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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.

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.

RationaleChanges in the density and diversity of gut microbiota in chronic use of methamphetamine have been mentioned as contributors to psychotic and anxiety symptoms, sleep problems, and loss of appetite.ObjectiveIn this placebo-controlled clinical trial, we investigated the effect of the probiotic Lactobacillus Acidophilus in improving psychiatric symptoms among hospitalized patients with chronic methamphetamine use along with psychotic symptoms.Methods60 inpatients with a history of more than 3 years of methamphetamine use, were randomly assigned to one of two groups receiving either a probiotic capsule or placebo along with risperidone for 8 weeks based on a simple randomization method. In weeks 0, 4, and 8, patients were evaluated using the Brief Psychiatric Rating Scale (BPRS), Beck Anxiety Inventory (BAI), Pittsburgh Sleep Quality Index (PSQI), Simple Appetite Nutritional Questionnaire (SANQ), and Body Mass Index (BMI).ResultsCompared to the control group, patients receiving probiotics had better sleep quality, greater appetite, and higher body mass index (there were significant interaction effects of group and time at Week 8 in these variables (t = -3.32, B = -1.83, p = .001, d = 0.89), (t = 10.50, B = 2.65, p <.001, d = 1.25) and (t = 3.40, B = 0.76, p <.001, d = 0.30), respectively. In terms of the improvement of psychotic and anxiety symptoms, there was no statistically significant difference between the two groups.ConclusionsThe use of probiotics was associated with improved sleep quality, increased appetite, and increased body mass index in patients with chronic methamphetamine use. Conducting more definitive clinical trials with larger sample sizes and longer-term follow-up of cases is recommended.

There is increasing interest in the role of mindfulness and mindfulness-based interventions to optimize recovery from a substance use disorder (SUD). However, relatively little is known about the theory-based psychological and social pathways whereby mindfulness could have beneficial effects for managing a chronic, relapsing SUD. Informed by Revised Stress and Coping Theory, the present cross-sectional study examined affective, cognitive, and social pathways whereby mindfulness is associated with lower methamphetamine craving. A total of 161 HIV-positive, methamphetamine-using sexual minority men completed a screening visit for a randomized controlled trial. Using a hybrid structural equation model, we examined pathways whereby mindfulness is associated with lower methamphetamine craving. We found that greater mindfulness was directly associated with lower negative affect and higher positive affect as well as indirectly associated with less methamphetamine craving. Interestingly, the indirect association between mindfulness and methamphetamine craving appeared to be uniquely attributable to positive affect. Only positive affect was indirectly associated with lower methamphetamine craving via higher positive re-appraisal coping and greater self-efficacy for managing triggers for methamphetamine use. Methamphetamine craving was supported by moderate associations with greater substance use severity and more frequent methamphetamine use. These findings support the role of mindfulness in cultivating positive affect, which could be crucial to build the capacity of individuals to manage methamphetamine craving as a chronic stressor that threatens recovery from SUD.

Digital interventions can help to overcome barriers to care, including stigma, geographical distance, and a lack of culturally appropriate treatment options. \"We Can Do This\" is a web-based app that was designed with input from cultural advisors and end users to support Aboriginal and Torres Strait Islander people seeking to stop or reduce their use of methamphetamine and increase psychosocial well-being. This study aimed to evaluate the effectiveness of the \"We Can Do This\" web-based app as a psychosocial treatment for Aboriginal and Torres Strait Islander people who use methamphetamine. The web app was evaluated using a randomized waitlist controlled parallel group trial. Participants were Aboriginal and Torres Strait Islander people aged 16 years or older who self-identified as having used methamphetamine at least weekly for the past 3 months. Participants were randomized on a 1:1 ratio to receive either access to the web-based app for 6 weeks or a waitlist control group. Both groups received access to a website with harm minimization information. The primary outcome was days of methamphetamine use in the past 4 weeks assessed at 1, 2, and 3 months post randomization. Secondary outcomes included severity of methamphetamine dependence (Severity of Dependence Scale [SDS]), psychological distress (Kessler 10 [K10]), help-seeking behavior, and days spent out of role due to methamphetamine use. Participants (N=210) were randomized to receive either access to the web-based app (n=115) or the waitlist control condition (n=95). Follow-up was 63% at 1 month, 57% at 2 months, and 54% at 3 months. There were no significant group differences in days of methamphetamine use in the past 4 weeks at 1 the month (mean difference 0.2 days, 95% CI -1.5 to -2), 2 months (mean difference 0.6 days, 95% CI -1 to 2.4 days) or 3 months (mean difference 1.4 days, 95% CI -0.3 to 3.3 days) follow-up. There were no significant group differences in K10 scores, SDS scores, days out of role, or help-seeking at any of the 3 follow-up timepoints. There was poor adherence to the web-based app, only 20% of participants in the intervention group returned to the web-based app after their initial log-in. Participants cited personal issues and forgetting about the web-based app as the most common reasons for nonadherence. We found poor engagement with this web-based app. The web-based app had no significant effects on methamphetamine use or psychosocial well-being. Poor adherence and low follow-up hindered our ability to accurately evaluate the effectiveness of the web-based app. Future web-based apps for this population need to consider methods to increase participant engagement. Australian New Zealand Clinical Trials Registry ACTRN12619000134123p; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376088. RR2-10.2196/14084.

Reducing psychological craving is critical for preventing relapse in methamphetamine use disorder (MUD). This study aimed to evaluate the efficacy of virtual reality (VR)-based cue exposure therapy (CET) and cue exposure with aversion therapy (CETA) in reducing methamphetamine craving in men with MUD. In this randomized controlled trial, 89 men with MUD were assigned to three groups: VR-based cue exposure therapy (CET, n  = 30), VR-based cue exposure combined with aversion therapy (CETA, n  = 29), and neutral scenes (NS, n  = 30). The intervention comprised 16 sessions over 8 weeks. Primary outcomes were tonic craving and cue-induced craving. Secondary outcomes included attentional bias, rehabilitation confidence, drug refusal self-efficacy, anxiety, and depression. Both CET and CETA groups demonstrated significant reductions in tonic craving post-intervention (CET: p  = 0.001; CETA: p  = 0.010), while the NS group showed no change ( p  = 0.217). The CET group demonstrated significantly lower post-intervention tonic craving compared to the NS group ( p  = 0.047). All groups showed decreased cue-induced craving in drug use scenes ( p  < 0.05). The CETA group showed significantly improved drug refusal self-efficacy compared to baseline ( p  = 0.001) and the NS group ( p  = 0.018). The CET group demonstrated reduced anxiety compared to the NS group ( p  = 0.014). No serious adverse events were reported during VR exposure. VR-based cue exposure therapy, particularly when combined with aversion therapy, effectively reduces psychological craving and improves drug refusal self-efficacy in MUD patients. This study provides evidence supporting VR-based interventions as a safe and promising tool for MUD treatment, though larger-scale trials are needed to confirm long-term efficacy. Clinical trial number : This randomized controlled trial was registered with the Chinese Clinical Trial Registry (Code: ChiCTR1800020014).

Background There are currently no approved pharmacotherapies for managing methamphetamine dependence. N -acetylcysteine (NAC) has been found to reduce the craving for methamphetamine and other drugs, but its effect on methamphetamine use and other clinically related endpoints are uncertain. The N-ICE trial is evaluating the safety and efficacy of NAC as a take-home pharmacotherapy for methamphetamine dependence. Methods/design This is a two-arm parallel double-blind placebo-controlled three-site randomised trial (ratio 1:1) using permuted block randomisation, with variable block sizes. It is stratified by site, sex and whether the methamphetamine is injected or not. Participants ( N  = 180; 60 per site) need to be dependent on methamphetamine, interested in reducing their methamphetamine use and not currently receiving treatment for substance use disorders. The trial is being conducted in outpatient settings in Melbourne, Geelong and Wollongong, Australia. Participants will receive either 2400 mg oral NAC or a matched placebo, delivered as a take-home medication for 12 weeks. Two 600 mg capsules are self-administered in the morning and two more in the evening. Adherence is being monitored using eCAP™ medication bottle lids, which record the date and time of each occasion the bottle is opened. The primary outcome is methamphetamine use during the 12-week trial medication period, measured as (a) days of use, assessed using the timeline followback, and (b) methamphetamine-positive saliva tests, taken weekly. Secondary measures include weekly assessment of methamphetamine craving, severity of methamphetamine dependence, methamphetamine withdrawal symptoms and psychiatric symptoms (depression, suicidality, psychotic symptoms and hostility). Adverse events are monitored at each weekly assessment. Tolerability is assessed using the Treatment Satisfaction Questionnaire for Medication. Discussion The N-ICE trial is the first clinical trial to assess whether NAC can reduce methamphetamine use. This trial will improve our understanding of the potential utility of NAC in managing methamphetamine dependence and clinically related outcomes. If found to be effective, take-home NAC could be a potentially scalable and affordable pharmacotherapy option for treating methamphetamine dependence. Trial registration Australian and New Zealand Clinical Trials Registry, ACTRN12618000366257 . Registered on 29 May 2018.

One known risk factor for drug use and abuse is sensitivity to rewarding effects of drugs. It is not known whether this risk factor extends to sensitivity to non-drug rewards. In this study with healthy young adults, we examined the association between sensitivity to the subjective rewarding effects of amphetamine and a neural indicator of anticipation of monetary reward. We hypothesized that greater euphorigenic response to amphetamine would be associated with greater neural activation to anticipation of monetary reward (Win > Loss). Healthy participants (N = 61) completed four laboratory sessions in which they received d-amphetamine (20 mg) and placebo in alternating order, providing self-report measures of euphoria and stimulation at regular intervals. At a separate visit 1–3 weeks later, participants completed the guessing reward task (GRT) during fMRI in a drug-free state. Participants reporting greater euphoria after amphetamine also exhibited greater neural activation during monetary reward anticipation in mesolimbic reward regions, including the bilateral caudate and putamen. This is the first study to show a relationship between neural correlates of monetary reward and sensitivity to the subjective rewarding effects of amphetamine in humans. These findings support growing evidence that sensitivity to reward in general is a risk factor for drug use and abuse, and suggest that sensitivity of drug-induced euphoria may reflect a general sensitivity to rewards. This may be an index of vulnerability for drug use or abuse.

Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse treatment clinics located west of the Mississippi participated in the study. One hundred and fifty-one treatment-seekers with DSM-IV diagnosis of methamphetamine dependence were consented and enrolled. Seventy-two participants were randomized to placebo and 79 to sustained-release bupropion 150 mg twice daily. Patients were asked to come to the clinic three times per week for assessments, urine drug screens, and 90-min group psychotherapy. The primary outcome was the change in proportion of participants having a methamphetamine-free week. Secondary outcomes included: urine for quantitative methamphetamine, self-report of methamphetamine use, subgroup analyses of balancing factors and comorbid conditions, addiction severity, craving, risk behaviors for HIV, and use of other substances. The generalized estimating equation regression analysis showed that, overall, the difference between bupropion and placebo groups in the probability of a non-use week over the 12-week treatment period was not statistically significant ( p =0.09). Mixed model regression was used to allow adjustment for baseline factors in addition to those measured (site, gender, level of baseline use, and level of symptoms of depression). This subgroup analysis showed that bupropion had a significant effect compared to placebo, among male patients who had a lower level of methamphetamine use at baseline ( p <0.0001). Comorbid depression and attention-deficit/hyperactivity disorder did not change the outcome. These data suggest that bupropion, in combination with behavioral group therapy, was effective for increasing the number of weeks of abstinence in participants with low-to-moderate methamphetamine dependence, mainly male patients, regardless of their comorbid condition.