Additional Table 3.

Recent preclinical and clinical studies evaluating methamphetamine (METH)-induced brain dysfunctions and neurotoxicity

Drug	Species (n, sex)/age	Treatment/duration	Main findings	References
	BALB/c male mice (n=27); 9 weeks old	Pre-treatment: anti-high mobility group box-1 (HMGB1) antibody, control immunoglobulin, or phosphate-buffered saline; treatment: saline or METH (2×4 mg/kg, s.c.)	The study revealed a potential role of HMGB1 in METH-induced neuroinflammation and dopaminergic neurotoxicity in the striatum.	Masai et al., 2021
	C57BL/6J male mice (sample size N.A.); 4-8 weeks old	Saline or METH (2 or 10 mg/kg, i.p.) for 4 days on alternate days	The study showed the divergent effects elicited by low and high METH doses on memory and synaptic plasticity in the cortex and hippocampus of mice.	Ding et al., 2022
	C57BL/6J male mice (sample size N.A.); 8 weeks old	Pre-treatment: saline or icariside (10 or 30 mg/kg, i.p.); treatment: saline or METH (from 1 to 5 mg/kg, i.p.) for 14 days	The study demonstrated that icariside treatment alleviated METH-induced neurotoxicity by activating the Keap1-Nrf2 pathway.	Huang et al., 2022
METH	C57BL/6 male mice (sample size N.A.); 8-10 weeks old	Saline or METH (2×15 mg/kg, i.p.) for 4 days	The study revealed the ability of METH to disrupt the gut microbiota and generate neurotoxic effects via the serum metabolism pathway.	Zhang et al., 2022
	Wistar male rats (n=60); age N.A.	Saline, crocin (90 mg/kg, i.p.), METH (4 × 40 mg/kg, i.p.), or METH plus crocin (30, 60, or 90 mg/kg, i.p.)	The study showed crocin's capacity to mitigate METH- induced neurotoxicity within the hippocampus through its anti-inflammatory, anti-apoptotic, and neuroprotective properties.	Shafahi et al., 2018
	Sprague-Dawley male rats (sample size N.A.); 20-25 weeks old	Saline or METH (9 mg/kg, s.c.)	The study revealed the negative effects caused by aversive and stressful conditions on METH-induced neurotoxicity.	Lafuente et al., 2018
	Sprague-Dawley male rats (sample size N.A.); 3 months old	Saline or METH (4 × 5 or 10 mg/kg, s.c.)	The study revealed that METH treatment in rats resulted in dose-dependent changes in the binding levels of 4-[18F]-ADAM.	Huang et al., 2019
	Wistar adult male rats (n=48); age	Saline, METH (4 × 10 mg/kg, i.p.) for 1 day, or	The study revealed that the neurochemical changes in	Schweppe et al.,
	N.A.	METH self-administration (0.1 mg/kg/infusion, i.v.) for 16 days	the dopaminergic and serotonergic systems in the CPu and hippocampus of METH-treated rats were not indicative of the presence of cognitive impairment.	2020
	Sprague-Dawley male rats (n=24); age N.A.	METH self-administration (0.1 mg/kg/infusion, i.v.) for 42 days	The study found that rats with compulsive METH self-administration had varying levels of striatal D1R, D2R, and dopamine metabolites compared to rats that did not self-administer METH.	Jayanthi et al., 2022
	Cynomolgus female monkeys (n=6); 6-7 years old	Saline, METH (2 mg/kg, i.m.), or escalating doses of METH (from 0.1 to 0.75 mg/kg, i.m.) for 8 weeks	The study revealed alterations in the hippocampal expression of genes associated with cell proliferation, synaptic plasticity, neuron differentiation, and neurogenesis in METH-treated monkeys.	Choi et al., 2018
	Humans (n=17 healthy volunteers, 8 women; n=23 METH users, 8 women); 18-55 years old	N.A.	The study indicated the presence of a negative association between cortical grey thickness and cumulative METH use.	Okita et al., 2016
	Humans (n=14 healthy volunteers, 7 women; n=11 METH users, 6 women; n=14 METH users with psychosis, 5 women); 26-29 years old	N.A.	The study demonstrated impairments in glucose metabolism and cerebral blood flow in individuals dependent on METH who were experiencing psychotic symptoms.	Vuletic et al., 2018
	Humans (n=65 healthy volunteers, 54 women; n=61 METH-dependent individuals, 53 women); 19-45 years old	N.A.	The study suggested decreased neuronal integrity, viability, number, and mitochondrial dysfunction in the mPFC of METH-dependent individuals.	Wu et al., 2018

The articles reported in the table were arranged by model/species (cells, mice, rats, monkeys, humans) and in chronological order. 4-[18F]-ADAM: N,N-dimethyl-2-(2-amino-4-(18)F- fluorophenylthio)benzylamine; CPu: caudate-putamen nucleus; D1R: dopamine D1 receptors; D2R: dopamine D2 receptors; HMGB1: high mobility group box 1 protein; i.m.: intramuscular injection; i.p.: intraperitoneal injection; i.v.: intravenous injection; keap-1: kelch-like ECH-associated protein 1; METH: methamphetamine; mPFC: medial prefrontal cortex; Nrf2: nuclear factor erythroid-2-related factor; p.o.: per os; s.c.: subcutaneous injection.