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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
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
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.
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
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
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
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
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 )
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 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
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
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
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.
MPH binds directly to noradrenergic receptors.44MPH 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.
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
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
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
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.
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
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
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
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
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
2.9.1. 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.
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
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
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.
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 transmission of information is usually done chemically 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 receiving nerve to the synaptic cleft, from where the sending nerve reabsorbs the neurotransmitter by special reuptake transporters (in the case of dopamine, the dopamine reuptake transporter, DAT) to be stored again in the vesicles for the next signal transmission.
In ADHD, the DAT reuptake transporters (located primarily in the striatum) are overactive. If 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”).80 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.80
The special feature of dopaminergic synapses is that, according to the latest findings (2019), there are no dopamine receptors at all on the receptor side of the dopaminergic synapse, but GABA receptors. Instead, the dopamine receptors are spatially arranged around the synapse and respond to dopamine diffusing out of the synapse or exiting in a different way.
It has been sporadically postulated that very early treatment with stimulants might permanently improve DAT overactivity (i.e., beyond intake).81
Early medication to cure 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.82
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 rats83
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.
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.
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.
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.
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
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.
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.
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
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
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.110
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
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
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
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
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
Trott, Wirth (2000): die Pharmakotherapie der hyperkinetischen Störungen; in: Steinhausen (Herausgeber) hyperkinetischen Störungen bei Kindern, Jugendlichen und Erwachsenen, 2. Aufl., Seite 211 ↥↥↥↥↥↥↥↥↥
Trott, Wirth (2000): die Pharmakotherapie der hyperkinetischen Störungen; in: Steinhausen (Herausgeber) hyperkinetischen Störungen bei Kindern, Jugendlichen und Erwachsenen, 2. Aufl., Seite 212, mit weiteren Nachweisen ↥