Single cell transcriptomics reveals distinct transcriptional responses to oxycodone and buprenorphine by iPSC-derived brain organoids from patients with opioid use disorder.

The opioid epidemic represents a national crisis. Oxycodone is one of the most prescribed opioid medications in the United States, whereas buprenorphine is currently the most prescribed medication for opioid use disorder (OUD) pharmacotherapy. Given the extensive use of prescription opioids and the global opioid epidemic, it is essential to understand how opioids modulate brain cell type function at the single-cell level. We performed single nucleus RNA-seq (snRNA-seq) using iPSC-derived forebrain organoids from three male OUD subjects in response to oxycodone, buprenorphine, or vehicle for seven days. We utilized the snRNA-seq data to identify differentially expressed genes following drug treatment using the Seurat integrative analysis pipeline. We utilized iPSC-derived forebrain organoids and single-cell sequencing technology as an unbiased tool to study cell-type-specific and drug-specific transcriptional responses. After quality control filtering, we analyzed 25787 cells and identified sixteen clusters using unsupervised clustering analysis. Our results reveal distinct transcriptional responses to oxycodone and buprenorphine by iPSC-derived brain organoids from patients with OUD. Specifically, buprenorphine displayed a significant influence on transcription regulation in glial cells. However, oxycodone induced type I interferon signaling in many cell types, including neural cells in brain organoids. Finally, we demonstrate that oxycodone, but not buprenorphine activated STAT1 and induced the type I interferon signaling in patients with OUD. These data suggest that elevation of STAT1 expression associated with OUD might play a role in transcriptional regulation in response to oxycodone. In summary, our results provide novel mechanistic insight into drug action at single-cell resolution.

Genome-wide association study for circulating FGF21 in patients with alcohol use disorder: Molecular links between the SNHG16 locus and catecholamine metabolism.

OBJECTIVE: Alcohol consumption can increase circulating levels of fibroblast growth factor 21 (FGF21). The effects of FGF21 in the central nervous system are associated with the regulation of catecholamines, neurotransmitters that play a crucial role in reward pathways. This study aims to identify genetic variants associated with FGF21 levels and evaluate their functional role in alcohol use disorder (AUD). METHODS: We performed a genome-wide association study (GWAS) using DNA samples from 442 AUD subjects recruited from the Mayo Clinic Center for the Individualized Treatment of Alcoholism Study. Plasma FGF21 levels were measured using Olink proximity extension immunoassays. Alcohol consumption at time of entry into the study was measured using the self-reported timeline followback method. Functional genomic studies were performed using HepG2 cells and induced pluripotent stem cell (iPSC)-derived brain organoids. RESULTS: Plasma FGF21 levels were positively correlated with recent alcohol consumption and gamma-glutamyl transferase levels, a commonly used marker for heavy alcohol use. One variant, rs9914222, located 5' of SNHG16 on chromosome 17 was associated with plasma FGF21 levels (p = 4.60E-09). This variant was also associated with AUD risk (ß: -3.23; p:0.0004). The rs9914222 SNP is an eQTL for SNHG16 in several brain regions, i.e., the variant genotype was associated with decreased expression of SNHG16. The variant genotype for the rs9914222 SNP was also associated with higher plasma FGF21 levels. Knockdown of SNHG16 in HepG2 cells resulted in increased FGF21 concentrations and decreased expression and enzyme activity for COMT, an enzyme that plays a key role in catecholamine metabolism. Finally, we demonstrated that ethanol significantly induced FGF21, dopamine, norepinephrine, and epinephrine concentrations in iPSC-derived brain organoids. CONCLUSIONS: GWAS for FGF21 revealed a SNHG16 genetic variant associated with FGF21 levels which are associated with recent alcohol consumption. Our data suggest that SNHG16 can regulate FGF21 concentrations and decrease COMT expression and enzyme activity which, in turn, have implications for the regulation of catecholamines. (The ClinicalTrials.gov Identifier: NCT00662571).

Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study.

BACKGROUND AND PURPOSE: Acamprosate is an anti-craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes. EXPERIMENTAL APPROACH: We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3-month follow-up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics. KEY RESULTS: Baseline plasma arginine, threonine, α-aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics-informed genome-wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell-derived forebrain astrocytes showed that a series of genes identified during the metabolomics-informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes. CONCLUSION AND IMPLICATIONS: These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients.

Medication-assisted treatment for opioid use disorder within a 12-step based treatment center: Feasibility and initial results.

RATIONALE: Opioid overdose deaths and healthcare costs associated with opioid use disorder (OUD) continue to escalate while the majority of addiction treatment providers in the United States do not use medication-assisted treatment (MAT) in spite of proven efficacy. The primary resistance to the use of MAT has been associated with the philosophical conflict many 12-step based treatment programs have with the use of these medications. OBJECTIVE: This study sought to determine whether patients self-selecting into a treatment program based upon the 12-step philosophy would elect to use MAT and, if so, what initial outcomes might result. METHODS: This naturalistic, prospective study of patients (N = 253) with OUD included a combination of OUD-specific group therapy and the use of buprenorphine-naloxone, oral naltrexone, injectable naltrexone, or no medication with standard 12-step treatment initiated in a residential or day treatment setting with outpatient follow-up. Baseline assessment of subjects with OUD included level of craving and opioid withdrawal symptom severity. Post-residential treatment outcomes at 1- and 6-months included craving, opioid withdrawal, residential treatment completion, continuing care compliance, medication compliance, substance use frequency and 12-step meeting attendance. RESULTS: Irrespective of medication condition, nearly all patients successfully completed residential treatment and the majority attended additional programming afterward. Among those who elected to take a medication (71%), differences were associated with medication compliance. Patients who reported compliance with their medication at 1 and 6 months following residential treatment had significantly higher abstinence rates than patients who reported noncompliance. Among those who relapsed post-discharge, neither medication use nor compliance was significantly related to a change in the frequency of alcohol use days or drug use days at 6 months. CONCLUSION: These preliminary results suggest that it is feasible to administer medications, including partial opioid agonists like buprenorphine, within the context of 12-step based treatment and taking these medications as prescribed is associated with favorable outcomes.

Sex-specific association of depressive disorder and transient emotional states with alcohol consumption in male and female alcoholics.

BACKGROUND: We assessed the impact of comorbid depression and anxiety disorders as well as positive and negative emotional states on alcohol consumption in alcohol dependent men and women. METHODS: Per day alcohol consumption during 90 days before enrolment was assessed by the Time Line Follow Back (TLFB) in 287 men and 156 women meeting DSM-IV-TR criteria for alcohol dependence. Propensity to drink in negative/positive emotional states was assessed using the Inventory of Drug Taking Situations (IDTS). Psychiatric comorbidities, including major depressive disorder (MDD), substance-induced depression (SID), anxiety disorders (AnxD), or substance-induced anxiety (SIA) were identified by Psychiatric Research Interview of Substance and Mood Disorders (PRISM). RESULTS: In the combined group, increased number of drinks per day and number of heavy drinking days correlated with increased IDTS scores (all p < 0.0001), while the lifetime history of MDD was associated with fewer drinking days (p = 0.045) but not average number of drinks per day. Male sex was associated with higher alcohol consumption per day (p < 0.0001), but not with the number of drinking days (p > 0.05). Lifetime MDD history was associated with less drinking days (p = 0.0084) and less heavy drinking days (p = 0.021) in alcohol dependent men, while current MDD was associated with higher alcohol use per day in alcohol dependent women (p = 0.044). CONCLUSIONS: Our findings suggest that emotional states and lifetime MDD history have sex-specific impact on alcohol use in alcohol dependent men and women. The mechanisms underlying these findings and their relevance to treatment outcomes need to be examined in future studies.

The three missing elements in the treatment of substance use disorders: Lessons from the physician health programs.

To make recovery, and not relapse, the expected outcome of the treatment of moderate to severe substance use disorders, 3 currently missing elements would need to be emphasized: (1) the definition of long-term recovery as the goal of all treatment and post-treatment interventions; (2) the provision of sustained post-treatment monitoring and professional and peer support, including drug testing; and (3) the insistence by others around the patients on sustained abstinence as crucial for those suffering from moderate to severe and prolonged substance use disorders. Each of these 3 elements is central to the distinctive care management system of the state physician health programs. This approach to the long-term management of substance use disorders fits with the new direction of healthcare for serious, chronic diseases-away from isolated, and expensive acute care episodes of care and toward sustained chronic disease management with long-term monitoring, support, and early re-intervention if and when needed.

A comprehensive response to the opioid epidemic: Hazelden's approach.

For years, treatment professionals have debated the virtues of medication maintenance versus psychosocial therapies for treating opioid addiction. In its response to the opioid crisis, Hazelden is attempting to bridge the difference by using a treatment protocol that involves both the conservative use of safe medications and psychosocial therapies while maintaining the ultimate goal of abstinence. This article discusses the recent and precipitous rise in opioid use, abuse, dependence and overdoses in the United States; the physician's role in creating and solving the problem; and Hazelden's unique approach to caring for people with opioid addiction.

The addicted physician. A rational response to an irrational disease.

Physicians are as likely to experience drug and alcohol addiction as anyone in the general population. They are more likely than others, however, to abuse prescription medications. Dealing with an impaired colleague is a difficult, emotionally charged job for physician leaders and hospital administrators, who've often had little training on how to handle such a situation. In addition to describing a case of an addicted physician, this article reviews data about the incidence of addiction among physicians and the challenges associated with confronting such a problem. It also describes the legal reporting requirements and resources such as the Minnesota Health Professionals Services Program and Physicians Serving Physicians that can help physicians get into treatment programs designed specifically for health care professionals. Physicians who go through such treatment programs and subsequent monitoring have been found to have remarkable recovery rates.

Chemical dependency and the physician.

Although the nature and scope of addictive disease are commonly reported in the lay press, the problem of physician addiction has largely escaped the public's attention. This is not due to physician immunity from the problem, because physicians have been shown to have addiction at a rate similar to or higher than that of the general population. Additionally, physicians' addictive disease (when compared with the general public) is typically advanced before identification and intervention. This delay in diagnosis relates to physicians' tendency to protect their workplace performance and image well beyond the time when their life outside of work has deteriorated and become chaotic. We provide an overview of the scope and risks of physician addiction, the challenges of recognition and intervention, the treatment of the addicted physician, the ethical and legal implications of an addicted physician returning to the workplace, and their monitored aftercare. It is critical that written policies for dealing with workplace addiction are in place at every employment venue and that they are followed to minimize risk of an adverse medical or legal outcome and to provide appropriate care to the addicted physician.

Patients with pain and addiction: what's a doctor to do?

Significant improvements in the evaluation and treatment of pain have led to more prescribing of and increased pressure to prescribe a variety of potentially addictive drugs to patients who are suffering from acute and chronic pain. Although these drugs serve an important purpose, they present risks to patients who are in recovery from addiction, are currently addicted, or have a family history of addiction. This article presents an overview of the concerns physicians face when treating such patients and outlines strategies for safely using these drugs.