MPH Part 1: Active Ingredients, Effects, Response

1. Active ingredient¶

Methylphenidate (MPH):¹

• belongs to the class of phenylethylamines.
• Chemical name: methyl 2-phenyl-2-(piperidin-2-yl)acetate
• Molecular formula: C14H19NO2
• Mass: 233.31 g/mol
• has four configurational isomers
• Since methylphenidate has two asymmetric carbon atoms, there are four different forms of this medication:²
  • (+)-Erythromethylphenidate
  • (-)-Erythromethylphenidate
  • (+)-threomethylphenidate
  • (-)-Threomethylphenidate.

Other names:³

• Methylphenidyl acetate
• methyl phenyl(piperidin-2-yl)acetate
• methyl α-phenyl-α-(2-piperidyl)acetate
• methyl α-phenyl-α-2-piperidinyl acetate
• Methylphenidate
• Methylphenidate
• Methylphenidate
• Methylphenidate
• MPH
• α-phenyl-2-piperidineacetic acid methyl ester

MPH is classified as a controlled substance worldwide because it can be abused as a drug when taken in extremely high doses or in a rapidly acting form. However, when taken in medicinal doses and in medicinal forms (oral / patch = slow-acting), MPH has no potential for intoxication or dependence. The actual risk of methylphenidate being abused as a recreational drug appears to be significantly overestimated. A study claiming widespread abuse of MPH as a recreational drug cited only sources in which methylphenidate is not even mentioned.⁴

1.1. Methylphenidate as a racemate¶

Methylphenidate is typically administered clinically as a racemate (mixture) consisting of 50% L-methylphenidate and 50% D-methylphenidate (levorotatory and dextrorotatory isomers), which is ten to one hundred times more potent than the (+/-)-erythroform.²
While a significant proportion of D-MPH crosses the blood-brain barrier into the CNS, L-MPH is not taken up into the CNS.¹⁵

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

Dosage ranges from 2.5 mg to an average of 15 mg per single dose, administered every 2.5 to 3.5 hours during the day (form with immediate release).¹⁶

1.2. Dexmethylphenidate (D-MPH)¶

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

Brand name: Focalin (Switzerland and the U.S. only)

It is three times more effective than racemic methylphenidate (a mixture of dextrorotatory (D-MPH) and levorotatory (L-MPH) methylphenidate).¹⁷ The greater efficacy of D-MPH compared to L-MPH relates to its binding to both dopamine and norepinephrine transporters.
Therefore, a half dose of D-MPH is recommended compared to racemic methylphenidate, and this dose is limited to a maximum of 20 mg per day for both children and adults.
D-MPH is also available as an extended-release formulation (Focalin XR).

Dexmethylphenidate acts as a¹⁸

• Dopamine reuptake inhibitors
• Norepinephrine reuptake inhibitors
• 5-HT1A receptor agonist
• Redistribution of vesicular monoamine transporter 2 (VMAT-2)
• α2-adrenoreceptor agonist

Dexmethylphenidate is metabolized by carboxylesterase 1A1 to D-ritalinic acid.¹⁸

1.3. Levomethylphenidate (L-MPH)¶

L-MPH is the pure form of the levorotatory isomers and is pharmacologically almost inactive.
L-MPH is metabolized primarily in the intestinal mucosa. The remaining L-MPH is metabolized during first-pass metabolism in the liver. L-MPH is almost completely metabolized within 10 minutes of administration.¹⁹
The small, unmetabolized amount of L-MPH competes with the dextrorotatory and pharmacologically active isomer D-MPH for binding sites in the brain and reduces its effectiveness.¹⁹
According to another source, the levorotatory MPH isomer L-MPH (unlike D-MPH) is not absorbed into the CNS.²⁰

1.4. Serdex Methylphenidate (SDX)¶

Serdex methylphenidate (SDX) is a prodrug of dexmethylphenidate (d-MPH) and is currently approved only in the United States (Azstarys®, KP415, containing 70% SDX and 30% MPH).²¹
For more information, see Serdex Methylphenidate for ADHD

2. How Methylphenidate Works¶

The first computer models capable of realistically simulating the effects of ADHD medications are now available. A computer model for simulating type 1 diabetes has already been approved by the FDA as a substitute for preclinical animal studies.²²
A model for comparing MPH and AMP in children and adults with ADHD takes into account the effects on 99 proteins involved in ADHD.²³

2.1. Effect on Neurotransmitters¶

MPH alters neurotransmitter levels in the brain.

2.1.1. MPH increases dopamine¶

2.1.1.1. MPH increases extracellular dopamine and may reduce phasic dopamine¶

Many sources merely report a general effect on dopamine and norepinephrine.
The blanket statement that MPH increases dopamine levels is ultimately unhelpful, since a distinction must be made between tonic and phasic dopamine release and extracellular dopamine levels, as well as between the effects in different brain regions.

• Increase in dopamine and norepinephrine in the PFC²⁴²⁵²⁶
• MPH doses whose plasma levels fall within the therapeutic range for ADHD, such as²⁷²⁸
  • 1.0 mg/kg in rats
    • Increase extracellular norepinephrine in the hippocampus by 100%
    • Do not significantly alter dopamine levels in the nucleus accumbens (striatum)
  • 2.5 mg/kg in rats
    • Increase extracellular norepinephrine in the hippocampus by 150–175%
    • Do not significantly alter dopamine levels in the nucleus accumbens (striatum).
• In healthy adult rats, MPH increases
  • Dopamine in the PFC, striatum, and nucleus accumbens, as well as²⁹
    • High concentration: DA levels increase due to release from noradrenergic cells³⁰
    • Low dose: DA not elevated³⁰
    • Chronic administration of 1 mg/kg increased extracellular dopamine and norepinephrine in the PFC³¹
  • Norepinephrine in the PFC, but not in the striatum or nucleus accumbens.²⁹
  • Dopamine and norepinephrine in the PFC, but barely in other brain regions³²
• In healthy monkeys, MPH caused:³³
  • Striatum: low and high doses: consistent increase in dopamine
  • PFC: Dopamine levels rise only at high doses
    In rats, a single dose of 1 mg/kg MPH had the same effect as chronic administration (21 days)
  • Striatum: no change in extracellular levels of norepinephrine, dopamine, or serotonin³¹

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

Tonic dopamine mediates the PFC’s regulatory (inhibitory) control over the ventral striatum, thereby inhibiting the striatum’s (phasic) activity. In response to unexpected positive reward stimuli, the striatum fires dopaminergic bursts and activates dopaminergic postsynaptic receptors. Tonic control is thus inhibitory and modulates the excitatory phasic firing in response to unexpected positive reward stimuli.³⁴

Stimulants:³⁵

• increases the sustained rate of fire
• reduces the frequency of postsynaptic multisecond oscillations in the basal ganglia from approximately 30 seconds to 5 to 10 seconds. Even doses as low as 1.0 mg/kg of MPH or 0.2 mg/kg of D-Amp were effective.
• However, 0.2 mg/kg of D-Amp showed only a slight presynaptic effect. D-Amp had a stronger postsynaptic effect.

MPH increases extracellular dopamine and decreases phasic dopamine in the striatum.
This is consistent with Grace’s hypothesis, according to which ADHD is characterized by reduced tonic and increased phasic dopamine. This model is likely to apply, at least, to most cases of ADHD. For more on this, see Dopamine Release (Tonic, Phasic) and Encoding

2.1.1.1.1. MPH increases extracellular dopamine¶

MPH increases extracellular dopamine^{3637 38} , particularly in the striatum³⁹³⁰ , but likely also in the PFC⁴⁰.

The statement “MPH increases tonic dopamine” would not be correct, however, because MPH itself does not increase tonic firing. Inhibition of reuptake merely leads to an increase in extracellular dopamine levels, not to a change in tonic firing.

The following were identified as reasons for the increase in extracellular dopamine caused by MPH:

• : inhibition of dopamine reuptake³⁶
• increased dopamine efflux due to the reversal of the dopamine reuptake transporter in the striatum³⁰

In a gambling task, MPH increased the magnitude of the response and the BOLD signals associated with reward anticipation in the ventral striatum,³⁸ suggesting that the striatal tonic dopamine level represents an average reward-expectancy signal that modulates the phasic dopaminergic response to reward.

2.1.1.1.2. MPH may reduce phasic dopamine levels¶

Several studies have found that MPH reduces phasic dopamine levels,^{3641 38} while others have found no change³⁷³⁰ or even an increase. This may depend on various factors (e.g., dosage, DAT sensitivity).

The significant reduction in phasic (synaptic) dopamine release is likely due to a decrease in synapsin phosphorylation³⁶
The inhibition of phasic dopamine is not a consequence of presynaptic D2 autoreceptor activation, since this³⁶
- a. even in the presence of the D2 antagonist sulpiride, and
- b. also occurs in DAT-CI striatal slices, in which increased extracellular DA levels cannot activate D2 autoreceptors
The inhibition of phasic dopamine could—as with cocaine—possibly be due to a reduction in synaptic vesicular neurotransmitter.³⁶ As a lipophilic weak base, cocaine could cause the vesicular pH gradient to collapse, similar to the “weak base effects” reported for amphetamines, or it could act on the vesicles. There is evidence that synaptic vesicles may be quite “leaky” and constantly lose dopamine into the cytosol. This impression is supported by the action of reserpine, which can rapidly deplete synaptic vesicles of dopamine.

A study found that MPH did not alter phasic dopamine levels; an inhibitory feedback mechanism via D2 autoreceptors was suspected because a D2 antagonist administered concurrently with MPH caused MPH to also increase phasic dopamine levels.³⁷

Acute administration of MPH increased the firing activity of PFC pyramidal neurons in rats and potentiated NMDA-induced neurotransmission.³⁰

The DAT blocker nomifensine enhanced phasic dopaminergic signaling³⁶, suggesting that dopamine reuptake inhibition alone cannot account for the reduction in phasic dopamine levels caused by MPH.
Animal studies also suggest that MPH and other ADHD medications affect ADHD symptoms by amplifying the phasic dopamine signal and/or altering the tonic noradrenergic signal (to increase the level of arousal).⁴²

2.1.1.1.3. Stimulants alter dopaminergic firing rates¶

Stimulants:³⁵

• increase the dopaminergic firing rate in the globus pallidus in a dose-dependent manner
  • MPH by up to 100%
  • D-AMP by up to 50%
• reduce the dopaminergic firing rate in the substantia nigra pars compacta
  • MPH by up to 100%
  • D-AMP by up to 100%

2.1.1.2. MPH binds to DAT (reuptake inhibition)¶

Methylphenidate, as a dopamine reuptake inhibitor, increases dopamine levels in the synaptic cleft.²⁴ MPH inhibits the dopamine transporter and the norepinephrine transporter.⁴³ From this, it could be concluded that the site of action of MPH is where there is a dopamine deficiency. In the mesocortical model of ADHD, this would be the PFC. However, SPECT and PET studies clearly show that MPH primarily increases dopamine activity in the striatum, which argues against the PFC as the (sole) site of action (a finding that correlates with the low DAT levels in the PFC and the high DAT levels in the striatum). Since, according to the mesocortical model of ADHD, dopamine activity in the ventral striatum is elevated, MPH—if it increases activity there—would be more likely to worsen symptoms than to improve them. At low doses, stimulants such as MPH can inhibit phasic dopamine release by strengthening inhibitory tonic control.⁴⁴ However, in an fMRI study, children with ADHD who were not taking medication showed increased frontal activation and decreased striatal activation, which contradicts the theory of mesocortical deficiency. MPH increased frontal blood flow in both children with and without ADHD, but it increased striatal blood flow only in children with ADHD. It therefore remains unclear whether the observed frontal deficits in ADHD reflect a central dysfunction in the PFC or a lack of input from other dopaminergic systems. Since almost all mental disorders exhibit some degree of frontal dysfunction, it is unclear whether the etiological deficits in ADHD might not have other causes.³⁴
Methylphenidate normalizes elevated dopamine transporter densities more effectively in ADHD-HI rats than in ADHD-I rats⁴⁵ In contrast, one study found that MPH increased DAT in rats in several subregions of the basal ganglia, particularly in the more caudal regions of the caudate nucleus and the putamen.⁴⁶

• MPH binds to dopamine transporters, which are most densely concentrated in the striatum. The binding of MPH in the cerebellum and hippocampus is less than one-tenth of that in the striatum.⁴⁷
• MPH does not bind to dopamine receptors, but only to DAT and NET.⁴⁸⁴⁹ (Alternatively: MPH is thought to activate postsynaptic D1 receptors.²⁴⁵⁰ )
  • D-MPH has the strongest binding affinity, specifically to
    • DAT with IC50 = 23 nM, Ki = 161 nM;
    • NET with IC50 = 39 nM, Ki = 206 nM
  • D/l-MPH racemate binds somewhat weaker, specifically to⁴⁸
    • DAT with IC50 = 20 nM, Ki = 121 nM
    • NET with IC15 = 51 nM, Ki = 788 nM
  • L-MPH has the weakest binding affinity, specifically to⁴⁸
    • DAT with IC50 = 1600 nM, Ki = 2250 nM
    • NET with IC50 > 104 nM, Ki > 104 nM
• MPH doses result in a plasma concentration of MPH of approximately 20 to 30 nM, which is sufficient to occupy a significant proportion of the dopamine transporters. This effect is consistent with that of D-AMP.⁴⁴
• MPH responders had an increased number of DAT neurons in the striatum, while nonresponders had a decreased number.⁵¹
• MPH increased the number of dopamine transporters.⁵²
• Otherwise:
  • A smaller increase in dopamine and norepinephrine in the striatum²⁴
  • In contrast, MPH does not cause a rise in dopamine levels in the striatum in DAT(-/-) mice, but it does in DAT(+/-) and DAT(+/+) mice⁵³ Apparently, the level of expression/sensitivity of DAT is decisive for the positive or negative modulation of phasic dopamine release.⁵⁴

2.1.1.3. MPH increases dopamine release via DAT (efflux)¶

While it was previously assumed that methylphenidate does not cause the release of dopamine, more recent research suggests that

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

The view that MPH is purely a DA reuptake inhibitor⁵⁵⁵⁶ is outdated.

• As well as the release of dopamine from vesicles (in this case: reserpine-sensitive granules)⁵⁷⁵⁸
  • Should only be administered at very high doses of more than 80 mg per day⁵⁹⁶⁰
• Unlike amphetamine, methylphenidate is not considered a substrate for transport into the cytoplasm, which is why it causes, at most, a slight presynaptic release of dopamine.⁶¹
• Dopamine efflux via DAT reversal in the PFC
  • In the striatum of rats at 4 mg/kg (measured ex vivo)³⁰
  • As a result, MPH increases extracellular dopamine levels
  • Efflux from both dopamine and norepinephrine terminals
  • Through vesicular dopamine release and through sodium-dependent mechanisms
• Increasing the firing rate of PFC pyramidal neurons
  • With chronic administration in the PFC of rats at 4 mg/kg (measured in vivo)³⁰
  • measured using extracellular single-cell electrophysiological recordings
  • Responses to locally applied NMDA remain unchanged
• Desensitization to both dopamine and MPH in striatal regions
  • In the striatum of rats following chronic administration at 4 mg/kg (measured in vivo)³⁰
  • reduced efficacy of extracellular dopamine in modulating NMDA-induced firing activity of medium spiny neurons in the striatum
  • reduced MPH-induced dopamine release
  • is consistent with the empirical observation that, when using a single-dose regimen ( ), a one-time adjustment of the MPH dose is required after a few weeks

2.1.1.4. MPH acts on DA via D2 autoreceptors; MPH normalizes TH¶

MPH causes the disinhibition of presynaptic D2 autoreceptors.⁶²
Nevertheless, the effect of stimulants at different doses on D2 autoreceptors is no greater than on postsynaptic heteroreceptors. Stimulants appear to have only a minor effect on the dopamine system via autoreceptors.³⁵
In individuals with a high number of D2 receptors, MPH increased metabolism in the frontal and temporal regions of the brain (including the striatum); in healthy individuals with a low number of D2 receptors, it decreased metabolism in these regions. In the cerebellum, metabolism was consistently increased.⁶³
This corresponds to a normalization of D2 receptor binding.⁶⁴
Similar findings have been reported with regard to tyrosine hydroxylase. While TH expression is reduced in the spontaneously hypertensive rat (SHR), it is increased in the Naples high-excitability rat (NHE). Subchronic MPH administration normalizes TH expression in both ADHD animal models.⁶⁵⁶⁶

Methylphenidate, when combined with fluoxetine, significantly reduced D2 receptors in rats in:⁵⁰

• dorsal caudate putamen (51.5%)
• dorsolateral caudate-putamen (50.4%)
• Nucleus accumbens core (44.8%)
• ventral caudate-putamen (47.7%)
• ventromedial caudate-putamen (49.1%)

The D1R binding remained unchanged.

2.1.1.5. MPH Increases DA via VMAT2¶

MPH affects the redistribution of the vesicular monoamine transporter-2 (VMAT-2; Solute Carrier Family 18 Member 2 - SLC18A2). VMAT-2 is involved in the sequestration of cytoplasmic dopamine and norepinephrine and is thus an important regulator of neurotransmission. MPH does not affect the total amount of VMAT-2 in presynaptic terminals, but only VMAT-2 transport.⁶⁷⁶⁸
MPH acts on monoaminergic neurons (but not on cholinergic, GABAergic, or glutamatergic neurons):⁴⁸

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

MPH thus protects the dopaminergic system from progressive “wear and tear” by ensuring a substantial reserve pool of DA in the presynaptic vesicles. Consequently, there is only a relatively low risk of neurotoxic or neuropsychiatric side effects in clinical practice with MPH.⁴⁸

According to earlier reports, MPH has no effect on vesicular monoamine transporters (VMAT).⁴³

2.1.1.6. MPH increases tyrosine hydroxylase¶

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine synthesis. TH converts tyrosine into the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA). Thus, MPH supports dopamine synthesis.
MPH (just like sports) can induce the expression of TH⁶⁹ and increase TH levels.⁷⁰
In vitro, d-MPH at concentrations of 100 nmol/l or higher significantly increased tyrosine hydroxylase activity; L-MPH or racemic MPH at the same concentration did not increase TH⁷¹
It is unclear whether the increase occurs only peripherally or also in the brain.⁷² Variants of the TH gene appear to influence the response to MPH.⁷²

2.1.1.7. MPH acts via L-DOPA receptors¶

The L-DOPA receptor GPR143 appears to be involved in the acute and chronic effects of MPH.
Although MPH increases dopamine release, it does not affect L-DOPA release from the dorsolateral striatum. Nevertheless, in L-DOPA receptor KO mice (mice with a defect in the Gpr143 L-DOPA receptor gene), the following is reduced:⁷³

• MPH-induced hyperlocomotion
• the reward effect
• MPH-induced c-fos expression.

2.1.1.8. MPH alters the D1R-to-D2R/D3R ratio in the frontoparietal region¶

A PET study involving 37 healthy participants found that:⁷⁴
Increased attentional and working memory load heightened the activity of a network comprising the lateral frontoparietal and visual cortices, correlating with the performance improvement induced by MPH.
A lower D1R-to-D2R/D3R ratio in the dorsomedial caudate correlated with reduced frontoparietal activity during sustained attention and a greater improvement in brain function and task performance following MPH administration, and could therefore serve as a biomarker for response to MPH
The increase in striatal dopamine was independent of the MPH-induced improvement in performance.
MPH is more effective in people with relatively more D2R; people with relatively more D1R benefit only slightly.

A study found that MPH increased D1R binding in rats in several subregions of the basal ganglia, particularly in the caudal portions of the caudate nucleus and the putamen.⁴⁶
A combination of MPH and fluoxetine did not alter D1R binding in rats.
⁵⁰

2.1.1.9. Dose-dependent effects of MPH¶

The effects of MPH are dose-dependent. MPH at normal doses produces different effects than MPH at high or very high doses.

• At low doses, methylphenidate increases dopamine and norepinephrine levels in the prefrontal cortex (PFC), which enhances its performance. In other areas of the brain, however, low-dose MPH has barely any effect on dopamine and norepinephrine levels.⁷⁵ This corresponds to the well-known increase in the cognitive performance of the PFC resulting from slight increases in dopamine and norepinephrine levels under mild stress.
• At a dose of 3 mg/kg MPH, one study found no increase in dopamine or norepinephrine levels in the striatum of rats⁷⁶

• In a laboratory study of rats, higher doses of MPH (as well as cocaine) were reported to reduce dopamine levels in the striatum. Only lower doses of MPH or cocaine caused increases in dopamine levels. Furthermore, this was not the case for all animals.⁵⁴
• At higher doses, MPH is also thought to stimulate the release of dopamine and norepinephrine via DAT and NET efflux⁷⁷
• At high doses, MPH is thought to increase the surface expression of DAT⁷⁸

2.1.1.10. Duration-Dependent Effects of MPH¶

Acute administration of MPH increased the firing activity of PFC pyramidal neurons in rats and potentiated NMDA-induced neurotransmission.
Chronic MPH administration (2 × 2 mg/kg/day) resulted in the following changes in pyramidal neurons of the PFC 28 days after the end of MPH administration:³⁰

• a long-term increase in combustion activity
• Unchanged burst activity
• unchanged total number of spontaneously firing neurons
• unchanged glutamatergic neurotransmission

Long-term administration of MPH or atomoxetine to juvenile Naples High-Excitability (NHE) rats resulted in the following in adulthood:⁷⁹

• Reduced dopamine in the PFC and striatum
• Increased norepinephrine in the ventral striatum

• In adolescent rats, this caused⁶⁷⁶⁸
  • A single dose of high-dose MPH (2 mg/kg, which is roughly twice the maximum therapeutic dose typically used in humans)
    • A reduction in the number of vesicular monoamine transporters (VMAT2) in the cerebellum
    • No increase in dopamine turnover in the cerebellum (as measured by the DA metabolite DOPAC)
    • No change in the protein levels of tyrosine hydroxylase (TH) and the dopamine D1 receptor
    • Unchanged levels of dopamine and homovanillic acid (HVA)
  • Chronic administration of high-dose MPH (2 mg/kg) over 14 days
    • Increased number of vesicular monoamine transporters (VMAT2) in the cerebellum
    • Significantly increased dopamine turnover in the cerebellum (as measured by the metabolite DOPAC)⁶⁷
    • Left the protein levels of tyrosine hydroxylase (TH) and the dopamine D1 receptor unchanged⁶⁷ – same authors elsewhere⁶⁸
    • Increased the number of DATs⁶⁸
      • In the left dorsal striatum
    • Did not change the DAT
      • In the right dorsal striatum
      • In the nucleus accumbens (ventral striatum)⁶⁷
    • Increased the expression of the
      • Norepinephrine Transporter (NET)
      • Monoamine Transporter 2 (VMAT2)⁶⁷⁶⁸
        • In contrast, amphetamine reduces VMAT2⁸⁰
      • Tyrosine hydroxylase
      • Dopamine D1 receptors
      • More pronounced in the nucleus accumbens (ventral striatum) than in the dorsal striatum
      • More pronounced in the parietal cortex than in the frontal cortex
      • This effect of chronic MPH on increasing DAT, NET, and VMAT2 transporter levels could suggest that, over the long term, the drug might lose some of its acute effect of raising dopamine and norepinephrine levels.⁶⁸⁵²
        This is consistent with our experience that, for some users, the dosage needs to be adjusted slightly (increased slightly) once after half a year to a year. However, a general habituation effect has not been reported either in studies⁸¹ or in clinical practice.
      • Elevated levels of vanillinmandelic acid in the urine of Wistar rats. This was prevented by the supplemental administration of buspirone.⁸²
        Vanillinmandelic acid is produced during the breakdown of epinephrine and norepinephrine by MAO-A and COMT, making vanillinmandelic acid an indicator of the activity of the autonomic nervous system (sympathetic nervous system).
    • A single dose of very high-dose MPH (5 mg/kg, which is about 5 to 20 times the standard treatment dose for humans) causes
      • Metabolite changes in the cerebellum similar to those seen with 2 mg
      • In general, metabolites associated with energy consumption and excitatory neurotransmission—specifically glutamate, glutamine, N-acetyl-L-aspartate, and inosine—were reduced in the cerebellum
      • Furthermore, the levels of certain metabolites associated with inhibitory neurotransmission—in this case, GABA and glycine, acetate, aspartate, and hypoxanthine—were reduced
• A study found that children with ADHD had basal oxytocin levels that were unchanged compared to people with ADHD. While oxytocin levels decreased in people with ADHD who were untreated following interaction with a parent, they increased in people with ADHD who were treated with MPH, just as they did in people without ADHD.⁸³

2.1.2. MPH increases norepinephrine¶

• MPH exerts a noradrenergic effect in the locus coeruleus, which improves arousal, alertness, and attention²⁴
• The effects of MPH are dose-dependent. MPH at normal doses produces different effects than MPH at high or very high doses.
• At low doses, methylphenidate increases dopamine and norepinephrine levels in the prefrontal cortex (PFC), which enhances its performance. In other areas of the brain, however, low-dose MPH has barely any effect on dopamine and norepinephrine levels.⁷⁵ This corresponds to the well-known increase in the cognitive performance of the PFC resulting from slight increases in dopamine and norepinephrine levels under mild stress.

2.1.2.1. Low-dose MPH increased extracellular norepinephrine, but not dopamine¶

Adolescent rats were administered 0.75–3.0 mg/kg of MPH orally during the dark-active phase of the circadian cycle, which remained below the threshold for locomotor activation. These doses:²⁸

• elevated extracellular norepinephrine in the hippocampus
• no changes in dopamine levels in the nucleus accumbens
• did not alter methamphetamine sensitivity
• did not cause any habituation effects

Doses of 10, 20, and 30 mg/kg of MPH (well above a therapeutic dose) resulted in:⁸⁴

• stereotypical behavior (a sign of a sharp increase in extracellular dopamine); 20 mg/kg is just as potent as 2.5 mg/kg of AMP
• Increased extracellular dopamine
• Increased extracellular norepinephrine
• Extracellular serotonin remains unchanged (unlike with AMP, where it is elevated)

2.1.2.2. MPH binds to NET (resumption inhibitor)¶

• Norepinephrine reuptake inhibitors²⁴³⁰⁸⁵
• This also leads to an increase in extracellular dopamine in the PFC, where there are few DAT receptors but abundant NET receptors. The NET receptors in the PFC reuptake approximately as much dopamine as norepinephrine.

2.1.2.3. MPH causes norepinephrine efflux in the PFC¶

At a dose of 100 µM, MPH appears to induce both dopamine and norepinephrine efflux in the PFC, originating from both dopamine and norepinephrine terminals.

• Norepinephrine efflux (67–83 nM) from noradrenergic terminals³⁰
  • Measured ex vivo
  • At 100 µM MPH, not at 10 µM MPH

2.1.2.4. MPH Increases NE via VMAT2¶

MPH 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 norepinephrine and is therefore an important regulator of neurotransmission.
MPH does not affect the total amount of VMAT-2 in presynaptic terminals, but only its transport.
MPH acts on monoaminergic neurons (but not on cholinergic, GABAergic, or glutamatergic neurons:⁴⁸

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

2.1.2.5. MPH binds to norepinephrine receptors¶

2.1.2.5.1. Alpha-1 receptor¶

MPH also improves attention via the alpha-1 receptor.⁸⁶

2.1.2.5.2. Alpha-2 receptor¶

MPH binds directly to noradrenergic alpha-2 receptors.⁸⁷ MPH binds to⁴⁸

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

The cognitive improvement produced by MPH was blocked by α2-adrenoceptor antagonists.⁸⁸ Guanfacine and clonidine, which also act as α2-adrenoceptor agonists, have a positive effect on ADHD.

• Blockade of the alpha-2 adrenoceptor²⁴
  • Several sources, however, report that MPH has an agonistic effect on the alpha-2 adrenoceptor.⁸⁷⁸⁸ See above.

2.1.3. MPH and Serotonin¶

Overall, the effect of MPH on serotonin levels appears to be negligible.⁸⁹
MPH is said to bind to DAT 2,200 times more strongly than to SERT, and to NET nearly 1,300 times more strongly than to SERT.⁴⁸

The point of contention is:

• Whether serotonin reuptake occurs at the synapse. There are sources supporting this⁹⁰ as well as those opposing it.⁹¹
  • The serotonergic effect of MPH is so weak that it is not relevant for treatment
  • Based on our observations, MPH does not have a significant mood-enhancing effect. MPH may act as an antidepressant by correcting the stimulus-filtering deficit that has consequences that trigger depression.

2.1.3.1. 5HT-1A serotonin receptor¶

D-threo-(R,R)-methylphenidate is a weak agonist of the 5HT-1A serotonin receptor. This can influence dopamine metabolism in the brain,⁹² although the extent of this effect is minimal.
Repeated administration of MPH reduced 5-HT-1A-R expression

• in the nucleus accumbens
  • significantly at 0.5 mg/kg to 2.5 mg/kg⁹³
  • what is relevant to the reinforcing effects of MPH⁹³
  • Buspirone
    • Doses of 0.1 and 0.3 mg/kg prevented downregulation, but doses of 1.0 and 2.0 mg/kg of buspirone did not⁹⁴
    • 10 mg/kg/day prevented the development of tolerance resulting from long-term administration of 2 mg/kg/day MPH ⁹⁵
    • Buspirone is a partial 5-HT1A agonist and a D2R antagonist
• in the PFC
  • not significant at 0.5 mg/kg to 2.5 mg/kg⁹³⁹⁶
  • clearly at 5 mg⁹⁶

Low doses (2.5 mg/kg) of MPH improved memory performance in the water maze test, while higher doses (5 mg/kg) impaired it. Improved performance correlated with high 5-HT metabolism in the PFC.⁹⁶

• GABAA receptor mRNA expression is reduced at low doses of MPH (2.5 mg/kg)
• GluN2A expression is reduced at high doses of MPH (5 mg/kg)
• Increased 5-HT-HT1A receptor mRNA expression and decreased GABAA receptor mRNA expression in the PFC appear to free excitatory glutamate neurons from the inhibitory influence of GABA.
• Reduced 5-HT1A receptor mRNA expression enhances the inhibitory effect of GABA on glutamate neurons and thereby impairs cognitive performance.

2.1.3.2. 5HT-1B serotonin receptor¶

It is unclear whether MPH also binds to the 5HT-1A serotonin receptor. Some sources support this view⁹⁷, while others oppose it⁹⁸.

2.1.3.3. MPH and Tryptophan Hydroxylase¶

Of the two tryptophan hydroxylase isoforms, TPH1 and TPH2, only TPH2 is found in the brain. TPH catalyzes the rate-limiting step in serotonin synthesis by converting tryptophan into the serotonin precursor 5-hydroxytryptophan.⁷²
The AATGGAGA (Yin) haplotype of TPH2 appears to respond less well to MPH than the CGCAAGAC (Yang) haplotype.⁷²

2.1.3.4. Effect of MPH on Tryptophan Metabolites¶

A study found that people with ADHD-HI (predominantly hyperactive) and comorbid depressive symptoms had significantly higher morning levels of indoleacetic acid than evening levels, compared to people with ADHD-I and healthy controls. MPH reduced this by 50%. At the same time, MPH reduced morning levels of indolepropionic acid and brought the daily profile back in line with the levels observed in healthy control subjects.⁹⁹

2.1.3.5. Effect of MPH on the dorsal raphe nuclei¶

Administration of MPH over several days caused

• behavioral sensitization in some rats (which correlated with neuronal excitation) and
• behavioral tolerance in other rats (which was accompanied by neural attenuation).

The neurons in the dorsal raphe nuclei (serotonergic) showed the strongest response to acute and chronic MPH administration and reacted differently at all three doses used compared to the neurons in the VTA (dopaminergic) or locus coeruleus (noradrenergic).¹⁰⁰
In the behavioral sensitization group, serotonergic activity in the dorsal raphe nuclei increased; in the behavioral tolerance group, it remained the same or decreased¹⁰¹
The dorsal raphe nuclei and serotonin appear to be involved in the acute and chronic effects of MPH and to play an independent role in the response to MPH.

2.1.4. Binding Affinity of MPH, AMP, and ATX to DAT, NET, and SERT¶

The active ingredients methylphenidate (MPH), d-amphetamine (d-AMP), l-amphetamine (l-AMP), and atomoxetine (ATX) bind with varying affinities to dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT). This binding inhibits the activity of the respective transporters.¹⁰²

Binding affinity: higher for smaller numbers (KD = Ki)	DAT	NET	SERT
MPH	34 - 200	339	> 10,000
d-AMP (Vyvanse, Attentin)	34–41	23.3–38.9	3,830–11,000
l-AMP	138	30.1	57,000
ATX	1451–1600	2.6–5	48–77

2.1.5. Effects of MPH, AMP, and ATX on Dopamine and Norepinephrine by Brain Region¶

The active ingredients methylphenidate (MPH), amphetamine (AMP), and atomoxetine (ATX) affect extracellular dopamine (DA) and norepinephrine (NE) to varying degrees in different regions of the brain. Table modified from Madras,¹⁰².

	PFC	; striatum	; nucleus accumbens
MPH	DA + NE (+)	DA + NE +/- 0	DA + NE +/- 0
AMP	DA + NE +	DA + NE +/- 0	DA + NE +/- 0
ATX	DA + NE +	DA +/- 0 NE +/- 0	DA +/- 0 NE +/- 0

2.1.6. Effect of MPH on MAO-A¶

MPH affects monoamine oxidase A (MAO-A) by¹⁰³

• Stimulation of non-vesicular release
• Inhibition of MAO-A activity⁵⁸¹⁰⁴

However, the impact appears to be limited and of little significance.

2.1.7. Effect of MPH on Glutamate¶

MPH caused a statistically significant decrease in glutamate levels in the frontal cerebellar circulation and the amygdala in children. In adults, most studies found no significant change in glutamate levels or glutamate-related metabolites following MPH exposure. (Meta-analysis, k = 10)¹⁰⁵

2.2. Effect of MPH on Cholesterol Metabolism in the OFC¶

A study found 12 altered metabolites in the PFC of SHR rats, which are considered a model for ADHD-HI, compared to WKY rats, which are considered a model for non-affected individuals. The abnormalities in 8 of these were normalized by MPH:¹⁰⁶

• 3-hydroxymethylglutaric acid
• 3-phosphoglyceric acid
• Adenosine monophosphate
• Cholesterol
• Lanosterin
• O-phosphoethanolamine
• 3-Hydroxymethylglutaric acid
• Cholesterol

The modified metabolites are part of the cholesterol metabolic pathways.
The SHR found the following in the PFC regarding this

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

2.3. Effect of MPH on the HPA axis¶

Stimulants (methylphenidate and amphetamine-based medications) are believed to increase the activity of the HPA axis.¹⁰⁷
MPH increases the cortisol wake-up response, which is a sign of increased reactivity of the HPA axis.¹⁰⁸

MPH increased physiological measures of stress (salivary cortisol and blood pressure). MPH modulated the effects of stress on the activation of brain regions associated with goal-directed behavior, including the insula, putamen, amygdala, mPFC, the frontal pole, and the OFC. However, MPH did not modulate stress’s tendency to cause a reduction in goal-directed behavior.¹⁰⁹

2.4. Effects of MPH on the Autonomic Nervous System (Sympathetic / Parasympathetic)¶

In ADHD, heart rate variability (HRV)—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, though they cannot raise it to the level seen in people without ADHD.¹¹⁰¹¹¹

The statement made elsewhere—¹¹² —that methylphenidate does not alter the HVR is not found in the cited source.¹¹³

2.5. Effect of MPH on Androgens¶

Stimulants (methylphenidate and amphetamine-based medications) reduce androgen levels.
Preclinical data on the role of androgens in the pathogenesis of ADHD suggest that elevated testosterone levels may reduce cerebral blood flow in the PFC by decreasing the levels of alpha-estrogen receptors and vascular endothelial growth factor (VEGF). This may disrupt memory processes. There is a correlation between ADHD and a polymorphism in the androgen receptor gene that leads to its increased expression. Nevertheless, little is known about the role of androgens in ADHD.¹⁰⁷

2.6. Effect of MPH on kynurenines¶

MPH appears to improve the homeostatic balance of various kynurenines (e.g., elevated kynurenic acid versus reduced quinolinic acid in plasma) in children with ADHD.¹¹⁴

2.7. Effect of MPH on ARAS¶

Methylphenidate increases the arousal of the reticular activating system (RAS).¹¹⁵

2.8. Effect of MPH on Oxidative/Nitrosative Stress¶

For more information on oxidative stress, see Oxidative Stress and ADHD Status

Oxidative stress is elevated in ADHD.¹¹⁶¹¹⁷
For more information on oxidative stress, see Oxidative Stress and ADHD

MPH improved the redox profile in humans by reducing levels of advanced oxidation protein products, lipid peroxidation, and nitrite plus nitrate (NOx), and by increasing the activity of the ROS-scavenging enzymes glutathione reductase and catalase.¹¹⁸

Single dose of MPH:¹¹⁹

• increased superoxide (ROS) levels in the cerebellum of young rats at both low and high doses, and in the hippocampus only at high doses (10 mg/kg)
• did not affect superoxide in adult rats

Chronic administration (as is common with ADHD medications):¹¹⁹

• did not affect superoxide in young rats
• Reduced superoxide levels in the cerebellum of adult rats at lower doses

MPH in vitro on retinal cells¹²⁰

• protected the viability of retinal cells
• induced oxidative stress through the activation of the NOX2 and PI3K/AKT/DRP1 signaling pathways
• induced mitochondrial dysfunction
  • Reduced mitochondria
  • Increased mitochondrial fragmentation
  • Impaired membrane potential
  • Reduced oxygen consumption
  • A shift in metabolism toward a glycolytic metabolic profile
  • In inflammatory conditions
    • Increased MPH boosted antioxidant defense
    • reduced oxidative stress
    • reduced intracellular calcium levels
    • improved the structure and function of the mitochondria

MPH had the following effect on rats¹²⁰

• at SHR
  • Reduces oxidative stress
  • Improved mitochondrial function
• in Wistar
  • increased oxidative stress

2.9. Effect of MPH on S100B¶

A study found that triple therapy (TT) with methylphenidate (MPH), melatonin (aMT), and omega-3 fatty acids (ω-3 PUFAs) increases S100B levels in people with ADHD. The authors interpret this as evidence that a potential neuroinflammatory cause of ADHD may impair glial function and thereby alter dopaminergic neurotransmission.¹²¹

Chronic administration of MPH (30 to 60 mg/kg—well above therapeutic doses) increased glial function in rats.¹²² Increased glial function is beneficial in the short term for clearing debris and fighting infections. Chronically elevated glial function (gliosis) can be harmful if it is a consequence of chronic neuroinflammation. Chronically activated glial cells continuously release pro-inflammatory signaling molecules (cytokines such as TNF-alpha), cytotoxic substances, and aggressive oxygen radicals. These directly attack and destroy healthy neighboring neurons and their protective layers (myelin sheaths). While microglia are actually supposed to remove cellular waste, when their activity is chronically elevated, they begin to massively break down healthy synapses (nerve connection points). This is a major driver of brain fog and memory loss. The latter is precisely what is not reported in the treatment of ADHD with MPH.

2.10. Effects of MPH on Brain Networks¶

2.10.1. MPH and Connectivity Between Brain Regions¶

Changes in interhemispheric connectivity have been reported in ADHD:¹²³

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

Functional connectivity between brain regions is not static; rather, it changes depending on the demands placed on the brain. The speed at which functional connectivity changes measures the brain’s flexibility relative to its stability.
The balance between flexibility and stability in brain function is largely regulated by catecholamines. MPH acts specifically on the catecholamines dopamine and norepinephrine.
MPH slowed the change in functional connectivity, thereby reducing the flexibility of the entire brain. The greater the decrease in whole-brain flexibility under the influence of MPH, the greater the improvements in task performance.¹²⁴

MPH increased resting-state functional connectivity in three subcortical-cortical and cerebellar-cortical clusters. MPH-induced increases in resting-state functional connectivity between the cerebellar vermis (Lobe 6) and the left precentral gyrus correlated with a higher likelihood of responding to MPH after 2 months and with an improvement in both inattentive and hyperactive/impulsive symptoms.¹²⁵

In one study, methylphenidate normalized the reduced global connectivity observed in ADHD 400–700 ms after a stimulus and reduced an increase in network disconnection 100–400 ms after the stimulus. These global changes induced by methylphenidate occurred primarily in the task-relevant frontal and parietal regions and were more significant and sustained than in the untreated control subjects. The study’s results suggest that methylphenidate corrects the impaired network flexibility observed in ADHD.¹²⁶

2.10.2. Effect of MPH on the Default Mode Network (DMN)¶

The increased, purely intrinsically motivated control of attention in ADHD means that, when interest is high, attention and its controllability are just as high as in individuals without ADHD, and differ from those of individuals without ADHD only when intrinsic interest is low. This is regulated by the DMN.
Stimulants can bring the attention control of people with ADHD in line with that of people without ADHD when there is a lack of intrinsic interest.¹²⁷ This explains why stimulants are just as helpful for ADHD-HI and ADHD-C as they are for ADHD-I.

For more information on the altered functioning of the DMN in ADHD and its normalization through stimulants, including additional references, visit ⇒ Normalization of the DMN through stimulants In the article ⇒ Brain Networks and Connectivity in ADHD in the chapter at ⇒ Neurological Aspects.

2.10.3. Effects of MPH on the Nucleus Accumbens and Cognitive Control Networks¶

Methylphenidate increased spontaneous neuronal activity in the nucleus accumbens and in cognitive control networks in children with ADHD. This resulted in more stable, sustained attention.¹²⁸

2.11. Effect of MPH on EEG¶

MPH caused¹²⁹

• Significant differences in the frontal-parietal region among people with ADHD at 250 ms–400 ms after the stimulus (P3)
• A reduction in the late 650 ms–800 ms ERP component (LC) at frontal electrodes in ADHD patients compared to controls
• A significant reduction in reaction time variability among people with ADHD, which correlated with increased P3 ERP activity at the frontoparietal electrodes

2.12. Effects on Brain Regions¶

Neuroimaging studies show numerous effects of MPH on various brain regions. These studies indicate that MPH acts primarily in the PFC and striatum. MPH

• Apparently reduces the loss of gray matter typical of ADHD
  • In the basal ganglia (primarily in children; the problem tends to diminish on its own in adults)
    • In the right lentiform nucleus¹³⁰
      • In the right globus pallidus¹³¹
      • In the putamen¹³¹
    • In the caudate nucleus¹³⁰
  • In the anterior cingulate cortex (ACC) in adults¹³⁰
• MPH exerts its acute and chronic effects on behavior via the dopaminergic system of the caudate nucleus.¹³²
• People with hyperactive and inattentive ADHD see an increase in the previously unusually low blood flow to the putamen with regular administration of methylphenidate. In people with ADHD who have average motor activity, regular methylphenidate administration resulted in a reduction in blood flow to the putamen. The thalamus was not affected by MPH.¹³³
  MPH increased activation in the bilateral inferior frontal cortex and insula while inhibiting temporal discrimination.¹³⁴
• Methylphenidate increases metabolic activity in the left posterior frontal and left superior parietal regions of the brain and decreases it in the left parietal, left parieto-occipital, and left medial anterior frontal regions.¹³⁵
• MPH had the following effect in healthy adults¹³⁶
  • Activation of the frontoparietal network
  • Activation of the somatomotor network
  • Impairment of the visual system

MPH appears to reduce dysfunction in the PFC in most people with ADHD.¹³⁷ Another meta-analysis found that MPH had no effect on working memory (in the dlPFC).¹³⁴

A study in rats using single and repeated doses of 0, 0.6, 2.5, and 10.0 mg MPH/kg found that MPH affected the PFC and the caudate nucleus. The same dose of MPH induced behavioral sensitization in some animals and tolerance in others, with activity in the PFC and caudate nucleus correlating with the animals’ behavioral responses to MPH. The response of the caudate nucleus was more intense than that in the PFC, following both single and repeated administrations. In addition, dose-dependent differences in responses were observed between the PFC and the caudate nucleus: some PFC and caudate nucleus cell units responded to the same dose of MPH with an increase in neuronal firing rate, while others responded with a decrease.¹³⁸

2.13. MPH in Preschoolers¶

Some studies show that MPH has a positive effect on preschool-aged children with ADHD.¹³⁹

2.14. MPH Normalizes Pain Perception in ADHD¶

People with ADHD often exhibit increased sensitivity to pain. MPH can alleviate this sensitivity to pain in people with ADHD.¹⁴⁰

2.15. MPH Improves Inflammation Markers¶

ADHD is associated with increased neuroinflammation.
Treatment with MPH improved inflammation markers.¹⁴¹

2.16. Serdex methylphenidate improved sleep in patients with ADHD¶

A study reports a significant improvement in sleep among children with ADHD between the ages of 6 and 12 who were treated with serdex methylphenidate or dex methylphenidate.¹⁴²

2.17. More about MPH¶

Methylphenidate and amphetamine-based medications increase alpha activity (in rats), while atomoxetine and guanfacine do not.¹⁴³

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

Some have suggested that very early treatment with stimulants could permanently improve DAT hyperactivity (that is, beyond the duration of treatment).¹⁴⁵

A very small fMRI study involving 16 participants that examined the effects of methylphenidate on boys with and without ADHD found that, prior to taking methylphenidate, the boys with ADHD showed, compared to people with ADHD, increased activation of the frontal cortex and decreased activation of the striatum during Go/NoGo tasks. Methylphenidate balanced out these differences.¹⁶⁰

It is unclear what concentrations of methylphenidate reach the synaptic cleft.³⁶
Methylphenidate may accumulate in the central nervous system through active accumulation processes, resulting in effective brain concentrations that are significantly higher than those in plasma.¹⁶¹ In animals, striatal concentrations of cocaine appear to be about 6 times higher than those in plasma.¹⁶²

It is unclear whether MPH affects prolactin levels.
In men, it did not affect serum prolactin levels.¹⁶³ Nor did it affect levels in unaffected individuals.¹⁶⁴
Neither amphetamine nor methylphenidate reduced serum prolactin levels in rats. Amphetamine, but not methylphenidate, blocked the increase in serum prolactin in response to reserpine.¹⁶⁵
MPH increases prolactin levels in children.¹⁶⁶

3. Differences in the Effects of Methylphenidate and Amphetamine-Based Medications¶

Methylphenidate may increase metabolic activity in the left posterior frontal and left superior parietal regions of the brain and decrease it in the left parietal, left parieto-occipital, and left medial anterior frontal regions.¹⁶⁷

In contrast, D-amphetamine may increase metabolism in the right caudate nucleus (part of the striatum) and decrease it in the right Rolandi region as well as in the right anterior inferior frontal regions.¹⁶⁸

The sample sizes (n) used to examine these findings—19 and 18—were very small. Samples that are too small carry a significant risk of producing misleading results.
For more information, visit ⇒ Studies show—sometimes nothing at all.

4. Effect on Symptoms¶

Methylphenidate improves symptoms in children with ADHD:¹⁶⁹

• Response time
• Variability in reaction time
• tonic attention
• phasic attention
• divided attention
• Flexibility/Shift in Attention/Task Switching
• selective attention
  • Inhibition
  • focused attention
• Task accuracy with respect to
  • Vigilance
  • divided attention
  • Inhibition
  • focused attention
  • Flexibility
  • Integrating sensory information
• Number of omissions and errors of commission in attention tasks

There is evidence that MPH has an effect on neuropathic pain.¹⁷⁰

4.1. Methylphenidate is particularly effective¶

• Hyperactivity ¹¹⁵
• Restlessness¹¹⁵
• Impulsivity¹¹⁵
  • People with ADHD have reported on forums that MPH is more effective at reducing impulsivity than Vyvanse.¹⁷¹
  • A study of monkeys (which, of course, do not have people with ADHD) concluded that low doses of MPH reduce impulsivity, while higher doses have a sedative effect.¹⁷²
    This is consistent with empirical findings that an overdose of MPH can cause apathy.
• Aggressiveness¹¹⁵¹⁷³
  • And, in fact, better than atomoxetine¹⁷⁴
  • In a study of children aged 6 to 12 with aggression and ADHD, systematically titrated stimulants eliminated aggression in 63% of the children.¹⁷⁵ In children for whom stimulants did not sufficiently reduce aggression, adjunctive treatment with risperidone (effect size 1.3) or valproic acid (effect size 0.9) improved aggression, although risperidone was associated with weight gain.
• Socially inappropriate behavior¹¹⁵
• Behavioral problems—and more effectively than atomoxetine¹⁷⁴
• Somatic symptoms, and it works better than atomoxetine¹⁷⁴
• Motivation Through Rewards¹⁷⁶
• Drive
  • People with ADHD report quite consistently that MPH improves motivation more than AMP

• Number of omissions and errors of commission in attention tasks¹⁷⁷
• Mind Wandering¹⁷⁸

MPH is effective in adults:¹⁷⁹

• for the core symptoms of ADHD (SMD: 0.49)
• against the associated emotional dysregulation (SMD: 0.34)

MPH is thought to be most effective for cognitive ADHD symptoms. Motor and social behavior may gradually require slightly higher doses.⁶⁵

4.2. The Positive Effects of Methylphenidate¶

• Perception¹⁸⁰

• Concentration¹¹⁵

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

• Attention¹¹⁵

  • Distractibility is reduced, and attention is increased
  • Task switching is reduced¹⁸¹

• Motor restlessness¹¹⁵

• Typography and Graphic Expression ¹⁸²

• Social perceptual ability and facial responsiveness

• Social interaction¹⁸³

  • A study found that children with ADHD had basal oxytocin levels that were unchanged compared to people without ADHD. While oxytocin levels rose in children without ADHD following interaction with a parent, they decreased in people with ADHD who were not treated. Methylphenidate caused the rise in oxytocin levels following interaction with a parent to match that of people with ADHD.¹⁸⁴

• Rejection Sensitivity (Sensitivity to Rejection)
  Almost all of the people with ADHD we surveyed reported an improvement in their rejection sensitivity (which nearly all of the people with ADHD we surveyed experience) as a result of MPH. A few people reported that their rejection sensitivity worsened while taking MPH. One of these people with ADHD later turned out to be a non-responder for MPH who was able to achieve better results with an amphetamine-based medication.

• Mathematical skills

  • Children with ADHD showed significantly improved math skills while taking MPH, to the point where their performance was indistinguishable from that of children without ADHD.¹⁸⁵

• Anxiety¹⁷³

• Tension¹⁷³

• Borderline traits¹⁷³

• Depression¹⁷³

• Emotional instability¹⁷³

• Dissatisfaction with Life¹⁷³

• Negative outlook on life¹⁷³

• Psychotic phenomena¹⁷³

• Social introversion¹⁷³

• Uncertainty¹⁷³

• Compulsiveness¹⁷³

• Inner Emptiness/Boredom¹⁸⁶

4.3. Limited Effect of Methylphenidate¶

• Delay Aversion (in Adults)¹⁸⁷
• Executive Functions (in Adults)¹⁸⁷

4.4. No effect of methylphendiate¶

• Reading the Mind in the Eye (in children). This test measures theory of mind.¹⁸⁸
• Fine Motor Skills (Handwriting)¹⁸⁹

4.5. Do stimulants have different time-dependent effects on symptoms?¶

A publication by a renowned scientist claims that there are different time-response and dose-response curves for the motor and cognitive effects of stimulants.¹⁹⁰ 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 cited sources do not support this claim. Nor do they align with empirical experience in practice.

4.6. Latency until the effect sets in¶

Immediate-release methylphenidate typically takes effect within 15 to 20 minutes.
The extensive body of scientific literature and empirical experience do not indicate any latency period in the sense of a multiple of doses or days until the effect is observed.

A study reports that, in children with ADHD taking methylphenidate, the Clinical Global Impression-Severity Scale indicated an improvement in ADHD symptoms only at the second follow-up visit after 12 weeks, and not at the first visit after 4 weeks.¹⁹¹

4.7. MPH and Smoking Cessation¶

It has been reported that sustained-release MPH contributed positively to nicotine abstinence/smoking abstinence, but only in more severe cases of ADHD, whereas in milder cases of ADHD, a paradoxical worsening occurred, which, however, resolved after discontinuation of the medication.¹⁹² This should be viewed in light of the fact that nicotine, as a stimulant, serves as a form of self-medication for ADHD, even though smoking involves the use of nicotine as a drug, whereas only nicotine patches or nicotine lozenges act as medication.
Furthermore, the results of this study, viewed in the context of the Inverted-U Theory—which posits that moderate neurotransmitter levels facilitate optimal brain function— whereas both reduced and elevated neurotransmitter levels cause nearly identical symptoms, suggest an overdose in the participants with milder ADHD symptoms (indicating a lesser deficiency of dopamine and norepinephrine) and a paradoxical reaction.

4.8. MPH and Creativity¶

One study found that MPH did not impair creativity,¹⁹³ Another study found increased creativity in children with ADHD who were not taking medication compared to children with ADHD who were taking medication and people with ADHD.¹⁹⁴

5. Response (Responding / Nonresponding)¶

“Response” refers to whether a positive effect on ADHD symptoms can be observed. People with ADHD who do not respond adequately to a medication are called nonresponders.
“Nonresponsive” does not mean that there is no effect, but simply that the effect falls short of the level of symptom improvement defined in the respective study.

A meta-analysis reports a 69% response rate to amphetamine-based medications and a 59% response rate to methylphenidate. 87% of people with ADHD reportedly responded to one of the two types of active ingredients.¹⁹⁵ A meta-analysis of 32 studies reaches the same conclusion (significantly better response rates to amphetamine medications than to MPH).¹⁹⁶
For people with ADHD in whom MPH is not effective, it is therefore recommended to try treatment with amphetamine-based medications.

In practice, it has not yet been possible to predict a patient’s response. A study of preschool children in the United States found that white children responded better to stimulants (MPH, lisdexamfetamine) than children of color; other factors (age, gender) had no effect.¹⁹⁷
Machine learning enabled a prediction accuracy for response to MPH of just under 85% (as of 2022).¹⁹⁸

MPH and Atomoxetine:

• About 50% of people with ADHD who do not respond to MPH are expected to respond to atomoxetine, and about 75% of people with ADHD who respond to MPH are also expected to respond to atomoxetine.¹⁹⁹
• 43% of MPH nonresponders responded to atomoxetine, and 42% of atomoxetine nonresponders responded to Oros-MPH²⁰⁰

Indicators suggesting a response to MPH included:

• Lower ADHD-RS-IV.es scores²⁰²
• The absence of comorbidities (ODD, depression, alcohol/cannabis use)²⁰²
• Less intrusive neuropsychological tests²⁰²
• A higher overall IQ²⁰²
• Minor commission errors (impulse control errors; responding to a signal that should not have been responded to) on the Conners Continuous Performance Test II (CPT-II)²⁰²
• Higher levels of hyperactivity, impulsivity, and oppositional symptoms prior to treatment²⁰³
  • Predictors of good outcomes with MPH monotherapy, guanfacine monotherapy, and MPH/guanfacine combination therapy
• Reduced anxiety before treatment²⁰³
  • Predictors of good outcomes with MPH monotherapy, guanfacine monotherapy, and MPH/guanfacine combination therapy
• High event-related beta power in the middle frontal cortex prior to treatment²⁰³
  • EEG activity from cortical sources localized in the middle frontal and middle occipital regions
  • Greater variations during encoding and retrieval predict good outcomes with MPH monotherapy and guanfacine monotherapy
• Weak event-related beta power in the middle frontal cortex prior to treatment²⁰³
  • EEG activity from cortical sources localized in the middle frontal and middle occipital regions
  • Predictor of good outcomes with MPH/guanfacine combination therapy

5.1. Subtypes and Probability of Nonresponse¶

Most older sources report that about 90% of people with the ADHD-HI subtype (with hyperactivity) and the combined subtype respond positively to methylphenidate and require relatively low doses.^{204205206207208}
More recent sources cite a response rate of up to 75% for MPH (²⁰⁹ ), which seems more accurate to us.

People with the ADHD-I subtype are reportedly more likely to be nonresponders to MPH,²¹⁰ with nonresponder rates cited as 24%²⁰⁴. People with ADHD-I who do respond to MPH also require higher doses.
According to a small study, children with a higher cortisol stress response—which corresponds to the ADHD-I subtype—tend to benefit more from higher doses of MPH than children with a blunted cortisol stress response (which corresponds to ADHD-HI). However, the stress test was not based on the TSST but on a venipuncture, which makes it less easy to detect the cortisol stress response.²¹¹

A particularly strong cortisol awakening response (CAR) was associated with reduced MPH responding in children.²¹¹

People with SCT (which, according to current understanding, is not a subtype of ADHD but rather a comorbidity that occurs with equal frequency in both ADHD-HI and ADHD-I) are particularly likely to be MPH nonresponders. In particular, elevated SCT Sluggish/Sleepy factor scores indicate non-response to MPH. In this study, neither elevated SCT “Daydreamy” symptoms nor the ADHD subtype (ADHD-HI or ADHD-I) were associated with differences in the MPH response rate.²¹²

According to one study, MPH is less effective in people with ADHD who have intellectual deficits. The study reported a response rate of 40 to 50%.²¹³ Another study, however, found that MPH was effective in people with intellectual deficits.²¹⁴

5.2. (Non-)Responders and EEG Subtypes¶

People with ADHD who have very low EEG theta values are said to be more likely to be nonresponders to stimulants.²¹⁵
According to our understanding, low theta values correspond to the overactive beta (EEG) subtype. Another source also reports reduced MPH responsiveness for the beta subtype (overactive type).⁵⁶
The beta subtype manifests externally as the classic ADHD-HI subtype (hyperactive/impulsive). Most people with ADHD-HI have too little theta and too much beta. For more information, visit ⇒ ADHD Subtypes According to EEG.

However, the (few) people with ADHD of the BETA subtype whom we know report that MPH has been extremely helpful.

A small study found that lower EEG stability at rest was a predictor of an MPH response.²¹⁶
Another study found a reduced 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 in this respect.²¹⁷
Compared to dextroamphetamine responders, MPH responders showed:²¹⁸

• fewer EEG abnormalities
• a lower relative delta value at all measurement points
• a smaller increase in the relative theta value in the midline of the frontal lobe
• a higher relative alpha value at all locations, which was more pronounced in the posterior regions than in the frontal regions
• a greater increase in overall performance in the posterior regions compared to the anterior regions

A low alpha-peak frequency was associated with a lack of response to methylphenidate in male adolescents.²¹⁹

5.3. (Non-)Responders and the D1R-to-D2R Ratio¶

A PET study involving 37 healthy participants found that:⁷⁴
MPH is more effective in people with relatively more D2R in the dorsomedial caudate; people with relatively more D1R benefit only slightly.
As MPH improved performance, it also increased the activity of a network comprising the lateral frontoparietal and visual cortices, while simultaneously increasing the load on attention and working memory.
A lower D1R-to-D2R/D3R ratio in the dorsomedial caudate correlated with reduced frontoparietal activity during sustained attention and a greater improvement in brain function and task performance following MPH administration, and could therefore serve as a biomarker for response to MPH
The increase in striatal dopamine was independent of the MPH-induced improvement in performance.

5.4. (Non-)Responders and MPH Dosage¶

Some observers suspect that nonresponders may be cases of underdosing—that is, that the required dosage was not achieved and a lack of response is merely being mistakenly assumed.²²⁰
In our experience, a dosage that is too low can cause what appears to be a lack of response. Nevertheless, there are genuine non-responders for whom even significantly higher doses do not produce satisfactory results.
In addition, different non-responder rates have been reported among children and adults.
We suspect that a more precise classification of ADHD subtypes will eventually provide some answers here.

5.5. Does the season affect MPH dosing?¶

A study found a seasonal pattern of inattention among people with ADHD who were treated with low-dose MPH. During the season when light levels increase (as days grow longer), people with ADHD on low doses exhibited relatively poorer attention. It was not the absolute amount of light, but rather its relative change, that was relevant. High doses of MPH led to higher levels of attention that fluctuated less over the course of the year. A greater reduction in sunlight intensity was associated with a better response to treatment. These results were also evident in omission errors on a CPT.²²¹
The authors interpreted this to mean that, when treatment begins as the days grow shorter, a low dose of MPH may be sufficient.
A link to the circadian rhythm is suspected. The authors hypothesize that in some people with ADHD (who require less MPH?) , there may be impaired function of the light-sensitive retinal cells in the ADHD subgroups, affecting the melatonin- and dopamine-producing cells in the retina. They raise the question of whether combining MPH with modulated light therapy could improve treatment response, as has already been reported for fluoxetine in cases of non-seasonal depression.²²²

5.6. Indicators of a Good Response to MPH¶

An increase in blood pressure is said to correlate with a particularly beneficial effect of MPH.²²³

A particularly marked improvement in symptoms with methylphenidate was observed in people with ADHD who²²⁴

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

A study found that certain genes of particular relevance to neural development (“Neurodevelopmental Network”) had little or no impact on the effects of MPH or atomoxetine in ADHD.²²⁵

A meta-analysis of 15 studies and 1,382 patients found that carriers of the T allele of the NET gene polymorphism rs28386840 responded to MPH significantly more often and showed a significantly greater improvement in hyperactive-impulsive symptoms than carriers of other NET polymorphisms. ADRA2A polymorphisms did not correlate significantly with response to MPH. However, carriers of the G allele of the MspI polymorphism showed an association with a significant improvement in inattentive symptoms.²²⁶

Elevated iron levels in the putamen and caudate nucleus correlated with better MPH response in ADHD. Elevated iron levels in the putamen correlated—not only in ADHD —with impaired inhibition.²²⁷

In preschool-aged children with ADHD, low levels of externalizing or internalizing symptoms correlated with a high probability of responding to stimulants. When externalizing or internalizing symptom severity was high, the response rate to stimulants approached that of alpha-2 agonists:²²⁸

Responder	Symptom severity:	mild	moderate	severe
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%

People with ADHD for whom ADHD medications were ineffective (nonresponders) reported higher levels of trauma on the Perceived Stress Scale (PSS) than people with ADHD for whom medications were effective (responders).²²⁹

A greater sulcus depth predicted greater treatment success in adults with ADHD after 12 weeks of group psychotherapy as well as after MPH treatment.²³⁰

5.7. Indicators of Poor Response to MPH¶

People with ADHD for whom ADHD medications were ineffective (nonresponders) reported higher levels of trauma on the Perceived Stress Scale (PSS) than people with ADHD for whom medications were effective (responders).²²⁹

Among those not affected, the number of traumatic childhood events correlated with the level of currently experienced stress, as well as with a stronger dopamine response in the ventral striatum to amphetamine.²³¹
This could be an indication that increased childhood trauma is associated with an increased striatal dopamine response to stimulants, suggesting that a significantly lower dose of stimulants would be more appropriate for these people with ADHD. We can immediately think of people with ADHD for whom this is true.

5.8. Gene Variants and the Effect of MPH¶

5.8.1. ADRA2A gene variants¶

The ADRA2A -1291 polymorphism influences the response to and effects of MPH.

• G/G genotype:
  • 76.9% responded well to MPH²³²
  • 25% greater reduction in symptoms after 3 months of MPH²³³
• C/G genotype:
  • 46.0% responded well to MPH²³²
• C/G genotype:
  • 41.7% responded well to MPH²³²

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

• C/C genotype
  • Diastolic blood pressure increased by 18.5% due to OROS-MPH²³⁴
• G/G genotype
  • Diastolic blood pressure decreased by 0.2% with OROS-MPH²³⁴
• G/C genotype
  • Diastolic blood pressure decreased by 0.2% with OROS-MPH²³⁴

5.8.2. NET gene variants¶

The genotype of the G1287A polymorphism in the NET gene (norepinephrine transporter, SLC6A2) may influence the response to MPH:

• G/G genotype:
  • 71.9% responded well to MPH²³⁵
  • A 7.15-point improvement on the hyperactivity subscale of the ADHD Rating Scale-IV, but not on the inattention subscale ²³⁶
  • No difference in response was observed
• G/A genotype:
  • 46.0% responded well to MPH²³⁵
  • A 6.94-point improvement on the hyperactivity subscale of the ADHD Rating Scale-IV, but not on the inattention subscale ²³⁶
• A/A genotype:
  • 57.1% responded well to MPH²³⁵
  • A 2.13-point improvement on the hyperactivity subscale of the ADHD Rating Scale-IV, but not on the inattention subscale ²³⁶

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

• T/T genotype
  • responded comparatively better to MPH²³⁷
  • 12.5% increase in resting heart rate due to OROS-MPHi²³⁴
• A/T genotype
  • responded comparatively better to MPH²³⁷ -
  • 3.5% increase in resting heart rate due to OROS-MPH²³⁴
• A/A genotype
  • responded less well to MPH, by comparison²³⁷
  • 2.5% increase in resting heart rate due to OROS-MPH²³⁴

A meta-analysis found a correlation between the effects of MPH and SLC6A2 gene variants²³⁸

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

5.9. CES1 plasma protein levels and MPH dosing¶

Methylphenidate is metabolized by the CES1 liver enzyme.
A higher CES1 plasma concentration correlated with a lower D-methylphenidate plasma level. In one study, the CES1 plasma protein level accounted for approximately 50% of the variability in D-methylphenidate plasma levels. An individualized dosing strategy based on CES1 measurements could potentially make titrating the dose of D-methylphenidate considerably easier.²³⁹

5.10. Response varies from person to person depending on the degree of retardation and the carrier substance¶

People with ADHD report that their individual responses to various MPH medications vary greatly from person to person.
While it is now generally recognized that there are intraindividual (within a single person) and interindividual (compared to other people with ADHD) differences in tolerance to extended-release MPH formulations are now generally recognized, it is less well known that tolerance and response can also vary greatly within the same individual when it comes to different MPH formulations with immediate release. We have received reports from numerous people with ADHD who consistently perceive very distinct differences in the effects of various immediate-release MPH formulations of the same strength.²⁴⁰²⁴¹

5.11. Responding to Fractional Anisotropy of the White Matter¶

A study that classified children with ADHD into subgroups based on microstructural features of white matter found no differences in ADHD symptoms, but:²⁴²

• better MPH response when
  • reduced fractional anisotropy of the white matter
  • correlated with
    • reduced processing speed
• poorer MPH response in
  • higher fractional anisotropy of the white matter
  • correlated with
    • reduced response inhibition
    • reduced sustained attention

6. Additional Genetic Factors Affecting the Efficacy of MPH¶

In addition to CES1, several other genes influence the efficacy of MPH.

6.1. Genes Involved in Neurotransmitter Synthesis and Degradation Influence the Effects of MPH¶

• TH-Gen²⁴³
  • Rs2070762 C/C: Reduced responsiveness (CGI-I)
• DBH gene²⁴³
  • Rs1541332 TC haplotype: Increased risk of treatment failure (CGI-S)
  • Rs2073833 TC haplotype: Increased risk of treatment failure (CGI-S)
  • Rs2073833 C/C: Increased treatment failure (CGI-I)
• DBH gene²⁴³
  • Rs2007153 AGC haplotype: Reduced risk of adverse events
  • Rs2797853 AGC haplotype: Reduced risk of adverse events
  • Rs77905 AGC haplotype: Reduced risk of adverse events
• TPH2 gene²⁴⁴
  • Rs1386488 CGCAAGAC (“Yang” haplotype): Greater improvement in score with MPH (TOVA) than with AATGGAGA (“Yin” haplotype)
  • Rs2220330 CGCAAGAC (“Yang” haplotype): Greater improvement in score with MPH (TOVA) than with AATGGAGA (“Yin” haplotype)
  • Rs1386495 CGCAAGAC (“Yang” haplotype): Greater improvement in score with MPH (TOVA) than with AATGGAGA (“Yin” haplotype)
  • Rs1386494 CGCAAGAC (“Yang” haplotype): Greater improvement in score with MPH (TOVA) than with AATGGAGA (“Yin” haplotype)
  • Rs6582072 CGCAAGAC (“Yang” haplotype): Greater improvement in score with MPH (TOVA) than with AATGGAGA (“Yin” haplotype)
  • Rs1386492 CGCAAGAC (“Yang” haplotype): Greater improvement in score with MPH (TOVA) than with AATGGAGA (“Yin” haplotype)
  • Rs4760814 CGCAAGAC (“Yang” haplotype): Greater improvement in score with MPH (TOVA) than with AATGGAGA (“Yin” haplotype)
  • Rs1386497 CGCAAGAC (“Yang” haplotype): Greater improvement in score with MPH (TOVA) than with AATGGAGA (“Yin” haplotype)
• MAOA
  • 30-bp promoter VNTR 4-repeat allele vs. 3-repeat allele Improved response (opposite to SNAP-IV)²⁴⁵
  • 30-bp promoter VNTR 4- and 5-repeat alleles Improved scores on the impulsivity scale (TOVA)²⁴⁶
• COMT
  • Rs4680 G/G
    • Increased response rate (ADHD-RS, CGI-S)²⁴⁷, (K-ARS)²⁴⁸, (meta-analysis)²⁴⁹
    • Increased irritability²⁵⁰
  • Rs4680 G: Increased sadness²⁵¹

There is evidence that reduced expression of the CACNA1C gene may lead to a prolonged effect of dopamine reuptake inhibitors.²⁵² Conversely, increased expression is likely to result in a shorter duration of action.

6.2. Neurotransmitter reuptake transporter genes influence the effects of MPH¶

• SLC6A2 - Norepinephrine transporter gene

  • Rs28386840 A/A Reduced response (CGI-I)²⁵³
  • Rs28386840 A/A Reduced response (TOVA)²⁵⁴
  • Rs28386840 A/A Reduced responsiveness (ADHD-RS and CGI-I)²⁵⁵
  • Rs28386840 T Enhanced response (meta-analysis) ²⁴⁹
  • Rs28386840 T/T Elevated HR²⁵⁶
  • Rs5569 G Hyperactivity (ADHD-RS)²⁵⁷
  • Rs5569 G/G Increased responsiveness (ADHD-RS and CGI-S)²⁵⁸
  • Rs5569 G/G Enhanced Response (TOVA)²⁵⁴
  • Rs5569 G/G Increased response (meta-analysis)²⁴⁹

• SLC6A3 - Dopamine Transporter Gene

  • Rs28363170 Absence of 10R alleles:
    • Improved scores on the hyperactivity-impulsivity subscale (Vanderbilt ADHD Parent and Teacher Rating Scales)²⁵⁹
    • DAT 9/9: stronger response to MPH than 9/10 and 10/10²⁶⁰
    • 9R/9R: Reduced responsiveness (ADHD-RS)²⁶¹
    • 10R/10R: Improvements in working memory (N-Back test)²⁶²
    • 10R/10R: Reduced responsiveness (meta-analysis, naturalistic studies)²⁶³
    • 10R/10R: Reduced response (meta-analysis)²⁴⁹
  • Rs2550948 G: Enhanced response (CGI-S)²⁶⁴

• SLC6A4 - Serotonin Transporter Gene

  • 5HTTLPR L/L (i.e., DRD4 7R carriers) Less improvement in symptoms (CGAS)²⁶⁵
  • 5HTTLPR L Lower math scores (PERMP)²⁵⁰
  • 5HTTLPR L/L Decreasing vegetative symptoms (sleep problems and loss of appetite)²⁵⁰
  • 5HTTLPR L Increased nail-biting²⁶⁶
  • 5HTTLPR L Increased tics²⁶⁶
  • 17-bp VNTR Absence of the 12R allele Less improvement in symptoms (ADHD-RS)²⁵⁰
  • 17-bp VNTR 12R/12R Reduced response rate (CGI-I and ABC subscale for hyperactivity)²⁶⁷

6.3. Receptor genes influence the effects of MPH¶

• DRD1
  • Rs4867798 G Enhanced Responsiveness (CGI-I and ABC Hyperactivity Subscale)²⁶⁷
  • Rs5326 A Increased responsiveness (CGI-I and ABC Hyperactivity Subscale)²⁶⁷
• DRD2
  • Rs2283265 T (MPH dose as a covariate) Increased risk of an adverse effect²⁴³
  • A2/A2 more pronounced response to MPH than A1/A1 and A1/A2²⁶⁰
• DRD3
  • Rs6280 A/A Increased responsiveness (CGI-I and ABC hyperactivity subscales)²⁶⁷
  • Rs2134655 Carriers of G for both SNPs Increased treatment failure (CGI-I)²⁴³
  • Rs1800828 Carriers of G at both SNPs Increased treatment failure (CGI-I)²⁴³
• DRD4
  • 48-bp VNTR
    • 4R/4R:
      • Hyperresponsiveness (ADHD-RS)²⁶⁸
      • Increased Response Rate (Meta-Analysis)²⁴⁹
    • Absence of 4R alleles: Less improvement in hyperactivity-impulsivity scores (Vanderbilt ADHD Parent and Teacher Rating Scales)²⁵⁹
    • 7R:
      • Enhanced Response and Gene Transfer (TDT)²⁶⁹
      • (combined with the L/L genotype of SLC6A4 5HTTLPR): Reduced response (CGAS)²⁶⁵
      • Increased dose required for a response (Conners’ Global Index—Parent)²⁷⁰
  • 120-bp promoter duplication
    • L/L: Enhanced Response (Teacher CLAM-SKAMP)²⁷¹
    • S/S: Reduced responsiveness (CGAS and CGI-S)²⁶⁴
  • Rs11246226 A/A: Increased responsiveness (CGI-S and ABC subscale for hyperactivity)²⁶⁷
• ADRA2A - Alpha-2A Adrenoceptor - Gene
  • Rs1800544 G
    • Reduced Inattention (SNAP-IV)²³³²⁷²
    • Increased Response Rate (meta-analysis)²⁴⁹
  • Rs1800544 G/G Increased responsiveness (ADHD-RS parent)²⁷³
  • Rs1800544 C/C Elevated diastolic blood pressure²⁵⁶

6.4. Genes Involved in Neurotransmitter Release Influence the Effects of MPH¶

• SNAP25
  • Rs3746544 T/T
    • Improved Response (ADHD-RS)²⁷⁴
    • Reduced responsiveness (CGI-S)²⁶⁴
  • Rs3746544 G: Reduced irritability²⁷¹
  • Rs1051312 C²⁷¹
    • Reduced motor tics
    • Reduced buccal-lingual movements
    • Reduced Picking/Biting
• ACT 1
  • Intron 3 VNTR: H/H > H/L > L/L: Increased DA release²⁷⁵

6.5. Genes Involved in Neural Plasticity and Synaptic Effector Functions Influence the Effects of MPH¶

• ADGRL3 - Latrophilin 3 (LPHN3) - Gene
  • Rs6858066 AAG Haplotype: Reduced Response (CGI-I)²⁷⁶
  • Rs1947274 AAG Haplotype: Reduced Response (CGI-I)²⁷⁶
  • Rs6858066 AAG Haplotype: Reduced Response (CGI-I)²⁷⁶
  • Rs6551665 GCA Haplotype: Enhanced Response (CGI-I)²⁷⁶
  • Rs1947274 GCA Haplotype: Enhanced Response (CGI-I)²⁷⁶
  • Rs6858066 GCA Haplotype: Enhanced Response (CGI-I)²⁷⁶
  • Rs6551665 G: Reduced response (RAST)²⁷⁷
  • Rs1947274 C: Diminished response (RAST)²⁷⁷
  • Rs6858066 G:
    • Increased Responsiveness (RAST)²⁷⁷
    • Diminished Response (RAST)²⁷⁷
  • Rs6813183 CGC haplotype:
    • Increased responsiveness (SNAP-IV)²⁷⁸²⁷⁸
  • Rs1355368 CGC Haplotype: Enhanced Response (SNAP-IV)²⁷⁸
  • Rs1868790 A/A Reduced response (CGI-S)²⁶⁴
• BDNF - Brain-Derived Neurotrophic Factor - Gene (growth factor)
  • Rs6265 G/G Increased response (CGI-S)²⁷⁹
• NTF3 - Neurotrophin-3 - Gene
  • Rs6332 A/A
    • Increased Emotionality²⁸⁰
    • Increased Overfocusing/Euphoria²⁸⁰
    • Increased tendency to cry²⁸⁰
    • Increased nail-biting²⁸⁰
• GRM7 - Metabotropic glutamate receptor 7 gene
  • Rs3792452 G/A Hyperresponsiveness (ADHD-RS Parents, CGI-I)²⁸¹
• GRIN2B - Glutamate [NMDA] receptor subtype epsilon-2 (also known as N-methyl-D-aspartate receptor subtype 2B) - gene
  • Rs2284411 C/C Improved response (ADHD-RS inattentive, CGI-I)²⁸²

7. Therapeutic Reference Range, Pharmacokinetics¶

The therapeutic reference range (Cmax ranges for therapeutically effective doses) was specified as follows:

• Methylphenidate:²⁸³

  • Children and adolescents:
    • 6 to 26 ng/ml, 2 hours after taking 20 mg of the IR formulation or 4 to 6 hours after taking 40 mg of the XR formulation
  • Adults:
    • 12 to 79 ng/mL, 2 hours after taking 20 mg of the IR formulation, or 4 to 6 hours after taking of the 40 mg XR formulation
  • Half-life: 2 h
  • Laboratory test result warning threshold: 50 ng/ml
  • At a dose of 0.3 mg/kg, children and adults exhibited identical pharmacokinetic parameters (Wargin 1983a).

• Dexmethylphenidate:²⁸³

  • 13 to 23 ng/ml, 4 hours after taking 20 mg
  • Half-life: 2 h
  • Laboratory value warning threshold: 44 ng/ml

There is therefore no objectively verifiable neurobiological correlation between blood levels and efficacy.²⁸⁴ The therapeutic reference ranges provided are population-based statistical values that cannot be applied directly to all patients. To properly assess neuropsychopharmacotherapy, the individual therapeutic concentration range for each person with ADHD must therefore be identified. To this end, for example, the blood level can be measured after determining the appropriate dose for optimal individual improvement.²⁸³

The pharmacokinetics of methylphenidate are nonlinear. Based on the AUC, plasma exposure to D-MPH increased disproportionately with dose (in dogs).²⁸⁵ An increase in dose from 20 to 40 mg resulted in a 3-fold decrease in clearance and a 7-fold increase in AUC, despite a constant elimination half-life.²⁸⁶ 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 the doses), suggesting that the dose-dependent changes in AUC may not be due to a change in intestinal MPH absorption. This could be a consequence of saturation of presystemic elimination.
Nevertheless, people with ADHD report quite consistently that the duration of action of MPH medications remains constant across different doses.

Maximum plasma concentration, Cmax

• l-methylphenidate²⁸⁷
  • 40 mg orally (immediate release): 2.98 ng/ml
  • 40 mg oral sustained release: 1.85 ng/ml

Time of maximum plasma concentration, Tmax

• dl-methylphenidate²⁸⁸
  • 0.15 mg/kg, oral: 2.2 hours (± 0.4)
  • 0.3 mg/kg, oral: 2.1 hours (± 0.3)

Elimination half-life

• d-methylphenidate²⁸⁷
  • 10 mg intravenously: 5.96 hours (± 1.7)
  • 40 mg oral, immediate release: 5.69 hours (± 1.1)
  • 40 mg oral sustained release: 5.04 hours (± 0.7)
• l-methylphenidate²⁸⁷
  • 10 mg intravenously: 3.61 hours (± 1.1)
  • 40 mg oral, immediate release: 3.93 hours (± 0.8)
  • 40 mg oral sustained release: 3.88 hours (± 0.6)