Methylphenidate
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| Image:Methylphenidate-2D-skeletal.png | |
| Image:Dexmethylphenidate-3D-balls.png | |
| Methylphenidate
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| Systematic (IUPAC) name | |
| methyl 2-phenyl-2-(2-piperidyl)acetate | |
| Identifiers | |
| CAS number | 113-45-1 |
| ATC code | N06BA04 |
| PubChem | 4158 |
| DrugBank | APRD00657 |
| Chemical data | |
| Formula | C14H19NO2 |
| Mol. weight | 233.306 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 11–52% |
| Metabolism | Liver |
| Half life | 2–4 hours |
| Excretion | Urine |
| Therapeutic considerations | |
| Pregnancy cat. |
C |
| Legal status | |
| Routes | ? |
| Indicated for: Recreational uses:
Other uses: |
Contraindications:
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| Side effects:
Atypical sensations:
Eye:
Skin:
Urogenital and reproductive:
Miscellaneous:
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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®, Rilatine®, Ritalin LA® (Long Acting)), Attenta®, Concerta® (a timed-release capsule), Metadate®, Methylin® and Rubifen®. Focalin® is a preparation containing only dextro-methylphenidate, rather than the usual racemic dextro- and levo-methylphenidate mixture of other formulations.
Contents |
[edit] History
Methylphenidate was patented in 1954 by the Ciba pharmaceutical company (one of the predecessors of 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. Methylphenidate has been used illegally by students for whom the drug has not been prescribed, to assist with coursework and examinations.<ref>Pittsburgh Tribune-Review. "More students abusing hyperactivity drugs".</ref>
While ADHD medication is directed for children, it has not been studied for children under the age of 6. It is also important to note that while ADHD is a condition that includes hyperactivity, problems holding still, and following directions, this is also typical of a child under the age of 6. This causes difficulty in diagnosing children under this age and should probably not be studied.[1]
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 in the United States). These generic versions of methylphenidate tend to outsell brand-name "Ritalin" four-to-one. In Belgium the product is sold under the name "Rilatine" for Novartis.
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.<ref name="steele">Steele, M., et al. (2006). "A randomized, controlled effectiveness trial 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.</ref><ref>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.</ref><ref>Keating, G.M., McClellan, K., Jarvis, B. (2001). "Methylphenidate (OROS formulation)". CNS Drugs. 2001;15(6):495-500; discussion 501-3.</ref> <ref> 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.</ref> 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.<ref>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.</ref> However, the patch must be applied several hours before the effect is desired, and the drug's effect remains for several hours after removal, making it necessary to remove the patch in the mid-to-late afternoon or else insomnia may result.
[edit] Effects
Methylphenidate is a central nervous system (CNS) stimulant. It is claimed to have a 'calming' effect on many children who have ADHD,<ref>Hyperactivity Paradox Resolved?. Journal Watch. Retrieved on 2006-11-11.</ref> reducing impulsive behavior and the tendency to "act out", and helps them concentrate on schoolwork and other tasks. Adults who have ADHD often claim 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.<ref>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.</ref> When prescribed at the correct dosage, methylphenidate is usually well-tolerated by patients.<ref name="steele"/>
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.<ref>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.</ref> An alternate explanation which has been explored is that the MPH affects the action of serotonin in the brain.<ref>Gainetdinov, Raul R., Caron, Marc G. (March 2001). "Genetics of Childhood Disorders: XXIV. ADHD, Part 8: Hyperdopaminergic Mice as an Animal Model of ADHD". Journal of the American Academy of Child & Adolescent Psychiatry 40 (3): 380-382. Retrieved on 2006-11-11.</ref>
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.<ref>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</ref> 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".
[edit] Side effects
Commonly reported side effects are<ref>MedicineNet</ref><ref>ADD ADHD Information</ref> difficulty sleeping (which can lead in turn to other problems); loss of appetite (thus its use as an appetite suppressant); depression; irritability; nervousness; stomach aches; headaches; dry mouth; blurry vision; nausea; large pupils; dizziness; drowsiness; and motor tics or tremors. Up to 5% of children experience disturbing hallucinations often involving worms, snakes, or insects (New Scientist, 31 March 2006).
Less common side effects include hypersensitivity, anorexia, palpitations, blood pressure and pulse changes, cardiac arrhythmia, anemia, scalp hair loss, and toxic psychosis.[citation needed]
There have also been reports of abnormal liver function, cerebral arteritis, leukopenia, and death.[citation needed] There have been at least 19 cases of sudden death in children taking methylphenidate, leading to calls by the Drug Safety and Risk Management Advisory Committee to the FDA to require the most serious type of health warning on the label, but this advice was rejected (New Scientist 18 Feb. 2006).
Medline<ref>MedLine</ref> lists a number of side-effects of unquantified frequency.
[edit] Formulations
Most products containing methylphenidate contain a 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 racemic 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.
[edit] 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;
Attenta: 10mg tablets;
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;
Equasym: 5 mg, 10 mg tablets;
Rubifen: 5 mg, 10 mg and 20 mg tablets;
Daytrana: 10 mg, 15 mg, 20 mg, 30 mg and 40 mg patches
[edit] Criticism
Methylphenidate has a role as a frequently-used treatment for ADHD, and as such criticism of methyphenidate is part of the controversy about ADHD.
[edit] Scientology's criticism of Ritalin
According to a 1990 article by Joel Sappell and Robert W. Welkos in the Los Angeles Times, part of a series of articles about Scientology, "the uproar over Ritalin was triggered almost single-handedly by the Scientology movement."<ref name="LA Times">Sappell, Joel, Welkos, Robert W.. "Suits, Protests Fuel a Campaign Against Psychiatry", Los Angeles Times, 1990-06-29, p. A48:1. Retrieved on 2006-11-29. Additional convenience link at [2].</ref> The Citizens Commission on Human Rights, an anti-psychiatry group formed by Scientology in 1969, conducted a major campaign against Ritalin in the 1980s and lobbied Congress for an investigation of Ritalin. Cass Ballenger, a member of the House Education and Labor Committee who met with the Citizens Commission said that "some of the information they provided did not 'add up.'" For example, the article mentions that the Committee claimed a figure of 10-20% of students under age 10 on Ritalin in a particular school district, to which the manager of health services for the district replied, "if they are saying that is the statistic ... they are lying," stating that the percentage of students taking Ritalin or any stimulant for hyperactivity was actually under 1%.<ref name="LA Times" />
Scientology publications identified the "real target of the campaign" as "the psychiatric profession itself" and claimed the campaign "brought wide acceptance of the fact that (the commission)[sic] and the Scientologists are the ones effectively doing something about [...] psychiatric drugging".<ref name="LA Times" />
[edit] Stimulant Effects
Methylphenidate and cocaine have similar chemical structures and both drugs were found to target the striatum and to give users "a similar 'high'".<ref name="IMLC?">http://archpsyc.ama-assn.org/cgi/content/abstract/52/6/456 Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley JS, Dewey S, Ashby C, Liebermann J, Hitzemann R, et al Medical Department, State University of New York, Stony Brook, USA, Arch Gen Psychiatry 1995 Jun; 52(6):456-63</ref> There have also been some medical reports showing a cross-tolerance between cocaine, methylphenidate, and a third common stimulant, amphetamine.<ref>http://www.springerlink.com/content/m4j5207r64367645/ Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate Nancy J. Lieth and Robert J. Barret. June 1981 Journal of Psychopharmacology</ref>
Pharmacokinetic researchers have found Methylphenidate is absorbed into the body at a much slower rate than cocaine. These researchers concluded that the fact the drug stays in the body for a long period, preventing additional 'highs' until it is absorbed by the body, may prevent addiction.<ref name="IMLC?" /> This conclusion was also supported by a recent study found no link between Methylphenidate and later substance abuse.<ref>http://www.nytimes.com/2003/01/06/health/06RITA.html?ex=1164690000&en=290ee38736803547&ei=5070</ref>
[edit] Overprescription
Some have asserted that Methylphenidate is overprescribed, however, 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.<ref>The New Yorker. 2 February 1999. "Running from Ritalin".</ref> In a small study of four American communities, the incidence of ADHD varied from 1.6% to 9.4%. The study also found that 12.5% of the children meeting the DSM-III-RADHD criteria for ADHD had been treated with stimulants during the past year.<ref>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.</ref>
[edit] Addiction
The question of whether or not MPH use in children leads to future addictive tendencies has sparked many inquiries and analyses. One study examined the history of a group of adults who had used cocaine at least once, and found that those who as children had been medically diagnosed with hyperactivity and had received methylphenidate treatment for between one and ten years had a percentage of cocaine abuse twice that of either of two control groups: one group of same-age individuals who had not been diagnosed with hyperactivity, and one group of individuals who had also been diagnosed with hyperactivity but had not been treated with stimulants. This research has been described as indicating that "... methylphenidate was still capable of explaining a small but significant proportion of the variance in cocaine use even after approximately 15 years."<ref>Schenk, Susan and Davidson, Emily S.. Stimulant Preexposure Sensitizes Rats and Humans to the Rewarding Effects of Cocaine. NIDA Res Monogr. 1998 Mar;169:56-82</ref> On the flip side, a 2003 project suggests that boys with ADHD who are treated with stimulants like MPH are actually less likely to abuse drugs (including alcohol) later in life.<ref>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.</ref>
[edit] Long-term effects
Ritalin has been used on a long-term basis since the mid-20th century, yet clinical studies of the effects of such use have not been undertaken. A great deal of controversy has been generated by non-expert groups, many of them basing 'research' on the negative effects of Ritalin on children. Many of these reports have been forwarded by Scientology-related groups.
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.<ref>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.</ref>
Still, some theoretical studies have raised questions. For example, Adriani et al (2005) found plastic changes in reward related behavior in rats after they were in a drug-free state.<ref>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.</ref> MPH may or may not have similar effects on human cognition.
[edit] Effects on stature
Researchers have also looked into the role of methylphenidate in affecting stature, with some studies finding slight decreases in height acceleration.<ref>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.</ref> Other studies indicate height may normalize by adolescence.<ref>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.</ref><ref>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.</ref>
[edit] Risk of death
As mentioned above, methylphenidate has been implicated in cases of sudden death by heart failure. The FDA decided against requiring warning labels, even though its advisory committee voted in favor of this. According to the Merck Index Methylphenidate had an LD50 of 150mg/kg body mass.
[edit] 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 researchers indicated that while their study was relatively small, the results should be reproduced one more time in a bigger population so that a definitive conclusion about the genotoxicity of methylphenidate can be drawn. The link between chromosomal aberrations and cancer risk has been established.<ref>El-Zein R.A., et al. (2005). "Cytogenetic effects in children treated with methylphenidate". Cancer Lett. 2005 Dec 18;230(2):284-91.</ref>
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 chromosomal aberrations. They concluded that none of the compounds present a carcinogenic risk to humans.<ref>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.</ref>
In 2005, the U.S. Food and Drug Administration issued a series of public health advisories warning that Ritalin and its sister drugs may cause visual hallucinations, suicidal thoughts and psychotic behavior, as well as aggressive or violent behavior.
[edit] 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.<ref> United Nations International Narcotics Control Board. 1995. Dramatic Increase in Methylphenidater Consumption in US: Marketing Methods Questioned [Web page]. Author, [cited 19 April 2004]. Available from http://www.incb.org/e/press/1995/pdf/e_bn_02.pdf.</ref><ref> 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 [Web page], [cited 19 April 2004]. Available from http://www.usdoj.gov:80/dea/pubs/cngrtest/ct051600.htm.</ref>
According to the DEA, "The increased use of this substance [MPH] 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."<ref>DEA, Briefs & Backgrounds, Drugs and Drugs of Abuse, Descriptions, Methylphenidate. Retrieved April 7, 2006 from http://www.usdoj.gov/dea/concern/methylphenidate.html.</ref>
Street names for Ritalin include: diet coke, kiddie cocaine, kiddie coke, vitamin R, R-ball, poor man's cocaine, rids, skittles, and smarties.
[edit] Trivia
The mathematician Paul Erdos took methylphenidate and other stimulants for much of his life. He stopped for a month in response to a bet that he would be unable to. Afterwords, he said that his work had been set back by a month. He described his time of abstention by saying "Before, when I looked at a piece of blank paper my mind was filled with ideas. Now all I see is a blank piece of paper."
[edit] See also
- Dexmethylphenidate (Focalin)
- Phenethylamines
- Psychoactive drug
- Stimulant
- Amphetamine
- Methamphetamine
- ADHD Patch
- Benzedrine
- Attention Deficit Disorder
- Citizens Commission on Human Rights – a Scientologist-backed organization that is extremely critical of widespread Ritalin use.
- We Drink Ritalin
- The PTA Disbands! – an episode of The Simpsons where Bart drinks Malk, which contains vitamin R.
[edit] Footnotes
[edit] External links
- Ritalin(R) 10mg Consumer Medicine Information (Australia)
- Erowid Methylphenidate Vault
- Information from the manufacturer on the methylphenidate ADHD Patch
- U.S. Drug Enforcement Administration statement on MPH abuse
- Dep't of Energy 1998 Sep 29 press release on Ritalin
- CBS: Kiddie Cocaine
- Children and Medication – a multimodal presentation
- Website of anti-Ritalin advocate Dr. Peter Breggin – see the Wikipedia article on Peter Breggin
- Students without ADHD are using Ritalin to help them study
- Why I Believe that Attention Deficit Disorder is a Myth
- Is methylphenidate like cocaine?
- Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain
- Dexmethylphenidate
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