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Chemical name: Methyl-2-phenyl-2-(piperidin-2-yl)acetate
Molecular formula: C14H19NO2
Mass: 233.31 g/mol
has four configuration isomers
As methylphenidate has two asymmetric carbon atoms, there are four different forms of this drug2
(+)-Erythromethylphenidate
(-)-Erythromethylphenidate
(+)-threomethylphenidate
(-)-threomethylphenidate.
MPH is classified worldwide as a narcotic because it can be abused as a drug when taken in extreme doses and forms. However, when taken in medication doses and in medication form (oral/patch), MPH has no potential for intoxication or dependence. The actual risk of abuse of methylphenidate as a drug appears to be considerably overestimated. A study that claimed frequent misuse of MPH as a drug merely referred to sources in which methylphenidate is not even mentioned3
With (especially older) studies on the effect of MPH, it must always be taken into account that these4
MPH usually used in significantly higher doses than for ADHD medication
Although rodents require higher doses than humans, doses are often used that correspond to drug intake and not to medication intake
use unretarded / not prolonged-acting MPH via prodrug
frequently inject MPH, which can result in much faster metabolism depending on the type of injection
IP injection should be similar to oral intake
these 3 factors multiply in their effect
There is no doubt that MPH in medication form has a different effect than MPH in drug form.
Helpful details for assessing the validity of MPH animal studies
Recording forms:
Intraperitoneal injections (IP, injections into the abdominal cavity)
IP in rodents is performed in the lower right quadrant of the abdomen below the midline. This video shows how such an IP injection is performed (German). IP injections should largely correspond to oral ingestion. Absorption is much slower intraperitoneally than with intravenous injections. IP allows for more efficient absorption of MPH in the mesenteric vessels that enter the portal vein and pass through the liver, allowing given drug to undergo hepatic metabolism before reaching the systemic circulation. In addition, a small amount of the intraperitoneally injected material can pass through small lacunae directly through the diaphragm into the thoracic lymph5
MPH administration via IP injection increases the DA concentration in the brain faster and much longer lasting than oral administration.6
IP injection of drugs in experimental studies with rodents is acceptable for pharmacological and proof-of-concept studies to investigate the effect(s) of the target effect. It is unsuitable for studies on the properties of a drug formulation and/or its pharmacokinetics for clinical implementation.7
The risks of IP injections are:
Injuries due to incorrect injection
Change in effect if injection too close to the surface (subcutaneous instead of intraperitoneal)
Subcutaneous injections have the following effects
Oral gavage
Oral gavage better mimics oral uptake and human MPH metabolism. Oral administration uses a suitable tube or administration needle that is inserted into the animal’s mouth and esophagus. However, the manual fixation required for oral gavage causes such severe stress in both rats and mice that it increases plasma corticosterone levels9
avoid the first-pass effect of hepatic metabolism, which often occurs with oral administration
therefore generally generate a higher bioavailability
avoid unpredictable effects associated with enteral absorption processes
orally (in the mouth)
directly into the stomach (gastric tube)
intravenously (into a blood vessel)
epicutaneous (on the skin)
intradermal (into the skin)
subcutaneously (under the skin)
transdermal (through the skin, e.g. plaster)
intramuscular (into the muscle)
transcorneal (on the eye)
intraocular (or into the eye)
intracerebral (into the brain)
epidural (in the space surrounding the dura mater)
intrathecal (in the space surrounding the distal spinal cord);
intraosseous (into the bone marrow cavity)
intranasal (sprayed into the nose for absorption via the nasal mucous membranes or the lungs)
intratracheal (into the lungs by direct tracheal instillation or inhalation)
The dosage does not differ between mice and rats on the basis of the species, but solely on the basis of the size of the respective animal. MPH doses act according to an inverted-U principle10
In rodents (mice such as rats):
Doses of 1 mg/kg MPH or less:
no effects on movement activity due to subcutaneous injection11
Doses of 2 to 5 mg/kg MPH appear to correspond to a drug dose in humans12
by subcutaneous injection: increase in movement activity
Doses of 10 to 20 mg/kg MPH are said to be more like drug intake13
by subcutaneous injection: increase in movement activity
Methylphenidate is usually offered clinically as a racemate (mixture) of 50 % L-methylphenidate and 50 % D-methylphenidate (levorotatory and dextrorotatory isomers), which is ten to a hundred times more effective than the (+/-) erythroform.2
While a significant proportion of D-MPH enters the CNS via the blood-brain barrier, L-MPH is not absorbed into the CNS.14
Brand names include Ritalin, Medikinet, Equasym, Concerta, Kinecteen, Daytrana (skin plaster). It is also offered as a generic. See below for more information.
Dosage from 2.5 mg to an average of 15 mg per single dose during the day every 2.5 to 3.5 hours (unretarded form).15
Dexmethylphenidate is the pure form of the dextrorotatory isomers and is pharmacologically active.
Brand name: Focalin (Switzerland and USA only)
It is 3 times more effective than racemic (mixture of dextrorotatory (D-MPH) and levorotatory (L-MPH) methylphenidate.16 The higher efficacy of D-MPH compared to L-MPH concerns the dopamine transporter as well as the noradrenaline transporter binding.
It is therefore recommended to halve the dosage of D-MPH compared to racemate methylphenidate and to limit it to a maximum of 20 mg/day in children and adults.
D-MPH is also available as a prolonged-release preparation (Focalin XR).
L-MPH is the pure form of the levorotatory isomers and is pharmacologically almost ineffective.
L-MPH is predominantly metabolized in the intestinal mucosa. The remaining L-MPH is metabolized by the liver during the first pass. L-MPH is almost completely metabolized within 10 minutes of ingestion17
The small, unmetabolized residue of L-MPH competes with the dextrorotatory and pharmacologically active isomer D-MPH for the binding sites in the brain and reduces its effectiveness.17
According to another source, the left-turning MPH isomer L-MPH (unlike D-MPH) is not absorbed into the CNS.18
Serdexmethylphenidate (SDX) is a prodrug of dexmethylphenidate (d-MPH) and is currently only approved in the USA (Azstarys®, KP415 with 70 % SDX and 30 % MPH).19
The advantage of prodrugs is a prolonged effect, as the conversion of product into active ingredient delays the release. See also lisdexamfetamine, which is first converted to dextroamphetamine (Elvanse).
The first computer models now exist that can seriously simulate the effect of ADHD drugs. A computer model for the simulation of type 1 diabetes has already been approved by the FDA as a replacement for preclinical animal studies20
A model comparing MPH and AMP in children and adults with ADHD takes into account the effect on 99 proteins involved in ADHD21
2.1.1.1. MPH increases extracellular and possibly decreases phasic dopamine¶
Many sources only report a general effect on dopamine and noradrenaline.
The blanket statement that MPH increases dopamine is ultimately not helpful, as a distinction must be made between tonic and phasic dopamine release and extracellular dopamine levels, as well as between the effect in different regions of the brain.
Increase in dopamine and noradrenaline in the PFC222324
MPH doses whose plasma levels are in the range of therapeutic use for ADHD, such as2526
1.0 mg/kg in rats
Increase extracellular noradrenaline in the hippocampus by 100
Do not significantly alter dopamine in the nucleus accumbens (striatum)
2.5 mg/kg in rats
Increase extracellular noradrenaline in the hippocampus by 150-175 %
Do not significantly alter dopamine in the nucleus accumbens (striatum).
In healthy adult rats, MPH increases
Dopamine in the PFC, striatum and nucleus accumbens and27
High doses: DA increased by release from noradrenergic cells28
Striatum: low and high doses: consistent increase in dopamine
PFC: increase in dopamine only at high doses
In rats, 1 mg/kg MPH as a single dose as chronic (21 days) caused
Striatum: no change in extracellular levels of noradrenaline, dopamine or serotonin29
In summary, MPH appears to affect only the PFC and hippocampus in rats, whereas in primates it also affects the striatum.
Tonic dopamine mediates the regulatory (inhibitory) control of the PFC on the ventral striatum, thus inhibiting the (phasic) activity of the striatum. In response to unexpected positive reward stimuli, the striatum fires phasically in a dopaminergic manner and activates dopaminergic postsynaptic receptors. Tonic control is therefore inhibitory and modulates excitatory phasic firing in response to unexpectedly positive reward stimuli.32
shortens the frequency of postsynaptic multisecond oscillations in the basal ganglia from around 30 seconds to 5 to 10 seconds. Already 1.0 mg/kg MPH or 0.2 mg/kg D-Amp showed an effect.
however, 0.2 mg/kg D-Amp showed only a slight presynaptic effect. D-Amp had a stronger postsynaptic effect.
MPH increases extracellular dopamine and decreases phasic dopamine in the striatum.
This is consistent with Grace’s hypothesis that ADHD is characterized by decreased tonic and increased phasic dopamine. This model is likely to apply at least to most cases of ADHD. More on this under Dopamine release (tonic, phasic) and coding
The statement “MPH increases tonic dopamine” would not be correct because tonic firing itself is not increased by MPH. The inhibition of reuptake only leads to an increase in the extracellular dopamine level, not to a change in tonic firing.
The following reasons for the increase in extracellular dopamine by MPH were identified
increased dopamine efflux due to reversal of the dopamine reuptake transporter in the striatum28
MPH increased response strength and reward expectancy-related BOLD signaling in the ventral striatum during a gambling task,36 suggesting that striatal tonic dopamine levels represent an average reward expectancy signal that modulates the phasic dopaminergic response to reward.
The DAT blocker nomifensine enhanced the phasic dopaminergic signal34, so dopamine reuptake inhibition per se cannot be the only reason for the reduction in tonic dopamine by MPH
Several studies found a reduction in phasic dopamine by MPH,343736 but some also found no change3528 or an increase. This could depend on the circumstances (e.g. dosage, DAT sensitivity).
The significant reduction in the phasic (synaptic) release of dopamine is probably due to a decrease in synapsin phosphorylation34
The inhibition of phasic dopamine is not a consequence of presynaptic D2 autoreceptor activation, since this34
- a. also in the presence of the D2 antagonist sulpiride and
- b. also occurs in DAT-CI striatal slices in which activation of D2 autoreceptors cannot occur due to an increased extracellular DA level
The inhibition of phasic dopamine could possibly be due to a reduction in synaptic vesicle neurotransmitter, as with cocaine.34 Cocaine, as a lipophilic weak base, could collapse the vesicular pH gradient, similar to the “weak base effects” reported for amphetamines, or act on vesicles. There is evidence that synaptic vesicles can be quite “leaky” and constantly leak dopamine into the cytosol. This impression is supported by the action of reserpine, which can rapidly deplete synaptic vesicles of dopamine.
One study found that MPH did not alter phasic dopamine, suggesting an inhibitory feedback mechanism via D2 autoreceptors, because a D2 antagonist given in parallel with MPH caused MPH to also increase phasic dopamine35
Dopamine reuptake inhibitors such as MPH should generally lead to increased phasic dopamine in the dorsolateral striatum37 Acute MPH administration increased the firing activity of PFC pyramidal neurons in rats and potentiated NMDA-induced neurotransmission28
2.1.1.1.3. Stimulants alter dopaminergic firing rate¶
Methylphenidate as a dopamine reuptake inhibitor increases the dopamine level in the synaptic cleft.22MPH inhibits the dopamine transporter and the noradrenaline transporter38 From this it could be concluded that the site of action of MPH is where there is a dopamine deficiency. In the mesocortical model of ADHD, this would be the PFC. However, SPECT and PET studies clearly show that MPH primarily increases dopamine activity in the striatum, which argues against the PFC as the (sole) site of action (which correlates with the low DAT count in the PFC and the high DAT count in the striatum). Since, according to the mesocortical model of ADHD, dopamine activity in the ventral striatum is excessive, MPH, if it has an increasing effect there, should worsen rather than improve symptoms. Low-dose stimulants such as MPH can inhibit phasic dopamine release by enhancing inhibitory tonic control.39 However, in an fMRI study, children with ADHD without medication showed increased frontal and decreased striatal activation, arguing against the mesocortical deficiency theory. MPH increased frontal blood flow in children with and without ADHD, but only increased striatal blood flow in children with ADHD. It is therefore unclear whether the observed frontal deficits in ADHD reflect a central dysfunction in the PFC or a lack of input from other dopaminergic systems. Since almost all mental disorders show a certain degree of frontal dysfunction, it is unclear whether the aetiological deficits in ADHD have other causes.32
MPH binds to the dopamine transporters whose density is highest in the striatum. The binding of MPH in the cerebellum and hippocampus is less than a tenth of this.40
MPH does not bind to dopamine receptors, but only to DAT and NET.4142 (In contrast: MPH is said to activate postsynaptic D1 receptors.22 )
MPH drug doses cause an MPH plasma concentration of around 20 to 30 nM, which is sufficient to occupy a significant proportion of the dopamine transporters. This effect coincides with that of D-AMP.39
MPH responders showed an increased DAT count in the striatum, non-responders a reduced DAT count.43
MPH increased the number of dopamine transporters.44
Different:
Lower increase in dopamine and noradrenaline in the striatum22
No increase in dopamine in the striatum by MPH in DAT(-/-) mice, but in DAT(+/-) and DAT(+/+) mice45 Apparently, the degree of expression/sensitivity of the DAT is decisive for the positive or negative modulation of phasic dopamine release.46
2.1.1.3. MPH increases dopamine release through DAT (efflux)¶
While it was previously assumed that methylphenidate does not cause dopamine release, more recent opinions assume that it does
a dopamine efflux from the DAT
dopamine release from vesicles at very high doses.
The view that MPH is a pure DA reuptake inhibitor4748 is outdated.
Also release of dopamine from vesicles (here: reserpine-sensitive granules)4950
Should only occur at very high doses of more than 80 mg / day5152
In contrast to amphetamine, methylphenidate is not considered a substrate for transport into the cytoplasm, which is why it causes at most a slight presynaptic release of dopamine.53
Dopamine efflux through DAT reversal in the PFC
In the striatum in rats at 4 mg/kg (measured ex vivo)28
MPH thereby increases the extracellular dopamine level
Efflux from dopamine and noradrenaline terminals
By vesicular dopamine release and by sodium-dependent mechanisms
Increase the firing rate of PFC pyramidal neurons
At chronic intake in PFC in rats at 4 mg/kg (measured in vivo)28
measured by extracellular electrophysiological single-cell recordings
Reactions to locally applied NMDA unchanged
Desensitization to both dopamine and MPH in striatal regions
With chronic ingestion in the striatum in rats at 4 mg/kg (measured in vivo)28
reduced efficacy of extracellular dopamine in modulating NMDA-induced firing activities of medial spinous process neurons in the striatum
lower MPH-induced dopamine outflow
is consistent with the empirical experience that a one-time adjustment of the MPH dose is required after a few weeks in the case of single dosing
MPH causes the disinhibition (removal of inhibition) of presynaptic D2 autoreceptors54
Nevertheless, the effect of stimulants in different doses on D2 autoreceptors is not greater than on the postsynaptic heteroreceptors. Stimulants appear to have little effect on the dopamine system above autoreceptors.33 * In people with a high number of D2 receptors, MPH increases metabolism in frontal and temporal brain areas (including the striatum), whereas in healthy people with a low number of D2 receptors, MPH decreases metabolism. Metabolism was consistently increased in the cerebellum.55
* This corresponds to a normalization of the D2 receptor binding.56
Methylphenidate normalizes increased dopamine transporter densities in ADHD-HI rats more than in ADHD-I rats57
MPH influences the redistribution of the vesicular monoamine transporter-2 (VMAT-2; Solute Carrier Family 18 Member 2 - SLC18A2). VMAT2 is involved in the sequestration of cytoplasmic dopamine and noradrenaline and is therefore an important regulator of neurotransmission. MPH does not affect the total amount of VMAT-2 in presynaptic terminals, but only VMAT-2 transport.5859 MPH has the following effects in monoaminergic neurons (but not in cholinergic, GABA-ergic or glutamatergic neurons)41
Decrease in VMAT-2 immunoreactivity in the membrane-associated fraction
Increase in the cytoplasmic fraction
no change in the entire synaptosomal pool
MPH thus protects the dopaminergic system from progressive “wear and tear” by securing a considerable DA reserve pool in the presynaptic vesicles. Therefore, there is only a relatively low risk of neurotoxic / neuropsychiatric side effects in treatment practice with MPH41
According to older reports, MPH has no effect on vesicular monoamine transporters (VMAT).38
Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the synthesis of dopamine. TH converts tyrosine into the DA precursor L-3,4-dihyroxyphenylalanine (L-DOPA). MPH thus supports dopamine synthesis. MPH (as well as sport) can induce the expression of TH60 and increase TH levels61
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 TH62
It is unclear whether the increase occurs only peripherally or also in the brain.63 TH gene variants appear to influence the response of MPH.63
The L-dopa receptor GPR143 appears to be involved in the acute and chronic effects of MPH.
Although MPH increases dopamine release, it does not affect L-DOPA release from the dorsolateral striatum. Nevertheless, in L-DOPA receptor KO mice (mice with a defect in the Gpr143 L-DOPA receptor gene), L-DOPA release is reduced:64
The effect of MPH is dose-dependent. Normal doses of MPH have different effects than high or very high doses of MPH.
At low doses, methylphenidate increases dopamine and noradrenaline levels in the PFC, which increases its performance. In contrast, low-dose MPH has hardly any effect on dopamine and noradrenaline levels in other areas of the brain.65 This corresponds to the known increase in cognitive performance of the PFC due to small increases in dopamine and noradrenaline levels during mild stress.
At 3 mg/kg MPH, one study found no increase in dopamine or noradrenaline in the striatum of rats66
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.46
Acute MPH administration increased the firing activity of PFC pyramidal neurons in rats and potentiated NMDA-induced neurotransmission. Chronic MPH administration (2 x 2 mg/kg/day) showed 28 days after the end of MPH administration on pyramidal neurons of the PFC28
long-term increase in firing activity
unchanged burst activities
unchanged total number of spontaneously discharging neurons
unaltered glutamatergic neurotransmission
Long-term administration of MPH or atomoxetine to juvenile Naples High-Excitability (NHE) rats in adulthood67
Stronger in the nucleus accumbens (ventral striatum) than in the dorsal striatum
Stronger in the parietal cortex than in the frontal cortex
This effect of chronic MPH on increasing DAT, NET and VMAT2 transporters may suggest that the drug could lose some of its acute effect of increasing dopamine and noradrenaline levels in the long term.5944
This is consistent with our experience that for some users the dosage has to be adjusted (slightly increased) once after six months to a year. However, a general habituation effect is neither reported in studies69 nor in practice.
Elevated vanillin mandelic acid in the urine of Wistar rats. This could be avoided by augmentative administration of buspirone.70
Vanillin mandelic acid is produced during the breakdown of adrenaline and noradrenaline by MAO-A and COMT, so that vanillin mandelic acid is an indicator of the activity of the autonomic nervous system (sympathetic nervous system).
A single administration of very high doses of MPH (5 mg/kg, i.e. about 5 to 20 times the usual treatment dose for humans) has the following effects
A similar metabolite change in the cerebellum as 2 mg
Metabolites in the cerebellum associated with energy expenditure and excitatory neurotransmission, here glutamate, glutamine, N-acetylapartate and inosine, tended to be reduced
Furthermore, the levels of some metabolites associated with inhibitory neurotransmission, in this case GABA and glycine, acetate, aspartate and hypoxanthine, were reduced
One study found that basal oxytocin levels in children with ADHD were unchanged compared to unaffected children. While oxytocin decreased in untreated ADHD sufferers after interaction with a parent, oxytocin increased in ADHD sufferers treated with MPH in the same way as in unaffected children.71
MPH has a noradrenergic effect in the locus coeruleus, which improves arousal, vigilance and attention22
The effect of MPH is dose-dependent. Normal doses of MPH have different effects than high or very high doses of MPH.
At low doses, methylphenidate increases dopamine and noradrenaline levels in the PFC, which increases its performance. In contrast, low-dose MPH has hardly any effect on dopamine and noradrenaline levels in other areas of the brain.65 This corresponds to the known increase in cognitive performance of the PFC due to small increases in dopamine and noradrenaline levels during mild stress.
2.1.2.1. MPH low dose increased extracellular noradrenaline, but not dopamine¶
Adolescent rats received 0.75-3.0 mg/kg MPH orally during the dark-active phase of the circadian cycle, which remained below the threshold for locomotor activation. These doses:26
increased extracellular norepinephrine in the hippocampus
altered dopamine in the nucleus accumbens does not
did not alter methamphetamine sensitivity
did not cause any habituation effects
10, 20 and 30 mg/kg MPH (far above a medicinal dosage):72
stereotypic behavior (a sign of strongly increased extracellular dopamine); 20 mg/kg as strong as 2.5 mg/kg AMP
extracellular dopamine increased
extracellular noradrenaline increased
extracellular serotonin unchanged (unlike AMP, as it is elevated)
This also increases extracellular dopamine in the PFC, where there is little DAT but plenty of NET
2.1.2.3. MPH causes noradrenaline efflux in the PFC¶
2.1. MPH induces dopamine and noradrenaline efflux in the prefrontal cortex
In the prefrontal cortex (PFC), administration of 100 µM methylphenidate (MPH) (Figure 1A) elicited significant ex vivo dopamine release (Bonferroni post-hoc test after significant two-way ANOVA, Supplementary Table S1). This effect was dependent on norepinephrine terminals, as incubation of radiolabeled dopamine (35 nM) in the presence of desipramine significantly attenuated the dopamine efflux induced by 100 µM MPH (Figure 1A, Bonferroni post-hoc test after significant two-way ANOVA). This was further confirmed by assessing radiolabeled norepinephrine efflux (67-83 nM) after MPH exposure in PFC samples. Indeed, MPH at 100 µM induced significant norepinephrine efflux in the PFC (Figure 1B, Tukey’s post hoc test after significant one-way ANOVA). A lower dose of 10 µM MPH did not elicit dopamine efflux under any conditions. These results suggest that MPH can induce both dopamine and norepinephrine efflux in the PFC, an effect that originates from both dopamine and norepinephrine terminals at a dose of 100 µM.
Noradrenaline efflux (67-83 nM) from noradrenaline terminals28
MPH influences the redistribution of the vesicular monoamine transporter-2 (VMAT-2; Solute Carrier Family 18 Member 2 - SLC18A2). VMAT2 is involved in the sequestration of cytoplasmic dopamine and noradrenaline and is therefore an important regulator of neurotransmission. MPH does not affect the total amount of VMAT-2 in presynaptic terminals, but only the VMAT-2 transport. MPH has an effect in monoaminergic neurons (but not in cholinergic, GABA-ergic or glutamatergic neurons41
Decrease in VMAT-2 immunoreactivity in the membrane-associated fraction
MPH binds directly to noradrenergic receptors.73MPH binds to41
α2A (Ki = 5.6 µM)
α2B (Ki = 2.420 µM)
α2C (Ki = 0.860 µM)
The cognitive improvement brought about by MPH could be prevented by α2-adrenoceptor antagonists.74 Guanfacine and clonidine also have a positive effect as α2-adrenoceptor agonists in ADHD.
The overall influence of MPH on serotonin levels appears to be negligible.75 D-threo-(R,R)-methylphenidate is a weak agonist of the 5HT-1A serotonin receptor, but not of the 5HT-2A receptor. This can influence the dopamine metabolism in the brain,76 but the extent is small. MPH is said to bind 2200 times more strongly to the DAT than to the SERT and almost 1300 times more strongly to the NET than to the SERT.41
Whether MPH binds to serotonin receptors is unclear. Various studies have produced contradictory results.41
Controversial:
Whether a reuptake inhibition of serotonin occurs at the synapse. There are sources for this77 as well as against it.78
The serotonergic effect of MPH is so weak that it is not relevant for the treatment
Our impression is that MPH has no significant mood-enhancing effect
Of the two tryptophan hydroxylase isoforms, TPH1 and TPH2, only TPH2 is present in the brain. TPH catalyzes the rate-limiting step in the synthesis of serotonin by converting tryptophan into the serotonin precursor 5-hydroxytryptophan.63
The AATGGAGA (Yin) haplotype of TPH2 appears to be less responsive to MPH than the CGCAAGAC (Yang) haplotype.63
In ADHD-HI sufferers (predominantly hyperactive) with comorbid depressive symptoms, one study found significantly higher morning than evening levels of indoleacetic acid compared to ADHD-I sufferers and healthy controls. MPH reduced this by 50 %. MPH also reduced the morning levels of indolepropionic acid and brought the daily profile back to the levels of healthy controls.79
behavioral sensitization in some rats (which correlated with neuronal arousal) and
behavioral tolerance (which was associated with neuronal attenuation) in other rats.
The neurons of the dorsal raphe nuclei (serotonergic) responded most strongly to acute and chronic MPH administration and differently to the neurons in VTA (dopaminergic) or locus coeruleus (noradrenergic) at all 3 doses used.80 Dorsal raphe nuclei and serotonin appear to be involved in the acute and chronic effects of MPH and play an independent role in the response to MPH.
2.1.4. Binding affinity of MPH, AMP, ATX to DAT / NET / SERT¶
The active ingredients methylphenidate (MPH), d-amphetamine (d-AMP), l-amphetamine (l-AMP) and atomoxetine (ATX) bind with different affinities to dopamine transporters (DAT), noradrenaline transporters (NET) and serotonin transporters (SERT). The binding causes an inhibition of the activity of the respective transporters.81
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 / noradrenaline per brain region¶
The active substances methylphenidate (MPH), amphetamine (AMP) and atomoxetine (ATX) alter extracellular dopamine (DA) and noradrenaline (NE) to different degrees in different regions of the brain. Table based on Madras,81 modified.
However, the influence appears to be limited and of little relevance.
2.2. Effect of MPH on cholesterol metabolism in the OFC¶
One study found 12 altered metabolic metabolites in the PFC in SHR rats, considered an ADHD-HI model, compared to WKY rats, considered a model of non-affected individuals. The deviations of 8 of these were equalized by MPH:84
3-Hydroxymethylglutaric acid
3-phosphoglyceric acid
Adenosine monophosphate
Cholesterol
Lanosterine
O-Phosphoethanolamine
3-Hydroxymethylglutaric acid
Cholesterol
The altered metabolites belong to the metabolic pathways of cholesterol.
In the case of the SHR, the PFC found that
Reduced activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase
Unchanged by MPH
Reduced expression of the sterol regulatory element-binding protein-2
Increased by MPH
Reduced expression of the ATP-binding cassette transporter A1
Stimulants (methylphenidate and amphetamine drugs) are said to increase the activity of the HPA axis.85 MPH increases the cortisol awakening response, which is a sign of reactivity of the HPA axis.86
MPH increased physiological measures of stress (salivary cortisol and blood pressure). MPH modulated the effects of stress on the activation of brain areas associated with goal-directed behavior, including the insula, putamen, amygdala, mPFC, frontal pole, and OFC. However, MPH did not modulate the tendency of stress to cause a reduction in goal-directed behavior.87
2.4. Effect of MPH on the autonomic nervous system (sympathetic / parasympathetic nervous system)¶
In ADHD, heart rate variability (HRV), which correlates with the health of the autonomic nervous system and in particular reflects the activity of the parasympathetic nervous system, is reduced. Stimulants such as methylphenidate improve (increase) heart rate variability without, however, being able to raise it to the level of non-affected people.8889
The statement made elsewhere,90, that methylphenidate does not change the HVR is not found in the source cited.91
Stimulants (methylphenidate and amphetamine drugs) reduce the concentration of androgens.
Preclinical data on the role of androgens in the pathogenesis of ADHD suggest that elevated testosterone levels may reduce cerebral blood flow in the PFC by decreasing the amount of alpha estrogen receptors and vascular endothelial growth factor (VEGF). This can interfere with memory processes. There is a correlation between ADHD and the polymorphism of the androgen receptor gene, which leads to its higher expression. Nevertheless, little is known about the question of androgen involvement in ADHD.85
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.92
Methylphenidate increases the excitation of the reticular activation system (ARAS).93
2.8. Effect of MPH on oxidative/nitrosative status¶
MPH improved the redox profile with a reduction in the levels of advanced oxidation protein products (AOPP), lipid peroxidation (LPO) and nitrite plus nitrate (NOx) and an increase in the enzymatic activities of glutathione reductase (GRd) and catalase (CAT).86
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 see this as an indication that a neuroinflammatory cause of ADHD may damage glial function and thereby alter dopaminergic (DA) neurotransmission.94
2.10.1. MPH and connectivity between brain regions¶
In one study, methylphenidate normalized reduced global connectivity in ADHD 400-700 ms after a stimulus and reduced an increase in network disconnection 100-400 ms after the stimulus. These global changes caused by methylphenidate occurred mainly in the task-relevant frontal and parietal regions and were more significant and lasting than in the non-treated comparison subjects. The results of the study indicate that methylphenidate corrects impaired network flexibility in ADHD.95
Another study reports interhemispheric connectivity changes in ADHD:96
Reduced interhemispheric coherence in the delta band in frontal brain regions
Increased coherence in the theta band in posterior regions (only with eyes open)
Increased coherence in the theta band in central areas
2.10.2. Effect of MPH on Default Mode Network (DMN)¶
The increased purely intrinsically motivated control of attention in ADHD means that attention and its controllability are just as high as in non-affected individuals when interest is high and only deviates from the attention of non-affected individuals when intrinsic interest is low. This is controlled by the DMN.
Stimulants are able to align the attentional control of ADHD sufferers with that of non-affected persons in the absence of intrinsic interest.97 This explains why stimulants are just as helpful for ADHD-HI and ADHD-C as they are for ADHD-I.
2.10.3. Effect of MPH on nucleus accumbens and cognitive control networks¶
Methylphenidate increased spontaneous neuronal activity in the nucleus accumbens and in cognitive control networks in children with ADHD. This resulted in more stable sustained attention.98
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 patients, which correlated with increased P3-ERP response at the frontoparietal electrodes
In the anterior cingulate cortex (ACC) in adults100
MPH mediates its acute and chronic effects on behavior via the dopaminergic system of the caudate nucleus.102
In hypermotor and inattentive ADHD sufferers, regular administration of methylphenidate increases the previously unusually low blood flow to the putamen. In ADHD-affected children with average motor activity, regular administration of methylphenidate caused a reduction in blood flow to the putamen. The thalamus was not affected by MPH.103 MPH increased activation in the bilateral inferior frontal cortex/insula during inhibition of temporal discrimination.104
Methylphenidate increases the metabolism in the brain on the left frontal posterior and left parietal superior and decreases it on the left parietal, left parietooccipital and frontal anterior medial.105
MPH appears to reduce dysfunction in the PFC in most affected individuals.106 Another meta-study found that MPH had no effect on working memory (in the dlPFC).104
A study in rats with 0, 0.6, 2.5 and 10.0 mg MPH/kg as single and repeated doses found that MPH acted on the PFC and caudate nucleus. The same dose of MPH induced behavioural sensitization in some animals and tolerance in others, with activity in the PFC and caudate nucleus correlating with the animals’ behavioural responses to MPH. The reaction of the caudate nucleus was more intense than that in the PFC, with both single and repeated administration. In addition, different dose-dependent responses were found between PFC and caudate nucleus: some PFC and caudate nucleus cell units responded to the same MPH dose with excitation and others with attenuation of the neuronal firing rate.107
ADHD sufferers often show an increased sensitivity to pain. MPH can eliminate this sensitivity to pain in ADHD sufferers.109
2.15. Serdexmethylphenidate improves sleep in ADHD¶
One study reports a significant improvement in sleep in children with ADHD between the ages of 6 and 12 with serdexmethylphenidate or dexmethylphenidate.110
Methylphenidate and amphetamine drugs increase the power of alpha (in rats), while atomoxetine and guanfacine do not.111
MPH acts (among other things) on the dopamine transporters in the brain. As the number of dopamine transporters decreases with increasing age (halving in 50-year-olds compared to 10-year-olds), adults require significantly lower doses.
Details on resumption inhibition
Cranial 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 carried out chemically by neurotransmitters (dopamine, noradrenaline, serotonin and others). The electrical signal causes a release of neurotransmitters (here: dopamine) into the synaptic cleft at the end of the nerve (presynaptic). At the receptor 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 when a threshold value of activated receptors is reached. The precious neurotransmitter is then returned to the synaptic cleft by the receiving nerve, from where the sending nerve takes up the neurotransmitter again through special reuptake transporters (in the case of dopamine, the dopamine reuptake transporter, DAT) in order to be stored in the vesicles again for the next signal transmission.
In ADHD, the DAT reuptake transporters (primarily located in the striatum) are overactive. If dopamine is released into the synaptic cleft by the transporters of the transmitter nerve, the DAT of the presynaptic transmitter nerve absorb the dopamine again before it can be taken up by the postsynaptic transporters of the receptor nerve. The signal chain is thus disrupted, comparable to the noise of a radio signal (“neural noise”) in relation to dopamine.112 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. In this way, MPH improves the neural noise in ADHD sufferers to the level of non-affected people.112
The special feature of dopaminergic synapses is that, according to the latest findings (2019), there are no dopamine receptors on the receptor side of the dopaminergic synapse, but rather GABA receptors. Instead, the dopamine receptors are arranged spatially around the synapse and react to dopamine diffusing or otherwise escaping from the synapse.
It is occasionally postulated that very early treatment with stimulants could permanently improve DAT overactivity (i.e. beyond the intake).113
Early medication to cure ADHD?
Early childhood stress exposure leads to long-term damage to the stress regulation systems if there is a corresponding genetic disposition. Such an establishment of stress exposure could possibly be prevented by timely drug treatment. In mice exposed to stress, the serotonin reuptake inhibitor fluoxetine reduced stress-induced increased risk-taking, while the GABA-A receptor agonist diazepam did not.114
Chronic administration of caffeine or MPH before puberty improved object recognition in adult SHR (a rat strain representing a genetic form of ADHD-HI), while the same treatment worsened it in adult Wistar rats115
As the neurotransmitter systems that regulate stress are formed, adjusted and then solidified in the first few years of life (presumably 6 years and earlier), medication that influences this should start much earlier. Whether this will work remains to be seen. What is certain, however, is that child-centered behavioral therapy is of little benefit for small children, while parent-centered therapy brings considerable benefits. This could indicate that the stress systems in young children can still be repaired by external influences.
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 reduced activation of the striatum in ADHD-affected boys before taking methylphenidate compared to unaffected boys in go/no-go tasks. Methylphenidate compensated for the differences.116
It remains to be seen what concentrations of methylphenidate reach the synaptic cleft.34
Methylphenidate could accumulate in the central nervous system through active accumulation processes, so that the effective brain concentrations are considerably higher than in plasma.117 For cocaine, the striatal concentration in animals appears to be about 6 times higher than in plasma.118
3. Differences in effect between methylphenidate and amphetamine medication¶
Methylphenidate may increase left frontal posterior and left parietal superior brain metabolism and decrease left parietal, left parietooccipital and frontal anterior medial metabolism.119
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 the right anterior inferior frontal regions.120
The samples (n) on which these findings were examined were very small at 19 and 18. Samples that are too small harbor the considerable risk of misleading results.
Find out more at ⇒ Studies say - sometimes nothing at all.
Those affected reported in forums that MPH works better against impulsivity than Elvanse.123
A study on monkeys (naturally not affected by ADHD) came to the conclusion that low doses of MPH reduced impulsivity, while higher doses had a sedative effect.124
This follows on from empirical experience that an overdose of MPH can have an apathetic effect.
In a study of 6- to 12-year-old children with aggression and ADHD, systematically titrated stimulants eliminated aggression in 63% of cases.127 In the children in whom stimulants did not sufficiently eliminate aggression, augmentative administration of risperidone (effect size 1.3) or valproic acid (effect size 0.9) improved aggression, with risperidone being associated with weight gain.
One study found that basal oxytocin levels in children with ADHD were unchanged compared to those without ADHD. While oxytocin increased in non-affected children after interaction with a parent, oxytocin decreased in untreated ADHD sufferers. Methylphenidate caused the oxytocin increase in ADHD sufferers after parent interaction to correspond to that of non-affected persons.135
Rejection sensitivity (offendingness)
Almost all of the people we interviewed reported an improvement in their rejection sensitivity (which affects almost all of the ADHD sufferers we interviewed) as a result of MPH. A few of those affected reported that their RS became stronger under MPH. One of these sufferers later turned out to be an MPH non-responder who was able to achieve a better effect with an amphetamine medication.
Mathematical skills
Children with ADHD on MPH showed significantly improved math skills that were indistinguishable from those of non-affected children.136
4.5. Different time-dependent effects of stimulants on symptoms?¶
A publication by a renowned scientist claims different time-response and dose-response curves for the motor and cognitive effects of stimulants.141 While the effect on motor activity lasts 7 to 8 hours, the effect on attention is said to last only 2 to 3 hours. However, the sources cited do not substantiate this claim. Nor do they correspond with empirical experience from practice.
It was reported that sustained-release MPH made a positive contribution to nicotine abstinence / smoking cessation, but only in more severe ADHD cases, whereas in milder ADHD cases a paradoxical worsening occurred, but remitted after discontinuation of the medication.142 This should be seen against the background that nicotine as a stimulant is a self-medication for ADHD, even if smoking uses nicotine as a drug and only nicotine patches or nicotine lozenges act as medication.
Further, in the context of the Inverted-U theory that intermediate neurotransmitter levels mediate optimal brain function, while decreased and elevated neurotransmitter levels cause nearly similar symptoms, the result of this study may indicate overdosing in the subjects with milder ADHD symptoms (indicating lower dopamine and norepinephrine deficiency) and a paradoxical response.
One study found no impairment of creativity by MPH,143 Another study found increased creativity in unmedicated children with ADHD compared to medicated children with ADHD and unaffected children.144
Response means whether there is an effect on the ADHD symptoms. Patients who do not respond sufficiently to a medication are called non-responders.
Non-responding does not mean having no effect, but merely that the effect remains below the level of symptom improvement specified in the respective study.
A meta-study reports a 69% response rate to amphetamine medication and a 59% response rate to methylphenidate. 87% of ADHD sufferers responded to one of the two types of medication.145 A meta-analysis of 32 studies came to the same conclusion (significantly better response rates to amphetamine medication than to MPH).146
For patients for whom MPH does not work, it is therefore advisable to test a medication with amphetamine drugs.
About 50% of patients who do not respond to MPH should respond to atomoxetine, and about 75% of patients who respond to MPH should also respond to atomoxetine.147
In MPH nonresponders, L-amphetamine and atomoxetine were compared in a randomized double-blind study with n = 200 subjects. L-amphetamine was significantly more effective than atomoxetine in 2 of 6 categories and in the overall assessment.148
Low commission errors (impulse control errors; reaction to signal that should not have been answered) in the Conners Continuous Performance Test II, CPT-II149
Higher hyperactivity-impulsivity and oppositional symptoms before treatment150
Predictor for good results with MPH monotherapy, guanfacine monotherapy and MPH/guanfacine combination medication
Most older sources report that about 90% of sufferers of the ADHD-HI subtype (with hyperactivity) and the mixed type respond positively to methylphenidate and require quite low doses.151152153154155
More recent sources speak of a response rate of up to 75% with MPH,156 which seems more accurate to us.
ADHD-I subtype sufferers are said to be more frequent MPH nonresponders,157 with nonresponder rates of 24%151 being reported. ADHD-I sufferers who respond to MPH also require higher doses.
According to a small study, children with a higher cortisol stress response, which corresponds to the ADHD-I subtype, are more likely to benefit from higher doses of MPH than children with a flattened cortisol stress response (which corresponds to ADHD-HI). However, the stress test was not based on the TSST but on venipuncture, which allows for a less distinct recognizability of the cortisol stress response.158
A particularly strong increase in cortisol awakening (CAR) correlated with reduced MPH responding in children.158
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 values indicate MPH nonresponding. Neither elevated SCT daydreamy symptoms nor ADHD subtype (ADHD-HI or ADHD-I) differed in MPH responding rates in this study.159
According to one study, ADHD sufferers with intellectual deficits are less likely to respond to MPH. A responder rate of 40 to 50 % was reported here.160 In contrast, another study found a good effect of MPH in patients with intellectual deficits.161
ADHD sufferers with very low EEG theta values are more likely to be non-responders to stimulants.162
According to this understanding, low theta values correspond to the overactivated beta (EEG) subtype. For the BETA subtype (overactivated type), another source reports reduced MPH responding.48
The beta subtype appears outwardly as the classic ADHD-HI subtype (hyperactive/impulsive). Most people with the ADHD-HI subtype have too low a theta and too high a beta. More on this at ⇒ ADHD subtypes according to EEG.
However, the (individual) ADHD sufferers of the BETA subtype known to us report an extremely helpful effect of MPH.
A small study found lower EEG stability at rest as a predictor of an MPH response.163
Another study found an attenuated P3 amplitude in responders compared to controls. Unexpectedly, nonresponders showed an atypically flat aperiodic spectral slope compared to controls, while responders did not differ from controls.164
Some people suspect cases of underdosing among non-responders, i.e. that the required dosage was not reached and a non-response is only wrongly assumed.165
Our impression is that too low a dosage can cause an apparent non-response. Nevertheless, there are genuine non-responders for whom even greatly increased doses do not produce satisfactory results.
In addition, a different non-responder rate is reported in children and adults.
We suspect that a more precise classification of ADHD subtypes will provide explanations here.
An increase in blood pressure is said to correlate with a particularly good effect of MPH.166
A particularly good improvement in symptoms on methylphenidate was observed in ADHD sufferers with167
Increased delta power at F8
Increased theta power for Fz, F4, C3, Cz, T5
Increased gamma power with T6
Reduced beta power at F8 and P3
Increased delta/beta power ratio at F8 (in relation to hyperactivity)
Increased theta/beta power ratio at F8, F3, Fz, F4, C3, Cz, P3 and T5 (in relation to hyperactivity)
One study found little or no relevance of certain genes that are particularly relevant for neuronal development (“neurodevelopmental network”) to the effect of MPH or atomoxetine in ADHD.168
A meta-analysis of 15 studies and 1382 patients found that carriers of the T allele of the NET gene polymorphism rs28386840 responded significantly more frequently to MPH and showed a significantly greater improvement in hyperactive-impulsive symptoms than carriers of other NET polymorphisms. ADRA2A polymorphisms did not correlate significantly with the response to MPH. However, carriers of the G allele of the MspI polymorphism showed a correlation with a significant improvement in inattention symptoms.169
Elevated iron levels in the putamen and caudate correlated with better MPH responding in ADHD. Elevated iron levels in the putamen correlated - not only in ADHD - with impaired inhibition170
In preschool ADHD, low externalizing or internalizing symptom severity correlated with a high likelihood of response to stimulants. At high externalizing or internalizing symptom levels, the response rate of stimulants approached that of alpha-2 agonists:171
Methylphenidate is broken down by the CES1 liver enzyme.
A higher CES1 plasma concentration correlated with a reduced d-methylphenidate plasma level. In one study, the CES1 plasma protein level could explain about 50 % of the variability of the d-methylphenidate plasma level. It is possible that an individualized dosing strategy based on the measurement of CES1 could considerably facilitate the dosing of d-methylphenidate.179
5.7. Response individually dependent on retardation and carrier substance¶
Those affected report a very different individual response to different MPH preparations.
While the intra-individual (within a person) and inter-individual (compared to other affected persons) differences in tolerability of MPH retard preparations are now generally recognized, it is less well known that tolerability and responding can also be very different intra-individually in relation to different unretarded MPH preparations. We have received reports from a number of patients who reproducibly perceive very clear differences in the effect of various equally strong unretarded MPH preparations.180181
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 ↥
