TABLE 1

Manifestations of METH neurotoxicity in human subjects and experimental animals, brain areas mediating the manifestations, and underlying molecular mechanisms

The focus is on the studies that compared early (up to approximately 6 months) to late abstinence (approximately >6 months) and studies that compared clinical manifestations with molecular or morphologic changes in the brain.

ManifestationDoseEffect and Molecular Mechanism (Current Use/Early Abstinence)Effect and Molecular Mechanism (Late Abstinence)Human StudiesAnimal Studies
Anxiety, dysphoria>30 mg▲Adrenergic alpha1 receptor stimulation (PFC)▼ DA, 5-HT and NE neurotransmissionMartin et al., 1971; Tong et al., 2003;Filip et al., 2005; Berridge et al., 2006; Kitanaka et al., 2008; Jang et al., 2013
▲5HT receptor and DA receptor stimulation (multiple areas), altered glucose metabolism (limbic and paralimbic areas)London et al., 2004; Newton et al., 2005
Elevated body temperature>30 mg▲DA, and 5-HT release (hypothalamus)Martin et al., 1971Bowyer et al., 1992, 1994; Shioda et al., 2010
Mind racing/Talkativeness>50 mg▲Anterior cingulate cortex and ventral striatum activityBell, 1973; Vollm et al., 2004
Paranoia/psychosis>55 mg▲DA release (striatum), ▼DAT (PFC, other areas)Bell, 1973; Drevets et al., 2001; Sekine et al., 2003; Ujike et al., 2009; Orikabe et al., 2011; Aoki et al., 2013; Mash, 2016
▼Gray-matter (anterior PFC, left perisylvian structures, amygdala, hippocampus), ▼white matter volume (total)
Hallucinations (auditory, visual)>55 mgAuditory/Visual: ▲thalamic and ventral striatum activity, paralimbic system and visual cortex activityBell, 1973; Silbersweig et al., 1995
Stereotypy (punding)HighD1/D2 receptor imbalance (dorsal striatum)(Rylander, 1972)(Ujike et al., 1989)
Choreoathetosis, DyskinesiaHigh▲D2 receptor activity (dorsal striatum)(Sperling and Horowitz, 1994)(Ujike et al., 1989)
Working Memory>0.25 g/day▼Working memory▼Working memory▼Dorsolateral PFC activity, ▼Regional CBF (putamen, insular cortex, and parietal cortex)(Ornstein et al., 2000; Chang et al., 2002; Paulus et al., 2002; Scott et al., 2007; Rendell et al., 2009)(Mizoguchi et al., 2011)
Learning>0.3 g/day▼Learning▼LearningVolkow et al., 2001d; Scott et al., 2007; Henry et al., 2009; Ghahremani et al., 2011Gutierrez et al., 2017
▼DAT (striatum)
▼Hippocampal volume
▼Frontal and cingulate cortex activity
Recall Memory>0.25 g/day▼Recall Memory▼Recall Memory (▲memory and ▲thalamic glucose metabolism vs. short abstinence)Rylander, 1969; Volkow et al., 2001d; Wang et al., 2004; Johanson et al. 2006Schröder et al., 2003; He et al., 2006; Reichel et al., 2012; Thanos et al., 2016
▼Hippocampal volume
▼Hippocampal gray matter
▼DAT, VMAT2 (striatum)
▼Glucose metabolism (thalamus, striatum)
Executive function>0.5 g/day▼Executive function▼Executive function (▲vs. short abstinence)Paulus et al., 2002; Sim et al., 2002; Kim et al., 2005, 2006; London et al., 2005; Chou et al., 2007; Chung et al., 2007; Salo et al., 2007; Scott et al., 2007; Berman et al., 2008; Kish et al., 2009; Salo et al., 2009a,b,c; Nestor et al., 2011Izquierdo et al., 2010; Parsegian et al., 2011
▼Dorsolateral PFC activity▼Gray-matter density (PFC) (▲vs. short abstinence)
▼Glucose metabolism (PFC)
▼DAT (right striatum)▼DAT (▲vs. short abstinence)
▼White-matter volume (PFC)
▼Gray-matter volume or density (PFC)▼NAA-Cr (cingulate cortex)
▼Glucose metabolism (PFC white matter)▲Cho-NAA (cingulate cortex)
▼White-matter integrity (PFC)
▼SERT (orbitofrontal cortex)
▼Cingulate and parietal cortex glucose metabolism
Impulsivity>0.5 g/day▼Impulsivity▼Impulsivity (▲vs. short abstinence)Monterosso et al., 2007; Hoffman et al., 2008; Lee et al, 2009; Schwartz et al., 2010; Wang et al., 2013; London et al., 2016; Uhlmann et al., 2016 Dalley et al., 2007
▼D2/D3 receptor (striatum)
▼Frontal gray-matter volume with ▲striatal gray-matter volume, ▼white-matter integrity ▲Fronto-parietal and striatal activity
Motor skills>0.25 g/day▼Motor skills▼D2 receptor (striatum)▼Motor skills (▲vs. short abstinence)Volkow et al., 2001a,d; Wang et al., 2004; Chang et al., 2005; Cherner et al., 2010Wallace et al., 1999
▼DAT (striatum)
▼Glucose metabolism (thalamus and striatum)▲Thalamic glucose metabolism
▲Putamen volume
Verbal skills>0.25 g/day▼Verbal fluency▼Verbal fluencyChang et al., 2005a; Scott et al., 2007; Salo et al., 2009; Kalechstein et al., 2014; Chen et al., 2015 Ornstein et al., 2000
▼Putamen volume
Information-processing speed>0.5 g/day▼Processing speed▼Processing speedScott et al., 2007Dalley et al., 2007
Visuospatial skills>0.5 g/day▼visuospatial skills
▼White-matter integrity (global)
▼Visuospatial abilityChang et al., 2002; Kalechstein et al., 2003; Jernigan et al., 2005; Scott et al., 2007; Kalechstein et al., 2014
▼Cerebral blood flow (striatal/parietal)▼Cerebral blood flow (striatal/parietal)
▲Parietal cortex and striatal volume
  • Abbreviations: CBF, cerebral blood flow; Cho-NAA, choline N-acetyl aspartate; DA, dopamine; DAT, dopamine receptor; 5-HT, serotonin; NAA-Cr, N-acetyl aspartate creatine and phosphocreatine; NE, noradrenaline; OFC, orbitofrontal cortex; PFC, prefrontal cortex; SERT, serotonin transporter; VMAT2, vesicular monoamine transporter 2; ▲/▼, increased/decreased vs. control subjects or long abstinence vs. short abstinence (when indicated)