Methylphenidate (MPH) is a first line treatment for ADHD and is also misused as a purported cognitive enhancer, yet its effects on brain function are still poorly understood. Recent functional magnetic resonance imaging (fMRI) studies showed that MPH altered cortico-striatal resting functional connectivity (RFC). Here we investigated the effects of MPH in thalamic connectivity since the thalamus modulates striato-cortical signaling. We hypothesized that MPH would increase thalamic connectivity and metabolism, and that this response would be blunted in cannabis abusers. For this purpose, we measured RFC in seven thalamic nuclei using fMRI and brain glucose metabolism using positron emission tomography (PET) and 18F-fluorodeoxyglucose (FDG) in sixteen healthy controls and thirteen participants with cannabis use disorder (CUD) twice after placebo and after MPH (0.5 mg/kg, iv). MPH significantly increased thalamo-cerebellar connectivity and cerebellar metabolism to the same extent in both groups. Group comparisons revealed that in CUD compared to controls, metabolism in nucleus accumbens was lower for the placebo and MPH measures, that MPH-induced increases in thalamic metabolism were blunted, and that enhanced negative connectivity between thalamus and accumbens in CUD was normalized by MPH (reducing negative connectivity). Our findings identify the thalamus as a target of MPH, which increased its metabolism and connectivity. The reduced metabolism in nucleus accumbens and the disrupted thalamo-accumbens connectivity (enhanced negative connectivity) in CUD is consistent with impaired reactivity of the brain reward’s circuit. MPH’s normalization of thalamo-accumbens connectivity (reduced negative connectivity) brings forth its potential therapeutic value in CUD, which merits investigation.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $46.31 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Linssen AM, Sambeth A, Vuurman EF, Riedel WJ. Cognitive effects of methylphenidate in healthy volunteers: a review of single dose studies. Int J Neuropsychopharmacol/Off Sci J Coll Int Neuropsychopharmacol. 2014;17:961–77.
Ashok AH, Mizuno Y, Volkow ND, Howes OD. Association of stimulant use with dopaminergic alterations in users of cocaine, amphetamine, or methamphetamine: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74:511–9.
Volkow ND, Wang GJ, Tomasi D, Kollins SH, Wigal TL, Newcorn JH, et al. Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J Neurosci: Off J Soc Neurosci. 2012b;32:841–9.
Solanto MV. Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav brain Res. 1998;94:127–52.
Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley JS, et al. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch General Psychiatry. 1995;52:456–63.
Volkow ND, Fowler JS, Wang G, Ding Y, Gatley SJ. Mechanism of action of methylphenidate: insights from PET imaging studies. J Atten Disord. 2002;6:S31–43.
Schabram I, Henkel K, Mohammadkhani Shali S, Dietrich C, Schmaljohann J, Winz O, et al. Acute and sustained effects of methylphenidate on cognition and presynaptic dopamine metabolism: an [18F] FDOPA PET study. J Neurosci: Off J Soc Neurosci. 2014;34:14769–76.
Volkow ND, Tomasi D, Wang GJ, Telang F, Fowler JS, Logan J, et al. Predominance of D2 receptors in mediating dopamine’s effects in brain metabolism: effects of alcoholism. J Neurosci: Off J Soc Neurosci. 2013;33:4527–35.
Volkow ND, Wang GJ, Fowler JS, Logan J, Angrist B, Hitzemann R, et al. Effects of methylphenidate on regional brain glucose metabolism in humans: relationship to dopamine D2 receptors. Am J Psychiatry. 1997a;154:50–55.
Wiers CE, Shokri-Kojori E, Wong CT, Abi-Dargham A, Demiral SB, Tomasi D, et al. Cannabis abusers show hypofrontality and blunted brain responses to a stimulant challenge in females but not in males. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol. 2016a;41:2596–605.
Volkow ND, Fowler JS, Wang GJ, Telang F, Logan J, Wong C, et al. Methylphenidate decreased the amount of glucose needed by the brain to perform a cognitive task. PloS One. 2008a;3:e2017.
Volkow ND, Tomasi D, Wang GJ, Telang F, Fowler JS, Logan J, et al. Evidence that sleep deprivation downregulates dopamine D2R in ventral striatum in the human brain. J Neurosci: Off J Soc Neurosci. 2012a;32:6711–7.
Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, et al. Dopamine increases in striatum do not elicit craving in cocaine abusers unless they are coupled with cocaine cues. NeuroImage. 2008b;39:1266–73.
Evers EA, Stiers P, Ramaekers JG. High reward expectancy during methylphenidate depresses the dopaminergic response to gain and loss. Soc Cogn Affect Neurosci. 2017;12:311–8.
Konova AB, Moeller SJ, Tomasi D, Volkow ND, Goldstein RZ. Effects of methylphenidate on resting-state functional connectivity of the mesocorticolimbic dopamine pathways in cocaine addiction. JAMA Psychiatry. 2013;70:857–68.
Farr OM, Zhang S, Hu S, Matuskey D, Abdelghany O, Malison RT, et al. The effects of methylphenidate on resting-state striatal, thalamic and global functional connectivity in healthy adults. Int J Neuropsychopharmacol/Off Sci J Coll Int Neuropsychopharmacol. 2014;17:1177–91.
Ramaekers JG, Evers EA, Theunissen EL, Kuypers KP, Goulas A, Stiers P. Methylphenidate reduces functional connectivity of nucleus accumbens in brain reward circuit. Psychopharmacology. 2013;229:219–26.
Volkow ND, Wise RA, Baler R. The dopamine motive system: implications for drug and food addiction. Nat Rev Neurosci. 2017;18:741–52.
Schwarz LA, Luo L. Organization of the locus coeruleus-norepinephrine system. Curr Biol: CB. 2015a;25:R1051–6.
ODonnell P, Lavin A, Enquist LW, Grace AA, Card JP. Interconnected parallel circuits between rat nucleus accumbens and thalamus revealed by retrograde transynaptic transport of pseudorabies virus. J Neurosci. 1997;17:2143–67.
Clark AM, Leroy F, Martyniuk KM, Feng W, McManus E, Bailey MR, et al. Dopamine D2 Receptors in the Paraventricular Thalamus Attenuate Cocaine Locomotor Sensitization. eNeuro. 2017;4:1–17.
Matzeu A, Weiss F, Martin-Fardon R. Transient inactivation of the posterior paraventricular nucleus of the thalamus blocks cocaine-seeking behavior. Neurosci Lett. 2015;608:34–39.
Navarra RL, Clark BD, Zitnik GA, Waterhouse BD. Methylphenidate and atomoxetine enhance sensory-evoked neuronal activity in the visual thalamus of male rats. Exp Clin Psychopharmacol. 2013;21:363–74.
Tomasi D, Volkow ND. Functional connectivity density mapping. Proc Natl Acad Sci USA. 2010;107:9885–90.
Konova AB, Moeller SJ, Tomasi D, Goldstein RZ. Effects of chronic and acute stimulants on brain functional connectivity hubs. Brain Res. 2015;1628:147–56.
Dasilva M, Grieve KL, Cudeiro J, Rivadulla C. Anandamide activation of CB1 receptors increases spontaneous bursting and oscillatory activity in the thalamus. Neuroscience. 2014;265:72–82.
Filbey FM, Schacht JP, Myers US, Chavez RS, Hutchison KE. Marijuana craving in the brain. Proc Natl Acad Sci USA. 2009;106:13016–21.
Manza P, Tomasi D, Volkow ND. Subcortical local functional hyperconnectivity in cannabis dependence. Biol Psychiatry Cogn Neurosci neuroimaging. 2018;3:285–93.
Brody AL, Hubert R, Mamoun MS, Enoki R, Garcia LY, Abraham P, et al. Nicotinic acetylcholine receptor availability in cigarette smokers: effect of heavy caffeine or marijuana use. Psychopharmacology. 2016;233:3249–57.
Cunningham SI, Tomasi D, Volkow ND. Structural and functional connectivity of the precuneus and thalamus to the default mode network. Human brain Mapp. 2017;38:938–56.
Behrens TE, Johansen-Berg H, Woolrich MW, Smith SM, Wheeler-Kingshott CA, Boulby PA, et al. Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging. Nat Neurosci. 2003;6:750–7.
O’Muircheartaigh J, Keller SS, Barker GJ, Richardson MP. White matter connectivity of the thalamus delineates the functional architecture of competing thalamocortical systems. Cereb cortex. 2015;25:4477–89.
Cho ZH, Son YD, Kim HK, Kim NB, Choi EJ, Lee SY, et al. Observation of glucose metabolism in the thalamic nuclei by fusion PET/MRI. J Nucl Med: Off Publ, Soc Nucl Med. 2011;52:401–4.
Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 2013;36:587–97.
Rothman DL, De Feyter HM, de Graaf RA, Mason GF, Behar KL. 13C MRS studies of neuroenergetics and neurotransmitter cycling in humans. NMR Biomed. 2011;24:943–57.
Volkow ND, Wang GJ, Telang F, Fowler JS, Alexoff D, Logan J, et al. Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc Natl Acad Sci USA. 2014a;111:E3149–56.
Wiers CE, Shumay E, Cabrera E, Shokri-Kojori E, Gladwin TE, Skarda E, et al. Reduced sleep duration mediates decreases in striatal D2/D3 receptor availability in cocaine abusers. Transl Psychiatry. 2016b;6:e752.
Friston KJ, Worsley KJ, Frackowiak RS, Mazziotta JC, Evans AC. Assessing the significance of focal activations using their spatial extent. Hum Brain Mapp. 1994;1:210–20.
RCoreTeam. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2013.
Volkow ND, Wang GJ, Gatley SJ, Fowler JS, Ding YS, Logan J, et al. Temporal relationships between the pharmacokinetics of methylphenidate in the human brain and its behavioral and cardiovascular effects. Psychopharmacology. 1996;123:26–33.
Zhu Y, Wienecke CF, Nachtrab G, Chen X. A thalamic input to the nucleus accumbens mediates opiate dependence. Nature. 2016;530:219–22.
Riano Barros DA, McGinnity CJ, Rosso L, Heckemann RA, Howes OD, Brooks DJ, et al. Test-retest reproducibility of cannabinoid-receptor type 1 availability quantified with the PET ligand [11C] MePPEP. NeuroImage. 2014;97:151–62.
Iversen L. Cannabis and the brain. Brain: a J Neurol. 2003;126:1252–70.
Schmahmann JD. The role of the cerebellum in cognition and emotion: personal reflections since 1982 on the dysmetria of thought hypothesis, and its historical evolution from theory to therapy. Neuropsychol Rev. 2010;20:236–60.
Canto CB, Onuki Y, Bruinsma B, van der Werf YD, De Zeeuw CI. The sleeping cerebellum. Trends Neurosci. 2017;40:309–23.
Oh M, Kim JS, Oh JS, Lee CS, Chung SJ. Different subregional metabolism patterns in patients with cerebellar ataxia by 18F-fluorodeoxyglucose positron emission tomography. PloS One. 2017;12:e0173275.
Benarroch EE. The locus ceruleus norepinephrine system: functional organization and potential clinical significance. Neurology. 2009;73:1699–704.
Ikemoto S. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev. 2007;56:27–78.
Madras BK. Dopamine challenge reveals neuroadaptive changes in marijuana abusers. Proc Natl Acad Sci USA. 2014;111:11915–6.
Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R, et al. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. 1997b;386:830–3.
Volkow ND, Wang GJ, Telang F, Fowler JS, Alexoff D, Logan J, et al. Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc Natl Acad Sci USA. 2014b;111:E3149–56.
Scofield MD, Heinsbroek JA, Gipson CD, Kupchik YM, Spencer S, Smith AC, et al. The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev. 2016;68:816–71.
Volkow ND, Wang GJ, Newcorn JH, Kollins SH, Wigal TL, Telang F, et al. Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway. Mol Psychiatry. 2011;16:1147–54.
Cools R, D’Esposito M. Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry. 2011;69:e113–25.
Bloomfield MA, Ashok AH, Volkow ND, Howes OD. The effects of Δ9-tetrahydrocannabinol on the dopamine system. Nature. 2016;539:369–77.
Woodward DJ, Moises HC, Waterhouse BD, Yeh HH, Cheun JE. The cerebellar norepinephrine system: inhibition, modulation, and gating. Progress brain Res. 1991;88:331–41.
Sanchez-Gonzalez MA, Garcia-Cabezas MA, Rico B, Cavada C. The primate thalamus is a key target for brain dopamine. J Neurosci: Off J Soc Neurosci. 2005;25:6076–83.
Schwarz LA, Miyamichi K, Gao XJ, Beier KT, Weissbourd B, DeLoach KE, et al. Viral-genetic tracing of the input-output organization of a central noradrenaline circuit. Nature. 2015b;524:88–92.
We would like to thank Karen Torres for her administrative assistance, and Chris Wong for his contribution in data collection. We also thank Joanna Fowler and Anna Konova for their valuable input for the discussions. We would like to thank David Schlyer and Michael Schueller for cyclotron operations; Donald Warner, David Alexoff, and Paul Vaska for PET operations; Colleen Shea, Youwen Xu, Lisa Muench, and Payton King for radiotracer preparation and analysis, Millard Jayne for subject recruitment and Barbara Hubbard and Pauline Carter for patient care.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.