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Reduced Striatal Dopamine Transporter Density in Abstinent Methamphetamine and Methcathinone Users: Evidence from Positron Emission Tomography Studies with [11C]WIN-35,428
Open accessAbstract
Methamphetamine and methcathinone are psychostimulant drugs with high potential for abuse. In animals, methamphetamine and related drugs are known to damage brain dopamine (DA) neurons, and this damage has recently been shown to be detectable in living nonhuman primates by means of positron emission tomography (PET) with [11C]WIN-35,428, a DA transporter (DAT) ligand. The present studies determined whether living humans with a history of methamphetamine or methcathinone abuse showed evidence of lasting decrements in brain DAT density. PET studies were performed in 10 control subjects, six abstinent methamphetamine users, four abstinent methcathinone users, and three patients with Parkinson's disease (PD). On average, subjects had abstained from amphetamine use for approximately 3 years. Before PET studies, all subjects underwent urine and blood toxicology screens to rule out recent drug use. Compared with controls, abstinent methamphetamine and methcathinone users had significant decreases in DAT density in the caudate nucleus (-23 and -24%, respectively) and putamen (-25 and -16%, respectively). Larger decreases in DAT density were evident in patients with PD (47 and 68% in caudate and putamen, respectively). Neither methamphetamine nor methcathinone users showed clinical signs of parkinsonism. Persistent reductions of DAT density in methamphetamine and methcathinone users are suggestive of loss of DAT or loss of DA terminals and raise the possibility that as these individuals age, they may be at increased risk for the development of parkinsonism or neuropsychiatric conditions in which brain DA neurons have been implicated.
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“Alternatively, studies in methamphetamine abusers show a consistent and long lasting decrease in the dopamine transporter, which is the main target of this drug (Chou et al., 2007; Johanson et al., 2006; McCann et al., 1998; McCann et al., 2008; Sekine et al., 2001; Volkow et al., 2001b).”
From Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity (2014) · cites this paper as McCann et al., 1998
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“METH is a known neurotoxin, causing damage primarily to the dopaminergic system in all species studied: monkeys (Seiden et al., 1976), rodents (Granado et al., 2010, 2011a,b; Krasnova et al., 2011) and humans (McCann et al., 1998; Volkow et al., 2001).”
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“Similarly, METH abusers also exhibit striatal DA decrements, and these alterations can persist for prolonged periods (McCann et al., 1998; Sekine et al., 2001; Volkow et al., 2001a).”
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“In humans, several (but not all) markers of dopamine nerve terminals are reduced in brains of chronic methamphetamine users (Wilson et al. 1996) and these effects may be longlasting (McCann et al. 1998).”
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Granado, N., Ares‐Santos, S., O’Shea, E., Vicario‐Abejón, C., Colado, M. I., & Moratalla, R. (2009) · Neurotoxicity Research · doi:10.1007/s12640-009-9106-1 · Cited by 83
“METH exposure causes long-term neurotoxicity in rodents, nonhuman primates, and humans, and although some serotonergic loss is reported, mainly in rats (Wagner et al. 1980; Green et al. 1992; Nowak et al. 2007; Bortolato et al. 2009; Cadet et al. 2009), it predominantly affects the dopaminergic system (Seiden et al. 1…”
BackgroundNarendran, R., & Martínez, D. (2008) · Synapse · doi:10.1002/syn.20566 · Cited by 84
“Similarly, imaging studies measuring the DAT in methamphetamine abuse have shown a decrease in BP (McCann et al., 1998; Volkow et al., 2001).”
BackgroundLi, X., Malcolm, R. J., Huebner, K., Hanlon, C. A., Taylor, J. J., Brady, K. T., George, M. S., & See, R. E. (2013) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2013.08.012 · Cited by 85
“These neurochemical findings are consistent with changes in neural integrity as well as glial cell proliferation or metabolism (McCann et al., 1998; Volkow et al., 2001b; Wilson et al., 1996).”
ResultSekine, Y. (2002) · Neuropsychopharmacology · doi:10.1016/s0893-133x(02)00321-4 · Cited by 82
“Human positron emission tomography (PET) studies have reported a significant reduction of dopamine transporter density in methamphetamine users (McCann et al. 1998; Volkow et al. 2001), and that the reduction observed in methamphetamine users is associated with psychomotor impairment (Volkow et al.”
BackgroundMethamphetamine-enhanced embryonic oxidative DNA damage and neurodevelopmental deficits
Jeng, W., Wong, A. W., Ting‐A‐Kee, R. A., & Wells, P. G. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.03.015 · Cited by 82
Clemens, K. J., van Nieuwenhuyzen, P. S., Li, K. M., Cornish, J. L., Hunt, G. E., & McGregor, I. S. (2004) · Psychopharmacology · doi:10.1007/s00213-004-1786-x · Cited by 81
“2000) and reduced dopamine transporter density (McCann et al. 1998; Volkow et al. 2001).”
BackgroundThe neurobiological mechanisms of physical exercise in methamphetamine addiction
Morais, A., Pita, I. R., Ribeiro, C., & Pereira, F. C. (2017) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12788 · Cited by 78
Methamphetamine use and future risk for Parkinson’s disease: Evidence and clinical implications
Lappin, J., Darke, S. G., & Farrell, M. (2018) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2018.02.032 · Cited by 80
Substance Abuse and Movement Disorders: Complex Interactions and Comorbidities
Deik, A., Saunders-Pullman, R. J., & Luciano, M. S. (2012) · Current Drug Abuse Reviews · doi:10.2174/1874473711205030243 · Cited by 80
“Positron emission tomography (PET) studies have shown decreased density of striatal DAT sites in abstinent users of these substances in a similar fashion as in PD, possibly indicating permanent damage of striatal dopamine axon and axon terminals [63].”
BackgroundMicroglial and astrocytic changes in the striatum of methamphetamine abusers.
Kitamura, O., Takeichi, T., Wang, E. L., Tokunaga, I., Ishigami, A., & Kubo, S. (2010) · Legal Medicine · doi:10.1016/j.legalmed.2009.11.001 · Cited by 82
Melega, W. P., Jorgensen, M. J., Laćan, G., Way, B. M., Pham, J., Morton, G. G., Cho, A. K., & Fairbanks, L. A. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301502 · Cited by 78
“(McCann et al, 1998; Sekine et al, 2001; Volkow et al, 2001; Wang et al, 2004; Johanson et al, 2006).”
Sambo, D. O., Lebowitz, J. J., & Khoshbouei, H. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.01.009 · Cited by 75
Dopamine-Induced Behavioral Changes and Oxidative Stress in Methamphetamine-Induced Neurotoxicity
Kita, T., Miyazaki, I., Asanuma, M., Takeshima, M., & Wagner, G. C. (2009) · International review of neurobiology · doi:10.1016/s0074-7742(09)88003-3 · Cited by 77
“McCann et al. (1998) next used PET scans and observed a similar loss of the dopaminergic transporter in the caudate nucleus of individuals with a history of METH use but who had been abstinent for approximately 3 years before testing.”
MethodManganese-Induced Parkinsonism due to Ephedrone Abuse
Sikk, K., Haldre, S., Aquilonius, S., & Taba, P. (2011) · Parkinson s Disease · doi:10.4061/2011/865319 · Cited by 77
Radiotracer imaging of dopaminergic transmission in neuropsychiatric disorders
Verhoeff, N. P. L. G. (1999) · Psychopharmacology · doi:10.1007/s002130051163 · Cited by 78
Potential of Glial Cell Modulators in the Management of Substance Use Disorders
Jones, J. D. (2020) · CNS Drugs · doi:10.1007/s40263-020-00721-9 · Cited by 79
“In both pre-clinical and clinical studies, psychostimulants are neurotoxic to striatal dopamine [190].”
BackgroundAmphetamine exposure is elevated in Parkinson's disease
Garwood, E. R., Bekele, W., McCulloch, C. E., & Christine, C. W. (2006) · NeuroToxicology · doi:10.1016/j.neuro.2006.03.015 · Cited by 76
Volkow, N. D., Wang, G., Smith, L. A., Fowler, J. S., Telang, F., Logan, J., & Tomasi, D. G. (2015) · NeuroImage · doi:10.1016/j.neuroimage.2015.07.035 · Cited by 76
“…(2015), http://dx.doi.org/10.1016/j.neu E D P R O OLoss of DAT in the striatum of METH abusers Our current findings of loss of DAT in the striatum of MA are consistent with prior brain imaging studies reporting lower DAT in MA (McCann et al., 1998; Volkow et al., 2001a;Wilson et al., 1996).”
InfluentialNorthrop, N. A., & Yamamoto, B. K. (2012) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9391-y · Cited by 76
“In addition, the dose of Meth was chosen because, in combination with 10 days of CUS, it causes damage to the dopaminergic system (Tata et al. 2007), to a similar extent to that observed in the human brain, as measured by DAT binding (Volkow et al. 2001a; Volkow et al. 2001b).”
BackgroundInfluentialPeroxynitrite Inactivates Tryptophan Hydroxylase via Sulfhydryl Oxidation
Kuhn, D. M., & Geddes, T. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.29726 · Cited by 75
The clinical challenges of synthetic cathinones
Schifano, F., Napoletano, F., Arillotta, D., Zangani, C., Gilgar, L., Guirguis, A., Corkery, J. M., & Vento, A. (2020) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14132 · Cited by 73
Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats
Byrnes-Blake, K. A., Laurenzana, E. M., Carroll, F. I., Abraham, P., Gentry, W. B., Landes, R. D., & Owens, S. M. (2003) · European Journal of Pharmacology · doi:10.1016/s0014-2999(03)01313-x · Cited by 73
Age‐Dependent Differential Responses of Monoaminergic Systems to High Doses of Methamphetamine
Kokoshka, J. M., Fleckenstein, A. E., Wilkins, D. G., & Hanson, G. R. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0752095.x · Cited by 73
“A recent study by McCann et al. (1998) reported an ;25% decrease in DAT density (assessed by positron emission tomography with the DAT ligand [11C]WIN 35,428) in the caudate nucleus and putamen of abstinent (average 3 years) users.”
BackgroundCamardese, G., Giuda, D. D., Nicola, M. D., Cocciolillo, F., Giordano, A., Janiri, L., & Guglielmo, R. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.12.006 · Cited by 72
Pharmacogenetic Treatments for Drug Addiction: Cocaine, Amphetamine and Methamphetamine
Haile, C. N., Kosten, T. R., & Kosten, T. A. (2009) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990902825447 · Cited by 76
“Individuals with METH abuse histories have significant decreases in DAT binding in the caudate and putamen as measured with the PET radioligand [11C]WIN-35,428 (255).”
MethodBurns, J. A., Kroll, D. S., Feldman, D. E., Liu, C. K., Manza, P., Wiers, C. E., Volkow, N. D., & Wang, G. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00626 · Cited by 75
Angoa‐Pérez, M., Kane, M. J., Briggs, D. I., Francescutti, D. M., Sykes, C. E., Shah, M. M., Thomas, D. M., & Kuhn, D. M. (2012) · Journal of Neurochemistry · doi:10.1111/jnc.12114 · Cited by 71
Methamphetamine Administration Causes Death of Dopaminergic Neurons in the Mouse Olfactory Bulb
Deng, X., Ladenheim, B., Jayanthi, S., & Cadet, J. L. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.09.010 · Cited by 70
Changes in cerebral glucose metabolism during early abstinence from chronic methamphetamine abuse
Berman, S. M., Voytek, B., Mandelkern, M. A., Hassid, B. D., Isaacson, A. J., Monterosso, J. R., Miotto, K. A., Ling, W. W., & London, E. D. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4002107 · Cited by 74
Neuropsychological deficits in adolescent methamphetamine abusers
King, G., Alicata, D., Cloak, C. C., & Chang, L. (2010) · Psychopharmacology · doi:10.1007/s00213-010-1949-x · Cited by 70
Hashimoto, K., Tsukada, H., Nishiyama, S., Fukumoto, D., Kakiuchi, T., Shimizu, E., & Iyo, M. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300512 · Cited by 70
Psychostimulants and Movement Disorders
Asser, A., & Taba, P. (2015) · Frontiers in Neurology · doi:10.3389/fneur.2015.00075 · Cited by 62
Methamphetamine Dysregulation of the Central Nervous System and Peripheral Immunity
Miller, D. R., Bu, M., Gopinath, A., Martinez, L. R., & Khoshbouei, H. (2021) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.121.000767 · Cited by 72
“Many of these effects persist even in prolonged abstinence (McCann et al., 1998; Volkow, Chang, Wang, Fowler, Franceschi, et al., 2001).”
BackgroundRole of nitrergic system in behavioral and neurotoxic effects of amphetamine analogs
Itzhak, Y., & Ali, S. F. (2005) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.08.004 · Cited by 67
McFadden, L. M., Hadlock, G. C., Allen, S. C., Vieira‐Brock, P. L., Stout, K. A., Ellis, J. D., Hoonakker, A. J., Andrenyak, D. M., Nielsen, S. M., Wilkins, D. G., et al. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.188433 · Cited by 67
“(McCann et al., 1998), as well as variable effects on caudate”
Kish, S. J., Boileau, I., Callaghan, R. C., & Tong, J. (2016) · European Journal of Neuroscience · doi:10.1111/ejn.13363 · Cited by 67
“…observed in a postmortem brain immunohistochemical study (Kitamura et al., 2007) and in seven independent PET/SPECT imaging studies of living brain (McCann et al., 1998, 2008; Sekine © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience,…”
BackgroundShepard, J. D., Chuang, D., Shaham, Y., & Morales, M. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0316-4 · Cited by 66
“Results from studies using brain imaging methods in humans indicate that chronic methamphetamine use decreases dopamine transporter (DAT) levels, an effect thatpersistsformonthsafter cessationofdruguse( McCann et al. 1998; Volkow et al. 2001a,b).”
BackgroundCurtin, K., Fleckenstein, A. E., Keeshin, B. R., Yurgelun-Todd, D. A., Renshaw, P. F., Smith, K. R., & Hanson, G. R. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0207-5 · Cited by 68
Rinaldi, R., Bersani, G., Marinelli, E., & Zaami, S. (2020) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.2727 · Cited by 65
“methcathinone users may present decreased striatal dopamine transporter density on positron emission tomography scans (McCann et al., 1998), suggesting the potential risk for long-term psychiatric problems”
BackgroundImaging Cognitive Deficits in Drug Abuse
Lundqvist, T. (2009) · Current topics in behavioral neurosciences · doi:10.1007/7854_2009_26 · Cited by 64
“…Iyo et al. 1997; Volkow et al. 2001a), changes in brain metabolites suggestive of neuronal injury in the basal ganglia and frontal cortex (Ernst et al. 2000), and decreased density of dopaminergic neurons in the caudate and putamen (McCann et al. 1998; Sekine et al. 2001; Volkow et al. 2001b).”
BackgroundZhu, J. P. Q., Xu, W., & Angulo, J. A. (2005) · Brain Research · doi:10.1016/j.brainres.2005.04.089 · Cited by 64
“These reductions may be due to toxicity (fewer DA terminals) rather than neuroadaptation (diminished number of DAT sites against an unchanged number of DA terminals) since a PET scan involving METH abusers showed reduced levels of DAT in the caudate after 3 years of abstinence from METH [21].”
BackgroundO’Dell, S. J., Galvez, B., Ball, A. J., & Marshall, J. F. (2011) · Synapse · doi:10.1002/syn.20989 · Cited by 64
“Neuroimaging studies on human mAMPH abusers show decreases in monoaminergic markers similar to those seen in animal models (McCann et al., 1998; Sekine et al., 2006; Volkow et al., 2001a,b,c) and widespread abnormalities in cerebral cortical structure and function (Kim et al., 2006, London et al.,…”
MethodSafety of intravenous methamphetamine administration during treatment with bupropion
Newton, T. F., Roache, J. D., Garza, R. D. L., Fong, T., Wallace, C. L., Li, S.-H., Elkashef, A. M., Chiang, N., & Kahn, R. (2005) · Psychopharmacology · doi:10.1007/s00213-005-0102-8 · Cited by 63
“…and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, Bethesda, MD, USA with neuroadaptations or neurotoxicity in presynaptic dopamine (DA) neurons, resulting in reduced striatal DA (McCann et al. 1998; Sekine et al. 2003; Volkow et al. 2001; Wilson et al. 1996).”
Metadata
- Authors
- McCann, U. D., Wong, D. F., Yokoi, F., Villemagne, V., Dannals, R. F., & Ricaurte, G. A.
- Affiliations
- National Institute of Mental Health (US)
- Johns Hopkins University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1998-10-15
- Volume
- 18
- Issue
- 20
- Pages
- 8417-8422
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6792853
- OpenAlex
- W2106287416
- Cited by
- 602
- References
- 46
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 12 · 2022: 10 · 2021: 19 · 2020: 11 · 2019: 12 · 2018: 14 · 2017: 16 · 2016: 16 · 2015: 27 · 2014: 32 · 2013: 38 · 2012: 34
- FWCI
- 8.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01da009482-05, 5r01da006275-03)
- National Institute of Mental Health
- National Institute on Drug Abuse (F32DA005707, DA05707, DA09482, DA-06275, R01DA005707)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- methamphetamine, methcathinone, amphetamine abuse, dopamine transporter density, striatum, caudate nucleus, putamen, dopamine neuron loss, Parkinson's disease, psychostimulants, neurotoxicity
- MeSH terms
- Adult, Central Nervous System Stimulants, Brain Chemistry, Carbon Radioisotopes, Carrier Proteins, Cocaine, Female, Humans, Male, Membrane Glycoproteins, Methamphetamine, Middle Aged, Nerve Tissue Proteins, Parkinson Disease, Secondary, Propiophenones, Tomography, Emission-Computed, Neostriatum, Dopamine Uptake Inhibitors, Amphetamine-Related Disorders, Membrane Transport Proteins, Dopamine Plasma Membrane Transport Proteins
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