Disruption of circadian rhythms promotes alcohol use: a systematic review.

This systematic review investigates the bidirectional relationship between alcohol consumption and disrupted circadian rhythms. The goal of this study was to identify (i) the types of circadian rhythm disruptors (i.e. social jet lag, extreme chronotypes, and night shift work) associated with altered alcohol use and (ii) whether sex differences in the consequences of circadian disruption exist. We conducted a search of PubMed, Embase, and PsycINFO exclusively on human research. We identified 177 articles that met the inclusion criteria. Our analyses revealed that social jet lag and the extreme chronotype referred to as eveningness were consistently associated with increased alcohol consumption. Relationships between night shift work and alcohol consumption were variable; half of articles reported no effect of night shift work on alcohol consumption. Both sexes were included as participants in the majority of the chronotype and social jet lag papers, with no sex difference apparent in alcohol consumption. The night shift research, however, contained fewer studies that included both sexes. Not all forms of circadian disruption are associated with comparable patterns of alcohol use. The most at-risk individuals for increased alcohol consumption are those with social jet lag or those of an eveningness chronotype. Direct testing of the associations in this review should be conducted to evaluate the relationships among circadian disruption, alcohol intake, and sex differences to provide insight into temporal risk factors associated with development of alcohol use disorder.

Mifepristone as a pharmacological intervention for stress-induced alcohol craving: A human laboratory study.

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.

Neuroendocrine Response to Exogenous Ghrelin Administration, Combined With Alcohol, in Heavy-Drinking Individuals: Findings From a Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study.

BACKGROUND: Accumulating evidence has established a role for the orexigenic hormone ghrelin in alcohol-seeking behaviors. Accordingly, the ghrelin system may represent a potential pharmacotherapeutic target for alcohol use disorder. Ghrelin modulates several neuroendocrine pathways, such as appetitive, metabolic, and stress-related hormones, which are particularly relevant in the context of alcohol use. The goal of the present study was to provide a comprehensive assessment of neuroendocrine response to exogenous ghrelin administration, combined with alcohol, in heavy-drinking individuals. METHODS: This was a randomized, crossover, double-blind, placebo-controlled human laboratory study, which included 2 experimental alcohol administration paradigms: i.v. alcohol self-administration and i.v. alcohol clamp. Each paradigm consisted of 2 counterbalanced sessions of i.v. ghrelin or placebo administration. Repeated blood samples were collected during each session, and peripheral concentrations of the following hormones were measured: leptin, glucagon-like peptide-1, pancreatic polypeptide, gastric inhibitory peptide, insulin, insulin-like growth factor-1, cortisol, prolactin, and aldosterone. RESULTS: Despite some statistical differences, findings were consistent across the 2 alcohol administration paradigms: i.v. ghrelin, compared to placebo, increased blood concentrations of glucagon-like peptide-1, pancreatic polypeptide, cortisol, and prolactin, both acutely and during the whole session. Lower levels of leptin and higher levels of aldosterone were also found during the ghrelin vs placebo session. CONCLUSION: These findings, gathered from a clinically relevant sample of heavy-drinking individuals with alcohol use disorder, provide a deeper insight into the complex interplay between ghrelin and appetitive, metabolic, and stress-related neuroendocrine pathways in the context of alcohol use.

A Combined Alcohol and Smoking Cue-Reactivity Paradigm in People Who Drink Heavily and Smoke Cigarettes: Preliminary Findings.

AIMS: Previous studies have shown that there may be an underlying mechanism that is common for co-use of alcohol and tobacco and it has been shown that treatment for alcohol use disorder can increase rates of smoking cessation. The primary aim of this study was to assess a novel methodological approach to test a simultaneous behavioral alcohol-smoking cue reactivity (CR) paradigm in people who drink alcohol and smoke cigarettes. METHODS: This was a human laboratory study that utilized a novel laboratory procedure with individuals who drink heavily (≥15 drinks/week for men; ≥8 drinks/week for women) and smoke (>5 cigarettes/day). Participants completed a CR in a bar laboratory and an eye-tracking (ET) session using their preferred alcohol beverage, cigarettes brand and water. RESULTS: In both the CR and ET session, there was a difference in time spent interacting with alcohol and cigarettes as compared to water (P's < 0.001), but no difference in time spent interacting between alcohol and cigarettes (P > 0.05). In the CR sessions, craving for cigarettes was significantly greater than craving for alcohol (P < 0.001), however, only time spent with alcohol, but not with cigarettes, was correlated with craving for both alcohol and cigarettes (P < 0.05). CONCLUSION: This study showed that it is feasible to use simultaneous cues during a CR procedure in a bar laboratory paradigm. The attention bias measured in the integrated alcohol-cigarettes ET procedure predicted participants' decision making in the CR. This novel methodological approach revealed that in people who drink heavily and smoke, alcohol cues may affect craving for both alcohol and cigarettes.

Andrographis paniculata and Its Main Bioactive Ingredient Andrographolide Decrease Alcohol Drinking and Seeking in Rats Through Activation of Nuclear PPARγ Pathway.

BACKGROUND AND AIMS: Andrographis paniculata is an annual herbaceous plant which belongs to the Acanthaceae family. Extracts from this plant have shown hepatoprotective, anti-inflammatory and antidiabetic properties, at least in part, through activation of the nuclear receptor Peroxisome Proliferator-Activated Receptor-gamma (PPAR γ). Recent evidence has demonstrated that activation of PPARγ reduces alcohol drinking and seeking in Marchigian Sardinian (msP) alcohol-preferring rats. METHODS: The present study evaluated whether A. paniculata reduces alcohol drinking and relapse in msP rats by activating PPARγ. RESULTS: Oral administration of an A. paniculata dried extract (0, 15, 150 mg/kg) lowered voluntary alcohol consumption in a dose-dependent manner and achieved ~65% reduction at the dose of 450 mg/kg. Water and food consumption were not affected by the treatment. Administration of Andrographolide (5 and 10 mg/kg), the main active component of A. paniculata, also reduced alcohol drinking. This effect was suppressed by the selective PPARγ antagonist GW9662. Subsequently, we showed that oral administration of A. paniculata (0, 150, 450 mg/kg) prevented yohimbine- but not cues-induced reinstatement of alcohol seeking. CONCLUSIONS: Results point to A. paniculata-mediated PPARγactivation as a possible therapeutic strategy to treat alcohol use disorder.

Brief Report: Relationship Between Cotinine Levels and Peripheral Endogenous Concentrations of Oxytocin, ß-Endorphin, and Orexin in Individuals With Both Alcohol and Nicotine Use Disorders.

BACKGROUND AND OBJECTIVES: In this secondary analysis of a pilot clinical trial with individuals with alcohol and nicotine use disorders, we investigate the relationship between serum concentrations of oxytocin, ß-endorphin, melatonin, α-melanocyte-stimulating hormone, substance P, and orexin, with objective biomarkers (salivary cotinine and serum γ-glutamyl transferase [GGT]) as well as with self-reported smoking and alcohol drinking. METHODS: Biomarkers for a total of N = 19 participants were analyzed using multiplexed, competitive format immune-assay (peptides) and enzyme competitive immunoassay (saliva). A regression analysis using Pearson's correlation coefficient was utilized to determine correlations. We controlled for multiple comparisons, checked for collinearities, and ran two-sided statistical tests. RESULTS: We found significant positive correlations for cotinine and oxytocin (P = .002), ß-endorphin (P = .008), and orexin (P < .001), but not for either GGT or self-reported smoking or alcohol drinking. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: These preliminary results suggest a relationship between cotinine and oxytocin, ß-endorphin, and orexin, which opens up new potential hypotheses on the potential role of these endocrine pathways in tobacco smokers. (Am J Addict 2021;30:88-91).

Alcohol-related changes in behaviors and characteristics from the baseline to the randomization session for treatment and non-treatment seeking participants with alcohol use disorder.

BACKGROUND: Participants who are enrolled in randomized controlled trials (RCTs) may be more motivated to change their behaviors after being enrolled in a study and that motivation may vary by treatment status. OBJECTIVES: The objectives of this secondary analysis were to investigate if changes in alcohol-related behaviors/characteristics from the baseline to the randomization session differed overall and to assess those differences between non-treatment and treatment seeking individuals with alcohol use disorder (AUD). METHODS: Our sample included participants from eight RCTs conducted at Brown University (N = 281, 34% female). To assess differences across alcohol-related behaviors/characteristics, we investigated changes in craving (obsessive compulsive drinking scale) and alcohol drinking (percent abstinent days, drinks per week (DPW) and percent heavy drinking days (HDD)) overall and between treatment status. RESULTS: Results showed that there were baseline differences, such as increased AUD severity and craving for alcohol in treatment seeking participants (p's < .05) in the overall sample. Next, we showed that craving, DPW and HDD decreased and percent abstinent days increased from baseline to randomization (p's < .05). When controlling for treatment status and sociodemographic characteristics, treatment seeking, compared to non-treatment seeking participants, had a greater reduction in alcohol craving (p < .001) and a greater increase in percentage of drinking days (p < .01). CONCLUSIONS: These findings demonstrated that alcohol-related behaviors and characteristics changed after enrollment. Severity, craving and drinking behaviors also differed between treatment-seeking status, which can potentially impact medication development stages for AUD such as clinical trial eligibility, enrollment and study outcomes.

Differences in Sociodemographic and Alcohol-Related Clinical Characteristics Between Treatment Seekers and Nontreatment Seekers and Their Role in Predicting Outcomes in the COMBINE Study for Alcohol Use Disorder.

BACKGROUND: One of the challenges in early-stage clinical research aimed at developing novel treatments for alcohol use disorder (AUD) is that the enrolled participants are heavy drinkers, but do not seek treatment for AUD. AIMS: To compare nontreatment seekers with alcohol dependence (AD) from 4 human laboratory studies conducted at Brown University (N = 240; 65.4% male) to treatment seekers with AD from the multisite COMBINE study (N = 1,383; 69.1% male) across sociodemographic and alcohol-related clinical variables and to evaluate whether the variables that significantly differentiate the 2 samples predict the 3 main COMBINE clinical outcomes: time to relapse, percent days abstinent (PDA), and good clinical outcome. METHODS: Sample characteristics were assessed by parametric and nonparametric testing. Three regression models measured the association between the differing variables and the 3 main COMBINE clinical outcomes. RESULTS: The nontreatment seekers, compared to the treatment seekers, were more ethnically diverse, less educated, single, and working part-time or unemployed (p's < 0.05); they met fewer DSM-IV AD criteria and had significantly lower scores on alcohol-related scales (p's < 0.05); they were less likely to have a father with alcohol problems (p < 0.0001) and had a significantly earlier age of onset and longer duration of AD (p's < 0.05); they also had significantly more total drinks, drinks per drinking day, heavy drinking days (HDD), and lower PDA in the 30 days prior to baseline (p's < 0.0001 to <0.05). Having more HDD in the 30 days prior to baseline predicted all of the 3 COMBINE clinical outcomes. All the other characteristics mentioned above that differed significantly between the 2 groups predicted at least 1 of the 3 COMBINE clinical outcomes, except for level of education, age of onset, and duration of AD. CONCLUSIONS: The observed differences between groups should be considered in efforts across participant recruitment at different stages of the development of new treatments for AUD.

Alcohol Tolerance in Human Laboratory Studies for Development of Medications to treat Alcohol Use Disorder.

AIMS: Human laboratory studies have contributed extensively in the research and development of novel medications to treat alcohol use disorder (AUD). Alcohol tolerance may represent one additional variable that can be utilized to expand the understanding of the AUD wide phenotypic profile and provide support to the medication development process. Tolerance is characterized as an individual's subjective response to alcohol and has been recognized as a predictor of AUD progression. Tolerance can be evaluated both by self-reported response (e.g. assessments) and objective measurements (e.g. motor impairment); as such, it represents an exploitable variable in the field of alcohol research. METHODS: This Narrative Review focuses on the use of alcohol tolerance, specifically within alcohol laboratory studies, for medication development. It seeks to identify a research gap and a research opportunity in clinical studies to evaluate biobehavioral responses captured in order to develop medications to treat AUD. RESULTS: Alcohol tolerance may provide additional information on the safety and tolerability of medications to treat AUD, in particular, when novel medications are co-administered with alcohol within the AUD population. CONCLUSIONS: As such, alcohol tolerance represents an additional outcome that may be included in randomized clinical trial (RCT) protocols designed for developing AUD pharmacotherapies.

Probenecid Reduces Alcohol Drinking in Rodents. Is Pannexin1 a Novel Therapeutic Target for Alcohol Use Disorder?

AIMS: The development of novel and more effective medications for alcohol use disorder (AUD) is an important unmet medical need. Drug repositioning or repurposing is an appealing strategy to bring new therapies to the clinic because it greatly reduces the overall costs of drug development and expedites the availability of treatments to those who need them. Probenecid, p-(di-n-propylsulfamyl)-benzoic acid, is a drug used clinically to treat hyperuricemia and gout due to its activity as an inhibitor of the kidneys' organic anion transporter that reclaims uric acid from urine. Probenecid also inhibits pannexin1 channels that are involved in purinergic neurotransmission and inflammation, which have been implicated in alcohol's effects and motivation for alcohol. Therefore, we tested the effects of probenecid on alcohol intake in rodents. METHODS: We tested the effects of probenecid on operant oral alcohol self-administration in alcohol-dependent rats during acute withdrawal as well as in nondependent rats and in the drinking-in-the-dark (DID) paradigm of binge-like drinking in mice. RESULTS: Probenecid reduced alcohol intake in both dependent and nondependent rats and in the DID paradigm in mice without affecting water or saccharin intake, indicating that probenecid's effect was selective for alcohol and not the result of a general reduction in reward. CONCLUSIONS: These results raise the possibility that pannexin1 is a novel therapeutic target for the treatment of AUD. The clinical use of probenecid has been found to be generally safe, suggesting that it can be a candidate for drug repositioning for the treatment of AUD.

Comparing and Combining Topiramate and Aripiprazole on Alcohol-Related Outcomes in a Human Laboratory Study.

AIMS: The goal of this study was to evaluate the efficacy of topiramate up to 200 mg/day and of aripiprazole up to 15 mg/day, alone and combined, in reducing alcohol-related outcomes in a human laboratory study. METHOD: This was a 5 week, between-subject, double-blind, placebo-controlled human laboratory study with topiramate [0 mg/day (placebo), 100 mg/day, 200 mg/day] and aripiprazole [0 mg/day (placebo), 7.5 mg/day, 15 mg/day] in 90 non-treatment seeking, heavy drinking, alcohol-dependent individuals. Main outcomes were the efficacy of 200 mg/day topiramate and 15 mg/day aripiprazole, alone and combined, in reducing drinks consumed during an alcohol self-administration procedure (human laboratory phase) and while receiving the study medications prior to the laboratory session (naturalistic drinking phase). Other outcomes in the laboratory phase included alcohol craving, and alcohol biphasic effects. RESULTS: In the human laboratory phase, topiramate 200 mg/day reduced alcohol craving [**P < 0.01] and amplified alcohol-induced stimulation [*P < 0.05], but did not reduce the number of drinks consumed. Topiramate 200 mg/day was also effective in reducing drinking days [*P < 0.05], and alcohol craving [*P < 0.05], in the naturalistic drinking phase. No significant findings were found for aripiprazole for any of the outcomes analyzed. CONCLUSION: Participants receiving 200 mg/day topiramate reported reduced alcohol drinking and craving, and increased alcohol-related stimulation. These findings provide further support for the role of topiramate as a pharmacological treatment for AUD. CLINICALTRIAL.GOV IDENTIFIER: NCT00884884. SHORT SUMMARY: This study tested topiramate and aripiprazole alone and in combination. The results replicate past findings and suggest that topiramate may be an effective treatment for alcohol use disorder. The present results suggest that the combination of topiramate and aripiprazole do not warrant further evaluation.

Serum Insulin Levels Are Reduced by Intravenous Ghrelin Administration but Do Not Correlate with Alcohol Craving in Alcohol-Dependent Individuals.

BACKGROUND: Increasing evidence supports a role for appetite-regulating pathways like ghrelin, insulin, and leptin in alcoholism. We previously reported that intravenous (i.v.) exogenous ghrelin increases alcohol craving. We also reported i.v. ghrelin reduces endogenous serum leptin, whose levels, in turn, negatively correlated with alcohol craving. Exogenous ghrelin administration decreases insulin secretion both in vitro and in vivo experiments. This study tested the hypothesis that i.v. ghrelin may also decrease endogenous serum insulin levels in alcoholic individuals. Additionally, we explored possible correlations between serum insulin and alcohol craving, since a correlation between insulin and alcohol craving was previously reported. METHODS: This was a double-blind, placebo-controlled human laboratory study ( n =43). Non-treatment-seeking, alcohol-dependent, heavy drinkers were randomized to receive i.v. ghrelin or placebo, followed by an alcohol cue-reactivity procedure. RESULTS: There was a main effect for i.v. ghrelin, compared to placebo in reducing serum insulin ( P <.05). There was also a time effect ( P <.001) but not ghrelin x time interaction ( P >.05). We did not find a correlation between the reduction of serum insulin and alcohol craving ( P >.05). The change in serum insulin was consistent with a parallel reduction in serum connective-peptide in the ghrelin group compared with placebo, although this difference did not reach statistical significance ( P =.076). No similar effects were found for other glucose-regulating hormones analyzed i.e. glucagon, glucagon-like peptide-1, and gastric inhibitory peptide ( P s>.05). CONCLUSIONS: These findings indicate i.v. ghrelin administration has an effect on reducing serum insulin in alcohol-dependent individuals; however, the reduction of insulin did not correlate with changes in alcohol cue-elicited craving. We speculate that, unlike for leptin, the interactions between ghrelin and insulin relationship are limited at the peripheral level. However, mechanistic studies are needed to investigate this hypothesis.

Role of the α1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial.

Evidence suggests that the norepinephrine system represents an important treatment target for alcohol dependence (AD) and the α1 -blocker prazosin may reduce alcohol drinking in rodents and alcoholic patients. The α1 -blocker doxazosin demonstrates a more favorable pharmacokinetic profile than prazosin, but has never been studied for AD. A double-blind placebo-controlled randomized clinical trial was conducted in AD individuals seeking outpatient treatment. Doxazosin or matched placebo was titrated to 16 mg/day (or maximum tolerable dose). Drinks per week (DPW) and heavy drinking days (HDD) per week were the primary outcomes. Family history density of alcoholism (FHDA), severity of AD and gender were a priori moderators. Forty-one AD individuals were randomized, 30 (doxazosin = 15) completed the treatment phase and 28 (doxazosin = 14) also completed the follow-up. There were no significant differences between groups on DPW and HDD per week. With FHDA as a moderator, there were significant FHDA × medication interactions for both DPW (pcorrected = 0.001, d = 1.18) and HDD (pcorrected = 0.00009, d = 1.30). Post hoc analyses revealed that doxazosin significantly reduced alcohol drinking in AD patients with high FHDA and by contrast increased drinking in those with low FHDA. Doxazosin may be effective selectively in AD patients with high FHDA. This study provides preliminary evidence for personalized medicine using α1 -blockade to treat AD. However, confirmatory studies are required.

Effects of idazoxan on alcohol pharmacokinetics and intoxication: a preliminary human laboratory study.

BACKGROUND: Preliminary basic and human studies suggest that the α2 -adrenergic antagonist idazoxan may represent a novel medication for alcohol dependence. The goal of this study was to evaluate the safety and tolerability of the co-administration of idazoxan with alcohol and explore whether pharmacokinetics (PK) and biobehavioral mechanisms of idazoxan may alter alcohol's effects. METHODS: This was a preliminary double-blind, single-dose, placebo-controlled, crossover, randomized human laboratory study. Ten social drinkers were dosed, in 2 different alcohol challenge studies (ACS), with a single oral dose of idazoxan (40 mg) or placebo, followed by a fixed alcohol dose 60 minutes later. Participants returned after a 1-week washout, and they were crossed over to the opposite medication condition. RESULTS: There were no significant differences in adverse events between idazoxan and placebo. Moreover, during the ACS paradigm, 40 mg idazoxan was well tolerated with no significant autonomic effects compared to placebo; idazoxan reduced the peak blood alcohol level (p < 0.01) and time to peak (p < 0.05) compared to placebo. A PK/pharmacodynamic model aligned the biobehavioral effects, demonstrating that the co-administration of 40 mg idazoxan with alcohol decreased alcohol-related stimulation (p < 0.05) and increased alcohol-related sedation (p < 0.05). CONCLUSIONS: This study supports the safety and tolerability of 40 mg idazoxan when co-administered with alcohol. Additionally, this study suggests that idazoxan may alter the biphasic effects of alcohol by decreasing stimulation and increasing sedation. These findings have implications for further investigation of using idazoxan as a probe to develop potential novel medications to treat alcoholic patients.

Relationship between the thyroid axis and 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.

Ondansetron reduces naturalistic drinking in nontreatment-seeking alcohol-dependent individuals with the LL 5'-HTTLPR genotype: a laboratory study.

BACKGROUND: One hypothesis suggests that the differential response to ondansetron- and serotonin-specific re-uptake inhibitors (SSRIs) may be due to a functional polymorphism of the 5'-HTTLPR promoter region in SLC6A4, the gene that codes for the serotonin transporter (5-HTT). The LL 5'-HTTLPR genotype is postulated to be specifically sensitive to the effects of ondansetron with SS/SL 5'-HTTLPR genotypes sensitive to SSRIs. This study tests this hypothesis by matching nontreatment-seeking alcohol-dependent (AD) individuals with LL genotype to ondansetron and SS/SL genotypes to the SSRI sertraline, and mismatching them assessing naturalistic and bar-laboratory alcohol drinking. METHODS: Seventy-seven AD individuals were randomized to 1 of 2 counterbalanced arms to receive sertraline 200 mg/d or ondansetron 0.5 mg/d for 3 weeks followed by an alcohol self-administration experiment (ASAE) and then received placebo for 3 weeks followed by a second ASAE. Individuals then received the alternate drug for 3 weeks followed by a third ASAE. Drinks per drinking day (DDD with drinks in standard drinking units) for 7 days prior to each ASAE and milliliters consumed during each ASAE were the primary outcomes. RESULTS: Fifty-five participants completed the study. The genotype × order interaction was significant, F(1, 47) = 8.42, p = 0.006, for DDD. Three analyses of covariance were conducted for DDD during the week before each ASAE. Ondansetron compared to sertraline resulted in a significant reduction in DDD during the week before the first, F(1, 47) = 7.64, p = 0.008, but not the third ASAE. There was no difference in milliliters consumed during each ASAE. CONCLUSIONS: This study modestly supports the hypothesis that ondansetron may reduce DDD in AD individuals with the LL genotype as measured naturalistically. By contrast, there was no support that ondansetron reduces drinking during the ASAEs or that sertraline reduces alcohol use in individuals who have SS/SL genotypes. We provide limited support that ondansetron may reduce drinking in nontreatment-seeking individuals with the LL genotype.

Evaluating the readability of online patient-facing resources for alcohol use disorder.

The goal of this study was to assess the readability of online resources pertaining to Alcohol Use Disorder (AUD) as perceived by patients seeking treatment. The National Institutes of Health (NIH) and American Medical Association (AMA) have recommended that medical resources should be written at a 6th-grade reading level. However, prior investigations in various medical fields have revealed that online materials often fail to adhere to these guidelines. An internet search was conducted to simulate the experience of patients seeking information on AUD treatment. The first 30 websites that did not require login credentials were examined using established readability tests. The main outcomes included: Flesch-Kincaid Reading Grade Level, Gunning Fog index, Simple Measure of Gobbledygook (SMOG) Readability Formula, and Coleman-Liau index. Thirty records were identified where the mean readability level was 12.37 (2.54). There were no significant differences in mean readability across readability indices or author type. None of the 30 records met the reading level recommendations as set by the NIH and AMA. In order to enhance accessibility and ultimately improve AUD health outcomes, it is recommended that patient-oriented resources be crafted with adherence to these guidelines. Consequently, future AUD resources ought to prioritize the enhancement of their readability.

In the new era of psychedelic assisted therapy: A systematic review of study methodology in randomized controlled trials.

Recent years have seen a resurgence in randomized, placebo controlled trials (RCTs) utilizing non-classical psychedelics (e.g. 3,4-methyl enedioxy methamphetamine [MDMA]), and classical psychedelics (e.g. psilocybin, lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT/ayahuasca]) in conjunction with assisted therapy (AT) for psychiatric disorders. A notable methodological challenge in psychedelic AT, however, is the complexity of blinding procedures. The lack of efficacious blinding can introduce considerable response bias, reduce internal validity, and compromise participant retention. This systematic review examines design and blinding techniques in RCTs utilizing psychedelics and placebo for the treatment of psychiatric disorders. The aim of this work is to identify factors that may inform future RTC design for conducting psychedelics research. We conducted a systematic review of PubMed, MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Psycinfo, Embase, and Web of Science Core Collection to examine: (1) placebo selection, (2) study design, and (3) integrity of blinding measures. Sixteen publications were identified as meeting the criteria for a systematic review. Our findings suggest that traditional placebo administration is insufficient to control for expectancy confounds. Consequently, experimental methodology that limits personnel unblinding and the use of an active placebo are important considerations when designing prospective clinical studies involving psychedelics.

Design and methodology of the first open-label trial of MDMA-assisted therapy for veterans with post-traumatic stress disorder and alcohol use disorder: Considerations for a randomized controlled trial.

Background: Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) commonly co-occur and are associated with more severe symptomatology than either disorder alone, increased risk of suicide, and poorer response to existing treatments. A promising therapeutic intervention is the integration of 3,4-methylenedioxymethamphetamine (MDMA) and psychotherapy. The Food and Drug Administration (FDA) designated MDMA- assisted therapy (MDMA-AT) as a Breakthrough Therapy for PTSD based on results from six Phase 2 clinical trials. Case data from the first study evaluating MDMA-AT study for AUD found the treatment was well tolerated and alcohol use was significantly reduced post treatment. Methods: This manuscript reports the premise, design, and methodology of the first open-label trial of MDMA-AT for military veterans (N = 12) with PTSD and AUD. Neuroimaging and biomarker data are included to evaluate brain changes, and neuroinflammation, pre-post treatment. Conclusions: The clinical component (comorbidity) and the regulatory processes (Schedule I drug) for setting up this clinical trial are long and complex. The research community will benefit from this work to establish common clinical trial outcomes, standardized protocols, and risk assessments for FDA approval. Clinicaltrialsgov: NCT05943665.