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Cognitive deficits are long-lasting consequences of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause similar deficits is unclear. We find that both phencyclidine and methamphetamine, despite differing in their targets in the brain, cause the same glutamatergic neurons in the medial prefrontal cortex of male mice to gain a GABAergic phenotype and decrease expression of their glutamatergic phenotype. Suppressing drug-induced gain of GABA with RNA-interference prevents appearance of memory deficits. Stimulation of dopaminergic neurons in the ventral tegmental area is necessary and sufficient to produce this gain of GABA. Drug-induced prefrontal hyperactivity drives this change in transmitter identity. Returning prefrontal activity to baseline, chemogenetically or with clozapine, reverses the change in transmitter phenotype and rescues the associated memory deficits. This work reveals a shared and reversible mechanism that regulates the appearance of cognitive deficits upon exposure to different drugs.

The pursuit of translational biomarkers is complex due to the heterogeneous human pathophysiology, but critical for disease diagnosis, prognosis, monitoring therapeutic efficacy, and for patient stratification. In HIV-associated neurocognitive impairment (NCI), biomarkers that delineate the trajectory of neuropathogenesis and neurocognitive sequelae are critical, particularly considering confounders such as substance use, including Methamphetamine (METH). METH use is a significant health concern among persons living with HIV (PWH), aggravating cognitive deficits and neuroinflammation despite of antiretrovirals, introducing elements in the microenvironment that are fundamentally differerent in relation to non-METH users, such as high levels of dopamine (DA) affecting HIV-innate immune targets. Yet, current biomarkers do not detect these differences. We hypothesized that predefined DA-induced signatures detectable in peripheral blood leukocytes, can distinguish HIV+ METH users compared to HIV-negative or PWH that are non METH users. The elevated expression of CD8A, CREBBP, CCL5, and combinations of dopaminergic pathway transcripts clustered METH users with detectable CSF viral load and major depressive disorder (MDD), indicating neuroimmune-mechanistic links. Cathecol-o-methyltransferase (COMT) gene polymorphisms affecting DA metabolism improved the identification of PWH using METH with biomarkers. The results indicate that underlying immunedopaminergic mechanisms provide signatures and genotypes that can identify PWH that are METH users and their attributes.

BACKGROUND: The group-I metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in methamphetamine exposure in animals and in human cognition. Because people with methamphetamine use disorder (MUD) exhibit cognitive deficits, we evaluated mGlu5 in people with MUD and controls and tested its association with cognitive performance. METHODS: Positron emission tomography was performed to measure the total VT of [18F]FPEB, a radiotracer for mGlu5, in brains of participants with MUD (abstinent from methamphetamine for at least 2 weeks, N = 14) and a control group (N = 14). Drug use history questionnaires and tests of verbal learning, spatial working memory, and executive function were administered. Associations of VT with methamphetamine use, tobacco use, and cognitive performance were tested. RESULTS: MUD participants did not differ from controls in global or regional VT, and measures of methamphetamine use were not correlated with VT. VT was significantly higher globally in nonsmoking vs smoking participants (main effect, P = .0041). MUD participants showed nonsignificant weakness on the Rey Auditory Verbal Learning Task and the Stroop test vs controls (P = .08 and P = .13, respectively) with moderate to large effect sizes, and significantly underperformed controls on the Spatial Capacity Delayed Response Test (P = .015). Across groups, Rey Auditory Verbal Learning Task performance correlated with VT in the dorsolateral prefrontal cortex and superior frontal gyrus. CONCLUSION: Abstinent MUD patients show no evidence of mGlu5 downregulation in brain, but association of VT in dorsolateral prefrontal cortex with verbal learning suggests that medications that target mGlu5 may improve cognitive performance.

BACKGROUND: We investigate the relationship between the supply of methamphetamine and overdose death risk in Ohio. Ohio and the overall US have experienced a marked increase in overdose deaths from methamphetamine combined with fentanyl over the last decade. The increasing use of methamphetamine may be increasing the risk of overdose death. However, if people are using it to substitute away from more dangerous synthetic opioids, it may reduce the overall risk of overdose death. METHODS: Ohios Bureau of Criminal Investigations crime lab data include a detailed list of the content of drug samples from law enforcement seizures, which are used as a proxy for drug supply. We use linear regressions to estimate the relationship between the proportion of methamphetamine in lab samples and unintentional drug overdose death rates from January 2015 through September 2021. RESULTS: Relatively more methamphetamine in crime lab data in a county-month has either no statistically significant relationship with overdose death rates (in small and medium population counties) or a negative and statistically significant relationship with overdose death rates (in large population counties). Past overdose death rates do not predict future increases in methamphetamine in crime lab data. CONCLUSIONS: The results are consistent with a relatively higher supply of methamphetamine reducing the general risk of overdose death, possibly due to substitution away from more dangerous synthetic opioids. However, the supply of methamphetamine appears unrelated to the past illicit drug risk environment. The non-lethal and yet serious health effects of MA use were not explored and, thus, even if the presence of MA reduces the population-level overdose mortality rate, the rise of other adverse health effects may counteract any public health benefits of fewer deaths.

BACKGROUND: Methamphetamine use has emerged as a major risk factor for cardiovascular and cerebrovascular disease in young adults. The aim of this study was to investigate a possible association of methamphetamine use with cardioembolic stroke. METHODS AND RESULTS: We performed a retrospective study of patients with acute ischemic stroke admitted at our medical center between 2019 and 2022. All patients were screened for methamphetamine use and cardiomyopathy, defined as left ventricular ejection fraction ≤45%. Among 938 consecutive patients, 46 (4.9%) were identified as using methamphetamine. Compared with the nonmethamphetamine group (n=892), the methamphetamine group was significantly younger (52.8±9.6 versus 69.7±15.2 years; P

BACKGROUND: The prosocial compound ± 3,4-methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that has shown promise as an adjunct to psychotherapy in the treatment of post-traumatic stress disorder. MDMA increases positive responses to social images, and it has been suggested that the ability of MDMA to positively bias social perception may underlie its therapeutic efficacy as a psychotherapy adjunct. However, the effect of the compound on affective responses to positive or negative social feedback has not been tested. AIMS: In this study, we aimed to test the effects of MDMA compared to placebo and the prototypical stimulant, methamphetamine (MA), on responses to positive and negative social feedback. METHODS: This was a double-blind, placebo-controlled, crossover trial (NCT03790618), comparing the effects of two doses of MDMA (0.75 mg/kg, 1.5 mg/kg) to both placebo and MA (20 mg) on responses to a personalized social feedback task, similar to a dating app, in healthy adult volunteers ages 18-40 (N = 36, 18 women, 18 men). RESULTS/OUTCOMES: The high dose of MDMA increased positive affective responses to social feedback. CONCLUSIONS/INTERPRETATIONS: These findings suggest one process by which MDMA may facilitate social connection. Further work is needed to understand how MDMA affects responses to more generalized types of social feedback and to understand these effects in clinical populations.

IntroductionMethamphetamine use is highly prevalent among men who have sex with men (MSM), but knowledge of the long-term dynamics, and how they are affected by substance use treatment, is limited. This study aimed to describe trajectories of methamphetamine use among MSM, and to evaluate the impact of treatment for any kind of substance use on frequency of methamphetamine use.MethodsThis analysis used data from a cohort of MSM in Los Angeles, CA, who participated in semi-annual study visits from 2014 to 2022. The study characterized trajectories of methamphetamine use using a continuous time multistate Markov model with three states. States were defined using self-reported frequency of methamphetamine use in the past six months: frequent (daily), occasional (weekly or less), and never. The model estimated the association between receiving treatment for any kind of substance use and changes in state of frequency of methamphetamine use.ResultsThis analysis included 2348 study visits among 285 individuals who were followed-up for an average of 4.4 years. Among participants who were in the frequent use state, 65 % (n = 26) of those who were receiving any kind of substance use treatment at a study visit had reduced their methamphetamine use at their next visit, compared to 33 % (n = 95) of those who were not receiving treatment. Controlling for age, race/ethnicity, and HIV-status, those who reported receiving current treatment for substance use were more likely to transition from occasional to no use (HR: 1.63, 95 % CI: 1.10-2.42) and frequent to occasional use (HR: 4.25, 95 % CI: 2.11-8.59) in comparison to those who did not report receiving current treatment for substance use.ConclusionsFindings from this dynamic modeling study provide a new method for assessing longitudinal methamphetamine use outcomes and add important evidence outside of clinical trials that substance use treatment may reduce methamphetamine use.

Craving is central to methamphetamine use disorder (MUD) and both characterizes the disease and predicts relapse. However, there is currently a lack of robust and reliable biomarkers for monitoring craving and diagnosing MUD. Here, we seek to identify a neurobiological signature of craving based on individual-level functional connectivity pattern differences between healthy control and MUD subjects. We train high-density electroencephalography (EEG)-based models using data recorded during the resting state and then calculate imaginary coherence features between the band-limited time series across different brain regions of interest. Our prediction model demonstrates that eyes-open beta functional connectivity networks have significant predictive value for craving at the individual level and can also identify individuals with MUD. These findings advance the neurobiological understanding of craving through an EEG-tailored computational model of the brain connectome. Dissecting neurophysiological features provides a clinical avenue for personalized treatment of MUD.

BackgroundThere 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.MethodsThis 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.DiscussionThis 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 registrationAustralian and New Zealand Clinical Trials Registry ACTRN12622000235707. Registered on February 9, 2022.

The authors describe a case of nylon foil implant infection caused by Fusarium brachygibbosum , and Lomentospora prolificans following medial orbital wall fracture repair in the setting of postoperative nasal methamphetamine use. A 61-year-old male presented with OS pain and swelling after a physical assault on his face. A CT of maxillofacial bones without contrast showed a moderately comminuted fracture of the medial wall of the left orbit with depression of fracture fragments into the left ethmoid air cells. Six days after repair of the medial wall fracture, the patient returned with a new onset headache, OS pain, and swelling to the left medial canthal area. He reported snorting methamphetamine approximately 48 hours before his current presentation. CT imaging showed fat stranding and soft tissue density in the extraconal space adjacent to the left medial rectus muscle and chronic fracture deformity of lamina papyracea with approximately 4 mm of medial displacement of the fracture fragments. The patient showed little clinical improvement after 48 hours of intravenous antibiotics, which led to the removal of the nylon foil implant by a left orbitotomy. Intraoperative tissue cultures grew coagulase-negative Staphylococcus , F. brachygibbosum , and Lomentospora (Scedosporium) prolificans . The patient was subsequently transitioned to oral clindamycin 600 mg three times daily and voriconazole 200 mg two times daily. To the authors' knowledge, this is the first case report to document an association between snorted methamphetamine and a fungal infection of an orbital implant.

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 recipients 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.

INTRODUCTION: While known animal exposures to human drugs of abuse (DA) were previously considered relatively uncommon in veterinary medicine, the trends are changing. Marijuana and amphetamines are among the 20 toxicants most frequently consulted about with the Pet Poison Helpline. When such exposures occur, they are typically considered emergencies. METHODS: This retrospective study describes confirmed cases of DA exposure in pets from the California Animal Health and Food Safety Laboratory System (CAHFS), 2013-2023. RESULTS: Fifty-seven samples tested positive for DA through liquid chromatography with tandem mass spectrometry analysis (qualitative method). In 75% (43/57) of the DA screen tests, the detected drugs included amphetamine-type stimulants and metabolites (methamphetamine, amphetamine, or both). In 47% (27/57) of cases, a combination of more than one drug group was found. Most cases were diagnosed from a urine specimen. In at least 32% (18/57) of cases, the samples were submitted due to suspicions of animal cruelty, and at least 41% (23/57) of the patients were deceased when the samples were submitted. DISCUSSION: More studies on the prevalence of illicit drugs in small animals, using confirmatory testing, are warranted to fully understand the significance of this emerging toxicological hazard in veterinary medicine.

ObjectiveMethamphetamine and cannabis are two widely used, and frequently co-used, substances with possibly opposing effects on the central nervous system. Evidence of neurocognitive deficits related to use is robust for methamphetamine and mixed for cannabis. Findings regarding their combined use are inconclusive. We aimed to compare neurocognitive performance in people with lifetime cannabis or methamphetamine use disorder diagnoses, or both, relative to people without substance use disorders.Method423 (71.9% male, aged 44.6 ± 14.2 years) participants, stratified by presence or absence of lifetime methamphetamine (M-/M+) and/or cannabis (C-/C+) DSM-IV abuse/dependence, completed a comprehensive neuropsychological, substance use, and psychiatric assessment. Neurocognitive domain T-scores and impairment rates were examined using multiple linear and binomial regression, respectively, controlling for covariates that may impact cognition.ResultsGlobally, M+C+ performed worse than M-C- but better than M+C-. M+C+ outperformed M+C- on measures of verbal fluency, information processing speed, learning, memory, and working memory. M-C+ did not display lower performance than M-C- globally or on any domain measures, and M-C+ even performed better than M-C- on measures of learning, memory, and working memory.ConclusionsOur findings are consistent with prior work showing that methamphetamine use confers risk for worse neurocognitive outcomes, and that cannabis use does not appear to exacerbate and may even reduce this risk. People with a history of cannabis use disorders performed similarly to our nonsubstance using comparison group and outperformed them in some domains. These findings warrant further investigation as to whether cannabis use may ameliorate methamphetamine neurotoxicity.

Evidence suggests that individuals who use methamphetamine are at a significantly higher risk of developing psychosis compared to non-users. This study aims to examine the rate of psychosis among methamphetamine users and to investigate factors related to methamphetamine-associated psychosis (MAP). Two thousand ninety-eight (2,098) individuals with methamphetamine use were admitted to outpatient care. Available admissions data included clinical interviews, the Addiction Profile Index (API), and API-clinical forms. MAP was identified in 267 (12.7%) participants. Our data analysis found significant sociodemographic, clinical, and personality differences between MAP and non-MAP cohorts on admission. Multivariate regression analysis revealed that older age (OR = 1.049), younger age of substance use onset (OR = 0.960), more frequent MA use (OR = 1.622), being single (OR = 1.974), lower education (OR = 0.46), increased number of withdrawal symptoms (OR = 1.100), higher lack of anger control scores (OR = 1.422), higher lack of assertiveness scores (OR = 1.396), and higher anxiety scores (OR = 1.715) were significantly associated with MAP. Although factors identified in this study represent state (on admission) rather than stable characterological traits, these results may nonetheless help us better characterize contextual factors associated with MAP in an outpatient population. [ABSTRACT FROM AUTHOR]

Aims Design, setting and participants Measurements Findings Conclusions This study (1) estimated changes in anxiety and depression throughout 3 years in a community‐recruited cohort who use methamphetamine and (2) modelled whether these changes were associated with patterns of methamphetamine use or other time‐varying or fixed covariates.We used a longitudinal analysis using data derived from surveys conducted between August 2016 and March 2020, set in metropolitan and rural locations in Victoria, Australia. Participants comprised a total of 849 adults with regular methamphetamine use history at baseline, recruited for the prospective VMAX study via snowball and respondent‐driven sampling.Anxiety and depression symptoms were measured using the Generalized Anxiety Disorder (GAD)‐7 and the Patient Health Questionnaire (PHQ)‐9 instruments. Frequency of methamphetamine use was measured by self‐reported number of days per week participants used any form of methamphetamine in the past month.Changes in anxiety and depression symptom scores were associated with change in route of administration from non‐injecting to injecting [adjusted coefficient (adj. coeff.) = 1.44, 95% confidence intervals (CI) = 0.39, 2.48, adj. coeff. = 1.49, 95% CI = 0.39, 2.58], change in severity of dependence for methamphetamine (adj. coeff. = 0.29, 95% CI = 0.21, 0.37, adj. coeff. = 0.34, 95% CI = 0.26, 0.42), starting treatment for drugs other than methamphetamine (adj. coeff. = −2.21, 95% CI = −3.70, −0.73, adj. coeff. = −2.09, 95% CI = −3.60, −0.58) and other covariates.Among regular methamphetamine users in Australia, changes in anxiety or depression scores are associated with changes in route of administration, dependence severity and starting treatment for other drugs, but do not appear to be associated with frequency of methamphetamine use. [ABSTRACT FROM AUTHOR]

Introduction: This study explored the effects of task-switching type and sex on the task-switching ability of methamphetamine abstainers, as well as the differences in brain mechanisms under drug cravings under drug cravings using near-infrared spectroscopy. Methods: Craving-inducing videos were used to arouse 20 methamphetamine abstainers (including 10 men), whose switching ability was then assessed using voluntary and cued task-switching exercises. Results: During task-switching under methamphetamine cravings, the activation of the premotor cortex (PMC), supplementary motor area (SMA), frontal eye field (FEF), and dorsolateral prefrontal cortex (DLPFC) in women was significantly stronger than in men, while the activation of FEF in men was significantly stronger than in women. Voluntary task-switching induced stronger FEF activation than cued task-switching. During the latter, women exhibited stronger activation in the anterior prefrontal cortex (aPFC) than men. Discussion: Both men and women showed brain lateralization during task-switching under methamphetamine cravings. Men tended to adopt proactive control and use a top-down dominant strategy to start a new task. Women, however, tend to use a bottom-up strategy focusing on inhibiting old tasks and emotional switching. Moreover, in cued task-switching, the result shows women paid more attention to emotional processing than did men, which suggests that different task-switching training programs should be developed according to sex. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) consumption is associated with aggression. Decoction derived from the kratom (Mitragyna speciosa Korth.) leaf has been used as a METH substitute in Southeast Asia. Given its perceived benefit, we investigated the relationship between kratom use and aggression in a treatment sample of METH users with and without kratom use history. Four hundred and three male METH users participated in this cross-sectional study. A semi-structured questionnaire and several objective clinical measures were administered. Results indicate that there were no significant differences in aggression and its dimensions between METH users with and without kratom use history. However, two distinct Clusters (1 and 2) of METH users with kratom use history were studied. Users in Cluster 1 were characterized by a higher quantity and frequency of daily kratom use, longer duration of kratom use, and use of kratom at a younger age. Users in Cluster 2 exhibited the opposite characteristics. Kratom dependence and the first age of kratom use were identified as risk factors for aggression in Cluster 1. The frequency of daily kratom use appeared as a protective factor against aggression in Cluster 2. The results offer partial support to the instrumental kratom use concept; lower frequency (1 to 3 times) of kratom use may potentially minimize aggression in METH users presenting with mild to moderate kratom dependence. [ABSTRACT FROM AUTHOR]

The ability to maintain and manipulate sequential information in working memory, referred to as sequential working memory, plays a vital role in our daily life. While research has shown that methamphetamine abuse affects the neural substrates and the overall functioning of working memory, its specific impact on sequential working memory remains unclear. In this study, we asked 62 abstinent methamphetamine-dependent participants and 59 control participants to complete a digit ordering task in which they saw four digits one-by-one over time and subsequently rearranged them in ascending order. The four digits were presented either randomly in the experimental condition or in ascending order in the control condition. Results show that methamphetamine-dependent participants performed worse than the controls in the experimental condition in which sequential working memory was needed to complete the task, but not in the control condition in which only short-term memory was needed. This finding demonstrates that methamphetamine abuse impairs sequential working memory. [ABSTRACT FROM AUTHOR]

Background: The substitution of cannabis for alcohol and other drugs has been conceptualised in a harm reduction framework as where cannabis is used to reduce the negative side-effects, addiction potential, and social stigma of other drugs. There is currently mixed evidence with recent reviews suggesting cannabis co-use patterns may vary by age and ethnicity. Yet few studies have had large enough samples to examine this demographic variation in detail. Aims: To explore the co-use of cannabis with alcohol and other drugs within demographic subgroups of a large sample of people who use cannabis. Specifically: (1) whether cannabis is being substituted for other drugs, and (2), whether cannabis use leads to more, less or the same level of other drug use. Method: Online convenience survey promoted via Facebook™ completed by 23,500 New Zealand respondents. Those who had used cannabis and any of eight other substances in the same six-month period were asked if their use of cannabis had any impact on their use of each other substance ("a lot more", "little more", "no impact/same", "little less", "a lot less"). Frequency and quantity used of each other drug was compared by co-use group. Generalised logistic regression models were developed to predict co-use categories. Results: Significant proportions reported cannabis use led to "less" alcohol (60%), synthetic cannabinoid (60%), morphine (44%) and methamphetamine (40%) use. Those who reported using "less" had lower frequency and amount used of other drugs. Approximately seven-out-ten reported cannabis use had "no impact" on LSD, MDMA, and cocaine use. One-in-five reported using cannabis led to "more" tobacco use. Young adults (21–35-years) were more likely to report cannabis use led to "less" drinking and methamphetamine use. Adolescent co-users (16–20 years) reported mixed impacts. Māori were more likely to report cannabis use resulted in "less" alcohol, tobacco, methamphetamine, and LSD use. Students and those living in cities were less likely to report cannabis use lowering use of other substances. Conclusion: Cannabis and other drug co-use patterns are moderated by life stages, lifestyles, cultural perspectives, and urbanicity. Harm reduction initiatives and policy reforms should take account of these moderating factors. [ABSTRACT FROM AUTHOR]