Pregnenolone for the Treatment of Alcohol Use Disorder

项目总结/摘要 酒精使用障碍（AUD）是一种慢性复发性疾病，复发率高，因此， 非常需要开发和评估新的治疗方法来减少复发和改善酒精使用 以澳元计算。我们以前进行了一个新的剂量发现人体实验室，安全性和试点疗效 一项研究，以评估是否神经活性类固醇（NAS）的前体双烯醇酮（PREG），影响 GABA能功能可能使酒精相关的应激障碍正常化，并改善酒精使用的结果， 澳元。初步数据显示，每天300毫克的PREG减少了压力和线索引起的酒精渴望，焦虑 使慢性酒精相关的应激生物学破坏正常化，并减少每天的饮酒量 在一个8- 10岁的受试者中，与安慰剂（PBO）相比， 周的临床研究。在这些发现的基础上，本项目提出了一个为期12周的双盲，随机 II期临床试验，以评估PREG治疗（300 mg/天）与PBO相比的安全性和有效性，150例 澳大利亚男人和女人将讨论以下具体目标：目标1：确定安全性和 在12周治疗期间，PREG（300 mg/天）与PBO相比在患有AUD的男性和女性中的耐受性 以及1个月随访时。目的#2：测试PREG与PBO对初级酒精使用的有效性 PSNHDD的结果和试验期间HDD%、DD%和AvgD的二次饮酒结果。目标3： 评估PREG与PBO对酒精渴望，焦虑， 抑郁症和患者相关功能。目的#4：评估PREG与PBO对 PREG和其他NAS水平，并检查它们与初级和二级酒精使用的关系以及相关的 结果。探索性目的1：评估PREG与PBO对原发性高血压的长期短期治疗效果 以及治疗后1个月随访时的其他次要结局。探索目标2：探索是否 治疗前患者特征（性别、创伤史、AUD严重程度和合并精神疾病） 影响PREG对主要和次要结局的影响。众所周知，长期饮酒 下调GABA，GABA在AUD的应激病理生理学中起重要作用，也在 控制饮酒。这项拟议中的研究是基于我们新颖的初步发现，并将测试我们的创新 提高内源性神经活性类固醇水平以增加其功能并从而改善 AUD结果。如果成功，拟议的研究将建立PREG和神经活性类固醇作为关键 治疗AUD的靶点，并提供关于神经活性类固醇水平的数据，以及它们是否可以 作为AUD治疗的生物标志物。

PROJECT SUMMARY/ABSTRACT Alcohol Use Disorder (AUD) is a chronic relapsing illness associated with high rates of relapse, and thus, there is great need to develop and evaluate novel treatments to decrease relapse and improve alcohol use outcomes in AUD. We previously conducted a novel dose finding human laboratory, safety and pilot efficacy study to assess whether the neuroactive steroid (NAS) precursor pregnenolone (PREG) that influences GABAergic functioning may normalize alcohol-related stress disruption and improve alcohol use outcomes in AUD. Pilot data showed that PREG at 300mg/day reduced stress- and cue- induced alcohol craving, anxiety and normalized chronic alcohol-related disruption in stress biology and also reduced alcohol drinks/day (AvgD), percent drinking days and heavy drinking days (%DD and %HDD) compared to placebo (PBO) in an 8- week clinical study. On the basis of these findings, this project proposes a 12-week double blind, randomized Phase II clinical trial to evaluate the safety and efficacy of PREG treatment (300 mg/day) versus PBO in 150 AUD men and women. The following specific aims will be addressed: Aim #1: To establish the safety and tolerability of PREG (300mg/day) vs. PBO in men and women with AUD over the 12-week treatment period and at the 1-month follow up. Aim #2: To test the efficacy of PREG vs. PBO on the primary alcohol use outcome of PSNHDD and secondary drinking outcomes of HDD%, DD% and AvgD during the trial. Aim #3: To assess the effects of PREG vs. PBO on other secondary stress-related outcomes of alcohol craving, anxiety, depression and patient-related functioning during the trial. Aim #4: To assess the effects of PREG vs. PBO on PREG and other NAS levels and examine their relationship to primary and secondary alcohol use and related outcomes. Exploratory Aim 1: To assess enduring short-term treatment effect of PREG vs. PBO on primary and other secondary outcomes at a 1-month post-treatment follow-up. Exploratory Aim 2: To explore whether pre-treatment patient characteristics (sex, trauma history, AUD severity and co-occurring psychiatric disorders) influence PREG effects on primary and secondary outcomes. It is well known that chronic alcohol use downregulates GABA which plays a significant role in the stress pathophysiology of AUD and also in loss of control drinking. The proposed study is based on our novel preliminary findings and will test our innovative approach of boosting endogenous neuroactive steroid levels to increase their function and thereby improve AUD outcomes. If successful, the proposed research will establish PREG and neuroactive steroids as key targets in the treatment of AUD, and also provide data on neuroactive steroid levels and whether they may serve as biomarkers in AUD treatment.