Methylphenidate: Difference between revisions

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	{{Phenethylamines}}		{{Phenethylamines}}

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Ritalin 20mg Sustained Release tablets.
Methylphenidate chemical structure Methylphenidate
IUPAC name: methyl a-phenyl-2-piperidine acetate
CAS number 113-45-1	ATC code N06B A04
Chemical formula	C₁₄H₁₉N O₂
Molecular weight	233.31
Bioavailability	11–52% (Oral)
Metabolism	Liver
Elimination half life	2–4 hours
Excretion	Urine
Pregnancy category	C
Legal status	Schedule II USA, Schedule 2 UK
Delivery	Ritalin: 5 mg, 10 mg, and 20 mg tablets; Ritalin SR: 20 mg tablets; Ritalin LA: 20 mg, 30 mg, and 40 mg capsules; Methylin: 5 mg, 10 mg, and 20 mg tablets; Methylin ER: 10 mg and 20 mg tablets; Metadate ER: 10 mg and 20 mg tablets; Metadate CD: 10 mg, 20 mg, and 30 mg capsules; Concerta: 18 mg, 27 mg, 36 mg, and 54 mg tablets; Rubifen: 5 mg, 10 mg, and 20 mg tablets

Indicated for:

Recreational uses:

Stimulant / "Speed" / "Uppers"

Other uses:

Contraindications:

Use of tricyclic antidepressants (e.g. desipramine), as MPH may dangerously increase their plasma concentrations, leading to potential toxic reactions (mainly, cardiovascular effects).
Use of MAO Inhibitors, such as phenelzine (Nardil) or tranylcypromine (Parnate), and certain other drugs.
MPH should not be given to patients who suffer from the following conditions: Severe Arrhythmia, Hypertension or Liver damage.
Drug-seeking behaviour
Pronounced agitation or nervousness

Side effects:

Atypical sensations:

Cardiovascular:

Ear, nose, and throat:

Endocrinal:

Appetite loss

Eye:

Blurred vision
Pupil dilation (If snorted)

Gastrointestinal:

Nausea/vomiting, abdominal pain

Hematological:

Musculo skeletal:

Muscle twitches

Neurological:

Insomnia, drowsiness, dizziness, headache

Psychological:

Respiratory:

Increased respiration rate

Skin:

Urogenital and reproductive:

Miscellaneous:

Methylphenidate (MPH) is an amphetamine-like prescription stimulant commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD) in children and adults. It is also one of the primary drugs used to treat symptoms of traumatic brain injury and the daytime drowsiness symptoms of narcolepsy and chronic fatigue syndrome. Brand names of drugs that contain methylphenidate include Ritalin® (Ritalina®), Concerta® (a timed-release capsule), Metadate®, Methylin® and Rubifen®. Focalin® is a preparation containing only dextro-methylphenidate, rather than the usual racemic dextro- and laevo-methylphenidate mixture of other formulations.

History

Methylphenidate patented in 1954 by the Ciba Pharmaceutical Company (a precursor to Novartis) and was initially prescribed as a treatment for depression, chronic fatigue, and narcolepsy, among other ailments. Beginning in the 1960s, it was used to treat children with ADHD, known at the time as hyperactivity or minimal brain dysfunction (MBD). Today methylphenidate is the medication most commonly prescribed to treat ADHD around the world. According to most estimates, more than 75 percent of methylphenidate prescriptions are written for children, with boys being about four times as likely to take methylphenidate as girls. Production and prescription of methylphenidate rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.

Most brand-name Ritalin is produced in the United States, although methylphenidate is also produced in Mexico and Argentina by respective contract pharmaceutical manufacturers and is most commonly marketed under the brand name "Ritalin" for Novartis. In the United States, various generic forms of methylphenidate are also produced by several pharmaceutical companies (such as Methylin, etc.), and Ritalin is also sold in the United Kingdom, Germany, and other European countries (although in much lower volumes than the United States).

Another medicine is Concerta, a once-daily extended release form of methylphenidate, which was approved in April 2000. Studies have demonstrated that long-acting methylphenidate preparations such as Concerta are just as effective, if not more effective, than IR (instant release) formulas. Time-release medications are also harder to misuse.

In April 2006, the FDA approved a transdermal patch for the treatment of ADHD, called Daytrana. The once-daily patch administers methylphenidate in doses of 10, 15, 20, or 30mg and will become available in June or July of 2006.

Effects

Methylphenidate is a central nervous system (CNS) stimulant. It has a "calming" effect on many children who have ADHD, reducing impulsive behavior and the tendency to "act out", and helps them concentrate on schoolwork and other tasks. Adults who have ADHD often find that MPH increases their ability to focus on tasks and organize their lives.

Methylphenidate has been found to have a lower incidence of side-effects compared to dextroamphetamine, a less commonly prescribed medication. When prescribed at the correct dosage, methylphenidate is usually well-tolerated by patients.

The means by which methylphenidate helps people with ADHD are not well understood. Some researchers have theorized that ADHD is caused by a dopamine imbalance in the brains of those affected. MPH is a dopamine reuptake inhibitor, which means that it increases the level of the dopamine neurotransmitter in the brain by partially blocking the transporters that remove it from the synapses. This could explain its clinical efficacy.

In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but which have a high potential for abuse because of their addictive potential. Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances. Some people abuse MPH by crushing the tablets and snorting them, the "high" resulting from the increased rate of dopamine transporter blockade due to quicker absorption into the bloodstream. In this manner, the effect of Ritalin is similar to that of cocaine or amphetamine and such abuse can lead to addiction. When taken orally in prescribed doses, MPH has a low addiction liability and rarely produces a "high".

Methylphenidate has been used illegally by students for whom the drug has not been prescribed, to assist with coursework and examinations.

Some may use it recreationally in combination with alcohol to attempt to counter the downing effects of excessive drinking, presumably allowing the user to stay fairly awake and social while heavily intoxicated. However, there is no scientific evidence to substantiate the validity of this claim, and the behavior could have serious negative consequences.

Formulations

Most products containing methylphenidate contain a 50/50 racemic mixture of dextro-methylphenidate and levo-methylphenidate, although it is only dextro-methylphenidate, the active enantiomer, which is considered to provide the pharmacologically useful effects of mental focus. However, with the introduction of Focalin, pure dextro-methylphenidate is available. Described as a fast-acting form of the drug, it is absorbed more quickly by the body, with a shorter time to peak concentration (and excretion) than with the heterogeneous compound.

The pharmacological profiles and relative usefulness of dextro- and levo-methylphenidate is analogous to what is found in amphetamine, where dextro-amphetamine is considered to have a more beneficial effect than levo-amphetamine.

Criticism

Overprescription

Some consider the treatment of children with stimulant medication to be controversial since the number of children taking them has increased dramatically over the years. However, criticism that methylphenidate is overprescribed may be unfounded; the incidence of ADHD is believed to be between three and five percent of the population, while the number of children in America taking Ritalin is estimated at one to two percent. In a small study of four American communities, the incidence of ADHD varied from 1.6% to 9.4%. The study also found that only 12.5% of the children meeting the DSM-III-RADHD criteria for ADHD had been treated with stimulants during the past year.

Addiction

Some have argued that prescription of stimulant medications sets children up for future addictions. However, recent research suggests that boys with ADHD who are treated with stimulants like MPH are actually less likely to abuse drugs including alcohol later in life. This study does not, however, address the question of the addictive properties of Ritalin, as a stimulant, itself.

Long-term effects

As long-term use of methylphenidate was relatively uncommon before the 1990s, the long-term neurological effects are not well researched. As documented for amphetamines, the potential of methylphenidate use over many years causing permanent neurological damage to dopaminergic systems exists at least in theory. For example, Adriani et al (2005) found plastic changes in reward related behavior in rats after they were in a drug-free state. Whether or not this would have any effect on human cognition is unknown.

In a 2005 study, no "clinically significant" effects on growth, vital signs, tics, or laboratory tests (including urinalysis, hematology/complete blood counts, electrolytes, and liver function tests) were observed after 2 years of treatment.

Effects on stature

Researchers have also looked into the role of methylphenidate in affecting stature, with some studies finding slight decreases in height acceleration. Other studies indicate height may normalize by adolesence.

Risk of death

Although extremely uncommon, Ritalin has been found by coroners to be the cause of a few deaths among children.

Potential Carcinogen

In February 2005, a team of researchers from The University of Texas M.D. Anderson Cancer Center led by R.A. El-Zein announced that a small scale study of 12 children indicated that methylphenidate may be carcinogenic. In the study, 12 children were given standard therapeutic doses of methylphenidate. At the conclusion of the 3 month study, all 12 children displayed significant, treatment induced chromosomal aberrations. The researches indicated that while their study was too small to derive meaningful conclusions, they indicated more studies should be done as the link between chromosomal aberrations and cancer is well documented.

The results are controversial, however, since there have been conflicting results regarding the mutagenicity of methylphenidate.

A 2003 study tested the effects of d-methylphenidate (Focalin), l-methylphenidate, and d,l-methylphenidate (Ritalin) on mice to search for any carcinogenic effects. The researchers found that all three compounds were non-genotoxic and non-clastogenic; d-MPH, d,l-MPH, and l-MPH did not cause mutations or chromosome abberations. They concluded that none of the compounds present a carcinogenic risk to humans.

Illicit use

Both the United States Drug Enforcement Administration (DEA) and the United Nations International Narcotics Control Board have expressed concern about the ease with which legally prescribed MPH is diverted to the illicit market.

According to the DEA, "The increased use of this substance for the treatment of ADHD has paralleled an increase in its abuse among adolescents and young adults who crush these tablets and snort the powder to get high. Youngsters have little difficulty obtaining methylphenidate from classmates or friends who have been prescribed it."

Reference

Internet Mental Health
^ Steele, M., et al. (2006). "A randomized, controlled effectiveness trail of OROS-methylphenidate compared to usual care with immediate-release methylphenidate in Attention Deficit-Hyperactivity Disorder". Can J Clin Pharmacol. 2006 Winter;13(1):e50-62.
Pelham, W.E., et al. (2001). "Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings". Pediatrics. 2001 Jun;107(6):E105.
Keating, G.M., McClellan, K., Jarvis, B. (2001). "Methylphenidate (OROS formulation)". CNS Drugs. 2001;15(6):495-500; discussion 501-3.
Hoare, P., et al. (2005). "12-month efficacy and safety of OROS® MPH in children and adolescents with attention-deficit/hyperactivity disorder switched from MPH". Eur Child Adolesc Psychiatry. 2005 Sep;14(6):305-9.
Peck, P. (2006, 7 April). FDA Approves Daytrana Transdermal Patch for ADHD. MedPage today. Retrieved April 7, 2006, from http://www.medpagetoday.com/ProductAlert/Prescriptions/tb/3027.
Barbaresi, W.J., et al. (2006). "Long-Term Stimulant Medication Treatment of Attention-Deficit/Hyperactivity Disorder: Results from a Population-Based Study". J Dev Behav Pediatr. 2006 Feb;27(1):1-10.
Volkow N., et al. (1998). "Dopamine Transporter Occupancies in the Human Brain Induced by Therapeutic Doses of Oral Methylphenidate". Am J Psychiatry 155:1325-1331, October 1998.
Green List: Annex to the annual statistical report on psychotropic substances (form P) 23rd edition. August 2003. International Narcotics Board, Vienna International Centre. Accessed 02 March 2006
Pittsburgh Tribune-Review. "More students abusing hyperactivity drugs".
The New Yorker. 2 February 1999. "Running from Ritalin".
Jensen, Peter S., Lori Kettle, Margaret T. Roper, Michael T. Sloan, Mina K. Dulcan, Christina Hoven, Hector R. Bird, Jose J. Bauermeister, and Jennifer D. Payne. 1999. Are stimulants overprescribed? Treatment of ADHD in four U.S. communities. Journal of the American Academy of Child and Adolescent Psychiatry 38 (7):797-804.
Mannuzza, S., Klein, R.G., Moulton, J.L. (2003). "Does Stimulant Treatment Place Children at Risk for Adult Substance Abuse? A Controlled, Prospective Follow-up Study". Journal of Child and Adolescent Psychopharmacology, Sep 2003, Vol. 13, No. 3: 273-282.
Adriani, W. et al. (2005). "Methylphenidate Administration to Adolescent Rats Determines Plastic Changes on Reward-Related Behavior and Striatal Gene Expression". Neuropsychopharmacology advance online publication 23 November 2005;doi:10.1038/sj.npp.1300962.
Wilens, T., et al. (2005). ADHD treatment with once-daily OROS methylphenidate: final results from a long-term open-label study". J Am Acad Child Adolesc Psychiatry. 2005 Oct;44(10):1015-23.
Rao J.K., Julius J.R., Breen T.J., Blethen S.L. (1996). "Response to growth hormone in attention deficit hyperactivity disorder: effects of methylphenidate and pemoline therapy". Pediatrics. 1998 Aug;102(2 Pt 3):497-500.
Spencer, T.J., et al. (1996). "Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays?". J Am Acad Child Adolesc Psychiatry. 1996 Nov;35(11):1460-9.
Klein R.G. & Mannuzza S. (1988). "Hyperactive boys almost grown up. III. Methylphenidate effects on ultimate height". Arch Gen Psychiatry. 1988 Dec;45(12):1131-4.
El-Zein R.A., et al. (2005). "Cytogenetic effects in children treated with methylphenidate". Cancer Lett. 2005 Dec 18;230(2):284-91.
Teo, S.K., et al. (2003). "D-Methylphenidate is non-genotoxic in vitro and in vivo assays". Mutat Res. 2003 May 9;537(1):67-79.
United Nations International Narcotics Control Board. 1995. Dramatic Increase in Methylphenidate Consumption in US: Marketing Methods Questioned . Author, . Available from http://www.incb.org/e/press/1995/pdf/e_bn_02.pdf.
United States Drug Enforcement Administration. 2000. Statement by Terrance Woodworth Deputy Director, Office of Diversion Control, Drug Enforcement Administration Before the Committee on Education and the Workforce: Subcommittee on Early Childhood, Youth and Families May 16, 2000 , . Available from http://www.usdoj.gov:80/dea/pubs/cngrtest/ct051600.htm.
DEA, Briefs & Backgrounds, Drugs and Drugs of Abuse, Descriptions, Methylphenidate. Retrieved April 7, 2006 from http://www.usdoj.gov/dea/concern/methylphenidate.html.

External links

v t e Phenethylamines
Phenethylamines	Psychedelics: 25B-NBOMe 25C-NBOMe 25D-NBOMe 25I-NBOMe 25N-NBOMe 2C-B 2C-B-AN 2C-Bn 2C-Bu 2C-C 2C-CN 2C-CP 2C-D 2C-E 2C-EF 2C-F 2C-G 2C-G-1 2C-G-2 2C-G-3 2C-G-4 2C-G-5 2C-G-6 2C-G-N 2C-H 2C-I 2C-iP 2C-N 2C-NH2 2C-O 2C-O-4 2C-P 2C-Ph 2C-SE 2C-T 2C-T-2 2C-T-3 2C-T-4 2C-T-5 2C-T-6 2C-T-7 2C-T-8 2C-T-9 2C-T-10 2C-T-11 2C-T-12 2C-T-13 2C-T-14 2C-T-15 2C-T-16 2C-T-17 2C-T-18 2C-T-19 2C-T-20 2C-T-21 2C-T-22 2C-T-22.5 2C-T-23 2C-T-24 2C-T-25 2C-T-27 2C-T-28 2C-T-30 2C-T-31 2C-T-32 2C-T-33 2C-TFE 2C-TFM 2C-YN 2C-V Allylescaline DESOXY Escaline Isoproscaline Jimscaline Macromerine MEPEA Mescaline Metaescaline Methallylescaline Proscaline Psi-2C-T-4 TCB-2 Stimulants: Phenylethanolamine Hordenine Phenethylamine Phenpromethamine α-Methylphenethylamine (amphetamine) β-Methylphenethylamine m-Methylphenethylamine N-Methylphenethylamine o-Methylphenethylamine p-Methylphenethylamine Methylphenidate Entactogens: Lophophine MDPEA MDMPEA Others: BOH DMPEA
Amphetamines	Psychedelics: 3C-AL 3C-BZ 3C-E 3C-MAL 3C-P Aleph Beatrice Bromo-DragonFLY D-Deprenyl DMA DMCPA DMMDA DOB DOC DOEF DOET DOI DOM DON DOPR DOTFM Ganesha MMDA MMDA-2 Psi-DOM TMA TeMA ZDCM-04 Stimulants: 2-FA 2-FMA 3-FA 3-FMA Acridorex Alfetamine Amfecloral Amfepentorex Amphetamine (Dextroamphetamine, Levoamphetamine) Amphetaminil Benfluorex Benzphetamine Cathine Clobenzorex Dimethylamphetamine Ephedrine Etilamfetamine Fencamfamin Fencamine Fenethylline Fenfluramine (Dexfenfluramine, Levofenfluramine) Fenproporex Flucetorex Fludorex Formetorex Furfenorex Gepefrine 4-Hydroxyamphetamine Iofetamine Isopropylamphetamine Lefetamine Lisdexamfetamine Mefenorex Metaraminol Methamphetamine (Dextromethamphetamine, Levomethamphetamine) Methoxyphenamine MMA Morforex Norfenfluramine L-Norpseudoephedrine N,alpha-Diethylphenylethylamine Oxifentorex Oxilofrine Ortetamine PBA PCA PFA PFMA PIA PMA PMEA PMMA Phenylpropanolamine Pholedrine Prenylamine Propylamphetamine Pseudoephedrine Sibutramine Tiflorex Tranylcypromine Xylopropamine Zylofuramine Entactogens: 4-FA 4-FMA 4-MA 4-MMA 4-MTA 5-APB 5-APDB 5-EAPB 5-IT 5-MAPB 5-MAPDB 6-APB 6-APDB 6-Chloro-MDMA 6-EAPB 6-IT 6-MAPB 6-MAPDB EDA IAP 2,3-MDA 3,4-MDA (tenamfetamine) MDEA MDHMA MDMA (midomafetamine) MDOH Methamnetamine MMDMA Naphthylaminopropane TAP Others: 3,4-DCA Amiflamine DiFMDA Selegiline (also D-Deprenyl)
Phentermines	Stimulants: Chlorphentermine Cloforex Clortermine Etolorex Mephentermine Pentorex Phentermine Entactogens: MDPH MDMPH Others: Cericlamine
Cathinones	Stimulants: 3-FMC 4-MC 4-BMC 4-CMC 4-EMC 4-FMC 4-MEC 4-MeMABP 4-MPD Amfepramone Benzedrone Brephedrone Buphedrone Bupropion Cathinone Dimethylcathinone Ethcathinone Eutylone Hydroxybupropion Methcathinone Methedrone NEB N-Ethylhexedrone N-Ethylpentedrone Pentedrone Pentylone Radafaxine Entactogens: 3,4-DMMC 3-MMC Butylone Ethylone Methylone Methylenedioxycathinone Mephedrone
Phenylisobutylamines	Entactogens: 4-CAB 4-MAB Ariadne BDB Butylone EBDB Eutylone MBDB Stimulants: Phenylisobutylamine
Phenylalkylpyrrolidines	Stimulants: α-PBP α-PHP α-PPP α-PVP MDPBP MDPPP MDPV 4-MePBP 4-MePHP 4-MePPP MOPPP MOPVP MPBP MPHP MPPP Naphyrone PEP Prolintane Pyrovalerone
Catecholamines (and close relatives)	6-FNE 6-OHDA a-Me-DA a-Me-TRA Adrenochrome Ciladopa D-DOPA (Dextrodopa) Dimetofrine Dopamine Epinephrine Epinine Etilefrine Ethylnorepinephrine Fenclonine Ibopamine Isoprenaline Isoetarine L-DOPA (Levodopa) L-DOPS (Droxidopa) L-Phenylalanine L-Tyrosine m-Tyramine Metanephrine Metaraminol Metaterol Metirosine Methyldopa N,N-Dimethyldopamine Nordefrin (Levonordefrin) Norepinephrine Norfenefrine (m-Octopamine) Normetanephrine Orciprenaline p-Octopamine p-Tyramine Phenylephrine Synephrine
Miscellaneous	AL-LAD Amidephrine Arbutamine Cafedrine Denopamine Desvenlafaxine Diphenidine Dizocilpine Dobutamine Dopexamine Ephenidine Etafedrine ETH-LAD Famprofazone Fluorolintane Hexapradol IP-LAD Lysergic acid amide Lysergic acid 2-butyl amide Lysergic acid 2,4-dimethylazetidide Lysergic acid diethylamide Methoxamine Methoxphenidine MT-45 PARGY-LAD Phenibut PRO-LAD Pronethalol Salbutamol (Levosalbutamol) Solriamfetol Theodrenaline Thiamphenicol UWA-101 Venlafaxine

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