Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate

Nora D. Volkow, Gene Jack Wang, Joanna S. Fowler, Samuel J. Gatley, Jean Logan, Yu Shin Ding, Robert Hitzemann, Naomi Pappas

Research output: Contribution to journalArticle

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Abstract

Objective: The therapeutic effects of methylphenidate in the treatment of attention deficit disorder have been attributed to its ability to increase the synaptic concentration of dopamine by blocking the dopamine transporters. However, the levels of dopamine transporter blockade achieved by therapeutic doses of methylphenidate are not known. This study measured, for the first time, dopamine transporter occupancy by orally administered methylphenidate in the human brain and its rate of uptake in the brain. Method: Positron emission tomography (PET) and [11C]cocaine were used to estimate dopamine transporter occupancies after different doses of oral methylphenidate in seven normal subjects (mean age=24 years, SD=7). In addition, the pharmacokinetics of oral methylphenidate were measured in the baboon brain through use of PET and [11C]methylphenidate administered through an orogastric tube. Results: At 120 minutes after administration oral methylphenidate produced a dose-dependent blockade of dopamine transporter; means=12% (SD= 4%) for 5 mg, 40% (SD=12%) for 10 mg, 54% (SD=5%) for 20 mg, 72% (SD=3%) for 40 mg, and 74% (SD=2%) for 60 mg. The estimated dose of oral methylphenidate required to block 50% of the dopamine transporter corresponded to 0.25 mg/kg. Oral methylphenidate did not reach peak concentration in brain until 60 minutes after its administration. Conclusions: Oral methylphenidate is very effective in blocking dopamine transporters, and at the weight-adjusted doses used therapeutically (0.3 to 0.6 mg/kg), it is likely to occupy more than 50% of the dopamine transporters. The time to reach peak brain uptake for oral methylphenidate in brain corresponds well with the reported time course to reach peak behavioral effects.

Original languageEnglish (US)
Pages (from-to)1325-1331
Number of pages7
JournalAmerican Journal of Psychiatry
Volume155
Issue number10
StatePublished - Oct 1998
Externally publishedYes

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Dopamine Plasma Membrane Transport Proteins
Methylphenidate
Brain
Therapeutics
Positron-Emission Tomography
Aptitude
Papio
Therapeutic Uses
Attention Deficit Disorder with Hyperactivity
Cocaine
Oral Administration
Dopamine
Pharmacokinetics

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Volkow, N. D., Wang, G. J., Fowler, J. S., Gatley, S. J., Logan, J., Ding, Y. S., ... Pappas, N. (1998). Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. American Journal of Psychiatry, 155(10), 1325-1331.

Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. / Volkow, Nora D.; Wang, Gene Jack; Fowler, Joanna S.; Gatley, Samuel J.; Logan, Jean; Ding, Yu Shin; Hitzemann, Robert; Pappas, Naomi.

In: American Journal of Psychiatry, Vol. 155, No. 10, 10.1998, p. 1325-1331.

Research output: Contribution to journalArticle

Volkow, ND, Wang, GJ, Fowler, JS, Gatley, SJ, Logan, J, Ding, YS, Hitzemann, R & Pappas, N 1998, 'Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate', American Journal of Psychiatry, vol. 155, no. 10, pp. 1325-1331.
Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. American Journal of Psychiatry. 1998 Oct;155(10):1325-1331.
Volkow, Nora D. ; Wang, Gene Jack ; Fowler, Joanna S. ; Gatley, Samuel J. ; Logan, Jean ; Ding, Yu Shin ; Hitzemann, Robert ; Pappas, Naomi. / Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. In: American Journal of Psychiatry. 1998 ; Vol. 155, No. 10. pp. 1325-1331.
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abstract = "Objective: The therapeutic effects of methylphenidate in the treatment of attention deficit disorder have been attributed to its ability to increase the synaptic concentration of dopamine by blocking the dopamine transporters. However, the levels of dopamine transporter blockade achieved by therapeutic doses of methylphenidate are not known. This study measured, for the first time, dopamine transporter occupancy by orally administered methylphenidate in the human brain and its rate of uptake in the brain. Method: Positron emission tomography (PET) and [11C]cocaine were used to estimate dopamine transporter occupancies after different doses of oral methylphenidate in seven normal subjects (mean age=24 years, SD=7). In addition, the pharmacokinetics of oral methylphenidate were measured in the baboon brain through use of PET and [11C]methylphenidate administered through an orogastric tube. Results: At 120 minutes after administration oral methylphenidate produced a dose-dependent blockade of dopamine transporter; means=12{\%} (SD= 4{\%}) for 5 mg, 40{\%} (SD=12{\%}) for 10 mg, 54{\%} (SD=5{\%}) for 20 mg, 72{\%} (SD=3{\%}) for 40 mg, and 74{\%} (SD=2{\%}) for 60 mg. The estimated dose of oral methylphenidate required to block 50{\%} of the dopamine transporter corresponded to 0.25 mg/kg. Oral methylphenidate did not reach peak concentration in brain until 60 minutes after its administration. Conclusions: Oral methylphenidate is very effective in blocking dopamine transporters, and at the weight-adjusted doses used therapeutically (0.3 to 0.6 mg/kg), it is likely to occupy more than 50{\%} of the dopamine transporters. The time to reach peak brain uptake for oral methylphenidate in brain corresponds well with the reported time course to reach peak behavioral effects.",
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AU - Volkow, Nora D.

AU - Wang, Gene Jack

AU - Fowler, Joanna S.

AU - Gatley, Samuel J.

AU - Logan, Jean

AU - Ding, Yu Shin

AU - Hitzemann, Robert

AU - Pappas, Naomi

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N2 - Objective: The therapeutic effects of methylphenidate in the treatment of attention deficit disorder have been attributed to its ability to increase the synaptic concentration of dopamine by blocking the dopamine transporters. However, the levels of dopamine transporter blockade achieved by therapeutic doses of methylphenidate are not known. This study measured, for the first time, dopamine transporter occupancy by orally administered methylphenidate in the human brain and its rate of uptake in the brain. Method: Positron emission tomography (PET) and [11C]cocaine were used to estimate dopamine transporter occupancies after different doses of oral methylphenidate in seven normal subjects (mean age=24 years, SD=7). In addition, the pharmacokinetics of oral methylphenidate were measured in the baboon brain through use of PET and [11C]methylphenidate administered through an orogastric tube. Results: At 120 minutes after administration oral methylphenidate produced a dose-dependent blockade of dopamine transporter; means=12% (SD= 4%) for 5 mg, 40% (SD=12%) for 10 mg, 54% (SD=5%) for 20 mg, 72% (SD=3%) for 40 mg, and 74% (SD=2%) for 60 mg. The estimated dose of oral methylphenidate required to block 50% of the dopamine transporter corresponded to 0.25 mg/kg. Oral methylphenidate did not reach peak concentration in brain until 60 minutes after its administration. Conclusions: Oral methylphenidate is very effective in blocking dopamine transporters, and at the weight-adjusted doses used therapeutically (0.3 to 0.6 mg/kg), it is likely to occupy more than 50% of the dopamine transporters. The time to reach peak brain uptake for oral methylphenidate in brain corresponds well with the reported time course to reach peak behavioral effects.

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