CNS Drugs

, Volume 27, Issue 7, pp 531–543 | Cite as

Overdose of Drugs for Attention-Deficit Hyperactivity Disorder: Clinical Presentation, Mechanisms of Toxicity, and Management

  • Henry A. SpillerEmail author
  • Hannah L. Hays
  • Alfred AleguasJr.
Review Article


The prevalence of attention-deficit hyperactivity disorder (ADHD) in the USA is estimated at approximately 4–9 % in children and 4 % in adults. It is estimated that prescriptions for ADHD medications are written for more than 2.7 million children per year. In 2010, US poison centers reported 17,000 human exposures to ADHD medications, with 80 % occurring in children <19 years old and 20 % in adults. The drugs used for the treatment of ADHD are diverse but can be roughly separated into two groups: the stimulants such as amphetamine, methylphenidate, and modafinil; and the non-stimulants such as atomoxetine, guanfacine, and clonidine. This review focuses on mechanisms of toxicity after overdose with ADHD medications, clinical effects from overdose, and management. Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin. The primary clinical syndrome involves prominent neurological and cardiovascular effects, but secondary complications can involve renal, muscle, pulmonary, and gastrointestinal (GI) effects. In overdose, the patient may present with mydriasis, tremor, agitation, hyperreflexia, combative behavior, confusion, hallucinations, delirium, anxiety, paranoia, movement disorders, and seizures. The management of amphetamine, dextroamphetamine, and methylphenidate overdose is largely supportive, with a focus on interruption of the sympathomimetic syndrome with judicious use of benzodiazepines. In cases where agitation, delirium, and movement disorders are unresponsive to benzodiazepines, second-line therapies include antipsychotics such as ziprasidone or haloperidol, central alpha-adrenoreceptor agonists such as dexmedetomidine, or propofol. Modafinil is not US FDA approved for treatment of ADHD; however, it has been shown to improve ADHD signs and symptoms and has been used as an off-label pharmaceutical for this diagnosis in both adults and children. The mechanism of action of modafinil is complex and not fully understood. It is known to cause an increase in extracellular concentrations of dopamine, norepinephrine, and serotonin in the neocortex. Overdose with modafinil is generally of moderate severity, with reported ingestions of doses up to 8 g. The most common neurological effects include increased anxiety, agitation, headache, dizziness, insomnia, tremors, and dystonia. The management of modafinil overdose is largely supportive, with a focus on sedation, and control of dyskinesias and blood pressure. Atomoxetine is a selective presynaptic norepinephrine transporter inhibitor. The clinical presentation after overdose with atomoxetine has generally been mild. The primary effects have been drowsiness, agitation, hyperactivity, GI upset, tremor, hyperreflexia, tachycardia hypertension, and seizure. The management of atomoxetine overdose is largely supportive, with a focus on sedation, and control of dyskinesias and seizures. Clonidine is a synthetic imidazole derivative with both central and peripheral alpha-adrenergic agonist actions. The primary clinical syndrome involves prominent neurological and cardiovascular effects, with the most commonly reported features of depressed sensorium, bradycardia, and hypotension. While clonidine is an anti-hypertensive medication, a paradoxical hypertension may occur early with overdose. The clinical syndrome after overdose of guanfacine may be mixed depending on central or peripheral alpha-adrenoreceptor effects. Initial clinical effects may be drowsiness, lethargy, dry mouth, and diaphoresis. Cardiovascular effects may depend on time post-ingestion and may present as hypotension or hypertension. The management of guanfacine overdose is largely supportive, with a focus on support of blood pressure. Overdose with ADHD medications can produce major morbidity, with many cases requiring intensive care medicine and prolonged hospital stays. However, fatalities are rare with appropriate care.


Amphetamine Clonidine Methylphenidate Dexmedetomidine Peak Plasma Concentration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors report no conflicts of interest. The authors report no external sources of funding.


  1. 1.
    Visser SN, Lesesne CA, Perou R. National estimates and factors associated with medication treatment for childhood attention-deficit/hyperactivity disorder. Pediatrics. 2007;119(Suppl 1):S99–106.PubMedCrossRefGoogle Scholar
  2. 2.
    Modesto-Lowe V, Meyer A, Soovajian V. A clinician’s guide to adult attention-deficit hyperactivity disorder. Conn Med. 2012;76(9):517–23.PubMedGoogle Scholar
  3. 3.
    Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med. 2011;365:1896–904.PubMedCrossRefGoogle Scholar
  4. 4.
    Centers for Disease Control and Prevention (CDC). Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children: United States, 2003 and 2007. MMWR Morb Mortal Wkly Rep. 2010;59(44):1439–43.Google Scholar
  5. 5.
    Setlik J, Bond GR, Ho M. Adolescent prescription ADHD medication abuse is rising along with prescriptions for these medications. Pediatrics. 2009;124:875–80.PubMedCrossRefGoogle Scholar
  6. 6.
    McGrath JC, Klein-Schwartz W. Epidemiology and toxicity of pediatric guanfacine exposures. Ann Pharmacother. 2002;36:1698–703.PubMedCrossRefGoogle Scholar
  7. 7.
    Hariharan S, Pomerantz W. Correlation between hospitalization for pharmaceutical ingestion and attention deficit disorder in children aged 5 to 9 years old. Clin Pediatr. 2008;47:15–20.CrossRefGoogle Scholar
  8. 8.
    Bond GR, Woodward RW, Ho M. The growing impact of pediatric pharmaceutical poisoning. J Pediatr. 2011;160:265–70.PubMedGoogle Scholar
  9. 9.
    Bronstein AC, Spyker DA, Cantilena LR, Green JL, Rumack BH, Dart RC. 2010 annual report of the American Association of Poison Control Center’ National Poison Data system (NPDS): 28th annual report. Clin Toxicol. 2011;49:910–41.CrossRefGoogle Scholar
  10. 10.
    Antshel KM, Hargrave TM, Simonescu M, Kaul P, Hendricks K, Faraone SV. Advances in understanding and treating ADHD. BMC Med. 2011;9:72.PubMedCrossRefGoogle Scholar
  11. 11.
    Howland MA. Antidotes in depth (A2): activated charcoal. In: Hoffman RS, Nelson LS, Goldfrank LR, Howland MA, Lewin NA, Flomenbaum NE, eds. Goldfrank’s toxicologic emergencies. 9th ed. New York: McGraw-Hill; 2011. Accessed January 9, 2013.
  12. 12.
    Tulloch SJ, Zhang Y, McLean A, Wolf KN. SLI381 (Adderall XR), a two-component extended-release formulation of mixed amphetamine salts: bioavailability of three test formulations and comparisons of fasted, fed, and sprinkled administration. Pharmacotherapy. 2002;22(11):1404–1415.Google Scholar
  13. 13.
    Albertson TE, Derlet RW, VanHoozen BE. Methamphetamine and the expanding complications of amphetamines. West J Med. 1999;170(4):214–9.PubMedGoogle Scholar
  14. 14.
    Baselt RC, Cravey RH: Disposition of toxic chemicals in man. 8th ed. Chicago: Year Book Medical; 2008;83–86Google Scholar
  15. 15.
    Anggard E. Pharmacokinetic and clinical studies on amphetamine dependent subjects. Eur J Clin Pharmacol. 1970;3:3.CrossRefGoogle Scholar
  16. 16.
    De La Torre R, Farre M, Navarro M, Pacifici R, Zuccaro P, et al. Clinical pharmacokinetic of amfetamine and related substances: monitoring in conventional and non-conventional matrices. Clin Pharmacokinet. 2004;43:157–85.PubMedCrossRefGoogle Scholar
  17. 17.
    Baselt R. Amphetamine. In: Baselt R, editor. Disposition of toxic drugs and chemicals in man. 5th ed. Foster: Chemical Toxicology Institute; 2000. p. 49–51.Google Scholar
  18. 18.
    Krishnan S, Zhang Y. Relative bioavailability of lisdexamfetamine 70-mg capsules in fasted and fed healthy adult volunteers and in solution: a single-dose, crossover pharmacokinetic study. J Clin Pharmacol. 2008;48(3):293–302.PubMedCrossRefGoogle Scholar
  19. 19.
    Krishnan SM, Pennick M, Stark JG. Metabolism, distribution and elimination of lisdexamfetamine dimesylate: open-label, single-centre, phase I study in healthy adult volunteers. Clin Drug Investig. 2008;28:745–55.PubMedCrossRefGoogle Scholar
  20. 20.
    Boellner SW, Stark JG, Krishnan S, Zhang Y. Pharmacokinetics of lisdexamfetamine dimesylate and its active metabolite, d-amphetamine, with increasing oral doses of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder: a single-dose, randomized, open-label, crossover study. Clin Ther. 2010;32:252–64.PubMedCrossRefGoogle Scholar
  21. 21.
    Mattingly G. Lisdexamfetamine dimesylate: a prodrug stimulant for the treatment of ADHD in children and adults. CNS Spectr. 2010;15:315–25.PubMedGoogle Scholar
  22. 22.
    Hoffman BB, Lefkowitz RJ. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In: Hardman JG, Limbird LE, Molinoff PB, et al., editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996. p. 199–227.Google Scholar
  23. 23.
    Chiang WK. Chapter 75. Amphetamines. In: Hoffman RS, Nelson LS, Goldfrank LR, Howland MA, Lewin NA, Flomenbaum NE, editors. Goldfrank’s toxicologic emergencies. 9th ed. New York: McGraw-Hill; 2011. Accessed 14 January 2013.
  24. 24.
    Seiden LS, Kleven MS. Methamphetamine and related drugs: toxicity and resulting behavioral changes in response to pharmacological probes. NIDA Res Monogr. 1997;173:146–60.Google Scholar
  25. 25.
    Gibb JW, Stone DM, Johnson M, Hanson GR. Role of dopamine in the neurotoxicity induced by amphetamines and related designer drugs. NIDA Res Monogr. 1997;173:161–78.Google Scholar
  26. 26.
    Gibb JW, Johnson M, Elayan I, et al. Neurotoxicity of amphetamines and their metabolites. NIDA Res Monogr. 1997;173:128–45.PubMedGoogle Scholar
  27. 27.
    Iversen L. Neurotransmitter transporters and their impact on the development of psychopharmacology. Br J Pharmacol. 2006;147:S82–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Frankel E. Overdose of amphetamine. Lancet. 1949;2(6576):490.Google Scholar
  29. 29.
    Curry SC, Chang D, Connor D. Drug and toxin-induced rhabdomyolysis. Ann Emerg Med. 1989;18:1068–84.PubMedCrossRefGoogle Scholar
  30. 30.
    Green SL, Kerr F, Braitberg G. Review article: amphetamines and related drugs of abuse. Emerg Med Australas. 2008;20:391–402.CrossRefGoogle Scholar
  31. 31.
    Callaway CW, Clark RF. Hyperthermia in psychostimulant overdose. Ann Emerg med. 1994;24:68–76.Google Scholar
  32. 32.
    Delert RW, Horowitz BZ, Lord RV. Amphetamine toxicity: experience with 127 cases. J Emerg Med. 1989;7:157–61.CrossRefGoogle Scholar
  33. 33.
    Sztajnkrycer MD, Hariharan S, Bond GR. Cardiac irritability and myocardial infarction in a 13-year-old girl following recreational amphetamine overdose. Pediatr Emerg Care. 2002;18:11–5.CrossRefGoogle Scholar
  34. 34.
    Wallace ME, Squires R. Fatal massive amphetamine ingestion associated with hyperpyrexia. J Am Board Fam Pract. 2000;13:302–4.PubMedGoogle Scholar
  35. 35.
    Maury E, Darondel JM, Buisinne A, Guitton C, Offenstadt G. Acute pulmonary edema following amphetamine ingestion. Intensive Care Med. 1999;25:332–3.PubMedCrossRefGoogle Scholar
  36. 36.
    Alldredge BK, Lowenstein DH, Simon RP. Seizures associated with recreational drug abuse. Neurology. 1989;39:1037–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Judge BS, Rusyniak DE. Chapter 27. Illicit drugs I: amphetamines. In: Dobbs MR, editor. Clinical neurotoxicology: syndromes, substances, environments. 1st ed. Philadelphia: Saunders; 2009.Google Scholar
  38. 38.
    Dihmis WC, Ridley P, Dhasmana JP, Wisheart JD. Acute dissection of the aorta with amphetamine misuse. BMJ. 1997;314(7095):1665.Google Scholar
  39. 39.
    Swalwell CH, Davis DG. Methamphetamine as a risk factor for acute aortic dissection. J Forensic Sci. 1999;44(1):23–6.PubMedGoogle Scholar
  40. 40.
    Wako E, LeDoux D, Mitsumori L, Aldea GS. The emerging epidemic of methamphetamine-induced aortic dissections. J Cardiac Surg. 2007;22(5):390–3.CrossRefGoogle Scholar
  41. 41.
    Kapetanovic S, Kim MA. Hemorrhagic stroke in a patient recently started on mixed amphetamine salts. Am J Psychiatry. 2010;167(10):1277–8.PubMedCrossRefGoogle Scholar
  42. 42.
    McEvoy AW, Kitchen ND, Thomas DGT. Lesson of the week: intracerebral hemorrhage in young adults: the emerging importance of drug misuse. Neurology. 1980;30(10):1125–8.CrossRefGoogle Scholar
  43. 43.
    DeSilva DA, Wont MC, Lee MP, Chen CL, Chang HM. Amphetamine-associated ischemic stroke: clinical presentation and proposed pathogenesis. J Stroke Cerebrovasc Dis. 2007;16(4):185–6.CrossRefGoogle Scholar
  44. 44.
    Sharma J, de Castro C, Chatterjee P, Pinto R. Acute myocardial infarction induced by concurrent use of adderall and alcohol in an adolescent. Pediatr Emer Care. 2013;29:84–8.CrossRefGoogle Scholar
  45. 45.
    Xiangyang J, Velez S, Ringstad J, Eyma J, Miller D, Bletberg M. Myocardial infarction associated with adderall XR and alcohol use in a young man. J Am Board Fam Med. 2009;22:197–201.CrossRefGoogle Scholar
  46. 46.
    Goldfrank LR, Hoffman RS. The cardiovascular effects of cocaine. Ann Emerg Med. 1991;20:165–75.PubMedCrossRefGoogle Scholar
  47. 47.
    Derlet RW, Rice P, Horowitz BZ, Lord RV. Amphetamine toxicity: experience with 127 cases. J Emerg Med. 1989;7:157–61.PubMedCrossRefGoogle Scholar
  48. 48.
    Lucas AR, Weiss M. Methylphenidate hallucinosis. JAMA. 1971;217:1079–81.PubMedCrossRefGoogle Scholar
  49. 49.
    CDC. Unintentional poisoning deaths—United States, 1999–2004. MMWR Morb Mortal Wkly Rep. 2007;56(5):93–6.Google Scholar
  50. 50.
    Krishnan S, Montcrief S. Toxicity profile of lisdexamfetamine dimeslate in three independent rat toxicology studies. Basic Clin Pharmacol Toxicol. 2007;101:231–40.PubMedCrossRefGoogle Scholar
  51. 51.
    Kearney TE. Charcoal, activated. In: Olson KR, editor. Poisoning and drug overdose. 5th ed. New York: McGraw-Hill; 2007. p. 467–8.Google Scholar
  52. 52.
    American Academy of Clinical Toxicology and European Association for Poisons Centres and Clinical Toxicologists. Position paper: single-dose activated charcoal. Clin Tox. 2005;43:61–87.Google Scholar
  53. 53.
    Goldfarb DS. Chapter 9. Principles and techniques applied to enhance elimination. In: Hoffman RS, Nelson LS, Goldfrank LR, Howland MA, Lewin NA, Flomenbaum NE, editors. Goldfrank’s toxicologic emergencies. 9th ed. New York: McGraw-Hill; 2011. Accessed January 24, 2013.
  54. 54.
    Hays H, Jolliff H, Casavant M. Letter to the Editor: the psychopharmacology of agitation: consensus statement of the American association for emergency psychiatry project BETA psychopharmacology workgroup. West J Emerg Med. 2012.
  55. 55.
    Roberts JR, Geeting GK. Intramuscular ketamine for the rapid tranquilization of the uncontrollable, violent, and dangerous adult patient. J Trauma. 2001;51:1008–10.PubMedCrossRefGoogle Scholar
  56. 56.
    Cong ML, Gynther B, Hunter E, Shuller P. Ketamine sedation for patients with acute agitation and psychiatric illness requiring aeromedical retrieval. Emerg Med J. 2012;29:335–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Derlet RW, Albertson TE, Rice P. Protection against d-amphetamine toxicity. Am J Emerg Med. 1990;8:105–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Wilson MP, Pepper D, Currier GW, Holloman GH, Feifel D. The psychopharmacology of agitation: consensus statement of the American association for emergency psychiatry project BETA psychopharmacology workgroup. West J Emerg Med. 2012;13:26–34.PubMedCrossRefGoogle Scholar
  59. 59.
    Espelin DE, Done AK. Amphetamine poisoning: effectiveness of chlorpromazine. N Engl J Med. 1968;278:1361–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Ruha AM, Yarema MC. Pharmacologic treatment of acute pediatric methamphetamine toxicity. Pediatr Emerg Care. 2006;22:782–5.PubMedCrossRefGoogle Scholar
  61. 61.
    Derlet RW, Albertson TE, Rice P. Antagonism of cocaine, amphetamine, and methamphetamine toxicity. Pharmacol Biochem Behav. 1990;36:745–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Greenblatt DJ, Gross P, Harris J, et al. Fatal hyperthermia following haloperidol therapy of sedative-hypnotic withdrawal. J Clin Psychiatry. 1978;39:673–5.PubMedGoogle Scholar
  63. 63.
    Akingbola OA, Singh D. Dexmedetomidine to treat lisdexamfetamine overdose and serotonin toxidrome in a 6-year-old girl. Am J Crit Care. 2012;21:456–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Wong GTC, Irwin MG. Poisoning with illicit substances: toxicology for the anesthetist. Anesthesia. 2013;68(suppl 1):117–24.CrossRefGoogle Scholar
  65. 65.
    Tobias JD. Dexmedetomidine to control agitation and delirium from toxic ingestions in adolescents. J Pediatr Pharmacol Ther. 2010;15:43–8.PubMedGoogle Scholar
  66. 66.
    Callaway CW, Clark RF. Hyperthermia in psychostimulant overdose. Ann Emerg Med. 1994;24(1):68–76.PubMedCrossRefGoogle Scholar
  67. 67.
    Barceloux DG. Chapter 1. Amphetamine and methamphetamine. In: Barceloux DG, editor. Medical toxicology of drug abuse: synthesized chemicals and psychoactive plants. 1st ed. New Jersey: John Wiley & Sons; 2012.Google Scholar
  68. 68.
    Greene SL, Kerr F, Braitberg G. Review article: amphetamines and related drugs of abuse. Emerg Med Australas. 2008;20:391–402.PubMedCrossRefGoogle Scholar
  69. 69.
    Product information: Methylin® oral chewable tablet, methylphenidate hydrochloride chewable tablet. Atlanta: Alliant Pharmaceuticals; 2004.Google Scholar
  70. 70.
    Kimko HC, Cross JT, Abernathy DR. Pharmacokinetics and clinical effectiveness of extended release methylphenidate. Clin Pharmacokin. 1999;37(6):457–70.CrossRefGoogle Scholar
  71. 71.
    Product information: Concerta® extended release oral tablets, methylphenidate HCl extended-release oral tablets. Fort Washington: McNeil Pediatrics; 2007.Google Scholar
  72. 72.
    Product information. Ritalin LA® extended release oral capsules, methylphenidate HCl extended release oral capsules. Novartis Pharmaceuticals; 2007.Google Scholar
  73. 73.
    Patrick KS, Straughn KS, Minhinnett RR, et al. Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2007;81(3):346–53.Google Scholar
  74. 74.
    Wilens TE. Effects of methylphenidate on the catecholinergic system in attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2008;28:S46–53.PubMedCrossRefGoogle Scholar
  75. 75.
    Klein-Schwartz W. Abuse and toxicity of methylphenidate. Cur Opin Pediatr. 2002;14:219–23.Google Scholar
  76. 76.
    Steyk O, Louidice T, Demeter S, Jacobs J. Multiple organ failure resulting from intravenous abuse of methylphenidate hydrochloride. Ann Emerg Med. 1985;14:597–9.CrossRefGoogle Scholar
  77. 77.
    Massello W, Carpenter DA. AS fatality to intranasal abuse of methylphenidate (Ritalin). J Forensic Sci. 1999;44:220–1.PubMedGoogle Scholar
  78. 78.
    Hill SL, El-Khayet RH, Sandilands EA, Thomas SHL. Electrocardiographic effects of methylphenidate overdose. Clin Toxicol. 2010;48:342–6.CrossRefGoogle Scholar
  79. 79.
    Schteinschnaider A, Plaghos L, Garbugino S, Riveros D, Lazarowski S, Intruvini S, Massaro M. Cerebral arteritis following methylphenidate use. J Child Neurol. 2000;15:2065–267.CrossRefGoogle Scholar
  80. 80.
    Sadeghiam H. Lucunar stroke associated with methylphenidate abuse. Can J Neurol Sci. 2004;31:109–11.Google Scholar
  81. 81.
    Klampfl K, Quattlander A, Burger R, Pfuhlmann B, Warnke A, Gerlach M. Case report: intoxication with high dose of long acting methylphenidate (Conderta) in a suicidal 14 year old girl. Attn Def Hyp Disord. 2010;2:221–4.CrossRefGoogle Scholar
  82. 82.
    Taylor FB, Russo J. Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. J Child Adolesc Psychopharmacol. 2000;10(4):311–20.PubMedCrossRefGoogle Scholar
  83. 83.
    Biederman J, Pliszka SR. Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescents. J Pediatr. 2008;152(3):394–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Wong YN, King SP, Simcoe D, Gorman S, Laughton W, McCormick GC, et al. Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects. J Clin Pharmacol. 1999;39:281–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Hellriegel ET, Arora S, Nelson M, Robertson P Jr. Steady-state pharmacokinetics and tolerability of modafinil administered alone or in combination with dextroamphetamine in healthy volunteers. J Clin Pharmacol. 2002;42:450–60.PubMedGoogle Scholar
  86. 86.
    Robertson P Jr, Hellriegel ET. Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet. 2003;42(2):123–37.PubMedCrossRefGoogle Scholar
  87. 87.
    Product information: Provigil®, modafinil. Cephalon, Inc.: Frazer; 2010.Google Scholar
  88. 88.
    Sweetman S. Martindale: the extra pharmacopeia (electronic version). London: The Pharmaceutical Press (internet version). Edition expires 2002, provided by Thomson Healthcare Inc, Greenwood Village.Google Scholar
  89. 89.
    Mitzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology. 2008;33:1477–502.CrossRefGoogle Scholar
  90. 90.
    Neuman G, Shehadeh N, Pillar G. Unsuccessful suicide attempt of a 15 year old adolescent with the ingestion of 5000 mg of modafinil. J Clin Seep Med. 2009;5:372–3.Google Scholar
  91. 91.
    Madras BK, Xie Z, Lin Z, Jassen A, Panas H, Lynch L, et al. Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Exp Ther. 2006;319:561–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Spiller HA, Borys D, Griffith JRK, Klein-Schwartz W, Aleguas A, Sollee D, Anderson DA, Sawyer TS. Toxicity from modafinil ingestion. Clin Toxicol. 2009;47:153–6.CrossRefGoogle Scholar
  93. 93.
    Carstairs SD, Urquhart A, Hoffman J, Clark RF, Cantrell FL. A retrospective review of supratherapeutic modafinil exposures. J Med Toxicol. 2010;6:307–10.PubMedCrossRefGoogle Scholar
  94. 94.
    Product information: Strattera ® capsules, atomoxetine HCl. Indianapolis: Eli Lilly and Company; 2011.Google Scholar
  95. 95.
    Farid NA, Bergstrom RF, Ziege EA, et al. Single-dose and steady-state pharmacokinetics of atomoxetine in normal subjects. J Clin Pharmacol. 1985;25:296–301.PubMedCrossRefGoogle Scholar
  96. 96.
    Ring BJ, Gillespie JS, Eckstein JA, et al. Identification of the human cytochromes p450 responsible for atomoxetine metabolism. Drug Metab Dispos. 2002;30:319–23.PubMedCrossRefGoogle Scholar
  97. 97.
    Sauer JM, Ring BJ, Witcher JW. Clinical pharmacokinetics of atomoxetine. Clin Pharmacokinet. 2005;44(6):571–90.PubMedCrossRefGoogle Scholar
  98. 98.
    Michelson D, Faries D, Wernicke J, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatr. 2001;108:U33–41.CrossRefGoogle Scholar
  99. 99.
    Spiller HA, Lintner C, Winter M. Atomoxetine ingestions in children: a report from poison centers. Ann Pharmacother. 2005;39:1045–8.PubMedCrossRefGoogle Scholar
  100. 100.
    LoVecchio F, Kashani J. Isolated atomoxetine (Strattera) ingestions commonly result in toxicity. J Emerg Med. 2006;31:267–8.PubMedCrossRefGoogle Scholar
  101. 101.
    Kashani J, Ruha AM. Isolated atomoxetine overdose resulting in seizure. J Emerg Med. 2007;32:175–8.PubMedCrossRefGoogle Scholar
  102. 102.
    Cantrell FL, Nestor M. Benign clinical course following atomoxetine overdose. Clin Toxicol. 2005;43:57.Google Scholar
  103. 103.
    Bond GR, Giarro AC, Gilbert DL. Dyskenesias associated with atomoxetine in combination with other psychoactive drugs. Clin Toxicol. 2007;45:182–5.CrossRefGoogle Scholar
  104. 104.
    Garside D, Ropero-miller JD,  Riemer EC. Postmortem tissue distribution of atomoxetine following fatal and nonfatal doses: three case reports. J Foren Sci. 2006;51: 170–82.Google Scholar
  105. 105.
    Davies DS, Wing LMH, Reid JL. Pharmacokinetics and concentration-effect relationships of intravenous and oral clonidine. Clin Pharmacol Ther. 1977;21:593–601.PubMedGoogle Scholar
  106. 106.
    Frisk-Holmberg M, Paalzow L, Edlund PO. Clonidine kinetics in man: evidence for dose dependency and changed pharmacokinetics during chronic therapy. Br J Clin Pharmacol. 1981; 12(5):653–8.Google Scholar
  107. 107.
    DeRoos FJ. Chapter 62. Other antihypertensives. In: Hoffman RS, Nelson LS, Goldfrank LR, Howland MA, Lewin NA, Flomenbaum NE, eds. Goldfrank’s toxicologic emergencies. 9th ed. New York: McGraw-Hill; 2011. Accessed January 23, 2013.
  108. 108.
    Reid JL. The clinical pharmacology of clonidine and related central antihypertensive agents. Br J Clin Pharmacol. 1981;12:295–302.PubMedCrossRefGoogle Scholar
  109. 109.
    Arndts D, MacMahon SW, Austin A, et al. New aspects of the pharmacokinetics and pharmacodynamics of clonidine in man. Eur J Clin Pharmacol. 1983;24:21–30.PubMedCrossRefGoogle Scholar
  110. 110.
    Product information. Catapres ®, clonidine HCl. Ridgefield: Boehringer-Ingelheim; 2001.Google Scholar
  111. 111.
    Lowenthal DT. Pharmacokinetics of clonidine. J Cardiovasc Pharmacol. 1980;2:529–37.Google Scholar
  112. 112.
    Pettinger WA. Clonidine, a new antihypertensive drug. N Engl J Med. 1975;293:1179–80.PubMedCrossRefGoogle Scholar
  113. 113.
    O’Prichard DC, Snyder SH. Distinct alpha-noradrenergic receptors differentiated by binding and physiologic relationships. Life Sci. 1979;24:79.CrossRefGoogle Scholar
  114. 114.
    Kobinger W, Pichler L. Centrally induced reduction in sympathetic tone: a postsynaptic alpha-adrenoceptor-stimulating action of imidazolines. Eur J Pharmacol. 1976;40:311–20.PubMedCrossRefGoogle Scholar
  115. 115.
    Farsang C, Ramirez-Gonzalez MD, Mucci L, Kunos G. Possible role of an endogenous opiate in the cardiovascular effects of central alpha adrenoceptor stimulation in spontaneously hypertensive rats. J Pharmacol Exp Ther. 1980;214:203–2088.PubMedGoogle Scholar
  116. 116.
    Lilja M, Hakala M, Jounela J. Hypertension after clonidine overdose. Ann Clin Res. 1984;16:10–2.PubMedGoogle Scholar
  117. 117.
    Frye CB, Vance MA. Hypertensive crisis and myocardial infarction following massive clonidine overdose. Ann Pharmacother. 2000;34:611–4.PubMedCrossRefGoogle Scholar
  118. 118.
    Kappagoda C, Schell DN, Hanson RM, Hutchin P. Clonidine overdose in childhood: implications of increased prescribing. J Pediatr Child Health. 1998;34:508–12.CrossRefGoogle Scholar
  119. 119.
    Spiller HA, Klein-Schwatz W, Colvin JM, Villalobos D, Johnson PB, Anderson DL. Toxic clonidine ingestion in children. J Pediatr. 2005;146:263–6.PubMedCrossRefGoogle Scholar
  120. 120.
    Wiley JF, Wiley CC, Torrey SB, Henretig FM. Clonidine poisoning in young children. J Pediatr. 1990;116:654–8.PubMedCrossRefGoogle Scholar
  121. 121.
    Anderson RJ, Hart GR, Crumpler CP, Lerman MJ. Clonidine overdose: report of six cases and review of the literature. Ann Emerg Med. 1981;10:107–12.PubMedCrossRefGoogle Scholar
  122. 122.
    Klein-Schwartz W. Trends and toxic effects from pediatric clonidine exposures. Arch Pediatr Adolesc Med. 2002;156:392–6.PubMedCrossRefGoogle Scholar
  123. 123.
    Artman M, Boerth RC. Clonidine poisoning: a complex problem. Am J Dis Child. 1983;137(2):171–4.PubMedGoogle Scholar
  124. 124.
    Anderson RJ, Hart GR, Crumpler CP, Lerman MH. Clonidine overdose: report of 6 cases and review of the literature. Ann Emerg Med. 1981;10(2):107–12.PubMedCrossRefGoogle Scholar
  125. 125.
    Perrone J, Hoffman RS, Jones B, Hollander JE. Guanabenz induced hypothermia in a poisoned elderly female. J Toxicol Clin Toxicol. 1994;32:445–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Knapp JF, Fowler MA, Wheeler CA, Wasserman GS. Case 01–1995: a two-year-old female with alteration of consciousness. Pediatr Emerg Care. 1995;11:62–5.CrossRefGoogle Scholar
  127. 127.
    Scaramuzza A, Torresani P, Arisi D, Rossoni R. Seizures following clonidine test for growth hormone reserve: an unusual presentation of benign partial epilepsy. J Pediatr Endocrinol Metabol. 2000;13:451–2.Google Scholar
  128. 128.
    Huang C, Banerjee K, Sochett E, Perlman K, Wherett D, Daneman D. Hypoglycemia associated with clonidine testing for growth hormone deficiency. J Pediatr. 2001;139:323–4.PubMedCrossRefGoogle Scholar
  129. 129.
    Mathew PM, Addy DP, Wright N. Clonidine overdose in children. Clin Toxicol. 1981;18:169–73.Google Scholar
  130. 130.
    Romano MJ, Dinh A. A 1000-fold overdose of clonidine caused by a compounding error in a 5-year-old child with attention deficit/hyperactive disorder. Pediatrics. 2001;108:471–3.PubMedCrossRefGoogle Scholar
  131. 131.
    Ciaccheri M, Dolara A, Manetti A, Botti P, Zorn M, Peruzzi S. A-V block by an overdose of clonidine. Acta Cardiologica. 1983;3:23–235.Google Scholar
  132. 132.
    Fisher DH, Moss MM, Walker W. Critical care for clonidine poisoning in children. Crit Care Med. 1990;18:1124–8.CrossRefGoogle Scholar
  133. 133.
    Domino LE, Domino SE, Stockstill MS. Relationship between plasma concentrations of clonidine and mean arterial pressure during an accidental clonidine overdose. Br J Clin Pharmacol. 1986;21:71–4.PubMedCrossRefGoogle Scholar
  134. 134.
    Caravati EM, Bennet DL. Clonidine transdermal patch poisoning. Ann Emerg Med. 1988;17:175–6.PubMedCrossRefGoogle Scholar
  135. 135.
    Maggi JC, Iskra MK, Nussbaum E. Severe clonidine overdose in children requiring critical care. Clin Paediatr. 1986;25:453–5.CrossRefGoogle Scholar
  136. 136.
    Conner CS, Watanabe AS. Clonidine overdose: a review. Amer J Hosp Pharm. 1979;36:906–11.Google Scholar
  137. 137.
    Marruecos L, Roglan A, Frati ME, Artigas A. Clonidine overdose. Crit Care Med. 1983;11:959–60.PubMedCrossRefGoogle Scholar
  138. 138.
    Bamshad MJ, Wasserman GS. Pediatric clonidine intoxications. Vet Hum Toxicol. 1990;32:220–3.PubMedGoogle Scholar
  139. 139.
    Kulig K, Duffy J, Rumack BH, et al. Naloxone for treatment of clonidine overdose. JAMA. 1982;247:1697.PubMedCrossRefGoogle Scholar
  140. 140.
    Tenenbein M. Naloxone in clonidine toxicity. Am J Dis Child. 1984;138:1084.PubMedGoogle Scholar
  141. 141.
    Banner W Jr, Lund ME, Clawson L. Failure of naloxone to reverse clonidine toxic effect. Am J Dis Child. 1983;137(12):1170–1.PubMedGoogle Scholar
  142. 142.
    Carchman SH, Crowe JT Jr, Wright GJ. The bioavailability and pharmacokinetics of guanfacine after oral and intravenous administration to healthy volunteers. J Clin Pharmacol. 1987;27:762–7.PubMedCrossRefGoogle Scholar
  143. 143.
    Markowitz JS, Patrick KS. Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder. Clin Pharmacokinet. 2001;40:753–72.PubMedCrossRefGoogle Scholar
  144. 144.
    Boellner SW, Pennick M, Fiske K, Lyne A, Shojaei A. Pharmacokinetics of a guanfacine extended-release formulation in children and adolescents with attention-deficit-hyperactivity disorder. Pharmacother. 2007;27:1253–62.CrossRefGoogle Scholar
  145. 145.
    Swearingen D, Pennick M, Shojaei A, Lyne A, Fiske K. A phase I, randomized, open-label, crossover study of the single-dose pharmacokinetic properties of guanfacine extended-release 1-, 2-, and 4-mg tablets in healthy adults. Clin Ther. 2007;29:617–25.PubMedCrossRefGoogle Scholar
  146. 146.
    Intuniv® (guanfacine) extended-release tablets, prescribing information. Wayne, PA: Shire; June, 2011. Available at: Accessed January 18, 2013.
  147. 147.
    Kirch W, Kohler H, Braun W. Elimination of guanfacine in patients with normal and impaired renal function. Br J Clin Pharmacol. 1980;10:33S–5S.PubMedCrossRefGoogle Scholar
  148. 148.
    Kiechel JR. Pharmacokinetics and metabolism of guanfacine in man: a review. Br J Pharmacol. 1980;10:25S–35S.CrossRefGoogle Scholar
  149. 149.
    Barber ND, Reid JL. Comparison of the actions of centrally and peripherally administered clonidine and guanfacine in the rabbit: investigation of the differences. Brit J Pharmacol. 1982;77:641–7.CrossRefGoogle Scholar
  150. 150.
    Frisk-Holmberg M, Wibelt L. Concentration-dependent blood pressure effects of guanfacine. Clin Pharmacol Ther. 1986;39:169–72.PubMedCrossRefGoogle Scholar
  151. 151.
    Minns AB, Clark RC, Schneir A. Guanfacine overdose resulting in initial hypertension and subsequent delayed persistent orthostatic hypotension. Clin Toxicol. 2010;48:146–8.CrossRefGoogle Scholar
  152. 152.
    Scalzo AJ, Tochtrop RM, Weber JA. Hypertensive emergency from guanfacine overdose. Clin Toxicol. 2010;48:607.Google Scholar
  153. 153.
    Van Dyke MW, Bonance AL, Ellenhorn MJ. Guanfacine overdose in a pediatric patient. Vet Human Toxicol. 1990;32:46–7.Google Scholar
  154. 154.
    Keitel JR. Pharmacokinetics and metabolism of guanfacine in man: a review. Br J Pharmacol. 1980;10:25S–32S.CrossRefGoogle Scholar
  155. 155.
    Hashikawa AN, Kostic MA, Gummin DD. Pediatric hypertensive encephalopathy after abrupt withdrawal of guanfacine. Clin Toxicol. 2008;46:616.Google Scholar
  156. 156.
    Wilson MF, Haring O, Lewin A, Bedsole G, Stepansky W, et al. Comparison of guanfacine versus clonidine for efficacy, safety and occurrence of withdrawal syndrome in step-2 treatment of mild to moderate essential hypertension. Am J Cardiol. 1986;57(9):43E–9E.PubMedCrossRefGoogle Scholar
  157. 157.
    Koike Y, Togashi H, Shimamura K, et al. Effects of abrupt cessation of treatment with clonidine and guanfacine on blood pressure and heart rate in spontaneously hypertensive rats. Clin Exp Hypertens. 1981;3:103–20.PubMedCrossRefGoogle Scholar
  158. 158.
    Kisicki JC, Fiske K, Lyne A. Phase I, double-blind, randomized, placebo-controlled, dose-escalation study of the effects on blood pressure of abrupt cessation versus taper down of guanfacine extended-release tablets in adults aged 19 to 24 years. Clin Ther. 2007;29(9): 1967–79.Google Scholar
  159. 159.
    Vitiello B. Understanding the risk of using medications for ADHD with respect to physical growth and cardiovascular function. Child Adolesc Psychiatr Clin N Am. 2008;17(2):459-xi.Google Scholar
  160. 160.
    Arnsten AF, Scahill L, Findling RL. Alpha-2 adrenergic receptor agonists for the treatment of attentiondeficit/hyperactivity disorder: emerging concepts from new data. J Child Adolesc Psychopharmacol. 2007;17:393–406.PubMedCrossRefGoogle Scholar
  161. 161.
    Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, Arnsten AFT, Cohen DJ, Leckman JF. Guanfacine in the treatment of children with tic disorders and ADHD: a placebo-controlled study. Am J Psychiatry. 2001;158:1067–74.PubMedCrossRefGoogle Scholar
  162. 162.
    Granier P, Arsac P, Debru JL. Intoxication par la guanfacine. Nouv Presse Med. 1982;11:1636–7.PubMedGoogle Scholar
  163. 163.
    Spiller HA, Griffith JR. Prolonged cardiovascular effects after unintentional ingestion of tetrahydrozoline. Clin Toxicol. 2008;46:171–2.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Henry A. Spiller
    • 1
    • 2
    Email author
  • Hannah L. Hays
    • 1
    • 3
  • Alfred AleguasJr.
    • 4
  1. 1.Central Ohio Poison CenterColumbusUSA
  2. 2.Department of Pediatrics, College of MedicineOhio State UniversityColumbusUSA
  3. 3.Department of Emergency MedicineThe Ohio State University Wexner Medical CenterColumbusUSA
  4. 4.Florida Poison Information Center-Tampa, Tampa General HospitalTampaUSA

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