Effect of Methamphetamine on the Fasting Blood Glucose in Methamphetamine Abusers

Metabolic Brain Disease https://doi.org/10.1007/s11011-018-0265-8

ORIGINAL ARTICLE

Effect of methamphetamine on the fasting blood glucose in methamphetamine abusers

Yanhong Zhang1 & Guofang Shu2 & Ying Bai1 & Jie Chao3 & Xufeng Chen4 & Honghong Yao1,5

Received: 21 March 2018 /Accepted: 4 June 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract Methamphetamine is a popular psychostimulant worldwide which causes neurotoxicity and neuroinflammation. Although previous studies have characterized potential associations between addictive drugs and fasting blood glucose, the influence of methamphetamine on the blood glucose is still largely unknown. The present study was designed to investigate the change of fasting blood glucose of methamphetamine abusers and to confirm the impairment of liver and kidney. Fasting blood glucose was significantly decreased in methamphetamine abusers and in a high-fat diet mouse model with methamphetamine treatment discontinuation. Serum level of ALT, creatine kinase and creatinine were increased in methamphetamine abusers. Serum level of ALT and AST were increased in a high-fat diet mouse model after methamphetamine injection, but there was no significant difference in the anatomy of the liver and kidney in high-fat diet treated mice with or without methamphetamine. The levels of ALT and creatinine were also increased in the methamphetamine abusers. This study demonstrated that the level of glucose was decreased in methamphetamine abusers and in high-fat diet-fed mice after methamphetamine treatment discontinuation. The effect of methamphetamine on the levels of blood glucose may provide the evidence that methamphetamine abusers should be keep energy balance due to the low blood glucose.

Keywords Methamphetamine . Serum biochemical parameters . Liver . Kidney

Abbreviations EDTA Ethylenediaminetetraacetic acid ALT Alanine aminotransferase HFD High fat diet AST Aspartate aminotransferase TG Triglyceride CNS Central nervous system TC Total Cholesterol CPK Creatinine phosphokinase LDL-C Low density lipoproteins cholesterol ALP Alkaline phosphatase HDL-C High density lipoproteins cholesterol CK Creatine Kinase Cr Creatinine BUN Urea nitrogen * Xufeng Chen [email protected] * Honghong Yao [email protected] Introduction 1 Department of Pharmacology, Medical School of Southeast University, Nanjing, China Methamphetamine is a widely-abused and addictive 2 Department of Clinical Laboratory, Zhongda Hospital, Southeast psychostimulant (Cretzmeyer et al. 2003) with addictive prop- University School of Medicine, Nanjing 210009, Jiangsu, China erties that can produce significant short term feelings of eu- 3 Department of Physiology, Medical School of Southeast University, phoria, empathogenic and psychedelic (Parrott 2007; Vearrier Nanjing, China et al. 2012) and has become a major social problem causing a 4 Department of Emergency, The First Affiliated Hospital of Nanjing huge economic burden. Methamphetamine possesses the abil- Medical University, Nanjing 210029, Jiangsu, China ity of stimulating the central nervous system (CNS) via acting 5 Institute of Life Sciences, Key Laboratory of Developmental Genes on the dopaminergic, noradrenergic, serotonergic, and and Human Disease, Southeast University, Nanjing, Jiangsu, China opioidergic neurotransmitter systems (Vearrier et al. 2012), Metab Brain Dis producing the sense of euphoria, increasing productivity and one of the criteria of methamphetamine-induced neurotoxicity. hypersexuality and decreasing anxiety, which contribute to the However, other animal experiment had observed temporal in- strong drug addiction (Courtney and Ray 2014). Thus, meth- crease in blood glucose (Herring et al. 2008;Shimaetal.2011). amphetamine use remains a significant burden to society as Therefore, it is not very clear the influence of methamphet- well as its associated disorders. In addition, methamphetamine amine on fasting blood glucose. could lead to cardiovascular disease (Yeo et al. 2007), hepatic Persistent methamphetamine abusing is metabolized largely pathology (Kamijo et al. 2002) and neurologic impairment in the liver (Caldwell et al. 1972; Cruickshank and Dyer 2009), (Sekine et al. 2003). Methamphetamine addiction causes not then excreted by the kidneys. Methamphetamine intoxication only overdose death, but also psychotic disorders including often results in peripheral organ injury including acute renal integration dysfunction syndrome and flashbacks (Homer et failure, which due to rhabdomyolysis (Ishigami et al. 2003; al. 2008; McKetin et al. 2017). So far, due to the lack of Richards 2000), cardiovascular (De La Garza et al. 2008; understanding of the specific mechanism of methamphet- Hassan et al. 2016), mitochondrial damage (Langford et al. amine toxicity, it is difficult to practically establish appropriate 2004;Tianetal.2009) and metabolism (Herring et al. 2008; and systematic diagnosis and treatment. It remains limited that Shin et al. 2017). Repeated methamphetamine administration effective therapy strategy for individuals seeking treatment for as a sub-acute or chronic model could cause oxidative DNA methamphetamine-induced psychiatirc disorders. damage and renal dysfunction with renal tubule damage be- Mounting evidence indicates that methamphetamine induces cause creatinine and creatinine phosphokinase (CPK) in blood neuroinflammation and neurotoxicity via promoting microglial increased significantly (Tokunaga et al. 2006). Most research (Wan et al. 2017;Xuetal.2017) and astrocyte (Zhang et al. shows that methamphetamine caused hepatic impairment via 2015) excessive activation, oxidative stress (Shah et al. 2013; increasing serum level of AST, ALT and ALP in the rats Shin et al. 2017) and causing blood-brain barrier endothelial (Koriem and Soliman 2014) or causing acute hyperthermia- dysfunction (Northrop and Yamamoto 2015;Parikhetal. dependent liver damage persisting for at least 24 h after drug 2015; Sajja et al. 2016). Methamphetamine can act directly on exposure (Halpin et al. 2013). The latest study had indicated nerve cell causing damage and inflammation, and also has the that methamphetamine caused hepatotoxicity through activat- potential to disrupt non-neuronal targets through systemically ing apoptosis and inducing cell cycle arrest (Wang et al. 2017). injection. Several studies in human have examined the effects The present study sought to investigate the effect of meth- of amphetamines including methamphetamine on blood chem- amphetamine on the levels of blood glucose in order to pro- istry and metabolism. Pinter et al. found that acute i.v. amphet- vide the evidence that methamphetamine abusers should be amine led to an increase in the plasma free fatty acid concen- alert to keep energy balance due to the low blood glucose. tration but failed to alter blood glucose level in humans (Pinter and Patee 1968). Peterfy et al. reported that i.v. methamphetamine 0.2 mg/kg/15 min had no significant difference in blood Materials and methods glucose (Peterfy et al. 1976). However, the study conducted by Dezhao et al. demonstrated that methamphetamine abusers had Reagents significantly decreased BMI andfastingbloodglucosein1091 human subjects who had a methamphetamine exposure history Methamphetamine was purchased from the National Institute and have been withdrawal for 1 to 7 days (Lv et al. 2016). for the Control of Pharmaceutical and Biological Products Consistent with this finding, it has been also reported that meth- (Beijing, China). amphetamine increased insulin secretion in rat with methamphetamine injection intraperitoneally (McMahon et al. 1971; Standard protocol approval and patient consent McMahon et al. 1975). Plasma insulin in the rats increased significantly at 15 min and remained elevated significantly The ethics committee of the Zhongda Hospitial affiliated to above control levels until 60 min after methamphetamine injec- SoutheastUniversityapprovedthisresearchprotocol(approv- tion (McMahon et al. 1971). Plasma glucose declined rapidly at al ID: 2016ZSDYLL057-P01) and the participant or their le- 30 min, recovered slightly but remained lower than the control. gally authorized representatives provided written informed Bowyer had observed that blood glucose levels had increased at consent to participate in the study. the start of methamphetamine exposure but it decreased below normal ultimately (Bowyer et al. 2017). Other studies have Human serum samples collection indicated that methamphetamine has the potential to impair glucose uptake in neurons and astrocyte (Abdul Muneer et al. The methamphetamine abusers were recruited from among 2011a) and cause blood-brain barrier dysfunction through im- those admitted to the Zhenjiang Jurong Female Detoxification pairment of glucose transporter (Abdul Muneer et al. 2011b), Institute in Zhenjiang City, Jiangsu province.. At the institute, which indicate the possibility that blood glucose levels may be all patients had to meet the following inclusion criteria: were Metab Brain Dis between 18 and 40 years of age; had at least 2 years of meth- treatment discontinuation. Then blood samples were centri- amphetamine addiction before they came to the institute; had a fuged at 3000 g for 30 min to separate serum, which was positive result on urine test for methamphetamine upon admis- stored at −20 °C for future analysis. Serum levels of aspartate sion to the institute; had been clean from methamphetamine aminotransferase (AST), alanine aminotransferase (ALT), exposure for 30 days. The human serum samples were obtained Triglyceride (TG), Total Cholesterol (TC), the amount of from methamphetamine abusers (n = 17) and the age-matched Cholesterol contained in low- or high-density lipoproteins healthy individual (n = 13) in Zhongda hospital affiliated to (LDL-C and HDL-C, respectively), glucose and other bio- Southeast university. The serum samples were collected in chemical parameters were measured using the UniCel D × C clean centrifuge tubes at 8:00 am after fasting overnight and 800 Synchron Clinical System (Beckman Coulter, Pasadena, immediately stored at −80 °C for future biochemical analysis. CA, USA). The collection and biochemical analyses of human serum were approved by IEC for Clinical Research of Zhongda Hospital Haematoxylin and eosin staining affiliated to Southeast University. Liver and kidney tissues were fixed overnight in 10% neutral Animals buffered formalin solution (1000 ml containing 40% formal-

dehyde 100 ml, 4 g NaH2PO4`2H2O,6.5gNa2HPO4). Male C57BL/6 N mice (weighting 20 to 25 g) were purchased Paraffin section of liver (5 μm) was stained with haematoxylin from the Model Animal Research Center of Nanjing and eosin, the histology of liver and kidney were examined University (Nanjing, China). All of the animals were housed under an Olympus BX51 light microscope (Olympus under conditions of constant temperature (22 °C ± 1 °C) and a America, Melville, NY, USA) at 400× magnification for ob- humidity level of 40–60% in a temperature-controlled room servation and photography. Haematoxylin and eosinstaining with a 12-h light/12-h dark cycle (lights on between 8:30 and was performed according to manufacturer’sprotocol. 20:30) with free access to food and water. After habituation, animals were randomly divided into two groups and were fed Oil red O staining a normal diet (Con) or a high fat diet (HFD, fat content 40% by calorie, 42.6% by carbohydrate and 17.4% by protein). Liver sections were stained with an oil red O staining to detect Animals fed with diets were all purchased from Jiangsu hepatic lipid accumulation and quantification following the Synergy Pharmaceutical and Biological Engineering manufacturer’s protocol. Images were captured using an (Jiangsu, China). After 16 weeks of high fat diet treatment, Olympus BX51 light microscope (Olympus America, animals became obese; body weight (35.6 ± 0.8 g vs. 28.4 ± Melville, NY, USA) at 400× magnification. 0.4 g, p ≤ 0.05) and fasting blood glucose (8.40 ± 0.2 mmol/L vs. 4.80 ± 0.2 mmol/L, p ≤ 0.05) were significantly higher Statistical analysis than lean control. The mice were randomly divided into four groups (n = 5, per group): (1) Normal control group (Con); (2) All data were expression as mean ± SD and were analyzed Methamphetamine-treated group (Meth); (3) HFD group using t-test and one-way analysis of variance (ANOVA). (HFD); (4) Methamphetamine -treated group with HFD The group difference was considered statistically significant (HFD + Meth). Each group injected with either saline or meth- for p < 0.05. For each parameter of all data presented,*p < amphetamine saline solution with a dosing schedule (injected 0.05, **p <0.01,#p <0.05. intraperitoneally, 3 times/week for 1 month). Three weeks after methamphetamine treatment discontinuation, all mice were fasted for 16 h followed by serum collection. Serum Result samples were determined for the serum biochemical parameters. Liver and kidney tissues were collected for future analy- Relative concentrations of serum biochemical sis via frozen immediately in liquid nitrogen. All animal pro- parameters in healthy controls cedures were performed in strict accordance with the and methamphetamine abusers ARRIVE guidelines and animal protocols approved by the Institutional Animal Care and Use Committee of the The human serum samples were obtained from methamphet- Medical School of Southeast University. amine abusers in Zhenjiang Jurong Detoxification Institute (n = 17) and the age-matched healthy individual (n =13)in Serum biochemical assays Zhongda hospital affiliated to Southeast university. The serum samples were obtained from the volunteers by centrifuging the Blood samples were collected from retroorbital plexus of mice tubes for 30 min at 3000 g and performed biochemical anal- into clean centrifuge tubes at 3 weeks after methamphetamine ysis. As shown in Fig. 1, a comparative study of the healthy Metab Brain Dis

Fig. 1 Some serum biochemical parameters were measured in clinical samples. Relative serum biochemical parameters were measured in healthy controls and methamphetamine abusers. Con: healthy controls; Meth: methamphetamine abusers. *p <0.05,**p < 0.01, ***p < 0.005, vs. Con controls and methamphetamine abusers on blood glucose 1.11 IU/L, p ≤ 0.05), Aspartate aminotransferase (AST, 16.5 ± (5.45 ± 0.20 mmol/L vs. 4.64 ± 0.09 mmol/L, p ≤ 0.005), 0.62 IU/L vs. 19.6 ± 1.63 IU/L, p = 0.11), Creatine kinase Alanine aminotransferase (ALT, 11.3 ± 1.29 IU/L vs. 14.8 ± (CK, 3.73 ± 0.26 IU/L vs. 4.31 ± 0.27 IU/L, p ≤ 0.01), Urea Metab Brain Dis nitrogen (BUN, 5.45 ± 0.20 mmol/L vs. 4.64 ± 0.09 mmol/L, Effect of methamphetamine on fasting blood glucose p = 0.15), Creatinine (Cr, 43.2 ± 13.5 μmol/L vs. 62.8 ± 6.39 μmol/L, p ≤ 0.005), the amount of Cholesterol contained Having observed that methamphetamine-mediated change of in low- or high-density lipoproteins (LDL-C, 2.45 ± fasting glucose in a clinical sample, we sought to experimen- 0.11 mmol/L vs. 2.53 ± 0.13 mmol/L, p =0.66andHDL-C, tally examine whether methamphetamine had effect on the 1.30 ± 0.07 mmol/L vs. 1.35 ± 0.05 mmol/L, p = 0.57, respec- fasting glucose. After 16 weeks of high fat diet treatment but tively), Triglyceride (TG, 0.86 ± 0.10 mmol/L vs. 0.64 ± prior to methamphetamine treatment for 4 weeks, fasting 0.06 mmol/L, p = 0.053) and Total Cholesterol (TC, 4.29 ± blood glucose values had significant difference than lean con- 0.17 mmol/L vs. 4.41 ± 0.21 mmol/L, p = 0.70). Therefore, trol (p ≤ 0.001; Fig. 2a). Animals fed with HFD were injected compared with the healthy controls, methamphetamine intraperitoneally methamphetamine (10 mg/kg) for 4 weeks, abusers had significantly lower fasting blood glucose indi- three times a week. Four weeks after methamphetamine treat- cating that methamphetamine could decrease the fasting ment, the level of blood glucose had a slight increase in blood glucose (Fig. 1a). In addition, Fig. 1b and c showed methamphetamine-treated HFD mice group comparing with that methamphetamine induced a significant increase in se- the saline-treated HFD group. However, 2 weeks after rum ALT and a slight increase in serum AST. methamphetamine discontinuation, the level of fasting Methamphetamine may cause the damage of kidney be- blood glucose decreased and had a significant difference cause serum levels of CK (Fig. 1d) and Cr (Fig. 1f) were between HFD group and methamphetamine-treated HFD increased. However, methamphetamine had no effect on the group (Fig. 2b). At the same time, methamphetamine had lipid metabolism (Fig. 1g-j). Table 1 shows some other no effect on the fasting blood glucose of mice fed with a serum biochemical parameters in two groups which had normal diet during the experimental period. We next no difference between two groups. sought to hypothesize the change of blood glucose is due to the methamphetamine withdrawal syndrome. After prolonged use of methamphetamine, symptoms of withdrawal may emerge such as dysphoric mood, anhedonia, Table 1 Serum biochemical parameters of healthy controls and fatigue, sleep disturbance, psychomotor impairment and methamphetamine abusers even major depressive disorder (Lee et al. 2013;Rawson Con (n = 13) Meth (n =17) P 2013). Two weeks after methamphetamine treatment discontinuation, as shown in Fig. 2c, there was a significantly K+ (mmol/L) 4.06 ± 0.07 3.98 ± 0.12 0.615 difference between HFD group and methamphetamine- Na+ (mmol/L) 140 ± 0.34 139 ± 0.26 0.094 treated with HFD group (p ≤ 0.05), which was consistent Cl− (mmol/L) 107 ± 0.48 105 ± 0.74 0.098 with the clinical research (Fig. 1a). However, by the end of Ca+ (mmol/L) 2.34 ± 0.02 2.27 ± 0.02 <0.05 7 weeks trial, the final fasting blood glucose had no sta- PHOS (mmol/L) 1.35 ± 0.03 1.29 ± 0.04 0.227 tistic different between control and methamphetamine-

CO2 (mmol/L) 22.7 ± 0.48 23.3 ± 0.37 0.322 treated group (Fig. 2b). These results indicated that meth- PA (g/L) 0.19 ± 0.004 0.25 ± 0.02 0.029 amphetamine had temporal decrease in fasting blood ALB (g/L) 43.4 ± 0.40 41.9 ± 0.50 <0.05 glucose. T.BIL (g/L) 12..0 ± 0.76 9.04 ± 0.86 <0.05 TBA (g/L) 5.36 ± 0.51 3.37 ± 0.34 <0.01 Methamphetamine had no effect on the body weight TP (g/L) 72.2 ± 0.38 70.5 ± 0.93 0.398 but increased the epididyma fat weight of normal D.BIL (μmol/L) 3.65 ± 0.16 3.36 ± 0.21 0.303 mice GGT (IU/L) 10.5 ± 1.01 13.8 ± 1.18 0.056 LDH (IU/L) 140 ± 6.29 152 ± 7.01 0.259 We next want to elucidate the effects of methamphetamine on AChE (IU/L) 8193 ± 471 8348 ± 390 0.800 the body weight of the experimental mice. After 16 weeks of UA (μmol/L) 216 ± 9.28 205 ± 12.3 0.482 high-fat feeding before methamphetamine treatment for ApoA1 (g/L) 1.14 ± 0.06 1.22 ± 0.04 0.247 4 weeks, body weight of HFD animals was significantly p ≤ ApoB (g/L) 0.78 ± 0.04 0.76 ± 0.03 0.726 heavier than lean control ( 0.001; Fig. 2d). Then body weights were collected at predetermined time intervals. As Lipoprotein(mg/L) 234 ± 39.6 263 ± 37.5 0.598 shown in Fig. 2e, there was no difference between saline Con: healthy controls; Meth: methamphetamine abusers; PHOS: inorgan- and methamphetamine treated animals for 1 month even ic phosphorus; PA: prealbumin; ALB: albumin; T.BIL: serum total bili- though the discontinuation of methamphetamine. However, rubin; TBA: total bile acid; TP: total protein; D.BIL: serum direct biliru- methamphetamine significantly increased the ratio of ep- bin; GGT: γ-glutamyl transpeptidase; LDH: lactate dehydrogenase; AChE: acetylcholin esterase; UA: uric acid; ApoA1: apolipoprotein A1; ididymal fat pad to body weight between the Control and ApoB: apolipoprotein B methamphetamine-treated group. Meanwhile, the ratio of Metab Brain Dis

Fig. 2 Effect of methamphetamine on fasting blood glucose and the body 0.01, vs. Con; #p < 0.05, vs. HFD. d Initial body weight of mice fed with weight. a Initial fasting blood glucose of mice fed with a normal diet or a normal diet or high fat diet prior to drug administration; e Alteration in high-fat diet prior to methamphetamine administration; b Alteration in body weight of mice fed with a normal diet or high fat diet after drug fasting blood glucose of mice fed with a normal diet or high fat diet after administration and discontinuation; fThe ratio of epididymal fat pad to drug administration. #p < 0.05, vs. HFD; c Fasting blood glucose was body weight of mice 3 weeks after methamphetamine discontinuation. measures in mice after methamphetamine withdrawal 2 weeks. ***p < *p <0.05,**p <0.01,and***p < 0.01, vs. Con

epididymal fat pad to body weight had a slight decrease in Effects of methamphetamine on the morphology methamphetamine-treated HFD group (p ≥ 0.05; Fig. 2f). and function of liver These results demonstrated that methamphetamine had no effect on the body weight but increased the epididyma fat Based on the premise that clinical samples had suggested that weight of normal mice. methamphetamine significantly increased serum ALT level Metab Brain Dis

(p ≤ 0.05; Fig. 1b), but serum AST levels was not statistically is higher in HFD group but the level of AST had no difference different between health and additive groups (p ≥ 0.05; Fig. between control group and HFD group. In order to further 1c). We next sought to assess hepatic damage by measuring elucidate the effect of methamphetamine on HFD-induced serum concentrations of the hepatocellular enzymes ALT and hepatic damage, the histopathology of livers were observed AST levels. Four weeks after methamphetamine treatment by Hematoxylin and eosin staining and Oil Red O staining. followed by 3-week of discontinuation, the concentration of Hematoxylin and eosin staining showed HFD group signifi- the serum ALT, AST were measured by extracting the eyeball cantly induced liver steatosis and cytoplasmic vacuolation. blood. Serum ALT and AST concentration had a significant However, the HFD-induced hepato-histiopathological chang- increase in methamphetamine-treated HFD group than that in es were aggravated by the administration of methamphet- HFD group, while had no effect on the normal mice (p ≥ 0.05; amine (Fig. 3c). On the other hand, we observed that hepatic Fig. 3a and b). Interestingly, we observed that the level of ALT inflammatory foci in HFD-fed mice and the number of it were

Fig. 3 Effects of methamphetamine on the morphology and function of inflammatory foci. Scale bar = 50 μm. d Oil O Red staining counter- liver. a-b Serum ALT, AST levels were assayed in mice fed with a normal stained with hematoxylin showed a decrease of liver lipid deposition by diet or high fat diet after drug administration and discontinuation; c methamphetamine in mice fed with high fat diet. Scale bar = 50 μm. e Representative pictures of Hematoxylin and eosin-stained liver section. The degree of liver steatosis was evaluated based on an Image-Pro Plus The black arrows showed the steatosis in fatty liver induced by the high software. ***p <0.01,vs.Con fat diet and the effect of methamphetamine, and the blue arrows showed Metab Brain Dis slight increase compared with HFD-fed mice injected with However, no significantly different in urea nitrogen levels methamphetamine (Fig. 3c). Consistent with the date of the were found between the health and additive groups (p ≥ liver steatosis, oil red O staining confirmed that high-fat diet 0.05; Fig. 1e).Wesoughttoexaminetheeffectofmetham- increased levels of lipid accumulation (Fig. 3d). The degree of phetamine on the histology of kidney. As mentioned above, liver steatosis was evaluated based on an Image-Pro Plus soft- mice were treated with methamphetamine for 4 weeks follow- ware. We found the fatty oil in liver of HFD group was more ed by 3-week of discontinuation, the concentration of the se- than 8 times than in normal group (Fig. 3e). rum creatinine and urea nitrogen level was measured by extracting the eyeball blood. As shown in Fig. 5a and b, serum Effects of methamphetamine on the lipid metabolism creatinine level was significantly decreased in mice of in mice methamphetamine-treated group. However, serum urea nitrogen level had no difference between the same groups. To Previous research has suggested that lipids play some role in further confirm the effect of methamphetamine on HFD- central nervous system functions related to drug addiction. induced nephritic injury, the histopathology of kidneys were Serum lipid may influence relapse of heroin use (Lin et al. observed by Hematoxylin and eosin staining. Exfoliation of 2012). To clear the effect of methamphetamine on lipid me- the renal tubule epithelium to the lumen was observed in tabolism, we next examine the serum HDL-C, LDL-C, TC HFD-treated animals. Meth-treatment mice showed visibly and TG levels. Our results showed that the levels of HDL-C, swelling and mild vacuolation of kidney tubules epithelial LDL-C, and TC in HFD group were markedly higher than cells, edemain the interstitium and inflammatory cell infiltra- those in the lean control (Fig. 4 a, b and c). Meanwhile, meth- tion (Fig. 5c). These result showed that methamphetamine had amphetamine had no effect on those serum biochemical pa- effect on the anatomy of the kidney. In addition, some other rameters expect the LDL-C level, which was significantly serum biochemical parameters in mice of four groups had no increased in methamphetamine-treated HFD group. In addi- statistics difference (Table 2). tion, there is no significant difference of serum TG level among four groups during the experimental period (Fig. 4d). Discussion Effects of methamphetamine on the morphology and function of kidney In the present study, we examined the influence of methamphetamine on fasting blood glucose, the function of liver and Clinical samples had determined that methamphetamine sig- kidney and lipid metabolism in a clinical sample containing nificantly increased serum creatinine level (p ≤ 0.05; Fig. 1f). 17 healthy people and 13 methamphetamine abusers. We

Fig. 4 Effects of methamphetamine on the lipid metabolism in mice. a, b, c, d Serum HDL-C, LDL-C, TC and TG levels were assayed in mice fed with a normal diet or high fat diet after drug administration and discontinuation. **p <0.05, ***p < 0.01, vs. Con; ###p < 0.01, vs. HFD Metab Brain Dis

Fig. 5 Effects of methamphetamine on the morphology and function of showed the exfoliation of the renal tubule epithelium to the lumen. The kidney. a-b Serum Cr and BUN levels were assayed in mice fed with a yellow arrow showed the vacuolation in renal tubular epithelia induced normal diet or high fat diet after drug administration and withdrawal; c by the high fat diet. The black arrows showed the swelling in the renal Hematoxylin and eosin staining showed the steatosis in kidney induced tubules. The blue arrow showed inflammatory foci. Scale bar = 50 μm. by the high fat diet and the effect of methamphetamine. The red arrows **p < 0.05, ***p <0.01,vs.Con found that fasting blood glucose had significantly decreased mice fed with high-fat diet 2 weeks after methamphetamine between two groups. In addition, we observed that metham- discontinuation. Methamphetamine had no effect on the body phetamine abusers had significantly increased in serum ALT, weight but it increased the epididyma fat weight of mice fed creatine and creatinine. Meanwhile, fasting blood glucose, with normal diet. Serum ALT and AST level had further in- body weight and serum biochemical parameters were mea- creased after methamphetamine exposure. However, we did sured in the mice treated with methamphetamine. We found not observe the significant difference in kidney and lipid that methamphetamine decreased fasting blood glucose in metabolism.

Table 2 Serum biochemical parameters in lean control and Con (mean ± SD, Meth (mean ± SD, HFD (mean ± SD, HFD + Meth (mean ± high fat diet group N =6) N =5) N =5) SD, N =5)

Na+ (mmol/L) 154 ± 2.22 154 ± 2.60 156 ± 1.72 159 ± 3.33 Ca+ (mmol/L) 2.38 ± 0.07 2.32 ± 0.07 2.48 ± 0.12 2.45 ± 0.12 PHOS(mmol/L) 3.38 ± 0.76 2.85 ± 0.40 3.50 ± 0.53 3.26 ± 0.51 ALB (g/L) 34.7 ± 1.50 33.4 ± 0.55 32.6 ± 1.82 31.4 ± 0.89 PA(g/L) 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 TBA(μmol/L) 5.13 ± 3.14 2.12 ± 0.94 2.12 ± 0.94 8.36 ± 14.4 ALP(IU/L) 66.2 ± 12.2 44.8 ± 9.58 44.8 ± 9.58 57.8 ± 13.2 GGT(IU/L) 1.67 ± 0.52 1.60 ± 1.14 1.60 ± 1.14 2.20 ± 0.45 AChE(IU/L) 4396 ± 460 6055 ± 793 6055 ± 793 4882 ± 1901 CK(IU/L) 2436 ± 1029 1851 ± 598 1851 ± 598 1876 ± 327 UA(μmol/L) 174 ± 23.1 148 ± 34.7 148 ± 34.7 123 ± 21.4

Con: control group; Meth: methamphetamine-treated group; HFD: high-fat diet group; HFD + Meth: methamphetamine-treated with HFD group; PHOS: inorganic phosphorus; ALB: albumin; PA: prealbumin; TBA: total bile acid; TP: total protein; ALP: alkaline phosphatase; GGT: γ-glutamyl transpeptidase; AChE: acetylcholin esterase; CK: creatine kinase; UA: uric acid Metab Brain Dis

Several studies showed that amphetamine and its deriva- In addition to blood glucose, body weights were collected tives had been demonstrated to cause marked decreased in at the same time intervals. There were no significant differ- blood glucose in experimental mice (Bressler et al. 1968; ences in body weight in all groups throughout an experiment Moore et al. 1965). Feldman et al. showed that methamphet- period (Fig. 3a). Herring et al. found methamphetamine treat- amine and amphetamine enhanced the release of insulin from ment decreased body weight compared with the saline-treated rats and mice independent on hyperglycemia partly due to a animals at 24 h after the first dose, however, this difference direct effect on the pancreas (McMahon et al. 1971; was disappeared at 48 h or 64 h (Herring et al. 2008). McMahon et al. 1975). The findings in the present study are The liver is one of the important organs to regulate the consistence with those previous reports regarding the decrease levels of blood glucose and particularly involved in glucose in blood glucose. However, our study is not consistent with homeostasis (Yang et al. 2016). Liver glycogen synthase is a the study that methamphetamine administration tended to key enzyme in glycogenesis by conversion excess glucose have temporal increase in blood glucose in animal experiment into glycogen in the liver (Ros et al. 2010). Multiple risk (Shima et al. 2011). In a large sample of methamphetamine- factors-induced liver inflammation and injury contributes to addict groups, the level of blood glucose was significantly the development of hyperglycemia though the disturbance of decreased compared with the control group (Zhang et al. hepatic glycogen accumulation (Ros et al. 2011). The serum 2017). Acute and chronic exposure to some stimulants was levels of ALT and AST, as biomarkers for hepatic tissue dam- reported to induce changes in brain metabolism. For example, age, were determined as that ALT, but not AST, had a signif- cocaine and 3, 4-methylenedioxy-N-methylamphetamine icant increase in drug abuser. Several studies showed that (MDMA) exposure result in an elevation of brain extracellular methamphetamine contribute to significant peripheral organ levels of glucose (Pachmerhiwala et al. 2010; Wakabayashi damage (Cook et al. 1993). Methamphetamine has been re- and Kiyatkin 2015). Interestingly, we have anecdotally ob- ported that it is largely metabolized in the liver (Caldwell et al. served that methamphetamine exposure lead to decrease 1972; Cruickshank and Dyer 2009), then excreted by the kid- events in the levels of fasting blood glucose, indicating the neys, with the majority excreted as unchanged methamphet- possibility that the levels of blood glucose may be predictive amine (30–50%) (Kim et al. 2004). Yamamoto B K et al. of methamphetamine-induced neurotoxicity. Evidence sug- showed that methamphetamine causes acute hyperthermia gests this hypothesis that methamphetamine was shown to (Hassan et al. 2016), which contributes to both structural liver significantly inhibit the glucose uptake by neural cells and damage and function associated with hepatotoxicity (Halpin et neurons were more sensitive to methamphetamine associated al. 2013). Soliman et al. found that methamphetamine (10 mg/ with reduction of glucose transporter protein-3 (GLUT3) kg) twice a day over 7-day period can cause acute hepatic (Abdul Muneer et al. 2011a). In preclinical and clinical stud- failure and induce oxidative stress in rats (Koriem and ies, psychostimulants such as methamphetamine, MDMA and Soliman 2014). In this study, methamphetamine treatment in- cocaine have been shown to contribute to neuroinflammation creased the level of serum ALT, AST and LDL-C, which was and blood brain barrier (BBB) dysfunction through produced consistent with our study. To our surprise, there was no sig- inflammatory factors, decreased tight junction protein expres- nificant difference of the level of AST between normal group sion, increased enzyme activation related to degrade extracel- and HFD group. However, in terms of level of ALT, there was lular matrix and increased glial activation (Carvalho et al. higher level of ALT in HFD group compared with control 2012; Huang et al. 2017; Jumnongprakhon et al. 2016; Yang group, indicating that the damage of liver was induced by et al. 2018). Sadiko et al. suggested that methamphetamine HFD. The reason for the different response of AST and ALT disrupts BBB function and integrity via impairment of brain change was due to the fact that AST is mitochondrial isoen- endothelial glucose transporter, which leads to an insufficient zymes and is found not only in the liver but also in cardiac supply of blood glucose to the brain (Sadiko et al. 1990). In muscle skeletal muscle, kidneys, brain, and red cells, but ALT other studies, methamphetamine-induced frequent hyperther- is highly expressed in the liver (Lala and Minter 2018). mic events play a key role in BBB permeability and develop- Moreover, we found no difference of AST and ALT in the ment of brain edema (Kiyatkin et al. 2007). methamphetamine-treated group compared with control Methamphetamine-induced alterations in glucose metabolism group. Several studies indicated that methamphetamine and tend to accompanied by oxidative stress (Capela et al. 2009; its metabolites amphetamine produced hyperthermia, causing Song et al. 2010). In turn, oxidative stress and hyperthermic indirect adverse effects on peripheral organs such as liver and can exacerbate BBB dysfunction and neuroinflammation after kidney (Bowyer and Hanig 2014). We observed that the in- methamphetamine exposure. Thus, it is essential to under- crease in blood CK, which could be due to renal or muscle stand a relationship between blood glucose levels, BBB dis- damage. Ishigami et al. had conducted an immunohistochem- ruption and methamphetamine neurotoxicity. Alternation of ical study indicated that methamphetamine abusers had cause blood glucose may influence or may be predictive of the skeletal muscle damage and myoglobin positive which methamphetamine-induced neurotoxicity. might induce oxidative damage (Ishigami et al. 2003). Thus, Metab Brain Dis we further examined the histological changes of kidney while Conflict of interest The authors declare that there are no conflicts of there is no difference between methamphetamine treated and interest. saline-treated HFD groups. In normal diet group, methamphetamine had decreased the level of creatine kinase which is not in accordance with above analysis. References Lipids may play a part role in the central nervous system functions that associate with drug addiction. The previous studies indicated that heroin users showed a significant in- Abdul Muneer PM, Alikunju S, Szlachetka AM, Haorah J (2011a) Methamphetamine inhibits the glucose uptake by human neurons crease in TC levels (Divsalar et al. 2014). In a previous study and astrocytes: stabilization by acetyl-L-carnitine. PLoS One 6: suggested that heroin- and opium-addict groups had lower TG e19258. https://doi.org/10.1371/journal.pone.0019258 levels which had no difference of TG levels (Kouros et al. Abdul Muneer PM, Alikunju S, Szlachetka AM, Murrin LC, Haorah J 2010). In addition, Serum TG and TC levels were significant- (2011b) Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction. Mol ly decreased in a large sample of methamphetamine abusers Neurodegener 6:23. https://doi.org/10.1186/1750-1326-6-23 (Zhang et al. 2017). (Koriem and Soliman 2014) found that Bowyer JF, Hanig JP (2014) Amphetamine- and methamphetamine- methamphetamine injection increased significantly serum induced hyperthermia: implications of the effects produced in brain cholesterol, LDL-C and TC as compared with control rats. vasculature and peripheral organs to forebrain neurotoxicity. – However, we did not observe the difference of lipid metabo- Temperature 1:172 182. https://doi.org/10.4161/23328940.2014. 982049 lism between methamphetamine abusers and healthy controls. Bowyer JF, Tranter KM, Sarkar S, George NI, Hanig JP, Kelly KA, In the current study, methamphetamine induced a signifi- Michalovicz LT, Miller DB, O'Callaghan JP (2017) Corticosterone cant decrease in fasting blood glucose both in methamphet- and exogenous glucose alter blood glucose levels, neurotoxicity, and amine abusers and methamphetamine-treated mice fed with vascular toxicity produced by methamphetamine. J Neurochem 143: 198–213. https://doi.org/10.1111/jnc.14143 high-fat diet. The effect of methamphetamine on the levels Bressler R, Vargas-Cord M, Lebovitz HE (1968) Tranylcypromine: a of blood glucose may provide the evidence that methamphet- potent insulin secretagogue and hypoglycemic agent. Diabetes 17: amine abusers should be alter to keep energy balance due to 617–624 the low blood glucose. Caldwell J, Dring LG, Williams RT (1972) Metabolism of ( 14 C)methamphetamine in man, the Guinea pig and the rat. Biochem J129:11–22 Capela JP, Carmo H, Remiao F, Bastos ML, Meisel A, Carvalho F (2009) Molecular and cellular mechanisms of ecstasy-induced neurotoxic- Conclusion ity: an overview. Mol Neurobiol 39:210–271. https://doi.org/10. 1007/s12035-009-8064-1 The findings in the present study highlight a decrease of Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos ML (2012) Toxicity of amphetamines: an up- fasting blood glucose in methamphetamine abusers. HFD date. Arch Toxicol 86:1167–1231. https://doi.org/10.1007/s00204- mice treated with methamphetamine resulted in decreased of 012-0815-5 fasting blood glucose than control group. Meanwhile, the Cook CE, Jeffcoat AR, Hill JM, Pugh DE, Patetta PK, Sadler BM, White study demonstrates that methamphetamine exerted toxicity WR, Perez-Reyes M (1993) Pharmacokinetics of methamphetamine self-administered to human subjects by smoking S-(+)-methamphet- on kidney with consequential acute renal damage via increas- amine hydrochloride. Drug Metab Dispos 21:717–723 ing serum level of creatine kinase and creatinine in the meth- Courtney KE, Ray LA (2014) Methamphetamine: an update on epidemi- amphetamine abusers. In addition, we observed the increase ology, pharmacology, clinical phenomenology, and treatment litera- of serum level of AST indicating the hepatic damage in the ture. Drug Alcohol Depend 143:11–21. https://doi.org/10.1016/j. methamphetamine abusers. drugalcdep.2014.08.003 Cretzmeyer M, Sarrazin MV, Huber DL, Block RI, Hall JA (2003) Treatment of methamphetamine abuse: research findings and clini- Acknowledgements This work was supported by grants from the cal directions. J Subst Abus Treat 24:267–277 National Natural Science Foundation of China (No. 81322048 and No. Cruickshank CC, Dyer KR (2009) A review of the clinical pharmacology 81473190). of methamphetamine. Addiction 104:1085–1099. https://doi.org/10. 1111/j.1360-0443.2009.02564.x Author contributions Y.H. planned and designed the research, supervised De La Garza R, Shoptaw S, Newton TF (2008) Evaluation of the cardio- and wrote the experiments; Y.H.Z carried out the experiments and wrote vascular and subjective effects of rivastigmine in combination with the manuscript; Y.B. participated in data acquisition and analysis; G.F.S methamphetamine in methamphetamine-dependent human volun- and J.C participated in the design of study, drafted manuscript and coor- teers. Int J Neuropsychopharmacol 11:729–741. https://doi.org/10. dinated the lab work; and X.F.C provided the comments on the manu- 1017/S1461145708008456 script, edited the writing, and involved in revising it critically for impor- Divsalar K, Meymandi MS, Afarinesh M, Zarandi MM, Haghpanah T, tant intellectual content. All authors read and approved the final Keyhanfar F, Mahmoodi M, Kruszewski SP (2014) Serum biochem- manuscript. ical parameters following heroin withdrawal: an exploratory study. Am J Addict 23:48–52. https://doi.org/10.1111/j.1521-0391.2013. Compliance with ethical standards 12062.x Metab Brain Dis

Halpin LE, Gunning WT, Yamamoto BK (2013) Methamphetamine Lv D, Zhang M, Jin X, Zhao J, Han B, Su H, Zhang J, Zhang X, Ren W, causes acute hyperthermia-dependent liver damage. Pharmacol He J (2016) The body mass index, blood pressure, and fasting blood Res Perspect 1:e00008. https://doi.org/10.1002/prp2.8 glucose in patients with methamphetamine dependence. Medicine Hassan SF, Wearne TA, Cornish JL, Goodchild AK (2016) Effects of 95:e3152. https://doi.org/10.1097/MD.0000000000003152 acute and chronic systemic methamphetamine on respiratory, car- McKetin R, Baker AL, Dawe S, Voce A, Lubman DI (2017) Differences diovascular and metabolic function, and cardiorespiratory reflexes. J in the symptom profile of methamphetamine-related psychosis and Physiol 594:763–780. https://doi.org/10.1113/JP271257 primary psychotic disorders. Psychiatry Res 251:349–354. https:// Herring NR, Schaefer TL, Tang PH, Skelton MR, Lucot JP, Gudelsky doi.org/10.1016/j.psychres.2017.02.028 GA, Vorhees CV, Williams MT (2008) Comparison of time- McMahon EM, Andersen DK, Feldman JM, Schanberg SM (1971) dependent effects of (+)-methamphetamine or forced swim on Methamphetamine-induced insulin release. Science 174:66–68 monoamines, corticosterone, glucose, creatine, and creatinine in McMahon EM, Feldman JM, Schanberg SM (1975) Further studies of rats. BMC Neurosci 9:49. https://doi.org/10.1186/1471-2202-9-49 methamphetamine-induced insulin release. Toxicol Appl Pharmacol Homer BD, Solomon TM, Moeller RW, Mascia A, DeRaleau L, Halkitis 32:62–72 PN (2008) Methamphetamine abuse and impairment of social func- Moore KE, Sawdy LC, Shaul SR (1965) Effects of D-amphetamine on tioning: a review of the underlying neurophysiological causes and blood glucose and tissue glycogen levels of isolated and aggregated behavioral implications. Psychol Bull 134:301–310. https://doi.org/ mice. Biochem Pharmacol 14:197–204 10.1037/0033-2909.134.2.301 Northrop NA, Yamamoto BK (2015) Methamphetamine effects on Huang R, Zhang Y, Han B, Bai Y, Zhou R, Gan G, Chao J, Hu G, Yao H blood-brain barrier structure and function. Front Neurosci 9:69. (2017) Circular RNA HIPK2 regulates astrocyte activation via co- https://doi.org/10.3389/fnins.2015.00069 operation of autophagy and ER stress by targeting MIR124-2HG. Pachmerhiwala R, Bhide N, Straiko M, Gudelsky GA (2010) Role of Autophagy 13:1722–1741. https://doi.org/10.1080/15548627.2017. serotonin and/or norepinephrine in the MDMA-induced increase 1356975 in extracellular glucose and glycogenolysis in the rat brain. Eur J – Ishigami A, Tokunaga I, Gotohda T, Kubo S (2003) Pharmacol 644:67 72. https://doi.org/10.1016/j.ejphar.2010.07.004 Immunohistochemical study of myoglobin and oxidative injury- Parikh NU, Aalinkeel R, Reynolds JL, Nair BB, Sykes DE, Mammen MJ, related markers in the kidney of methamphetamine abusers. Legal Schwartz SA, Mahajan SD (2015) Galectin-1 suppresses metham- Med 5:42–48 phetamine induced neuroinflammation in human brain microvascu- lar endothelial cells: Neuroprotective role in maintaining blood brain Jumnongprakhon P, Govitrapong P, Tocharus C, Tocharus J (2016) – Melatonin promotes blood-brain barrier integrity in barrier integrity. Brain Res 1624:175 187. https://doi.org/10.1016/j. methamphetamine-induced inflammation in primary rat brain mi- brainres.2015.07.033 crovascular endothelial cells. Brain Res 1646:182–192. https://doi. Parrott AC (2007) The psychotherapeutic potential of MDMA (3,4- org/10.1016/j.brainres.2016.05.049 methylenedioxymethamphetamine): an evidence-based review. Psychopharmacology 191:181–193. https://doi.org/10.1007/ Kamijo Y, Soma K, Nishida M, Namera A, Ohwada T (2002) Acute liver s00213-007-0703-5 failure following intravenous methamphetamine. Vet Hum Toxicol Peterfy G, Pinter EJ, Pattee CJ (1976) Psychosomatic aspects of catechol- 44:216–217 amine depletion: comparative studies of metabolic, Endocrine and Kim I, Oyler JM, Moolchan ET, Cone EJ, Huestis MA (2004) Urinary Affective Changes. Psychoneuroendocrinology 1:243–253 pharmacokinetics of methamphetamine and its metabolite, amphet- Pinter EJ, Patee CJ (1968) Fat-mobilizing action of amphetamine. J Clin amine following controlled oral administration to humans. Ther Invest 47:394–402. https://doi.org/10.1172/JCI105736 Drug Monit 26:664–672 Rawson RA (2013) Current research on the epidemiology, medical and Kiyatkin EA, Brown PL, Sharma HS (2007) Brain edema and breakdown psychiatric effects, and treatment of methamphetamine use. J Food of the blood-brain barrier during methamphetamine intoxication: – – Drug Anal 21:S77 S81. https://doi.org/10.1016/j.jfda.2013.09.039 critical role of brain hyperthermia. Eur J Neurosci 26:1242 1253. Richards JR (2000) Rhabdomyolysis and drugs of abuse. J Emerg Med https://doi.org/10.1111/j.1460-9568.2007.05741.x 19:51–56 Koriem KM, Soliman RE (2014) Chlorogenic and caftaric acids in liver Ros S, Zafra D, Valles-Ortega J, García-Rocha M, Forrow S, Domínguez toxicity and oxidative stress induced by methamphetamine. Journal J, Calbó J, Guinovart JJ (2010) Hepatic overexpression of a consti- of Toxicology 2014:583494. https://doi.org/10.1155/2014/583494 tutively active form of liver glycogen synthase improves glucose Kouros D, Tahereh H, Mohammadreza A, Minoo MZ (2010) Opium and homeostasis. J Biol Chem 285:37170–37177. https://doi.org/10. heroin alter biochemical parameters of human's serum. Am J Drug 1074/jbc.M110.157396 – Alcohol Abuse 36:135 139. https://doi.org/10.3109/ Ros S, Garcia-Rocha M, Calbo J, Guinovart JJ (2011) Restoration of 00952991003734277 hepatic glycogen deposition reduces hyperglycaemia, hyperphagia Lala V, Minter DA (2018) Liver Function Tests. In: StatPearls. Treasure and gluconeogenic enzymes in a streptozotocin-induced model of Island (FL), diabetes in rats. Diabetologia 54:2639–2648. https://doi.org/10. Langford D, Grigorian A, Hurford R, Adame A, Crews L, Masliah E 1007/s00125-011-2238-x (2004) The role of mitochondrial alterations in the combined toxic Sadiko GN, Lavrinenko VI, Koloiarov PG (1990) The dynamics of visual effects of human immunodeficiency virus tat protein and metham- analyzer sensitivity under industrial conditions in an arid zone. phetamine on calbindin positive-neurons. J Neurovirol 10:327–337. Fiziol Cheloveka 16:107–111 https://doi.org/10.1080/13550280490520961 Sajja RK, Rahman S, Cucullo L (2016) Drugs of abuse and blood-brain Lee N, Pennay A, Hester R, McKetin R, Nielsen S, Ferris J (2013) A pilot barrier endothelial dysfunction: a focus on the role of oxidative randomised controlled trial of modafinil during acute methamphet- stress. J Cereb Blood Flow Metab 36:539–554. https://doi.org/10. amine withdrawal: feasibility, tolerability and clinical outcomes. 1177/0271678X15616978 Drug Alcohol Rev 32:88–95. https://doi.org/10.1111/j.1465-3362. Sekine Y, Minabe Y, Ouchi Y, Takei N, Iyo M, Nakamura K, Suzuki K, 2012.00473.x Tsukada H, Okada H, Yoshikawa E, Futatsubashi M, Mori N (2003) Lin SH, Yang YK, Lee SY, Hsieh PC, Chen PS, Lu RB, Chen KC (2012) Association of dopamine transporter loss in the orbitofrontal and Association between cholesterol plasma levels and craving among dorsolateral prefrontal cortices with methamphetamine-related psy- heroin users. J Addict Med 6:287–291. https://doi.org/10.1097/ chiatric symptoms. Am J Psychiatry 160:1699–1701. https://doi. ADM.0b013e318262a9a1 org/10.1176/appi.ajp.160.9.1699 Metab Brain Dis

Shah A, Kumar S, Simon SD, Singh DP, Kumar A (2013) HIV gp120- Wan F, Zang S, Yu G, Xiao H, Wang J, Tang J (2017) Ginkgolide B and methamphetamine-mediated oxidative stress induces astrocyte suppresses methamphetamine-induced microglial activation apoptosis via cytochrome P450 2E1. Cell Death Dis 4:e850. https:// through TLR4-NF-kappaB signaling pathway in BV2 cells. doi.org/10.1038/cddis.2013.374 Neurochem Res 42:2881–2891. https://doi.org/10.1007/s11064- Shima N, Miyawaki I, Bando K, Horie H, Zaitsu K, Katagi M, Bamba T, 017-2309-6 Tsuchihashi H, Fukusaki E (2011) Influences of methamphetamine- Wang Q, Wei LW, Xiao HQ, Xue Y, Du SH, Liu YG, Xie XL (2017) induced acute intoxication on urinary and plasma metabolic profiles Methamphetamine induces hepatotoxicity via inhibiting cell divi- in the rat. Toxicology 287:29–37. https://doi.org/10.1016/j.tox. sion, arresting cell cycle and activating apoptosis: in vivo and in 2011.05.012 vitro studies. Food Chem Toxicol 105:61–72. https://doi.org/10. Shin EJ, Tran HQ, Nguyen PT, Jeong JH, Nah SY, Jang CG, Nabeshima 1016/j.fct.2017.03.030 T, Kim HC (2017) Role of mitochondria in methamphetamine- Xu E, Liu J, Liu H, Wang X, Xiong H (2017) Role of microglia in induced dopaminergic neurotoxicity: involvement in oxidative methamphetamine-induced neurotoxicity. Int J Physiol stress, Neuroinflammation, and pro-apoptosis-a review. Pathophysiol Pharmacol 9:84–100 – Neurochem Res 43:57 69. https://doi.org/10.1007/s11064-017- Yang C, Liu Y, Yang JD, Li YH, Li X, Cheng JP (2016) Amination of 3- 2318-5 substituted Benzofuran-2(3H)-ones triggered by single-electron Song BJ, Moon KH, Upreti VV, Eddington ND, Lee IJ (2010) transfer. Org Lett 18:1036–1039. https://doi.org/10.1021/acs. Mechanisms of MDMA (ecstasy)-induced oxidative stress, mito- orglett.6b00163 chondrial dysfunction, and organ damage. Curr Pharm Biotechnol – Yang L, Han B, Zhang Y, Bai Y, Chao J, Hu G, Yao H (2018) 11:434 443 Engagement of circular RNA HECW2 in the nonautophagic role Tian C, Murrin LC, Zheng JC (2009) Mitochondrial fragmentation is of ATG5 implicated in the endothelial-mesenchymal transition. involved in methamphetamine-induced cell death in rat hippocam- Autophagy 14:404–418. https://doi.org/10.1080/15548627.2017. pal neural progenitor cells. PLoS One 4:e5546. https://doi.org/10. 1414755 1371/journal.pone.0005546 Yeo KK, Wijetunga M, Ito H, Efird JT, Tay K, Seto TB, Alimineti K, Tokunaga I, Kubo S, Ishigami A, Gotohda T, Kitamura O (2006) Changes Kimata C, Schatz IJ (2007) The association of methamphetamine in renal function and oxidative damage in methamphetamine-treated use and cardiomyopathy in young patients. Am J Med 120:165–171. rat. Legal Med 8:16–21. https://doi.org/10.1016/j.legalmed.2005. https://doi.org/10.1016/j.amjmed.2006.01.024 07.003 Vearrier D, Greenberg MI, Miller SN, Okaneku JT, Haggerty DA (2012) Zhang Y, Zhu T, Zhang X, Chao J, Hu G, Yao H (2015) Role of high- Methamphetamine: history, pathophysiology, adverse health effects, mobility group box 1 in methamphetamine-induced activation and current trends, and hazards associated with the clandestine manufac- migration of astrocytes. J Neuroinflammation 12:156. https://doi. ture of methamphetamine. Dis Mon 58:38–89. https://doi.org/10. org/10.1186/s12974-015-0374-9 1016/j.disamonth.2011.09.004 Zhang M, Lv D, Zhou W, Ji L, Zhou B, Chen H, Gu Y, Zhao J, He J Wakabayashi KT, Kiyatkin EA (2015) Central and peripheral contribu- (2017) The levels of triglyceride and total cholesterol in metham- tions to dynamic changes in nucleus accumbens glucose induced by phetamine dependence. Medicine 96:e6631. https://doi.org/10. intravenous cocaine. Front Neurosci 9:42. https://doi.org/10.3389/ 1097/MD.0000000000006631 fnins.2015.00042