Acute methamphetamine and alcohol usage alters gaze behaviour during driving: A randomised, double-blind, placebo-controlled study.

BACKGROUND: Methamphetamine is frequently co-consumed with alcohol, yet combined effects on visually guided behaviours have not been experimentally assessed. This study examined whether methamphetamine and alcohol-induced changes in gaze behaviour can be accurately detected and indexed during a simulated driving task to establish characteristic patterns relevant to traffic safety. METHODS: In a randomised, placebo-controlled, cross-over study design, the effects of acute oral methamphetamine (0.42 mg/kg) were assessed with and without low doses of alcohol (target 0.04% blood alcohol content) on gaze behaviour during driving. Twenty healthy adults (mean age 29.5 years (SD ± 4.9), 40% female) completed four, 1-h simulated drives with simultaneous eye monitoring using the SensoMotoric Instruments cap-mounted eye tracker over a 4-week experimental paradigm. Gaze entropy measures were used to quantify visual scanning efficiency, expressed as gaze transition entropy and stationary gaze entropy. Fixations, recorded as duration (milliseconds, ms) and rate (count) per minute, were examined in 10-min bins over the duration of the drive. Driving performance was assessed by the standard deviation of lateral position, standard deviation of speed and steering variability. RESULTS: Methamphetamine increased the rate and duration of fixations and produced a less dispersed but more disorganised pattern of gaze during highway driving while preserving performance. Alcohol alone impaired both oculomotor control and driving performance, even when consumed at levels well below the legal limit stipulated in many international jurisdictions. CONCLUSIONS: Methamphetamine-affected drivers display inefficient exploration in a limited visual range during driving. Eye-tracking metrics thus show potential for indexing intoxication due to psychoactive substance usage.

3-CMC, 4-CMC, and 4-BMC Human Metabolic Profiling: New Major Pathways to Document Consumption of Methcathinone Analogues?

Synthetic cathinones represent one of the largest and most abused new psychoactive substance classes, and have been involved in numerous intoxications and fatalities worldwide. Methcathinone analogues like 3-methylmethcathinone (3-MMC), 3-chloromethcathinone (3-CMC), and 4-CMC currently constitute most of synthetic cathinone seizures in Europe. Documenting their consumption in clinical/forensic casework is therefore essential to tackle this trend. Targeting metabolite markers is a go-to to document consumption in analytical toxicology, and metabolite profiling is crucial to support investigations. We sought to identify 3-CMC, 4-CMC, and 4-bromomethcathinone (4-BMC) human metabolites. The substances were incubated with human hepatocytes; incubates were screened by liquid chromatography-high-resolution tandem mass spectrometry and data were mined with Compound Discoverer (Themo Scientific). 3-CMC-positive blood, urine, and oral fluid and 4-CMC-positive urine and saliva from clinical/forensic casework were analyzed. Analyses were supported by metabolite predictions with GLORYx freeware. Twelve, ten, and ten metabolites were identified for 3-CMC, 4-CMC, and 4-BMC, respectively, with similar transformations occurring for the three cathinones. Major reactions included ketoreduction and N-demethylation. Surprisingly, predominant metabolites were produced by combination of N-demethylation and ω-carboxylation (main metabolite in 3-CMC-positive urine), and combination of ß-ketoreduction, oxidative deamination, and O-glucuronidation (main metabolite in 4-CMC-positive urine). These latter metabolites were detected in negative-ionization mode only and their non-conjugated form was not detected after glucuronide hydrolysis; this metabolic pathway was never reported for any methcathinone analogue susceptible to undergo the same transformations. These results support the need for comprehensive screening strategies in metabolite identification studies, to avoid overlooking significant metabolites and major markers of consumption.

A phase 3 randomised double-blind placebo-controlled trial of mirtazapine as a pharmacotherapy for methamphetamine use disorder: a study protocol for the Tina Trial.

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.

Effects of electroacupuncture combined with paliperidone palmitate long-acting injection on withdrawal symptoms and neurotransmitters in methamphetamine addicts.

OBJECTIVE: To investigate the effects of electroacupuncture combined with paliperidone palmitate long-acting injection (PP-LAI) on withdrawal symptoms and neurotransmitters in methamphetamine (MA) addicts. MATERIALS AND METHODS: A total of 109 methamphetamine addicts, who were treated in the hospital from October 2021 to October 2022, were selected. According to the random number table, the patients were divided into the study group (n=54) and the control group (n=55), in which the control group was treated with PP-LAI and the study group was treated with electroacupuncture on the basis of the control group; the methamphetamine withdrawal symptom score scale was used to assess the therapeutic effect before treatment and within 12 months after treatment; the changes of brain neurotransmitters dopamine, γ-aminobutyric acid, serotonin, acetylcholine values were compared between the two groups. RESULTS: 1) There was no statistical difference in MA withdrawal symptom scores between the two groups before treatment (p>0.05); 2) MA withdrawal symptom scores have a statistically significant difference between the study group and the control group after 3 and 6 months of treatment; 3) dopamine levels in the study group were significantly higher than those in the control group after 6 months of completion of treatment, and γ-aminobutyric acid values and 5- serotonin values in the study group were significantly lower than those in the control group (p<0.05). CONCLUSIONS: Electroacupuncture combined with PP-LAI can partially improve the withdrawal symptoms and anxiety of methamphetamine addicts. This is a potential treatment for preventing relapse of withdrawal symptoms.

Regional-specific changes in rat brain BDNF in a model of methamphetamine abuse.

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays key roles in neuronal protection and synaptic plasticity. Changes in BDNF are associated with various pathological conditions, including methamphetamine (meth) addiction, although the effects of meth on BDNF expression are not always consistent. We have previously demonstrated region-specific effects of a chronic meth regime on BDNF methylation and expression in the rat brain. This study aims to determine the effect of chronic meth administration on the expression of BDNF protein using immunohistochemistry in the rat frontal cortex and hippocampus. Novel object recognition (NOR) as a measure of cognitive function was also determined. Male Sprague Dawley rats were administered a chronic escalating dose (0.1-4 mg/kg over 14 days) (ED) of meth or vehicle; a subgroup of animals receiving meth were also given an acute "binge" (4x6mg) dose on the final day before NOR testing. The results showed that hippocampal CA1 BDNF protein was significantly increased by 72 % above control values in the ED-binge rats, while other hippocampal regions and frontal cortex were not significantly affected. Meth-administered animals also demonstrated deficits in NOR after 24 h delay. No significant effect of the additional binge dose on BDNF protein or NOR findings was apparent. This finding is consistent with our previous results of reduced DNA methylation and increased expression of the BDNF gene in this region. The hippocampal BDNF increase may reflect an initial increase in a protective factor produced in response to elevated glutamate release resulting in neurodegenerative excitotoxicity.

Inhibition of GSDMD-dependent pyroptosis decreased methamphetamine self-administration in rats.

It is widely believed that the activation of the central dopamine (DA) system is crucial to the rewarding effects of methamphetamine (METH) and to the behavioral outcomes of METH use disorder. It was reported that METH exposure induced gasdermin D (GSDMD)-dependent pyroptosis in rats. The membrane pore formation caused by METH-induced pyroptosis may also contribute to the overflow of DA into the extracellular space and subsequently increase the DA levels in the brain. The present study firstly investigated whether the membrane pore information induced by GSDMD-dependent pyroptosis was associated with the increased DA levels in the ventral tegmental area (VAT) and nucleus accumbens (NAc) of rats self-administering METH and SY-SH5Y cells treated by METH. Subsequently, the effect of pore formation blockade or genetic inhibition of GSDMD on the reinforcing and motivational effect of METH was determined in rats, using the animal model of METH self-administration (SA). METH exposure significantly increased the activity of NLRP1/Cas-1/GSDMD pathway and the presence of pyroptosis, accompanied by the significantly increased DA levels in VTA and NAc. Moreover, intraperitoneal injections of disulfiram (DSF) or microinjection of rAAV-shGSDMD into VTA/NAc significantly reduced the reinforcing and motivational effect of METH, accompanied by the decreased level of DA in VTA and NAc. The results provided novel evidence that METH-induced pyroptosis could increase DA release in VTA and NAc via the NLRP1/Cas-1/GSDMD pathway. Additionally, membrane pores or GSDMD blockade could significantly reduce the reinforcing and motivational effect of METH. In conclusion, blocking GSDMD and membrane pore formation could be a promising potential target for the development of agents to treat METH use disorder.

Injection preparation filtration and health concerns among indigenous people who inject methamphetamine.

Introduction: Injecting methamphetamine poses significant health risks, but little is known about how methamphetamine injectors filter their injection preparations and experience related health concerns. Methods: A chain-referral sample of Indigenous people who inject methamphetamine (n = 30) was recruited and semistructured interviews were conducted to collect information on filtration practices and health concerns. Results: Filtration of the injection preparation was described by 53% of injectors. Elevated levels of concern for kidney disease, cancer and heart disease were observed among those who filtered their preparations (ranging from 50 to 56.3%). Concern about liver disease was the most frequent concern among those who filtered their preparations (62.5%) and was elevated in comparison to those who did not use filters (7.1%). Grouped logistic regression revealed a positive association between filtration of the injection preparation and overall health concerns expressed by injectors, after adjusting for gender and age. The marginal posterior distribution of the adjusted odds ratio for filtration of the injection preparation had a posterior median = 35.7, and 95% HPD interval = (5.1, 512.4). Discussion: Results illustrate a positive relationship between filtration of the injection preparation and health concerns among Indigenous people who inject methamphetamine. This likely reflects the use of filtration to reduce harms, and further research is needed to understand the full scope of prevention that may be associated with filtration of methamphetamine injection preparations.

Can Methamphetamine-Induced Cardiotoxicity be Ameliorated by Aerobic Training and Nutrition Bio-shield Superfood Supplementation in Rats After Withdrawal?

The abuse of methamphetamine is a significant threat to cardiovascular health and has detrimental effects on the myocardium. The present study aims to explore potential interventions that can mitigate myocardial pyroptosis in rats following methamphetamine withdrawal. A total of 104 male Wistar rats were randomly assigned to eight groups. The rats underwent a methamphetamine administration protocol, receiving intraperitoneal injections of 10 mg/kg during the 1st week, followed by a weekly dose escalation of 1 mg/kg from the second to the 6th week and two times per day. Concurrently, the rats engaged in 6 weeks of moderate-intensity treadmill aerobic training, lasting 60 min per day, 5 days a week. Simultaneously, the Nutrition bio-shield Superfood (NBS) supplement was administered at a dosage of 25 g/kg daily for 6 weeks. The study assessed the expression levels of Caspase-1, Interleukin-1beta (IL-1ß), and Interleukin-18 (IL-18) genes in myocardial tissue. Data analysis utilized a one-way analysis of variance (p ≤ 0.05). The findings revealed that methamphetamine usage significantly elevated the expression of Caspase-1, IL-1ß, and IL-18 genes (p ≤ 0.05). Conversely, methamphetamine withdrawal led to a notable reduction in the expression of these genes (p ≤ 0.05). Noteworthy reductions in Caspase-1, IL-1ß, and IL-18 expression were observed following aerobic training, supplementation, and the combined approach (p ≤ 0.05). The chronic use of methamphetamine was associated with cardiac tissue damage. This study highlights the potential of aerobic training and NBS Superfood supplementation in mitigating the harmful effects of methamphetamine-induced myocardial pyroptosis. The observed reductions in gene expression levels indicate promising interventions to address the cardiovascular consequences of methamphetamine abuse. The findings of this study suggest that a combination of aerobic exercise and NBS Superfood supplementation can provide a promising approach to mitigate the deleterious effects of methamphetamine on the heart. These findings can be useful for healthcare professionals and policymakers to design effective interventions to prevent and manage the adverse effects of methamphetamine abuse.

Safety strategies and harm reduction for methamphetamine users in the era of fentanyl contamination: A qualitative analysis.

INTRODUCTION: In the United States, methamphetamine use is increasing and the context of its use has changed, with reports of illicitly manufactured fentanyl being mixed with methamphetamine (either deliberately or inadvertently). We explore risk-mitigating actions taken by people who use drugs to protect their health when using methamphetamine in that context. METHODS: We conducted qualitative interviews with 48 adults (18+) who used methamphetamine in the past three months at two sites in Nevada, USA and two sites in New Mexico, USA. Interviews were recorded, transcribed, and analyzed using thematic analysis. RESULTS: Respondents described two rationales for employing harm reduction strategies. First, to prevent harm from methamphetamine containing illicit fentanyl, and second, to maintain their general wellbeing while using methamphetamine. Regarding methamphetamine containing illicit fentanyl, our findings highlight how respondents employ primary strategies like buying from trusted sources and secondary strategies such as spotting and selective use of harm reduction tools (i.e., fentanyl test strips) to reduce risks. To maintain their general wellbeing, participants reduced their use of methamphetamine as reasonably as possible, and used other substances like marijuana and alcohol alongside methamphetamine to counter the unwanted side effects of methamphetamine (i.e., hallucinations and paranoia). Use of these harm reduction strategies varied within situational and social contexts, and respondents usually developed these strategies based on their lived experiences. CONCLUSION: Our findings uniquely demonstrate that people who use methamphetamine prioritize community driven, trust-based strategies within their social networks to mitigate risks in a fentanyl-contaminated drug environment. Additionally, our results indicate that harm reduction behaviors are influenced by multilevel risk environments, which include social, physical, economic, and political factors. Overall, these results highlight the potential for targeted interventions at the network level, which are responsive to complexities and shifts in drug market dynamics- such as illicit fentanyl in methamphetamine.

Adolescent alcohol binge drinking and withdrawal: behavioural, brain GFAP-positive astrocytes and acute methamphetamine effects in adult female rats.

RATIONALE: Alcopop beverages are generally the first alcoholic beverage that young females drink which contain high levels of sugar and alcohol. The over-consumption of these drinks may encourage alcohol co-administration with methamphetamine (METH) impacting on drinking behaviour and glial function. AIMS: The aims of this study were to evaluate the effect of adolescent binge alcohol exposure on consumption level, anxiety-like behaviour, cross-sensitization with METH and on astrocyte expression in reward related brain regions. METHODS: Adolescent female Sprague-Dawley rats had daily 1-hour oral alcohol consumption of alcopop (ALCP; with sucrose) or ethanol-only (ETOH; without sucrose), transitioned from 5 to 15% (v/v) ethanol content for 34 days. Water and sucrose groups act as controls. During alcohol withdrawal, rats were tested for anxiety on the elevated plus maze (EPM) and locomotor activity following saline or METH (1 mg/kg i.p) treatment. Brains were then collected to assess astrocyte immunofluorescence for glial fibrillary acidic protein (GFAP) in reward-related brain regions. RESULTS: Rats pretreated with 5% ALCP consumed significantly more volume and ethanol intake when compared to 5% EtOH rats. Both ALCP and EtOH groups had a higher preference ratio for 5% than 15% alcohol solutions and ALCP rats had greater ethanol intake at 15% than EtOH rats. Alcohol withdrawal showed no significant differences between groups on anxiety, METH cross-sensitization effects or GFAP intensity in the regions studied. CONCLUSIONS: Overall, the addition of sucrose to alcoholic solutions encouraged female rats to consume larger volumes and greater ethanol intake compared to ethanol-only solutions, yet did not have long lasting effects on behaviour and astrocytes.

Changes in injecting versus smoking heroin, fentanyl, and methamphetamine among people who inject drugs in San Diego, California, 2020-2023.

BACKGROUND: Amidst an increasingly toxic drug supply in North America, people who inject drugs may be transitioning to smoking them. We aimed to assess changes in injecting and smoking opioids and methamphetamine among a cohort of people who inject drugs from San Diego, California. METHODS: Over five six-month periods spanning October 2020-April 2023, we assessed prevalence of injecting and smoking opioids or methamphetamine and whether participants used these drugs more frequently by smoking than injecting. Multivariable Poisson regression via generalized estimating equations was used to examine time trends. RESULTS: Of 362 participants, median age was 40 years; a minority were female (29%), Hispanic/Latinx/Mexican (45%), and housed (33%). Among this cohort, of whom 100% injected (and 84% injected and smoked) in period one (October 2020-April 2021), by period five (November 2022-April 2023), 34% only smoked, 59% injected and smoked, and 7% only injected. By period five, the adjusted relative risk (aRR) of injecting opioids was 0.41 (95% Confidence Interval [CI]: 0.33, 0.51) and the aRR for injecting methamphetamine was 0.50 (95% CI: 0.39, 0.63) compared to period one. Risks for smoking fentanyl rose significantly during period three (aRR=1.44, 95% CI: 1.06, 1.94), four (aRR=1.65, 95% CI: 1.24, 2.20) and five (aRR=1.90, 95% CI: 1.43, 2.53) compared to period one. Risks for smoking heroin and methamphetamine more frequently than injecting these drugs increased across all periods. CONCLUSIONS: Opioid and methamphetamine injection declined precipitously, with notable increases in smoking these drugs. Research is needed to understand the health consequences of these trends.

Innovation and adaptation: The rise of a fentanyl smoking culture in San Francisco.

BACKGROUND: Illicitly manufactured fentanyls and stimulants are implicated in the escalating US mortality from drug overdose. San Francisco, California (SF) has seen declining fentanyl injection while smoking has increased. Beliefs and behaviors surrounding this development are not well understood. METHODS: The study used rapid ethnography to explore fentanyl and methamphetamine use in SF. The team conducted semi-structured interviews (n = 34) with participants recruited from syringe service programs. Video-recorded smoking sequences (n = 12), photography and daily field notes supplemented interview data. RESULTS: Difficulty injecting and fear of overdose motivated transitions from injecting to smoking. Fentanyl was extremely cheap-$10/gram-with variability in quality. Foil was the most commonly used smoking material but glass bubbles, bongs and dabbing devices were also popular. No reliable visible methods for determining fentanyl quality existed, however, participants could gauge potency upon inhalation, and developed techniques to regulate dosage. Several participants reported at least hourly use, some reporting one or more grams of daily fentanyl consumption. Smoking was also very social, with people sharing equipment, drugs and information. Participants raised concerns about hygiene and overdose risk to others arising from shared equipment. Reportedly potent fentanyl 'residue' accumulated on smoking materials and was commonly shared/traded/stolen or consumed accidentally with diverse preferences for its use. CONCLUSION: Our data highlight fentanyl residue as a new overdose risk with potential mismatch between the potency of the residual drug and the recipient's tolerance. Further, large doses of fentanyl are being consumed (estimated at approximately 50 mg of pure fentanyl/day). Smoking fentanyl has potential health benefits over injecting and may be protective against overdose, but substantial uncertainty exists. However, SF overdose mortality hit a record high in 2023. Recommendations to reduce fentanyl smoking overdose risks through pacing, greater awareness of dosages consumed and checking tolerance of residue recipients are potentially viable interventions deserving further exploration.

Co-administration of naloxone and dexmedetomidine to simultaneously reverse acute effects of fentanyl and methamphetamine in rats.

BACKGROUND: The incidence of combination methamphetamine (METH)-opioid overdose has substantially increased in recent years. While agitation is uncommon after the naloxone (NLX) reversal of opioids, it is a major clinical concern in acute METH intoxication and can be physiologically antagonized by opioid-induced sedation. This study aimed to perform initial preclinical analysis of the safety and efficacy of dexmedetomidine (DEXMED) co-administered with NLX to attenuate METH-induced locomotor activity, as a rat model of agitation, after the reversal of fentanyl (FENT)-induced sedation. METHODS: Male Sprague Dawley rats were administered subcutaneous (SC) 0.1mg/kg FENT ± 1mg/kg METH. Fifteen min later, SC 0.1mg/kg NLX ± an increasing (0, 0.032, 0.056, and 0.1mg/kg) DEXMED dose was administered prior to the measurement of locomotor activity. After a washout period, the FENT ± METH and NLX ± DEXMED administration with the highest dose of DEXMED was administered for measurement of blood oxygen saturation and heart rate. RESULTS: After the NLX reversal of FENT-induced sedation, adjunct DEXMED substantially and significantly reduced METH-induced locomotor activity (p<0.05) at all doses tested. While the addition of DEXMED did not significantly reduce blood oxygenation in METH treated rats, it did so in the absence of METH. Also, DEXMED significantly reduced heart rate compared to non-DEXMED treated groups and resulted in further significant reductions in the animals not exposed to METH (p<0.05). CONCLUSIONS: These data provide preclinical evidence that DEXMED may be a safe and effective chemical restraint for METH-induced agitation after NLX opioid reversal.

Chemical cousins with contrasting behavioural profiles: MDMA users and methamphetamine users differ in social-cognitive functions and aggression.

Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") share structural-chemical similarities but have distinct psychotropic profiles due to specific neurochemical actions. Previous research has suggested that their impact on social cognitive functions and social behaviour may differ significantly, however, direct comparisons of METH and MDMA users regarding social cognition and interaction are lacking. Performances in cognitive and emotional empathy (Multifaceted Empathy Test) and emotion sensitivity (Face Morphing Task), as well as aggressive social behaviour (Competitive Reaction Time Task) were assessed in samples of n = 40 chronic METH users, n = 39 chronic MDMA users and n = 86 stimulant-naïve controls (total N = 165). Self-reports and hair samples were used to obtain subjective and objective estimates of substance use patterns. METH users displayed diminished cognitive and emotional empathy towards positive stimuli, elevated punitive social behaviour regardless of provocation, and self-reported heightened trait anger relative to controls. MDMA users diverged from the control group only by exhibiting a distinct rise in punitive behaviour when faced with provocation. Correlation analyses indicated that both higher hair concentrations of MDMA and METH may be associated with reduced cognitive empathy. Moreover, greater lifetime MDMA use correlated with increased punitive behaviour among MDMA users. Our findings confirm elevated aggression and empathy deficits in chronic METH users, while chronic MDMA users only displayed more impulsive aggression. Dose-response correlations indicate that some of these deficits might be a consequence of use. Specifically, the dopaminergic mechanism of METH might be responsible for social-cognitive deficits.

Methamphetamine effects in zebrafish (Danio rerio) depend on behavioral endpoint, dose and test session duration.

Research using zebrafish (Danio rerio) has begun to provide novel information in many fields, including the behavioral pharmacology of drug use and misuse. There have been limited studies on the effects of methamphetamine in adult zebrafish and the parameters of exposure (dose, test session length) have not been well-documented. Behavior following drug exposure is generally measured during relatively short sessions (6-10 min is common) in a novel tank environment. Many procedural variables (isolation, netting, novel tank) elicit anxiety-like behavior that is most apparent during the initial portion of a test session. This anxiety-like behavior might mask the initial effects of methamphetamine. During longer test sessions, these anxiety-like responses would be expected to habituate and drug effects should become more apparent. To test this idea, we measured several locomotor activity responses for 50-min following a range of methamphetamine doses (0.1-3.0 mg/L via immersion in methamphetamine solution). Methamphetamine failed to alter swimming velocity, distance travelled, or freezing time. In contrast, methamphetamine produced a dose-dependent decrease in time spent in the bottom of the tank, an increase in the number of visits to the top of the tank, and an increase in the number of transitions along the sides of the tank. The effects of methamphetamine were apparent 10-20 min following exposure and generally persisted throughout the session. These findings indicate that longer test sessions are required to measure methamphetamine-induced changes in behavior in zebrafish, as has been shown in other laboratory animals. The results also suggest that anxiety-like responses associated with various procedural aspects (netting, isolation, novel test apparatus) likely interfere with the ability to observe many behavioral effects of methamphetamine in zebrafish. Based on the current results, habituation to testing procedures to reduce anxiety-like behaviors is recommended in determining the effects of methamphetamine in zebrafish.

Transient receptor potential ankyrin 1 channel modulates the abuse-related mechanisms of methamphetamine through interaction with dopamine transporter.

BACKGROUND AND PURPOSE: Methamphetamine (METH) use disorder has risen dramatically over the past decade, and there are currently no FDA-approved medications due, in part, to gaps in our understanding of the pharmacological mechanisms related to METH action in the brain. EXPERIMENTAL APPROACH: Here, we investigated whether transient receptor potential ankyrin 1 (TRPA1) mediates each of several METH abuse-related behaviours in rodents: self-administration, drug-primed reinstatement, acquisition of conditioned place preference, and hyperlocomotion. Additionally, METH-induced molecular (i.e., neurotransmitter and protein) changes in the brain were compared between wild-type and TRPA1 knock-out mice. Finally, the relationship between TRPA1 and the dopamine transporter was investigated through immunoprecipitation and dopamine reuptake assays. KEY RESULTS: TRPA1 antagonism blunted METH self-administration and drug-primed reinstatement of METH-seeking behaviour. Further, development of METH-induced conditioned place preference and hyperlocomotion were inhibited by TRPA1 antagonist treatment, effects that were not observed in TRPA1 knock-out mice. Similarly, molecular studies revealed METH-induced increases in dopamine levels and expression of dopamine system-related proteins in wild-type, but not in TRPA1 knock-out mice. Furthermore, pharmacological blockade of TRPA1 receptors reduced the interaction between TRPA1 and the dopamine transporter, thereby increasing dopamine reuptake activity by the transporter. CONCLUSION AND IMPLICATIONS: This study demonstrates that TRPA1 is involved in the abuse-related behavioural effects of METH, potentially through its modulatory role in METH-induced activation of dopaminergic neurotransmission. Taken together, these data suggest that TRPA1 may be a novel therapeutic target for treating METH use disorder.

PrEP Uptake and Methamphetamine Use Patterns in a 4-Year U.S. National Prospective Cohort Study of Sexual and Gender Minority People, 2017-2022.

Methamphetamine use is on the rise among sexual and gender minority people who have sex with men (SGMSM), escalating their HIV risk. Despite pre-exposure prophylaxis (PrEP) being an effective biomedical HIV prevention tool, its uptake in relation to methamphetamine use patterns in SGMSM has not been studied. In a U.S. cohort study from 2017 to 2022, 6,253 HIV-negative SGMSM indicated for but not using PrEP were followed for four years. Methamphetamine use was categorized (i.e., newly initiated, persistently used, never used, used but quit), and PrEP uptake assessed using generalized estimating equation (GEE), adjusted for attrition. Participants had a median age of 29, with 51.9% White, 11.1% Black, 24.5% Latinx, and 12.5% other races/ethnicities. Over the four years, PrEP use increased from 16.3 to 27.2%. GEE models identified risk factors including housing instability and food insecurity. In contrast, older age, health insurance, clinical indications, and prior PrEP use increased uptake. Notably, Latinx participants were more likely to use PrEP than Whites. Regarding methamphetamine use, those who newly initiated it were more likely to use PrEP compared to non-users. However, those who quit methamphetamine and those who persistently used it had PrEP usage rates comparable to those of non-users. Though PrEP uptake increased, it remained low in SGMSM. Methamphetamine use was associated with PrEP uptake. Healthcare providers should assess methamphetamine use for harm reduction. Prioritizing younger, uninsured SGMSM and addressing basic needs can enhance PrEP uptake and reduce HIV vulnerabilities.

Methamphetamine increases risky choice in rats, but only when magnitude and probability of reinforcement are manipulated within a session.

Risky choice is associated with maladaptive behaviors, particularly substance use disorders. Current animal models of risky choice are often confounded by other constructs like behavioral flexibility and suboptimal choice. The purpose of the current experiment was to determine if the psychostimulant methamphetamine, a drug whose popularity has increased in recent years, increases risky choice in an equivalent expected value (EEV) task. In the EEV task, rats are given a choice between two reinforcer alternatives that differ in magnitude and probability of delivery, but have equivalent expected value. Forty-eight Sprague Dawley rats were tested in three versions of the EEV task. In the first version of the EEV task, both reinforcer magnitude and probability were adjusted across blocks of trials for both alternatives. In the second and the third versions of the EEV task, reinforcer magnitude was held constant across each block of trials (either 1 vs. 2 pellets or 4 vs. 5 pellets). We found that male rats preferred the "riskier" option, except when reinforcer magnitudes were held constant at 4 and 5 pellets across each block of trials. Methamphetamine (0.5 mg/kg) increased preference for the risky option in both males and females, but only when both reinforcer magnitude and probability were manipulated across blocks of trials for each alternative. The current results demonstrate that both magnitude of reinforcement and probability of reinforcement interact to influence risky choice. Overall, this study provides additional support for using reinforcers with expected value to measure risky choice.

SMART Family and Friends: Feasibility and outcomes of a video-conference delivered intervention for families impacted by another's methamphetamine use.

INTRODUCTION: Families affected by another's substance use, including methamphetamine, experience harms to their mental and physical health. Yet, research has paid little attention to support and service needs of this population. This pilot study examines the feasibility and outcomes of SMART Family and Friends, a video-conference-delivered mutual-support group targeting families affected by another's methamphetamine use. METHODS: Recruitment for this study occurred between March-October 2021 via the SMART Recovery Australia website. Participants were English-speaking Australian residents, ≥18 years, affected by another's methamphetamine use, interested in participating in a manualised eight-module group delivered via video-conferencing. Feasibility was evaluated by attendance rates, participant satisfaction, fidelity ratings, and semi-structured interviews. Measures of distress, quality of life, and family functioning assessed outcomes at baseline and one-month post-treatment conclusion. RESULTS: Forty-three participants commenced SMART Family and Friends groups. 84 % (n = 36) completed ≥4 modules, 67 % (n = 29) completed ≥6, and 42 % (n = 18) completed all 8 modules. Participant satisfaction (M = 4.32, SD = 0.66, out of 5) and facilitator fidelity (>94 % for all modules) were high. A within-group analysis, without comparison condition demonstrated significant improvements in psychological distress (d = 0.38), family impact (d = 0.64), family strain symptoms (d = 0.48), and total family burden (d = 0.69) post-treatment. Qualitative findings illustrated the benefits and challenges of the video-conference-delivered group, as well as recommendations for improvement. CONCLUSIONS: Results provide initial support for the feasibility and positive outcomes of the SMART Family and Friends program. These findings demonstrate the successful provision of a mutual-support group for affected families delivered via video-conferencing, and merit further sufficiently powered randomised-control-trials to evaluate efficacy.

Participant experiences in a pilot study for methamphetamine withdrawal treatment: Implications for retention.

INTRODUCTION: There is little knowledge of the perspectives of people who use methamphetamine and have participated in clinical trials, and none for interventions not intended to address abstinence. A better understanding of these experiences could lead to more patient centred clinical trial design. This study seeks to understand the experiences of people who completed a clinical trial of lisdexamfetamine for the treatment of acute methamphetamine withdrawal. METHODS: Thematic analysis of open-ended, semi-structured interviews with eight people who participated in an inpatient clinical trial of lisdexamfetamine for acute methamphetamine withdrawal. Interviews were conducted between days 3 and 6 of admission to an inner-city Sydney hospital. RESULTS: Participants described how research procedures, the research setting, and the investigational product affected their experiences while enrolled in a clinical trial. Of particular importance to participants were transparent and low burden trial procedures, a welcoming trial environment, trusting relationships and effective communication, which were linked with the participants' subsequent decision to remain enrolled in the trial. DISCUSSION: The experiences of participants in this clinical trial can be distilled into four meta-themes: agency, caring-trust, safety, and communication. Participants spontaneously linked these experiences with a capacity to remain enrolled in the study. By considering the experiences of trial participants in clinical trial design, researchers can improve the experiences of future trial participants and facilitate their choice to remain enrolled in clinical trials.