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食品补充剂与医学用途食品在大脑功能中的作用：基于机制锚定的证据图谱

发布日期: 12 June 2026·Olympia R&D Bulletin·Permalink: olympiabiosciences.com/rd-hub/brain-function-supplements-evidence-map/·113 引用来源·≈ 92 分钟阅读
Therapeutic Rd Matrix 10 Vibrant Glowing Pharmace 2 Fcd50D7Ba5 scientific R&D visualization

行业挑战

由于在评估不同大脑功能领域的成分功效和支持性人体数据质量时缺乏清晰、基于机制锚定的框架，配方设计师在开发基于证据的脑部健康补充剂时面临重大挑战。

Research context

This article summarizes third-party research. It does not establish a product-specific result or commercial capability.

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通俗解读

由于缺乏关于这些补充剂如何影响大脑的明确信息以及坚实的科学证据，通常很难辨别哪些脑部健康补充剂真正有效。为了解决这一问题，一项新的综述创建了一个指南，根据成分在思维能力或应激反应等四个关键大脑区域中的具体作用对它们进行了分类。他们发现某些成分（如用于改善记忆的银杏和用于缓解压力的L-茶氨酸）具有强有力的证据支持。然而，许多热门补充剂目前缺乏坚实的研究来支持其声称的功效。该指南有助于消费者和医生对脑部健康产品做出更明智的决策。

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摘要

背景：

针对脑功能的膳食补充剂和特医食品市场正在迅速扩张，然而消费者和临床医生缺乏一个清晰的框架来根据特定的生物学机制和支持证据的质量评估成分。综述通常按商业类别而不是按其分子或系统水平靶点来对成分进行分组。

目的：

本叙述性综述旨在为声称支持脑功能的常见膳食补充剂和特医食品创建一个机制锚定的证据图谱。我们根据四个域的生物学框架组织成分：(1) 认知表现与神经可塑性，(2) 应激抵抗力、抗焦虑与睡眠结构，(3) 细胞能量与线粒体功能，以及 (4) 收敛节点（跨域主调节因子）。

方法：

针对这四个域中的每一个，在多个学术数据库和网络资源中进行了广泛的文献检索。对来源进行筛选，以评估其与脑功能的相关性、人类证据（或强有力的机制数据）的存在性以及对特定命名成分的测试。随后，对筛选出的成分列表进行有针对性的富集检索，以寻找高质量证据（荟萃分析、系统综述和随机对照试验）。对每种成分的机制、临床结果、证据水平和安全性进行了分析。

结果：

绘制了四个域中众多成分的证据图谱。域 1（认知）得到诸如银杏叶提取物 (EGb 761) 和假马齿苋等成分的支持，这些成分对特定的认知终点具有强有力的荟萃分析证据[1, 2]。域 2（应激/睡眠）具有诸如 L-茶氨酸、藏红花、薰衣草油 (Silexan) 和维生素 D 等成分，所有这些成分都具有针对焦虑或睡眠结果的强有力证据[3–6]。域 3（能量）以用于记忆的一水肌酸和用于认知表现的外源性酮为最佳代表[7, 8]。域 4（收敛）包括叶酸/L-甲基叶酸，它作为抑郁症的辅助疗法具有强有力的证据[9, 10]。人们发现许多流行成分对于特定的脑相关终点证据有限或“迄今尚无证据（NO PROOFS TO DATE）”。

结论：

机制锚定的方法为评估使用膳食补充剂和特医食品改善脑功能的科学基础提供了一种结构化方法。虽然几种成分对于特定的靶向结果具有稳健的证据，但许多其他成分缺乏严格的人类数据。该图谱突出了最具前景的干预措施以及研究中的关键空白，从而指导更具鉴别力的使用和未来的研究。

关键词：

促智药, 营养保健品, 认知增强, 膳食补充剂, 特医食品, 大脑健康, 基于证据, 作用机制

引言

为大脑健康而销售的膳食补充剂、营养保健品和特医食品的激增，给消费者、临床医生和研究人员带来了重大挑战。与受监管的药物不同，这些产品通常根据广泛的、定义不清的类别（如“记忆支持”或“缓解压力”）进行评估，很少提及特定且合理的生物学作用机制。缺乏这种结构化的、机制锚定的框架，使得评估证据质量、比较不同的成分以及做出明智的决定变得十分困难。需要更严格的方法来超越类别级别的综述，并根据大脑中特定分子和系统水平的靶点来评估每种成分。

本综述根据旨在将分子靶点与可观察到的脑功能结果相连接的四域机械图谱组织证据。这些域包括：(1) 认知表现与神经可塑性，靶向神经递质合成、神经营养因子、脑血管支持和膜完整性；(2) 应激抵抗力、抗焦虑与睡眠结构，重点关注 HPA 轴、GABA 能/血清素能系统和昼夜节律机制；(3) 细胞能量、线粒体功能与体力耐力，涵盖电子传递链、NAD+ 代谢以及对大脑高代谢需求至关重要的抗氧化防御系统；以及 (4) 收敛节点，它们是跨域的主调节因子，例如 BDNF、NF-kB、AMPK、mTOR、Nrf2、甲基化循环和肠脑轴，它们整合来自多条通路的信号。

对于所调查的每一种成分，本手稿明确记录了两条关键信息：(i) 它合理参与机制图谱上的哪些靶点，以及 (ii) 可用于其功效和安全性的最高质量人类证据。这包括在缺乏严格的人类临床试验证据时，明确标注“迄今尚无证据”的成分，从而对当前科学状态提供透明的评估。

方法

本叙述性综述采用结构化的多阶段过程来识别、评估和综合与脑功能相关的膳食补充剂和特医食品的证据。

最初的检索策略旨在实现广泛的召回，利用多个学术数据库查询（例如 PubMed、Google Scholar）以及针对四个机制域中每一个域的有针对性的网络检索。查询将成分术语（例如“促智药”、“适应原”、“精神益生菌”）、机制（例如“BDNF”、“HPA 轴”、“线粒体”）和研究类型（例如“随机对照试验”、“荟萃分析”）结合起来。

然后根据三个主要标准对来源进行筛选。来源必须是：(1) 与脑功能相关，涉及测试的用于与认知、心理、睡眠、应激或神经功能相关的结果的可摄入化合物，或支持这些功能的机制；(2) 提供人类证据或强有力的机制数据，例如随机对照试验 (RCT)、荟萃分析、系统综述，或明确将成分与分子靶点相联系的临床前研究；以及 (3) 命名特定的、可识别的成分或标准化提取物。

在此广泛的发现阶段之后，生成了规范成分的精选列表。然后对该列表中的每种成分进行每种成分的富集检索，专门针对最高水平的证据，例如 RCT 的荟萃分析和系统综述。

每种成分的证据都根据评分标准进行了综合和评分：强（多个荟萃分析和/或大量确证性 RCT）、中等（多个具有一致效应方向的 RCT）、有限（单个 RCT 或少量不一致的研究）、仅限机制/临床前（缺乏人类功效数据）以及迄今尚无证据（NO PROOFS TO DATE）（在检索中未找到严格的人类证据）。

最终数据，包括机制、证据水平、临床结果和安全性注意事项，汇编在作为本文本附录 A 提供的主证据表中。

结果

域 1 — 认知表现与神经可塑性

选择域 1 成分是使用机制图谱进行的，因为人类中大多数可测量的、近期的“脑功能”终点（注意力、记忆力、执行功能、痴呆量表和功能状态）很可能受到一组有限的收敛性生物学杠杆的影响：(1) 神经递质前体供应和信号传导（尤其是胆碱能和儿茶酚胺能张力），(2) 神经元膜和突触底物可用性，以及 (3) 神经营养和血管支持，其可以调节可塑性和脑灌注。胆碱能杠杆由被描述为乙酰胆碱 (ACh) 生物合成和/或神经元膜磷脂（如磷脂酰胆碱和 CDP-胆碱（胞磷胆碱））前体的化合物代表[11–13]。儿茶酚胺杠杆由 L-酪氨酸代表，它被明确描述为多巴胺和去甲肾上腺素的前体，并被提出用于在要求苛刻的条件下缓冲认知[14]。神经营养信号传导是该域中的第二个主要基本原理，因为一些干预措施显示出神经营养通路的生物标志物发生了转变（例如，通过猴头菇 (Hericium erinaceus) 增加了循环 pro-BDNF，并且在姜黄素的 RCT 荟萃分析中增加了血清 BDNF）[15, 16]。最后，几个域 1 候选者受到与认知相关的血管和代谢支持信号的推动，包括增加脑血流量（omega-3 来源）和血流/血管生成机制（可可黄烷醇）的声明[9, 17]。

胞磷胆碱 (CDP-choline)

胞磷胆碱 (CDP-choline) 被描述为磷脂酰胆碱合成必不可少的前体，并且在给药后释放胞苷和胆碱，综述文献指出它“激活神经元膜中结构磷脂的生物合成”并且“对乙酰胆碱生物合成至关重要”[12, 13, 18]。在认知障碍人群中，一项系统综述/荟萃分析报告称，胞磷胆碱改善了认知状态，合并的标准化均数差从 0.56 到 1.57 不等（在敏感性分析中），同时也指出总体研究质量较差[19]。在急性创伤性脑损伤中，一项针对 11 项临床研究（n=2771）的系统综述/荟萃分析报告称，胞磷胆碱的独立性发生率更高（RR 1.18，95% CI 1.05–1.33）[20]。临床试验中的有效剂量总结为 500–2,000 毫克/天，据报告该干预措施耐受性良好，在 TBI 荟萃分析中“无安全性问题”[20–22]。

结论：强（荟萃分析 + 多项临床研究，但认知试验存在质量问题）[19]。

Alpha-GPC

Alpha-GPC 被描述为一种含胆碱的磷脂，用于治疗认知障碍，并被表征为乙酰胆碱生物合成的前体（在综述文本中具有额外的“神经保护信号传导”声明）[23, 24]。一项纳入了七项 RCT 的系统综述/荟萃分析报告称，当 Alpha-GPC 与多奈哌齐联合使用时，认知、功能和行为显著改善（例如，认知 MD 1.72，95% CI 0.20 至 3.25）[25]。在一项针对轻度认知障碍患者（n=100）的为期 12 周的多中心随机安慰剂对照试验中，600 毫克/天的 Alpha-GPC 导致 ADAS-cog 相对安慰剂下降 2.34 分，并且报告无严重不良事件，没有因不良事件而停药[23]。

结论：中等（多项 RCT；一些最强的定量效果是在联合疗法中）[25]。

胆碱（酒石酸盐 / 氯化物）

胆碱（酒石酸盐 / 氯化物）被明确描述为甜菜碱和乙酰胆碱的前体，因此被假设会影响认知结果[3]。然而，一项综述得出结论，对于成人认知结果而言，“缺乏高质量的（干预）研究”[3]。在一项针对健康绝经后妇女的随机、双盲、安慰剂对照试验中，1 克/天的酒石酸胆碱显著增加了循环游离胆碱和甜菜碱，并使血浆总同型半胱氨酸减少，在第 6 周时接近统计学显着性 (P=0.058)，在摘要中对血浆脂质没有影响[26]。综述文本中提出的一个关键警告是，可能产生的有害心脏代谢效应需要仔细评估[3]。

结论： 有限（存在生物化学随机对照试验证据，但成年人认知试验被描述为缺乏高质量）[3]。

磷脂酰丝氨酸 (PS)

磷脂酰丝氨酸 (PS) 被描述为与认知功能相关的大脑皮层的重要组成部分[27]。一项系统评价/Meta分析（包含9项研究，其中包括5项随机对照试验）得出结论：PS对有认知功能下降的老年人的记忆力有积极影响，并总结认为PS“似乎能改善与年龄相关的认知功能下降，尤其是记忆力”，在纳入的研究中PS剂量从100–300毫克/天不等[27]。在一项针对伴有记忆主诉的非痴呆老年人的随机试验中，据报道PS-DHA（300毫克 PS/天，持续15周）安全且耐受性良好，在测试的参数中没有产生负面影响[28]。在精英射击运动员的一项独立小型试验中，PS补充剂降低了恐慌评分并改变了皮质醇相关指标（伴随睡眠质量呈改善趋势，但未达到统计学显著性）[29]。

结论： 中等（多项随机对照试验以及支持记忆的Meta分析；小型研究中显示出一些辅助性的压力/睡眠信号）[27]。

磷脂酰胆碱 (PC)

磷脂酰胆碱 (PC) 被介绍用于脑部疾病试验，因为它既是ACh生物合成的前体，又是神经元膜的组成部分[11]。在一项孕妇双盲随机对照试验中（n=140），从妊娠18周至产后90天每天补充750毫克磷脂酰胆碱耐受性良好，但婴儿在10个月和12个月时的认知结果在各组之间没有显著差异（语言、全面发育和记忆测量指标）[30]。痴呆小鼠的临床前研究结果表明，给予PC可增加大脑胆碱/ACh并改善记忆，但这不能替代人类成年人认知功效的直接证据[31]。

结论： 有限（人体随机对照试验显示出耐受性，但婴儿结果为阴性；在提供的来源中尚未确立成年人认知证据）[30]。

欧米伽-3 EPA/DHA（鱼油）

欧米伽-3 EPA/DHA（鱼油）被描述为对大脑发育和认知表现很重要，其中DHA被表征为大脑中占主导地位的欧米伽-3，会影响神经递质和大脑功能[9, 10]。在一项针对孕妇和/或哺乳期女性补充鱼油随机试验的系统评价/Meta分析中，纳入了11项试验，未发现DHA/EPA补充剂与儿童评估的认知参数之间存在显着相关性[10]。其他以随机对照试验为重点的综述文本指出，摄入欧米伽-3脂肪酸可以增强学习、记忆、认知健康和脑血流量，这说明结论会根据人群和研究集的不同而有所差异[9]。

结论： 中等（存在多项随机对照试验和Meta分析，但在提供的证据中认知效应并不一致）[10]。

假马齿苋（bacosides）

一项评估Bacopa是否能增强人类认知的系统评价报告称，在各项研究中，Bacopa在自由回忆记忆的17项测试中的9项上改善了表现，而在其他认知领域几乎没有发现增强的证据；纳入的研究中通常进行超过12周的试验，使用300–450毫克/天的提取物[32]。一项针对符合条件的随机对照试验参与者的Meta分析报告称，在长期（≥12周）服用标准化提取物后，认知能力有所改善，表现为连线测验B（Trail B test）表现缩短且选择反应时间缩短[2]。在轻度认知障碍的另一项随机对照试验中，睡眠质量总分的组间无统计学显著差异（所描述的剂量为160毫克提取物，持续2个月），这表明并非所有人群和结果都显示出益处[7]。

结论： 强（针对特定认知指标的Meta分析随机对照试验证据，具有领域特异性而非广谱效应）[2, 32]。

银杏叶提取物 (EGb 761)

痴呆症领域的系统评价/Meta分析使用经过验证的认知、日常生活活动能力 (ADL) 和全局评估来评估EGb 761[1]。在合并分析中，认知、ADL和全局评级的变化评分显著倾向于EGb 761组而非安慰剂组（例如，认知SMD −0.52，95% CI −0.98至−0.05；P=0.03），且一项独立的Meta分析强调，益处主要与240毫克/天的EGb 761持续22–24周相关[1, 33, 34]。Meta分析中的安全性结果报告称，没有重要的安全性问题，且不良事件发生率与安慰剂相似[1, 33, 35]。

结论： 强（多项随机对照试验和Meta分析，具有一致的痴呆相关终点改善和可接受的耐受性）[1, 33]。

猴头菇 (Hericium erinaceus)

综述描述了Hericium erinaceus已被用于测试认知下降/阿尔茨海默病和心理健康状况，一项随机对照试验报告称，口服补充8周可减轻抑郁、焦虑和睡眠障碍，同时增加循环中的pro-BDNF（循环中的BDNF没有显着变化）[15, 36]。一项包含一项随机对照试验和一项临床预试验的综述报告称，干预组的简易精神状态检查量表（MMSE）评分组合加权平均增加1.17，但也指出其他总结中各症状领域的发现呈现混合状态[36, 37]。各项综述中报告的副作用并不常见且通常较轻（例如胃肠不适），不过也提及了头痛和过敏反应等潜在效应[4, 37]。

结论： 中等（存在多项对照试验，认知和情绪信号呈现混合状态；证据基础仍然相对较小）[37]。

石杉碱甲

Meta分析总结报告称，与安慰剂相比，石杉碱甲在8–16周时改善了通过MMSE测量的认知功能，在阿尔茨海默病群体中，ADL在多个时间点也倾向于石杉碱甲[38]。一项系统评价纳入了20项随机对照试验（n=1823），但指出大多数纳入的试验存在较高的偏倚风险，尽管有积极的发现，但这限制了对效应估计的信心[38]。安全性总结表明，不良事件多属于胆碱能性质，在Meta分析摘要中描述的纳入试验中未报告严重不良事件[38, 39]。

结论： 中等（存在许多随机对照试验，但高偏倚风险降低了确定性）[38]。

长春西汀

一项针对痴呆症双盲随机试验的Cochrane系统评价（总n=583）得出结论：长春西汀获益的证据尚无定论，不支持临床应用，同时指出一些获益与30毫克/天和60毫克/天相关，但接受治疗≥6个月的人数较少[40]。在系统评价中引用的另一项合并分析中，长春西汀组的MMSE变化优于安慰剂组（合并WMD 0.92，95% CI 0.02–1.82）[41]。痴呆症试验中的不良事件报告不一致，Cochrane总结中的任何试验均无意向性治疗数据可用[40]。

结论： 中等（存在多项随机对照试验，但最高级别的痴呆症综述得出结论认为证据尚无定论）[40]。

Souvenaid / Fortasyn Connect（医用食品）

Souvenaid / Fortasyn Connect（医用食品）被描述为一种旨在支持阿尔茨海默病突触合成的医用食品，其Fortasyn Connect配方包括用于神经元膜形成的前体和辅助因子（例如，尿苷一磷酸、胆碱、磷脂、EPA/DHA以及维生素和硒）[8]。在针对527名接受标准AD药物治疗的轻度至中度AD患者进行的S-Connect 24周双盲随机对照试验中，通过ADAS-cog评估的认知在两组中均有下降，活性组和对照组之间没有显着差异（差异0.37分；p=0.513）[8]。安全性报告显示不良事件发生率没有组间差异，且Souvenaid与AD药物联用时耐受性良好，系统评价总结中未观察到严重不良事件[8, 42]。

结论： 中等（存在多项结果呈混合状态的随机对照试验；一项大型随机对照试验显示，在接受药物治疗的轻度至中度AD患者中，对ADAS-cog无影响）[8]。

左旋酪氨酸

酪氨酸被明确描述为多巴胺和去甲肾上腺素的前体，综述综合报告称，在认知负荷或极端天气等严苛条件下，补充酪氨酸可以急性抵消工作记忆和信息处理能力的下降[14]。个别随机对照试验报告了警觉性/精神运动结果的改善（例如减少失误）以及认知灵活性的改善（减少转换成本）[43, 44]。然而，一项系统评价也得出结论，现有证据不足以对减轻压力对表现的影响提出有信心的建议，并强调了异质性和语境依赖性[45]。

结论： 中等（在压力情境下具有合理急性效应的多项试验，但综合水平的不确定性仍然存在）[14, 45]。

氯芬酯（甲氯芬酯）

在患有阿尔茨海默型老年痴呆症的老年患者中，一项双盲对照随机试验报告称，长期治疗降低了精神老年学评分，并改善了多项认知表现指标（注意力、集中力、记忆力、智商），其中含有甲氯芬酯的神经代谢复合物被报告为显著优于单纯的甲氯芬酯[46]。在老年人的另一项双盲试验中，在以2克/天（如研究方案所述）的剂量进行氯芬酯治疗8周后，48%的活性组表现出记忆功能的改善，而安慰剂组这一比例为28%[5]。慢性脑缺血模型中的临床前研究结果报告称，口服氯芬酯可改善记忆障碍并减少氧化/炎性介质的变化，但这并不是机制或功效的直接人类证据[47]。 结论： 有限（带有积极信号的小型/较老随机对照试验；在提供的来源中未显示当代高质量的重复研究）[5]。

咖啡因

在睡眠剥夺/受限环境下，急性摄入咖啡因显示出跨认知领域的Meta分析改进，包括改善了注意力反应时间和执行功能（例如，反应时间 g=0.86；执行功能 g=0.35）[48]。同一组证据表明咖啡因会损害睡眠，通常会延长睡眠潜伏期并减少总睡眠时间/效率及慢波睡眠，并报告了剂量和时间反应关系[49]。个体间敏感性得到了基因关联总结的支持，该总结将ADORA2A变异与焦虑/睡眠干扰联系起来，并将CYP1A2变异与认知功能联系起来[50]。 结论： 中等（稳健的急性表现证据，由可靠的睡眠中断效应相平衡）[48, 49]。

领域 2 — 压力弹性、抗焦虑与睡眠结构

第二领域的成分映射至大脑功能结局，当应激系统、抑制性神经传递以及昼夜睡眠-觉醒调节朝具有临床意义的方向转变时，这些结局便会显现，这反映在测量感知压力、焦虑严重程度、皮质醇、睡眠发作/质量以及次日机能的试验中。因此，该领域在机制上锚定于

  1. 下丘脑-垂体-肾上腺轴与神经内分泌应激反应调节（例如，明确讨论了HPA轴的适应原如红景天，以及镁在HPA轴调节中所述的参与作用）[51, 52],
  2. GABA能调节（例如，缬草对“……GABA功能的调整”、蛇麻草的GABA_A受体调节以及卡瓦的GABA相关机制）[53–55],
  3. 影响情绪和睡眠生物学特征的5-羟色胺前体（例如，色氨酸和5-HTP作为5-羟色胺前体，以及5-HTP在大脑中转化为5-羟色胺）[56–58], 以及
  4. 肠脑轴干预措施（精神益生菌和益生元），其通过与应激和睡眠表型相关的神经调节代谢产物和炎症控制发挥作用[59]。

红景天（红景天苷/红景天苷类化合物）

在机制上，红景天被描述为可调节HPA轴和神经递质系统，在所审查的来源中还额外讨论了抗氧化通路和线粒体功能[51]。在临床上，系统评价总结了安慰剂对照的随机对照试验（RCT），并得出结论：红景天“可能会减轻轻度至中度抑郁和轻度焦虑的症状”同时改善情绪，但也强调鉴于实验数据有限，研究结果“并非确定性的”，并且在一篇纳入研究存在高偏倚风险/报告缺陷的评价中，其功效被描述为“矛盾的”[60, 61]。这些总结中的安全性信号通常较轻（“仅报告了少数轻度不良事件”）[62]。 结论：中度。

南非醉茄（Withania somnifera；KSM-66 / Sensoril）

在一项荟萃分析（5项RCT；400名参与者）总结的人类睡眠试验中，南非醉茄提取物显示出对整体睡眠的小幅但显著的改善（SMD −0.59，95% CI −0.75至 −0.42），其中在被诊断为失眠的成年人中以及在剂量≥600 mg/天、持续时间≥8周时亚组效应更大；同一综合研究报告了清醒时的精神警觉性和焦虑水平的改善[63]。在以应激/焦虑为重点的荟萃分析中，与安慰剂相比，南非醉茄配方降低了感知压力（PSS MD −4.72）、汉密尔顿焦虑量表（MD −2.19）和血清皮质醇（MD −2.58），并且部分纳入的研究报告了轻度至中度不良事件[64]。尽管在该荟萃分析总结的睡眠RCT证据基础中报告了“无严重副作用”，但长期严重不良反应数据明确被描述为有限[63]。 结论：中度。

L-茶氨酸

在一项系统评价/荟萃分析（纳入18项研究；N=897）中，L-茶氨酸显著改善了多项主观睡眠结局，包括入睡潜伏期（SMD 0.15）、日间功能障碍（SMD 0.33）和总体主观睡眠质量评分（SMD 0.43）[65]。一项独立的证据综合报告称，在暴露于应激条件的人群中，每天200–400毫克“可能有助于减轻应激和焦虑”[66]。正如试验摘要中所报告的那样，在无重大精神疾病的成人的RCT中，每天200毫克、持续4周降低了抑郁、焦虑和PSQI评分，并改善了与基线/安慰剂比较的言语流畅度和执行功能评分[67, 68]。 结论：强。

镁（甘氨酸镁/苏糖酸镁/柠檬酸镁）

镁被描述为“参与神经传递、HPA轴调节和睡眠-觉醒控制的关键阳离子”，为跨配方的应激和睡眠终点提供了符合映射的机制基本原理[52]。对于失眠相关结局，一项系统评价/荟萃分析确定了三项RCT（151名老年人），发现与安慰剂相比，入睡潜伏期合并减少了17.36分钟，同时还指出了中到高偏倚风险以及低到极低证据质量[69]。具体针对L-苏糖酸镁，睡眠问题成人的RCT报告称，与安慰剂相比，客观测量的深睡眠和REM睡眠评分（Oura指环指标）以及多项日间指标（精力、生产力、情绪、警觉性）有所改善，并报告其安全且耐受性良好；一项独立的RCT报告称，Magtein®改善了整体认知性能，对工作记忆和情景记忆的影响更大[70, 71]。 结论：中度。

甘氨酸

甘氨酸被描述为通过NMDA型谷氨酸受体和甘氨酸受体在兴奋性和抑制性神经传递中发挥作用，一项综述提出核心体温下降“可能是甘氨酸对睡眠产生影响的潜在机制。”[72] 然而，一项综述指出，虽然长期给予甘氨酸改善了健康人群的睡眠，但这些研究样本量小且偏倚风险高，限制了该数据集中睡眠适应症的置信度[73]。在独立的精神病学背景下，NMDA受体共激动剂甘氨酸和D-丝氨酸对减轻精神分裂症阴性症状有效（固定效应SMD −0.66），而合并的认知功能未显示出显著效应（随机效应WMD −2.79，p=0.11）[74]。 结论：有限。

GABA（外源性）

一项仅限于安慰剂对照人体试验的系统评价得出结论：口服GABA摄入对于应激的证据是“有限的”，对于睡眠益处的证据是“非常有限的”，同时也指出在得出推论之前需要更多研究[75]。纳入集中的个别试验报告了特定领域的信号，例如第6周时活力-活动度（POMS2）增加、在急性睡前交叉设计中非REM睡眠第2期的变化，以及在一项90天补充剂研究中改善的习惯性睡眠效率（降低PSQI），该研究还观察到与更高副交感神经优势一致的HRV增加[76–78]。 结论：有限。

牛磺酸

在一项评估认知的随机对照试验系统评价/荟萃分析中，牛磺酸（单独使用或与运动训练结合使用）对认知评分没有显示出显著影响，作者得出结论认为，证据不足以支持其增强认知功能的功效[79]。一项较晚的系统评价将急性牛磺酸给药研究总结为：充其量显示出对认知功能的小幅且不一致的改善（通常为1–3克，最高约50毫克/公斤）[80]。 结论：中度（多项RCT，在现有综合研究中对认知大体上无效）。

第三领域 — 细胞能量、线粒体功能与体能耐力

第三领域的成分是使用机制图选择的，因为大脑表现受到细胞能量供应（ATP生成）、底物灵活性和线粒体氧化还原平衡的严格制约，这些因素可以继发塑造认知、疲劳、情绪和应激耐受性。纳入的成分映射到

  1. 生物能辅助因子和电子传递/氧化还原系统（例如，辅酶Q10“与能量产生密切相关”并能防止过氧化损伤）[81],
  2. NAD+前体策略（NR、NMN和烟酰胺作为与NAD+相关的途径）[82, 83],
  3. 磷酸肌酸缓冲（肌酸作为大脑生物能量学的关键组成部分）[84], 以及
  4. 替代燃料策略（MCT、辛酸甘油三酯和外源性酮体，在葡萄糖利用受损时提高酮体水平）[85, 86]。

乙酰-L-肉碱（ALCAR）

乙酰-L-肉碱（ALCAR）在第三领域中定位，因为作为乙酰供体以及在β-氧化期间促进脂肪酸转移至线粒体中，它“在intermediary metabolism（中间代谢）中发挥着至关重要的作用”，同时在脑能量/磷脂代谢和突触传递方面具有额外的已报道的神经调节作用[87, 88]。与这种以能量为中心的基本原理一致，随机试验的荟萃分析报告了以下方面的临床信号：(a) 抑郁症（跨九项RCT合并，与安慰剂/无干预相比，ALC降低了抑郁症状，SMD = -1.10）[89]，以及 (b) 轻度认知障碍（MCI）/轻度阿尔茨海默病（与安慰剂相比，在综合临床/心理测量结局和临床医生全局变化方面具有显著优势，3个月时显效且随时间推移而增加）[90]。MCI/轻度AD证据基础中的剂量在1.5–3.0克/天之间变化，在该荟萃分析的所有研究中，耐受性被描述为良好[90]。 结论：中度。（多项RCT，具有针对情绪和MCI/轻度AD结局的荟萃分析支持。）[89, 90].

Axona（辛酸甘油三酯医用食品）

Axona（辛酸甘油三酯医用食品）通过替代燃料策略靶向第三领域：它并非改善葡萄糖利用，而是旨在提供能够穿过血脑屏障并在葡萄糖利用受损时提供替代能量来源的酮体[86, 91]。在大型双盲RCT（NOURISH AD；26周；按APOE基因型分层的413名患者）中，AC-1204（辛酸甘油三酯）未能改善主要的认知终点（ADAS-Cog11），且次要结局“未能检测到任何药物效应”[92]。较小的研究报告了混合的发现，包括总体消极的陈述（“未改善认知功能”），同时在基线MMSE≥14的一些ApoE4阴性患者中存在亚组信号[93]。一个实际考虑因素是胃肠道耐受性，在一项临床干预中该耐受性“良好，无严重胃肠道不良反应”，并且采用从10克/天到40克/天的剂量滴定来减少胃肠道不良反应（其中40克粉末包含20克辛酸甘油三酯）[93]。 结论：中度（在最大的RCT中对认知呈混合/大多为阴性结果）。[92, 93].

辅酶Q10（泛醇/泛醌）

辅酶Q10（泛醇/泛醌）被纳入第三领域，是因为它被描述为具有“生物能和抗氧化活性”，并且“与能量产生密切相关”并能防止膜磷脂发生过氧化损伤[81]。在人体中，一项针对抑郁症随机试验的荟萃分析报告称，与对照组相比，抑郁症状有所减轻（5项RCT，474名参与者；SMD = -0.68），而基于仅两项试验，未显示出对疲劳有统计学意义的显著益处[94]。独立的荟萃分析生物标志物证据表明，辅酶Q10增加了总抗氧化能力和超氧化物歧化酶（SOD）并降低了丙二醛，这与系统性抗氧化信号相一致，该信号与第三领域的氧化还原防御节点保持一致[95]。 结论：中度。（多项RCT，具有针对抑郁症状改善和抗氧化生物标志物变化的荟萃分析证据。）[94, 95].

第四领域 — 收敛节点（跨领域主调节因子）

第四领域的成分被优先考虑，因为它们靶向“收敛节点”，这些节点貌似合理地同时影响多个大脑相关结局——例如，神经炎症和氧化应激（可影响认知和情绪）、血管和代谢因素（可影响脑灌注和能量可用性）以及一碳/甲基化途径（可影响单胺类神经递质合成及相关的抑郁症状）。这种跨领域逻辑与人参等植物药的多途径机制描述（神经炎症、抗氧化能力、线粒体代谢、突触可塑性）相一致，也与将营养保健品与认知终点（例如，再认记忆）和全身炎症标志物（例如，CRP、TNF-α）联系起来的人类文献相一致[96–99]。

人参

从机制上讲，人参被认为通过与收敛生物学相关的多条途径发挥作用，包括抑制神经炎症、增强抗氧化能力、改善线粒体代谢以及调节突触可塑性；在情绪调节的背景下，它也被描述为调节 HPA/HPG 轴信号传导、神经递质和 BDNF–TrkB 途径[96]。在临床上，一项包含 15 项 RCT（分析 n=671）的荟萃分析报告称，记忆力有小幅但统计学意义上的显著改善（总体 SMD=0.19，95% CI 0.02–0.36），在“高剂量”亚组分析中效果更大（SMD=0.33，95% CI 0.04–0.61），但对整体认知、注意力或执行功能结果没有积极的合并效应[100]。另一项系统评价识别出 9 项符合纳入标准的随机、双盲、安慰剂对照试验，表明存在多项 RCT，但终点和结果各不相同[101]。一项示例性 RCT 给予 3 g/天的人参粉，持续 6 个月，报告无严重不良事件；跨试验的更广泛安全性综合同样发现“无严重不良事件”，同时指出大多数研究的偏倚风险不明确[102, 103]。证据水平裁决：中等。

厚朴树皮（和厚朴酚/厚朴酚）

所提供来源中的当前证据是机制性和临床前研究：和厚朴酚与厚朴酚可抑制神经元中 NMDA 刺激的超氧化物产生（涉及 NADPH 氧化酶的途径），并通过依赖于 p‑ERK 的途径抑制小胶质细胞中 IFNγ±LPS 诱导的 iNOS 表达、一氧化氮和 ROS 产生[104]。一篇综述明确指出，需要更多的研究来提高生物利用度并在临床研究中测试这些化合物，这强调了该证据包中缺乏严谨的人类功效证据[105]。证据水平裁决：仅机制研究。

白藜芦醇（反式白藜芦醇）

人类对各种认知结果的证据呈混合状态。一项针对干预试验的系统评价报告称，在纳入的 10 项研究中，一些发现有改善，一些发现结果混合，另一些则没有效果，并且合并分析显示，延迟再认（合并 SMD=0.39，95% CI 0.08–0.70；n=3 项研究，n=166 名参与者）和负面情绪（合并 SMD=-0.18，95% CI −0.31 至 −0.05；n=3 项研究，n=163 名参与者）具有统计学意义上的显著益处[97]。相比之下，另一项荟萃分析报告称，通过听觉词语学习测试评估的记忆和认知性能没有显著影响，这支持了终点特异性的不一致性[106]。长期血管认知证据包括一项在 125 名绝经后妇女中进行的为期 24 个月的随机、安慰剂对照交叉试验，使用 75 毫克反式白藜芦醇每天两次，该研究报告与安慰剂相比，“总体认知性能显着改善 33%”，并且脑血管指标（静息平均 CBFV 和 CVR）有所改善[107]。补充白藜芦醇后系统性炎症标志物（CRP 和 TNF-α）的荟萃分析减少支持了收敛节点合理性，尽管一项分析指出在该特定数据集中可能存在 CRP 降低而 IL-6 和 TNF-α 没有一致变化[98, 99]。证据水平裁决：中等。

讨论

这篇以机制为锚定的综述对用于大脑功能的食品补充剂和特医食品进行了结构化评估。结果突显了明确的证据等级，某些成分有强有力的临床数据支持特定结果，而许多其他成分则依赖于临床前理论依据或具有不一致的人类试验结果。

跨领域最佳证据精选

根据“结果”部分综合的证据，可以为四个领域中的每一个领域确定一个“最佳证据精选”，代表对相关大脑功能结果具有最一致和最高质量人类数据的成分：

  • 领域 1（认知）：银杏叶提取物 EGb 761 展示了来自多项 RCT 荟萃分析的强有力证据，显示出对痴呆症的认知、日常生活活动和全球评级的持续益处，并具有有据可查的安全性特征[1]。
  • 领域 2（压力/睡眠）：褪黑素脱颖而出，其拥有来自众多 RCT 和荟萃分析的广泛证据基础，证明了其在改善各种人群的入睡潜伏期和总睡眠时间方面的功效，且耐受性良好[108]。
  • 领域 3（能量/线粒体）：一水肌酸得到了来自 RCT 的强有力荟萃分析支持，显示出对记忆表现的显着积极影响，特别是在老年人中，这与其在大脑生物能学中的作用一致[84, 109]。
  • 领域 4（收敛）：叶酸 / L-甲基叶酸 (5-MTHF) 拥有来自多项 RCT 和荟萃分析的强有力证据，支持其作为辅助疗法以显着减轻抑郁症状、提高应答率和增加缓解率[110]。

机制收敛

几种成分通过同时作用于多个调节节点展示了“机制收敛”的原理。例如，欧米伽-3 脂肪酸（EPA/DHA）参与维持神经元膜完整性（领域 1），具有抗炎特性（领域 4），并可能影响诸如 BDNF 等神经营养因子信号传导（领域 4）[9]。同样，肌酸不仅通过磷酸肌酸系统支持大脑能量（领域 3），还在研究其神经保护特性[84]。B 族维生素（叶酸、B6、B12）是甲基化循环（领域 4）的核心，这对于多种神经递质的合成（领域 1）、同型半胱氨酸（血管和神经元健康标志物）的调节以及 SAMe 的产生至关重要[111, 112]。这些多靶点作用可以解释为什么某些补充剂似乎在不同的功能领域都具有益处。

迄今尚无证据的成分

本综述的一个关键发现是，在所提供的来源中，许多受欢迎的成分缺乏针对大脑特定终点的人类严谨证据。对于这些成分，关于认知或情绪益处的宣称尚未得到高质量临床试验的证实。明确声明这一点非常重要：迄今尚无证据。例如：

  • 口服 GABA 补充剂：虽然机制上合理，但系统评价得出结论，口服时其对睡眠或压力的功效证据非常有限[75]。
  • 亚精胺：关于认知的人类 RCT 产生了不一致的结果，一些显示出益处，另一些发现对记忆没有显着影响[113]。

尿苷一磷酸、紫檀芪、棕榈酰乙醇酰胺（PEA）：对于这些成分，在初始证据基础中未识别出支持大脑相关宣称的严谨人类试验。

安全考量与监管状态

安全性是首要考量因素，几种成分具有值得注意的注意事项。卡瓦虽然显示出抗焦虑的中等证据，但具有肝毒性风险，监管机构建议谨慎行事、进行例行肝功能检查并避免饮酒[55]。石杉碱甲是一种乙酰胆碱酯酶抑制剂，可引起胆碱能副作用，其使用需要谨慎，特别是在服用其他胆碱能药物的个体中[39]。这些例子强调了评估不仅包括功效，还包括不良事件和药物相互作用潜力的重要性，这一过程对于补充剂而言通常不如对药物那般严谨。

局限性

本综述存在几个局限性。最初的广泛检索和筛选基于标题和摘要，这可能导致排除相关研究。证据基础的特点是成分配方（例如，不同的南非醉茄或姜黄提取物）、剂量、治疗持续时间和所研究人群存在显着异质性，使得直接比较变得困难。倾向于积极结果的发表偏倚可能会影响现有文献。最后，本综述不涉及从头荟萃分析，而是依赖于现有系统评价中报告的数据和质量评估。大多数成分缺乏头对头试验，这意味着无法确定相对功效。

研究优先事项

以机制为锚定的图谱揭示了几个缺乏深入研究成分的节点。例如，类淋巴清除系统的直接调节剂（例如，靶向水通道蛋白-4）代表了一个具有有限现有干预措施的新前沿。同样，虽然许多成分声称具有抗氧化作用，但很少有人体认知试验对其特异性调节通过 Nrf2/Keap1 途径等靶点的神经元氧化还原信号传导的能力进行了严格测试。未来的研究应优先测试针对这些探索较少但生物学上重要靶点的新化合物或现有化合物，以填补证据图谱中的关键空白。

结论

本手稿将用于大脑功能的食品补充剂和特医食品的复杂领域组织成一个连贯的、以机制为锚定的框架。这种方法超越了模棱两可的营销类别，根据其特定的生物学靶点和相应临床证据的强度来评估成分。

结果揭示了证据质量上的鲜明差异。一小部分成分，包括用于痴呆症的银杏叶（EGb 761）、用于睡眠的褪黑素、用于记忆的肌酸以及用于抑郁症辅助治疗的 L-甲基叶酸，得到了来自多项 RCT 和荟萃分析的大量证据的支持。更大的一组成分显示出中等或有限的证据，具有前景但结果不一致，值得进行进一步、更严格的调查。至关重要的是，许多广泛销售的成分没有强有力的人类临床试验数据来支持其在脑部相关结果方面的使用。

通过将成分映射到机制和证据，本综述为临床医生、研究人员和消费者提供了一个有价值的工具。它有助于更知情、更安全地使用这些产品，突出了对特定应用具有最强科学支持的化合物。同时，它阐明了文献中的重大空白，为未来研究建立一个更完整、更可靠的证据基础以通过营养增强和保护大脑功能提供了清晰的指南。

附录 A

附录 A：主证据表（交叉参考表 1 — 另行交付）

注：主证据表是一个综合附录，为本手稿分析的 70 多种成分中的每一种提供详细的、逐行的数据。它作为本文档的单独补充文件交付。

附录 A — 补充证据表

整合的补充来源：附录 A — 大脑功能成分主证据表.xlsx

成分领域机制靶点主要临床结果证据级别最佳证据总结典型剂量安全性注意事项
胞磷胆碱 (CDP-choline)领域 1 认知与神经可塑性[1, 2]磷脂酰胆碱/结构性磷脂膜合成（胞磷胆碱前体）[3, 4]；支持乙酰胆碱生物合成[5]；在综述文献中可增加脑代谢并影响神经递质水平[4]。认知功能/认知状态与记忆/行为结局[1, 3]；创伤性脑损伤后的功能独立性（格拉斯哥预后量表）。[2, 6]强：Meta 分析 + 多项随机对照试验 (RCT)[2, 1]针对急性创伤性脑损伤 (TBI) 的系统评价/Meta 分析（11 项临床研究；n=2771）发现，与对照组相比，胞磷胆碱组的独立率更高（RR 1.18，95% CI 1.05–1.33）。[2]500–2,000 毫克/天（临床试验中报道的有效给药剂量范围）。[7]急性 TBI Meta 分析报告无安全性问题[2]；在一项考克兰（Cochrane）综述中，胞磷胆碱被认为“耐受性良好”。[8]
假马齿苋 (bacosides)领域 1 认知与神经可塑性[9]源材料中未提及。记忆自由回忆（跨研究的 17 个测试中有 9 个改善）[9]；Meta 分析中的注意力/速度（连线测验 B；选择反应时间）[10]；在一项随机对照试验中评估了睡眠质量但无显著差异。[11]强：Meta 分析 + 多项随机对照试验[10]Meta 分析（9 项研究；518 名受试者）报告称，长期（≥12 周）补充假马齿苋提取物可改善认知，包括缩短连线测验 B 时间和减少选择反应时间。[10]常见的随机对照试验提取物剂量：约 12 周内 300–450 毫克/天。[9]源材料中未提及。
银杏 (EGb 761)领域 1 认知与神经可塑性[12]源材料中未提及。痴呆结局：认知、日常生活活动和全球评估[12]；神经精神症状（例如 NPI 复合评分）和认知测试（例如 SKT）。[13]强：Meta 分析 + 多项随机对照试验[12, 14, 15]针对痴呆症门诊患者的系统评价/Meta 分析发现，在认知、ADL 和全球评分方面，EGb 761 优于安慰剂；与安慰剂相比，治疗相关的不良事件风险没有显着差异。[12]120–240 毫克/天（在合并试验中通常为 240 毫克/天）。[12, 14, 15]Meta 分析发现无重大安全性问题，且不良事件发生率与安慰剂相似。[14, 16, 12]
胞磷胆碱 + 其他（注：保留独立的成分行）源材料中未提及。源材料中未提及。源材料中未提及。迄今尚无证据 — 在提供的来源中未发现严谨的人体证据。迄今尚无证据 — 在提供的来源中未发现严谨的人体证据。源材料中未提及。
α-GPC领域 1 认知与神经可塑性[17]含胆碱的磷脂，充当乙酰胆碱生物合成的前体，并在讨论中被视为神经营养保护信号通路的调节剂。[18]认知（例如 ADAS-cog）。[19] 成人认知障碍研究中的功能和行为结局。[17]中等：多项随机对照试验[17, 19]在轻度认知障碍中进行的 12 周多中心随机对照试验（n=100；600 毫克 αGPC）报告称，与安慰剂相比，ADAS-cog 降低幅度更大（−2.34 分），且无严重不良事件。[19]12 周随机对照试验中的 600 毫克/天 αGPC；交叉设计中的急性补充方案使用了 315–630 毫克。[19, 20]在一项 12 周的 MCI 随机对照试验中，无严重不良事件 (AE)，且 AE 发生率与安慰剂相似。[19] 在一项大型开放式多中心试验中，2.14% 的患者报告了 AE，常见主诉包括胃灼热、恶心/呕吐、失眠/兴奋和头痛。[21]
磷脂酰丝氨酸领域 1 认知与神经可塑性（也针对压力/睡眠结局进行研究）[22]源材料中未提及。与年龄相关的认知衰退/记忆[22]；某些试验中的情绪/压力（POMS 上的恐慌评分）和睡眠质量 (PSQI)。[23]中等：多项随机对照试验 + 系统评价/Meta 分析[22, 24]系统评价/Meta 分析（9 项研究；5 项随机对照试验）得出的结论是，磷脂酰丝氨酸对有认知衰退的老年人的记忆力有积极影响，且未报告不良反应。[22]老年人认知衰退研究中为 100–300 毫克/天；PS-DHA 试验中为 300 毫克/天 PS；短期压力/睡眠研究中为 400–800 毫克/天。[22, 24, 23]据报道，300 毫克/天的 PS-DHA 持续 15 周（或 100 毫克/天持续 30 周）安全/耐受性良好，对受试参数无负面影响。[24]
胆碱（酒石酸氢盐 / 氯化物）领域 1 认知与神经可塑性；也与甲基供体途径相关（领域 4）。[25]乙酰胆碱和甜菜碱（甲基供体）的前体。[25, 26] 1 克/天增加了循环游离胆碱和甜菜碱，可能增强 tHcy 再甲基化（BHMT 途径）。[26]成人的认知（描述为缺乏高质量干预数据）[25]；审查了妊娠期补充剂对儿童认知结局的影响[27]；生化结局（血浆胆碱/甜菜碱/tHcy）。[26]有限：单次随机对照试验或小型研究（描述为缺乏认知随机对照试验证据）。[25, 26]《营养学评论》综合得出结论，成人认知获益是可能的，但缺乏高质量的干预研究。[25]在一项针对绝经后女性的随机安慰剂对照试验中，胆碱（作为酒石酸氢胆碱）剂量为 1 克/天；孕期试验剂量为第三孕期 480–930 毫克/天。[26, 28]综述指出，可能的有害心血管代谢影响需要仔细评估。[25] 在一项 1 克/天的随机对照试验中，血浆脂质未受影响。[26]
欧米伽-3 EPA/DHA（鱼油）领域 1 认知与神经可塑性[29]DHA/EPA 被描述为对大脑发育和认知表现很重要[29]；DHA 影响神经递质和大脑功能（机制描述）。[30]认知结局（随机对照试验中的多个参数）；一项针对妊娠期/哺乳期的 Meta 分析发现，与儿童认知参数无显著关联。[29]中等：多项随机对照试验（证据总结自系统评价/Meta 分析；结果参差不齐）。[29, 30]系统评价/Meta 分析（11 项试验）报告称，孕期补充 DHA/EPA 与评估的儿童认知参数之间没有显著关联。[29]源材料中未提及。源材料中未提及。
磷脂酰胆碱领域 1 认知与神经可塑性[31]乙酰胆碱生物合成的前体和完整的神经元膜成分（针对脑部疾病试验的基本原理）。[31]母亲补充后婴儿神经发育结局（视觉空间记忆、情景记忆、语言/全球发育）；据报道无显着差异。[32]有限：单次随机对照试验或小型研究[32]孕 18 周至产后 90 天母亲补充磷脂酰胆碱 750 毫克/天，与安慰剂相比，在 10–12 个月大时的婴儿全球发育、语言或记忆结局方面未显示出显着差异。[32]自孕 18 周至产后 90 天，每天 750 毫克。[32]源材料中未提及。
人参领域 1 认知与神经可塑性（也被描述为多通路）。[33]描述的多通路作用：抑制神经炎症、增强抗氧化能力、改善线粒体代谢、调节突触可塑性[33]；通过 HPA/HPG 轴调节实现情绪调节、神经递质平衡以及 BDNF–TrkB 通路激活。[33]Meta 分析显示记忆结局得到改善；在合并分析中对整体认知、注意力或执行功能没有积极影响。[34]中等：多项随机对照试验（系统评价/Meta 分析包括 15 项随机对照试验）。[34]对 15 项随机对照试验（671 名患者）的 Meta 分析发现，记忆力显著改善 (SMD 0.19)，但对整体认知、注意力或执行功能没有积极影响。[34]在一项随机对照试验中，每天服用 3 克人参粉，持续 6 个月。[35]综述报告没有严重的不良事件，但大多数研究的偏倚风险不明确。[36]
猴头菇 (Hericium erinaceus)Domain 1 认知与神经可塑性；也针对情绪/睡眠结局进行了研究。[37, 38]一项试验中循环 pro-BDNF 增加[38]；综述文献中提出的神经营养效应（增强的 pro-BDNF/BDNF 和海马神经发生）[39]；一项研究报告了通过增加微生物群多样性的可能肠-脑机制。[40]认知测试结局（例如，随机对照试验/PCT 中的 MMSE 复合效应）[39]；一项研究表明，8 周后情绪/睡眠障碍有所减少。[38]中等：多项随机对照试验（系统评价包括多项随机对照试验）。[37, 39]口服猴头菇 8 周可减轻抑郁、焦虑和睡眠障碍，并增加循环 pro-BDNF（试验结果）。[38]源材料中未提及。潜在副作用包括胃部不适、头痛和过敏反应；在一篇综述中，不良反应罕见且通常为轻度胃肠道不适。[39, 40]
石杉碱甲领域 1 认知与神经可塑性[41]提供的摘要中未完全明确；综述文献提及 NMDA 拮抗作用、NGF 增加、抗氧化和抗淀粉样蛋白生成作用。[42]阿尔茨海默病的认知和功能结局（MMSE；ADL；某些分析中的 ADAS-Cog/HDS）。[41, 43]中等：多项随机对照试验（纳入 20 项随机对照试验；指出高偏倚风险）。[41]系统评价/Meta 分析（20 项随机对照试验；n=1823）发现在多个时间点与安慰剂相比有认知改善（MMSE），但大多数试验存在高偏倚风险。[41]源材料中未提及。一项 Meta 分析中，大多数不良事件本质上是胆碱能的，并且没有发生严重不良事件；另一篇综述报告没有严重不良事件。[43, 41]
长春西汀领域 1 认知与神经可塑性[44]源材料中未提及。痴呆/认知障碍中的认知结局（例如 MMSE；ADAS-Cog）。[45, 46]中等：多项随机对照试验（系统评价包括 3 项痴呆随机对照试验；还报告了其他安慰剂对照随机对照试验）。[44, 45]痴呆试验的考克兰综述（3 项研究；n=583）得出结论，长春西汀获益的证据尚无定论，且不支持临床使用。[44]痴呆研究中报告口服 30–60 毫克/天。[44]痴呆试验中不良反应报告不一致且无法获得意向性治疗数据；审稿人呼吁在卒中常规使用前开展更大规模、设计良好的随机对照试验。[44, 45]
氯芬酯 (meclofenoxate)领域 1 认知与神经可塑性（老年痴呆试验；还有临床前记忆效应）。[47, 48]源材料中未提及。老年痴呆/记忆结局（一项试验报告记忆功能较安慰剂有所改善）。[48]有限：单次随机对照试验或小型研究[47, 48, 49]在一项针对患有痴呆/记忆障碍的老年人的双盲随机试验中，与安慰剂相比，氯芬酯治疗与更高比例的记忆改善显示相关（48% 对比 28%）。[48]一项试验中每天 2 克，持续 8 周；在一项安慰剂对照交叉研究中，每次 600 毫克，每天两次，持续 12 周。[48, 49]源材料中未提及。
咖啡因领域 1 认知与神经可塑性以及领域 2 睡眠（睡眠干扰）。[50]资料中未将其提及为受体水平机制；综述强调了影响睡眠干扰敏感性的腺苷相关通路的遗传变异，以及 CYP1A2/ADORA2A 与认知/焦虑/睡眠障碍的关联。[50, 51]在睡眠剥夺情况下认知表现（注意力、执行功能、反应时间）有所改善[52, 53]；睡眠结局（入睡潜伏期、总睡眠时间、睡眠效率；慢波睡眠减少）。[50]中等：系统评价/荟萃分析中的多项随机对照试验 (RCT)[50, 52]针对睡眠剥夺/限制人群的荟萃分析（45 篇文献；327 个效应量估计值）发现，与安慰剂/对照组相比，咖啡因改善了注意力反应时间和准确性，并改善了执行功能。[52]资料中未提及。咖啡因通常会延长入睡潜伏期并减少总睡眠时间/睡眠效率；慢波睡眠通常会减少（具有剂量和时间依赖性）。[50]
麦角硫因领域 1 认知与神经可塑性（亦评估了睡眠结局）。[54]通过 OCTN1/SLC22A4 转运体摄入大脑[55]；在机制综合分析中提出具有抗氧化/抗炎特性。[56]复合记忆（主要结局）及次要认知领域、主观记忆和睡眠质量结局。[54]有限：单项随机对照试验 (RCT) 或小型研究[54]针对 55–79 岁伴有主观记忆减退的成人的为期 16 周的随机、双盲、安慰剂对照试验测试了 10 毫克/天和 25 毫克/天麦角硫因与安慰剂的对比（主要终点：复合记忆）。[54]16 周随机对照试验中的 10–25 毫克/天。[54]据报道，在试验队列中补充麦角硫因是安全且耐受性良好的。[54]
可可黄烷醇领域 1 认知与神经可塑性（急性认知需求表现）。[57]拟议的作用包括神经保护/神经调节蛋白质级联反应以及改善脑血流量/血管生成。[58]认知需求电池测试（连续减三/减七、RVIP）和精神疲劳评分。[57]有限：单项随机对照试验 (RCT) 或小型研究（证据被描述为对于即时作用而言有限/不确定）。[58]在一项双盲交叉试验中，与对照组相比，可可黄烷醇饮料（520 毫克和 994 毫克）改善了连续减三测试的表现，且 520 毫克饮料减轻了自我报告的精神疲劳。[57, 59]交叉研究中急性摄入 520–994 毫克可可黄烷醇；另一项随机对照试验中每日补充 250 毫克可可，持续四周。[57, 59]资料中未提及。
Souvenaid / Fortasyn Connect（医用食品）领域 1 认知与神经可塑性[60]旨在利用前体/辅助因子（尿苷一磷酸；胆碱；磷脂；DHA/EPA；维生素 E/C/B12/B6；叶酸；硒）支持突触合成和神经元膜形成。[60]通过 ADAS-cog 及其他记忆/认知测试（例如，神经心理学复合 z 分数；亚组中的延迟言语回忆）评估认知。[60, 61]中等：多项随机对照试验 + 系统评价/荟萃分析（3 项研究；总样本量 n=1011）。[61]S-Connect 为期 24 周的随机对照试验（n=527 名接受药物治疗的轻度至中度阿尔茨海默病患者）发现，在 ADAS-cog 下降方面与对照组相比无显著差异（差异 0.37 分；p=0.513）。[60]在 S-Connect 试验中为 125 毫升/天（125 千卡），持续 24 周。[60]不良事件发生率或临床相关的血液安全性参数无组间差异；被描述为与阿尔茨海默病药物联合使用时耐受性良好。[60]
尿苷一磷酸资料中未提及。资料中未提及。资料中未提及。迄今尚无证据——在提供的资料中未发现严谨的人体证据。迄今尚无证据——在提供的资料中未发现严谨的人体证据。资料中未提及。资料中未提及。
南非醉茄（Withania somnifera；KSM-66 / Sensoril）领域 2 压力/抗焦虑/睡眠[62, 63]资料中未提及。睡眠数量/质量（主要结局）和精神警觉性/焦虑/生活质量 (QoL)（次要结局）。[62] 压力/焦虑和皮质醇结局也在荟萃分析中报告（PSS、HAS、血清皮质醇）。[63]中等：多项随机对照试验（系统评价/荟萃分析）。[62, 63, 64]对 5 项随机对照试验（400 名参与者）的荟萃分析发现，与安慰剂相比，南非醉茄可使总体睡眠获得小幅但显著的改善（SMD −0.59；95% CI −0.75 至 −0.42）。[62]在失眠亚组中，当剂量 ≥600 毫克/天且持续时间 ≥8 周时，睡眠益处更为显著；一项随机对照试验使用 600 毫克/天，持续 8 周。[62, 65]睡眠随机对照试验中未报告严重副作用，但长期使用的严重不良事件数据有限；部分研究报告了轻度至中度不良事件 (AE)。[62, 63]
茶氨酸领域 2 压力/抗焦虑/睡眠[66, 67]资料中未提及。睡眠（主观入睡潜伏期、日间功能障碍、整体睡眠质量）在荟萃分析中得到改善[66]；一项随机对照试验中言语流畅度和执行功能等认知结局有所改善。[68]强：荟萃分析 + 多项随机对照试验[66, 69]荟萃分析报告称，茶氨酸改善了主观入睡潜伏期（SMD 0.15；95% CI 0.01–0.29；p=0.04）。[66]针对睡眠结局的试验考察了 50–900 毫克/天的剂量；随机对照试验中使用 200 毫克/天；在证据综合中建议在压力/焦虑情况下使用 200–400 毫克/天。[70, 68, 67]资料中未提及。
镁（甘氨酸盐 / 苏糖酸盐 / 柠檬酸盐）领域 2 压力/抗焦虑/睡眠（亦通过睡眠/情绪研究认知）。[71]镁涉及神经传递、下丘脑-垂体-肾上腺 (HPA) 轴调节以及睡眠-觉醒控制。[72]失眠/睡眠质量（包括入睡潜伏期）[73]；通过苏糖酸镁 (MgT) 改善日间功能（精力/生产力）[71]；一项随机对照试验中通过苏糖酸镁 (MgT) 改善认知（美国国立卫生研究院全套认知复合评分、工作/情景记忆）。[74]中等：多项随机对照试验（睡眠）+ 系统评价/荟萃分析[73, 75]对 3 项随机对照试验（151 名伴有失眠的老年人）进行的系统评价/荟萃分析发现，与安慰剂相比，镁使入睡潜伏期缩短了 17.36 分钟（95% CI −27.27 至 −7.44；p=0.0006）。[73]伴有睡眠问题的成人口服 1 克/天苏糖酸镁，持续 21 天[71]；另一项睡眠随机对照试验中使用 2 克/天苏糖酸镁[74]；一项为期 4 周的随机对照试验中使用 250 毫克元素镁/天的双甘氨酸镁。[76]随机对照试验报告苏糖酸镁安全/耐受性良好。[71, 74] 一项失眠荟萃分析中指出了证据质量局限性（中至高偏倚风险；低至极低确定性）。[73]
甘氨酸领域 2 压力/抗焦虑/睡眠[77]通过兴奋性/抑制性神经传递（NMDA 受体和甘氨酸受体）起作用。[78] 睡眠效应可能涉及降低核心体温（机制假说）。[78]健康人群的睡眠结局（证据被总结为小型/高偏倚风险）[77]；一项荟萃分析显示，使用 NMDA 共同激动剂（甘氨酸/D-丝氨酸）可改善精神分裂症的阴性症状。[79]有限：小型研究；睡眠证据被总结为小型/高偏倚风险。[77]综述综合报告称，长期服用甘氨酸可改善健康人群的睡眠，但研究规模较小且偏倚风险较高。[77]在一项急性缺血性中风随机对照试验中，甘氨酸剂量为 0.5–2.0 克/天，持续 5 天。[80]在一项急性中风试验中，4.5% 的患者出现轻度镇静，无其他显著不良事件。[80]
GABA（外源性）领域 2 压力/抗焦虑/睡眠[81]资料中未提及。安慰剂对照试验中的压力和睡眠结局（情绪和睡眠问卷）。[81, 82] 一项交叉研究报告了脑电图 (EEG) 睡眠分期变化。[83]中等：多项随机对照试验（安慰剂对照人体试验的系统评价）。[81]系统评价得出结论：口服 GABA 对缓解压力的证据有限，对改善睡眠益处的证据非常有限；需要开展更多研究。[81]示例：一项随机对照试验中 100 毫克/天，持续 12 周[82]；一项交叉睡眠研究中睡前 100 毫克[83]；一项为期 90 天的试验中 200 毫克/天；一项交叉认知试验中急性给予 800 毫克。[84, 85]资料中未提及。
牛磺酸领域 2 压力/抗焦虑/睡眠（认知证据混合/无效）。[86]资料中未提及。认知评分（荟萃分析报告无显著影响）。[86]中等：多项随机对照试验（荟萃分析包含 7 项随机对照试验）。[86]随机对照试验的荟萃分析（7 项随机对照试验；402 名受试者）报告称，牛磺酸对认知评分没有表现出显著影响。[86]在认知试验中，急性剂量通常为 1–3 克（最高约 50 毫克/公斤）（综述摘要）。[87]资料中未提及。
褪黑素领域 2 压力/抗焦虑/睡眠[88]资料中未提及。睡眠结局（入睡潜伏期、总睡眠时间）以及轻度认知障碍 (MCI)/痴呆老年患者简易智能精神状态检查量表 (MMSE)。[89, 88]强：荟萃分析 + 多项随机对照试验[89, 88]对 10 项针对 ≥65 岁伴有轻度认知障碍/痴呆成人的随机对照试验（n=516）进行的荟萃分析发现，褪黑素增加了总睡眠时间（+12.4 分钟）并改善了简易智能精神状态检查量表评分（+1.8 分）。[89]资料中未提及。资料中未提及。
5-羟色氨酸 (5-HTP)领域 2 压力/抗焦虑/睡眠（血清素前体）。[90, 91]5-羟色氨酸是血清素生物合成的中间体[92]，在脑内转化为血清素；据报道补充后血清中血清素增加。[93, 90]系统评价/荟萃分析中的情绪/抑郁结局[94]；部分研究中睡眠质量成分有所改善。[91]中等：伴有荟萃分析的多项随机对照试验（指出了研究质量局限性）。[95, 94]荟萃分析报告，在 13 项研究中抑郁缓解率为 0.65（95% CI 0.55–0.78）；由于安慰剂组较少，总体偏倚风险被判定为相对较弱。[94]一项为期 4 周的交叉研究中使用 50 毫克/天[96]；在一项侧重于睡眠的研究中，老年人使用 100 毫克/天，持续 12 周。[91]综述讨论了与潜在致命的嗜酸性粒细胞增多-肌痛综合征可能存在尚未阐明的关联；证据质量不足以得出确定性结论。[97]
L-色氨酸领域 2 压力/抗焦虑/睡眠（血清素/褪黑素前体）。[98, 99]色氨酸是血清素的前体；向下游转化为褪黑素被描述为会影响昼夜节律和睡眠质量。[98, 99]睡眠效率和入睡后觉醒时间（在荟萃分析中得到改善）。[100] 随机对照试验综述中的健康成人情绪结局（对消极/快乐感受的影响）。[98]中等：多项随机对照试验（系统评价包含 11 项随机对照试验）。[100, 98]双盲安慰剂对照交叉试验使用 1000 毫克/天色氨酸，并报告与安慰剂相比，客观睡眠效率和入睡后觉醒时间有所改善（与 5-HTTLPR 等位基因变异无关）。[101]安慰剂对照交叉随机对照试验中使用 1000 毫克/天；综述摘要包括各项随机对照试验中 0.14–3 克/天的范围。[101, 98]纳入的睡眠障碍研究中未发现严重不良事件（系统评价声明）。[102]
藏红花 (Crocus sativus; affron)领域 2 压力/抗焦虑/睡眠（情绪/焦虑/睡眠结局）。[103, 104]来源中未提及。抑郁（BDI；DASS-21）、焦虑（BAI）及睡眠质量（PSQI；睡眠质量评分）。[104, 105, 106]强：Meta 分析 + 多项 RCT[103, 104]Meta 分析（21 项试验）发现，与对照组相比，藏红花可降低 BDI（WMD −4.86）、BAI（WMD −5.29）和 PSQI（WMD −2.22）。[104]Affron® 28 mg/天，用于情绪 RCT 以及睡眠 RCT（于睡前 1 小时给药）。[106, 107]据报道，藏红花/affron® 在 RCT 中耐受性良好，无显著不良反应；审阅者指出，部分证据来源于存在潜在偏倚风险的研究。[106, 108]
缬草 (Valeriana officinalis)领域 2 压力/抗焦虑/睡眠[109]镇静特性归因于对中枢神经系统中 GABA 功能的调节（成分包括缬草酸和缬草三酯）。[110]随机安慰剂对照试验和 Meta 分析中的睡眠质量/失眠结局。[109, 111]中等：多项 RCT（各试验间结果不一致）。[109, 112, 113]系统评价/Meta 分析（16 项符合标准的研究所包含 1093 名患者）发现其对二分类睡眠质量结局有益（RR 改善睡眠 = 1.8；95% CI 1.2–2.9），并有发表偏倚的证据。[109]来源中未提及。缬草通常被描述为安全性高且不良事件罕见；评价指出在 7–80 岁年龄段中无严重不良事件。[113, 114]
香蜂草 (Melissa officinalis)领域 2 压力/抗焦虑/睡眠[115]迷迭香酸可能调节 GABA 转氨酶活性（产生睡眠质量效应）。[116] 体外胆碱能受体结合/置换表明其可能与阿尔茨海默病 (AD) 的认知缺陷相关。[117]Meta 分析显示焦虑和抑郁症状评分有所改善；在 RCT 中测量了睡眠质量。[115, 118]中等：多项 RCT（Meta 分析和临床试验）。[115, 118]Meta 分析报告称，与安慰剂相比，香蜂草可改善焦虑 (SMD −0.98) 和抑郁 (SMD −0.47)，且无严重副作用（由于异质性需谨慎对待）。[115]在临床试验中采用 1.5 g/天的干燥叶粉 7 天方案改善了冠脉搭桥术 (CABG) 术后患者的焦虑和睡眠质量；交叉研究中测试了 300/600/900 mg 的急性单次剂量。[118, 117]Meta 分析报告无严重副作用，但强调了异质性和有限的试验数量。[115]
西番莲 (Passiflora incarnata)领域 2 压力/抗焦虑/睡眠[119, 120]抗焦虑/镇静作用被描述为通过 GABA 能调节和 5-羟色胺能途径介导（综述）。[121]多项试验中的焦虑减轻[119]；在 RCT 中，多导睡眠图总睡眠时间和主观睡眠质量得到改善。[120, 122]中等：多项 RCT（系统评价包含 9 项临床试验）。[119]双盲安慰剂对照失眠研究报告称，与安慰剂相比，多导睡眠图总睡眠时间增加 (P=0.049)。[120]来源中未提及。系统评价报告无不良反应，包括无记忆丧失；其他综述警告称，许多临床研究的方法学和产品描述不充分。[119, 123]
薰衣草油 (Silexan)领域 2 压力/抗焦虑/睡眠[124]来源中未提及。焦虑严重程度 (HAMA) 和睡眠质量 (PSQI)。[124, 125]强：Meta 分析 + 多项 RCT[124]对 3 项随机安慰剂对照试验（697 名患者）的 Meta 分析发现，在 10 周内，80 mg/天的 Silexan 较安慰剂降低了 HAMA 总分（平均差 3.83 分；95% CI 1.28–6.37）。[124]80 mg/天，持续 10 周（部分研究评估了 160 mg/天）。[124, 126]不良事件发生率与安慰剂相当（RR 1.06）；综述指出可能会出现轻度胃肠道症状，但在 80–160 mg/天剂量下无镇静或戒断现象，且无药物相互作用。[124, 127]
啤酒花 (Humulus lupulus)领域 2 压力/抗焦虑/睡眠[128]调节 GABA(A) 受体[128]；据报道可在体外与 5-羟色胺/褪黑素受体结合[129]；睡眠作用归因于结合 GABA(A) 受体上的 GABA 位点并增强 δ 波睡眠。[130]非器质性睡眠障碍患者的睡眠潜伏期和睡眠后觉醒减少，同时慢波睡眠增加；在缬草-啤酒花联合试验中，睡眠发作潜伏期得到改善。[129, 131]有限：小型人体研究（通常为缬草-啤酒花联合应用）。[129]人体研究报告显示睡眠潜伏期和睡眠后觉醒减少，同时慢波睡眠扩大；一项试验报告称，与安慰剂相比，联合制剂形式的啤酒花增加了临床疗效并缩短了延长的睡眠发作潜伏期。[129, 131]来源中未提及。来源中未提及。
α-S1 酪蛋白水解物 (Lactium)领域 2 压力/抗焦虑/睡眠[132]来源中未提及。睡眠质量和心理痛苦结局（ISI/GSDS/PSQI/ESS/HADS）以及多导睡眠图睡眠发作潜伏期。[132]中等：多项 RCT[132]为期 4 周的随机双盲安慰剂对照失眠试验 (n=36) 显示，与安慰剂相比，主观睡眠指标得到改善，且 PSG 睡眠发作潜伏期缩短 (p=0.012)。[132]在一项 RCT 中，最初为 600 mg/天，随后两周为 300 mg/天；其他试验在胶囊中使用 150 mg（有时与 L-茶氨酸联用）。[132, 133]来源中未提及。
洋甘菊 (Matricaria chamomilla)领域 2 压力/抗焦虑/睡眠[134, 135]来源中未提及。睡眠质量（PSQI；觉醒次数；睡眠发作潜伏期）和广泛性焦虑障碍结局 (HAM-A)。[134, 135]中等：多项 RCT（系统评价/Meta 分析）。[134, 135]系统评价/Meta 分析（10 项研究；772 名参与者）发现洋甘菊降低了 PSQI 评分（WMD −1.88；95% CI −3.46 至 −0.31）。[134]来源中未提及。部分试验报告了轻度不良事件；另一项综述报告无不良事件（被动监测）。[135, 134]
卡瓦胡椒 (Piper methysticum)领域 2 压力/抗焦虑/睡眠 (GAD)。[136]通过脂膜效应和钠通道功能调节 GABA 活性；MAO-B 抑制；去甲肾上腺素/多巴胺再摄取抑制。[137]焦虑严重程度（HAM-A 及相关量表，如 STAI-状态）。[138]中等：多项 RCT（Cochrane 分析中的 12 项双盲 RCT）。[139]Cochrane Meta 分析（12 项双盲 RCT；n=700）发现，与安慰剂相比，卡瓦胡椒降低了 HAM-A 总分（WMD 3.9；95% CI 0.1–7.7；p=0.05；n=380）。[139]短期（4–8 周）使用 120–280 mg/天的卡瓦内酯。[136]应考虑安全性问题；指导意见建议采用传统水溶性提取物，避免饮酒，对精神类药物/驾驶保持谨慎，且常规使用者需进行肝功能检查。[137]
红景天 (Rhodiola rosea)（红景天苷/红景天苷类）领域 2 压力/抗焦虑/睡眠（适应原；抑郁/焦虑/压力）。[140, 141]讨论的机制包括 HPA 轴调节、神经递质系统效应和抗氧化途径；综述描述了线粒体功能改善和细胞能量产生增加（机制总结）。[141]主观压力和疲劳、轻度至中度抑郁和轻度焦虑症状、情绪、精神运动表现/认知处理速度（临床研究中报告，引自综述）。[141, 140]中等：多项 RCT（某综述中包含 11 项安慰剂对照 RCT）。[142]系统评价证据：共识别出 11 项针对红景天的安慰剂对照 RCT；由于实验数据有限（确定性局限），总体结论被描述为不确定。[142, 140]来源中未提及。系统评价仅报告了少数轻度不良事件；由于纳入研究存在高偏倚风险/报告缺陷，证据确定性受限。[142, 143, 140]
维生素 D3（胆钙化醇）领域 2 压力/抗焦虑/睡眠（睡眠质量结局）。[144]来源中未提及。干预 Meta 分析中的睡眠质量 (PSQI) 和抑郁症状 (BDI)。[145, 146]强：Meta 分析 + 多项 RCT[144, 145]系统评价/Meta 分析发现，补充维生素 D 显著降低了 PSQI（与安慰剂相比，平均差 −2.33；95% CI −3.09 至 −1.57；p<0.001；I²=0%）。[144]来源中未提及。Meta 分析报告称，补充维生素 D 未引起副作用（在纳入的研究中）。[145]
乙酰左卡尼汀 (ALCAR)领域 3 能量与线粒体（亦针对抑郁/认知进行了研究）。[147]支持β-氧化和乙酰辅酶 A 维持[148]；调节脑能量/磷脂代谢和突触形态/传递（多种神经递质）[148]；讨论了抗氧化、抗细胞凋亡活性及神经炎症获益。[147]RCT Meta 分析中的抑郁症状[149]；MCI/轻度 AD Meta 分析中的临床全球变化和认知结局。[150]中等：多项 RCT（针对抑郁和 MCI/轻度 AD 的 Meta 分析）。[149, 150]抑郁 Meta 分析：合并的 RCT 显示，与安慰剂/无干预相比，ALC 显著减轻了抑郁症状 (SMD −1.10；95% CI −1.65 至 −0.56)。[149]1.5–3.0 g/天（MCI/轻度 AD 试验中的每日剂量范围）。[150]在与抗抑郁药的 RCT 相比中，ALC 的不良反应显著较低；总体而言，ALC 在认知试验中耐受性良好。[149, 150]
辅酶 Q10（泛醇/泛醌）领域 3 能量与线粒体（生物能量/抗氧化）。[151]生物能量和抗氧化活性；参与能量产生并防止过氧化膜损伤/自由基氧化。[151]RCT Meta 分析中的抑郁症状和疲劳结局（抑郁改善；疲劳不显著）。[152]中等：多项 RCT（Meta 分析）。[152, 153]对 5 项 RCT（474 名参与者）的 Meta 分析发现，与对照组相比，辅酶 Q10 减轻了抑郁症状 (SMD −0.68；95% CI −1.02 至 −0.33；P<0.01)。[152]某项分析描述，持续 6–8 周使用 100–200 mg/天的低剂量与抑郁症状的改善相关。[153]来源中未提及。
吡咯喹啉醌 (PQQ)领域 3 能量与线粒体（亦针对压力/疲劳/睡眠进行了研究）。[154]机制总结描述了 Nrf2/ARE 抗氧化途径的激活、AMPK/PGC-1α 线粒体生物发生/功能以及用于炎症调节的 NF-κB 抑制。[154]开放标签试验中的压力/疲劳/生活质量/睡眠[155]；以 Cognitrax 作为主要终点的 RCT 中的认知表现结局。[156]有限：小型人体研究（一项 RCT 加上一项小型开放标签试验）。[156, 155]为期 12 周的随机双盲安慰剂对照 RCT 评估了 64 名健康志愿者每日服用 21.5 mg 吡咯喹啉醌二钠盐对认知功能/表现结局的影响。[156]开放标签试验中 20 mg/天，持续 8 周；RCT 中 21.5 mg/天（吡咯喹啉醌二钠盐），持续 12 周。[155, 156]认知 RCT 中未报告不良事件；毒理学评估报告了广泛的安全性且无致突变潜力。[156]
一水肌酸领域 3：能量与线粒体（脑生物能量学）。[157]改善 ATP 的可用性/磷酸肌酸缓冲，支持线粒体功能（综述文献中的机制解释）。[158]Meta 分析显示记忆结果有所改善；报告了注意力时间和处理速度结果；在一项 Meta 分析中，整体认知/执行功能无显著改善。[159, 157]强：Meta 分析 + 多项随机对照试验 (RCT)[157, 159]系统评价/Meta 分析（16 项 RCT；492 名参与者）发现肌酸可改善记忆力和处理速度，但不能改善整体认知功能或执行功能。[159]示例：在一项 RCT 中，每日 4 次，每次 5 克，持续 7 天；在一项交叉研究中，负荷剂量为每日 20 克，持续 7 天。[160, 161]通常耐受性良好，但在精神病学综述中，2/17 的参与者出现了轻度躁狂/躁狂；肾脏疾病患者或使用影响肾脏药物的患者应谨慎使用。[162, 163]
MCT 油（中链甘油三酯）领域 3：能量与线粒体（酮体/替代燃料）。[164, 165]诱导轻度生酮状态，并可能改善轻度认知障碍 (MCI)/阿尔茨海默病 (AD) 患者的认知；在葡萄糖利用受损时，提升 β-羟基丁酸作为替代底物。[164, 165]MCI/AD 患者的认知表现（例如 ADAS-Cog 和 MMSE）以及记忆指数（重点关注工作记忆）。[164, 166]中等：多项随机对照试验 (RCT)（系统评价/Meta 分析；存在偏倚风险）。[164, 167]针对 RCT 的 Meta 分析（12 项记录；422 名参与者）发现，MCT 可增加 β-羟基丁酸并改善复合认知结果（ADAS-Cog+MMSE SMD −0.289；95% CI −0.551 至 −0.027）。[164]示例：MCI 患者每日 56 克，持续 24 周；健康年轻成人每日 12–18 克，持续 4 周；在一项交叉试验中，总日脂肪剂量约为每日 17.3 克。[168, 169, 170]主要报告了胃肠道副作用；综述指出，由于方案异质性/设计不佳以及利益冲突，证据存在局限性。[167]
β-羟基丁酸（酮酯/盐）领域 3：能量与线粒体（大脑替代燃料）。[171]外源性酮体可提高血液 β-OHB 并降低血糖（急性代谢转变）。[172]RCT/系统评价中的认知功能测量指标；代谢结果包括血糖/β-OHB 的变化。[173, 172]强：Meta 分析 + 多项随机对照试验 (RCT)[171]系统评价/Meta 分析（38 项研究/41 个方案；1,602 名参与者）发现，补充外源性酮体可改善认知表现，安慰剂对照组的 SMD 为 0.29（95% CI 0.16–0.41；p<0.001）。[171]来源中未提及。静脉输注 β-羟基丁酸耐受性良好，不良事件较少；血糖偶尔降低，但保持在正常范围内。口服外源性酮体会急剧降低血糖（在低血糖风险中监测可能具有相关性）。[174, 172]
Axona（辛酸甘油三酯医用食品）领域 3：能量与线粒体（酮体替代燃料）。[165, 175]向葡萄糖利用受损的大脑提供酮体（通过中链甘油三酯），为葡萄糖提供替代能源。[175, 165]通过 ADAS-Cog11 和 MMSE 测量的轻度至中度阿尔茨海默病患者的认知能力；临床医师整体变化评估 (C-GIC)。[176, 177]中等：多项随机对照试验 (RCT)（例如，26 周 RCT；其他小型临床干预）。[176, 177]为期 26 周的双盲安慰剂对照 RCT（AC-12-010；NOURISH AD）报告称，在主要 ADAS-Cog11 结果上未检测到显著的药物作用（最小二乘均数差 −0.761；p=0.2458），次要结果也未能检测到药物作用。[176]示例方案：每日 40 克粉末，含 20 克辛酸甘油三酯，持续 3 个月，在 7 天内滴定至 10→40 克/天。[177]耐受性良好，无严重胃肠道不良反应；滴定法减少了胃肠道不良反应。[177]
D-核糖领域 3：能量与线粒体（所提供来源中的证据为临床前证据，且表明存在认知损害）。[178]来源中未提及。临床前认知结果：动物模型中的平台穿越次数和认知障碍；大脑和血液中的晚期糖基化终产物 (AGE) 增加。[178]仅机制/临床前研究[178]啮齿动物系统评价/Meta 分析得出结论：D-核糖会导致认知障碍，并具有剂量相关性恶化，同时增加大脑和血液中的晚期糖基化终产物 (AGE)。[178]来源中未提及。来源中未提及。
烟酰胺核糖核苷 (NR)领域 3：能量与线粒体（NAD+ 前体；神经保护基础）。[179, 180]NAD+ 前体支持线粒体/神经功能以及减少炎症（试验背景中有所描述）；大脑 NAD+ 验证是轻度认知障碍 (MCI)/轻度 AD 试验设计中明确的目标。[180, 181]在为期 24 周的长新冠 (long-COVID) 随机对照试验 (RCT) 中的认知（ECog/RBANS/TMT-B）以及疲劳/抑郁/焦虑/睡眠质量结果；在叙述性综述背景中描述了睡眠效率效应。[180, 179]中等：多项 RCT/临床试验[180, 182, 183]为期 24 周的双盲安慰剂对照 RCT（长新冠）显示，NR 增加了 NAD+ 水平（5–10 周后增加 2.6–3.1 倍），但在认知结果（ECog/RBANS/TMT-B）方面，组间无显著差异。[180]示例：在 24 周试验中 NR 2000 毫克/天；在 8 周交叉试验中 NR 1 克/天；在老年男性 21 天交叉试验中 NR 1 克/天。[180, 182, 183]长新冠试验中报告的一起严重不良事件被认为与 NR 无关；综述将 NR 描述为具有生物利用度且耐受性良好，对人类的不良反应有限。[180, 184]
烟酰胺单核苷酸 (NMN)领域 3：能量与线粒体（NAD+ 前体；睡眠和身体机能终点）。[185, 186]来源中未提及。睡眠质量终点（PSQI；一项方案中的主要终点）和身体表现（例如 4 米步行时间），同时血液 NAD+ 及其代谢物增加。[186, 187]中等：多项 RCT（关于 NAD+ 增加的证据；睡眠 RCT 正在进行中/方案阶段）。[188, 185]为期 12 周的双盲安慰剂对照研究（n=60；NMN 250 毫克/天）报告称，与安慰剂相比，4 米步行时间显著缩短，血液 NAD+ 及其代谢物显著升高。[187]一项 RCT 中 250 毫克/天，持续 12 周；一项慢性失眠 RCT 方案中 320 毫克/天；一项系统评价中各项 RCT 的剂量为 250–900 毫克/天。[187, 186, 185]系统评价报告称，在纳入的研究中仅观察到轻微的不良反应，未观察到严重的不良反应。[185, 189]
烟酰胺 / 尼克酰胺 (B3)领域 3：能量与线粒体（NAD+ 前体；人类认知亚研究为阴性结果）。[190]NAD+ 前体作用以及讨论的机制，包括维持细胞能量和抑制 SIRT1（综述讨论）；临床前 AD 模型中的神经保护作用涉及维持线粒体完整性和自噬（临床前）。[191, 192]在一项为期 12 个月的亚研究（n=310）中，口服烟酰胺对认知功能或生活质量无显著影响。[193]有限：小型临床研究/RCT 亚研究；在所提供的来源中，临床前证据强于人类认知获益。[193]III 期亚研究（n=310）发现，在 12 个月内，口服烟酰胺对认知功能或生活质量无显著影响。[193]12 个月亚研究中口服 500 毫克，每天两次；一项 N-of-1 设计（焦虑试验）中 3000 毫克/天。[193, 194]在一项 N-of-1 试验中，在 3000 毫克/天烟酰胺治疗期间，转氨酶保持正常；综述指出高水平可能会导致神经毒性（一般注意事项）。[194, 191]
姜黄素（Longvida / Theracurmin / Meriva）领域 4：收敛/多靶点（同时也是老年人的认知结果）。[195, 196]在 Meta 分析中，姜黄素增加了血清 BDNF（WMD 约 1789 皮克/毫升；注意到异质性）。[197] 临床前综合中引用的机制通路包括 NF-κB/Nrf2/BDNF–TrkB 等（临床前）。[198]系统评价中 >50 岁成人的认知结果（记忆/注意力测试）[195]；在随机对照试验 (RCT) 的 Meta 分析中，抑郁/焦虑症状得到改善。[198]中等：多项 RCT（系统评价/Meta 分析；异质性/制剂变异性）。[195, 198]针对 >50 岁成人的安慰剂对照 RCT 的系统评价报告称，某些研究中的认知能力有所改善，其中包括一项使用 90 毫克姜黄素每日两次的试验，该试验在 18 个月内改善了选择性提醒、视觉记忆和注意力。[195]示例：每日两次，每次 90 毫克（一项长期试验）；另一项试验中 1,500 毫克/天（52 周）。[195]胃肠道症状是认知 RCT 中最常见的不良事件（58 起不良事件；34 起为胃肠道不良事件）。[195] 一些试验报告无不良事件；由于异质性和潜在的发表偏倚，审稿人提醒需谨慎。[199, 198]
白藜芦醇（反式白藜芦醇）领域 4：收敛/多靶点（混合的认知/情绪证据）。[200]Meta 分析报告了抗炎生物标志物（hs-CRP/TNF-α）的降低。[201]认知表现域（例如延迟再认）和情绪/负面情绪；在一项 Meta 分析中，延迟再认和负面情绪的合并效应显著。[200]中等：多项随机对照试验 (RCT)（系统评价/Meta 分析；各终点结果不一致）。[200]系统评价/Meta 分析报告了延迟再认（SMD 0.39；n=166）和负面情绪（SMD −0.18；n=163）的合并获益，但总体文献被描述为不一致/有限。[200]来源中未提及。来源中未提及。
萝卜硫素（源自萝卜硫苷）领域 4：收敛/多靶点（Keap1/Nrf2；表观遗传效应）。[202]Keap1/Nrf2 轴和组蛋白去乙酰化酶抑制（表观遗传机制）。[202]孤独症谱系障碍的症状改善和精神分裂症的认知获益（综述总结）；在一项安慰剂对照试验中测试了健康成人的睡眠质量。[202, 203]有限：所提供来源中的人类证据包括针对睡眠的小型安慰剂对照研究以及针对脑部疾病的综述级综合。[203, 202]安慰剂对照试验：睡眠质量较差的成人食用西兰花芽胶囊（30 毫克萝卜硫苷）持续 4 周（探索睡眠质量影响）。[203]每日 30 毫克萝卜硫苷，持续 4 周（西兰花芽胶囊）。[203]来源中未提及。
S-腺苷蛋氨酸 (SAMe)领域 4：收敛/多靶点（甲基供体；抑郁焦点）。[204, 205]所提供的摘要中未完全明确；综述指出 SAMe 可能促进神经传递（与甲基化相关的基本原理）。[206]系统评价和随机对照试验 (RCT) 中的抑郁症状和可接受性。[207, 208]中等：多项 RCT/Meta 分析，但确定性各不相同。[207, 208]Cochrane 综述（8 项试验）发现，作为单药疗法，SAMe 与安慰剂在抑郁症状变化方面没有强有力的证据表明存在差异（SMD −0.54；95% CI −1.54 至 0.46；证据质量非常低）。[208]各项试验的每日剂量在 200–3200 毫克/天之间；一项 RCT 测试了 800 毫克/天，持续 8 周。[204, 205]不良事件在一项综述中大多为轻度/短暂的胃肠道紊乱；报告了躁狂/轻度躁狂（441 名参与者中有 2 份报告），并指出了关于双相情感障碍中躁狂发作的警告。[209, 208, 206]
叶酸 / 左旋甲基叶酸 (5-MTHF)靶点 4 整合/多靶点（一碳循环；抑郁症的辅助治疗）。[210]左旋甲基叶酸是蛋氨酸合成酶的甲基供体，可将同型半胱氨酸转化为蛋氨酸[210]，支持 SAMe 的生成[210]，并通过 BH4 相关通路（多巴胺、去甲肾上腺素、5-羟色胺）支持下游单胺合成。[210]作为抗抑郁药的辅助治疗时，抑郁评分/有效率/缓解率。[211]强：荟萃分析 + 多项 RCT[211, 212]系统评价/荟萃分析（6 项 RCT）发现，辅助补充叶酸（左旋甲基叶酸/叶酸）可降低 HAM-D（MD −2.16），并提高与单用 SSRI/SNRI 相比的有效率（RR 1.36）和缓解率（RR 1.39）。[211]证据表明，当作为 SSRI 治疗的辅助手段且限制叶酸 <5 毫克/天或甲基叶酸 15 毫克/天时具有益处。[213]潜在担忧包括掩盖维生素 B12 缺乏以及有争议的癌症风险关联；评价指出临床试验未发现叶酸存在安全性/耐受性问题。[210, 214]
维生素 B12（甲钴胺）靶点 4 整合/多靶点（在无缺乏人群中总体无认知/抑郁益处）。[215]源材料中未提及。荟萃分析报告称，在无明显缺乏/无晚期神经系统疾病的人群中，对认知功能或抑郁症状无显著影响。[216]中等：多项 RCT + 荟萃分析（在无缺乏人群中对认知/抑郁总体无效）。[215]系统评价/荟萃分析（16 项 RCT；n=6276）发现，在无明显维生素 B12 缺乏/无晚期神经系统疾病的患者中，没有证据表明单用维生素 B12 或 B 族复合维生素可改善认知亚域或抑郁指标。[215]一项针对认知障碍的 RCT 使用了肌内注射维生素 B12 500 毫克/天 ×7 天，随后给予钴胺酰胺 0.25 毫克/天加甲钴胺 0.50 毫克/天。[217]自闭症谱系障碍 (ASD) 荟萃分析报告了轻度不良事件（例如多动、易怒、睡眠困难），与安慰剂相比无显著差异；所提供的摘要中未提及更广泛的禁忌症。[218]
维生素 B6 (P5P)靶点 4 整合/多靶点（一碳代谢辅酶；未显示出认知益处）。[219, 220]P5P 参与一碳代谢和神经递质生物合成；一项试验摘要显示补充剂增加了血浆磷酸吡哆醛。[220, 221]健康老年人的认知和情绪结局（无显著益处）。[221]有限：小型 RCT（2 项试验；109 名健康老年人）。[221]Cochrane 评价发现，尽管改善了维生素 B6 状态标志物，但在 2 项安慰剂对照 RCT（n=109）中，维生素 B6 对认知或情绪没有显著益处。[221]老年女性 75 毫克/天，持续 5 周；老年男性 20 毫克/天，持续 12 周（盐酸吡哆醇）。[221]纳入的试验中未报告不良反应。[221]
维生素 C（抗坏血酸）靶点 4 整合/多靶点（情绪/认知与维生素 C 状态相关；RCT 结果不一）。[222]源材料中未提及。抑郁症状/情绪和心理痛苦结局（荟萃分析总体无效）。[223]中等：多项 RCT + 荟萃分析（总体无效；亚组效应）。[223]对 10 项试验（n=836）的荟萃分析发现，情绪状态无显著总体改善（Hedges’ g 0.09），但亚组分析表明，对于未开具抗抑郁药的亚临床抑郁受试者有益（Hedges’ g −0.18）。[223]住院患者每次 500 毫克，每天两次（情绪/痛苦试验）；学生补充剂试验中 500 毫克/天。[224, 225]源材料中未提及。
锌靶点 4 整合/多靶点（认知证据不一；对 BDNF/炎症和抑郁的证据更强）。[226, 227]在一项 RCT 荟萃分析中，补充锌增加了循环 BDNF；荟萃分析显示全身炎症标志物（CRP、TNF-α）和 MDA 降低。[226, 228]儿童认知（6 项 RCT 总体无显著影响）[229]；抑郁患者荟萃分析中抑郁症状有所改善（WMD −4.15）。[227]中等：多项 RCT/荟萃分析（认知结果不一；对抑郁/BDNF 为阳性）。[229, 227]儿童认知荟萃分析（6 项 RCT）发现，锌对智力、执行功能或运动技能没有显著的总体影响。[229]源材料中未提及。源材料中未提及。
硒靶点 4 整合/多靶点（人类 RCT 证据包括中风结局）。[230]源材料中未提及。RCT 荟萃分析中的中风结局（1 个月后的格拉斯哥昏迷量表评分）和呼吸道感染结局。[230]中等：多项 RCT（系统评价/荟萃分析包含 5 项 RCT）。[230]包含 5 项 RCT 的系统评价/荟萃分析发现，与安慰剂相比，硒改善了 1 个月时的格拉斯哥昏迷量表评分（OR 1.54；95% CI 1.10–2.15）并减少了呼吸道感染（OR 0.55；95% CI 0.34–0.88）。[230]源材料中未提及。源材料中未提及。
铁靶点 4 整合/多靶点（脑能量代谢、神经递质合成；认知和疲劳结局）。[231]铁支持大脑能量代谢和神经递质合成[231]，并参与髓鞘生成、线粒体功能、ATP/DNA 合成以及神经递质循环。[232]荟萃分析/RCT：疲劳、焦虑、身体健康、认知智力、短时记忆结局（对注意力和抑郁的某些结果为无显著差异）。[231]强：荟萃分析 + 多项 RCT[231]系统评价/荟萃分析（18 项研究中的 12 项 RCT；总 n=1,340）报告称，在非贫血人群中补充铁剂可改善焦虑、疲劳、认知智力和短时记忆。[231]源材料中未提及。源材料中未提及。
碘靶点 4 整合/多靶点（轻度缺乏时的儿童认知结局）。[233]源材料中未提及。学龄儿童的认知结局（知觉推理；全球认知评分）以及孕期补充试验中的孕妇甲状腺结局（评价）。[234]中等：多项 RCT/系统评价（温和/混合的认知影响）。[234, 235]一项针对轻度碘缺乏儿童（10–13 岁）的随机安慰剂对照试验报告称，在 28 周内每天补充 150 微克碘，总体认知评分有所改善（+0.19 SD），并且 4 个认知亚测验中有 2 个得到改善。[233]儿童每天服用 150 微克碘片，持续 28 周。[233]源材料中未提及。
谷胱甘肽（脂质体型 / S-乙酰基）靶点 4 整合/多靶点（GSH/氧化还原；通过 GlyNAC 前体补充产生的认知信号）。[236, 237]谷胱甘肽是一种关键的细胞内抗氧化剂，支持氧化还原稳态及相关的免疫/神经递质系统。[236]预试验证据报告称，老年人在补充 GlyNAC（谷胱甘肽前体）后认知能力得到改善，且多种衰老相关缺陷得以逆转；停止补充会导致缺陷再次出现。[237]有限：针对认知终点的小型人体研究（GlyNAC 试验证据）；更广泛的证据侧重于非脑部结局。[237]一项人体预试验报告称，补充 GlyNAC 24 周可逆转老年人的缺陷并改善认知能力；停止 12 周会导致缺陷重新发展。[237]源材料中未提及。结核病背景下的系统评价报告称，GSH/NAC 的不良反应大多轻微且可控；评价指出，GSH/前体补充剂背景需要进一步的临床研究。[238, 236]
N-乙酰半胱氨酸 (NAC)靶点 4 整合/多靶点（抗氧化/抗炎；认知/情绪试验）。[239, 240]具有抗氧化、促进神经发生和抗炎特性的谷胱甘肽前体；评价引用了其在氧化应激、线粒体功能障碍、神经炎症以及谷氨酸/多巴胺失调中的作用。[240, 239]跨疾病的认知结局（系统评价）以及精神/神经背景下的抑郁症状。[240]中等：多项 RCT（针对认知和更广泛的精神/神经用途的系统评价证据）。[240]关于 NAC 与人类认知的系统评价报告称，现有数据表明 NAC 治疗后认知能力有统计学显著改善，但由于缺乏针对 NAC 的研究，证据有限且难以解释。[240]纳入研究中的剂量为 1000–3000 毫克/天；总结试验中的治疗持续时间为 8–24 周。[241]总体而言，NAC 治疗显得安全且耐受性良好（系统评价）。[239]
鼠李糖乳杆菌 / 长双歧杆菌（精神益生菌）靶点 4 整合/多靶点（肠-脑轴）。[242]精神益生菌株产生神经调节代谢物（短链脂肪酸、诸如 GABA/5-羟色胺等神经递质），并可以调节神经递质、肠道菌群组成和炎症反应。[242]荟萃分析显示抑郁和焦虑症状得到改善；一项 RCT 混合物改善了健康志愿者的抑郁情绪状态和睡眠质量。[243, 244]中等：多项 RCT + 荟萃分析[243, 245]16 项 RCT（n=1,125）的荟萃分析报告称，使用益生菌可改善抑郁症状（BDI MD −3.20）和焦虑（STAI MD −6.88）（确定性根据结局评定为中等/低）。[243]源材料中未提及。源材料中未提及。
益生元纤维（GOS / FOS / 菊粉）靶点 4 整合/多靶点（影响情绪/困意的肠道-微生物群-脑轴）。[246]益生元可增加双歧杆菌丰度并可调节炎症通路（机制研究中报告了 TLR4–Myd88–NF-kB 下调）。[247, 248]在一项小型交叉试验中，在睡眠受限/昼夜节律错位情况下的情绪/困意和认知表现；尽管微生物群发生改变，但某些试验发现压力/炎症生物标志物或心理健康症状没有变化。[249, 250]有限：小型 RCT（结果不一）。[249, 250]随机双盲交叉试验（n=11）发现，在睡眠受限/昼夜节律错位情况下，与安慰剂相比，益生元饮食降低了困意 (KSS) 并增加了积极/平静情绪 (PANAS)；PVT 反应时间更快，但一致的斯特鲁普（Stroop）反应时间更慢。[249]示例：交叉试验中 5 克/天 FOS + 5 克/天 GOS；在睡眠受限/昼夜节律错位研究中，聚葡萄糖和 GOS 各 7.5 克/天，持续 14 天；肥胖 RCT 中 16 克/天菊粉，持续 3 个月。[250, 249, 251]源材料中未提及。
乳铁蛋白领域 4 趋同/多靶点（免疫调节；同时涉及睡眠结局）。[252, 253]涉及 NF-κB 信号通路的免疫调节效应（Meta 分析目标）。[253]在一项脂质体乳铁蛋白试验中，睡眠质量结局（起床时的困倦感/疲劳感；睡眠诱导/维持）得到改善；情绪（POMS 抑郁-沮丧）亦有所改善。[252]受限：针对睡眠结局的小型随机安慰剂对照试验。[254]在一项为期 4 周的随机安慰剂对照试验中，与安慰剂相比，脂质体乳铁蛋白 270 毫克/天改善了睡眠量表领域（“起床时的困倦感和疲劳感”；“睡眠的诱导与维持”）以及 POMS 抑郁-沮丧情绪。[252]一项试验中 270 毫克/天的脂质体乳铁蛋白，持续 4 周；儿科 RCT 中 48 毫克/天的乳铁蛋白强化配方。[252, 254]儿科 RCT 报告无药物不良反应；更广泛的综述指出成人临床研究有限。[254, 255]
亚精胺领域 4 趋同/多靶点（自噬/线粒体与认知结局的关联）。[256, 257]与增强的自噬相关（机制基础），在临床前模型中，提示有线粒体功能效应；假说认为认知获益依赖于自噬/线粒体的维持。[256, 258]老年人的认知表现和记忆结局（RCT；结果不一）。[256]中等：多项 RCT（60–96 岁成人；结果不一）。[256]在小型综述总结的各 RCT 中，结果不一：两项试验（Wirth 2018；Pekar 2021）显示 3 个月后认知有所改善，而一项为期 12 个月的试验（Schwarz 2022）发现与安慰剂相比无显著记忆变化。[256]纳入的各个 RCT 中为 0.9–3.3 毫克/天。[256]来源中未提及。
α-硫辛酸 (ALA / R-ALA)来源中未提及。来源中未提及。来源中未提及。迄今尚无证据 — 在提供的来源中未发现严谨的人体证据。迄今尚无证据 — 在提供的来源中未发现严谨的人体证据。来源中未提及。来源中未提及。
维生素 E（混合生育酚 / 三烯生育酚）来源中未提及。来源中未提及。来源中未提及。迄今尚无证据 — 在提供的来源中未发现严谨的人体证据。迄今尚无证据 — 在提供的来源中未发现严谨的人体证据。来源中未提及。来源中未提及。
紫檀芪来源中未提及。来源中未提及。来源中未提及。迄今尚无证据 — 在提供的来源中未发现紫檀芪特异性的严谨人体证据。迄今尚无证据 — 在提供的来源中未发现紫檀芪特异性的严谨人体证据。来源中未提及。来源中未提及。
棕榈酰乙醇胺 (PEA)来源中未提及。来源中未提及。来源中未提及。迄今尚无证据 — 在提供的来源中未发现严谨的人体证据。迄今尚无证据 — 在提供的来源中未发现严谨的人体证据。来源中未提及。来源中未提及。
绿茶 / EGCG领域 4 趋同/多靶点（情绪/认知信号；睡眠证据不一）。[259]EGCG 与脑电图 α/β/θ 活性增加相关（急性）。[260] Meta 分析报告茶氨酸+咖啡因以及单独的茶氨酸可能对认知/情绪有益（茶成分证据）。[69]综述中的精神病理学症状（例如焦虑）、认知（记忆/注意），以及关于睡眠结局的不一证据。[259, 261]中等：多项 RCT + 系统评价/Meta 分析[262, 261]Meta 分析发现，在摄入后的最初 1–2 小时内，在某些认知和情绪结局（例如选择反应时间；数字警觉准确性；整体情绪）方面，茶氨酸+咖啡因相比安慰剂显示出小到中等程度的改善，倾向于前者。[69]来源中未提及。来源中未提及。
花青素（蓝莓 / 康科德葡萄）领域 1 认知与神经可塑性（有多项 RCT Meta 分析支持）。[263, 264]来源中未提及。Meta 分析中全球认知得到改善（SMD 0.46），并报告了特定领域的获益（注意力、处理速度、流利度、情景记忆和工作记忆）。[264]强：Meta 分析 + 多项 RCT[263, 265]Meta 分析报告，与对照组相比，花青素干预显著改善了全球认知（SMD 0.46；95% CI 0.30–0.63；I²=0%）。[264]来源中未提及。来源中未提及。
厚朴（和厚朴酚 / 厚朴酚）来源中未提及。来源中未提及。来源中未提及。迄今尚无证据 — 证据仅限于机制/临床前研究。[266]迄今尚无证据 — 呼吁开展临床研究：“需要更多研究……在临床研究中进行实验”，针对厚朴酚/和厚朴酚。[266]来源中未提及。来源中未提及。

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Appendix A — Supplementary Evidence Table

Supplementary source integrated: Appendix A — Master Evidence Table Brain-Function Ingredients.xlsx

IngredientDomainMechanism TargetsPrimary Clinical OutcomesEvidence LevelBest Proof SummaryTypical DoseSafety Caveats
Citicoline (CDP-choline)Domain 1 cognition & neuroplasticity[1, 2]Phosphatidylcholine/structural phospholipid membrane synthesis (CDP-choline precursor)[3, 4]; acetylcholine biosynthesis support[5]; increases cerebral metabolism and affects neurotransmitter levels in review literature[4].Cognitive function/cognitive status and memory/behaviour outcomes[1, 3]; functional independence after traumatic brain injury (Glasgow Outcome Scale).[2, 6]Strong: meta-analyses + multiple RCTs[2, 1]Systematic review/meta-analysis in acute TBI (11 clinical studies; n=2771) found higher independence rates with citicoline vs control (RR 1.18, 95% CI 1.05–1.33).[2]500–2,000 mg/day (effective dosing range reported across clinical trials).[7]Meta-analysis in acute TBI reported no safety concerns[2]; citicoline was “well tolerated” in a Cochrane review.[8]
Bacopa monnieri (bacosides)Domain 1 cognition & neuroplasticity[9]Not mentioned in source(s).Memory free recall (improved on 9/17 tests across studies)[9]; attention/speed (Trail B; choice reaction time) in meta-analysis[10]; sleep quality assessed but not significantly different in one RCT.[11]Strong: meta-analyses + multiple RCTs[10]Meta-analysis (9 studies; 518 subjects) reported improved cognition including shorter Trail B time and reduced choice reaction time with chronic (≥12 weeks) Bacopa extract supplementation.[10]Common RCT extract doses: 300–450 mg/day over ~12 weeks.[9]Not mentioned in source(s).
Ginkgo biloba (EGb 761)Domain 1 cognition & neuroplasticity[12]Not mentioned in source(s).Dementia outcomes: cognition, activities of daily living, and global assessment[12]; neuropsychiatric symptoms (e.g., NPI composite) and cognitive tests (e.g., SKT).[13]Strong: meta-analyses + multiple RCTs[12, 14, 15]Systematic review/meta-analysis in dementia outpatients found EGb 761 favored vs placebo on cognition, ADLs, and global rating; treatment-associated adverse event risks did not differ noticeably vs placebo.[12]120–240 mg/day (often 240 mg/day in pooled trials).[12, 14, 15]Meta-analyses found no important safety concerns and similar adverse-event rates vs placebo.[14, 16, 12]
Citicoline + other (note: separate ingredient row preserved)Not mentioned in source(s).Not mentioned in source(s).Not mentioned in source(s).NO PROOFS TO DATE — no rigorous human evidence found in provided sources.NO PROOFS TO DATE — no rigorous human evidence found in provided sources.Not mentioned in source(s).Not mentioned in source(s).
Alpha-GPCDomain 1 cognition & neuroplasticity[17]Choline-containing phospholipid acting as a precursor to acetylcholine biosynthesis and discussed as a modulator of neuroprotective signaling pathways.[18]Cognition (e.g., ADAS-cog).[19] Also function and behavior outcomes in adult-onset cognitive impairment studies.[17]Moderate: multiple RCTs[17, 19]12-week multicenter RCT in mild cognitive impairment (n=100; 600 mg αGPC) reported greater ADAS-cog reduction vs placebo (−2.34 points) with no serious adverse events.[19]600 mg/day αGPC in a 12-week RCT; acute supplementation protocols used 315–630 mg in crossover designs.[19, 20]In a 12-week MCI RCT, no serious AEs and AE incidence similar to placebo.[19] In a large open multicenter trial, AEs reported in 2.14% and common complaints included heartburn, nausea/vomiting, insomnia/excitation, and headache.[21]
PhosphatidylserineDomain 1 cognition & neuroplasticity (also studied for stress/sleep outcomes)[22]Not mentioned in source(s).Age-associated cognitive decline/memory[22]; mood/stress (panic score on POMS) and sleep quality (PSQI) in some trials.[23]Moderate: multiple RCTs + systematic review/meta-analysis[22, 24]Systematic review/meta-analysis (9 studies; 5 RCTs) concluded phosphatidylserine had a positive effect on memory in older adults with cognitive decline, with no adverse effects reported.[22]100–300 mg/day in older-adult cognitive-decline studies; 300 mg/day PS in PS-DHA trial; 400–800 mg/day in a short stress/sleep study.[22, 24, 23]PS-DHA at 300 mg/day for 15 weeks (or 100 mg/day for 30 weeks) was reported as safe/well tolerated with no negative effects in tested parameters.[24]
Choline (bitartrate / chloride)Domain 1 cognition & neuroplasticity; also relevant to methyl-donor pathways (Domain 4).[25]Precursor of acetylcholine and betaine (methyl donor).[25, 26] 1 g/day increased circulating free choline and betaine, potentially enhancing tHcy remethylation (BHMT pathway).[26]Cognition in adults (high-quality intervention data described as lacking)[25]; pregnancy supplementation reviewed for child cognition outcomes[27]; biochemical outcomes (plasma choline/betaine/tHcy).[26]Limited: single RCT or small studies (cognition RCT evidence described as lacking).[25, 26]Nutrition Reviews synthesis concluded adult cognitive benefits are possible, but high-quality intervention studies are lacking.[25]1 g/day choline (as choline bitartrate) in a randomized placebo-controlled trial in postmenopausal women; pregnancy trial doses 480–930 mg/day in the third trimester.[26, 28]Review notes possible harmful cardiometabolic effects require careful evaluation.[25] In a 1 g/day RCT, plasma lipids were not affected.[26]
Omega-3 EPA/DHA (fish oil)Domain 1 cognition & neuroplasticity[29]DHA/EPA are described as important for brain development and cognitive performance[29]; DHA impacts neurotransmitters and brain function (mechanistic description).[30]Cognitive outcomes (multiple parameters in RCTs); one meta-analysis in pregnancy/breastfeeding found no significant associations with children’s cognitive parameters.[29]Moderate: multiple RCTs (evidence summarized across systematic reviews/meta-analyses; mixed findings).[29, 30]Systematic review/meta-analysis (11 trials) reported no significant association between maternal DHA/EPA supplementation and assessed cognitive parameters in children.[29]Not mentioned in source(s).Not mentioned in source(s).
PhosphatidylcholineDomain 1 cognition & neuroplasticity[31]Precursor for acetylcholine biosynthesis and integral neuronal membrane component (rationale for trials in brain diseases).[31]Infant neurodevelopment outcomes (visuospatial memory, episodic memory, language/global development) after maternal supplementation; no significant differences reported.[32]Limited: single RCT or small studies[32]Maternal phosphatidylcholine 750 mg/day from 18 weeks gestation through 90 days postpartum showed no significant differences in infant global development, language, or memory outcomes at 10–12 months vs placebo.[32]750 mg/day from 18 weeks gestation through 90 days postpartum.[32]Not mentioned in source(s).
Panax ginsengDomain 1 cognition & neuroplasticity (also described as multi-pathway).[33]Multi-pathway actions described: inhibition of neuroinflammation, enhanced antioxidant capacity, improved mitochondrial metabolism, regulation of synaptic plasticity[33]; emotional regulation via HPA/HPG axis modulation, neurotransmitter balance, and BDNF–TrkB pathway activation.[33]Memory outcomes improved in meta-analysis; no positive effects on overall cognition, attention, or executive function in pooled analyses.[34]Moderate: multiple RCTs (systematic review/meta-analysis includes 15 RCTs).[34]Meta-analysis of 15 RCTs (671 patients) found significant memory improvement (SMD 0.19) but no positive effects on overall cognition, attention, or executive function.[34]3 g/day Panax ginseng powder for 6 months in one RCT.[35]Review reported no serious adverse events, but risk of bias was unclear in most studies.[36]
Lion's Mane (Hericium erinaceus)Domain 1 cognition & neuroplasticity; also studied for mood/sleep outcomes.[37, 38]Increased circulating pro-BDNF in one trial[38]; proposed neurotrophic effects (enhanced pro-BDNF/BDNF and hippocampal neurogenesis) in review literature[39]; possible gut–brain mechanism via increased microbiota diversity reported in one study.[40]Cognitive test outcomes (e.g., MMSE composite effects in RCT/PCT)[39]; mood/sleep disorders decreased after 8 weeks in one study.[38]Moderate: multiple RCTs (systematic reviews include several RCTs).[37, 39]8-week oral H. erinaceus supplementation decreased depression, anxiety, and sleep disorders and increased circulating pro-BDNF (trial finding).[38]Not mentioned in source(s).Potential side effects include stomach discomfort, headache, and allergic reactions; adverse effects were rare and typically mild gastrointestinal discomfort in one review.[39, 40]
Huperzine ADomain 1 cognition & neuroplasticity[41]Not fully specified in provided abstracts; review literature mentions NMDA antagonism, increased NGF, antioxidant and anti-amyloidogenic effects.[42]Cognitive and functional outcomes in Alzheimer’s disease (MMSE; ADL; ADAS-Cog/HDS in some analyses).[41, 43]Moderate: multiple RCTs (20 RCTs included; high risk of bias noted).[41]Systematic review/meta-analysis (20 RCTs; n=1823) found cognitive improvements (MMSE) vs placebo at multiple time points, but most trials had high risk of bias.[41]Not mentioned in source(s).Most adverse events were cholinergic in nature and no serious adverse events occurred in one meta-analysis; another review reported no severe adverse events.[43, 41]
VinpocetineDomain 1 cognition & neuroplasticity[44]Not mentioned in source(s).Cognitive outcomes in dementia/cognitive impairment (e.g., MMSE; ADAS-Cog).[45, 46]Moderate: multiple RCTs (systematic reviews include 3 dementia RCTs; additional placebo-controlled RCTs also reported).[44, 45]Cochrane review of dementia trials (3 studies; n=583) concluded evidence for vinpocetine benefit is inconclusive and does not support clinical use.[44]30–60 mg/day orally reported in dementia studies.[44]Adverse effects inconsistently reported and intention-to-treat data unavailable in dementia trials; reviewers call for larger well-designed RCTs in stroke before routine use.[44, 45]
Centrophenoxine (meclofenoxate)Domain 1 cognition & neuroplasticity (elderly dementia trials; also preclinical memory effects).[47, 48]Not mentioned in source(s).Elderly dementia/memory outcomes (memory function improvements vs placebo reported in one trial).[48]Limited: single RCT or small studies[47, 48, 49]In a double-blind randomized trial in older adults with dementia/memory impairment, centrophenoxine treatment was associated with higher proportion showing memory improvement vs placebo (48% vs 28%).[48]2 g/day for 8 weeks in one trial; 600 mg twice daily for 12 weeks in a placebo-controlled crossover study.[48, 49]Not mentioned in source(s).
CaffeineDomain 1 cognition & neuroplasticity and Domain 2 sleep (sleep disruption).[50]Not mentioned in source(s) as a receptor-level mechanism; reviews highlight genetic variation in adenosine-related pathways influencing sleep disruption sensitivity and CYP1A2/ADORA2A associations with cognition/anxiety/sleep disturbance.[50, 51]Cognitive performance (attention, executive function, reaction time) improved in sleep-deprived contexts[52, 53]; sleep outcomes (sleep latency, total sleep time, sleep efficiency; reduced slow-wave sleep).[50]Moderate: multiple RCTs within systematic reviews/meta-analyses[50, 52]Meta-analysis in sleep-deprived/restricted individuals (45 publications; 327 effect estimates) found caffeine improved attention response time and accuracy and improved executive function vs placebo/control.[52]Not mentioned in source(s).Caffeine typically prolongs sleep latency and reduces total sleep time/sleep efficiency; slow-wave sleep is typically reduced (dose- and timing-dependent).[50]
ErgothioneineDomain 1 cognition & neuroplasticity (also assessed for sleep outcomes).[54]Brain uptake via OCTN1/SLC22A4 transporter[55]; proposed antioxidant/anti-inflammatory properties in mechanistic syntheses.[56]Composite memory (primary outcome) and secondary cognitive domains, subjective memory, and sleep quality outcomes.[54]Limited: single RCT or small studies[54]16-week randomized, double-blind, placebo-controlled trial in adults 55–79 with subjective memory complaints tested 10 mg/day and 25 mg/day ergothioneine vs placebo (primary endpoint: composite memory).[54]10–25 mg/day in a 16-week RCT.[54]Ergothioneine supplementation was reported as safe and well tolerated in the trial cohort.[54]
Cocoa flavanolsDomain 1 cognition & neuroplasticity (acute cognitive demand performance).[57]Proposed actions include neuroprotective/neuromodulatory protein cascades and improved cerebral blood flow/angiogenesis.[58]Cognitive Demand Battery tasks (Serial Threes/Sevens, RVIP) and mental fatigue ratings.[57]Limited: single RCT or small studies (evidence described as limited/inconclusive for immediate action).[58]In a double-blind crossover trial, cocoa flavanol drinks (520 mg and 994 mg) improved Serial Threes performance and 520 mg attenuated self-reported mental fatigue vs control.[57, 59]520–994 mg cocoa flavanols acutely in a crossover study; 250 mg cocoa supplementation daily for four weeks in another RCT.[57, 59]Not mentioned in source(s).
Souvenaid / Fortasyn Connect (medical food)Domain 1 cognition & neuroplasticity[60]Designed to support synapse synthesis and neuronal membrane formation using precursors/cofactors (uridine monophosphate; choline; phospholipids; DHA/EPA; vitamins E/C/B12/B6; folic acid; selenium).[60]Cognition assessed by ADAS-cog and other memory/cognitive tests (e.g., neuropsychological composite z-score; delayed verbal recall in a subgroup).[60, 61]Moderate: multiple RCTs + systematic review/meta-analysis (3 studies; total n=1011).[61]S-Connect 24-week RCT (n=527 mild-to-moderate AD on medications) found no significant difference vs control on ADAS-cog decline (difference 0.37 points; p=0.513).[60]125 mL/day (125 kcal) for 24 weeks in S-Connect trial.[60]No group differences in adverse event rates or clinically relevant blood safety parameters; described as well tolerated with AD medications.[60]
Uridine monophosphateNot mentioned in source(s).Not mentioned in source(s).Not mentioned in source(s).NO PROOFS TO DATE — no rigorous human evidence found in provided sources.NO PROOFS TO DATE — no rigorous human evidence found in provided sources.Not mentioned in source(s).Not mentioned in source(s).
Ashwagandha (Withania somnifera; KSM-66 / Sensoril)Domain 2 stress/anxiolysis/sleep[62, 63]Not mentioned in source(s).Sleep quantity/quality (primary outcomes) and mental alertness/anxiety/QoL (secondary outcomes).[62] Stress/anxiety and cortisol outcomes also reported in meta-analysis (PSS, HAS, serum cortisol).[63]Moderate: multiple RCTs (systematic reviews/meta-analyses).[62, 63, 64]Meta-analysis of 5 RCTs (400 participants) found a small but significant improvement in overall sleep with ashwagandha vs placebo (SMD −0.59; 95% CI −0.75 to −0.42).[62]Sleep benefits were more prominent in insomnia subgroup with dosage ≥600 mg/day and duration ≥8 weeks; one RCT used 600 mg/day for 8 weeks.[62, 65]No serious side effects reported in sleep RCTs, but serious-adverse-effect data are limited for long-term use; some studies reported mild-to-moderate AEs.[62, 63]
L-theanineDomain 2 stress/anxiolysis/sleep[66, 67]Not mentioned in source(s).Sleep (subjective sleep onset latency, daytime dysfunction, overall sleep quality) improved in meta-analysis[66]; cognitive outcomes such as verbal fluency and executive function improved in one RCT.[68]Strong: meta-analyses + multiple RCTs[66, 69]Meta-analysis reported L-theanine improved subjective sleep onset latency (SMD 0.15; 95% CI 0.01–0.29; p=0.04).[66]Trials examined 50–900 mg/day for sleep outcomes; 200 mg/day used in RCTs; 200–400 mg/day suggested for stress/anxiety contexts in evidence syntheses.[70, 68, 67]Not mentioned in source(s).
Magnesium (glycinate / threonate / citrate)Domain 2 stress/anxiolysis/sleep (also studied for cognition via sleep/mood).[71]Magnesium is implicated in neurotransmission, HPA-axis regulation, and sleep–wake control.[72]Insomnia/sleep quality (including sleep onset latency)[73]; daytime functioning (energy/productivity) with MgT[71]; cognition (NIH Total Cognition Composite, working/episodic memory) with MgT in one RCT.[74]Moderate: multiple RCTs (sleep) + systematic reviews/meta-analyses[73, 75]Systematic review/meta-analysis of 3 RCTs (151 older adults with insomnia) found magnesium reduced sleep onset latency by 17.36 minutes vs placebo (95% CI −27.27 to −7.44; p=0.0006).[73]MgT 1 g/day for 21 days in adults with sleep problems[71]; MgT 2 g/day in another sleep RCT[74]; magnesium bisglycinate 250 mg elemental magnesium/day in a 4-week RCT.[76]MgT reported safe/well tolerated in RCTs.[71, 74] Evidence quality limitations noted (moderate-to-high risk of bias; low-to-very-low certainty) in an insomnia meta-analysis.[73]
GlycineDomain 2 stress/anxiolysis/sleep[77]Acts via excitatory/inhibitory neurotransmission (NMDA receptors and glycine receptors).[78] Sleep effects may involve lowering core body temperature (mechanistic hypothesis).[78]Sleep outcomes in healthy populations (evidence summarized as small/high risk of bias)[77]; negative symptoms in schizophrenia improved with NMDA co-agonists (glycine/D-serine) in a meta-analysis.[79]Limited: small studies; sleep evidence summarized as small/high risk of bias.[77]Review synthesis reported longer-term glycine improved sleep in healthy populations, but studies were small with high risk of bias.[77]In an acute ischemic stroke RCT, glycine doses were 0.5–2.0 g/day for 5 days.[80]In an acute stroke trial, slight sedation occurred in 4.5% and other marked adverse events were absent.[80]
GABA (exogenous)Domain 2 stress/anxiolysis/sleep[81]Not mentioned in source(s).Stress and sleep outcomes in placebo-controlled trials (mood and sleep questionnaires).[81, 82] EEG sleep-stage changes reported in a crossover study.[83]Moderate: multiple RCTs (systematic review of placebo-controlled human trials).[81]Systematic review concluded evidence is limited for stress and very limited for sleep benefits of oral GABA intake; more studies needed.[81]Examples: 100 mg/day for 12 weeks in an RCT[82]; 100 mg pre-bedtime in a crossover sleep study[83]; 200 mg/day in a 90-day trial; acute 800 mg in a crossover cognition trial.[84, 85]Not mentioned in source(s).
TaurineDomain 2 stress/anxiolysis/sleep (cognition evidence mixed/null).[86]Not mentioned in source(s).Cognitive scores (meta-analysis reports no significant effects).[86]Moderate: multiple RCTs (meta-analysis includes 7 RCTs).[86]Meta-analysis of RCTs (7 RCTs; 402 individuals) reported taurine did not exhibit significant effects on cognitive scores.[86]Acute doses typically 1–3 g (up to ~50 mg/kg) in cognition trials (review summary).[87]Not mentioned in source(s).
MelatoninDomain 2 stress/anxiolysis/sleep[88]Not mentioned in source(s).Sleep outcomes (sleep onset latency, total sleep time) and MMSE in older adults with MCI/dementia.[89, 88]Strong: meta-analyses + multiple RCTs[89, 88]Meta-analysis of 10 RCTs (n=516) in adults ≥65 with MCI/dementia found melatonin increased total sleep time (+12.4 min) and improved MMSE (+1.8 points).[89]Not mentioned in source(s).Not mentioned in source(s).
5-HTPDomain 2 stress/anxiolysis/sleep (serotonin precursor).[90, 91]5-HTP is an intermediate in serotonin biosynthesis[92] and is converted to serotonin in the brain; serum serotonin increases reported with supplementation.[93, 90]Mood/depression outcomes in systematic reviews/meta-analyses[94]; sleep quality components improved in some studies.[91]Moderate: multiple RCTs with meta-analyses (study quality limitations noted).[95, 94]Meta-analysis reported depression remission rate 0.65 (95% CI 0.55–0.78) across 13 studies; overall risk of bias judged relatively weak due to few placebo groups.[94]50 mg/day in a 4-week crossover study[96]; 100 mg/day for 12 weeks in older adults in a sleep-focused study.[91]Review discusses a possible association with potentially fatal eosinophilia-myalgia syndrome that has not been elucidated; evidence quality insufficient for firm conclusions.[97]
L-tryptophanDomain 2 stress/anxiolysis/sleep (serotonin/melatonin precursor).[98, 99]Tryptophan is a serotonin precursor; downstream conversion to melatonin is described as influencing circadian rhythm and sleep quality.[98, 99]Sleep efficiency and wake after sleep onset (improved in meta-analysis).[100] Mood outcomes in healthy adults (effects on negative/happy feelings) in RCT reviews.[98]Moderate: multiple RCTs (systematic reviews include 11 RCTs).[100, 98]Double-blind placebo-controlled crossover trial used 1000 mg/day tryptophan and reported improved objective sleep efficiency and wake after sleep onset vs placebo (irrespective of 5-HTTLPR allelic variation).[101]1000 mg/day used in a placebo-controlled crossover RCT; review summaries include 0.14–3 g/day ranges across RCTs.[101, 98]No serious adverse events were noted in included sleep-disorder studies (systematic review statement).[102]
Saffron (Crocus sativus; affron)Domain 2 stress/anxiolysis/sleep (mood/anxiety/sleep outcomes).[103, 104]Not mentioned in source(s).Depression (BDI; DASS-21), anxiety (BAI), and sleep quality (PSQI; sleep quality ratings).[104, 105, 106]Strong: meta-analyses + multiple RCTs[103, 104]Meta-analysis (21 trials) found saffron reduced BDI (WMD −4.86), BAI (WMD −5.29), and PSQI (WMD −2.22) vs controls.[104]Affron® 28 mg/day used in mood RCTs and in sleep RCTs (administered 1 hour before bed).[106, 107]Saffron/affron® was reported as well tolerated with no significant adverse effects in RCTs; reviewers note some evidence derives from studies with potential risk of bias.[106, 108]
Valerian (Valeriana officinalis)Domain 2 stress/anxiolysis/sleep[109]Calming properties attributed to modulation of GABA function in the CNS (components include valerenic acid and valepotriates).[110]Sleep quality/insomnia outcomes in randomized placebo-controlled trials and meta-analyses.[109, 111]Moderate: multiple RCTs (inconsistent findings across trials).[109, 112, 113]Systematic review/meta-analysis (16 eligible studies; 1093 patients) found benefit on a dichotomous sleep-quality outcome (RR improved sleep = 1.8; 95% CI 1.2–2.9), with evidence of publication bias.[109]Not mentioned in source(s).Valerian generally described as safe with rare adverse events; review notes no severe adverse events in ages 7–80 years.[113, 114]
Lemon balm (Melissa officinalis)Domain 2 stress/anxiolysis/sleep[115]Rosmarinic acid may modulate GABA transaminase activity (sleep-quality effects).[116] In vitro cholinergic receptor-binding/displacement suggests potential relevance to cognitive deficits in AD.[117]Anxiety and depression symptom scores improved in meta-analysis; sleep quality measured in RCTs.[115, 118]Moderate: multiple RCTs (meta-analysis and clinical trials).[115, 118]Meta-analysis reported lemon balm improved anxiety (SMD −0.98) and depression (SMD −0.47) vs placebo, without serious side effects (caution due to heterogeneity).[115]7-day regimen of 1.5 g/day dried leaf powder in a clinical trial improved anxiety and sleep quality in post-CABG patients; acute single doses 300/600/900 mg tested in a crossover study.[118, 117]Meta-analysis reported no serious side effects but highlighted heterogeneity and limited number of trials.[115]
Passionflower (Passiflora incarnata)Domain 2 stress/anxiolysis/sleep[119, 120]Anxiolytic/sedative effects described as mediated through GABAergic modulation and serotonergic pathways (review).[121]Anxiety reduction in multiple trials[119]; polysomnographic total sleep time and subjective sleep quality improved in RCTs.[120, 122]Moderate: multiple RCTs (systematic review included nine clinical trials).[119]Double-blind placebo-controlled insomnia study reported increased polysomnographic total sleep time vs placebo (P=0.049).[120]Not mentioned in source(s).Systematic review reported no adverse effects including memory loss; other reviews caution that many clinical studies have inadequate methodology and product descriptions.[119, 123]
Lavender oil (Silexan)Domain 2 stress/anxiolysis/sleep[124]Not mentioned in source(s).Anxiety severity (HAMA) and sleep quality (PSQI).[124, 125]Strong: meta-analyses + multiple RCTs[124]Meta-analysis of 3 randomized placebo-controlled trials (697 patients) found 80 mg/day Silexan reduced HAMA total score vs placebo over 10 weeks (mean difference 3.83 points; 95% CI 1.28–6.37).[124]80 mg/day for 10 weeks (some studies evaluated 160 mg/day).[124, 126]Adverse event incidence comparable to placebo (RR 1.06); review notes mild GI symptoms may occur but otherwise no sedation or withdrawal and no drug interactions at 80–160 mg/day.[124, 127]
Hops (Humulus lupulus)Domain 2 stress/anxiolysis/sleep[128]Modulates GABA(A) receptors[128]; in vitro binding to serotonin/melatonin receptors reported[129]; sleep effects attributed to binding at GABA site on GABA(A) receptor and enhancement of δ-wave sleep.[130]Sleep latency and wake after sleep onset reduction with increased slow-wave sleep in patients with non-organic sleep disturbances; sleep onset latency improved in a valerian–hops combination trial.[129, 131]Limited: small human studies (often in valerian–hops combinations).[129]Human studies reported reduced sleep latency and wake after sleep onset with enlarged slow-wave sleep; a trial reported hops added clinical efficacy and reduced prolonged sleep onset latency vs placebo (combination preparation).[129, 131]Not mentioned in source(s).Not mentioned in source(s).
Alpha-s1 casein hydrolysate (Lactium)Domain 2 stress/anxiolysis/sleep[132]Not mentioned in source(s).Sleep quality and psychological distress outcomes (ISI/GSDS/PSQI/ESS/HADS) and polysomnographic sleep onset latency.[132]Moderate: multiple RCTs[132]4-week randomized double-blind placebo-controlled insomnia trial (n=36) showed improvements in subjective sleep measures and decreased PSG sleep onset latency vs placebo (p=0.012).[132]In one RCT, 600 mg/day initially then 300 mg/day for the latter two weeks; other trials used 150 mg in capsules (sometimes combined with L-theanine).[132, 133]Not mentioned in source(s).
Chamomile (Matricaria chamomilla)Domain 2 stress/anxiolysis/sleep[134, 135]Not mentioned in source(s).Sleep quality (PSQI; awakenings; sleep onset latency) and generalized anxiety disorder outcomes (HAM-A).[134, 135]Moderate: multiple RCTs (systematic reviews/meta-analyses).[134, 135]Systematic review/meta-analysis (10 studies; 772 participants) found chamomile reduced PSQI score (WMD −1.88; 95% CI −3.46 to −0.31).[134]Not mentioned in source(s).Mild adverse events reported in some trials; another review reported no adverse events (passive surveillance).[135, 134]
Kava (Piper methysticum)Domain 2 stress/anxiolysis/sleep (GAD).[136]Modulation of GABA activity via lipid membrane effects and sodium channel function; MAO-B inhibition; noradrenaline/dopamine reuptake inhibition.[137]Anxiety severity (HAM-A and related scales such as STAI-state).[138]Moderate: multiple RCTs (12 double-blind RCTs in Cochrane analysis).[139]Cochrane meta-analysis (12 double-blind RCTs; n=700) found kava reduced HAM-A total score vs placebo (WMD 3.9; 95% CI 0.1–7.7; p=0.05; n=380).[139]120–280 mg/day kavalactones for short-term (4–8 weeks).[136]Safety issues should be considered; guidance advises traditional water-soluble extracts, avoid alcohol, caution with psychotropics/driving, and routine liver function tests for regular users.[137]
Rhodiola rosea (rosavins/salidroside)Domain 2 stress/anxiolysis/sleep (adaptogen; depression/anxiety/stress).[140, 141]Discussed mechanisms include HPA-axis modulation, neurotransmitter system effects, and antioxidant pathways; review describes improved mitochondrial function and increased cellular energy production (mechanistic summary).[141]Perceived stress and fatigue, mild-to-moderate depression and mild anxiety symptoms, mood, psychomotor performance/cognitive processing speed (reported in clinical studies, per review).[141, 140]Moderate: multiple RCTs (11 placebo-controlled RCTs in one review).[142]Systematic review evidence: 11 placebo-controlled RCTs were identified for Rhodiola; overall conclusions were described as not definite due to limited experimental data (certainty limitations).[142, 140]Not mentioned in source(s).Systematic review reported only few mild adverse events; evidence certainty limited due to high risk of bias/reporting flaws in included studies.[142, 143, 140]
Vitamin D3 (cholecalciferol)Domain 2 stress/anxiolysis/sleep (sleep quality outcomes).[144]Not mentioned in source(s).Sleep quality (PSQI) and depressive symptoms (BDI) in intervention meta-analyses.[145, 146]Strong: meta-analyses + multiple RCTs[144, 145]Systematic review/meta-analysis found vitamin D supplementation significantly decreased PSQI vs placebo (mean difference −2.33; 95% CI −3.09 to −1.57; p<0.001; I²=0%).[144]Not mentioned in source(s).Meta-analysis reported vitamin D supplementation did not cause side effects (in included studies).[145]
Acetyl-L-carnitine (ALCAR)Domain 3 energy & mitochondria (also studied for depression/cognition).[147]Supports beta-oxidation and acetyl-CoA maintenance[148]; modulates brain energy/phospholipid metabolism and synaptic morphology/transmission (multiple neurotransmitters)[148]; antioxidant and anti-apoptotic activity and neuroinflammation benefits discussed.[147]Depressive symptoms in RCT meta-analysis[149]; clinical global change and cognitive outcomes in MCI/mild AD meta-analysis.[150]Moderate: multiple RCTs (meta-analyses in depression and MCI/mild AD).[149, 150]Depression meta-analysis: pooled RCTs showed ALC significantly reduced depressive symptoms vs placebo/no intervention (SMD −1.10; 95% CI −1.65 to −0.56).[149]1.5–3.0 g/day (daily dose range across MCI/mild AD trials).[150]In RCTs versus antidepressants, adverse effects were significantly lower with ALC; overall ALC was well tolerated in cognitive trials.[149, 150]
Coenzyme Q10 (ubiquinol / ubiquinone)Domain 3 energy & mitochondria (bioenergetic/antioxidant).[151]Bioenergetic and antioxidant activity; involved in energy production and prevention of peroxidative membrane damage/free-radical oxidation.[151]Depressive symptoms and fatigue outcomes in RCT meta-analyses (depression improved; fatigue not significant).[152]Moderate: multiple RCTs (meta-analyses).[152, 153]Meta-analysis of 5 RCTs (474 participants) found CoQ10 reduced depressive symptoms vs control (SMD −0.68; 95% CI −1.02 to −0.33; P<0.01).[152]Low doses 100–200 mg/day for 6–8 weeks were described as associated with depressive-symptom improvement in one analysis.[153]Not mentioned in source(s).
Pyrroloquinoline quinone (PQQ)Domain 3 energy & mitochondria (also studied for stress/fatigue/sleep).[154]Mechanistic summaries describe activation of Nrf2/ARE antioxidant pathways, AMPK/PGC-1α mitochondrial biogenesis/function, and NF-κB inhibition for inflammatory regulation.[154]Stress/fatigue/QoL/sleep in an open-label trial[155]; cognitive performance outcomes in an RCT using Cognitrax as primary endpoint.[156]Limited: small human studies (one RCT plus one small open-label trial).[156, 155]12-week randomized, double-blind, placebo-controlled RCT evaluated PQQ disodium salt 21.5 mg/day in 64 healthy volunteers for cognitive function/performance outcomes.[156]20 mg/day for 8 weeks in an open-label trial; 21.5 mg/day (PQQ disodium salt) for 12 weeks in an RCT.[155, 156]No adverse events reported in the cognition RCT; toxicology battery reported broad safety and no mutagenic potential.[156]
Creatine monohydrateDomain 3 energy & mitochondria (brain bioenergetics).[157]Improved ATP availability/phosphocreatine buffering supporting mitochondrial function (mechanistic interpretation in review literature).[158]Memory outcomes improved in meta-analyses; attention time and processing speed outcomes reported; overall cognition/executive function not significantly improved in one meta-analysis.[159, 157]Strong: meta-analyses + multiple RCTs[157, 159]Systematic review/meta-analysis (16 RCTs; 492 participants) found creatine improved memory and processing speed but not overall cognitive function or executive function.[159]Examples: 5 g four times daily for 7 days in one RCT; 20 g/day loading for 7 days in a crossover study.[160, 161]Generally well tolerated, but hypomania/mania occurred in 2/17 participants in a psychiatric review; caution advised in kidney disease or with kidney-affecting medications.[162, 163]
MCT oil (medium-chain triglycerides)Domain 3 energy & mitochondria (ketone-body/alternative fuel).[164, 165]Induces mild ketosis and may improve cognition in MCI/AD; raises β-hydroxybutyrate as alternative substrate when glucose utilization is impaired.[164, 165]Cognitive performance in MCI/AD (e.g., ADAS-Cog and MMSE) and memory indices (working memory highlighted).[164, 166]Moderate: multiple RCTs (systematic reviews/meta-analyses; risk of bias noted).[164, 167]Meta-analysis of RCTs (12 records; 422 participants) found MCTs increased β-hydroxybutyrate and improved combined cognition outcome (ADAS-Cog+MMSE SMD −0.289; 95% CI −0.551 to −0.027).[164]Examples: 56 g/day for 24 weeks in MCI; 12–18 g/day for 4 weeks in healthy young adults; ~17.3 g/day total daily fat dose in a crossover trial.[168, 169, 170]Primarily gastrointestinal side effects reported; reviews note evidence limitations due to heterogeneous/poorly designed protocols and conflicts of interest.[167]
Beta-hydroxybutyrate (ketone esters/salts)Domain 3 energy & mitochondria (alternative cerebral fuel).[171]Exogenous ketones raise blood β-OHB and decrease blood glucose (acute metabolic shift).[172]Cognitive function measures in RCTs/systematic reviews; metabolic outcomes include blood glucose/β-OHB changes.[173, 172]Strong: meta-analyses + multiple RCTs[171]Systematic review/meta-analysis (38 studies/41 protocols; 1,602 participants) found exogenous ketone supplementation improved cognitive performance vs placebo (SMD 0.29; 95% CI 0.16–0.41; p<0.001).[171]Not mentioned in source(s).IV β-hydroxybutyrate infusions were well tolerated with few adverse events; glucose occasionally reduced but stayed in normal range. Oral exogenous ketones decrease blood glucose acutely (monitoring may be relevant in hypoglycemia risk).[174, 172]
Axona (caprylic triglyceride medical food)Domain 3 energy & mitochondria (ketone-body alternative fuel).[165, 175]Supplies ketone bodies (via medium-chain triglycerides) to provide an alternative energy source to glucose when glucose utilization is impaired.[175, 165]Cognition in mild-to-moderate Alzheimer’s disease measured by ADAS-Cog11 and MMSE; clinician global change (C-GIC).[176, 177]Moderate: multiple RCTs (e.g., 26-week RCT; additional smaller clinical interventions).[176, 177]26-week double-blind placebo-controlled RCT (AC-12-010; NOURISH AD) reported no detectable drug effects on primary ADAS-Cog11 outcome (LS mean difference −0.761; p=0.2458) and secondary outcomes also failed to detect drug effects.[176]Example regimen: 40 g/day powder containing 20 g caprylic triglycerides for 3 months with titration 10→40 g/day over 7 days.[177]Tolerance reported as good with no severe gastrointestinal adverse effects; titration reduced gastrointestinal adverse effects.[177]
D-riboseDomain 3 energy & mitochondria (evidence in provided sources is preclinical and suggests cognitive harm).[178]Not mentioned in source(s).Preclinical cognitive outcomes: platform crossings and cognition impairment in animal models; AGEs increased in brain and blood.[178]Mechanistic/preclinical only[178]Rodent systematic review/meta-analysis concluded D-ribose caused cognitive impairment with dose-related worsening and increased advanced glycation end products (AGEs) in brain and blood.[178]Not mentioned in source(s).Not mentioned in source(s).
Nicotinamide riboside (NR)Domain 3 energy & mitochondria (NAD+ precursor; neuroprotection rationale).[179, 180]NAD+ precursor support for mitochondrial/neurological function and inflammation reduction (described in trial background); brain NAD+ validation is a stated objective in MCI/mild AD trial design.[180, 181]Cognition (ECog/RBANS/TMT-B) and fatigue/depression/anxiety/sleep quality outcomes in a 24-week long-COVID RCT; sleep efficiency effects described in narrative review context.[180, 179]Moderate: multiple RCTs/clinical trials[180, 182, 183]24-week double-blind placebo-controlled RCT (long-COVID) showed NR increased NAD+ levels (2.6–3.1-fold after 5–10 weeks) but no significant between-group differences in cognitive outcomes (ECog/RBANS/TMT-B).[180]Examples: NR 2000 mg/day in a 24-week trial; NR 1 g/day in 8-week crossover trial; NR 1 g/day in 21-day crossover trial in older men.[180, 182, 183]One serious adverse event reported in the long-COVID trial was deemed unrelated to NR; review describes NR as bioavailable and well tolerated with limited adverse effects in humans.[180, 184]
Nicotinamide mononucleotide (NMN)Domain 3 energy & mitochondria (NAD+ precursor; sleep and physical function endpoints).[185, 186]Not mentioned in source(s).Sleep quality endpoints (PSQI; primary outcome in one protocol) and physical performance (e.g., 4-m walking time) with increased blood NAD+ and metabolites.[186, 187]Moderate: multiple RCTs (evidence for NAD+ increase; sleep RCTs in progress/protocols).[188, 185]12-week double-blind placebo-controlled study (n=60; NMN 250 mg/day) reported significantly shorter 4-m walking time and higher blood NAD+ and metabolites vs placebo.[187]250 mg/day for 12 weeks in an RCT; 320 mg/day in a chronic insomnia RCT protocol; 250–900 mg/day across RCTs in one systematic review.[187, 186, 185]Systematic reviews report only mild adverse effects and no serious adverse effects observed in included studies.[185, 189]
Nicotinamide / niacinamide (B3)Domain 3 energy & mitochondria (NAD+ precursor; human cognitive substudy negative).[190]NAD+ precursor role and discussed mechanisms including maintenance of cellular energy and inhibition of SIRT1 (review discussion); neuroprotective action in preclinical AD models involved preserved mitochondrial integrity and autophagy (preclinical).[191, 192]In a 12-month substudy (n=310), oral nicotinamide showed no significant effect on cognitive function or quality of life.[193]Limited: small clinical studies/RCT substudy; preclinical evidence stronger than human cognitive benefit in provided sources.[193]Phase III substudy (n=310) found no significant effect of oral nicotinamide on cognitive function or quality of life over 12 months.[193]500 mg PO twice daily in the 12-month substudy; 3000 mg/day in an N-of-1 design (anxiety trial).[193, 194]In an N-of-1 trial, transaminases remained normal during 3000 mg/day niacinamide; review notes high levels may cause neurotoxicity (general caution).[194, 191]
Curcumin (Longvida / Theracurmin / Meriva)Domain 4 convergence/multi-target (also cognitive outcomes in older adults).[195, 196]Curcumin increased serum BDNF in meta-analysis (WMD ~1789 pg/mL; heterogeneity noted).[197] Mechanistic pathways cited in preclinical syntheses include NF-κB/Nrf2/BDNF–TrkB and others (preclinical).[198]Cognitive outcomes in adults >50 (memory/attention tests) in systematic review[195]; depression/anxiety symptoms improved in meta-analysis of RCTs.[198]Moderate: multiple RCTs (systematic reviews/meta-analyses; heterogeneity/formulation variability).[195, 198]Systematic review of placebo-controlled RCTs in adults >50 reported cognitive improvements in some studies, including one trial using 90 mg curcumin twice daily with improvements in selective reminding, visual memory, and attention over 18 months.[195]Examples: 90 mg twice daily (one long trial); 1,500 mg/day in another trial (52 weeks).[195]GI symptoms were the most common adverse events in cognitive RCTs (58 AEs; 34 GI).[195] Some trials reported no AEs; reviewers caution due to heterogeneity and potential publication bias.[199, 198]
Resveratrol (trans-resveratrol)Domain 4 convergence/multi-target (mixed cognition/mood evidence).[200]Anti-inflammatory biomarker reductions (hs-CRP/TNF-α) reported in meta-analyses.[201]Cognitive performance domains (e.g., delayed recognition) and mood/negative mood; pooled effects significant for delayed recognition and negative mood in one meta-analysis.[200]Moderate: multiple RCTs (systematic reviews/meta-analyses; inconsistent across endpoints).[200]Systematic review/meta-analysis reported pooled benefit for delayed recognition (SMD 0.39; n=166) and negative mood (SMD −0.18; n=163), but overall literature described as inconsistent/limited.[200]Not mentioned in source(s).Not mentioned in source(s).
Sulforaphane (from glucoraphanin)Domain 4 convergence/multi-target (Keap1/Nrf2; epigenetic effects).[202]Keap1/Nrf2 axis and histone deacetylase inhibition (epigenetic mechanisms).[202]Symptomatic improvements in autism spectrum disorder and cognitive benefits in schizophrenia (review summary); sleep quality in healthy adults tested in a placebo-controlled trial.[202, 203]Limited: human evidence in provided sources includes small placebo-controlled study for sleep and review-level synthesis for brain disorders.[203, 202]Placebo-controlled trial: adults with poor sleep quality consumed broccoli sprout capsules (30 mg glucoraphanin) for 4 weeks (exploring sleep-quality effects).[203]30 mg glucoraphanin daily for 4 weeks (broccoli sprout capsules).[203]Not mentioned in source(s).
S-adenosylmethionine (SAMe)Domain 4 convergence/multi-target (methyl donor; depression focus).[204, 205]Not fully specified in provided abstracts; review states SAMe may facilitate neurotransmission (methylation-related rationale).[206]Depressive symptoms and acceptability in systematic reviews and RCTs.[207, 208]Moderate: multiple RCTs/meta-analyses, but certainty varies.[207, 208]Cochrane review (8 trials) found no strong evidence of difference between SAMe and placebo as monotherapy for depressive symptom change (SMD −0.54; 95% CI −1.54 to 0.46; very low quality evidence).[208]Daily dose ranged 200–3200 mg/day across trials; one RCT tested 800 mg/day for 8 weeks.[204, 205]Adverse events mostly mild/transient GI disturbances in one review; mania/hypomania reported (2 reports in 441 participants) and warnings about mania in bipolar disorder are noted.[209, 208, 206]
Folate / L-methylfolate (5-MTHF)Domain 4 convergence/multi-target (one-carbon cycle; adjunct in depression).[210]L-methylfolate is a methyl donor for methionine synthetase converting homocysteine to methionine[210], supporting SAMe formation[210] and downstream monoamine synthesis via BH4-related pathways (dopamine, norepinephrine, serotonin).[210]Depression scores/response/remission when used as adjunct to antidepressants.[211]Strong: meta-analyses + multiple RCTs[211, 212]Systematic review/meta-analysis (6 RCTs) found adjunct folate (L-methylfolate/folic acid) reduced HAM-D (MD −2.16) and improved response (RR 1.36) and remission (RR 1.39) vs SSRI/SNRI alone.[211]Evidence noted benefit when restricted to folate <5 mg/day or methylfolate 15 mg/day as adjunct to SSRI therapy.[213]Potential concerns include masking B12 deficiency and controversial cancer-risk associations; reviews note trials did not find safety/acceptability problems for folate.[210, 214]
Vitamin B12 (methylcobalamin)Domain 4 convergence/multi-target (overall no cognitive/depression benefit in non-deficient populations).[215]Not mentioned in source(s).Meta-analyses report no significant effects on cognitive function or depressive symptoms in populations without overt deficiency/advanced neurological disorders.[216]Moderate: multiple RCTs + meta-analyses (overall null for cognition/depression in non-deficient populations).[215]Systematic review/meta-analysis (16 RCTs; n=6276) found no evidence B12 alone or B-complex improved cognitive subdomains or depression measures in patients without overt B12 deficiency/advanced neurological disorders.[215]One RCT in cognitive impairment used IM vitamin B12 500 mg/day ×7 days, then cobamamide 0.25 mg/day plus methylcobalamin 0.50 mg/day.[217]Meta-analysis in ASD reported mild AEs (e.g., hyperactivity, irritability, trouble sleeping) not significantly different vs placebo; no broader contraindications noted in provided abstracts.[218]
Vitamin B6 (P5P)Domain 4 convergence/multi-target (one-carbon metabolism cofactor; cognition benefit not shown).[219, 220]P5P involved in one-carbon metabolism and neurotransmitter biosynthesis; supplementation increased plasma pyridoxal-5'-phosphate in one trial summary.[220, 221]Cognition and mood outcomes in healthy older adults (no significant benefits).[221]Limited: small RCTs (2 trials; 109 healthy older adults).[221]Cochrane review found no significant benefit of vitamin B6 on cognition or mood in 2 placebo-controlled RCTs (n=109), despite improved vitamin B6 status markers.[221]75 mg/day for 5 weeks in older women; 20 mg/day for 12 weeks in older men (pyridoxine HCl).[221]No adverse effects reported in included trials.[221]
Vitamin C (ascorbic acid)Domain 4 convergence/multi-target (mood/cognition linked to vitamin C status; mixed RCT results).[222]Not mentioned in source(s).Depressive symptoms/mood and psychological distress outcomes (meta-analysis overall null).[223]Moderate: multiple RCTs + meta-analysis (overall null; subgroup effects).[223]Meta-analysis of 10 trials (n=836) found no significant overall improvement in mood status (Hedges’ g 0.09), but subgroup analysis suggested benefit in subclinical depressed participants not prescribed antidepressants (Hedges’ g −0.18).[223]500 mg twice daily in hospitalized patients (mood/distress trial); 500 mg/day in student supplementation trial.[224, 225]Not mentioned in source(s).
ZincDomain 4 convergence/multi-target (mixed cognition evidence; stronger for BDNF/inflammation and depression).[226, 227]Zinc supplementation increased circulating BDNF in RCT meta-analysis; systemic inflammation markers (CRP, TNF-α) and MDA reduced in meta-analysis.[226, 228]Cognition in children (no significant overall effect across 6 RCTs)[229]; depressive symptoms improved in depressed patients meta-analysis (WMD −4.15).[227]Moderate: multiple RCTs/meta-analyses (mixed for cognition; positive for depression/BDNF).[229, 227]Children cognition meta-analysis (6 RCTs) found no significant overall effects of zinc on intelligence, executive function, or motor skills.[229]Not mentioned in source(s).Not mentioned in source(s).
SeleniumDomain 4 convergence/multi-target (human RCT evidence includes stroke outcomes).[230]Not mentioned in source(s).Stroke outcome (Glasgow Outcome Scale after 1 month) and respiratory infection outcomes in RCT meta-analysis.[230]Moderate: multiple RCTs (systematic review/meta-analysis included 5 RCTs).[230]Systematic review/meta-analysis of 5 RCTs found selenium vs placebo improved Glasgow Outcome Scale at 1 month (OR 1.54; 95% CI 1.10–2.15) and reduced respiratory infection (OR 0.55; 95% CI 0.34–0.88).[230]Not mentioned in source(s).Not mentioned in source(s).
IronDomain 4 convergence/multi-target (brain energy metabolism, neurotransmitter synthesis; cognitive and fatigue outcomes).[231]Iron supports brain energy metabolism and neurotransmitter synthesis[231] and is involved in myelin generation, mitochondrial function, ATP/DNA synthesis, and neurotransmitter cycling.[232]Meta-analyses/RCTs: fatigue, anxiety, physical well-being, cognitive intelligence, short-term memory outcomes (with some null findings for attention/depression).[231]Strong: meta-analyses + multiple RCTs[231]Systematic review/meta-analysis (12 RCTs within 18 studies; total n=1,340) reported improvements in anxiety, fatigue, cognitive intelligence, and short-term memory with iron supplementation in non-anemic populations.[231]Not mentioned in source(s).Not mentioned in source(s).
IodineDomain 4 convergence/multi-target (child cognition outcomes in mild deficiency).[233]Not mentioned in source(s).Cognitive outcomes in school-age children (perceptual reasoning; global cognitive score) and maternal thyroid outcomes in pregnancy supplementation trials (review).[234]Moderate: multiple RCTs/systematic reviews (modest/mixed cognitive effects).[234, 235]Randomized placebo-controlled trial in mildly iodine-deficient children (10–13 y) reported improved overall cognitive score (+0.19 SD) and improvements in 2 of 4 cognitive subtests with 150 µg/day iodine for 28 weeks.[233]150 µg/day iodine tablet for 28 weeks in children.[233]Not mentioned in source(s).
Glutathione (liposomal / S-acetyl)Domain 4 convergence/multi-target (GSH/redox; cognition signals via GlyNAC precursor supplementation).[236, 237]Glutathione is a key intracellular antioxidant supporting redox homeostasis and related immune/neurotransmitter systems.[236]Pilot trial evidence reports improved cognition in older adults after GlyNAC (glutathione precursors) supplementation and reversal of multiple aging-related defects; stopping supplementation led to recurrence of defects.[237]Limited: small human studies for cognition endpoints (GlyNAC trial evidence); broader evidence focuses on non-brain outcomes.[237]Pilot human trial reported that 24 weeks of GlyNAC supplementation reversed defects and improved cognition in older adults; stopping for 12 weeks led to redevelopment of defects.[237]Not mentioned in source(s).Systematic review in TB context reported mostly mild/manageable adverse effects for GSH/NAC; review notes further clinical study is needed for GSH/precursor supplementation contexts.[238, 236]
N-acetylcysteine (NAC)Domain 4 convergence/multi-target (antioxidant/anti-inflammatory; cognition/mood trials).[239, 240]Glutathione precursor with antioxidant, pro-neurogenesis and anti-inflammatory properties; reviews cite roles in oxidative stress, mitochondrial dysfunction, neuroinflammation, and glutamate/dopamine dysregulation.[240, 239]Cognitive outcomes across disorders (systematic review) and depressive symptoms in psychiatric/neurologic contexts.[240]Moderate: multiple RCTs (systematic review evidence for cognition and broader psychiatric/neurologic use).[240]Systematic review of NAC and human cognition reported that available data suggested statistically significant cognitive improvements following NAC treatment, but evidence is limited and difficult to interpret due to paucity of NAC-specific research.[240]1000–3000 mg/day in included studies; treatment duration 8–24 weeks in summarized trials.[241]Overall NAC treatment appears safe and tolerable (systematic review).[239]
Lactobacillus rhamnosus / Bifidobacterium longum (psychobiotics)Domain 4 convergence/multi-target (gut–brain axis).[242]Psychobiotic strains produce neuromodulatory metabolites (SCFAs, neurotransmitters such as GABA/serotonin) and can regulate neurotransmitters, gut microbiota composition, and inflammatory responses.[242]Depression and anxiety symptoms improved in meta-analyses; one RCT mixture improved depressive mood state and sleep quality in healthy volunteers.[243, 244]Moderate: multiple RCTs + meta-analyses[243, 245]Meta-analysis of 16 RCTs (n=1,125) reported improvement in depression symptoms (BDI MD −3.20) and anxiety (STAI MD −6.88) with probiotics (certainty rated moderate/low depending on outcome).[243]Not mentioned in source(s).Not mentioned in source(s).
Prebiotic fibers (GOS / FOS / inulin)Domain 4 convergence/multi-target (gut–microbiota–brain axis affecting mood/sleepiness).[246]Prebiotics increase Bifidobacterium abundance and may modulate inflammatory pathways (TLR4–Myd88–NF-κB downregulation reported in mechanistic study).[247, 248]Mood/sleepiness and cognitive performance under sleep restriction/circadian misalignment in a small crossover trial; some trials found no changes in stress/inflammation biomarkers or mental health symptoms despite microbiome shifts.[249, 250]Limited: small RCTs (mixed outcomes).[249, 250]Randomized double-blind crossover trial (n=11) found a prebiotic diet reduced sleepiness (KSS) and increased positive/calm mood (PANAS) vs placebo under sleep restriction/circadian misalignment; PVT reaction time faster but congruent Stroop reaction times slower.[249]Examples: 5 g/day FOS + 5 g/day GOS in a crossover trial; 7.5 g/day each of polydextrose and GOS for 14 days in a sleep restriction/circadian misalignment study; 16 g/day inulin for 3 months in an obesity RCT.[250, 249, 251]Not mentioned in source(s).
LactoferrinDomain 4 convergence/multi-target (immune modulation; also sleep outcomes).[252, 253]Immunomodulatory effects involving NF-κB signaling pathway (meta-analysis aim).[253]Sleep quality outcomes (sleepiness/fatigue on rising; initiation/maintenance of sleep) improved in a liposomal lactoferrin trial; also mood (POMS depression-dejection).[252]Limited: small randomized placebo-controlled trials for sleep outcomes.[254]In a 4-week randomized placebo-controlled trial, liposomal lactoferrin 270 mg/day improved sleep inventory domains (“sleepiness and fatigue on rising”; “initiation and maintenance of sleep”) and POMS depression-dejection vs placebo.[252]270 mg/day liposomal lactoferrin for 4 weeks in one trial; 48 mg/day lactoferrin-fortified formula in a pediatric RCT.[252, 254]Pediatric RCT reported no adverse drug reactions; broader reviews note adult clinical studies are limited.[254, 255]
SpermidineDomain 4 convergence/multi-target (autophagy/mitochondrial links to cognitive outcomes).[256, 257]Linked to enhanced autophagy (mechanistic rationale) and, in preclinical models, mitochondrial function effects are suggested; cognitive benefit hypothesized to depend on autophagic/mitochondrial maintenance.[256, 258]Cognitive performance and memory outcomes in older adults (RCTs; mixed results).[256]Moderate: multiple RCTs (adults 60–96; mixed results).[256]Across RCTs summarized in a mini-review, results were mixed: two trials (Wirth 2018; Pekar 2021) showed cognitive improvements after 3 months, while a 12-month trial (Schwarz 2022) found no significant memory change vs placebo.[256]0.9–3.3 mg/day across included RCTs.[256]Not mentioned in source(s).
Alpha-lipoic acid (ALA / R-ALA)Not mentioned in source(s).Not mentioned in source(s).Not mentioned in source(s).NO PROOFS TO DATE — no rigorous human evidence found in provided sources.NO PROOFS TO DATE — no rigorous human evidence found in provided sources.Not mentioned in source(s).Not mentioned in source(s).
Vitamin E (mixed tocopherols / tocotrienols)Not mentioned in source(s).Not mentioned in source(s).Not mentioned in source(s).NO PROOFS TO DATE — no rigorous human evidence found in provided sources.NO PROOFS TO DATE — no rigorous human evidence found in provided sources.Not mentioned in source(s).Not mentioned in source(s).
PterostilbeneNot mentioned in source(s).Not mentioned in source(s).Not mentioned in source(s).NO PROOFS TO DATE — no pterostilbene-specific rigorous human evidence found in provided sources.NO PROOFS TO DATE — no pterostilbene-specific rigorous human evidence found in provided sources.Not mentioned in source(s).Not mentioned in source(s).
Palmitoylethanolamide (PEA)Not mentioned in source(s).Not mentioned in source(s).Not mentioned in source(s).NO PROOFS TO DATE — no rigorous human evidence found in provided sources.NO PROOFS TO DATE — no rigorous human evidence found in provided sources.Not mentioned in source(s).Not mentioned in source(s).
Green tea / EGCGDomain 4 convergence/multi-target (mood/cognition signals; mixed sleep evidence).[259]EGCG associated with increased EEG alpha/beta/theta activity (acute).[260] Meta-analysis reports theanine+caffeine and theanine alone could benefit cognition/mood (tea-constituent evidence).[69]Psychopathological symptoms (e.g., anxiety), cognition (memory/attention), and mixed evidence for sleep outcomes in reviews.[259, 261]Moderate: multiple RCTs + systematic reviews/meta-analyses[262, 261]Meta-analysis found small-to-moderate improvements favoring theanine+caffeine vs placebo on some cognitive and mood outcomes (e.g., choice reaction time; digit vigilance accuracy; overall mood) in the first 1–2 hours after intake.[69]Not mentioned in source(s).Not mentioned in source(s).
Anthocyanins (blueberry / Concord grape)Domain 1 cognition & neuroplasticity (supported by multiple RCT meta-analyses).[263, 264]Not mentioned in source(s).Global cognition improved in meta-analysis (SMD 0.46) and domain-specific benefits reported (attention, processing speed, fluency, episodic and working memory).[264]Strong: meta-analyses + multiple RCTs[263, 265]Meta-analysis reported anthocyanin interventions significantly improved global cognition vs controls (SMD 0.46; 95% CI 0.30–0.63; I²=0%).[264]Not mentioned in source(s).Not mentioned in source(s).
Magnolia bark (honokiol / magnolol)Not mentioned in source(s).Not mentioned in source(s).Not mentioned in source(s).NO PROOFS TO DATE — evidence is limited to mechanistic/preclinical work.[266]NO PROOFS TO DATE — call for clinical studies: “More research is needed … to experiment in clinical studies” for magnolol/honokiol.[266]Not mentioned in source(s).Not mentioned in source(s).

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作者贡献

O.B.: Conceptualization, Literature Review, Writing — Original Draft, Writing — Review & Editing. The author has read and approved the published version of the manuscript.

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The author is affiliated with Olympia Biosciences™ (IOC sp. z o.o.), a registered manufacturer of food supplements and FSMP in Poland.

Olimpia Baranowska

Olimpia Baranowska

首席执行官兼科学总监 · 技术物理与应用数学工程硕士（抽象量子物理与有机微电子学）· 医学科学博士候选人（静脉学）

Founder of Olympia Biosciences™ (IOC Ltd.) · Specialising in dietary supplement formulation and clinical nutrition.

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引用

APA

Baranowska, O. (2026). 食品补充剂与医学用途食品在大脑功能中的作用：基于机制锚定的证据图谱. Olympia R&D Bulletin. https://olympiabiosciences.com/rd-hub/brain-function-supplements-evidence-map/

Vancouver

Baranowska O. 食品补充剂与医学用途食品在大脑功能中的作用：基于机制锚定的证据图谱. Olympia R&D Bulletin. 2026. Available from: https://olympiabiosciences.com/rd-hub/brain-function-supplements-evidence-map/

BibTeX
@article{Baranowska2026brainfun,
  author  = {Baranowska, Olimpia},
  title   = {食品补充剂与医学用途食品在大脑功能中的作用：基于机制锚定的证据图谱},
  journal = {Olympia R\&D Bulletin},
  year    = {2026},
  url     = {https://olympiabiosciences.com/rd-hub/brain-function-supplements-evidence-map/}
}

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