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Methylphenidate: Difference between revisions
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'''Methylphenidate''' (also known as '''MPH''', '''MPD''', and the trade names '''Ritalin''', '''Concerta''', and '''Methylin''', among others) is a classical [[psychoactive class::stimulant]] substance of the [[chemical class::phenidate]] class. It is the parent compound of the [[substituted phenidates]], a family of stimulants that includes [[ethylphenidate]], [[isopropylphenidate]], and others. The mechanism of action involves increasing concentrations of the [[neurotransmitters]] [[dopamine]] and [[norepinephrine]]. | '''Methylphenidate''' (also known as '''MPH''', '''MPD''', and the trade names '''Ritalin''', '''Concerta''', and '''Methylin''', among others) is a classical [[psychoactive class::stimulant]] substance of the [[chemical class::phenidate]] class. It is the parent compound of the [[substituted phenidates]], a family of stimulants that includes [[ethylphenidate]], [[isopropylphenidate]], and others. The mechanism of action involves increasing concentrations of the [[neurotransmitters]] [[dopamine]] and [[norepinephrine]]. | ||
It was first synthesized in 1944 and was approved for medical use in the United States in 1955. It was originally sold by Swiss company CIBA (now Novartis).<ref>Lange | It was first synthesized in 1944 and was approved for medical use in the United States in 1955. It was originally sold by Swiss company CIBA (now Novartis).<ref>{{cite journal | vauthors=((Lange, K. W.)), ((Reichl, S.)), ((Lange, K. M.)), ((Tucha, L.)), ((Tucha, O.)) | journal=ADHD Attention Deficit and Hyperactivity Disorders | title=The history of attention deficit hyperactivity disorder | volume=2 | issue=4 | pages=241–255 | date= December 2010 | url=http://link.springer.com/10.1007/s12402-010-0045-8 | issn=1866-6116 | doi=10.1007/s12402-010-0045-8}}</ref> It is approved for treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy. It is often used by students with or without ADHD as a cognitive enhancer and study aid. | ||
[[Subjective effects]] include [[stimulation]], [[focus enhancement]], [[motivation enhancement]], [[increased libido]], [[appetite suppression]], and [[euphoria]]. It is usually taken orally, but can also be [[Routes of administration|insufflated or administered rectally]]. The effects are comparable to those of amphetamine; however, it is reported to produce less euphoria and generally have less recreational value. Some users also report it produces a stronger comedown relative to amphetamine. | [[Subjective effects]] include [[stimulation]], [[focus enhancement]], [[motivation enhancement]], [[increased libido]], [[appetite suppression]], and [[euphoria]]. It is usually taken orally, but can also be [[Routes of administration|insufflated or administered rectally]]. The effects are comparable to those of amphetamine; however, it is reported to produce less euphoria and generally have less recreational value. Some users also report it produces a stronger comedown relative to amphetamine. | ||
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==History and culture== | ==History and culture== | ||
{{historyStub}} | {{historyStub}} | ||
Methylphenidate was first licensed by the U.S. Food and Drug Administration (FDA) in 1955 for treating what was then known as "hyperactivity."{{citation needed}} 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.<ref>Diller, | Methylphenidate was first licensed by the U.S. Food and Drug Administration (FDA) in 1955 for treating what was then known as "hyperactivity."{{citation needed}} 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.<ref>{{cite book | vauthors=((Diller, L. H.)) | date= 1999 | title=Running on ritalin: a physician reflects on children, society, and performance in a pill | publisher=Bantam Books | isbn=9780553379068}}</ref><ref>{{cite journal | vauthors=((Lange, K. W.)), ((Reichl, S.)), ((Lange, K. M.)), ((Tucha, L.)), ((Tucha, O.)) | journal=Attention Deficit and Hyperactivity Disorders | title=The history of attention deficit hyperactivity disorder | volume=2 | issue=4 | pages=241–255 | date= 2010 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000907/ | issn=1866-6116 | doi=10.1007/s12402-010-0045-8}}</ref> | ||
It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012.<ref> | It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012.<ref>{{cite journal | journal=The Pharmaceutical Journal | title=Narcotics monitoring board reports 66% increase in global consumption of methylphenidate | date= 2015 | url=http://www.pharmaceutical-journal.com/news-and-analysis/news-in-brief/narcotics-monitoring-board-reports-66-increase-in-global-consumption-of-methylphenidate/20068042.article | issn=2053-6186 | doi=10.1211/PJ.2015.20068042}}</ref> In 2019, it was the 51st most commonly prescribed medication in the United States, with more than 14 million prescriptions.<ref>{{cite web |title=The Top 300 of 2019 |url=https://clincalc.com/DrugStats/Top300Drugs.aspx |website=ClinCalc |access-date=16 October 2021 }}</ref><ref>{{cite web | title=Methylphenidate - Drug Usage Statistics | website=ClinCalc | url=https://clincalc.com/DrugStats/Drugs/Methylphenidate | access-date=16 October 2021}}</ref> It is available as a generic medication. | ||
==Chemistry== | ==Chemistry== | ||
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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'''. | 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.<ref>Heal | 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.<ref>{{cite journal | vauthors=((Heal, D. J.)), ((Pierce, D. M.)) | journal=CNS Drugs | title=Methylphenidate and its Isomers: Their Role in the Treatment of Attention-Deficit Hyperactivity Disorder Using a Transdermal Delivery System | volume=20 | issue=9 | pages=713–738 | date= 2006 | url=http://link.springer.com/10.2165/00023210-200620090-00002 | issn=1172-7047 | doi=10.2165/00023210-200620090-00002}}</ref> | ||
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 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 (2''R'',2'''R'')-(+)-''threo''-methylphenidate hydrochloride has been published.<ref>Prashad M | 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 (2''R'',2'''R'')-(+)-''threo''-methylphenidate hydrochloride has been published.<ref>{{cite journal | vauthors=((Prashad, M.)) | journal=Advanced Synthesis & Catalysis | title=Approaches to the Preparation of Enantiomerically Pure (2R,2′R)-(+)-threo-Methylphenidate Hydrochloride | volume=343 | issue=5 | pages=379–392 | date= July 2001 | url=https://onlinelibrary.wiley.com/doi/10.1002/1615-4169(200107)343:5<379::AID-ADSC379>3.0.CO;2-4 | issn=1615-4150 | doi=10.1002/1615-4169(200107)343:5<379::AID-ADSC379>3.0.CO;2-4}}</ref> | ||
[[File:Dexmethylphenidate-2D-skeletal.png|thumb|right|upright|250px|Dexmethylphenidate in skeletal formula]] | [[File:Dexmethylphenidate-2D-skeletal.png|thumb|right|upright|250px|Dexmethylphenidate in skeletal formula]] | ||
==Pharmacology== | ==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.<ref>Methylphenidate and its Isomers | | 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.<ref>{{cite journal | vauthors=((Heal, D. J.)), ((Pierce, D. M.)) | journal=CNS Drugs | title=Methylphenidate and its Isomers | volume=20 | issue=9 | pages=713–738 | date=1 September 2006 | url=https://doi.org/10.2165/00023210-200620090-00002 | issn=1179-1934 | doi=10.2165/00023210-200620090-00002}}</ref> Methylphenidate binds to and blocks dopamine transporters and norepinephrine transporters.<ref name="Iversen2006">{{cite journal | vauthors=((Iversen, L.)) | journal=British Journal of Pharmacology | title=Neurotransmitter transporters and their impact on the development of psychopharmacology | volume=147 | issue=Suppl 1 | pages=S82–S88 | date= January 2006 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760736/ | issn=0007-1188 | doi=10.1038/sj.bjp.0706428}}</ref> | ||
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. | 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.<ref>Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. | 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.<ref>{{cite journal | vauthors=((Volkow, N. D.)), ((Wang, G. J.)), ((Fowler, J. S.)), ((Gatley, S. J.)), ((Logan, J.)), ((Ding, Y. S.)), ((Hitzemann, R.)), ((Pappas, N.)) | journal=The American Journal of Psychiatry | title=Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate | volume=155 | issue=10 | pages=1325–1331 | date= October 1998 | issn=0002-953X | doi=10.1176/ajp.155.10.1325}}</ref><ref name="Iversen2006"/><ref>Focalin XR review | http://www.pharma.us.novartis.com/product/pi/pdf/focalinXR.pdf</ref><ref>Concerta Xl slow release | http://www.medicines.org.uk/emc/medicine/8382/SPC/Concerta#PHARMACOLOGICAL_PROPSSPC</ref> | ||
==Subjective effects== | ==Subjective effects== | ||
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*'''[[Effect::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. | *'''[[Effect::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. | ||
*'''[[Effect::Increased heart rate]]'''<ref name="Montastruc">Montastruc, F., Montastruc, G., Montastruc, J. L., | *'''[[Effect::Increased heart rate]]'''<ref name="Montastruc">{{cite journal | vauthors=((Montastruc, F.)), ((Montastruc, G.)), ((Montastruc, J.-L.)), ((Revet, A.)) | journal=BMJ | title=Cardiovascular safety of methylphenidate should also be considered in adults | pages=i3418 | date=22 June 2016 | url=https://www.bmj.com/lookup/doi/10.1136/bmj.i3418 | issn=1756-1833 | doi=10.1136/bmj.i3418}}</ref><ref name="Leonard">{{cite journal | vauthors=((Leonard, B. E.)), ((McCartan, D.)), ((White, J.)), ((King, D. J.)) | journal=Human Psychopharmacology: Clinical and Experimental | title=Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects | volume=19 | issue=3 | pages=151–180 | date= April 2004 | url=https://onlinelibrary.wiley.com/doi/10.1002/hup.579 | issn=0885-6222 | doi=10.1002/hup.579}}</ref> | ||
*'''[[Effect::Abnormal heartbeat]]'''<ref name="Montastruc" /><ref name="Leonard" /> | *'''[[Effect::Abnormal heartbeat]]'''<ref name="Montastruc" /><ref name="Leonard" /> | ||
*'''[[Effect::Dehydration]]''' | *'''[[Effect::Dehydration]]''' | ||
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*'''[[Effect::Focus enhancement]]''' - This component is most effective at low to moderate dosages as anything higher will usually impair concentration. | *'''[[Effect::Focus enhancement]]''' - This component is most effective at low to moderate dosages as anything higher will usually impair concentration. | ||
*'''[[Effect::Wakefulness]]''' | *'''[[Effect::Wakefulness]]''' | ||
*'''[[Effect::Memory enhancement]]''' - Therapeutic doses of methylphenidate improve performance on working memory tests both in normal functioning individuals and those with ADHD.<ref> | *'''[[Effect::Memory enhancement]]''' - Therapeutic doses of methylphenidate improve performance on working memory tests both in normal functioning individuals and those with ADHD.<ref>{{cite book | vauthors=((Nestler, E. J.)), ((Hyman, S. E.)), ((Malenka, R. C.)) | date= 2009 | title=Molecular neuropharmacology: a foundation for clinical neuroscience | publisher=McGraw-Hill Medical | edition=2nd ed | isbn=9780071481274}}</ref> | ||
*'''[[Effect::Time distortion]]''' - This can be described as the experience of time speeding up and passing much quicker than it usually would when sober. | *'''[[Effect::Time distortion]]''' - This can be described as the experience of time speeding up and passing much quicker than it usually would when sober. | ||
*'''[[Effect::Thought acceleration]]''' | *'''[[Effect::Thought acceleration]]''' | ||
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==Toxicity and harm potential== | ==Toxicity and harm potential== | ||
{{toxicity}} | {{toxicity}} | ||
[[File:harmchart.png|thumb|right|300px|Radar plot showing relative physical harm, social harm, and dependence of methylphenidate<ref>Development of a rational scale to assess the harm of drugs of potential misuse | [[File:harmchart.png|thumb|right|300px|Radar plot showing relative physical harm, social harm, and dependence of methylphenidate<ref>{{cite journal | vauthors=((Nutt, D.)), ((King, L. A.)), ((Saulsbury, W.)), ((Blakemore, C.)) | journal=The Lancet | title=Development of a rational scale to assess the harm of drugs of potential misuse | volume=369 | issue=9566 | pages=1047–1053 | date=24 March 2007 | url=https://www.sciencedirect.com/science/article/pii/S0140673607604644 | issn=0140-6736 | doi=10.1016/S0140-6736(07)60464-4}}</ref>]] | ||
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.<ref>Methylphenidate poisoning: | 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.<ref>{{cite journal | vauthors=((Scharman, E. J.)), ((Erdman, A. R.)), ((Cobaugh, D. J.)), ((Olson, K. R.)), ((Woolf, A. D.)), ((Caravati, E. M.)), ((Chyka, P. A.)), ((Booze, L. L.)), ((Manoguerra, A. S.)), ((Nelson, L. S.)), ((Christianson, G.)), ((Troutman, W. G.)), ((American Association of Poison Control Centers)) | journal=Clinical Toxicology (Philadelphia, Pa.) | title=Methylphenidate poisoning: an evidence-based consensus guideline for out-of-hospital management | volume=45 | issue=7 | pages=737–752 | date= November 2007 | issn=1556-3650 | doi=10.1080/15563650701665175}}</ref> 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.<ref>Characterization of Methylphenidate Exposures Reported to a Regional Poison Control Center | http://archpedi.jamanetwork.com/article.aspx? | However, a significant amount of patients (31%) in the study developed symptoms typical of stimulant overdose, most commonly tachycardia, agitation, and paradoxically lethargy.<ref>{{cite journal | vauthors=((White, S. R.)), ((Yadao, C. M.)) | journal=Archives of Pediatrics & Adolescent Medicine | title=Characterization of Methylphenidate Exposures Reported to a Regional Poison Control Center | volume=154 | issue=12 | pages=1199 | date=1 December 2000 | url=http://archpedi.jamanetwork.com/article.aspx?doi=10.1001/archpedi.154.12.1199 | issn=1072-4710 | doi=10.1001/archpedi.154.12.1199}}</ref> 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.<ref>2012 Annual Report of the American Association | ||
of Poison Control Centers ’ National Poison | 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</ref> | Data System (NPDS): 28th Annual Report | https://aapcc.s3.amazonaws.com/pdfs/annual_reports/2012_NPDS_Annual_Report.pdf</ref> | ||
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===Dependence and abuse potential=== | ===Dependence and abuse 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.<ref>Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children. ( | 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.<ref>{{cite journal | vauthors=((Swanson, J.)), ((Gupta, S.)), ((Guinta, D.)), ((Flynn, D.)), ((Agler, D.)), ((Lerner, M.)), ((Williams, L.)), ((Shoulson, I.)), ((Wigal, S.)) | journal=Clinical Pharmacology and Therapeutics | title=Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children | volume=66 | issue=3 | pages=295–305 | date= September 1999 | issn=0009-9236 | doi=10.1016/S0009-9236(99)70038-X}}</ref> | ||
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}} | 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}} | ||
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As with other [[stimulant|stimulants]], the chronic use of methylphenidate can be considered [[Addiction potential::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. | As with other [[stimulant|stimulants]], the chronic use of methylphenidate can be considered [[Addiction potential::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 [[stimulant]]s, 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.<ref>Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of | Methylphenidate has some potential for abuse due to its action on dopamine transporters. Methylphenidate, like other [[stimulant]]s, 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.<ref name="Volkow1999">{{cite journal | vauthors=((Volkow, N. D.)), ((Wang, G. J.)), ((Fowler, J. S.)), ((Gatley, S. J.)), ((Logan, J.)), ((Ding, Y. S.)), ((Dewey, S. L.)), ((Hitzemann, R.)), ((Gifford, A. N.)), ((Pappas, N. R.)) | journal=The Journal of Pharmacology and Experimental Therapeutics | title=Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of “high” | volume=288 | issue=1 | pages=14–20 | date= January 1999 | issn=0022-3565}} | ||
</ref> The abuse and addiction potential of methylphenidate is therefore significantly lower than other dopaminergic stimulants.<ref name="Volkow1999"/><ref>{{cite journal | vauthors=((Volkow, N. D.)), ((Swanson, J. M.)) | journal=American Journal of Psychiatry | title=Variables That Affect the Clinical Use and Abuse of Methylphenidate in the Treatment of ADHD | volume=160 | issue=11 | pages=1909–1918 | date= November 2003 | url=https://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.160.11.1909 | issn=0002-953X | doi=10.1176/appi.ajp.160.11.1909}}</ref> | |||
The abuse potential is increased when methylphenidate is crushed and [[Routes_of_administration#Insufflation|insufflated]] (snorted) or [[Routes_of_administration#Intravenous|injected]].<ref>Methylphenidate Abuse and Psychiatric Side Effects | The abuse potential is increased when methylphenidate is crushed and [[Routes_of_administration#Insufflation|insufflated]] (snorted) or [[Routes_of_administration#Intravenous|injected]].<ref name="Morton2000">{{cite journal | vauthors=((Morton, W. A.)), ((Stockton, G. G.)) | journal=Primary Care Companion to The Journal of Clinical Psychiatry | title=Methylphenidate Abuse and Psychiatric Side Effects | volume=2 | issue=5 | pages=159–164 | date= October 2000 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC181133/ | issn=1523-5998}}</ref>. 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.<ref>{{cite journal | vauthors=((Klein-Schwartz, W.)) | journal=Current Opinion in Pediatrics | title=Abuse and toxicity of methylphenidate: | volume=14 | issue=2 | pages=219–223 | date= April 2002 | url=http://journals.lww.com/00008480-200204000-00013 | issn=1040-8703 | doi=10.1097/00008480-200204000-00013}}</ref> | ||
===Psychosis=== | ===Psychosis=== | ||
{{Main|Stimulant psychosis}} | {{Main|Stimulant psychosis}} | ||
Chronic use (i.e. high dose, repeat dosing) may increase the risk of [[psychosis]].<ref>Methylphenidate Abuse | Chronic use (i.e. high dose, repeat dosing) may increase the risk of [[psychosis]].<ref name="Morton2000"/><ref>{{cite journal | vauthors=((Spensley, J.)), ((Rockwell, D. A.)) | journal=New England Journal of Medicine | title=Psychosis during Methylphenidate Abuse | volume=286 | issue=16 | pages=880–881 | date=20 April 1972 | url=https://doi.org/10.1056/NEJM197204202861607 | issn=0028-4793 | doi=10.1056/NEJM197204202861607}}</ref> 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.<ref>Ritalin & Ritalin-SR Prescribing Information | http://www.pharma.us.novartis.com/product/pi/pdf/ritalin_ritalin-sr.pdf</ref> | ||
Psychotic symptoms from methylphenidate can include [[Auditory hallucinations|hearing voices]], [[external hallucinations|visual hallucinations]], urges to harm oneself, severe [[anxiety]], [[mania]], [[disinhibition]], [[delusions|paranoid and grandiose delusions]], [[confusion]], [[emotion suppression|emotional suppression]], increased [[aggression]], and [[irritability]]. | Psychotic symptoms from methylphenidate can include [[Auditory hallucinations|hearing voices]], [[external hallucinations|visual hallucinations]], urges to harm oneself, severe [[anxiety]], [[mania]], [[disinhibition]], [[delusions|paranoid and grandiose delusions]], [[confusion]], [[emotion suppression|emotional suppression]], increased [[aggression]], and [[irritability]]. | ||
===Combination with alcohol=== | ===Combination with alcohol=== | ||
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%.<ref>Influence of Ethanol and Gender on Methylphenidate Pharmacokinetics and Pharmacodynamics | 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%.<ref>{{cite journal | vauthors=((Patrick, K.)), ((Straughn, A.)), ((Minhinnett, R.)), ((Yeatts, S.)), ((Herrin, A.)), ((DeVane, C.)), ((Malcolm, R.)), ((Janis, G.)), ((Markowitz, J.)) | journal=Clinical pharmacology and therapeutics | title=Influence of Ethanol and Gender on Methylphenidate Pharmacokinetics and Pharmacodynamics | volume=81 | issue=3 | pages=346–353 | date= March 2007 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188424/ | issn=0009-9236 | doi=10.1038/sj.clpt.6100082}}</ref> A metabolite called [[ethylphenidate]] is also formed.<ref>{{cite journal | vauthors=((Markowitz, J. S.)), ((DeVane, C. L.)), ((Boulton, D. W.)), ((Nahas, Z.)), ((Risch, S. C.)), ((Diamond, F.)), ((Patrick, K. S.)) | journal=Drug Metabolism and Disposition: The Biological Fate of Chemicals | title=Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol | volume=28 | issue=6 | pages=620–624 | date= June 2000 | issn=0090-9556}}</ref> | ||
===Dangerous interactions=== | ===Dangerous interactions=== | ||
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*'''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}} | *'''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).<ref>{{cite web|url=http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-32.html#h-28|title=SCHEDULE III|publisher=Department of Justice|access-date=December 24, 2019|archive-url=https://web.archive.org/web/20110416090043/http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-32.html#h-28|archive-date=April 16, 2011}}</ref> 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. | *'''Canada''': Methylphenidate is listed in Schedule III of the Controlled Drugs and Substances Act (along with LSD, psychedelic mushrooms, and mescaline).<ref>{{cite web|url=http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-32.html#h-28|title=SCHEDULE III|publisher=Department of Justice|access-date=December 24, 2019|archive-url=https://web.archive.org/web/20110416090043/http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-32.html#h-28|archive-date=April 16, 2011}}</ref> 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.<ref>http://www.gesetze-im-internet.de/btmg_1981/anlage_iii.html</ref> | *'''Germany''': Methylphenidate is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form.<ref>{{Citation | title=Anlage III BtMG - Einzelnorm | url=http://www.gesetze-im-internet.de/btmg_1981/anlage_iii.html}}</ref> | ||
*'''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}} | *'''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.<ref>Narkotikastrafflag (1968:64) | https://lagen.nu/1968:64</ref> | *'''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.<ref>{{Citation | title=Narkotikastrafflag (1968:64) (NSL), Lagen.nu | url=https://lagen.nu/1968:64}}</ref> | ||
*'''Switzerland''': Methylphenidate is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.<ref>{{cite web|url=https://www.admin.ch/opc/de/classified-compilation/20101220/index.html|title=Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien|publisher=Bundeskanzlei [Federal Chancellery of Switzerland]|access-date=January 1, 2020|language=de}}</ref> | *'''Switzerland''': Methylphenidate is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.<ref>{{cite web|url=https://www.admin.ch/opc/de/classified-compilation/20101220/index.html|title=Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien|publisher=Bundeskanzlei [Federal Chancellery of Switzerland]|access-date=January 1, 2020|language=de}}</ref> | ||
*'''Turkey''': Methylphenidate is a 'red prescription' only substance<ref>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</ref> and illegal when sold or possessed without a prescription.{{citation needed}} | *'''Turkey''': Methylphenidate is a 'red prescription' only substance<ref>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</ref> 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.<ref>Misuse of Drugs Act 1971 | | *'''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.<ref>{{Citation | title=Misuse of Drugs Act 1971 | url=https://www.legislation.gov.uk/ukpga/1971/38/schedule/2}}</ref> | ||
*'''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}} | *'''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}} | ||