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MPH Part 1: Active ingredients, effect, responding

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MPH Part 1: Active ingredients, effect, responding

  1. Active ingredients

1.1. Methylphenidate as racemate

Methylphenidate is commercially available as a racemate (mixture) of L-methylphenidate and D-methylphenidate (levorotatory and dextrorotatory isomers).

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).1

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) methylphenidate2 The higher potency of D-MPH over L-AMP 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 PFC3

  • In healthy adult rats, MPH increases4

    • Dopamine in the PFC, striatum and nucleus accumbens as well as
    • Norepinephrine in the PFC, but not in the striatum or nucleus accumbens.
  • 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.5 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.

However, the increase in dopamine caused by short-term MPH could be dose-dependent. 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 produced increases in dopamine levels. Moreover, this was not the case in all animals.6

On the long-term effects of MPH, one study found that adolescent Naples High-Excitability (NHE) rats given MPH (as well as atomoxetine) for long periods of time in adulthood decreased dopamine levels in the PFC and striatum and increased norepinephrine in the ventral striatum.7

  • In juvenile rats induced89

    • A single administration of high-dose MPH (2 mg/kg, which is approximately 2 to 8 times the usual treatment dose 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)8
      • Left the protein levels of tyrosine hydroxylase (TH) and the dopamine D1 receptor unchanged8 - differently the same authors9
      • Increased the number of DAT9
        • In the left dorsal striatum
      • Did not change the DAT
        • In the right dorsal striatum
        • In the nucleus accumbens (ventral striatum)8
      • Increased the expression of the
        • Norepinephrine transporter (NET)
        • Monoamine transporter 2 (VMAT2)89
          • In contrast, amphetamine decreases VMAT210
        • 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.911
          This is in line with our experience that for some users, the dosage has to be adjusted (slightly increased) once after half a year to a year. However, a general habituation effect is neither reported in studies12 nor in practice.
        • Increased vanillic mandelic acid in the urine of Wistar rats. This could be avoided by augmenting administration of buspirone.13
          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 non-affected individuals.14

2.1.1.1. MPH and tonic / phasic DA

Methylphenidate seems to raise only tonic dopamine. Phasic dopamine is not changed by MPH, apparently because a feedback mechanism via D2 receptors inhibits it. If a D2 antagonist is given in parallel with MPH, MPH also increases phasic dopamine.15 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
According to another study, dopamine reuptake inhibitors lead to increased phasic dopamine in the dorsolateral striatum.16

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.17

2.1.1.2. MPH binds to DAT (reuptake inhibition)

Methylphenidate as a dopamine reuptake inhibitor increases dopamine levels in the synaptic cleft.3 and norepinephrine transporter18 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 is 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 children with as well as 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 frontal dysfunction, it is unclear whether the etiologic deficits in ADHD do not have other causes.17

  • 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.19
  • MPH does not bind to dopamine receptors, but only to DAT and NET.2021 (Different: MPH is supposed to activate postsynaptic D1 receptors.3 )
    • 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 to20
      • DAT with IC50 = 20 nM, Ki = 121 nM
      • NET with IC15 = 51 nM, Ki = 788 nM
    • L-MPH binds most weakly, to20
      • 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.22
  • MPH increased the number of dopamine transporters.11
  • Different:
    • Lower dopamine and noradrenaline increase in the striatum3
    • In contrast, no increase in dopamine in the striatum by MPH in DAT(-/-) mice, but in DAT(+/-) and DAT(+/+) mice23
2.1.1.3. Dopamine release by MPH?

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

  • Pure DA reuptake inhibitor2425
  • Also release of dopamine from reserpine-sensitive granules2627
  • 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.2829
  • Unlike amphetamine, methylphenidate is not considered a substrate for transport into the cytoplasm, so at best it causes little presynaptic dopamine release.30
2.1.1.4. MPH acts on DA via D2 autoreceptors

MPH causes unblocking of presynaptic D2 autoreceptors3

  • Methylphenidate normalizes increased dopamine transporter densities in ADHD-HI rats more than in ADHD-I rats31
  • 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.32
    • This corresponds to a normalization of D2 receptor binding.33
2.1.1.5. 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.89
MPH induces in monoaminergic neurons (but not in cholinergic, GABA-ergic, or glutamatergic neurons:20

  • 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 practice.20

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 (as well as exercise) can induce the expression of TH34 and increase TH levels.35
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 TH36
It is unclear whether the increase occurs only peripherally or also in the brain.37 TH gene variants seem to influence the response of MPH.37

2.1.2. MPH increases norepinephrine

  • MPH acts noradrenergically in the locus coeruleus, improving arousal, vigilance, and attention3
  • 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.5 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.38 MPH binds to20

  • 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.39 Guanfacine and clonidine also act positively as α2-adrenoceptor agonists in ADHD.

  • Blockade of the alpha-2-adrenoceptor3
    • In contrast, several sources report an agonistic effect of MPH on the alpha-2 adrenergic receptor.3839 See above.
2.1.2.2. MPH binds to NET (reuptake inhibition)
  • Norepinephrine reuptake inhibition3
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 neurons:20

  • 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.40 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,41 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.20

Whether MPH binds to serotonin receptors is unclear. Different studies come to contradictory results.20

Controversial:

  • Whether reuptake inhibition of serotonin occurs at the synapse. There are sources for this42 as well as against it.43
    • 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.37
The AATGGAGA (yin) haplotype of TPH2 appears to be less responsive to MPH than the CGCAAGAC (yang) haplotype.37

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.44

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.45

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,45 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) by46

  • Stimulation of non-vesicular release
  • Inhibition of MAO-A activity2747

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 nonaffected models. The abnormalities of 8 of them were equalized by MPH:48

  • 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 SHRs, the PFC found that

  • 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.49

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.50

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.5152

The statement made elsewhere,53 that methylphenidate does not alter HVR, is not reflected in the source cited.54

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 decrease cerebral blood flow in the PFC by reducing 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 the polymorphism of the androgen receptor gene leading to its higher expression. Nevertheless, little is known about the issue of androgen involvement in ADHD.49

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.55

2.7. Effect of MPH on ARAS

Methylphenidate increases the excitation of the reticular activating system (ARAS).56

2.8. Effect of MPH on brain networks

2.8.1. 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 due to 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.57

Another study reported interhemispheric connectivity changes in ADHD:58

  • 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

2.8.2. 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 non-affected individuals when interest is appropriately high and to deviate from the attention of non-affected 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.59 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 further references, see Normalization of the DMN by stimulants In the article Brain networks and connectivity in ADHD in the chapter Neurological aspects.

2.9. Effect of MPH on EEG

MPH caused60

  • Significant differences in ADHD sufferers 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 ADHD sufferers, which correlated with increased P3-ERP response at frontoparietal electrodes

2.10. 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 nucleus61
        • In the right globus pallidum62
        • In putamen62
      • In the caudate nucleus61
    • In the anterior cingulate cortex (ACC) in adults61
  • In hypermotor and inattentive ADHD subjects, regular methylphenidate administration increases the 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.63
    MPH increased activation in bilateral inferior frontal cortex/insula during inhibition of temporal discrimination.64
  • 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.65

MPH appears to reduce dysfunction in the PFC in most affected individuals.66 Another metastudy found that MPH showed no effect on working memory (in dlPFC).64

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.67

2.11. MPH in preschool children

Some studies show a positive effect of MPH in preschool children with ADHD.68

2.12. More about MPH

  • MPH has no effect on vesicular monoamine transporters (VMAT).18
  • MPH mediates its acute and chronic effects on behavior via the dopaminergic system of the caudate nucleus.69
  • Methylphenidate and amphetamine drugs increase the power of alpha (in rats), whereas atomoxetine and guanfacine do not.70

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.

Details on reuptake inhibition

Cerebral nerves transmit their information electrically. At a point of contact between a nerve and another nerve (synapse), the signal is passed on to another brain nerve via the synaptic cleft. This information transfer is carried out by neurotransmitters (dopamine, norepinephrine, serotonin and others). At the end of the nerve (presynaptic), the electrical signal causes a release of neurotransmitters (here: dopamine) into the synaptic cleft. At the receiving nerve on the other side of the synaptic cleft (postsynaptic), the neurotransmitter (here: dopamine) is taken up by (here: dopamine) receptors and triggers (electrical) signal transmission there when a threshold of activated receptors is reached. Afterwards, the precious neurotransmitter is returned by the receiver nerve to the synaptic cleft, from where the transmitter nerve takes up the neurotransmitter again by special reuptake transporters (in the case of dopamine, the dopamine reuptake transporter, DAT) to be stored in the vesicles for the next signal transmission.
In ADHD, the DAT reuptake transporters (located primarily in the striatum) are overactive. When dopamine is released from the transporters of the transmitter nerve into the synaptic cleft, the DAT of the presynaptic transmitter nerve already reabsorb the dopamine before it could be taken up by the postsynaptic transporters of the receiver nerve. The signal chain is thus disturbed, in terms of dopamine comparable to the noise of a radio signal (“neural noise”).71 Stimulants such as methylphenidate slow down the activity of the DAT so that the dopamine remains in the synaptic cleft long enough for the signal to be transmitted cleanly. Thus, MPH improves neural noise in ADHD sufferers to the level of non-affected individuals.71

It has been sporadically postulated that very early treatment with stimulants might permanently improve DAT overactivity (i.e., beyond intake).72

Early medication to cure from ADHD?

Early childhood stress exposure leads to long-term damage to stress regulatory systems if there is a genetic predisposition. Such an arrest of stress exposure could potentially be prevented by timely drug treatment. In mice exposed to stress, the serotonin reuptake inhibitor fluoxetine reduced stress-induced increased risk-taking, whereas the GABA-A receptor agonist diazepam did not.73

Chronic administration of caffeine or MPH prior to puberty produced improved ocular recognition in adult SHR (a strain of rats representing a genetic form of ADHD-HI), whereas the same treatment worsened it in adult Wistar rats.74

Since the neurotransmitter systems that cause stress regulation are formed and adjusted in the first years of life (presumably 6 years and earlier) and are then solidified, medication that influences this would have to begin much earlier. Whether this works is an open question. What is certain, however, is that child-centered behavioral therapy is of little benefit in young children, whereas parent-centered therapy is of considerable benefit. This may indicate that the stress systems in young children are still repairable by external influence.

An fMRI study of the effect of methylphenidate on ADHD-affected and unaffected boys, which was very small with 16 subjects, found increased activation of the frontal cortex and decreased activation of the striatum in ADHD-affected boys before taking methylphenidate compared with unaffected boys during Go/NoGo tasks. Methylphenidate counterbalanced the differences.75

3. Differences in action between methylphenidate and amphetamine medications

Methylphenidate possibly increases metabolism in the brain left frontal posterior and left parietal superior and decreases it left parietal, left parietal occipital, and frontal anterior medial.76

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.77

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.
See more 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 56

  • Unrest56

  • Impulsivity56

    • Sufferers reported in forums that MPH worked better against impulsivity than Elvanse.78
    • A study in monkeys (naturally not ADHD-affected) concluded that low doses of MPH reduced impulsivity, while higher doses had a sedative effect.79
      This follows empirical experience that an overdose of MPH can be apathetic.
  • Aggressiveness5680

    • And better than atomoxetine81
    • In a study of 6- to 12-year-old children with aggression and ADHD, systematically titrated stimulants eliminated aggression in 63%.82 Among children in 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 behavior56

  • Behavioral problems, and better than atomoxetine81

  • Somatic complaints, and better than atomoxetine81

  • Motivability through reward83

  • Drive

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

MPH works in adults:84

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

4.2. Good effect of methylphenidate

  • Perception85

  • Concentration56

    • Many adults report that MPH provides greater focus than Elvanse, while Elvanse makes them more relaxed overall and has a more consistent effect
  • Attention56

    • Distractibility is reduced, attention is increased
    • Task changes are reduced86
  • Agitation56

  • Writing and drawing expression 87

  • 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 children after interaction with a parent, oxytocin decreased in untreated ADHD sufferers. Methylphenidate caused the oxytocin increase after parent interaction in ADHD sufferers to match that of nonaffected individuals.88
  • 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 mathematical skills under MPH, which were indistinguishable from those of non-affected individuals.89
  • Anxiety80

  • Tension80

  • Borderline aspects80

  • Depressiveness80

  • Emotional instability80

  • Life dissatisfaction80

  • Negative attitude to life80

  • Psychotic phenomena80

  • Social introversion80

  • Uncertainty80

  • Compulsivity80

  • Inner emptiness/boredom90

4.3. Low effect of methylphenidate

  • Delay Aversion (in adults)91
  • Executive functions (in adults)91
    .

4.4. No effect of methylphendiate

  • Reading the Mind in the Eye (for children). This test measures the theory of mind.92

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.93 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.94 This should be considered in light of the fact that nicotine as a stimulant is self-medication in ADHD, even though smoking uses nicotine as a drug and only nicotine patches or nicotine lozenges act as medication.
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,95 Another study found increased creativity in unmedicated children with ADHD versus medicated children with ADHD and unaffected children.96

5. Responding (Responding / Nonresponding)

A summary of several studies 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.97 A meta-analysis of 32 studies came to the same conclusion (significantly better response rates to amphetamine drugs than to MPH).98
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.99

In MPH nonresponders, L-amphetamine and atomoxetine were compared in a randomized double-blind trial with n = 200 subjects. L-amphetamine was significantly more effective than atomoxetine in 2 of 6 categories and in the overall assessment.100

One study found as positive indications of MPH response:101

  • Lower ADHD RS-IV.es scores,
  • The absence of comorbidities (ODD, depression, alcohol/cannabis use)
  • Less conspicuous neuropsychological tests
  • A higher overall IQ
  • Low commission errors (impulse control errors; response to signal that should not have been responded to) in Conners Continuous Performance Test II, CPT-II

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.102103104105106
More recent sources speak of up to 75% response rate with MPH,107 which seems more accurate to us.

ADHD-I subtype sufferers were reported to be more frequent MPH nonresponders,108 citing nonresponder rates of 24%102. 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.109

A particularly strong cortisol awakening response (CAR) correlated with decreased MPH responding in children.109

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 indicate MPH nonresponding. Neither elevated SCT Daydreamy symptoms nor ADHD subtype (ADHD-HI or ADHD-I) differed in MPH responding rates in this study.110

According to one study, MPH is said to be less responsive in ADHD sufferers with intellectual deficits. A responder rate of 40 to 50 % was reported.111 Another study, however, found a good effect of MPH in patients with intellectual deficits.112

5.2. (Non-)responding and EEG subtypes

ADHD sufferers with very low EEG theta values are reported to be more frequent nonresponders to stimulants.113
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.25
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.114
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 here.115

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.116
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.117

Particularly good symptom improvement on methylphenidate has been observed in ADHD sufferers with118

  • 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.119

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.120


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