsive symptoms
  • fewer internal complaints
  • lower body weight
  • younger age
  • a more positive attitude toward diagnosis and medication.

There was considerable variation among the children, and higher doses did not lead to greater improvement in all of them. In practice, this means that a higher dose produces a better effect only on average across the group; however, it is not a reliable rule in individual cases.⁶

1.4. Monitoring and Improving Medication Adherence¶

1.4.1. Taking Medication¶

The use of a medication reminder app significantly improved medication adherence and reduced the time between prescription refills from 46 to 34 days. (E 4)⁷ This was a small-scale project without a control group.

Educational programs for parents increase medication adherence in children. In a randomized study, parents of children with ADHD received a brief, targeted educational program. The education consisted of a presentation with slides and a parent handbook, two professionally led parent group sessions, and an invitation to join a professionally moderated online community. The program was based on the theory of planned behavior. In addition to medication adherence, the study measured parents’ knowledge of ADHD and the components of this behavioral model. The greatest improvement was observed in the intention to adhere to the medication regimen (p < 0.001). Medication adherence was subsequently significantly higher than in the control group. After one month, 97.7% versus 75.6%; after three months, 86.4% versus 53.3%. Accordingly, symptom scores were also lower (33.7 versus 45.1 points). In the control group, after three months, only about one in two children was still taking the medication as prescribed.⁸ Although the authors measured adherence, they did not measure the actual titration dose taken. Treatment typically begins with the lowest dose and is gradually increased over time to the target dose. However, it became apparent over the course of the study that some parents did not follow this regimen and remained on the low dose due to side effects. In such studies, patients who take the medication regularly but remain below the effective dose are considered treatment-compliant, yet the treatment still fails. Future studies should therefore also assess whether the prescribed titration regimen was followed at all.

1.4.2. Prescription Filling¶

The idea that ADHD medications—especially stimulants—could be addictive is a well-known myth. However, in this case, people would not frequently forget to take their medication. The fact is that oral use of ADHD medications as directed does not increase the risk of addiction. (E 4)⁹ If anything, the risk of addiction is reduced. For more on this, see Substance Abuse / Addiction Comorbid with ADHD in the article Choice of medication for ADHD or ADHD with comorbid conditions

Reminders such as alarm clocks, pill boxes, or apps can help improve medication adherence among people with ADHD—especially during the initial dosing phase.

Even simple text message reminders to pick up prescriptions have had a significant impact.

87 children aged 6 to 12 received SMS support, compared with 246 children from the same healthcare organization who were matched for age, background, and gender. 85% of the text message group filled their prescriptions on time, compared with 62% in the standard care group (OR 3.46; 95% CI 1.82 to 6.58; p < 0.001).¹⁰

Two studies by the same research group examined whether text messages promote timely prescription fulfillment among adults receiving stimulant treatment. In the first study, 68% of the text message group filled their prescriptions on time (defined as within 37 days), compared with 34% in the standard care group (OR 4.04; 95% CI 2.49 to 6.56; p < 0.001).¹¹The second study applied the approach to primary care. 117 adults aged 18 to 55 received the SMS support. 96% (n = 112) completed the 37-day program in full. 81% filled their prescriptions on time, compared to 36% under standard care (OR 7.54; 95% CI 4.46 to 12.77; p < 0.001). The messages covered four areas: reminders to take the prescribed medication, reminders to renew prescriptions on time, information about ADHD and its treatment, and tips on time management and organizing daily life. Both studies are open-label, non-randomized, retrospective matched-control studies using medical record databases, and participants had to actively enroll, which may explain part of the difference.¹²

2. Avoiding Side Effects¶

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

• Dry mouth (a few days)

• mild, temporary loss of appetite

Side effects and effect size must be weighed against one another.

To achieve a 1 percentage point lower risk of side effects, adults with ADHD were willing to forgo percentage points of improvement in ADHD symptoms: (E 3)¹³

• 0.59 Insomnia (a one-percentage-point reduction in the risk of insomnia was worth 0.59 percentage points less improvement in symptoms)
• 0.57 Nausea
• 0.49 Anxiety
• 0.32 Nervousness or trembling
• 0.17 Dry mouth

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

2.1. Side Effects of Placebo, Effects of Nocebo¶

Side effects also occur with placebos, and to such an extent that it is impossible to attribute individual symptoms to the active ingredient in each specific case.¹⁴

Some of the side effects reported during the titration of ADHD medications are not attributable to the active ingredient. In a meta-analysis of k = 105 RCTs involving n = 8,743 patients in the placebo arms, 55.5% of those receiving placebo reported at least one adverse effect. Therefore, a side effect occurring during the first dose level does not, in and of itself, justify discontinuation, but rather requires observation over several days. ¹⁵
Based on k = 128 RCTs on ADHD involving 10,578 children and adolescents and 9,175 adults, significant placebo effects were found for all measures of efficacy, with no evidence of publication bias. The placebo effect was greatest when clinicians performed the assessment and less pronounced when other evaluators did so. Regarding tolerability, corresponding nocebo effects—that is, side effects under placebo—were found. There were no differences in placebo and nocebo effects between the individual active ingredients. However, baseline severity and the type of rating scale used did significantly influence the results. Those who responded strongly to the placebo also responded strongly to the active ingredient. Healthcare providers should strive to incorporate the factors associated with the placebo effect into treatment—that is, to consciously shape expectations, care, and the overall context. With regard to dosing, this also means that early improvement within the first few days should not automatically be taken as proof that the dose is correct.¹⁶

In a comparison of nine psychiatric disorders, the placebo response for ADHD falls within the mid-range. It is clearly present, but not exceptionally high. This puts into perspective both the expectation that any early improvement is due to the medication and the assumption that ADHD studies are particularly susceptible to the placebo effect.¹⁷

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

(ADxS experience): In our experience, people with ADHD or high anxiety scores often experience more severe side effects.

Anxiety is not a common side effect of stimulants, as shown by a meta-analysis of 23 RCTs involving 2,959 children. The risk of anxiety was lower with stimulants than with placebo (RR 0.86; 95% CI 0.77 to 0.95), and higher doses were associated with a greater reduction in risk. Newly emerging or increased anxiety during treatment should therefore not automatically be attributed to the active ingredient and, on its own, does not preclude continued treatment.¹⁸The meta-regression revealed a significant negative association between dose and risk of anxiety (b = −0.0039; 95% CI −0.00718 to −0.00064; p = 0.019). MPH significantly reduced the risk of anxiety (RR 0.85; 0.76 to 0.94; k = 17), while amphetamine preparations did not alter it (RR 1.02; 0.69 to 1.50; k = 6). Short-acting formulations significantly reduced the risk of anxiety (RR 0.83; 0.74 to 0.93), while long-acting formulations did not affect it (RR 0.99; 0.77 to 1.27). The duration of treatment had no effect. These findings thus contradict a widespread belief and the information provided in U.S. package inserts; however, they apply to the average patient rather than to individual cases.

For more information, see Treatment Guidelines for Specific Comorbidities: ADHD and Anxiety in the article “Guidelines for ADHD Treatment.”

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

(ADxS experience): When dosing stimulants, caffeine should be completely omitted without exception.

Since the side effects of caffeine and stimulants can accumulate (E 4)¹⁹, consuming them together can lead to side effects that do not occur when caffeine or stimulants are taken alone. Therefore, caffeine must be completely and consistently avoided when titrating stimulant doses. This may be subjectively difficult for people with ADHD who previously managed their symptoms with high caffeine intake. However, the role of symptom reduction is now (and much more effectively) fulfilled by the stimulants.

Caffeine and stimulants are both sympathomimetics. When two or more sympathomimetic substances are administered simultaneously, there is an increased risk of nervousness, irritability, and an elevated heart rate. Additive increases in blood pressure and heart rate may result from enhanced peripheral sympathetic activity. Caution is recommended when using these substances concurrently, along with close monitoring of pulse and blood pressure. Both substances block adenosine receptors or increase dopamine levels, respectively, which results in additive effects. This supports the recommendation to omit caffeine during the titration phase, as it would otherwise be impossible to determine which substance is causing a side effect.²⁰

In addition to the overdose side effects mentioned above, other symptoms have occasionally been reported during the use of stimulants, which disappeared abruptly when caffeine was discontinued, such as tremors, rapid heartbeat, circulatory problems, high blood pressure, nausea, mottled skin, or Raynaud’s syndrome.

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

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

Once stimulants have been successfully tapered off, caffeine can be cautiously reintroduced. The difference is that people with ADHD then know that any side effects that occur at this point are not caused by the stimulants.

We are also aware of reports from some people with ADHD who—after years of taking stimulants—still experience mild tremors even when drinking decaffeinated coffee.

Some people with ADHD report that they can use caffeine to prolong the stimulating effects that begin to wear off in the afternoon.

2.4. No concurrent nicotine withdrawal¶

Nicotine is a stimulant that increases dopamine and norepinephrine levels. Heavy smokers have therefore experienced a profound change in the balance of these neurotransmitters in the brain. Quitting smoking—especially overnight—leads to severe adjustment reactions and withdrawal symptoms. When we had him gradually reduce his intake, a former heavy smoker reported very severe and intolerable side effects, which disappeared when he started smoking again.

Even though smoking is harmful to one’s health, it should not be stopped at the same time as starting a new medication.

In addition, when monitoring the effects of medication during dosing, it is helpful to avoid any distortion caused by external factors.

Unlike with caffeine, we have received reports of interactions involving nicotine much less frequently.

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

2.5. Alcohol and Stimulants¶

Alcohol significantly increases blood levels of MPH and must be completely avoided when taking a single dose of MPH. This is because the enzyme carboxylesterase 1 (CES1), which breaks down MPH, instead converts l-MPH to ethylphenidate in the presence of alcohol. As a result, less of the active d-MPH is broken down, and blood levels rise. (E 1b)²¹

2.6. Signs of an overdose¶

The problem is that an underdose can feel very similar. If such symptoms occur even at very low doses, the correct course of action is usually not to reduce the dose, but rather to first increase it cautiously in consultation with the doctor.

Symptoms of an overdose are usually the same as those of excessive caffeine consumption: (E 4)²⁴

• Tremors

• mild dysphoria

• Nervousness

• Heart palpitations

• Rapid heartbeat

• Headaches

• Irritability

• Circulatory problems

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

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

2.7. Headaches¶

This description is based on Simchen (E 4)²⁵ and is consistent with our experience.

2.7.1. Hypoglycemia¶

(ADxS experience): Headaches as a side effect of stimulant use are often consequences of low blood sugar.

Stimulants increase activity in the PFC, which boosts glucose consumption and lowers blood sugar levels.

Symptoms of hypoglycemia include

• Headaches

• Fatigue (yawning)

• Pallor

• Dizziness

• Tremors (though these may also result from an overdose or an interaction with caffeine).

Solution:

• Eat a good breakfast or meal before taking each dose

• Snacks for in between meals

• If you get a headache, eat easily digestible carbohydrates right away

  • glucose

  • Bananas

  • Fruit juices (without sweeteners)

During prolonged hypoglycemia, the brain produces acidic metabolic byproducts through lactic acid metabolism, which lead to headaches that last longer and are more difficult to relieve.

People with ADHD often report that, as the effects of stimulants wear off, eating quickly can help them regain their concentration.

2.7.2. Dehydration¶

(ADxS experience): Another common cause of headaches when titrating stimulant doses is insufficient fluid intake.

2.7.3. Histamine intolerance¶

(ADxS assessment): A third possible cause is histamine hypersensitivity or histamine intolerance, since all ADHD medications (with the possible exception of viloxazine) increase histamine levels. In such cases, however, the headaches occur alongside other typical symptoms of histamine intolerance.

Although ADHD medications are said to increase histamine levels only centrally and not peripherally, people with ADHD repeatedly report histaminergic side effects from these medications on the ADxS forum. It remains unclear whether these side effects could be caused by the excipients.

Learn more about the symptoms of histamine intolerance at Histamine Intolerance, Histamine Sensitivity in the article Differential Diagnosis of ADHD

2.8. Gastrointestinal symptoms¶

Stimulants can increase gastrointestinal motility, which may be perceived as painful by people with ADHD (if at all, then more likely in children). (E 4)²⁵

Higher doses taken on an empty stomach, in particular, can cause a strange, cramp-like sensation under the right rib cage about 30 minutes after ingestion. This is thought to be triggered by a spasm of the smooth muscle in the duodenum due to the sudden rise in stimulant levels. (E 4)²⁴

(E 4): Solution: (E 4)²⁵ (E 4)²⁴

Eat a sufficient meal before taking the medication.

A longer interval before taking the medication (one hour) may be even more effective than a shorter interval (15 minutes).

It is noteworthy that the widely accepted rule of taking methylphenidate 30 to 45 minutes before a meal^{2627 28 29 30} was not originally based on data. One study reports that this recommendation was based on the assumption that absorption or metabolism would change when the medication is taken with meals. There was no behavioral or pharmacological data to support this. The double-blind, placebo-controlled crossover study involving 11 people with ADHD administered MPH at or before breakfast and compared the results based on parental assessments, a brief learning test, and auditory evoked potentials. Taking the medication at a different time from a meal is a sensible measure for people with stomach discomfort, but it is not a universal rule. For some people with ADHD, taking it with a meal is unproblematic or even more beneficial.³¹

If you experience severe nausea or a loss of appetite, consider taking the medication with a meal, although it is best taken on an empty stomach.³²

2.9. Trouble falling asleep¶

A meta-analysis of 35 RCTs involving 3,079 children and adolescents treated with medication and 2,606 treated with placebo is available regarding the extent and nature of sleep disturbances caused by MPH. MPH increased the relative risk (all p < 0.001) by:³³

• 1.61 for sleep disorders in general
• 2.78 for difficulty falling asleep
• 2.97 for difficulty staying asleep
• 2.97 for combined sleep disorders
• 1.99 for sleep disorder as a standalone diagnosis

The various MPH formulations had significantly different effects on the risk of sleep-related events. The magnitude of the relative risk depended heavily on the rate of side effects in the placebo group, which is why figures from different studies cannot be directly compared.³³The authors offer three practical tips:

• Sleep problems should be systematically assessed before starting methylphenidate treatment and at each follow-up visit
• Specific questions should be asked about difficulty falling asleep, difficulty staying asleep, and combined sleep disorders, as well as about sleep quality and the restorative value of sleep
• Relative risks from different studies cannot be compared if the incidence of side effects varies in the placebo group.

 

Conversely, for some people with ADHD, a very small dose of immediate-release MPH taken in the evening can help them fall asleep. This should be tried cautiously and in consultation with a doctor.

(ADxS experience): Many people with ADHD report that since taking stimulants, they have been able to fall asleep more easily and get a more restful night’s sleep.

However, some people with ADHD may experience difficulty falling asleep as a side effect of the initial dose. These symptoms usually subside within the first few weeks.

A meta-analysis of k = 9 RCTs with objective sleep measurement (actigraphy or polysomnography, n = 246 children and adolescents) found that stimulants were associated with prolonged sleep latency (ES 0.54), reduced sleep efficiency (ES -0.32), and a shorter total sleep duration (ES -0.59). The number of daily doses was a significant moderator. For each additional daily dose, the effect on sleep onset latency increased by 0.42. Sustained-release formulations had a lesser effect on sleep onset latency. The effect on sleep efficiency was smaller the longer the medication had been taken. When assessed in a sleep laboratory, the effect was significantly stronger than when measured with accelerometers, and the more nights measured, the weaker the effect became. Among boys, the effect on sleep efficiency was stronger than among girls.³⁴

Solution:

• Take the last dose early enough so that its effects wear off at least one hour before bedtime

  • This requires knowledge of the typical duration of action of the respective medication. See Effects and Duration of Action of ADHD Medications

  • Increase the time interval if necessary

  • If necessary, skip the afternoon dose for the first 1 to 2 weeks and take only one dose of half-day-release MPH in the morning

• Consider the possibility of slowed metabolism (prolonged duration of action)

  • For more information, see Effects and Duration of Action of ADHD Medications

• For some people with ADHD (we suspect this is more common in ADHD-I than in ADHD-HI), a reduced dose (1/5 to 1/2 of an optimized single dose) in an immediate release form may help them fall asleep

  • Try administering it as a sleep aid in very small doses (1/10 of the single daily dose)

  • Sustained-release daily doses must be converted to the equivalent dose of the immediate release form based on its shorter duration of action (Example: 20 mg of a sustained-release formulation with a duration of action of 5 to 6 hours is equivalent to 10 mg of the immediate release form with a duration of action of 2.5 to 3 hours).

• Avoid OROS-MPH (Concerta)

  • (E 2b): In two separate open-label one-year studies, a higher rate of difficulty falling asleep was reported with OROS-MPH than with long-acting MPH of the Ritalin-LA type.(E 2b)³⁵ (E 2b)³⁶ Since this is not a direct comparison within a single study, no reliable difference between the formulations can be inferred from these findings.

 

The rule about taking the last dose early enough does not apply without exception. A review study indicates that, conversely, some children benefit from extending the stimulant effect further into the evening—namely, when it is not the medication itself that prevents them from falling asleep, but rather the rebound effect, i.e., irritability or defiance that makes going to bed impossible. This could also explain why long-acting stimulants were not consistently associated with sleep problems in randomized trials. Before taking any action, it is therefore essential to determine whether the difficulty falling asleep stems from the onset of the medication’s effects or from the waning of those effects. The appropriate interventions are opposite. Although newer, long-acting formulations have shown benefits extending into the evening in recent studies, they have had only a minor impact on sleep. The authors describe ADHD as a 24-hour disorder, the treatment of which must address both daytime symptoms and nighttime difficulties.³⁷

The evidence base for treating the sleep disorder itself is limited. A systematic review conducted through January 2024 identified only 16 RCTs on interventions for sleep disorders in ADHD—eight on pharmacological interventions and eight on nonpharmacological ones. Behavioral interventions and melatonin have been shown to be effective. For all other approaches, a reliable evidence base was lacking. In some cases, sleep problems can be resolved simply by adjusting the dose or timing of ADHD medication. The data do not clearly support the need to generally avoid taking stimulants in the evening.³⁸As of 2024, nine additional RCTs were ongoing or registered but had not yet reported results, including studies on parent-based and behavioral sleep interventions, cognitive behavioral therapy for insomnia, weighted blankets, atomoxetine, and a comparison of melatonin and methylphenidate in adults. The recommendations regarding sleep disorders in ADHD are therefore likely to change in the coming years.

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

(ADxS assessment): If these symptoms occur after taking stimulants, the first step should be to ensure that caffeine has been completely avoided.

Stimulants stimulate the sympathetic nervous system. (E 4)²⁵

A network meta-analysis of 102 RCTs (13,315 children and adolescents, 9,387 adults, median duration of 7 weeks) found moderate increases compared with placebo in children and adolescents of

• systolic
  • 1.07 mmHg (atomoxetine) to 1.81 mmHg (MPH)
• diastolic
  • 1.93 mmHg (amphetamines) to 2.42 mmHg (MPH)
• Pulse
  • 2.79/min (viloxazine) to 5.58/min (atomoxetine)

Stimulants and norepinephrine reuptake inhibitors did not differ significantly. Blood pressure and pulse should therefore also be monitored when using non-stimulant medications. The evidence is limited to the short term. For adults, it was predominantly rated as very low.³⁹

(E 4): The American Heart Association (AHA) recommends taking a personal and family medical history regarding cardiac abnormalities before starting stimulant therapy, as well as monitoring blood pressure and pulse during follow-up visits. A routine ECG is not required for children with healthy hearts. (E 4)⁴¹ (E 4)⁴² Common ADHD medications do not cause any detectable ECG changes other than an increase in heart rate.
When it comes to congenital heart defects, the AHA’s statement is significantly more cautious than the package inserts. Although the prescribing information expresses concerns regarding all individuals with structural heart disease, there are no clinical studies or data indicating that children with most forms of congenital heart defects would be at a significant risk of sudden cardiac death while taking these medications. The use of stimulants is therefore considered acceptable in cases of congenital heart defects—whether operated on or not—that do not currently present circulatory or arrhythmia problems, as well as in cases deemed stable by the treating pediatric cardiologist, provided that no specific concerns are raised by that physician. (E 4)⁴²

In particular, people with ADHD appear to experience a further increase in blood pressure when taking stimulants, even at carefully adjusted doses. If high blood pressure is under control before ADHD treatment begins, stimulants may be used, although blood pressure should be monitored at every follow-up visit. (E 4)²⁴

(ADxS Assessment): In people with ADHD who are particularly sensitive, a greater increase in heart rate may occur when the dose is adjusted. This should always be discussed with a doctor immediately.

Solution:

• slower dispensing

• lower dosage

• Testing for cross-reactions

• Check whether caffeine has been completely omitted

2.11. Rebound¶

A rebound is a temporary increase in symptoms immediately after the effects of stimulants wear off.

Among 149 hospitalized children receiving short-acting stimulants—primarily methylphenidate—nursing staff on the evening shift observed a worsening of behavior in 30.2% of the patients after at least one dose. Only in 8.7% of cases was the deterioration severe enough to warrant discontinuation of treatment. In slightly more than half of the cases, this involved a single week with notable changes among several weeks with no such changes. 27.4% of those with worse evening readings also performed worse in the evening without medication; thus, a poor evening is not necessarily a result of the medication.⁴³ The data were based on nursing assessments from the day shift (7 a.m. to 3 p.m.) and the evening shift (3 p.m. to 11 p.m.) over 1,252 weeks, of which 514 were without medication and 738 were on stimulants in doses of 5 to 20 mg, usually twice daily. While on stimulants, irritability and sadness decreased significantly during the day (p < 0.001) without worsening in the evening. The only measure that was significantly elevated in the evening was insomnia (p = 0.019). Children with rebound did not differ clinically from the others, neither in terms of age, gender, comorbidities, nor in terms of scores for mania or behavioral problems. Rebound therefore has no diagnostic significance and cannot be predicted. A single poor evening does not justify a change in treatment.

A rebound effect is unpleasant but harmless and does not indicate any problems with the medication. (E 4)²⁴ Nevertheless, in some cases it can be so severe that people with ADHD may consider discontinuing the medication.

(ADxS experience): In our experience, rebound occurs primarily with immediate release and half-day-retard MPH. The rebound lasts approximately 20 to 30 minutes.

Full-day extended-release formulations show less of a rebound effect.

Solution:

• (ADxS experience): Taking the next dose on time so that its effects begin just as the rebound is expected to occur

• A rebound effect after the last daily dose can be prevented by taking a small amount of immediate release MPH

  • approximately 1/5 to 1/2 of the amount that would correspond to an optimal single daily dose (for medications with sustained release, this must be converted; see above under “Difficulty Falling Asleep”)

  • About 15 minutes before the expected rebound

Similarly low rates were observed for a long-acting amphetamine formulation. In a four-week RCT involving children aged 6 to 12, parents completed symptom questionnaires throughout the day. Of the 207 children treated with lisdexamfetamine, seven (3.4%) experienced a rebound in the afternoon or evening; among those receiving placebo, the figure was seven out of 72 (9.7%). In both groups, most rebound events occurred in the evening. Over the course of the day, 50.7 to 55.6% of those on lisdexamfetamine were considered responders, compared with 11.1 to 22.2% on placebo. Rebound was more common in the placebo group than in the group receiving the active ingredient, which again demonstrates that an evening worsening of symptoms cannot automatically be attributed to the medication.⁴⁴ Emotional lability was significantly higher among people with ADHD and nonresponders on lisdexamfetamine (mean values 4.2 to 9.0) than among responders (1.3 to 1.6) and than among people with ADHD on placebo (0.7 to 1.9). Rebound is thus associated with pronounced emotional lability, which makes it recognizable as such in everyday life. The authors note, however, that while their definition of rebound appears plausible, it has not yet been empirically tested. The study was funded by Shire; four authors were employed there.
Rebound is rare with once-daily extended-release formulations. In a four-week randomized, double-blind study, 3.4% of children (7 out of 207) taking lisdexamfetamine experienced rebound in the afternoon or evening, compared with 9.7% (7 out of 72). In both groups, rebound occurred predominantly in the evening. Children who experienced rebound and nonresponders showed significantly higher scores for emotional lability than responders. Rebound is therefore not necessarily a consequence of the medication; it may also reflect untreated symptoms at the end of the day.⁴⁴

Amphetamines carry a lower risk of rebound than methylphenidate. (E 4)²⁴ In our experience, the slow-release form of lisdexamfetamine rarely causes a rebound, if at all, and only during the first few weeks of treatment. When rebound is reported with Vyvanse, our impression is that it particularly affects people with ADHD for whom a single dose of Vyvanse has a shorter duration of action (7 hours or less, instead of the 12 to 14 hours specified by the manufacturer).

2.12. Gaps in coverage¶

(ADxS experience): With sustained-release MPH formulations, some people with ADHD notice gaps in efficacy between the first and second releases. This is a clear indication of rapid metabolism.

Sustained-release MPH formulations release multiple doses of MPH over time. If the first release is metabolized too quickly, its effect may already begin to wear off before the second release begins. In cases of such problems with fluctuations in active ingredient levels in MPH, it may be appropriate to switch, within the range of MPH formulations, to full-day-acting MPH formulations such as Concerta, Kinecteen, or (the bioidentical alternative to Concerta) Neuraxpharm methylphenidate hydrochloride, which also provide 12-hour coverage. Alternatively, switching to amphetamine-based medications should be considered, as these are metabolized differently, thereby increasing the likelihood of normal metabolism.

2.13. Loss of appetite / Weight loss¶

Stimulants and desipramine are often associated with the side effect of a decreased appetite and, as a consequence, weight loss.

A systematic review with meta-analysis found statistically significant but small effects on height and weight when MPH was taken for more than six months. The clinical effect is likely to be minimal. The sensitivity analysis did not reveal any significant moderating effects for dose, age, or prior medication naivety. Given the limited data, no effect on pubertal development could be demonstrated. It is recommended that growth parameters be assessed before starting treatment and monitored regularly using standardized percentile curves, especially in preschool-aged children.⁴⁵

In most cases, this is simply a side effect of the initial dose and resolves on its own over the course of a few weeks or months.

In addition to diet, practical recommendations identify three areas of focus:⁴⁶

• Adjusting the dosing schedule, such as combining an immediate release morning dose with a sustained release afternoon dose, so that breakfast falls during a drug-free period
• Dose reduction in combination with an additional non-stimulant
• Switch to a non-stimulant medication that does not suppress appetite. It is recommended to regularly track height, weight, and BMI.

In cases of clinically significant weight loss, the following is recommended: (E 4)⁹

• Take medication not before, but during or after meals

• Additional meals or snacks early in the morning or late in the evening (outside the times when the medication is effective)

• Nutrition Counseling

• High-calorie foods with high nutritional value

• planned break in treatment

• Change in medication

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

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

(ADxS experience): A survey conducted on the ADxS forum revealed (113 participants, as of April 2026):

• Lisdexamfetamine (LDX) was 44% more effective at suppressing appetite than methylphenidate (MPH)

• LDX and MPH were equally effective at suppressing appetite (30%)

• MPH was 26% more effective at suppressing appetite than LDX

Nortriptyline is said to be associated with weight gain as a side effect. (E 1a)⁴⁹

(ADxS Assessment): In isolated cases, the use of low-dose antipsychotics to counteract weight loss caused by stimulants is being considered. This is expressly not a recommended course of action. Antipsychotics are not approved for this purpose and carry significant risks of their own (metabolic syndrome, movement disorders, and, in children and adolescents, elevated prolactin levels).

Another option is to administer cyproheptadine. (E 4)⁵⁴

For more information, see Cyproheptadine for ADHD

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

2.14. Impaired growth¶

Long-term studies on growth have yielded varying results. Many found no clinically significant change in height by adulthood. In the MTA follow-up study through age 25, people with ADHD who received continuous treatment were, on average, 2.36 cm (± 1.13 cm) shorter than people with ADHD who received irregular treatment. Despite the inconsistent data, pediatric guidelines recommend monitoring height using growth charts throughout the entire duration of treatment. In cases of noticeable growth retardation, alpha-2 agonists such as clonidine or guanfacine, or norepinephrine reuptake inhibitors such as atomoxetine or viloxazine, should be considered. The authors cite changes in diet, loss of appetite, dopaminergic effects on growth hormones, and reduced thyroxine secretion as possible causes.⁴⁶

In parallel-group studies, methylphenidate increased the risk of decreased appetite (RR 3.66; 95% CI 2.56 to 5.23) and weight loss (RR 3.89; 1.43 to 10.59); in crossover studies, it increased the risk of abdominal pain (RR 1.61; 1.27 to 2.04). No differences were found based on type, dose, or duration of use. In this analysis, reduced appetite and abdominal pain could not be prevented by a lower dose, unlike, for example, sleep disturbances, which occur in a dose-dependent manner. ⁵⁵ Although studies using low doses differed with regard to loss of appetite (RR 2.87; 95% CI 0.87 to 9.45) and those with medium-to-high doses (RR 2.57; 1.96 to 3.35) did not differ significantly from one another (p = 0.86). However, an increased risk was detectable only in the medium- to high-dose group. The wide confidence interval for the low-dose group indicates that there was simply too little data available for that group. The authors note that all included studies had a high risk of bias.

568 children with ADHD and 258 classmates were studied eight times over a 16-year period (mean age at the end of the study: 24.7 years). Three groups of self-reported treatment patterns were identified: consistently treated (9%, n = 53), irregularly treated (66%, n = 374), and barely treated (25%, n = 141). At the endpoint, the consistently treated group was 4.06 cm shorter than the barely treated group and 2.74 cm shorter than the irregularly treated group, while also weighing 7.47 kg more than the comparison group without ADHD. The greatest difference occurred during the pubertal growth spurt at ages 11.7 and 14.9 years.⁵⁶ The difference in height is related to the cumulative dose. The cumulative methylphenidate-equivalent dose was 2,153 mg for those who received barely any treatment, 60,567 mg for those who received irregular treatment, and 117,102 mg for those who received continuous treatment. Follow-up studies from the 1960s through the 1980s, involving doses of 34,350, 36,710, and 42,268 mg, found no association between dose, duration of treatment, and adult height. To compare with these cohorts, the authors formed a pooled group of treated cases with 66,003 mg, which represents a 92% increase compared to the 1960s, 80% compared to the 1970s, and 56% compared to the 1980s. This group was 2.0 cm shorter than the comparison group without ADHD (p < 0.01; d = 0.32), and the consistently treated subgroup of 33 people with ADHD was 4.0 cm shorter (p < 0.001; d = 0.65).⁵⁷

These findings also support the approach of aiming for the lowest dose that produces a good effect when titrating the dose, which is why a slow titration in small increments is preferred.
In addition, it is important to maintain a healthy diet.

Otherwise, unfortunately, we have no choice but to accept this slight reduction in growth as the price required for adequate ADHD treatment. Failing to provide necessary treatment would have far more serious Consequences. For more information, see Consequences of ADHD.

To put it another way: If a person with ADHD had the choice between being 2 to 4 cm shorter as an adult than he could have been, or having comorbid depression or an anxiety disorder and a significantly poorer education—which would he choose?

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

In people with ADHD, particularly those with ADHD-HI and ADHD-C (E 4)²⁴, slowed thinking and flattened affect (emotional blunting) may occur (“zombie syndrome”). In such cases, avoiding an overdose or reducing the stimulant dose while using combination therapy with non-stimulants can help. For more information, see Combination Therapy for ADHD

(ADxS Experience): A reduction in emotionality caused by ADHD medications is by no means something that must be accepted. ADHD medications are working properly when the person with ADHD feels more like themselves. Any form of perceiving oneself as a stranger or feeling less like oneself is an indication that the medication is not appropriate.

Stimulants suppress the limbic system. A small number of people with ADHD are particularly sensitive in this regard. In most cases, persistent trying out different medications and active ingredients helps.

In our experience, the consequences of an overdose are often emotional blunting. In such cases, it should be considered to restart the dosing regimen in the smallest possible increments. Some (albeit very few) people with ADHD require only a few milligrams of a stimulant over the course of the entire day.

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

• Atomoxetine or guanfacine instead of stimulants

  • Non-stimulants

    • do not inhibit the limbic system

    • Do not improve the drive system

• Reducing the dose of stimulants when taken in combination with non-stimulants (benefit: the motivation provided by stimulants is maintained, and emotional dysregulation is improved throughout the day)

  • Adults: Stimulants and atomoxetine

  • Children: Stimulants and guanfacine or stimulants and atomoxetine

2.16. Cycle-Related Fluctuations in Symptoms in Women¶

Dopamine homeostasis is influenced, among other factors, by COMT. COMT is the primary degradation mechanism in the PFC, whereas degradation in the striatum is primarily regulated by DAT.

Degradation is strongly influenced by the COMT gene variant. Estrogen inhibits COMT activity and, consequently, dopamine degradation in the PFC in a cycle-dependent manner. (E 2b)⁵⁸

In 16 healthy women, a single dose of 15 mg of D-amphetamine had a stronger effect during the follicular phase than during the mid-luteal phase. During the follicular phase, the potency of the effect correlated positively with estrogen levels. In the luteal phase, when progesterone levels were high, this correlation was not present. A comparison of the early and late follicular phases, however, revealed no difference; thus, estrogen levels alone do not explain the variation—the ratio to progesterone appears to be the decisive factor.⁵⁹

A significant proportion of women with ADHD report more severe symptoms during the premenstrual phase.

In a clinical case series, nine women with ADHD and premenstrual symptom exacerbation received an increased dose of stimulants during the premenstrual week. All nine reported improved ADHD and mood symptoms with few side effects. Premenstrual inattention, irritability, and drive became comparable to those in the other weeks. All participants decided to continue taking the increased premenstrual dose. This is an uncontrolled, open-label case series. A controlled study is currently in preparation.⁶⁰

In cases where stimulants are prescribed, treatment outcomes can be improved during this phase by temporarily increasing the stimulant dose. A case series from a specialized outpatient clinic in the Netherlands reports positive results from increasing the stimulant dose during the premenstrual week: In nine women, the dose was increased by 30 to 50% (average 41%); all reported improved ADHD and mood symptoms with minimal side effects, and all decided to continue the increased premenstrual dosage.(E 4)⁶⁰ Controlled studies on this topic are currently lacking.

A dosing guide that also helps track menstruation and its effects can be found at ADHD-Forum.ADxS.org (download section, free registration required).

2.17. Variable Effect¶

(ADxS experience): Sometimes, even after a prolonged period of stable response, people with ADHD report fluctuations in the drug’s effectiveness.

There are many possible causes. For more information, see Effects and Duration of ADHD Medications

Examples:

• other medications that have been added or discontinued

  • In particular, for ADHD medications:

    • Antacids

• Interactions with food

  • There are many options here. Keep a food diary

  • in particular

    • Grapefruit
      • Grapefruit irreversibly inhibits CYP3A4 in the small intestine and liver via furanocoumarins. The inhibition persists until the enzyme is regenerated. However, methylphenidate and amphetamines are not significantly metabolized by CYP3A4. Methylphenidate is hydrolyzed by carboxylesterase 1, while amphetamine is primarily excreted renally in an unchanged form or metabolized via CYP2D6. A grapefruit interaction via CYP3A4 is therefore not plausible for these active ingredients. The acid effect remains, however, because grapefruit juice—like other fruit acids—lowers urinary pH and thereby accelerates the excretion of amphetamine. In the case of guanfacine, however, the CYP3A4 interaction has been documented and is addressed in the prescribing information. There, a half dose is recommended when CYP3A4 inhibitors are used.⁶²
      • For guanfacine, a single grapefruit or 200 ml of juice is sufficient to cause a clinically significant increase in concentration, and this applies to all dosage forms as well as bitter oranges, limes, and pomelos—but not to navel and Valencia oranges. Because the inhibition is persistent, simply spacing out consumption is not sufficient; the fruit must be avoided throughout the entire duration of treatment.
    • Vitamin C
      • If necessary, delay taking the medication by one or more hours after taking the other medication
      • This effect applies to amphetamine-based medications, not methylphenidate. Prescribing information states that food generally does not interact significantly with amphetamine-based medications, but that stomach-acidifying substances, such as certain fruit juices, can reduce the oral absorption of amphetamines. It is recommended to avoid citrus fruits and citrus juices one hour before, at the time of, and one hour after taking the medication. Urine-acidifying foods such as cranberry juice, orange juice, or products containing ascorbic acid increase renal amphetamine excretion, while urine-alkalizing foods such as beets, dairy products, kale, and spinach slightly slow it down. Methylphenidate is not significantly affected by either process; less than 1% is excreted unchanged.⁶³

• Changes in stomach acid

  • MPH and AMP are sensitive to changes in stomach acid
    • Stomach acid suppressants such as antacids, proton pump inhibitors, and H2 blockers raise the stomach’s pH, in some cases above 6.0. If the pH rises above the pKa value of an active ingredient, the solubility of weak bases may decrease, leading to a loss of efficacy. Methylphenidate and amphetamine are both weak bases (amphetamine pKa 9.9). Proton pump inhibitors remain effective for more than 24 hours and do not reach their full effect until after about four days of repeated dosing; therefore, any change in effect following the start of such treatment occurs with a delay and is thus easily overlooked.⁶⁴
    • Since acid-suppressing medications are widely used and some are available over the counter, there is a significant potential for drug interactions. Among the approved acid-suppressing medications, proton pump inhibitors have the longest-lasting effect on stomach pH; therefore, the guideline recommends conducting interaction studies using a proton pump inhibitor.

• Measure the urine’s acidity, if necessary

• Defective drug batches

  • rare, but we’ve actually experienced it several times

    • Possible cause: storage at excessively high temperatures during transport, especially during heat waves

  • Did the effect change when you started a new package?

• Medications stored in excessively hot conditions

• Adaptive responses

  • rare after prolonged use with consistent results

  • For more information, see Medications: Development of Tolerance

 

Taking the medication with a meal affects not only appetite but also the release profile. In 25 healthy subjects, Ritalin LA showed the expected biphasic profile when taken on an empty stomach, whereas Medikinet retard exhibited a steady absorption with only one peak. After a meal, both formulations exhibited a biphasic profile. Total absorption was comparable between the two (AUC 99.7%), while the peak concentration was lower for Medikinet retard (Cmax 85.9%). A change in the dosing regimen also alters the course of action throughout the day.⁶⁵

In a randomized crossover study of healthy subjects, 36 mg of OROS methylphenidate and 20 mg of mixed sustained-release amphetamine salts were administered both on an empty stomach and 15 minutes after a high-fat breakfast. Methylphenidate exposure during the first 8 hours fluctuated less from day to day with varying eating habits than did amphetamine exposure. When using amphetamine preparations, the meal schedule on the day of administration should be kept as consistent as possible to prevent fluctuations in effect from being mistakenly attributed to the dose.⁶⁶ In the first four hours, the drug concentration for amphetamine salts after breakfast was only 44.5% of the fasting value, 57.5% after six hours, and 65.0% after eight hours. For methylphenidate, there was virtually no change over the same time periods (103.0%, 109.2%, and 110.0%). The difference between the formulations was highly significant in each case. In 32 of the 36 participants, the early amphetamine concentration after breakfast decreased by 20 to 80%. The time to peak concentration was delayed by about two hours for both formulations. Anyone taking an amphetamine formulation should keep their morning meal routine consistent throughout the titration phase. Otherwise, the drug concentration in the morning may fluctuate by up to half from day to day, which could be misinterpreted as an insufficient dose and lead to a dose increase, even though the actual problem is the varying time of administration relative to breakfast. Conversely, taking OROS methylphenidate with breakfast is not a problem. The study was conducted in healthy subjects, involved only a single dose, and plasma levels should not be equated with efficacy.

The interpretation of this study has been challenged by experts. Critics pointed out that the bioequivalence of amphetamine from the extended-release formulation with and without food is documented in the marketing authorization and that no data are available on how closely plasma levels correlate with clinical efficacy.⁶⁷

2.18. Symptoms of Overwork¶

(ADxS experience): After starting medication, many people with ADHD become highly active as they tackle their problems and tasks.

For some people with ADHD, this can lead to symptoms of stress overload and, in some cases, even to a breakdown.

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

Thanks to the medication, many people with ADHD are now better able to motivate themselves and therefore believe they can now accomplish everything they want, think they should, or feel they must. They want to make up for the guilt they feel about not having been as productive before as they should have been or would have liked to be.

But there’s a difference between being able to do “more” and being able to do “everything.”

While medication does allow you to get more done now, it doesn’t restore your full capacity. Although it often enables people to reach the same level of performance as those without the condition, this isn’t always the case, nor does it apply to everyone. Medication also doesn’t give you superpowers that would suddenly let you accomplish everything you’ve always wanted to do.

Subjectively, however, this isn’t noticeable. From the inside, you just feel that you’re doing better now. You can’t sense that this still isn’t the whole story, because you’ve never known anything else and don’t know what it would be like if you no longer had ADHD. This is also where a conflict with an inner, dysfunctional perfectionism might come to light.

Therefore, especially shortly after taking the dose, people with ADHD should be particularly careful not to overexert themselves.

When taking medication, you first have to get to know your new limits—what’s possible now and what you can reasonably expect of yourself.

Medications can shift these limits, but they cannot eliminate them.

2.19. Raynaud’s (Finger Circulation Disorder)¶

ADHD medications can trigger or worsen Raynaud’s phenomenon. Raynaud’s phenomenon has been observed less frequently with atomoxetine than with stimulants. (E 3)⁶⁸ It has been reported that reducing the dose, discontinuing the medication, or switching to a different active ingredient can alleviate the symptoms. Very rare cases of severe complications have also been described.

(ADxS experience): We are aware of cases in which Raynaud’s was triggered by caffeine consumption while taking ADHD medication and resolved after caffeine was eliminated from the diet.

A review of the literature through August 2020 identified 9 relevant studies involving 70 people with ADHD, six of which focused on children or adolescents. The triggering substances identified were methylphenidate (5 studies), dexamfetamine (4), atomoxetine (2), and lisdexamfetamine (2) were identified as triggering substances. In addition to new-onset or worsened Raynaud’s attacks, sensitivity to cold, acrocyanosis, and pernio were described; in isolated cases, irreversible circulatory damage occurred, including self-amputation of finger joints. In half of the studies, the symptoms completely resolved after discontinuation of the medication. Other recommended approaches include dose reduction and switching medications; discontinuation is not necessarily the first course of action.⁶⁹

A systematic review through June 2024 identified 61 cases from 15 case reports, 5 case series, one retrospective case-control study, and one cohort study. There are no randomized trials. The drugs involved were methylphenidate, (dex)amphetamine, and, less commonly, atomoxetine. Most cases were mild and resolved within weeks after discontinuation, dose reduction, or a change in medication. A few cases with concomitant systemic disease led to ulceration, gangrene, and amputation. Because of these rare severe outcomes, routine monitoring for signs of Raynaud’s syndrome is recommended, especially at the start of treatment and with each dose increase.⁷⁰

Raynaud’s syndrome affects approximately 3 to 5% of the general population, depending on the climate. Therefore, its occurrence while taking ADHD medication is not automatically caused by the medication. Cold, stress, and medications are considered equally likely triggers for episodes.⁷¹ This could support the observation that an additional factor, such as caffeine, can be the deciding factor.

2.20. Irritability¶

The classes of active ingredients differ significantly in terms of the risk of irritability. In a meta-analysis of 37 studies, methylphenidate preparations reduced the risk of irritability compared with placebo (RR 0.89; 95% CI 0.82 to 0.96; k = 32), whereas amphetamine preparations increased it (RR 2.90; 95% CI 1.26 to 6.71; k = 5). The difference between the classes was significant. Anyone who experiences irritability while taking an amphetamine-based medication should consider switching to a different active ingredient.