MPH Part 1: Active ingredients, effect, responding

• 1. Active ingredient
  • 1.1. Methylphenidate as racemate
  • 1.2. Dexmethylphenidate (D-MPH)
  • 1.3. Levomethylphenidate (L-MPH)
  • 1.4. Serdex methylphenidate (SDX)
• 2. Mode of action of methylphenidate
  • 2.1. Effect on neurotransmitters
    • 2.1.1. MPH and dopamine
      • 2.1.1.1. MPH increases extracellular and possibly decreases phasic dopamine
        • 2.1.1.1.1. MPH increases extracellular dopamine
        • 2.1.1.1.2. MPH can reduce phasic dopamine
        • 2.1.1.1.3. Stimulants alter dopaminergic firing rate
      • 2.1.1.2. MPH binds to DAT (reuptake inhibition)
      • 2.1.1.3. MPH increases dopamine release through DAT (efflux)
      • 2.1.1.4. MPH acts on DA via D2 autoreceptors, MPH normalizes TH
      • 2.1.1.5. MPH increases DA via VMAT2
      • 2.1.1.6. MPH increases tyrosine hydroxylase
      • 2.1.1.7. MPH acts via L-DOPA receptors
      • 2.1.1.8. Dose-dependent effect of MPH
      • 2.1.1.9. Duration-dependent effect of MPH
    • 2.1.2. MPH increases noradrenaline
      • 2.1.2.1. MPH low dose increased extracellular noradrenaline, but not dopamine
      • 2.1.2.2. MPH binds to NET (reuptake inhibition)
      • 2.1.2.3. MPH causes noradrenaline efflux in the PFC
      • 2.1.2.4. MPH increases NE via VMAT2
      • 2.1.2.5. MPH binds to noradrenaline receptors
      • 2.1.2.5.1. Alpha-1 receptor
      • 2.1.2.5.2. Alpha-2 receptor
    • 2.1.3. MPH and serotonin
    • 2.1.3.1. 5HT-1A serotonin receptor
      • 2.1.3.1. MPH and tryptophan hydroxylase
      • 2.1.3.2. Effect of MPH on tryptophan metabolites
      • 2.1.3.3. Effect of MPH on dorsal raphe nuclei
    • 2.1.4. Binding affinity of MPH, AMP, ATX to DAT / NET / SERT
    • 2.1.5. Effect of MPH, AMP, ATX on dopamine / noradrenaline per brain region
    • 2.1.6. Effect of MPH on MAO-A
  • 2.2. Effect of MPH on cholesterol metabolism in the OFC
  • 2.3. Effect of MPH on the HPA axis
  • 2.4. Effect of MPH on the autonomic nervous system (sympathetic / parasympathetic nervous system)
  • 2.5. Effect of MPH on androgens
  • 2.6. Effect of MPH on kynurenine
  • 2.7. Effect of MPH on ARAS
  • 2.8. Effect of MPH on oxidative/nitrosative status
  • 2.9. Effect of MPH on S100B
  • 2.10. Effect of MPH on brain networks
    • 2.10.1. MPH and connectivity between brain regions
    • 2.10.2. Effect of MPH on Default Mode Network (DMN)
    • 2.10.3. Effect of MPH on nucleus accumbens and cognitive control networks
  • 2.11. Effect of MPH on EEG
  • 2.12. Effects on brain regions
  • 2.13. MPH for preschool children
  • 2.14. MPH normalizes pain sensation in ADHD
  • 2.15. Serdexmethylphenidate improved sleep in ADHD
  • 2.16. More about MPH
• 3. Differences in effect between methylphenidate and amphetamine medication
• 4. Effect on symptoms
  • 4.1. Particularly good effect of methylphenidate
  • 4.2. Good effect of methylphenidate
  • 4.3. Low effect of methylphenidate
  • 4.4. No effect of methylphendiate
  • 4.5. Different time-dependent effects of stimulants on symptoms?
  • 4.6. MPH and smoking cessation
  • 4.7. MPH and creativity
• 5. Responding (responding / non-responding)
  • 5.1. Subtypes and non-response probability
  • 5.2. (Non-)responding and EEG subtypes
  • 5.3. (Non-)responding and dosing of MPH
  • 5.4. Seasonal influence on MPH dosage?
  • 5.5. Indications of good MPH responding
  • 5.6. Gene variants and MPH effect
    • 5.6.1. ADRA2A gene variants
    • 5.6.2. NET gene variants
  • 5.7. CES1 plasma protein level and MPH dosage
  • 5.8. Response individually dependent on retardation and carrier substance
  • 5.9. Therapeutic reference range, pharmacokinetics

1. Active ingredient¶

Methylphenidate (MPH):¹

• 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 drug²
  • (+)-Erythromethylphenidate
  • (-)-Erythromethylphenidate
  • (+)-threomethylphenidate
  • (-)-threomethylphenidate.

Other names:³

• 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
• MPH
• α-phenyl-2-piperidineacetic acid methyl ester

MPH 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), MPH 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 MPH as a drug merely referred to sources in which methylphenidate is not even mentioned⁴

1.1. Methylphenidate as racemate¶

Methylphenidate is usually offered clinically 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.²
While a significant proportion of D-MPH enters the CNS via the blood-brain barrier, L-MPH is not absorbed into the CNS.¹⁵

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).¹⁶

1.2. Dexmethylphenidate (D-MPH)¶

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 racemic (mixture of dextrorotatory (D-MPH) and levorotatory (L-MPH) methylphenidate.¹⁷ The higher efficacy of D-MPH compared to L-MPH concerns the dopamine transporter as well as the noradrenaline transporter binding.
It is therefore recommended to halve the dosage of D-MPH compared to racemate methylphenidate and to limit it to a maximum of 20 mg/day in children and adults.
D-MPH is also available as a prolonged-release preparation (Focalin XR).

1.3. Levomethylphenidate (L-MPH)¶

L-MPH is the pure form of the levorotatory isomers and is pharmacologically almost ineffective.
L-MPH is predominantly metabolized in the intestinal mucosa. The remaining L-MPH is metabolized by the liver during the first pass. L-MPH is almost completely metabolized within 10 minutes of ingestion¹⁸
The small, unmetabolized residue of L-MPH competes with the dextrorotatory and pharmacologically active isomer D-MPH for the binding sites in the brain and reduces its effectiveness.¹⁸
According to another source, the left-turning MPH isomer L-MPH (unlike D-MPH) is not absorbed into the CNS.¹⁹

1.4. Serdex methylphenidate (SDX)¶

Serdexmethylphenidate (SDX) is a prodrug of dexmethylphenidate (d-MPH) and is currently only approved in the USA (Azstarys®, KP415 with 70 % SDX and 30 % MPH).²⁰

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 ADHD drugs. A computer model for the simulation of type 1 diabetes has already been approved by the FDA as a replacement for preclinical animal studies²¹
A model comparing MPH and AMP in children and adults with ADHD takes into account the effect on 99 proteins involved in ADHD²²

2.1. Effect on neurotransmitters¶

MPH changes the neurotransmitter levels in the brain.

2.1.1. MPH and dopamine¶

2.1.1.1. MPH increases extracellular and possibly decreases phasic dopamine¶

Many sources only report a general effect on dopamine and noradrenaline.
The blanket statement that MPH increases dopamine is ultimately not helpful, as a distinction must be made between tonic and phasic 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 PFC²³²⁴²⁵
• MPH doses whose plasma levels are in the range of therapeutic use for ADHD, such as²⁶²⁷
  • 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, MPH increases
  • Dopamine in the PFC, striatum and nucleus accumbens and²⁸
    • High doses: DA increased by release from noradrenergic cells²⁹
    • Low dosage: DA not increased²⁹
    • Chronic administration of 1 mg/kg increased extracellular dopamine and noradrenaline in the PFC³⁰
  • Noradrenaline in the PFC, but not in the striatum or nucleus accumbens.²⁸
  • Dopamine and noradrenaline in the PFC, but barely in other brain areas³¹
• In healthy monkeys, MPH:³²
  • Striatum: low and high doses: consistent increase in dopamine
  • PFC: increase in dopamine only at high doses
    In rats, 1 mg/kg MPH as a single dose as chronic (21 days) caused
  • Striatum: no change in extracellular levels of noradrenaline, dopamine or serotonin³⁰

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

Tonic dopamine mediates the regulatory (inhibitory) control of the PFC on the ventral striatum, thus inhibiting the (phasic) activity of the striatum. In response to unexpected positive reward stimuli, the striatum fires phasically in a dopaminergic manner and activates dopaminergic postsynaptic receptors. Tonic control is therefore inhibitory and modulates excitatory phasic firing in response to unexpectedly positive reward stimuli.³³

Stimulants³⁴

• increases the tonic rate of fire
• shortens the frequency of postsynaptic multisecond oscillations in the basal ganglia from around 30 seconds to 5 to 10 seconds. Already 1.0 mg/kg MPH or 0.2 mg/kg D-Amp showed an effect.
• however, 0.2 mg/kg 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 that ADHD is characterized by decreased tonic and increased phasic dopamine. This model is likely to apply to at least most cases of ADHD. More on this under Dopamine release (tonic, phasic) and coding

2.1.1.1.1. MPH increases extracellular dopamine¶

MPH increases extracellular dopamine^{3536 37} , especially in the striatum³⁸²⁹ .

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

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

• an inhibition of dopamine reuptake³⁵
• increased dopamine efflux due to reversal of the dopamine reuptake transporter in the striatum²⁹

MPH increased response strength and reward expectancy-related BOLD signaling in the ventral striatum during a gambling task,³⁷ suggesting that striatal tonic dopamine levels represent an average reward expectancy signal that modulates the phasic dopaminergic response to reward.

2.1.1.1.2. MPH can reduce phasic dopamine¶

Several studies found a reduction in phasic dopamine by MPH,^{3539 37} but some also found no change³⁶²⁹ or an increase. This could depend on the circumstances (e.g. dosage, DAT sensitivity).

The significant reduction in the phasic (synaptic) release of dopamine is probably due to a decrease in synapsin phosphorylation³⁵
Inhibition of phasic dopamine is not a consequence of presynaptic D2 autoreceptor activation, as these³⁵
- a. also in the presence of the D2 antagonist sulpiride and
- b. also occurs in DAT-CI striatal slices in which activation of D2 autoreceptors cannot occur due to an increased extracellular DA level
The inhibition of phasic dopamine could possibly be due to a reduction in synaptic vesicle neurotransmitter, as with cocaine.³⁵ 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 MPH did not alter phasic dopamine, suggesting an inhibitory feedback mechanism via D2 autoreceptors, because a D2 antagonist given in parallel with MPH caused MPH to also increase phasic dopamine³⁶

Dopamine reuptake inhibitors such as MPH should generally lead to increased phasic dopamine in the dorsolateral striatum³⁹
Acute MPH administration increased the firing activity of PFC pyramidal neurons in rats and potentiated NMDA-induced neurotransmission²⁹

The DAT blocker nomifensine enhanced phasic dopaminergic signaling³⁵, so dopamine reuptake inhibition per se cannot be the reason for the reduction in phasic dopamine by MPH.

2.1.1.1.3. Stimulants alter dopaminergic firing rate¶

Stimulants³⁴

• 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 the dopamine level in the synaptic cleft.²³ MPH inhibits the dopamine transporter and the noradrenaline transporter⁴⁰ 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 (which correlates with the low DAT count in the PFC and the high DAT count in the striatum). Since, according to the mesocortical model of ADHD, dopamine activity in the ventral striatum is excessive, MPH, if it has an increasing effect there, should worsen rather than improve symptoms. At low doses, stimulants such as MPH can inhibit phasic dopamine release by enhancing inhibitory tonic control.⁴¹ However, in an fMRI study, children with ADHD without medication showed increased frontal and decreased striatal activation, arguing against the mesocortical deficiency theory. MPH increased frontal blood flow in children with and without ADHD, but only increased striatal blood flow in children with ADHD. It is therefore an open question 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 show some degree of frontal dysfunction, it is unclear whether the etiological deficits in ADHD have other causes.³³

• MPH binds to the dopamine transporters whose density is highest in the striatum. The binding of MPH in the cerebellum and hippocampus is less than a tenth of this.⁴²
• MPH does not bind to dopamine receptors, but only to DAT and NET.⁴³⁴⁴ (In contrast: MPH is said to activate postsynaptic D1 receptors.²³ )
  • D-MPH binds most strongly, namely to
    • DAT with IC50 = 23 nM, Ki = 161 nM;
    • NET with IC50 = 39 nM, Ki = 206 nM
  • D/l-MPH racemate binds somewhat weaker, namely to⁴³
    • DAT with IC50 = 20 nM, Ki = 121 nM
    • NET with IC15 = 51 nM, Ki = 788 nM
  • L-MPH binds the weakest, namely to⁴³
    • DAT with IC50 = 1600 nM, Ki = 2250 nM
    • NET with IC50 > 104 nM, Ki > 104 nM
• MPH drug doses cause an MPH plasma concentration of around 20 to 30 nM, which is sufficient to occupy a significant proportion of the dopamine transporters. This effect coincides with that of D-AMP.⁴¹
• MPH responders showed an increased DAT count in the striatum, non-responders a reduced DAT count.⁴⁵
• MPH increased the number of dopamine transporters.⁴⁶
• Different:
  • Lower increase in dopamine and noradrenaline in the striatum²³
  • No increase in dopamine in the striatum by MPH in DAT(-/-) mice, but in DAT(+/-) and DAT(+/+) mice⁴⁷ Apparently, the degree of expression/sensitivity of the DAT is decisive for the positive or negative modulation of phasic dopamine release.⁴⁸

2.1.1.3. MPH increases dopamine release through DAT (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 DAT
• dopamine release from vesicles at very high doses.

The view that MPH is a pure DA reuptake inhibitor⁴⁹⁵⁰ is outdated.

• Also release of dopamine from vesicles (here: reserpine-sensitive granules)⁵¹⁵²
  • Should only occur at very high doses of more than 80 mg / day⁵³⁵⁴
• In contrast to 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.⁵⁵
• Dopamine efflux through DAT reversal in the PFC
  • In the striatum in rats at 4 mg/kg (measured ex vivo)²⁹
  • MPH thereby increases the extracellular dopamine level
  • Efflux from dopamine and noradrenaline terminals
  • By vesicular dopamine release and by sodium-dependent mechanisms
• Increase the firing rate of PFC pyramidal neurons
  • At chronic intake in PFC in rats at 4 mg/kg (measured in vivo)²⁹
  • measured by extracellular electrophysiological single-cell recordings
  • Reactions to locally applied NMDA unchanged
• Desensitization to both dopamine and MPH in striatal regions
  • With chronic ingestion in the striatum in rats at 4 mg/kg (measured in vivo)²⁹
  • reduced efficacy of extracellular dopamine in modulating NMDA-induced firing activities of medial spinous process neurons in the striatum
  • lower MPH-induced dopamine outflow
  • is consistent with the empirical experience that a one-time adjustment of the MPH dose is required after a few weeks in the case of single dosing

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

MPH causes the disinhibition (removal of inhibition) of presynaptic D2 autoreceptors.⁵⁶
Nevertheless, the effect of stimulants in different doses on D2 autoreceptors is not greater than on postsynaptic heteroreceptors. Stimulants appear to have little effect on the dopamine system via autoreceptors.³⁴
In people with a high number of D2 receptors, MPH increases metabolism in frontal and temporal brain areas (including the striatum), while in healthy people with a low number of D2 receptors, MPH decreases metabolism. Metabolism was consistently increased in the cerebellum.⁵⁷
This corresponds to a normalization of the D2 receptor binding.⁵⁸
Similar findings are reported with regard to tyrosine hydroxylase. While TH expression is decreased 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 model animals.⁵⁹⁶⁰

Methylphenidate normalizes increased dopamine transporter densities in ADHD-HI rats to a greater extent than in ADHD-I rats⁶¹

2.1.1.5. MPH increases DA 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 noradrenaline and is therefore an important regulator of neurotransmission. MPH does not affect the total amount of VMAT-2 in presynaptic terminals, but only VMAT-2 transport.⁶²⁶³
MPH has the following effects in monoaminergic neurons (but not in cholinergic, GABA-ergic or glutamatergic neurons)⁴³

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

MPH thus protects the dopaminergic system from progressive “wear and tear” by securing a considerable DA reserve pool in the presynaptic vesicles. Therefore, there is only a relatively low risk of neurotoxic / neuropsychiatric side effects in treatment practice with MPH⁴³

According to older reports, MPH has no effect on vesicular monoamine transporters (VMAT).⁴⁰

2.1.1.6. MPH increases tyrosine hydroxylase¶

Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the synthesis of dopamine. TH converts tyrosine into the DA precursor L-3,4-dihyroxyphenylalanine (L-DOPA). MPH thus supports dopamine synthesis.
MPH (as well as sports) can induce the expression of TH⁶⁴ and increase TH levels⁶⁵
d-MPH from 100 nmol/l significantly increased tyrosine hydroxylase activity in vitro; L-MPH or racemic MPH at the same concentration did not increase TH⁶⁶
It is unclear whether the increase occurs only peripherally or also in the brain.⁶⁷ TH gene variants appear to influence the response of MPH.⁶⁷

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), L-DOPA release is reduced:⁶⁸

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

2.1.1.8. Dose-dependent effect of MPH¶

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

• At low doses, methylphenidate increases dopamine and noradrenaline levels in the PFC, which increases its performance. In contrast, low-dose MPH has barely any effect on dopamine and noradrenaline levels in other areas of the brain.⁶⁹ This is consistent with the known increase in cognitive performance of the PFC due to small increases in dopamine and noradrenaline levels during mild stress.
• At 3 mg/kg MPH, one study found no increase in dopamine or noradrenaline in the striatum of rats⁷⁰

• At higher doses of MPH (as well as cocaine), a reduction in dopamine levels in the striatum was reported in a laboratory study in rats. Only lower doses of MPH or cocaine caused increases in dopamine levels. Moreover, this was not the case in all animals.⁴⁸
• At higher doses, MPH is also said to have a dopamine and noradrenaline-releasing effect via DAT and NET efflux⁷¹
• At high doses, MPH is said to enhance the surface expression of DAT⁷²

2.1.1.9. Duration-dependent effect of MPH¶

Acute MPH administration increased the firing activity of PFC 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 MPH administration on pyramidal neurons of the PFC²⁹

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

Long-term administration of MPH or atomoxetine to juvenile Naples High-Excitability (NHE) rats in adulthood⁷³

• Dopamine in the PFC and striatum reduced
• Noradrenaline increased in the ventral striatum

• In juvenile rats⁶²⁶³
  • A single administration of high-dose MPH (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 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)
  • Continuous 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 (measured with the metabolite DOPAC)⁶²
    • Left the protein levels of tyrosine hydroxylase (TH) and the dopamine D1 receptor unchanged⁶² - unlike the same authors⁶³
    • Increased the number of DAT⁶³
      • In the left dorsal striatum
    • Did not change the DAT
      • In the right dorsal striatum
      • In the nucleus accumbens (ventral striatum)⁶²
    • Increased the expression of the
      • Noradrenaline transporter (NET)
      • Monoamine transporter 2 (VMAT2)⁶²⁶³
        • In contrast, amphetamine reduces VMAT2⁷⁴
      • Tyrosine hydroxylase
      • Dopamine D1 receptors
      • Stronger in the nucleus accumbens (ventral striatum) than in the dorsal striatum
      • Stronger in the parietal cortex than in the frontal cortex
      • This effect of chronic MPH on increasing DAT, NET and VMAT2 transporters may suggest that the drug could lose some of its acute effect of increasing dopamine and noradrenaline levels in the long term.⁶³⁴⁶
        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 studies⁷⁵ nor in practice.
      • Elevated vanillin mandelic acid in the urine of Wistar rats. This could be avoided by augmentative administration of buspirone.⁷⁶
        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 MPH (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
      • Metabolites associated with energy consumption and excitatory neurotransmission, here glutamate, glutamine, N-acetylapartate and inosine, tended to be reduced in the cerebellum
      • Furthermore, the levels of some metabolites associated with inhibitory neurotransmission, in this case GABA and glycine, acetate, aspartate and hypoxanthine, were reduced
• One study found that basal oxytocin levels in children with ADHD were unchanged compared to unaffected children. While oxytocin decreased in untreated people with ADHD after interaction with a parent, oxytocin increased in people with ADHD treated with MPH as well as in unaffected people.⁷⁷

2.1.2. MPH increases noradrenaline¶

• MPH has a noradrenergic effect in the locus coeruleus, which improves arousal, vigilance and attention²³
• The effect of MPH is dose-dependent. Normal doses of MPH have different effects than high or very high doses of MPH.
• At low doses, methylphenidate increases dopamine and noradrenaline levels in the PFC, which increases its performance. In contrast, low-dose MPH has barely any effect on dopamine and noradrenaline levels in other areas of the brain.⁶⁹ This corresponds to the known increase in cognitive performance of the PFC due to small increases in dopamine and noradrenaline levels during mild stress.

2.1.2.1. MPH low dose increased extracellular noradrenaline, but not dopamine¶

Adolescent rats received 0.75-3.0 mg/kg MPH orally during the dark-active phase of the circadian cycle, which remained below the threshold for locomotor activation. These doses:²⁷

• 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 MPH (far above a medicinal dosage):⁷⁸

• stereotypic behavior (a sign of strongly increased extracellular dopamine); 20 mg/kg as strong as 2.5 mg/kg AMP
• extracellular dopamine increased
• extracellular noradrenaline increased
• extracellular serotonin unchanged (unlike AMP, as it is elevated)

2.1.2.2. MPH binds to NET (reuptake inhibition)¶

• Noradrenaline reuptake inhibitors²³²⁹
• This also increases extracellular dopamine in the PFC, where there is little DAT but plenty of NET

2.1.2.3. MPH causes noradrenaline efflux in the PFC¶

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

• Noradrenaline efflux (67-83 nM) from noradrenaline terminals²⁹
  • 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 noradrenaline and is therefore an important regulator of neurotransmission.
MPH does not affect the total amount of VMAT-2 in presynaptic terminals, but only the VMAT-2 transport.
MPH has an effect in monoaminergic neurons (but not in cholinergic, GABA-ergic or glutamatergic neurons⁴³

• 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. MPH binds to noradrenaline receptors¶

2.1.2.5.1. Alpha-1 receptor¶

MPH also improves attention via the alpha-1 receptor.⁷⁹

2.1.2.5.2. Alpha-2 receptor¶

MPH binds directly to noradrenergic alpha-2 receptors.⁸⁰ MPH binds to⁴³

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

The cognitive improvement brought about by MPH could be prevented by α2-adrenoceptor antagonists.⁸¹ Guanfacine and clonidine also have a positive effect as α2-adrenoceptor agonists in ADHD.

• Blockade of the alpha-2-adrenoceptor²³
  • In contrast, several sources report an agonistic effect of MPH on the alpha-2-adrenoceptor.⁸⁰⁸¹ See above.

2.1.3. MPH and serotonin¶

The influence of MPH on serotonin levels appears to be negligible overall⁸²
MPH is said to bind 2200 times more strongly to the DAT than to the SERT and almost 1300 times more strongly to the NET than to the SERT.⁴³

Controversial is:

• Whether a reuptake inhibition of serotonin occurs at the synapse. There are sources for this⁸³ as well as against it.⁸⁴
  • The serotonergic effect of MPH is so weak that it is not relevant for the treatment
  • Our impression is that MPH has no significant mood-enhancing effect. MPH 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,⁸⁵ but the extent is small.

Whether MPH binds to serotonin receptors is unclear. Various studies have produced contradictory results.⁴³

2.1.3.1. MPH 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.⁶⁷
The AATGGAGA (Yin) haplotype of TPH2 appears to be less responsive to MPH than the CGCAAGAC (Yang) haplotype.⁶⁷

2.1.3.2. Effect of MPH on tryptophan metabolites¶

In persons with ADHD-HI (predominantly hyperactive) with comorbid depressive symptoms, one study found significantly higher morning than evening levels of indoleacetic acid compared to ADHD-I sufferers and healthy controls. MPH reduced this by 50 %. MPH also reduced the morning levels of indolepropionic acid and brought the daily profile back to the levels of healthy controls.⁸⁶

2.1.3.3. Effect of MPH on dorsal raphe nuclei¶

Several days of MPH administration triggered

• behavioral sensitization in some rats (which correlated with neuronal arousal) and
• behavioral tolerance (which was associated with neuronal attenuation) in other rats.
  Neurons in the dorsal raphe nuclei (serotonergic) responded most strongly to acute and chronic MPH administration and differently from neurons in VTA (dopaminergic) or locus coeruleus (noradrenergic) at all 3 doses used.⁸⁷
  Dorsal raphe nuclei and serotonin appear to be involved in the acute and chronic effects of MPH and play an independent role in the response to MPH.

2.1.4. Binding affinity of MPH, AMP, ATX to DAT / NET / SERT¶

The active ingredients methylphenidate (MPH), d-amphetamine (d-AMP), l-amphetamine (l-AMP) and atomoxetine (ATX) bind with different affinities to dopamine transporters (DAT), noradrenaline transporters (NET) and serotonin transporters (SERT). The binding causes an inhibition of the activity of the respective transporters.⁸⁸

Binding affinity: stronger with smaller number (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. Effect of MPH, AMP, ATX on dopamine / noradrenaline per brain region¶

The active ingredients methylphenidate (MPH), amphetamine (AMP) and atomoxetine (ATX) alter extracellular dopamine (DA) and noradrenaline (NE) to different degrees in different regions of the brain. Table based on Madras,⁸⁸ modified.

	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 influences monoamine oxidase A (MAO-A) by⁸⁹

• Stimulation of non-vesicular release
• Inhibition of MAO-A activity⁵²⁹⁰

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

2.2. Effect of MPH on cholesterol metabolism in the OFC¶

One study found 12 altered metabolic metabolites in the PFC in SHR rats, considered an ADHD-HI model, compared to WKY rats, considered a model of non-affected individuals. The deviations of 8 of these were equalized by MPH:⁹¹

• 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 SHR, the PFC found that

• Reduced activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase
  • Unchanged by MPH
• Reduced expression of the 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 drugs) are said to increase the activity of the HPA axis.⁹²
MPH increases the cortisol awakening response, which is a sign of reactivity of the HPA axis.⁹³

MPH increased physiological measures of stress (salivary cortisol and blood pressure). MPH modulated the effects of stress on the activation of brain areas associated with goal-directed behavior, including the insula, putamen, amygdala, mPFC, frontal pole, and OFC. However, MPH did not modulate the tendency of stress to cause a reduction in goal-directed behavior.⁹⁴

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

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 without, however, being able to raise it to the level of non-affected people.⁹⁵⁹⁶

The statement made elsewhere,⁹⁷, that methylphenidate does not change the HVR is not found in the source cited.⁹⁸

2.5. Effect of MPH on androgens¶

Stimulants (methylphenidate and amphetamine drugs) reduce the concentration of androgens.
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 amount of alpha estrogen receptors and vascular endothelial growth factor (VEGF). This can interfere with memory processes. There is a correlation between ADHD 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 ADHD.⁹²

2.6. Effect of MPH on kynurenine¶

MPH appears to improve the homeostatic ratio of various kynurenines (e.g., increased kynurenic acid vs. decreased quinolinic acid in plasma) in children with ADHD.⁹⁹

2.7. Effect of MPH on ARAS¶

Methylphenidate increases the excitation of the reticular activation system (ARAS).¹⁰⁰

2.8. Effect of MPH on oxidative/nitrosative status¶

MPH 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).⁹³

2.9. Effect of MPH on S100B¶

One study found that triple therapy (TT) with methylphenidate (MPH), melatonin (aMT) and omega-3 fatty acids (ω-3 PUFAs) increased S100B in people with ADHD. The authors see this as an indication that a neuroinflammatory cause of ADHD may damage glial function and thereby alter dopaminergic (DA) neurotransmission.¹⁰¹

2.10. Effect of MPH on brain networks¶

2.10.1. MPH and connectivity between brain regions¶

In one study, methylphenidate normalized reduced global connectivity in ADHD 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 frontal and parietal regions and were more significant and lasting than in the non-treated comparison subjects. The results of the study indicate that methylphenidate corrects impaired network flexibility in ADHD.¹⁰²

Another study reports interhemispheric connectivity changes in ADHD:¹⁰³

• 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 areas

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

The increased purely intrinsically motivated attentional control in ADHD 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 intrinsic interest is lower. This is controlled by the DMN.
Stimulants are able to align the attentional control of persons with ADHD with that of non-affected persons in the absence of intrinsic interest.¹⁰⁴ This explains why stimulants are just as helpful in ADHD-HI and ADHD-C as in ADHD-I.

More on the deviant function of the DMN in ADHD 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 MPH on 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.¹⁰⁵

2.11. Effect of MPH on EEG¶

MPH caused¹⁰⁶

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

2.12. Effects on brain regions¶

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

• Apparently reduces the reduction in gray matter typical of ADHD
  • In the basal ganglia (mainly in children, problem probably decreasing per se in adults)
    • In the right lentiform nucleus¹⁰⁷
      • In the right globus pallidus¹⁰⁸
      • In the putamen¹⁰⁸
    • In the caudate nucleus¹⁰⁷
  • In the anterior cingulate cortex (ACC) in adults¹⁰⁷
• MPH mediates its acute and chronic effects on behavior via the dopaminergic system of the caudate nucleus.¹⁰⁹
• In hypermotor and inattentive people with ADHD, regular administration of methylphenidate increases the previously unusually low blood flow to the putamen. In children with ADHD with average motor activity, regular administration of methylphenidate reduced blood flow to the putamen. The thalamus was not affected by MPH.¹¹⁰
  MPH increased activation in the bilateral inferior frontal cortex/insula during inhibition of temporal discrimination.¹¹¹
• Methylphenidate increases the metabolism in the brain on the left frontal posterior and left parietal superior and decreases it on the left parietal, left parietooccipital and frontal anterior medial.¹¹²

MPH appears to reduce dysfunction in the PFC in most people with ADHD.¹¹³ Another meta-analysis found that MPH had no effect on working memory (in the dlPFC).¹¹¹

A study in rats with 0, 0.6, 2.5 and 10.0 mg MPH/kg as single and repeated doses found that MPH acted on the PFC and caudate nucleus. The same dose of MPH induced behavioural sensitization in some animals and tolerance in others, with activity in the PFC and caudate nucleus correlating with the animals’ behavioural responses to MPH. The reaction of the caudate nucleus was more intense than that in the PFC, with both single and repeated administration. In addition, different dose-dependent responses were found between PFC and caudate nucleus: some PFC and caudate nucleus cell units responded to the same MPH dose with excitation and others with attenuation of the neuronal firing rate.¹¹⁴

2.13. MPH for preschool children¶

Some studies show a positive effect of MPH in preschool children with ADHD.¹¹⁵

2.14. MPH normalizes pain sensation in ADHD¶

People with ADHD often show an increased sensitivity to pain. MPH can eliminate this sensitivity to pain in people with ADHD.¹¹⁶

2.15. Serdexmethylphenidate improved sleep in ADHD¶

One study reports a significant improvement in sleep in children with ADHD between the ages of 6 and 12 with serdexmethylphenidate or dexmethylphenidate.¹¹⁷

2.16. More about MPH¶

Methylphenidate and amphetamine drugs increase the power of alpha (in rats), while atomoxetine and guanfacine do not.¹¹⁸

MPH 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.

It is occasionally postulated that very early treatment with stimulants could permanently improve DAT overactivity (i.e. beyond the intake).¹²⁰

A very small fMRI study of 16 subjects on the effect of methylphenidate on boys with ADHD and unaffected boys found increased activation of the frontal cortex and decreased activation of the striatum in the people with ADHD before taking methylphenidate compared to the unaffected in go/no-go tasks. Methylphenidate compensated for the differences.¹³³

It remains to be seen what concentrations of methylphenidate reach the synaptic cleft.³⁵
Methylphenidate could accumulate in the central nervous system through active accumulation processes, so that the effective brain concentrations are considerably higher than in plasma.¹³⁴ For cocaine, the striatal concentration in animals appears to be about 6 times higher than in plasma.¹³⁵

Whether MPH influences prolactin is unclear.
It did not affect prolactin serum levels in men.¹³⁶ Nor did it affect those not affected.¹³⁷
Neither amphetamine nor methylphenidate decreased serum prolactin in rats. Amphetamine, but not methylphenidate, blocked the increase in serum prolactin in response to reserpine.¹³⁸
In children, MPH increases prolactin.¹³⁹

3. Differences in effect between methylphenidate and amphetamine medication¶

Methylphenidate may increase left frontal posterior and left parietal superior brain metabolism and decrease left parietal, left parietooccipital and frontal anterior medial metabolism.¹⁴⁰

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 anterior inferior frontal regions.¹⁴¹

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 ADHD:¹⁴²

• Response time
• Response time variability
• tonic attention
• phasic attention
• divided attention
• Flexibility/shifting attention/task switching
• selective attention
  • Escapement
  • focused attention
• Task accuracy in relation to
  • Vigilance
  • 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 MPH on neuropathic pain.¹⁴³

4.1. Particularly good effect of methylphenidate¶

• Hyperactivity ¹⁰⁰
• Restlessness¹⁰⁰
• Impulsiveness¹⁰⁰
  • People with ADHD reported in forums that MPH works better against impulsivity than Vyvanse.¹⁴⁴
  • A study on monkeys (naturally not people with ADHD) came to the conclusion that low doses of MPH reduced impulsivity, while higher doses had a sedative effect.¹⁴⁵
    This follows on from empirical experience that an overdose of MPH can have an apathetic effect.
• Aggressiveness¹⁰⁰¹⁴⁶
  • And better than atomoxetine¹⁴⁷
  • In a study of 6- to 12-year-old children with aggression and ADHD, systematically titrated stimulants eliminated aggression in 63%.¹⁴⁸ 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 behavior¹⁰⁰
• Behavioral problems, and better than atomoxetine¹⁴⁷
• Somatic complaints, and better than atomoxetine¹⁴⁷
• Motivate through reward¹⁴⁹
• Drive
  • People with ADHD report quite consistently that MPH improves drive more than AMP

• Number of errors of omission and commission in attention tasks¹⁵⁰
• Gedankenwandern / Mind Wandering¹⁵¹

MPH is effective in adults:¹⁵²

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

MPH is said to work best on the cognitive ADHD symptoms. Motor and social behavior may gradually require slightly higher doses.⁵⁹

4.2. Good effect of methylphenidate¶

• Perception¹⁵³

• Concentration¹⁰⁰

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

• Attention¹⁰⁰

  • Distractibility is reduced, attention is increased
  • Task changes are reduced¹⁵⁴

• Motor restlessness¹⁰⁰

• Typeface and graphic expression ¹⁵⁵

• Social perceptiveness and mimic responsiveness

• Social interaction

  • One study found that basal oxytocin levels in children with ADHD 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 ADHD. Methylphenidate caused the oxytocin increase in persons with ADHD after parent interaction to correspond to that of non-affected people.¹⁵⁶

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

• Mathematical skills

  • Children with ADHD under MPH showed significantly improved math skills that were indistinguishable from those of unaffected children.¹⁵⁷

• Anxiety¹⁴⁶

• Tension¹⁴⁶

• Borderline aspects¹⁴⁶

• Depressiveness¹⁴⁶

• Emotional instability¹⁴⁶

• Dissatisfaction with life¹⁴⁶

• Negative attitude to life¹⁴⁶

• Psychotic phenomena¹⁴⁶

• Social introversion¹⁴⁶

• Uncertainty¹⁴⁶

• Compulsiveness¹⁴⁶

• Inner emptiness/boredom¹⁵⁸

4.3. Low effect of methylphenidate¶

• Delay aversion (for adults)¹⁵⁹
• Executive functions (in adults)¹⁵⁹

4.4. No effect of methylphendiate¶

• Reading the Mind in the Eye (for children). This test measures the theory of mind.¹⁶⁰
• Fine motor skills (handwriting)¹⁶¹

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.¹⁶² 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. MPH and smoking cessation¶

Sustained release MPH was reported to make a positive contribution to nicotine abstinence/smoking cessation, but only in more severe ADHD cases, whereas in milder ADHD cases there was a paradoxical worsening, but this remitted after discontinuation of the medication.¹⁶³ This should be considered against the background that nicotine as a stimulant is a self-medication for ADHD, 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 ADHD symptoms (indicating lower dopamine and norepinephrine deficiency) and a paradoxical response.

4.7. MPH and creativity¶

One study found no impairment of creativity by MPH,¹⁶⁴ Another study found increased creativity in unmedicated children with ADHD compared to medicated children with ADHD and unaffected children.¹⁶⁵

5. Responding (responding / non-responding)¶

Response means whether there is an effect on the ADHD symptoms. People with ADHD 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 ADHD responded to one of the two types of medication.¹⁶⁶ A meta-analysis of 32 studies came to the same conclusion (significantly better response rates to amphetamine medication than to MPH).¹⁶⁷
For people with ADHD for whom MPH does not work, it is therefore advisable to test a medication with amphetamine drugs.
About 50% of persons with ADHD who do not respond to MPH are expected to respond to atomoxetine, and about 75% of persons with ADHD who respond to MPH are expected to respond to atomoxetine.¹⁶⁸

Positive indications for a response to MPH were:

• Lower ADHD-RS-IV.es scores¹⁷⁰
• The absence of comorbidities (ODD, depression, alcohol/cannabis use)¹⁷⁰
• Less conspicuous neuropsychological tests¹⁷⁰
• A higher overall IQ¹⁷⁰
• Low commission errors (impulse control errors; reaction to signal that should not have been answered) in the Conners Continuous Performance Test II, CPT-II¹⁷⁰
• Higher hyperactivity-impulsivity and oppositional symptoms before treatment¹⁷¹
  • Predictor for good results with MPH monotherapy, guanfacine monotherapy and MPH/guanfacine combination medication
• Less anxiety before the treatment¹⁷¹
  • Predictor for good results with MPH monotherapy, guanfacine monotherapy and MPH/guanfacine combination medication
• High event-related mid-frontal beta power before treatment¹⁷¹
  • EEG activity from cortical sources localized in the regions of the middle frontal bone and middle occipital bone
  • Stronger modulations during encoding and retrieval predictor for good results with MPH monotherapy and guanfacine monotherapy
• Weak event-related mid-frontal beta power before treatment¹⁷¹
  • EEG activity from cortical sources localized in the regions of the middle frontal bone and middle occipital bone
  • Predictor for good results with MPH/guanfacine combination medication

5.1. Subtypes and non-response probability¶

Most older sources report that about 90% of people with ADHD-HI subtype (with hyperactivity) and mixed type respond positively to methylphenidate and require quite low doses.^{172173174175176}
More recent sources speak of a response rate of up to 75% with MPH,¹⁷⁷ which seems more accurate to us.

People with ADHD-I subtype are said to be more frequent MPH nonresponders,¹⁷⁸ with nonresponder rates of 24%¹⁷² being mentioned. People with ADHD-I who 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, are more likely to benefit from higher doses of MPH than children with a flattened cortisol stress response (which corresponds to ADHD-HI). However, the stress test was not based on the TSST, but on venipuncture, which allows for a less distinct recognizability of the cortisol stress response.¹⁷⁹

A particularly strong increase in cortisol awakening (CAR) correlated with reduced MPH responding in children.¹⁷⁹

SCT people with ADHD (which, according to current understanding, is not a subtype of ADHD, but a comorbidity that is equally common in ADHD-HI and ADHD-I) are particularly frequent MPH nonresponders. In particular, elevated SCT sluggish/sleepy factor values indicate MPH nonresponding. Neither elevated SCT daydreamy symptoms nor ADHD subtype (ADHD-HI or ADHD-I) differed in MPH responding rates in this study.¹⁸⁰

According to one study, people with ADHD with intellectual deficits are less likely to respond to MPH. A responder rate of 40 to 50 % was reported here.¹⁸¹ In contrast, another study found a good effect of MPH in people with ADHD with intellectual deficits.¹⁸²

5.2. (Non-)responding and EEG subtypes¶

People with ADHD with very low EEG theta values are said to be more frequent nonresponders to stimulants.¹⁸³
According to this understanding, low theta values correspond to the overactivated beta (EEG) subtype. For the BETA subtype (overactivated type), another source reports reduced MPH responding.⁵⁰
The beta subtype appears outwardly as the classic ADHD-HI subtype (hyperactive/impulsive). Most people with ADHD-HI 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 ADHD of the BETA subtype known to us report an extremely helpful effect of MPH.

A small study found lower EEG stability at rest as a predictor of MPH response.¹⁸⁴
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.¹⁸⁵

5.3. (Non-)responding and dosing of MPH¶

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.¹⁸⁶
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 ADHD subtypes will one day provide explanations here.

5.4. Seasonal influence on MPH dosage?¶

One study found a seasonal pattern of inattention in people with ADHD treated with low-dose MPH. 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 MPH 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.¹⁸⁷
The authors interpreted this to mean that a low MPH 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 ADHD (who need less MPH?) there could be a disturbed function of the light-sensitive retinal cells in the ADHD subgroups on the melatonin- and dopamine-producing cells in the retina. They raise the question of whether a combination of MPH with modulated light therapy could improve responding, as has already been reported with fluoxetine in non-seasonal depression.¹⁸⁸

5.5. Indications of good MPH responding¶

An increase in blood pressure is said to correlate with a particularly good effect of MPH.¹⁸⁹

Particularly good symptom improvement on methylphenidate was observed in people with ADHD with¹⁹⁰

• 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 MPH or atomoxetine in ADHD.¹⁹¹

A meta-analysis of 15 studies and 1382 patients found that carriers of the T allele of the NET gene polymorphism rs28386840 responded significantly more frequently to MPH and showed a significantly greater improvement in hyperactive-impulsive symptoms than carriers of other NET polymorphisms. ADRA2A polymorphisms did not correlate significantly with the response to MPH. However, carriers of the G allele of the MspI polymorphism showed a correlation with a significant improvement in inattention symptoms.¹⁹²

Elevated iron levels in the putamen and caudate correlated with better MPH responding in ADHD. Elevated iron levels in the putamen correlated - not only in ADHD - with impaired inhibition¹⁹³

In preschool-aged ADHD, 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:¹⁹⁴

Responder	Symptom 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 MPH effect¶

5.6.1. ADRA2A gene variants¶

ADRA2A -1291 polymorphism influences responding and effect of MPH.

• G/G genotype:
  • 76.9 % responded well to MPH¹⁹⁵
  • 25% greater reduction in symptoms after 3 months of MPH¹⁹⁶
• C/G genotype:
  • 46.0 % responded well to MPH¹⁹⁵
• C/G genotype:
  • 41.7 % responded well to MPH¹⁹⁵

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

• C/C genotype
  • diastolic blood pressure increased by 18.5 % with OROS-MPH¹⁹⁷
• G/G genotype
  • diastolic blood pressure decreased by 0.2 % with OROS-MPH¹⁹⁷
• G/C genotype
  • diastolic blood pressure decreased by 0.2 % with OROS-MPH¹⁹⁷

5.6.2. NET gene variants¶

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

• G/G genotype:
  • 71.9 % responded well to MPH¹⁹⁸
  • 7.15 points improvement on the hyperactivity subscale of the ADHD Rating Scale-IV, but not on the inattention subscale ¹⁹⁹
  • no responding difference detected
• G/A genotype:
  • 46.0 % responded well to MPH¹⁹⁸
  • 6.94 points improvement on the hyperactivity subscale of the ADHD Rating Scale-IV, but not on the inattention subscale ¹⁹⁹
• A/A genotype:
  • 57.1 % responded well to MPH¹⁹⁸
  • 2.13 points improvement on the hyperactivity subscale of the ADHD Rating Scale-IV, but not on the inattention subscale ¹⁹⁹

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

• T/T genotype
  • responded comparatively better to MPH²⁰⁰
  • Increase in resting heart rate by 12.5 % due to OROS-MPHi¹⁹⁷
• A/T genotype
  • responded comparatively better to MPH²⁰⁰ -
  • Increase in resting heart rate by 3.5 % due to OROS-MPH¹⁹⁷
• A/A genotype
  • responded comparatively worse to MPH²⁰⁰
  • Increase in resting heart rate by 2.5 % due to OROS-MPH¹⁹⁷

A meta-analysis found a correlation between MPH effect and the SLC6A2 gene variants²⁰¹

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

5.7. CES1 plasma protein level and MPH 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.²⁰²

5.8. Response individually dependent on retardation and carrier substance¶

People with ADHD report a very different individual response to different MPH preparations.
While the intra-individual (within a person) and inter-individual (compared to other people with ADHD) differences in tolerability of MPH 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 ADHD who reproducibly perceive very clear differences in the effect of various equally strong unretarded MPH preparations.²⁰³²⁰⁴

5.9. Therapeutic reference range, pharmacokinetics¶

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

• Methylphenidate:²⁰⁵

  • 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
  • Half-life: 2 h
  • Laboratory value warning threshold: 50 ng/ml
  • At 0.3 mg/kg, children and adults showed identical pharmacokinetic parameters (Wargin 1983a).

• Dexmethylphenidate:²⁰⁵

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

There is therefore no objectifiable neurobiological correlation between blood levels and efficacy.²⁰⁶ 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 ADHD would therefore have to be identified. For example, the blood level can be measured after determining the appropriate dose for the optimal individual improvement.²⁰⁵

The pharmacokinetics of methylphenidate are not linear. Based on the AUC, the plasma exposure of D-MPH was disproportionate to the dose (in dogs).²⁰⁷ 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.²⁰⁸ 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 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 preparations is constant at different dose levels.

Maximum plasma concentration, Cmax

• l-Methylphenidate²⁰⁹
  • 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-methylphenidate²¹⁰
  • 0.15 mg / kg, oral: 2.2 hours (± 0.4)
  • 0.3 mg / kg, oral: 2.1 hours (± 0.3)

Elimination half-life

• d-methylphenidate²⁰⁹
  • 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-Methylphenidate²⁰⁹
  • 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)