ADxS.org Logo
Header Image
MPH Part 1: Active ingredients, effect, responding

Sitemap

The ADxS.org project
Abstract from ADxS.org
Symptoms
Consequences of ADHD
Origin
Stress
Neurological aspects
Diagnostics
Prevention
Treatment: Guide and Effect size
Treatment: Medication for ADHD
Treatment: Medication for ADHD - Overview
Choice of medication for ADHD or ADHD with comorbidity
Dosing of medication for ADHD
Suitable medication for ADHD
Experimental medication for ADHD
Sleep disorder-related medication for ADHD
Appetite-enhancing medication for ADHD
Medication for ADHD in development
Less suitable medication for ADHD
Vitamins, minerals, dietary supplements for ADHD
Plant extracts for ADHD
Medication and drugs - the difference
Substance abuse with self-medication effect in ADHD
Non-drug treatment
Addresses
This and that about ADHD
Tests and surveys
Forum

MPH Part 1: Active ingredients, effect, responding

1. Active ingredient

Methylphenidate ():

  • belongs to the phenylethylamine class.
  • Chemical name: Methyl-2-phenyl-2-(piperidin-2-yl)acetate
  • Molecular formula: C14H19NO2
  • Mass: 233.31 g/mol
  • has four configuration isomers
  • As methylphenidate has two asymmetric carbon atoms, there are four different forms of this drug
    • (+)-Erythromethylphenidate
    • (-)-Erythromethylphenidate
    • (+)-threomethylphenidate
    • (-)-threomethylphenidate.

Other names:

  • Methyl phenidylacetate
  • methyl phenyl(piperidin-2-yl)acetate
  • methyl α-phenyl-α-(2-piperidyl)acetate
  • methyl α-phenyl-α-2-piperidinylacetate
  • Methylphenidan
  • Methylphenidate
  • Methylphenidatum
  • Metilfenidato
  • α-phenyl-2-piperidineacetic acid methyl ester

is classified worldwide as a narcotic because it can be abused as a drug when taken in extreme doses and in a fast-acting form. However, when taken in drug doses and in drug form (oral/patch = slow-acting), has no potential for intoxication or dependence. The actual risk of abuse of methylphenidate as a drug appears to be considerably overestimated. A study claiming frequent abuse of as a drug merely referred to sources in which methylphenidate is not even mentioned

With (especially older) studies on the effect of , it must always be taken into account that these

  • usually used in significantly higher doses than for medication
    • Although rodents require higher doses than humans, doses are often used that correspond to drug intake and not to medication intake
  • use immediate release / not prolonged-acting via prodrug
  • frequently inject , which can result in much faster metabolism depending on the type of injection
    • IP injection should be similar to oral intake
  • these 3 factors multiply in their effect

There is no doubt that in medication form has a different effect than in drug form.

Helpful details for assessing the validity of MPH animal studies

Recording forms:

Intraperitoneal injections (IP, injections into the abdominal cavity)

  • IP in rodents is performed in the lower right quadrant of the abdomen below the midline. This video shows how such an IP injection is performed (German). IP injections should largely correspond to oral ingestion. Absorption is much slower intraperitoneally than with intravenous injections. IP allows for more efficient absorption of in the mesenteric vessels that enter the portal vein and pass through the liver, allowing given active ingredient to undergo hepatic metabolism before reaching the systemic circulation. In addition, a small amount of the intraperitoneally injected material can pass through small lacunae directly through the diaphragm into the thoracic lymph

  • administration via IP injection increases the concentration in the brain faster and much longer lasting than oral administration.

  • IP injection of drugs in experimental studies with rodents is acceptable for pharmacological and proof-of-concept studies to investigate the effect(s) of the target effect. It is unsuitable for studies on the properties of a drug formulation and/or its pharmacokinetics for implementation.

  • The risks of IP injections are:

    • Injuries due to incorrect injection
    • Change in effect if injection too close to the surface (subcutaneous instead of intraperitoneal)

  • Subcutaneous injections have the following effects

    • half-life shortened
    • Peak release of dopamine in the brain increased

Oral gavage
Oral gavage better mimics oral uptake and human metabolism. Oral administration uses a suitable tube or administration needle that is inserted into the animal’s mouth and esophagus. However, the manual fixation required for oral gavage causes such severe stress in both rats and mice that it increases plasma corticosterone levels

Further recording channels:

  • enteral (through the digestive tract)
  • parenteral (outside the digestive tract)
    • avoid the first-pass effect of hepatic metabolism, which often occurs with oral administration
      • therefore generally generate a higher bioavailability
    • avoid unpredictable effects associated with enteral absorption processes
  • orally (in the mouth)
  • directly into the stomach (gastric tube)
  • intravenously (into a blood vessel)
  • epicutaneous (on the skin)
  • intradermal (into the skin)
  • subcutaneously (under the skin)
  • transdermal (through the skin, e.g. plaster)
  • intramuscular (into the muscle)
  • transcorneal (on the eye)
  • intraocular (or into the eye)
  • intracerebral (into the brain)
  • epidural (in the space surrounding the dura mater)
  • intrathecal (in the space surrounding the distal spinal cord);
  • intraosseous (into the bone marrow cavity)
  • intranasal (sprayed into the nose for absorption via the nasal mucous membranes or the lungs)
  • intratracheal (into the lungs by direct tracheal instillation or inhalation)

The dosage does not differ between mice and rats on the basis of the species, but solely on the basis of the size of the respective animal.
doses act according to an inverted-U principle

  • In rodents (mice such as rats):
    • Doses of 1 mg/kg or less:
      • no effects on movement activity due to subcutaneous injection
    • Doses of 2 to 5 mg/kg should correspond to a medicinal dose in humans. However, the cited reference does not prove this.
      • by subcutaneous injection: increase in movement activity
    • Doses of 10 to 20 mg/kg are said to be more like drug intake
      • by subcutaneous injection: increase in movement activity
        • Maximum at 10 mg / kg
    • Doses of 40 mg / kg
      • by subcutaneous injection: more concentrated, stereotyped activity that reduced the amount of forward movement

1.1. Methylphenidate as racemate

Methylphenidate is usually offered ly as a racemate (mixture) of 50 % L-methylphenidate and 50 % D-methylphenidate (levorotatory and dextrorotatory isomers), which is ten to a hundred times more effective than the (+/-) erythroform.
While a proportion of D- enters the via the blood-brain barrier, L- is not absorbed into the .

Brand names include Ritalin, Medikinet, Equasym, Concerta, Kinecteen, Daytrana (skin plaster). It is also offered as a generic. See below for more information.

Dosage from 2.5 mg to an average of 15 mg per single dose during the day every 2.5 to 3.5 hours (immediate release form).

1.2. Dexmethylphenidate (D-)

Dexmethylphenidate is the pure form of the dextrorotatory isomers and is pharmacologically active.

Brand name: Focalin (Switzerland and USA only)

It is 3 times more effective than (mixture of dextrorotatory (D-) and levorotatory (L-) methylphenidate. The higher efficacy of D- compared to L- concerns the dopamine transporter as well as the noradrenaline transporter binding.
It is therefore recommended to halve the dosage of D- compared to racemate methylphenidate and to limit it to a maximum of 20 mg/day in children and adults.
D- is also available as a prolonged-release preparation (Focalin XR).

1.3. Levomethylphenidate (L-)

L- is the pure form of the levorotatory isomers and is pharmacologically almost ineffective.
L- is predominantly metabolized in the intestinal mucosa. The remaining L- is metabolized by the liver during the first pass. L- is almost completely metabolized within 10 minutes of ingestion
The small, unmetabolized residue of L- competes with the dextrorotatory and pharmacologically active isomer D- for the binding sites in the brain and reduces its effectiveness.
According to another source, the left-turning isomer L- (unlike D-) is not absorbed into the .

1.4. Serdex methylphenidate (SDX)

Serdexmethylphenidate (SDX) is a prodrug of dexmethylphenidate (d-) and is currently only approved in the USA (Azstarys®, KP415 with 70 % SDX and 30 % ).

The advantage of prodrugs is a prolonged effect, as the conversion of product into active ingredient delays release. See also lisdexamfetamine, which is first converted to dextroamphetamine (Vyvanse).

2. Mode of action of methylphenidate

The first computer models now exist that can seriously simulate the effect of drugs. A computer model for the simulation of type 1 diabetes has already been approved by the FDA as a replacement for pre animal studies
A model comparing and in children and adults with takes into account the effect on 99 proteins involved in

2.1. Effect on neurotransmitters

changes the neurotransmitter levels in the brain.

2.1.1. and dopamine

2.1.1.1. increases extracellular and possibly decreases dopamine

Many sources only report a general effect on dopamine and noradrenaline.
The blanket statement that increases dopamine is ultimately not helpful, as a distinction must be made between and dopamine release and extracellular dopamine levels, as well as between the effect in different regions of the brain.

  • Increase in dopamine and noradrenaline in the
  • doses whose plasma levels are in the range of therapeutic use for , such as
    • 1.0 mg/kg in rats
      • Increase extracellular noradrenaline in the hippocampus by 100
      • Do not significantly alter dopamine in the nucleus accumbens (striatum)
    • 2.5 mg/kg in rats
      • Increase extracellular noradrenaline in the hippocampus by 150-175 %
      • Do not significantly alter dopamine in the nucleus accumbens (striatum).
  • In healthy adult rats, increases
    • in the , striatum and nucleus accumbens and
      • High doses: increased by release from cells
      • Low dosage: not increased
      • Chronic administration of 1 mg/kg increased extracellular dopamine and noradrenaline in the
    • Noradrenaline in the , but not in the striatum or nucleus accumbens.
    • and noradrenaline in the , but barely in other brain areas
  • In healthy monkeys, :
    • : low and high doses: consistent increase in dopamine
    • : increase in dopamine only at high doses
      In rats, 1 mg/kg as a single dose as (21 days) caused
    • : no change in extracellular levels of noradrenaline, dopamine or serotonin

In summary, appears to affect only the and hippocampus in rats, whereas in primates it also affects the striatum.

Tonic dopamine mediates the regulatory () control of the on the striatum, thus the () activity of the striatum. In response to unexpected positive reward stimuli, the striatum fires phasically in a manner and activates postsynaptic receptors. Tonic control is therefore and modulates phasic firing in response to unexpectedly positive reward stimuli.

Stimulants

  • increases the rate of fire
  • shortens the frequency of multisecond oscillations in the ganglia from around 30 seconds to 5 to 10 seconds. Already 1.0 mg/kg or 0.2 mg/kg D-Amp showed an effect.
  • however, 0.2 mg/kg D-Amp showed only a slight effect. D-Amp had a stronger effect.

increases extracellular dopamine and decreases dopamine in the striatum.
This is consistent with Grace’s hypothesis that is characterized by decreased and increased dopamine. This model is likely to apply to at least most cases of . More on this under Dopamine release (tonic, phasic) and coding

2.1.1.1.1. increases extracellular dopamine

increases extracellular dopamine , especially in the striatum .

The statement “ increases dopamine”, on the other hand, would not be correct because firing itself is not increased by . The inhibition of reuptake only leads to an increase in the extracellular dopamine level, not to a change in firing.

The following reasons for the increase in extracellular dopamine by were identified

  • an inhibition of dopamine reuptake
  • increased dopamine efflux due to reversal of the dopamine reuptake transporter in the striatum

increased response strength and reward expectancy-related BOLD signaling in the striatum during a gambling task, suggesting that striatal dopamine levels represent an average reward expectancy signal that modulates the dopaminergic response to reward.

2.1.1.1.2. can reduce dopamine

Several studies found a reduction in dopamine by , but some also found no change or an increase. This could depend on the circumstances (e.g. dosage, sensitivity).

The reduction in the (synaptic) release of dopamine is probably due to a decrease in synapsin phosphorylation
of dopamine is not a consequence of D2 autoreceptor activation, as these
- a. also in the presence of the D2 antagonist sulpiride and
- b. also occurs in -CI striatal slices in which activation of D2 autoreceptors cannot occur due to an increased extracellular level
The inhibition of dopamine could possibly be due to a reduction in synaptic vesicle neurotransmitter, as with cocaine. Cocaine, as a lipophilic weak base, could collapse the vesicular pH gradient, similar to the “weak base effects” reported for amphetamines, or act on vesicles. There is evidence that synaptic vesicles can be quite “leaky” and constantly leak dopamine into the cytosol. This impression is supported by the action of reserpine, which can rapidly deplete synaptic vesicles of dopamine.

One study found that did not alter dopamine, suggesting an feedback mechanism via D2 autoreceptors, because a D2 antagonist given in parallel with caused to also increase dopamine

reuptake inhibitors such as should generally lead to increased dopamine in the striatum
Acute MPH administration increased the firing activity of pyramidal neurons in rats and potentiated NMDA-induced neurotransmission

The blocker nomifensine enhanced dopaminergic signaling, so dopamine reuptake inhibition per se cannot be the reason for the reduction in dopamine by .

2.1.1.1.3. Stimulants alter firing rate

Stimulants

  • increase the firing rate in the globus pallidus in a dose-dependent manner
    • by up to 100 %
    • D- by up to 50 %
  • reduce the firing rate in the substantia nigra pars compacta
    • by up to 100 %
    • D- by up to 100 %
2.1.1.2. binds to (reuptake inhibition)

Methylphenidate as a dopamine reuptake inhibitor increases the dopamine level in the synaptic cleft. inhibits the dopamine transporter and the noradrenaline transporter From this it could be concluded that the site of action of is where there is a dopamine deficiency. In the mesocortical model of , this would be the . However, and studies clearly show that primarily increases dopamine activity in the striatum, which argues against the as the (sole) site of action (which correlates with the low count in the and the high count in the striatum). Since, according to the mesocortical model of , dopamine activity in the striatum is excessive, , if it has an increasing effect there, should worsen rather than improve symptoms. At low doses, stimulants such as can inhibit dopamine release by enhancing tonic control. However, in an study, children with without medication showed increased and decreased striatal activation, arguing against the mesocortical deficiency theory. increased blood flow in children with and without , but only increased striatal blood flow in children with . It is therefore an open question whether the observed deficits in reflect a central dysfunction in the or a lack of input from other systems. Since almost all mental disorders show some degree of dysfunction, it is unclear whether the etiological deficits in have other causes.

  • binds to the dopamine transporters whose density is highest in the striatum. The binding of in the cerebellum and hippocampus is less than a tenth of this.
  • does not bind to dopamine receptors, but only to and . (In contrast: is said to activate D1 receptors. )
    • D- binds most strongly, namely to
      • with IC50 = 23 nM, Ki = 161 nM;
      • with IC50 = 39 nM, Ki = 206 nM
    • D/l- racemate binds somewhat weaker, namely to
      • with IC50 = 20 nM, Ki = 121 nM
      • with IC15 = 51 nM, Ki = 788 nM
    • L- binds the weakest, namely to
      • with IC50 = 1600 nM, Ki = 2250 nM
      • with IC50 > 104 nM, Ki > 104 nM
  • drug doses cause an plasma concentration of around 20 to 30 nM, which is sufficient to occupy a proportion of the dopamine transporters. This effect coincides with that of D-.
  • responders showed an increased count in the striatum, non-responders a reduced count.
  • increased the number of dopamine transporters.
  • Different:
    • Lower increase in dopamine and noradrenaline in the striatum
    • No increase in dopamine in the striatum by in (-/-) mice, but in (+/-) and (+/+) mice Apparently, the degree of expression/sensitivity of the is decisive for the positive or negative modulation of dopamine release.
2.1.1.3. increases dopamine release through (efflux)

While it was previously assumed that methylphenidate does not cause dopamine release, more recent opinions assume that it does

  • a dopamine efflux from the
  • dopamine release from vesicles at very high doses.

The view that is a pure reuptake inhibitor is outdated.

  • Also release of dopamine from vesicles (here: reserpine-sensitive granules)
    • Should only occur at very high doses of more than 80 mg / day
  • In contrast to amphetamine, methylphenidate is not considered a substrate for transport into the cytoplasm, which is why it causes at most a slight release of dopamine.
  • efflux through reversal in the
    • In the striatum in rats at 4 mg/kg (measured )
    • thereby increases the extracellular dopamine level
    • from dopamine and noradrenaline terminals
    • By vesicular dopamine release and by sodium-dependent mechanisms
  • Increase the firing rate of pyramidal neurons
    • At intake in in rats at 4 mg/kg (measured )
    • measured by extracellular electrophysiological single-cell recordings
    • Reactions to locally applied NMDA unchanged
  • Desensitization to both dopamine and in striatal regions
    • With ingestion in the striatum in rats at 4 mg/kg (measured )
    • reduced efficacy of extracellular dopamine in modulating NMDA-induced firing activities of spinous process neurons in the striatum
    • lower -induced dopamine outflow
    • is consistent with the empirical experience that a one-time adjustment of the dose is required after a few weeks in the case of single dosing
2.1.1.4. acts on via D2 autoreceptors, normalizes TH

causes the disinhibition (removal of inhibition) of D2 autoreceptors.
Nevertheless, the effect of stimulants in different doses on D2 autoreceptors is not greater than on heteroreceptors. Stimulants appear to have little effect on the dopamine system via autoreceptors.
In people with a high number of D2 receptors, increases metabolism in and brain areas (including the striatum), while in healthy people with a low number of D2 receptors, decreases metabolism. Metabolism was consistently increased in the cerebellum.
This corresponds to a normalization of the D2 receptor binding.
Similar findings are reported with regard to tyrosine hydroxylase. While TH expression is decreased in the spontaneously hypertensive rat (), it is increased in the Naples high-excitability rat (NHE). Sub MPH administration normalizes TH expression in both model animals.

Methylphenidate normalizes increased dopamine transporter densities in rats to a greater extent than in rats

2.1.1.5. increases via VMAT2

influences the redistribution of the vesicular monoamine transporter-2 (VMAT-2; Solute Carrier Family 18 Member 2 - SLC18A2). VMAT2 is involved in the sequestration of cytoplasmic dopamine and noradrenaline and is therefore an important regulator of neurotransmission. does not affect the total amount of VMAT-2 in terminals, but only VMAT-2 transport.
has the following effects in monoaminergic neurons (but not in cholinergic, -ergic or glutamatergic neurons)

  • Decrease in VMAT-2 immunoreactivity in the membrane-associated fraction
  • Increase in the cytoplasmic fraction
  • no change in the entire synaptosomal pool

thus protects the system from progressive “wear and tear” by securing a considerable reserve pool in the vesicles. Therefore, there is only a relatively low risk of neurotoxic / neuropsychiatric side effects in treatment practice with

According to older reports, has no effect on vesicular monoamine transporters (VMAT).

2.1.1.6. increases tyrosine hydroxylase

(TH) is the rate-limiting enzyme for the synthesis of dopamine. TH converts tyrosine into the precursor L-3,4-dihyroxyphenylalanine (L-DOPA). thus supports dopamine synthesis.
(as well as sports) can induce the expression of TH and increase TH levels
d- from 100 nmol/l significantly increased tyrosine hydroxylase activity ; L- or MPH at the same concentration did not increase TH
It is unclear whether the increase occurs only ly or also in the brain. TH gene variants appear to influence the response of .

2.1.1.7. acts via L-DOPA receptors

The L-dopa receptor GPR143 appears to be involved in the and effects of .
Although increases dopamine release, it does not affect L-DOPA release from the striatum. Nevertheless, in L-DOPA receptor KO mice (mice with a defect in the Gpr143 L-DOPA receptor gene), L-DOPA release is reduced:

  • the hyperlocomotion induced by
  • the reward effect
  • the c-fos expression induced by .
2.1.1.8. Dose-dependent effect of

The effect of is dose-dependent. Normal doses of have different effects than high or very high doses of .

  • At low doses, methylphenidate increases dopamine and noradrenaline levels in the , which increases its performance. In contrast, low-dose has barely any effect on dopamine and noradrenaline levels in other areas of the brain. This is consistent with the known increase in cognitive performance of the due to small increases in dopamine and noradrenaline levels during mild stress.
  • At 3 mg/kg , one study found no increase in dopamine or noradrenaline in the striatum of rats
  • At higher doses of (as well as cocaine), a reduction in dopamine levels in the striatum was reported in a laboratory study in rats. Only lower doses of or cocaine caused increases in dopamine levels. Moreover, this was not the case in all animals.
  • At higher doses, is also said to have a dopamine and noradrenaline-releasing effect via and efflux
  • At high doses, is said to enhance the surface expression of
2.1.1.9. Duration-dependent effect of

Acute MPH administration increased the firing activity of pyramidal neurons in rats and potentiated NMDA-induced neurotransmission.
Chronic MPH administration (2 x 2 mg/kg/day) showed 28 days after the end of administration on pyramidal neurons of the

  • long-term increase in firing activity
  • unchanged burst activities
  • unchanged total number of spontaneously discharging neurons
  • unaltered glutamatergic neurotransmission

Long-term administration of or atomoxetine to juvenile Naples High-Excitability (NHE) rats in adulthood

  • in the and striatum reduced
  • Noradrenaline increased in the striatum
  • In juvenile rats
    • A single administration of high-dose (2 mg/kg, i.e. approximately twice the maximum treatment dose normally used in humans)
      • A reduction in the number of vesicular monoamine transporters (VMAT2) in the cerebellum
      • No increase in dopamine turnover in the cerebellum (measured by the metabolite DOPAC)
      • No change in the protein levels of tyrosine hydroxylase (TH) and the dopamine D1 receptor
      • Unchanged levels of dopamine and homovanillic acid ()
    • Continuous administration of high-dose (2 mg/kg) over 14 days
      • Increased number of vesicular monoamine transporters (VMAT2) in the cerebellum
      • Significantly increased dopamine turnover in the cerebellum (measured with the metabolite DOPAC)
      • Left the protein levels of tyrosine hydroxylase (TH) and the dopamine D1 receptor unchanged - unlike the same authors
      • Increased the number of
        • In the left striatum
      • Did not change the
        • In the right striatum
        • In the nucleus accumbens ( striatum)
      • Increased the expression of the
        • Noradrenaline transporter ()
        • transporter 2 (VMAT2)
          • In contrast, amphetamine reduces VMAT2
        • D1 receptors
        • Stronger in the nucleus accumbens ( striatum) than in the striatum
        • Stronger in the cortex than in the cortex
        • This effect of MPH on increasing , and VMAT2 transporters may suggest that the drug could lose some of its effect of increasing dopamine and noradrenaline levels in the long term.
          This is consistent with our experience that for some users the dosage has to be adjusted (slightly increased) once after six months to a year. However, a general habituation effect is neither reported in studies nor in practice.
        • Elevated vanillin mandelic acid in the urine of Wistar rats. This could be avoided by augmentative administration of buspirone.
          Vanillin mandelic acid is produced during the breakdown of adrenaline and noradrenaline by MAO-A and COMT, so that vanillin mandelic acid is an indicator of the activity of the autonomic nervous system (sympathetic nervous system).
      • A single administration of very high doses of (5 mg/kg, i.e. about 5 to 20 times the usual treatment dose for humans) has the following effects
        • A similar metabolite change in the cerebellum as 2 mg
        • s associated with energy consumption and neurotransmission, here glutamate, glutamine, N-acetylapartate and inosine, tended to be reduced in the cerebellum
        • Furthermore, the levels of some metabolites associated with neurotransmission, in this case and glycine, acetate, aspartate and hypoxanthine, were reduced
  • One study found that oxytocin levels in children with were unchanged compared to unaffected children. While oxytocin decreased in untreated people with after interaction with a parent, oxytocin increased in people with treated with as well as in unaffected people.

2.1.2. increases noradrenaline

  • has a effect in the locus coeruleus, which improves arousal, vigilance and attention
  • The effect of is dose-dependent. Normal doses of have different effects than high or very high doses of .
  • At low doses, methylphenidate increases dopamine and noradrenaline levels in the , which increases its performance. In contrast, low-dose has barely any effect on dopamine and noradrenaline levels in other areas of the brain. This corresponds to the known increase in cognitive performance of the due to small increases in dopamine and noradrenaline levels during mild stress.
2.1.2.1. low dose increased extracellular noradrenaline, but not dopamine

Adolescent rats received 0.75-3.0 mg/kg orally during the dark-active phase of the circadian cycle, which remained below the threshold for locomotor activation. These doses:

  • increased extracellular norepinephrine in the hippocampus
  • altered dopamine in the nucleus accumbens does not
  • did not alter methamphetamine sensitivity
  • did not cause any habituation effects

10, 20 and 30 mg/kg (far above a medicinal dosage):

  • stereotypic behavior (a sign of strongly increased extracellular dopamine); 20 mg/kg as strong as 2.5 mg/kg
  • extracellular dopamine increased
  • extracellular noradrenaline increased
  • extracellular serotonin unchanged (unlike , as it is elevated)
2.1.2.2. binds to (reuptake inhibition)
  • Noradrenaline reuptake inhibitors
  • This also increases extracellular dopamine in the , where there is little but plenty of
2.1.2.3. causes noradrenaline efflux in the

2.1. induces dopamine and noradrenaline efflux in the pre cortex
In the pre cortex (), administration of 100 µM methylphenidate () (Figure 1A) elicited ex vivo dopamine release (Bonferroni post-hoc test after two-way ANOVA, Supplementary Table S1). This effect was dependent on norepinephrine terminals, as incubation of radiolabeled dopamine (35 nM) in the presence of desipramine significantly attenuated dopamine efflux induced by 100 µM (Figure 1A, Bonferroni post-hoc test after two-way ANOVA). This was further confirmed by assessing radiolabeled norepinephrine efflux (67-83 nM) after exposure in samples. Indeed, at 100 µM induced norepinephrine efflux in the (Figure 1B, Tukey’s post hoc test after one-way ANOVA). A lower dose of 10 µM did not elicit dopamine efflux under any conditions. These results suggest that can induce both dopamine and norepinephrine efflux in the , an effect that originates from both dopamine and norepinephrine terminals at a dose of 100 µM.

  • Noradrenaline efflux (67-83 nM) from noradrenaline terminals
    • Measured
    • At 100 µM , not at 10 µM
2.1.2.4. increases via VMAT2

influences the redistribution of the vesicular monoamine transporter-2 (VMAT-2; Solute Carrier Family 18 Member 2 - SLC18A2). VMAT2 is involved in the sequestration of cytoplasmic dopamine and noradrenaline and is therefore an important regulator of neurotransmission.
does not affect the total amount of VMAT-2 in terminals, but only the VMAT-2 transport.
has an effect in monoaminergic neurons (but not in cholinergic, -ergic or glutamatergic neurons

  • Decrease in VMAT-2 immunoreactivity in the membrane-associated fraction
  • Increase in the cytoplasmic fraction
  • no change in the entire synaptosomal pool
2.1.2.5. binds to noradrenaline receptors
2.1.2.5.1. Alpha-1 receptor

also improves attention via the alpha-1 receptor.

2.1.2.5.2. Alpha-2 receptor

binds directly to alpha-2 receptors. binds to

  • α2A (Ki = 5.6 µM)
  • α2B (Ki = 2.420 µM)
  • α2C (Ki = 0.860 µM)

The cognitive improvement brought about by could be prevented by α2-adrenoceptor antagonists. Guanfacine and clonidine also have a positive effect as α2-adrenoceptor agonists in .

  • Blockade of the alpha-2-adrenoceptor
    • In contrast, several sources report an agonistic effect of on the alpha-2-adrenoceptor. See above.

2.1.3. and serotonin

The influence of on serotonin levels appears to be negligible overall
is said to bind 2200 times more strongly to the than to the and almost 1300 times more strongly to the than to the .

Controversial is:

  • Whether a reuptake inhibition of serotonin occurs at the synapse. There are sources for this as well as against it.
    • The serotonergic effect of is so weak that it is not relevant for the treatment
    • Our impression is that has no mood-enhancing effect. can have an antidepressant effect by eliminating the stimulus filter weakness that subsequently triggers depression.

    2.1.3.1. 5HT-1A serotonin receptor

D-threo-(R,R)-methylphenidate is a weak agonist of the 5HT-1A serotonin receptor, but not of the 5HT-2A receptor. This can influence the dopamine metabolism in the brain, but the extent is small.

Whether binds to serotonin receptors is unclear. Various studies have produced contradictory results.

2.1.3.1. and tryptophan hydroxylase

Of the two tryptophan hydroxylase isoforms, TPH1 and TPH2, only TPH2 is present in the brain. TPH catalyzes the rate-limiting step in the synthesis of serotonin by converting tryptophan into the serotonin precursor 5-hydroxytryptophan.
The AATGGAGA (Yin) haplotype of TPH2 appears to be less responsive to than the CGCAAGAC (Yang) haplotype.

2.1.3.2. Effect of on tryptophan metabolites

In persons with (predominantly hyperactive) with depressive symptoms, one study found significantly higher morning than evening levels of indoleacetic acid compared to sufferers and healthy controls. reduced this by 50 %. also reduced the morning levels of indolepropionic acid and brought the daily profile back to the levels of healthy controls.

2.1.3.3. Effect of on raphe nuclei

Several days of administration triggered

  • behavioral sensitization in some rats (which correlated with neuronal arousal) and
  • behavioral tolerance (which was associated with neuronal attenuation) in other rats.
    s in the raphe nuclei (serotonergic) responded most strongly to and MPH administration and differently from neurons in () or locus coeruleus () at all 3 doses used.
    Dorsal raphe nuclei and serotonin appear to be involved in the and effects of and play an independent role in the response to .

2.1.4. Binding affinity of , , ATX to / /

The active ingredients methylphenidate (), d-amphetamine (d-), l-amphetamine (l-) and atomoxetine (ATX) bind with different affinities to dopamine transporters (), noradrenaline transporters () and serotonin transporters (). The binding causes an inhibition of the activity of the respective transporters.

Binding affinity: stronger with smaller number (KD = Ki)
34 - 200 339 > 10,000
d- (Vyvanse, Attentin) 34 - 41 23.3 - 38.9 3,830 - 11,000
l- 138 30.1 57,000
ATX 1451 - 1600 2.6 - 5 48 - 77

2.1.5. Effect of , , ATX on dopamine / noradrenaline per brain region

The active ingredients methylphenidate (), amphetamine () and atomoxetine (ATX) alter extracellular dopamine () and noradrenaline () to different degrees in different regions of the brain. Table based on Madras, modified.
+
(+)		 +
+/- 0		 +
+/- 0
+
+		 +
+/- 0		 +
+/- 0
ATX +
+		 +/- 0
+/- 0		 +/- 0
+/- 0

2.1.6. Effect of on MAO-A

influences monoamine oxidase A (MAO-A) by

  • Stimulation of non-vesicular release
  • of MAO-A activity

However, the influence appears to be limited and of little relevance.

2.2. Effect of on cholesterol metabolism in the

One study found 12 altered metabolic metabolites in the in rats, considered an model, compared to WKY rats, considered a model of non-affected individuals. The deviations of 8 of these were equalized by :

  • 3-Hydroxymethylglutaric acid
  • 3-phosphoglyceric acid
  • Adenosine monophosphate
  • Cholesterol
  • Lanosterine
  • O-Phosphoethanolamine
  • 3-Hydroxymethylglutaric acid
  • Cholesterol

The altered metabolites belong to the metabolic pathways of cholesterol.
In the case of the , the found that

  • Reduced activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase
    • Unchanged by
  • Reduced expression of the sterol regulatory element-binding protein-2
    • Increased by
  • Reduced expression of the ATP-binding cassette transporter A1
    • Increased by

2.3. Effect of on the

Stimulants (methylphenidate and amphetamine drugs) are said to increase the activity of the .
increases the cortisol awakening response, which is a sign of reactivity of the .

increased measures of stress (salivary cortisol and blood pressure). modulated the effects of stress on the activation of brain areas associated with goal-directed behavior, including the insula, putamen, amygdala, , pole, and . However, did not modulate the tendency of stress to cause a reduction in goal-directed behavior.

2.4. Effect of on the autonomic nervous system (sympathetic / parasympathetic nervous system)

In , heart rate variability (), which correlates with the health of the autonomic nervous system and in particular reflects the activity of the parasympathetic nervous system, is reduced. Stimulants such as methylphenidate improve (increase) heart rate variability without, however, being able to raise it to the level of non-affected people.

The statement made elsewhere,, that methylphenidate does not change the HVR is not found in the source cited.

2.5. Effect of on androgens

Stimulants (methylphenidate and amphetamine drugs) reduce the concentration of androgens.
Pre data on the role of androgens in the pathogenesis of suggest that elevated testosterone levels may reduce cerebral blood flow in the by decreasing the amount of alpha estrogen receptors and vascular endothelial growth factor (VEGF). This can interfere with memory processes. There is a between and the polymorphism of the androgen receptor gene, which leads to its higher expression. Nevertheless, little is known about the issue of androgen involvement in .

2.6. Effect of on kynurenine

appears to improve the homeostatic ratio of various kynurenines (e.g., increased kynurenic acid vs. decreased quinolinic acid in plasma) in children with .

2.7. Effect of on

Methylphenidate increases the excitation of the reticular activation system ().

2.8. Effect of on oxidative/nitrosative status

improved the redox profile with a reduction in the levels of advanced oxidation protein products (AOPP), lipid peroxidation (LPO) and nitrite plus nitrate (NOx) and an increase in the enzymatic activities of glutathione reductase (GRd) and catalase (CAT).

2.9. Effect of on S100B

One study found that triple therapy (TT) with methylphenidate (), melatonin (aMT) and omega-3 fatty acids (ω-3 PUFAs) increased S100B in people with . The authors see this as an indication that a neuroinflammatory cause of may damage glial function and thereby alter () neurotransmission.

2.10. Effect of on brain networks

2.10.1. and connectivity between brain regions

In one study, methylphenidate normalized reduced global connectivity in 400-700 ms after a stimulus and reduced an increase in network disconnection 100-400 ms after the stimulus. These global changes caused by methylphenidate occurred mainly in the task-relevant and regions and were more and lasting than in the non-treated comparison subjects. The results of the study indicate that methylphenidate corrects impaired network flexibility in .

Another study reports interhemispheric connectivity changes in :

  • Reduced interhemispheric coherence in the delta band in brain regions
  • Increased coherence in the theta band in regions (only with eyes open)
  • Increased coherence in the theta band in central areas

2.10.2. Effect of on Default Mode Network ()

The increased purely ally motivated attentional control in means that attention and its controllability is just as high as in non-affected individuals when interest is correspondingly high and only deviates from the attention of non-affected individuals when interest is lower. This is controlled by the .
Stimulants are able to align the attentional control of persons with with that of non-affected persons in the absence of interest. This explains why stimulants are just as helpful in and as in .

More on the deviant function of the in and its normalization by stimulants, including further references at ⇒ Normalization of the DMN by stimulants In the article ⇒ Brain networks and connectivity in ADHD in the chapter ⇒ Neurological aspects.

2.10.3. Effect of on nucleus accumbens and cognitive control networks

Methylphenidate increased spontaneous neuronal activity in the nucleus accumbens and in cognitive control networks in children with . This resulted in more stable sustained attention.

2.11. Effect of on

caused

  • Significant differences in people with in the -parietal area at 250 ms-400 ms after the stimulus (P3)
  • A decrease in the late 650 ms-800 ms ERP component (LC) at electrodes of patients compared to controls
  • A reduction in reaction time variability in people with , which correlated with increased P3-ERP response at the fronto electrodes

2.12. Effects on brain regions

Neuroimaging studies show several effects of on different brain regions. These show that acts primarily in the and striatum.

  • Apparently reduces the reduction in gray matter typical of
    • In the ganglia (mainly in children, problem probably decreasing per se in adults)
      • In the right lentiform nucleus
        • In the right globus pallidus
        • In the putamen
      • In the caudate nucleus
    • In the cingulate cortex (ACC) in adults
  • mediates its and effects on behavior via the system of the caudate nucleus.
  • In hypermotor and inattentive people with , regular administration of methylphenidate increases the previously unusually low blood flow to the putamen. In children with with average motor activity, regular administration of methylphenidate reduced blood flow to the putamen. The thalamus was not affected by .
    increased activation in the inferior cortex/insula during inhibition of discrimination.
  • Methylphenidate increases the metabolism in the brain on the left posterior and left superior and decreases it on the left , left parieto and anterior .

appears to reduce dysfunction in the in most people with . Another meta-analysis found that had no effect on working memory (in the ).

A study in rats with 0, 0.6, 2.5 and 10.0 mg /kg as single and repeated doses found that acted on the and caudate nucleus. The same dose of induced behavioural sensitization in some animals and tolerance in others, with activity in the and caudate nucleus correlating with the animals’ behavioural responses to . The reaction of the caudate nucleus was more intense than that in the , with both single and repeated administration. In addition, different dose-dependent responses were found between and caudate nucleus: some and caudate nucleus cell units responded to the same dose with excitation and others with attenuation of the neuronal firing rate.

2.13. for preschool children

Some studies show a positive effect of in preschool children with .

2.14. normalizes pain sensation in

People with often show an increased sensitivity to pain. can eliminate this sensitivity to pain in people with .

2.15. Serdexmethylphenidate improved sleep in

One study reports a improvement in sleep in children with between the ages of 6 and 12 with serdexmethylphenidate or dexmethylphenidate.

2.16. More about

Methylphenidate and amphetamine drugs increase the power of alpha (in rats), while atomoxetine and guanfacine do not.

acts (among other things) on the dopamine transporters in the brain. As the number of dopamine transporters decreases with increasing age (halving in 50-year-olds compared to 10-year-olds), adults require significantly lower doses.

Details on resumption inhibition

Cranial nerves transmit their information electrically. At a point of contact between a nerve and another nerve (synapse), the signal is passed on to another brain nerve via the synaptic cleft. This transmission of information is usually carried out chemically by neurotransmitters (dopamine, noradrenaline, serotonin and others). The electrical signal causes a release of neurotransmitters (here: dopamine) into the synaptic cleft at the end of the nerve (). At the receptor nerve on the other side of the synaptic cleft (), the neurotransmitter (here: dopamine) is taken up by (here: dopamine) receptors and triggers (electrical) signal transmission when a threshold value of activated receptors is reached. The precious neurotransmitter is then returned to the synaptic cleft by the receiving nerve, from where the sending nerve takes up the neurotransmitter again through special reuptake transporters (in the case of dopamine, the dopamine reuptake transporter, ) in order to be stored in the vesicles again for the next signal transmission.
In , the reuptake transporters (primarily located in the striatum) are overactive. If dopamine is released into the synaptic cleft by the transporters of the transmitter nerve, the of the transmitter nerve absorb the dopamine again before it can be taken up by the transporters of the receptor nerve. The signal chain is thus disrupted, comparable to the noise of a radio signal (“neural noise”) in relation to dopamine. Stimulants such as methylphenidate slow down the activity of the so that the dopamine remains in the synaptic cleft long enough for the signal to be transmitted cleanly. In this way, improves the neural noise in persons with to the level of non-affected people.
The special feature of synapses is that, according to the latest findings (2019), there are no dopamine receptors on the receptor side of the synapse, but rather receptors. Instead, the dopamine receptors are arranged spatially around the synapse and react to dopamine diffusing or otherwise escaping from the synapse.

It is occasionally postulated that very early treatment with stimulants could permanently improve overactivity (i.e. beyond the intake).

Early medication to cure ?

Early childhood stress exposure leads to long-term damage to the stress regulation systems if there is a corresponding genetic disposition. Such an establishment of stress exposure could possibly be prevented by timely drug treatment. In mice exposed to stress, the serotonin reuptake inhibitor fluoxetine reduced stress-induced increased risk-taking, while the -A receptor agonist diazepam did not.

Chronic administration of caffeine or before puberty improved object recognition in adult (a rat strain representing a genetic form of ), while the same treatment worsened it in adult Wistar rats

Administration of 2 mg / kg injected into the abdominal cavity before puberty (day 25 to 35) in non- model rats resulted in the following effects in adulthood (each reversible by fluoxetine)

  • increased anxiety
  • increased symptoms of depression
  • reduced motivation
    • due to drugs (morphine place preference)
    • lower sucrose preference

One oral administration to non- model rats from day 27 for 4 to 7 weeks on 5 days/week against

  • did not increase anxiety
  • transiently altered hippocampus-sensitive learning but did not cause cognitive impairment

Wistar rats (a non- model) that received drug doses of , but injected, for 14 days during adolescence (days 30 to 44) showed decreased impulsivity as adults. In addition, total creatine and taurine were decreased in the striatum and increased in the nucleus accumbens nucleus

One study investigated choice preference between regular no rewards and infrequent high rewards (nudging food on switch). Adult rats that had received in adolescence showed a preference shift that can be considered as increased efficiency and/or flexibility, leading to a “better” (i.e. more optimal) decision-making process.

Sprague-Dawley rats (a non- model) that had been injected with (2 mg/kg) or cocaine into the abdominal cavity during adolescence showed as adults in place conditioning tests

  • an aversive reaction to moderate doses of cocaine
  • a reduced rewarding effect to high doses of cocaine
  • depression-like effects on early exposure in the forced swim test
  • attenuated habituation to the activity chambers after early exposure (a sign of higher stress sensitivity)

Sprague-Dawley rats (a non- model) injected twice daily with (2 mg/kg) into the abdominal cavity during adolescence (day 20 to 35) showed as adults:

  • lower reward responsiveness to sucrose, novelty-induced activity and sex
  • significantly more sensitive reactions to stress situations and increased plasma levels of corticosterone
  • more frequent anxiety-like behavior

In adult rats that received during adolescence, changes in taurine levels were observed that could lead to hyperfunction of the striatum and the correlating hypofunction of the nucleus accumbens. Taurine could influence the extent to which the respective brain region is able to process neuronal information and regulate behavior. The taurine level in a brain region could serve as an index for the regional reactivity to synaptic input signals and thus for the function of the brain region in question as a whole.
Furthermore, adult rats that received in adolescence showed an increase in the phosphocreatine/creatinine ratio in the , which could be a consequence of improved energy metabolism. The authors hypothesize that the increased function of the may be responsible for downregulating the functional activity of the nucleus accumbens and increasing the activity of the striatum. Studies suggest separate functional roles of projections to these two target regions. While the circuit from the to the striatum serves attention, which influences executive planning and action selection, the pathway from the to the nucleus accumbens serves the integration of information about the motivational consequences of an action. This could explain how areas redirect subcortical activity.

While treatment of rats with for 20 days in adolescence caused a change in the expression of 700 genes in the striatum at the end of treatment, only 2 genes (Grik2 and Htr7) were found whose expression was still increased in adulthood.

Slight changes were also found in the average N-acetylaspartate and glutamide levels in the nucleus accumbens and in the total choline content in the striatum.
N-acetylaspartate Ageing and neurodegenerative processes reduce N-acetylaspartate levels. -exposed rats also showed a reduction in N-acetylaspartate as adults.

To the extent that the tests listed above were conducted with non- model animals, we believe that they have very limited predictive value for the effects of in rats with . When drugs are administered to animals that do not exhibit the deficit that the drug is intended to compensate for, negative effects of the drug are to be expected.
However, the tests are valuable in that stimulants given at an early stage theoretically have the potential to have a healing effect.
Tests on model animals would be valuable.

As the neurotransmitter systems that regulate stress develop in the first few years of life (presumably 6 years and earlier), medication that influences this should start much earlier. Whether this will work remains to be seen. What is certain, however, is that child-centered behavioral therapy barely brings any benefits for young children, while parent-centered therapy brings considerable benefits. This could indicate that the stress systems in young children can still be repaired by external influences.

A very small study of 16 subjects on the effect of methylphenidate on boys with and unaffected boys found increased activation of the cortex and decreased activation of the striatum in the people with before taking methylphenidate compared to the unaffected in go/no-go tasks. Methylphenidate compensated for the differences.

It remains to be seen what concentrations of methylphenidate reach the synaptic cleft.
Methylphenidate could accumulate in the central nervous system through active accumulation processes, so that the effective brain concentrations are considerably higher than in plasma. For cocaine, the striatal concentration in animals appears to be about 6 times higher than in plasma.

Whether influences prolactin is unclear.
It did not affect prolactin serum levels in men. Nor did it affect those not affected.
Neither amphetamine nor methylphenidate decreased serum prolactin in rats. Amphetamine, but not methylphenidate, blocked the increase in serum prolactin in response to reserpine.
In children, increases prolactin.

3. Differences in effect between methylphenidate and amphetamine medication

Methylphenidate may increase left posterior and left superior brain metabolism and decrease left , left parieto and anterior metabolism.

In contrast, D-amphetamine may increase metabolism in the right caudate nucleus (part of the striatum) and decrease it in the right Rolandi region and in the right inferior regions.

The samples (n) on which these findings were examined were very small at 19 and 18. Samples that are too small harbor the considerable risk of misleading results.
Find out more at ⇒ Studies say - sometimes nothing at all.

4. Effect on symptoms

Methylphenidate improves in children with :

  • Response time
  • Response time variability
  • attention
  • attention
  • divided attention
  • Flexibility/shifting attention/task switching
  • selective attention
    • Escapement
    • focused attention
  • Task accuracy in relation to
    • divided attention
    • Escapement
    • focused attention
    • Flexibility
    • Obtain integration of sensory information
  • Number of errors of omission and commission in attention tasks

There is evidence for an effect of on neuropathic pain.

4.1. Particularly good effect of methylphenidate

  • Hyperactivity
  • Restlessness
  • Impulsiveness
    • People with reported in forums that works better against impulsivity than Vyvanse.
    • A study on monkeys (naturally not people with ) came to the conclusion that low doses of reduced impulsivity, while higher doses had a sedative effect.
      This follows on from empirical experience that an overdose of can have an apathetic effect.
  • Aggressiveness
    • And better than atomoxetine
    • In a study of 6- to 12-year-old children with aggression and , systematically titrated stimulants eliminated aggression in 63%. In the children in whom stimulants did not sufficiently eliminate aggression, augmentative administration of risperidone (Effect size 1.3) or valproic acid (Effect size 0.9) improved aggression, with risperidone being associated with weight gain.
  • Socially maladjusted behavior
  • Behavioral problems, and better than atomoxetine
  • Somatic complaints, and better than atomoxetine
  • Motivate through reward
  • Drive
    • People with report quite consistently that improves drive more than
  • Number of errors of omission and commission in attention tasks
  • Gedankenwandern / Mind Wandering

is effective in adults:

  • against the core symptoms of (SMD: 0.49)
  • against the accompanying emotional dysregulation (SMD: 0.34)

is said to work best on the cognitive symptoms. Motor and social behavior may gradually require slightly higher doses.

4.2. Good effect of methylphenidate

  • Perception

  • Concentration

    • Many adults report that allows for greater focus than Vyvanse, while Vyvanse makes them more relaxed overall and has a more even effect

  • Attention

    • Distractibility is reduced, attention is increased
    • Task changes are reduced

  • Motor restlessness

  • Typeface and graphic expression

  • Social perceptiveness and mimic responsiveness

  • Social interaction

    • One study found that oxytocin levels in children with were unchanged compared to those without the disorder. While oxytocin increased in non-affected people after interaction with a parent, oxytocin decreased in untreated people with . Methylphenidate caused the oxytocin increase in persons with after parent interaction to correspond to that of non-affected people.

  • Rejection sensitivity (offendingness)
    Almost all of the people with we interviewed reported an improvement in their rejection sensitivity (which almost all of the people with we interviewed suffer from) as a result of . A few persons with reported that their RS became stronger under . One of these people with later turned out to be an nonresponder who was able to achieve a better effect with an amphetamine medication.

  • Mathematical skills

    • Children with under showed significantly improved math skills that were indistinguishable from those of unaffected children.

  • Anxiety

  • Tension

  • Borderline aspects

  • Depressiveness

  • Emotional instability

  • Dissatisfaction with life

  • Negative attitude to life

  • Psychotic phenomena

  • Social introversion

  • Uncertainty

  • Compulsiveness

  • Inner emptiness/boredom

4.3. Low effect of methylphenidate

  • Delay aversion (for adults)
  • Executive functions (in adults)

4.4. No effect of methylphendiate

  • Reading the Mind in the Eye (for children). This test measures the theory of mind.
  • Fine motor skills (handwriting)

4.5. Different time-dependent effects of stimulants on symptoms?

A publication by a renowned scientist claims different time-response and dose-response curves for the motor and cognitive effects of stimulants. While the effect on motor activity lasts 7 to 8 hours, the effect on attention is said to last only 2 to 3 hours. However, the sources cited do not substantiate this claim. Nor do they correspond with empirical experience from practice.

4.6. and smoking cessation

Sustained release MPH was reported to make a positive contribution to nicotine abstinence/smoking cessation, but only in more severe cases, whereas in milder cases there was a paradoxical worsening, but this after discontinuation of the medication. This should be considered against the background that nicotine as a stimulant is a self-medication for , even though smoking uses nicotine as a drug and only nicotine patches or nicotine lozenges act as a medication.
Further, in the context of the Inverted-U theory that intermediate neurotransmitter levels mediate optimal brain function, while decreased as well as excessive neurotransmitter levels cause nearly similar symptoms, the result of this study may indicate overdosing in the subjects with milder symptoms (indicating lower dopamine and norepinephrine deficiency) and a paradoxical response.

4.7. and creativity

One study found no impairment of creativity by , Another study found increased creativity in unmedicated children with compared to medicated children with and unaffected children.

5. Responding (responding / non-responding)

Response means whether there is an effect on the symptoms. People with who do not respond sufficiently to a medication are called non-responders.
Non-responding does not mean having no effect, but merely that the effect remains below the level of symptom improvement specified in the respective study.

A meta-analysis reports a 69% response rate to amphetamine medication and a 59% response rate to methylphenidate. 87% of people with responded to one of the two types of medication. A meta-analysis of 32 studies came to the same conclusion (significantly better response rates to amphetamine medication than to ).
For people with for whom does not work, it is therefore advisable to test a medication with amphetamine drugs.
About 50% of persons with who do not respond to are expected to respond to atomoxetine, and about 75% of persons with who respond to are expected to respond to atomoxetine.

In nonresponders, L-amphetamine and atomoxetine were compared in a randomized double-blind study with n = 200 subjects. L-amphetamine was significantly more effective than atomoxetine in 2 of 6 categories and in the overall assessment.

Positive indications for a response to were:

  • Lower -RS-IV.es scores
  • The absence of comorbidities (, depression, alcohol/cannabis use)
  • Less conspicuous neuropsychological tests
  • A higher overall IQ
  • Low commission errors (impulse control errors; reaction to signal that should not have been answered) in the Conners Continuous Performance Test II, CPT-II
  • Higher hyperactivity-impulsivity and oppositional symptoms before treatment
    • for good results with monotherapy, guanfacine monotherapy and /guanfacine combination medication
  • Less anxiety before the treatment
    • for good results with monotherapy, guanfacine monotherapy and /guanfacine combination medication
  • High event-related mid- beta power before treatment
    • activity from cortical sources localized in the regions of the middle bone and middle bone
    • Stronger modulations during encoding and retrieval predictor for good results with monotherapy and guanfacine monotherapy
  • Weak event-related mid- beta power before treatment
    • activity from cortical sources localized in the regions of the middle bone and middle bone
    • for good results with /guanfacine combination medication

5.1. Subtypes and non-response probability

Most older sources report that about 90% of people with subtype (with hyperactivity) and mixed type respond positively to methylphenidate and require quite low doses.
More recent sources speak of a response rate of up to 75% with , which seems more accurate to us.

People with subtype are said to be more frequent nonresponders, with nonresponder rates of 24% being mentioned. People with who respond to also require higher doses.
According to a small study, children with a higher cortisol stress response, which corresponds to the subtype, are more likely to benefit from higher doses of than children with a flattened cortisol stress response (which corresponds to ). However, the stress test was not based on the , but on venipuncture, which allows for a less distinct recognizability of the cortisol stress response.

A particularly strong increase in cortisol awakening (CAR) correlated with reduced responding in children.

people with (which, according to current understanding, is not a subtype of , but a comorbidity that is equally common in and ) are particularly frequent nonresponders. In particular, elevated sluggish/sleepy factor values indicate nonresponding. Neither elevated daydreamy symptoms nor subtype ( or ) differed in responding rates in this study.

According to one study, people with with intellectual deficits are less likely to respond to . A responder rate of 40 to 50 % was reported here. In contrast, another study found a good effect of in people with with intellectual deficits.

5.2. (Non-)responding and subtypes

People with with very low theta values are said to be more frequent nonresponders to stimulants.
According to this understanding, low theta values correspond to the overactivated beta () subtype. For the BETA subtype (overactivated type), another source reports reduced responding.
The beta subtype appears outwardly as the classic subtype (hyperactive/impulsive). Most people with subtype have theta that is too low and beta that is too high. More on this at ⇒ ADHD subtypes according to EEG.

However, the (individual) persons with of the BETA subtype known to us report an extremely helpful effect of .

A small study found lower stability at rest as a predictor of response.
Another study found an attenuated P3 amplitude in responders compared to controls. Unexpectedly, nonresponders showed an atypically flat aperiodic spectral slope compared to controls, while responders did not differ from controls.

5.3. (Non-)responding and dosing of

Some people suspect cases of underdosing among non-responders, i.e. that the required dosage was not reached and a non-response is only wrongly assumed.
Our impression is that too low a dosage can cause an apparent non-response. Nevertheless, there are genuine non-responders for whom even greatly increased doses do not produce satisfactory results.
In addition, a different non-responder rate is reported in children and adults.
We suspect that a more precise classification of subtypes will one day provide explanations here.

5.4. Seasonal influence on dosage?

One study found a seasonal pattern of inattention in people with treated with low-dose . During the season of increasing light levels (longer days), low-dose patients showed relatively poorer attention. It was not the amount of light that was relevant, but its relative change. High doses of led to a higher level of alertness that fluctuated less over the year. A greater reduction in sun intensity was associated with a better response to treatment. These results were also seen in the omission errors in a CPT.
The authors interpreted this to mean that a low dose may be sufficient when starting treatment with decreasing day length.
A connection with the circadian rhythm is suspected. The authors hypothesize that in some persons with (who need less ?) there could be a disturbed function of the light-sensitive retinal cells in the subgroups on the melatonin- and dopamine-producing cells in the retina. They raise the question of whether a combination of with modulated light therapy could improve responding, as has already been reported with fluoxetine in non-seasonal depression.

5.5. Indications of good responding

An increase in blood pressure is said to correlate with a particularly good effect of .

Particularly good symptom improvement on methylphenidate was observed in people with with

  • Increased delta power at F8
  • Increased theta power for Fz, F4, C3, Cz, T5
  • Increased gamma power with T6
  • Reduced beta power at F8 and P3
  • Increased delta/beta power ratio at F8 (in relation to hyperactivity)
  • Increased theta/beta power ratio at F8, F3, Fz, F4, C3, Cz, P3 and T5 (in relation to hyperactivity)

One study found little or no relevance of certain genes that are particularly relevant for neuronal development (“neurodevelopmental network”) to the effect of or atomoxetine in .

A meta-analysis of 15 studies and 1382 patients found that carriers of the T allele of the gene polymorphism rs28386840 responded significantly more frequently to and showed a significantly greater improvement in hyperactive-impulsive symptoms than carriers of other polymorphisms. ADRA2A polymorphisms did not correlate significantly with the response to . However, carriers of the G allele of the MspI polymorphism showed a with a improvement in inattention symptoms.

Elevated iron levels in the putamen and caudate correlated with better responding in . Elevated iron levels in the putamen correlated - not only in - with impaired inhibition

In preschool-aged , low externalizing or internalizing symptom severities correlated with a high likelihood of responding to stimulants. At high externalizing or internalizing symptom levels, the response rate of stimulants approached that of alpha-2 agonists:

Responder severity: weak medium strong
Stimulants Externalizing 96.4 % 74.3 % 66.6 %
Alpha-2 agonists Externalizing 40 % 50 % 67 %
Stimulants Internalizing 80.6 % 77.5 % 50 %
Alpha-2 agonists Internalizing 57.7 % 70 % 57.7 %

5.6. Gene variants and effect

5.6.1. ADRA2A gene variants

ADRA2A -1291 polymorphism influences responding and effect of .

  • G/G genotype:
    • 76.9 % responded well to
    • 25% greater reduction in symptoms after 3 months of
  • C/G genotype:
    • 46.0 % responded well to
  • C/G genotype:
    • 41.7 % responded well to

The genotype of the MspI polymorphism of the ADRA2A gene may influence side effects on OROS :

  • C/C genotype
    • diastolic blood pressure increased by 18.5 % with OROS-
  • G/G genotype
    • diastolic blood pressure decreased by 0.2 % with OROS-
  • G/C genotype
    • diastolic blood pressure decreased by 0.2 % with OROS-

5.6.2. gene variants

The genotype of the G1287A polymorphism of the gene (noradrenaline transporter, SLC6A2) may influence the response to :

  • G/G genotype:
    • 71.9 % responded well to
    • 7.15 points improvement on the hyperactivity subscale of the Rating Scale-IV, but not on the inattention subscale
    • no responding difference detected
  • G/A genotype:
    • 46.0 % responded well to
    • 6.94 points improvement on the hyperactivity subscale of the Rating Scale-IV, but not on the inattention subscale
  • A/A genotype:
    • 57.1 % responded well to
    • 2.13 points improvement on the hyperactivity subscale of the Rating Scale-IV, but not on the inattention subscale

The genotype of the -3081(A/T) polymorphism of the gene (noradrenaline transporter, SLC6A2) may influence the response to :

  • T/T genotype
    • responded comparatively better to
    • Increase in resting heart rate by 12.5 % due to OROS-MPHi
  • A/T genotype
    • responded comparatively better to -
    • Increase in resting heart rate by 3.5 % due to OROS-
  • A/A genotype
    • responded comparatively worse to
    • Increase in resting heart rate by 2.5 % due to OROS-

A meta-analysis found a between effect and the SLC6A2 gene variants

  • rs5569 (OR: 1.73)
  • rs28386840 (OR: 2.93)

5.7. CES1 plasma protein level and dosage

Methylphenidate is broken down by the CES1 liver enzyme.
A higher CES1 plasma concentration correlated with a reduced d-methylphenidate plasma level. In one study, the CES1 plasma protein level could explain about 50 % of the variability of the d-methylphenidate plasma level. It is possible that an individualized dosing strategy based on the measurement of CES1 could considerably facilitate the dosing of d-methylphenidate.

5.8. Response individually dependent on retardation and carrier substance

People with report a very different individual response to different preparations.
While the intra-individual (within a person) and inter-individual (compared to other people with ) differences in tolerability of retard preparations are now generally recognized, it is less well known that tolerability and responding can also vary greatly between individuals in relation to different immediate release MPH preparations. We have received reports from a number of people with who reproducibly perceive very clear differences in the effect of various equally strong unretarded preparations.

5.9. Therapeutic reference range, pharmacokinetics

The therapeutic reference range (Cmax ranges of therapeutically effective doses) was indicated:

  • Methylphenidate:

    • Children and young people:
      • 6 to 26 ng/ml, 2 hours after ingestion of 20 mg IR or 4 to 6 hours after ingestion of 40 mg XR formulation
    • Adults:
      • 12 bs 79 ng/ml, 2 hours after ingestion after 20 mg IR or 4 to 6 hours after ingestion after 40 mg XR formulation
    • : 2 h
    • Laboratory value warning threshold: 50 ng/ml
    • At 0.3 mg/kg, children and adults showed identical pharmacokinetic parameters (Wargin 1983a).

  • Dexmethylphenidate:

    • 13 to 23 ng/ml, 4 hours after ingestion of 20 mg
    • : 2 h
    • Laboratory value warning threshold: 44 ng/ml

There is therefore no objectifiable neurobiological between blood levels and efficacy. The therapeutic reference ranges given are population-related statistical values that cannot be transferred 1:1 to all patients. In order to measure neuropsychopharmacotherapy, the individual therapeutic concentration range of the person with would therefore have to be identified. For example, the blood level can be measured after determining the appropriate dose for the optimal individual improvement.

The pharmacokinetics of methylphenidate are not linear. Based on the AUC, the plasma exposure of D- was disproportionate to the dose (in dogs). A dose increase from 20 to 40 mg caused a 3-fold decrease in clearance and a 7-fold increase in AUC despite a constant elimination half-life. However, the mean total excretion rates (sum of the enantiomers of methylphenidate and its metabolite ritalinic acid in urine) remained relatively constant (63-78% of doses), suggesting that the dose-dependent AUC changes may not be due to a change in intestinal absorption. This could be a consequence of saturation of presystemic elimination.
Nevertheless, people with report quite consistently that the duration of action of preparations is constant at different dose levels.

Maximum plasma concentration, Cmax

  • l-Methylphenidate
    • 40 mg orally immediate release: 2.98 ng/ml
    • 40 mg orally sustained release: 1.85 ng/ml

Time of maximum plasma concentration, Tmax

  • dl-methylphenidate
    • 0.15 mg / kg, oral: 2.2 hours (± 0.4)
    • 0.3 mg / kg, oral: 2.1 hours (± 0.3)

Elimination half-life

  • d-methylphenidate
    • 10 mg intravenously: 5.96 hours (± 1.7)
    • 40 mg orally immediate release: 5.69 hours (± 1.1)
    • 40 mg orally sustained release: 5.04 hours (± 0.7)
  • l-Methylphenidate
    • 10 mg intravenously: 3.61 hours (± 1.1)
    • 40 mg orally immediate release: 3.93 hours (± 0.8)
    • 40 mg orally sustained release: 3.88 hours (± 0.6)

  1. Jaeschke RR, Sujkowska E, Sowa-Kućma M (2021): Methylphenidate for attention-deficit/hyperactivity disorder in adults: a narrative review. Psychopharmacology (Berl). 2021 Oct;238(10):2667-2691. doi: 10.1007/s00213-021-05946-0. PMID: 34436651; PMCID: PMC8455398. REVIEW ↥

  2. Buckner CK, Patil PN, Tye A, Malspeis L (1969): Steric aspects of adrenergic drugs. XII. Some peripheral effects of (+-)-erythro- and (+-)-threo-methylphenidate. J Pharmacol Exp Ther. 1969 Apr;166(2):308-19. PMID: 5813368. ↥ ↥

  3. Methylphenidat bei Drugbank.com Abruf 16.03.24 ↥

  4. Vadivelu N, Singh-Gill H, Kodumudi G, Kaye AJ, Urman RD, Kaye AD (2014): Practical guide to the management of acute and chronic pain in the presence of drug tolerance for the healthcare practitioner. Ochsner J. 2014 Fall;14(3):426-33. PMID: 25249810; PMCID: PMC4171802. ↥

  5. Arnsten AF, Dudley AG (2005): Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder. Behav Brain Funct. 2005 Apr 22;1(1):2. doi: 10.1186/1744-9081-1-2. PMID: 15916700; PMCID: PMC1143775. ↥

  6. Turner PV, Brabb T, Pekow C, Vasbinder MA (2011): Administration of substances to laboratory animals: routes of administration and factors to consider. J Am Assoc Lab Anim Sci. 2011 Sep;50(5):600-13. PMID: 22330705; PMCID: PMC3189662. REVIEW ↥ ↥

  7. Gerasimov MR, Franceschi M, Volkow ND, Gifford A, Gatley SJ, Marsteller D, Molina PE, Dewey SL (2000): Comparison between intraperitoneal and oral methylphenidate administration: A microdialysis and locomotor activity study. J Pharmacol Exp Ther. 2000 Oct;295(1):51-7. PMID: 10991960. ↥

  8. Al Shoyaib A, Archie SR, Karamyan VT. Intraperitoneal Route of Drug Administration: Should it Be Used in Experimental Animal Studies? Pharm Res. 2019 Dec 23;37(1):12. doi: 10.1007/s11095-019-2745-x. PMID: 31873819; PMCID: PMC7412579. REVIEW ↥

  9. Thanos PK, Robison LS, Steier J, Hwang YF, Cooper T, Swanson JM, Komatsu DE, Hadjiargyrou M, Volkow ND (2015): A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior. Pharmacol Biochem Behav. 2015 Apr;131:143-53. doi: 10.1016/j.pbb.2015.01.005. PMID: 25641666; PMCID: PMC4461871. ↥

  10. Senior D, Ahmed R, Arnavut E, Carvalho A, Lee WX, Blum K, Komatsu DE, Hadjiargyrou M, Badgaiyan RD, Thanos PK (2023): Behavioral, Neurochemical and Developmental Effects of Chronic Oral Methylphenidate: A Review. J Pers Med. 2023 Mar 23;13(4):574. doi: 10.3390/jpm13040574. PMID: 37108960; PMCID: PMC10144804. REVIEW ↥

  11. Jager A, Kanters D, Geers F, Buitelaar JK, Kozicz T, Glennon JC. Methylphenidate Dose-Dependently Affects Aggression and Improves Fear Extinction and Anxiety in BALB/cJ Mice. Front Psychiatry. 2019 Oct 25;10:768. doi: 10.3389/fpsyt.2019.00768. PMID: 31708820; PMCID: PMC6823535. ↥

  12. Gaytan O, Ghelani D, Martin S, Swann A, Dafny N (1996): Dose response characteristics of methylphenidate on different indices of rats’ locomotor activity at the beginning of the dark cycle. Brain Res. 1996 Jul 15;727(1-2):13-21. doi: 10.1016/0006-8993(96)00296-x. PMID: 8842378. ↥ ↥ ↥

  13. Senior D, Ahmed R, Arnavut E, Carvalho A, Lee WX, Blum K, Komatsu DE, Hadjiargyrou M, Badgaiyan RD, Thanos PK. Behavioral, Neurochemical and Developmental Effects of Chronic Oral Methylphenidate: A Review. J Pers Med. 2023 Mar 23;13(4):574. doi: 10.3390/jpm13040574. PMID: 37108960; PMCID: PMC10144804. REVIEW ↥

  14. Senior D, Ahmed R, Arnavut E, Carvalho A, Lee WX, Blum K, Komatsu DE, Hadjiargyrou M, Badgaiyan RD, Thanos PK (2023): Behavioral, Neurochemical and Developmental Effects of Chronic Oral Methylphenidate: A Review. J Pers Med. 2023 Mar 23;13(4):574. doi: 10.3390/jpm13040574. PMID: 37108960; PMCID: PMC10144804. REVIEW; angegebene Fundstellen belegen dies nicht / references given do not prove this ↥

  15. Childress, Komolova, Sallee (2019): An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019 Nov;15(11):937-974. doi: 10.1080/17425255.2019.1675636. PMID: 31581854. REVIEW ↥

  16. Ching, Eslick, Poulton (2019): Evaluation of Methylphenidate Safety and Maximum-Dose Titration Rationale in Attention-Deficit/Hyperactivity Disorder: A Meta-analysis. JAMA Pediatr. 2019 May 28. doi: 10.1001/jamapediatrics.2019.0905. ↥

  17. Krause, Krause (2014): ADHS im Erwachsenenalter: Symptome – Differenzialdiagnose – Therapie, Seite 246 ↥

  18. Dodson WW (2005): Pharmacotherapy of adult ADHD. J Clin Psychol. 2005 May;61(5):589-606. doi: 10.1002/jclp.20122. PMID: 15723384. REVIEW ↥ ↥

  19. Childress AC, Komolova M, Sallee FR (2019): An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019 Nov;15(11):937-974. doi: 10.1080/17425255.2019.1675636. PMID: 31581854. REVIEW ↥

  20. Barnhardt EA, Narayanan AR, Coury DL. Evaluating serdexmethylphenidate and dexmethylphenidate capsules as a once-daily treatment option for ADHD. Expert Opin Pharmacother. 2023 May-Aug;24(11):1215-1219. doi: 10.1080/14656566.2023.2218544. PMID: 37226489. ↥

  21. Visentin R, Dalla Man C, Kovatchev B, Cobelli C (2014): The university of Virginia/Padova type 1 diabetes simulator matches the glucose traces of a clinical trial. Diabetes Technol Ther. 2014 Jul;16(7):428-34. doi: 10.1089/dia.2013.0377. PMID: 24571584; PMCID: PMC4074748. ↥

  22. Gutiérrez-Casares JR, Quintero J, Segú-Vergés C, Rodríguez Monterde P, Pozo-Rubio T, Coma M, Montoto C (2023): In silico clinical trial evaluating lisdexamfetamine’s and methylphenidate’s mechanism of action computational models in an attention-deficit/hyperactivity disorder virtual patients’ population. Front Psychiatry. 2023 Jun 2;14:939650. doi: 10.3389/fpsyt.2023.939650. PMID: 37333910; PMCID: PMC10273406. ↥

  23. Steinhausen, Rothenberger, Döpfner (2010): Handbuch ADHS, Seite 84, 85 ↥ ↥ ↥ ↥ ↥ ↥ ↥

  24. Berridge CW, Stalnaker TA (2002): Relationship between low-dose amphetamine-induced arousal and extracellular norepinephrine and dopamine levels within prefrontal cortex. Synapse. 2002 Dec 1;46(3):140-9. doi: 10.1002/syn.10131. PMID: 12325041. ↥

  25. Arnsten AF, Dudley AG (2005). Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder. Behav Brain Funct. 2005 Apr 22;1(1):2. doi: 10.1186/1744-9081-1-2. PMID: 15916700; PMCID: PMC1143775. ↥

  26. Kuczenski R, Segal DS (2001): Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine. J Pharmacol Exp Ther. 2001 Mar;296(3):876-83. PMID: 11181919. ↥

  27. Kuczenski R, Segal DS (2002): Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci. 2002 Aug 15;22(16):7264-71. doi: 10.1523/JNEUROSCI.22-16-07264.2002. PMID: 12177221; PMCID: PMC6757883. ↥ ↥

  28. Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002;27:699–711. ↥ ↥

  29. Di Miceli, Derf, Gronier (2022): Consequences of Acute or Chronic Methylphenidate Exposure Using Ex Vivo Neurochemistry and In Vivo Electrophysiology in the Prefrontal Cortex and Striatum of Rats. Int J Mol Sci. 2022 Aug 2;23(15):8588. doi: 10.3390/ijms23158588. PMID: 35955717; PMCID: PMC9369023. ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥

  30. Koda K, Ago Y, Cong Y, Kita Y, Takuma K, Matsuda T (2010): Effects of acute and chronic administration of atomoxetine and methylphenidate on extracellular levels of noradrenaline, dopamine and serotonin in the prefrontal cortex and striatum of mice. J Neurochem. 2010 Jul;114(1):259-70. doi: 10.1111/j.1471-4159.2010.06750.x. PMID: 20403082. ↥ ↥

  31. Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B, Hamilton C, Spencer RC (2006):Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry. 2006 Nov 15;60(10):1111-20. doi: 10.1016/j.biopsych.2006.04.022. PMID: 16806100. ↥

  32. Kodama T, Kojima T, Honda Y, Hosokawa T, Tsutsui KI, Watanabe M (2017): Oral Administration of Methylphenidate (Ritalin) Affects Dopamine Release Differentially Between the Prefrontal Cortex and Striatum: A Microdialysis Study in the Monkey. J Neurosci. 2017 Mar 1;37(9):2387-2394. doi: 10.1523/JNEUROSCI.2155-16.2017. PMID: 28154152; PMCID: PMC6596846. ↥

  33. Gatzke-Kopp, Beauchaine (2007): Central nervous system substrates of impulsivity: Implications for the development of attention-deficit/hyperactivity disorder and conduct disorder. In: Coch, Dawson, Fischer ( Eds): Human behavior, learning, and the developing brain: Atypical development. New York: Guilford Press; 2007. pp. 239–263; 245 ↥ ↥

  34. Ruskin DN, Bergstrom DA, Shenker A, Freeman LE, Baek D, Walters JR (2001): Drugs used in the treatment of attention-deficit/hyperactivity disorder affect postsynaptic firing rate and oscillation without preferential dopamine autoreceptor action. Biol Psychiatry. 2001 Feb 15;49(4):340-50. doi: 10.1016/s0006-3223(00)00987-2. PMID: 11239905. ↥ ↥ ↥

  35. Federici M, Latagliata EC, Ledonne A, Rizzo FR, Feligioni M, Sulzer D, Dunn M, Sames D, Gu H, Nisticò R, Puglisi-Allegra S, Mercuri NB (2014): Paradoxical abatement of striatal dopaminergic transmission by cocaine and methylphenidate. J Biol Chem. 2014 Jan 3;289(1):264-74. doi: 10.1074/jbc.M113.495499. PMID: 24280216; PMCID: PMC3879549. ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥

  36. Fuller, Burrell, Yee, Liyanagama, Lipski, Wickens, Hyland (2019): Role of homeostatic feedback mechanisms in modulating methylphenidate actions on phasic dopamine signaling in the striatum of awake behaving rats. Prog Neurobiol. 2019 Nov;182:101681. doi: 10.1016/j.pneurobio.2019.101681. PMID: 31412279. ↥ ↥ ↥

  37. Evers EA, Stiers P, Ramaekers JG (2017): High reward expectancy during methylphenidate depresses the dopaminergic response to gain and loss. Soc Cogn Affect Neurosci. 2017 Feb 1;12(2):311-318. doi: 10.1093/scan/nsw124. PMID: 27677943; PMCID: PMC5390715. ↥ ↥ ↥

  38. Swanson JM, Volkow ND (2002): Pharmacokinetic and pharmacodynamic properties of stimulants: implications for the design of new treatments for ADHD. Behav Brain Res. 2002 Mar 10;130(1-2):73-8. doi: 10.1016/s0166-4328(01)00433-8. PMID: 11864720. REVIEW ↥

  39. Zhang, Zhang, Liang, Siapas, Zhou, Dani (2009): Dopamine signaling differences in the nucleus accumbens and dorsal striatum exploited by nicotine. J Neurosci. 2009 Apr 1;29(13):4035-43. doi: 10.1523/JNEUROSCI.0261-09.2009. PMID: 19339599; PMCID: PMC2743099. ↥ ↥

  40. Stahl (2013): Stahl’s Essential Psychopharmacology, 4. Auflage, Chapter 12: Attention deficit hyperactivity disorder and its treatment, Seite 490 ↥ ↥

  41. Seeman P, Madras BK (1998): Anti-hyperactivity medication: methylphenidate and amphetamine. Mol Psychiatry. 1998 Sep;3(5):386-96. doi: 10.1038/sj.mp.4000421. PMID: 9774771. REVIEW ↥ ↥

  42. Hauger, Angel, Janowsky, Berger, Hulihan-Giblin (1990): Brain Recognition Sites for Methylphenidate and the Amphetamines; Their Relationship to the Dopamine Transport Complex, Glucoreceptors, and Serotonergic Neurotransmission in the Central Nervous System; in: Application of Basic Neuroscience to Child Psychiatry, Seiten 77-100 ↥

  43. Jaeschke, Sujkowska, Sowa-Kućma (2021): Methylphenidate for attention-deficit/hyperactivity disorder in adults: a narrative review. Psychopharmacology (Berl). 2021 Oct;238(10):2667-2691. doi: 10.1007/s00213-021-05946-0. PMID: 34436651; PMCID: PMC8455398. REVIEW ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥

  44. Gatley, Pan, Chen, Chaturvedi, Ding (1996): Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. Life Sci. 1996;58(12):231-9. doi: 10.1016/0024-3205(96)00052-5. PMID: 8786705. ↥

  45. Krause, la Fougere, Krause, Ackenheil, Dresel (2005): Influence of striatal dopamine transporter availability on the response to methylphenidate in adult patients with ADHD; European Archives of Psychiatry and Clinical Neuroscience; December 2005, Volume 255, Issue 6, pp 428–431, Achtung, geringe Probandenzahl von n = 18 ↥

  46. Wang, Volkow, Wigal, Kollins, Newcorn, Telang, Logan, Jayne, Wong, Han, Fowler, Zhu, Swanson (2013): Long-Term Stimulant Treatment Affects Brain Dopamine Transporter Level in Patients with Attention Deficit Hyperactive Disorder. PLoS ONE 8(5): e63023. https://doi.org/10.1371/journal.pone.0063023 ↥ ↥

  47. Takamatsu, Hagino, Sato, Takahashi, Nagasawa, Kubo, Mizuguchi, Uhl, Sora, Ikeda (2015):Improvement of Learning and Increase in Dopamine Level in the Frontal Cortex by Methylphenidate in Mice Lacking Dopamine Transporter; 1 Curr Mol Med. 2015 Mar; 15(3): 245–252. doi: 10.2174/1566524015666150330144018, PMCID: PMC5384353 ↥

  48. Federici, Latagliata, Ledonne, Rizzo, Feligioni, Sulzer, Dunn, Sames, Gu, Nisticò, Puglisi-Allegra, Mercuri (2014): Paradoxical abatement of striatal dopaminergic transmission by cocaine and methylphenidate. J Biol Chem. 2014 Jan 3;289(1):264-74. doi: 10.1074/jbc.M113.495499. PMID: 24280216; PMCID: PMC3879549. ↥ ↥

  49. Diamond: Attention-deficit disorder (attention-deficit/hyperactivity disorder without hyperactivity): A neurobiologically and behaviorally distinct disorder from attention-deficit (with hyperactivity), Development and Psychopathology 17 (2005), 807–825, Seite 811 ↥

  50. Müller, Candrian, Kropotov (2011), ADHS – Neurodiagnostik in der Praxis, Springer ↥ ↥

  51. Porrino, Lucignani (1987): Different patterns of local brain energy metabolism associated with high and low doses of methylphenidate. Relevance to its action in hyperactive children.Biol Psychiatry. 1987 Feb;22(2):126-38. ↥

  52. Solanto (1998): Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res. 1998 Jul;94(1):127-52. doi: 10.1016/s0166-4328(97)00175-7. PMID: 9708845. REVIEW ↥ ↥

  53. https://www.kinderaerzte-im-netz.de/media/53ec94e833af614b730097d1/source/20080530092715_adhs2.pdf ↥

  54. Markowitz, Patrick (2001): Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder. Clin Pharmacokinet. 2001;40(10):753-72 ↥

  55. Markowitz, Patrick (2001): Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder. Clin Pharmacokinet. 2001;40(10):753-72 unter Verweis auf Volkow, Ding, Fowler, Wang, Logan, Gatley, Dewey, Ashby, Liebermann, Hitzemann, et al. (1995): Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry. 1995 Jun;52(6):456-63 und Hitri, Hurd, Wyatt, Deutsch (1994): Molecular, functional and biochemical characteristics of the dopamine transporter: regional differences and clinical relevance. Clin Neuropharmacol 1994; 17: 1-22 ↥

  56. Steinhausen, Rothenberger, Döpfner (2020): Handbuch ADHS 2. Aufl., Seite 92 ↥

  57. Volkow, Wang, Fowler, Logan, Angrist, Hitzemann, Lieberman, Pappas (1997): Effects of methylphenidate on regional brain glucose metabolism in humans: relationship to dopamine D2 receptors.Am J Psychiatry. 1997 Jan;154(1):50-5, sehr niedrige Probandenzahl von n = 15 ↥

  58. Steinhausen, Rothenberger, Döpfner (2010): Handbuch ADHS, Seite 78 ↥

  59. Oades RD, Sadile AG, Sagvolden T, Viggiano D, Zuddas A, Devoto P, Aase H, Johansen EB, Ruocco LA, Russell VA (2005): The control of responsiveness in ADHD by catecholamines: evidence for dopaminergic, noradrenergic and interactive roles. Dev Sci. 2005 Mar;8(2):122-31. doi: 10.1111/j.1467-7687.2005.00399.x. PMID: 15720370. REVIEW ↥ ↥

  60. Marco EM, Adriani W, Ruocco LA, Canese R, Sadile AG, Laviola G (2011): Neurobehavioral adaptations to methylphenidate: the issue of early adolescent exposure. Neurosci Biobehav Rev. 2011 Aug;35(8):1722-39. doi: 10.1016/j.neubiorev.2011.02.011. PMID: 21376076. REVIEW ↥ ↥ ↥ ↥ ↥ ↥

  61. Roessner, Sagvolden, Dasbanerjee, Middleton, Faraone, Walaas, Becker, Rothenberger, Bock (2010): Neuroscience. 2010 Jun 2;167(4):1183-91. doi: 10.1016/j.neuroscience.2010.02.073. ↥

  62. Quansah, Ruiz-Rodado, Grootveld, Zetterström (2018): Methylphenidate alters monoaminergic and metabolic pathways in the cerebellum of adolescent rats. Eur Neuropsychopharmacol. 2018 Feb 22. pii: S0924-977X(18)30043-9. doi: 10.1016/j.euroneuro.2018.02.002. ↥ ↥ ↥ ↥ ↥ ↥

  63. Quansah, Zetterström (2019): Chronic methylphenidate preferentially alters catecholamine protein targets in the parietal cortex and ventral striatum. Neurochem Int. 2019 Jan 17;124:193-199. doi: 10.1016/j.neuint.2019.01.016. ↥ ↥ ↥ ↥ ↥ ↥

  64. Kim, Heo, Kim, Ko, Lee, Kim, Kim, Kim, Ji, Kim, Shin, Choi, Kim (2011): Treadmill exercise and methylphenidate ameliorate symptoms of attention deficit/hyperactivity disorder through enhancing dopamine synthesis and brain-derived neurotrophic factor expression in spontaneous hypertensive rats. Neurosci Lett. 2011 Oct 17;504(1):35-9. doi: 10.1016/j.neulet.2011.08.052. PMID: 21907264. ↥

  65. Panos, O’Callaghan, Miller, Ferguson (2014): Effects of developmental methylphenidate (MPH) treatment on monoamine neurochemistry of male and female rats. Neurotoxicol Teratol. 2014 Sep-Oct;45:70-4. doi: 10.1016/j.ntt.2014.08.001. PMID: 25132048. ↥

  66. Bartl, Palazzesi, Parrinello, Hommers, Riederer, Walitza, Grünblatt (2017): The impact of methylphenidate and its enantiomers on dopamine synthesis and metabolism in vitro. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):281-288. doi: 10.1016/j.pnpbp.2017.07.002. PMID: 28690202. ↥

  67. Stevens, Sangkuhl, Brown, Altman, Klein (2019): PharmGKB summary: methylphenidate pathway, pharmacokinetics/pharmacodynamics. Pharmacogenet Genomics. 2019 Aug;29(6):136-154. doi: 10.1097/FPC.0000000000000376. PMID: 30950912; PMCID: PMC6581573. ↥ ↥ ↥ ↥

  68. Uchimura H, Kanai K, Arai M, Inoue M, Hishimoto A, Masukawa D, Goshima Y (2023): Involvement of the L-DOPA receptor GPR143 in acute and chronic actions of methylphenidate. J Pharmacol Sci. 2023 Jul;152(3):178-181. doi: 10.1016/j.jphs.2023.04.006. PMID: 37257945. ↥

  69. Berridge, Devilbiss, Andrzejewski, Arnsten, Kelley, Schmeichel, Hamilton, Spencer (2006): Methylphenidate Preferentially Increases Catecholamine Neurotransmission within the Prefrontal Cortex at Low Doses that Enhance Cognitive Function; Biological Psychiatry; Volume 60, Issue 10, 15 November 2006, Pages 1111-1120 ↥ ↥

  70. Koda, Ago, Cong, Kita, Takuma, Matsuda (2010): Effects of acute and chronic administration of atomoxetine and methylphenidate on extracellular levels of noradrenaline, dopamine and serotonin in the prefrontal cortex and striatum of mice. J Neurochem. 2010 Jul;114(1):259-70. doi: 10.1111/j.1471-4159.2010.06750.x. PMID: 20403082. ↥

  71. Methylphenidat bei Drugbank.com ↥

  72. Calipari ES, Ferris MJ, Salahpour A, Caron MG, Jones SR (2013): Methylphenidate amplifies the potency and reinforcing effects of amphetamines by increasing dopamine transporter expression. Nat Commun. 2013;4:2720. doi: 10.1038/ncomms3720. PMID: 24193139; PMCID: PMC4017736. ↥

  73. Ruocco, Carnevale, Treno, Sadile, Melisi, Arra, Ibba, Schirru, Carboni (2010): Prepuberal subchronic methylphenidate and atomoxetine induce different long-term effects on adult behaviour and forebrain dopamine, norepinephrine and serotonin in Naples high-excitability rats. Behav Brain Res. 2010 Jun 26;210(1):99-106. doi: 10.1016/j.bbr.2010.02.020. ↥

  74. Mulvihill (2019): Presynaptic regulation of dopamine release: Role of the DAT and VMAT2 transporters. Neurochem Int. 2019 Jan;122:94-105. doi: 10.1016/j.neuint.2018.11.004. PMID: 30465801. REVIEW ↥

  75. Lam, Matthies, Graf, Colla, Jacob, Sobanski, Alm, Rösler, Retz, Retz-Junginger, Kis, Abdel-Hamid, Müller, Lücke, Huss, Jans, Berger, Tebartz van Elst, Philipsen (2019): Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS) Consortium. Long-term Effects of Multimodal Treatment on Adult Attention-Deficit/Hyperactivity Disorder Symptoms: Follow-up Analysis of the COMPAS Trial. JAMA Netw Open. 2019 May 3;2(5):e194980. doi: 10.1001/jamanetworkopen.2019.4980. PMID: 31150084; PMCID: PMC6547099. ↥

  76. Alam, Wasi, Naeem, Kashif, Siddiqui, Bashir, Naz, Ikram (2019): Methylphenidate increases the urinary excretion of vanillylmandelic acid in rats that is attenuated by buspirone co-administration. Pak J Pharm Sci. 2019 Mar;32(2):895-898. ↥

  77. Levi-Sachar, Gvirts, Goldwin, Bloch, Shamay-Tsoory, Zagoory-Sharon, Feldman, Maoz (2019): The effect of methylphenidate on social cognition and oxytocin in children with attention deficit hyperactivity disorder. Neuropsychopharmacology. 2019 Sep 12. doi: 10.1038/s41386-019-0522-5. n = 90 ↥

  78. Kuczenski R, Segal DS (1997): Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem. 1997 May;68(5):2032-7. doi: 10.1046/j.1471-4159.1997.68052032.x. Erratum in: J Neurochem 1997 Sep;69(3):1332. PMID: 9109529. ↥

  79. Berridge CW, Shumsky JS, Andrzejewski ME, McGaughy JA, Spencer RC, Devilbiss DM, Waterhouse BD (2012): Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic α₁ - and α₂-receptors. Biol Psychiatry. 2012 Mar 1;71(5):467-73. doi: 10.1016/j.biopsych.2011.07.022. PMID: 21890109; PMCID: PMC3233638. ↥

  80. Faraone (2018): The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev. 2018 Apr;87:255-270. doi: 10.1016/j.neubiorev.2018.02.001. PMID: 29428394. ↥ ↥

  81. Gamo, Wang, Arnsten (2010): Methylphenidate and atomoxetine enhance prefrontal function through α2-adrenergic and dopamine D1 receptors. J Am Acad Child Adolesc Psychiatry. 2010 Oct;49(10):1011-23. doi: 10.1016/j.jaac.2010.06.015. PMID: 20855046; PMCID: PMC2999884. ↥ ↥

  82. Dinis-Oliveira (2017): Metabolomics of Methylphenidate and Ethylphenidate: Implications in Pharmacological and Toxicological Effects. Eur J Drug Metab Pharmacokinet. 2017 Feb;42(1):11-16. doi: 10.1007/s13318-016-0362-1. PMID: 27438788. REVIEW ↥

  83. Garattini, Mennini (1988): Critical Notes on The Specificity of Drugs in The Study of Metabolism and Functions of Brain Monoamines; International Review of Neurobiology; Volume 29, 1988, Pages 259–280, http://dx.doi.org/10.1016/S0074-7742(08)60089-6, zitiert nach Trott, Wirth (2000): die Pharmakotherapie der hyperkinetischen Störungen; in: Steinhausen (Herausgeber): Hyperkinetischen Störungen bei Kindern, Jugendlichen und Erwachsenen, 2. Aufl., Seite 210 REVIEW ↥

  84. Leonard, McCartan, White, King (2004): Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Hum. Psychopharmacol. Clin. Exp., 19: 151–180. REVIEW ↥

  85. Markowitz, DeVane, Ramamoorthy, Zhu (2009): The psychostimulant d-threo-(R,R)-methylphenidate binds as an agonist to the 5HT(1A) receptor. Pharmazie. 2009 Feb;64(2):123-5. ↥

  86. Fernández-Lópe, Molina-Carballo, Cubero-Millán, Checa-Ros, Machado-Casas, Blanca-Jover, Jerez-Calero, Madrid-Fernández, Uberos, Muñoz-Hoyos (2020): Indole Tryptophan Metabolism and Cytokine S100B in Children with Attention-Deficit/Hyperactivity Disorder: Daily Fluctuations, Responses to Methylphenidate, and Interrelationship with Depressive Symptomatology. J Child Adolesc Psychopharmacol. 2020 Feb 12. doi: 10.1089/cap.2019.0072. PMID: 32048862. ↥

  87. Yuan A, Claussen C, Jones Z, Tang B, Dafny N (2023): Methylphenidate induces a different response in the dorsal raphe as compared to ventral tegmental area and locus coeruleus: behavioral and concomitant neuronal recordings in adult rats. J Neural Transm (Vienna). 2023 Jul 1. doi: 10.1007/s00702-023-02665-y. PMID: 37391573. ↥

  88. Madras, Miller, Fischman (2005): The dopamine transporter and attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005 Jun 1;57(11):1397-409. doi: 10.1016/j.biopsych.2004.10.011. PMID: 15950014. ↥ ↥

  89. Masellis, Basile, Kennedy (2006): Neuropsychopharmacogenetics: ‘stimulating’ rationale therapy in attention-deficit/hyperactivity disorder (ADHD): pharmacogenetics of psychostimulants in ADHD. In: Gorwood, Hamon (editors): Psychopharmacogenetics. Boston: Springer US; 2006. p. 231 - 248. ↥

  90. Mefford, Potter (1989): A neuroanatomical and biochemical basis for attention deficit disorder with hyperactivity in children: a defect in tonic adrenaline mediated inhibition of locus coeruleus stimulation; Med Hypotheses. 1989 May;29(1):33-42., zitiert nach Trott, Wirth (2000): die Pharmakotherapie der hyperkinetischen Störungen; in: Steinhausen (Herausgeber) hyperkinetischen Störungen bei Kindern, Jugendlichen und Erwachsenen, 2. Aufl., Seite 210 ↥

  91. Chen, Yuan, Sun, Song, Lu, Ni, Han (2019): Metabolomics study of the prefrontal cortex in a rat model of attention deficit hyperactivity disorder reveals the association between cholesterol metabolism disorder and hyperactive behavior. Biochem Biophys Res Commun. 2019 Dec 18. pii: S0006-291X(19)32336-8. doi: 10.1016/j.bbrc.2019.12.016. ↥

  92. Budziszewska, Basta-Kaim, Kubera, Lasoń (2010); [Immunological and endocrinological pattern in ADHD etiopathogenesis]. Przeglad Lekarski [01 Jan 2010, 67(11):1200-1204], PMID:21442976 ↥ ↥

  93. Garre-Morata L, de Haro T, Villén RG, Fernández-López ML, Escames G, Molina-Carballo A, Acuña-Castroviejo D (2024): Changes in Cortisol and in Oxidative/Nitrosative Stress Indicators after ADHD Treatment. Antioxidants (Basel). 2024 Jan 12;13(1):92. doi: 10.3390/antiox13010092. PMID: 38247516; PMCID: PMC10812591. ↥ ↥

  94. van Ruitenbeek, Quaedflieg, Hernaus, Hartogsveld, Smeets (2021): Dopaminergic and noradrenergic modulation of stress-induced alterations in brain activation associated with goal-directed behaviour. J Psychopharmacol. 2021 Sep 14:2698811211044679. doi: 10.1177/02698811211044679. PMID: 34519561. ↥

  95. Negrao, Crafford, Viljoen (2009): The effect of sympathomimetic medication on cardiovascular functioning of children with attention-deficit/hyperactivity disorder. Cardiovasc J Afr. 2009;20(5):296-9 ↥

  96. Hammerness, Wilens, Mick, Spencer, Doyle, McCreary, Becker, Biederman (2009): Cardiovascular effects of longer-term, high-dose OROS methylphenidate in adolescents with attention deficit hyperactivity disorder. J Pediatr. 2009;155(1):84-9, 89.e1 ↥

  97. von http://www.hrv24.de/HRV-Medikamente.htm ↥

  98. Vetter, Elia, Erickson, Berger, Blum, Uzark, Webb (2008): Cardiovascular Monitoring of Children and Adolescents With Heart Disease Receiving Medications for Attention Deficit/Hyperactivity Disorder. A Scientific Statement From the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation. 2008;117:2407-23. ↥

  99. Molina-Carballo, Cubero-Millán, Fernández-López, Checa-Ros, Machado-Casas, Jerez-Calero, Blanca-Jover, Cantarero-Malagón, Uberos, Muñoz-Hoyos (2021): Methylphenidate ameliorates the homeostatic balance between levels of kynurenines in ADHD children. Psychiatry Res. 2021 Jun 17;303:114060. doi: 10.1016/j.psychres.2021.114060. PMID: 34175711. n = 179 ↥

  100. Trott, Wirth (2000): die Pharmakotherapie der hyperkinetischen Störungen; in: Steinhausen (Herausgeber) hyperkinetischen Störungen bei Kindern, Jugendlichen und Erwachsenen, 2. Aufl., Seite 211 ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥

  101. Ouadih-Moran M, Muñoz-Hoyos A, D’Marco L, Molina-Carballo A, Seiquer I, Checa-Ros A (2023): Is S100B Involved in Attention-Deficit/Hyperactivity Disorder (ADHD)? Comparisons with Controls and Changes Following a Triple Therapy Containing Methylphenidate, Melatonin and ω-3 PUFAs. Nutrients. 2023 Jan 31;15(3):712. doi: 10.3390/nu15030712. PMID: 36771418. ↥

  102. Rubinson, Horowitz, Naim-Feil, Gothelf, Moses, Levit-Binnun (2019): EEG functional networks reveal global effects of Methylphenidate in youth with Attention Deficit/Hyperactivity Disorder. Brain Connect. 2019 Mar 28. doi: 10.1089/brain.2018.0630. ↥

  103. Markovska-Simoska, Pop-Jordanova, Pop-Jordanov (2019): Inter- and Intra-Hemispheric EEG Coherence Study in Adults with Neuropsychiatric Disorders. Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2018 Dec 1;39(2-3):5-19. doi: 10.2478/prilozi-2018-0037. ↥

  104. Liddle, Hollis, Batty, Groom, Totman, Liotti, Scerif, Liddle (2011): Task-related default mode network modulation and inhibitory control in ADHD: effects of motivation and methylphenidate. J Child Psychol Psychiatry. 2011 Jul;52(7):761-71. doi: 10.1111/j.1469-7610.2010.02333.x. ↥

  105. Mizuno Y, Cai W, Supekar K, Makita K, Takiguchi S, Silk TJ, Tomoda A, Menon V (2022): Methylphenidate Enhances Spontaneous Fluctuations in Reward and Cognitive Control Networks in Children With Attention-Deficit/Hyperactivity Disorder. Biol Psychiatry Cogn Neurosci Neuroimaging. 2022 Oct 23:S2451-9022(22)00247-6. doi: 10.1016/j.bpsc.2022.10.001. PMID: 36717325. ↥

  106. Rubinson, Horowitz, Naim-Feil, Gothelf, Levit-Binnun, Moses (2019): Effects of methylphenidate on the ERP amplitude in youth with ADHD: A double-blind placebo-controlled cross-over EEG study. PLoS One. 2019 May 31;14(5):e0217383. doi: 10.1371/journal.pone.0217383. eCollection 2019. ↥

  107. Nakao, Radua, Rubia, Mataix-Cols (2011): Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication. Am J Psychiatry. 2011 Nov;168(11):1154-63. doi: 10.1176/appi.ajp.2011.11020281. 14 Studien mit n = 722 ↥ ↥ ↥

  108. Frodl, Skokauskas (2012): Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects. Acta Psychiatr Scand. 2012 Feb;125(2):114-26. doi: 10.1111/j.1600-0447.2011.01786.x. ↥ ↥

  109. King, Floren, Kharas, Thomas, Dafny (2019): Glutaminergic signaling in the caudate nucleus is required for behavioral sensitization to methylphenidate. Pharmacol Biochem Behav. 2019 Sep;184:172737. doi: 10.1016/j.pbb.2019.172737. ↥

  110. Teicher, Anderson, Polcari, Glod, Maas, Renshaw (2000): Functional deficits in basal ganglia of children with attention-deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry.Nat Med. 2000 Apr;6(4):470-3. ↥

  111. Rubia, Alegria, Cubillo, Smith, Brammer, Radua (2014): Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Biol Psychiatry. 2014 Oct 15;76(8):616-28. doi: 10.1016/j.biopsych.2013.10.016. 14 Studien mit n = 222 REVIEW ↥ ↥

  112. Matochik, Liebenauer, King, Szymanski, Cohen, Zametkin (1994): Cerebral glucose metabolism in adults with attention deficit hyperactivity disorder after chronic stimulant treatment. Am J Psychiatry 151: 658–664; Achtung, geringes N von 37; Vorsicht, geringe Stichprobe mit n = 19; zitiert nach Edel, Vollmoeller (2006): Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung bei Erwachsenen, Springer, Seite 10 ↥

  113. Spencer, Brown, Seidman, Valera, Makris, Lomedico, Faraone, Biederman (2013) Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies. J Clin Psychiatry. 2013 Sep;74(9):902-17. doi: 10.4088/JCP.12r08287. REVIEW ↥

  114. Venkataraman, Claussen, Kharas, Dafny (2020): The prefrontal cortex and the caudate nucleus respond conjointly to methylphenidate (Ritalin). Concomitant behavioral and neuronal recording study. Brain Res Bull. 2020 Jan 24;157:77-89. doi: 10.1016/j.brainresbull.2019.10.009. PMID: 31987926. ↥

  115. Wigal, Chappell, Palumbo, Lubaczewski, Ramaker, Abbas (2020): Diagnosis and Treatment Options for Preschoolers with Attention-Deficit/Hyperactivity Disorder. J Child Adolesc Psychopharmacol. 2020 Jan 20;10.1089/cap.2019.0116. doi: 10.1089/cap.2019.0116. PMID: 31967914. ↥

  116. Treister R, Eisenberg E, Demeter N, Pud D (2015): Alterations in pain response are partially reversed by methylphenidate (Ritalin) in adults with attention deficit hyperactivity disorder (ADHD). Pain Pract. 2015 Jan;15(1):4-11. doi: 10.1111/papr.12129. PMID: 24134430. ↥

  117. Mattingly GW, Childress AC, Cutler AJ, Estrada J, Corliss M (2023): Serdexmethylphenidate/dexmethylphenidate effects on sleep in children with attention-deficit/hyperactivity disorder. Front Psychiatry. 2023 Jun 23;14:1193455. doi: 10.3389/fpsyt.2023.1193455. PMID: 37426086; PMCID: PMC10327472. ↥

  118. Takahashi, Ohmiya, Honda, Ni (2018): The KCNH3 inhibitor ASP2905 shows potential in the treatment of attention deficit/hyperactivity disorder. PLoS One. 2018 Nov 21;13(11):e0207750. doi: 10.1371/journal.pone.0207750. eCollection 2018. ↥

  119. Pertermann, Bluschke, Roessner, Beste (2019): The Modulation of Neural Noise Underlies the Effectiveness of Methylphenidate Treatment in Attention-Deficit/Hyperactivity Disorder. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019 Apr 3. pii: S2451-9022(19)30080-1. doi: 10.1016/j.bpsc.2019.03.011. ↥ ↥

  120. Edel, Vollmoeller (2006): Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung bei Erwachsenen, Springer, Seite 13 ↥

  121. Wang, Li, Sawmiller, Fan, Ma, Tan, Ren, Li (2013): Chronic mild stress-induced changes of risk assessment behaviors in mice are prevented by chronic treatment with fluoxetine but not diazepam.Pharmacol Biochem Behav. 2014 Jan;116:116-28. doi: 10.1016/j.pbb.2013.11.028. ↥

  122. Pires, Pamplona, Pandolfo, Prediger, Takahashi (2010): Chronic caffeine treatment during prepubertal period confers long-term cognitive benefits in adult spontaneously hypertensive rats (SHR), an animal model of attention deficit hyperactivity disorder (ADHD). Behav Brain Res. 2010 Dec 20;215(1):39-44. doi: 10.1016/j.bbr.2010.06.022. PMID: 20600342. ↥

  123. Wiley MD, Poveromo LB, Antapasis J, Herrera CM, Bolaños Guzmán CA (2009): Kappa-opioid system regulates the long-lasting behavioral adaptations induced by early-life exposure to methylphenidate. Neuropsychopharmacology. 2009 Apr;34(5):1339-50. doi: 10.1038/npp.2008.188. PMID: 18923399; PMCID: PMC2656574. ↥

  124. Bolaños CA, Willey MD, Maffeo ML, Powers KD, Kinka DW, Grausam KB, Henderson RP (2008): Antidepressant treatment can normalize adult behavioral deficits induced by early-life exposure to methylphenidate. Biol Psychiatry. 2008 Feb 1;63(3):309-16. doi: 10.1016/j.biopsych.2007.06.024. PMID: 17884021. ↥

  125. Britton GB, Bethancourt JA (2009): Characterization of anxiety-related responses in male rats following prolonged exposure to therapeutic doses of oral methylphenidate. Pharmacol Biochem Behav. 2009 Oct;93(4):451-9. doi: 10.1016/j.pbb.2009.06.007. PMID: 19540871. ↥

  126. Bethancourt JA, Camarena ZZ, Britton GB (2009): Exposure to oral methylphenidate from adolescence through young adulthood produces transient effects on hippocampal-sensitive memory in rats. Behav Brain Res. 2009 Aug 24;202(1):50-7. doi: 10.1016/j.bbr.2009.03.015. PMID: 19447280. ↥

  127. Adriani W, Canese R, Podo F, Laviola G (2007): 1H MRS-detectable metabolic brain changes and reduced impulsive behavior in adult rats exposed to methylphenidate during adolescence. Neurotoxicol Teratol. 2007 Jan-Feb;29(1):116-25. doi: 10.1016/j.ntt.2006.11.010. PMID: 17196789. ↥ ↥

  128. Adriani W, Leo D, Greco D, Rea M, di Porzio U, Laviola G, Perrone-Capano C (2006): Methylphenidate administration to adolescent rats determines plastic changes on reward-related behavior and striatal gene expression. Neuropsychopharmacology. 2006 Sep;31(9):1946-56. doi: 10.1038/sj.npp.1300962. PMID: 16319916. ↥

  129. Carlezon WA Jr, Mague SD, Andersen SL (2003): Enduring behavioral effects of early exposure to methylphenidate in rats. Biol Psychiatry. 2003 Dec 15;54(12):1330-7. doi: 10.1016/j.biopsych.2003.08.020. PMID: 14675796. ↥

  130. Bolaños CA, Barrot M, Berton O, Wallace-Black D, Nestler EJ (2003): Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood. Biol Psychiatry. 2003 Dec 15;54(12):1317-29. doi: 10.1016/s0006-3223(03)00570-5. PMID: 14675795. ↥

  131. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM (2007): N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol. 2007 Feb;81(2):89-131. doi: 10.1016/j.pneurobio.2006.12.003. PMID: 17275978; PMCID: PMC1919520. REVIEW ↥

  132. Chen JG, Charles HC, Barboriak DP, Doraiswamy PM (2000): Magnetic resonance spectroscopy in Alzheimer’s disease: focus on N-acetylaspartate. Acta Neurol Scand Suppl. 2000;176:20-6. doi: 10.1034/j.1600-0404.2000.00303.x. PMID: 11261801. REVIEW ↥

  133. Vaidya, Austin, Kirkorian, Ridlehuber, Desmond, Glover, Gabrieli (1998): Selective effects of methylphenidate in attention deficit hyperactivity disorder: a functional magnetic resonance study. Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14494-9. ↥

  134. Balcioglu A, Ren JQ, McCarthy D, Spencer TJ, Biederman J, Bhide PG (2009): Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice. Neuropharmacology. 2009 Dec;57(7-8):687-93. doi: 10.1016/j.neuropharm.2009.07.025. PMID: 19631228; PMCID: PMC2783341. ↥

  135. Bystrowska B, Adamczyk P, Moniczewski A, Zaniewska M, Fuxe K, Filip M (2012): LC/MS/MS evaluation of cocaine and its metabolites in different brain areas, peripheral organs and plasma in cocaine self-administering rats. Pharmacol Rep. 2012;64(6):1337-49. doi: 10.1016/s1734-1140(12)70931-3. PMID: 23406744. ↥

  136. Janowsky DS, Leichner P, Parker D, Judd L, Huey L, Clopton P (1978): Methylphenidate and serum prolactin in man. Psychopharmacology (Berl). 1978 Jun 15;58(1):43-7. doi: 10.1007/BF00426788. PMID: 97718. ↥

  137. Schmid Y, Hysek CM, Simmler LD, Crockett MJ, Quednow BB, Liechti ME (2014): Differential effects of MDMA and methylphenidate on social cognition. J Psychopharmacol. 2014 Sep;28(9):847-56. doi: 10.1177/0269881114542454. PMID: 25052243. ↥

  138. Clemens JA, Fuller RW (1979): Differences in the effects of amphetamine and methylphenidate on brain dopamine turnover and serum prolactin concentration in reserpine-treated rats. Life Sci. 1979 May 28;24(22):2077-81. doi: 10.1016/0024-3205(79)90081-x. PMID: 459703. ↥

  139. Shaywitz BA, Shaywitz SE, Sebrechts MM, Anderson GM, Cohen DJ, Jatlow P, Young JG (1990): Growth hormone and prolactin response to methylphenidate in children with attention deficit disorder. Life Sci. 1990;46(9):625-33. doi: 10.1016/0024-3205(90)90131-a. PMID: 2308471. ↥

  140. Matochik, Liebenauer, King, Szymanski, Cohen, Zametkin (1994): Cerebral glucose metabolism in adults with attention defi cit hyperactivity disorder after chronic stimulant treatment. Am J Psychiatry 151: 658–664; n = 18; zitiert nach Edel, Vollmoeller (2006): Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung bei Erwachsenen, Springer, Seite 10 ↥

  141. Matochik, Liebenauer, King, Szymanski, Cohen, Zametkin (1994): Cerebral glucose metabolism in adults with attention defi cit hyperactivity disorder after chronic stimulant treatment. Am J Psychiatry 151: 658–664; geringe Stichprobe mit n = 19; zitiert nach Edel, Vollmoeller (2006): Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung bei Erwachsenen, Springer, Seite 10 ↥

  142. Pitzianti MB, Spiridigliozzi S, Bartolucci E, Esposito S, Pasini A (2020): New Insights on the Effects of Methylphenidate in Attention Deficit Hyperactivity Disorder. Front Psychiatry. 2020 Sep 30;11:531092. doi: 10.3389/fpsyt.2020.531092. PMID: 33132928; PMCID: PMC7561436. REVIEW ↥

  143. Panušková K, Voděrová L, Vaculín Š (2024): Methylphenidate attenuates signs of evoked neuropathic pain in animal model. Physiol Res. 2023 Dec 29;72(S5):S551-S558. doi: 10.33549/physiolres.935215. PMID: 38165759; PMCID: PMC10861255. ↥

  144. http://www.adhs-anderswelt.de/viewtopic.php?p=659654 ↥

  145. Martinez, Pasquereau, Drui, Saga, Météreau, Tremblay (2020): Ventral striatum supports Methylphenidate therapeutic effects on impulsive choices expressed in temporal discounting task. Sci Rep. 2020 Jan 20;10(1):716. doi: 10.1038/s41598-020-57595-6. PMID: 31959838. ↥

  146. Steckel (2006): Persönlichkeitsmerkmale erwachsener ADHS-Patienten – Veränderungen unter der Behandlung mit Methylphenidat; Dissertation; n = 24 ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥

  147. Shih, Shang, Gau (2018): Comparative Efficacy of Methylphenidate and Atomoxetine on Emotional and Behavioral Problems in Youths with Attention-Deficit/Hyperactivity Disorder. J Child Adolesc Psychopharmacol. 2018 Nov 17. doi: 10.1089/cap.2018.0076. ↥ ↥ ↥

  148. Blader, Pliszka, Kafantaris, Foley, Carlson, Crowell, Bailey, Sauder, Daviss, Sinha, Matthews, Margulies (2020): Stepped Treatment for Attention-Deficit/Hyperactivity Disorder and Aggressive Behavior: A Randomized, Controlled Trial of Adjunctive Risperidone, Divalproex Sodium, or Placebo After Stimulant Medication Optimization. J Am Acad Child Adolesc Psychiatry. 2020 Jan 30:S0890-8567(20)30064-2. doi: 10.1016/j.jaac.2019.12.009. PMID: 32007604. ↥

  149. Furukawa, Molina da Costa, Bado, Hoefle, Vigne, Monteiro, Wickens, Moll, Tripp, Mattos (2019): Methylphenidate modifies reward cue responses in adults with ADHD: An fMRI study. Neuropharmacology. 2019 Nov 2:107833. doi: 10.1016/j.neuropharm.2019.107833. ↥

  150. Tucha O, Prell S, Mecklinger L, Bormann-Kischkel C, Kübber S, Linder M, Walitza S, Lange KW (2006): Effects of methylphenidate on multiple components of attention in children with attention deficit hyperactivity disorder. Psychopharmacology (Berl). 2006 Apr;185(3):315-26. doi: 10.1007/s00213-006-0318-2. PMID: 16521033. ↥

  151. Takım U, Gökçay H (2024): Examination of Excessive Mind-Wandering Following Attention-Deficit and Hyperactivity Disorder Treatment in Adults. Psychol Rep. 2024 Sep 3:332941241281816. doi: 10.1177/00332941241281816. PMID: 39227056. ↥

  152. Jaeschke, Sujkowska, Sowa-Kućma (2021): Methylphenidate for attention-deficit/hyperactivity disorder in adults: a narrative review. Psychopharmacology (Berl). 2021 Oct;238(10):2667-2691. doi: 10.1007/s00213-021-05946-0. PMID: 34436651; PMCID: PMC8455398. ↥

  153. Trott, Wirth (2000): die Pharmakotherapie der hyperkinetischen Störungen; in: Steinhausen (Herausgeber) hyperkinetischen Störungen bei Kindern, Jugendlichen und Erwachsenen, 2. Aufl., Seite 211 ↥

  154. Rajala, Populin, Jenison (2020): Methylphenidate affects task-switching and neural signaling in non-human primates. Psychopharmacology (Berl). 2020 May;237(5):1533-1543. doi: 10.1007/s00213-020-05478-z. PMID: 32067136; PMCID: PMC7196524. ↥

  155. Trott, Wirth (2000): die Pharmakotherapie der hyperkinetischen Störungen; in: Steinhausen (Herausgeber) hyperkinetischen Störungen bei Kindern, Jugendlichen und Erwachsenen, 2. Aufl., Seite 212, mit weiteren Nachweisen ↥

  156. Levi-Sachar, Gvirts, Goldwin, Bloch, Shamay-Tsoory, Zagoory-Sharon, Feldman, Maoz (2019): The effect of methylphenidate on social cognition and oxytocin in children with attention deficit hyperactivity disorder. Neuropsychopharmacology. 2019 Sep 12. doi: 10.1038/s41386-019-0522-5. ↥

  157. Rezende, Pacheco, Branco, Fernandes, Boldrini, Doria Filho, Bazán, Amaro Junior, Reed, Casella (2020): Combining neuropsychological tests to improve the assessment of arithmetic difficulties in children with ADHD. Arq Neuropsiquiatr. 2020 Apr;78(4):193-198. doi: 10.1590/0004-282X20190178. PMID: 32130296. n = 42 ↥

  158. Golubchik, Manor, Shoval, Weizman (2020): Levels of Proneness to Boredom in Children with Attention-Deficit/Hyperactivity Disorder On and Off Methylphenidate Treatment. J Child Adolesc Psychopharmacol. 2020 Feb 7:10.1089/cap.2019.0151. doi: 10.1089/cap.2019.0151. PMID: 32031873. n = 30 ↥

  159. Low, le Sommer, Vangkilde, Fagerlund, Glenthøj, Sonuga-Barke, Habekost, Jepsen (2018): Delay aversion and Executive Functioning in adults with Attention-Deficit/Hyperactivity Disorder: Before and after stimulant treatment. Int J Neuropsychopharmacol. 2018 Aug 16. doi: 10.1093/ijnp/pyy070. ↥ ↥

  160. Golubchik, Weizman (2019): Poor performance of the ‘child Reading the Mind in the Eyes Test’ correlates with poorer social-emotional functioning in children with attention-deficit/hyperactivity disorder. Int Clin Psychopharmacol. 2019 Nov 22. doi: 10.1097/YIC.0000000000000299. ↥

  161. Rothe J, Kattlun FA, Kaufmann J, Uhlmann A, Wanderer S, Bluschke A, Beste C, Roessner V (2023): Effects of methylphenidate and physiotherapeutic treatment on graphomotor movements in children with ADHD. Eur Child Adolesc Psychiatry. 2023 Jan 23. doi: 10.1007/s00787-023-02144-5. PMID: 36688969. ↥

  162. Solanto (2001): Dopamine dysfunction in AD/HD: integrating clinical and basic neuroscience research. Behavioural Brain Research 130 (2002) 65–71 ↥

  163. Luo, Covey, Hu, Winhusen, Nunes (2019): Differential posttreatment outcomes of methylphenidate for smoking cessation for individuals With ADHD. Am J Addict. 2019 Sep 19. doi: 10.1111/ajad.12961. ↥

  164. Baas, Boot, van Gaal, de Dreu, Cools (2019): Methylphenidate does not affect convergent and divergent creative processes in healthy adults. Neuroimage. 2019 Oct 17:116279. doi: 10.1016/j.neuroimage.2019.116279. ↥

  165. Ten, Tseng, Chiang, Wu, Chen (2019): Creativity in children with ADHD: Effects of medication and comparisons with normal peers. Psychiatry Res. 2019 Nov 5:112680. doi: 10.1016/j.psychres.2019.112680. n = 86 ↥

  166. Arnold: Journal of Attention Disorders Vol. 3(4):200-211 (2000) Methylphenidate vs. amphetamine: Comparative review, n = 174 REVIEW ↥

  167. Roskell, Setyawan, Zimovetz, Hodgkins (2014): Systematic evidence synthesis of treatments for ADHD in children and adolescents: indirect treatment comparisons of lisdexamfetamine with methylphenidate and atomoxetine. Curr Med Res Opin. 2014 Aug;30(8):1673-85. doi: 10.1185/03007995.2014.904772. ↥

  168. Prasad, Steer (2008): Switching from neurostimulant therapy to atomoxetine in children and adolescents with attention-deficit hyperactivity disorder : clinical approaches and review of current available evidence. Paediatr Drugs. 2008;10(1):39-47. doi: 10.2165/00148581-200810010-00005. PMID: 18162007. REVIEW ↥

  169. Nagy, Häge, Coghill, Caballero, Adey, Anderson, Sikirica, Cardo (2015): Functional outcomes from a head-to-head, randomized, double-blind trial of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder and an inadequate response to methylphenidate.Eur Child Adolesc Psychiatry. 2016 Feb;25(2):141-9. doi: 10.1007/s00787-015-0718-0. ↥

  170. Vallejo-Valdivielso, de Castro-Manglano, Díez-Suárez, Marín-Méndez, Soutullo (2020): Clinical and Neuropsychological Predictors of Methylphenidate Response in Children and Adolescents with ADHD: A Naturalistic Follow-up Study in a Spanish Sample. Clin Pract Epidemiol Ment Health. 2019 Dec 31;15:160-171. doi: 10.2174/1745017901915010160. PMID: 32174998; PMCID: PMC7040471. ↥ ↥ ↥ ↥ ↥

  171. Michelini, Lenartowicz, Vera, Bilder, McGough, McCracken, Loo SK (2022): Electrophysiological and Clinical Predictors of Methylphenidate, Guanfacine, and Combined Treatment Outcomes in Children With Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2022 Aug 8:S0890-8567(22)01229-1. doi: 10.1016/j.jaac.2022.08.001. PMID: 35963559. n = 181 ↥ ↥ ↥ ↥

  172. Barkley, DuPaul, McMurray (1991): Attention deficit disorder with and without hyperactivity: Clinical response to three dose levels of methylphenidate. Pediatrics, 87, 519–531 ↥ ↥

  173. Barkley (2001): The inattentive type of ADHD as a distinct disorder: What remains to be done. Clinical Psychology: Science and Practice, 8, 489– 493 ↥

  174. Milich, Balentine, Lynam (2001): ADHD combined type and ADHD predominantly inattentive type are distinct and unrelated disorders. Clinical Psychology: Science and Practice, 8, 463– 488 ↥

  175. Weiss, Worling, Wasdell: (2003). A chart review study of the inattentive and combined types of ADHD. Journal of Attention Disorders, 7, 1–9 REVIEW ↥

  176. Diamond: Attention-deficit disorder (attention-deficit/hyperactivity disorder without hyperactivity): A neurobiologically and behaviorally distinct disorder from attention-deficit (with hyperactivity), Development and Psychopathology 17 (2005), 807–825, Seite 811 ↥

  177. Safren, Perlman, Sprich et al (2008): Kognitive Verhaltenstherapie der ADHS des Erwachsenenalters, Seite 9 ↥

  178. Diamond: Attention-deficit disorder (attention-deficit/hyperactivity disorder without hyperactivity): A neurobiologically and behaviorally distinct disorder from attention-deficit (with hyperactivity), Development and Psychopathology 17 (2005), 807–825, Seite 811 ↥

  179. Menneh (2008): Prediction of the clinical response to psychostimulant by the basal and reactive salivary cortisol in children with ADHD. ↥ ↥

  180. Froehlich, Becker, Nick, Brinkman, Stein, Peugh, Epstein (2018): Sluggish Cognitive Tempo as a Possible Predictor of Methylphenidate Response in Children With ADHD: A Randomized Controlled Trial. J Clin Psychiatry. 2018 Feb 27;79(2). pii: 17m11553. doi: 10.4088/JCP.17m11553. ↥

  181. Tarrant, Roy, Deb, Odedra, Retzer, Roy (2018): The effectiveness of methylphenidate in the management of Attention Deficit Hyperactivity Disorder (ADHD) in people with intellectual disabilities: A systematic review. Res Dev Disabil. 2018 Sep 25;83:217-232. doi: 10.1016/j.ridd.2018.08.017. REVIEW ↥

  182. Sun, Tseng, Wu, Li, Chen, Stubbs, Carvalho, Chen, Lin, Cheng, Wu (2019): Therapeutic effects of methylphenidate for attention-deficit/hyperactivity disorder in children with borderline intellectual functioning or intellectual disability: A systematic review and meta-analysis. Sci Rep. 2019 Nov 4;9(1):15908. doi: 10.1038/s41598-019-52205-6. n = 423 REVIEW ↥

  183. Ogrim, Kropotov, Brunner, Candrian, Sandvik, Hestad (2014): Predicting the clinical outcome of stimulant medication in pediatric attention-deficit/hyperactivity disorder: data from quantitative electroencephalography, event-related potentials, and a go/no-go test. Neuropsychiatr Dis Treat. 2014 Feb 3;10:231-42. doi: 10.2147/NDT.S56600. N = 188 ↥

  184. Strauß, Reif, Ulke, Paucke, Sander, Hegerl, Weber, Heupel, Kopf, Kittel-Schneider (2019): Is brain arousal regulation a predictor of response to psychostimulant therapy in adult ADHD patients? Eur Arch Psychiatry Clin Neurosci. 2019 Nov 26. doi: 10.1007/s00406-019-01085-y. ↥

  185. Arnett, Rutter, Stein (2022): Neural Markers of Methylphenidate Response in Children With Attention Deficit Hyperactivity Disorder. Front Behav Neurosci. 2022 May 6;16:887622. doi: 10.3389/fnbeh.2022.887622. PMID: 35600991; PMCID: PMC9121006. ↥

  186. Milich, Balentine, Lynam (2001): ADHD combined type and ADHD predominantly inattentive type are distinct and unrelated disorders. Clinical Psychology: Science and Practice, 8, 463– 488, zitiert nach Diamond: Attention-deficit disorder (attention-deficit/hyperactivity disorder without hyperactivity): A neurobiologically and behaviorally distinct disorder from attention-deficit (with hyperactivity), Development and Psychopathology 17 (2005), 807–825, Seite 811 ↥

  187. Vollebregt MA, Kenemans JL, Buitelaar JK, Deboer T, Cain SW, Palmer D, Elliott GR, Gordon E, Fallahpour K, Arns M (2020): Annual variation in attentional response after methylphenidate treatment. Eur Child Adolesc Psychiatry. 2020 Sep;29(9):1231-1236. doi: 10.1007/s00787-019-01434-1. PMID: 31748987. ↥

  188. Lam RW, Levitt AJ, Levitan RD, Michalak EE, Cheung AH, Morehouse R, Ramasubbu R, Yatham LN, Tam EM (2016): Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2016 Jan;73(1):56-63. doi: 10.1001/jamapsychiatry.2015.2235. Erratum in: JAMA Psychiatry. 2016 Jan;73(1):90. PMID: 26580307. ↥

  189. Traicu, Grizenko, Fortier, Fageera, Sengupta, Joober (2019): Acute blood pressure change with methylphenidate is associated with improvement in attention performance in children with ADHD. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Aug 12;96:109732. doi: 10.1016/j.pnpbp.2019.109732. ↥

  190. Gokten, Tulay, Beser, Yuksel, Arikan, Tarhan, Metin (2019): Predictive Value of Slow and Fast EEG Oscillations for Methylphenidate Response in ADHD. Clin EEG Neurosci. 2019 Sep;50(5):332-338. doi: 10.1177/1550059419863206. ↥

  191. Zhong, Yang, Su, Qian, Cao, Chang, Wang, Yang (2020): The Association with Quantitative Response to Attention-Deficit/Hyperactivity Disorder Medication of the Previously Identified Neurodevelopmental Network Genes. J Child Adolesc Psychopharmacol. 2020 Jul;30(6):348-354. doi: 10.1089/cap.2018.0164. PMID: 32175767. n = 241 ↥

  192. Yuan, Zhang, Huang, Wang, Jiao, Huang (2021): Noradrenergic genes polymorphisms and response to methylphenidate in children with ADHD: A systematic review and meta-analysis. Medicine (Baltimore). 2021 Nov 19;100(46):e27858. doi: 10.1097/MD.0000000000027858. PMID: 34797323; PMCID: PMC8601359. n = 1.382 ↥

  193. Cascone AD, Calabro F, Foran W, Larsen B, Nugiel T, Parr AC, Tervo-Clemmens B, Luna B, Cohen JR (2023): Brain tissue iron neurophysiology and its relationship with the cognitive effects of dopaminergic modulation in children with and without ADHD. Dev Cogn Neurosci. 2023 Jul 7;63:101274. doi: 10.1016/j.dcn.2023.101274. PMID: 37453207; PMCID: PMC10372187. ↥

  194. Blum NJ, Shults J, Barbaresi W, Bax A, Cacia J, Deavenport-Saman A, Friedman S, Loe IM, Mittal S, Vanderbilt D, LaRosa A, Harstad E. Do Externalizing and Internalizing Symptoms Moderate Medication Response in Preschool Attention-Deficit/Hyperactivity Disorder? A DBPNet Study. J Dev Behav Pediatr. 2023 Sep 1;44(7):e447-e454. doi: 10.1097/DBP.0000000000001209. PMID: 37696030 ↥

  195. Cheon KA, Cho DY, Koo MS, Song DH, Namkoong K (2009): Association between homozygosity of a G allele of the alpha-2a-adrenergic receptor gene and methylphenidate response in Korean children and adolescents with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2009 Apr 1;65(7):564-70. doi: 10.1016/j.biopsych.2008.12.003. PMID: 19150055. ↥ ↥ ↥

  196. Polanczyk, Zeni, Genro, Guimarães, Roman, Hutz, Rohde (2007): Association of the adrenergic alpha2A receptor gene with methylphenidate improvement of inattentive symptoms in children and adolescents with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2007 Feb;64(2):218-24. doi: 10.1001/archpsyc.64.2.218. PMID: 17283289. ↥

  197. Cho SC, Kim BN, Cummins TD, Kim JW, Bellgrove MA. (2012): Norepinephrine transporter -3081(A/T) and alpha-2A-adrenergic receptor MspI polymorphisms are associated with cardiovascular side effects of OROS-methylphenidate treatment. J Psychopharmacol. 2012 Mar;26(3):380-9. doi: 10.1177/0269881111405356. PMID: 21628343. n = 101 ↥ ↥ ↥ ↥ ↥ ↥

  198. Song J, Song DH, Jhung K, Cheon KA (2011): Norepinephrine transporter gene (SLC6A2) is involved with methylphenidate response in Korean children with attention deficit hyperactivity disorder. Int Clin Psychopharmacol. 2011 Mar;26(2):107-13. doi: 10.1097/YIC.0b013e32834152d1. PMID: 21127421. n = 114 ↥ ↥ ↥

  199. Yang L, Wang YF, Li J, Faraone SV (2004): Association of norepinephrine transporter gene with methylphenidate response. J Am Acad Child Adolesc Psychiatry. 2004 Sep;43(9):1154-8. doi: 10.1097/01.chi.0000131134.63368.46. PMID: 15322419. ↥ ↥ ↥

  200. Kim BN, Kim JW, Hong SB, Cho SC, Shin MS, Yoo HJ. (2010): Possible association of norepinephrine transporter -3081(A/T) polymorphism with methylphenidate response in attention deficit hyperactivity disorder. Behav Brain Funct. 2010 Oct 7;6:57. doi: 10.1186/1744-9081-6-57. PMID: 20929549; PMCID: PMC2959002. n = 112 ↥ ↥ ↥

  201. Myer NM, Boland JR, Faraone SV (2018): Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD. Mol Psychiatry. 2018 Sep;23(9):1929-1936. doi: 10.1038/mp.2017.234. PMID: 29230023; PMCID: PMC7039663. METASTUDY ↥

  202. Shi J, Xiao J, Wang X, Jung SM, Bleske BE, Markowitz JS, Patrick KS, Zhu HJ. (2022): Plasma Carboxylesterase 1 Predicts Methylphenidate Exposure: A Proof-of-Concept Study Using Plasma Protein Biomarker for Hepatic Drug Metabolism. Clin Pharmacol Ther. 2022 Apr;111(4):878-885. doi: 10.1002/cpt.2486. PMID: 34743324; PMCID: PMC9249567. ↥

  203. https://www.adhs365.de/adhs/medikamente/kartoffelm%C3%BCsli/ ↥

  204. https://adhs-forum.adxs.org/t/wirkstoff-probleme/6920/16; Forumsanmeldung erforderlich ↥

  205. Unterecker S, Hefner G, Baumann P, Gründer G, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G, Egberts K, Gerlach M, Greiner C, Haen E, Havemann-Reinecke U, Helmer R, Janssen G, Jaquenoud E, Laux G, Messer T, Mössner R, Müller MJ, Paulzen M, Pfuhlmann B, Riederer P, Saria A, Schoppek B, Schoretsanitis G, Schwarz M, Gracia MS, Stegmann B, Steimer W, Stingl JC, Uhr M, Ulrich S, Waschgler R, Zernig G, Zurek G, Hiemke C (2019): Therapeutisches Drug-Monitoring in der Neuropsychopharmakologie : Zusammenfassung der Konsensusleitlinien 2017 der TDM-Arbeitsgruppe der AGNP [Therapeutic drug monitoring in neuropsychopharmacology : Summary of the consensus guidelines 2017 of the TDM task force of the AGNP]. Nervenarzt. 2019 May;90(5):463-471. German. doi: 10.1007/s00115-018-0643-9. Erratum in: Nervenarzt. 2019 Jul 15;: PMID: 30446893. REVIEW ↥ ↥ ↥

  206. Waltereit, Müller (2018): Weiterbildungs-Curriculum Psychopharmakologie/Pharmakotherapie, Teil 4: Psychopharmakologie und klinische Psychopharmakotherapie der Stimulanzien, Psychopharmakotherapie 2018;25: 199–207. german ↥

  207. Bakhtiar R, Ramos L, Tse FL (2004): Toxicokinetic assessment of methylphenidate (Ritalin) in a 13-week oral toxicity study in dogs. Biomed Chromatogr. 2004 Jan;18(1):45-50. doi: 10.1002/bmc.290. PMID: 14872548. ↥

  208. Aoyama T, Kotaki H, Sasaki T, Sawada Y, Honda Y, Iga T (1993): Nonlinear kinetics of threo-methylphenidate enantiomers in a patient with narcolepsy and in healthy volunteers. Eur J Clin Pharmacol. 1993;44(1):79-84. doi: 10.1007/BF00315285. PMID: 8436161. ↥

  209. Srinivas NR, Hubbard JW, Korchinski ED, Midha KK (1993): Enantioselective pharmacokinetics of dl-threo-methylphenidate in humans. Pharm Res. 1993 Jan;10(1):14-21. doi: 10.1023/a:1018956526016. PMID: 8430051. ↥ ↥ ↥

  210. Wargin W, Patrick K, Kilts C, Gualtieri CT, Ellington K, Mueller RA, Kraemer G, Breese GR (1983): Pharmacokinetics of methylphenidate in man, rat and monkey. J Pharmacol Exp Ther. 1983 Aug;226(2):382-6. PMID: 6410043. ↥