Search

Key Points: Question: What are the efficacy and safety of psilocybin in patients with major depressive disorder? Findings: In a randomized, placebo-controlled, 6-week trial in 104 adults, a 25-mg dose of psilocybin administered with psychological support was associated with a rapid and sustained antidepressant effect, measured as change in depressive symptom scores, compared with active placebo. No serious treatment-emergent adverse events occurred. Meaning: A 25-mg dose of psilocybin was well tolerated and may hold promise as a treatment for major depressive disorder when combined with psychological support. Importance: Psilocybin shows promise as a treatment for major depressive disorder (MDD). Objective: To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. Design, Setting, and Participants: In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing. Interventions: Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support. Main Outcomes and Measures: The primary outcome was change in central rater–assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment. Results: A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,−12.3 [95% CI, −17.5 to −7.2]; P <.001) and from baseline to day 8 (mean difference, −12.0 [95% CI, −16.6 to −7.4]; P <.001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, −2.31 [95% CI, 3.50-1.11]; P <.001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs. Conclusions and Relevance: Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin—when administered with psychological support—may hold promise as a novel intervention for MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT03866174 This randomized clinical trial examines the timing of onset of action, durability of benefit, and safety profile of single-dose psilocybin in patients with major depressive disorder compared with placebo. [ABSTRACT FROM AUTHOR]

Importance: Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous μ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines.Observations: Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications.Conclusions and Relevance: Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD. [ABSTRACT FROM AUTHOR]

Background: Rates of opioid prescribing tripled in the USA between 1999 and 2015 and were associated with significant increases in opioid misuse and overdose death. Roughly half of all opioids are prescribed in primary care. Although clinical guidelines describe recommended opioid prescribing practices, implementing these guidelines in a way that balances safety and effectiveness vs. risk remains a challenge. The literature offers little help about which implementation strategies work best in different clinical settings or how strategies could be tailored to optimize their effectiveness in different contexts. Systems consultation consists of (1) educational/engagement meetings with audit and feedback reports, (2) practice facilitation, and (3) prescriber peer consulting. The study is designed to discover the most cost-effective sequence and combination of strategies for improving opioid prescribing practices in diverse primary care clinics.Methods/design: The study is a hybrid type 3 clustered, sequential, multiple-assignment randomized trial (SMART) that randomizes clinics from two health systems at two points, months 3 and 9, of a 21-month intervention. Clinics are provided one of four sequences of implementation strategies: a condition consisting of educational/engagement meetings and audit and feedback alone (EM/AF), EM/AF plus practice facilitation (PF), EM/AF + prescriber peer consulting (PPC), and EM/AF + PF + PPC. The study's primary outcome is morphine-milligram equivalent (MME) dose by prescribing clinicians within clinics. The study's primary aim is the comparison of EM/AF + PF + PPC versus EM/AF alone on change in MME from month 3 to month 21. The secondary aim is to derive cost estimates for each of the four sequences and compare them. The exploratory aim is to examine four tailoring variables that can be used to construct an adaptive implementation strategy to meet the needs of different primary care clinics.Discussion: Systems consultation is a practical blend of implementation strategies used in this case to improve opioid prescribing practices in primary care. The blend offers a range of strategies in sequences from minimally to substantially intensive. The results of this study promise to help us understand how to cost effectively improve the implementation of evidence-based practices.Trial Registration: NCT04044521 (ClinicalTrials.gov). Registered 05 August 2019. [ABSTRACT FROM AUTHOR]

Aim: The aim of the current study was to investigate the relationship between escalating higher doses of psilocybin and the potential psilocybin occasioned positive subjective effects.Methods: Healthy participants ( n=12) were given three escalating doses of oral psilocybin (0.3 mg/kg; 0.45 mg/kg; 0.6 mg/kg) or (18.8-36.6 mg; 27.1-54.0 mg; 36.3-59.2 mg) a minimum of four weeks apart in a supervised setting. Blood and urine samples, vital signs, and electrocardiograms were obtained. Subjective effects were assessed using the Mystical Experience Questionnaire and Persisting Effects Questionnaire.Results: There was a significant linear dose-related response in Mystical Experience Questionnaire total score and the transcendence of time and space subscale, but not in the rate of a complete mystical experience. There was also a significant difference between dose 3 compared to dose 1 on the transcendence of time and space subscale, while no dose-related differences were found for Mystical Experience Questionnaire total scores or rate of a mystical experience. Persisting Effects Questionnaire positive composite scores 30 days after completion of the last dose were significantly higher than negative composite scores. Persisting Effects Questionnaire results revealed a moderate increase in sense of well-being or life satisfaction on average that was associated with the maximum Mystical Experience Questionnaire total score. Pharmacokinetic measures were associated with dose but not with Mystical Experience Questionnaire total scores or rate of a mystical experience.Conclusions: High doses of psilocybin elicited subjective effects at least as strong as the lower doses and resulted in positive persisting subjective effects 30 days after, indicating that a complete mystical experience was not a prerequisite for positive outcomes. [ABSTRACT FROM AUTHOR]

Background: This paper reports on the feasibility, acceptability, and effectiveness of an innovative implementation strategy named "systems consultation" aimed at improving adherence to clinical guidelines for opioid prescribing in primary care. While clinical guidelines for opioid prescribing have been developed, they have not been widely implemented, even as opioid abuse reaches epidemic levels.Methods: We tested a blended implementation strategy consisting of several discrete implementation strategies, including audit and feedback, academic detailing, and external facilitation. The study compares four intervention clinics to four control clinics in a randomized matched-pairs design. Each systems consultant aided clinics on implementing the guidelines during a 6-month intervention consisting of monthly site visits and teleconferences/videoconferences. The mixed-methods evaluation employs the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Quantitative outcomes are compared using time series analysis. Qualitative methods included focus groups, structured interviews, and ethnographic field techniques.Results: Seven clinics were randomly approached to recruit four intervention clinics. Each clinic designated a project team consisting of six to eight staff members, each with at least one prescriber. Attendance at intervention meetings was 83%. More than 80% of staff respondents agreed or strongly agreed with the statements: "I am more familiar with guidelines for safe opioid prescribing" and "My clinic's workflow for opioid prescribing is easier." At 6 months, statistically significant improvements were noted in intervention clinics in the percentage of patients with mental health screens, treatment agreements, urine drug tests, and opioid-benzodiazepine co-prescribing. At 12 months, morphine-equivalent daily dose was significantly reduced in intervention clinics compared to controls. The cost to deliver the strategy was $7345 per clinic. Adaptations were required to make the strategy more acceptable for primary care. Qualitatively, intervention clinics reported that chronic pain was now treated using approaches similar to those employed for other chronic conditions, such as hypertension and diabetes.Conclusions: The systems consultation implementation strategy demonstrated feasibility, acceptability, and effectiveness in a study involving eight primary care clinics. This multi-disciplinary strategy holds potential to mitigate the prevalence of opioid addiction and ultimately may help to improve implementation of clinical guidelines across healthcare.Trial Registration: ClinicalTrials.gov (NCT02433496). https://clinicaltrials.gov/ct2/show/NCT02433496 Registered May 5, 2015. [ABSTRACT FROM AUTHOR]

Introduction: Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults.Methods: Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods.Results: No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied.Conclusions: The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose.Clinical Trials Identifier: NCT02163707. [ABSTRACT FROM AUTHOR]

Background: Adoption of evidence-based practices takes place at a glacial place in healthcare. This research will pilot test an innovative implementation strategy - systems consultation -intended to speed the adoption of evidence-based practice in primary care. The strategy is based on tenets of systems engineering and has been extensively tested in addiction treatment. Three innovations have been included in the strategy - translation of a clinical practice guideline into a checklist-based implementation guide, the use of physician peer coaches ('systems consultants') to help clinics implement the guide, and a focus on reducing variation in practices across prescribers and clinics. The implementation strategy will be applied to improving opioid prescribing practices in primary care, which may help ultimately mitigate the increasing prevalence of opioid abuse and addiction.Methods/design: The pilot test will compare four intervention clinics to four control clinics in a matched-pairs design. A leading clinical guideline for opioid prescribing has been translated into a checklist-based implementation guide in a systematic process that involved experts who wrote the guideline in consultation with implementation experts and primary care physicians. Two physicians with expertise in family and addiction medicine are serving as the systems consultants. Each systems consultant will guide two intervention clinics, using two site visits and follow-up communication by phone and email, to implement the translated guideline. Mixed methods will be used to test the feasibility, acceptability, and preliminary effectiveness of the implementation strategy in an evaluation that meets standards for 'fully developed use' of the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance). The clinic will be the primary unit of analysis.Discussion: The systems consultation implementation strategy is intended to generalize to the adoption of other clinical guidelines. This pilot test is intended to prepare for a large randomized clinical trial that will test the strategy against other implementation strategies, such as audit/feedback and academic detailing, used to close the gap between knowledge and practice. The systems consultation approach has the potential to shorten the famously long time it takes to implement evidence-based practices and clinical guidelines in healthcare. [ABSTRACT FROM AUTHOR]

Background and aims Brief alcohol interventions in medical settings are efficacious in improving self-reported alcohol consumption among those with low-severity alcohol problems. Screening, Brief Intervention and Referral to Treatment initiatives presume that brief interventions are efficacious in linking patients to higher levels of care, but pertinent evidence has not been evaluated. We estimated main and subgroup effects of brief alcohol interventions, regardless of their inclusion of a referral-specific component, in increasing the utilization of alcohol-related care. Methods A systematic review of English language papers published in electronic databases to 2013. We included randomized controlled trials (RCTs) of brief alcohol interventions in general health-care settings with adult and adolescent samples. We excluded studies that lacked alcohol services utilization data. Extractions of study characteristics and outcomes were standardized and conducted independently. The primary outcome was post-treatment alcohol services utilization assessed by self-report or administrative data, which we compared across intervention and control groups. Results Thirteen RCTs met inclusion criteria and nine were meta-analyzed ( n = 993 and n = 937 intervention and control group participants, respectively). In our main analyses the pooled risk ratio (RR) was = 1.08, 95% confidence interval (CI) = 0.92-1.28. Five studies compared referral-specific interventions with a control condition without such interventions (pooled RR = 1.08, 95% CI = 0.81-1.43). Other subgroup analyses of studies with common characteristics (e.g. age, setting, severity, risk of bias) yielded non-statistically significant results. Conclusions There is a lack of evidence that brief alcohol interventions have any efficacy for increasing the receipt of alcohol-related services. [ABSTRACT FROM AUTHOR]

Background Healthcare reform in the United States is encouraging Federally Qualified Health Centers and other primary-care practices to integrate treatment for addiction and other behavioral health conditions into their practices. The potential of mobile health technologies to manage addiction and comorbidities such as HIV in these settings is substantial but largely untested. This paper describes a protocol to evaluate the implementation of an E-Health integrated communication technology delivered via mobile phones, called Seva, into primary-care settings. Seva is an evidence-based system of addiction treatment and recovery support for patients and real-time caseload monitoring for clinicians. Methods/Design Our implementation strategy uses three models of organizational change: the Program Planning Model to promote acceptance and sustainability, the NIATx quality improvement model to create a welcoming environment for change, and Rogers's diffusion of innovations research, which facilitates adaptations of innovations to maximize their adoption potential. We will implement Seva and conduct an intensive, mixed-methods assessment at three diverse Federally Qualified Healthcare Centers in the United States. Our non-concurrent multiple-baseline design includes three periods — pretest (ending in four months of implementation preparation), active Seva implementation, and maintenance — with implementation staggered at six-month intervals across sites. The first site will serve as a pilot clinic. We will track the timing of intervention elements and assess study outcomes within each dimension of the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework, including effects on clinicians, patients, and practices. Our mixedmethods approach will include quantitative (e.g., interrupted time-series analysis of treatment attendance, with clinics as the unit of analysis) and qualitative (e.g., staff interviews regarding adaptations to implementation protocol) methods, and assessment of implementation costs. Discussion If implementation is successful, the field will have a proven technology that helps Federally Qualified Health Centers and affiliated organizations provide addiction treatment and recovery support, as well as a proven strategy for implementing the technology. Seva also has the potential to improve core elements of addiction treatment, such as referral and treatment processes. A mobile technology for addiction treatment and accompanying implementation model could provide a cost-effective means to improve the lives of patients with drug and alcohol problems. Trial registration ClinicalTrials.gov (NCT01963234). [ABSTRACT FROM AUTHOR]

This study of participants in a US drug treatment court describes the relationship between the imposition of short-term jail sanctions and substance abuse treatment dropout, and examines offender characteristics moderating or modifying the impact of jail sanctions on treatment dropout. Data were derived from administrative information collected by the Dane County Wisconsin Drug Treatment Court from 1996-2004 on all 573 participants achieving a final disposition of treatment completion or failure during those program years. Iterative Cox proportional hazards models of time to treatment failure were created; jail sanctions during drug court participation were framed as time-dependent covariates. A theoretical framework and specific statistical criteria guided construction of a final parsimonious model of time to treatment drop-out. Treatment failure was associated with unemployment [hazard ratio (HR) in unemployed versus employed = 1.41, P-value 0.0079], lower educational attainment (HR in high school non-graduate versus graduate = 1.41, P = 0.02) and application of the first jail sanction (HR 2.71, P < 0.001). The association between treatment failure and a first sanction was considerably stronger for sanctions administered earlier in participation (HR for sanction 1 at <30 days 11.34, P-value 0.0002). An initial jail sanction for non-adherence may be more likely to foster treatment compliance in less refractory individuals (i.e. those not already acclimated or socialized to incarceration or other corrections interventions). More stringent supervisory conditions and individualized services may be required to reintegrate such offenders and promote longer-term public safety. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented discussing the response by N. Simioni et al. to the authors' study on screening, brief intervention, and referral to treatment (SBIRT) in substance use disorder services.

The article reflects on prescription drug monitoring programs aimed at preventing drug misuse in the U.S. In New York and California, prescribers are required to track their prescription by creating three copies of prescription sent to drug stores and a central government-authorized location. It states that the programs impede drug access and misidentify high-frequency and high-volume use of prescriptions. It argues that such programs will not totally prevent patients from obtaining medication.

Background: Healthcare reform in the United States is encouraging Federally Qualified Health Centers and other primary-care practices to integrate treatment for addiction and other behavioral health conditions into their practices. The potential of mobile health technologies to manage addiction and comorbidities such as HIV in these settings is substantial but largely untested. This paper describes a protocol to evaluate the implementation of an E-Health integrated communication technology delivered via mobile phones, called Seva, into primary-care settings. Seva is an evidence-based system of addiction treatment and recovery support for patients and real-time caseload monitoring for clinicians.Methods/design: Our implementation strategy uses three models of organizational change: the Program Planning Model to promote acceptance and sustainability, the NIATx quality improvement model to create a welcoming environment for change, and Rogers's diffusion of innovations research, which facilitates adaptations of innovations to maximize their adoption potential. We will implement Seva and conduct an intensive, mixed-methods assessment at three diverse Federally Qualified Healthcare Centers in the United States. Our non-concurrent multiple-baseline design includes three periods - pretest (ending in four months of implementation preparation), active Seva implementation, and maintenance - with implementation staggered at six-month intervals across sites. The first site will serve as a pilot clinic. We will track the timing of intervention elements and assess study outcomes within each dimension of the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework, including effects on clinicians, patients, and practices. Our mixed-methods approach will include quantitative (e.g., interrupted time-series analysis of treatment attendance, with clinics as the unit of analysis) and qualitative (e.g., staff interviews regarding adaptations to implementation protocol) methods, and assessment of implementation costs.Discussion: If implementation is successful, the field will have a proven technology that helps Federally Qualified Health Centers and affiliated organizations provide addiction treatment and recovery support, as well as a proven strategy for implementing the technology. Seva also has the potential to improve core elements of addiction treatment, such as referral and treatment processes. A mobile technology for addiction treatment and accompanying implementation model could provide a cost-effective means to improve the lives of patients with drug and alcohol problems.Trial Registration: ClinicalTrials.gov (NCT01963234). [ABSTRACT FROM AUTHOR]