Efficacy and Duration of Action of ADHD Medications

Completely revised 08/2026

Only in theory is the drug concentration proportional to the administered dose. In general pharmacological practice, there are significant interindividual variations 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, 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 considered 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, illicit 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)
• Elimination (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.
However, in cases of ADHD, medications must always be tested and adjusted on a highly individualized basis.
This article focuses on 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 alone 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. comes 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. The typical duration of action for immediate release methylphenidate is 3 to 4 hours, but it can also be as short as 1 hour; this is due to variations in the activity of the esterases that break down the drug from person to person.⁵ With the half-day sustained-release formulation, the duration can therefore range from 5 to 6 hours down to 1.5 to 2 hours. Similarly, although apparently less frequently, there are people with ADHD for whom a formulation has a significantly longer duration of action.
The duration of the MPH’s effects is said to be stable and predictable for each individual and to remain unchanged throughout their entire lifespan. ⁵

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.
A half-day treatment session is not effective. ADHD is not a “morning disorder.”

	Active ingredient Typical duration of action in hours (according to the manufacturer) Empirical data from the ADxS survey Sustained release Country
Ritalin, Methylphenidate HEXAL, Methylpheni TAD (immediate release), Medikinet (immediate release), generic methylphenidate	Methylphenidate	2.5–3.5;5	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	Duration of action: 5–8 hours (theoretical), 3–5 hours (practical)7, 84		sustained-release7	EU
Focalin	Dexmethylphenidate	4–6		immediate release	USA
Equasym Retard/XL	Methylphenidate	6 - 88 / 8 9		Two-phase sustained-release	EU
Medikinet Adult (adults), Medikinet Retard (children) (same extended-release formulation, different marketing authorization)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 (same extended-release formulation, different marketing authorization)	Methylphenidate	6–87 / 8 8	4.6 hours (3.38 to 6.0 / 1st quartile to 3rd quartile)12		EU; U.S. only Ritalin LA
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), , 10–12 , 12 10.2 hours (7.5 to 11.5 / 1st quartile to 3rd quartile) sustained release D, CH, USA8713	14
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 effect in hours (according to the manufacturer)	Empirical data from the ADxS survey	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
				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)	7 hours or less in 57% of people with ADHD; up to 5 hours in about one-third (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	once daily; plasma half-life varies individually from approximately 5 hours (rapid metabolizers) to approximately 22 hours (slow CYP2D6 metabolizers)17	immediate release	EU (Germany), USA
Intuniv	Guanfacine	throughout the day; peak concentration after approximately 5 hours; elimination half-life approximately 18 hours	sustained release	EU (D), USA

The course 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 Medication Duration 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	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%

The perceived duration of effect is thus significantly shorter than the 13 hours (children) and 14 hours (adults) reported in the Shire-funded review conducted by former Shire employees. The underlying studies measured not only significant but also pronounced effects even after 13 and 14 hours, respectively.¹⁹

For about one in three people, a single dose lasts only up to 5 hours; for more than half (57.3%), it lasts 7 hours or less. Less than a quarter of people with ADHD (23.7%) experience a duration of effect of 10 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 generally being lower than the preceding ones).
The three surveys are self-reported data from self-selected samples (forum, subreddit, ADxS form). People who are dissatisfied with the duration of the medication’s effect are more likely to participate in such surveys than those who are satisfied. The results therefore cannot be generalized to all patients receiving treatment.

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 showed barely any variation among adults based on age. Even among users aged 60 and older, the average dose was 38.9 mg.

There is evidence that lisdexamfetamine has a delayed, but not prolonged, effect compared to dextroamphetamine. In a randomized, double-blind, placebo-controlled crossover study involving 24 healthy subjects (100 mg of lisdexamfetamine versus 40 mg of dextroamphetamine at an equimolar dose), the rise in plasma amphetamine levels following lisdexamfetamine began 0.6 ± 0.6 hours later and reached its peak 1.1 ± 1.5 hours later; Cmax, AUC, and the elimination constant did not differ. The concentration curves were nearly identical, differing only in their timing.²⁰²¹ (Dolder used 100 mg of lisdexamfetamine—above the maximum approved dose of 70 mg—in healthy subjects, not in people with ADHD. The applicability to the therapeutic setting is therefore limited.)
Nevertheless, this strongly calls into question the manufacturer’s claim of 13 to 14 hours per single dose and is consistent with the findings discussed above under empirical data on the duration of action of a single dose of lisdexamfetamine experiences of people with ADHD.
In a crossover study comparing the daily profiles of once-daily lisdexamfetamine versus twice-daily dexamfetamine in adults with ADHD, the treatment effects were comparable, despite the bioequivalence limits being exceeded. The effect of LDX was perceived as more consistent. Patient satisfaction was higher with dexamfetamine 2 hours after the first dose than with LDX, while with LDX it was higher than with dexamfetamine for the remainder of the day. The desire for more of the active ingredient was significantly lower with LDX throughout the day, which was attributed to the slower decline in dAMP levels. Sleep quality did not differ. ²² Dexamfetamine’s greater flexibility in adjusting the dose and dosing schedule to individual daily routines and needs could be advantageous for some patients.

The time to reach maximum dAMP levels following oral administration of LDX was determined using

• 3 hours (healthy adults in a steady state)²³
• 3.5 hours (children)²⁴
• 4 hours²⁵
• 4.23 hours (preschoolers)²⁶
• 4.4 hours (adults with ADHD undergoing treatment for less than five weeks)²⁷.

Following intravenous administration, the time to reach maximum dAMP levels was measured at 2.1 hours.²⁸

Adler et al. (2017) ²⁷ studied 21 adults with ADHD who underwent five weeks of treatment with up to 70 mg of lisdexamfetamine daily. They simultaneously measured plasma levels of d-amphetamine and symptom severity using the Time-Sensitive ADHD Symptom Scale, both before the morning dose and then at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours. Results: Tmax 4.4 hours, AUC 641.6, Cmax 67.9, half-life 17.0 hours—and, to quote the study directly, no statistically significant correlations were found between d-amphetamine levels and symptom scores.

Exposure to dexamfetamine released from lisdexamfetamine may be prolonged by taking alkalizing agents. ²¹

Impaired renal function did not alter the absorption of the prodrug lisdexamfetamine in cases of mild to severe impairment; only in patients with end-stage renal failure requiring dialysis were the Cmax and AUC of the prodrug elevated. For the active ingredient d-amphetamine, total exposure (AUC) increased with increasing renal impairment, while the peak concentration (Cmax) decreased. In patients with end-stage renal disease, the weight-adjusted clearance of d-amphetamine was approximately 50% lower than that in patients with normal renal function. Neither lisdexamfetamine nor d-amphetamine is dialysable.²⁹ (This work was conducted by Shire; Ermer is a former Shire employee and holds shares and options.)
This leads to the following maximum doses: for severe renal impairment (GFR 15 to less than 30 mL/min/1.73 m²), 50 mg of lisdexamfetamine daily; for end-stage renal failure (GFR less than 15), 30 mg daily. The consequences of the altered pharmacokinetics for the clinical duration of action have not been determined.

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 Elvanse/Vyvanse but also methylphenidate had a much shorter duration of action. Since dextroamphetamine and MPH are metabolized in different ways and 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 with 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 genes for CYP2D6 and POR in people with ADHD. For more information, see Metabolism of Amphetamine as well as 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 (n = 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%
> 5 to 7 hours	, 14.1%
8 hours or more	, 4.9%

Thus, 67.5% of people with ADHD report that a single dose remains effective for > 3 to 5 hours, and 81.6% report a duration of action of > 3 to 7 hours. The results are therefore significantly more consistent and closer to the manufacturer’s specifications than those for lisdexamfetamine.

Medikinet Retard and Medikinet Adult (which have the same drug release profile) had an average duration of action of 4.58 hours (n = 132) at an average dose of 20.64 mg, Ritalin Adult and Ritalin LA (which also use the same extended-release formulation) 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 individually influence the duration of a medication’s effects (particularly in the case of ADHD medications).

2. Single-dose amount¶

Some people with ADHD report that higher single doses of amphetamine (especially lisdexamfetamine) have a longer-lasting effect for them.
Pharmacological tests of various doses of lisdexamfetamine show, however, that Tmax remains approximately the same. In children with ADHD (ages 6 to 12), Tmax for d-amphetamine was less than 30, 50, and 70 mg LDX, respectively, was approximately 3.5 hours, while the peak concentration increased in a dose-proportional manner from 53.2 to 93.3 to 134.0 ng/mL.²⁴ Ermer et al. ³⁰ reached a comparable conclusion in adults.
Tests using doses above the therapeutic range showed that lysine cleavage is neither saturated nor slowed by higher doses; dAMP exposure increased linearly with dose over the range of 50 to 250 mg.³⁰
Ermer et al. ³⁰ report low inter-individual variability—whereas the findings, based in part on the ADxS surveys (Section 19), indicate high inter-individual variability.
This discrepancy could be explained by the fact that manufacturer studies measure plasma levels in a small number of healthy volunteers under standardized conditions, whereas the ADxS surveys capture the perceived duration of effect among people with ADHD in their everyday lives. A consistent blood level does not automatically mean a consistent effect, and variations in everyday life also include diet, urine pH, concomitant medications, and circadian rhythms.

With lisdexamfetamine, food affects only the onset of action, not the potency. In healthy adults, following a single 70-mg dose, the total amount of dexamfetamine absorbed (AUC) and the peak concentration (Cmax) were independent of whether the dose was taken on an empty stomach or after a meal. ³¹ The only change was in the time to peak concentration, which shifted from 3.8 hours when taken on an empty stomach to 4.2 hours after a soft food such as yogurt and to 4.7 hours after a high-fat meal. Stirring the capsule into yogurt delays the onset of action by about 25 minutes; after a high-fat breakfast, it delays it by just under an hour.
Dissolving the capsule contents in orange juice—which is expressly permitted in the prescribing information—does not alter the amount of active ingredient absorbed.³²

The duration of action of a single dose of methylphenidate is believed to be independent of the dose.³³
For amphetamine-based medications, Dodson reported a longer duration of action at higher single doses.⁵

3. Gastric Transit Rate¶

In addition to the rate of passage through the small intestine, stomach function 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 the blood plasma. Delayed or accelerated gastric emptying can thus fundamentally influence the kinetics of orally administered drugs, so that, for example, the necessary therapeutic levels are not reached or are reached only after a delay.³⁴

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.³⁵³⁶

Lisdexamfetamine is absorbed as an intact prodrug via the PEPT1 peptide transporter, which is highly expressed in the small intestine but barely expressed in the large intestine.³⁷ Consistent with this, a study examining targeted release at various sites along the gastrointestinal tract found that d-amphetamine exposure was equivalent to that of oral administration when released in the small intestine, but was reduced when released in the ascending colon. (18 healthy men, ages 18–48).³⁸
In practice, anything that shortens the transit time through the small intestine can reduce the amount absorbed—for example, diarrhea, laxatives, or a shortened intestine following surgery.

Anticholinergic drugs can slow the movement of medications from the stomach into the small intestine.³⁵³⁶

Following gastric reduction surgery or gastric bypass surgery, dexamfetamine levels increased when lisdexamfetamine was administered (n = 4); Tmax tended to be reduced (n = 5). With atomoxetine (n = 2), total exposure (AUC0–24) remained unchanged, the peak concentration was higher, and Tmax was shorter. For methylphenidate, the AUC0–24 of ritalin acid was unchanged (n = 1).³⁹

Malabsorptive bariatric procedures (e.g., small intestine bypass) result in measurably more acidic urine. The 24-hour urine pH was significantly more frequently reduced compared with restrictive procedures (e.g., sleeve gastrectomy, gastric banding) (odds ratio 3.76; 95% confidence interval 1.33 to 10.64), as were hypocitraturia and hypomagnesuria.⁴⁰

This points to a second mechanism of action independent of absorption: Following gastric bypass surgery, not only does the absorption of the active ingredient change, but so does its excretion due to more acidic urine; moreover, acidic urine shortens the duration of the amphetamine’s effects (see section 5.1. on this page). The opposing nature of these two effects could explain the inconsistent findings reported by Krabseth et al. ³⁹. In particular, patients taking lisdexamfetamine should be closely monitored following bariatric surgery (gastric sleeve, gastric bypass), and the dose should be adjusted based on their response. A case study reports methylphenidate and lisdexamfetamine intoxication in a female patient with ADHD following gastric bypass surgery.⁴¹

4. Small intestine¶

4.1. Small Intestine Length¶

In children, the small intestine is shorter, resulting in reduced absorption through the small intestine.⁴²⁴³

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.”⁴⁴

This time may vary from person to person, just as the rate of intestinal transit varies. This is likely why there are a few individuals with very fast metabolisms 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 stomach⁴⁵
  • 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
  • Premature 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 urine⁴⁶
  • 5.85 Average
  • 6.6 and above at 10%
  • 7.2 and higher at 1%
  • Intra-individual fluctuations throughout the day ranged from 0.77 to 2.48, with an average of 1.5.
    • The daily variation is thus greater than the effect of almost all dietary measures (vegan diet +0.52, high-protein diet -0.65).
  • Urine pH below 6.6 over the full 24-hour period in 39% of cases
  • The 24-hour average did not exceed 6.34 for any of the participants.

 Urine pH is the sole determining factor for the duration of action of amphetamine medications, because it is related to the renal reabsorption of amphetamine.

Depending on the duration of exposure to acid, the pH value can affect:⁴⁵

• Solubility of active ingredients
• Stability of active ingredients

Foods affect the body’s pH level.⁴⁷
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.^48495051

• Reduced duration of action due to high urinary acidity (low pH), e.g., caused by (see detailed list below)
  • Ascorbic acid (vitamin C) – according to the Vyvanse prescribing information⁵¹; however, the available studies do not support a significant acidifying effect
    • Ascorbic acid taken at the usual dose left the urine pH level virtually unchanged (+0.03; 5 studies, 7 individual results, none of which were statistically significant)⁵²
      • Vitamin C is metabolized quickly, and its PRAL value (potential renal acid load) is close to zero (= neutral)
      • High doses of vitamin C can temporarily acidify the urine because excess ascorbic acid is excreted by the kidneys. This applies to high doses taken as dietary supplements, but barely to normal dietary intake.
      • Ascorbic acid (vitamin C) taken in an appropriate dose left the pH value virtually unchanged (+0.03)⁵²
      • Vitamin C (ascorbic acid) is metabolized quickly, 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
  • Proton pump inhibitors⁵³
    • LDX: no effect on total exposure or the time to tMax
    • sustained release amphetamine salts: no effect on total exposure; in approximately 50% of subjects taking omeprazole, tMax occurred earlier
      • suggests an unexpected release of the active ingredient from the second MAS XR capsule, presumably due to reduced stomach acid while taking a PPI
• Prolonged duration of action due to low (alkalized) urinary acid content (high pH)²¹, e.g., through (see below for a detailed list)
  • Potassium citrate
  • Sodium hydrogen carbonate = sodium bicarbonate
  • Mineral water with bicarbonate⁵⁴
  • A diet high in fruits, vegetables, and whole grains
  • Urinary tract infections
  • Vomiting
  • A change in diet, for example, from a meat-based diet to a vegetarian diet⁵⁵
  • heavy use of medications to neutralize stomach acid⁵⁵

The highest d-AMP level reached (Cmax) also correlates with urine pH, though to a much lesser extent than the AUC. Acidic urine is therefore primarily associated with a shorter duration of effect and, to a lesser extent, with a weaker effect.⁵⁶

While 54.5% of orally administered amphetamine was excreted unchanged via the kidneys at a urine pH of 5.0 (acidic urine), this value was 2.9% at a pH of 8.0 (alkaline urine). When the pH was uncontrolled, the figure was 14.5% (computer simulation, calibrated using measurement data from two subjects from the 1960s).⁴⁸⁵⁶ Study design: Six young men received 10 to 15 mg of dexamfetamine sulfate on three separate occasions, one week apart. All urine produced over the following 16 hours was collected hourly. On the first visit, urine pH was left uncontrolled; on the second, it was lowered to approximately 5.0 using ammonium chloride tablets; and on the third, it was raised to approximately 8.0 using sodium bicarbonate.
The participants experienced a significantly prolonged stimulant effect when their urine was alkaline. Several reported sleep disturbances after taking 10 mg of dexamfetamine sulfate at 8 a.m. When their urine was acidic, however, the subjective effect began to wear off after just four to eight hours.
This direct observation of the duration of action as a function of urine pH in humans corresponds remarkably well with the empirical findings from the ADxS surveys in Section 1.2.
The authors subsequently warn against “normal” doses of amphetamine in cases of unusually alkaline urine, particularly with extended-release capsules. In our view, this warning should now be extended to include prodrugs (lisdexamfetamine). Conversely, in the event of an amphetamine overdose, excretion can be accelerated by acidifying the urine.
In another study, eight subjects received 10 mg of sustained-release d-methamphetamine four times a day for seven days, followed by five subjects receiving 20 mg four times a day. Gas chromatography–mass spectrometry analysis of the urine samples showed that urine pH has an inverse effect on the excretion rate: ⁴⁹⁴⁸

• Acidic urine: up to 76% unchanged excretion
• Alkaline urine: 2% unchanged excretion
• On average, 57.5 ± 21.7% (low dose) and 40.9 ± 8.5% (high dose) of the dose was recovered in the urine as methamphetamine plus amphetamine. In a computer simulation, an 11 mg dose of amphetamine resulted in an exposure of:
  • pH 5.0: 361 µg·h/L
  • pH 6.5: 692 µg·h/L
  • pH 8.0: 1,325 µg·h/L

The highest available value of the pharmacological d-AMP concentration (Cmax) also correlates—albeit to a much lesser extent—with urine pH, meaning that acidic urine correlates with a slightly weaker effect, but above all with a significantly shorter duration of action.⁴⁸
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.⁴⁸⁵⁶

A 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) using bacterial cultures and culture media—not from the human body—up to 60% of the methylphenidate was spontaneously hydrolyzed to (pharmacologically inactive) ritalinic acid, and this hydrolysis was pH-dependent. In bacterial cultures in which MPH was not hydrolyzed, the pH after 24 hours ranged from 4.0 to 5.5; in cultures with high MPH hydrolysis, it 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%. The correlation between MPH hydrolysis and the pH of the cultures after 24 hours was high (r = 0.89, r² = 0.79, p = 0.0006). In pure culture medium without bacteria, approximately 20% of the MPH was hydrolyzed to ritalinic acid at pH 6.0, and approximately 80% at pH 8.0. Bacterial esterases did not contribute to the hydrolysis: An E. coli mutant lacking the yjfP esterase gene hydrolyzed MPH to the same extent as the wild-type strain.⁵⁷
To put bioavailability into perspective: In healthy adults, only 22% (± 8%) of d-MPH and 5% (± 3%) of l-MPH reach the systemic circulation; in children with ADHD, the systemic bioavailability of total MPH averages 31% (± 16%), ranging from 11% to 52%.⁵⁸ Of the MPH metabolized in the liver, approximately 80% is hydrolyzed and approximately 20% is oxidized.⁵⁸ 80% of the ingested MPH is excreted in the urine within 48 hours (of which 80% is as ritalinic acid and less than 1% is excreted unchanged), and approximately 3% is excreted in the feces.⁵⁸ Model calculations assume that a very large proportion of orally ingested MPH is metabolized in the small intestine before it reaches the liver; this is an assumption made by the models to explain the low bioavailability, not a direct measurement.^{5859 60} U

The absorption model accurately reproduced the measured plasma concentration profiles for a multilayer sustained-release formulation and for Metadate CD, but deviated noticeably from the measured values, particularly for Ritalin LA and Medikinet Retard.⁵⁹
For the latter two medications, the duration of action reported in the ADxS surveys in Section 1.2.3 was significantly shorter than the manufacturers’ specifications.

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)⁵⁷ Published under the terms of the Creative Commons Attribution (CC-BY)license.

However, these lab results pertain to the pH level in the small intestine, not the urine pH level.
A person with ADHD can benefit simultaneously from a low intestinal pH (favorable for MPH) and a high urine pH (favorable for amphetamine).

Whether the laboratory findings regarding MPH in humans are confirmed has not yet been investigated. The occasionally reported simultaneous shortening of the duration of action of amphetamine medications and MPH preparations in some people with ADHD cannot be explained by either of these mechanisms; no plausible mechanism for this is currently known.

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. ³⁵³⁶ This can be caused by

• Proton pump inhibitors (e.g., pantoprazole, omeprazole)
  • The pH level in the stomach is significantly increased
  • Urine pH
    • There is no evidence that proton pump inhibitors alter urine pH⁷⁴
    • Omeprazole has barely any effect on urine pH (+0.10)⁵²
  • We found no studies on MPH and proton pump inhibitors. The warnings appear to be based solely on theoretical considerations.
• Antacids
• H2 blockers (e.g., ranitidine, famotidine) (less likely)
• age-related increase
• atrophic gastritis

One 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 cites reduced absorption as a likely interaction with antacids.⁷⁵

5.3. Acid-Base Balance and Memantine¶

Memantine has a prolonged effect when urine is alkalized.
In cases of alkaline urine (high pH), the renal clearance rate of memantine may be reduced by a factor of 7 to 9. The prescribing information lists the following causes: drastic changes in diet (e.g., switching from a meat-based to a vegetarian diet), massive intake of alkalizing antacids, renal tubular acidosis, and severe urinary tract infections caused by Proteus bacteria.⁵⁵

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

Information in the following list that does not include a specific source citation is currently unsubstantiated. It originates from a website that is no longer accessible. In several cases, this information has proven to be incorrect 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:⁴⁶
      • 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 real fluctuations
      • a single afternoon peak with almost no morning fluctuation
      • Inversion of the “normal” curve, with a low daytime level and a high nighttime plateau
  • Body surface area
    • Cited as a factor, but the direction of the relationship is not specified⁷⁶.

• Body mass

  • A higher body mass index was associated (at least in men) with a lower urine pH⁷⁷
    • This results in a shorter duration of action for AMP

• Cadmium exposure

• Heparin

• Reduced air pressure; hypobaric ventilation⁷⁸

• Mercury contamination

• Youth:

  • Stomach acid production is higher at a younger age
  • Urine pH, on the other hand , decreases With age—see Section 5.5 for more on this.⁷⁹⁸⁰
    • in both men and women, especially those between the ages of 20 and 50⁸⁰

• female gender⁸¹⁸⁰

• low income⁸²⁸³ (socioeconomic status?) – the data is contradictory; see the conflicting entry in Section 5.5

  • Income correlates with the proportion of meat in the diet, which in turn affects urine pH

• Storing the urine at too high a temperature after collection⁸⁴

• Diseases:

  • 21-hydroxylase deficiency
  • 3-Hydroxydecahydrogenase deficiency
  • Rejection of a kidney transplant
  • Acute post-streptococcal glomerulonephritis
  • Amyloidosis
    *, atrophic gastritis (age-related gastritis)
  • Calcium deficiency⁴⁶
  • Carbonic anhydrase II deficiency
  • Chronic obstructive pulmonary disease
  • Vomiting
  • acquired adrenal insufficiency
  • Familial methyl oxidase deficiency
  • Galactosemia
  • Gout
  • Glycogen storage disease
  • Urine dilution⁴⁶
  • Increased urine flow⁴⁶
  • Hereditary fructose intolerance
  • Hyperventilation⁴⁶
  • Hypoxia (lack of oxygen, such as at high altitudes)
    • Hyperventilation leads to respiratory alkalosis and raises the urine pH⁸⁵
    • Acute exposure to high altitude triggers hyperventilation and, consequently, respiratory alkalosis. The kidneys compensate for this by excreting bicarbonate, which temporarily makes the urine more alkaline. In a study of 48 healthy men and women in a low-pressure chamber (simulated altitudes of 1,780, 2,085, 2,455, and 2,800 meters, for 24 hours each), the urine pH rose significantly after six hours at all altitudes (p < 0.01). At the lower altitudes, it returned to baseline after 24 hours, while at the highest altitudes, it remained elevated.⁸⁶This could explain an altered effect of amphetamine-based medications during mountain hiking or skiing.

• Lactosuria

• Light-chain multiple myeloma

• Lowe syndrome

• Lupus nephritis

• Malabsorption

• Medullary cystic disease

• Metabolic alkalosis

• Metachromatic leukodystrophy

• Mineralocorticoid deficiency, temporary 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 administration⁵²
    • Long-term treatment with acetazolamide is associated with an increased risk of urolithiasis⁸⁷
    • Acetazolamide inhibits carbonic anhydrase in the renal tubular cells. As a result, bicarbonate is not reabsorbed but excreted, and the urine becomes more alkaline (+2.00 intravenously; +0.39 orally)⁵². Acetazolamide is thus one of the most potent urine alkalizers. Pharmacologically, this would be the most effective way to alkalize the urine and prolong the effects of amphetamines. However, it is not approved for this purpose and is also unsuitable due to its significant side effects (common: risk of kidney stones, paresthesias, fatigue, taste disturbances, electrolyte imbalances). Acetazolamide causes systemic metabolic acidosis in the blood and, at the same time, alkalizes the urine

• ADV7103 (citrate + bicarbonate): Increase in urine pH by +1.27 (significant)⁵²

• Ambroxol (Note: Not when used as a cough suppressant; only in a rat study using a very high dose administered by subcutaneous injection (60 mg/kg). Not applicable to the use of cough suppressants in humans (1.3 mg/kg orally))⁸⁸

• Amiloride

• Aminoglycosides

• Antibiotics⁸⁹

• Ascorbic acid (vitamin C): Increase in urine pH by +0.03 (neutral)⁵²

• Bicarbonates (= hydrogen carbonates)

  • mineral water rich in bicarbonate
    • Increase in urine pH by +0.56 (moderate)^{5290 91 92} . The key factor is the bicarbonate content, not the label “alkaline”—waters containing 1,715 to 3,388 mg of bicarbonate per liter were effective.
    • Mineral water rich in bicarbonate should not be confused with “alkaline water.” While many waters marketed as alkaline have a high pH in the bottle, they contain barely any alkali. Their ability to significantly raise urine pH has not been proven. The key factor is the “hydrogen carbonate” content listed on the label. German medicinal waters often contain 1,800 to over 3,000 mg per liter, while common table waters often contain less than 300 mg.

• Bicarbonate loading (soda loading, baking soda loading): Increase in urine pH by +1.44 (very significant)⁵²

  • 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)⁵²⁹⁰

  • Citrus juices
  • Orange juice: Increases urine pH by +0.68 (moderate)⁵²

• Citro-Soda: Increase in urine pH by +1.56 (very strong)⁵²

  • 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

• Melon juice (cantaloupe): Increases urine pH by +0.36 (slightly)⁵²; in the original study, this effect was roughly equivalent to that of orange juice⁹³

• Exenatide: Increase in urine pH by +0.51 when administered intravenously (moderate)⁵² (diabetes medication)

• Glycine combined with L-tryptophan: Increase in urine pH by +0.20 (neutral)⁵²

• Indomethacin: Increase in urine pH by +1.0 (marked)⁵²

• Potassium citrate⁵²

  • Recommendation from the American Urological Association (AUA) on increasing the pH level of urine
  • Food additive E332
  • Dietary supplements, available over the counter as powders or capsules
  • Avoid in cases of hyperkalemia—therefore, always consult a doctor
    • Prevalence of hyperkalemia in the general population: 2 to 3%

• Potassium gluconate: Increase in urine pH by +0.46 (mild)⁵²

  • Potassium gluconate, a medication used to treat potassium deficiency

• Potassium hydrogen carbonate (potassium bicarbonate): Increase in urine pH by +0.89 (moderate)⁵² by 10% ⁹⁴ at a fairly high dose of 90 mmol daily (one liter of bicarbonate-rich medicinal water containing 3,400 mg of hydrogen carbonate provides approximately 56 mmol).

• Potassium sodium hydrogen carbonate (also known as potassium sodium hydrogen citrate)⁹⁵

  • Medication to increase urine pH

• Magnesium salts without chloride (e.g., magnesium oxide, magnesium citrate, magnesium carbonate) (studies in rats)⁹⁶

  • Magnesium chloride, on the other hand, causes hyperchloremic acidosis and lowers the urine pH—see below
  • Monomagnesium L-aspartate hydrochloride contains equal amounts of magnesium and chloride and therefore does not alter the balance of non-metabolizable acids and bases; rather, it is pH-neutral
    People with ADHD who take magnesium but do not want to shorten the duration of action of amphetamine-based medications should avoid magnesium chloride and choose a chloride-free form: magnesium citrate, oxide, or carbonate. In contrast, supplements based on magnesium L-aspartate hydrochloride (such as Magnesiocard) have no such effect.

• Metolazone

• Monosodium glutamate (flavor enhancer)⁹⁷

  • Demonstrated only in animal studies; at high doses (1.5 g/kg, many times the amount consumed by humans), it is unclear whether the findings are applicable to typical consumption levels

• Sodium hydrogen carbonate (sodium bicarbonate, baking soda): Increases urine pH by +1.19 when taken orally; +1.12 when administered intravenously; strong⁵²

• Sodium L-ascorbate and sodium saccharin – evidence is limited to rat studies in which these substances constituted 5% of the diet; irrelevant to human nutrition⁹⁸

• Niacin

• Omeprazole (proton pump inhibitor): Increase in urine pH by +0.10 (neutral)⁵²

• Spironolactone

• Streptozocin

• Topiramate: Increase in urine pH by +0.45 (mild)⁵²

• Food

  • DASH diet: Increase in urine pH of +0.50; not statistically significant in the only underlying study (n = 21, 56 days)⁵²

    • A diet rich in fruits, vegetables, whole grains, low-fat dairy products, fish, poultry, nuts, and seeds

  • Pickled cucumbers (pickles): Increase in urine pH of +0.17 (neutral, not significant)⁵²

  • Potatoes: Increase in urine pH of +0.28 (slight)⁵²

  • Lime juice: Increases urine pH by +0.25 (neutral, not significant)⁵²

    • It is unclear whether “lime juice” refers to lime syrup, water, and sugar, or pure lime juice

  • Lime powder (containing potassium and citrate): +0.52 (moderate)⁵²

  • Melon juice (cantaloupe): Increases urine pH by +0.36 (slight)⁵²; in the original study, it was roughly equivalent to orange juice⁹³

  • Milk: Increase in urine pH of +0.36 (slight)⁵²

  • Diet rich in fruits and vegetables: Increase in urine pH of +0.35 (slight)⁵²

  • Orange juice: Increases urine pH by +0.68 (moderate)⁵²

  • French fries: Increase in urine pH by +0.25 (neutral)⁵²

  • vegetarian diet

    • Lacto-ovo-vegetarian diet: Increase in urine pH of +0.85 (moderate)⁵²
    • Mixed Western vegetarian diet: Increase in urine pH of +0.56 (moderate)⁵²

  • Vitamin C: Increase in urine pH by +0.03 (neutral)⁵²

  • see below (PRAL value table)

5.5. Factors that increase acidity (lower the pH)¶

Information in the following list that does not include a specific source citation is currently unsubstantiated. According to earlier reports, it originated from a website that is no longer accessible. In several cases, this information has proven to be incorrect 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 exposure – documented only in animal studies involving high doses; the drop in pH was observed there as a sign of kidney damage⁹⁹

  • Cadmium¹⁰⁰

    • Administration of cadmium to rats via drinking water in increasing concentrations ranging from 100 to 1,600 mg/liter over a period of 20 weeks (= toxicological exposure doses)

  • Toluene

  • Vanadium

  • Age

    • Stomach acid decreases, while uric acid levels rise steadily (at least in people with kidney stones) with age ⁷⁹⁸⁰
      • in both men and women, especially those between the ages of 20 and 50⁸⁰

  • male gender⁸¹

  • high income⁸²⁸³ (socioeconomic status?)

  • physical exertion in a hot environment

    • 189 sugarcane cutters in El Salvador: a significant drop in pH over the course of a work shift ¹⁰¹
    • Work as a rice field laborer in Thailand – Cross-sectional findings using pH test strips, without a control group ¹⁰²
    • A cross-sectional study of 194 male workers between the ages of 17 and 39 on the Pacific coast of Nicaragua: 86 sugarcane cutters, 56 construction workers, and 52 smallholder farmers ¹⁰³ Impaired kidney function was most common among the sugarcane cutters, less common among construction workers, and barely observed among smallholder farmers (trend p = 0.003). The authors attribute this to heat stress and dehydration. The endpoint of this study is kidney function, not urine pH.

• Time spent in the desert: - 0.5 pHt¹⁰⁴

  • despite a daily fluid intake of 17 liters and a simultaneous 68% decrease in daily urine output to 0.52 liters
  • A change of 0.5 pH units is comparable to a high-protein diet (-0.65)
  • Full recovery within two weeks of returning

• Sleep deprivation: 0.00 – no effect⁵²

• 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 Syndrome¹⁰⁵

    • Low urine pH was associated with abdominal obesity, even after adjusting for environmental and lifestyle factors affecting urine pH (4,626 individuals with a urinepH of 5.0 and 4,185 individuals with a urine pH above 5.0 from a Korean genome and epidemiology study, age 52.2 ± 8.9 years, body mass index 24.6 ± 3.2; cross-sectional analysis. No conclusions can be drawn regarding the direction of the association—whether the low urine pH is a consequence of metabolic status)
    • Clinical relevance: Abdominal obesity is associated with more acidic urine, suggesting a shorter duration of amphetamine effects. This is consistent with the relationship between a rising body mass index and a decreasing urine pH.

• Kidney transplant rejection

• Kidney failure

• Polyarteritis nodosa

• Primary biliary cirrhosis

• Proximal renal tubular acidosis (Type II)

• Sickle cell anemia

• Sjögren’s syndrome

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

• Vitamin D toxicity

• Medications:

  • Acetaminophen = Paracetamol

  • Amiloride

  • Ammonium chloride (sal ammoniac): - 1.63; the highest single value found, based on only a small short-term study (n = 10, approximately 8 hours); not statistically significant in that study⁵²⁴⁸

  • 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: Decrease in urine pH by -0.05 (neutral, not significant)⁵²

  • Dapagliflocin: Decrease in urine pH by -0.10 (neutral)⁵² (diabetes medication)

  • Diclofenac

    • inhibits prostaglandins, which protect the stomach lining from acid
    • 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 by -0.52 following intravenous administration (not statistically significant)⁵²

  • 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

  • Saline infusion (sodium chloride), intravenous, for inpatients (METASTUDY, k = 2, n = 226)⁵²: -0.48

  • Lithium

  • Mafenid

  • Methionine: Decrease in urine pH by -0.72 (moderate)⁵²

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

  • Monomagnesium L-aspartate hydrochloride⁹⁶

  • Mefenamic acid

  • Naproxen

  • Niacinamide

  • Ofloxacin

  • Orthophosphate

  • Parathyroid extract

  • Proton pump inhibitors: Decrease in urine pH by -1.5 (very strong, n = 10)⁷⁴

  • Ranitidine

  • Triamterene

• Food

  • Apple cider vinegar: Decrease in urine pH by -0.21 (very slight)⁵²
  • Cranberry: Decrease in urine pH by -0.16 (neutral)⁵²
  • Protein: a high intake of animal protein in the diet¹⁰⁶
    • Eight patients with recurrent idiopathic calcium oxalate stones on a high-protein diet: urinary citrate decreased by 25%, serum bicarbonate decreased, and urinary pH decreased. Urinary calcium excretion increased by 35%. Oxalate excretion remained unchanged.

• Fasting: Decrease in urine pH by -1.2 (very significant)⁵²

• Fructose: Decrease in urine pH by -0.26 (very slight)⁵²

• ketogenic diet: decrease in urine pH of -0.55 (moderate)⁵²

• Low-oxalate diet: Decrease in urine pH of -0.10 (neutral, not significant)⁵²

• High-protein diet: Decrease in urine pH of -0.65 (moderate)⁵²

• See below (PRAL value table)

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

The ability of a food to produce acid or base is called the potential renal acid load (PRAL); Diets with a high PRAL lead to mild metabolic acidosis, which is associated with insulin resistance, diabetes, high blood pressure, kidney disease, bone loss, and low muscle mass.

Foods can significantly influence the pH of urine, but not that of blood. It is not so much an acidic taste that is decisive, but rather the PRAL value. The consumption of foods with a negative PRAL value correlates with an alkaline urine pH; an acid-forming diet correlates with acidic urine pH levels below 6.0. The blood pH level in healthy adults remains unaffected by this, as it is maintained at a constant level between 7.35 and 7.45 by buffer systems, respiration, and the kidneys.
Within a single day, the urine pH in the same individuals fluctuated between its lowest and highest values by 0.77 to 2.48 units, with an average fluctuation of 1.5 units. ¹⁰⁷
This daily fluctuation is thus greater than the effect of nearly all dietary measures (vegan diet +0.52, high-protein diet -0.65). The timing of intake and the time of day are therefore likely to have a greater influence on the duration of effect than the choice of individual foods.

When it comes to proteins, a distinction must be made between plant-based and animal-based proteins. In a randomized study of healthy young adults, the 24-hour urine pH increased by 0.52 ± 0.69 after seven consecutive days on a vegan diet. In contrast, when only two or three vegan days were incorporated throughout the week, the urine pH remained unchanged (-0.02 ± 0.56; difference between groups p = 0.048). The PRAL value decreased significantly in both groups. (Study of healthy college students, 21.8 ± 2.4 years) ¹⁰⁸ A consistently plant-based diet is thus mathematically associated with a prolonged effect of amphetamine medications, whereas occasional meat-free days per week are not expected to have this effect.
Foods high in oxalates can increase acid production.¹⁰⁹
The standard calculation formula is:⁵⁴¹¹⁰ PRAL (mEq/d) = 0.49 × Protein (g/d) + 0.037 × Phosphorus (mg/d) − 0.021 × potassium (mg/d) − 0.026 × magnesium (mg/d) − 0.013 × calcium (mg/d). There is a strong correlation between net renal acid excretion and urine pH (r = 0.83; p < 0.001), so that the PRAL value of a diet can be used to estimate the direction in which urine pH will shift.⁵⁴

In other words: Foods with a strongly negative PRAL value result in alkaline urine (less acidic, higher pH) and thus prolong the effects of amphetamine-based medications. Foods with a highly positive PRAL value cause the urine to be acidic (lower pH) and thus shorten the effects of amphetamine medications.

 

A table based solely on PRAL values does not adequately reflect the effect on urine pH of foods that contain hydrogen carbonate. The following table calculates, for foods containing hydrogen carbonate, the hypothetical PRAL value that a hydrogen carbonate-free food would need to have in order to produce the same effect on urine pH. Only then do the tables become a useful comparison tool.
Calculation: 1 mEq of base raises the balance just as much as 1 mEq of PRAL lowers it. The fictitious PRAL is therefore simply the negative base equivalent: mEq = mg of bicarbonate ÷ 61.02.

To achieve the same effect on urine pH as 1.5 liters of Apollinaris through PRAL alone, a food containing no hydrogen carbonate would need a PRAL value of −44.5 per daily serving. No single food achieves this. Spinach has the most negative PRAL value at −28.0. Therefore, one would have to eat 1.6 daily servings of spinach or 7 daily servings of broccoli to achieve the same effect.

One level teaspoon of baking soda, at −36 mEq, is roughly equivalent to 1.2 liters of Apollinaris. With a hypothetical PRAL of −1,190 per 100 g, baking soda is 19 times more potent than dried chanterelles (−61.9).

The hypothetical PRAL value of baking powder is approximately zero. German baking powder consists of sodium bicarbonate and an acidulant—usually disodium diphosphate—as well as starch as an anti-caking agent. During baking, the first two ingredients react with each other: The bicarbonate is consumed stoichiometrically and escapes as CO₂. Thus, practically no base equivalent reaches the body. What remains is the sodium salt of phosphoric acid. In the PRAL formula, phosphorus is counted as an acid with a value of +0.037. This is why, although the actual PRAL of baking powder is +297.99, baking powder is still an acid-forming substance despite its bicarbonate content. Pure baking soda, on the other hand, is a very strong base-forming substance.

A negative PRAL value increases urine pH, making the urine more alkaline; a positive value decreases it, making the urine more acidic.

Food (unsweetened, untreated)	PRAL per daily serving	daily serving	PRAL per individual serving	individual serving	PRAL per 100 g/ml
Medicinal water 3388 mg/l, Hydrogen carbonate equivalent (as in the Siener 2004 study)	-83.3 fictitious	1500 ml – 1.5 l	-11.1 fictitious	200 ml – 1 glass	-5.6 fictitious
Apollinaris Classic, hydrogen carbonate equivalent (1810 mg/l)	-44.5 (fictitious)	1500 ml – 1.5 l	-5.9 (fictitious)	200 ml – 1 glass	-3.0 (fictitious)
Medicinal water 1715 mg/l, Hydrogen carbonate equivalent (as in the Keßler & Hesse 2000 study)	-42.2 (fictitious)	1500 ml – 1.5 l	-5.6 (fictitious)	200 ml – 1 glass	-2.8 (fictitious)
Baking soda, hydrogen carbonate equivalent (pure)	-36 fictional	3 g – 1 level tsp	-36 fictional	3 g – 1 level tsp	-1190 fictional
Minimum threshold for medicinal water: 1,300 mg/l, bicarbonate equivalent:	-32.0 (fictitious)	1,500 ml – 1.5 l	-4.3 (fictitious)	200 ml – 1 glass	-2.1 (fictitious)
Spinach	-28.0	200 g – cooked	-28.0	200 g – cooked	-14.054
Apollinaris Mineral Water	-27.0	1500 ml – 1.5 l	-3.6	200 ml – 1 glass	-1.854
	Fruit Tea -21.0 600 ml – 3 cups -7.0 200 ml – 1 cup -3.5				109
Spinach leaves	-19.4	200 g	-19.4	200 g	-9.7111
Carrot juice	-19.2	400 ml – 2 glasses	-9.6	200 ml – 1 glass	-4.8
Potatoes	-17.0	200 g – (3 medium)	-17.0	200 g – (3 medium)	-8.5109 -4.0110 stored -4.054
Kale	-16.0	200 g	-16.0	200 g	-8.0109
Fennel	-15.8	200 g – 1 bulb	-15.8	200 g – 1 bulb	-7.9
Swiss chard	-15.2	200 g	-15.2	200 g	-7.6111
Beans	-14.8	200 g	-14.8	200 g	unclear: -7.4109 or 1.1109
Orange juice	-14.8	400 ml – 2 glasses	-7.4	200 ml – 1 glass	-3.7109 -2.954
Parsnip	-14.4	200 g	-14.4	200 g	-7.2111
Kale	-13.6	200 g	-13.6	200 g	-6.8111
Avocado	-12.8	150 g – 1 small	-12.8	150 g – 1 small	-8.5111
	Mineral Water -12.0 1,500 ml – 1.5 L -1.6 200 ml – 1 glass -0.8				109
Soy bread	-12.0	150 g – 3 slices	-4.0	50 g – 1 slice	-8111
Raw spinach	-11.8	100 g – 1 serving of salad	-11.8	100 g – 1 serving of salad	-11.8109
Brussels sprouts	-11.4	200 g	-11.4	200 g	-5.7111
Tomato juice	-11.2	400 ml – 2 glasses	-5.6	200 ml – 1 glass	-2.854
Zucchini	-9.2	200 g	-9.2	200 g	-4.654
Unsweetened apple juice	-8.8	400 ml – 2 glasses	-4.4	200 ml – 1 glass	-2.254
Beets	-8.8	150 g	-8.8	150 g	-5.9111
Dried apricots	-8.5	40 g – 4 pieces	-8.5	40 g – 4 pieces	-21.2111
Coffee (beverage)	-8.4	600 ml – 3 cups	-2.8	200 ml – 1 cup	-1.454
Bananas	-8.3	120 g – 1 piece	-8.3	120 g – 1 piece	-6.9109
Celery	-7.5	150 g	-7.5	150 g	-5.0109 -5.254
Chestnuts, precooked and vacuum-sealed	-7.4	100 g	-7.4	100 g	-7.4111
Mineral water, low in bicarbonate 300 mg/l, bicarbonate equivalent	-7.4 fictitious	1500 ml – 1.5 l	-1.0 fictitious	200 ml – 1 glass	-0.5 fictitious
Broccoli	-7.2	200 g	-7.2	200 g	-3.6109 -1.254
Dried kidney beans	-7.2	60 g – dry	-7.2	60 g – dry	-12111
Dried figs	-7.2	40 g – 3 pieces	-7.2	40 g – 3 pieces	-18.1
Daikon radish	-7.1	100 g	-7.1	100 g	-7.1111
Black currant	-6.5	100 g	-6.5	100 g	-6.554
Grapefruit	-6.4	200 g – 1/2	-6.4	200 g – 1/2	-3.2109 -1.054
Mushrooms	-6.3	150 g	-6.3	150 g	-4.2109 -1.454
Raisins	-6.3	30 g – 1 handful	-6.3	30 g – 1 handful	-21.054
Beet syrup/sugar beet molasses	-6.3	20 g – 1 EL	-6.3	20 g – 1 EL	-31.6111
Green beans	-6.2	200 g	-6.2	200 g	-3.154
Chanterelles, dried	-6.2	10 g – 1 handful	-6.2	10 g – 1 handful	-61.9111
Tomatoes	-6.2	150 g – 2 pieces	-6.2	150 g – 2 pieces	-4.1109 -3.154
Beans, white, dried	-5.9	60 g – dried	-5.9	60 g – dried	-9.9111
Dark chocolate	-5.8	50 g – half a bar	-3.5	30 g – 3 pieces	-11.5
Tomato paste	-5.8	30 g – 2 EL	-5.8	30 g – 2 EL	-19.4111
Carrots, raw	-5.7	100 g – 2 pieces	-5.7	100 g – 2 pieces	-5.7109 young -4.954
Regular spaghetti	-5.5	250 g – cooked	-5.5	250 g – cooked	-2.2109 6.554 8.0110
Asparagus	-5.5	250 g	-5.5	250 g	-2.2109
Oranges	-5.4	150 g – 1 piece	-5.4	150 g – 1 piece	-3.6109 -2.754
Banana chips (dried banana)	-4.9	25 g – 1 handful	-4.9	25 g – 1 handful	-19.6111
Cocoa powder, highly defatted	-4.9	10 g – 1 EL	-4.9	10 g – 1 EL	-49111
Prunes	-4.9	40 g – 4 pieces	-4.9	40 g – 4 pieces	-12.3111
Apricots	-4.8	100 g – 3 pieces	-4.8	100 g – 3 pieces	-4.854
Kiwi	-4.5	80 g – 1 piece	-4.5	80 g – 1 piece	-5.6109 -4.154
Mango	-4.5	150 g – 1/2	-4.5	150 g – 1/2	-3.0109
Red wine	-4.4	200 ml – 1 glass	-4.4	200 ml – 1 glass	-2.2109 -2.411054
Pears	-4.3	150 g – 1 piece	-4.3	150 g – 1 piece	-2.954
Dried fruit, mixed	-4.1	40 g – 1 handful	-4.1	40 g – 1 handful	-10.3111
Pineapple	-4.0	150 g – 2 slices	-4.0	150 g – 2 slices	-2.754
Eggplant	-4.0	200 g	-4.0	200 g	-2.0109 -3.454
Dried dates	-4.0	40 g – 4 pieces	-4.0	40 g – 4 pieces	-10.1111
Watermelon	-4.0	200 g	-4.0	200 g	-2.0109 -1.954
Strawberries	-3.8	150 g	-3.8	150 g	-2.5109 -2.254
Peaches	-3.6	150 g – 1 piece	-3.6	150 g – 1 piece	-2.454
Soy flour	-3.5	30 g – baking portion	-3.5	30 g – baking portion	-11.5111
Lamb’s lettuce	-3.3	50 g	-3.3	50 g	-6.6
Cherries	-3.1	100 g	-3.1	100 g	-3.1109 3.654
Lamb’s lettuce	-3.0	50 g – 1 serving of salad	-3.0	50 g – 1 serving of salad	-6111
Dried pineapple	-2.9	30 g – 1 handful	-2.9	30 g – 1 handful	-9.6111
Dried apple rings	-2.9	30 g – 1 handful	-2.9	30 g – 1 handful	-9.6111
Soya	-2.9	100 g	-2.9	100 g	-2.9109
Apples	-2.9	150 g – 1 piece	-2.9	150 g – 1 piece	-1.9109 -2.254
Cauliflower	-2.6	200 g	-2.6	200 g	-1.3109 -4.054
Lettuce	-2.6	60 g – 1 serving of lettuce	-2.6	60 g – 1 serving of lettuce	-4.3109 -2.554
Cucumbers	-2.4	100 g – 1/3 cucumber	-2.4	100 g – 1/3 cucumber	-2.4109 -0.854
Soy milk	-2.4	400 ml – 2 glasses	-1.2	200 ml – 1 glass	-0.6
	drinking chocolate milk -2.4 400 ml – 2 glasses -1.2 200 ml – 1 glass -0.6 -0.4				10954
White wine	-2.4	200 ml – 1 glass	-2.4	200 ml – 1 glass	-1.2109 dry, -1.254
Apple concentrate/fruit syrup	-2.2	20 g – 1 EL	-2.2	20 g – 1 EL	-11.2111
Arugula	-2.2	30 g – 1 serving of salad	-2.2	30 g – 1 serving of salad	-7.5
Chicory	-2.0	100 g – 1 head	-2.0	100 g – 1 head	-2.054
Radishes	-1.9	50 g – 1 bunch	-1.9	50 g – 1 bunch	-3.754
Volvic, hydrogen carbonate equivalent (74 mg/l)	-1.8 fictional	1500 ml – 1.5 l	-0.2 fictional	200 ml – 1 glass	-0.1 fictional
Green tea	-1.8	600 ml – 3 cups	-0.6	200 ml – 1 cup	-0.3109
Indian tea (beverage)	-1.8	600 ml – 3 cups	-0.6	200 ml – 1 cup	-0.354
Leeks	-1.8	100 g	-1.8	100 g	-1.854
Potato starch	-1.7	15 g – 1 EL	-1.7	15 g – 1 EL	-11.5111
Volvic Mineral Water	-1.6	1500 ml – 1.5 l	-0.2	200 ml – 1 glass	-0.154
Green bell pepper	-1.4	100 g – 1/2	-1.4	100 g – 1/2	-1.454
Apple pectin	-1.1	5 g – for gelling	-1.1	5 g – for gelling	-21.4111
Iceberg lettuce	-1.0	60 g – 1 serving of salad	-1.0	60 g – 1 serving of salad	-1.654
Draught beer	-1.0	500 ml – 0.5 l	-0.4	200 ml – 1 glass	-0.254
Asparagus	-1.0	250 g	-1.0	250 g	-0.454
Onions	-1.0	50 g – 1 medium	-1.0	50 g – 1 medium	-2.0109 -1.554
Hazelnuts	-0.7	25 g – 1 handful	-0.7	25 g – 1 handful	-2.854
Guar gum	-0.6	5 g – 1 tsp	-0.6	5 g – 1 tsp	-11.5111
Carob flour	-0.6	5 g – 1 tsp	-0.6	5 g – 1 tsp	-11.5111
	Jam -0.6 40 g – 2 EL -0.3 20 g – 1 EL on bread -1.5				54
Parsley	-0.6	5 g – 1 bunch	-0.6	5 g – 1 bunch	-12.0
Agar	-0.5	2 g – for gelling	-0.5	2 g – for gelling	-25.5111
Hazelnuts	-0.5	25 g – 1 handful	-0.5	25 g – 1 handful	-1.9109
Tofu	-0.5	150 g	-0.5	150 g	-0.3
Onions, dried	-0.5	5 g – 1 tsp	-0.5	5 g – 1 tsp	-9.7111
Basil	-0.4	5 g – Seasoning amount	-0.4	5 g – Seasoning amount	-7.3
	Milk Chocolate -0.4 30 g – 3 bars -0.4 30 g – 3 bars -1.3
Lemons	-0.4	20 g – juice, 2 squirts	-0.2	10 g – juice, 1 squirt	-2.3109 Lemon juice -2.554
Chives	-0.3	5 g – Seasoning amount	-0.3	5 g – Seasoning amount	-5.3
	Strong Beer -0.3 330 ml – 1 bottle -0.2 200 ml – 1 glass -0.1				54
Honey	-0.2	40 g – 2 tsp	-0.1	20 g – 1 tsp	-0.354
Margarine	-0.2	20 g – 2 servings	-0.1	10 g – 1 serving on bread	-0.8109 -0.554
Cream	-0.2	50 g – in coffee and dishes	-0.1	30 g – 2 EL	-0.2109
Butter	0.0	20 g – 2 servings	0.0	10 g – 1 serving on bread	0.1109 0.654
Olive oil	0.0	30 g – Daily amount	0.0	10 g – 1 EL	010954
Sunflower oil	0.0	30 g – Daily amount	0.0	10 g – 1 tbsp	010954
White sugar	0.0	30 g – Daily amount	0.0	10 g – 2 tsp	-0.154
Sour cream, fresh	+0.4	30 g – 2 EL	+0.4	30 g – 2 EL	1.254
Almonds	+0.5	25 g – 1 handful	+0.5	25 g – 1 handful	2.0109
Pistachios	+0.5	25 g – 1 handful	+0.5	25 g – 1 handful	2.0109
Vegetable broth, granulated (powder)	+0.6	5 g – 1 tsp	+0.6	5 g – 1 tsp	11.1111
Milk ice cream	+0.6	100 g – 2 scoops	+0.6	100 g – 2 scoops	0.654
Chicken egg white	+0.7	35 g – 1 egg white	+0.7	35 g – 1 egg white	2.1109 1.154
Milk chocolate	+0.7	30 g – 3 bars	+0.7	30 g – 3 bars	2.454
Milk (whole milk, skim milk)	+0.8	400 ml – 2 glasses	+0.4	200 ml – 1 glass	0.2109 0.7110 1.154 pasteurized UHT milk 0.754
Biscuit	+0.9	30 g – 3 pieces	+0.9	30 g – 3 pieces	3.0110
Cola	+1.1	500 ml – 0.5 l	+0.4	200 ml – 1 glass	0.2109 0.454
Yeast	+1.1	10 g – 1/4 cube	+1.1	10 g – 1/4 cube	10.6111
Lentils	+1.3	60 g dry	+1.3	60 g dry	2.1109 3.554
Pine nuts	+1.3	15 g – 1 tbsp	+1.3	15 g – 1 tbsp	8.8111
Rice, unhusked	+1.4	60 g raw	+1.4	60 g raw	2.3109
Rye crispbread	+1.4	40 g – 4 slices	+0.7	20 g – 2 slices	3.354
Peanuts	+1.6	25 g – 1 handful	+1.6	25 g – 1 handful	6.2109
Chickpeas	+1.6	60 g dry	+1.6	60 g dry	2.6109
Walnuts	+1.7	25 g – 1 handful	+1.7	25 g – 1 handful	6.854
	Fruit Yogurt +1.8 150 g – 1 cup +1.8 150 g – 1 cup 1.2				54
Buttermilk	+1.9	400 ml – 2 glasses	+1.0	200 ml – 1 glass	0.554
Peanuts, unsalted	+2.1	25 g – 1 handful	+2.1	25 g – 1 handful	8.354
Sunflower seeds	+2.1	20 g – 1 tbsp	+2.1	20 g – 1 tbsp	10.3111
Beans	+2.2	200 g	+2.2	200 g	unclear: 1.1109 or -7.4109
Madeira cake	+2.2	60 g – 1 piece	+2.2	60 g – 1 piece	3.754
	Natural Yogurt +2.2 150 g – 1 cup +2.2 150 g – 1 cup 1.5				54
Pumpkin seeds	+2.3	20 g – 1 EL	+2.3	20 g – 1 EL	11.3111
Cornflakes	+2.4	40 g	+2.4	40 g	6.054
Peas	+2.4	200 g	+2.4	200 g	1.254
Corn tortilla	+2.4	50 g – 1 piece	+2.4	50 g – 1 piece	4.8109
Zwieback	+2.4	40 g – 4 slices	+1.2	20 g – 2 slices	5.9
Chia seeds	+2.6	15 g – 1 EL	+2.6	15 g – 1 EL	17.3111
Rice, hulled, raw	+2.7	60 g raw	+2.7	60 g raw	4.5110 4.654
Whole-wheat bread	+2.7	150 g – 3 slices	+1.8	100 g – 2 slices	1.854
Sponge fingers	+2.8	20 g – 4 pieces	+2.8	20 g – 4 pieces	13.8111
Macadamia nuts	+2.9	25 g – 1 handful	+2.9	25 g – 1 handful	11.5111
Brazil nuts	+3.2	20 g – 1 handful	+3.2	20 g – 1 handful	16111
Rice, cooked	+3.2	200 g cooked	+3.2	200 g cooked	1.654
Nuts	+3.5	25 g – 1 handful	+3.5	25 g – 1 handful	13.8109
Pork sausage	+3.5	60 g – 1 piece	+3.5	60 g – 1 piece	5.8109
Egg yolk	+3.6	20 g – 1 yolk	+3.6	20 g – 1 yolk	18.1109 23.454
Hemp seeds, hulled	+4.3	20 g – 1 tbsp	+4.3	20 g – 1 tbsp	21.34111
Wheat tortilla	+4.3	60 g – 1 piece	+4.3	60 g – 1 piece	7.2109
White bread	+4.4	120 g – 4 slices	+2.2	60 g – 2 slices	3.711054
Spelt (green spelt, whole grain)	+4.5	60 g raw	+4.5	60 g raw	7.5
Full-bodied beer, light	+4.5	500 ml – 0.5 l	+1.8	200 ml – 1 glass	0.954
Egg noodles	+5.1	80 g dry	+5.1	80 g dry	6.454
Smoked salmon	+5.2	50 g	+5.2	50 g	10.5111
Quinoa, raw	+5.3	60 g raw	+5.3	60 g raw	8.9111
Chicken egg (whole egg)	+5.4	60 g – 1 egg	+5.4	60 g – 1 egg	9.0109 8.254 4.0110
Blue cheese	+5.6	60 g – 2 servings	+2.8	30 g	9.3111
Wheat-blend bread	+5.7	150 g – 3 slices	+3.8	100 g – 2 slices	3.854
Whole-grain spaghetti	+5.8	80 g dry	+5.8	80 g dry	7.354
	Whole-Grain Rye Flour +5.9 100 g – Baking portion +5.9 100 g – Baking portion 5.9				54
Rye-wheat bread	+6.0	150 g – 3 slices	+4.0	100 g – 2 slices	4.054
Roquefort	+6.0	60 g – 2 servings	+3.0	30 g	10111
Lunch Meat	+6.1	60 g – 2 slices	+6.1	60 g – 2 slices	10.254
Rye bread	+6.2	150 g – 3 slices	+4.1	100 g – 2 slices	4.154
Oatmeal (whole grain)	+6.4	60 g	+6.4	60 g	10.754
Liver sausage	+6.4	60 g – 2 servings	+3.2	30 g on bread	10.654
Parmesan	+6.4	30 g – 2 tbsp grated	+3.2	15 g – 1 tbsp grated	21.4109 34.254
Sheep’s milk cheese	+6.6	80 g – 2 servings	+4.1	50 g	8.2111
Viennese Sausages / Frankfurters	+6.7	100 g – 2 pieces	+6.7	100 g – 2 pieces	6.754
Wheat flour, extract	+6.9	100 g – baking portion	+6.9	100 g – baking portion	6.954
Salami	+7.0	60 g – 2 servings	+3.5	30 g on bread	11.654
White bread	+7.2	120 g – 4 slices	+3.6	60 g – 2 slices	6.0110
	cream cheese +7.4 60 g – 2 servings +3.7 30 g – 1 serving on bread 12.4				109
Brown rice	+7.5	60 g raw	+7.5	60 g raw	12.554
Shrimp	+7.6	100 g	+7.6	100 g	7.6
Edam cheese	+7.8	60 g – 2 slices	+3.9	30 g – 1 slice	13.1111
Corned beef	+7.9	60 g – 2 slices	+7.9	60 g – 2 slices	13.254
Cottage cheese	+7.9	100 g	+7.9	100 g	7.9109 8.754
	Mountain Cheese +8.0 60 g – 2 slices +4.0 30 g – 1 slice 13.3				111
Greek yogurt	+8.0	150 g – 1 cup	+8.0	150 g – 1 cup	5.3109
Butter cheese	+8.2	60 g – 2 slices	+4.1	30 g – 1 slice	13.7111
Whole-grain wheat flour	+8.4	100 g – baking portion	+8.4	100 g – baking portion	8.454
Camembert	+9.0	60 g – 2 servings	+4.5	30 g	15.0112 14.654
Cornmeal, whole grain	+9.6	100 g – baking portion	+9.6	100 g – baking portion	9.6111
Haddock	+10.2	150 g – 1 fillet	+10.2	150 g – 1 fillet	6.854
Hering	+10.5	150 g	+10.5	150 g	7.054
Shrimp	+11.1	100 g	+11.1	100 g	11.1111
Baking powder (sodium bicarbonate + acid + anti-caking agent)	+11.9	4 g – 1 packet	+11.9	4 g – 1 packet	297.99111
Cheddar	+12.0	60 g – 2 slices	+6.0	30 g – 1 slice	20.0110
Einkorn flour	+12.0	100 g – baking ratio	+12.0	100 g – baking ratio	12111
Fish	+12.0	150 g	+12.0	150 g	8.0112
Meat	+12.0	150 g	+12.0	150 g	8.0112
Gouda	+12.0	60 g – 2 slices	+6.0	30 g – 1 slice	20.0109 18.654
Mozzarella	+12.9	125 g – 1 ball	+6.2	60 g – 1/2 ball	10.4111
Emmentaler	+13.0	60 g – 2 slices	+6.5	30 g – 1 slice	21.5
Shrimp	+13.2	100 g	+13.2	100 g	13.2109
Kasseler	+13.2	150 g	+13.2	150 g	8.8111
Veal fillet	+13.5	150 g	+13.5	150 g	9.054
Salmon	+13.7	150 g – 1 fillet	+13.7	150 g – 1 fillet	9.1111
Redfish	+13.7	150 g – 1 fillet	+13.7	150 g – 1 fillet	9.1111
Schnitzel, pork	+13.9	150 g – 1 schnitzel	+13.9	150 g – 1 schnitzel	9.3111
Gruyère	+14.0	60 g – 2 slices	+7.0	30 g – 1 slice	23.32111
Duck	+14.2	150 g	+14.2	150 g	9.5111
Turkey meat	+14.8	150 g	+14.8	150 g	9.954
Herring	+15.2	150 g	+15.2	150 g	10.1111
Shrimp	+15.5	100 g	+15.5	100 g	15.5
Cheddar, low-fat	+15.8	60 g – 2 slices	+7.9	30 g – 1 slice	26.454
Turkey	+15.8	150 g	+15.8	150 g	10.5111
Oil-packed sardines	+15.9	100 g – 1 can, drained	+15.9	100 g – 1 can, drained	15.9109
Brown trout, steamed	+16.2	150 g – 1 fillet	+16.2	150 g – 1 fillet	10.854
Veal liver, raw	+16.4	150 g	+16.4	150 g	10.9111
Rump steak	+17.6	200 g – 1 small steak	+17.6	200 g – 1 small steak	8.854
Lamb	+18.0	150 g	+18.0	150 g	12111
Beef	+18.8	150 g	+18.8	150 g	12.5109 lean 7.854
Salmon	+21.0	150 g – 1 fillet	+21.0	150 g – 1 fillet	14.0109
Veal liver	+21.3	150 g	+21.3	150 g	14.2
Beef liver	+22.1	150 g	+22.1	150 g	14.7111
Pork	+22.1	150 g	+22.1	150 g	14.7109 lean 7.954
Quark	+22.2	200 g	+22.2	200 g	11.154
Mussels	+22.8	150 g	+22.8	150 g	15.2109
Chicken	+24.8	150 g	+24.8	150 g	16.5109, 11.81111, 8.754
Cod	+29.7	150 g – 1 fillet	+29.7	150 g – 1 fillet	19.8109 fillet 7.154

5.7. Measuring Urine pH¶

You can measure your urine pH at home. pH test strips available at drugstores or online are perfectly adequate for this purpose (Spearman: 0.94 to 0.95 in the lab; 0.86 to 0.87 when measured by the subjects themselves).¹⁰⁷ Another study reports an accuracy of 70 to 80%:¹¹³ In 114 patients with urinary stones treated with potassium citrate, test strips showed values of 6.07 ± 0.74 in the 24-hour urine sample and 6.02 ± 0.82 in the fasting sample. In contrast, a digital meter measured 5.8 ± 0.78 and 5.75 ± 0.83 (p > 0.05). These would still be useful values. However, measurements of the same samplee Using test strips and the digital meter differed significantly from one another (p < 0.05).

6. Mechanical Effects of Food Intake¶

6.1. Food Intake as a Prerequisite for the Sustained-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. The prescribing information specifies that the medication should be taken with or immediately after breakfast. When taken on an empty stomach, MPH is released more rapidly; peak plasma concentrations increase, and the duration of action is correspondingly shortened.

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 duration of action and tMax¶

Regardless of the need for a delayed-release effect in some MPH formulations and regardless of the effect on urine 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.
Lisdexamfetamine (Vyvanse) has a maximum blood level that is delayed by one hour when taken with high-fat meals (4.7 hours instead of 3.8 hours after ingestion) ^{31 51 114} . When taken with soft foods such as yogurt, Tmax is 4.2 hours. Taking the medication mixed into yogurt therefore delays the onset of action by about 25 minutes, whereas taking it after a high-fat breakfast delays it by just under an hour. Other parameters, such as the duration of action, the total amount absorbed, or the peak concentration of the active ingredient, are not affected by food.^{114 31}
Orange juice for oral administration: Dissolving the capsule contents in orange juice—which is expressly permitted in the prescribing information—does not affect the AUC or Cmax and therefore leaves the amount of active ingredient absorbed unchanged. In contrast, the effect of orange juice on urinary pH (+0.68), as mentioned in Section 5.4, affects excretion over several hours, not absorption.
In adult women, the values for AUC—normalized for body weight and dose—are 22% lower, and those for Cmax are 12% lower, than in adult men. These are significant differences that were not observed in children. ³¹

6.3. Absorption of the active ingredient¶

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

• Psyllium seeds¹¹⁵¹¹⁶ , which is why it is recommended to wait half an hour to an hour before taking other medications¹¹⁷

7. Physical Activity / Sports¶

Some people with ADHD report that intense sports can significantly shorten the duration of action of stimulants (one person estimated a 40% reduction)¹¹⁸. No systematic studies on the drug’s effects are available. However, the underlying mechanism is well documented: strenuous physical work in hot conditions measurably lowers the urine pH.¹⁰¹ Intense physical exertion causes lactic acidosis, which acidifies the urine, potentially shortening the duration of action of amphetamine-based medications.

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 feel 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 caused by medication dependence:
  • Vyvanse + nicotine: reduced effectiveness, negative feelings
  • MPH + nicotine: enhanced effect, rush (but also a greater crash/rebound)
• An occasional smoker:
  • Even just one or two cigarettes can cause Vyvanse and MPH to stop 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 get the urge to smoke—either as a way to cope or as a way to keep pushing myself.
  • 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 steamship passenger:
  • After taking MPH, vaping makes me feel tired and gives me a headache
  • Nicotine enhances the effects of MPH

9. Alcohol¶

An increase in dexamfetamine levels has been reported with alcohol; however, the underlying measurement data show no clinically significant effect with d-amphetamine and even a reverse trend (single dose of 0.09 mg/kg): AUC over four hours of 46.3 with ethanol (850 mg/kg) vs. 49.4 without).¹¹⁹
The situation is different with methylphenidate: When taken with alcohol, the metabolite ethylphenidate is formed, and exposure to d-methylphenidate increases significantly.¹²⁰

10. Cycle¶

The female menstrual cycle affects dopamine levels. Estrogen influences COMT, which breaks down dopamine in the prefrontal cortex (PFC).¹²¹
People with certain COMT gene variants are particularly susceptible.
The required dose of stimulants may vary depending on the phase of the cycle.¹²²¹²³
When adjusting the dosage of stimulants, women should keep a tracking chart to monitor both cycle fluctuations and the medication’s effects. This is the only way to determine whether the medication 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.²¹²⁴

Reduced CYP metabolism in older adults is known to occur with the following psychotropic drugs:³⁵³⁶

• 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 dosing, 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 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 rapidly metabolized or inactivated in the liver (presystemic elimination).”⁴⁴

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, for the same dose, serum levels are higher in older adults.³⁵³⁶

11.4. Smoking¶

Smoking can affect metabolism by liver enzymes.

12. Kidney function¶

The metabolism of sympathomimetics depends on kidney function.¹²⁵ With regard to amphetamine-based medications, it is also important to note that kidney function affects the pH level, which in turn influences the metabolism of amphetamine.¹²⁶

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 that encode the 5-HT2A, 5-HT2C, histamine H2 receptors, and the serotonin transporter, predicted response to clozapine in schizophrenia with a 76.6% accuracy rate, according to an early study.¹²⁷¹²⁸ The six polymorphisms were selected from 33 polymorphisms examined in 19 genes. When selecting the most suitable combinations from 33 candidates, a high hit rate in the same sample is statistically to be expected. The results could not be reproduced.¹²⁹
• Lack of efficacy of tamoxifen in breast cancer in the absence of estrogen receptor expression¹³⁰
• Regarding ADHD medications, there has been discussion about the influence of the DAT gene on the response to MPH, but this has not yet been confirmed¹³¹
• Even when blood levels of vitamin D are sufficient, less sensitive receptors can still lead to a functional vitamin D deficiency

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

The blood-brain barrier tightly seals off 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.¹³²
A basic introduction to the blood-brain barrier in German can be found at Physiologie.cc¹³³, and in English in Daneman and Prat.¹³²

Example:

• P-glycoprotein (MDR1 gene): regulates the transport of drugs into the brain
  • MDR1 gene variants affect its efficacy. Reduced MDR1 function weakens the blood-brain barrier, allowing drugs to cross into the brain more easily, which can increase their effect even though the plasma concentration remains unchanged.¹³⁰

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. For more on this, see 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¶

It is believed that several hundred genes or gene products can alter a drug’s effect. As the active ingredient travels through the body—from absorption to excretion—it comes into contact with about 30 to 40 proteins. ¹³⁴ This explains why the effect can vary so greatly from person to person.
Many drugs are broken down by enzymes, primarily in the liver.
Some active ingredients are produced only after an initial enzymatic conversion of the drug substances.
Effect strength: Depending on the gene variant, the enzyme encoded by the gene is synthesized in greater or lesser amounts, which affects its 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 reactions¹³⁰

• 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 what follows, we will focus only on those enzymes that are relevant to ADHD medications. However, this already covers the most important enzymes.
CYP3A4 (guanfacine) is involved in the metabolism of about half of all drugs, while CYP2D6 (atomoxetine, and to a lesser extent, amphetamine-based medications) is involved in the metabolism of about a quarter.

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.
Gene polymorphisms also have such an effect. A well-studied example is the COMT Val158Met polymorphism. In individuals with the Val/Val genotype—who have comparatively low dopamine levels in the prefrontal cortex due to high COMT activity—amphetamine enhanced PFC efficiency by increasing dopamine levels. In contrast, in individuals with the Met/Met genotype, amphetamine had no effect under low- to moderate-work-memory-load conditions and impaired cortical efficiency under high-work-memory-load conditions. This is due to the inverted U-shaped relationship between prefrontal dopamine and performance: Val/Val lies to the left of the optimum and is shifted toward the optimum by amphetamine, while Met/Met is already close to the optimum and is pushed beyond it by amphetamine.
People with the Met/Met genotype—about 15 to 20% of populations of European descent—appear to have an increased risk of an adverse reaction to amphetamine.¹³⁵ In carriers of 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.¹³⁵
However, this could not be replicated.¹³⁶

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: CYP2B6-¹³⁰, as well as some information about CYP2A6
Guanfacine: CYP3A4
Clonidine: unknown
Buspirone: CYP3A4
Memantine: unknown; likely not metabolized by CYP⁵⁵
Viloxazine: CYP2D6, UGT1A9, UGT2B15; 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 Metabolic Enzyme:

• Methylphenidate (MPH)

CYP2D6 Metabolizing Enzyme:

• Amphetamine-based medications (AMP)
• Atomoxetine
• Bupropion: CYP2B6-¹³⁰, as well as some CYP2A6 inhibition, but 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. ¹³⁴

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 was prescribed by a doctor.

As of September 2023, a laboratory test 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.¹³⁷ Genetic analyses of individual metabolism-related genes cost approximately €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 signaling pathways 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 lisdexamfetamine within 5–6 hours reported to us that combining it with 150 mg of bupropion was very helpful in prolonging the duration of action of the lisdexamfetamine. Vyvanse is metabolized via CYP2D6; bupropion and its metabolites weakly and reversibly inhibit CYP2D6 in vitro and cause genetic downregulation of CYP2D6. ¹³⁸ Only both of these mechanisms acting together can explain the strong effect observed in vivo.
However, bupropion lowers the seizure threshold, which is why combining these medications is not a harmless adjustment but should be managed by a physician. For clinically significant drug interactions involving ADHD medications, see also Schoretsanitis et al. (2019). ¹¹⁹

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 if 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, bupropion and its metabolites are only weak inhibitors of CYP2D6 in vitro—too weak to explain the extent of the interaction observed in vivo. In liver cell cultures, downregulation of CYP2D6 was also observed. Only both mechanisms together—reversible inhibition and downregulation—explain the strong CYP2D6 inhibition caused by bupropion in the body.¹³⁸

16. Excretion: Renal Blood Flow¶

Since amphetamine is excreted through 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
The glomerular filtration rate decreases on average by 8 ml/min/1.73 m² per decade (0.1 ml/s/m² per decade) starting at age 40. There are significant individual differences.³⁵³⁶

• Brexpiprazole
• Lurasidone
• Paliperidone
• Risperidone

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 medications excreted by the kidneys is reduced in older adults.³⁵³⁶

17. Gene Variants and Response¶

A study that combined a genome-wide association study (GWAS) with machine learning methods identified the effects of various genes on the response to MPH and ATX:¹³⁹

• on chromosome 12, SNP: rs10880574 (p = 2.39 × 10⁻⁹), 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 (p = 3.31 × 10⁻⁹). Nearest gene: MYO5B (myosin 5B), 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 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 effect¹⁴⁰

• 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 are¹⁴⁰

• for basic active ingredient molecules
  • hydrochloride
  • mesylate
    • high water solubility; in a comparative study of thirteen salt forms of a basic active ingredient, the dimesylate was the most soluble, at 59.1 mg/mL¹⁴¹
  • hydrobromide
  • Acetate
  • Fumarate
  • sulfonate¹⁴¹
    • Methanesulfonate
    • Kampfersulfonate
• for weakly acidic active ingredients
  • Sodium
  • Calcium
  • Potassium

19. Red Blood Cell Function with Lisdexamfetamine¶

The current body of research shows that the rate at which LDX is converted to dAMP by red blood cells in humans can vary by at least 56%. This range is based on data from only six individuals in whom 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.
LDX is taken up as an intact prodrug via the peptide transporter PEPT1, which is highly expressed in the small intestine but is barely present in the large intestine. Following perfusion of the rat small intestine, LDX and d-amphetamine were detectable in the blood; following perfusion of the large intestine, they were not. ³⁷
This explains why absorption may be impaired when intestinal transit is accelerated, and is consistent with the observation in Section 3 regarding gastrointestinal influences.

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 people, 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*	56%	6 people
Total human	0.39 – 1.6 h	0.43 – 1.78*	310%	see above

* Kₑ values calculated using k = ln2/t½

A range of 310% means that the person who converted the slowest took 4.1 times as long as the fastest.

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)37
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)142
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)143
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)143
Isolated erythrocytes, 2 donors	in vitro	Ø 1.0 h	0.87 h	1.10 h	26.4% ‡	—	Pennick (2010)37
Red blood cells, varying hematocrit (10–90%)	in vitro	published only as a figure	n. b.	n. b.	n. b.	—	Pennick (2010)37Fig. 8; Pennick (2013)143
Erythrocyte lysate (diluted 1:5)	in vitro	no t½ calculated; 24% loss / 4 h	—	—	—	102 ng/mL	Sharman & Pennick (2014)142
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)142
Erythrocyte membrane fraction	in vitro	no measurable degradation	—	—	—	29 ng/mL	Sharman & Pennick (2014)142
Human plasma	in vitro	completely stable over 4 hours	—	—	—	< LOD (10 ng/mL)	Sharman & Pennick (2014)142
PBMC, PMN, platelets	in vitro	stable	—	—	—	negligible	Pennick (2010)37
Human kidney homogenate	in vitro	2.3 h	—	—	—	—	Pennick (2010)37
Human liver homogenate	in vitro	9.7 h	—	—	—	—	Pennick (2010)37
Comparison: Rat whole blood	in vitro	1.0 h	—	—	—	—	Pennick (2010)37
Comparison: Rat liver	in vitro	2.5 h	—	—	—	—	Pennick (2010)37
Across studies: all individuals, undiluted matrix	in vitro	—	0.87 h	1.36 h	56.3%	—	Pennick (2010)37Pennick (2013)143

* Derived from the mean ± 1 SD, unpublished; SD from repeat experiments with 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)144, 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)31, Table III
LDX Plasma-t½, 70 mg as a solution (n = 17)	in vivo	0.44 ± 0.10 h	—	—	—	Group mean	Krishnan & Zhang (2008)31
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)31
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)30, 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)144
LDX tmax, 70 mg	in vivo	1.2 ± 0.3 h	0.8 h	1.5 h	87.5%	individual	Comiran et al. (2021)144
LDX tmax, fasting / solution / with food	in vivo	1.15 / 0.97 / 2.08 h	—	—	(114.4%) †	Group mean, effect of food	Krishnan & Zhang (2008)31
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)30
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)144, Table 2
d-amphetamine plasma half-life (t½), fasted / fed / solution	, in vivo	9.69 / 9.59 / 9.37 h	—	—	(3.4%) †	group mean	Krishnan & Zhang (2008)31, 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)30, Table I
d-amphetamine plasma t½, 50 mg (n = 35)	in vivo	11.43 ± 1.94 h				group mean	Faison et al. (2021)145, Table 1.
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)144
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)144
d-amphetamine tmax, fasted / fed / solution	in vivo	3.78 / 4.72 / 3.33 h	—	—	(41.7%) †	group mean	Krishnan & Zhang (2008)31
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)30
d-amphetamine tmax, 50 mg (n = 35)	in vivo	3.00 h (median)	2.0 h	5.03 h	151.5%	individual	Faison et al. (2021)145, Table 1.
Across studies: LDX plasma t½, all conditions	in vivo	—	0.39 h	0.90 h	130.8%	mixed	Comiran et al. (2021)144 Krishnan & Zhang (2008)31; Ermer et al. (2010)30

† 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 a single statement.

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