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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: February 13, 2014.



Methylphenidate is a central nervous system stimulant used for the therapy of attention deficit disorder and narcolepsy. Methylphenidate has been linked to a low rate of serum aminotransferase elevations during therapy and to rare instances of acute, clinically apparent liver injury, generally after its intravenous abuse.


Methylphenidate (meth" il fen' i date) is a piperidine derivative that is structurally related to amphetamine which acts as a central nervous system (CNS) sympathomimetic stimulant, probably by causing release of norepinephrine at CNS nerve terminals promoting neurotransmission. Methylphenidate may also affect dopaminergic neurotransmission. Therapy with methylphenidate has been shown to increase cognitive abilities and improve psychological functioning and performance in children and adults with suspected attention deficit disorders. It has a paradoxical calming action in children with hyperactivity. Methylphenidate is also used in the therapy of narcolepsy. Methylphenidate was initially approved for use in the United States in 1955 and its indications have been broadened to include children above the age of 6 and adolescents with attention deficit disorder. Methylphenidate is available in multiple forms for oral administration including capsules, tablets, oral solutions and as extended release and long acting forms in concentrations varying from 2.5 to 54 mg in generic forms and under several brand names including Ritalin, Concerta and Metadate. Transdermal formulations are also available. The usual dose in adults is 10 mg two or three times daily and average maintenance dosage is 40 to 60 mg daily. The dosage in children varies by formulation. Methylphenidate is a controlled substance (Schedule II) and has abuse potential. Common side effects include headache, insomnia, irritability, palpitations, tachycardia, nasal stuffiness, decreased appetite, cough and rash.


In prelicensure clinical trials, methylphenidate was not associated with serum aminotransferase elevations or instances of hepatic injury, but reports of enzyme elevations have been received by the sponsor after it was marketed. The elevations were transient, mild-to-moderate in severity and not associated with jaundice or symptoms. In addition, there have been several case reports of marked serum enzyme elevations and clinically apparent acute liver injury attributed to methylphenidate given intravenously. These cases occurred largely after illicit intravenous use of methylphenidate and frequently in patients with underlying chronic hepatitis C. The onset was generally soon after initiation of therapy. The pattern of liver enzyme elevations was hepatocellular and the clinical phenotype typical of acute hepatic necrosis with rapid onset and rapid recovery. Immunoallergic features were uncommon. A single case associated with low levels of autoantibodies has been published. Some cases have been severe and at least one fatality after intravenous abuse has been reported. Recurrence upon rechallenge was been documented in one instance (Case 1).

Mechanism of Injury

The mechanism by which methylphenidate might cause liver injury is unknown, but the injury occurring after intravenous use is likely due to direct toxicity. Methylphenidate is extensively metabolized in the liver and has many drug-drug interactions.

Outcome and Management

The liver injury due to oral methylphenidate is usually self-limited and resolves rapidity. Injury from intravenous use can be severe and fatalities have been reported. There have been no instances of chronic liver injury or vanishing bile duct syndrome associated with either oral or intravenous methylphenidate. Cross reactivity with other amphetamine related chemicals has not been demonstrated. However, recurrence of injury with reexposure has been demonstrated.

Central nervous system stimulants used for attention deficit disorder, narcolepsy or excessive sleepiness include methylphenidate, atomoxetine, modafinil, armodafinil and the amphetamines. Stimulants that are no longer used for medical conditions, but that are abused, include cocaine and ecstasy or methylenedioxymetamphetamine.

Drug Class: CNS Stimulants


Case 1. Acute hepatic necrosis after intravenous injection of methylphenidate.

[Modified from: Mehta H, Murray B, LoIudice TA. Hepatic dysfunction due to intravenous abuse of methylphenidate hydrochloride. J Clin Gastroenterol 1984; 6: 149-51. PubMed Citation]

A 19 year old woman who had been abusing methylphenidate developed fatigue, fever and jaundice. She admitted to intravenous injection of methylphenidate tablets that had been dissolved in water. She had no history of liver disease or alcohol abuse. She was not taking other medications. On physical examination, she was jaundiced and had an enlarged, slightly tender liver. There were no peripheral manifestations of cirrhosis or chronic liver disease. Laboratory tests showed elevations in serum bilirubin (13 mg/dL) and AST (4,942 U/L), with minimal increase in alkaline phosphatase (100 U/L) (Table). Tests for hepatitis A and B were negative. Tests for hepatitis C were not available at the time of this report. A liver biopsy showed focal necrosis and portal inflammation with lymphocytes, plasma cells and eosinophils, typical of drug induced liver injury. Rechallenge with 4 injections of 20 mg of methylphenidate over two days led to rapid recurrence with a similar pattern of injury.

Key Points

Medication:Methylphenidate (by injection)
Pattern:Hepatocellular (R=~100)
Severity:3+ (jaundice, hospitalization)
Latency:Few days
Recovery:Two weeks
Other medications:None mentioned

Laboratory Values

Days After StoppingAST* (U/L)Alk P (U/L)Bilirubin* (mg/dL)Other
Intravenous abuse of methylphenidate
3494210013.0Admission for jaundice
6209016.0Liver Biopsy
Rechallenge with four injections of 20 mg of methylphenidate
0150.5Started rechallenge
04502.5Stopped rechallenge

* Values estimated from Figure 1.


Abuse of methylphenidate and intravenous injections of dissolved tablets led to marked jaundice and serum enzyme elevations. Tests for hepatitis C were not available at the time of the report, but intravenous rechallenge led to recurrence with a similar pattern of injury. This degree of severity of liver injury has not been reported with oral methylphenidate which is a widely used medication with excellent tolerance. The pattern of injury associated with intravenous methylphenidate abuse is similar to that described with amphetamine, methylenedioxymetamphetamine and cocaine use, with acute hepatic necrosis (often with other organ damage) arising within 2 to 4 days of the exposure or overdose. Typical of methylphenidate, cocaine and amphetamine hepatotoxicity from intravenous exposure is both the rapidity of the rise and rapidity of the fall in serum aminotransferase levels. LDH levels can be similarly elevated, while alkaline phosphatase values are usually normal or near normal.



Methylphenidate – Generic, Concerta®, Ritalin®


Central Nervous System Stimulants


Product labeling at DailyMed, National Library of Medicine, NIH


Chemical Structure for Methylphenidate


References updated: 13 February 2014

  • Zimmerman HJ. Methylphenidate. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 712.
    (Expert review of hepatotoxicity published in 1999; methylphenidate has been implicated in at least 3 instances of hepatic injury including two with positive rechallenge).
  • Larrey D, Ripault MP. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 443-62. (Review of hepatotoxicity of antidepressants mentions that.
    methylphenidate has been implicated in hepatocellular injury).
  • Wesfall TC, Westfall DP. Methylphenidate. Adrenergic agonists and antagonists. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 299-300.
    (Textbook of pharmacology and therapeutics).
  • Goodman CR. Hepatotoxicity due to methylphenidate hydrochloride. N Y State J Med 1972; 72: 2339-40. [PubMed: 4506888]
    (67 year old woman with depression developed mild elevations in ALT [56 U/L] and AST [72 U/L] without symptoms or jaundice 2 weeks after starting methylphenidate, and with rapid resolution on stopping and recurrence after 5 day rechallenge [bilirubin 0.6 mg/dL, ALT 145 U/L, AST 535 U/L, Alk P 18 U/L]).
  • Mehta H, Murray B, LoIudice TA. Hepatic dysfunction due to intravenous abuse of methylphenidate hydrochloride. J Clin Gastroenterol 1984; 6: 149-51. [PubMed: 6715854]
    (19 year old woman developed jaundice soon after starting injecting methylphenidate [bilirubin 13.0 mg/dL, AST 4,942 U/L, Alk P 100 U/L], resolving over next few weeks; upon challenge injection of methylphenidate [20 mg] AST rose to ~900 U/L and bilirubin to 5.2 mg/dL in 3-4 days: Case 1).
  • Stecyk O, Loludice TA, Demeter S, Jacobs J. Multiple organ failure resulting from intravenous abuse of methylphenidate hydrochloride. Ann Emerg Med 1985; 14: 597-9. [PubMed: 3994088]
    (32 year old woman developed weakness, nausea and dyspnea 2 hours after injecting methylphenidate which she had been doing for ~5 months [bilirubin 1.4 mg/dL, ALT 2,560 U/L, Alk P 174 U/L, lactate 18 mEq/L, arterial pH 7.23, protime 23.7 sec and creatinine 4.0 mg/dL], requiring ICU care, but ultimate recovery over next few weeks).
  • Hoover-Stevens S, Kovacevic-Ristanovic R. Management of narcolepsy in pregnancy. Clin Neuropharmacol 2000; 23: 175-81.
    (Review of the efficacy of medications for narcolepsy and their safety during pregnancy and breast feeding; there have been no studies on the safety of methylphenidate in pregnancy).
  • Leonard BE, McCartan D, White J, King DJ. Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Hum Psychopharmacol 2004; 19: 151-80. [PubMed: 15079851]
    (Review of mechanism of action, clinical efficacy and safety of methylphenidate; no mention of hepatotoxicity or serum ALT elevations).
  • Lewis JJ, Iezzoni JC, Berg CL. Methylphenidate-induced autoimmune hepatitis. Dig Dis Sci 2007; 52: 594-7. [PubMed: 17219064]
    (57 year old man developed marked enzyme elevations 4 years after liver transplantation for hepatitis C and 1 month after starting methylphenidate [bilirubin 2.7 rising to 4.1 mg/dL, ALT 338 U/L, ANA 1:80, IgG 1950 mg/dL], improving upon stopping methylphenidate and falling to baseline on prednisone therapy).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 3 cases were attributed to atomoxetine and one to methylphenidate, but none to cocaine or ecstasy).
  • Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. [PMC free article: PMC2997312] [PubMed: 21039766]
    (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, 2 agents used for attention deficit disorder were among the top 40 causes; methylphenidate [11th, 96 cases] and atomoxetine [14th, 64 cases]).
  • Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105: 2396-404. [PubMed: 20648003]
    (Among 313 cases of drug induced liver injury seen between 1997 and 2008 at a large hospital in Bangalore, India, one case was attributed to atomoxetine, none to methylphenidate).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, including one attributed to cocaine and one to ecstasy but none to methylpenidate).
  • Molleston JP, Fontana RJ, Lopez MJ, Kleiner DE, Gu J, Chalasani N: Drug-induced Liver Injury Network. Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study. J Pediatr Gastroenterol Nutr 2011; 53: 182-9. [PMC free article: PMC3634369] [PubMed: 21788760]
    (Among 30 children with suspected drug induced liver injury, 3 were attributed to atomoxetine and one to methylphenidate).
  • Cantrell FL, Ogera P, Mallett P, McIntyre IM. Fatal oral methylphenidate intoxication with postmortem concentrations. J Forensic Sci 2014 Feb 6. [Epub ahead of print] [PubMed: 24502813]
    (62 year old woman with chronic hepatitis C was found dead at home and autopsy showed high levels of methylphenidate consistent with drug overdose; liver histology showed chronic hepatitis and mild fatty change and no evidence of acute liver injury).


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