Visual functions, ocular characteristics and visual quality of life in patients with homocystinuria.

BACKGROUND: Homocystinuria (HCU) is a rare metabolic disease that affects many organs, including the eyes. Aims: to assess visual functions, ocular characteristics, visual quality of life and time from the onset of ocular manifestations to HCU-diagnosis in patients with HCU. MATERIAL AND METHODS: Eighteen patients underwent ophthalmological examinations and visual quality of life questionnaires. RESULTS: Best corrected decimal visual acuity was median 1.0 (range amaurosis - 1.3) right eye and 1.0 (range amaurosis -1.3) left eye. Five patients presented with severe myopia as first HCU manifestation, duration to HCU diagnosis was mean 13.6 years (range 2-25). Two patients had suffered ectopia lentis as first HCU manifestation, HCU diagnosis was established mean 8.0 years (range 7-9) later. One patient had suffered both from thrombosis and ectopia lentis prior to diagnosis. Another four patients suffered thromboembolic events before diagnosis. Median VFQ-25 composite score was 93 (68-98). CONCLUSIONS: The prevalence of myopia, ectopia lentis and monocular blindness was high in HCU-patients, which was reflected in their visual quality of life. Diagnosis was often delayed after the first ocular manifestation, increasing the risk of other severe non-ocular complications.

Economic assessment of abemaciclib for the adjuvant treatment of luminal HER2- breast cancer from the perspective of the Spanish health system.

INTRODUCTION: Abemaciclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). Data from the clinical trial monarchE (2023) showed improved survival from invasive disease. The aim of the present article was to conduct an economic assessment of adjuvant treatment with abemaciclib in women with luminal, HER2- and node-positive breast cancer. METHODS: A Markov model was constructed with four mutually exclusive health states (disease-free, local recurrence, distal recurrence and death). Analyses were based on the clinical trial monarchE which compared an intervention group (abemaciclib + hormone therapy [HT]) with HT alone. The effectiveness measure used was quality-adjusted life years (QALY), with unit costs and utilities being obtained from existing literature. The incremental cost-utility ratio (ICUR) was used to compare the two treatment strategies. RESULTS: Total costs were €98,765 and €17,935 for the abemaciclib plus HT group and the HT alone group, respectively. The health outcome was 10.076QALY for the intervention group and 9.495QALY for the control group, with the ICUR being€139,173/QALY. CONCLUSION: Despite the significant gains of abemaciclib as adjuvant treatment in terms of progression-free survival, this treatment is not cost-effective for the Spanish National Health System at published prices. It may be cost-effective with an appropriate discount on the official price.

Defining and Grading Infections in Clinical Trials Involving Hematopoietic Cell Transplantation: A Report From the BMT CTN Infectious Disease Technical Committee.

The Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) was established in 2001 to conduct large multi-institutional clinical trials addressing important issues towards improving the outcomes of HCT and other cellular therapies. Trials conducted by the network investigating new advances in HCT and cellular therapy not only assess efficacy but require careful capturing and severity assessment of adverse events and toxicities. Adverse infectious events in cancer clinical trials are typically graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). However, there are limitations to this framework as it relates to HCT given the associated immunodeficiency and delayed immune reconstitution. The BMT-CTN Infection Grading System is a monitoring tool developed by the BMT CTN to capture and monitor infectious complications and differs from the CTCAE by its classification of infections based on their potential impact on morbidity and mortality for HCT recipients. Here we offer a report from the BMT CTN Infectious Disease Technical Committee regarding the rationale, development, and revising of BMT-CTN Infection Grading System and future directions as it applies to future clinical trials involving HCT and cellular therapy recipients.

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.

Public Acceptance of Measures to Control Infectious Diseases Under Different Scenarios of Severity and Transmissibility.

OBJECTIVES: Public health measures to control future epidemic threats of contagious disease, such as new variants of COVID-19, may be usefully informed by evidence about how acceptable they are likely to be, and the circumstances that condition this acceptance. This study considers how the acceptability of nonpharmaceutical interventions (NPIs) might depend on scenarios about the severity and transmissibility of the disease. METHODS: A telephone survey was conducted among a representative cross-sectional sample of the Spanish adult population. Each respondent was randomly assigned to 1 of 4 possible hypothetical scenarios about the severity and transmissibility of the disease. Participants' responses about the acceptability of 11 NPI under this scenario were analyzed using multivariate regression and latent class cluster analysis. RESULTS: A high risk of severe disease increases the acceptability of mask wearing, social distancing outdoors, lockdown, and isolation of infected cases, close contacts, and the vulnerable. A scenario in which the disease is highly transmissible would increase the acceptability of NPI that restrict movement and isolation. Most respondents would broadly accept most NPI in situations when either the severity or transmissibility was high. CONCLUSIONS: This study showed that people are more willing to accept NPIs such as mask wearing, social distancing outdoors, lockdown, and isolation in severe disease scenarios. A highly transmissible disease scenario increases the acceptability of NPIs that isolate. A majority would broadly accept NPIs to counter public health emergencies, whereas 3% to 9% of the population would always be strongly against.

Retinal vein occlusions before and during the COVID-19 pandemic. Visual outcomes and treatment patterns in a country with no mandatory lockdown.

PURPOSE: To investigate the incidence, treatment patterns and visual outcomes in patients with branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) before and during the COVID-19 pandemic in a country with no mandatory lockdown. METHODS: This retrospective study included 788 patients presenting with a retinal vein occlusion (RVO) during 2019-2022 at St. Erik Eye Hospital. The control group and study groups consisted of patients presenting before and during the pandemic respectively. RESULTS: The incidence of diagnosed RVO cases decreased from 281 patients before the pandemic to 236 patients during the first year of the pandemic (p<0.05). In BRVO patients at the end of follow-up, the best-corrected visual acuity (BCVA) improved 10.3 letters (95% CI 7.6-12.9) in the control group compared to 14.3 letters (95% CI 12.6-16.0) in the study groups (p<0.05). In CRVO patients the BCVA improved 6.3 letters (95% CI 2.7-10.0) in the control group compared to 8.6 letters (95% CI 5.7-11.4) in the study groups (p=NS). Overall, the number of intravitreal anti-vascular endothelial growth factor (VEGF) injections increased from 7.0 (95% CI 6.6-7.3) in the control group to 7.6 (95% CI 7.4-7.8) in the study groups (p<0.05). CONCLUSION: Good visual and anatomical outcomes were sustained, and the number of intravitreal anti-VEGF injections increased significantly in RVO patients during the COVID-19 pandemic.

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.

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.

Activity space during treatment with medication for opioid use disorder: Relationships with personality, mood, and drug use.

INTRODUCTION: Activity space in people with substance use disorders (SUDs) has been assessed for theoretical reasons and for detection/prevention of relapse. In this observational study, we relate passively obtained activity space measures to mental states and behaviors relevant to the success of treatment for opioid use disorder. Our long-term goal is to use such data to assess risk in real time and to recognize when SUD patients might benefit from a just-in-time intervention. METHODS: We used GPS data from 238 urban residents in the first 16 weeks of stabilization on medication for opioid use disorder to test preregistered hypotheses about activity space (distance traveled, number of locations, time spent moving, and psychosocial-hazard levels of neighborhoods where participants spent time) in relation to certain static variables (personality, mood propensities) and time-varying treatment-relevant behaviors such as craving and use of opioids and cocaine. RESULTS: The most consistent findings were that 1) mobility decreased over the course of the study; 2) neuroticism was associated with overall lower mobility; 3) trait-like positive mood (averaged from momentary ratings) was associated with higher mobility; 4) participants who used cocaine more frequently had lower mobility; 5) early in treatment, participants spent less time moving (i.e., were more sedentary) on days when they were craving. Some of these findings were in the expected direction (i.e., the ones involving neuroticism and positive mood), and some were opposite to the expected direction (i.e., we expected cocaine use to be associated with higher mobility); others (e.g., changes in mobility over time or in relation to craving) involved nondirectional hypotheses. CONCLUSIONS: Real-time information that patients actively provide is valuable for assessing their current state, but providing this information can be burdensome. The current results indicate that certain static or passively obtained data (personality variables and GPS-derived mobility information) are relevant to time-varying, treatment-relevant mental states and drug-related behavior, and therefore might be useful when incorporated into algorithms for detecting need for intervention in real time. Further research should assess how population-specific these relationships are, and how these passive measures can best be combined with low temporal-density, actively-provided data to obtain valid, reliable assessments with minimal burden.

Pricing and reimbursement mechanisms for advanced therapy medicinal products in 20 countries.

Introduction: Advanced Therapy Medicinal Products are a type of therapies that, in some cases, hold great potential for patients without an effective current therapeutic approach but they also present multiple challenges to payers. While there are many theoretical papers on pricing and reimbursement (P&R) options, original empirical research is very scarce. This paper aims to provide a comprehensive international review of regulatory and P&R decisions taken for all ATMPs with centralized European marketing authorization in March 2022. Methods: A survey was distributed in July 2022 to representatives of 46 countries. Results: Responses were received from 20 countries out of 46 (43.5%). 14 countries reimbursed at least one ATMP. Six countries in this survey reimbursed no ATMPs. Conclusion: Access to ATMPs is uneven across the countries included in this study. This arises from regulatory differences, commercial decisions by marketing authorization holders, and the divergent assessment processes and criteria applied by payers. Moving towards greater equality of access will require cooperation between countries and stakeholders, for example, through the WHO Regional Office for Europe's Access to Novel Medicines Platform.

INES: Interactive tool for construction and extrapolation of partitioned survival models.

BACKGROUND: INES (INteractive model for Extrapolation of Survival and cost) provides an open-access tool powered by R that implements three-state partitioned survival models (PSM). This article describes the properties of the tool, and the situations where INES may or may not be suitable. METHODS: INES is designed to be used by investigators or healthcare professionals who have a good grasp of the principles of economic evaluation and understand the strengths and weaknesses of partitioned survival models, but are not sufficiently familiar with a statistical package such as Excel or R to be able to construct and test a de-novo PSM themselves. INES is delivered to the user via a batch file. Once downloaded to the user's hard drive, it interacts with the user via a portable version of R with web interactivity built in Shiny. INES requires absolutely no knowledge of R and the user does not need to have R or any of its dependences installed. Hence the user will deal with a standalone Shiny app. Inputs (digitalized survival curves, unit costs, posology, hazard ratios, discount rate) can be uploaded from a template spreadsheet. RESULTS: The INES application provides a seamlessly integrated package for estimating a set of parametric hazard functions for progression free and overall survival, selecting an appropriate function from this menu, and applying this as an input to a PSM to calculate mean costs and quality-adjusted life years. Examples are given that may serve as a tutorial. CONCLUSION: INES offers a rapid, flexible, robust and transparent tool for parametric survival analysis and calculating a PSM that can be used in many different contexts.

Noninfectious causes of fever in hematologic malignancies. Are antibiotics still indicated?

PURPOSE OF REVIEW: Fever is a common manifestation of both infectious and noninfectious processes in recipients of hematopoietic cell transplantation (HCT) and chimeric antigen receptor T-cell (CAR-T) therapy. Understanding the diverse causes of fever in these settings allows for accurate diagnosis and optimal use of antibiotics. RECENT FINDINGS: Herein we review common noninfectious syndromes seen in HCT and CAR-T recipients and discuss best practices in the management of these complex clinical scenarios regarding diagnosis and antibiotic use. In recent years, adverse effects of antimicrobials have highlighted the importance of antimicrobial stewardship in HCT and CAR-T patients, and an antibiotic de-escalation strategy is a safe and important tool in mitigating these adverse events, even in patients with ongoing neutropenia who become afebrile without a known infection. Common adverse events associated with antibiotics include an increased risk of Clostridiodes difficile infection (CDI), a higher incidence of multidrug-resistant organisms (MDROs), and microbiome dysbiosis. SUMMARY: Clinicians should be aware of noninfectious causes of fever in these immunocompromised patients and utilize best antibiotic practices while managing these patients.

The Opioid Overdose Resuscitation Education for Addiction Counselors and Trainees (Opioid Overdose REACT) naloxone response education pilot project improved confidence and knowledge among addiction counselors and trainees.

INTRODUCTION: Community programs to teach nonmedical laypeople how to recognize an opioid overdose and effectively resuscitate the victim using naloxone have proliferated recently as a significant component of harm-reduction efforts. Although many such programs target laypeople like first responders or friends and family members of people who use drugs, there are currently no programs that specifically target addiction counselors, despite their work with a client population at high risk of an opioid overdose. METHODS: The four-hour curriculum designed by the authors covered opioid agonist and antagonist pharmacology; opioid toxidrome signs; legal implications and indications for using the naloxone kits; and hands-on training. Participants were two cohorts of addiction counselors and addiction counseling trainees at our institution and an affiliated Opioid Treatment Program methadone clinic. Surveys testing participant knowledge and confidence were conducted at baseline, immediately post-training, six months post-training, and 12 months post-training. RESULTS: Overall, opioid and naloxone pharmacology knowledge, as well as the confidence to intervene in an overdose emergency, improved among participants in both cohorts. Knowledge scores at baseline (n = 36, median 5/10) improved significantly immediately post-training (n = 31, median 7/10, P < 0.0001, Wilcoxon signed-rank test) and were sustained six (n = 19) and 12 months (n = 11) later. Two participants reported using their naloxone kits to successfully reverse a client overdose in the 12 months after taking the course. DISCUSSION: These results from our knowledge translation pilot project suggest that our educational program to train addiction counselors in opioid pharmacology and toxicology, allowing them to recognize and respond to an opioid overdose, is feasible and could be effective. Specific barriers to implementing such educational programs include cost, stigma, and unclear best practice for designing and conducting these programs. CONCLUSIONS: Further study of providing opioid pharmacology education and overdose and naloxone training to addiction counselors and counseling trainees appears to be warranted.

Health Outcomes by Neighborhood (HON): Effects of Neighborhood, Social Instability, and Health Factors on 12-Month Trajectories of Substance-Use Disorder Symptoms.

BACKGROUND: Previous studies have shown that environment and health can influence drug use trajectories and the effects of substance use disorder (SUD) treatments. We hypothesized that trajectories of drug use-related problems, based on changes in DSM-5 symptoms, would vary by type(s) of drugs used, health factors, and neighborhood characteristics. METHODS: We assessed mental and physical health, stress, social instability, neighborhood characteristics (disorderliness and home value), and DSM-5 symptom counts at two study visits, 12 months apart, in a community sample (baseline N = 735) in Baltimore, MD. Three prominent categories of drug-use trajectory were identified with K-means cluster analysis of symptom counts: Persistent (4 or more symptoms at both visits or at Visit 2), Improved (decrease from 4 or more symptoms at Visit 1 to 3 or fewer symptoms at Visit 2), and Low-Stable (3 or fewer symptoms at both visits). Baseline health and neighborhood measures were tested as predictors of trajectory in mediation and moderation models. RESULTS: Among people with current opioid- and/or stimulant-use, odds of an Improved trajectory were (1) decreased with neighborhood disorder and social instability, or (2) increased with home value and social instability. Odds of a Low-Stable trajectory were decreased by social instability and stress but increased in those who were older or self-identified as white. CONCLUSIONS: Trajectories of drug use-related problems are influenced by sociodemographic variables, neighborhood factors, and health. Assessing DSM-5 symptom counts as an outcome measure may be valuable in monitoring or predicting long-term trajectories and treatment effectiveness.

Overdose mortality rates for opioids and stimulant drugs are substantially higher in men than in women: state-level analysis.

Drug overdoses from opioids and stimulants are a major cause of mortality in the United States. It is unclear if there are stable sex differences in overdose mortality for these drugs across states, whether these differ across the lifespan, and if so, whether they can be accounted for by different levels of drug misuse. This was a state-level analysis of epidemiological data on overdose mortality, across 10-year age bins (age range: 15-74), using the CDC WONDER platform for decedents in the United States in 2020-1. The outcome measure was rate of overdose death (per 100,000) for: synthetic opioids (e.g., fentanyl), heroin, psychostimulants with potential for misuse (e.g., methamphetamine), and cocaine. Multiple linear regressions controlled for ethnic-cultural background, household net worth, and sex-specific rate of misuse (from NSDUH, 2018-9). For all these drug categories, males had greater overall overdose mortality than females, after controlling for rates of drug misuse. The mean male/female sex ratio of mortality rate was relatively stable across jurisdictions: synthetic opioids (2.5 [95% CI, 2.4-7]), heroin, (2.9 [95% CI, 2.7-3.1], psychostimulants (2.4 [95% CI, 2.3-5]), and cocaine (2.8 [95% CI, 2.6-9]). With data stratified in 10-year age bins, the sex difference generally survived adjustment (especially in the 25-64 age range). Results indicate that males are significantly more vulnerable than females to overdose deaths caused by opioid and stimulant drugs, taking into account differing state-level environmental conditions and drug misuse levels. These results call for research into diverse biological, behavioral, and social factors that underlie sex differences in human vulnerability to drug overdose.

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) 2023 APA, all rights reserved).

Examining the paradoxical effects of kratom: a narrative inquiry.

Introduction: Surveys and case reports have documented kratom use in the United States (US) for over a decade. However, those reports have generally not examined in depth the role kratom plays in the lives of those who use it regularly for sustained periods. Until there are controlled studies of the pharmacology and subjective effects of kratom alkaloids in humans, one of the best sources of insight on kratom-product use remains qualitative data with nuanced descriptions of kratom effects from those who use it regularly. Method: We conducted semistructured qualitative interviews with adults who regularly use kratom products, as part of a laboratory study of kratom-product self-administration. This qualitative component of the study was conducted as a narrative case-report series (n = 10). Results: Despite some differences among participants, all experienced acute combination effects that were largely, even simultaneously, analgesic and stimulatory. Most participants had decreased their dosages over time, and one planned to quit. Five of the 10 participants met DSM-5-based criteria for kratom-use disorder (3 mild, 1 moderate, 1 severe, by symptoms counts). When kratom was inadvertently taken in larger than intended doses, participants described a constellation of symptoms that they called "the wobbles" (a jittery feeling accompanied by what seemed to be nystagmus); this was rare, but could be of scientific and clinical interest as a possible manifestation of serotonin syndrome. Most participants described tolerance but considered kratom generally safe at low-moderate doses, providing perceived benefits with less potential risk for adverse effects compared to pharmaceuticals or illicit drugs. Discussion: In-depth interview data like these help confirm and clarify findings from larger survey studies and clinician-driven case reports. They are needed to inform the policy practice regarding kratom and may also help inform future experimental designs.

Effectiveness of Conditioned Open-label Placebo With Methadone in Treatment of Opioid Use Disorder: A Randomized Clinical Trial.

Importance: Methadone treatment is the most effective evidence-based treatment for opioid use disorder (OUD), but challenges related to dosing and premature treatment dropout argue for adjunct interventions to improve outcomes. One potential behavioral intervention with low risk involves harnessing placebo effects. Objective: To determine the effect of a pharmacologically conditioned open-label placebo (C-OLP) on 90-day methadone dose, retention, drug use, withdrawal, craving, quality of life, and sleep. Design, Setting, and Participants: This 2-arm, open-label, single-blind randomized clinical trial was conducted between December 5, 2017, and August 2, 2019, in an academically affiliated community opioid treatment program. Analyses were conducted between October 1, 2019, and April 30, 2020. A total of 320 newly enrolled adults seeking treatment for moderate to severe OUD were assessed for study eligibility; 131 met eligibility criteria, provided informed consent, and were randomized to either C-OLP or treatment as usual (TAU) in an unequal-block (3:2) manner. Exclusion criteria were pregnancy, hospital/program transfers, and court-ordered treatment. Interventions: Participants randomized to C-OLP received pharmacologic conditioning and a placebo pill and methadone, and participants randomized to TAU were given methadone only. Participants met with the study team 5 times: at baseline (treatment intake) and 2, 4, 8, and 12 weeks postbaseline. Interactions were balanced between the 2 groups. Main Outcomes and Measures: Outcomes included 90-day methadone dose (primary) and treatment retention, drug use, withdrawal, craving, quality of life, and sleep quality (secondary). Analyses were conducted as intention-to-treat. Results: Of the 131 people enrolled in the study, 54 were randomized to TAU and 77 to C-OLP. Mean (SD) age was 45.9 (11.2) years; most of the participants were Black or African American (83 [63.4%]) and male (84 [64.1%]). No significant group differences were observed in the mean (SD) 90-day methadone dose (83.1 [25.1] mg for group TAU, 79.4 [19.6] mg for group C-OLP; t = 0.621991; P = .43), but the groups differed significantly in their retention rates: 33 (61.1%) for TAU and 60 (77.9%) for C-OLP (χ21 = 4.356; P = .04; number needed to treat for the beneficial outcome of 3-month treatment retention, 6; 95% CI, 4-119). C-OLP participants also reported significantly better sleep quality. Conclusions and Relevance: In this randomized clinical trial, C-OLP had no effect on the primary outcome of 90-day methadone dose. However, C-OLP participants were significantly more likely to remain in treatment. These findings support the use of C-OLP as a methadone treatment adjunct, but larger trials are needed to further examine the use of C-OLP. Trial Registration: ClinicalTrials.gov Identifier: NCT02941809.