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Methylphenidate

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Collated from PsychonautWiki, TripSit, Pharmacology, DrugCentral, DailyMed. Where sources differ (e.g. dosing), Compare shows them side by side.

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StimulantSubstituted phenidatesHabit-formingCommonPW

Also known as Methylphenidate, Concerta, Methylin, Ritalin, Equasym XL, mph, biphentinPW

A psychostimulant commonly used in the treatment of ADHD, narcolepsy and obesity, particularly in the EU instead of Adderall. Methylphenidate is also a 5HT1A receptor agonist. Sometimes prescribed off-label to help the withdrawals from cocaine and other stimulants.TS

Addiction potentialPW
moderately addictive with a high potential for abuse

Insufflated

Route dataPsychonautWiki

Dose
WeakerStronger
ThresholdLightCommonStrongHeavy
1 mg2–10 mg10–30 mg30–60 mg60 mg+
075 mg
LightCommonStrongHeavy
Duration
ShorterLonger
Onset5–20 minutes
Come-up15–40 minutes
Peak30–45 minutes
Offset2–4 hours
Total2–4 hours
After-effects1–4 hours
OnsetCome-upPeakOffset

Oral

Route dataPsychonautWiki

Dose
WeakerStronger
ThresholdLightCommonStrongHeavy
5 mg10–20 mg20–40 mg40–60 mg60 mg+
075 mg
LightCommonStrongHeavy
Duration
ShorterLonger
Onset30–60 minutes
Come-up20–45 minutes
Peak60–90 minutes
Offset45–60 minutes
Total2.5–4 hours
After-effects2–6 hours
OnsetCome-upPeakOffset

Dangerous interactionsPW

25x-NBOMe25x-NBOHTramadolMAOIs

Unsafe interactionsPW

DXMMDMAStimulants

Caution / uncertainPW

AlcoholMXEDissociatives

🧬 Receptor activityPHDC

TargetActionAffinitySource
Sodium-dependent dopamine transporter—Ki 34 nMCHEMBL
Sodium-dependent noradrenaline transporter—Ki 340 nMCHEMBL
Sodium-dependent serotonin transporter—Ki 10000 nMCHEMBL
Sodium-dependent dopamine transporter (SLC6A3)Inhibitor6.96 KiDRUGCENTRAL
Sodium-dependent noradrenaline transporter (SLC6A2)Inhibitor6.18 KiDRUGCENTRAL
Alpha-2A adrenergic receptor (ADRA2A)—5.252 KiDRUGCENTRAL
Alpha-2B adrenergic receptor (ADRA2B)—5.615 KiDRUGCENTRAL
Alpha-2C adrenergic receptor (ADRA2C)—6.068 KiDRUGCENTRAL
Sodium-dependent dopamine transporter (Slc6a3)—7.08 IC50DRUGCENTRAL
Sodium-dependent serotonin transporter (SLC6A4)—4.19 KiDRUGCENTRAL
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Mechanism of actionPHDM

While its exact mechanism is unclear, methylphenidate (MPH) has been shown to act as a norepinephrine and dopamine reuptake inhibitor (NDRI), thereby increasing the presence of these neurotransmitters in the extraneuronal space and prolonging their action. There is a dose-related effect of psychostimulants on receptor stimulation, where higher doses are shown to increase norepinephrine (NE) and dopamine (DA) efflux throughout the brain which can result in impaired cognition and locomotor-activating effects. In contrast, low doses are found to selectively activate NE and DE neurotransmission within the prefrontal cortex which is an area of the brain thought to play a prominent role in ADHD pathophysiology, thereby improving clinical efficacy and preventing side effects. The lower doses used to treat ADHD are not associated with the locomotor-activating effects associated with higher doses and instead reduce movement, impulsivity, and increase cognitive function including sustained attention and working memory. Methylphenidate's beneficial effects in sustaining attention have also been shown to be mediated by alpha-1 adrenergic receptor activity. Clinical findings have shown that children with ADHD have an abnormality in the dopamine transporter gene (DAT1), the D4 receptor gene (DRD-4), and/or the D2 receptor gene that may be at least partly overcome by the dopaminergic effects of methylphenidate, suggesting a possible mode of action.
Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.
Although the primary mechanism is largely unknown, the effects of methylphenidate appear to be mediated by blockage of the reuptake mechanism of dopaminergic neurons. In children with attention deficit disorder, methylphenidate decreases motor restlessness and enhances the ability to pay attention. In narcolepsy, methylphenidate appears to act at the cerebral cortex and subcortical structures, including the thalamus, to produce CNS stimulation, resulting in increaed motor activity, increased mental alertness, diminished sense of fatigue, brighter spirits, and mild euphoria.
Mode of action: Appears to exert most or all of its effect in the CNS by causing release of biogenic amines, especially norepinephrine and dopamine, from storage sites in nerve terminals. It may also slow down catecholamine metabolism by inhibiting monoamine oxidase.

PharmacodynamicsPHDM

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer. Radioligand binding studies demonstrate that binding of methylphenidate in the brain is localized to dopamine-rich areas, in particular in the prefrontal cortex which has been demonstrated to play a prominent role in ADHD pathophysiology. In a number of animal models, methylphenidate enhances locomotor activity and induces stereotypic behaviours.

Pharmacokinetics

Half-lifePH

Concerta: The half-life of methylphenidate in adults following oral administration of Concerta® was approximately 3.5 h. Biphentin: Methylphenidate is eliminated from plasma with a mean half-life of 2.4 hours in children and 2.1 hours in adults. Methylphenidate (immediate release): Methylphenidate is eliminated from the plasma with a mean half-life of 2.4 hours in children and 2.1 hours in adults.
Methylphenidate ... is a racemate; /in plasma/ its more potent (+) enantimoer has a t(1/2) of approximately 6 hr, and the less potent (-) enantiomer has a t(1/2) of approximately 4 hr. Concentrations in the brain exceed those in plasma.
The mean terminal half-life (t1/2) of methylphenidate following administration of 20 mg Methylphenidate HCl Oral Solution (t1/2 = 2.7 hours) is comparable to the mean terminal t1/2 following administration of Ritalin (methylphenidate hydrochloride immediate-release tablets) (t1/2 = 2.8h) in healthy adult volunteers.

AbsorptionPHDM

Concerta®: Methylphenidate is readily absorbed. Following oral administration of Concerta, plasma methylhphenidate concentrations reach an initial maximum at about 1 hour followed by gradual ascending concentrations over the next 5-9 hours. Mean times to reach peak plasma concentrations across all doses of Concerta occurred between 6-10 hours. Once daily dosing minimizes the fluctuations between peak and trough concentrations associated with multiple doses of immediate-release methylphenidate treatments. Depending on the doses provided, Cmax was found to range from 6.0-15.0ng/mL, Tmax ranged from 8.1-9.4h, and AUC ranged from 50.4-121.5 ng·h/mL in children. When provided as Concerta®, methylphenidate is released through the patented Osmotic Controlled-Release Oral Delivery (OROS) system where 22% of the dose is provided as an immediate release and 78% is provided through a gradual release. OROS is comprised of an osmotically active trilayer core surrounded by a semipermeable membrane with an immediate-release drug overcoat. Within an aqueous environment, such as the stomach, the drug overcoat, which consists of 22% of the dose, dissolves within one hour, providing an initial immediate-release formulation of methylphenidate. Water then permeates through the membrane into the tablet core where the osmotically active polymer excipients expand, allowing methylphenidate to release slowly through the orifice over a period of 6-7 hours. Concerta also provides a sustained 10-12 hour effect, allowing for once-daily dosing. Biphentin®: Methylphenidate is rapidly and extensively absorbed following oral administration, with peak blood levels obtained in 1-3 hours. When provided as Biphentin®, methylphenidate is released through a multi-layer release delivery system (MLRTM) where 40% of the dose is provided as an immediate release and 60% is provided through a gradual release. Biphentin was designed to be an alternative to separate doses of immediate-release (IR) methylphenidate by providing a biphasic concentration-time profile when given as a single dose. The MLRTM release system allows for a sustained effect for 10-12 hours, allowing for once-daily dosing that covers the major times that ADHD impairment might occur (such as school, homework periods, during the workday, etc). Methylphenidate (immediate release): Methylphenidate hydrochloride is rapidly and extensively absorbed from the tablets following oral administration; however, owing to extensive first-pass metabolism, bioavailability is low (approx. 30%) and large individual differences exist (11-52%). In one study, the administration of methylphenidate hydrochloride with food accelerated absorption but had no effect on the amount absorbed. Peak plasma concentrations of 10.8 and 7.8 ng/mL were observed, on average, 2 hours after administration of 0.30 mg/kg in children and adults, respectively. Peak plasma concentrations showed marked variability between subjects. Both the area under the concentration-time curve (AUC), and the peak plasma concentrations (Cmax) showed dose-proportionality.
After oral administration of an immediate release formulation of methylphenidate, 78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60%-86%), the remainder being accounted for by minor metabolites.
Concerta: Plasma methylphenidate concentrations in adults decline bi-exponentially following oral administration. Biphentin: The apparent distribution volume of methylphenidate in children is approximately 20 L/kg, with substantial variability (11 to 33 L/kg). Methylphenidate (immediate release): The apparent distribution volume of methylphenidate in children was approximately 20 L/kg, with substantial variability (11-33 L/kg). The volume of distribution after an intravenous dose (Vss) is 2.23 L/kg for the racemate in healthy adult volunteers.
The apparent mean systemic clearance after an oral dose is 10.2 and 10.5 L/h/kg in children and adults, respectively for a 0.3 mg/kg dose, and 0.565 L/h/kg after an intravenous dose of the racemate in healthy adult volunteers.
Methylphenidate HCl Oral Solution is readily absorbed. Following oral administration of Methylphenidate HCl Oral Solution, peak plasma methylphenidate concentrations are achieved at 1 to 2 hours.
Methylphenidate is readily absorbed after oral administration and reaches peak concentrations in plasma in about 2 hr.

MetabolismPH

Methylphenidate is hepatically metabolized. More specifically, it is rapidly and extensively metabolized by carboxylesterase CES1A1. Via this enzyme, methylphenidate undergoes de-esterification to ritalinic acid (a-phenyl-2-piperidine acetic acid, PPAA), which has little to no pharmacologic activity.
In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenylpiperidine acetic acid (PPA, ritalinic acid). The metabolite has little or no pharmacologic activity.
Methylphenidate is hepatically metabolized. More specifically, it is rapidly and extensively metabolized by carboxylesterase CES1A1. Via this enzyme, methylphenidate undergoes de-esterification to ritalinic acid (a-phenyl-2-piperidine acetic acid, PPAA), which has little to no pharmacologic activity.
Route of Elimination: After oral administration of an immediate release formulation of methylphenidate, 78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60%-86%), the remainder being accounted for by minor metabolites.
Half Life: d-methylphenidate = 3-4 hours;
l-methylphenidate = 1-3 hours;
Ritalinic acid = 3-4 hours;

Protein bindingPH

Concerta: In humans, 15 ± 5% of methylphenidate in the blood is bound to plasma proteins. Biphentin: In blood, methylphenidate and its metabolites are distributed between plasma (57%) and erythrocytes (43%). Methylphenidate and its metabolites exhibit low plasma protein binding (approximately 15%). Methylphenidate (immediate release): In blood, methylphenidate and its metabolites are distributed between plasma (57%) and erythrocytes (43%). Methylphenidate and its metabolites exhibit low plasma protein binding (approx. 15%).

Plan when to take Methylphenidate — see where onset, peak and comedown land on the clock

Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.