Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial

IntroductionAnimal and clinical studies suggest complementary effects of magnesium and high-dose pyridoxine (vitamin B6) on stress reduction. This is the first randomized trial evaluating the effects of combined magnesium and vitamin B6 supplementation on stress in a stressed population with low magnesemia using a validated measure of perceived stress.MethodsIn this Phase IV, investigator-blinded trial (EudraCT: 2015-003749-24), healthy adults with Depression Anxiety Stress Scales (DASS-42) stress subscale score >18 and serum magnesium concentration 0.45 mmol/L–0.85 mmol/L, were randomized 1:1 to magnesium–vitamin B6 combination (Magne B6 [Mg–vitamin B6]; daily dose 300 mg and 30 mg, respectively) or magnesium alone (Magnespasmyl [Mg]; daily dose 300 mg). Outcomes included change in DASS-42 stress subscale score from baseline to Week 8 (primary endpoint) and Week 4, and incidence of adverse events (AEs).ResultsIn the modified intention-to-treat analysis (N = 264 subjects), both treatment arms substantially reduced DASS-42 stress subscale score from baseline to Week 8 (Mg–vitamin B6, 44.9%; Mg 42.4%); no statistical difference between arms was observed (p>0.05). An interaction (p = 0.0097) between baseline stress level and treatment warranted subgroup analysis (as per statistical plan); adults with severe/extremely severe stress (DASS-42 stress subscale score ≥25; N = 162) had a 24% greater improvement with Mg–vitamin B6 versus Mg at Week 8 (3.16 points, 95% CI 0.50 to 5.82, p = 0.0203). Consistent results were observed in the per protocol analysis and at Week 4. Overall, 12.1% of Mg–vitamin B6 treated and 17.4% of Mg-treated subjects experienced AEs potentially treatment related.ConclusionsThese findings suggest oral Mg supplementation alleviated stress in healthy adults with low magnesemia and the addition of vitamin B6 to Mg was not superior to Mg supplementation alone. With regard to subjects with severe/extremely severe stress, this study provides clinical support for greater benefit of Mg combined with vitamin B6.引言 动物实验与临床研究均表明，镁与高剂量吡哆醇（pyridoxine，维生素B6）在缓解应激方面具有协同补充效应。本研究为首项采用经过验证的感知应激量表，针对低镁血症应激人群评估镁与维生素B6联合补充对缓解应激效果的随机对照试验。 方法 本研究为一项IV期、研究者单盲临床试验（EudraCT注册号：2015-003749-24），纳入抑郁焦虑应激量表（Depression Anxiety Stress Scales，DASS-42）应激分量表得分＞18、血清镁浓度介于0.45 mmol/L~0.85 mmol/L的健康成年人，按1:1比例随机分为镁-维生素B6联合组（Magne B6 [Mg-维生素B6]，每日剂量分别为300 mg与30 mg）与单用镁组（Magnespasmyl [Mg]，每日剂量300 mg）。研究结局指标包括：基线至第8周时DASS-42应激分量表得分的变化（主要终点）、第4周时的得分变化，以及不良事件（AE）发生率。 结果 在改良意向治疗分析（n=264例受试者）中，两组受试者基线至第8周时的DASS-42应激分量表得分均出现显著降低（Mg-维生素B6组降低44.9%，单用Mg组降低42.4%），两组间差异无统计学意义（p＞0.05）。基线应激水平与治疗方案间存在交互作用（p=0.0097），因此按照统计方案需进行亚组分析；在重度及极重度应激人群（DASS-42应激分量表得分≥25，n=162）中，第8周时Mg-维生素B6组的得分改善幅度较单用Mg组高24%（差值为3.16分，95%置信区间：0.50~5.82，p=0.0203）。符合方案集分析及第4周时的结果均与此一致。总体而言，Mg-维生素B6组与单用Mg组中分别有12.1%、17.4%的受试者出现了可能与治疗相关的不良事件。 结论 本研究结果表明，口服镁补充剂可缓解低镁血症健康成年人的应激症状，而在镁补充剂基础上加用维生素B6并不优于单用镁补充剂。但针对重度及极重度应激人群，本研究为镁与维生素B6联合使用可带来更优获益提供了临床证据。