Medication duration for ADHD

There are few generally valid data on the use and effect of ADHD medications. In the case of ADHD, medications must be tested and adapted to the individual to a particular extent. Also, the standard data on the duration of action do not fit unseen to all affected persons.
This paper is devoted to the factors that individually influence the response and duration of action of a single dose of ADHD medication.

• 1. Duration of action of active substances and preparations in ADHD
  • 1.1. Manufacturer’s specifications of the duration of action
  • 1.2. Experience values of the duration of action
• 2. Stomach passage speed
• 3. Small intestine passage speed
• 4. Liver function
  • 4.1. Age
  • 4.2. Diseases
  • 4.3. First pass effect
• 5. Acid balance
• 7. Food intake
  • 7.1. Food intake as a prerequisite for sustained release
  • 7.2. Food intake influences duration of action
• 8. Receptor/transporter sensitivity
• 9. Blood-brain barrier
  • 9.1. Competition of the use of transport
  • 9.2. Blocking function of the blood-brain barrier
• 10. Metabolizing enzymes
  • 10.1. ADHD active substances and their main degradation enzymes
  • 10.2. Pharmacogenetic diagnostics
  • 10.3. Metabolizing enzymes and their gene variants

1. Duration of action of active substances and preparations in ADHD¶

1.1. Manufacturer’s specifications of the duration of action¶

Data for drugs available in the USA are from Rodden.¹ Data in the table are mean values unless otherwise noted,
The actual duration of action varies from person to person and depends heavily on the metabolism of the individual affected. Approximately 5% of patients are super fast metabolizers. In these patients, the effect of a half-day retard product may last only 1.5 or 2 hours instead of 5 to 6 hours. Likewise, there are sufferers for whom a preparation has a much longer effect.
For metabolism of methylphenidate and amphetamine drugs, see under. There you will also find more detailed information on pharmacokinetics, e.g. speed of action and distribution of the effect curve.

Particularly in the case of half-day retard preparations, a second drug dose, which is regularly lower, is generally required at lunchtime for daily coverage.
Only half-day treatment is not appropriate. ADHD is not a morning disorder.

Methylphenidate drugs	Active ingredient	Duration of action in hours (according to manufacturer)	retarded	Country
Ritalin, Methylphenidate HEXAL, Methylpheni TAD unretarded, Medikinet unretarded, Methylphenidate generic	Methylphenidate	2,5 - 3,5	unretarded	EU, USA
Methylin Liquid	methylphenidate	3 - 4	unretarded	USA
Ritalin SR	methylphenidate	5-8 hours effective time theoretically, 3-5 hours effective time practically2, 81	continuous release2	EU
Focalin	dexmethylphenidate	4 - 6	unretarded	CH, USA
Equasym Retard/XL	methylphenidate	6 - 83 / 8 4	two-phase retard	EU
Medikinet adult (adults), Medikinet retard (children) (bioequivalent)5	methylphenidate	6 - 83	two-phase retardation	EU
Ritalin LA, Ritalin Adult (bioequivalent)	methylphenidate	6 - 82 / 8 3		EU
Methysym	Methylphenidate	up to 8	retarded	since 01.06.2021 in D
Metadate CD	methylphenidate	8 - 10	sustained release	USA
Daytrana	methylphenidate	10 (if worn for 9 hours)	patches	USA
Concerta, methylphenidate hydrochloride-neuraxpharm (bioequivalent)	methylphenidate	8 - 123, 10 - 122, 121	sustained release	D, CH, USA
Ritalin LA	methylphenidate	8 - 12	sustained release	USA
Focalin XR	Dexmethylphenidate	8 - 12	retarded	CH, USA
Methylphenidate hydrochloride Ratiopharm6	Methylphenidate	12	sustained release	EU
Methylphenidate hydrochloride Hexal7	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 drugs	active ingredient	duration of action in hours (according to manufacturer)	sustained release	country
Dexedrine	dextroamphetamine	3 - 4	unretarded	USA
ProCentra	dextroamphetamine	3 - 6	unretarded	USA
Zenzedi	dextroamphetamine	3 - 6	unretarded	USA
Desoxyn	methamphetamine	4 - 6	unretarded	USA
Adderall	amphetamine mixed salts	4 - 6	unretarded	USA
Evekeo	amphetamine sulfate	4 - 6	unretarded	USA
Attentin	dextroamphetamine	5 - 6	unretarded	Germany, since end 2011
Dexamine	Dextroamphetamine	5 - 6	unretarded	Switzerland, as extemporaneous formulation
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
Elvanse (pediatric), Elvanse adult (adult) Vyvanse (bioequivalent)	Lisdexamfetamine	10 - 13	sustained release	EU, USA
Dyanavel XR	amphetamine	13	sustained release	USA
Mydayis	amphetamine mixed salts	14 - 16	sustained release	USA

Non-stimulants	Active ingredient	Duration of action in hours (according to manufacturer)	retarded	Country
Strattera, agakalin	atomoxetine	all-day/individual 8 to 21 hours8	unretarded	USA
Intuniv	DGuanfacin	all day; peak concentration after approximately 5 hours; elimination half-life approximately 18 hours	sustained release	USA
The course of the effect curves differs considerably depending on the preparation.9

1.2. Experience values of the duration of action¶

An online survey of sufferers at adhs-forum.adxs.org on how long a single dose of Vyvanse worked for them found among 71 participants (as of Feb. 04, 2023):¹⁰

Duration of action Single dose Vyvanse	Participants (of 71)
5 hours and less	30 %
6 hours	18 %
7 hours	10%
8 hours	8 %
9 hours	6 %
10 hours	14 %
11 hours	4 %
12 hours	1%
13 hours	-
14 hours	9 %

Such a survey could attract an above-average number of users who have had a deviating experience compared to the manufacturer’s specification of 10 to 12 hours. Nevertheless, the distribution in the direction of a much shorter duration of action than according to the manufacturer’s specifications of 10 to 12 hours is very clear. For one third, a single dose is effective for only up to 5 hours, for another third 6 to 8 hours. Only just under 20% of those affected achieve the duration of action of 10 to 12 hours specified by the manufacturer. This is also in line with the numerous reports of Elvanse users in the forum who need more than one single dose per day. Some users need 3 doses (with decreasing dose levels at the same time).

Interestingly, several sufferers were also found in whom not only Vyvanse but also methylphenidate had a much shorter effect. Since Vyvanse and MPH are metabolized by different enzymes, this suggests mechanisms other than overactive enzyme gene variants, as also explained in this paper.

In the following, we explain the influencing factors that can individually affect the duration of medication effects (especially with ADHD medications).

2. Stomach passage speed¶

In addition to small intestine passage speed, gastric function plays a role. Gastric motility and emptying rate influence how quickly a substance reaches the small intestine. For paracetamol, for example, gastric emptying is the rate-determining step for the appearance of the substance in the blood plasma. Delayed or accelerated gastric emptying can thus fundamentally influence the kinetics of orally absorbed drugs, so that, for example, the necessary active levels are not reached or are reached only with a delay¹¹

3. Small intestine passage speed¶

“For drugs that are ingested, the passage time through the stomach and small intestine represents a natural upper limit for drug release: Once the tablet has left the small intestine, nothing more can be absorbed, and release is thus limited to a period of about 8-10 hours.”¹²

Individually, this time may differ, just as the speed of intestinal passage differs. This may be the reason why there are isolated super fast metabolizers who report a duration of action of Medikinet of 1 to 2 hours and of Elvanse of 3 hours. These likewise report having to eat much more frequently during the day than others.
For a longer duration of action (not only on average) than intestinal passage, mechanisms are therefore needed that go beyond absorption from the small intestine.

4. Liver function¶

4.1. Age¶

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

4.2. Diseases¶

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

4.3. First pass effect¶

“The intestinal veins are routed to the heart via the liver, so that a substance absorbed in the intestine undergoes a liver passage before it can be distributed further via the great vena cava and heart. If a substance survives this first liver passage only to a small extent, it 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 substance are available systemically. Due to the first-pass effect, substances can be rapidly altered or inactivated in the liver (presystemic elimination).”¹²

The first-pass effect is also subject to individual differences.

5. Acid balance¶

pH value can influence - depending on the duration of acid exposure:¹³

• Solubility of active ingredients
• Stability of active ingredients

The usual pH in the stomach is:¹³

• sober pH 1-2
• increasing with food intake
  • depending on the type and quantity up to pH 5-6
  • thereafter decrease to initial value

Examples:

Amphetamine drugs:¹⁴

• shortened duration of action due to high urine acidity, e.g. due to
  • Ascorbic acid (vitamin C)
  • Thiazide diuretics
  • Animal protein rich diet
  • Diabetes
  • respiratory acidosis
• prolonged duration of action due to low (alkalized) urine acidity, e.g. due to
  • Sodium hydrogen carbonate
  • Diet high in fruits and vegetables
  • Urinary tract infections
  • Vomiting
  • Change of diet, e.g. from a meat-based to a vegetarian diet¹⁵
  • massive intake of agents for neutralization of gastric acid¹⁵

Memantine:

• Prolonged effect due to alkalized urine
  • In alkaline urine (high pH), the renal elimination rate of memantine may be reduced by a factor of 7 to 9.¹⁵

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

• Proton pump inhibitors (e.g. pantoprazole, omeprazole)
• Antacids
• H2 antagonists (e.g., ranitidine, famotidine) (less likely)

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

Ritalin adult
Ritalin adult, on the other hand, releases MPH independently of pH. The technical information mentions a reduction in absorption as a probable interaction with antacids.¹⁶

7. Food intake¶

7.1. Food intake as a prerequisite for sustained release¶

For Medikinet adult and Medikinet retard, prior or concomitant food intake is a prerequisite for sustained release. In the absence of food intake, the MPH is released twice as fast. The released MPH dose is therefore approximately doubled and the duration of action approximately halved.

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

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

7.2. Food intake influences duration of action¶

Regardless of the need for the retarding effect in some MPH preparations, certain forms of food intake influence the effect and duration of action of stimulants.
Lisdexamfetamine (Elvanse) has a one-hour delay in maximum blood level (4.7 hours instead of 3.8 hours after ingestion) with high-fat meals.¹⁷ However, other parameters, such as duration of action, do not change.

8. Receptor/transporter sensitivity¶

Drugs can bind to receptors, ion channels or enzymes and trigger effects there. The sensitivity of these receptor structures influences efficacy.
The sensitivity of the receiver structures can be influenced by variants of the d’sie coding genes.

Examples:

• A combination of six polymorphisms in genes encoding the 5-HT2A, 5-HT2C, histamine H2 receptors, and SERT predicted response to clozapine in schizophrenia with nearly 80% confidence¹⁸
• Lack of effect of tamoxifen in breast carcinoma in the absence of estrogen receptor expression¹⁹
• For ADHD medications, an influence of the DAT gene on MPH response is discussed

9. Blood-brain barrier¶

A basic introduction to the blood-brain barrier in German can be found at Psysiologie.cc.²⁰

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

9.1. Competition of the use of transport¶

Competition between different substances with regard to transport across the brain barrier can influence the effect of drugs.
Example:
Memantine, opiates (oxycodone, codeine), tramadol, cocaine, and nicotine are transported across the blood-brain barrier by means of the same transporter family (organic cation transporter, OCT). Since OCT are subject to a saturation limit, this common transport mechanism could influence memantine levels in the brain and thus its effects.²¹

9.2. Blocking function of the blood-brain barrier¶

The P-glycoprotein encoded by the MDR1 gene is a component of the blood-brain barrier. It is one of many expressed in the endothelial cells of the blood capillaries of the brain
Transporters that control the transfer of drugs into the brain. Gene variants of the MDR-1 gene influence the efficacy of the P-glycoprotein.
When the function or expression of P-glycoprotein is reduced, the blood-brain barrier is weakened and drugs can increasingly cross over into the brain, which can increase their effect even though the blood plasma level is unchanged.¹⁹

10. Metabolizing enzymes¶

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

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

• Competition from other substrates
  If several active ingredients bind to the same enzyme (substrates) and are degraded by it, they compete for the available amount of degradation enzymes when administered simultaneously. This can delay the degradation.
• Inhibition or
  Drugs can inhibit the action of enzymes, even if they are degraded by completely different enzymes
• Induction
  Arneimittel can enhance (induce) the effect of enzymes
• genetic regulation
  Drug substances can also influence metabolization enzymes through genetic regulation. For example, bupropion is a rather weak inhibitor of CYP2D6 in vitro. In vivo, however, bupropion strongly inhibits CYP2D6 by causing genetic downregulation of CYP2D6 mRNA.²²

In humans, metabolizing enzymes catalyze two types of biotransformation reactions¹⁹

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

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

10.1. ADHD active substances and their main degradation enzymes¶

ADHD agents are degraded by different enzymes:

Methylphenidate: CES1
Amphetamine drugs: CYP2D6 (unclear if this is really the main degradation pathway)
Atomoxetine: CYP2D6
Bupropion: CYP2B6¹⁹ as well as something about CYP2A6
Guanfacine: CYP3A4
Clonidine: unknown
Buspirone: CYP3A4
Memantine: unknown, probably not through CYP¹⁵
Viloxazine: CYP2D6, UGT1A9, UGT2B15, possibly also by CYP1A2
Melatonin: CYP1A
Dasotralin: unknown
Agomelatine: CYP1A2 (90%), CYP2C9/2C19 (10%)

10.2. Pharmacogenetic diagnostics¶

Genetic studies can identify the gene variants of metabolizing enzymes.²³

Suitable laboratories can be found by searching for laboratory CES1 (for MPH) or laboratory CYP2D6 (amphetamine drugs, atomoxetine). The laboratory service should be billable via health insurance in Germany if it is prescribed by a physician.

10.3. Metabolizing enzymes and their gene variants¶

See the articles on this subject:

CYP3A4 metabolizing enzyme

CYP2D6 Metabolizing enzyme

CES1 Metabolizing enzyme