MPH Part 4: Miscellaneous, preparations

• 15. Long-term effects: No habituation effects with MPH
• 16. Gender differences of MPH
• 17. Applications of methylphenidate in relation to other ADHD medications
• 18. Methylphenidate in other disorders
• 19. Taking methylphenidate abroad
• 20. MPH medication significantly reduces risk of addiction
• 21. Methylphenidate preparations
  • 21.1. Unretarded preparations
  • 21.2. Retarded preparations
    • 21.2.1. Half day dosage
      • 21.2.1.1. Two-phase retardation / Extended release (XR) / Long acting (LA)
      • 21.2.1.2. Continuous release
    • 21.2.2. All-day retardation
• 22. Different MPH preparations have individually different effects - despite identical active ingredient
• 23. Further sources on methylphenidate

15. Long-term effects: No habituation effects with MPH¶

A study of ADHD sufferers taking MPH for 2 years showed a marked worsening of hyperactivity and inattention on discontinuation of MPH, consistent with a recurrence of symptoms improved by MPH.¹
A placebo-controlled discontinuation trial in subjects who had taken MPH for more than 2 years showed that discontinuation of MPH caused a significant increase in ADHD symptoms.² Nevertheless, in individual sufferers, continuation of medication seems to be dispensable after some time, which justifies regular discontinuation trials.

A meta-analysis of 87 randomized placebo-controlled double-blind trials found no evidence of diminishing effects of methylphenidate, amphetamine medications, atomoxetine, or α2-antagonists with prolonged use.³

16. Gender differences of MPH¶

One study observed a higher increase in dopamine in the ventral striatum (including the nucleus accumbens) in women than in men. The increase in the dorsal striatum was the same.⁴

17. Applications of methylphenidate in relation to other ADHD medications¶

• According to the current European consensus, methylphenidate is the first-choice ADHD medication in children (before amphetamine medications) and the second-choice medication in adults (after amphetamine medications)⁵⁶
• For children who are MPH nonresponders, that is, who do not respond to MPH, test the efficacy of amphetamine medications.
• Affected individuals with marked dysphoria with inactivity or with comorbid depression particularly benefit from amphetamine medications.
• Along with this, sufferers who need more activation may do better with amphetamine medications.
• Highly gifted individuals are reported to respond better to amphetamine medications than to MPH.⁷

18. Methylphenidate in other disorders¶

MPH proved helpful in treating attention problems in children with brain injuries (traumatic brain injury).⁸

MPH is also used successfully in the treatment of narcolepsy. In 2007, Ritalin® was the only MPH preparation approved for the treatment of narcolepsy.⁹

In children with ASD, MPH appears to additionally increase cognitive processing speed, unlike in ADHD.¹⁰

19. Taking methylphenidate abroad¶

Taking methylphenidate abroad is possible under certain conditions.

Schengen countries:
A medical certificate is required here, which must be countersigned by the head of the health department.

Other states, USA:
Special provisions apply here.

Muslim countries in particular have draconian penalties for drug possession. This may include stimulants and amphetamine drugs.¹¹

20. MPH medication significantly reduces risk of addiction¶

The updated 2018 European consensus on the diagnosis and treatment of ADHD concludes that stimulants significantly reduce the risk of addiction while taking them.¹²
ADHD sufferers with comorbid cocaine addiction showed a significant reduction in addictive behavior when treated with stimulants. This corresponded to the decrease in ADHD symptoms.¹³
The international consensus on screening, diagnosis, and treatment of adults with addiction and ADHD recommends treatment with long-acting stimulants at increasing doses to high doses, in combination with psychotherapeutic treatment.¹⁴
A meta-analysis of 6 studies with n = 1,014 subjects showed a significantly reduced risk of later addiction for participants medicated with stimulants (here: MPH).¹⁵ According to this analysis, the risk of later addiction, whether to alcohol or other substances, is 1.9-fold lower, i.e. almost halved.¹⁶

These findings could be supported by the fact that adolescents with marked novelty-seeking, who were found to have reduced decreased BOLD activity in mesolimbic (nucleus accumbens (ventral striatum) and midbrain) and prefrontal cortical (dlPFC) regions during reward anticipation at age 14, were more likely to engage in problematic drug use at age 16.¹⁷ This could be interpreted to mean that ADHD medications that raise dopamine and norepinephrine levels, such as MPH or amphetamine medications, contribute in a direct way to reduce the risk of addiction.

ADHD medication reduced the influence of preference for short-term rewards and frustration intolerance on Internet addiction.¹⁸

One study found no increased addiction affinity in adult rodents from treatment with MPH in youth.¹⁹ Other studies also found evidence that stimulants do not increase the risk of addiction.²⁰

21. Methylphenidate preparations¶

There are a large number of methylphenidate preparations.

Although they all contain the same active ingredient, those affected respond to them differently from person to person. Individual means that some people tolerate preparation A very well and it works well, while preparation B hardly works at all and shows unpleasant side effects, while for others the effect is exactly the opposite.²¹

A solid MPH drug regimen should therefore always include taking different preparations, even if one preparation is already effective and has no unpleasant side effects. Because whether another preparation does not work even significantly better, can only be determined after its testing.

Depending on the preparation, a high-fat food intake before / during ingestion may delay or accelerate the maximum effect and attenuate or increase the intensity of the effect.²¹ We do not have any concrete data on this for the preparations available in Europe.

21.1. Unretarded preparations¶

• In general:
  • Onset of action after 10 to 20 minutes²²
  • Peak effect after 60 minutes
    • Delayed maximum effect when taken with / on a high-fat meal²¹
  • Duration of action 2.5 - 4 hours
  • If taken twice, maximum of the 2nd intake is higher than that of the first intake²³
  • Half-life after 2.9 hours on average (2 to 4 hours)²¹

Preparations Germany:

• Ritalin® unretarded
  • 1-3 hours effective time
• Methylphenidate HEXAL®
  • 1-3 hours effective time
• Methylpheni TAD® unretarded
  • 1-3 hours effective time
• Medikinet® unretarded
  • 1-3 hours effective time
• Various generics

Preparations USA (as of 2021):

• Focalin®
  • Dexmethylphenidate hydrochloride
  • Unretarded tablets
  • 2.5, 5, 10 mg
• Methylin®
  • Methylphenidate hydrochloride
  • Unretarded
  • 5 mg/5 ml, 10 mg/5 ml
• Ritalin®
  • 1-3 hours effective time
  • Methylphenidate hydrochloride
  • Unretarded tablets
  • 5, 10, 20 mg
• Various generics

One (only) pharmacy in Switzerland produces MPH drops. These are even easier to dose, so that exact dosage settings are possible even for sufferers who need very small doses, such as young children. Ryffel reports on one application.²⁴²⁵

21.2. Retarded preparations¶

21.2.1. Half day dosage¶

21.2.1.1. Two-phase retardation / Extended release (XR) / Long acting (LA)¶

Preparations Germany:

• Equasym Retard/XL®
  • Duration until onset of action: 30 minutes²²
  • Duration of action (6-)8 hours,²² 8 hours²⁶
  • Impact Profile:
    • First maximum after 45 minutes, remains at this level until 2nd maximum²³
      Active level here higher than with Concerta
    • Second maximum after 5 hours²³
      only slightly increased compared to morning plateau
  • No food intake required before / during ingestion
  • Capsule may be opened²²
• Medikinet Adult®
  • Must be taken with food
  • Also approved for adults
  • 6-8 hours²²
  • Food intake required before / during ingestion²²
  • Bioequivalent to Medikinet Retard²⁷
• Medikinet Retard®
  • Must be taken with food
  • Bioequivalent to Medikinet Adult²⁷
  • Gluten free
  • Contains lactose
  • Duration until onset of action: 30 minutes²²
  • Duration of action 6(-8) hours²²
  • Impact Profile:²³
    • Maximum after 2.5 hours
    • Then drop until after 4 hours
    • Plateau from hour 4 to hour 6 (lower than maximum)
    • Thereafter waste to the end of action
  • Food intake required before / during ingestion²²
  • Capsule may be opened²²
• Ritalin LA®
  • Bioequivalent to Ritalin Adult
  • Duration of action: 8 hours²²6-8 hours²¹
  • Impact Profile:²³
    • 50% immediate effect due to beads in capsule²¹
      • First maximum after 2 hours
      • After that slight drop
    • 50% retarded by beads in capsule²¹
      • Second maximum after 6 1/2 hours
      • Thereafter waste until end of action
  • No food intake required before / during ingestion²²
  • Delayed maximum effect when taken with / on a high-fat meal²¹
  • Capsule may be opened and sprinkled on food²²²¹
• Ritalin Adult®
  • Bioequivalent to Ritalin LA²⁷
  • No food intake required before / during ingestion
  • Also approved for adults
  • 8 hours effective time according to manufacturer²²
  • Gluten free
  • Contains lactose
• Methysym®
  • Since 01.06.2021 in D
  • 30 % immediate release, 70 % sustained release
  • 10, 20, 30, 40, 50, 60 mg
  • Up to 8 hours effective time
  • No food intake required for ingestion

Preparations USA (as of 2021):

• Adhansia XR®
  • Methylphenidate hydrochloride
  • Extended-release capsules
  • 25, 35, 45, 55, 70, 85 mg
• Aptensio XR®
  • Methylphenidate hydrochloride
  • Extended-release capsules
  • 10, 15, 20, 30, 40, 50, 60 mg
• Cotempla XR-ODT®
  • Methylphenidate
  • Extended-release orally disintegrating tablets
  • 8.6, 17.3, 25.9 mg
• Daytrana®
  • Methylphenidate
  • Skin patch
  • 10 mg / 9 h (1.1 mg/h)
  • 15 mg / 9 h (1.6 mg/h)
  • 20 mg / 9 h (2.2 mg/h)
  • 30 mg / 9 h (3.3 mg/h)
• Focalin®
  • Dexmethylphenidate hydrochloride
  • Unretarded tablets
  • 2.5; 5; 10 mg
• Focalin XR®
  • Dexmethylphenidate hydrochloride
  • Extended-release capsules
  • 5, 10, 15, 20, 25, 30, 35, 40 mg
• Jornay PM®
  • Methylphenidate hydrochloride
  • Extended-release capsules
  • 20, 40, 60, 80, 100 mg
• Metadate CD®
  • Methylphenidate hydrochloride
  • Extended-release capsules
  • 10, 20, 30, 40, 50, 60 mg
• Methylin ER®
  • Methylphenidate hydrochloride
  • Extended-release chewable tablets
  • 10, 20 mg
• Quillichew ER®
  • Methylphenidate hydrochloride
  • Extended-release chewable tablets
  • 20, 30, 40 mg
• Quillichew XR®
  • Methylphenidate hydrochloride
  • Extended-release suspension
  • 5 mg/ml
• Ritalin LA®
  • Methylphenidate hydrochloride
  • Extended-release capsules
  • 10, 20, 30, 40 mg

21.2.1.2. Continuous release¶

• Ritalin SR®
  • 5-8 hours effective time theoretically, 3-5 hours effective time practically²¹
  • Continuous release of active ingredient from wax matrix²¹
  • Half-life after 3.4 hours²¹

21.2.2. All-day retardation¶

Preparations Germany, Austria, Switzerland:

• Concerta®
  • Methylphenidate hydrochloride
  • Extended-release tablets
  • 18, 27, 36, 54 mg
  • Bioequivalent: methylphenidate hydrochloride-neuraxpharm
  • Duration until onset of action: 60 minutes²²
    • Therefore, often good effect with simultaneous intake of small dose of unretarded MPHs
    • Ingestion with / after food may delay maximum effect (Tmax) by up to 1 hour and reduce by 10 to 30% (serum concentration maximum, Cmax)²¹
  • Duration of action 8-12 hours,²² 10-12 hours²¹
  • Impact Profile:
    • 22 % Immediate effect of the coating²¹
      • First maximum after 1 hour²¹ (up to 2 hours) (low), remains at this level until 2nd maximum
    • 78 % retarded by osmotic mechanism²¹
      • Second maximum after 6 (to 8) hours (significantly higher),²² 6.8 hours²¹
    • Half-life after 3.4 hours²¹
  • Intake:
    • No food intake required before / during ingestion²²
    • Capsule must not be opened²²²¹
• Methylphenidate hydrochloride-neuraxpharm
  • 12 hours effective time
  • Bioequivalent to Concerta
  • No food intake required before / during ingestion
• Kinecteen®
  • 12 hours effective time
  • No food intake required before / during ingestion
• Methylphenidate hydrochloride Ratiopharm²⁸
  • 12 hours effective time
• Methylphenidate hydrochloride Hexal²⁹
  • 12 hours effective time

Preparations USA:

• Concerta®
  • Details see above
• Azstarys® (KP415)³⁰
  • Mixture of 70% serdex methylphenidate (SDX, prodrug of dexmethylphenidate) and 30% dexmethylphenidate (d-MPH) with immediate release (IR)
  • 26.1/5.2mg; 39.2/7.8 mg; 52.3/10.4 mg SDX/d-MPH
  • 13 hours effective time
  • Approval 2021
  • No food intake required with ingestion, but prolongs effect
  • Degradation of SDX: unknown enzymes
  • Degradation of d-MPH: CES1
  • No interaction with CYP2D6, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2E1 or CYP3A
  • No interaction with alcohol
  • SDX does not prolong the QT interval to a clinically relevant extent

The course of the effect curve differs considerably depending on the MPH preparation. ADHSpedia shows a graph comparing different efficacy curves.³¹

22. Different MPH preparations have individually different effects - despite identical active ingredient¶

So far not scientifically substantiated, but empirically recognized beyond doubt, is the fact that methylphenidate preparations can have very different effects in different individuals.³² We suspect a connection with the different effect (time) profiles and different fillers.
We know sufferers who reacted to one MPH preparation with aggression and responded quite excellently to another preparation - and other sufferers who reacted to the two preparations with exactly the opposite reactions.
The phenomenon is widely known in sufferer forums and testing of various MPH preparations is regularly recommended by sufferers among themselves.

Among adults, however, methylphenidate is increasingly being replaced by Elvanse since Elvanse Adult was approved in May 2019. In adults, amphetamine medications are the drug of choice over methylphenidate.

A graph illustrates the active ingredient profile of

• Concerta
• Ritalin Adult / LA
• Medikinet adult
• MPH unretarded

https://www.pharmazeutische-zeitung.de/fileadmin/_processed_/1/1/csm_15489_d3da8723e2.jpg ³³

23. Further sources on methylphenidate¶

A detailed graphical and explanatory account of the pathway of action of methylphenidate can be found at www.pharmgkb.org.³⁴ Another comprehensive account of methylphenidate can be found at drugbank.com.³⁵