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MPH Part 1 - Active Ingredient

MPH Part 1 - Active Ingredient

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Methylphenidate (MPH) is the active ingredient in well-known ADHD medications such as Ritalin, Medikinet, and Concerta. The medication typically consists of a mixture of two mirror-image forms (a racemate). Its effects are primarily due to the dextrorotatory form, D-MPH. The levorotatory form, L-MPH, is virtually ineffective and is largely broken down in the intestines and liver. When taken orally (by mouth) in therapeutic doses, MPH has no potential for intoxication or dependence.

In the brain, MPH primarily inhibits the transporters that reuptake the neurotransmitters dopamine and norepinephrine into nerve cells. As a result, more dopamine and norepinephrine remain active outside the cells, particularly in the striatum and the frontal lobe (prefrontal cortex, PFC). MPH has barely any effect on serotonin. The effect depends on the dose; low and high doses can have opposite effects. Studies have also examined effects on stress hormones, the autonomic nervous system, inflammatory markers, brain networks, EEG, pain sensitivity, and sleep. The findings in these areas are often inconsistent. Many detailed findings regarding the mechanisms of action come from animal studies, which often used significantly higher doses, and are only partially applicable to humans or human dosages.

MPH and amphetamine-based medications have different effects on the brain. Both are considered highly effective. However, some people with ADHD respond better to one of the two active ingredients or tolerate it better.

MPH improves the core symptoms of inattention, hyperactivity, and impulsivity in children, adolescents, and adults. In children and adolescents, the effect was moderate to large; in adults, it was moderate. MPH is particularly effective in reducing restlessness, impulsivity, aggression, and hyperactivity. It also has a positive effect on concentration, handwriting, social skills, and emotional lability. The effect was less pronounced on executive functions and working memory in performance tests, as well as on academic performance. Immediate-release MPH typically takes effect within 15 to 20 minutes. There are no known cases of a delay of days or even weeks before the medication takes effect.

Not all people with ADHD respond to MPH. To date, it has not been possible to reliably predict whether MPH will be effective in an individual case based on subtype, EEG, imaging, or genetic testing. True nonresponders to both classes of stimulants are rare when both are carefully tested across a wide range of doses. If MPH is not sufficiently effective, it is therefore recommended to try an amphetamine-based medication. Ultimately, response can only be determined through careful trial and error.

Blood levels of MPH vary considerably from person to person even at the same dose, but remain stable in the same individual. The highest concentration in the blood is reached about 2 hours after administration.

1. Active ingredient

Implications for People with ADHD

Methylphenidate (MPH) is an active ingredient in the phenylethylamine class. Due to its chemical structure, there are four different forms (isomers) of the molecule. As a medication, a mixture of two enantiomers is usually used: the dextrorotatory D-MPH and the levorotatory L-MPH.

MPH is classified as a controlled substance worldwide. The reason is that, when taken in extremely high doses and in fast-acting forms, it can be abused as a drug. At therapeutic doses and in slow-acting forms (orally or as a patch), MPH has no potential for intoxication or dependence. The actual risk of abuse appears to be significantly overestimated.

Many older animal studies on MPH are only partially applicable to human treatment. In these studies, MPH was often administered in significantly higher doses than those used for ADHD treatment and was frequently given by injection. Injections produced significantly higher levels of MPH in the blood and brain than oral administration. Such studies therefore reflect drug use rather than medication administration. Some of these limitations have not yet been sufficiently substantiated. Administration via a feeding tube is also not free of confounding factors, because the restraint required for this procedure causes significant stress to the animals. In animal studies, the effects of MPH followed an inverted U-shaped curve (inverted-U principle), such that moderate doses had a different effect than very low or very high doses.

The standard dosage form is a mixture of D-MPH and L-MPH (racemate). The effect is primarily due to D-MPH. In children with ADHD, half the dose of pure D-MPH was as effective as the full dose of the racemate. L-MPH is virtually ineffective and is largely broken down in the intestines and liver. Whether the remaining L-MPH weakens the effect of D-MPH is a matter of debate. Serdex methylphenidate is a prodrug of D-MPH that is converted into the active ingredient only after it enters the body. It has so far been approved only in the United States.

MPH is classified as a controlled substance worldwide because it can be abused as a drug when taken in extremely high doses or in a rapidly acting form. When taken in medicinal doses and in medicinal forms (oral / patch = slow-acting), however, MPH has no potential for intoxication or dependence. The actual risk of methylphenidate being abused as a recreational drug appears to be significantly overestimated. A study claiming frequent abuse of MPH as a recreational drug cited only sources in which methylphenidate is not even mentioned. (Narrative Review, E 4)1

Methylphenidate (MPH): (Narrative review, E 4)2

  • belongs to the class of phenylethylamines.
  • Chemical name: methyl 2-phenyl-2-(piperidin-2-yl)acetate
  • Molecular formula: C14H19NO2
  • Mass: 233.31 g/mol
  • has four configurational isomers
  • Since methylphenidate has two asymmetric carbon atoms, there are four different forms of this drug: (animal study, cats, rats; full text not available to us; E 2b)3
    • (+)-erythromethylphenidate
    • (-)-Erythromethylphenidate
    • (+)-threomethylphenidate
    • (-)-Threomethylphenidate.

Other names: (E 4)4

  • Methylphenidyl acetate
  • methyl phenyl(piperidin-2-yl)acetate
  • methyl α-phenyl-α-(2-piperidyl)acetate
  • methyl α-phenyl-α-2-piperidinyl acetate
  • Methylphenidate
  • Methylphenidate
  • Methylphenidate
  • Methylphenidate
  • MPH
  • α-phenyl-2-piperidineacetic acid methyl ester

When considering studies (especially older ones) on the effects of MPH, it is important to note that these (animal study, rats, E 2b)5

  • MPH is usually administered in significantly higher doses than ADHD medication
    • Although rodents require higher doses than humans, the doses used often correspond to drug use rather than medical treatment.
  • Use immediate release MPH (i.e., MPH that is not extended-release via a prodrug)
  • frequently inject MPH, which, depending on the method of injection, can result in much faster metabolism
    • IP injection produced significantly higher MPH levels in the blood and brain than oral administration (animal study, rats, E 2b.)56
  • these three factors have a synergistic effect

There is no doubt that MPH in its pharmaceutical form has a different effect than MPH in its illicit form.

Types of admission:

  • Intraperitoneal injections (IP, injections into the abdominal cavity)
    • IP injections in rodents are administered in the lower right abdominal quadrant, away from the midline, to avoid injecting into the bladder or cecum. This video demonstrates how to perform such an IP injection (in German). The pharmacokinetics following IP injections are more similar to those after oral administration than to those after intravenous injection. Absorption is much slower via the intraperitoneal route than with intravenous injection. It occurs primarily via the mesenteric vessels, which drain into the portal vein and pass through the liver, allowing the active ingredient to undergo hepatic metabolism before reaching the systemic circulation. In addition, a small amount of the intraperitoneally injected material can enter the thoracic lymph directly through the diaphragm via small lacunae. (Review, E 4.)7
    • Administration of MPH via intraperitoneal (IP) injection increased extracellular DA in the nucleus accumbens of rats more rapidly and to a greater extent than intragastric (oral) administration. Within the first 20 minutes, DA levels roughly doubled following IP administration, whereas after intragastric administration, they rose by only about 30%. DA levels peaked after 40 minutes for both routes of administration, and after approximately 2.5 hours, DA levels had returned to baseline for both routes. IP administration (5 and 10 mg/kg) had approximately twice the effect on DA and motor activity compared to intragastric administration, with higher uptake of MPH into the brain. Only motor activity persisted longer following a 10 mg/kg IP dose. A 2 mg/kg dose significantly increased DA and motor activity when administered intraperitoneally, but not when administered intragastrically. (Animal study, n = 6 to 8 per group, Sprague-Dawley rats, E 2b.)6
    • Intraperitoneal (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 mechanism. However, it is unsuitable for studies investigating the properties of a drug formulation and/or its pharmacokinetics for clinical application. (Review, E 4)8
    • The risks of IP injections are:
      • Injuries caused by improper injection
      • Change in effect if the injection is administered too close to the surface (subcutaneously instead of intraperitoneally)

  • Subcutaneous injections cause

    • An accidental subcutaneous injection instead of an intraperitoneal one is said to shorten the half-life of MPH and cause a rapid peak release of dopamine in the brain, which triggers behavioral sensitization (Secondary citation from Senior (2023); the primary source cited there, Thanos (2015), does not support this conclusion). (Narrative review, E 4.)9
    • rapid peak release of dopamine in the brain (animal study, rats, E 2b.)10

  • Oral Pharyngeal Probe

    • The oral esophageal probe better mimics oral intake and human MPH metabolism. For oral administration, a suitable tube or administration needle is used, which is inserted into the animal’s mouth and into the esophagus. However, the manual restraint required for the oral esophageal probe causes such severe stress in rats, as in mice, that it elevates plasma corticosterone levels. (Narrative Review, E 4)9

For more information on other forms of medication administration, see: Forms of Medication Administration in the article “ : Neurological Basics of ADHD”.

The procedure for IP injections differs between mice and rats solely due to the size of the respective animal. (Narrative Review, E 4.)9
MPH doses follow an inverted-U curve. (animal study, n = 36, BALB/cJ mice, E 2b)11

  • In rodents (mice and rats):
    • Doses of 1 mg/kg MPH or less:
      • No significant increase in motor activity following subcutaneous injection (0.6 mg/kg in rats) (animal study, rats, E 2b.)12
    • Doses are selected in the range of human doses (Narrative review, E 4)9
      • by subcutaneous injection: increased physical activity
    • Doses of 10 to 20 mg/kg of MPH are more likely to correspond to drug use (Narrative review, E 4)9
      • by subcutaneous injection: increased physical activity
        • significant at 2.5 mg/kg (animal study, rats, E 2b)12
        • Maximum at 10 mg/kg; concentrations greater than 40 mg/kg (animal study, rats, E 2b)12
    • Doses of 40 mg/kg MPH
      • by subcutaneous injection: more concentrated, stereotyped activity that reduced the extent of forward movement (animal study, rats, E 2b)12

1.1. Methylphenidate as a racemate

Implications for People with ADHD

Methylphenidate medications typically contain a racemate. This is a mixture consisting of 50% D-MPH and 50% L-MPH, two mirror-image forms of the same molecule. One review noted that only D-MPH crosses the blood-brain barrier into the brain to any significant extent, whereas L-MPH does not. An animal study partially contradicted this finding (see 1.3).

The first MPH preparation, developed around 1950, still contained a mixture of several forms, only some of which had a central stimulant effect. Ritalin (1955) then contained only the active racemate, while Focalin (2001) contained only pure D-MPH. To this day, pure D-MPH has not displaced the racemate from the market.

Brand names for racemate include Ritalin, Medikinet, Equasym, Concerta, Kinecteen, and Daytrana (skin patch). There are also generic versions available.

Immediate-release MPH (without delayed-release formulation) is taken in single doses starting at 2.5 mg several times a day. There is currently no evidence supporting the specific single doses and dosing intervals mentioned. In studies, the maximum doses ranged from 0.8 to 1.8 mg per kg of body weight per day, or 20 to 72 mg per day. A meta-analysis found no scientific justification for a specific maximum dose.

Methylphenidate is typically administered clinically as a racemate (mixture) consisting of 50% L-methylphenidate and 50% D-methylphenidate (levorotatory and dextrorotatory isomers), which is ten to one hundred times more potent than the (+/-)-erythroform. (animal study, cats, rats; full text not available to us; E 2b)3
While a significant proportion of D-MPH crosses the blood-brain barrier into the CNS, L-MPH is not taken up into the CNS. (Review, E 4)13

Brand names include Ritalin, Medikinet, Equasym, Concerta, Kinecteen, and Daytrana (skin patch). It is also available as a generic medication. See below for more information.

Dosage ranges from 2.5 mg to an average of 15 mg per single dose, taken every 2.5 to 3.5 hours during the day (immediate release form).

The maximum doses of MPH ranged from 0.8 to 1.8 mg/kg/day in studies, from 20 to 72 mg/day in RCTs, and from 20 to 60 mg/day in cohort studies using immediate release MPH. The meta-analysis did not find scientific justification for a specific maximum dose. (meta-analysis, k = 49, including 11 RCTs, N = 7,715, E 2b.)14

The first MPH preparation (Centedrin, circa 1950) contained an 80:20 mixture of two racemates (erythro- and threo-racemate), with the central stimulant effect originating solely from the threo-racemate. The FDA approval of Ritalin (1955) marked the first chiral switch from a mixture of two racemates to the threo-racemate; the approval of Focalin (dexmethylphenidate, 2001) marked a second chiral switch to the pure D-threo enantiomer, (+)-(αR,2R)-methylphenidate. The enantiomer did not displace the racemate from the market (global sales in 2024: racemic formulations $5.2 billion, dexmethylphenidate formulations $1.5 billion). The terms “threo” and “erythro” are considered outdated in stereochemistry. (Perspective, narrative, E 4.)15

1.2. Dexmethylphenidate (D-MPH)

Implications for People with ADHD

Dexmethylphenidate (D-MPH) is the pure dextrorotatory form of methylphenidate and the active component of the racemic mixture. It is available as Focalin in Switzerland and the United States, including as an extended-release formulation (Focalin XR).

According to a textbook, D-MPH is three times more effective than the racemate. This claim is likely based solely on animal data. In clinical trials involving children with ADHD, half the dose of D-MPH was just as effective as the full dose of the racemate. This corresponds to approximately twice the potency. Therefore, half the dose of the racemate is recommended, limited to a maximum of 20 mg per day for both children and adults.

A study suggested that D-MPH has a longer duration of action. At 6:00 p.m., only D-MPH—not the racemate—improved parents’ assessments compared with placebo. A post-hoc analysis of the same study found a more frequent, substantial reduction in symptoms with D-MPH. The authors themselves considered this result to be only preliminary. After switching from D-MPH to placebo, treatment failure occurred significantly more frequently than when treatment was continued. After taking the racemate, blood levels of D-MPH were lower in the first few hours than after taking pure D-MPH, but were comparable overall.

Several of these studies were funded by the manufacturer or included authors employed by the manufacturer.

D-MPH inhibits the reuptake (the return into the nerve cell) of the neurotransmitters dopamine and norepinephrine. Other mechanisms of action are considered only possible, not proven. D-MPH is broken down by the enzyme carboxylesterase 1A1 into D-ritalinic acid.

Dexmethylphenidate is the pure form of the dextrorotatory isomers and is pharmacologically active.

Brand name: Focalin (Switzerland and the U.S. only)

In animal studies, it was three times more effective than racemic methylphenidate (a mixture of 50% dextrorotatory (D-MPH) and 50% levorotatory (L-MPH) methylphenidate) in treating hyperactivity. (Textbook, E 4.)16 The greater efficacy of D-MPH compared to L-MPH relates to its binding to both dopamine and norepinephrine transporters. (Textbook, E 4.)17
Therefore, a dosage of D-MPH equal to half that of racemic methylphenidate is recommended, limited to a maximum of 20 mg per day for both children and adults.
D-MPH is also available as an extended-release formulation (Focalin XR).

(E 1b): The effect of the racemate was primarily due to D-MPH. (Double-blind, randomized, placebo-controlled crossover study, N = 32, n = 31, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)18 * (Double-blind, randomized, 4-way crossover study, n = 9, E 1b.)19 * (Narrative review, E 4.)20 * (Narrative review, E 4.)*21 In rats with neonatal dopamine lesions, D-MPH was 3.3 times more potent than the racemate (secondary citation via Quinn (2008) from Davids et al. (2002)). (Narrative Review, E 4.)20

(E 1b): Half the dose of D-MPH was just as effective in children with ADHD as the full dose of racemate, according to:

  • 4 weeks of treatment with an average of 18.25 mg/day of D-MPH versus 32.14 mg/day of racemate: Effect size on teacher ratings (SNAP-ADHD) compared to placebo: 1.0 , respectively (RCT, n = 132, 4 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)22
  • Single doses of 2.5, 5, and 10 mg of D-MPH compared with 5, 10, and 20 mg racemate: equivalent effects on ADHD symptoms and arithmetic performance in a lab-based classroom setting over 8 hours, with indistinguishable D-MPH plasma levels and negligible L-MPH levels (Double-blind, randomized, placebo-controlled crossover study, N = 32, n = 31, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)18
  • Single doses of 5 mg D-MPH versus 10 mg racemate: The improvement in sustained attention is fully explained by D-MPH (double-blind, randomized, 4-way crossover study, n = 9, E 1b.)19

There were indications that D-MPH had a longer duration of action. At 6:00 p.m., only D-MPH—not the racemate—improved the parental rating (SNAP-ADHD) compared to placebo. According to the CGI-I, 67% of patients on D-MPH and 49% on the racemate showed improvement. (RCT, n = 132, 4 weeks, manufacturer-funded, author(s) employed by the manufacturer, E 1b.)22 A post-hoc analysis of the same study found a higher rate of remission based on teacher assessment with D-MPH (72.1% vs. 51.2%) and no worsening (racemate: 11.1%). The authors considered these findings exploratory due to small sample sizes and multiple tests. (Post-hoc analysis of an RCT, N = 132, manufacturer-funded, author(s) employed by the manufacturer, E 2b.)23

In a withdrawal study, treatment failure occurred in 61.5% of patients after switching to placebo and in 17.1% of patients who continued on D-MPH. In an open-label study, ADHD symptoms were controlled throughout the school day in 68% (teacher assessment) and 86% (parent assessment) of cases, with a median duration of action of 6.3 and 7.5 hours, respectively. (Review, n = 75 and n = 22, E 4.)24

Immediate release racemate (0.3 mg/kg) and immediate release D-MPH (0.15 mg/kg) were bioequivalent for D-MPH in terms of Cmax and AUC. However, early D-MPH exposure (pAUC from 0 to 3 hours) was lower following administration of the racemate (ratio 0.76, 90% CI 0.67 to 0.87). The D-MPH concentration at 1 hour following administration of the racemate was 56% of that following administration of pure D-MPH. (Randomized crossover study, n = 24, Phase 2b.)25

1.2.1. Mechanism of Action and Metabolism of Dexmethylphenidate

 

Dexmethylphenidate acts as a (Review, E 4)26

  • Dopamine reuptake inhibitors
  • Norepinephrine reuptake inhibitors
  • presumably (“plausibly”) also as “ * ” (Review, E 4.)*26
    • 5-HT1A receptor agonist
    • Redistribution of vesicular monoamine transporter 2 (VMAT-2)
    • α2-adrenoreceptor agonist

Dexmethylphenidate is metabolized by carboxylesterase 1A1 to D-ritalinic acid. (Review, E 4)26

1.3. Levomethylphenidate (L-MPH)

Implications for People with ADHD

Levomethylphenidate (L-MPH) is the pure levorotatory form of methylphenidate. It is considered virtually ineffective. According to a review, when taken orally, L-MPH is largely broken down in the intestinal mucosa and during its first pass through the liver. Studies confirmed that, after ingestion of the racemic mixture, L-MPH reached only a fraction of the D-MPH levels in the blood. In healthy men, approximately 22% of the D-MPH but only about 5% of the L-MPH entered the bloodstream. This was primarily due to the enzyme carboxylesterase CES1A1, which broke down L-MPH more rapidly than D-MPH.

When administered via a transdermal patch, there is no metabolism in the intestines or liver. L-MPH then reached 50 to 60% of D-MPH levels. A manufacturer-funded review estimated that L-MPH contributed no more than 5 to 10% to the drug’s effects and side effects even in these cases.

It is unclear whether L-MPH crosses the blood-brain barrier. According to a review, L-MPH is not taken up by the brain. In an animal study, however, labeled L-MPH reached the brain, but was present there primarily as a metabolite and appeared to be ineffective. D-MPH inhibited the reuptake of dopamine and norepinephrine significantly more strongly than L-MPH and bound specifically to the dopamine transporter, whereas L-MPH bound nonspecifically. In rat studies, L-MPH had a significantly weaker effect than D-MPH on dopamine, impulsivity, and behavior.

There is conflicting evidence as to whether the small amount of L-MPH present attenuates the effects of D-MPH. One review hypothesized that L-MPH competes with D-MPH for binding sites in the brain, thereby reducing its efficacy. In contrast, a study of children with ADHD found no evidence that L-MPH impairs the effects of D-MPH. A rat study also found no such attenuation. Only one other rat study, which was cited in a review, reported an attenuation.

Some of the studies were funded by manufacturers or had authors employed by the manufacturers.

L-MPH is the pure form of the levorotatory isomers and is pharmacologically almost inactive.
L-MPH is metabolized primarily in the intestinal mucosa. The remaining L-MPH is metabolized during first-pass metabolism in the liver. L-MPH is almost completely metabolized within 10 minutes of absorption. (Narrative Review, E 4)27
The small, unmetabolized amount of L-MPH competes with the dextrorotatory and pharmacologically active isomer D-MPH for binding sites in the brain and reduces its efficacy. (Narrative Review, E 4)27
According to another source, the levorotatory MPH isomer L-MPH (unlike D-MPH) is not absorbed into the CNS. (Review, E 4)13

Following oral administration of the racemic mixture, L-MPH reached only a fraction of the D-MPH levels, with:

  • an absolute oral bioavailability (healthy men) of:
    • D-MPH 22% (± 8) (pharmacokinetic studies, n = 23, Phase 2b)28
    • L-MPH 5% (± 3) (pharmacokinetic studies, n = 23, Phase 2b)28
  • a ratio of plasma levels of D-MPH to L-MPH in children with ADHD of:
    • 5- to 10-fold increase following administration of sustained-release MPH (20 mg) (Pharmacokinetic studies, n = 23, Phase 2b.)28
    • 4- to 10-fold increase following administration of immediate release MPH (5 or 10 mg). In some cases, L-MPH was no longer detectable after just 4 hours. (Pharmacokinetic studies, n = 23, E 2b.)28
  • an AUC for L-MPH ranging from 1 to 15 percent of that for D-MPH (Narrative Review, E 4.)21
  • a proportion of D-MPH in circulating MPH of:
    • approximately 99% according to recent liquid chromatography measurements (Comment, E 4.)29
    • 82% based on earlier gas chromatographic measurements, which, according to the authors, underestimated D-MPH due to methodological limitations (Comment, E 4.)29

This was due to stereoselective hydrolysis by the carboxylesterase CES1A1, whose catalytic efficiency for L-MPH (kcat/Km 7.7 per mM per minute) was higher than for D-MPH (1.3 to 2.1 per mM per minute). The carboxylesterases CES2 and CES3 did not hydrolyze either enantiomer. (In vitro study, purified human carboxylesterases, E 2b.)30

With transdermal administration (without first-pass metabolism), L-MPH reached 50 to 60% of D-MPH levels. According to a review, the contribution of L-MPH to the effects and side effects of the racemate was estimated to be no more than 5 to 10%. (Narrative review, manufacturer-funded, author(s) employed by the manufacturer, E 4.)31

(E 2b): D-MPH inhibited the reuptake of dopamine and norepinephrine more strongly than L-MPH (Animal study, rats, synaptosomes, full text not available to us, E 2b.)32 , approximately 10-fold according to two reviews. (Narrative review, manufacturer-funded, author(s) employed by the manufacturer, E 4.)31 * (Review, manufacturer-funded, E 4.)*33 None of the enantiomers released catecholamines from synaptosomes. (Animal study, rats, synaptosomes, full text not available to us, E 2b.)32

(E 4): Radioactively labeled D-MPH bound selectively, saturably, and reversibly to the dopamine transporter in the brains of rodents and primates, whereas L-MPH bound diffusely and nonspecifically. (Narrative review, E 4.)21 * (Narrative review, E 4.)*20

Oral administration of C-11-labeled L-MPH resulted in higher overall radioactivity uptake in the brain of baboons and rats than D-MPH. In the rat brain, however, radioactivity following L-MPH was predominantly present as a labeled metabolite, whereas following D-MPH it was predominantly present as unchanged MPH. L-MPH (3 mg/kg i.p.) neither increased locomotor activity in mice nor inhibited the cocaine-induced increase in locomotor activity. L-MPH and its metabolites thus reached the brain, but L-MPH was likely pharmacologically inactive. (Animal study, baboons, rats, mice, E 2b.)34

(E 2b): L-MPH had a significantly weaker effect in rats than D-MPH and the racemic mixture:

  • Striatal dopamine efflux in SHR rats (10 mg/kg): slight increase to 200% (± 24) of baseline; norepinephrine in the PFC not significantly increased (117% (± 15)) (Review, manufacturer-funded, E 4.)33
  • Impulsivity (delay discounting): D-MPH and racemate reduced it in a dose-dependent manner, while L-MPH did not (animal study, n = 5, rats, E 2b.)35
  • Behavioral abnormalities in a functional observation battery following high single oral doses (L-MPH 1, 100, 500 mg/kg): least frequent with L-MPH. Females were more sensitive to racemate and L-MPH than males. (Animal study, rats, 10 animals per sex and dose, manufacturer-funded, author(s) employed by the manufacturer, E 2b.)36

Findings were inconsistent regarding the question of whether L-MPH interferes with the effects of D-MPH:

  • No evidence that L-MPH impairs the effects of D-MPH in children with ADHD. The enantiomers did not interconvert in vivo. D-MPH altered the pharmacokinetics of L-MPH, but L-MPH did not alter those of D-MPH. (Double-blind, randomized, 4-way crossover study, n = 9, E 1b.)19
  • an additive effect of the racemate in rats, with no attenuation or potentiation of D-MPH by L-MPH (animal study, n = 5, rats, E 2b.)35
  • a reduction in the effects of D-MPH following pretreatment with L-MPH in rats (secondary citation via Markowitz (2008) from Davids et al. (2002)) (Narrative review, E 4.)21

1.4. Serdex Methylphenidate (SDX)

Serdex methylphenidate (SDX) is a prodrug of dexmethylphenidate (d-MPH) and is currently approved only in the United States (Azstarys®, KP415, containing 70% SDX and 30% MPH). (Review; full text not available to us; E 4)37
For more information, see Serdex Methylphenidate for ADHD

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