Efficacy and Duration of Action of ADHD Medications

Only in theory is the drug concentration proportional to the administered dose. In general pharmacological practice, there are significant interindividual differences ranging from a factor of 8 to 30.¹
Data from clinical trials are of little help in determining the appropriate dose of a medication for an individual. These trials examine only the dose-response relationship, but not the drug concentration. Dosages for a medication listed in prescribing information, package inserts, and textbooks are based on the average across the entire population of people with ADHD. While this information is certainly helpful as a general guide, it should not be regarded as the definitive standard for individual people with ADHD, who differ in many ways:¹

• Gender
• Size
• Weight
• Age
• Compliance
• Liver and kidney diseases
• Comorbidities
• Interactions
  • pharmacokinetic ((other) drugs)
  • xenobiotic (dietary)
  • Drugs (nicotine, alcohol, caffeine, recreational drugs)
• Genetics
  • Metabolisable gene variants

Pharmacology encompasses the fields of pharmacodynamics (how an active ingredient affects the body) and pharmacokinetics (how the body processes the active ingredient).
The most important processes in pharmacokinetics are:²³

• Absorption
• Bioavailability
• Distribution
• Breakdown (metabolism)
• Excretion

In addition, the release (liberation) of the active pharmaceutical ingredient is also relevant.

There is very little universally applicable data regarding ADHD medications, their use, and their effects. While the manufacturers’ claims regarding the duration of action of methylphenidate are reasonably realistic—and any variations tend to be individual in nature—the stated duration of action for Vyvanse is achieved by only a small group of people with ADHD.
In the case of ADHD, however, medications must always be tested and adjusted on a highly individualized basis.
This article examines the factors that individually influence the response to and duration of action of a single dose of ADHD medication.

Although blood levels are an important factor in determining drug dosage, they cannot measure factors such as blood-brain barrier permeability or receptor activity, among others; therefore, this value cannot serve as an objective criterion for assessing a drug’s efficacy.

1. Duration of Action of Active Ingredients and Medications for ADHD¶

1.1. Manufacturer’s information on duration of action¶

The information on medications available in the U.S. is sourced from Rodden.⁴ The figures in the table represent average values, unless otherwise noted.
The actual duration of action varies from person to person and depends heavily on the individual’s metabolism. Approximately 5% of people with ADHD are ultra-rapid metabolizers. In these individuals, due to increased CES1 activity, the effect of immediate release MPH may last only 1 hour⁵, or the effect of a half-day extended-release formulation may last only 1.5 or 2 hours instead of 5 to 6 hours. Similarly, although apparently less frequently, there are people with ADHD for whom a formulation has a significantly longer duration of action.
For information on the metabolism of methylphenidate and amphetamine-based medications, see below. There you will also find more detailed information on pharmacokinetics, such as the onset of action and the shape of the dose-response curve.

Especially with half-day sustained-release formulations, a second dose of medication—which is typically lower in dosage—is usually required at lunchtime to ensure full daily coverage.
Treatment for only half a day is not effective. ADHD is not a “morning disorder.”

Methylphenidate preparations	Active ingredient	Typical duration of action in hours (according to the 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 (theoretical), 3–5 hours duration of action (practical)7, 84	sustained-release7	EU
Focalin	Dexmethylphenidate	4–6	immediate release	CH, USA
Equasym Retard/XL	Methylphenidate	6–88 / 8 9	Two-phase sustained-release	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 sustained-release	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: Ritalin LA only
Methysym	Methylphenidate	up to 8	sustained release	available in Germany since June 1, 2021
Metadate CD	Methylphenidate	8–10	sustained release	USA
Daytrana	Methylphenidate	10 (for a 9-hour wear time)	Patch	USA
Concerta, Methylphenidate Hydrochloride-neuraxpharm (bioequivalent), Methylphenidate AL Retard (bioequivalent)	Methylphenidate	8–128, 10–127, 1213; 10.2 hours (7.5 to 11.5 / 1st quartile to 3rd quartile)14	sustained release	Germany, Switzerland, 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 the 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	Amphetamine mixed salts	4–6	immediate release	USA
Evekeo	Amphetamine sulfate	4–6	immediate release	USA
Attentin	Dextroamphetamine	5–6	immediate release	Germany, since late 2011
Dexamin	Dextroamphetamine	5–6	immediate release	Switzerland, as a compounded prescription
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, Tyvanse, generic versions	Lisdexamfetamine	13 (children); 14 (adults) (in practice, sometimes significantly lower values); 7 hours or less in 60% of people with ADHD (see below)	Prodrug	EU, USA
Dyanavel XR	Amphetamine	13	sustained release	USA
Mydayis	Amphetamine mixed salts	14–16	sustained release	USA

Non-stimulants	Active ingredient	Duration of effect in hours (according to the manufacturer)	sustained release	Country
Strattera, Agakalin	Atomoxetine	all-day / individualized 8 to 21 hours17	immediate release	USA
Intuniv	Guanfacine	once daily; peak concentration after approximately 5 hours; elimination half-life approximately 18 hours	sustained release	USA
The shape of the response curves varies considerably depending on the drug.18

1.2. Empirical Data on Duration of Effect¶

1.2.1. Empirical data on the duration of action of a single dose of lisdexamfetamine¶

Three online surveys of people with ADHD in the German-speaking adhs-forum.adxs.org (80 participants, through 2022), and in an English-language subreddit about Vyvanse (466 participants, through 2022), and in the ADxS Drug Duration of Action Survey (781 participants for LDX, as of May 3, 2026), regarding how long a single dose of lisdexamfetamine (LDX, e.g., Vyvanse) lasts for them, collectively revealed:

Duration of action of a single dose of LDX	% of participants (out of 1,327)
5 hours or less	, 31.5%
6 to 7 hours	25.8%
8 to 9 hours	19.1%
10 to 11 hours	, 12.7%
12 hours or more	, 11.0%

There is a very clear trend toward a much shorter duration of action than the 10 to 12 hours specified by the manufacturer. For about one in three users, a single dose lasts only up to 5 hours, and for more than half, 7 hours or less. Fewer than one-quarter of the people with ADHD experience the duration of action specified by the manufacturer—10 to 12 hours or longer. This is consistent with the numerous reports from Vyvanse users on the forum who require more than one single dose per day. Some users require 3 doses (with subsequent doses typically being lower than the preceding ones).

There is evidence that the duration of action of lisdexamfetamine is merely delayed by 1 to 1.5 hours compared to dextroamphetamine, but not prolonged.¹⁹²⁰ This strongly calls into question the manufacturer’s claims of 12 to 14 hours per single dose and is consistent with the empirical data on the duration of action of a single dose of lisdexamfetamine .

The time to reach maximum dAMP levels after LDX administration was determined to be 2.1 hours²¹, 3 hours²², 3.5 hours²³, 4 hours²⁴, 4.23 hours²⁵, and 4.4 hours²⁶, respectively.

Impaired kidney function did not slow the breakdown of LDX, but it did slow the breakdown of dAMP, thereby prolonging its effect.²⁷²⁸

Among the participants in the ADxS Drug Duration of Action Survey , the average single dose among the n = 391 users with a duration of action of up to 7 hours (43.6 mg) was slightly higher than the single dose among the n = 390 users with a duration of action of 8 hours or more (42.8 mg). The values differed barely among adults by age. Even among users aged 60 and older, the average dose was 38.9 mg.
The dose also did not differ significantly by weight (up to 50 kg: 42.5 mg; 51 to 70 kg: 41.9 mg; 71 to 90 kg: 43.0 mg; over 90 kg: 47.1 mg).

Interestingly, there were also several people with ADHD for whom not only Vyvanse/Elvanse but also methylphenidate had a much shorter duration of action. Since Vyvanse/Elvanse and MPH are metabolized by different enzymes, this suggests mechanisms other than overactive enzyme gene variants, as is also explained in this article.

The duration of action of lisdexamfetamine depends on erythrocyte activity. For more information, see Red Blood Cell Function and Lisdexamfetamine. The duration of action of dextroamphetamine—whether derived from lisdexamfetamine or taken directly—depends on the body’s pH level and possibly (in relation to food intake) also on the activity of the CYP2D6 and POR gene variants in the person with ADHD. For more information, see Metabolism of Amphetamine as well as under CYP2D6 Metabolizing Enzyme

1.2.2. Empirical data on the duration of action of a single dose of immediate release MPH¶

Among the participants in the ADxS Drug Duration of Action Survey (as of Dec. 19, 23), 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 (mean: 9 mg), and for single doses of 15 to 20 mg (average: 18.75 mg), it was 3.43 hours (n = 8). The overall average was 3.18 hours and 14.8 mg.

1.2.3. Empirical data on the duration of action of a single dose of MPH half-day sustained-release¶

Among the participants in the ADxS Drug Duration of Action Survey , the duration of action of a single dose of half-day-release MPH (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 of a single dose of MPH Half-Day Extended-Release	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 or more	, 4.9%

Thus, 67.7% of people with ADHD report that a single dose is effective for 3 to 5 hours, while 81.8% report a duration of effect of 3 to 7 hours. The results are therefore significantly more consistent and closer to the manufacturer’s specifications than those for Vyvanse.
Medikinet Retard and Medikinet Adult (which are bioidentical) had an average duration of action of 4.58 hours (n = 132) at an average dose of 20.64 mg, while Ritalin Adult and Ritalin LA (which are also bioidentical) had an average duration of action of 4.74 hours (n = 31) at an average dose of 26.3 mg.

Below, we explain the factors that can influence the duration of a medication’s effects (particularly for ADHD medications) on an individual basis.

2. Single-dose amount¶

Some people with ADHD report that higher single doses of amphetamine (especially lisdexamfetamine) have a longer-lasting effect for them.
However, pharmacological tests of various doses of lisdexamfetamine show that Tmax is approximately the same.²³ Tests using doses higher than the therapeutic dose showed that lysine cleavage is neither saturated nor slowed by higher doses.²⁹

The duration of action of methylphenidate preparations is independent of the dose.³⁰

3. Gastric Transit Rate¶

In addition to the rate of passage through the small intestine, gastric function also plays a role. Gastric motility and the rate of gastric emptying influence how quickly a substance reaches the small intestine. For example, with acetaminophen, gastric emptying is the rate-limiting step for the substance’s appearance in blood plasma. Delayed or accelerated gastric emptying can therefore fundamentally affect the kinetics of orally administered drugs, such that, for example, the necessary therapeutic levels are not reached or are reached only after a delay.³¹

With age, the surface area of the small intestine and the rate of gastric emptying decrease. At the same time, the pH of the stomach increases. However, these changes usually have no effect on drug absorption.³²³³

Anticholinergic drugs can slow the passage of medications from the stomach into the small intestine.³²³³

Gastric bypass surgery or gastric reduction surgery increased dexamfetamine levels when lisdexamfetamine was administered. Tmax tended to be reduced. For Ritalin acid (from MPH) and atomoxetine, no changes in AUC0-24 were observed; atomoxetine showed a higher Cmax and a shorter Tmax. The number of subjects was very small.³⁴

4. Small intestine¶

4.1. Small Intestine Length¶

In children, the small intestine is shorter, resulting in reduced absorption through the small intestine.³⁵³⁶

4.2. Small Intestine Transit Time¶

“For oral medications, the transit 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 the release is limited to a period of about 8–10 hours.”³⁷

This time may vary from person to person, just as the speed of intestinal transit varies. This is likely the reason why there are a few individuals with a very fast metabolism who report that Medikinet lasts 1 to 2 hours and Vyvanse lasts 3 hours. They also report that they need to eat much more frequently throughout the day than others.
To achieve a duration of action that is longer (not just on average) than intestinal transit time, mechanisms are therefore required that go beyond absorption from the small intestine.

5. Acid-base 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 there are in a solution, the lower the pH value.
The pH scale ranges from 0 to 14 and indicates how alkaline something is. 7 is neutral. The higher the pH (above 7), the more alkaline it is; the lower the pH (below 7), the more acidic it is.
The typical pH value is:

• in the stomach³⁸
  • on an empty stomach, pH 1.5 (1–2)
  • increases when eating
    • depending on the type and amount, up to a pH of 5–6
    • followed by a decline back to the initial value
  • Preterm infants have less acidic stomachs (pH > 4) and are prone to intestinal infections
  • Older adults have lower stomach acidity (pH 6.6 in 80% of study participants) and are susceptible to bacterial infections in the stomach and intestines
  • Stomach acid (hydrochloric acid) is produced in parietal cells by the proton pump
    • That is why proton pump inhibitors reduce stomach acid (omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole)
  • Excess acids are neutralized by buffer systems and excreted through respiration and the kidneys
• in the urine³⁹
  • 6.0 Average
  • 6.6 and higher in 10% of people
  • 7.2 and higher at 1%

Depending on the duration of exposure to acid, the pH value can affect:³⁸

• Solubility of active ingredients
• Stability of active ingredients

Foods affect the body’s pH level.⁴⁰
Foods high in animal protein (meat, fish, cheese, eggs) produce acids as metabolic byproducts.
Plant-based foods (fruits, vegetables, leafy greens, whole-grain products) are primarily alkaline.

5.1. Acid-Base Balance and Amphetamine Medications¶

Amphetamine-based medications:
The amount of dextroamphetamine that is excreted unchanged—and thus the amount of pharmacologically active dextroamphetamine that remains—depends on the pH of the urine.^41424344

• Reduced duration of action due to high urinary acidity (low pH), e.g., caused by (see detailed list below)
  • Ascorbic acid (vitamin C)⁴⁴
    • Ascorbic acid (vitamin C) taken in an appropriate dose left the pH value virtually unchanged (+0.03)⁴⁵
    • Vitamin C (ascorbic acid) is rapidly metabolized, and its PRAL value (potential renal acid load) is close to zero (= neutral). However, high doses of vitamin C can temporarily acidify the urine because excess ascorbic acid is excreted by the kidneys and can lower the pH of the urine. This applies to high doses taken as dietary supplements, but barely to normal dietary intake.
  • Thiazide diuretics
  • A diet rich in animal protein
  • Diabetes
  • respiratory acidosis
• Prolonged duration of action due to low (alkalized) urinary acid content (high pH)²⁰, e.g., through (see detailed list below)
  • Potassium citrate
  • Sodium hydrogen carbonate = sodium bicarbonate
  • Mineral water with bicarbonate⁴⁶
  • A diet rich in fruits, vegetables, and whole grains
  • Urinary tract infections
  • Vomiting
  • A change in diet, e.g., from a meat-based diet to a vegetarian diet⁴⁷
  • heavy use of medications to neutralize stomach acid⁴⁷

A urine pH of 5.0 (acidic) can reduce the pharmacologically active amount of d-AMP to one-quarter of the amount present at a urine pH of 8.0 (alkaline).⁴⁸ AUC of amphetamine after a 11 mg dose at a urine pH of:

• 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 for the pharmacological concentration of d-AMP (Cmax) also correlates with urine pH, albeit to a much lesser extent; thus, while acidic urine does correlate with a slightly weaker effect, it is primarily associated with a significantly shorter duration of action.⁴¹
While 54.5% of orally administered amphetamine was excreted unchanged at pH = 5.0 (acidic urine), this value was 2.9% at pH = 8 (alkaline urine). When the pH was uncontrolled, 14.5% was excreted.⁴¹⁴⁸

One person with ADHD for whom lisdexamfetamine’s effects were too short-lived (a single 50-mg dose lasted 4 hours) reported that drinking 1.5 liters of sparkling water containing 1,800 mg nhc/L in the morning enhanced the effect to such an extent that he now needed only 30 mg of LDX, which then had the same intensity and duration of effect as the previous 50 mg dose.

5.2. Acid-Base Balance and Methylphenidate¶

In a laboratory study (= in vitro), up to 60% of the methylphenidate was spontaneously hydrolyzed to (pharmacologically inactive) ritalinic acid, and this hydrolysis was pH-dependent.⁴⁹
In bacterial cultures in which MPH was not metabolized, the pH after 24 hours ranged from 4.0 to 5.5; in cultures with high MPH hydrolysis, the pH ranged from 7.5 to 8.0. E. coli BW25113 cultures with an average pH of 7.8 hydrolyzed 70% of the MPH; E. coli DSM1058 and E. coli DSM12250, with an average pH of 7.6, hydrolyzed 50% of the MPH. The correlation between MPH-hydrolyzing bacterial cultures and the pH 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 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 metabolism of MPH.⁴⁹
In adults, only 22% (+/- 8%) of dMPH and 5% (+/- 3%) reach the systemic circulation; in children, the figures are 31% (+/- 16%).⁵⁰ Schematically, 20% of MPH is oxidized in the liver.⁵¹ 80% of ingested MPH is excreted in the urine within 48 hours (of which 80% is in the form of Ritalin acid and 1% is unmetabolized), and 3% is excreted in the feces. ⁵⁰

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). July 27, 2021;14(8):733. doi: 10.3390/ph14080733. PMID: 34451830; PMCID: PMC8398889 (unchanged)⁴⁹ Published under the terms of the Creative Commons Attribution (CC BY)license.

Medikinet Retard, Medikinet Adult:
If the stomach pH is above 5.5, dose-dumping phenomena may occur with Medikinet retard and Medikinet adult: The active ingredient is released too quickly, resulting in increased effects and side effects. This can be caused by, among other things,

• Proton pump inhibitors (e.g., pantoprazole, omeprazole)
  • questionable for omeprazole, which, according to another source, has barely any effect on the pH value (+0.10)⁴⁵
  • Inconsistent: Proton pump inhibitors generally caused a very significant decrease in pH (-1.5; n = 10)⁵²
• Antacids
• H2 blockers (e.g., ranitidine, famotidine) (less likely)
• age-related increase
• atrophic gastritis

A person with ADHD reported that Medikinet had barely any effect at doses ranging from 20 to 60 mg. Eating dry rice cakes in addition to the medication resulted in a temporary effect that was unpredictable. Taking antacids (stomach acid inhibitors) in addition to MPH produced a reliable effect.

Ritalin for adults:
Ritalin for adults, on the other hand, releases MPH regardless of pH. The prescribing information lists reduced absorption as a likely interaction with antacids.⁵³

5.3. Acid-Base Balance and Memantine¶

Memantine:

• Prolonged effect due to alkalized urine
  • In patients with alkaline urine (high pH), the renal clearance of memantine may be reduced by a factor of 7 to 9.⁴⁷

5.4. Factors that increase alkalinity (raise the pH)¶

Information in the following list that does not include its own source citation is taken from ⁵⁴. The website cited there as the source is no longer accessible. The information has proven to be incorrect in several cases and should therefore be verified on a case-by-case basis.

Factors that contribute to alkaline urine (high pH) include:

• Environmental factors:

  • Daily fluctuations
    • There are various profiles:³⁹
      • A “normal” pH curve with three peaks corresponding to morning and postprandial (after-meal) fluctuations, with a low nighttime pH value
        • Meals cause a spontaneous increase in alkalinity (urine pH reaches at least 6.8 1 to 2 hours after meals)
      • A consistently low pH level with no significant fluctuations
      • a single afternoon peak with almost no morning fluctuation
      • Inversion of the “normal” curve, with low daytime levels and a high nighttime plateau
  • Body surface area (it is unclear whether high or low)⁵⁵
  • Cadmium exposure
  • Heparin
  • Reduced air pressure; hypobaric ventilation⁵⁶
  • Mercury pollution
  • female gender⁵⁷⁵⁸
  • Age: Stomach acid decreases, while uric acid levels rise steadily (at least in people with kidney stones) with age⁵⁹⁵⁸
  • low income⁶⁰⁶¹ (socioeconomic status?)
  • Storing the urine at too high a temperature after collection⁵⁴

• Diseases:

  • 21-hydroxylase deficiency
  • 3-Hydroxydehydrogenase deficiency
  • Rejection of a kidney transplant
  • Acute post-streptococcal glomerulonephritis
  • Amyloidosis
    * Atrophic gastritis (age-related gastritis)
  • Calcium deficiency³⁹
  • Carbonic anhydrase II deficiency
  • Chronic obstructive pulmonary disease
  • Vomiting
  • acquired adrenal insufficiency
  • Familial methyl oxidase deficiency
  • Galactosemia
  • Gout
  • Glycogen storage disease
  • Urine dilution³⁹
  • Increased urine flow³⁹
  • Hereditary fructose intolerance
  • Hyperventilation³⁹
  • Hypoxia⁶²
  • 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-loss nephritis
  • Sjögren’s syndrome
  • Tubulointerstitial disease
  • Tyrosinemia
  • Vitamin D deficiency
  • Vitamin D resistance

• Medications:

  • Acetazolamide: Increase in urine pH of +2.0 with intravenous administration (very strong); +0.39 (weak) with oral administration⁴⁵
    • Long-term treatment with acetazolamide is associated with an increased risk of urolithiasis⁶³
  • ADV7103 (citrate + bicarbonate): Increase in urine pH by +1.27 (significant)⁴⁵
  • Ambroxol⁶⁴
  • Amiloride
  • Aminoglycosides
  • Ammonium chloride
  • Antibiotics⁶⁵
  • Ascorbic acid (vitamin C): Increase in urine pH by +0.03 (neutral)⁴⁵
  • Bicarbonates (= hydrogen carbonates)
    • Mineral water rich in bicarbonate⁶⁶
    • Bicarbonate loading (soda loading, baking soda loading): Increase in urine pH by +1.44 (very significant)⁴⁵
      • Taking sodium bicarbonate (= sodium hydrogen carbonate, baking soda, bicarbonate of soda, baking powder, Bullrich salt)
      • 10 minutes before physical activity
      • Dose: 0.2 to 0.3 g/kg
        • one teaspoon of baking soda dissolved in a glass of still water
        • Should not be used for more than 2 weeks
      • Long-term use may trigger increased stomach acid production as a counter-reaction
      • Baking soda in the stomach produces CO2—risk of distension of the stomach wall
  • Citrate: 0.61 (moderate)⁴⁵⁶⁶
    • Citrus juices
    • Orange juice: Increases urine pH by +0.68 (moderate)⁴⁵
  • Citro-Soda: Increases urine pH by +1.56 (very strong)⁴⁵
    • 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 of +0.51 following intravenous administration (moderate)⁴⁵ (diabetes medication)
  • Glycine: Increases urine pH by +0.20 (neutral)⁴⁵
  • Indomethacin: Increase in urine pH by +1.0 (marked)⁴⁵
  • Potassium citrate⁴⁵
    • Recommendation from the American Urological Association (AUA) on increasing the pH level of urine
    • Food additive E332
    • Dietary supplements, available over the counter in powder or capsule form
      • Avoid in cases of hyperkalemia—therefore, always consult a doctor; the prevalence of hyperkalemia in the general population is 2 to 3%
  • Potassium gluconate: Increases urine pH by +0.46 (slight)⁴⁵
    • Potassium gluconate, a medication used to treat potassium deficiency
  • Potassium hydrogen carbonate (potassium bicarbonate): Increase in urine pH by +0.89 (moderate)⁴⁵⁶⁷
  • Potassium sodium hydrogen carbonate (also known as potassium sodium hydrogen citrate)⁶⁸
    • Medication to increase urine pH
  • L-tryptophan: Increase in urine pH by +0.20 (neutral)⁴⁵
  • Magnesium salts without chlorides⁶⁹
  • Metolazone
  • Monosodium glutamate⁷⁰
  • Sodium hydrogen carbonate (sodium bicarbonate, baking soda): Increases urine pH by +1.19 when taken orally; +1.12 when administered intravenously; strong⁴⁵
  • Sodium L-ascorbate with sodium saccharin⁷¹
  • Niacin
  • Omeprazole (proton pump inhibitor): Increase in urine pH by +0.10 (neutral)⁴⁵
  • Spironolactone
  • Streptozocin
  • Topiramate: Increase in urine pH by +0.45 (mild)⁴⁵

• Food

  • DASH Diet: Increase in urine pH of +0.5 (moderate)⁴⁵
    • A diet rich in fruits, vegetables, whole grains, low-fat dairy products, fish, poultry, nuts, and seeds
  • Cucumbers: Increase in urine pH by +0.17 (neutral)⁴⁵
  • Potatoes: Increase in urine pH of +0.28 (slight)⁴⁵
  • Lime Juice: Increases urine pH by +0.25 (neutral)⁴⁵
    • It is unclear whether “lime syrup” refers to a mixture of lime juice, water, and sugar or to pure lime juice
  • Melon juice: Increases urine pH by +0.36 (cantaloupe; slight)⁴⁵; higher than orange juice (moderate)⁷²
  • Milk: Increase in urine pH of +0.36 (slight)⁴⁵
  • Diet rich in fruits and vegetables: Increase in urine pH of +0.35 (slight)⁴⁵
  • Orange juice: Increases urine pH by +0.68 (moderate)⁴⁵
  • French fries: Increase in urine pH by +0.25 (neutral)⁴⁵
  • vegetarian diet
    • Lacto-ovo-vegetarian diet: Increase in urine pH of +0.85 (moderate)⁴⁵
    • Mixed Western vegetarian diet: Increase in urine pH of +0.56 (moderate)⁴⁵
  • Vitamin C: Increase in urine pH by +0.03 (neutral)⁴⁵
  • see below (PRAL value table)

5.5. Factors That Increase Acidity (Lower the pH)¶

Information in the following list that does not include its own source citation is taken from ⁵⁴. The website cited there as the source is no longer accessible. The information has proven to be incorrect in several cases and should therefore be verified on a case-by-case basis.

Factors that contribute to acidic urine (low pH) include:

• Environmental factors:

  • Bed rest
  • Aldosterone
  • Lead exposure⁷³
  • Cadmium⁷⁴
  • Toluene
  • Vanadium
  • Age: Stomach acid decreases, while uric acid levels rise steadily (at least in people with kidney stones) as people age ⁵⁹⁵⁸
  • male gender⁵⁷
  • high income⁶⁰⁶¹ (socioeconomic status?)
  • physical exertion in a hot environment
    • Working as a rice field laborer in Thailand⁷⁵
    • Work as a sugarcane harvester in El Salvador⁷⁶ or Nicaragua⁷⁷
    • Desert trip⁷⁸
  • Sleep deprivation: - 0.0 (neutral)⁴⁵

• Diseases:

  • Breathing problems

    • Obstruction of the airways or impairment of gas exchange in the lungs, e.g., in cases of pulmonary edema (fluid in the lungs)

    • Pneumonia

    • Loss of functional lung tissue, e.g., due to tuberculosis

    • insufficient respiratory drive, such as in cases of sleeping pill poisoning

    • Paralysis of the respiratory muscles, e.g., in polio

    • Malfunction of the respiratory reflexes

  • Adrenal hyperfunction

  • Adrenal insufficiency

  • Amyloidosis

  • Autoimmune thyroiditis

  • Balkan nephropathy

  • Chronic active hepatitis

  • Chronic kidney disease

  • Chronic kidney disease

  • Chronic pyelonephritis

  • Cystinosis

  • Diabetes mellitus

  • Distal renal tubular acidosis

  • Gastrinoma

    • Zollinger-Ellison syndrome, a rare pancreatic tumor
    • increases stomach acid

  • Fibrosing alveolitis

  • Urinary tract obstruction (a blockage in the urinary system that prevents urine from flowing 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 Syndrome⁷⁹

  • Kidney transplant rejection

  • Kidney failure

  • Polyarteritis nodosa

  • Primary biliary cirrhosis

  • Proximal renal tubular acidosis (Type II)

  • Sickle cell anemia

  • Sjögren’s syndrome

  • Volumetric-dependent distal renal tubular acidosis (Type 1)

  • Vitamin D toxicity

• Medications:

  • Acetaminophen = Paracetamol

  • Acetazolamide

  • Amiloride

  • Ammonium chloride (sal ammoniac): - 1.63 (very strong)⁴⁵⁴¹

  • Amphotericin B

  • Acetylsalicylic acid (aspirin)

    • inhibits prostaglandins, which protect the stomach lining from acid
    • A prostaglandin deficiency leads to inflammation of the mucous membrane, which damages the parietal cells that produce stomach acid (gastritis)

  • Carbenoxolone

  • Cefdinir

  • Cimetidine

  • Citric acid: Reduces urine pH by -0.06 (neutral)⁴⁵

  • Dapagliflocin: Decrease in urine pH by -0.10 (neutral)⁴⁵ (diabetes medication)

  • Diclofenac

    • inhibits prostaglandins, which protect the stomach lining from acid
    • A prostaglandin deficiency leads to inflammation of the mucous membrane, which damages the parietal cells that produce stomach acid (gastritis) * Diflunisal

  • Etodolac

  • Fenoprofen

  • Flurbiprofen

  • Furosemide: Decrease in urine pH of -0.52 following intravenous administration (not statistically significant)⁴⁵

  • Ibuprofen

    • inhibits prostaglandins, which protect the stomach lining from acid
    • A prostaglandin deficiency leads to inflammation of the mucous membrane, which damages the parietal cells that produce stomach acid (gastritis)

  • Ifosfamide

  • Indomethacin

  • Ketoprofen

  • Lithium

  • Mafenid

  • Methionine: Decrease in urine pH by -0.71 (moderate)⁴⁵

    • essential amino acid
    • available without a prescription
    • takes a few days to take effect

  • Monomagnesium L-aspartate hydrochloride⁶⁹

  • Mefenamic acid

  • Naproxen

  • Niacinamide

  • Ofloxacin

  • Orthophosphate

  • Parathyroid extract

  • Proton pump inhibitors: Decrease in urine pH by -1.5 (very strong, n = 10)⁵²

  • Ranitidine

  • Triamterene

• Food

  • Apple cider vinegar: Decrease in urine pH of -0.21 (very slight)⁴⁵
  • Cranberry: Decrease in urine pH by -0.16 (neutral)⁴⁵
  • Protein: high intake of animal protein in the diet⁸⁰
  • Fasting: Decrease in urine pH of -1.2 (very significant)⁴⁵
  • Fructose: Decrease in urine pH by -0.26 (very slight)⁴⁵
  • Sodium chloride (table salt): Decrease in urine pH by -0.47 (mild)⁴⁵’
  • ketogenic diet: decrease in urine pH of -0.55 (moderate)⁴⁵
  • Low-oxidant diet: Reduction in urine pH by -0.10 (neutral)⁴⁵
  • High-protein diet: Decrease in urine pH of -0.65 (moderate)⁴⁵
  • See below (PRAL value table)

5.6. The Effect of Food on Acid-Base Balance (PRAL Value)¶

Foods can significantly influence the body’s pH level. It is not so much the sour taste that matters, but rather the PRAL value. Consuming foods with a negative PRAL value correlates with an alkaline urine pH, while an acid-forming diet correlates with alkaline urine pH values below 6.0. The blood pH level in healthy adults ranges between 7.35 and 7.45.
You can measure your urine pH yourself using simple pH test strips available at drugstores or online. Fats and carbohydrates do not normally affect the acid-base balance.
When it comes to proteins, a distinction must be made between plant-based and animal-based proteins. After 7 days on a vegetarian diet, the urine pH level rises and the PRAL value decreases; the same is true for a vegetarian diet of 2 or 3 days per week.⁸¹ A vegetarian diet is thus associated with a prolonged effect of amphetamine-based medications.
Foods high in oxalate can increase acid production.⁴⁶
A study provides the following calculation formula:⁸² PRAL (mEq/d) = 0.49 × Protein (g/d) + 0.037 × Phosphorus (mg/d) − 0.021 × Potassium (mg/d) - 0.026 × magnesium (mg/day) - 0.013 × calcium (mg/day).

In other words: Foods with a strongly negative PRAL value result in alkaline urine (less acidic, increasing the pH) and thus promote a prolonged effect of amphetamine medications. Foods with a high PRAL value result in acidic urine (lowering the pH) and thus promote a shorter duration of action for amphetamine medications. According to this model, hard cheese is suitable for shortening the duration of action of amphetamine medications, while raisins could prolong it.

Note: Do not confuse the PRAL value with the increase in urine pH shown in the figure above. These values are inversely related.

6. Mechanical Effects of Food Intake¶

6.1. Food Intake as a Prerequisite for the Extended-Release Effect of Medikinet¶

For Medikinet Adult and Medikinet Retard, prior or simultaneous food intake is a prerequisite for the sustained release of the active ingredient. If no food is consumed, the MPH is released twice as fast. Consequently, the released dose of MPH is approximately doubled, and the duration of action is approximately halved.

Other sustained-release formulations use different mechanisms for sustained release that do not depend on simultaneous food intake, such as

• Ritalin for adults
• Ritalin LA
• Methysym
• Equasym Retard/XL
• Methylphenidate Hydrochloride - Neuraxpharm
• Kinecteen
• Methylphenidate Hydrochloride Ratiopharm
• Methylphenidate Hydrochloride Hexal

6.2. Food intake affects the duration of action¶

Regardless of the need for a delayed-release effect in some MPH formulations and regardless of the effect on urinary pH (with regard to amphetamine medications) or gastric pH (with regard to MPH), certain patterns of food intake influence the effects and duration of action of stimulants in a more mechanical manner.
With high-fat meals, lisdexamfetamine (Vyvanse) reaches its peak blood level one hour later (4.7 hours instead of 3.8 hours after administration).⁸⁶ However, other parameters, such as the duration of action, remain unchanged.

6.3. Food intake delays the peak AMP level¶

With high-fat meals, lisdexamfetamine (Vyvanse) reaches its peak blood level one hour later (4.7 hours instead of 3.8 hours after administration).⁸⁶ However, other parameters, such as the duration of action, remain unchanged.

6.4. Absorption of the active ingredient¶

Some foods have the ability to absorb active ingredients, thereby delaying the onset and duration of their effects.
Example:

• Psyllium seeds⁸⁷⁸⁸ , which is why it is recommended to wait half an hour to an hour before taking other medications⁸⁹

7. Physical Activity / Sports¶

Some people with ADHD report that intense sports can shorten the duration of stimulants by up to 40%.⁹⁰

8. Nicotine / Smoking¶

Several people with ADHD reported that smoking altered the effects of stimulants.
The following were reported (in each individual case as a specific occurrence associated with stimulant use):

• A person with ADHD shares:
  • Increased nicotine cravings 4 hours after taking Vyvanse
  • After the first cigarette of the day, I feel a bit sluggish and start to get tired
  • A day without cigarettes and just taking Vyvanse is going okay, aside from the restlessness caused by nicotine withdrawal, but I’m still feeling motivated and the effects last into the afternoon and evening
  • Switching to nicotine “gum” instead of smoking or vaping resulted in significantly greater feelings of calm and an end to midday fatigue
• One person with ADHD described an effect similar to drug dependence:
  • Vyvanse + nicotine: reduced effectiveness, negative feelings
  • MPH + nicotine: enhanced effect, “kick” (but also a greater drop/rebound)
• An occasional smoker:
  • Even just one or two cigarettes can prevent Vyvanse and MPH from working properly
  • It takes a few days for them to start working properly again
  • I usually sleep well with Vyvanse these days. When I’ve been smoking, I sleep worse.
  • The difference in how Vyvanse works when I haven’t smoked for a while is enormous
• A person with ADHD:
  • When I take on too much, I feel the urge to smoke—either as a way to cope or as a way to push myself further.
  • It works at first, but after a few days, things take a turn for the worse. I start to feel less energetic, and my mood gets worse.
  • In the long run, it’s not good for me, and it doesn’t mix well with my medication. The medication becomes less effective, and in the end, I feel worse.
• A woman on the steamboat:
  • After taking MPH, vaping makes me feel tired and gives me a headache
  • Nicotine enhances the effects of MPH

9. Alcohol¶

Alcohol can increase amphetamine levels.⁹¹

10. Cycle¶

The female menstrual cycle affects dopamine levels. Estrogen influences COMT, which breaks down dopamine in the PFC.
People with ADHD who have certain COMT gene variants are particularly susceptible.
The required dose of stimulants may vary depending on the phase of the cycle.
When adjusting the dosage of stimulants, women should be sure to keep a detailed log to track cycle fluctuations and the medication’s effects. This is the only way to determine whether the dosage needs to be adjusted during certain phases of the cycle. The dosage adjustment guide, available in the download section of ADHD-forum.adxs.org , makes it easier to track medication intake, symptom progression, and the menstrual cycle.

11. Liver function¶

11.1. Age¶

Hepatic metabolism may slow down with age, due in part to reduced blood flow to the liver.²⁹²

Reduced CYP metabolism in older adults is known to occur with the following psychotropic drugs:³²³³

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

The rate of breakdown decreases by an average of 30 to 40 percent; however, this varies so much from person to person that, as with dosage determination, each case must be considered individually.

11.2. Diseases¶

Liver diseases can (severely) impair liver function. Reduced protein synthesis in the liver automatically decreases plasma protein binding, which impairs the breakdown of substances by enzymes in the liver.
When bile production in the liver is impaired, the excretion of large molecules is reduced and the enterohepatic circulation is disrupted.
Heart failure reduces blood flow to the liver.

11.3. First-pass effect¶

“The intestinal veins carry blood to the heart via the liver, so that a substance absorbed in the intestine undergoes first-pass metabolism in the liver before it can be distributed further via the vena cava and the heart. If a substance survives this first-pass metabolism only to a limited 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 rapidly metabolized or inactivated in the liver (presystemic elimination).”³⁷

The first-pass effect also varies from person to person.
Starting at age 40, the first-pass effect decreases by about 1% each year, so that serum levels are higher in older adults when the same dose is administered.³²³³

11.4. Smoking¶

Smoking can affect metabolism by liver enzymes.

12. Kidney function¶

The metabolism of sympathomimetics depends on kidney function. With regard to amphetamine-based medications, it is important to note that kidney function also affects the pH level, which in turn influences the metabolism of amphetamine.²⁸⁹³

13. 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 the drug’s efficacy.
The sensitivity of the receptor structures can be influenced by variants in the genes that encode them.

Examples:

• A combination of six polymorphisms in genes encoding the 5-HT2A, 5-HT2C, and histamine H2 receptors, as well as SERT, predicted a response to clozapine in schizophrenia with a probability of just under 80%⁹⁴
• Lack of efficacy of tamoxifen in breast cancer in the absence of estrogen receptor expression⁹⁵
• Regarding ADHD medications, the influence of the DAT gene on the response to MPH is discussed
• Even when blood levels of vitamin D3 are sufficient, receptors with reduced sensitivity can still lead to a vitamin D3 deficiency

14. Blood-Brain Barrier: Passage into the Brain¶

The blood-brain barrier tightly seals off the blood vessels in the brain to prevent uncontrolled exchange of substances into the brain. Ideally, only a controlled exchange via transporters and vesicles should take place.
The blood-brain barrier comprises a series of physiological properties that must either be induced (tight junctions, transporters, metabolic enzymes) or inhibited (transcytosis, LAM) in the brain’s endothelial cells compared to those in the rest of the body.⁹⁶
A basic introduction to the blood-brain barrier in German can be found at Psysiologie.cc⁹⁷, and in English in Daneman and Prat.⁹⁶

Example:

• P-glycoprotein (MDR1 gene): controls the transport of drugs into the brain
  • MDR1 gene variants influence its effectiveness. Reduced MDR1 function weakens the blood-brain barrier, allowing more drugs to cross into the brain, which can increase their effect even though the blood plasma level remains unchanged.⁹⁵

Imbalances in the gut microbiome can affect the blood-brain barrier, thereby impairing the brain’s protection against toxins and pathogens or its supply of nutrients. Learn more at Gut-Brain Axis and ADHD in the chapter “ : Causes”

Learn more about the blood-brain barrier at Blood-Brain Barrier and ADHD in the chapter “ : Causes”

15. Metabolic Enzymes: Degradation¶

Many drugs are broken down by enzymes, primarily in the liver.
Some active ingredients are formed only after a drug has undergone enzymatic conversion.
Effect strength: Depending on the gene variant, the enzyme encoded by the gene is synthesized in greater or lesser amounts, which affects the degradation capacity.
Competition: When multiple medications that are metabolized by the same enzyme are taken, they compete for that enzyme, which prolongs the duration of action of these medications and increases the risk of side effects.
In addition, there are active ingredients that inhibit (inhibitors) or stimulate (inducers) an enzyme, which accordingly affects their effectiveness in terms of drug metabolism.

In humans, metabolic enzymes catalyze two types of biotransformation reactions⁹⁵

• Phase 1 reactions:
  • Functionalization reactions
    • Oxidation, reduction, hydrolysis, and hydration
  • Mechanism of action:
    • Introduction of a functional group (or groups) (e.g., a hydroxyl group) into the nonpolar molecule, or
    • Identification of relevant functional groups
• Phase 2 reactions
  • Conjugation reactions
    • Glucuronidation, sulfation, methylation, acetylation, and conjugation with amino acids and glutathione
  • Mechanism of action:
    • Binding of functional groups to highly polar, negatively charged endogenous molecules (e.g., glucuronic acid)

In the following, we will focus only on those enzymes that are relevant to ADHD medications. However, this already covers the most important enzymes.
CYP3A4 (guanfacine) metabolizes 40 to 50% of all medications.
CYP2D6 (amphetamine-based medications, atomoxetine) metabolizes about 25% of all medications.

15.1. Metabolism increases or decreases depending on the metabolizing enzyme gene variant¶

The breakdown of active ingredients or neurotransmitters is influenced by how active the gene variant is that expresses the protein responsible for synthesizing their metabolic enzymes. Some gene variants result in increased or excessive protein production, while others result in reduced or no protein production at all.
In individuals with the COMT Val-158-Met gene polymorphism, amphetamine increases PFC efficiency in subjects with presumably low dopamine levels in the PFC. In contrast, in carriers of the COMT Met-158-Met polymorphism, amphetamine had no effect on cortical efficiency under low- to moderate-level working memory load and caused a deterioration under high working memory load. Individuals with the Met-158-Met polymorphism appear to have an increased risk of an adverse reaction to amphetamine.⁹⁸

15.1.1. ADHD Active Ingredients and Their Primary Metabolizing Enzymes¶

ADHD active ingredients are broken down by various enzymes:

Methylphenidate: CES1
Amphetamine-based medications: CYP2D6 (also highly dependent on pH)
Atomoxetine: CYP2D6
Bupropion: CYP2B6⁹⁵ and a bit about CYP2A6
Guanfacine: CYP3A4
Clonidine: unknown
Buspirone: CYP3A4
Memantine: unknown; likely not metabolized by CYP⁴⁷
Viloxazine: CYP2D6, UGT1A9, UGT2B15, and possibly also via CYP1A2
Melatonin: CYP1A
Dasotralin: unknown
Agomelatine: CYP1A2 (90%), CYP2C9/2C19 (10%)

See the comprehensive articles on the metabolic enzymes associated with the respective ADHD medications:

CES1 Metabolizing Enzyme:

• Methylphenidate (MPH)

CYP2D6 Metabolizing Enzyme:

• Amphetamine-based medications (AMP)
• Atomoxetine
• Bupropion: CYP2B6-⁹⁵, and to a lesser extent CYP2A6; however, it is a potent CYP2D6 inhibitor

CYP3A4 Metabolizing Enzyme:

• Guanfacine
• Buspirone

15.1.2. Pharmacogenetic Diagnostics¶

Genetic testing can be used to identify genetic variants of metabolic enzymes.⁹⁹

You can find suitable laboratories by searching for “Laboratory CES1” (for MPH) or “Laboratory CYP2D6” (amphetamine medications, atomoxetine). In Germany, the cost of the laboratory test should be covered by health insurance if it has been prescribed by a doctor.

As of September 2023, laboratory testing for the 22 most important metabolism-related genes (including the POR gene, which is important for the CYP gene family) cost approximately €600.
A sample diagnostic report is available from CeGaT, a provider of genetic diagnostics in Tübingen.¹⁰⁰ Genetic analyses of individual metabolism-related genes cost around €300 in September 2023.

15.2. Competition for Depletion and Cross-Effects¶

The effects of medications can be influenced in various ways by the enzymes that break them down.

Risk:
The mechanisms of competition, inhibition, induction, or modulation of gene expression described below must be taken into account when planning medication regimens. Failure to do so poses a risk or may even constitute medical malpractice. A new medication can affect the effect of a medication already being administered (and vice versa), thereby creating a risk of reduced efficacy and/or overdose of the new medication or the existing medication(s).

Benefits:
However, these same mechanisms of action can also be harnessed intentionally and can then be beneficial.
Conversely, a deliberate combination of drugs that compete with, inhibit, or genetically regulate one another can be helpful in enhancing the effectiveness of individual drugs. Thus, when drugs are administered simultaneously, their dosages can be adjusted—either more cautiously or more aggressively—depending on the interactions involved. Similarly, such combinations can be used strategically, for example, to enhance the effect in ultra-rapid metabolizers or to improve drug clearance in slow metabolizers.
Example: A person with ADHD who metabolized a dose of Vyvanse within 5–6 hours reported to us that combining it with 150 mg of bupropion was very helpful in prolonging the duration of Vyvanse’s effect. Vyvanse is metabolized via CYP2D6; bupropion genetically inhibits CYP2D6.

15.2.1. Competition¶

Competition from other substrates: When multiple active ingredients bind to the same enzyme (substrates) and are broken down by it, they compete for the available amount of breakdown enzymes when administered simultaneously. This can delay the breakdown process.

15.2.2. Inhibition¶

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

15.2.3. Induction¶

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

15.2.4. Genetic Regulation¶

Genetic Regulation: Active pharmaceutical ingredients can also influence metabolic enzymes through genetic regulation.
For example, in vitro, bupropion is only a relatively weak inhibitor of CYP2D6. In vivo, however, bupropion strongly inhibits CYP2D6 because it also causes genetic downregulation of CYP2D6 mRNA.¹⁰¹

16. Excretion: Renal Blood Flow¶

Since amphetamine is excreted by the kidneys, renal blood flow—in addition to the total dose—plays a small but measurable role in the duration of action.⁵
Another consequence of this is that blood levels of amphetamine change more slowly and are less prone to rebound than with methylphenidate,⁵

Starting at age 40, the glomerular filtration rate decreases by an average of 8 ml/min/1.73 m² per decade (0.1 ml/s/m² per decade). There are significant individual differences.
Serum creatinine levels often remain within the normal range in older adults despite a decrease in glomerular filtration rate, due to reduced muscle mass and decreased physical activity; as a result, serum creatinine levels no longer reflect normal kidney function in older adults. The clearance of psychotropic drugs excreted by the kidneys is reduced in older adults:³²³³

• Brexpiprazole
• Lurasidone
• Paliperidone
• Risperidone

17. Gene Variants and Response¶

A GWAS identified the effects of various genes on the response to MPH and ATX:¹⁰²

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

18. Dosage Forms¶

The binding of ionizable active ingredients to salts has a pharmacological effect⁹³¹⁰³

• physical and chemical properties
  • Improving the water solubility of weakly acidic and basic active ingredients
• Characteristics of the dosage form
• biopharmaceutical characteristics
  • e.g., safety and tolerability
• therapeutic efficacy

The most commonly used counterions are⁹³

• for basic active ingredient molecules
  • hydrochloride
  • mesylate
    • highest solubility of all salts at 25 °C (39 mg/ml)
  • hydrobromide
  • Acetate
  • Fumarate
  • sulfonate¹⁰⁴
    • Methanesulfonate
    • Kampfersulfonate
• for weakly acidic active ingredients
  • Sodium
  • Calcium
  • Potassium

 

19. Red Blood Cell Function with Lisdexamfetamine¶

The available studies to date show that the rate at which LDX is converted to dAMP by erythrocytes in humans can vary by at least 60%. This 60% represents the range observed in just six individuals whose erythrocyte hydrolysis was measured individually (not pooled, not diluted)—four of them in Pennick (2013) and two in Pennick (2010). A larger range is expected when analyzing a larger number of subjects. Other studies suggest an even wider possible range.

A short t½ corresponds to a rapid transformation. The minimum value of the velocity therefore corresponds to the maximum value of the half-life.

Level	t½-span	k (h⁻¹)	bandwidth	basis
In vivo, individual	0.39–0.55 h	1.26–1.77	40%	6 individuals, kₑ reported in the original
In vivo, all group means (dose + food)	: 0.41–0.9 h	: 0.77–1.69*	: 120%	: 4 studies
In vitro, individual (undiluted)	0.87–1.36 h	0.51–0.80*	60%	6 people
Total human	0.39–1.6 h	0.43–1.78*	410%	see above

* Kₑ values calculated using k = ln2/t½

The in vivo t½ therefore appears to reflect not the rate of hydrolysis, but rather the sum of hydrolysis, distribution, and renal excretion, and must therefore be distinguished from the in vitro t₁/₂.

19.1. In vitro¶

LDX 1 µg/mL, 37 °C, incubation for up to 4 hours, LC-MS/MS

Matrix / Condition	Design	t½ reported	t½ min	t½ max	Range	d-amphetamine after 4 h	Source
Human whole blood	in vitro	1.6 h	—	—	—	—	Pennick (2010)105
Human whole blood (pooled, n = 3 donors)	in vitro	1.6 h (SD 0.5); 82% (SD 8) loss after 4 h	1.1 h *	2.1 h *	91% *	446 ng/mL (SD 20)	Sharman & Pennick (2014)106
Human whole blood, 2 healthy donors	in vitro	1.15 / 1.13 h; Residual 13.1% / 10.5%	1.13 h	1.15 h	1.8% ‡	297.0 / 324.3 ng/mL	Pennick (2013)107
Human whole blood, 2 donors with sickle cell disease	in vitro	1.30 / 1.36 h; Residual 14.1% / 15.3%	1.30 h	1.36 h	4.6% ‡	304.5 / 286.6 ng/mL	Pennick (2013)107
Isolated erythrocytes, 2 donors	in vitro	Ø 1.0 h	0.87 h	1.10 h	26.4% ‡	—	Pennick (2010)105
Red blood cells, varying hematocrit (10–90%)	in vitro	published only as a figure	n. b.	n. b.	n. b.	—	Pennick (2010)105Fig. 8; Pennick (2013)107
Erythrocyte lysate (diluted 1:5)	in vitro	no t½ calculated; 24% loss / 4 h	—	—	—	102 ng/mL	Sharman & Pennick (2014)106
Erythrocyte cytosol extract (diluted 1:3)	in vitro	4.1 h (SD 0.99); approx. 50% loss / 4 h	3.1 h *	5.1 h *	65% *	223 ng/mL (SD 53)	Sharman & Pennick (2014)106
Erythrocyte membrane fraction	in vitro	no measurable degradation	—	—	—	29 ng/mL	Sharman & Pennick (2014)106
Human plasma	in vitro	completely stable over 4 hours	—	—	—	< LOD (10 ng/mL)	Sharman & Pennick (2014)106
PBMC, PMN, platelets	in vitro	stable	—	—	—	negligible	Pennick (2010)105
Human kidney homogenate	in vitro	2.3 h	—	—	—	—	Pennick (2010)105
Human liver homogenate	in vitro	9.7 h	—	—	—	—	Pennick (2010)105
Comparison: Rat whole blood	in vitro	1.0 h	—	—	—	—	Pennick (2010)105
Comparison: Rat liver	in vitro	2.5 h	—	—	—	—	Pennick (2010)105
Across studies: all individuals, undiluted matrix	in vitro	—	0.87 h	1.36 h	56.3%	—	Pennick (2010)105Pennick (2013)107

* Derived from the mean ± 1 SD, unpublished; SD from repeat experiments using pooled blood (assay variation), no interindividual variability.

‡ Calculated from only two data points — describes the distance between these two people; not a reliable estimate of the spread.

19.2. In vivo¶

Healthy adults, single oral dose

Parameter	Design	Reported value	min	max	Bandwidth	Type of range	Source
LDX Plasma-t½, 70 mg (n = 6)	in vivo	0.45 ± 0.06 h	0.39 h	0.55 h	41.0%	individual	Comiran et al. (2021)108, Table 1
LDX Plasma-t½, 70 mg on an empty stomach (n = 13)	in vivo	0.41 ± 0.07 h	—	—	—	Group mean	Krishnan & Zhang (2008)109, Table III
LDX Plasma-t½, 70 mg as a solution (n = 17)	in vivo	0.44 ± 0.10 h	—	—	—	Group mean	Krishnan & Zhang (2008)109
LDX Plasma-t½, 70 mg with a high-fat meal (n = 16)	in vivo	0.63 ± 0.20 h	—	—	(53.7 %) †	Group mean, dietary effect	Krishnan & Zhang (2008)109
LDX plasma t½, 50–250 mg (n = 9–20 per dose)	in vivo	0.6 / 0.7 / 0.7 / 0.9 / 0.9 h	—	—	(50.0%) †	Dose trend	Ermer et al. (2010)29, Table II
LDX kₑ Plasma, 70 mg	in vivo	1.57 ± 0.19 h⁻¹	1.26	1.77	40.5%	individual	Comiran et al. (2021)108
LDX tmax, 70 mg	in vivo	1.2 ± 0.3 h	0.8 h	1.5 h	87.5%	individual	Comiran et al. (2021)108
LDX tmax, fasting / solution / with food	in vivo	1.15 / 0.97 / 2.08 h	—	—	(114.4%) †	Group mean, food effect	Krishnan & Zhang (2008)109
LDX tmax, 50–250 mg	in vivo	1.0–1.5 h (median)	1.0 h	1.5 h	50.0%	dose groups	Ermer et al. (2010)29
d-amphetamine plasma half-life (t½), 70 mg	in vivo	10.70 ± 2.09 h	7.77 h	13.95 h	79.5%	individual	Comiran et al. (2021)108, Table 2
d-amphetamine plasma half-life (t½), fasting / fed / solution	, in vivo	, 9.69 / 9.59 / 9.37 h	—	—	(3.4 %) †	group mean	, Krishnan & Zhang (2008)109, Table I
d-amphetamine plasma half-life (t½), 50–250 mg	in vivo	10.9–12.4 h (mean)	—	—	(13.8%) †	dose groups	Ermer et al. (2010)29, Table I
d-amphetamine kₑ plasma, 70 mg	in vivo	0.07 ± 0.01 h⁻¹	0.05	0.09	80.0%	individual	Comiran et al. (2021)108
d-amphetamine tmax, 70 mg	in vivo	3.8 ± 0.8 h	3.0 h	5.0 h	66.7%	individual	Comiran et al. (2021)108
d-amphetamine tmax, fasted / fed / solution	in vivo	3.78 / 4.72 / 3.33 h	—	—	(41.7%) †	group mean	Krishnan & Zhang (2008)109
d-amphetamine tmax, 50–250 mg	in vivo	4 to 6 h (median)	4 h	6 h	50.0%	dose groups	Ermer et al. (2010)29
Across studies: LDX plasma t½, all conditions	in vivo	—	0.39 h	0.90 h	130.8%	mixed	Comiran et al. (2021)108Krishnan & Zhang (2008)109; Ermer et al. (2010)29

† Value in parentheses: calculated from group means where the min/max cells are empty. This reflects a dietary or dose effect, not interindividual variability. Do not compare this with the values without parentheses in any statement.

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