Skip to main content
Log in

Plasma levels of d-amphetamine in hyperactive children

Serial behavior and motor responses

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Amphetamine has been clearly documented to be an efficacious treatment for hyperactive children. The pharmacokinetics of amphetamine have been studied in adults, but not in children. Sixteen male children who scored >2 SD from norms on Factors I and IV of Conners's Teacher Rating Scale and who were not excluded for reasons to do with medical or psychiatric conditions, intelligence, or age, had a plasma d-amphetamine apparent elimination half-life of 6.8±0.5 h. Peak plasma level occurred between 3 and 4 h (62.7±3.8 and 65.9±3.6 ng/ml, respectively). Six of these children had a repeat study and there were no significant differences within subject in apparent elimination half-lives and attained peak blood levels. The variation in plasma levels was greater during absorption than during elimination. Both behavioral and motor activity resonses as analyzed by differences between amphetamine and placebo days (by paired t-tests) indicate significant responses between hours 1–4; however, these responses do not correlate with plasma amphetamine levels; they occur during the absorption phase. The decreased response to later similar plasma levels of d-amphetamine may be related to depletion of catecholamine stores, to replacement by a ‘false neurotransmitter’ metabolite of amphetamine, or to alteration in receptor sensitivity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Arnold, L. E., Wender, P. H., McCloskey, K., Snyder, S. H.: Levoamphetamine and dextroamphetamine: Comparative efficacy in the hyperkinetic syndrome. Arch. Gen. Psychiatry 27, 816–822 (1972)

    Google Scholar 

  • Barkley, R. A., Ullman, D. G.: A comparison of objective measures of activity and distractibility in hyperactive and nonhyperactive children. J. Abnorm. Child Psychol. 3, 231–244 (1975)

    Google Scholar 

  • Beckett, A. H., Salmon, J. A., Mitchord, M.: The relations between blood levels and urinary excretion of amphetamine under controlled acidic and under fluctuating urinary pH values using [14C]amphetamine. J. Pharm. Pharmacol. 21, 251–258 (1969)

    Google Scholar 

  • Bender, L., Cottington, F.: The use of amphetamine sulfate (benzedrine) in child psychiatry. Am. J. Psychiatry 99, 116–121 (1943)

    Google Scholar 

  • Bradley, C.: The behavior of children receiving benzedrine. Am. J. Psychiatry 94, 577–585 (1937)

    Google Scholar 

  • Bradley, C.: Benzedrine and dexedrine in the treatment of children's behavior disorders. Pediatrics 5, 24–36 (1950)

    Google Scholar 

  • Buchsbaum, M., Wender, P. H.: Average evoked responses in normal and minimally brain dysfunctioned children treated with amphetamine. Arch. Gen. Psychiatry 29, 764–770 (1973)

    Google Scholar 

  • Burks, H. F.: Effects of amphetamine therapy on hyperkinetic children. Arch. Gen. Psychiatry 11, 604–609 (1964)

    Google Scholar 

  • Cantwell, D. P.: The hyperactive child; diagnosis, management, current research. New York: Spectrum 1975a

    Google Scholar 

  • Cantwell, D. P.: Genetics of hyperactivity. J. Child Psychol. Psychiatry 16, 261–264 (1975b)

    Google Scholar 

  • Cheng, L. T., Kim, S. Y., Chung, A., Castro, A.: Amphetamine: New radioimmunoassay. FEBS Lett. 36, 339–342 (1973)

    Google Scholar 

  • Cohen, D. J., Caparulo, B. K., Shaywitz, B. A., Bowers, M. D., Jr.: Dopamine and serotonin metabolism in neuropsychiatrically disturbed children. Arch. Gen. Psychiatry 34, 545–550 (1977)

    Google Scholar 

  • Colburn, T. R., Smith, B. A., Guarini, J. J., Simmons, N. N.: An ambulatory activity monitor with solid state memory. ISA Trans. 15, 149–154 (1976)

    Google Scholar 

  • Coleman, M.: Serotonin concentrations in whole blood of hyperactive children. J. Pediatr. 78, 985–990 (1971)

    Google Scholar 

  • Conners, C. K.: The effect of dexedrine on rapid discrimination and motor control of hyperkinetic children under mild stress. J. Nerv. Ment. Dis. 142, 429–433 (1966)

    Google Scholar 

  • Conners, C. K.: A teacher rating scale for use in drug studies with children. Am. J. Psychiatry 126, 152–156 (1969)

    Google Scholar 

  • Conners, C. K.: Symptom patterns in hyperkinetic, neurotic, and normal children. Child Dev. 41, 667–682 (1970)

    Google Scholar 

  • Conners, C. K.: Pharmacotherapy of psychopathology in children. In: Psychopathological disorders of childhood, H. C. Quay and J. S. Werry, eds., pp. 316–347. New York, Wiley 1972

    Google Scholar 

  • Conners, C. K.: Rating scales for use in drug studies with children. In: Pharmacotherapy in children, pp. 24–42. Special Issuc-Psychopharm. Bull., NIMH 1973

  • Conners, C. K., Eisenberg, L., Barcai, A.: Effects of dextroamphetamine on children. Arch. Gen. Psychiatry 17, 478–485 (1967)

    Google Scholar 

  • Conners, C. K., Taylor, E., Meo, G., Kurtz, M. A., Fournier, M.: Magnesium pemoline and dextroamphetamine: a controlled study in children with minimal brain dysfunction. Psychopharmacologia 26, 321–336 (1972)

    Google Scholar 

  • Cook, J. D., Schanberg, S. M.: The effects of methamphetamine on behavior and on the uptake, release, and metabolism of norepinephrine. Biochem. Pharmacol. 19, 1165–1179 (1970)

    Google Scholar 

  • Creak, M., Committee: Schizophrenic syndrome in childhood. Br. Med. J. 1961 II, 889–890

  • Davis, J. M., Kopin, I., Lemberger, L., Axelrod, J.: Effects of urinary pH on amphetamine metabolism. Ann. N.Y. Acad. Sci. 179, 493–501 (1971)

    Google Scholar 

  • Downs, D. A., Braude, M. C.: Time-action and behavioral effects of amphetamine, ethanol, and acetylmethadol. Pharmacol. Biochem. Behav. 6, 671–676 (1977)

    Google Scholar 

  • Dubois, A., Watanabe, A., Kopin, I.: Postoperative gastric ileum. Digestive Dis. 18, 39–42 (1973a)

    Google Scholar 

  • Dubois, A., Weise, V., Kopin, I.: Postoperative ileus in the rat: physiology, etiology and treatment. Ann. Surg. 178, 781–786 (1973b)

    Google Scholar 

  • Ebert, M. H., van Kammen, D. P., Murphy, D. L.: Plasma levels of amphetamine and behavioral response. In: Pharmacokinetics of psychoactive drugs: Blood levels and clinical response, L. A. Gottschalk and S. Merlis, eds., pp. 157–169. New York: Spectrum, Wiley 1976

    Google Scholar 

  • Eisenberg, L., Lachman, R., Molling, P. A., Lockner, A., Mizelle, J. D., Conners, C. K.: A psychopharmacologic experiment in a training school for delinquent boys: methods, problems, findings. Am. J. Orthopsychiatry 33, 431–446 (1963)

    Google Scholar 

  • Epstein, L. C., Lasagna, L., Conners, C. K., Rodriquez, A.: Correlation of dextroamphetamine excretion and drug response in hyperkinetic children. J. Nerv. Ment. Dis. 146, 136–146 (1969)

    Google Scholar 

  • Fish, B.: Drug use in psychiatric disorders of children. Am. J. Psychiatry 124, 31–36 (1968)

    Google Scholar 

  • Fish, B.: Problems of diagnosis and the definition of comparable groups: a neglected issue in drug research with children. Am. J. Psychiatry 125, 72–80 (1969)

    Google Scholar 

  • Greenberg, A., Coleman, M.: Use of blood serotonin levels for the classification and treatment of hyperactive behavior disorders. Neurology 23, 428 (1973)

    Google Scholar 

  • Greenberg, A., Coleman, M.: Depressed 5-hydroxyindole levels associated with hyperactive and aggressive behavior: relationship to drug response. Arch. Gen. Psychiatry 33, 331–336 (1976)

    Google Scholar 

  • Greenberg, L. M., Deem, M. A., McMahon, S.: Effect of dextroamphetamine, chlorpromazine, and hydroxyzine on behavior and performance in hyperactive children. Am. J. Psychiatry 129, 532–539 (1972)

    Google Scholar 

  • Greenblatt, D. J., Koch-Weser, J.: Clinical pharmacokinetics. New Engl. J. Med. 293, 702–705, 964–970 (1975)

    Google Scholar 

  • Guy, W.: Physical and neurological examination for soft signs. In: ECDEU assessment manual, pp. 384–393. Rockville, Maryland: DHEW, ADAMHA, NIMH, Psychopharmacology Research Branch, 1976

    Google Scholar 

  • Hollingshead, A. B., Redlich, F. C.: Social class and mental illness community study. New York: Wiley 1958

    Google Scholar 

  • Huestis, R. D., Arnold, L. E., Smeltzer, D. J.: Caffeine versus methylphenidate and d-amphetamine in minimal brain dysfunction: A double-blind comparison. Am. J. Psychiatry 132, 868–870 (1975)

    Google Scholar 

  • Kallman, W. M., Isacc, W.: The effect of age and illumination on the dose-response curves for three stimulants. Psychopharmacologia 40, 313–318 (1975)

    Google Scholar 

  • Knobel, M.: Psychopharmacology for the hyperkinetic child. Arch. Gen. Psychiatry 6, 198–202 (1962)

    Google Scholar 

  • Knopp, W., Arnold, L. E., Andras, R. L., Smeltzer, D. J.: Predicting amphetamine response in hyperkinetic children by electronic pupillography. Pharmakopsychiatr. 6, 158–166 (1973)

    Google Scholar 

  • Koch-Weser, J.: Bioavailability of drugs. N. Engl. J. Med. 291, 503–506 (1974)

    Google Scholar 

  • Kopin, I. J.: False adrenergic transmitters. Ann. Rev. Pharmacol. 8 377–394 (1968a)

    Google Scholar 

  • Kopin, I. J.: The influence of false neurotransmitters on adrenergic transmission. In: Adrenergic neurotransmission, G. E. W. Wolsteinholme and M. O'Connor, eds., pp. 95–104. Boston: Little, Brown 1968b

    Google Scholar 

  • Kornetsky, C.: Psychoactive drugs in the immature organism. Psychopharmacologia 17, 105–136 (1970)

    Google Scholar 

  • Kreuz, D. S., Axelrod, J.: Amphetamine in human plasma: a sensitive and specific enzymatic assay. Science 182, 420–421 (1974)

    Google Scholar 

  • Laufer, M. W., Denhoff, E.: Hyperkinetic behavior syndrome in children. J. Pediatr. 50, 463–474 (1957)

    Google Scholar 

  • Millichap, J. G.: Drugs in management of minimal brain dysfunction. Ann. N.Y. Acad. Sci. 205, 321–334 (1973)

    Google Scholar 

  • Millichap, J. G., Fowler, G. W.: Treatment of minimal brain dysfunction syndromes. Pediatr. Clin. North Am. 14, 767–777 (1967)

    Google Scholar 

  • Millichap, J. G., Johnson, F.: Methylphenidate in hyperkinetic behavior: Relation of response to degree of activity in brain damage. In: Clinical use of stimulant drugs in children, C. K. Conners, ed., pp. 130–139. Amsterdam: Excerpta Medica, 1975

    Google Scholar 

  • Montague, J.: The hyperactive child: behavior, electrodermal and EEG investigation. Dev. Med. Child Neurol. 17, 299–305 (1975)

    Google Scholar 

  • Norton, S.: Amphetamine as a model for hyperactivity in the rat. Physiol. Behav. 11, 181–186 (1973)

    Google Scholar 

  • Rapoport, J. L., Lott, I., Alexander, D., Abramson, A.: Urinary noradrenaline and playroom behavior in hyperactive boys. Lancet 1970 II, 1141

  • Rapoport, J. L., Quinn, P. O., Lamprecht, F.: Minor physical anomalies and plasma dopamine-beta-hydroxylase activity in hyperactive boys. Am. J. Psychiatry 131, 386–390 (1974)

    Google Scholar 

  • Rapoport, J. L., Quinn, P. O., Scribanu, N., Murphy, D. L.: Platelet serotonin in hyperactive school age boys. Br. J. Psychiatry 125, 138–140 (1973)

    Google Scholar 

  • Rapoport, J. L., Buchsbaum, M. S., Zahn, T. P., Weingartner, H., Ludlow, C., Mikkelsen, E. J.: Dextroamphetamine: Cognitive and behavioral effects in normal prepubertal boys. Science 199, 560–562 (1978)

    Google Scholar 

  • Ritschel, W. A.: Bioavailability in the clinical evaluation of drugs. Drug Intell. Clin. Pharm. 6, 246–256 (1972)

    Google Scholar 

  • Routh, D., Schroeder, C., O'Tuma, L.: Development of activity level in children. Dev. Psychol. 10, 163–168 (1974)

    Google Scholar 

  • Rowland, M.: Amphetamine blood and urine levels in man. J. Pharm. Sci. 58, 508–509 (1969)

    Google Scholar 

  • Saletu, B., Saletu, M., Simeon, J., Viamontes, G., Itil, T. M.: Comparative symptomatological and evoked potential studies with d-amphetamine, thioridazine, and placebo in hyperkinetic children. Biol. Psychiatry 10, 253–275 (1975)

    Google Scholar 

  • Satterfield, J. H., Cantwell, D. P., Satterfield, B. T.: Pathophysiology of the hyperactive child syndrome. Arch. Gen. Psychiatry 31, 839–844 (1974)

    Google Scholar 

  • Schulman, J. L., Reisman, J. M.: An objective measure of hyperactivity. Am. J. Ment. Defic. 64, 455–456 (1959)

    Google Scholar 

  • Shaffer, D., McNamara, N., Pincus, J.: Controlled observations on patterns of activity, attention, and impulsivity in brain damaged and psychiatrically disturbed boys. J. Psychol. Med. 4, 4–18 (1974)

    Google Scholar 

  • Shaywitz, B. A., Cohen, D. J., Bowers, M. B., Jr.: CSF amine metabolites in children with minimal brain dysfunction (MBD) — evidence for alteration of brain dopamine. Pediatr. Res. 9, 385 (1975)

    Google Scholar 

  • Shaywitz, B. A., Cohen, D. J., Bowers, M. B., Jr.: CSF monoamine metabolites in children with minimal brain dysfunction: Evidence for alteration of brain dopamine — a preliminary report. J. Pediatr. 90, 67–71 (1977)

    Google Scholar 

  • Shaywitz, B. A., Klopper, J. H., Yager, R. D., Gordon, J. W.: Paradoxical response to amphetamine in developing rats treated with 6-hydroxydopamine. Nature 261, 153–155 (1976a)

    Google Scholar 

  • Shaywitz, B. A., Yager, R. D.: An experimental model of minimal brain dysfunction (MBD) in developing rats — ‘threshold’ brain dopamine concentrations after 6-hydroxydopamine (6-OHDA). Pediatr. Res. 9, 385 (1975)

    Google Scholar 

  • Shaywitz, B. A., Yager, R. D., Klopper, J. H.: Selective brain dopamine depletion in developing rats: An experimental model of minimal brain dysfunction. Science 191, 305–308 (1976b)

    Google Scholar 

  • Shekim, W., Dekirmenjian, H., Chapel, J. L.: Urinary excretion of MHPG in hyperactive child syndrome and the effect of dextroamphetamine. Am. J. Psychiatry 134, 1276–1279 (1977)

    Google Scholar 

  • Shetty, T., Chase, T. N.: Central monoamines and hyperkinesis of childhood. Neurology 26, 1000–1002 (1976)

    Google Scholar 

  • Silbergeld, E. K., Goldberg, A. M.: Hyperactivity: A lead-induced behavior disorder. Environ. Health Perspect. 7, 227–232 (1974)

    Google Scholar 

  • Silbergeld, E. K., Goldberg, A. M.: Pharmacological and neurochemical investigations of lead-induced hyperactivity. Neuropharmacology 14, 431–444 (1975)

    Google Scholar 

  • Silbergeld, E. K.: Neuropharmacology of hyperkinesis. In: Current developments in psychopharmacology, vol. IV, pp. 180–214. New York: Spectrum 1977

    Google Scholar 

  • Simon, P., Larousse, C., Boissier, J.-R.: Behavioral pharmacology of p-chloramphetamine — comparison with amphetamine. In: Amphetamines and related compounds, E. Costa and S. Garattini, eds., pp. 729–746. New York: Raven 1970

    Google Scholar 

  • Sorenson, C. A., Vayer, J. S., Goldberg, C. S.: Amphetamine reduction of motor activity in rats after neonatal administration of 6-hydroxydopamine. Biol. Psychiatry 12, 133–137 (1977)

    Google Scholar 

  • Sprague, R., Barnes, K., Werry, J.: Methylphenidate and thioridazine: Learning, reaction time, activity in classroom behavior in emotionally disturbed children. Am. J. Orthopsychiatry 40, 615–628 (1970)

    Google Scholar 

  • Task Force on Nomenclature and Statistics of the American Psychiatric Assoc. Early childhood psychosis. In: DSM-III Draft, pp. M9–M14, 1978

  • Wender, P. H.: Platelet serotonin levels in children with minimal brain dysfunction. Lancet 1969 II, 1012

  • Wender, P. H.: Minimal brain dysfunction in children. New York, London, Sydney, Toronto: Wiley-Interscience 1971

    Google Scholar 

  • Wender, P. H., Epstein, A. S., Kopin, I. J., Gordon, E. K.: Urinary monoamine metabolites in children with minimal brain dysfunction. Am. J. Psychiatry 127, 1411–1415 (1971)

    Google Scholar 

  • Werry, J.: Developmental hyperactivity. Pediatr. Clin. North Am. 15, 581–599 (1968)

    Google Scholar 

  • Werry, J. S., Aman, M. G.: Methylphenidate and haloperidol in children: Effects on attention, memory and activity. Arch. Gen. Psychiatry 32, 790–795 (1975)

    Google Scholar 

  • Werry, J. S., Minde, K., Guzman, A., Weiss, G., Dogan, K., Hoy, E.: studies on the hyperactive child — VII: Neurological status compared with neurotic and normal children. Am. J. Orthopsychiatry 42, 441–450 (1972)

    Google Scholar 

  • Werry, J. S., Sprague, R.: Hyperactivity. In: Symptoms of psychopathology, a handbook, C. Costello, ed. pp. 397–416. New York: Wiley 1970

    Google Scholar 

  • Werry, J. S., Sprague, R. L., Cohen, M. N.: Conners' teacher rating scale for use in drug studies with children — an empirical study. J. Abnorm. Child Psychol. 3, 217–229 (1975)

    Google Scholar 

  • Zahn, T. P., Abate, F., Little, B. C., Wender, P. H.: Minimal brain dysfinction, stimulant drugs and autonomic nervous system activity. Arch. Gen. Psychiatry 32, 381–387 (1975)

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

forerly, Laboratory of Clinical Science, NIMH, Bethesda, Maryland, U.S.A.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brown, G.L., Hunt, R.D., Ebert, M.H. et al. Plasma levels of d-amphetamine in hyperactive children. Psychopharmacology 62, 133–140 (1979). https://doi.org/10.1007/BF00427126

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00427126

Key words

Navigation