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Rationale Stimulant drugs like methamphetamine (MA) activate brain reward circuitry, which is linked to the development of problematic drug use. It is not clear how drugs like MA alter neural response to a non-drug reward. Objectives We examined how acute MA impacts neural response to receipt of a monetary reward relative to a loss in healthy adults. We hypothesized that MA (vs. placebo) would increase mesolimbic neural activation to reward, relative to loss. Methods In a within-subject, randomized, cross-over, double-blind, placebo-controlled design, 41 healthy adults completed the Doors monetary reward task during fMRI after ingestion of placebo or 20 mg MA. We examined drug effects on neural response to reward receipt (Win vs. Loss) using a priori anatomical striatal regions of interest (nucleus accumbens (NAcc), caudate, putamen). Results MA decreased NAcc BOLD activation to reward vs loss compared to placebo ( p =.007) without altering caudate or putamen BOLD activation. Similar effects for reward vs. loss were obtained using whole brain analysis. Additional exploratory ROI analysis comparing reward and loss activation relative to a neutral “fixation” period indicated that MA increased NAcc BOLD activation during loss trials, without decreasing activation during win trials. Conclusions This preliminary evidence suggests that MA increases NAcc neural response to the receipt of monetary loss. Additional studies are needed to replicate our findings and clarify the mechanisms contributing to altered mesolimbic neural response to reward and loss receipt during stimulant intoxication.

Abstract Background Although transcranial direct current stimulation (tDCS) has shown to potentially mitigate drug craving and attentional bias to drug-related stimuli, individual differences in such modulatory effects of tDCS are less understood. In this study, we aimed to investigate a source of the inter-subject variability in the tDCS effects that can be useful for tDCS-based treatments of individuals with methamphetamine (MA) use disorder (IMUD). Methods Forty-two IMUD (all male) were randomly assigned to receive a single-session of either sham or real bilateral tDCS (anodal right/cathodal left) over the dorsolateral prefrontal cortex. The tDCS effect on MA craving and biased attention to drug stimuli were investigated by quantifying EEG-derived P3 (a measure of initial attentional bias) and late positive potential (LPP; a measure of sustained motivated attention) elicited by these stimuli. To assess the association of changes in P3 and LPP with brain connectivity network (BCN) topology, the correlation between topology metrics, specifically those related to the efficiency of information processing, and the tDCS effect was investigated. Results The P3 amplitude significantly decreased following the tDCS session, whereas the amplitudes increased in the sham group. The changes in P3 amplitudes were significantly correlated with communication efficiency measured by BCN topology metrics (r = −0.47, P = .03; r = −0.49, P = .02). There was no significant change in LPP amplitude due to the tDCS application. Conclusions These findings validate that tDCS mitigates initial attentional bias, but not the sustained motivated attention, to MA stimuli. Importantly, however, results also show that the individual differences in the effects of tDCS may be underpinned by communication efficiency of the BCN topology, and therefore, these BCN topology metrics may have the potential to robustly predict the effectiveness of tDCS-based interventions on MA craving and attentional bias to MA stimuli among IMUD.

Background There are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic antidepressant, to be effective in reducing methamphetamine use. The proposed Tina Trial is the first phase 3 placebo-controlled randomised trial to examine the effectiveness and safety of mirtazapine as an outpatient pharmacotherapy for methamphetamine use disorder. Methods This is a multi-site phase 3 randomised, double-blind, placebo-controlled parallel trial. Participants are randomly allocated (1:1) to receive either mirtazapine (30 mg/day for 12 weeks) or matched placebo, delivered as a take-home medication. The target population is 340 people aged 18–65 years who have moderate to severe methamphetamine use disorder. The trial is being conducted through outpatient alcohol and other drug treatment clinics in Australia. The primary outcome is measured as self-reported days of methamphetamine use in the past 4 weeks at week 12. Secondary outcomes are methamphetamine-negative oral fluid samples, depressive symptoms, sleep quality, HIV risk behaviour and quality of life. Other outcomes include safety (adverse events), tolerability, and health service use. Medication adherence is being monitored using MEMS® Smart Caps fitted to medication bottles. Discussion This trial will provide information on the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder when delivered as an outpatient medication in routine clinical practice. If found to be safe and effective, this trial will support an application for methamphetamine use disorder to be included as a therapeutic indication for the prescription of mirtazapine. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12622000235707. Registered on February 9, 2022.

Patients and psychotherapists often exhibit behavioral, psychological, and physiological similarity. Here, we test whether oxytocin—a neuropeptide that can enhance expressivity and social perception—influences time-lagged “linkage” of autonomic nervous system responses among participants and facilitators during group therapy. Physiological linkage estimates ( n  = 949) were created from ten cohorts, each with two facilitators ( n  = 5) and four to six participants ( n  = 48), over six weekly sessions of group therapy for methamphetamine use disorder. All participants of a cohort received oxytocin or placebo intranasally in a randomized double-blind procedure before each session. Cardiac interbeat intervals (IBI) were measured continuously during sessions to estimate physiological linkage, operationalized as one cohort-mate’s IBI reactivity during one minute predicting another cohort-mate’s IBI reactivity during the following minute. In oxytocin cohorts, participants and facilitators experienced significant physiological linkage to their cohort-mates (i.e., their physiological responses were predicted by the prior responses of their cohort-mates) and significantly more linkage than people in placebo cohorts. Both effects occurred during the first and second sessions but not later sessions. Results suggest that oxytocin may enhance psychosocial processes often associated with linkage—such as social engagement—in groups and highlight oxytocin’s potential to improve group cohesion during group therapy. Clinical Trials Registration: NCT02881177, First published on 26/08/2016.

Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo-controlled human laboratory study of NTX. Non-treatment-seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5-day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared with placebo. NTX decreased overall subjective ratings of 'crave drug,' 'stimulated,' and 'would like drug access,' decreased the the post-MA administration timecourse of 'anxious' and increased ratings of 'bad drug effects,' as compared with placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence, as well as ongoing clinical trials for MA.

Background The purpose of this study was to compare the effect of 300 mg of bupropion and 8 mg of buprenorphine per day on the treatment of methamphetamine withdrawal cravings over a 2-week treatment interval. Method Sixty-five methamphetamine-dependent men who met the DSM-IV-TR ( Diagnostic and Statistical Manual of Mental Disorders , 4th edition, text revision) criteria for methamphetamine dependence and withdrawal were randomly divided into two groups. Subjects randomly received 300 mg of bupropion or 8 mg of buprenorphine per day in a psychiatric ward. Of the 65 subjects, 35 (53.8%) received buprenorphine and 30 (46.2%) received bupropion. The subjects were assessed by using methamphetamine craving score, interview, and negative urine drug test. Findings There were no statistically significant differences between the two groups in regard to age, education, duration of methamphetamine dependency, marital status, employment, and income. The mean ages were 32.8 years (standard deviation (SD) = 7.26, range = 22 to 59) for the buprenorphine group and 32.21 years (SD = 8.45, range = 17 to 51) for the bupropion group. All 65 patients completed the 2-week study. Both medications were effective in the reduction of methamphetamine cravings. Reduction of craving in the buprenorphine group was significantly more than the bupropion group ( P = 0.011). Overall, a significant main effect of day ( P <0.001) and group ( P = 0.011) and a non-significant group-by-day interaction ( P >0.05) were detected. Conclusions The results support the safety and effectiveness of buprenorphine and bupropion in the treatment of methamphetamine withdrawal craving. Administration of 8 mg of buprenorphine per day can be recommended for the treatment of methamphetamine withdrawal cravings. We should note that it is to be expected that craving decreases over time without any medication. So the conclusion may not be that bupropion and buprenorphine both lower the craving. As the buprenorphine is superior to bupropion, only buprenorphine does so for sure. Trial registration Iranian Registry of Clinical Trials (IRCT) registration number: IRCT2015010320540N1 . Date registered: April 10, 2015.

Impulsivity during periods of abstinence is a critical symptom of patients who use methamphetamine (MA). To evaluate changes in impulse inhibition elicited by repetitive transcranial magnetic stimulation (rTMS) in patients with MA addiction. This randomized clinical trial was conducted in Da Lian Shan Addiction Rehabilitation Center, Nanjing, China, from December 1, 2018, to April 20, 2019. Effects of the intervention were examined at 3 time points: after a single session (day 1), 24 hours after 10 repeated sessions (day 11), and at 3 weeks of follow-up (day 31). Men with MA addiction and healthy male control participants were recruited for this study. Data analysis was performed from March 2019 to October 2019. Patients who use MA were randomized to undergo sham rTMS (36 patients) and or 1-Hz rTMS (37 patients) to the left prefrontal cortex, receiving daily TMS treatments for 10 consecutive days. The primary outcome was impulse inhibition, which is primarily embodied by accuracy reduction (ie, accuracy cost) from standard to deviant trials in a 2-choice oddball task (80% standard and 20% deviant trials). The study included 73 men with MA addiction (mean [SD] age, 38.49 [7.69] years) and 33 male healthy control participants without MA addiction (mean [SD] age, 35.15 [9.68] years). The mean (SD) duration of abstinence for the men with MA addiction was 9.27 (4.61) months. Compared with the control group, patients with MA addiction exhibited greater impulsivity (accuracy cost, 3.3% vs 6.2%). The single session of 1-Hz rTMS over the left prefrontal cortex significantly increased accuracy from 91.4% to 95.7% (F1,36 = 9.58; P < .001) and reaction time delay from 50 milliseconds to 77 milliseconds (F1,36 = 22.66; P < .001) in deviant trials. These effects were seen consistently after 10 sessions of 1-Hz rTMS treatment (day 11 vs day 1, t26 = 1.59; P = .12), and the behavioral improvement was maintained at least for 3 weeks after treatment (day 31 vs day 1, t26 = 0.26; P = .80). These improvement effects of impulse inhibition were coupled with a reduction in addictive symptoms as measured by cue-induced craving. The pretest accuracy cost was positively correlated with the change in impulse inhibition (r = 0.615; P < .001) and change in craving (r = 0.334; P = .01), suggesting that these 2 behaviors may be modified simultaneously. These findings suggest that repeated rTMS sessions have sustained effects on impulse inhibition in patients with MA addiction and provide novel data on impulsivity management strategies for addiction rehabilitation. ChiCTR-ROC-16008541.

RationaleAttentional bias toward drug-related stimuli is a feature of drug addiction that is linked to craving and drug-seeking behavior.Objectives/methodAn attentional bias modification (ABM) program was tested in 42 methamphetamine-dependent clients (DSM-IV criteria) receiving residential treatment for their drug use. Participants were randomly assigned to one of two groups (N = 21 each), receiving 12 sessions of either computerized ABM training (designed to train attention away from methamphetamine stimuli 100% of the time) or an attentional control condition (designed to train attention away from methamphetamine stimuli 50% of the time). Outcome measures included attentional bias to methamphetamine-related stimuli on a probe detection task, self-reported craving, and preferences to view methamphetamine-related images on a Simulated Drug Choice Task. A subset of participants (N = 17) also underwent fMRI in a cue-induced craving paradigm.ResultsPoor split-half reliability was observed for the probe detection task. Using this task, attentional bias toward methamphetamine-related stimuli was greater after training than at baseline, irrespective of group (p = 0.037). Spontaneous and cue-induced methamphetamine craving diminished with time (ps < 0.01), but ABM training did not influence these effects (group by time interactions, ps > 0.05). ABM training did not influence selection of methamphetamine-related pictures in the Simulated Drug Choice task (p > 0.05). In the fMRI assessment, cue-induced activation in the ventromedial prefrontal cortex was reduced over time, without an effect of ABM training.ConclusionsABM training did not improve several clinically relevant variables in treatment-seeking methamphetamine users. Additional research is needed to improve the measurement of attentional bias.

Interactions between dopaminergic and opioidergic systems have been implicated in the reinforcing properties of drugs of abuse. The present study investigated the effects of opioid blockade, via naltrexone, on functional magnetic resonance imaging (fMRI) measures during methamphetamine cue-reactivity to elucidate the role of endogenous opioids in the neural systems underlying drug craving. To investigate this question, non-treatment seeking individuals with methamphetamine use disorder (N=23; 74% male, mean age=34.70 (SD=8.95)) were recruited for a randomized, placebo controlled, within-subject design and underwent a visual methamphetamine cue-reactivity task during two blood-oxygen-level dependent (BOLD) fMRI sessions following 3 days of naltrexone (50 mg) and matched time for placebo. fMRI analyses tested naltrexone-induced differences in BOLD activation and functional connectivity during cue processing. The results showed that naltrexone administration reduced cue-reactivity in sensorimotor regions and related to altered functional connectivity of dorsal striatum, ventral tegmental area, and precuneus with frontal, visual, sensory, and motor-related regions. Naltrexone also weakened the associations between subjective craving and precuneus functional connectivity with sensorimotor regions and strengthened the associations between subjective craving and dorsal striatum and precuneus connectivity with frontal regions. In conclusion, this study provides the first evidence that opioidergic blockade alters neural responses to drug cues in humans with methamphetamine addiction and suggests that naltrexone may be reducing drug cue salience by decreasing the involvement of sensorimotor regions and by engaging greater frontal regulation over salience attribution.

Methamphetamine (METH) is a widely abused stimulant that affects the central nervous system. The persistent maladaptive conditioned stimuli (CS, drug cues)-drug associative memories represent a primary factor precipitating relapse. Interfering with the reconsolidation of these memories may help disrupt and modify these maladaptive CS-drug associations, potentially reducing their influence on drug-seeking behavior. The present study explored the effect of CS-triggered memory retrieval-extinction on METH craving, potentially offering a new treatment strategy for addiction. This was a single-center, randomized, controlled trial involving individuals with METH use disorder (MUD). Participants completed one of three interventions on consecutive days (days 2 and 3): CS-triggered memory retrieval followed by extinction after a 10-min interval, CS-triggered memory retrieval followed by extinction after a 6-h interval, or extinction without prior retrieval. Self-report cue-induced craving for METH, salivary cortisol and sympathetic responses were measured at baseline (day 1), post intervention (day 4) and two follow-up timepoints (days 34 and 184), with cue-induced craving and salivary cortisol as primary outcomes. Ninety-eight MUD individuals (mean age 28.15 ± 6.31) were analyzed. After two-day’s interventions, cue-induced METH craving (time × cue interaction: F (1,94)  = 60.02, p  < 0.001) reduced in all groups. Results from follow-up data indicated, when the extinction was performed 10 min, but not 6 h after memory retrieval or no retrieval, the intervention decreased experimental cue-induced METH craving (intervention × time × cue: F (2,94)  = 14.32, p  < 0.001; intervention: F (2,94)  = 24.28, p  < 0.001) and saliva cortisol increases (F (2,90)  = 9.51, p  < 0.001), with effects lasting up to 6-month follow-up. The results revealed a substantial reduction in cue-elicited craving and saliva cortisol in the retrieval-10 min-extinction group over the 6-month follow-up. These findings provide compelling evidence that a brief reconsolidation-based intervention can effectively diminish METH-related craving and cortisol levels, underscoring its potential as a supportive measure in METH treatment. Salivary cortisol is a readily accessible and sensitive biomarker for evaluating intervention effects.