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Effect and duration of action of ADHD medication


Effect and duration of action of ADHD medication

Only theoretically is the drug concentration proportional to the administered drug dose. In general pharmacological practice, there are high inter-individual differences by a factor of 8 to 30.1
Data from approval studies are of little help in determining the appropriate individual dose of a drug. These studies only examine the dose-effect relationship, not the drug concentration. Dosages for a drug given in specialist information, package inserts and textbooks refer to the average of the entire population of people with ADHD. This information is helpful as a guide, but should not be taken as a measure for the individual person with ADHD, who will vary in many ways:1

  • Gender
  • Size
  • Weight
  • Age
  • Compliance
  • Liver and kidney diseases
  • Comorbidities
  • pharmacokinetic drug interactions
  • Nutritional interactions (xenobiotic interactions)
  • Interactions through drugs
  • Metabilization gene variants.

Pharmacology covers the areas of pharmacodynamics (what an active ingredient does to the body) and pharmacokinetics (what the body does to the active ingredient).
The most important processes of pharmacokinetics are:23

  • Absorption (absorption)
  • Bioavailability
  • Distribution
  • Degradation (metabolism)
  • Excretion (excretion)

The release (liberation) of the active pharmaceutical ingredient is also relevant.

There is little generally applicable data on ADHD medication and its use and effects. While the manufacturer’s information on methylphenidate is reasonably realistic and deviations tend to be of an individual nature, the stated duration of action of Vyvanse is only achieved by a small group of people with ADHD.
In the case of ADHD, however, medication must always be individually tested and adjusted.
This article is dedicated to the factors that individually influence the response and duration of action of a single dose of ADHD medication.

Although blood level values are an important factor for measuring a drug dosage, they cannot measure factors such as blood-brain barrier permeability or receptor activity, so that this value cannot represent an objective criterion for a drug effect.

1. Duration of action of active ingredients and preparations for ADHD

1.1. Manufacturer’s information on the duration of action

The data for drugs available in the USA are from Rodden.4 The figures in the table are mean values unless otherwise stated.
The actual duration of action varies from person to person and depends heavily on the metabolism of the person with ADHD. Approximately 5% of people with ADHD are super fast metabolizers. Due to increased CES1 activity, the effect of immediate release MPH may only last for 1 hour5 or that of a half-day sustained release preparation may only last 1.5 or 2 hours instead of 5 to 6 hours. Similarly, although apparently less frequently, there are people with ADHD for whom a preparation has a much longer effect.
For the metabolism of methylphenidate and amphetamine drugs, see below. There you will also find more detailed information on pharmacokinetics, e.g. speed of action and distribution of the effect curve.

In the case of half-day Retard preparations in particular, a second dose of medication is generally required at lunchtime to cover the day, which is usually at a lower dose.
Half-day treatment is not appropriate. ADHD is not a morning disorder.

Methylphenidate preparations Active ingredient Typical duration of action in hours (according to manufacturer) Sustained release Country
Ritalin, Methylphenidate HEXAL, Methylpheni TAD immediate release, Medikinet immediate release, Generic methylphenidate Methylphenidate 2.5 - 3.5; 3 - 45; 3.06 hours (2.5 to 3.875 / 1st quartile to 3rd quartile)6 immediate release EU, USA
Methylin Liquid Methylphenidate 3 - 4 immediate release USA
Ritalin SR Methylphenidate 5-8 hours duration of action theoretically, 3-5 hours duration of action practically7, 84 continuous release7 EU
Focalin Dexmethylphenidate 4 - 6 immediate release CH, USA
Equasym Retard/XL Methylphenidate 6 - 88 / 8 9 Two-phase retardation EU
Medikinet adult (adults), Medikinet retard (children) (bioequivalent)10 Methylphenidate 6 - 88; 4.65 hours (4.0 to 5.0 / 1st quartile to 3rd quartile)11 Two-phase retardation EU
Ritalin LA, Ritalin Adult (bioequivalent) Methylphenidate 6 - 87 / 8 8; 4.6 hours (3.38 to 6.0 / 1st quartile to 3rd quartile)12 EU; USA only Ritalin LA
Methysym Methylphenidate up to 8 sustained release since 01.06.2021 in D
Metadate CD Methylphenidate 8 - 10 sustained release USA
Daytrana Methylphenidate 10 (when worn for 9 hours) Patch USA
Concerta, methylphenidate hydrochloride-neuraxpharm (bioequivalent) Methylphenidate 8 - 128, 10 - 127, 124; 10.2 hours (7.5 to 11.5 / 1st quartile to 3rd quartile)13 sustained release D, CH, USA
Focalin XR Dexmethylphenidate 8 - 12 sustained release CH, USA
Methylphenidate hydrochloride Ratiopharm14 Methylphenidate 12 sustained release EU
Methylphenidate hydrochloride Hexal15 Methylphenidate 12 sustained release EU
Kinecteen Methylphenidate 12 sustained release EU
Aptensio XR Methylphenidate 12 sustained release USA
Cotempla XR-ODT Methylphenidate 12 - 13 sustained release USA
Quillichew ER Methylphenidate 12 - 13 sustained release USA
Quillivant XR Methylphenidate 12 - 13 sustained release USA
Jornay PM Methylphenidate 12 - 14 sustained release USA
Amphetamine preparations Active ingredient Duration of action in hours (according to manufacturer) Sustained release Country
Dexedrine Dextroamphetamine 3 - 4 immediate release USA
ProCentra Dextroamphetamine 3 - 6 immediate release USA
Zenzedi Dextroamphetamine 3 - 6 immediate release USA
Desoxyn Methamphetamine 4 - 6 immediate release USA
Adderall Mixed amphetamine salts 4 - 6 immediate release USA
Evekeo amphetamine sulfate 4 - 6 immediate release USA
Attentin Dextroamphetamine 5 - 6 immediate release Germany, since end of 2011
Dexamine Dextroamphetamine 5 - 6 immediate release Switzerland, as extemporaneous preparation
Dexedrine ER Dextroamphetamine 5 - 10 sustained release USA
Adderall XR amphetamine mixed salts 10 - 12 sustained release USA
Adzenys ER Amphetamine 10 - 12 sustained release USA
Adzenys XR-ODT Amphetamine 10 - 12 sustained release USA
Vyvanse (children), Vyvanse adult (adults) Lisdexamfetamine 13 (children); 14 (adults) (in practice sometimes significantly lower values); 8.53 hours (6.0 to 10.0 / 1st quartile to 3rd quartile)16 Prodrug EU, USA
Dyanavel XR Amphetamine 13 sustained release USA
Mydayis Mixed amphetamine salts 14 - 16 sustained release USA
Non-stimulants Active ingredient Duration of action in hours (according to manufacturer) Sustained release Country
Strattera, Agakalin Atomoxetine all day / individual 8 to 21 hours17 immediate release USA
Intuniv Guanfacine all day; peak concentration after approx. 5 hours; elimination half-life approx. 18 hours sustained release USA
The course of the effect curves differs considerably depending on the preparation.18

1.2. Experience of the duration of action

1.2.1. Experience of the duration of action of a single dose of Vyvanse

Three online surveys among people with ADHD in German-speaking countries (80 participants), in an english-language subreddit on Vyvanse (467 participants) and in the ADxS medication duration survey (223 participants for Vyvanse, as of December 19, 2023) on how long a single dose of Vyvanse worked for them:

Duration of action Single dose Vyvanse Participants (out of 770)
5 hours and less 36.2 %
6 to 7 hours 25.2 %
8 to 9 hours 17.3 %
10 to 11 hours 12.5 %
12 hours and more 8.8 %

The distribution towards a much shorter duration of action than the 10 to 12 hours specified by the manufacturer is very clear. In over a third of cases, a single dose is only effective for up to 5 hours, and in just under two thirds for 7 hours or less. Only 21.3% of the people with ADHD achieve the duration of action of 10 to 12 hours or longer specified by the manufacturer. This is also consistent with the numerous reports of Vyvanse users in the forum who require more than a single dose per day. Some users require 3 doses (with the last dose usually being lower than the previous ones).

Among the participants in the ADxS drug duration of action survey the single dose of 43.3 mg for the n = 104 users with a duration of action of up to 7 hours was slightly higher than the single dose of 40.7 mg for the n = 119 users with a duration of action of 8 hours or more. The values barely differed by age in adults.
The dose level also did not differ significantly according to weight (up to 70 kg 40.4 mg, 71 to 90 kg 42.1 mg, over 90 kg 44.4 mg).

Interestingly, there were also several people with ADHD in whom not only Vyvanse/Vyvanse but also methylphenidate had a much shorter effect. As Vyvanse/Vyvanse and MPH are metabolized by different enzymes, this points to mechanisms other than overactive enzyme gene variants, as also explained in this article.

1.2.2. Empirical values of the duration of action of a single dose of MPH immediate release

Among the participants in the ADxS drug duration of action survey (as of 12/19/2013), the duration of action of a single dose of immediate release MPH was on average 2.95 hours (n = 20) for single doses of up to 12.5 mg (average: 9 mg) and 3.43 hours (n = 8) for single doses of 15 to 20 mg (average: 18.75 mg). The overall average was 3.18 hours and 14.8 mg.

1.2.3. Empirical values for the duration of action of a single dose of MPH Half-Day Retard

Among the participants in the ADxS drug duration of action survey the duration of action of a single dose of half-day sustained-release MPHs (Medikinet retard, Medikinet adult, Ritalin adult, Ritalin LA) was 4.61 hours (n = 163). The average single dose was 21.7 mg.

Duration of action Single dose MPH Half-day retard Participants (out of 163)
up to 1 hour 0.6 %
> 1 to 2 hours 5.5 %
> 2 to 3 hours 7.4 %
> 3 to 4 hours 23.9 %
> 4 to 5 hours 43.6 %
6 to 7 hours 14.1 %
8 hours and more 4.9 %

60.1% of the people with ADHD reported a duration of action of a single dose of 4 to 5 hours, 81.6% a duration of action of 3.5 to 7 hours. The results are therefore significantly more consistent and closer to the manufacturer’s specifications than with Vyvanse.
Medikinet retard and Medikinet adult (which are bioidentical) had an average duration of action of 4.58 hours (n = 132) at an average of 20.64 mg, Ritalin adult and Ritalin LA (which are also bioidentical) had an average duration of action of 4.74 hours (n = 31) at an average of 26.3 mg.
In the following, we explain the influencing factors that can individually affect the duration of the medication effect (especially with ADHD medication).

2. Dose level

Within a person, higher doses of amphetamine have a longer effect.5
The duration of action of methylphenidate preparations, on the other hand, is dose-independent.

3. Stomach passage speed

In addition to the speed of passage through the small intestine, gastric function also plays a role. Gastric motility and emptying rate influence how quickly a substance reaches the small intestine. In the case of paracetamol, for example, gastric emptying is the speed-determining step for the appearance of the substance in the blood plasma. Delayed or even accelerated gastric emptying can therefore fundamentally influence the kinetics of orally absorbed drugs, so that, for example, the necessary drug levels are not reached or only reached with a delay19

With age, the surface area of the small intestine and the speed of gastric emptying decrease. At the same time, the gastric pH increases. Nevertheless, these changes usually have no effect on drug adsorption.2021

Anticholinergics can slow down the movement of drugs through the stomach into the small intestine.2021

4. Small intestine

4.1. Small intestine length

In children, the small intestine is shortened so that absorption through the small intestine is reduced.2223

4.2. Small intestine passage speed

“With ingested medicines, the passage time through the stomach and small intestine represents a natural upper limit for the release of the active ingredient: Once the tablet has left the small intestine, nothing more can be absorbed, so release is limited to a period of around 8-10 hours.”24

This time can vary from individual to individual, as can the speed of intestinal transit. This is probably the reason why some super fast metabolizers report a duration of action of 1 to 2 hours for Medikinet and 3 hours for Vyvanse. They also report that they have to eat much more often during the day than others.
For a longer duration of action (not only on average) than the intestinal passage, mechanisms are therefore required that go beyond absorption from the small intestine.

5. Acid balance

the pH value can be influenced depending on the duration of acid exposure:25

  • Solubility of active ingredients
  • Stability of active ingredients

The usual pH value in the stomach is:25

  • fasting pH 1-2
  • increasing with food intake
    • up to pH 5-6 depending on species and quantity
    • then decrease to initial value

The pH value ranges from 0 to 14. A low pH value (<7) is acidic, a high value is alkaline.
Excess acids are absorbed by buffer systems and excreted via the respiratory system and kidneys

Foods rich in animal protein form acids as metabolic end products:26
E.g. meat, fish, cheese, eggs

Plant foods are predominantly alkaline.
E.g. fruit, vegetables, leafy salads, wholegrain products

Fats and carbohydrates do not normally affect the acid-base balance.

5.1. Acid balance and amphetamine medication

Amphetamine drugs:27

  • shortened duration of action due to high urine acidity (low pH value), e.g. due to
    • Ascorbic acid (vitamin C)
    • Thiazide diuretics
    • Animal protein-rich diet
    • Diabetes
    • respiratory acidosis
    • Treatment option: Mineral water with bicarbonate28
  • prolonged duration of action due to low (alkalized) urine acidity (high pH value), e.g. due to
    • Sodium hydrogen carbonate
    • A diet with a high proportion of fruit, vegetables, whole grains
    • Urinary tract infections
    • Vomiting
    • Change of diet, e.g. from a meat-based to a vegetarian diet29
    • massive intake of agents to neutralize stomach acid29

Urine pH has been shown to be a good PRAL marker. An alkaline urine pH value correlates with a diet with a negative PRAL value, while urine pH values below 6.0 correlate with an acidifying diet.
A distinction must be made between plant and animal proteins. After 7 days of a vegetarian diet, the pH urine value increases and the PRAL value decreases, as does 2 or 3 days of a vegetarian diet per week.30 A vegetarian diet thus correlates with a prolonged amphetamine drug effect.
Foods with a high oxalate content can increase acid formation.28
One study gives the following calculation method:31 PRAL (mEq/d) = 0.49 x protein (g/d) + 0.037 x phosphorus (mg/d) - 0.021 x potassium (mg/d) - 0.026 x magnesium (mg/d) - 0.013 x calcium (mg/d).

In other words, foods with a strongly negative PRAL value cause alkaline (less acidic) urine and thus promote a prolonged effect of amphetamine drugs. Foods with a high PRAL value cause acidic urine and thus promote a shortened effect of amphetamine drugs. According to this model, hard cheese is suitable for shortening the effects of amphetamine drugs, while raisins could prolong them.

Food (unsweetened, untreated) PRAL value per 100 g (higher: urine more acidic)
Raisins -21.032
Dried figs -18.1
Spinach -14.032
Parsley -12.0
Spinach raw -11.828
Dark chocolate -11.5
Potatoes -8.528 -4.031 stored -4.032
Kale -8.028
Fennel -7.9
Rocket -7,5
Beans unclear: -7.428 or 1.128
Basil -7.3
Bananas unclear: -6.928 5.532
Lamb’s lettuce -6.6
Blackcurrant -6.532
Carrots, raw -5.728 young -4.932
Kiwi -5.628 -4.132
Chives -5.3
Celery -5.028 -5.232
Apricots -4.832
Carrot juice -4.8
Zucchini -4.632
Lettuce -4.328 -2.532
Mushrooms -4.228 -1.432
Tomatoes -4.128 -3.132
Radish -3.732
Orange juice -3.728 -2.932
Oranges -3.628 -2.732
Broccoli -3.628 -1.232
Fruit tea -3.528
Grapefruit -3.228 -1.032
Green beans -3.132
Cherries -3.128 3.632
Mango -3.028
Soya -2.928
Pears -2.932
Tomato juice -2.832
Hazelnuts -2.832
Pineapple -2.732
Strawberries -2.528 -2.232
Cucumbers -2.428 -0.832
Peaches -2.432
Lemons -2.328 Lemon juice -2.532
Red wine -2.228 -2.43132
Asparagus -2.228
Normal spaghetti -2.228 6.532 8.031
Apple juice, unsweetened -2.232
Chicory -2.032
Watermelon -2.028 -1.932
Onions -2.028 -1.532
Eggplant -2.028 -3.432
Apples -1.928 -2.232
Hazelnuts -1.928
Leek -1.832
Apollinaris mineral water -1.832
Iceberg lettuce -1.632
Jam -1.532
Coffee (drink) -1.432
Paprika, green -1.432
Cauliflower -1.328 -4.032
Milk chocolate -1.3
White wine -1.228 dry, -1.232
Mineral water -0.828
Margarine -0.828 -0.532
Soy milk -0.6
Drinking chocolate milk -0.628 -0.432
Asparagus -0.432
Honey -0.332
Tofu -0.3
Indian tea (drink) -0.332
Green tea -0.328
Draught beer -0.232
Cream -0.228
Volvic mineral water -0.132
Strong beer -0.132
White sugar -0.132
Olive oil 02832
Sunflower oil 02832
Butter 0.128 0.632
Milk (whole milk, skimmed milk) 0.228 0.731 1.1 32 Pasteurized UHT milk 0.732
Cola 0.228 0.432
Buttermilk 0.532
Milk ice 0,632
Full-bodied beer, light 0.932
Beans unclear: 1.128 or -7.428
Peas 1.232
Sour cream, fresh 1.232
Fruit yogurt 1.232
Natural yogurt 1,532
Rice, cooked 1.632
Wholemeal wheat bread 1.832
Pistachios 2.028
Almonds 2.028
Chicken egg white 2.128 1.132
Lenses 2.128 3.532
Rice, unpeeled 2.328
Milk chocolate 2.432
Chickpeas 2.628
Biscuit 3.031
Rye crispbread 3.332
Madeira cake 3.732
White bread 3,73132
Mixed wheat bread 3.832
Mixed rye bread 4.032
Rye bread 4.132
Rice, hulled, raw 4.531 4.632
Corn tortilla 4.828
Greek yogurt 5.328
Bananas unclear: 5.532 -6.928
Pork sausage 5.828
Rusk 5.9
Wholemeal rye flour 5.932
White bread 6.031
Cornflakes 6.032
Peanuts 6.228
Egg noodles 6.432
Vienna sausages / Frankfurter sausages 6.732
Walnuts 6,832
Haddock 6.832
Wheat flour, extract 6.932
Herring 7.032
Wheat tortilla 7.228
Wholemeal spaghetti 7.332
Spelt (green spelt, wholemeal) 7.5
Shrimps 7.6
Cottage cheese 7.928 8.732
Meat 8.033
Fish 8.033
Peanuts, unsalted 8.332
Wheat flour, wholemeal 8.432
Rump steak 8,832
Hen’s egg (whole egg) 9.028 8.232 4.031
Veal fillet 9.032
Turkey meat 9.932
Lunch meat 10.232
Liver sausage 10.632
Oat flakes (wholegrain) 10.732
Trout, brown, steamed 10.832
Quark 11.132
Salami 11,632
Cream cheese 12.428
Brown rice 12.532
Beef 12.528 lean 7.832
Prawns 13.228
Corned beef 13,232
Nuts 13.828
Salmon 14.028
Calf’s liver 14.2
Pork 14.728 lean 7.932
Camembert 15.033 14.632
Mussels 15.228
Crabs 15,5
Oil sardines 15.928
Chicken 16.528 8.732
Chicken egg yolk 18.128 23.432
Cod 19.828 Fillet 7.132
Gouda 20.028 18.632
Cheddar 20.031
Emmental 21.5
Parmesan 21.428 34.232
Cheddar, low-fat 26.432

5.2. Acid balance and methylphenidate

Medikinet retard, Medikinet adult:
If the gastric pH is above 5.5, Medikinet retard and Medikinet adult may cause dose dumping phenomena: The active ingredient is released too quickly and thus develops increased effects and side effects. This can be caused by, among other things

  • Proton pump inhibitors (e.g. pantoprazole, omeprazole)
  • Antacids
  • H2 antagonists (e.g. ranitidine, famotidine) (less likely)
  • age-related increase
  • atrophic gastritis

One person with ADHD reported a barely given effect of Medikinet from 20 to 60 mg. The additional consumption of dry rice cakes led to a temporary effect that was not predictable. The additional intake of antacids (gastric acid inhibitors) resulted in a reliable effect of MPH.

Ritalin adult:
Ritalin adult, on the other hand, releases MPH independently of pH. The prescribing information mentions a reduction in absorption as a probable interaction with antacids.34

5.3. Acid balance and memantine


  • Prolonged effect due to alkalized urine
    • In alkaline urine (high pH), the renal elimination rate of memantine may be reduced by a factor of 7 to 9.29

6. Mechanical effect of food intake

6.1. Food intake as a prerequisite for the retarding effect of Medikinet

For Medikinet adult and Medikinet sustained release, prior or simultaneous food intake is a prerequisite for sustained release. If there is no food intake, the MPH is released twice as quickly. The released MPH dose is therefore approximately doubled and the duration of action is approximately halved.

Other sustained release preparations use other sustained release mechanisms that do not rely on simultaneous food intake, such as

  • Ritalin adult
  • Ritalin LA
  • Methysym
  • Equasym Retard/XL
  • Methylphenidate hydrochloride-neuraxpharm
  • Kinecteen
  • Methylphenidate hydrochloride Ratiopharm
  • Methylphenidate hydrochloride Hexal

6.2. Food intake influences duration of action

Regardless of the need for the retarding effect of some MPH preparations and regardless of the influence on urine ph (in relation to amphetamine drugs) or gastric ph (in relation to MPH), certain forms of food intake influence the effect and duration of action of stimulants in a rather mechanical way.
Lisdexamfetamine (Vyvanse) has a maximum blood level that is delayed by one hour with high-fat meals (4.7 hours instead of 3.8 hours after ingestion).35 However, other parameters, such as the duration of action, do not change.

A person with ADHD reports:
“I have been taking Medikinet adult continuously for three months now and it took me a long time to find the right setting. In addition to the dose (20-10-0 for me), other food intake conditions have also been important for me. Too much food while taking it is problematic for me, as is too little. And I have a better effect if I eat something carbohydrate-heavy when I take it.”

6.3. Food intake delays maximum AMP levels

Lisdexamfetamine (Vyvanse) has a maximum blood level that is delayed by one hour with high-fat meals (4.7 hours instead of 3.8 hours after ingestion).35 However, other parameters, such as the duration of action, do not change.

7. Physical activity / sports

Individual persons with ADHD report that intensive sports can shorten the duration of effect of stimulants by up to 40 %.36

8. Nicotine / Smoking

Several people with ADHD reported a change in the stimulant effect due to smoking.
Was reported (in each individual case as a special feature of stimulant use):

  • A person with ADHD reports:
    • increased nicotine craving 4h after taking Vyvanse
    • somewhat listless and tired after the first cigarette of the day
    • A day without a cigarette and only with Vyvanse goes ok except for the restlessness caused by nicotine withdrawal, but motivation and effect is there until the afternoon/evening
    • Switching to nicotine “chewing gum” instead of smoking/vaping resulted in a significantly higher level of balance and no more tiredness at lunchtime
  • One person with ADHD described a drug-dependent effect:
    • Vyvanse + nicotine: weakened effect, negative feelings
    • MPH + nicotine enhanced effect, kick (at the same time greater fall/rebound)
  • An occasional smoker:
    • just one or two cigarettes can cause Vyvanse and MPH to stop working properly
    • it then takes a few days for them to work properly again
    • I usually sleep well with Vyvanse now. When I have smoked, I sleep worse.
    • the difference in the effect of Vyvanse when I haven’t smoked for a while is enormous
  • A person with ADHD:
    • When I feel overwhelmed, I feel like smoking as a means of compensation or as a means of driving myself on.
    • It works at first, but after a few days it changes. I become less energetic and my mood deteriorates.
    • It doesn’t do me any good in the long term and is not compatible with the medication. The effect gets worse and I end up feeling worse
  • A steamer:
    • After taking MPH, vaping causes me tiredness and headaches
    • Nicotine enhances the MPH effect

9. Alcohol

Alcohol can increase amphetamine levels.37

10. Cycle

The female cycle influences dopamine levels. Oestrogen influences COMT, which breaks down dopamine in the PFC.
People with ADHD with certain COMT gene variants are particularly susceptible.
The required stimulant dose may vary depending on the cycle phase.
When taking stimulants, women should always keep a corresponding observation sheet to record cycle fluctuations and the effect of the medication. This is the only way to recognize whether the dose of medication needs to be changed in certain phases of the cycle. The dosing aid table, which is available in the Download area of the free of charge, facilitates the recording of medication intake, symptom development and cycle

11. Liver function

11.1. Age

Hepatic metabolization can slow down with age, partly due to poorer blood flow to the liver.238

Reduced CYP metabolism in old age is known for the following psychotropic drugs:2021

  • Alprazolam (men only)
  • Chlordiazepoxide
  • Desipramine (men only)
  • Diazepam
  • Imipramine
  • Nortriptyline
  • Trazodone
  • Triazolam (men only)

Degradation is reduced by 30 to 40 % on average, but varies so much from individual to individual that, as with the dosage, each individual case must be considered.

11.2. Diseases

Diseases of the liver can (severely) restrict liver functionality. Reduced protein synthesis in the liver automatically reduces plasma protein binding, which weakens the breakdown of substances by the enzymes in the liver.
If bile production in the liver is restricted, the excretion of large molecules is reduced and the enterohepatic circulation is impaired.
Heart failure reduces liver blood flow.

11.3. First-pass effect

“The intestinal veins are led to the heart via the liver, so that a substance absorbed in the intestine undergoes a liver passage before it can be further distributed via the great vena cava and the heart. If a substance only survives this first passage through the liver to a small extent, this is referred to as a high first-pass effect. The result of this effect is that, despite good absorption, only small amounts of the active ingredient are available systemically. Due to the “first-pass effect”, substances can be quickly altered or inactivated in the liver (pre-systemic elimination).”24

The first-pass effect is also subject to individual differences.
From the age of 40, the first-pass effect decreases by around 1 % per year, so that blood serum levels are increased in older people at the same dose.2021

11.4. Smoking

Smoking can affect metabolization by liver enzymes.

12. Renal blood flow

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.5
Another Consequences of this is that amphetamine blood levels change more slowly and are less prone to rebound than with methylphenidate,5

The glomerular filtration rate decreases on average by 8 ml/min/1.73 m²/decade (0.1 ml/s/m²/decade) from the age of 40. There are considerable individual differences.
Serum creatinine levels often remain within the normal range in old age despite a decrease in glomerular filtration rate, due to decreased muscle mass and reduced physical activity, so that serum creatinine levels in old age no longer reflect normal renal function. The breakdown of psychotropic drugs excreted by the kidneys is reduced in old age:2021

  • Brexpiprazole
  • Lurasidone
  • Paliperidone
  • Risperidone

13. Receptor/transporter sensitivity

Active pharmaceutical ingredients can bind to receptors, transporters, ion channels or enzymes and trigger effects there. The sensitivity of these receptor structures influences efficacy.
The sensitivity of the receiver structures can be influenced by variants of the genes coding for them.


  • A combination of six polymorphisms in genes coding for the 5-HT2A, 5-HT2C, histamine H2 receptors and SERT predicted response to clozapine in schizophrenia with almost 80% probability39
  • Lack of effect of tamoxifen in breast cancer in the absence of estrogen receptor expression40
  • An influence of the DAT gene on the MPH response is discussed for ADHD medications
  • If the blood D3 level is sufficient, less sensitive receptors can nevertheless mediate a D3 deficiency

In addition, variants of genes that are responsible for the breakdown of neurotransmitters (here: COMT in relation to dopamine) can influence the effect of medication.
In carriers of the COMT Val-158-Met gene polymorphism, amphetamine increased the efficiency of the PFC in subjects with presumably low levels of dopamine in the PFC. In contrast, in carriers of the COMT Met-158-Met polymorphism, amphetamine had no effect on cortical efficiency at low to moderate working memory load and caused a deterioration at high working memory load. Individuals with the Met-158-Met polymorphism appear to be at increased risk for an adverse response to amphetamine.41

14. Blood-brain barrier

A basic introduction to the blood-brain barrier in German can be found at

Transport: Transport proteins are involved in the absorption into and excretion from the organism as well as the transfer of drugs from the blood into the tissue.

14.1. Competition for the use of transportation

Competition between different substances with regard to transport through the brain barrier can influence the effect of medication.
Memantine, opiates (oxycodone, codeine), tramadol, cocaine and nicotine are transported through the blood-brain barrier by the same transporter family (organic cation transporter, OCT). Since OCT are subject to a saturation limit, this common transport mechanism could influence the memantine level in the brain and thus its effect.43

14.2. Blocking function of the blood-brain barrier

The P-glycoprotein encoded by the MDR1 gene is a component of the blood-brain barrier. It is one of many proteins expressed in the endothelial cells of the brain’s blood capillaries
Transporters that control the transfer of drugs into the brain. Gene variants of the MDR-1 gene influence the effectiveness of the P-glycoprotein.
If the function or expression of P-glycoprotein is reduced, the blood-brain barrier is weakened and drugs can increasingly enter the brain, which can increase their effect even though the blood plasma level is unchanged.40

15. Metabolizing enzymes

Many drugs are broken down by enzymes, primarily in the liver.
Some active ingredients are only formed through a prior enzymatic conversion of drugs.
If several drugs are taken that are broken down by the same enzyme, they compete for the enzyme that breaks them down, which prolongs the duration of action of these drugs and increases side effects.
In addition, there are active ingredients that inhibit (inhibitors) or promote (inducers) an enzyme, which influences their effectiveness in terms of drug degradation accordingly.

Metabolic enzymes catalyze two types of biotransformation reactions in humans40

  • Phase 1 reactions:
    • Functionalization reactions
      • Oxidation, reduction, hydrolysis and hydration
    • Mode of action:
      • Introduction of functional group(s) (e.g. a hydroxyl group) into the non-polar molecule or
      • Exposure of corresponding functional groups
  • Phase 2 reactions
    • Conjugation reactions
      • Glucuronidation, sulfation, methylation, acetylation and conjugation with amino acids and glutathione
    • Mode of action:
      • Coupling of functional groups with very polar, negatively charged endogenous molecules (e.g. glucuronic acid)

In the following, we will only deal with those enzymes that concern ADHD medications. However, this already covers the most important enzymes.
CYP3A4 (guanfacine) breaks down 40 to 50 % of all drugs.
CYP2D6 (amphetamine drugs, atomoxetine) breaks down around 25 % of all drugs.

15.1. Metabolization cross effects

15.1.1. Competition, inhibition, induction, genetic regulation

The effect of drugs can be influenced by their degradation enzymes in various ways:

  • Competition from other substrates
    If several active ingredients bind to the same enzyme (substrates) and are degraded by it, they compete for the available amount of degradation enzymes when administered at the same time. This can delay degradation.
  • Inhibition
    Drugs can hinder (inhibit) the action of enzymes, even if they are broken down by completely different enzymes
  • Induction
    Medicines can enhance (induce) the effect of enzymes
  • genetic regulation
    Drug substances can also influence metabolization enzymes through genetic regulation. For example, bupropion is a rather weak inhibitor of CYP2D6 in vitro. In vivo, however, bupropion strongly inhibits CYP2D6 because it causes genetic downregulation of CYP2D6 mRNA.44

15.1.2. Risk: unintended cross-effects

The unintentional combination of competing, inhibiting or genetically regulating drugs is highly risky. This means that a new drug can influence the effect of a drug that has already been dosed - and vice versa, resulting in a risk of loss of efficacy and/or overdose.

15.1.3. Benefit: intended cross-effects

In contrast, a deliberate combination of competing, inhibiting or genetically regulating drugs is less risky. Drugs that are administered at the same time can be dosed with the appropriate caution or emphasis if the interactions are taken into account. It is also possible to deliberately use such combinations, for example to improve the effect of super-rapid metabolizers. A person with ADHD who metabolized a dose of Vyvanse in 5-6 hours, reported to us that a combination with 150 mg bupropion very helpfully prolonged the duration of effect of Vyvanse. Vyvanse is metabolized via CYP2D6; bupropion genetically inhibits CYP2D6.

15.2. ADHD active ingredients and their main degradation enzymes

ADHD active ingredients are broken down by different enzymes:

Methylphenidate: CES1
Amphetamine drugs: CYP2D6 (unclear whether this is really the main degradation pathway)
Atomoxetine: CYP2D6
Bupropion: CYP2B640 and something about CYP2A6
Guanfacine: CYP3A4
Clonidine: unknown
Buspirone: CYP3A4
Memantine: unknown, probably not through CYP29
Viloxazine: CYP2D6, UGT1A9, UGT2B15, possibly also by CYP1A2
Melatonin: CYP1A
Dasotraline: unknown
Agomelatine: CYP1A2 (90 %), CYP2C9/2C19 (10 %)

15.3. Pharmacogenetic diagnostics

The gene variants of metabolization enzymes can be determined by genetic testing.45

Suitable laboratories can be found by searching for laboratory CES1 (for MPH) or laboratory CYP2D6 (amphetamine drugs, atomoxetine). In Germany, the laboratory service can be billed via health insurance companies if it has been prescribed by a doctor.

A laboratory diagnosis of the 22 most important metabolization genes (including the POR gene, which is important for the CYP gene family) costs around €600 as of September 2023.
A sample diagnostic report can be found at CeGaT, a provider of genetic diagnostics in Tübingen.46 Genetic analyses of individual metabilization genes were around € 300 in September 2023.

15.4. Metabolization enzymes and their gene variants

See the articles and the people with ADHD medication:

CES1 Metabolizing enzyme

  • Methylphenidate (MPH)

CYP2D6 Metabolizing enzyme

  • Amphetamine medication (AMP)
  • Atomoxetine
  • Bupropion: CYP2B640 and slightly above CYP2A6, but strong CYP2D6 inhibitor

CYP3A4 Metabolizing enzyme

  • Guanfacine
  • Buspirone

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