A Randomized, Double-Blind, Placebo-Controlled Pilot Trial of the Acute Antisuicidal and Antidepressant Effects of Intranasal (R,S)-Ketamine in Severe Unipolar and Bipolar Depression With and Without Comorbid Alcohol Use Disorder.

Objective: Although individuals with a family history of alcohol use disorder (AUD) have a superior antidepressant response to ketamine, outcomes in patients with current AUD remain unclear. This study sought to investigate whether intranasal (IN) racemic (R,S)-ketamine had antisuicidal and antidepressant effects in unipolar and bipolar depression and whether comorbid AUD conferred superior antisuicidal outcomes for patients.Methods: This was a double-blind, randomized, placebo-controlled trial (May 2018 to January 2022) of single administration, fixed-dose (50 mg) IN (R,S)-ketamine (or saline comparator) in unmedicated inpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for a current major depressive episode (bipolar or unipolar), with current suicidal ideation (SI) and past attempt. Patients with and without comorbid AUD were enrolled. Change in Scale for Suicide Ideation score was the primary outcome measure, and change in Montgomery-Åsberg Depression Rating Scale score was the secondary outcome measure.Results: No significant group × time effect was noted for SI (F = 1.1, P = .36). A statistical trend toward superior improvement in suicidality was observed in participants with comorbid AUD. The group × time interaction was significant for improvements in depression (F = 3.06, P = .03) and largely unaffected by comorbid AUD or primary mood disorder type. Within the ketamine group, a significant correlation was observed between improvement in depressive symptoms and SI for patients without comorbid AUD (r =0.927, P = .023) that was absent in patients with AUD (r = 0.39, P = .44).Conclusion: IN ketamine induced rapid antidepressant effects compared to placebo but did not significantly alter SI scores. The treatment was well tolerated. Continued investigation with IN ketamine as a practical alternative to current formulations is warranted.Trial Registration: ClinicalTrials.gov identifier: NCT03539887.

Pharmacotherapy for alcohol use disorder among adults with medical disorders in Sweden.

BACKGROUND: Alcohol-attributable medical disorders are prevalent among individuals with alcohol use disorder (AUD). However, there is a lack of research on prescriptions of pharmacological treatment for AUD in those with comorbid conditions. This study aims to investigate the utilization of pharmacological treatment (acamprosate, disulfiram and naltrexone) in specialist care among patients with AUD and comorbid medical diagnoses. METHODS: This was a descriptive register-based Swedish national cohort study including 132,728 adults diagnosed with AUD (N = 270,933) between 2007 and 2015. The exposure was alcohol-attributable categories of comorbid medical diagnoses. Odds ratios (OR) were calculated using mixed-effect logistic regression analyses for any filled prescription of acamprosate, disulfiram or oral naltrexone within 12 months post AUD diagnosis. RESULTS: Individuals with comorbid alcohol-attributable medical diagnoses had lower odds of filling prescriptions for any type of AUD pharmacotherapy compared to those without such comorbidities. Cardiovascular (OR = 0.41 [95% CI: 0.39-0.43]), neurological (OR = 0.52 [95% CI: 0.48-0.56]) and gastrointestinal (OR = 0.57 [95% CI: 0.54-0.60]) diseases were associated with the lowest rates of prescription receipt. The presence of diagnoses which are contraindications to AUD pharmacotherapy did not fully explain the low prescription rate. CONCLUSION: There is a substantial underutilization of AUD pharmacotherapy in patients with AUD and comorbid medical disorders in specialist care. Increasing the provision of pharmacotherapy to this group of patients is essential and may prevent morbidity and mortality. There is a need to further understand barriers to medical treatment both from the patient and prescriber perspective.

Topiramate Versus Naltrexone for Alcohol Use Disorder: A Genotype-Stratified Double-Blind Randomized Controlled Trial.

OBJECTIVE: There have been no well-controlled and well-powered comparative trials of topiramate with other pharmacotherapies for alcohol use disorder (AUD), such as naltrexone. Moreover, the literature is mixed on the effects of two polymorphisms-rs2832407 (in GRIK1) and rs1799971 (in OPRM1)-on response to topiramate and naltrexone, respectively. The authors sought to examine the comparative effectiveness of topiramate and naltrexone in improving outcomes in AUD and to examine the role of the rs2832407 and rs1799971 polymorphisms, respectively, on response to these medications. METHODS: In a 12-week, double-blind, placebo-controlled, randomized, multisite, genotype-stratified (rs2832407 and rs1799971) clinical trial comparing topiramate and naltrexone in treating AUD, 147 patients with AUD were randomly assigned to treatment with topiramate or naltrexone, stratified by genotype (rs2832407*CC and *AC/AA genotypes and rs1799971*AA and *AG/GG genotypes). The predefined primary outcome was number of heavy drinking days per week. Predefined secondary outcomes included standard drinks per drinking day per week, body mass index (BMI), craving, markers of liver injury, mood, and adverse events. RESULTS: For the number of heavy drinking days per week, there was a near-significant time-by-treatment interaction. For the number of standard drinks per drinking day per week, there was a significant time-by-treatment interaction, which favored topiramate. There were significant time-by-treatment effects, with greater reductions observed with topiramate than naltrexone for BMI, craving, and gamma-glutamyltransferase level. Withdrawal due to side effects occurred in 8% and 5% of the topiramate and naltrexone groups, respectively. Neither polymorphism showed an effect on treatment response. CONCLUSIONS: Topiramate is at least as effective and safe as the first-line medication, naltrexone, in reducing heavy alcohol consumption, and superior in reducing some clinical outcomes. Neither rs2832407 nor rs1799971 had effects on topiramate and naltrexone treatments, respectively.

Positive allosteric modulators of the GABAB receptor: a new class of ligands with therapeutic potential for alcohol use disorder.

BACKGROUND: Positive allosteric modulators (PAMs) of the GABAB receptor constitute a new class of GABAB-receptor ligands. GABAB PAMs reproduce several pharmacological effects of the orthosteric GABAB receptor agonist, baclofen, although displaying a better safety profile. AIMS: This paper reviews the reducing or, frequently, even suppressing effects of all GABAB PAMs tested to date on multiple alcohol-related behaviours in laboratory rodents exposed to validated experimental models of human alcohol use disorder. RESULTS: Acute or repeated treatment with CGP7930, GS39783, BHF177, rac-BHFF, ADX71441, CMPPE, COR659, ASP8062, KK-92A, and ORM-27669 reduced excessive alcohol drinking, relapse- and binge-like drinking, operant alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced conditioned place preference in rats and mice. CONCLUSIONS: These effects closely mirrored those of baclofen; notably, they were associated to remarkably lower levels of tolerance and toxicity. The recent transition of ASP8062 to clinical testing will soon prove whether these highly consistent preclinical data translate to AUD patients.

The potential of 5-methoxy-N,N-dimethyltryptamine in the treatment of alcohol use disorder: A first look at therapeutic mechanisms of action.

Alcohol use disorder (AUD) remains one of the most prevalent psychiatric disorders worldwide with high economic costs. Current treatment options show modest efficacy and relapse rates are high. Furthermore, there are increases in the treatment gap and few new medications have been approved in the past 20 years. Recently, psychedelic-assisted therapy with psilocybin and lysergic acid diethylamide has garnered significant attention in the treatment of AUD. Yet, they require significant amounts of therapist input due to prolonged subjective effects (~4-12 h) leading to high costs and impeding implementation. Accordingly, there is an increasing interest in the rapid and short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). This paper offers a first look at potential therapeutic mechanisms for AUD by reviewing the current literature on 5-MeO-DMT. Primarily, 5-MeO-DMT is able to induce mystical experiences and ego-dissolution together with increases in psychological flexibility and mindfulness. This could decrease AUD symptoms through the alleviation of psychiatric mood-related comorbidities consistent with the negative reinforcement and self-medication paradigms. In addition, preliminary evidence indicates that 5-MeO-DMT modulates neural oscillations that might subserve ego-dissolution (increases in gamma), psychological flexibility and mindfulness (increases in theta), and the reorganization of executive control networks (increases in coherence across frequencies) that could improve emotion regulation and inhibition. Finally, animal studies show that 5-MeO-DMT is characterized by neuroplasticity, anti-inflammation, 5-HT2A receptor agonism, and downregulation of metabotropic glutamate receptor 5 with clinical implications for AUD and psychiatric mood-related comorbidities. The paper concludes with several recommendations for future research to establish the purported therapeutic mechanisms of action.

Effects of novel GLT-1 modulator, MC-100093, on neuroinflammatory and neurotrophic biomarkers in mesocorticolimbic brain regions of male alcohol preferring rats exposed chronically to ethanol.

Chronic ethanol consumption can lead to increased extracellular glutamate concentrations in key reward brain regions, such as medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), and consequently leading to oxidative stress and neuroinflammation. Previous studies from our lab tested ß-lactam antibiotics and novel beta-lactam non-antibiotic, MC-100093, and showed these ß-lactam upregulated the major astrocytic glutamate transporter, GLT-1, and consequently reduced ethanol intake and normalized glutamate homeostasis. This present study tested the effects of novel synthetic ß-lactam non-antibiotic drug, MC-100093, in chronic ethanol intake and neuroinflammatory and trophic factors in subregions of the NAc (NAc core and shell) and mPFC (Prelimbic, PL; and Infralimbic, IL) of male P rats. MC-100093 treatment reduced ethanol intake after 5-week drinking regimen. Importantly, MC-100093 attenuated ethanol-induced downregulation of brain derived neurotrophic factor (BDNF) expression in these brain regions. In addition, MC-100093 attenuated ethanol-induced upregulation of pro-inflammatory cytokines such as TNF-a and HMGB1 in all these brain regions. Furthermore, MC-100093 treatment attenuated ethanol-induced increase in RAGE in these brain regions. MC-100093 prevented neuroinflammation caused by ethanol intake as well as increased neurotrophic factor in mesocorticolimbic brain regions. MC-100093 treatment reduced ethanol intake and this behavioral effect was associated with attenuation of reduced trophic factors and increased pro-inflammatory factors. MC-100093 is considered a small molecule that may have potential therapeutic effects for the treatment of the effects of chronic exposure to ethanol.

[Disulfiram encephalopathy: an underrecognized complication of accidental overdose]. / Disulfiramencefalopathie: een mogelijke complicatie bij accidentele overdosering.

In this paper we discuss the case of a 52-year-old man who consulted the emergency department because of confusion. Based on anamnesis, clinical presentation, various technical investigations and recovery after discontinuation of disulfiram, the diagnosis of disulfiram encephalopathy is made. This is a less common but serious complication of a frequently used therapy and underscores the importance of early recognition and careful but also controlled prescription of disulfiram. We describe the pathophysiology behind this complication and reflect on some important numbers.

Reductions in World Health Organization risk drinking level are associated with improvements in sleep problems among individuals with alcohol use disorder.

AIMS: Among individuals with alcohol use disorder (AUD), sleep disturbances are pervasive and contribute to the etiology and maintenance of AUD. However, despite increased attention toward the relationship between alcohol use and sleep, limited empirical research has systematically examined whether reductions in drinking during treatment for AUD are associated with improvements in sleep problems. METHODS: We used data from a multisite, randomized, controlled trial that compared 6 months of treatment with gabapentin enacarbil extended-release with placebo for adults with moderate-to-severe AUD (N = 346). The Timeline Follow-back was used to assess WHO risk drinking level reductions and the Pittsburgh Sleep Quality Index was used to assess sleep quality over the prior month at baseline and the end of treatment. RESULTS: Sleep problem scores in the active medication and placebo groups improved equally. Fewer sleep problems were noted among individuals who achieved at least a 1-level reduction (B = -0.99, 95% confidence interval (CI) [-1.77, -0.20], P = .014) or at least a 2-level reduction (B = -0.80, 95% CI [-1.47, -0.14], P = .018) in WHO risk drinking levels at the end of treatment. Reductions in drinking, with abstainers excluded from the analysis, also predicted fewer sleep problems at the end of treatment (1-level: B = -1.01, 95% CI [-1.83, -0.20], P = .015; 2-level: B = -0.90, 95% CI [-1.59, -0.22], P = .010). CONCLUSIONS: Drinking reductions, including those short of abstinence, are associated with improvements in sleep problems during treatment for AUD. Additional assessment of the causal relationships between harm-reduction approaches to AUD and improvements in sleep is warranted.

LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence.

Alcohol use disorder (AUD) remains a major public health concern. The dynorphin (DYN)/κ-opioid receptor (KOP) system is involved in actions of alcohol, particularly its withdrawal-associated negative affective states. This study tested the ability of LY2444296, a selective, short-acting, KOP antagonist, to decrease alcohol self-administration in dependent male and female Wistar rats at 8 h abstinence. Animals were trained to orally self-administer 10% alcohol (30 min/day for 21 sessions) and were made dependent via chronic intermittent alcohol vapor exposure for 6 weeks or exposed to air (nondependent). After 6 weeks, the effect of LY2444296 (0, 3, and 10 mg/kg, p.o.) was tested on alcohol self-administration at 8 h of abstinence. A separate cohort of rats was prepared in parallel, and their somatic withdrawal signs and alcohol self-administration were measured after LY2444296 administration at 8 h, 2 weeks, and 4 weeks abstinence. LY2444296 at 3 and 10 mg/kg significantly reduced physical signs of withdrawal in dependent rats at 8 h abstinence, only. Furthermore, 3 and 10 mg/kg selectively decreased alcohol self-administration in dependent rats at only 8 h abstinence. These results highlight the DYN/KOP system in actions of alcohol during acute abstinence, suggesting KOP antagonism could be beneficial for mitigating acute withdrawal signs and, in turn, significantly reduce excessive alcohol consumption associated with AUD.

Amylin in Alcohol Addiction: A Potential New Treatment Target or an Adjuvant to Other Treatments?

Amylin is a neuroendocrine hormone with a potential role in addictive disorders, including alcohol use disorder (AUD). In addition to reducing appetitive behavior, amylin has been shown to affect alcohol-related behaviors in rodents. Delineating the biobehavioral correlates of amylin in relation to alcohol seeking and consumption has the potential of identifying new treatment targets for AUD, yet additional translational and human research is needed.

Outcomes After Initiation of Medications for Alcohol Use Disorder at Hospital Discharge.

Importance: US Food and Drug Administration-approved medications for alcohol use disorder (MAUD) are significantly underused. Hospitalizations may provide an unmet opportunity to initiate MAUD, but few studies have examined clinical outcomes of patients who initiate these medications at hospital discharge. Objective: To investigate the association between discharge MAUD initiation and 30-day posthospitalization outcomes. Design, Setting, and Participants: This cohort study was conducted among patients with Medicare Part D who had alcohol-related hospitalizations in 2016. Data were analyzed from October 2022 to December 2023. Exposures: Discharge MAUD initiation was defined as oral naltrexone, acamprosate, or disulfiram pharmacy fills within 2 days of discharge. Main outcomes: The primary outcome was a composite of all-cause mortality or return to hospital (emergency department visits and hospital readmissions) within 30 days of discharge. Secondary outcomes included these components separately, return to hospital for alcohol-related diagnoses, and primary care or mental health follow-up within 30 days of discharge. Propensity score 3:1 matching and modified Poisson regressions were used to compare outcomes between patients who received and did not receive discharge MAUD. Results: There were 6794 unique individuals representing 9834 alcohol-related hospitalizations (median [IQR] age, 54 [46-62] years; 3205 hospitalizations among females [32.6%]; 1754 hospitalizations among Black [17.8%], 712 hospitalizations among Hispanic [7.2%], and 7060 hospitalizations among White [71.8%] patients). Of these, 192 hospitalizations (2.0%) involved discharge MAUD initiation. After propensity matching, discharge MAUD initiation was associated with a 42% decreased incidence of the primary outcome (incident rate ratio, 0.58 [95% CI, 0.45 to 0.76]; absolute risk difference, -0.18 [95% CI, -0.26 to -0.11]). These findings were consistent among secondary outcomes (eg, incident rate ratio for all-cause return to hospital, 0.56 [95% CI, 0.43 to 0.73]) except for mortality, which was rare in both groups (incident rate ratio, 3.00 [95% CI, 0.42 to 21.22]). Discharge MAUD initiation was associated with a 51% decreased incidence of alcohol-related return to hospital (incident rate ratio, 0.49 [95% CI, 0.34 to 0.71]; absolute risk difference, -0.15 [95% CI, -0.22 to -0.09]). Conclusion and relevance: In this cohort study, discharge initiation of MAUD after alcohol-related hospitalization was associated with a large absolute reduction in return to hospital within 30 days. These findings support efforts to increase uptake of MAUD initiation at hospital discharge.

Repurposing drugs for treatment of alcohol use disorder.

Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in reducing alcohol use or preventing relapse. This approach can offer a more cost-effective and time-efficient alternative to developing new drugs from scratch. Currently approved medications for alcohol use disorder (AUD) include acamprosate, disulfiram, naltrexone, nalmefene, baclofen, and sodium oxybate. Acamprosate was developed specifically for AUD, while disulfiram's alcohol-deterrent effects were discovered incidentally. Naltrexone and nalmefene were originally approved for opioids but found secondary applications in AUD. Baclofen and sodium oxybate were repurposed from neurological conditions. Other drugs show promise. Topiramate and zonisamide, anticonvulsants, demonstrate efficacy in reducing alcohol consumption. Another anticonvulsant, gabapentin has been disappointing overall, except in cases involving alcohol withdrawal symptoms. Varenicline, a nicotinic receptor agonist, benefits individuals with less severe AUD or concurrent nicotine use. Ondansetron, a 5-HT3 antagonist, has potential for early-onset AUD, especially when combined with naltrexone. Antipsychotic drugs like aripiprazole and quetiapine have limited efficacy. Further investigation is needed for potential repurposing of α1 adrenergic receptor antagonists prazosin and doxazosin, glucocorticoid receptor antagonist mifepristone, the phosphodiesterase inhibitor Ibudilast, the cysteine prodrug N-acetylcysteine, and the OX1R and OX2R blocker Suvorexant. This review supports repurposing drugs as an effective strategy for expanding treatment options for AUD.

Substitution therapy for patients with alcohol dependence: Mechanisms of action and efficacy.

New approaches for the treatment of alcohol dependence (AD) may improve patient outcomes. Substitution maintenance therapy is one of the most effective treatment options for opioid and nicotine use disorders. So far, there has been little attention to substitution therapy for the treatment of AD. Here, we explain the mechanistic foundations of alcohol substitution maintenance therapy. Alcohol has many primary targets in the brain (and other organs) and the physical interaction of ethanol molecules with these specific ethanol-sensitive sites on a variety of ionotropic receptors (e.g. GABA-A, NMDA, and nicotinic acetylcholine (nACh) receptors) and ion channels provides the rationale for substitution. As such, a variety of compounds can interact with those ethanol-sensitive sites and can thus substitute for some of the effects of alcohol. For some of these compounds, alcohol discrimination studies have shown their substitution potential. Accordingly, potential substitution treatments include agonists acting at GABA receptors such as sodium oxybate, baclofen and benzodiazepines, NMDA receptor antagonists such as ketamine and memantine, or nAChRs agonists such as varenicline. All these compounds are already approved for other indications and we present clinical evidence for these drugs in the treatment of alcohol withdrawal syndrome (AWS) and in the long-term treatment of AD, and outline future steps for their acceptance as substitution treatment in AD. Finally, we discuss the substitution approach of managed alcohol programs for the most severely affected homeless populations. Results showed that sodium oxybate is probably the closest to a substitution therapy for AD and is already approved for the treatment of AWS and in the long-term treatment of AD in some countries. In conclusion, we argue that better AD treatment can be provided if substitution maintenance treatments for alcohol are implemented at a similar scale as for opioid and nicotine use disorder.

Epigenetic drugs and psychedelics as emerging therapies for alcohol use disorder: insights from preclinical studies.

Alcohol use disorder (AUD) is a public health issue that affects millions of people worldwide leading to physical, mental and socio-economic consequences. While current treatments for AUD have provided relief to individuals, their effectiveness on the long term is often limited, leaving a number of affected individuals without sustainable solutions. In this review, we aim to explore two emerging approaches for AUD: psychedelics and epigenetic drugs (i.e., epidrugs). By examining preclinical studies, different animal species and procedures, we delve into the potential benefits of each of these treatments in terms of addictive behaviors (alcohol drinking and seeking, motivation to drink alcohol and prevention of relapse). Because psychedelics and epidrugs may share common and complementary mechanisms of action, there is an exciting opportunity for exploring synergies between these approaches and their parallel effectiveness in treating AUD and the diverse associated psychiatric conditions.

Patterns of publicly funded naltrexone use among patients diagnosed with alcohol use disorder in Ontario.

AIMS: Naltrexone is recommended first-line to manage alcohol use disorder (AUD). With previous studies indicating poor retention on naltrexone, we determined duration of naltrexone use and assessed the association between prescription setting and time to discontinuation in Ontario. METHODS: We conducted a retrospective population-based cohort study among Ontario public drug beneficiaries diagnosed with AUD who initiated publicly funded naltrexone from June 2018 to September 2019. The primary outcome was time to naltrexone discontinuation, with a secondary analysis assessing receipt of at least one prescription refill. We used Cox proportional hazards models and logistic regression to test the association between prescription setting and each medication persistence outcome. RESULTS: Among 2531 new naltrexone patients with AUD, the median duration of naltrexone use was 31 days and 394 (15.6%) continued naltrexone for 6 months or longer. There was no association between setting of initiation and duration of naltrexone use; however, those initiating naltrexone following an acute inpatient hospital stay were more likely to fill a second prescription (aOR 1.43, 95% CI 0.96-2.14), while those initiating after an ED visit were less likely to be dispensed a second prescription (aOR = 0.69, 95% CI 0.52-0.90) compared to those starting in a physician's office. CONCLUSION: Persistence on naltrexone to treat an AUD is low, regardless of the setting of initiation. Further research is needed to elucidate the barriers encountered by patients with AUD that lead to poor treatment persistence in order to develop interventions that facilitate patient-centered access to evidence-based treatment for AUD in the province.