Fentanyl, Heroin, Methamphetamine, and Cocaine Analyte Concentrations in Urine Drug Testing Specimens.

Importance: The US is experiencing a protracted drug overdose crisis primarily associated with exposure to illicitly manufactured fentanyl (IMF), methamphetamine, and cocaine. Overdose risk and treatment responses may be directly affected by absolute drug exposure concentrations and drug use prevalence. Objective: To quantify changes in absolute drug exposure concentrations from 2013 to 2023. Design, Setting, and Participants: This cross-sectional study analyzed urine drug testing (UDT) results from urine specimens collected between January 1, 2013, and August 22, 2023, in 49 states and the District of Columbia. Urine specimens were obtained from patients aged 18 years or older who presented to substance use disorder treatment clinics. The UDT was ordered by clinicians based on medical necessity. Exposures: Urine specimens were analyzed for the following drugs or metabolites (analytes tested in parentheses): fentanyl (fentanyl), heroin (6-monoacetylmorphine), cocaine (benzoylecgonine), and methamphetamine (methamphetamine) using liquid chromatography with tandem mass spectrometry. Main Outcomes and Measures: Relative concentrations of fentanyl, heroin, cocaine, and methamphetamine. Creatinine-normalized drug concentration values were log-transformed prior to visualization and statistical analyses. The Mann-Kendall trend test was performed to examine trends over time. To estimate the geospatial and temporal patterns of drug concentration, a second series of models (1 for each drug) with an interaction effect for clinic location and collection year were fit. Results: A total of 921 931 unique UDT samples were collected from patients (549 042 males [59.6%]; median [IQR] age, 34 [27-44] years). The adjusted fentanyl concentration in urine specimens was 38.23 (95% CI, 35.93-40.67) ng/mg creatinine in 2023 and 4.61 (95% CI, 3.59-5.91) ng/mg creatinine in 2013. The adjusted methamphetamine concentration was 3461.59 (95% CI, 3271.88-3662.30) ng/mg creatinine in 2023 and 665.27 (95% CI, 608.51-727.32) ng/mg creatinine in 2013. The adjusted cocaine concentration was 1122.23 (95% CI, 1032.41-1219.87) ng/mg creatinine in 2023 and 559.71 (95% CI, 524.69-597.06) ng/mg creatinine in 2013. The adjusted heroin concentration was 58.36 (95% CI, 48.26-70.58) ng/mg creatinine in 2023 and 146.59 (95% CI, 136.06-157.92) ng/mg creatinine in 2013. Drug concentrations varied across US Census divisions. Conclusions and Relevance: This cross-sectional study found that absolute concentrations of fentanyl, methamphetamine, and cocaine in urine specimens increased from 2013 to 2023, with a decrease in heroin concentration during that period. The findings suggest that exposure to these substances, as well as the illicit drug supply, has fundamentally changed in many parts of the US, highlighting the need to reinforce surveillance initiatives and accelerate efforts to treat individuals with IMF and/or stimulant exposure.

Trajectories of craving in the course of pharmacotherapy trials for methamphetamine use disorder.

AIMS: The aim of this study was to measure trajectories of craving for methamphetamine during the course of pharmacotherapy trials for methamphetamine use disorder. DESIGN, SETTING AND PARTICIPANTS: Craving trajectories were identified using Group-Based Trajectory Modeling. The association of craving trajectories with drug use trajectories was examined using a dual trajectory model. Association of craving trajectories with other health and social outcomes was also examined. The study used pooled data from five randomized controlled pharmacotherapy trials for methamphetamine use disorder. A total of 866 adults with methamphetamine use disorder participated in randomized controlled pharmacotherapy trials. MEASUREMENT: Craving was assessed weekly using the Brief Substance Craving Scale. Drug use was assessed using urine toxicology. Alcohol- and drug-related problems, as well as psychiatric, medical, legal, employment and relationship problems, were measured using the Addiction Severity Index. FINDINGS: A three-trajectory model with high, medium and low craving trajectories was selected as the most parsimonious model. Craving trajectories were associated with methamphetamine use trajectories in the course of trial; 88.4% of those in the high craving trajectory group had a consistently high frequency of methamphetamine use compared with 18.7% of those in the low craving group. High craving was also associated with less improvement in most other outcomes and higher rate of dropout from treatment. In turn, low craving was associated with a rapidly decreasing frequency of methamphetamine use, greater improvement in most other outcomes and a lower rate of dropout. Participants on modafinil daily and ondansetron 1 mg twice daily were less likely to be in the high craving group compared with those on placebo. CONCLUSIONS: Trajectories of methamphetamine craving in the course of clinical trials for methamphetamine use disorder appear to be both highly variable and strongly associated with greater frequency of drug use, other drug-related outcomes and dropout from trials. Two medications, modafinil daily and ondansetron at a dose of 1 mg two times daily, appear to be associated with greater reduction in craving in the course of treatment compared with placebo. A decrease in methamphetamine craving shows promise as an early indicator of recovery from methamphetamine use disorder.

Availability and Opportunities for Expansion of Buprenorphine for the Treatment of Opioid Use Disorder.

There is an urgent need to expand access to treatment for persons with opioid use disorder (OUD). As neurologists may frequently encounter patients with chronic pain who have developed OUD, they are in a position to serve as advocates for treatment. Buprenorphine is the most scalable medication for OUD in the United States, yet expansion has plateaued in recent years despite growing treatment needs. Reluctance of providers to establish treatment with new patients, challenges with rural expansion, stigma related to buprenorphine-based care, and pharmacy pressures that incentivize low dispensing and inventories may have stalled expansion. This review introduces these challenges before outlining actionable and evidenced-based strategies that warrant investigation, including methods to improve patient access to care (remotely delivered care, mobile delivery programs, Bridge programs) and provider retention and confidence in prescribing (expert consults, Extension for Community Healthcare Outcomes, a telementoring model, hub-and-spoke services), as well as novel innovations (virtual reality, artificial intelligence, wearable technologies). Overall, fortifying existing delivery systems while developing new transformative models may be necessary to achieve more optimal levels of buprenorphine treatment expansion.

Harm Reduction for Opioid Use Disorder: Strategies and Outcome Metrics.

Tweet: The authors discuss harm reduction strategies and associated outcome metrics in relation to the ongoing opioid crisis.

Pain and withdrawal are common among patients receiving medications for opioid use disorder and associated with pain catastrophizing, negative affect, and poor sleep.

Substantial percentages of persons receiving medications for opioid use disorder (MOUD) continue to experience clinically significant levels of pain and opioid withdrawal, which may pose barriers to reducing opioid use. Continued pain, in particular, may increase the risk for psychiatric problems and poorer treatment retention, especially with a lack of adequate care for pain. The goals of these analyses were to characterize the prevalence of, and patient-level variables associated with, pain and opioid withdrawal, as well as utilization of related coping strategies and treatments. Participants were 18 years of age or older and received methadone or buprenorphine for opioid use disorder (n = 179). Participants completed this survey in person, within their MOUD clinic. Participants completed patient-level and demographic questions as well as measures of pain, withdrawal, utilization of related coping strategies, and pain treatment. Numerous participants endorsed chronic pain (41.9%) or opioid withdrawal (89.4%) and indicated reliance upon over-the-counter medications and prayer for pain management. Multiple linear regression models showed greater pain catastrophizing and negative affect accounted for variability in pain severity and pain interference, as well as opioid withdrawal. Persons who slept less and endorsed chronic pain also reported greater pain severity and interference, and pain interference was higher with increased age. These and previous findings combine to further highlight the detrimental role that pain catastrophizing and negative affect can play in pain perception and withdrawal, but also represent promising treatment targets to facilitate pain and withdrawal management and improved quality of life. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Effects of kratom on driving: Results from a cross-sectional survey, ecological momentary assessment, and pilot simulated driving Study.

OBJECTIVES: Despite widespread kratom use, there is a lack of knowledge regarding its effects on driving. We evaluated the self-reported driving behaviors of kratom consumers and assessed their simulated-driving performance after self-administering kratom products. METHODS: We present results from: 1) a remote, national study of US adults who regularly use kratom, and 2) an in-person substudy from which we re-recruited participants. In the national study (N = 357), participants completed a detailed survey and a 15-day ecological momentary assessment (EMA) that monitored naturalistic kratom use. For the remote study, outcomes were self-reported general and risky driving behaviors, perceived impairment, and driving confidence following kratom administration. For the in-person substudy, 10 adults consumed their typical kratom products and their driving performance on a high-fidelity driving simulator pre- and post-kratom administration was evaluated. RESULTS: Over 90% of participants surveyed self-reported driving under the influence of kratom. Most reported low rates of risky driving behavior and expressed high confidence in their driving ability after taking kratom. This was consistent with EMA findings: participants reported feeling confident in their driving ability and perceived little impairment within 15-180 min after using kratom. In the in-person substudy, there were no significant changes in simulated driving performance after taking kratom. CONCLUSIONS: Using kratom before driving appears routine, however, self-reported and simulated driving findings suggest kratom effects at self-selected doses among regular kratom consumers do not produce significant changes in subjective and objective measures of driving impairment. Research is needed to objectively characterize kratom's impact on driving in regular and infrequent consumers.

Establishing a research agenda for the study and assessment of opioid withdrawal.

The opioid crisis is an international public health concern. Treatments for opioid use disorder centre largely on the management of opioid withdrawal, an aversive collection of signs and symptoms that contribute to opioid use disorder. Whereas in the past 50 years more than 90 medications have been developed for depression, only five medications have been developed for opioid use disorder during this period. We posit that underinvestment has occurred in part due to an underdeveloped understanding of opioid withdrawal syndrome. This Personal View summarises substantial gaps in our understanding of opioid withdrawal that are likely to continue to limit major advancements in its treatment. There is no firm consensus in the field as to how withdrawal should be precisely defined; 10-550 symptoms of withdrawal can be measured on 18 scales. The imprecise understanding of withdrawal is likely to result in overestimating or underestimating the severity of an individual's withdrawal syndrome or potential therapeutic effects of different candidate medications. The severity of the opioid crisis is not remitting, and an international research agenda for the study and assessment of opioid withdrawal is necessary to support transformational changes in withdrawal management and treatment of opioid use disorder. Nine actionable targets are delineated here: develop a consensus definition of opioid withdrawal; understand withdrawal symptomatology after exposure to different opioids (particularly fentanyl); understand precipitated opioid withdrawal; understand how co-exposure of other drugs (eg, xylazine and stimulants) influences withdrawal expression; examine individual variation in withdrawal phenotypes; precisely characterise the protracted withdrawal syndrome; identify biomarkers of opioid withdrawal severity; identify predictors of opioid withdrawal severity; and understand which symptoms are most closely associated with treatment attrition or relapse. The US Food and Drug Administration recently established a formal indication for opioid withdrawal that has invigorated interest in drug development for opioid withdrawal management. Action is now needed to support these interests and help industry identify new classes of medications so that real change can be achieved for people with opioid use disorder.

The IMPOWR Network Divided or Single Exposure Study (DOSE) Protocol: A Randomized Controlled Comparison of Once Versus Split Dosing of Methadone for the Treatment of Comorbid Chronic Pain and Opioid Use Disorder.

BACKGROUND: The Divided or Single Exposure (DOSE) trial is a double-blind, placebo-controlled examination of once versus split dosing of methadone for comorbid pain and opioid use disorder (OUD) among persons receiving methadone for OUD treatment. METHODS: This multisite trial consists of a 12-week active intervention phase and 6-month follow-up period. Persons receiving methadone who endorse clinically-significant chronic pain are randomized into once-daily dosing or split dosing that is managed remotely via an electronic pillbox. Clinical pain is assessed weekly and using ecological momentary assessments. Experimentally-evoked pain is assessed using a quantitative sensory testing battery. Additional outcomes related to OUD, including withdrawal and craving, are also collected. RESULTS: The study hypothesizes that persons assigned to the split dosing condition will report lower pain and opioid withdrawal relative to persons assigned to the traditional once-daily dosing strategy. CONCLUSIONS: Split dosing is a relatively common technique in OUD treatments; therefore, if data support this hypothesis, there is high potential for implementation.

Virtual focus groups among individuals with use disorders: assessing feasibility and acceptability in an underserved clinical population.

Objective: There are substantial barriers to conducting research among individuals with stigmatized and complicated health conditions like substance use disorders. These barriers slow progress when developing, refining, and assessing interventions to better treat underserved populations. Virtual focus groups are an innovative method for collecting data from individuals via a discreet and accessible platform which can inform novel as well as existing treatment approaches. This article reports on the feasibility and acceptability of virtual focus groups as a mechanism to recruit and engage geographically and demographically diverse samples of participants with substance use disorders that are otherwise logistically difficult to assess. Method: Participants were assessed for eligibility for a virtual focus group study based on demographic features, drug use history, and psychiatric history via a remote, interview-based screening. Focus groups were completed anonymously without video or name-sharing. Discussion contributions, quantified with number of times speaking and total number of words spoken, were compared across gender, and treatment status. Participants provided quantitative and qualitative feedback on the focus group experience in a follow-up survey. Results: Focus groups (N=26) based in geographical areas throughout the United States were conducted with 88 individuals with opioid use disorder or stimulant use disorder. Discussion contributions were comparable between genders and among individuals in treatment versus those seeking treatment. A follow-up survey (n=50, 57% of focus group participants) reflected high levels of enjoyment, comfort, and honesty during focus group discussions. Discussion: Findings suggest virtual focus groups can be an effective and efficient tool for substance use research.

Intersectional Risk and the Significant Gap in Care for Persons With Co-occurring Chronic Pain and Opioid Withdrawal.

OBJECTIVES: Persons with chronic pain and women tend to enter treatment for opioid use disorder with greater opioid withdrawal severity than persons without chronic pain and men, respectively. This study examined characteristics of facilities with opioid withdrawal treatment, including gender-based services, as a function of whether they reported having a tailored pain management program. METHODS: The National Survey of Substance Abuse Treatment Services 2020 was used to examine 3942 facilities with opioid withdrawal treatment in the United States. Using a multivariable binary logistic regression model, facilities were examined for the presence of a tailored program for individuals with co-occurring pain. Regional location of the facility, ownership status, and availability of tailored gender programs, nonhospital residential services, and outpatient services served as independent variables in the analysis. RESULTS: A slight majority of the sample had a program for both adult men and adult women ( n = 2010, 51.0%). Most facilities had outpatient services ( n = 3289, 83.4%) and did not have a tailored program for addressing co-occurring pain ( n = 2756, 69.9%). Binary logistic regression analysis showed that among opioid withdrawal facilities, programs with nonhospital residential services, government or private nonprofit funding, or tailored gender programming had higher odds of reporting having a tailored program for pain and substance use disorder. Facilities in the Western United States were most likely to have tailored programs for pain and substance use disorder. CONCLUSIONS: Future research should investigate what support patients may receive and how to better scale access to pain management during opioid withdrawal treatment.

Knowledge, Preference, and Adverse Effects of Xylazine Among Adults in Substance Use Treatment.

This cross-sectional study evaluates aspects of xylazine adulteration of opioids among individuals entering substance use disorder treatment.

Responses to a "Typical" Morning Dose of Kratom in People Who Use Kratom Regularly: A Direct-Observation Study.

INTRODUCTION: Use of kratom has outpaced systematic study of its effects, with most studies reliant on retrospective self-report. METHODS: We aimed to assess acute effects following kratom use in adults who use regularly, and quantify alkaloids in the products, urine, and plasma. Between July and November 2022, 10 adults came to our clinic and orally self-administered their typical kratom dose; blinding procedures were not used. Physiological measures included blood pressure, respiratory rate, heart rate, pulse oximetry, temperature, and pupil diameter. Subjective outcomes included Subjective Opioid Withdrawal Scale, Addiction Research Center Inventory, and Drug Effects Questionnaire. Psychomotor performance was also assessed. RESULTS: Participants were 6 men and 4 women, mean age 41.2 years. Nine were non-Hispanic White; 1 was biracial. They had used kratom for 6.6 years (SD, 3.8 years) on average (2.0-14.1). Sessions were 190.89 minutes on average (SD, 15.10 minutes). Mean session dose was 5.16 g (median, 4.38 g; range, 1.1-10.9 g) leaf powder. Relative to baseline, physiological changes were minor. However, pupil diameter decreased (right, b = -0.70, P < 0.01; left, b = -0.73, P < 0.01) 40-80 minutes postdose and remained below baseline >160 minutes. Subjective Opioid Withdrawal Scale pre-dosing was mild (5.5 ± 3.3) and decreased postdose (b = [-4.0, -2.9], P < 0.01). Drug Effects Questionnaire "feeling effects" increased to 40/100 (SD, 30.5) within 40 minutes and remained above baseline 80 to 120 minutes (b = 19.0, P = 0.04), peaking at 72.7/100; 6 participants rated euphoria as mild on the Addiction Research Center Inventory Morphine-Benzedrine-scale. Psychomotor performance did not reliably improve or deteriorate postdosing. CONCLUSIONS: Among regular consumers, we found few clinically significant differences pre- and post-kratom dosing. Alkaloidal contents in products were within expected ranges.

Polymorphisms in the A118G SNP of the OPRM1 gene produce different experiences of opioids: A human laboratory phenotype-genotype assessment.

Allelic variations in the A118G SNP of the OPRM1 gene change opioid signaling; however, evaluations of how allelic differences may influence opioid effects are lacking. This human laboratory paradigm examined whether the AA versus AG/GG genotypes determined opioid response profiles. Individuals with limited opioid exposure (N = 100) completed a five-day within-subject, double-blind, placebo-controlled, residential study. Participants were admitted (Day 1), received 4 mg hydromorphone (Day 2) and 0 mg, 2 mg and 8 mg hydromorphone in randomized order (Days 3-5) and completed self-reported visual analog scale (VAS) ratings and Likert scales, observed VAS, and physiological responses at baseline and for 6.5 h post-dose. Outcomes were analysed as peak/nadir effects over time as a function of genotype (available for N = 96 individuals; AG/GG = 13.5%, AA = 86.4%). Participants with AG/GG rated low and moderate doses of hydromorphone as significantly more positive (e.g., Good Effects VAS, coasting, drive, friendly, talkative, stimulation) with fewer negative effects (e.g., itchy skin, nausea, sleepiness), and were also observed as being more talkative and energetic relative to persons with AA. Persons with AG/GG were less physiologically reactive as determined by diastolic blood pressure and heart rate, but had more changes in core temperature compared with those with AA. Persons with AA also demonstrated more prototypic agonist effects across doses; persons with AG/GG showed limited response to 2 mg and 4 mg. Data suggest persons with AG/GG genotype experienced more pleasant and fewer unpleasant responses to hydromorphone relative to persons with AA. Future studies should replicate these laboratory findings in clinical populations to support a precision medicine approach to opioid prescribing.

Moving forward while looking back: Reflections on the history and future of the journal Experimental and Clinical Psychopharmacology.

In this editorial, the incoming editor for Experimental and Clinical Psychopharmacology (ECP) reflects on the history and future of the journal. The author looks forward to working together with the American Psychological Association publishing community and ECP authors, reviewers, and board members as they navigate changes to their publishing policies and procedures. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Suvorexant alters dynamics of the sleep-electroencephalography-power spectrum and depressive-symptom trajectories during inpatient opioid withdrawal.

STUDY OBJECTIVES: Opioid withdrawal is an aversive experience that often exacerbates depressive symptoms and poor sleep. The aims of the present study were to examine the effects of suvorexant on oscillatory sleep-electroencephalography (EEG) band power during medically managed opioid withdrawal, and to examine their association with withdrawal severity and depressive symptoms. METHODS: Participants with opioid use disorder (N = 38: age-range:21-63, 87% male, 45% white) underwent an 11-day buprenorphine taper, in which they were randomly assigned to suvorexant (20 mg [n = 14] or 40 mg [n = 12]), or placebo [n = 12], while ambulatory sleep-EEG data was collected. Linear mixed-effect models were used to explore: (1) main and interactive effects of drug group, and time on sleep-EEG band power, and (2) associations between sleep-EEG band power change, depressive symptoms, and withdrawal severity. RESULTS: Oscillatory spectral power tended to be greater in the suvorexant groups. Over the course of the study, decreases in delta power were observed in all study groups (ß = -189.082, d = -0.522, p = <0.005), increases in beta power (20 mg: ß = 2.579, d = 0.413, p = 0.009 | 40 mg ß = 5.265, d = 0.847, p < 0.001) alpha power (20 mg: ß = 158.304, d = 0.397, p = 0.009 | 40 mg: ß = 250.212, d = 0.601, p = 0.001) and sigma power (20 mg: ß = 48.97, d = 0.410, p < 0.001 | 40 mg: ß = 71.54, d = 0.568, p < 0.001) were observed in the two suvorexant groups. During the four-night taper, decreases in delta power were associated with decreases in depressive symptoms (20 mg: ß = 190.90, d = 0.308, p = 0.99 | 40 mg: ß = 433.33, d = 0.889 p = <0.001), and withdrawal severity (20 mg: ß = 215.55, d = 0.034, p = 0.006 | 40 mg: ß = 192.64, d = -0.854, p = <0.001), in both suvorexant groups and increases in sigma power were associated with decreases in withdrawal severity (20 mg: ß = -357.84, d = -0.659, p = 0.004 | 40 mg: ß = -906.35, d = -1.053, p = <0.001). Post-taper decreases in delta (20 mg: ß = 740.58, d = 0.964 p = <0.001 | 40 mg: ß = 662.23, d = 0.882, p = <0.001) and sigma power (20 mg only: ß = 335.54, d = 0.560, p = 0.023) were associated with reduced depressive symptoms in the placebo group. CONCLUSIONS: Results highlight a complex and nuanced relationship between sleep-EEG power and symptoms of depression and withdrawal. Changes in delta power may represent a mechanism influencing depressive symptoms and withdrawal.

Ecological Momentary Assessment of Self-Reported Kratom Use, Effects, and Motivations Among US Adults.

Importance: Kratom products, which are sold legally in most of the US, contain alkaloids with opioidergic, adrenergic, and serotonergic activity. Millions of people use kratom to relieve pain, improve mood, or self-manage substance use disorders (SUDs). Kratom use has primarily been examined via surveys, in which recall biases among satisfied users may lead to minimization of transient negative outcomes. Further prospective study of kratom use, such as with ecological momentary assessment (EMA), is needed. Objective: To characterize proximal motivators, effects, and patterns of kratom use and to assess whether use frequency is associated with motivations, effects, past-year criteria for SUD for kratom (KUD), or other substance use. Design, Setting, and Participants: For this prospective cross-sectional study, an intensive longitudinal smartphone-based EMA in which participants' current behaviors and experiences were repeatedly sampled in real time was conducted between July 1 and October 31, 2022. Participants comprised a convenience sample of US adults who used kratom at least 3 days per week for at least 4 weeks at the time of online screening. Criteria for past-year KUD were based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Data analysis was performed between November 2022 and November 2023. Exposure: The exposure was 13 401 kratom-use events across 15 days. Main Outcomes and Measures: A baseline survey covering demographics, health, kratom attitudes and behaviors, use motivations, other substance use, and KUD was administered before EMA. Data for the following EMA entries were then collected: event-contingent entries for kratom use (product, dose, and proximal motivations), follow-up entries (short-term effects and consequences of use events), random-prompt entries (mood), beginning-of-day entries (effects of kratom on sleep), and end-of-day entries (daily subjective descriptions of kratom effects). Bayesian regression was used to estimate means and credible intervals. Results: A total of 357 participants completed the EMA. Their mean (SD) age was 38.0 (11.1) years; more than half were men (198 [55.5%]). Participants reported overall motivators of use on the baseline survey that involved managing psychiatric and SUD problems, but proximal motivators evaluated during the EMA involved situation-specific needs such as increasing energy and productivity and decreasing pain. Acute effects were considered congruent with daily obligations. Use patterns, despite having some distinguishing features, were generally similar in their motivators and effects; participants used kratom predominantly during the daytime and seemed to find use frequencies that suited their needs. Higher use patterns were associated with symptoms of physical dependence (eg, withdrawal or tolerance). Co-used substances included caffeine, nicotine, vitamins, and cannabis. Conclusions and Relevance: Most participants in this study reported using kratom in a seemingly nonproblematic way. When such use appeared problematic, the key element was usually that withdrawal avoidance became a proximal motivator. Longitudinal studies examining changes in kratom use patterns and effects over time are needed.

Xylazine suppresses fentanyl consumption during self-administration and induces a unique sex-specific withdrawal syndrome that is not altered by naloxone in rats.

Prescription and illicit opioid use are a public health crisis, with the landscape shifting to fentanyl use. Since fentanyl is 100-fold more potent than morphine, its use is associated with a higher risk of fatal overdose that can be remediated through naloxone (Narcan) administration. However, recent reports indicate that xylazine, an anesthetic, is increasingly detected in accidental fentanyl overdose deaths. Anecdotal reports suggest that xylazine may prolong the fentanyl "high," alter the onset of fentanyl withdrawal, and increase resistance to naloxone-induced reversal of overdose. To date, no preclinical studies have evaluated the impacts of xylazine on fentanyl self-administration (SA; 2.5 µg/kg/infusion) or withdrawal to our knowledge. We established a rat model of xylazine/fentanyl co-SA and withdrawal and evaluated outcomes as a function of biological sex. When administered alone, chronic xylazine (2.5 mg/kg, intraperitoneal) induced unique sex-specific withdrawal symptomatology, whereby females showed delayed onset of signs and a possible enhancement of sensitivity to the motor-suppressing effects of xylazine. Xylazine reduced fentanyl consumption in both male and female rats regardless of whether it was experimenter-administered or added to the intravenous fentanyl product (0.05, 0.10, and 0.5 mg/kg/infusion) when compared to fentanyl SA alone. Interestingly, this effect was dose-dependent when self-administered intravenously. Naloxone (0.1 mg/kg, subcutaneous injection) did not increase somatic signs of fentanyl withdrawal, regardless of the inclusion of xylazine in the fentanyl infusion in either sex; however, somatic signs of withdrawal were higher across time points in females after xylazine/fentanyl co-SA regardless of naloxone exposure as compared to females following fentanyl SA alone. Together, these results indicate that xylazine/fentanyl co-SA dose-dependently suppressed fentanyl intake in both sexes and induced a unique withdrawal syndrome in females that was not altered by acute naloxone treatment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Novel methods for the remote investigation of emerging substances: Application to kratom.

The botanical product commonly called "kratom" is still relatively novel to the United States. Like other natural products marketed as supplements, kratom is highly variable, both in terms of the alkaloids naturally occurring in kratom leaves and in terms of processing and formulation. Kratom products sold in the United States are not well-characterized, nor are daily use patterns among regular users. Surveys and case reports have comprised most of the literature on kratom use among humans. To advance our understanding of real-world kratom use, we developed a protocol for the remote study of regular kratom-using adults in the United States. Our study had three aspects implemented in one pool of participants nationwide: an in-depth online survey, 15 days of ecological momentary assessment (EMA) via smartphone app, and the collection and assay of the kratom products used by participants during EMA. Here, we describe these methods, which can be used to investigate myriad drugs or supplements. Recruiting, screening, and data collection occurred between July 20, 2022 and October 18, 2022. During this time, we demonstrated that these methods, while challenging from a logistical and staffing standpoint, are feasible and can produce high-quality data. The study achieved high rates of enrollment, compliance, and completion. Substances that are emerging or novel, but still largely legal, can be productively studied via nationwide EMA combined with assays of shipped product samples from participants. We discuss challenges and lessons learned so other investigators can adapt these methods. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Impacts of xylazine on fentanyl demand, body weight, and acute withdrawal in rats: A comparison to lofexidine.

The opioid use landscape has recently shifted to include xylazine, a veterinary anesthetic, as an adulterant in the fentanyl supply. The health impacts of xylazine as an emerging fentanyl adulterant has raised alarm regarding xylazine as a public health threat, warranting research on the impacts of xylazine on fentanyl's behavioral effects. No prior studies have evaluated the effects of xylazine on fentanyl consumption at various unit doses, fentanyl demand, or withdrawal as compared to the Food and Drug Administration-approved opioid withdrawal medication, lofexidine (Lucemyra®). This is important because lofexidine and xylazine are both adrenergic α2a (A2aR) agonists, however, lofexidine is not a noted fentanyl adulterant. Here we evaluated xylazine and lofexidine combined with self-administered fentanyl doses in male and female rats and evaluated fentanyl demand, body weight, and acute withdrawal. Consumption of fentanyl alone increased at various unit doses compared to saline. Xylazine but not lofexidine shifted fentanyl consumption downward at a number of unit doses, however, both lofexidine and xylazine suppressed fentanyl demand intensity as compared to a fentanyl alone control group. Further, both fentanyl + lofexidine and fentanyl + xylazine reduced behavioral signs of fentanyl withdrawal immediately following SA, but signs increased by 12 h only in the xylazine co-exposed group. Weight loss occurred throughout fentanyl SA and withdrawal regardless of group, although the xylazine group lost significantly more weight during the first 24 h of withdrawal than the other two groups. Severity of weight loss during the first 24 h of withdrawal was also correlated with severity of somatic signs of fentanyl withdrawal. Together, these results suggest that body weight loss may be an important indicator of withdrawal severity during acute withdrawal from the xylazine/fentanyl combination, warranting further translational evaluation.