Gao Huaze, Sinha Rajita, Wemm Stephanie, Milivojevic Verica
Department of Psychiatry, The Yale Stress Center, Yale University School of Medicine, New Haven, Connecticut, USA.
Alcohol Clin Exp Res (Hoboken). 2025 Mar;49(3):619-628. doi: 10.1111/acer.15529. Epub 2025 Jan 8.
Chronic alcohol consumption in alcohol use disorder (AUD) is associated with autonomic nervous system dysregulation, increasing cardiovascular risk, and high alcohol cravings. Heart rate variability (HRV), a marker of autonomic nervous system responsiveness to stressors, may mediate alcohol's impact on the cardiovascular system. While pregnenolone (PREG) has been shown to normalize heart rate and blood pressure in individuals with AUD, its effects on sympathetic and parasympathetic components of HRV and related alcohol craving are not known.
Fifty-five treatment-seeking individuals with AUD were randomized to placebo (n = 21) or daily pregnenolone at 300 mg (n = 18) or 500 mg (n = 16), in a double-blind, 8-week pilot clinical trial. In week 2, participants underwent three randomized, counterbalanced 5-minute personalized guided imagery provocations (stress, alcohol, and neutral/relaxing cues) on separate days. HRV indices were assessed during each session and analyzed using linear mixed-effects models (LMEs), including association between HRV indices and anxiety and alcohol craving.
A medication group × condition interaction was found for parasympathetic, high-frequency (HF) (p = 0.028) and sympathetic/parasympathetic, low-frequency/high-frequency (LF/HF) ratio (p = 0.017) indices of HRV. Placebo had higher HF during alcohol cue (p = 0.011), while 500 mg PREG demonstrated lower HF in response to stress (p = 0.050) and alcohol cues (p = 0.047). Placebo showed lower LF/HF ratio during stress (p = 0.006) and alcohol cue (p = 0.001), while the PREG groups showed no changes. Overall, the LF/HF response to alcohol cue was significantly lower in placebo compared to the 300 mg PREG (p = 0.012) and 500 mg PREG (p = 0.037) groups. Lastly, HF was found to predict alcohol craving regardless of PREG doses.
We found a normalization of autonomic response in PREG groups. These findings suggest that PREG holds therapeutic potential for enhancing autonomic function in AUD.
酒精使用障碍（AUD）患者长期饮酒与自主神经系统失调、心血管风险增加以及强烈的酒精渴望有关。心率变异性（HRV）是自主神经系统对应激源反应性的一个指标，可能介导酒精对心血管系统的影响。虽然孕烯醇酮（PREG）已被证明可使AUD患者的心率和血压恢复正常，但其对HRV交感和副交感成分以及相关酒精渴望的影响尚不清楚。
在一项为期8周的双盲试点临床试验中，55名寻求治疗的AUD患者被随机分为安慰剂组（n = 21）或每日服用300mg孕烯醇酮组（n = 18）或500mg孕烯醇酮组（n = 16）。在第2周，参与者在不同日期接受三次随机、平衡的5分钟个性化引导想象刺激（压力、酒精和中性/放松提示）。在每次刺激期间评估HRV指标，并使用线性混合效应模型（LME）进行分析，包括HRV指标与焦虑和酒精渴望之间的关联。
在HRV的副交感高频（HF）（p = 0.028）和交感/副交感低频/高频（LF/HF）比值（p = 0.017）指标上发现了药物组×条件交互作用。安慰剂在酒精提示期间HF较高（p = 0.011），而500mg孕烯醇酮在应激（p = 0.050）和酒精提示（p = 0.047）时HF较低。安慰剂在应激（p = 0.006）和酒精提示（p = 0.001）期间LF/HF比值较低，而孕烯醇酮组无变化。总体而言，与每日300mg孕烯醇酮组（p = 0.012）和500mg孕烯醇酮组（p = 0.037）相比，安慰剂组对酒精提示的LF/HF反应显著更低。最后，发现无论孕烯醇酮剂量如何，HF都可预测酒精渴望。
我们发现孕烯醇酮组的自主反应恢复正常。这些发现表明，孕烯醇酮在增强AUD患者自主功能方面具有治疗潜力。
