MPH Part 1: Active ingredients, effect, responding

• 1. Active ingredient
  • 1.1. Methylphenidate as racemate
  • 1.2. Dexmethylphenidate (D-MPH)
• 2. Mode of action of methylphenidate
  • 2.1. Effect on neurotransmitters
    • 2.1.1. MPH increases dopamine
      • 2.1.1.1. Dose-dependent effect of MPH
      • 2.1.1.2. Duration-dependent effect of MPH
      • 2.1.1.3. MPH and tonic / phasic DA
      • 2.1.1.4. MPH binds to DAT (reuptake inhibition)
      • 2.1.1.5. Dopamine release by MPH?
      • 2.1.1.6. MPH acts on DA via D2 autoreceptors
      • 2.1.1.7. MPH increases DA via VMAT2
      • 2.1.1.8. MPH increases tyrosine hydroxylase
    • 2.1.2. MPH increases norepinephrine
      • 2.1.2.1. MPH binds to norepinephrine receptors
      • 2.1.2.2. MPH binds to NET (reuptake inhibition)
      • 2.1.2.1. MPH increases NE via VMAT2
    • 2.1.3. MPH and serotonin
      • 2.1.3.1. MPH and tryptophan hydroxylase
      • 2.1.3.2. Effect of MPH on tryptophan metabolites
    • 2.1.4. Binding affinity of MPH, AMP, ATX to DAT / NET / SERT
    • 2.1.5. Effect of MPH, AMP, ATX on dopamine / norepinephrine per brain region
    • 2.1.6. Effect of MPH on MAO-A
  • 2.2. Effect of MPH on cholesterol metabolism in OFC
  • 2.3. Effect of MPH on HPA axis
  • 2.4. Effect of MPH on Vegetative Nervous System (Sympathetic / Parasympathetic)
  • 2.5. Effect of MPH on androgens
  • 2.6. Effect of MPH on kynurenines
  • 2.7. Effect of MPH on ARAS
  • 2.8. Effect of MPH on S100B
  • 2.9. Effect of MPH on brain networks
    • 2.9.1. MPH and connectivity between brain regions
    • 2.9.2. Effect of MPH on Default Mode Network (DMN)
    • 2.9.3. Effect of MPH on nucleus accumbens and cognitive control networks
  • 2.10. Effect of MPH on EEG
  • 2.11. Effects on brain regions
  • 2.12. MPH in preschool children
  • 2.13. MPH normalizes pain sensation in ADHD
  • 2.14. More about MPH
• 3. Differences in action between methylphenidate and amphetamine medications
• 4. Symptom effect
  • 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. Differential time-dependent effects of stimulants on symptoms?
  • 4.6. MPH and smoking cessation
  • 4.7. MPH and creativity
• 5. Responding (Responding / Nonresponding)
  • 5.1. Subtypes and nonresponse probability
  • 5.2. (Non-)responding and EEG subtypes
  • 5.3. (Non-)responding and dosing of MPH
  • 5.4. Indications of good symptom improvement with MPH
  • 5.5. Gene variants and MPH action
    • 5.5.1. ADRA2A gene variants
    • 5.5.2 NET gene variants
  • 5.6. CES1 plasma protein level and MPH dosage

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
• four configuration isomers
  • d-threo enantiomer is pharmacologically most active

MPH is a narcotic because it can be abused as a drug. When taken as a medication (orally / patch), however, MPH has no intoxication or dependence potential. The actual risk of abuse of methylphenidate as a drug, however, seems to be overestimated. A study that claimed a frequent abuse of MPH as a drug, referred to this only to sources in which methylphenidate is not even mentioned²

1.1. Methylphenidate as racemate¶

Methylphenidate is commercially available as a racemate (mixture) of L-methylphenidate and D-methylphenidate (levorotatory and dextrorotatory isomers).
While D-MPH enters the CNS in a significant proportion through the blood-brain barrier, L-MPH is not absorbed into the CNS.³

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

Dosage from 2.5 mg to a mean of 15 mg per single dose during the day every 2.5 to 3.5 hours (unretarded form).⁴

1.2. Dexmethylphenidate (D-MPH)¶

Dexmethylphenidate is the pure form of the dextrorotatory isomers.

Brand name: Focalin (Switzerland and USA only)

It is 3-fold more potent than racemic (mixture of dextrorotatory (D-MPH) and levorotatory (L-MPH) methylphenidate.⁵ The higher efficacy of D-MPH over L-MPH affects both dopamine transporter and noradrenaline transporter binding.
Therefore, half the dosage of D-MPH compared to racemate methylphenidate is recommended, also limited to a maximum of 20 mg / day in children as in adults.

2. Mode of action of methylphenidate¶

2.1. Effect on neurotransmitters¶

MPH alters neurotransmitter levels in the brain.

2.1.1. MPH increases dopamine¶

• Increase in dopamine and norepinephrine in the PFC⁶
• In healthy adult rats, MPH increases
  • Dopamine in the PFC, striatum and nucleus accumbens as well as⁷
    • High dose: DA increased by release from noradrenergic cells⁸
    • Low dose: DA not increased⁸
  • Norepinephrine in the PFC, but not in the striatum or nucleus accumbens.⁷
• In healthy monkeys, MPH induced:⁹
  • Striatum: low and high doses: consistent dopamine increase
  • PFC: dopamine increase only at high dose

2.1.1.1. Dose-dependent effect of MPH¶

• The effect of MPH is dose-dependent. Normal dosed MPH shows different effects than high or very high dosed MPH.
  • At low doses, methylphenidate increases dopamine and norepinephrine levels in the PFC, which increases its performance. In contrast, in other brain areas, low-dose MPH has little effect on dopamine and norepinephrine levels.¹⁰ This is consistent with the known increase in cognitive performance of the PFC due to small increases in dopamine and norepinephrine levels during mild stress.
  • At 3 mg/kg MPH, one study found no increase in dopamine or noradrenaline in the striatum of rats¹¹
  • 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.¹²

2.1.1.2. Duration-dependent effect of MPH¶

Acute MPH administration increased the firing activity of PFC pyramidal neurons and potentiated NMDA-induced neurotransmission in rats.
Chronic MPH administration (2 x 2 mg/kg/day) showed 28 days after the end of MPH administration on pyramidal neurons of the PFC⁸

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

Prolonged administration of MPH or atomoxetine to juvenile Naples High-Excitability (NHE) rats produced the following effects in adults¹³

• Dopamine decreased in the PFC and striatum
• Norepinephrine increased in ventral striatum

• In juvenile rats induced¹⁴¹⁵

  • A single administration of high-dose MPH (2 mg/kg, which is approximately twice the maximum treatment dose 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 protein levels of tyrosine hydroxylase (TH) and dopamine D1 receptor
    • Unchanged levels of dopamine and homovanillic acid (HVA)
  • A permanent administration of high-dose MPH (2 mg/kg) for 14 days
    • Increased number of vesicular monoamine transporters (VMAT2) in the cerebellum
    • Significantly increased dopamine turnover in the cerebellum (measured with the metabolite DOPAC)¹⁴
    • Left the protein levels of tyrosine hydroxylase (TH) and the dopamine D1 receptor unchanged¹⁴ - differently the same authors¹⁵
    • Increased the number of DAT¹⁵
      • In the left dorsal striatum
    • Did not change the DAT
      • In the right dorsal striatum
      • In the nucleus accumbens (ventral striatum)¹⁴
    • Increased the expression of the
      • Norepinephrine transporter (NET)
      • Monoamine transporter 2 (VMAT2)¹⁴¹⁵
        • In contrast, amphetamine decreases VMAT2¹⁶
      • 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 in the long term the drug may lose some of its acute effect of increasing dopamine and norepinephrine levels.¹⁵¹⁷
        This is consistent with our experience that for some users, the dosage has to be slightly adjusted after half a year to a year. However, a general habituation effect is neither reported in studies¹⁸ nor in practice.
      • Increased vanillic mandelic acid in the urine of Wistar rats. This could be avoided by augmenting administration of buspirone.¹⁹
        Vanillic mandelic acid is formed during the degradation of adrenaline and noradrenaline by MAO-A and COMT, so that vanillic mandelic acid is an indicator of the activity of the vegetative nervous system (sympathetic nervous system).
    • A single administration of very high-dose MPH (5 mg/kg, or about 5 to 20 times the usual treatment dose in humans) causes
      • A similar metabolite change in the cerebellum as 2 mg
      • Tended to decrease metabolites in the cerebellum associated with energy expenditure and excitatory neurotransmission, here glutamate, glutamine, N-acetylapartate, and inosine
      • Further, the levels of some metabolites associated with inhibitory neurotransmission, here GABA and glycine, acetate, aspartate and hypoxanthine were reduced

• One study found basal oxytocin levels unchanged in children with ADHD compared to unaffected individuals. While oxytocin decreased in untreated ADHD sufferers after interaction with a parent, oxytocin increased in ADHD sufferers treated with MPH, as it did in unaffected individuals.²⁰

2.1.1.3. MPH and tonic / phasic DA¶

Study evidence suggests that MPH raises tonic dopamine in the striatum but not phasic dopamine.

One study found that MPH only raised tonic dopamine. Phasic dopamine was not altered by MPH, apparently because a feedback mechanism via D2 receptors inhibits it. When a D2 antagonist was given in parallel with MPH, MPH also increased phasic dopamine.²¹ In our view, this raises the question of how much the amount and binding sensitivity of the available D2 receptors in affected individuals leads to an individually different effect of MPH.

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 unexpectedly positive reward stimuli, the striatum fires phasically dopaminergically and activates dopaminergic postsynaptic receptors. Thus, tonic control is inhibitory and modulates excitatory phasic firing to unexpectedly positive reward stimuli.²²

It is true that dopamine reuptake inhibitors are thought to lead to increased phasic dopamine in the dorsolateral striatum.²³ However, this does not seem to be the case with MPH, as MPH in the striatum⁸
* Induce (tonic) dopamine efflux by reversing the dopamine reuptake transporter
* Not increase the vesicular (phasic) dopamine release

2.1.1.4. MPH binds to DAT (reuptake inhibition)¶

Methylphenidate as a dopamine reuptake inhibitor increases dopamine levels in the synaptic cleft.⁶ and norepinephrine transporter²⁴ 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 raises dopamine activity in the striatum, which argues against the PFC as a 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 would be excessive, MPH, if elevating there, should exacerbate rather than ameliorate symptoms. At low doses, stimulants such as MPH can inhibit phasic dopamine release by enhancing inhibitory tonic control. 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 both children with and without ADHD, but it increased striatal blood flow only in children with ADHD. It is therefore an open question whether the observed frontal deficits in ADHD reflect 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 etiologic deficits in ADHD do not have other causes.²²

• 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 one tenth of this.²⁵
• MPH does not bind to dopamine receptors, but only to DAT and NET.²⁶²⁷ (Different: MPH is supposed to activate postsynaptic D1 receptors.⁶ )
  • D-MPH binds most strongly to
    • DAT with IC50 = 23 nM, Ki = 161 nM;
    • NET with IC50 = 39 nM, Ki = 206 nM
  • D/l-MPH racemate binds more weakly to²⁶
    • DAT with IC50 = 20 nM, Ki = 121 nM
    • NET with IC15 = 51 nM, Ki = 788 nM
  • L-MPH binds most weakly, to²⁶
    • DAT with IC50 = 1600 nM, Ki = 2250 nM
    • NET with IC50 > 104 nM, Ki > 104 nM
• MPH responders had increased DAT numbers in the striatum, and nonresponders had decreased DAT numbers.²⁸
• MPH increased the number of dopamine transporters.¹⁷
• Different:
  • Lower dopamine and noradrenaline increase in the striatum⁶
  • In contrast, no increase in dopamine in the striatum by MPH in DAT(-/-) mice, but in DAT(+/-) and DAT(+/+) mice²⁹

2.1.1.5. Dopamine release by MPH?¶

It is controversial whether methylphenidate is a pure dopamine reuptake inhibitor or whether dopamine is additionally released.

• Pure DA reuptake inhibitor³⁰³¹
• Also release of dopamine from reserpine-sensitive granules³²³³
• With medication dosing, a pure reuptake inhibition is to be assumed. A release of dopamine from the vesicles of the granules is likely to occur only at very high doses of more than 80 mg / day.³⁴³⁵
• Unlike amphetamine, methylphenidate is not considered a substrate for transport into the cytoplasm, so at best it causes little presynaptic dopamine release.³⁶
• MPH appears in the striatum⁸
  • Induce dopamine efflux by reversing the dopamine reuptake transporter
  • Not to increase vesicular (phasic) dopamine release

2.1.1.6. MPH acts on DA via D2 autoreceptors¶

MPH causes unblocking of presynaptic D2 autoreceptors⁶

• Methylphenidate normalizes increased dopamine transporter densities in ADHD-HI rats more than in ADHD-I rats³⁷
• In people with high D2 receptor numbers, MPH increases metabolism in frontal and temporal brain areas (including striatum), while in healthy people with low D2 receptor numbers, MPH decreases metabolism. In the cerebellum, metabolism was consistently increased.³⁸
  • This corresponds to a normalization of D2 receptor binding.³⁹

2.1.1.7. MPH increases DA via VMAT2¶

MPH affects the redistribution of vesicular monoamine transporter-2 (VMAT-2; Solute Carrier Family 18 Member 2 - SLC18A2). VMAT2 is involved in the sequestration of cytoplasmic dopamine and norepinephrine, making it an important regulator of neurotransmission. MPH does not affect the total amount of VMAT-2 in presynaptic terminals, but only VMAT-2 transport.¹⁴¹⁵
MPH induces in monoaminergic neurons (but not in cholinergic, GABA-ergic, or glutamatergic neurons²⁶

• 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 securing a substantial DA reserve pool in the presynaptic vesicles. Therefore, there is relatively little risk of neurotoxic / neuropsychiatric side effects in MPH treatment practice²⁶

2.1.1.8. 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). Thus, MPH supports dopamine synthesis.
MPH (as well as exercise) can induce the expression of TH⁴⁰ and increase TH levels⁴¹
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 TH⁴²
It is unclear whether the increase occurs only peripherally or also in the brain.⁴³ TH gene variants seem to influence the response of MPH.⁴³

2.1.2. MPH increases norepinephrine¶

• MPH acts noradrenergically in the locus coeruleus, improving arousal, vigilance, and attention⁶
• The effect of MPH is dose-dependent. Normal dosed MPH shows different effects than high or very high dosed MPH.
• At low doses, methylphenidate increases dopamine and norepinephrine levels in the PFC, which increases its performance. In contrast, in other brain areas, low-dose MPH has little effect on dopamine and norepinephrine levels.¹⁰ This is consistent with the known increase in cognitive performance of the PFC due to small increases in dopamine and norepinephrine levels during mild stress.

2.1.2.1. MPH binds to norepinephrine receptors¶

MPH binds directly to noradrenergic receptors.⁴⁴ MPH binds to²⁶

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

The resulting cognitive improvement induced by MPH could be suppressed by α2-adrenoceptor antagonists.⁴⁵ Guanfacine and clonidine also act positively as α2-adrenoceptor agonists in ADHD.

• Blockade of the alpha-2-adrenoceptor⁶
  • In contrast, several sources report an agonistic effect of MPH on the alpha-2 adrenergic receptor.⁴⁴⁴⁵ See above.

2.1.2.2. MPH binds to NET (reuptake inhibition)¶

• Norepinephrine reuptake inhibition⁶

2.1.2.1. MPH increases NE via VMAT2¶

MPH affects the redistribution of vesicular monoamine transporter-2 (VMAT-2; Solute Carrier Family 18 Member 2 - SLC18A2). VMAT2 is involved in the sequestration of cytoplasmic dopamine and norepinephrine, making it an important regulator of neurotransmission.
MPH does not affect the total amount of VMAT-2 in presynaptic terminals, but only affects VMAT-2 transport.
MPH induces in monoaminergic neurons (but not in cholinergic, GABA-ergic, or glutamatergic neurons²⁶

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

2.1.3. MPH and serotonin¶

The overall effect of MPH on serotonin levels appears negligible.⁴⁶ D-threo-(R,R)-methylphenidate is a weak agonist of the 5HT-1A serotonin receptor, but not of the 5HT-2A receptor. This may affect dopamine metabolism in the brain,⁴⁷ but the extent is small.
MPH is reported to bind to the DAT 2200 times as strongly as to the SERT and to the NET almost 1300 times as strongly as to the SERT.²⁶

Whether MPH binds to serotonin receptors is unclear. Different studies come to contradictory results.²⁶

Controversial:

• Whether reuptake inhibition of serotonin occurs at the synapse. There are sources for this⁴⁸ as well as against it.⁴⁹
  • The serotonergic effect of MPH is so weak that it is not relevant to treatment
  • According to our impression, MPH has no significant mood elevating effect

2.1.3.1. 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 the synthesis of serotonin by converting tryptophan to the serotonin precursor 5-hydroxytryptophan.⁴³
The AATGGAGA (yin) haplotype of TPH2 appears to be less responsive to MPH than the CGCAAGAC (yang) haplotype.⁴³

2.1.3.2. Effect of MPH on tryptophan metabolites¶

In ADHD-HI sufferers (predominantly hyperactive) with comorbid depressive symptoms, one study found significantly higher morning than evening levels of indole acetic acid compared to ADHD-I sufferers and healthy controls. MPH reduced this by 50%. MPH simultaneously reduced morning levels of indolepropionic acid and returned the diurnal profile to that of healthy control subjects.⁵⁰

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 inhibition of the activity of the respective transporters.⁵¹

Binding affinity: stronger with smaller number (KD = Ki)	DAT	NET	SERT
MPH	34 - 200	339	> 10,000
d-AMP (Elvanse, 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 / norepinephrine per brain region¶

The drugs methylphenidate (MPH), amphetamine (AMP), and atomoxetine (ATX) alter extracellular dopamine (DA) and norepinephrine (NE) differently in different brain regions. Table based on Madras,⁵¹ 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 affects monoamine oxidase A (MAO-A) by⁵²

• Stimulation of non-vesicular release
• Inhibition of MAO-A activity³³⁵³

However, the influence seems limited and only slightly relevant.

2.2. Effect of MPH on cholesterol metabolism in OFC¶

One study found 12 altered metabolites in the PFC of SHR rats, considered ADHD-HI models, compared with WKY rats, considered non-affected models. The abnormalities of 8 of them were equalized by MPH:⁵⁴

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

The altered metabolites belong to the metabolic pathways of cholesterol.
In the case of the SHRs, the PFC found for this purpose

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

2.3. Effect of MPH on HPA axis¶

Stimulants (methylphenidate and amphetamine drugs) are thought to increase HPA axis activity.⁵⁵

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 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.⁵⁶

2.4. Effect of MPH on Vegetative Nervous System (Sympathetic / Parasympathetic)¶

In ADHD, heart rate variability (HRV), which correlates with the health of the autonomic nervous system and in particular the activity of the parasympathetic nervous system, is reduced. Stimulants such as methylphenidate improve (increase) heart rate variability, but without being able to raise it to the value of non-affected persons.⁵⁷⁵⁸

The statement made elsewhere,⁵⁹ that methylphenidate does not alter HVR, is not reflected in the source cited.⁶⁰

2.5. Effect of MPH on androgens¶

Stimulants (methylphenidate and amphetamine drugs) decrease the concentration of androgens.
Preclinical data on the role of androgens in the pathogenesis of ADHD suggest that elevated testosterone may reduce cerebral blood flow in the PFC by decreasing the amount of alpha estrogen receptors and vascular endothelial growth factor (VEGF). This may interfere with memory processes. There is a correlation between ADHD and polymorphism of the androgen receptor gene leading to its higher expression. Nevertheless, little is known about the issue of androgen involvement in ADHD.⁵⁵

2.6. Effect of MPH on kynurenines¶

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.⁶¹

2.7. Effect of MPH on ARAS¶

Methylphenidate increases the excitation of the reticular activating system (ARAS).⁶²

2.8. 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 ADHD sufferers. The authors consider this to indicate that a neuroinflammatory cause of ADHD may be damaging glial function, thereby altering dopaminergic (DA) neurotransmission.⁶³

2.9. Effect of MPH on brain networks¶

2.9.1. MPH and connectivity between brain regions¶

Methylphenidate normalized reduced global connectivity existing in ADHD 400-700 ms after a stimulus and reduced an increase in network separation 100-400 ms after the stimulus in one study. These global changes by methylphenidate occurred mainly in task-relevant frontal and parietal regions and was more significant and sustained than in non-treated comparison subjects. The results of the study suggest that methylphenidate corrects impaired network flexibility that exists in ADHD.⁶⁴

Another study reported interhemispheric connectivity changes in ADHD:⁶⁵

• 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

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

The increased purely intrinsically motivated attentional control in ADHD causes attention and its controllability to be as high as in unaffected individuals when interest is appropriately high, and to deviate from the attention of unaffected individuals only when intrinsic interest is lower. This is controlled by the DMN.
Stimulants are able to match the attentional control of ADHD sufferers to that of non-affected individuals in the absence of intrinsic interest.⁶⁶ This explains why stimulants are as helpful in ADHD-HI and ADHD-C as in ADHD-I.

For more on the aberrant function of the DMN in ADHD and its normalization by stimulants, including additional references, see ⇒ Normalization of the DMN by stimulants In the article ⇒ Brain networks and connectivity in ADHD in the chapter ⇒ Neurological aspects.

2.9.3. 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.⁶⁷

2.10. Effect of MPH on EEG¶

MPH caused⁶⁸

• Significant differences in ADHD sufferers in the frontal-parietal area at 250 ms-400 ms post-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 ADHD sufferers, which correlated with increased P3-ERP response at frontoparietal electrodes

2.11. 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 nucleus⁶⁹
      • In the right globus pallidum⁷⁰
      • In putamen⁷⁰
    • In the caudate nucleus⁶⁹
  • In the anterior cingulate cortex (ACC) in adults⁶⁹
• MPH mediates its acute and chronic effects on behavior via the dopaminergic system of the caudate nucleus.⁷¹
• In hypermotor and inattentive ADHD sufferers, regular methylphenidate administration increases previously abnormally low blood flow to the putamen. In ADHD-affected children with average motor activity, regular methylphenidate administration decreased blood flow to the putamen. The thalamus was not affected by MPH.⁷²
  MPH increased activation in bilateral inferior frontal cortex/insula during inhibition of temporal discrimination.⁷³
• Methylphenidate increases metabolism in the brain left frontal posterior and left parietal superior and decreases it left parietal, left parietal occipital, and frontal anterior medial.⁷⁴

MPH appears to reduce dysfunction in the PFC in most affected individuals.⁷⁵ Another metastudy found that MPH showed no effect on working memory (in dlPFC).⁷³

A study in rats at 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 produced behavioral sensitization in some animals and tolerance in others, and activity in the PFC and caudate nucleus correlated with the animals’ behavioral responses to MPH. The caudate nucleus response was more intense than that in the PFC, with both single and repeated doses. In addition, dose-dependent differential 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 neuronal firing rate.⁷⁶

2.12. MPH in preschool children¶

Some studies show a positive effect of MPH in preschool-aged children with ADHD.⁷⁷

2.13. MPH normalizes pain sensation in ADHD¶

ADHD sufferers often show increased sensitivity to pain. MPH can remedy this pain sensitivity in ADHD sufferers.⁷⁸

2.14. More about MPH¶

• MPH has no effect on vesicular monoamine transporters (VMAT).²⁴
• Methylphenidate and amphetamine drugs increase the power of alpha (in rats), whereas atomoxetine and guanfacine do not.⁷⁹

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.

It has been sporadically postulated that very early treatment with stimulants might permanently improve DAT overactivity (i.e., beyond intake).⁸¹

A very small fMRI study of 16 subjects on the effect of methylphenidate on ADHD-affected and unaffected boys found increased activation of the frontal cortex and decreased activation of the striatum in ADHD-affected boys before methylphenidate compared with unaffected boys during Go/NoGo tasks. Methylphenidate counterbalanced the differences.⁸⁴

3. Differences in action between methylphenidate and amphetamine medications¶

Methylphenidate possibly increases left frontal posterior and left parietal superior brain metabolism and decreases left parietal, left parietal occipital, and frontal anterior medial metabolism.⁸⁵

In contrast, D-amphetamine possibly increases metabolism in the right caudate nucleus (part of the striatum) and decreases it in the right Rolandi region and in right anterior inferior frontal regions.⁸⁶

The sample (n) on which these findings were examined were very small, 19 and 18, respectively. Samples that are too small carry a significant risk of misleading results.
More on this at ⇒ Studies say - sometimes nothing at all.

4. Symptom effect¶

Methylphenidate improves the following symptoms of ADHD:

4.1. Particularly good effect of methylphenidate¶

• Hyperactivity ⁶²

• Unrest⁶²

• Impulsivity⁶²

  • Sufferers reported in forums that MPH worked better against impulsivity than Elvanse.⁸⁷
  • A study in monkeys (not ADHD-affected by nature) concluded that low doses of MPH reduced impulsivity, while higher doses had a sedating effect.⁸⁸
    This follows empirical experience that an overdose of MPH can be apathetic.

• Aggressiveness⁶²⁸⁹

  • And better than atomoxetine⁹⁰
  • In a study of 6- to 12-year-old children with aggression and ADHD, systematically titrated stimulants eliminated aggression in 63%.⁹¹ Among children for whom stimulants did not adequately eliminate aggression, augmenting administration of risperidone (effect size 1.3) or valproic acid (effect size 0.9) improved aggression, with risperidone associated with weight gain.

• Socially maladjusted behavior⁶²

• Behavioral problems, and better than atomoxetine⁹⁰

• Somatic complaints, and better than atomoxetine⁹⁰

• Motivability through reward⁹²

• Drive

  • Affected individuals report fairly consistently that MPH improves drive more than AMP does

MPH works in adults:⁹³

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

4.2. Good effect of methylphenidate¶

• Perception⁹⁴

• Concentration⁶²

  • Many adults report that MPH provides greater focus than Elvanse, while Elvanse makes them more relaxed overall and has a more consistent effect

• Attention⁶²

  • Distractibility is reduced, attention is increased
  • Task changes are reduced⁹⁵

• Agitation⁶²

• Writing and drawing expression ⁹⁶

• Social perceptiveness and mimic responsiveness

• Social interaction

  • One study found basal oxytocin levels unchanged in children with ADHD compared to unaffected individuals. While oxytocin increased in unaffected individuals after interaction with a parent, oxytocin decreased in untreated ADHD sufferers. Methylphenidate caused the oxytocin increase after parent interaction in ADHD-affected individuals to match that of unaffected individuals.⁹⁷

• Rejection Sensitivity (Offense Sensitivity)
  Almost all of the ADHD sufferers we interviewed reported an improvement in their Rejection Sensitivity (from which almost all of the ADHD sufferers we interviewed suffer) as a result of MPH. Sporadically, sufferers reported that their RS became stronger on MPH. One of these sufferers 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 showed significantly improved math skills under MPH that were indistinguishable from those of unaffected individuals.⁹⁸

• Anxiety⁸⁹

• Tension⁸⁹

• Borderline aspects⁸⁹

• Depressiveness⁸⁹

• Emotional instability⁸⁹

• Life dissatisfaction⁸⁹

• Negative attitude to life⁸⁹

• Psychotic phenomena⁸⁹

• Social introversion⁸⁹

• Uncertainty⁸⁹

• Compulsivity⁸⁹

• Inner emptiness/boredom⁹⁹

4.3. Low effect of methylphenidate¶

• Delay Aversion (in adults)¹⁰⁰
• Executive functions (in adults)¹⁰⁰
  .

4.4. No effect of methylphendiate¶

• Reading the Mind in the Eye (for children). This test measures the theory of mind.¹⁰¹
• Fine motor skills (writing)¹⁰²

4.5. Differential time-dependent effects of stimulants on symptoms?¶

A publication by a well-known scientist claims different time-response and dose-response curves for the motor and cognitive effects of stimulants.¹⁰³ 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 the claim. They also do not correspond to empirical experience from practice.

4.6. MPH and smoking cessation¶

It was reported that sustained-release MPH contributed positively to nicotine abstinence/smoking abstinence, but only in more severe ADHD cases, whereas in milder ADHD cases a paradoxical worsening occurred but remitted after discontinuation of the medication.¹⁰⁴ This should be considered in light of the fact that nicotine as a stimulant is self-medication for ADHD, even though smoking uses nicotine as a drug and only nicotine patches or nicotine lozenges act as a drug.
Further, in the context of the Inversed-U theory, according to which intermediate neurotransmitter levels mediate optimal brain function, whereas decreased as well as excessive neurotransmitter levels cause nearly similar symptoms, the result of this study may indicate an overdose 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,¹⁰⁵ Another study found increased creativity in unmedicated children with ADHD versus medicated children with ADHD and unaffected children.¹⁰⁶

5. Responding (Responding / Nonresponding)¶

One metastudy reported 69% response rates to amphetamine medication and 59% response rates to methylphenidate. 87% of ADHD sufferers would have responded to either type of drug.¹⁰⁷ A meta-analysis of 32 studies came to the same conclusion (significantly better response rates to amphetamine medication than to MPH).¹⁰⁸
For sufferers for whom MPH does not work, it is therefore advisable to test medication with amphetamine drugs.
About 50% of sufferers who do not respond to MPH should respond to atomoxetine, and about 75% of sufferers who respond to MPH should also respond to atomoxetine.¹⁰⁹

Positive indications for a response of MPH were:

• Lower ADHD RS-IV.es scores¹¹¹
• The absence of comorbidities (ODD, depression, alcohol/cannabis use)¹¹¹
• Less conspicuous neuropsychological tests¹¹¹
• A higher overall IQ¹¹¹
• Low commission errors (impulse control errors; response to signal that should not have been responded to) in Conners Continuous Performance Test II, CPT-II¹¹¹
• Higher hyperactivity-impulsivity and oppositional symptoms before treatment¹¹²
  • Predictor of good outcomes with MPH monotherapy, guanfacine monotherapy, and MPH/guanfacine combination medication
• Less anxiety before the treatment¹¹²
  • Predictor of good outcomes with MPH monotherapy, guanfacine monotherapy, and MPH/guanfacine combination medication
• High event-related midfrontal beta power before treatment¹¹²
  • EEG activity from cortical sources localized in the regions of the middle frontal bone and the middle occipital bone
  • Stronger modulations during encoding and retrieval predictor of good outcomes with MPH monotherapy and guanfacine monotherapy
• Weak event-related midfrontal beta power before treatment¹¹²
  • EEG activity from cortical sources localized in the regions of the middle frontal bone and the middle occipital bone
  • Predictor of good outcomes with MPH/guanfacine combination medication

5.1. Subtypes and nonresponse probability¶

Most older sources report that about 90% of those with the ADHD-HI (with hyperactivity) subtype and the mixed type respond positively to methylphenidate and require fairly low doses.^{113114115116117}
More recent sources speak of up to 75% response rate with MPH,¹¹⁸ which seems more accurate to us.

ADHD-I subtype sufferers were reported to be more frequent MPH nonresponders,¹¹⁹ citing nonresponder rates of 24%¹¹³. ADHD-I sufferers who responded to MPH also required higher doses.
According to a small study, children with a higher cortisol stress response, corresponding to the ADHD-I subtype, are more likely to benefit from higher doses of MPH than children with a flattened cortisol stress response (corresponding to ADHD-HI). However, the stress test was not based on the TSST but on venipuncture, which allows for less distinct detection of the cortisol stress response.¹²⁰

A particularly strong cortisol awakening response (CAR) correlated with decreased MPH responding in children.¹²⁰

SCT sufferers (which, according to current understanding, is not a subtype of ADHD, but a comorbidity equally common in ADHD-HI and ADHD-I) are particularly frequent MPH nonresponders. In particular, elevated SCT sluggish/sleepy factor scores suggest MPH nonresponding. Neither elevated SCT Daydreamy symptoms nor ADHD subtype (ADHD-HI or ADHD-I) differed in MPH responding rates in this study.¹²¹

According to one study, ADHD sufferers with intellectual deficits are said to respond worse to MPH. A responder rate of 40 to 50 % was reported.¹²² Another study, however, found a good effect of MPH in patients with intellectual deficits.¹²³

5.2. (Non-)responding and EEG subtypes¶

ADHD sufferers with very low EEG theta values are reported to be more frequent nonresponders to stimulants.¹²⁴
Low theta values correspond to the overactivated beta (EEG) subtype according to this understanding. For the BETA subtype (overactivated type), yet another source reports reduced MPH responding.³¹
The beta subtype appears outwardly as a classic ADHD-HI subtype (hyperactive/impulsive). Most ADHD-HI subtype sufferers have too low a theta and too high a beta. See more at ⇒ ADHD subtypes according to EEG.

The (individual) ADHD sufferers of the BETA subtype known to us, however, report an extremely helpful effect of MPH.

One small study found lower resting-state EEG stability as a predictor of MPH response.¹²⁵
Another study found an attenuated P3 amplitude in responders compared to controls. Unexpectedly, nonresponders showed an atypically flat aperiodic spectral slope compared to controls, whereas responders did not differ from controls in this respect.¹²⁶

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

Individual voices suspect cases of underdosing among nonresponders, i.e., that the required dosage was not reached and that a nonresponse was only falsely assumed.¹²⁷
In our impression, too low a dosage can cause apparent nonresponding. Nevertheless, there are true nonresponders in whom even greatly increased doses do not produce satisfactory results.
In addition, a different nonresponder 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. Indications of good symptom improvement with MPH¶

An increase in blood pressure is thought to correlate with a particularly good effect of MPH.¹²⁸

Particularly good symptom improvement on methylphenidate was observed in ADHD sufferers with¹²⁹

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

One study found little or no relevance of specific genes of particular relevance to neuronal development (“Neurodevelopmental Network”) on the effect of MPH or atomoxetine in ADHD.¹³⁰

A meta-analysis across 15 studies and 1382 patients found that carriers of the T allele of the NET gene polymorphism rs28386840 were significantly more likely to respond to MPH and showed 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 significant improvement in inattention symptoms.¹³¹

5.5. Gene variants and MPH action¶

5.5.1. ADRA2A gene variants¶

ADRA2A -1291 polymorphism affects responding and effect of MPH.

• G/G Genotype:
  • 76.9% responded well to MPH¹³²
  • 25% greater symptom reduction after 3 months of MPH¹³³
• C/G genotype:
  • 46.0% responded well to MPH¹³²
• C/G genotype:
  • 41.7% responded well to MPH¹³²

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 % by OROS-MPH¹³⁴
• G/G genotype
  • diastolic blood pressure decreased by 0.2% by OROS-MPH¹³⁴
• G/C genotype
  • diastolic blood pressure decreased by 0.2% by OROS-MPH¹³⁴

5.5.2 NET gene variants¶

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

• G/G Genotype:
  • 71.9% responded well to MPH¹³⁵
  • no responding difference detected
• G/A genotype:
  • 46.0% responded well to MPH¹³⁵
• A/A genotype:
  • 57.1% responded well to MPH¹³⁵

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

• T/T genotype
  • responded comparatively better to MPH¹³⁶
  • 12.5% increase in resting heart rate by OROS-MPHi¹³⁴
• A/T genotype
  • responded comparatively better to MPH¹³⁶ -
  • Increase in resting heart rate by 3.5% due to OROS-MPH¹³⁴
• A/A genotype
  • responded comparatively worse to MPH¹³⁶
  • 2.5% increase in resting heart rate due to OROS-MPH¹³⁴

5.6. CES1 plasma protein level and MPH dosage¶

CES1 is a liver enzyme that degrades methylphenidate.
One study found that a higher plasma CES1 concentration correlated with a decreased plasma d-methylphenidate level. Plasma CES1 protein level could explain approximately 50% of the variability in plasma d-methylphenidate level. An individualized dosing strategy based on the measurement of CES1 could greatly facilitate the dosing of d-methylphenidate.¹³⁷