Chronic Methamphetamine Users Research Articles

Is it dopamine or serotonin?: Contrasting social cognition and aggression between chronic MDMA and methamphetamine users

Is it dopamine or serotonin?: Contrasting social cognition and aggression between chronic MDMA and methamphetamine users

Cases of Phenotypic Switching From Dilated Cardiomyopathy to Pulmonary Arterial Hypertension in Chronic Methamphetamine Users

Cases of Phenotypic Switching From Dilated Cardiomyopathy to Pulmonary Arterial Hypertension in Chronic Methamphetamine Users

Imaging oxidative stress in brains of chronic methamphetamine users: A combined 1H-magnetic resonance spectroscopy and peripheral blood biomarker study.

Preclinical data suggest methamphetamine (MA), a widely used stimulant drug, can harm the brain by causing oxidative stress and inflammation, but only limited information is available in humans. We tested the hypothesis that levels of glutathione (GSH), a major antioxidant, would be lower in the brains of chronic human MA preferring polysubstance users. We also explored if concentrations of peripheral immunoinflammatory blood biomarkers were related with brain GSH concentrations. 20 healthy controls (HC) (33 years; 11 M) and 14 MA users (40 years; 9 M) completed a magnetic resonance spectroscopy (MRS) scan, with GSH spectra obtained by the interleaved J-difference editing MEGA-PRESS method in anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC). Peripheral blood samples were drawn for measurements of immunoinflammatory biomarkers. Independent samples t-tests evaluated MA vs. HC differences in GSH. GSH levels did not differ between HC and MA users (ACC p = 0.30; DLPFC p = 0.85). A total of 17 of 25 immunoinflammatory biomarkers were significantly elevated in MA users and matrix metalloproteinase (MMP)-2 (r = 0.577, p = 0.039), myeloperoxidase (MPO) (r = -0.556, p = 0.049), and MMP-9 (r = 0.660, p = 0.038) were correlated with brain levels of GSH. Normal brain GSH in living brain of chronic MA users is consistent with our previous postmortem brain finding and suggests that any oxidative stress caused by MA, at the doses used by our participants, might not be sufficient to cause either a compensatory increase in, or substantial overutilization of, this antioxidant. Additionally, more research is required to understand how oxidative stress and inflammatory processes are related and potentially dysregulated in MA use.

Disruption of regional homogeneity in the brains of chronic methamphetamine users.

Previous studies have reported evidence supporting structural and functional alterations in the brains of methamphetamine (MA) users. The aim of the present study was to extend current knowledge regarding brain function(s) in MA users by examining regional homogeneity (ReHo).Chronic MA users (51 male, 46 female), who were undergoing supervised abstinence for 12 to 621 days, and 79 healthy controls (43 male, 36 female) underwent resting-state functional brain magnetic resonance imaging. Voxel-wise whole-brain scale group differences in ReHo were examined. The mean ReHo values of significant clusters were extracted, and linear regression was used to identify factors that contributed to these mean ReHo values.MA users exhibited lower ReHo values in the left orbital part of the inferior frontal gyrus extending to the left insula and left temporal pole, left amygdala, and left fusiform gyrus. MA users also exhibited greater ReHo values in the bilateral pre- and postcentral gyri and right cerebellum. Characteristics of MA use, including duration, duration of abstinence from MA, and age at onset of MA use, demonstrated no reliable contribution to ReHo of the significant clusters.Findings of the present study demonstrated that chronic MA use was associated with regional specific disruption of ReHo, which is relatively independent of structural and functional alterations and, apparently, does not recover after relatively long-term abstinence. This disruption may underlie overall neurocognitive deficits in MA users, which is difficult to recover.

The relationship between serum brain-derived neurotrophic level and neurocognitive functions in chronic methamphetamine users

Methamphetamine (METH) is a highly addictive psychostimulant with serious neurotoxic effects. Given evidence indicating that brain-derived neurotrophic factor (BDNF) is associated with addictive behaviors, this study aimed to investigate the serum level of BDNF and cognitive functions in chronic METH users and healthy participants. Thirty-seven chronic METH users and 37 healthy participants were recruited in this study. Cognitive functioning, including executive functions and working memory, were assessed using the Wisconsin Card Sorting Test (WCST) and Wechsler Memory Scale (WMS), respectively. The levels of serum BDNF were also examined using an enzyme-linked immunosorbent assay kit. METH users showed significant impairment in executive function and working memory compared to healthy participants. The serum BDNF concentrations of METH users were significantly higher than healthy participants (42 ± 13.34 ng/ml vs. 24 ± 7 ng/ml). BDNF concentration was significantly correlated with duration (r = 0.37, p = 0.02) and dose of METH use (r = 0.35, p = 0.02). Besides, the BDNF level was not associated with any subscales of WCST and WMS. These results provide further evidence regarding the role of BDNF in the pathophysiology of METH addiction. Besides, these findings suggest that increased BDNF level is not related to cognitive impairments in METH users.

Elevated serum levels of TNF-α, IL-6, and IL-18 in chronic methamphetamine users.

Chronic methamphetamine use causes aberrant changes in cytokines. Our aim was to analyze the serum levels of tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-18 in chronic methamphetamine users. Associations between cytokines levels with the demographic properties, methamphetamine use properties, and psychiatric symptoms in chronic methamphetamine users were also evaluated. Seventy-eight chronic methamphetamine users who did not continue methamphetamine exposure since hospitalization and 64 healthy controls were enrolled. Serum levels of TNF-α, IL-6, and IL-18 were detected using an enzyme-linked immunosorbent assay. Psychopathological symptoms of chronic methamphetamine users were evaluated by the Positive and Negative Syndrome Scale, Beck Depression Inventory (BDI), and Beck Anxiety Inventory. Serum levels of TNF-α, IL-6, and IL-18 were significantly increased in methamphetamine users who did not continue methamphetamine exposure since hospital admission (average days since last methamphetamine use=39.06±7.48) when compared to those in controls. Serum IL-6 levels showed significant positive associations with BDI score and current frequency of methamphetamine use in chronic methamphetamine users. Our results suggest that increased TNF-α, IL-6, and IL-18 levels may have an important role in chronic methamphetamine use-associated psychopathological symptoms.

Methamphetamine-Triggered Neurotoxicity in Human Dorsolateral Prefrontal Cortex.

Background:Methamphetamine (MA), is an extremely addictive stimulant that adversely affects the central nervous system. Accumulating evidence indicates that molecular mechanisms such as oxidative stress, apoptosis, and autophagy are involved in the toxicity of MA. Considering experimental animal studies exhibiting MA-induced neurotoxicity, the relevance of these findings needs to be evidently elucidated in human MA users. It is generally assumed that multiple chemical substances released in the brain following MA-induced metabolic activation are primary factors underlying damage of neural cells. Hence, this study aimed to investigate the role of autophagy and apoptosis as well as oxidative stress in the brain of postmortem MA-induced toxicity.Materials and Methods:In this study, we determine the gene expression of autophagy and apoptosis, including BECN1, MAP1ALC3, CASP8, TP53, and BAX genes in ten healthy controls and ten chronic users of MA postmortem dorsolateral prefrontal cortex (DLPFC) by real-time polymerase chain reaction. Also, we applied immunohistochemistry in formalin-fixed and paraffin-embedded human brain samples to analyze brain-derived neurotrophic factor (BDNF). Also, spectrophotometry was performed to measure glutathione (GSH) content.Results:The expression level of apoptotic and autophagic genes (BECN1, MAP1ALC3, CASP8, TP53, and BAX) were significantly elevated, while GSH content and BDNF showed substantial reductions in DLPFC of chronic MA users. Discussion: Our data showed that MA addiction provokes transduction pathways, namely apoptosis and autophagy, along with oxidative mechanisms in DLPFC. Also, MA induces multiple functional and structural perturbations in the brain, determining its toxicity and possibly contributing to neurotoxicity. Discussion:Our study showed BDNF-positive cells as well as GSH amount, displayed significant declines in DLPFC of MA user. MA addiction provokes transduction pathways, namely apoptosis and autophagy, along with oxidative mechanisms in DLPFC. However, further investigations are needed to throw light on the cellular and molecular mechanisms that act in the various regions of the addicted brain, especially in DLPFC.

Methamphetamine-Triggered Neurotoxicity in Human Dorsolateral Prefrontal Cortex

Background: Methamphetamine (MA), is an extremely addictive stimulant that adversely affects the central nervous system. Accumulating evidence indicates that molecular mechanisms such as oxidative stress, apoptosis, and autophagy are involved in the toxicity of MA. Considering experimental animal studies exhibiting MA-induced neurotoxicity, the relevance of these findings needs to be evidently elucidated in human MA users. It is generally assumed that multiple chemical substances released in the brain following MA-induced metabolic activation are primary factors underlying damage of neural cells. Hence, this study aimed to investigate the role of autophagy and apoptosis as well as oxidative stress in the brain of postmortem MA-induced toxicity. Materials and Methods: In this study, we determine the gene expression of autophagy and apoptosis, including BECN1, MAP1ALC3, CASP8, TP53, and BAX genes in ten healthy controls and ten chronic users of MA postmortem dorsolateral prefrontal cortex (DLPFC) by real-time polymerase chain reaction. Also, we applied immunohistochemistry in formalin-fixed and paraffin-embedded human brain samples to analyze brain-derived neurotrophic factor (BDNF). Also, spectrophotometry was performed to measure glutathione (GSH) content. Results: The expression level of apoptotic and autophagic genes (BECN1, MAP1ALC3, CASP8, TP53, and BAX) were significantly elevated, while GSH content and BDNF showed substantial reductions in DLPFC of chronic MA users. Conclusion: Our data showed that MA addiction provokes transduction pathways, namely apoptosis and autophagy, along with oxidative mechanisms in DLPFC. Also, MA induces multiple functional and structural perturbations in the brain, determining its toxicity and possibly contributing to neurotoxicity. [GMJ.2021;10:e2016]

Successful Use of Minocycline for the Treatment of Methamphetamine-Induced Psychosis and Cognitive Impairments: An Open-Label Case Series.

Methamphetamine-induced psychosis and neuropsychological impairments are common among patients with methamphetamine use disorder. Given some preclinical and clinical studies reporting potential effects of minocycline, a second-generation tetracycline, on correcting manifestations of drug addiction, this study aimed to examine the effectiveness of minocycline in attenuating psychotic symptoms and neuropsychological impairments in chronic methamphetamine users. Five men with treatment-resistant methamphetamine use disorder and psychotic symptoms were selected using a convenience sampling method, and they were administered a daily dose of 200-mg minocycline for 8 weeks; within this period, psychiatric and neuropsychological assessments (including memory and executive functions) were carried out at the baseline, week 2, week 4, week 8, and 2-month follow-up. The findings showed that minocycline attenuated both positive (Cohen d = 0.63) and negative (Cohen d = 0.53) methamphetamine-induced psychotic symptoms and also improved patients' neuropsychological functions, particularly their auditory working memory (Cohen d = 0.45). These results provide promising evidence regarding the positive effects of minocycline as adjunctive pharmacotherapy for patients with methamphetamine use disorder. However, given that this was an open-label study, further research is warranted to draw a firm conclusion about the effectiveness of minocycline for methamphetamine-induced psychosis and neuropsychological deficits.

The Role of α-Synuclein in Methamphetamine-Induced Neurotoxicity.

Methamphetamine (METH), a highly addictive psychostimulant, is the second most widely used illicit drug. METH produces damage dopamine neurons and apoptosis via multiple inter-regulating mechanisms, including dopamine overload, hyperthermia, oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, protein degradation system dysfunction, and neuroinflammation. Increasing evidence suggests that chronic METH abuse is associated with neurodegenerative changes in the human brain and an increased risk of Parkinson's disease (PD). METH use and PD may share some common steps in causing neurotoxicity. Accumulation of α-synuclein, a presynaptic protein, is the pathological hallmark of PD. Intriguingly, α-synuclein upregulation and aggregation are also found in dopaminergic neurons in the substantia nigra in chronic METH users. This suggests α-synuclein may play a role in METH-induced neurotoxicity. The mechanism of α-synuclein cytotoxicity in PD has attracted considerable attention; however, how α-synuclein affects METH-induced neurotoxicity has not been reviewed. In this review, we summarize the relationship between METH use and PD, interdependent mechanisms that are involved in METH-induced neurotoxicity and the significance of α-synuclein upregulation in response to METH use. The identification of α-synuclein overexpression and aggregation as a contributor to METH-induced neurotoxicity may provide a novel therapeutic target for the treatment of the deleterious effect of this drug and drug addiction.

The relationship between duration of abstinence and gray-matter brain structure in chronic methamphetamine users

ABSTRACT Background: Brain structural findings in chronic methamphetamine users have been inconsistent. Identifying contributing influences (e.g., sex, abstinence duration) can help clarify the clinical course of recovery. Objectives: We studied the effects of long-term methamphetamine abstinence on gray-matter volume. Our hypothesis was that smaller volume early in abstinence would precede long-term recovery. Methods: Individuals who used methamphetamine (≥100 g lifetime use, mandated to residential treatment for methamphetamine-positive urine; 40 men, 21 women), undergoing supervised abstinence (men: 12–400 days; women: 130–594 days), were compared to healthy controls (49 men, 36 women) using T1-weighted MRI. Volumes of orbitofrontal, anterior cingulate and parietal cortex, hippocampus, and striatum were measured using Freesurfer software. Associations of volumes with abstinence duration were tested in males and females separately because their abstinence times differed (121.5 ± 124.5 vs. 348.0 ± 128.6 days, p < 0.001); only males were studied in early abstinence. The General Linear Model was used to test effects of abstinence duration and group (methamphetamine users vs. controls). Results: In males, duration of abstinence was multivariate significant for gray-matter volumes (p = 0.017). Abstinence duration was associated with increases in volumes of the orbitofrontal and parietal cortices (ps = 0.031, 0.016) and hippocampi (ps = 0.044). Irrespective of abstinence, male methamphetamine users had smaller hippocampi than male controls (p = 0.008). Females showed no significant effects of group or abstinence. Conclusions: In males, abstinence from methamphetamine appears to result in volumetric increases in regions important for cognitive function, which may affect recovery during the course of treatment. Data from the period of early abstinence are required to evaluate volumetric changes in females.

The Relationship between Serum Brain-Derived Neurotrophic Level and Neurocognitive Functions in Chronic Methamphetamine Users

The Relationship between Serum Brain-Derived Neurotrophic Level and Neurocognitive Functions in Chronic Methamphetamine Users

No significant elevation of translocator protein binding in the brains of recently abstinent methamphetamine users

BackgroundRadioligands for the translocator protein (TSPO) 18 kDa have been used with positron emission tomography (PET) to assess neuroinflammation and microglial activation in psychiatric disorders. One study using this approach showed substantial TSPO elevation throughout the brain in chronic methamphetamine users following long-term abstinence (0.5–4 years), but clients typically present for treatment earlier in abstinence. MethodsWe used PET with [11C]DAA1106 to compare standardized uptake values (SUVs) as an index of TSPO binding in the brains of methamphetamine-dependent participants who were abstinent for < 6 months (n = 11) and healthy controls (n = 12). We also assayed other typical correlates of Methamphetamine Dependence (e.g., striatal D2-type dopamine receptor deficits, depressed mood, anxiety and impaired emotion regulation). ResultsMethamphetamine users exhibited depression (p < 0.0001), anxiety (p = 0.002), difficulties in emotional regulation (p = 0.01), and lower striatal dopamine D2-type receptor availability vs. controls (p = 0.02). SUVs for [11C]DAA1106 were larger in all brain regions of methamphetamine-dependent participants vs. controls, but the effect size was small to medium and not statistically significant. ConclusionsThe discrepancy between the lack of significant difference in TSPO binding in early-abstinent methamphetamine users vs. controls in this study and a previous report of elevated binding in longer-abstinent methamphetamine users may reflect methodological differences or limitations of TSPO binding as an index of neuroinflammation. It also seems possible that gliosis increases over time during the first 6 months of abstinence; longitudinal studies could clarify this possibility.

LC3 and ATG5 overexpression and neuronal cell death in the prefrontal cortex of postmortem chronic methamphetamine users

Methamphetamine (METH) abuse is accompanied by oxidative stress, METH-induced neurotoxicity, and apoptosis. Oxidative stress has devastating effects on the structure of proteins and cells. Autophagy is an evolutionarily conserved intracellular regulated mechanism for orderly degradation of dysfunctional proteins or removing damaged organelles. The precise role of autophagy in oxidative stress-induced apoptosis of dopaminergic neuronal cells caused by METH has not clarified completely. In this study, we sought to evaluate the effects of METH abuse on autophagy in the prefrontal cortex of postmortem users, mainly focusing on the ATG5 and LC3 during neuroinflammation. Postmortem molecular and histological examination was done for two groups containing 12 non-addicted and 14 METH addicted cases. ATG5 and LC3 expression were analyzed by real-time PCR and immunohistochemistry (IHC) methods. Histopathological analysis was performed by stereological cell counting of neuronal cells using Hematoxylin and Eosin (H & E) staining technique. In order to detect DNA damage in the prefrontal lobe, Tunnel staining was performed. Real-time PCR and IHC assay showed overexpression of ATG5 and LC3 protein in the prefrontal cortex of Meth users. The cell death and neuronal degeneration were increased significantly based on Tunel assay and the stereological analysis in the Prefrontal cortex. Chronic METH exposure probably induces ATG5 and LC3 overexpression and neuronal cell death in the Prefrontal cortex of the postmortem cases.

The intermediate role of substance use indices in relation between trait impulsivity and emotional dysregulation with state impulsivity in chronic methamphetamine users

The intermediate role of substance use indices in relation between trait impulsivity and emotional dysregulation with state impulsivity in chronic methamphetamine users

Differential Responses of LINE-1 in the Dentate Gyrus, Striatum and Prefrontal Cortex to Chronic Neurotoxic Methamphetamine: A Study in Rat Brain.

Methamphetamine (METH) is a widely abused psychostimulant with the potential to cause a broad range of severe cognitive deficits as well as neurobehavioral abnormalities when abused chronically, particularly at high doses. Cognitive deficits are related to METH neurotoxicity in the striatum and hippocampus. The activation of transposable Long INterspersed Nuclear Element 1 (LINE-1) is associated with several neurological diseases and drug abuse, but there are very limited data regarding the effects of high-dose METH on the activity of LINE-1 in the adult brain. Using real-time quantitative PCR, the present study demonstrates that the chronic administration of neurotoxic METH doses results in the increased expression of LINE-1-encoded Open Reading Frame 1 (ORF-1) in rat striatum shortly after the last dose of the drug and decreased ORF-1 expression during METH withdrawal, with dentate gyrus potentially developing “tolerance” to these METH effects. LINE-1 activation may be a new factor mediating the neurotoxic effects of chronic METH in the striatum and, therefore, a new drug target against METH-induced psychomotor impairments in chronic METH users.

Microglia imaging in methamphetamine use disorder: a positron emission tomography study with the 18 kDa translocator protein radioligand [F-18]FEPPA.

Activation of brain microglial cells, microgliosis, has been linked to methamphetamine (MA)-seeking behavior, suggesting that microglia could be a new therapeutic target for MA use disorder. Animal data show marked brain microglial activation following acute high-dose MA, but microglial status in human MA users is uncertain, with one positron emission tomography (PET) investigation reporting massively and globally increased translocator protein 18 kDa (TSPO; [C-11](R)-PK11195) binding, a biomarker for microgliosis, in MA users. Our aim was to measure binding of a second-generation TSPO radioligand, [F-18]FEPPA, in brain of human chronic MA users. Regional total volume of distribution (VT ) of [F-18]FEPPA was estimated with a two-tissue compartment model with arterial plasma input function for 10 regions of interest in 11 actively using MA users and 26 controls. A RM-ANOVA corrected for TSPO rs6971 polymorphism was employed to test significance. There was no main effect of group on [F-18]FEPPA VT (P = .81). No significant correlations between [F-18]FEPPA VT and MA use duration, weekly dosage, blood MA concentrations, regional brain volumes, and self-reported craving were observed. Our preliminary findings, consistent with our earlier postmortem data, do not suggest substantial brain microgliosis in MA use disorder but do not rule out microglia as a therapeutic target in MA addiction. Absence of increased [F-18]FEPPA TSPO binding might be related to insufficient MA dose or blunting of microglial response following repeated MA exposure, as suggested by some animal data.

Adverse effect of catechol-O-methyltransferase (COMT) Val158Met met/met genotype in methamphetamine-related executive dysfunction

IntroductionThe Val allele of the Val158Met single-nucleotide polymorphism of the catechol-o-methyltransferase gene (COMT) confers greater catabolism of dopamine (DA) in the prefrontal cortex (PFC) than the Met allele. Met/Met homozygotes typically outperform Val-carriers on tests of executive function (EF), perhaps resulting from increased DA bioavailability. Methamphetamine (METH) causes large releases of DA, which is associated with neurotoxicity and executive dysfunction in chronic METH users. We hypothesized that, contrary to its effect in non-METH-using populations, slower DA clearance conferred by Met/Met will relate to worse EF in METH users. Methods149 non-Hispanic White men, stratified by METH dependence (METH+/−) and COMT (Val/Val, Val/Met, Met/Met), completed three tests of EF: Wisconsin Card Sorting Test (WCST), Stroop Color-Word Test (Stroop), and Trail Making Test Part B (Trails B). Demographically-adjusted test scores were averaged to create an EF composite T-score. We examined the interaction of METH and COMT on the EF composite and individual test T-scores, controlling for premorbid functioning and alcohol use. ResultsMETH group differences in EF were evident only among Met/Met carriers (beta = −9.36, p < .001) but not among Val carriers: Val/Met (beta = −1.38, p = .44) and Val/Val (beta = −4.34, p = .10). These effects were most salient on the WCST. ConclusionsIn the pre-frontal hyperdopaminergic state triggered by methamphetamine, greater DA inactivation conferred by the Val allele may protect against METH-related executive dysfunction, suggesting genetically-driven differences in vulnerability to METH.

Mitochondrial Oxidative Metabolism and Dopamine Neurodegeneration in the Mesolimbic Pathway after Prolonged Methamphetamine Self‐Administration in Mice

The dopaminergic mesolimbic pathway mediates the reinforcing properties of methamphetamine. Postmortem and brain imaging studies indicate that chronic methamphetamine users develop injury and neurodegeneration in the brain structures that form part of this pathway. Moreover, methamphetamine exposure produces an increase of oxidative molecules derived from increased release and metabolism of dopamine, which in turn is thought to initiate an imbalance of the redox metabolism in the mesolimbic pathway. Here we use a model of methamphetamine self‐administration in mice to determine how the oxidative environment produced by chronic methamphetamine exposure affects 1) mitochondrial oxygen consumption rate (OCR) and redox balance of the antioxidant molecule glutathione (GSH) in the ventral tegmental area (VTA) and striatum and, 2) electrophysiological function and survival of dopamine neurons in the VTA. Adult mice were implanted with a jugular catheter and were trained to nose poke to self‐administer methamphetamine in operant chambers in daily two hours sessions. Mice were trained with a schedule that gradually increased the number of nose pokes required to receive an infusion of methamphetamine from a fixed ratio (FR) 1 to a FR3. After training was complete, mice were placed in a FR3 schedule to complete 35–40 days of total methamphetamine self‐administration exposure. Our results showed that drug‐seeking behavior, evaluated with a progressive ratio protocol, was enhanced after 20 days of methamphetamine self‐administration exposure. Using high resolution respirometry and HPLC we detected an increase of mitochondrial OCR accompanied by a decrease of GSH levels in the VTA. Conversely, GSH levels were decreased in the striatum. A decrease in dopamine neuron firing rate and an increase of cell excitability was also detected in whole cell recordings in VTA slices. The number of immunoreactive tyrosine hydroxylase positive neurons was also decreased in the VTA. Our results suggest that prolonged methamphetamine self‐administration exposure produces an oxidative environment along the mesolimbic pathway that affects dopamine neurotransmission and dopamine cell survival in the VTA. The results are consistent with increased oxidative damage in VTA dopamine neurons contributing to neurodegeneration of the mesolimbic pathway and to the development of drug‐seeking behavior with prolonged methamphetamine exposure.Support or Funding InformationThis project was supported by National Institutes of Health Grants R01 DA32701 and AG52606 to MJBThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Amphetamine enantiomers inhibit homomeric α7 nicotinic receptor through a competitive mechanism and within the intoxication levels in humans

Amphetamine-type stimulants (ATS) are the second most consumed illicit drug worldwide and lack good treatments for associated substance use disorders, lagging behind other addictive drugs. For this reason, a deeper understanding of the pharmacodynamics of ATS is required. The present study seeks to determine amphetamine (AMPH) enantiomers' effects on the homomeric α7 nicotinic acetylcholine receptor (α7 nAChR). Here we have shown that AMPH enantiomers bind to the α7 nAChR and competitively inhibit acetylcholine responses. Our in silico docking analysis suggests that AMPH binds close to the β7 strand of the B-loop of a chimera comprising of the human α7 nAChR and the acetylcholine binding protein from Lymnaea stagnalis. This may inhibit the required movement of the C-loop for channel opening, due to steric hindrance, providing a structural mechanism for its antagonist effect. Finally, we have shown that, in α7 nAChR full knockout mice, the behavioral response to D-AMPH is attenuated, providing direct evidence for the role of α7 nAChRs on the physiological response to D-AMPH. Importantly, D-AMPH exerts these effects at concentrations predicted to be pharmacologically relevant for chronic methamphetamine users and during binges. In conclusion, our data present new findings that implicate the α7 nAChR on the pharmacodynamics of ATS, which may be important for behavioral responses to these drugs, indicating a potential role for α7 nAChRs in ATS substance-use disorders.