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Abstract

Objective: This paper examines clinical and neuroscientific evidence to address the question whether high doses of stimulant drugs offer additional advantages in the treatment of adult attention deficit hyperactivity disorder (ADHD) and at what cost. It attempts to arrive at a reasonable upper limit of dosage for clinical purposes.

Method: The study involves a selective review of the treatment studies of ADHD in children and adults and an examination of the pharmacokinetic and pharmaco-dynamic data on psychostimulants in humans and animals.

Results and Conclusions: The clinical and experimental data justify the use of chronic low-dose stimulant treatment of ADHD in adults, with the recommended upper limit of dose being 1 mg/kg for methylphenidate and 0.5 mg/kg for dexamphetamine. There is no empirical evidence of greater improvement with higher doses and any beneficial effect is likely to be compromised by the adverse effects, some of which can be very serious. The recommended doses should be exceeded only after careful consideration and objective documentation of beneficial and adverse consequences. Monitoring of drug levels in blood may be of some value for compliance or pharmacokinetic considerations, as there is a direct relationship between blood and brain levels as well as dopamine transporter occupancy. These recommendations are tentative and further clinical research is warranted.

Keywords

ADHD dosage psychostimulants

Not only has attention deficit hyperactivity disorder (ADHD) become firmly established in the panoply of psychiatric diagnoses, its treatment with psychostimulants is a growing phenomenon in clinical practice [1]. In Australia, the total number of prescriptions issued for stimulants across all age groups increased more than 10-fold in the years 1990–1998 [McManus P: personal communication, 1999]. Many patients have benefited from this trend, with an increased ability to perform at work or study and an improvement in the quality of their lives [2]. Most psychiatrists, however, approach the prescription of stimulants with some trepidation. Psychostimulants are commonly thought of as drugs of abuse rather than therapy, their long-term effects are not fully known and beneficial effects are hard to quantify objectively. When a patient makes a request for an increased dose of the drug for the treatment of ADHD, it immediately arouses the suspicion of abuse or the fear of adverse consequences. The problem is particularly acute in adolescents and adults because the validity of the diagnosis of ADHD in adults is often questioned [3], the empirical basis for treatment is less well-established than for children [1,3], the co-occurrence of drug abuse is common [4] and many patients have the additional diagnosis of personality disorder [4].

Dosage

If one does accept the legitimacy of stimulant drug treatment in adult ADHD, is there a maximum daily dosage that should not be exceeded? The answer needs to be sought from the efficacy data available, the neuroscientific information that underpins the treatment, the pharmacokinetics and bioavailability data on stimulants in adults in comparison with children and the differential likelihood of long-term side-effects with higher doses. Considerable discrepancy exists between the states and territories of Australia regarding maximum allowable stimulant doses in adults with ADHD. In New South Wales and Tasmania, a prescriber is permitted a maximum of six tablets of dexamphetamine (5 mg each) or methylphenidate (10 mg each) per day, beyond which a second opinion has to be sought. In Western Australia, up to 12 tablets per day can be prescribed. Other Australian states and territories do not set a specific upper limit and allow this to be largely clinician determined.

The efficacy of stimulants, in particular methylphenidate, in adult ADHD has been examined in at least seven studies (n = 193 subjects), five of which were controlled, with an overall report of significant reduction of symptoms of ADHD (for review see [5]). In four of the five controlled studies [6–9], the average daily dose of methylphenidate used was 0.6 mg/kg and the average response rate was about 50%. In the fifth study, a dose of 1 mg/kg was used and a response rate of 70% was reported, the authors arguing for the acceptance of the higher dose in clinical practice [10]. The limitation of such data is that, unless there has been a direct comparison of different doses in the same study, caution is necessary for the acceptance of the differential improvement rates. Furthermore, the maximum dose examined was 1 mg/kg, thereby providing no information on even higher doses, the question that is raised by many clinicians and patients. Higher doses were used in one open study treating predominantly children [11], with the range for dexamphetamine in this study being 1.6–3.6 mg/kg and for methylphenidate 1.4–7.7 mg/kg. The highest dose of dexamphetamine used in this report was 230 mg/day. The open nature of this report is a serious limitation and makes it an unlikely basis to guide therapy [12]. There has been one controlled trial of dexamphetamine in adult ADHD [13] which, together with anecdotal reports [14], supports its being as useful as methylphenidate. The relative dose of dexamphetamine in mg/kg, if usage in children is a guide, is about one-half the methylphenidate dose [15], that is, the standard tablet sizes available for the two drugs are equipotent.

Behavioural pharmacology

An examination of the behavioural pharmacology of stimulants is instructive. Dopaminomimetic drugs, which include stimulants, have a biphasic response in animals, with lower doses reducing locomotor activity and higher doses stimulating locomotion [16–18]. This has been observed in spontaneously active rodents [19], as well as in rats made hyperactive with a neonatal dopaminergic lesion [20]. The dose of amphetamine that reduces activity in mice is in the range of 0.5–1.0 mg/kg, with activity levels increasing progressively with doses from 1.0 to 5.0 mg/kg [18]. The biphasic nature of the response is seen in humans as well, and the commonly used clinical dose of dexamphetamine (0.2–0.6 mg/kg) is in the same range as that in the hypolocomotor animal model. Higher doses in humans lead to excitation, sleeplessness and anorexia, all features of excessive brain stimulation, again like the hyperlocomotor animal.

The pharmacological basis of the biphasic response is incompletely understood, but data from animals have generated some cogent theories. The dopaminergic effect of a drug depends on its influence on the resting level of extracellular dopamine and the increase it produces in the pulsatile dopamine associated with the nerve impulse [21]. In a drug-free condition, a nerve impulse produces a transient 60-fold rise in synaptic dopamine level above the baseline level of about 4 nmol/L [22]. Methylphenidate and dexamphetamine, like cocaine, block the dopamine transporter leading to an increase in dopamine in the synaptic cleft, and dexamphetamine additionally has a direct dopamine-releasing action [23]. These drugs therefore raise the baseline level of extracellular dopamine, as well as the nerve impulse-associated rise. At low doses of stimulants in the rat, the rise in baseline values is about sixfold, and that in the impulse-related levels is twofold [24,25]. The relative rise of dopamine, when expressed as a percentage of the baseline values, is therefore lowered by stimulants at low doses. At higher doses of dexamphetamine (> 1 mg/kg), the rise in baseline is seven-to 35-fold and that in the pulsatile output about sevenfold [26]. This differential effect of low and high doses may account for the biphasic response of stimulants [21]. Since the response in humans is similarly biphasic, and the commonly used dose range for the treatment of ADHD is similar to the hypolocomotor dose in animals, it could be argued that higher dexamphetamine doses (for example greater than 1 mg/kg) will have a stimulating effect and could possibly worsen the features of ADHD.

This argument can be further informed by recent work using positron emission tomography (PET). It has been shown that for cocaine to produce a ‘high', at least 60% of the dopamine transporters must be blocked and this effect should occur and dissipate rapidly [27]. Methylphenidate, which is similar in its action to cocaine except for a more sustained effect, produces a 50% blockade at an oral dose of 0.25 mg/kg, with the peak concentration in the brain being reached at 60 min [28]. The plasma levels of methylphenidate correspond to the dopamine transporter occupancy [28]. Clinical doses of methylphenidate, therefore, can be expected to produce a greater than 50% occupancy which should be pharmacologically meaningful. At a dose of 1 mg/kg, 80% or greater occupancy should be expected [28], arguing against the value of further increases in clinical doses. In fact, adverse effects are likely to outweigh an advantage at very high doses.

Tolerance

If the clinical and experimental evidence does not support the use of high doses of stimulants (e.g. above 1 mg/kg dexamphetamine or 2 mg/kg methylphenidate), is there an argument that the dose would need an escalation, owing to tolerance, beyond the usual recommendation, when the drug is used chronically? Tolerance to some actions of stimulant drugs has been demonstrated in animal studies [29,30]. Long-term administration of dexamphetamine has been shown in monkeys to lead to long-lasting down-regulation of D₂ dopamine receptors [31]. Tolerance does not, however, develop to all actions of these drugs [29]. The clinical evidence does not suggest the development of tolerance to the therapeutic effects [15]. In a recent randomised, double-blind, placebo-controlled study of dexamphetamine treatment in children with ADHD, no evidence of tolerance was noted over a period of 15 months [32]. This was a sufficiently long period for tolerance to develop if that was a likely outcome. There is experimental evidence that long-term use of dopamine agonists leads to a reduced density of D₂ receptors [33]. Whether this occurs with stimulants as they are used clinically, and what the practical implications are, is not known. It is also possible that chronic stimulant treatment could alter the functional state of both D₁ and D₂ receptors, but the significance of this is also not known [21]. In conclusion, the empirical basis is weak, but clinical experience argues against the need for an escalation of dose with continuing treatment once the therapeutic effect has been established.

Pharmacokinetics

Examination of the pharmacokinetics of orally administered stimulant medication is an important step in determining a rationale for dosing regimens. After oral administration, both methylphenidate and dexamphetamine are almost completely absorbed [34], with food having little impact on this process [35,36]. In adults, methylphenidate has a pharmaco-kinetic profile similar to that in children [34,35], reaching a peak concentration at 1.5–2.5 h and having an elimination half-life of 2–3.5 h after oral administration of a single dose [34,35,37]. Nonlinear kinetics have been observed with higher doses of methylphenidate [38,39] and have also been proposed with repeated doses [40], probably as a result of saturation of presystemic metabolism. Dose escalation therefore carries the theoretical potential for sudden increase in adverse effects. Dexamphetamine typically takes 2–3 h to reach peak concentration after a single oral dose [34], but its half-life (approximately 7 h) is considerably longer than that of methylphenidate. As is the case in children, peak serum concentrations of both stimulants for the same oral dose may vary by four- to fivefold in adults [35,36,38]. Such variability may arise from differences in presystemic metabolism between individuals [38]. Inter-individual variability in plasma clearance is seen with both drugs [34] and, contrary to earlier suggestions [41], does not appear to be less likely with methylphenidate. As inter-individual differences in pharmacokinetics may be less dramatic when dose is adjusted for body weight [36], it would seem appropriate to use mg/kg as a general guide for determining maximum dose in individual patients. Inter-subject variability might provide an argument for high dosing of individuals failing to respond to conventional dosing strategies. However, as it remains unclear whether clinical response in children and adults is related to peak brain concentration or the rate of increase of the drug in the brain [42], dose escalation purely on the basis of ‘inadequate’ response cannot be recommended. Although there may be an argument for examining the individual pharmacokinetics of stimulants in those patients failing to respond to conventional dosing strategies, this requires ready access to a laboratory with an established assay, and is not feasible in routine clinical practice. Furthermore, data from children suggest that mean serum levels do not differ between drug responders and non-responders [35].

Side-effects

The dose of stimulants is significantly associated with the presence of side-effects [43,44]. As the dose of methylpenidate exceeds 0.5 mg/kg, the rates of insomnia and appetite suppression increase. Within the recommended therapeutic range, this is not generally a problem in adults [2], but at higher doses this could be a major limiting factor. The cardiovascular effects of stimulants (e.g. increases in pulse and blood pressure) have not been well examined, but they cannot be ignored at higher doses, especially in adults with pre-existing cardiovascular disease. The risk of convulsions also goes up with higher doses [43]. In long-term usage, the concerns in adults have been the possibility of drug abuse [45], the precipitation of psychosis [46], the production of tic disorders as has been seen in children [45] and the possibility of as yet unknown permanent brain dysfunction although this seems unlikely. The development of amphetamine psychosis has been associated with frequent high-dose administration of amphetamines, and this has been replicated in an escalating-dose ‘binge’ model of amphetamine psychosis in the rodent [31].

The therapeutic use of drugs of potential abuse raises the important question of whether their prescription encourages abuse or dependence and whether such a problem may be more prevalent at higher therapeutic doses. It is believed that use of stimulants in children does not increase the risk for later abuse or dependence [15]. A recent study demonstrated that treatment of childhood ADHD dramatically decreased the risk of substance-abuse in adolescence [47]. The same cannot be said with confidence when treatment is initiated in adolescence and adulthood [48]. Intranasal and intravenous abuse of prescription stimulants (one's own or from a friend) has been reported [48–50]; oral abuse is also recognised [51]. Since the effect of stimulants on the dopamine transporter is similar to cocaine, and dose is important for the ‘high', large therapeutic doses raises concern. Volkow et al. [28,52] have demonstrated that dopamine transporter blockade by both oral and intravenous methylphenidate is necessary, but not sufficient, to produce self-reports of a ‘high', and postulate that it is the rate of uptake of methylphenidate into the brain that determines its reinforcing effect. This work, and the preference for abuse of stimulants by non-oral routes, suggest that prescribed stimulants themselves, when taken orally in modest doses, are unlikely to encourage abuse or dependence. Clinical practice, however, is complicated by the high prevalence of personality disorders and substance abuse in adults with ADHD [4]. Clinicians hesitate to prescribe stimulants to a patient with a history of drug abuse, even when a diagnosis of ADHD is confidently made. Drug abuse cannot, however, be considered an absolute contraindication [2], but it is advisable to remain within therapeutic doses and monitor patients closely.

Stimulants are recognised as producing a psychosis with persecutory delusions and auditory and visual hallucinations [46]. This is usually associated with intravenous use and high doses, and has not been described with therapeutic use [53]. The possible use of large doses, however, raises this concern. Behaviours such as extreme vigilance, tracking of non-apparent stimuli, constant checking, hyper-responsiveness and grasping in mid-air have been reported in non-human primates treated chronically with high-dose amphetamine [54]. Other behaviours in monkeys include posturing and other catatonic features [55]. Castner and Goldman-Rakic [56] reported that, in monkeys, repeated intermittent but escalating (up to 0.8 mg/kg) low-dose amphetamine treatment led to behavioural sensitisation. While low-dose, chronic treatment may produce similar behaviours at a lesser severity [56], high doses are more likely to cause them. Although both amphetamine and methylphenidate sensitise stereotypic behaviours in rats, only amphetamine induces loco-motor sensitisation [57]. This may reflect the different methods by which the drugs increase synaptic dopamine [57]. There is interest in elucidating alterations in dopamine-stimulated signal transducing mechanisms that may be responsible for different components of behavioural sensitisation [58]. Chronic and high-dose amphetamine exposure in monkeys and rodents has also been reported to produce nigros-triatal toxicity [59,60]. This can be prevented if an intermittent, low-dose schedule is used [61]. Yuan et al. observe [62] that methylphenidate appears to lack the dopaminergic neurotoxic effect shown by dexamphetamine in rats 2 weeks after a high dose. The contrast in neurotoxic potential of these two drugs at high doses suggests that dopaminergic efflux may not be the direct mediator of such damage [62]. While implications of laboratory findings are unclear, they prompt an appraisal of chronic stimulant use, even at low doses, and its adverse consequences. Meanwhile, doses should be restricted to low levels.

Conclusion

Our data justify the use of chronic, low-dose stimulant treatment of ADHD in adults. High-dose treatment is not recommended. There no evidence of greater improvement and any beneficial effect is likely to be compromised by adverse effects. Some short- and long-term side-effects of high doses can be serious. The upper limit is difficult to decide in the absence of data. We recommend limits of 1 mg/kg for methylphenidate and 0.5 mg/kg for dexamphetamine. These doses should be exceeded only after consideration and objective documentation of beneficial and adverse consequences. Monitoring drug levels may be of value if poor compliance or failure of the dose to produce adequate serum levels are being considered, as there is a direct relationship of blood to brain levels as well as to dopamine transporter occupancy. Further research is needed to achieve a sound basis.

Footnotes

Acknowledgements

We thank F. Levy for her help.

References

1. Sachdev

. Attention deficit hyperactivity disorder in adults. Psychological Medicine 1999; 29: 507–514.

2. Biederman

. A 55-year-old man with attention-deficit/hyperactivity disorder. Journal of the American Medical Association 1998; 280: 1086–1092.

3. Spencer

Biederman

Wilens

Faraone

. Is attention-deficit hyperactivity disorder in adults a valid disorder?. Harvard Review of Psychiatry 1994; 1: 326–335.

4. Biedernam

Faraone

Spencer

. Patterns of psychiatric comorbidity, cognition and psychosocial functioning in adults with attention deficit hyperactivity disorder. American Journal of Psychiatry 1993; 150: 1792–1798.

5. Wilens

Biederman

Spencer

Prince

. Pharmacotherapy of adult attention deficit hyperactivity disorder: a review. Journal of Clinical Psychopharmacology 1995; 15: 270–279.

6. Wood

Reimherr

Wender

Johnson

. Diagnosis and treatment of minimal brain dysfunction in adults: a preliminary report. Archives of General Psychiatry 1976; 33: 1453–1460.

7. Wender

Reimherr

Wood

. Attention deficit disorder ((minimal brain dysfunction)) in adults: a replication study of diagnosis and drug treatment. Archives of General Psychiatry 1981; 142: 547–552.

8. Mattes

Boswell

Oliver

. Methylphenidate effects on symptoms of attention deficit disorder in adults. Archives of General Psychiatry 1984; 41: 1059–1063.

9. Gualtieri

Ondrusek

Finley

. Attention deficit disorder in adults. Clinical Neuropharmacology 1985; 8: 343–356.

10.

10. Spencer

Wilens

Biederman

Faraone

Ablon

Lapsley

. A double blind, crossover comparison of methylphenidate and placebo in adults with childhood onset attention deficit hyperactivity disorder. Archives of General Psychiatry 1995; 52: 434–443.

11.

11. Kessler

. Drug therapy in attention-deficit hyperactivity disorder. Southern Medical Journal 1996; 89: 33–38.

12.

12. Block

. Medication for attention-deficit hyperactivity disorder. Southern Medical Journal 1996; 89: 95–96.

13.

13. Paterson

Douglas

Hallmayer

Hagan

Krupenia

. A randomised, double-blind, placebo-controlled trial of dexamphetamine in adults with attention deficit hyperactivity disorder. Australian and New Zealand Journal of Psychiatry 1999; 33: 494–502.

14.

14. Wender

. Attention-deficit hyperactivity disorder in adults. Oxford University Press, New York 1995.

15.

15. Dulcan

. AACAP Guidelines. Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry 1997; 36(Suppl. 10S)85S–121S.

16.

16. Hornykiewicz

. Dopamine ((3-hydroxytyramine)) and brain function. Pharmacological Reviews 1966; 18: 925–964.

17.

17. Boissier

Simon

. On the potentiation of DOPA effects by monoamine oxidase inhibitors. Psychopharmacologia 1966; 8: 428–436, in French.

18.

18. Helmeste

Seeman

. Amphetamine-induced hyperlocomotion in mice with more brain D2 dopamine receptors. Psychiatry Research 1982; 7: 351–359.

19.

19. Steiner

Delay

Isaac

. Effects of drugs, age and illumination on response speed of squirrel monkeys. Pharmacology Biochemistry and Behavior 1986; 24: 503–506.

20.

20. Luthman

Fredriksson

Lewander

Jonsson

Archer

. Effects of D-amphetamine and methylphenidate on hyperactivity by neonatal 6-hydroxydopamine treatment. Psychopharmacology 1989; 99: 550–557.

21.

21. Seeman

Madras

. Anti-hyperactivity medication: methylphenidate and amphetamine. Molecular Psychiatry 1998; 3: 386–396.

22.

22. Parsons

Justice

Jr . Extracellular concentration and in vivo recovery of dopamine in the nucleus accumbens using microdialysis. Journal of Neurochemistry 1992; 58: 212–218.

23.

23. Wall

Rudnick

. Biogenic amine flux mediated by cloned transporters stably expressed in cultured cell lines: amphetamine specificity for inhibition and efflux. Molecular Pharmacology 1995; 47: 544–550.

24.

24. Sharp

Zetterström

Ljungberg

Ungerstedt

. A direct comparison of amphetamine-induced behaviours and regional brain dopamine release in the rat using intracerebral dialysis. Brain Research 1987; 401: 322–330.

25.

25. Kuczenski

Segal

. Concomitant characterization of behavioral and striatal neurotransmitter response to amphetamine using in vivo microdialysis. Journal of Neuroscience 1989; 9: 2051–2086.

26.

26. Gonon

. Non-linear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied by in vivo electrochemistry. Neuroscience 1988; 24: 19.

27.

27. Volkow

Ding

Y-S

Fowler

. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in human brain. Archives of General Psychiatry 1995; 52: 456–463.

28.

28. Volkow

Wang

G-J

Fowler

. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral mehtylphenidate. American Journal of Psychiatry 1998; 155: 1325–1331.

29.

29. Ginovart

Farde

Halldin

Swahn

. Changes in striatal D₂-receptor density following chronic treatment with amphetamine as assessed with PET in nonhuman primates. Synapse 1999; 31: 154–162.

30.

30. Persico

Schindler

O'Hara

Brannock

Uhl

. Brain transcription factor expression – effects of acute and chronic amphetamine and injection stress. Brain Research Molecular Brain Research 1993; 20: 91–100.

31.

31. Segal

Kuczenski

. An escalating dose binge model of amphetamine psychosis – behavioural and neurochemical characteristics. Journal of Neuroscience 1997; 17: 2551–2566.

32.

32. Gillberg

Melander

von Knorring

A-L

. Long-term stimulant treatment of children with attention-deficit hyperactivity disorder symptoms: a randomized, double-blind, placebo-controlled trial. Archives of General Psychiatry 1997; 54: 857–864.

33.

33. Seeman

. Brain dopamine receptors. Pharmacology Review 1980; 32: 229–313.

34.

34. Patrick

Markowitz

. Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder. Human Psychopharmacology 1997; 12: 527–546.

35.

35. Gualtieri

Wargin

Kanoy

. Clinical studies of methylphenidate serum levels in children and adults. Journal of the American Academy of Child Psychiatry 1982; 21: 19–26.

36.

36. Angrist

Corwin

Bartlik

Cooper

. Early pharmacokinetics and clinical effects of oral d-amphetamine in normal subjects. Biological Psychiatry 1987; 22: 11357–11368.

37.

37. Wargin

Patrick

Kilts

. Pharmacokinetics of methylphenidate in man, rat and monkey. Journal of Pharmacology and Experimental Therapeutics 1983; 226: 382–386.

38.

38. Aoyama

Sasaki

Kotaki

. Pharmacokinetics and pharmacodynamics of ((+)) -threo-methylphenidate enantiomer in patients with hypersomnia. Clinical Pharmacology and Therapeutics 1994; 55: 270–276.

39.

39. Aoyama

Kotaki

Sasaki

Sawada

Honda

Iga

. Nonlinear kinetics of threo-methylphenidate enantiomers in a patient with narcolepsy and in healthy volunteers. European Journal of Clinical Pharmacology 1993; 44: 79–84.

40.

40. Shader

Harmatz

Oesterheld

Parmelee

Sallee

Greenblatt

. Population pharmacokinetics of methylphenidate in children with attention-deficit hyperactivity disorder. Journal of Clinical Pharmacology 1999; 39: 775–785.

41.

41. Hungund

Perel

Hurwic

Sverd

Winsberg

. Pharmacokinetics of methylphenidate in hyperkinetic children. British Journal of Clinical Pharmacology 1979; 8: 571–576.

42.

42. Birmaher

Greenhill

Cooper

Fried

Maminski

. Sustained release methylphenidate: pharmacokinetic studies in ADDH males. Journal of the American Academy of Child and Adolescent Psychiatry 1989; 28: 768–772.

43.

43. Wilens

Biederman

. The stimulants. Psychiatric clinics of North America, Schaffer

. W.B. Saunders, Philadelphia 1992; 191–222.

44.

44. Levy

. Side effects of stimulant use. Journal of Paediatrics and Child Health 1993; 29: 250–254.

45.

45. Castellanos

. Stimulants and tic disorders: from dogma to data [[commentary]]. Archives of General Psychiatry 1999; 56: 337–338.

46.

46. Connell

. Amphetamine psychosis. Oxford University Press, London 1958, Maudsley Monograph No 5.

47.

47. Biederman

Wilens

Mick

Spencer

Faraone

. Pharmacotherapy of attention deficit/hyperactivity disorder reduces risk for substance use disorder. Pediatrics 1999; 104: 293–294.

48.

48. Garland

. Intranasal abuse of precribed methylphenidate. Journal of the American Academy of Child and Adolescent Psychiatry 1998; 37: 573–574.

49.

49. Jaffe

. Intranasal abuse of prescribed methylphenidate by an alcohol and drug abusing adolescent with ADHD. Journal of the American Academy of Child and Adolescent Psychiatry 1991; 30: 774–775.

50.

50. Parran

Jasinski

. Intravenous methylphenidate abuse: prototype for prescription drug abuse. Archives of Internal Medicine 1991; 151: 781–783.

51.

51. Goyer

Davis

Rapoport

. Abuse of prescribed stimulant medication by a 13-year-old hyperactive boy. Journal of the American Academy of Child Psychiatry 1979; 18: 170–175.

52.

52. Volkow

Wang

G-J

Fowler

. Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of ‘high’. Journal of Pharmacology and Experimental Therapeutics 1999; 228: 14–20.

53.

53. Angrist

. Amphetamine psychosis: clinical variations of the syndrome. Amphetamine and its analogs: psychopharmacology, toxicology, and abuse, Cho

Segal

. Academic Press, San Diego 1994; 387–414.

54.

54. Ridley

Baker

Owen

Cross

Crow

. Behavioral and biochemical effects of chronic amphetamine treatment in the vervet monkey. Psychopharmacology 1982; 78: 245–251.

55.

55. Ellison

Morris

. Opposed stages of continuous amphetamine administration: parallel alterations in motor stereotypies and in vivo spiroperidol accumulation. European Journal of Pharmacology 1981; 74: 207–214.

56.

56. Castner

Goldman-Rakic

. Long-lasting psychotomimetic consequences of repeated low-dose amphetamine exposure in rhesus monkeys. Neuropsychopharmacology 1999; 20: 10–28.

57.

57. McNamara

Davidson

Schenk

. A comparison of the motor-activating effects of acute and chronic exposure to amphetamine and methylphenidate. Pharmacology Biochemistry and Behaviour 1993; 45: 729–732.

58.

58. Crawford

McDougall

Meier

Collins

Watson

. Repeated methylphenidate treatment induces behavioral sensitization and decreases protein kinase A and dopamine-stimulated adenylyl cyclase activity in the dorsal striatum. Psychopharmacology 1998; 136: 34–43.

59.

59. Ridley

Baker

Owen

Cross

Crow

. Behavioral and biochemical effects of chronic treatment with amphetamine in the vervet monkey. Neuropharmacology 1983; 22: 551–554.

60.

60. Ellison

Ratan

. The late stage following continuous amphetamine administration to rats is correlated with altered dopamine but not serotonin metabolism. Life Sciences 1982; 31: 771–777.

61.

61. Robinson

Becker

. Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Research 1986; 396: 157–198.

62.

62. Yuan

McCann

Ricaurte

. Methylphenidate and brain dopamine toxicity. Brain Research 1997; 767: 172–175.

How High a Dose of Stimulant Medication in Adult Attention Deficit Hyperactivity Disorder?

Abstract

Keywords

Dosage

Behavioural pharmacology

Tolerance

Pharmacokinetics

Side-effects

Conclusion

Footnotes

Acknowledgements

References