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This national prospective multicohort study examined the relationship between US adolescents' use of stimulant therapy for attention-deficit/hyperactivity disorder (ADHD) and subsequent risk of nonmedical stimulant use (i.e., nonmedical use of prescription stimulants and cocaine use) during young adulthood, relative to nonstimulant therapy and population controls. Nationally representative multicohort panels of 11,905 US 12th-grade students were surveyed via self-administered questionnaires at baseline (age 18) and followed prospectively over six years into young adulthood (ages 19‒24). There were no statistically significant differences between adolescents who used stimulant therapy for ADHD compared to those who used only nonstimulant medications and population controls in their adjusted odds of nonmedical stimulant use incidence or prevalence during young adulthood, after adjusting for baseline covariates. The findings offer preliminary support that adolescents who use prescription stimulant or nonstimulant medications for ADHD when clinically indicated are not at greater risk for nonmedical stimulant use during young adulthood. [ABSTRACT FROM AUTHOR]

Chest pain (CP), a common presentation in the emergency department (ED) setting, is associated with significant morbidity and mortality if emergency clinicians miss the diagnosis of acute coronary syndrome (ACS). The HEART (History, Electrocardiogram, Age, Risk Factors, Troponin) score had been validated for risk-stratification patients who are at high risk for ACS and major adverse cardiac events (MACE). However, the use of cocaine as a risk factor of the HEART score was controversial. We hypothesized that patients with cocaine-positive (COP) would not be associated with higher risk of 30-day MACE than cocaine-negative (CON) patients. This retrospective study included adult patients who presented to 13 EDs of a University's Medical System between August 7, 2017 to August 19, 2021. Patients who had CP and prospectively calculated HEART scores and urine toxicology tests as part of their clinical evaluation were eligible. Areas Under The Receiver Operating Curve (AUROC) were calculated for the performance of HEART score and 30-day MACE for each group. This study analyzed 46,210 patients' charts, 663 (1.4%) were COP patients. Mean age was statistically similar between groups but there were fewer females in the COP group (26.2% vs 53.2%, p < 0.001). Mean (+/− SD) HEART score was 3.7 (1.4) comparing to 3.1 (1.8, p < 0.001) between COP vs CON groups, respectively. Although more COP patients (54%) had moderate HEART scores (4–6) vs. CON group (35.2%, p < 0.001), rates of 30-day MACE were 1.1% for both groups. HEART score's AUROC was 0.72 for COP and 0.78 for CON groups. AUROC for the Risk Factor among COP patients, which includes cocaine, was poor (0.54). This study, which utilized prospective calculated HEART scores, demonstrated that overall performance of the HEART score was reasonable. Specifically, our analysis showed that the rate of 30-day MACE was not affected by cocaine use as a risk factor. We would recommend clinicians to consider the HEART score for this patient group. [ABSTRACT FROM AUTHOR]

Cocaine use has tended to increase over the past decade, particularly among younger populations. Cocaine is the second most commonly used illicit substance in France. Over the past few years, there has been an uptick in cocaine consumption in the country. The observed increase in consumption raises questions about the underlying motives. The goal of the present study is to construct and validate a questionnaire that explores the motivation behind cocaine use. This paper consists of two studies conducted on different data collections. In the first study, one thousand, one hundred and thirteen (n = 1113) individuals participated and six hundred and seventy (n = 670) individuals participated in the second study. All participants were current or former cocaine users. These participants completed an online sociodemographic questionnaire, a constructed questionnaire exploring motivations for cocaine use. This questionnaire was developed using the self-determination theory of (Deci & Ryan, 1985) and 11 semi-structured interviews with users. The purpose of these interviews was to explore the motivation for cocaine use, the expected benefits, and the negative consequences. From literature and the corpus of previously completed interviews, a first version of the questionnaire with 31 items was produced. The research respects the ethical recommendations of Helsinki and has received a favorable opinion from the research ethics committee. The data was collected anonymously and on a voluntary basis. In the first study, 574 (51.6%) men and 539 (48.4%) women participated. The mean age of the participants was 25.0 years (SD = 5.83) ranging from 18 to 65 years old. In the second study 310 (46.3%) men and 360 (53.7%) women participated. The mean age of the participants was 25.7 years (SD = 4.23) ranging from 18 to 48 years old. Initially, an exploratory factor analysis was carried out. This first analysis resulted in a 23-item questionnaire with a four-factor solution: pleasant sensations, social pressure and self-image, absence of motivation, and curiosity and experience. The psychometric indicators were quite satisfactory with X2 (465) = 15951, P < 0.001 for the Bartlett test and 0.91 for the KMO (Kaiser-Meyer-Olkin) test. In the second part of the research, the confirmatory factor analysis indicated a solution with three factors and 21 items. Psychometric indicators showed CFI (Comparative Fit Index) = 0.89, RMSEA (Root Mean Square Error of Approximation) = 0.06 and SRMR (Standardized Root Mean Square Residual) = 0.06. The three main factors for cocaine use were: pleasant and positive sensations, social pressure and self-esteem, and amotivation. This study laid the groundwork for the development of a valid questionnaire to explore and better understand the cocaine users' motivations, thereby enabling preventive and therapeutic measures to be adjusted accordingly. This questionnaire can also be used for future research on cocaine use, which is focused on mental health as well as family history and history of traumatic life events, as associated with cocaine use. We may also consider replicating this study on a clinical population with a cocaine-dependency diagnosis, potentially revealing additional motivations. [ABSTRACT FROM AUTHOR]

• A/G and G/G mice self-administered more oxycodone. • A/G and G/G mice self-administered more oxycodone when combined with cocaine. • A/G and G/G mice self-administered more cocaine. • Gene expression levels of Pdyn, Fkbp5, Oprk1 and Oprm1 changed after SA. The use of mu-opioid receptor (MOP-r) agonists such as oxycodone together with cocaine is prevalent, and deaths attributed to using these combinations have increased. Rationale: It is unknown if functional single nucleotide polymorphisms (SNPs), such as the OPRM1 (MOP-r gene) SNP A118G, can predispose individuals to more dual opioid and psychostimulant intake. The dual self-administration (SA) of MOP-r agonists and cocaine has not been thoroughly examined, especially with regard to neurobiological changes. Objectives: We examined oxycodone SA and subsequent dual oxycodone and cocaine SA in male and female A112G (A/G and G/G, heterozygote and homozygote, respectively) mice, models of human A118G carriers, versus wild-type (A/A) mice. Methods: Adult male and female A/G, G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, 4hr/session, FR 1.) for 10 consecutive days (sessions 1–10). Mice then self-administered cocaine (2 hr) following oxycodone SA (4 hr, as above) in each session for a further 10 consecutive days (sessions 11–20). Message RNA transcripts of 24 reward-related genes were examined in the dorsal striatum. Results: Male and female A/G and G/G mice had greater oxycodone SA than A/A mice did in the initial 10 days and in the last 10 sessions. Further, A/G and G/G mice showed greater cocaine intake than A/A mice. Dorsal striatal mRNA levels of Pdyn , Fkbp5 , Oprk1, and Oprm1 were altered following oxycodone and cocaine SA. Conclusions: These studies demonstrated that this functional genetic variation in Oprm1 affected dual opioid and cocaine SA and altered specific gene expression in the striatum. [ABSTRACT FROM AUTHOR]

Both psychostimulant use and engagement with probabilistic schedules of reward sensitize the mesocorticolimbic dopamine (DA) system. Such behaviors may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation. To probe these interactions, we sensitized ventral tegmental area DA neurons via chronic chemogenetic stimulation while rats (n = 134) learned a rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort (n = 25), we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine and potentiated phasic excitability of ventral tegmental area DA neurons through in vivo electrophysiological recordings. In the absence of cues, sensitization promoted risk taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males while attenuating cue-induced risk taking in females. While these results provide further confirmation that ventral tegmental area DA neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact that dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision making on the cued rat gambling task increased as both males and females learned to self-administer cocaine. The combination of DA sensitization and win-paired cues while gambling led to significantly greater cocaine taking, but these rats did not show any increase in risky choice as a result. Therefore, cocaine and heavily cued gambles may partially substitute for each other once the DA system has been rendered labile through sensitization, thereby compounding addiction risk across modalities. [ABSTRACT FROM AUTHOR]

Opioid-involved deaths are continuing to increase across the United States, exceeding 100,000 for the first time in 2021. Contamination with, and intentional use of, synthetic opioids such as fentanyl are a major driver of this increase. Utilizing self-report substance use data of patients being treated in the emergency department (ED) can be useful to determine which substances patients are intentionally seeking. 1) Examine changes in self-reported illicit substance use (including fentanyl) over time; 2) Examine changes in the co-occurrence of self-reported fentanyl with other illicit substance use over time. All patients presenting to the study EDs that answered anything other than "never" on the National Institute on Drug Abuse Quick Screen and were seen by a peer recovery specialist in the ED between July 1, 2020 and December 31, 2022 were included for analysis. The substance of use as reported by each patient was recorded by the peer recovery specialist. Differences in substance use by type over time were examined using chi-squared tests of proportions. There were 7568 patients that met inclusion criteria. Self-reported fentanyl (1760%; p < 0.0001) and cocaine (82%; p = 0.034) use increased, whereas heroin use (16%; p < 0.0001) decreased. Self-reported fentanyl and cocaine use has increased significantly in South Carolina ED patients between 2020 and 2022. Given the high morbidity and mortality associated with fentanyl and fentanyl analog use, further measures to identify these patients and provide harm reduction and treatment from the ED setting are warranted. [ABSTRACT FROM AUTHOR]

Most efforts in addiction research have focused on the involvement of the medial prefrontal cortex, including the infralimbic, prelimbic, and anterior cingulate cortical areas, in cocaine-seeking behaviors. However, no effective prevention or treatment for drug relapse is available. We focused instead on the motor cortex, including both the primary and supplementary motor areas (M1 and M2, respectively). Addiction risk was evaluated by testing cocaine seeking after intravenous self-administration (IVSA) of cocaine in Sprague Dawley rats. The causal relationship between the excitability of cortical pyramidal neurons (CPNs) in M1/M2 and addiction risk was explored by ex vivo whole-cell patch clamp recordings and in vivo pharmacological or chemogenetic manipulation. Our recordings showed that on withdrawal day 45 (WD45) after IVSA, cocaine, but not saline, increased the excitability of CPNs in the cortical superficial layers (primarily layer 2, denoted L2) but not in layer 5 (L5) in M2. Bilateral microinjection of the GABA A (gamma-aminobutyric acid A) receptor agonist muscimol to the M2 area attenuated cocaine seeking on WD45. More specifically, chemogenetic inhibition of CPN excitability in L2 of M2 (denoted M2-L2) by the DREADD (designer receptor exclusively activated by designer drugs) agonist compound 21 prevented drug seeking on WD45 after cocaine IVSA. This chemogenetic inhibition of M2-L2 CPNs had no effects on sucrose seeking. In addition, neither pharmacological nor chemogenetic inhibition manipulations altered general locomotor activity. Our results indicate that cocaine IVSA induces hyperexcitability in the motor cortex on WD45. Importantly, the increased excitability in M2, particularly in L2, could be a novel target for preventing drug relapse during withdrawal. [ABSTRACT FROM AUTHOR]

• Geospatial intelligence contributes to the formulation of public drug policies. • Concentrated individual cocaine seizures linked to specific geographical features. • News websites provide valuable insights into drug trafficking dynamics. • The identified routes and trends align with current literature on drug trafficking. • São Paulo: key node for Brazil's cocaine traffic and its international distribution. Cocaine trafficking threatens countries' national security and is a major public health challenge. Cocaine is transported from producer countries to consumer markets using various routes, methods, and transportation means. These routes develop in the geographical environment, are carefully planned and are geo-strategic objects that respond to the opportunities that drug trafficking organisations (DTOs) find to reduce the risks of interdiction. In this sense, individual drug seizure data (IDS) become essential indicators for identifying trends and understanding trafficking flows associated with drug trafficking routes. However, due to the illicit nature of DTOs, the availability of these data is considerably limited, hindering the ability to analyse and identify trends. This study presents a methodology for collecting and processing data from open-source information reported by Brazil's federal government news website. Using geospatial intelligence and natural language processing methods, we created a dataset with 939 records and 44 variables related to cocaine seizures in Brazil in 2022. We applied geospatial analysis techniques from this dataset to identify trends and potential cocaine trafficking flows. The results were broadly consistent with existing literature on drug trafficking. They demonstrated the potential of open-source information for environmental scanning and knowledge generation through geographic information science. The approach proposed in our research provides tools that can be used to complement drug trafficking monitoring and formulate public policies to strengthen prevention and enforcement strategies. [ABSTRACT FROM AUTHOR]

Opioid overdose deaths in 2021 were the highest ever, driven by fentanyl and polysubstance use. The aim of the study was to characterize drug use, assessed by urine drug screens (UDSs), in patients with untreated opioid use disorder (OUD) presenting to 28 emergency departments (EDs) nationally and by region. We analyzed UDSs from patients enrolled in the CTN-0099 ED-INNOVATION (Emergency Department-Initiated Buprenorphine Validation) trial between July 12, 2020 and March 9, 2022. Participants were adult ED patients with OUD not engaged in addiction treatment with a UDS positive for an opioid, but negative for methadone. Sites were divided into "East" and "West" regions. A UDS was available for all 925 enrolled participants, 543 from East and 382 from West. Fentanyl was in 702 specimens (76%) (n = 485 [89%] East vs. n = 217 [57%] West; p < 0.01) and was the only opioid in 269 (29%). After fentanyl, the most common opioids were morphine (presumably heroin; n = 411 [44%]; n = 192 [35%] East vs. n = 219 [57%] West; p < 0.01) and buprenorphine (n = 329 [36%]; n = 186 [35%] East vs. n = 143 [37%] West; p = 0.32). The most common drugs found with opioids were stimulants (n = 545 [59%]), tetrahydrocannabinol (n = 417 [45%]), and benzodiazepines (n = 151 [16%]). Amphetamine-type stimulants were more common in West (n = 209 [55%] vs. East (n = 125 [23%]). Cocaine was more common in East (n = 223 [41%]) vs. West (n = 82 [21%]). The presence of multiple drugs was common (n = 759 [82%]). Most participants had UDS specimens containing multiple substances; a high proportion had fentanyl, stimulants, and buprenorphine. Regional differences were noted. Given the increased risk of death with fentanyl and polysubstance use, ED providers should be providing risk reduction counseling, treatment, and referral. [ABSTRACT FROM AUTHOR]

[Display omitted] Despite significant advancements in our understanding of addiction at the neurobiological level, a highly effective extinction procedure for preventing relapse remains elusive. In this study, we report that bright light treatment (BLT) administered during cocaine withdrawal with extinction training prevents cocaine-driven reinstatement by acting through the thalamic-habenular pathway. We found that during cocaine withdrawal, the lateral habenula (LHb) was recruited, and inhibition of the LHb via BLT prevented cocaine-driven reinstatement. We also demonstrated that the effects of BLT were mediated by activating LHb-projecting neurons in the ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL) or by inhibiting postsynaptic LHb neurons. Furthermore, BLT was found to improve aversive emotional states induced by drug withdrawal. Our findings suggest that BLT administered during the cocaine withdrawal may be a promising strategy for achieving drug abstinence. [ABSTRACT FROM AUTHOR]

Unbalanced activity of medium spiny neurons (MSNs) of the direct and indirect pathways mediates reward-related behaviors induced by addictive drugs. Prelimbic (PL) input to MSNs in the nucleus accumbens core (NAcC) plays a key role in cocaine-induced early locomotor sensitization (LS). However, the adaptive plastic changes at PL-to-NAcC synapses underlying early LS remain unclear. Using transgenic mice and retrograde tracing, we identified NAcC-projecting pyramidal neurons (PNs) in the PL cortex based on the expression of dopamine receptor types (D1R or D2R). To examine cocaine-induced alterations in PL-to-NAcC synapses, we measured excitatory postsynaptic current amplitudes evoked by optostimulation of PL afferents to MSNs. Riluzole was chosen to test the effects of PL excitability on cocaine-induced changes of PL-to-NAcC synapses. NAcC-projecting PNs were segregated into D1R- and D2R-expressing PNs (D1- and D2-PNs, respectively), and their excitability was opposingly regulated by respective dopamine agonists. Both D1- and D2-PNs exhibited balanced innervation of direct MSNs and indirect MSNs in naïve animals. Repeated cocaine injections resulted in biased synaptic strength toward direct MSNs through presynaptic mechanisms in both D1- and D2-PNs, although D2R activation reduced the D2-PN excitability. Under group 1 metabotropic glutamate receptors coactivation, however, D2R activation enhanced the D2-PN excitability. The cocaine-induced rewiring accompanied LS, and both rewiring and LS were precluded by PL infusion of riluzole, which reduced the intrinsic excitability of PL neurons. These findings indicate that cocaine-induced rewiring of PL-to-NAcC synapses correlates well with early behavioral sensitization and that rewiring and LS can be prevented by riluzole-induced reduction of excitability of PL neurons. [ABSTRACT FROM AUTHOR]

The ability of neurons to respond to external stimuli involves adaptations of gene expression. Induction of the transcription factor ΔFOSB in the nucleus accumbens, a key brain reward region, is important for the development of drug addiction. However, a comprehensive map of ΔFOSB's gene targets has not yet been generated. We used CUT&RUN (cleavage under targets and release using nuclease) to map the genome-wide changes in ΔFOSB binding in the 2 main types of nucleus accumbens neurons—D1 or D2 medium spiny neurons—after chronic cocaine exposure. To annotate genomic regions of ΔFOSB binding sites, we also examined the distributions of several histone modifications. Resulting datasets were leveraged for multiple bioinformatic analyses. The majority of ΔFOSB peaks occur outside promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with ΔFOSB peaks, a finding consistent with earlier studies of ΔFOSB's interacting proteins. Chronic cocaine use induces broad changes in ΔFOSB binding in both D1 and D2 nucleus accumbens medium spiny neurons of male and female mice. In addition, in silico analyses predict that ΔFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors. These novel findings uncover key elements of ΔFOSB's molecular mechanisms in transcriptional regulation at baseline and in response to chronic cocaine exposure. Further characterization of ΔFOSB's collaborative transcriptional and chromatin partners specifically in D1 and D2 medium spiny neurons will reveal a broader picture of the function of ΔFOSB and the molecular basis of drug addiction. [ABSTRACT FROM AUTHOR]

Drug use is prevalent in patients with schizophrenia spectrum disorders (SSD) but there is limited knowledge about the influence of drug use on the effectiveness of antipsychotic medication. This secondary explorative study compared the effectiveness of three antipsychotics in patients with SSD, with and without drug use. The BeSt InTro multi-centre, head to head, rater-blinded randomised study compared amisulpride, aripiprazole and olanzapine over a 1-year follow-up period. All patients (n = 144) were aged ≥18 years and met the ICD-10 criteria for SSD (F20–29). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The primary outcome was reduction of a PANSS positive subscale score. At baseline, 38% of all patients reported drug use in the last 6 months before inclusion, with cannabis as the main drug (85%), followed by amphetamine-type stimulants (45%), sedatives (26%), hallucinogens (19%), cocaine (13%), opiates (4%), GHB (4%), solvents (4%), analgesics (4%) and anabolic steroids (2%). The predominant pattern was the use of several drugs. There were no significant overall differences in the PANSS positive subscale score reduction for the three studied antipsychotics among patients either with or without drug use. In the drug use group, older patients treated with amisulpride showed a greater PANSS positive subscale score reduction during the treatment period compared to younger patients. The current study showed that drug use does not appear to affect the overall effectiveness of amisulpride, aripiprazole and olanzapine in patients with SSD. However, amisulpride may be a particularly suitable choice for older patients with drug use. [ABSTRACT FROM AUTHOR]

There are indications that drug conditioned stimuli (CS) may activate neurochemical systems of memory modulation that are activated by the drugs themselves. To directly test this hypothesis, a cholinergic nicotinic receptor antagonist (mecamylamine; MEC: 0, 10 or 30 µg/side) and a dopamine D2 receptor antagonist (l -741,626: 0, 0.63, 2.5 µg/side) were infused in the perirhinal cortex (PRh) to block modulation of object recognition memory consolidation induced by 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs. To establish these CSs, male Sprague-Dawley rats were confined for 2 h in a chamber, the CS+, after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, and in another chamber, the CS−, after injections of vehicle. This was repeated over 10 days (5 drug/CS+ and 5 vehicle/CS− pairings in total). It was found that the memory enhancing action of post-sample nicotine was blocked by intra-PRh infusions of both MEC doses, and 30 µg/side MEC also blocked the memory enhancing action of the nicotine CS. Interestingly, intra-PRh MEC did not block the memory enhancing effect of cocaine, nor that of the cocaine CS. In contrast, the memory enhancing action of post-sample cocaine administration was blocked by both l -741,626 doses, and 2.5 µg/side also blocked the effect of the cocaine CS, but not the memory effects of nicotine or of the nicotine CS. This functional double dissociation strongly indicates that drug CSs modulate memory consolidation by activating neural systems that are activated by the drugs themselves. [ABSTRACT FROM AUTHOR]

Over the course of chronic drug use, brain transcriptional neuroadaptation is thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within the NAc of mice. To investigate the role of the CREB- Zfp189 interaction in cocaine use, we virally delivered modified clustered regularly interspaced short palindromic repeats (CRISPR)/dCas9 constructs capable of selectively localizing CREB to the Zfp189 gene promoter in the NAc of mice. We observed that CREB binding to the Zfp189 promoter increased Zfp189 expression and diminished the reinforcing responses to cocaine. Furthermore, we showed that NAc Zfp189 expression increased within D1 medium spiny neurons in response to acute cocaine but increased in both D1- and D2-expressing medium spiny neurons in response to chronic cocaine. CREB-mediated induction of Zfp189 potentiated electrophysiological activity of D1- and D2-expressing medium spiny neurons, recapitulating the known effect of CREB on these neurons. Finally, targeting CREB to the Zfp189 promoter within NAc Drd2- expressing neurons, but not Drd1- expressing neurons, was sufficient to diminish cocaine-conditioned behaviors. Together, these findings point to the CREB- Zfp189 interaction within the NAc Drd2+ neurons as a molecular signature of chronic cocaine use that is causal in counteracting the reinforcing effects of cocaine. [ABSTRACT FROM AUTHOR]

Although hyperthermia is described after cocaine intoxication, the two hyperthermic cases discussed were unusual in severity and duration for cocaine alone. Synephrine was found in biological samples of these patients in high concentrations and was suspected to be an adulterant in illicitly obtained drugs. Two patients presented to a tertiary care university hospital within 2 days of each other after recreational drug use with delayed and protracted hyperthermia. Synephrine was later found in high concentrations in biological samples as an unexpected drug adulterant. The first patient's presentation came with delayed recognition of hyperthermia and implementation of aggressive cooling measures; he entered multisystem organ failure with prolonged intensive care unit stay and significant morbidity. The second patient's hyperthermia was recognized promptly, and she received early, aggressive cooling, including deep sedation and ice water submersion. She left against medical advice from the hospital at her baseline 3 days after presentation. Synephrine is a suspected adulterant that may be associated with profound hyperthermia. Early recognition of drug overdose and working knowledge of common adulterants can facilitate early targeted management, such as aggressive cooling measures, which may prevent morbidity and mortality. [ABSTRACT FROM AUTHOR]

[Display omitted] • Exposure to morphine and cocaine induces changes in the transcriptome of zebrafish embryos. • Pathways related to lipid metabolism appear to be overrepresented for both treatments. • Other deregulated pathways are detoxification, response to chemicals and calcium signalling. • Morphine and cocaine modify global DNA methylation. Morphine and other opioid analgesics are the drugs of election to treat moderate-to-severe pain, and they elicit their actions by binding to the opioid receptors. Cocaine is a potent inhibitor of dopamine, serotonin, and noradrenaline reuptake, as it blocks DAT, the dopamine transporter, causing an increase in the local concentration of these neurotransmitters in the synaptic cleft. The molecular effects of these drugs have been studied in specific brain areas or nuclei, but the systemic effects in the whole organism have not been comprehensively analyzed. This study aims to analyze the transcriptomic changes elicited by morphine (10 uM) and cocaine (15 uM) in zebrafish embryos. An RNAseq assay was performed with tissues extracts from zebrafish embryos treated from 5 hpf (hours post fertilization) to 72 hpf, and the most representative deregulated genes were experimentally validated by qPCR. We have found changes in the expression of genes related to lipid metabolism, chemokine receptor ligands, visual system, hemoglobins, and metabolic detoxification pathways. Besides, morphine and cocaine modified the global DNA methylation pattern in zebrafish embryos, which would explain the changes in gene expression elicited by these two drugs of abuse. [ABSTRACT FROM AUTHOR]

In 2014, we proposed that orexin signaling transformed motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a threat, a process we referred to as motivational activation. Advancements in animal models since then have permitted higher-resolution measurements of motivational states; in particular, the behavioral economics approach for studying drug demand characterizes conditions that lead to the enhanced motivation that underlies addiction. This motivational plasticity is paralleled by persistently increased orexin expression in a topographically specific manner—a finding confirmed across species, including in humans. Normalization of orexin levels also reduces drug motivation in addiction models. These new advancements lead us to update our proposed framework for the orexin function. We now propose that the capacity of orexin neurons to exhibit dynamic shifts in peptide production contributes to their role in adaptive motivational regulation and that this is achieved via a pool of reserve orexin neurons. This reserve is normally bidirectionally recruited to permit motivational plasticity that promotes flexible, adaptive behavior. In pathological states such as addiction, however, we propose that the orexin system loses capacity to adaptively adjust peptide production, resulting in focused hypermotivation for drug, driven by aberrantly and persistently high expression in the orexin reserve pool. This mechanistic framework has implications for the understanding and treatment of several psychiatric disorders beyond addiction, particularly those characterized by motivational dysfunction. [ABSTRACT FROM AUTHOR]

Social experiences influence susceptibility to substance use disorder. The adolescent period is associated with the development of social reward and is exceptionally sensitive to disruptions to reward-associated behaviors by social experiences. Social isolation (SI) during adolescence alters anxiety- and reward-related behaviors in adult males, but little is known about females. The medial amygdala (meA) is a likely candidate for the modulation of social influence on drug reward because it regulates social reward, develops during adolescence, and is sensitive to social stress. However, little is known regarding how the meA responds to drugs of abuse. We used adolescent SI coupled with RNA sequencing to better understand the molecular mechanisms underlying meA regulation of social influence on reward. We show that SI in adolescence, a well-established preclinical model for addiction susceptibility, enhances preference for cocaine in male but not in female mice and alters cocaine-induced protein and transcriptional profiles within the adult meA particularly in males. To determine whether transcriptional mechanisms within the meA are important for these behavioral effects, we manipulated Crym expression, a sex-specific key driver gene identified through differential gene expression and coexpression network analyses, specifically in meA neurons. Overexpression of Crym, but not another key driver that did not meet our sex-specific criteria, recapitulated the behavioral and transcriptional effects of adolescent SI. These results show that the meA is essential for modulating the sex-specific effects of social experience on drug reward and establish Crym as a critical mediator of sex-specific behavioral and transcriptional plasticity. [ABSTRACT FROM AUTHOR]

Persistent sleep disruptions following withdrawal from abused drugs may hold keys to battle drug relapse. It is posited that there may be sleep signatures that predict relapse propensity, identifying which may open new avenues for treating substance use disorders. We trained male rats (approximately postnatal day 56) to self-administer cocaine. After long-term drug withdrawal (approximately postnatal day 100), we examined the correlations between the intensity of cocaine seeking and key sleep features. To test for causal relationships, we then used behavioral, chemogenetic, or optogenetic methods to selectively increase rapid eye movement sleep (REMS) and measured behavioral and electrophysiological outcomes to probe for cellular and circuit mechanisms underlying REMS-mediated regulation of cocaine seeking. A selective set of REMS features was preferentially associated with the intensity of cue-induced cocaine seeking after drug withdrawal. Moreover, selectively increasing REMS time and continuity by environmental warming attenuated a withdrawal time-dependent intensification of cocaine seeking, or incubation of cocaine craving, suggesting that REMS may benefit withdrawal. Warming increased the activity of lateral hypothalamic melanin-concentrating hormone (MCH) neurons selectively during prolonged REMS episodes and counteracted cocaine-induced synaptic accumulation of calcium-permeable AMPA receptors in the nucleus accumbens—a critical substrate for incubation. Finally, the warming effects were partly mimicked by chemogenetic or optogenetic stimulations of MCH neurons during sleep, or intra-accumbens infusions of MCH peptide during the rat's inactive phase. REMS may encode individual vulnerability to relapse, and MCH neuron activities can be selectively targeted during REMS to reduce drug relapse. [ABSTRACT FROM AUTHOR]

L'objectif de ce travail est de déterminer la fréquence des symptômes psychotiques induits par les psychostimulants, dont les nouveaux produits de synthèse (NPS), leurs caractéristiques cliniques, leur évolution et leurs traitements. Une revue de documents sélectionnés est effectuée suivant les principes de recherche systématique dans le Medline. La recherche retrouve 41 articles portant sur les psychostimulants hors NPS et 9 articles portant sur les NPS. Les symptômes psychotiques induits par les psychostimulants, y compris NPS, sont fréquents, présentent des caractéristiques typiques avec d'importants signes positifs malgré un insight en partie conservé, une possible évolution sur un mode chronique et répondent à des traitements comme les benzodiazépines et les antipsychotiques. Un récapitulatif des implications pratiques est proposé. Les symptômes psychotiques induits par les psychostimulants pourraient constituer un trouble à part ou une vulnérabilité qui devraient faire l'objet d'une prise en charge intégrée portant à la fois sur les consommations et la symptomatologie psychiatrique. Psychostimulants such as cocaine, amphetamines and their derivatives, methamphetamine or novel synthetic drugs such as cathinones are known to cause psychotic symptoms. The objective of this study is to determine the frequency of psychotic symptoms induced by psychostimulants, including novel psychoactive substances (NPS), their clinical characteristics, their evolution, and their treatments. A review of selected documents was carried out following the principles of systematic research in Medline from 02/12/2017 to 02/12/2022. We included articles in French or English dealing with psychotic symptoms, episodes and disorders induced by psychostimulants in humans, and excluded articles dealing with animal models, those not distinguishing between substances other than psychostimulants, and NPS and non-NPS psychostimulants, and articles focusing exclusively on individuals with previously diagnosed schizophrenia. The data was input in a table for non-NPS psychostimulants and another table for NPS psychostimulants. The search found 41 articles on non-NPS psychostimulants and 9 articles on NPS. Psychotic symptoms induced by psychostimulants, including NPS, are frequent in a population of medicalized consumers: 18 to 80% according to studies. Psychotic symptoms show typical features with prominent positive symptoms, especially persecutory delirium, auditory, visual and tactile hallucinations, less negative, and cognitive symptoms. We noted more agitation, even auto-aggressiveness or hetero-aggressiveness. The clinical presentation is frequently accompanied by signs of toxic impregnation, in particular tachycardia, palpitations, hypertension, sweating or mydriasis. The data suggest a possible evolution in a chronic presentation. Psychostimulant-induced psychotic symptoms appear to be improved by treatments such as benzodiazepines for agitation and antipsychotics. The data was less rich regarding NPS but broadly consistent with the findings presented above. A summary of practical implications is provided. The psychotic symptoms induced by psychostimulants present specific, although not exclusive, characteristics. They should be the subject of particular attention, in especially looking for urinary toxins, although certain substances such as cathinones are not detected by current laboratory practices. They may be subject to a specific treatment depending on their severity and duration. In some cases, they could evolve into a chronic presentation and constitute a separate disorder or a vulnerability that should be the subject of integrated care covering both consumptions and psychiatric symptoms. [ABSTRACT FROM AUTHOR]

• Cocaine dependence (CD) is a common comorbidity of HIV infection. • The effect of former cocaine dependence on brain integrity in HIV+ individuals was explored. • Higher caudate volume was observed in abstinent CD participants. • HIV identified as the primary driver of reduced cognitive performance on neurocognitive testing. • No interactions between HIV and CD history were identified. Evidence from animal research, postmortem analyses, and magnetic resonance imaging (MRI) investigations indicate substantial morphological alteration in brain structure as a function of human immunodeficiency virus (HIV) or cocaine dependence (CD). Although previous research on HIV+ active cocaine users suggests the presence of deleterious morphological effects in excess of either condition alone, a yet unexplored question is whether there is a similar deleterious interaction in HIV+ individuals with CD who are currently abstinent. To this end, the combinatorial effects of HIV and CD history on regional brain volume, cortical thickness, and neurocognitive performance was examined across four groups of participants in an exploratory study: healthy controls (n = 34), HIV-negative individuals with a history of CD (n = 21), HIV+ individuals with no history of CD (n = 20), HIV+ individuals with a history of CD (n = 15). Our analyses revealed no statistical evidence of an interaction between both conditions on brain morphometry and neurocognitive performance. While descriptively, individuals with comorbid HIV and a history of CD exhibited the lowest neurocognitive performance scores, using Principle Component Analysis of neurocognitive testing data, HIV was identified as the primary driver of neurocognitive impairment. Higher caudate volume was evident in CD+ participants relative to CD− participants. Findings indicate no evidence of compounded differences in neurocognitive function or structural measures of brain integrity in HIV+ individuals in recovery from CD relative to individuals with only one condition. [ABSTRACT FROM AUTHOR]

Street cocaine is often mixed with various substances that intensify its harmful effects. This paper proposes a framework to identify attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) intervals that best predict the concentration of adulterants in cocaine samples. Wavelengths are ranked according to their relevance through ReliefF and mRMR feature selection approaches, and an iterative process removes less relevant wavelengths based on the ranking suggested by each approach. Gaussian Process (GP) regression models are constructed after each wavelength removal and the prediction performance is evaluated using RMSE. The subset balancing a low RMSE value and a small percentage of retained wavelengths is chosen. The proposed framework was validated using a dataset consisting of 345 samples of cocaine with different amounts of levamisole, caffeine, phenacetin, and lidocaine. Averaged over the four adulterants, the GP regression coupled with the mRMR retained 1.07 % of the 662 original wavelengths, outperforming PLS and SVR regarding prediction performance. • A new framework for predicting cocaine adulterant concentration • Two feature selection approaches integrated to Gaussian Process are tested • Predictions were substantially improved when using reduced regions of the spectra • The proposed framework was validated in four adulterants [ABSTRACT FROM AUTHOR]

Individual differences in drug use emerge soon after initial exposure, and only a fraction of individuals who initiate drug use go on to develop a substance use disorder. Variability in vulnerability to establishing drug self-administration behavior is also evident in preclinical rodent models. Latent characteristics that underlie this variability and the relationship between early drug use patterns and later use remain unclear. Here, we attempt to determine whether propensity to establish cocaine self-administration is related to subsequent cocaine self-administration behavior in male Sprague-Dawley rats (n = 14). Prior to initiating training, we evaluated basal locomotor and anxiety-like behavior in a novel open field test. We then trained rats to self-administer cocaine in daily 3 h cocaine (0.75 mg/kg/infusion) self-administration sessions until acquisition criteria (≥30 active lever presses with ≥70 % responding on the active lever in one session) was met and divided rats into Early and Late groups by median-split analysis based on their latency to meet acquisition criteria. After each rat met acquisition criteria, we gave them 10 additional daily cocaine self-administration sessions. We then conducted a progressive ratio, cocaine-induced locomotor sensitivity test, and non-reinforced cocaine seeking test after two weeks of forced abstinence. Early Learners exhibited significantly less locomotion after an acute injection of cocaine, but the groups did not differ in any other behavioral parameter examined. These results indicate that cocaine self-administration acquisition latency is not predictive of subsequent drug-taking behavior, but may be linked to physiological factors like drug sensitivity that can predispose rats to learn the operant task. [ABSTRACT FROM AUTHOR]

During the COVID-19 pandemic, one of Australia's biggest cities, Melbourne, experienced three major isolation ("lockdown") periods in 2020 (160 days) and in 2021 (111 days) which makes it one of the most locked down cities world-wide. This study assessed how the pandemic affected temporal trends in methamphetamine, MDMA and cocaine consumption using wastewater-based epidemiology. Daily samples were collected for most of 2020 and 2021 (n = 660 days). Concentrations were measured using direct-injection LC-MS/MS and back-calculated to consumption estimates. Results indicate that methamphetamine use was increasing before the first lockdown and decreased after the end of the first lockdown in 2020. Methamphetamine trends appeared to have remained steady throughout the second lockdown period before increasing steeply after it ended. For most of 2020, cocaine use remained steady, with an increase after the second lockdown. MDMA use decreased after the start of the first lockdown and remained steady throughout most of 2020 and 2021. In comparison to 2020, trends in 2021 were less variable and stimulant use did not appear to be as associated with COVID-19 restrictions. Overall, this study was able to show the impact of lockdown periods and the related social restrictions on illicit stimulant use. Illicit drugs are hazardous chemicals, of concern both to humans and the environment. While studies have been undertaken to understand their temporal trends, this work utilizes wastewater-based epidemiology and daily sampling to provide a comprehensive understanding of the impact of the COVID-19 pandemic on the use of methamphetamine, MDMA and cocaine on one of the most locked-down cities in the world. Understanding the consequences of this significant intervention on illicit drug use could provide valuable insights into its potential environmental impact. [Display omitted] • First study to examine daily wastewater samples for illicit drugs across a two-year period. • MDMA, methamphetamine and cocaine analysed in a city with significant lockdowns. • COVID-19 restrictions in 2021 had less impact on illicit drug use than those in 2020. [ABSTRACT FROM AUTHOR]

Controls on essential/precursor chemicals from commercial companies have been associated with many large downturns in illicit drug markets and attendant problems. My colleagues and I brought this to light in the studies that are the subject of Giommoni's review. McKetin et al. in an earlier review considered several of our studies on chemical controls for methamphetamine, all centered in North America. Giommoni discusses not only those studies but also our later work on chemical controls for cocaine and heroin. This later work evaluates US essential/precursor chemical policies targeting illicit drug producers outside of North America, and it examines impacts on illicit drug availability and use (the studies reviewed by McKetin et al. predominantly focused on outcomes such as drug-related hospitalizations, arrests, and treatment). Giommoni's review is a new resource that will help make the varied topics in essential/precursor chemical control research more accessible to many readers. After noting this, I discuss some common methodological misconceptions about our studies. For example, our studies generally used multi-replication interrupted time series analysis, a research design among the most powerful of all quasi-experimental designs. Authors, however, typically discuss the studies as if they used single-intervention interrupted time series analysis, a less powerful design. Multi-replication and single-intervention interrupted time series analyses also differ regarding likely confounders; awareness of this is critical to accurately assessing our findings and critiquing alternative explanations. Finally, I note that commercial chemical companies function as the silent, albeit usually unwitting, partners in the large-scale production of several illicit drugs, including fentanyl. And many governments are implementing essential/precursor chemical controls to help stymie this partnership. But they are doing so largely without evaluation and study—a poor policy practice. To remedy this, I suggest establishing multi-disciplinary applied research teams to help assess, guide and improve essential/precursor chemical control efforts. [ABSTRACT FROM AUTHOR]

The main urinary cocaine metabolites are benzoylecgonine and ecgonine methyl ester. These molecules possess two chemical functional groups that can be charged within the conventional pH range, this is the tertiary amine group (both) and the carboxylic group (benzoylecgonine). We have found that in the pH range from 2 to 6 (for benzoylecgonine) and pH from 2 to 4 (for ecgonine methyl ester) both molecules can be detected at the electrified liquid-liquid interface (eLLI) by following the interfacial ion transfer reactions triggered in the presence of the concerned metabolites in the aqueous phase. The presence of the benzene ring in the benzoylecgonine structure increases its hydrophobicity (on the formal Galvani potential difference scale) by around 200 mV as compared with ecgonine methyl ester which transfer is overlaid with the inorganic cations crossing the LLI at the positive end of the potential window. Macroscopic eLLI was used during physicochemical ecgonine methyl ester and benzoylecgonine characterization as we have defined their diffusion coefficients, ion partition, and concentration fraction diagrams (only for the latter). The miniaturized platform was used during electroanalytical studies focused on benzoylecgonine giving a few µM limit of detection. For this purpose, we have used the fused silica capillary as the eLLI support. All our findings allowed us to use this system first to develop the electroanalytical protocol for benzoylecgonine quantification to finally detect it in the spiked urine sample with nearly 100 % recovery. [Display omitted] • Benzoylecgonine and ecgonine methyl ester are active at the ITIES. • Benzoylecgonine and ecgonine methyl ester signals can be separated. • Detection was performed at microscopic ITIES with 5 µL of the organic phase. • Both cocaine metabolites limits of detection are equal to a few µM. • Only benzoylecgonine can be detected in urine samples. [ABSTRACT FROM AUTHOR]

A systematic review of functional neuroimaging studies on drug (self-) administration in rodents is lacking. Here, we summarized effects of acute or chronic drug administration of various classes of drugs on brain function and determined consistency with human literature. We performed a systematic literature search and identified 125 studies on in vivo rodent resting-state functional magnetic resonance imaging (n = 84) or positron emission tomography (n = 41) spanning depressants (n = 27), opioids (n = 23), stimulants (n = 72), and cannabis (n = 3). Results primarily showed alterations in the striatum, consistent with the human literature. The anterior cingulate cortex and (nonspecific) prefrontal cortex were also frequently implicated. Upregulation was most often found after shorter administration and downregulation after long chronic administration, particularly in the striatum. Importantly, results were consistent across study design, administration models, imaging method, and animal states. Results provide evidence of altered resting-state brain function in rodents upon drug administration, implicating the brain's reward network analogous to human studies. However, alterations were more dynamic than previously known, with dynamic adaptation depending on the length of drug administration. • Rodent brain function upon drug administration implicates the reward network. • Upregulation of brain function was consistently seen after short drug administration. • Long chronic administration resulted in downregulation, particularly in the striatum. • Results highlight the utility of preclinical models for neuroimaging substance use. [ABSTRACT FROM AUTHOR]

Acute stimulation of M 1 or M 4 muscarinic cholinergic receptors reduces cocaine abuse-related effects in mice and rats. The combined activation of these receptor subtypes produces synergistic effects on some behavioural endpoints in mice. M 1 and M 1 + M 4 receptor stimulation in a cocaine vs. food choice assay in rats and microdialysis in rats showed delayed and lasting "anticocaine effects". Here, we tested whether these putative lasting neuroplastic changes are sufficient to occlude the reinforcing effects of cocaine at the behavioural level in mice. Mice were pre-treated with the M 1 receptor partial agonist VU0364572, M 4 receptor positive allosteric modulator VU0152100, or VU0364572 + VU0152100 two weeks prior to acquisition of cocaine intravenous self-administration (IVSA). Male C57BL/6JRj mice received vehicle, VU0364572, VU0152100, or VU0364572 + VU0152100. Female mice were tested with two VU0364572 + VU0152100 dose combinations or vehicle. To attribute potential effects to either reduced rewarding effects or increased aversion to cocaine, we tested VU0364572 alone and VU0364572 + VU0152100 in acquisition of cocaine-conditioned place preference (CPP) in male mice using an unbiased design. The acquisition of cocaine IVSA was drastically reduced and/or slowed in male and female mice receiving VU0364572 + VU0152100, but not either drug alone. Food-maintained operant behaviour was unaffected, indicating that the treatment effects were cocaine-specific. No treatment altered the acquisition of cocaine-CPP, neither in the post-test, nor in a challenge 14 days later. The cocaine IVSA findings confirm unusual long-lasting "anticocaine" effects of muscarinic M 1 + M 4 receptor stimulation. Thus, in mice, simultaneous stimulation of both receptor subtypes seems to produce potential neuroplastic changes that yield lasting effects. [Display omitted] • M 1 + M 4 receptor stimulation blunts cocaine reinforcement two weeks later. • Female mice need higher doses of M 1 + M 4 treatment than males to show similar effect. • M 1 or M 4 stimulation alone did not affect later cocaine reinforcement. • Cocaine CPP acquisition is unaffected by M 1 + M 4 treatment in mice. • Pretreatments showed no place conditioning per se (preference or avoidance). [ABSTRACT FROM AUTHOR]

Abuse-related drug usage is a public health issue. Drosophila melanogaster has been used as an animal model to study the biological effects of these psychoactive substances in preclinical studies. Our objective in this review is to evaluate the adverse effects produced by cocaine, nicotine, and marijuana during the development of D. melanogaster. We searched experimental studies in which D. melanogaster was exposed to these three psychoactive drugs in seven online databases up to January 2023. Two reviewers independently extracted the data. Fifty-one studies met eligibility criteria and were included in the data extraction: nicotine (n = 26), cocaine (n = 20), and marijuana (n = 5). Fifteen studies were eligible for meta-analysis. Low doses (∼0.6 mM) of nicotine increased locomotor activity in fruit flies, while high doses (≥3 mM) led to a decrease. Similarly, exposure to cocaine increased locomotor activity, resulting in decreased climbing response in D. melanogaster. Studies with exposure to marijuana did not present a profile for our meta-analysis. However, this drug has been less associated with locomotor changes, but alterations in body weight and fat content and changes in cardiac function. Our analyses have shown that fruit flies exposed to drugs of abuse during different developmental stages, such as larvae and adults, exhibit molecular, morphological, behavioral, and survival changes that are dependent on the dosage. These phenotypes resemble the adverse effects of psychoactive substances in clinical medicine. The cartoon depicts the effects of cocaine, marijuana, and nicotine on the development of Drosophila melanogaster. The articles included in this systematic review indicate that exposure to these drugs of abuse can cause changes at molecular, morphophysiological, and behavioral levels, depending on the dose and route of administration. The chemical structures of the nicotine and cocaine molecules used in this cartoon were taken from the PubChem Compound Summary. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 89594, Nicotine, and CID 446220, Cocaine. Retrieved August 21, 2023 from https://pubchem.ncbi.nlm.nih.gov/compound/Nicotine and https://pubchem.ncbi.nlm.nih.gov/compound/Cocaine. [Display omitted] • Nicotine alters the locomotion of fruit flies in a dose-dependent manner. • Exposure of fruit fly eggs to nicotine increases eclosion by 50%. • Reduced climbing ability in fruit flies after cocaine exposure is sex-dependent. • Repeated cocaine exposure increases locomotor activity in fruit flies. [ABSTRACT FROM AUTHOR]

• Determination of psychoactive substances in sweat samples. • Extraction of psychoactive substances using disposable pipette extraction and GC–MS. • Analysis of psychoactive substances in sweat samples collected from drug users. Widespread consumption of drugs of abuse worldwide has caused concern: it adversely affects public health, individual safety, and social structures. Experts are particularly alarmed because new psychoactive substances have been increasingly detected in biological samples. In recent years, several studies have focused on developing methods to identify psychoactive substances in alternative biological matrices, such as sweat. This approach holds promise for monitoring substance use, especially in individuals undergoing rehabilitation. Among the commonly employed analytical procedures, extraction using disposable DPX tips stands out as a novel, miniaturized, and promising technique. This study aimed to validate and to apply a method to analyze various substances, including amphetamine, methamphetamine, MDMA, MDA, MDEA, cocaine, cocaethylene, anhydroecgonine methyl ester, dibutylone, N-ethylpentylone, 25E-NBOMe, 25C NBOMe, 2C C, 2C-E, fentanyl, and carfentanil, in sweat samples simultaneously. In this method, sweat is collected by using laboratory-developed patches, and extraction is conducted with DPX-SCX tips. Gas chromatography coupled to mass spectrometry is employed to separate, to identify, and to quantify the analytes. Validation results indicated that the quantification limit ranged from 2 to 30 ng of analyte/patch, and that the method was linear for analyte concentrations ranging from 2 to 1100 ng/patch. The validated method was applied to analyze 30 sweat samples collected from volunteers drug users and processed by using both the selected ion mode (SIM) and full scan. The method was able to detect and to quantify substances such as cocaine, cocaethylene, anhydroecgonine methyl ester, MDMA, MDA, nicotine, cotinine, caffeine, procaine, lidocaine, and ethylamphetamine simultaneously. The recovery rates ranged from 72.4 % to 97.1 %. The analytes were stable in the biological matrix. In conclusion, the validated method proved effective and allowed the target analytes to be quantified in sweat samples, highlighting that sweat is a viable matrix for analyzing drugs of abuse. [ABSTRACT FROM AUTHOR]

[Display omitted] • Capitainer qDBS enables accurate 10-µL blood microsampling for UHPLC-MS analysis. • Sustainable, miniaturised approach reduces environmental impact in cocaine monitoring. • Innovative method allows accurate assessment of cocaine and its main metabolites. • Successful validation with reliable results, low detection limits and high precision. • Forensic cocaine confirmation made efficient and sound by means of whole blood microsampling. This study introduces for the first time a reliable whole blood microsampling method for forensic analysis of cocaine and its metabolites using quantitative dried blood spot (qDBS) technology and UHPLC-MS analysis. This methodology offers accurate and less invasive sampling and aligns with the current trend towards sustainable and accessible analytical methods. Microsampling is subject-friendly, improves logistics, stability and efficiency, marking a shift towards modern forensic practices with wide-ranging application potential. The qDBS-UHPLC-MS method underwent comprehensive validation, confirming its linearity, sensitivity, precision, extraction efficiency and stability. UHPLC-MS achieved effective chromatographic separation and suitable sensitivity, with detection limits between 1.0 and 2.5 ng/mL, and quantitation limits from 2.5 to 7.5 ng/mL. Analytes showed over 85.1 % extraction yield and less than 7.5 % relative standard deviation in precision. Stability tests indicated superior analyte preservation in qDBS at room temperature versus refrigerated plasma, while minimal matrix effect highlighted the sample clean-up efficiency. Application to real samples yielded consistent quali-quantitative results between qDBS and plasma samples, confirming method suitability for forensic cocaine bioanalysis, thus addressing critical needs in drug testing and pharmaco-toxicological analysis. [ABSTRACT FROM AUTHOR]

There is a need to identify clinically meaningful non-abstinent endpoints for cocaine use disorder (CUD) clinical trials. In this study, we sought to replicate and extend prior work validating reductions in cocaine use frequency levels as an endpoint by examining associations between reductions in cocaine use frequency and long-term functioning outcomes. We conducted a secondary analysis of two randomized clinical trials (N = 445; 77.5 % male; mean age = 42.18 years; 86.5 % Black, 10.8 % non-Hispanic white) that evaluated telephone-based continuing care for a 12- and 24-month period. Cocaine use frequency levels, measured with the Timeline Followback, were (1) abstinence (no past-month cocaine use), (2) low-frequency use (1–4 days of use/month), and (3) high-frequency use (5+ days of use/month). Among those who completed the 12-month follow-up (n = 392), most reduced from high-frequency use at baseline to abstinence at the 12-month follow-up (n = 243; 62.0 %). An additional 21.2 % (n = 83) reported either high-to-low-frequency use (n = 35; 8.9 %) or low use-to-abstinence (n = 48; 12.2 %); 16.8 % of participants (n = 66) did not change or increased their cocaine frequency level. Compared to those who had no change/increases in frequency levels, at least a one-level reduction from baseline to 12-month follow-up (i.e., high-to-low-frequency use, high-to-abstinence, low-to-abstinence) was concurrently associated with lower levels of negative consequences at the 12-month follow-up and prospectively with lower levels of cocaine use and consequences at 24-month follow-up, with effect sizes in the medium-to-large range. Those who reduced to abstinence generally had fewer drug use consequences at the 12-month follow-up than those who reduced to a low-frequency level; however, these groups did not significantly differ on any outcomes at the 24-month follow-up. Categorical reductions in cocaine use frequency levels, including those short of abstinence, are associated with less cocaine use and lower problem severity up to two years following treatment entry. Low-frequency cocaine use following the initial treatment phase does not appear to forebode worsening functioning, such as escalations in cocaine use. • Reduced cocaine frequency predicts long-term drug-related and psychosocial outcomes. • Reductions in cocaine use frequency were sustained over long-term follow-ups. • Low-frequency cocaine use outcomes do not forebode worsening outcomes. • Low-frequency cocaine use might be a precursor to later abstinence for some people. [ABSTRACT FROM AUTHOR]

• Cocaine conditioned place preference (CPP) was established in control rats. • Oxytocin administration directly into the dorsal hippocampus blocked the expression of cocaine CPP. • Results were consistent in both male and female rats, indicating no sex differences in the mechanism. Cocaine addiction is the third largest cause of overdose-related deaths in the United States. Research investigating therapeutic targets for cocaine reward processes is key to combating this issue. The neuropeptide oxytocin (OXT) has been shown to reduce cocaine reward processes, though specific mechanisms are not understood. This study examines the effect of intra-dorsal hippocampal (DH) OXT on the expression of cocaine context associations using a conditioned place preference (CPP) paradigm. In this paradigm, one of two visually distinct chambers is paired with a drug. With repeated pairings, control animals display preference for the drug-associated context by spending more time in that context at test. In the present study, four conditioning days took place where male and female rats were injected with either cocaine or saline and placed into the corresponding chamber. On test day, rats received infusions of OXT or saline (VEH) into the DH and were allowed access to both chambers. The results show that while VEH-infused rats displayed cocaine CPP, OXT-infused rats did not prefer the cocaine-paired chamber. These findings implicate the DH as necessary in the mechanism by which OXT acts to block the expression of cocaine-context associations, providing insight into how OXT may exert its therapeutic effect in cocaine reward processes. [ABSTRACT FROM AUTHOR]

There are currently no FDA-approved treatments for cocaine use disorder. Recent preclinical and clinical studies showed that deep brain stimulation (DBS) in limbic regions reduced drug seeking behavior. Our previous work indicated that DBS of the nucleus accumbens shell attenuated reinstatement of cocaine seeking, a model of relapse, in male rats. The current experiments were designed to evaluate the effect of electrical DBS on cocaine reinstatement in female rats across the estrous cycle. Rats were allowed to self-administer cocaine and lever responding was subsequently extinguished. Cocaine seeking was reinstated by an acute injection of experimenter-delivered cocaine. The effect of nucleus accumbens shell DBS vs. sham stimulation on cocaine-primed reinstatement was evaluated in female and male rats using a within-subjects counterbalanced design. Consistent with previous work, accumbens shell DBS suppressed cocaine seeking in male rats. In sharp contrast, accumbens shell DBS had no effect on cocaine reinstatement in female rats evaluated in either the estrus or non-estrus phases. These results suggest that changes across the estrous cycle are not responsible for the differences in the effect of DBS on cocaine reinstatement between female and male rats. [ABSTRACT FROM AUTHOR]

This study aimed to validate a modified QuEChERS method, followed by liquid chromatography-tandem mass spectrometry, for the determination of 51 psychoactive substances and screening of 22 ones in oral fluid from electronic dance music party (EDM) attendees. Unstimulated oral fluid was collected in a polypropylene tube and stored in a glass vial at −20 ºC. The sample was extracted with acetonitrile:water and MgSO 4 /NaOAc, followed by cleanup with primary secondary amine and MgSO 4. The effectiveness of the sample storage conditions was shown to be comparable to when the Quantisal™ buffer was used, with no substantial concentration loss (< 15%) for all the substances after up to 72 hours at −20º C. The method was satisfactorily validated, with limits of detection (LOD) and quantification (LOQ) ranging from 0.04 to 0.5 ng/mL and 0.1–1.5 ng/mL, respectively, and was applied to the analysis of 62 real samples. The main substances detected were 3,4-methylenedioxymethamphetamine (MDMA) (<0.5–829 ng/mL) and/or methylenedioxyamphetamine (MDA) (10.1 – 460.6 ng/mL), found in 27 samples, and cocaine (13.0–407.3 ng/mL) and its metabolites (benzoylecgonine 0.17–214.1 ng/mL; ecgonine methyl ester 1.8–150.1 ng/mL) in eight samples. Methamphetamine (11–439 ng/mL) was detected in eight samples, along with MDMA and MDA; eutylone was detected in two cases (4.7 and 24.1 ng/mL) reported as "ecstasy" ingestion. A comparison between self-reported drug use and results of oral fluid analysis indicated that the use of illicit substances is often underreported among EDM attendees, who are often unaware of the substances they consume. • QuEChERS LC-MS/MS method was validated for 51 psychoactive substances in oral fluid • Samples collected from 62 electronic dance music party attendees. • LOD and LOQ ranging from 0.04 to 0.5 ng/mL and 0.1–1.5 ng/mL, respectively • MDMA and/or MDA found in 27 samples, cocaine and in 8 samples. • Eutylone detected in two samples reported as "ecstasy" ingestion. [ABSTRACT FROM AUTHOR]

Cocaine use disorder (CUD) is a global health problem with no approved medications. One potential treatment target is the gut microbiome, but it is unknown if cocaine induces long-lasting effects on gut microbes. A novel therapeutic candidate for CUD, cannabidiol (CBD), can improve gut function in rodent models. It is possible that protective effects of CBD against cocaine use are mediated by improving gut health. We examined this question in this experiment. Cocaine conditioned place preference (CPP) was conducted in adult male C57BL/6JArc mice. Mice were treated with vehicle or 20 mg/kg CBD prior to all cocaine CPP sessions (N = 11–13/group). Mice were tested drug free 1, 14 and 28 days after cessation of cocaine and CBD treatment. Fecal samples were collected prior to drug treatment and after each test session. Gut microbiome analyses were conducted using 16 s rRNA sequencing and correlated with behavioural parameters. We found a persistent preference for a cocaine-environment in mice, and long-lasting changes to gut microbe alpha diversity. Cocaine caused persistent changes to beta diversity which lasted for 4 weeks. CBD treatment reduced cocaine-environment preference during abstinence from cocaine and returned gut beta diversity measures to control levels. CBD treatment increased the relative abundance of Firmicutes phyla and Oscillospira genus, but decreased Bacteroidetes phyla and Bacteroides acidifaciens species. Preference score in cocaine-treated mice was positively correlated with abundance of Actinobacteria , whereas in mice treated with CBD and cocaine, the preference score was negatively correlated with Tenericutes abundance. Here we show that CBD facilitates cocaine extinction memory and reverses persistent cocaine-induced changes to gut microbe diversity. Furthermore, CBD increases the abundance of gut microbes which have anti-inflammatory properties. This suggests that CBD may act via the gut to reduce the memory of cocaine reward. Our data suggest that improving gut health and using CBD could limit cocaine abuse. • Cocaine caused persistent changes to alpha and beta diversity. • Cannabidiol returned cocaine-induced changes to gut beta diversity to control levels. • Cannabidiol combined with cocaine increased anti-inflammatory gut microbes. • Cannabidiol facilitated extinction of cocaine reward memory. [ABSTRACT FROM AUTHOR]

This systematic review aims to comprehensively explore the impact of psychostimulant substances on neurotrophic and inflammatory pathways, including brain-derived neurotrophic factor (BDNF), pro-BDNF, cortisol, dehydroepiandrosterone sulfate (DHEAS), thiobarbituric acid reactive substances (TBARS), interleukins, and the role of genetic factors. The study seeks to address existing gaps in the literature by providing a thorough evaluation of neurotrophic and inflammatory system alterations associated with different stages of psychostimulant dependence for a more nuanced understanding of substance use disorder (SUD) neurobiology. A systematic review was conducted in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. The research encompasses 50 studies with a participant pool totaling 6792 individuals using psychostimulant substances. Key findings include diverse impacts of cocaine on BDNF levels, mainly consisting of their significant increase during withdrawal. In contrast, NGF showed an opposite behavior, reducing during withdrawal. Cortisol and DHEAS levels exhibited relevant increases after psychostimulant use, while TBARS showed conflicting results. Genetic investigations predominantly focused on the Val66Met polymorphism of the BDNF gene, revealing associations with susceptibility to stimulant addiction. Neurotrophins and inflammatory molecules play a significant role in the pathophysiological mechanisms following psychostimulant use. A better understanding of their complex interplay could aid clinicians in identifying biomarkers of different disease stages. Moreover, clinical interventions designed to interfere with neurotrophic and inflammatory pathways could possibly lead to craving-modulatory strategies and reduce pathological neuronal and systemic consequences of psychostimulant use. • During withdrawal from psychostimulants, peripheral BDNF levels tend to increase over time, while NGF levels decrease. • Cortisol and DHEAS blood levels increase short after psychostimulant use. • The allelic variants of the BDNF gene are linked to psychostimulant addiction and neurobiological resilience. • Taken together, proBDNF and BDNF provide more insights into the stage of addiction. • Neurotrophins and inflammatory pathways manifest complex and still unclear interactions. [ABSTRACT FROM AUTHOR]

The widespread consumption of cocaine poses a significant threat to modern society. The most effective way to combat this problem is to control the distribution of cocaine, based on its accurate and sensitive detection. Here, we proposed the detection of cocaine in human blood plasma using a combination of surface enhanced Raman spectroscopy and machine learning (SERS-ML). To demonstrate the efficacy of our proposed approach, cocaine was added into blood plasma at various concentrations and drop-deposited onto a specially prepared disposable SERS substrate. SERS substrates were created by deposition of metal nanoclusters on electrospun polymer nanofibers. Subsequently, SERS spectra were measured and as could be expected, the manual distinguishing of cocaine from the spectra proved unfeasible, as its signal was masked by the background signal from blood plasma molecules. To overcome this issue, a database of SERS spectra of cocaine in blood plasma was collected and used for ML training and validation. After training, the reliability of proposed approach was tested on independently prepared samples, with unknown for SERS-ML cocaine presence or absence. As a result, the possibility of rapid determination of cocaine in blood plasma with a probability above 99.5% for cocaine concentrations up to 10-14 M was confirmed. Therefore, it is evident that the proposed approach has the ability to detect trace amounts of cocaine in bioliquids in an express and simple manner. [Display omitted] • A simple, sensitive and fast approach for detecting trace amounts of cocaine in human blood plasma is proposed. • The detection approach is based on the SERS-ML combination. • The presence of cocaine is demonstrated at up to 10-14 M concentration with reliability greater than 99%. • The proposed approach significantly outperforms the existing one in terms of sensitivity, reliability, and can be applied in outdoor conditions. [ABSTRACT FROM AUTHOR]

In this essay we want to foreground a question: what happens to 'addiction' when we take seriously cultural scripts informing its trajectories? Can this bring us to unthink addiction as problematic notion and move it onto new paradigms that fit better the now acknowledged fluidity and pluralistic episteme of 'addiction' and more broadly of chronic life conditions? Indeed, 'addiction' has become a pivotal concept in the contemporary world. A powerful diagnostic framework in interpreting human behaviour, for some 'addiction' has become the 'new normal' with chronic relations with different things such as food, sex, gambling, and mind-altering substances touching upon the lifestyle of a majority of individuals, making everyone 'addicts in practice'. Perhaps this has something to do with the constituent force that 'habit' – as in 'addiction' – has in defining our present and future. Though 'addiction' goes beyond the question of mind-altering drugs, the politics of 'addiction' is intimately tied to substances such as opioids and opiates, cocaine, cannabis, and psychedelics that have been the object of durable systemic political control and security repression. Contextually the line between licit/illicit substances is softening and blurring, the 'dual' purpose that drugs serve is now recognised in scientific and popular analysis moving the question of 'addiction' beyond the medicine/drug dichotomy. Yet, culture is generally absent in understanding 'addiction.' When it is referred to, this happens in diminutive terms limited to Anglo-American modern culture. Culture matters and it matters with different weights and measures as it moves across the world. There are cultural environments of health informed by practices and epistemologies of well-being that have evolved in lines opposites from or only intersecting with the Anglo-American, and generally Western, world. Exploring these spaces and cultural scripts enables our scholarship on drugs and 'addiction' to move the barycentre of discussion towards novel considerations around the historical trajectories and potential futures of our diagnostic terms and policy interventions. [ABSTRACT FROM AUTHOR]

Select Drug Category Stimulants Topic Imaging Abstract Detail Preclinical - In Vivo Abstract Category Original Research There remains no FDA-approved pharmacotherapy for cocaine use disorder (CUD). The kappa opioid receptor (KOR) and its endogenous ligand, dynorphin, are implicated in the neurobiological regulation of stress and CUD. Using positron emission tomography (PET) imaging with the KOR agonist [11C]EKAP in socially housed drug-naïve cynomolgus monkeys, we found significant interactions between sex and social rank in KOR binding potential (BP) that correlated positively with social rank in males and negatively in females (Johnson et al., 2023). The present study extended the investigation of the dynorphin/KOR system using a homologous nonhuman primate model of CUD, involving cocaine self-administration (SA), social behavior, and PET imaging (n=8/sex). Utilizing a longitudinal, within-subject design, starting in drug-naïve monkeys, Experiment 1 examined how chronic cocaine SA affected KOR BPs. Following total cocaine intakes of ~100 mg/kg, KOR BP increased (13.0%±1.4%) across all 15 brain regions of interest (ROI) in males; the relationship between baseline BP and cocaine-induced changes correlated positively in 10/15 ROIs. There were no social rank differences observed. In females, the effect of chronic cocaine SA on KOR BP was influenced by social rank, such that cocaine increased KOR BP in dominant females (52%±11%, n=2) and decreased KOR BP in subordinate (-12%±1.6%, n=3) females across all ROI. The second experiment assessed the neural plasticity of KOR system following protracted time-off from cocaine, by allowing monkeys to respond for 1.0 g food pellets instead of cocaine. Monkeys were rescanned with [11 C]EKAP after ~30- and ~100-days off from cocaine. Rate of recovery of KOR BP varied across monkeys and, in some, did not return to baseline after ~100 days off from cocaine. Future studies will examine how sex and social rank differences in cocaine-induced changes in KOR neurobiology, influence pharmacological interventions, such as KOR antagonists on cocaine-food choice and KOR agonists on punished cocaine SA. [ABSTRACT FROM AUTHOR]