New psychoactive substances (NPSs) are compounds designed to mimic illegal recreational drugs. In particular, there are difficulties in legal restrictions because there is no fast NPS detection method to suppress the initial spread of NPS with criminal records; thus, they expose the public to serious health threats, including toxicity and dependence. However, the effects of NPSs on the brain and the related cellular mechanisms are well unknown. One of the recently emerging drugs is 4-ethylamphetamine-NBOMe (4-EA-NBOMe), a member of the 2 C phenylalanine family with a similar structure to methamphetamine (methA). In this study, we tested the effect of methA analogs on the glutamatergic synaptic transmission on primary cultured cortical neurons of SpragueDawley (SD) rats and C57BL/6 mice, and also layer 2/3 pyramidal neurons of the medial prefrontal cortex (mPFC) of C57BL/6 mice. We found that acute treatment with 4-EA-NBOMe inhibits spontaneous excitatory postsynaptic currents (EPSCs) and that withdrawal after chronic inhibition by 4-EA-NBOMe augments glutamatergic synaptic transmission. These modifications of synaptic responses are mediated by 5-HT1A receptors. These findings suggest that 4-EA-NBOMe directly affects the central nervous system by changing the efficacy of glutamatergic synaptic transmission.

Synthetic cathinones are β-keto amphetamine derivatives whose appearance has increased dramatically in the past decades. N-Ethyl substituted cathinones have been proven to potently inhibit dopamine (DA) uptake and induce psychostimulant and rewarding effects in mice. However, little is known about the influence of the alpha-carbon side-chain length of N-ethyl cathinones on their pharmacological and toxicological effects. Thus, the aim of this study was to synthesize and investigate the in vitro and in vivo effects of five N-ethyl substituted cathinones: N-ethyl-cathinone (NEC), N-ethyl-buphedrone (NEB), N-ethyl-pentedrone, N-ethyl-hexedrone (NEH), and N-ethyl-heptedrone. HEK293 cells expressing the human DA or serotonin transporter (hDAT and hSERT) were used for uptake inhibition and binding assays. PC12 cells were used for the cytotoxicity assays. Swiss CD-1 mice were used to study the in vivo psychostimulant, anxiogenic, and rewarding properties. Our results show that all tested cathinones are able to inhibit DA uptake and are DAT-selective. The potency of DA uptake inhibitors increases with the elongation of the aliphatic side chain from methyl to propyl and decreases when increasing from butyl to pentyl, which correlates with an inverted U-shape psychostimulant response in mice at the medium dose tested. On the other hand, an increase in the α-carbon side-chain length correlates with an increase in the cytotoxic properties in PC12 cells, probably due to better membrane penetration. Moreover, all the cathinones tested have shown higher cytotoxicity than methamphetamine. Finally, our study not only demonstrated the rewarding properties of NEC and NEB but also the anxiety-like behavior induced at high doses by all the cathinones tested.

We sought to understand the effect of current treatments for ADHD on executive functioning deficits, which are often comorbid with ADHD, via a systematic analysis of adult ADHD treatment studies evaluating change in behavioral measures beyond the core symptoms of DSM ADHD. The Standardized Mean Difference for behavioral measures of executive functioning was determined from controlled trials of adults with ADHD and compared with effects on core ADHD symptoms. Several studies of atomoxetine revealed small to large standardized mean differences. Non-replicated studies revealed small to medium effects for triple-bead mixed amphetamine salts, lisdexamfetamine, and forms of cognitive behavioral therapy. Proportional effect versus core ADHD symptoms ranged from .78 to 1.16 for atomoxetine, and 0.65 to 1.44 across all the studies. ADHD treatments have effects on executive functioning behavior beyond core ADHD symptoms in adults. Clinicians can measure and treat this morbidity using available clinical tools. This article is protected by copyright. All rights reserved.

Objective: To evaluate the treatment effect size throughout the day of amphetamine extended-release oral suspension (AMPH EROS; Tris Pharma, Inc., Monmouth Junction, NJ, USA) in a laboratory classroom study conducted in children aged 6-12 years with attention-deficit/hyperactivity disorder (ADHD). Methods: A post hoc analysis was performed to assess the overall effect size as well as the effect size at each time point from early morning through evening (1, 2, 4, 6, 8, 10, 12, and 13 hours postdose) for each efficacy measure evaluated in a 5-week, randomized, dose-optimized, double-blind, placebo-controlled, laboratory classroom assessment, efficacy, and safety study of AMPH EROS (N = 99). Change from baseline of the primary (Swanson, Kotkin, Agler, M-Flynn, Pelham [SKAMP]-C) and key secondary (secondary efficacy assessments included the SKAMP attention [SKAMP-A], SKAMP-deportment subscale [SKAMP-D], Permanent Product Measure of Performance-number of problems attempted [PERMP-A], PERMP-number of problems correct [PERMP-C]) efficacy measures were analyzed using a linear mixed model repeated-measures analysis model. Comparisons among treatments were adjusted for multiple comparisons using the Bonferroni method. The effect size was estimated using Cohen's d, to determine "small," (0.2), "medium," (0.5), or "large" (0.8) magnitudes of treatment effects. Results: Large overall effect sizes were observed for all primary and key secondary efficacy assessments. Moreover, the SKAMP-C, PERMP-number of problems attempted, and PERMP-C scores showed large effect sizes at each time point evaluated across the day, from 1 to 13 hours postdose. The SKAMP-A and SKAMP-D scores showed a medium to large effect size at each time point. Conclusions: AMPH EROS demonstrated a large and consistent effect size across the day, including early in the morning, in the treatment of symptoms of ADHD in children aged 6-12 years. Trial Registration: clinicaltrials.gov identifier: NCT02083783.

The clinical symptoms and signs of methamphetamine-associated psychosis (MAP) and schizophrenia are highly similar, but the situation is completely different when MAP and schizophrenia patients need to be assessed for criminal responsibility after they comitted a harmful behavior. Therefore, the distinction between the two psychoses is very important in forensic psychiatry. At present, the identification of these two psychoses is mainly dependent on the corresponding criteria such as the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the Chinese Classification of Mental Disorders Version 3 (CCMD-3). It's challenging to diagnose and distinguish between the two in practical cases due to their similar clinical symptoms and the lack of effective objective indexes. Different from the limitations of single omics, integrative omics intergrates data from multiple dimensions and has been extensively studied in the field of schizophrenia and has achieved some preliminary results. In view of the correlation between MAP and schizophrenia and the potential application value of integrative omics, this paper proposes an integrative omics strategy for MAP pathogenesis and forensic identification, aiming to improve the further understanding of the relationship between the two psychoses and the corresponding pathogenesis. It also provides references for the future exploration of integrative omics in forensic precise identification and effective monitoring and early warning methods.

Adolescents are known to be particularly vulnerable, compared to children and adults, to initiation of substance use and progression to problematic use. This study aimed to examine the prevalence and type of illicit drug use in a population of adolescents and young adults who were hospitalized in a psychiatric hospital. The purpose of the study was also to find the link between age, sex, type of admission and particular mental disorders and using psychoactive substances at least once in a lifetime. A 12-month retrospective cross-sectional analysis of medical records compiled for adolescent and youth psychiatric patients who had been admitted to the Regional Psychiatric Hospital in Olsztyn, Poland, between October 1, 2018, and September 30, 2019, was conducted. After analyzing the available medical records, 506 cases were included and analyzed. Data for the study were collected in an Excel spreadsheet from discharge reports, including data from psychiatric examinations, especially anamnesis. Subsequently, statistical calculations were performed. Lifetime prevalence of any illicit substance use (34.0%) was common. The most frequently used drug was Cannabis (29.2%), the next New Psychoactive Substance-NPS (14.2%) and Amphetamine (13.0%). The higher number of people declaring to take illicit substances was proportional to the increasing age. Except for the group 10-15 years, the subject group was dominated by males. The highest, statistically significant percentage of patients who declared taking illicit substances in general, was found in people with diagnoses F20-F29 (schizophrenia, schizotypal and delusional disorders) (55%), additionally, we found a statistically significant association between NPS use and these diagnoses. Only in the group of patients diagnosed with eating disorders no one declared taking psychoactive substances. However, the correlation between taking illicit drugs and the subgroups with diagnosed psychiatric diseases should be treated with caution because of the small sample size in some cases. Our findings have shown the significant prevalence of the phenomenon in this population. These data highlight the need to explore this population at high risk carefully.

Drug use causes significant social and financial problems and these are exacerbated by difficulties in stopping use and subsequent maintenance of abstinence. There is also difficulty in identifying the beneficial treatment for an individual, made more problematic given the high drop-out rates in treatment programs. Here, the effects of transcranial direct current stimulation (tDCS) on the amplitude of the P300 event-related potential component, previously suggested to be indicative of successful remission, was measured in recently abstinent amphetamine users. This component was collected during a Posner cuing task which was presented to this group and to control (non-user) participants, using task cues of neutral and drug-related images. The abstinent drug users were divided into two groups, one of which received tDCS daily for five days, with the cathode over the left dorsolateral prefrontal cortex (DLPFC) and the anode over the right DLPFC, and one receiving sham stimulation over the same time period. Behavioral performance and P300 amplitudes were measured before and after the period of tDCS delivery. Control participants were tested with the same time-schedule of task presentation but without administration of tDCS. Drug users initially showed a larger cost of invalid cues on task performance compared to control (non-drug user) participants and this was reduced following delivery of tDCS. Additionally, tDCS resulted in increased amplitude of the P300 component, significantly so for neutral cues, with the resulting pattern being more similar to that of the non-users. This provides a good basis for further investigation of both the utility of tDCS in modulation of cognition in addict groups, and to investigate the effects of modulating the P300 component on remission rates, a relationship that seems to be the case for this measure without use of tDCS modulation. Importantly, this study also provides a further addiction group showing P300 amplitude modulation as a result of tDCS administration.

In this report, we present an unusual and multifactorial case of severe hyponatremia with important clinical implications. The decedent was a 42-year-old woman who was discovered at her place of residence with altered mental status and profuse watery diarrhea. The scene was significant for numerous empty water bottles. She was transported to the emergency department of a local medical center and rapidly became obtunded. Imaging demonstrated cerebral edema with impending herniation. Serum chemistry was significant for severe hyponatremia (116 mEq/L) with decreased serum osmolality (245 mOsm/kg), suggestive of water overload. Over a brief course of hospitalization, she continued to deteriorate and brain death was pronounced. After brain death, she underwent organ donation. Subsequent autopsy examination demonstrated global cerebral edema with evidence of herniation. Toxicology examination of antemortem blood was positive for methamphetamine (1900 ng/mL) and amphetamine (100 ng/mL). An incidentally identified colon polyp was submitted for microscopic evaluation, which revealed the presence of Cryptosporidium, the likely cause of her diarrheal illness. Death was attributed to severe hyponatremia through the combined effects of excessive water consumption and loss of fluid and electrolytes from cryptosporidiosis, in turn leading to cerebral edema and brain herniation. Acute methamphetamine intoxication was a contributing condition.

Introduction: The centrally projecting Edinger-Westphal nucleus (EWcp) contributes to the control of alcohol consumption by its urocortin 1 (UCN1) and cocaine- and amphetamine-regulated transcript (CART) co-expressing peptidergic neurons. Our group recently showed that the urocortinergic centrally projecting EWcp is the primary seat of central nervous system transient receptor potential ankyrin 1 (TRPA1) cation channel mRNA expression. Here, we hypothesized that alcohol and its metabolites, that pass through the blood-brain barrier, may influence the function of urocortinergic cells in centrally projecting EWcp by activating TRPA1 ion channels. We aimed to examine the functional activity of TRPA1 in centrally projecting EWcp and its possible role in a mouse model of acute alcohol exposure. Methods: Electrophysiological measurements were performed on acute brain slices of C57BL/6J male mice containing the centrally projecting EWcp to prove the functional activity of TRPA1 using a selective, potent, covalent agonist JT010. Male TRPA1 knockout (KO) and wildtype (WT) mice were compared with each other in the morphological studies upon acute alcohol treatment. In both genotypes, half of the animals was treated intraperitoneally with 1 g/kg 6% ethanol vs. physiological saline-injected controls. Transcardial perfusion was performed 2 h after the treatment. In the centrally projecting EWcp area, FOS immunohistochemistry was performed to assess neuronal activation. TRPA1, CART, and urocortin 1 mRNA expression as well as urocortin 1 and CART peptide content was semi-quantified by RNAscope in situ hybridization combined with immunofluorescence. Results: JT010 activated TRPA1 channels of the urocortinergic cells in acute brain slices. Alcohol treatment resulted in a significant FOS activation in both genotypes. Alcohol decreased the Trpa1 mRNA expression in WT mice. The assessment of urocortin 1 peptide immunoreactivity revealed lower basal urocortin 1 in KO mice compared to WTs. The urocortin 1 peptide content was affected genotype-dependently by alcohol: the peptide content decreased in WTs while it increased in KO mice. Alcohol exposure influenced neither CART and urocortin 1 mRNA expression nor the centrally projecting EWcp/CART peptide content. Conclusion: We proved the presence of functional TRPA1 receptors on urocortin 1 neurons of the centrally projecting EWcp. Decreased Trpa1 mRNA expression upon acute alcohol treatment, associated with reduced neuronal urocortin 1 peptide content suggesting that this cation channel may contribute to the regulation of the urocortin 1 release.

South America's substance use profile, poverty, income inequality, and cocaine-supplier role make it a unique place for substance use research. This study investigated the burden of disease attributable to amphetamine use disorder, cannabis use disorder (CAD), cocaine use disorder, and opioid use disorder (OUD) in South America from 1990 to 2019, on the basis of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019.

Methamphetamine-associated cardiomyopathy (MaCM) is an increasingly recognised serious complication from methamphetamine (MA) use. It is characterised as the development of otherwise unexplained heart failure in the context of MA use. MaCM predominantly affects a young and vulnerable population with high morbidity and mortality. It is the second leading cause of mortality in patients with MA use disorder (MUD). Our understanding of MaCM pathogenesis is based on observational cohorts and autopsy studies. Currently, the treatment of MaCM is predicated on abstinence. Medical therapies offer some benefit to a minority of patients; however, without abstinence, medical therapies are often ineffective. Abstinence is difficult for most patients to achieve; all clinicians require an understanding of MaCM and how to educate patients on the risks of ongoing use. Where available, referral to addiction medicine specialists to assist with treatment of MUD is recommended. This review aims to: (i) explain the proposed pathologic mechanisms of MaCM; (ii) summarise recent recommendations of the screening and treatment of MaCM; and (iii) highlight the role of addiction medicine in the management of patient with MaCM.

This cross-sectional study examines the correlation between childhood trauma, intimate partner violence (IPV), and parenting self-efficacy among women who reported using amphetamine-type stimulants (ATS) in an institutional drug rehabilitation center.

Troubling disparities in viral suppression persist among transgender (trans) women living with HIV in the US. We utilized baseline data from a randomized controlled trial of a behavioral intervention among trans women living with HIV in San Francisco and Los Angeles, to identify the socio-ecological correlates of biologically confirmed viral suppression (< 200 HIV-1 RNA copies/mL). Among 253 participants, the mean age was 43 (SD = 11), 46% identified as Black or African American and 35% were virally non-suppressed. In adjusted Poisson regression models, the following barriers to viral suppression were identified: injection drug use [adjusted risk ratio (aRR) 0.78, 95% CI 0.65-0.93, Z = - 2.64, p = 0.008], methamphetamine use (aRR 0.65, 95% CI 0.51-0.83, Z = - 3.45, p = 0.001), amphetamine use (aRR 0.62, 95% CI 0.44-0.87, Z = - 2.75, p = 0.006), homelessness (aRR 0.79, 95% CI 0.63-0.98, Z = - 2.06, p = 0.039), and sex work (aRR 0.60, 95% CI 0.41-0.86, Z = - 2.77, p = 0.009). These findings underscore the importance of interventions that address the socio-ecological barriers to viral suppression among trans women in urban settings.

Cocaine- and amphetamine-regulated transcript (CART) peptides are involved in several physiological and pathological processes, but their mechanism of action is unrevealed due to the lack of identified receptor(s). We provided evidence for the antihyperalgesic effect of CART(55-102) by inhibiting dipeptidyl-peptidase 4 (DPP4) in astrocytes and consequently reducing neuroinflammation in the rat spinal dorsal horn in a carrageenan-evoked inflammation model. Both naturally occurring CART(55-102) and CART(62-102) peptides are present in the spinal cord. CART(55-102) is not involved in acute nociception but regulates spinal pain transmission during peripheral inflammation. While the full-length peptide with a globular motif contributes to hyperalgesia, its N-terminal inhibits this process. Although the anti-hyperalgesic effects of CART(55-102), CART(55-76), and CART(62-76) are blocked by opioid receptor antagonists in our inflammatory models, but not in neuropathic Seltzer model, none of them bind to any opioid or G-protein coupled receptors. DPP4 interacts with Toll-like receptor 4 (TLR4) signalling in spinal astrocytes and enhances the TLR4-induced expression of interleukin-6 and tumour necrosis factor alpha contributing to inflammatory pain. Depending on the state of inflammation, CART(55-102) is processed in the spinal cord, resulting in the generation of biologically active isoleucine-proline-isoleucine (IPI) tripeptide, which inhibits DPP4, leading to significantly decreased glia-derived cytokine production and hyperalgesia.

For the past decade, the prevalence and mortality of methamphetamine (METH) use have doubled, suggesting that METH use could be the next substance use crisis worldwide. Ingested METH is transformed into other products in the liver, a major metabolic organ. Studies have revealed that METH causes deleterious inflammatory response, oxidative stress, and extensive DNA damage. These pathological damages are driving factors of hepatocellular carcinoma (HCC). Nonetheless, the potential role of METH in HCC and the underlying mechanisms remain unknown. Herein, we found a higher HCC incidence in METH abusers. METH promoted cellular proliferation, migration, and invasion in two human-derived HCC cells. Consistently, METH uptake promoted HCC progression in a xenograft mouse model. Mechanistically, METH exposure induced ROS production, which activated the Ras/MEK/ERK signaling pathway. Clearance of ROS by NAC suppressed METH-induced activation of Ras/ERK1/2 pathways, leading to arrest of HCC xenograft formation in nude mice. To the best of our knowledge, this is the first study to substantiate that METH promotes HCC progression and inhibition of ROS may reverse this process.

Background: Men who have sex with men (MSM) who use stimulants are at increased risk for HIV infection. Adherence to pre-exposure prophylaxis (PrEP) reduces the risk of HIV infection. We evaluated the efficacy of the individualized Texting for Adherence Building (iTAB) intervention for PrEP adherence compared to standard of care (SoC) among 119 MSM who use stimulants (cocaine, methamphetamine and/or other amphetamine) from the California Collaborative Treatment Group 595 randomized control trial.Method: Three ordered levels of PrEP adherence (non-adherence, adequate adherence, and near-perfect adherence) were compared between intervention arms across study visits (weeks 12 and 48) using ordinal logistic regressions.Results: The effect of intervention arm was not significant in the final model; however, there was a 38% decrease in odds (OR = 0.62, p=.023) of having near-perfect adherence (versus non-adherence or adequate adherence) at week 48 compared to week 12, indicating a significant effect of time. In a follow-up analysis examining week 48 only, logistic regression examining PrEP adherence showed that receiving iTAB (compared to SoC) trended toward higher odds of near-perfect adherence relative to adequate adherence (OR = 2.48, p=.061). Higher HIV knowledge resulted in higher odds (OR = 1.72, p=.020) of near-perfect adherence (versus non-adherence or adequate adherence).Conclusion: HIV knowledge may influence PrEP adherence, and most notably, the iTAB intervention may support near-perfect adherence relative to adequate adherence.

Neurons in the lateral hypothalamus expressing the neuropeptide Hypocretin, also known as orexin, are known critical modulators of arousal stability. However, their role in the different components of the arousal construct such as attention and decision making is poorly understood. Here we study Hypocretin neuronal circuit dynamics during stop action impulsivity in a Go/NoGo task in mice. We show that Hypocretin neuronal activity correlates with anticipation of reward. We then assessed the causal role of Hypocretin neuronal activity using optogenetics in a Go/NoGo task. We show that stimulation of Hypocretin neurons during the cue period dramatically increases the number of premature responses. These effects are mimicked by amphetamine, reduced by atomoxetine, a norepinephrine uptake inhibitor, and blocked by a Hypocretin receptor 1 selective antagonist. We conclude that Hypocretin neurons have a key role in the integration of salient stimuli during wakefulness to produce appropriate and timely responses to rewarding and aversive cues.

We have developed and characterized a novel D2R antagonist with exceptional GPCR selectivity - ML321. In functional profiling screens of 168 different GPCRs, ML321 showed little activity beyond potent inhibition of the D2R and to a lesser extent the D3R, demonstrating excellent receptor selectivity. The D2R selectivity of ML321 may be related to the fact that, unlike other monoaminergic ligands, ML321 lacks a positively charged amine group and adopts a unique binding pose within the orthosteric binding site of the D2R. PET imaging studies in non-human primates demonstrated that ML321 penetrates the CNS and occupies the D2R in a dose-dependent manner. Behavioral paradigms in rats demonstrate that ML321 can selectively antagonize a D2R-mediated response (hypothermia) while not affecting a D3R-mediated response (yawning) using the same dose of drug, thus indicating exceptional in vivo selectivity. We also investigated the effects of ML321 in animal models that are predictive of antipsychotic efficacy in humans. We found that ML321 attenuates both amphetamine- and phencyclidine-induced locomotor activity and restored pre-pulse inhibition (PPI) of acoustic startle in a dose-dependent manner. Surprisingly, using doses that were maximally effective in both the locomotor and PPI studies, ML321 was relatively ineffective in promoting catalepsy. Kinetic studies revealed that ML321 exhibits slow-on and fast-off receptor binding rates, similar to those observed with atypical antipsychotics with reduced extrapyramidal side effects. Taken together, these observations suggest that ML321, or a derivative thereof, may exhibit ″atypical″ antipsychotic activity in humans with significantly fewer side effects than observed with the currently FDA-approved D2R antagonists.