Methylphenidate

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Summary sheet: Methylphenidate
Methylphenidate
Methylphenidate.svg
Chemical Nomenclature
Common names Methylphenidate, Concerta, Methylin, Ritalin, Equasym XL
Substitutive name Methylphenidate
Systematic name Methyl 2-phenyl-2-piperidin-2-ylacetate
Class Membership
Psychoactive class Stimulant
Chemical class Phenidate
Routes of Administration

WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. See responsible use section.



⇣ Oral
Dosage
Bioavailability 11-52%[1]
Threshold 5 mg
Light 10 - 20 mg
Common 20 - 40 mg
Strong 40 - 60 mg
Heavy 60 mg +
Duration
Total 4 - 6 hours
Onset 20 - 60 minutes
Come up 20 - 60 minutes
Peak 1.5 - 2.5 hours
Offset 1 - 2 hours
After effects 2 - 6 hours



⇣ Insufflated
Dosage
Threshold 5 mg
Light 10 - 15 mg
Common 15 - 30 mg
Strong 30 - 60 mg
Heavy 60 mg +
Duration
Total 2 - 4 hours
Onset 5 - 20 minutes
Come up 15 - 40 minutes
Peak 30 - 45 minutes
Offset 2 - 4 hours
After effects 1 - 4 hours






DISCLAIMER: PW's dosage information is gathered from users and resources for educational purposes only. It is not a recommendation and should be verified with other sources for accuracy.

Interactions
Alcohol
MXE
Dissociatives
MDMA
Stimulants
DXM
25x-NBOMe
25x-NBOH
Tramadol
MAOIs


Methylphenidate (also known as MPH, MPD, and its brand names Ritalin, Concerta, and Methylin, among others) is a stimulant substance of the phenidate class. Methylphenidate is the parent compound of the substituted phenidates, a family of compounds that includes ethylphenidate, isopropylphenidate, and others. It acts primarily by enhancing the activity of the neurotransmitters dopamine and norepinephrine in the brain.

Methylphenidate was first licensed by the U.S. Food and Drug Administration (FDA) in 1955 for treating what was then known as "hyperactivity." Although it was prescribed to patients as early as 1960, it only became heavily prescribed in the 1990s when the diagnosis of ADHD itself became more widely accepted.[2][3]

Methylphenidate is approved for treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy. It is often used by students with or without ADHD to enhance their mental abilities, improve their concentration, and help them study.

Chemistry

Methylphenidate is a synthetic molecule of the substituted phenethylamine and substituted phenidate classes. It contains a phenethylamine core featuring a phenyl ring bound to an amino (-NH2) group through an ethyl chain. It is structurally similar to amphetamine, featuring a substitution at Rα which is incorporated into a piperidine ring ending at the terminal amine of the phenethylamine chain. Additionally, it contains a methyl acetate bound to Rβ of its structure.

Methylphenidate is a chiral compound, presumably produced as a racemic mixture. It has an enantiopure also sold as a pharmaceutical; the dextrorotary enantiopure is known as "dexmethylphenidate" and is commonly sold as Focalin and Focalin XR.

Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects.[4] The erythro diastereomers are pressor amines, a property not shared with the threo diastereomers. When the drug was first introduced it was sold as a 4:1 mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. "TMP" refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used and it is much more commonly referred to as dexmethylphenidate, d-MPH, or d-threo-methylphenidate. A review on the synthesis of enantiomerically pure (2R,2'R)-(+)-threo-methylphenidate hydrochloride has been published.[5]

Dexmethylphenidate in skeletal formula

Pharmacology

Methylphenidate primarily acts as a norepinephrine-dopamine reuptake inhibitor (NDRI). It is most active at modulating levels of dopamine and, to a lesser extent, norepinephrine.[6] Methylphenidate binds to and blocks dopamine transporters and norepinephrine transporters.[7]

While both amphetamine and methylphenidate are dopaminergic, it should be noted that their methods of action are somewhat distinct. Specifically, methylphenidate is a dopamine reuptake inhibitor while amphetamine is both a releasing agent and reuptake inhibitor of dopamine and norepinephrine. Each of these drugs have a corresponding effect on norepinephrine which are weaker than their effects on dopamine. Methylphenidate's mechanism of action at dopamine-norepinephrine release is still debated, but is fundamentally different from most other phenethylamine derivatives as methylphenidate is thought to increase general firing rate, whereas amphetamine reduces firing rate and reverses the flow of the monoamines via TAAR1 activation.[8][9][10][11]

Subjective effects

Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWiki contributors. As a result, they should be viewed with a healthy degree of skepticism.

It is also worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become increasingly likely with higher doses and may include addiction, severe injury, or death ☠.

Physical effects
Child.svg

    • Stimulation - Methylphenidate is usually reported to be energetic and stimulating in a fashion that is distinct but much weaker than that of amphetamine or methamphetamine and stronger than that of modafinil and caffeine. At lower to moderate doses, it encourages general productivity but at higher dosages it can encourage physical activities such as dancing, socializing, running, or cleaning. The particular style of stimulation which methylphenidate presents can be described as forced. This means that at higher dosages, it becomes difficult or impossible to keep still as jaw clenching, involuntarily bodily shakes and vibrations become present, resulting in extreme shaking of the entire body, unsteadiness of the hands, and a general lack of motor control.
    • Increased heart rate[12][13]
    • Abnormal heartbeat[12][13]
    • Dehydration
    • Frequent urination
    • Dry mouth
    • Appetite suppression[13]
    • Increased perspiration
    • Nausea[13] - May occur at higher doses, although tends to fade after a short period.
    • Dizziness[13] - May occur at higher doses, although tends to fade after a short period.
    • Teeth grinding - Teeth grinding is present, but typically at higher doses and not to the same extent as other stimulants like amphetamine, or more severely, MDMA.
    • Vasoconstriction
    • Increased libido - Higher doses of methylphenidate can increase sexual desire, although this enhancement is reported to be less intense and reliable than amphetamines and cocaine.
    • Pupil dilation

Cognitive effects
User.svg

After effects
Aftereffects (3).svg

Experience reports

Anecdotal reports which describe the effects of this compound within our experience index include:

Additional experience reports can be found here:

Toxicity and harm potential

Radar plot showing relative physical harm, social harm, and dependence of methylphenidate[15]

A toxic dose of methylphenidate is considered to be more than 2 mg/kg or 60 mg of an immediate-release formulation, or more than 4 mg/kg or 120 mg of an intact extended-release formulation.[16] In the majority of cases in one study, methylphenidate overdose was asymptomatic or characterized by minor symptoms even in children under age 6. However, a significant amount of patients (31%) in the study developed symptoms typical of stimulant overdose, most commonly tachycardia, agitation, and paradoxically lethargy.[17] In the 2012 National Poison Data System report, methylphenidate exposure was reported 9,787 times, with 1,609 reporting no adverse effects, 1,009 reporting mild effects, 662 reporting moderate effects, 33 reporting major symptoms, and no cases resulting in death.[18]

It is strongly recommended that one use harm reduction practices when using this substance.

Tolerance and addiction potential

In terms of its tolerance, methylphenidate can be used multiple days in a row for extended periods of time and is often prescribed to be used in this way. Tolerance to many of the effects of methyphenidate develops with prolonged and repeated use. This results in users having to administer increasingly large doses to achieve the same effects.[19] In the case of acute (i.e. one-off) exposure, it generally takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption).[citation needed] Methylphenidate presents cross-tolerance with all dopaminergic stimulants, meaning that after the consumption of methyphenidate all stimulants will have a reduced effect."[citation needed]

As with other stimulants, the chronic use of methylphenidate can be considered moderately addictive with a high potential for abuse and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal effects may occur if a person suddenly stops their usage. Methylphenidate has some potential for abuse due to its action on dopamine transporters. Methylphenidate, like other stimulants, increases dopamine levels in the brain. However, at therapeutic doses this increase is slow and thus euphoria only rarely occurs even when it is administered intravenously.[20] The abuse and addiction potential of methylphenidate is therefore significantly lower than other dopaminergic stimulants.[21][22]

The abuse potential is increased when methylphenidate is crushed and insufflated (snorted) or injected.[23]. It should be noted that due to the fillers in the pill, however, that this can be harmful to the nasal cavities. The primary source of methylphenidate for abuse is the diversion from legitimate prescriptions rather than illicit synthesis. Those who use methylphenidate medicinally generally take it orally as instructed while intranasal and intravenous are the preferred means for recreational use.[24]

Psychosis

Main article: Stimulant psychosis

Chronic abuse of methylphenidate can potentially lead to psychosis.[25][26] The safety profile of short-term methylphenidate therapy has been well-established, with short-term clinical trials revealing a very low incidence (0.1%) of methylphenidate-induced psychosis at therapeutic dose levels.[27] Psychotic symptoms from methylphenidate can include hearing voices, visual hallucinations, urges to harm oneself, severe anxiety, mania, disinhibition, paranoid and grandiose delusions, confusion, emotional suppression, increased aggression, and irritability.

Alcohol & Methylphenidate

Methylphenidate (when taken orally) has a low bioavailability around 30%. If taken with alcohol (ethanol), blood plasma levels of dexmethylphenidate are increased by up to 40%.[28] A metabolite called ethylphenidate is also formed.[29]

Dangerous interactions

Warning: Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous or even life-threatening when combined with certain other substances. The following lists some known dangerous interactions (although it is not guaranteed to include all of them).

Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.

  • 25x-NBOMe & 25x-NBOH - 25x compounds are highly stimulating and physically straining. Combinations with Methylphenidate should be strictly avoided due to the risk of excessive stimulation and heart strain. This can result in increased blood pressure, vasoconstriction, panic attacks, thought loops, seizures, and heart failure in extreme cases.
  • Alcohol - Combining alcohol with stimulants can be dangerous due to the risk of accidental over-intoxication. Stimulants mask alcohol's depressant effects, which is what most people use to assess their degree of intoxication. Once the stimulant wears off, the depressant effects will be left unopposed, which can result in blackouts and severe respiratory depression. If mixing, the user should strictly limit themselves to only drinking a certain amount of alcohol per hour.
  • DXM - Combinations with DXM should be avoided due to its inhibiting effects on serotonin and norepinephrine reuptake. There is an increased risk of panic attacks and hypertensive crisis, or serotonin syndrome with serotonin releasers (MDMA, methylone, mephedrone, etc.). Monitor blood pressure carefully and avoid strenuous physical activity.
  • MDMA - Any neurotoxic effects of MDMA are likely to be increased when other stimulants are present. There is also a risk of excessive blood pressure and heart strain (cardiotoxicity).
  • MXE - Some reports suggest combinations with MXE may dangerously increase blood pressure and increase the risk of mania and psychosis.
  • Dissociatives - Both classes carry a risk of delusions, mania and psychosis, and these risk may be multiplied when combined.
  • Stimulants - Methylphenidate may be dangerous to combine with other stimulants like cocaine as they can increase one's heart rate and blood pressure to dangerous levels.
  • Tramadol - Tramadol is known to lower the seizure threshold[30] and combinations with stimulants may further increase this risk.
  • MDMA - The neurotoxic effects of MDMA may be increased when combined with other stimulants.

Legal status

Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.[32]

  • Australia: Methylphenidate is a 'Schedule 8' controlled substance. Such drugs must be kept in a lockable safe before being handed out and possession without prescription carries hefty fines and even imprisonment.[33]
  • Austria: Methylphenidate is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).[citation needed]
  • Canada: Methylphenidate is listed in Schedule III of the Controlled Drugs and Substances Act (along with LSD, psychedelic mushrooms, and mescaline).[34] It is illegal to possess without a prescription pursuant to Part G (section G.01.002) of the Food and Drug Regulations under the Food and Drugs Act.
  • Germany: Methylphenidate is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form.[35]
  • New Zealand: Methylphenidate is a 'Class B2 controlled substance'. Unlawful possession is punishable by six-month prison sentence and the distribution of it is punishable by a 14-year sentence.[citation needed]
  • Sweden: Methylphenidate is a List II controlled substance with recognized medical value. Possession without a prescription is punishable by up to three years in prison.[36]
  • Switzerland: Methylphenidate is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.[37]
  • Turkey: Methylphenidate is a 'red prescription' only substance[38] and illegal when sold or possessed without a prescription.[citation needed]
  • United Kingdom: Methylphenidate is a controlled 'Class B' substance. Possession without prescription carries with a sentence up to 5 years and/or an unlimited fine and supplying it is 14 years and/or an unlimited fine.[39]
  • United States: Methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but present a high potential for abuse.[citation needed]

It is a widespread myth that methylphenidate could lead to false-positives for amphetamine in drug screenings. However, there was found no immunoassay cross reactivity in laboratory study.[40]

See also

External links

Literature

  • Leonard, B. E., McCartan, D., White, J., & King, D. J. (2004). Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Human Psychopharmacology: Clinical and Experimental, 19(3), 151-180. https://doi.org/10.1002/hup.579

References

  1. ↑ "https://s3-us-west-2.amazonaws.com/drugbank/cite_this/attachments/files/000/004/483/original/Health_Canada_-_Ritalin.PDF?1556050208"
  2. ↑ Diller, Lawrence (1999). Running on Ritalin. ISBN 978-0553379068.
  3. ↑ The history of attention deficit hyperactivity disorder (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000907/
  4. ↑ Heal DJ, Pierce DM (2006). "Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system". CNS Drugs. 20 (9): 713–38. doi:10.2165/00023210-200620090-00002. PMID 16953648. S2CID 39535277.
  5. ↑ Prashad M (2001). "Approaches to the Preparation of Enantiomerically Pure (2R,2′R)-(+)-threo-Methylphenidate Hydrochloride". Adv. Synth. Catal. 343 (5): 379–92. doi:10.1002/1615-4169(200107)343:5<379::AID-ADSC379>3.0.CO;2-4.
  6. ↑ Methylphenidate and its Isomers | http://link.springer.com/article/10.2165%2F00023210-200620090-00002
  7. ↑ Neurotransmitter transporters and their impact on the development of psychopharmacology (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760736/
  8. ↑ Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/9766762
  9. ↑ Neurotransmitter transporters and their impact on the development of psychopharmacology (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760736/
  10. ↑ Focalin XR review | http://www.pharma.us.novartis.com/product/pi/pdf/focalinXR.pdf
  11. ↑ Concerta Xl slow release | http://www.medicines.org.uk/emc/medicine/8382/SPC/Concerta#PHARMACOLOGICAL_PROPSSPC
  12. ↑ 12.0 12.1 Montastruc, F., Montastruc, G., Montastruc, J. L., & Revet, A. (2016). Cardiovascular safety of methylphenidate should also be considered in adults. BMJ: British Medical Journal (Online), 353.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 Leonard, B. E., McCartan, D., White, J., & King, D. J. (2004). Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Human Psychopharmacology: Clinical and Experimental, 19(3), 151-180. https://doi.org/10.1002/hup.579
  14. ↑ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 318. ISBN 9780071481274.
  15. ↑ Development of a rational scale to assess the harm of drugs of potential misuse (ScienceDirect) | http://www.sciencedirect.com/science/article/pii/S0140673607604644
  16. ↑ Methylphenidate poisoning: An evidence-based consensus guideline for out-of-hospital management (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/18058301
  17. ↑ Characterization of Methylphenidate Exposures Reported to a Regional Poison Control Center | http://archpedi.jamanetwork.com/article.aspx?articleid=352627
  18. ↑ 2012 Annual Report of the American Association of Poison Control Centers ’ National Poison Data System (NPDS): 28th Annual Report | https://aapcc.s3.amazonaws.com/pdfs/annual_reports/2012_NPDS_Annual_Report.pdf
  19. ↑ Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/10511066
  20. ↑ Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of "high" (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/9862747
  21. ↑ Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of "high" (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/9862747
  22. ↑ Variables That Affect the Clinical Use and Abuse of Methylphenidate in the Treatment of ADHD | http://ajp.psychiatryonline.org/article.aspx?articleID=176483
  23. ↑ Methylphenidate Abuse and Psychiatric Side Effects (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC181133/
  24. ↑ Abuse and toxicity of methylphenidate | http://journals.lww.com/co-pediatrics/pages/articleviewer.aspx?year=2002&issue=04000&article=00013&type=abstract
  25. ↑ Methylphenidate Abuse and Psychiatric Side Effects | http://www.psychiatrist.com/PCC/article/Pages/2000/v02n05/v02n0502.aspx
  26. ↑ http://www.nejm.org/doi/full/10.1056/NEJM197204202861607
  27. ↑ Ritalin & Ritalin-SR Prescribing Information | http://www.pharma.us.novartis.com/product/pi/pdf/ritalin_ritalin-sr.pdf
  28. ↑ Influence of Ethanol and Gender on Methylphenidate Pharmacokinetics and Pharmacodynamics (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188424/
  29. ↑ Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/10820132
  30. ↑ Talaie, H.; Panahandeh, R.; Fayaznouri, M. R.; Asadi, Z.; Abdollahi, M. (2009). "Dose-independent occurrence of seizure with tramadol". Journal of Medical Toxicology. 5 (2): 63–67. doi:10.1007/BF03161089. eISSN 1937-6995. ISSN 1556-9039. OCLC 163567183. 
  31. ↑ Gillman, P. K. (2005). "Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity". British Journal of Anaesthesia. 95 (4): 434–441. doi:10.1093/bja/aei210 Freely accessible. eISSN 1471-6771. ISSN 0007-0912. OCLC 01537271. PMID 16051647. 
  32. ↑ "Green List: Annex to the annual statistical report on psychotropic substances (form P)" (PDF). Archived from the original (PDF) on 31 August 2012. (1.63 MB) 23rd edition. August 2003. International Narcotics Board, Vienna International Centre. Retrieved 2 March 2006.
  33. ↑ "POISONS STANDARD DECEMBER 2019". Office of Parliamentary Counsel. Retrieved December 24, 2019. 
  34. ↑ "SCHEDULE III". Department of Justice. Archived from the original on April 16, 2011. Retrieved December 24, 2019. 
  35. ↑ http://www.gesetze-im-internet.de/btmg_1981/anlage_iii.html
  36. ↑ Narkotikastrafflag (1968:64) | https://lagen.nu/1968:64
  37. ↑ "Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien" (in German). Bundeskanzlei [Federal Chancellery of Switzerland]. Retrieved January 1, 2020. 
  38. ↑ KIRMIZI REÇETEYE TABİ İLAÇLAR | https://www.titck.gov.tr/storage/Archive/2019/contentFile/K%C4%B1rm%C4%B1z%C4%B1%20Re%C3%A7eteye%20Tabi%20%C4%B0la%C3%A7lar%2005072019_ebcc7e92-6661-4983-870a-fe8983a9c2b7.pdf
  39. ↑ Misuse of Drugs Act 1971 | http://www.legislation.gov.uk/ukpga/1971/38/schedule/2
  40. ↑ Breindahl, Torben; Hindersson, Peter (2012). "Methylphenidate is Distinguished from Amphetamine in Drug-of-Abuse Testing". Journal of Analytical Toxicology. 36 (7): 538–539. doi:10.1093/jat/bks056. ISSN 0146-4760. 


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