Strength 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
• Interactions
  • pharmacokinetic ((other) drugs)
  • xenobiotic (nutrition)
  • Drugs (nicotine, alcohol, caffeine, narcotics)
• Genetics
  • 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 valid data on ADHD medication and its use and effects. While the manufacturer’s information on the duration of action of 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
  • 1.2. Experience of the duration of action
    • 1.2.1. Experience of the duration of action of a single dose of lisdexamfetamine
    • 1.2.2. Empirical values of the duration of action of a single dose of MPH immediate release
    • 1.2.3. Empirical values for the duration of action of a single dose of MPH Halbtagesretard
• 2. Single dose level
• 3. Stomach passage speed
• 4. Small intestine
  • 4.1. Small intestine length
  • 4.2. Small intestine passage speed
• 5. Acid balance
  • 5.1. Acid balance and amphetamine medication
  • 5.2. Acid balance and methylphenidate
  • 5.3. Acid balance and memantine
  • 5.4. Factors that increase alkalinity (high pH value)
  • 5.5. Factors that increase acidity (low pH value)
  • 5.6. Influence of food on acid-base balance (PRAL value)
• 6. Mechanical effect of food intake
  • 6.1. Food intake as a prerequisite for the retarding effect of Medikinet
  • 6.2. Food intake influences duration of action
  • 6.3. Food intake delays maximum AMP levels
  • 6.4. Absorption of active ingredients
• 7. Physical activity / sports
• 8. Nicotine / Smoking
• 9. Alcohol
• 10. Cycle
• 11. Liver function
  • 11.1. Age
  • 11.2. Diseases
  • 11.3. First-pass effect
  • 11.4. Smoking
• 12. Receptor sensitivity
• 13. Blood-brain barrier: Crossing into the brain
• 14. Metabolizing enzymes: Degradation
  • 14.1. Degradation increased / decreased depending on metabolization enzyme gene variant
    • 14.1.1. ADHD active ingredients and their main degradation enzymes
    • 14.1.2. Pharmacogenetic diagnostics
  • 14.2. Competition for mining and cross effects
    • 14.2.1. Competition
    • 14.2.2. Inhibition
    • 14.2.3. Induction
    • 14.2.4. Genetic regulation
• 15. Excretion: Renal blood flow
• 16. Gene variants and response

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 AL sustained release (bioequivalent)	Methylphenidate	8 - 128, 10 - 127, 1213; 10.2 hours (7.5 to 11.5 / 1st quartile to 3rd quartile)14	sustained release	D, CH, USA
Focalin XR	Dexmethylphenidate	8 - 12	sustained release	CH, USA
Methylphenidate hydrochloride Ratiopharm15	Methylphenidate	12	sustained release	EU
Methylphenidate hydrochloride Hexal16	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, Vyvanse, Tyvanse, generics	Lisdexamfetamine	13 (children); 14 (adults) (in practice sometimes significantly lower values); in 60 % of people with ADHD 7 hours and less (see below)	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 lisdexamfetamine¶

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

Duration of action Single dose LDX	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 (whereby the subsequent doses are generally 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 Halbtagesretard¶

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 %

This means that 67.7% of people with ADHD reported a duration of action of a single dose of 3 to 5 hours and 81.8% reported a duration of action of 3 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. Single dose level¶

Some people with ADHD report that higher single doses of amphetamine (especially lisdexamfetamine) have a longer effect.
However, the pharmacological tests of different lisdexamfetamine doses show that the Tmax is approximately the same.¹⁹ Tests with doses above the drug dosage showed that lysine cleavage is not saturated or slowed down by higher doses.²⁰
There are indications that the duration of action of lisdexamfetamine is only delayed by 1 to 1.5 hours compared to dextroamphetamine, but not prolonged.²¹ This casts serious doubt on the manufacturer’s claims of 12 to 14 hours per single dose and is consistent with the data presented above under Experience of the duration of action of a single dose of lisdexamfetamine Above from people with ADHD.

The duration of action of methylphenidate preparations is dose-independent.²²

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 delay²³

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 absorption.²⁴²⁵

Anticholinergics can slow down the movement of drugs through the stomach into the small intestine.²⁴²⁵

Gastric reduction or gastric bypass increased the dexamphetamine level during lisdexamfetamine intake. Tmax tended to be reduced. For ritalinic acid (from MPH) and atomoxetine there was no change in AUC0-24, atomoxetine showed a higher Cmax and a shorter Tmax. The number of subjects was very small.²⁶

4. Small intestine¶

4.1. Small intestine length¶

In children, the small intestine is shortened so that absorption through the small intestine is reduced.²⁷²⁸

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.”²⁹

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¶

pH is the abbreviation for potentia hydrogenii and is a logarithmic measure of the proton concentration (H+ or H3O+) in an aqueous solution. The more protons present in a solution, the lower the pH value.
The pH value ranges from 0 to 14 and indicates how alkaline something is. 7 is neutral. The higher the pH value (above 7), the more alkaline, the lower (below 7), the more acidic.
The usual pH value is:

• in the stomach³⁰
  • fasting pH 1.5 (1-2)
  • increasing with food intake
    • depending on species and quantity up to pH 5-6
    • then decrease to initial value
  • Premature babies have less acidic stomachs (pH > 4) and are susceptible to intestinal infections
  • Older people have lower stomach acidity (pH 6.6 in 80% of study participants) and are susceptible to bacterial infections in the stomach and intestines
  • Gastric acid (hydrochloric acid) is produced in parietal cells by the proton pump
    • This is why proton pump inhibitors reduce stomach acid (omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole)
  • Excess acids are absorbed by buffer systems and excreted via the respiratory system and kidneys
• in urine³¹
  • 6.0 Average value
  • 6.6 and more for 10 % of people
  • 7.2 and more at 1 %

Depending on the duration of acid exposure, the pH value can be influenced:³⁰

• Solubility of active ingredients
• Stability of active ingredients

Food influences the body pH value³²
Foods with a high proportion of animal protein (meat, fish, cheese, eggs) form acids as metabolic end products.
Plant foods (fruit, vegetables, leafy salads, wholemeal products) are predominantly alkaline.

5.1. Acid balance and amphetamine medication¶

Amphetamine drugs:
The amount of dextroamphetamine excreted unchanged and thus the remaining pharmacologically active dextroamphetamine depends on the pH value of the urine.^33343536

• shortened duration of action due to high urine acidity (low pH value), e.g. due to (see below for a detailed list)
  • Ascorbic acid (vitamin C)³⁶
    • doubtful. Ascorbic acid (vitamin C) taken orally left the pH value almost unchanged (+ 0.03)³⁷
  • Thiazide diuretics
  • Animal protein-rich diet
  • Diabetes
  • respiratory acidosis
• prolonged duration of action due to low (alkalized) urine acidity (high pH value)³⁸, e.g. through (see below for a detailed list)
  • Potassium citrate
  • Sodium hydrogen carbonate
  • Mineral water with bicarbonate³⁹
  • 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 diet⁴⁰
  • massive intake of agents to neutralize stomach acid⁴⁰

A urine pH value of 5.0 (acidic) can reduce the pharmacologically effective amount of d-AMP to a quarter of the value at a urine pH value of 8.0 (basic).⁴¹ AUC of amphetamine after 11 mg at urine pH:

• pH 5.0: 361 µg-h/L
• pH 6.5: 692 µg-h/L
• pH 8.0: 1325 µg-h/L

The highest available value of the pharmacological d-AMP quantity (Cmax) also correlates with the urine pH value, but to a much lesser extent, so that an acidic urine also correlates with a somewhat weaker, but above all with a significantly shorter effect³³
While 54.5% of orally ingested amphetamine was excreted unchanged at pH = 5.0 (acidic urine), this value was 2.9% at pH = 8 (alkaline urine). At uncontrolled pH, 14.5 % was excreted ³³⁴¹

One person with ADHD, in whom lisdexamfetamine had too short an effect (single dose of 50 mg worked for 4 hours), reported that drinking 1.5 liters of sparkling water with 1,800 mg nhc/L in the morning increased the effect so much that he now only needed 30 mg LDX, which then had the same strength and duration of effect as 50 mg before.

5.2. Acid balance and methylphenidate¶

In a laboratory study (= in vitro), up to 60 % of the methylphenidate was spontaneously hydrolyzed to (pharmacologically inactive) ritalinic acid, whereby this hydrolysis was pH-dependent.⁴²
In bacterial cultures in which MPH was not metabolized, the pH value after 24 hours was between 4.0 and 5.5; with high MPH hydrolysis, the pH value was between 7.5 and 8.0. E. coli BW25113 cultures with an average pH value of 7.8 hydrolyzed 70 % of the MPH; E. coli DSM1058 and E. coli DSM12250 with an average pH value of 7.6 hydrolyzed 50 % of the MPH. The correlation between MPH-hydrolyzing bacterial cultures and the pH value of the bacterial cultures after 24 hours was very high (r = 0.89, r2 = 0.79, p-value = 0.0006). In pure culture medium, less than 20 % of the MPH was hydrolyzed to ritalinic acid at a pH of 6.0 and 80 % at a pH of 8.0. Bacteria did not contribute to the metabolization of MPH.⁴²
In adults, only 22 % (+/- 8 %) of dMPH and 5 % (+/- 3 %) reach the systemic circulation; in children the figure is 31 % (+/- 16 %).⁴³ Schematically, 20 % of MPH is oxidized in the liver.⁴⁴ 80 % of the MPH ingested is excreted in the urine within 48 hours (80 % of which is excreted as ritalinic acid and 1 % unmetabolized), 3 % in the faeces. ⁴³

Source: Aresti-Sanz J, Schwalbe M, Pereira RR, Permentier H, El Aidy S (2021): Stability of Methylphenidate under Various pH Conditions in the Presence or Absence of Gut Microbiota. Pharmaceuticals (Basel). 2021 Jul 27;14(8):733. doi: 10.3390/ph14080733. PMID: 34451830; PMCID: PMC8398889 (unchanged)⁴² Published under the terms of the Creative Commons Attribution (CC BY).

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)
  • doubtful for omeprazole, which according to another source barely affects the pH value (+ 0.10)³⁷
  • contradictory: proton pump inhibitors in general reduced the pH value very strongly (- 1.5; n = 10)⁴⁵
• 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.⁴⁶

5.3. Acid balance and memantine¶

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 9.⁴⁰

5.4. Factors that increase alkalinity (high pH value)¶

Information in the following list that does not have its own source is taken from ⁴⁷. The website cited as the source is no longer accessible. The information was found to be incorrect in several cases and should therefore be checked individually.

Factors that favor alkaline urine (high pH value) are:

• Environmental factors:
  • Fluctuations during the day
    • There are different profiles:³¹
      • “normal” pH curve with three peaks at the morning and after-meal (postprandial) fluctuations, with a low night-time pH value
        • Meals cause a spontaneous increase in alkalinity (urine pH value reaches at least 6.8 1 to 2 hours after meals)
      • Sustained low pH value without real fluctuations
      • A single afternoon peak with almost complete absence of a morning fluctuation
      • Reversal of the “normal” curve with low daytime level and high nocturnal plateau
  • Body surface area (unclear whether high or low)⁴⁸
  • Cadmium exposure
  • Heparin
  • Air pressure reduced; hypobaric ventilation⁴⁹
  • Mercury exposure
  • Female gender⁵⁰⁵¹
  • Age: stomach acid decreases, uric acid increases continuously (at least in people with kidney stones) with age⁵²⁵¹
  • Low income⁵³⁵⁴ (socio-economic status?)
  • Urine stored too warm after collection⁴⁷

• Diseases:
  • 21-hydroxylase deficiency
  • 3-hydroxydehydrogenase deficiency
  • Rejection of a kidney transplant
  • Acute post-streptococcal glomerulonephritis
  • Amyloidosis
  • Atrophic gastritis (age-related gastritis)
  • Calcium deficiency³¹
  • Carbonic anhydrase II deficiency
  • Chronic obstructive pulmonary disease
  • Vomiting
  • Acquired adrenal insufficiency
  • Familial methyl oxidase deficiency
  • Galactosemia
  • Gout
  • Glycogen storage disease
  • Urine dilution³¹
  • Increased urine flow³¹
  • Hereditary fructose intolerance
  • Hyperventilation³¹
  • Hypoxia⁵⁵
  • Lactosuria
  • Light chain multiple myeloma
  • Lowe syndrome
  • Lupus nephritis
  • Malabsorption
  • Medullary cystic disease
  • Metabolic alkalosis
  • Metachromatic leukodystrophy
  • Mineralocorticoid deficiency, transient in infancy
  • Wilson’s disease
  • Multiple myeloma
  • Kidney transplant
  • Renal vein thrombosis
  • Obstructive nephropathy
  • Pseudohypoaldosteronism
  • Renovascular hypertension
  • Salt-wasting nephritis
  • Sjögren’s syndrome
  • Tubulointerstitial disease
  • Tyrosinemia
  • Vitamin D deficiency
  • Vitamin D resistance
• Medication:
  • Acetazolamide: urine pH increase of + 2.0 with intravenous administration (very strong); + 0.39 (weak) with oral administration³⁷
    • Long-term treatment with acetazolamide is associated with an increased risk of urolithiasis⁵⁶
  • ADV7103 (citrate + bicarbonate): Increase in urine pH by + 1.27 (strong)³⁷
  • Ambroxol⁵⁷
  • Amiloride
  • Aminoglycosides
  • Ammonium chloride
  • Antibiotics⁵⁸
  • Ascorbic acid (vitamin C): Increase in urine pH value by + 0.03 (neutral)³⁷
  • Bicarbonates
    • Bicarbonate-rich mineral water⁵⁹
    • Bicarbonate loading (soda loading, sodium bicarbonate loading): + 1.44 (very strong)³⁷
      • Ingestion of sodium bicarbonate (= baking soda, double-carbonated sodium bicarbonate, baking powder, baking soda, Bullrich salt)
      • Dose 0.2 to 0.3 g/kg
      • 10 minutes before physical exertion
      • Long-term intake can trigger increased acid production in the stomach as a counter-reaction
      • Sodium bicarbonate in the stomach produces CO2 - risk of overstretching the stomach wall
  • Citrate: 0.61 (moderate)³⁷⁵⁹
    • Citrus juices
    • Orange juice: increase in urine pH by + 0.68 (moderate)³⁷
  • Citro-soda: increase in urine pH by + 1.56 (very strong)³⁷
    • Ingredients: Sodium bicarbonate 1.716 g, sodium citrate 0.613 g, citric acid 0.702 g, tartaric acid 0.858 g
  • Cholestyramine
  • Converting enzyme inhibitors
  • Corticotropin
  • Coumarin
  • Diazoxide
  • Exenatide: increase in urine pH by + 0.51 intravenously (moderate)³⁷ (diabetes medication)
  • Glycine: increase in urine pH by + 0.20 (neutral)³⁷
  • Indomethacin: increase in urine pH by + 1.0 (strong)³⁷
  • Potassium citrate³⁷
    • Recommendation of the American Urological Association (AUA) to increase the pH value of the urine
    • Food additive E332
    • Food supplement, freely available as a powder or in capsule form
      • Avoid in case of hyperkalemia - therefore always consult a doctor, population prevalence of hyperkalemia is 2 to 3 %
  • Potassium gluconate: increase in urine pH by + 0.46 (weak)³⁷
    • Potassium salt of gluconic acid, medication against potassium deficiency
  • Potassium hydrogen carbonate (potassium bicarbonate): Increase in urine pH value by + 0.89 (moderate)³⁷⁶⁰
  • Potassium sodium hydrogen carbonate (also potassium sodium hydrogen citrate)⁶¹
    • Drug to increase the urine pH value
  • L-tryptophan: increase in urine pH by + 0.20 (neutral)³⁷
  • Magnesium salts without chlorides⁶²
  • Metolazone
  • Monosodium glutamate⁶³
  • Sodium hydrogen carbonate (sodium bicarbonate, baking soda): Increase in urine pH by + 1.19 orally; + 1.12 intravenously; strong³⁷
  • Sodium L-ascorbate with sodium saccharin⁶⁴
  • Niacin
  • Omeprazole (proton pump inhibitor): Increase in urine pH by + 0.10 (neutral)³⁷
  • Spironolactone
  • Streptozocin
  • Topiramate: increase in urine pH by + 0.45 (weak)³⁷

• Foodstuffs
  • DASH diet: increase in urine pH value by + 0.5 (moderate)³⁷
    • A diet rich in fruit, vegetables, wholegrain products, low-fat dairy products, fish, poultry, nuts and seeds
  • Cucumbers: increase in urine pH by + 0.17 (neutral)³⁷
  • Potatoes: increase in urine pH by + 0.28 (weak)³⁷
  • Lime Juice: increase in urine pH by + 0.25 (neutral)³⁷
    • Unclear whether lime syrup made from lime juice, water and sugar or pure lime juice is meant
  • Melon juice: urine pH increase by + 0.36 (cantaloupe; weak)³⁷; higher than orange juice (moderate)⁶⁵
  • Milk: increase in urine pH by + 0.36 (weak)³⁷
  • Fruit + vegetable rich diet: urine pH increase by + 0.35 (weak)³⁷
  • Orange juice: increase in urine pH by + 0.68 (moderate)³⁷
  • French fries: Increase in urine pH value by + 0.25 (neutral)³⁷
  • Vegetarian diet
    • Lacto-ovo vegetarian diet: increase in urine pH by + 0.85 (moderate)³⁷
    • Mixed western vegetarian diet: urine pH increase of + 0.56 (moderate)³⁷
  • Vitamin C: increase in urine pH by + 0.03 (neutral)³⁷
  • See below (PRAL value table)

5.5. Factors that increase acidity (low pH value)¶

Information in the following list that does not have its own source is taken from ⁴⁷. The website cited as the source is no longer accessible. The information was found to be incorrect in several cases and should therefore be checked individually.

Factors that favor acidic urine (low pH value) are:

• Environmental factors:
  • Bed rest
  • Aldosterone
  • Lead exposure⁶⁶
  • Cadmium⁶⁷
  • Toluene
  • Vanadium
  • Age: stomach acid decreases, uric acid increases continuously (at least in people with kidney stones) with age ⁵²⁵¹
  • Male gender⁵⁰
  • High income⁵³⁵⁴ (socio-economic status?)
  • Physical strain in a hot environment
    • Working as a rice field worker in Thailand⁶⁸
    • Work as a sugar cane harvester in El Salvador⁶⁹ or Nicaragua⁷⁰
    • Stay in the desert⁷¹
  • Sleep deprivation: - 0.0 (neutral)³⁷

• Diseases:
  • Breathing problems
    • Obstruction of the airways or prevention of gas exchange in the lungs, e.g. pulmonary edema (water in the lungs)
    • Pneumonia (lung inflammation)
    • Loss of functional lung tissue, e.g. in tuberculosis
    • Insufficient respiratory drive, for example in the case of sleeping pill intoxication
    • Paralysis of the respiratory muscles, e.g. in polio
    • Malfunction of the respiratory reflexes
  • Adrenal cortical hyperfunction
  • Adrenal cortical hypofunction
  • Amyloidosis
  • Autoimmune thyroiditis
  • Balkan nephropathy
  • Chronic active hepatitis
  • Chronic kidney disease
  • Chronic renal insufficiency
  • Chronic pyelonephritis
  • Cystinosis
  • Diabetes mellitus
  • Distal renal tubular acidosis
  • Gastrinoma
    • Zollinger-Ellison syndrome, rare pancreatic dry tumor
    • Increases stomach acid
  • Fibrosing alveolitis
  • Urinary tract obstruction (blockage in the urinary system that prevents the flow of urine from the kidneys to the urethra)
  • Helicobacter pylori infection
    • Increases stomach acid
  • Hepatolenticular degeneration
  • Hereditary fructose intolerance
  • Hypercalciuria, idiopathic
  • Hypergammaglobulinemia
  • Hyperparathyroidism
    • Increased stomach acid in 30 % of people with ADHD
  • Cryoglobulinemia
  • Fabry disease
  • Wilson’s disease
  • Marfan syndrome
  • Medullary sponge kidney
  • Metabolic acidosis
  • Metabolic syndrome⁷²
  • Kidney transplant rejection
  • Kidney failure
  • Polyarteritis nodosa
  • Primary biliary cirrhosis
  • Proximal renal tubular acidosis (type II)
  • Sickle cell anemia
  • Sjögren’s syndrome
  • Tension-dependent distal renal tubular acidosis (type 1)
  • Vitamin D intoxication
• Medication:
  • Acetaminophen = Paracetamol
  • Acetazolamide
  • Amiloride
  • Ammonium chloride (ammonia): - 1.63 (very strong)³⁷³³
  • Amphotericin B
  • Acetylsalicylic acid (Aspirin)
    • Inhibits prostaglandins that protect the stomach lining from acidity
    • Protaglandin deficiency leads to inflammation of the mucous membrane, which damages the parietal cells that produce stomach acid (gastritis)
  • Carbenoxolone
  • Cefdinir
  • Cimetidine
  • Citric acid: urine pH reduction by - 0.06 (neutral)³⁷
  • Dapagliflocin: urine pH reduction by - 0.10 (neutral)³⁷ (diabetes drug)
  • Diclofenac
    • Inhibits prostaglandins that protect the stomach lining from acidity
    • Protaglandin deficiency leads to inflammation of the mucous membrane, which damages the parietal cells that produce stomach acid (gastritis) * Diflunisal
  • Etodolac
  • Fenoprofen
  • Flurbiprofen
  • Furosemide: reduction in urine pH by - 0.52 intravenously (not statistically significant)³⁷
  • Ibuprofen
    • Inhibits prostaglandins that protect the stomach lining from acidity
    • Protaglandin deficiency leads to inflammation of the mucous membrane, which damages the parietal cells that produce stomach acid (gastritis)
  • Ifosfamide
  • Indomethacin
  • Ketoprofen
  • Lithium
  • Mafenide
  • Methionine: reduction in urine pH by - 0.71 (moderate)³⁷
    • Essential amino acid
    • Without prescription
    • Only takes effect after a few days
  • Monomagnesium-L-aspartate hydrochloride⁶²
  • Mefenamic acid
  • Naproxen
  • Niacinamide
  • Ofloxacin
  • Orthophosphate
  • Parathyroid extract
  • Proton pump inhibitors: reduction in urine pH by - 1.5 (very strong, n = 10)⁴⁵
  • Ranitidine
  • Triamteren

• Foodstuffs
  • Apple cider vinegar: Urine pH reduction by - 0.21 (very weak)³⁷
  • Cranberry: reduction in urine pH value by - 0.16 (neutral)³⁷
  • Protein: high intake of animal protein in the diet⁷³
  • Fasting: reduction in urine pH value by - 1.2 (very strong)³⁷
  • Fructose: reduction in urine pH by - 0.26 (very weak)³⁷
  • Sodium chloride (table salt): urine pH reduction by - 0.47 (weak)³⁷’
  • Ketogenic diet: reduction in urine pH by - 0.55 (moderate)³⁷
  • Low-oxidant diet: reduction in urine pH by - 0.10 (neutral)³⁷
  • High-protein diet: reduction in urine pH by - 0.65 (moderate)³⁷
  • See below (PRAL value table)

5.6. Influence of food on acid-base balance (PRAL value)¶

Food can significantly influence the pH value of urine. The decisive factor here is not so much an acidic taste, but rather the PRAL value. The intake of foods with a negative PRAL value correlates with an alkaline pH urine value, an acid-forming diet correlates with alkaline pH urine values below 6.0. The urine pH value can be measured with simple pH test strips from the drugstore or the Internet. Fats and carbohydrates do not normally affect the acid-base balance.
In the case of proteins, 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.⁷⁴ A vegetarian diet thus correlates with a prolonged amphetamine drug effect.
Foods with a high oxalate content can increase acid formation.³⁹
One study gives the following calculation method:⁷⁵ 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 urine (less acidic, increase the pH value) and thus promote a prolonged effect of amphetamine drugs. Foods with a high PRAL value cause acidic urine (lower pH) 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.

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).⁷⁹ However, other parameters, such as the duration of action, do not change.

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).⁷⁹ However, other parameters, such as the duration of action, do not change.

6.4. Absorption of active ingredients¶

Some foods have the ability to absorb active ingredients and thus delay the onset and duration of action.
Example:

• Psyllium seeds⁸⁰⁸¹ , which is why it is recommended to take them half an hour to an hour apart from other medicines⁸²

7. Physical activity / sports¶

Individual persons with ADHD report that intensive sports can shorten the duration of effect of stimulants by up to 40 %.⁸³

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 4 h 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 have not smoked for a long time 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 it doesn’t go well with the medication. The effect gets worse and I end up feeling worse
• A steamer:
  • After taking MPH, vaping causes me fatigue and headaches
  • Nicotine enhances the MPH effect

9. Alcohol¶

Alcohol can increase amphetamine levels.⁸⁴

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 effects 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 adhs-forum.adxs.org 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.²⁸⁵

Reduced CYP metabolism in old age is known for the following psychotropic drugs:²⁴²⁵

• 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).”²⁹

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.²⁴²⁵

11.4. Smoking¶

Smoking can affect metabolization by liver enzymes.

12. Receptor 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.

Examples:

• A combination of six polymorphisms in genes coding for the 5-HT2A, 5-HT2C, histamine H2 receptors and SERT predicted the response to clozapine in schizophrenia with a probability of almost 80%⁸⁶
• Lack of effect of tamoxifen in breast cancer in the absence of estrogen receptor expression⁸⁷
• An influence of the DAT gene on the MPH response is discussed for ADHD medications
• If the blood D3 level is sufficient, reduced sensitive receptors can nevertheless cause a D3 deficiency

13. Blood-brain barrier: Crossing into the brain¶

The blood-brain barrier seals blood vessels in the brain very tightly against the uncontrolled exchange of substances into the brain. As far as possible, only a controlled exchange via transporters and vesicles should take place.
The blood-brain barrier comprises a number of physiological properties that must be either induced (tight junctions, transporters, metabolic enzymes) or inhibited (transcytosis, LAM) in the endothelial cells of the brain compared to those in the body⁸⁸
A basic introduction to the blood-brain barrier in German can be found at Psysiologie.cc⁸⁹, in English at Daneman, Prat.⁸⁸

Example:

• P-glycoprotein (MDR1 gene): controls the transfer of drugs into the brain
  • MDR1 gene variants influence its efficacy. Reduced MDR1 function weakens the blood-brain barrier, drugs can increasingly enter the brain, which can increase their effect even though the blood plasma level is unchanged.⁸⁷

Imbalances in the gut microbiome can affect the blood-brain barrier and thus impair the brain’s protection against toxins, pathogens or the supply of nutrients. More on this at Gut-brain axis and ADHD in the chapter Development

More about the blood-brain barrier at Blood-brain barrier and ADHD In the chapter Development

14. Metabolizing enzymes: Degradation¶

Many drugs are broken down by enzymes, primarily in the liver.
Some active ingredients are only formed through a prior enzymatic conversion of drugs.
Strength of action: Depending on the gene variant, the enzyme encoded by the gene is synthesized to a greater or lesser extent, which influences the degradation capacity.
Competition: 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 humans⁸⁷

• 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.

14.1. Degradation increased / decreased depending on metabolization enzyme gene variant¶

The degradation of active ingredients or neurotransmitters is influenced by how active the gene variant is that expresses the protein that synthesizes their metabolizing enzymes. Some gene variants cause increased or excessive protein production, while others cause reduced or no protein production.
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.⁹⁰

14.1.1. ADHD active ingredients and their main degradation enzymes¶

ADHD active ingredients are broken down by different enzymes:

Methylphenidate: CES1
Amphetamine drugs: CYP2D6 (also strongly dependent on pH value)
Atomoxetine: CYP2D6
Bupropion: CYP2B6⁸⁷ and something about CYP2A6
Guanfacine: CYP3A4
Clonidine: unknown
Buspirone: CYP3A4
Memantine: unknown, probably not through CYP⁴⁰
Viloxazine: CYP2D6, UGT1A9, UGT2B15, possibly also by CYP1A2
Melatonin: CYP1A
Dasotraline: unknown
Agomelatine: CYP1A2 (90 %), CYP2C9/2C19 (10 %)

See the comprehensive articles on the metabolizing enzymes of the respective ADHD medications:

CES1 Metabolizing enzyme:

• Methylphenidate (MPH)

CYP2D6 Metabolizing enzyme:

• Amphetamine medication (AMP)
• Atomoxetine
• Bupropion: CYP2B6⁸⁷ and slightly above CYP2A6, but strong CYP2D6 inhibitor

CYP3A4 Metabolizing enzyme:

• Guanfacine
• Buspirone

14.1.2. Pharmacogenetic diagnostics¶

The gene variants of metabolization enzymes can be determined by genetic testing.⁹¹

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) cost around €600 as of September 2023.
A sample diagnostic report can be found at CeGaT, a provider of genetic diagnostics in Tübingen.⁹² Genetic analyses of individual metabolization genes were around € 300 in September 2023.

14.2. Competition for mining and cross effects¶

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

Risk:
The mechanisms of competition, inhibition, induction or influencing gene expression described below must be taken into account when planning medication. Disregarding them represents a risk or even a treatment error. A new medication can influence the effect of an existing medication (and vice versa), resulting in a risk of loss of efficacy and/or overdose of the new or existing medication(s).

Benefit:
However, the same paths of action can also be used in a planned way and then have a helpful effect.
However, a deliberate combination of competing, inhibiting or genetically regulating drugs can be helpful in improving the effectiveness of individual drugs. For example, drugs that are administered at the same time can be dosed with the appropriate caution or emphasis if the interactions are taken into account. The deliberate use of such combinations is also possible, for example to improve the effect in super-rapid metabolizers or to improve degradation in slow metabolizers.
Example: 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 action of Vyvanse. Vyvanse is metabolized via CYP2D6; bupropion genetically inhibits CYP2D6.

14.2.1. Competition¶

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.

14.2.2. Inhibition¶

Inhibition: Drugs can hinder (inhibit) the action of enzymes, even if they are broken down by completely different enzymes

14.2.3. Induction¶

Induction: Drugs can enhance (induce) the effect of enzymes

14.2.4. Genetic regulation¶

Genetic regulation: Drug substances can also influence metabolization enzymes through genetic regulation.
For example, bupropion is only a rather weak inhibitor of CYP2D6 in vitro. In vivo, however, bupropion strongly inhibits CYP2D6 because it also causes genetic downregulation of CYP2D6 mRNA.⁹³

15. Excretion: 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:²⁴²⁵

• Brexpiprazole
• Lurasidone
• Paliperidone
• Risperidone

16. Gene variants and response¶

A GWAS found influences of various genes on the response to MPH and ATX:⁹⁴

• on chromosome 12, SNP: rs10880574, in the 5-prime UTR intron region of the gene TMEM117 (transmembrane protein 117). TMEM117 is found in the plasma membrane and is also involved in the intrinsic apoptotic signaling pathway in the response to stress in the endoplasmic reticulum.
• on chromosome 18, SNP: rs2000900. closest gene: MYO5B (myosin 5 B), which is involved in vesicular transport and is required in a complex with RAB11A and RAB11FIP2 for the transport of NPC1L1 to the plasma membrane. MYO5B is mainly expressed in digestive organs and plays a role in metabolic processes.
• NKAIN2, an ADHD candidate gene
• PUS7L
• CTD-2561J22.3.