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Preclinical and clinical work suggests that mifepristone may be a viable treatment for alcohol use disorder (AUD). This was a Phase 1/2, outpatient, cross-over, randomized, double-blind, placebo-controlled trial with non-treatment-seeking individuals with AUD (N = 32). We assessed safety, alcohol craving and consumption, after 1-week mifepristone 600 mg/day administration, in a human laboratory study comprised of a single oral yohimbine administration (32.4 mg), a cue-reactivity procedure and alcohol self-administration. Safety was monitored by adverse events and hemodynamic parameters, alcohol craving by alcohol craving questionnaire and cue-induced saliva output. During the alcohol self-administration, we assessed alcohol pharmacokinetics, subjective effects and consumption. Outcomes were assessed using Generalized Estimating Equations and mediation analysis. Mild-moderate adverse events were reported in both conditions. There was no statistically significant difference between mifepristone and placebo in alcohol pharmacokinetics and subjective effects. Furthermore, blood pressure increased only in the placebo condition after the stress-induced laboratory procedures. Mifepristone, compared to placebo, significantly reduced alcohol craving and increased cortisol levels. Mifepristone-induced cortisol increase was not a mediator of alcohol craving. Mifepristone, compared to placebo, did not reduce alcohol consumption in the laboratory or in a naturalistic setting. This study successfully translated a developed preclinical procedure to a human laboratory study, confirming the safety of mifepristone in people with AUD and providing evidence to its role in reducing alcohol craving under stress procedures. The lack of effects on alcohol drinking may be related to the selection of non-treatment seekers and suggests future treatment-oriented trials should investigate mifepristone in people with AUD., (© 2023 Society for the Study of Addiction.)

Preclinical and clinical work suggests that mifepristone (glucocorticoid receptor antagonist), may be a viable treatment for alcohol use disorder (AUD). The aim of this work was to translate our preclinical mifepristone study using yohimbine (α2 receptor antagonist) stress-induced reinstatement of alcohol-seeking to a clinical setting. This was a Phase 1/2, outpatient, cross-over, randomized, double-blind, placebo-controlled trial with non-treatment-seeking individuals with AUD ( N =32). We investigated the safety, alcohol craving and consumption after oral administration of mifepristone (600mg daily for a week) in a human laboratory study comprised of administration of yohimbine in a cue-reactivity procedure and alcohol self-administration. Outcomes were assessed using Generalized Estimating Equations and mediation and moderation analyses assessed mechanisms of action and precision medicine targets. We did not observe serious adverse events related to the study drugs or study procedure and mild to moderate non-serious adverse events were reported by both study conditions. Also, there was no statistically-significant difference between the mifepristone and placebo in the hemodynamic response, alcohol subjective effects and pharmacokinetics parameters. Mifepristone significantly reduced alcohol craving and increased cortisol levels. Mifepristone-induced cortisol increase was not a mediator of alcohol craving. Moderation analysis with family history density of AUD (FHDA) and mifepristone, suggested that reduced craving was present in individuals with low , but not high FHDA. Mifepristone, compared to placebo, did not reduce alcohol consumption in the laboratory or in a naturalistic setting. This study successfully translated a preclinical paradigm to a human laboratory study confirming safety, tolerability and efficacy of mifepristone in an alcohol paradigm. Mediation analysis showed that the effect of mifepristone on craving was not related to mifepristone-induced increases in cortisol and moderation of FHDA suggested the importance of evaluating AUD endophenotypes for pharmacotherapies., Clinical Trial Registration: Clinicaltrials.gov ; NCT02243709., Ind/fda: 121984, mifepristone and yohimbine (Holder: Haass-Koffler).

Background: We examine the performance of the Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5) persistent complex bereavement-related disorder (PCBD) criteria in bereaved adults to identify prolonged grief cases determined prospectively., Methods: Bereaved adults (n = 138) were assessed at 8, 21, 32, 67, and 90 months after the sudden death of a spouse or close relative. We used latent class growth analysis to identify the longitudinal trajectories of grief assessed using the Inventory for Complicated Grief. To validate the trajectory that corresponded to prolonged grief, we examined the baseline predictors of these trajectories and their relationship with functional impairment., Results: We found three distinct trajectories of grief reactions. One of these trajectories (13.8%) showed high and sustained grief reactions that persisted for almost 7.5 years after the death. Participants with prolonged grief showed greater functional impairment [relative risk ratio (RRR) = 0.82, 95% confidence interval (CI): 0.70 to -0.97; p = 0.02] and higher self-reported depression (RRR = 1.21, 95% CI 1.09 to 1.96; p = 0.001) than participants whose grief reactions subsided over time. The original PCBD (requiring 6 criterion C symptoms) criteria correctly identified cases (57.9-94.7%) with perfect specificity (100%) but low to high sensitivity (5.6-81.3%); however, its sensitivity increased when revising criterion C to require ⩾3 (45.5-94.1%). The dimensional approach showed high sensitivity (0.50-1) and specificity (0.787-0.97)., Conclusions: We recommend revisions to the PCBD criteria, which are overly restrictive and may exclude cases with clinically significant grief-related distress and impairment. In the meantime, clinicians need to monitor grief symptoms over time using available dimensional approaches to reduce the burden of grief.

Objective: Title I of the Americans with Disabilities Act (ADA) provides protection against discrimination on the basis of disability. This article explores how the courts have dealt with provisions limiting these protections for persons with substance use disorders. Specifically, the ADA allows employees with substance use disorders to be held to the same standards as other employees, suggesting that employers may not be required to provide reasonable accommodations. Moreover, employees "currently engaging in the illegal use of drugs" are excluded from ADA coverage., Methods: This article reviewed all published federal appellate court opinions involving cases in which a substance use disorder was the basis for a claim of employment-related discrimination in violation of the ADA., Results: In 26 cases identified, the lower courts ruled in favor of the employer 25 times, and the appellate courts reversed four of these rulings. The cases highlight three important limitations of ADA protections for persons with substance use disorders: the dilemma of needing to prove that one's substance use disorder limits major life activities while simultaneously arguing that one is qualified for the job; expansive interpretations of "current" drug use and the period of sobriety needed to qualify for ADA protections; and restrictions on the extent to which a qualifying disability can serve as a legal excuse for substance use-related misconduct., Conclusions: The protections afforded by the ADA for individuals with substance use disorders are restricted by what appears to be the statute's moralizing on drug and alcohol use and those who use these substances.

This column describes the Internet System for Tracking Over-Prescribing (I-STOP), New York State's prescription monitoring program, and its compatibility with HIPAA and Part 2 of Volume 42 of the Code of Federal Regulations (CFR). The authors review use of information that is permitted by I-STOP and CFR for health care operations, including disclosure, and present information from the state Bureau of Narcotics Enforcement about appropriate use of the program. Physicians are permitted, for example, to contact other prescribers in I-STOP, even without explicit permission from the patient, an area in which physicians need more training. Common clinical scenarios encountered while navigating I-STOP are described.

Aldosterone regulates electrolyte and fluid homeostasis through binding to the mineralocorticoid receptors (MRs). Previous work provides evidence for a role of aldosterone in alcohol use disorders (AUDs). We tested the hypothesis that high functional activity of the mineralocorticoid endocrine pathway contributes to vulnerability for AUDs. In Study 1, we investigated the relationship between plasma aldosterone levels, ethanol self-administration and the expression of CYP11B2 and MR (NR3C2) genes in the prefrontal cortex area (PFC) and central nucleus of the amygdala (CeA) in monkeys. Aldosterone significantly increased after 6- and 12-month ethanol self-administration. NR3C2 expression in the CeA was negatively correlated to average ethanol intake during the 12 months. In Study 2, we measured Nr3c2 mRNA levels in the PFC and CeA of dependent and nondependent rats and the correlates with ethanol drinking during acute withdrawal. Low Nr3c2 expression levels in the CeA were significantly associated with increased anxiety-like behavior and compulsive-like drinking in dependent rats. In Study 3, the relationship between plasma aldosterone levels, alcohol drinking and craving was investigated in alcohol-dependent patients. Non-abstinent patients had significantly higher aldosterone levels than abstinent patients. Aldosterone levels positively correlated with the number of drinks consumed, craving and anxiety scores. These findings support a relationship between ethanol drinking and the aldosterone/MR pathway in three different species.

Increasing evidence supports the role of appetite-regulating pathways, including ghrelin and leptin, in alcoholism. This study tested the hypothesis that intravenous exogenous ghrelin administration acutely decreases endogenous serum leptin levels, and that changes in leptin levels negatively correlate with alcohol craving. This was a double-blind, placebo-controlled human laboratory study. Non-treatment-seeking, alcohol-dependent, heavy drinkers (n=45) were randomized to receive intravenous ghrelin or placebo, followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol trial cues. There was a main effect for intravenous ghrelin administration, compared with placebo, in reducing serum leptin levels (P<0.01). Post hoc analysis showed significant differences in serum leptin levels at the alcohol trial (P<0.05) that persisted at the end of the experiment (P<0.05). By contrast, there were no significant differences in serum leptin levels at the juice trial (P=not significant (NS)). The change of serum leptin level at the alcohol trial correlated with the increase in alcohol urge (P<0.05), whereas urge to drink juice was not correlated with the leptin change at the juice trial (P=NS). These findings provide preliminary evidence of ghrelin-leptin cross-talk in alcoholic individuals and suggest that their relationship may have a role in alcohol craving.

Aims: A few studies have suggested a relationship between thyroid hormones and alcohol dependence (AD) such as a blunted increase of thyroid stimulating hormone (TSH) in response to thyrotropin-releasing hormone (TRH), lower levels of circulating free triiodothyronine (fT3) and free thyroxine (fT4) levels and down regulation of the TRH receptors. The current study aimed to explore the relationship between the hormones of the thyroid axis and alcohol-seeking behaviors in a sample of alcohol-dependent patients., Methods: Forty-two treatment-seeking alcohol-dependent individuals enrolled in a 12-week treatment study were considered. The Timeline Follow Back (TLFB) was used to assess the number of drinks consumed during the 12-week period. Blood levels of thyroid hormones (TSH, fT3 and fT4) were measured prior to and at the end of treatment. Questionnaires were administered to evaluate craving for alcohol [Penn Alcohol Craving Scale (PACS) and the Obsessive Compulsive Drinking Scale (OCDS) and its two subscales ODS for obsessions and CDS for compulsions] as well as anxiety [State and Trait Inventory (STAI)], depression [the Zung Self-Rating Depression Scale (Zung)] and aggression [the Aggressive Questionnaire (AQ)]., Results: At baseline, we found significant positive correlations between fT3 and OCDS (r = 0.358, P = 0.029) and CDS (r = 0.405, P = 0.013) and negative correlations between TSH levels and STAI (r = -0.342, P = 0.031), and AQ (r = -0.35, P = 0.027). At the end of the 12-week study period, abstinent patients had a greater change in TSH than those who relapsed (-0.4 vs. -0.25, F(1,24) = 5.4, P = 0.029)., Conclusion: If confirmed in larger samples, these findings could suggest that the thyroid axis might represent a biomarker of alcohol craving and drinking., (Published by Oxford University Press on behalf of Medical Council on Alcohol 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Over the past several decades, nontraditional drugs of abuse, including bath salts, synthetic cannabinoids, and salvia, have increased in popularity and use. Despite this fact, they remain unfamiliar to many healthcare providers. Commonly marketed as "legal highs," these substances are being used for their desired neuropsychiatric effects, taking advantage of their accessibility, low cost, variable legality, and limited detection on traditional urine drug screens. Similar to traditional drugs of abuse, these substances have varying degrees of toxicity and may lead to potentially adverse effects, ranging from benign to life threatening. This paper offers a review of three of the more widely-used emerging drugs (or classes of drugs): bath salts, synthetic cannabinoids, and salvia. For each we review its history and development, the neurochemical basis for its clinical effects, the nature and route of ingestion, the range of desired effects, potential toxicities, diagnostic and therapeutic approaches, as well as social and legal considerations. [Full text available at http://rimed.org/rimedicaljournal-2014-06.asp, free with no login].

Although the use of recombinant activated factor VII (rFVIIa) to control intractable bleeding in nonhemophiliac patients is expanding, several issues pertinent to its potential thrombotic complications and effect on patient mortality are still of concern. We herein describe our experience at a developing country tertiary care center over a period of 4 years. A total of 49 patients were identified of whom 28.6% belong to the pediatric age group. The most common bleeding settings were intracerebral hemorrhage, abdominal aortic surgery, general surgery, and disseminated intravascular coagulopathy. All patients achieved cessation or significant reduction in bleeding. Only 1 patient had a documented postuse thrombotic complication. Of the whole group, 12 patients (24.4%) eventually died with only 1 death having a possible association to rFVIIa use. There was a statistically significant reduction in the need for blood product transfusion after the use of rFVIIa. The use of rFVIIa was in accordance with the hospital's algorithm (identifying salvageable patients, preconditioning, blood product replacement, and dosing) in 30 (61.2%) patients. We conclude that rFVIIa should continue to be considered in nonhemophiliac patients failing to respond to conventional measures of bleeding control. However, this off-label use should be coupled with strict adherence to the treatment algorithms, which remains essential in developing countries with limited health care resources.

Increasing evidence is highlighting the relationship between malignancy and hypercoagulability as a bidirectional association. We herein share our experience with a patient in whom such an association may be entertained. The patient, who had a history of venous thromboembolism, presented to our care with manifestation of stroke. Extensive workup revealed that the patient carries prothrombotic mutations in the prothrombin and methylenetetrahydrofolate reductase genes. The patient, a non-smoker, was also diagnosed with non-small cell lung carcinoma. The possible association between the patient's malignancy and prothrombotic state are further discussed.

Myeloproliferative disorders and the inherited thrombophilias have been described as the main causes underlying the Budd-Chiari syndrome. Moreover, the presence of the JAK2V617F was associated with a higher frequency of Budd-Chiari syndrome in patients who have overt or even latent myeloproliferative disorder. We herein describe a 28-year-old woman who was diagnosed with Budd-Chiari syndrome and later developed an overt myeloproliferative disorder. The patient was found to carry both the JAK2V617F and the prothrombin G20210A mutation in the heterozygous form. The significance of the chronology of diagnosis is highlighted.