摘要

背景：

针对脑功能的膳食补充剂和医学食品市场正在迅速扩大，然而消费者和临床医生仍缺乏一个清晰的框架，来基于特定的生物学机制和支持性证据的质量对相关成分进行评估。现有的综述往往根据商业类别对成分进行归类，而非基于其分子或系统水平的靶点。

目的：

本叙述性综述旨在为声称具有支持脑功能作用的常见膳食补充剂和医学食品建立一个机制锚定的证据图谱。我们根据四维生物学框架对相关成分进行组织：（1）认知表现与神经塑性，（2）压力韧性、抗焦虑与睡眠架构，（3）细胞能量与线粒体功能，以及（4）汇聚节点（跨领域主调节剂）。

方法：

针对上述四个领域，我们在多个学术数据库和网络资源中进行了广泛的文献检索。筛选文献的标准包括：与脑功能的相关性、是否存在人体临床证据（或强有力的机制数据）以及是否对特定的、具名的成分进行了测试。随后，对精选出的成分列表进行了针对性的强化检索，以获取高质量证据（荟萃分析、系统评价和随机对照试验）。我们对每种成分的机制、临床结果、证据级别和安全性进行了详细分析。

结果：

我们对四个领域中众多成分的证据进行了绘制。领域 1（认知）得到了 Ginkgo biloba (EGb 761) 和 Bacopa monnieri 等成分的支持，这些成分在特定认知终点上具有强大的荟萃分析证据支持[1, 2]。领域 2（压力/睡眠）的特色成分包括 L-theanine、藏红花、薰衣草油 (Silexan) 以及 Vitamin D，这些成分在改善焦虑或睡眠结果方面均拥有强有力的证据[3–6]。领域 3（能量）最具代表性的是用于改善记忆力的 Creatine monohydrate 和用于提升认知表现的外源性酮[7, 8]。领域 4（汇聚）包括 Folate/L-methylfolate，它作为抑郁症的辅助疗法拥有强有力的证据[9, 10]。研究发现，许多热门成分针对特定大脑相关终点的证据有限，或处于“迄今未证实 (NO PROOFS TO DATE)”的状态。

结论：

机制锚定的方法为评估使用膳食补充剂和医学食品改善脑功能的科学依据提供了一种结构化的途径。虽然有几种成分在特定针对性结果上拥有确凿的证据，但许多其他成分仍缺乏严谨的人体临床数据。该图谱不仅突出了最具前景的干预措施，也指出了研究中的关键空白，为更理性的应用和未来的学术研究提供了指导。

关键词：

促智药，营养保健品，认知提升，膳食补充剂，医学食品，大脑健康，循证，作用机制

引言

市面上宣称具有大脑健康益处的膳食补充剂、营养保健品及医学食品层出不穷，这给消费者、临床医生和研究人员带来了严峻的挑战。与受严格监管的药品不同，这些产品通常基于“记忆力支持”或“压力缓解”等宽泛且定义模糊的类别进行评估，极少提及具体、合理的生物学作用机制。这种缺乏结构化、以机制为锚定框架的现状，导致难以评估证据质量、比较不同的成分并做出明智的决策。因此，需要一种更严谨的方法，以超越类别层面的评估，并根据各成分在大脑内特定的分子和系统水平靶点对其进行评价。

本综述根据一个四维度机制图谱来组织相关证据，旨在将分子靶点与可观察的大脑功能表现联系起来。这四个维度分别是：（1）认知表现与神经塑性，针对神经递质合成、神经营养因子、脑血管支持和细胞膜完整性；（2）压力韧性、抗焦虑与睡眠结构，侧重于 HPA 轴、GABAergic/serotonergic 系统以及昼夜节律机制；（3）细胞能量、线粒体功能与身体耐力，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）汇聚节点，即跨领域的关键调节因子，如 BDNF、NF-κB、AMPK、mTOR、Nrf2、甲基化循环和肠脑轴，它们整合了来自多条通路的信号。

对于本研究调研的每种成分，本篇文献明确记录了两个关键信息：（i）其合理作用于机制图谱中的哪些靶点，以及（ii）关于其有效性和安全性的现有最高质量人体临床证据。这包括在缺乏严谨的人体临床试验证据时，将相关成分明确标记为“迄今无证据”，从而对当前的科学研究现状提供透明的评估。

方法

本叙述性综述采用结构化的多阶段流程，旨在识别、评估并整合与脑功能相关的膳食补充剂和医学食品的证据。

初始检索策略旨在实现广泛召回，利用了多个学术数据库查询（例如 PubMed、Google Scholar）以及针对四个机制领域中每一个的针对性网页搜索。查询词结合了成分（例如“nootropic”、“adaptogen”、“psychobiotic”）、机制（例如“BDNF”、“HPA axis”、“mitochondria”）和研究类型（例如“randomized controlled trial”、“meta-analysis”）的术语。

随后根据三个主要标准对来源进行筛选。来源必须满足以下条件：（1）与脑功能相关，涉及一种经测试对认知、精神、睡眠、压力或神经功能相关结果有影响的可摄入化合物，或支持这些功能的机制；（2）提供人体证据或强有力的机制数据，例如随机对照试验（RCT）、荟萃分析、系统评价，或明确将成分与分子靶点联系起来的临床前研究；（3）命名一种特定的、可识别的成分或标准化提取物。

在这一广泛发现阶段之后，生成了一份精选的经典成分清单。随后，对清单上的每种成分进行了针对性强化检索，特别针对最高级别的证据，如 RCT 的荟萃分析和系统评价。

每种成分的证据均根据以下标准进行整合和评分：强（多项荟萃分析和/或大量验证性 RCT）、中等（多项具有一致效应方向的 RCT）、有限（单项 RCT 或少量结果不一致的研究）、仅限机制/临床前（缺乏人体有效性数据）以及迄今无证据（检索中未发现严格的人体证据）。

最终数据（包括机制、证据级别、临床结果和安全性说明）汇总于主证据表中，作为本手稿的附录 A 提供。

结果

领域 1 — 认知表现与神经塑性

领域 1 的成分是基于机制图谱进行筛选的，因为人类大多数可测量的短期“脑功能”终点（注意力、记忆力、执行功能、痴呆量表和功能状态）在逻辑上都受到一组有限的趋同生物学杠杆的影响：(1) 神经递质前体供应与信号传导（特别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) 神经营养与血管支持（可调节可塑性和脑灌注）。胆碱能杠杆以被描述为乙酰胆碱 (ACh) 生物合成和/或神经元膜磷脂前体的化合物为代表，例如磷脂酰胆碱和 CDP-choline (citicoline)[11–13]。儿茶酚胺杠杆则以 L-tyrosine 为代表，它被明确描述为多巴胺和去甲肾上腺素的前体，并被认为在严苛条件下能够对认知起到缓冲作用[14]。神经营养信号传导是该领域的第二大主要依据，因为某些干预措施显示出神经营养通路中的生物标志物变化（例如，使用 Hericium erinaceus 后循环 pro-BDNF 增加，以及在姜黄素的 RCT 荟萃分析中血清 BDNF 增加）[15, 16]。最后，几种领域 1 的候选成分是基于与认知相关的血管和代谢支持信号，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）的主张[9, 17]。

Citicoline (CDP-choline)

Citicoline (CDP-choline) 被描述为磷脂酰胆碱合成所必需的前体，并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”，并且是“乙酰胆碱生物合成所必需的”[12, 13, 18]。在认知障碍人群中，一项系统评价/荟萃分析报告称，citicoline 改善了认知状态，合并标准化均数差 (SMD) 范围为 0.56 至 1.57（在敏感性分析中），同时指出研究的整体质量较差[19]。在急性脑外伤中，一项针对 11 项临床研究（n=2771）的系统评价/荟萃分析报告称，使用 citicoline 的独立生活率更高（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 mg/day，且在 TBI 荟萃分析中该干预措施被报告为耐受性良好，“无安全疑虑”[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 被描述为一种用于治疗认知障碍的含胆碱磷脂，并被定性为乙酰胆碱生物合成的前体（综述文献中还提出了额外的“神经保护信号传导”主张）[23, 24]。一项纳入了 7 项 RCT 的系统评价/荟萃分析报告称，当 alpha-GPC 与 donepezil 联合使用时，认知、功能和行为有显著改善（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的为期 12 周、多中心、随机、安慰剂对照试验（n=100）中，600 mg/day 的 alpha-GPC 导致 ADAS-cog 评分较安慰剂组降低了 2.34 分，且未报告严重不良事件，也无因不良事件而中止试验的情况[23]。

结论： 中等（多项 RCT；部分最强的定量效应出现在联合治疗中）[25]。

Choline (bitartrate / chloride)

Choline (bitartrate / chloride) 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，一篇综述得出结论，针对成人认知结果，“缺乏高质量（干预）研究”[3]。在一项针对健康绝经后女性的随机、双盲、安慰剂对照试验中，1 g/day 的 choline bitartrate 显著增加了循环游离胆碱和 betaine，并在第 6 周时使血浆总同型半胱氨酸降幅接近统计学显著性（P=0.058），摘要中未提及对血浆脂质有影响[26]。综述文献中提出的一个关键警示是，可能有害的心脏代谢影响需要仔细评估[3]。

结论： 有限（存在生化 RCT 证据，但成人认知试验被描述为缺乏高质量研究）[3]。

Phosphatidylserine (PS)

Phosphatidylserine (PS) 被描述为与认知功能相关的大脑皮层重要组成部分[27]。一项系统评价/荟萃分析（纳入 9 项研究，包括 5 项 RCT）得出结论，PS 对伴有认知衰退的老年人的记忆力有积极影响，并总结称 PS “似乎可以改善与年龄相关的认知衰退，尤其是记忆力”，纳入研究中的 PS 剂量在 100–300 mg/day 之间不等[27]。在一项针对有记忆诉求的非痴呆老年人的随机试验中，每天 300 mg PS 的 PS-DHA 持续 15 周被报告为安全且耐受性良好，对测试参数无负面影响[28]。在另一项针对精英射击运动员的小型试验中，补充 PS 降低了恐慌评分并改变了皮质醇相关指标（伴有睡眠质量改善的趋势，但未达到统计学显著性）[29]。

结论： 中等（多项 RCT 以及支持记忆力改善的荟萃分析；在小型研究中观察到一些辅助的压力/睡眠信号）[27]。

Phosphatidylcholine (PC)

Phosphatidylcholine (PC) 被介绍用于脑部疾病试验，因为它是 ACh 生物合成的前体，且是神经元膜不可分割的组成部分[11]。在一项针对孕妇的双盲 RCT（n=140）中，从妊娠 18 周至产后 90 天每天服用 750 mg/day 的 phosphatidylcholine 耐受性良好，但 10 个月和 12 个月时的婴儿认知结果（语言、整体发育和记忆指标）在各组之间无显著差异[30]。在痴呆小鼠中进行的临床前研究结果表明，给予 PC 增加了大脑中的胆碱/ACh 并改善了记忆，但这并不能代替人类成人认知疗效的直接证据[31]。

结论： 有限（人类 RCT 显示出良好的耐受性，但婴儿结果呈阴性；所提供的文献中未建立成人认知证据）[30]。

Omega-3 EPA/DHA (鱼油)

Omega-3 EPA/DHA (鱼油) 被描述为对大脑发育和认知表现非常重要，其中 DHA 被定性为大脑中起主导作用的 omega-3，会影响神经递质和脑功能[9, 10]。在一项针对孕期和/或哺乳期女性补充鱼油的随机试验的系统评价/荟萃分析中，共纳入了 11 项试验，未发现补充 DHA/EPA 与评估的儿童认知参数之间存在显著关联[10]。其他以 RCT 为重点的综述文献指出，摄入 omega-3 脂肪酸可改善学习、记忆、认知健康和脑血流量，这说明了结论如何因人群和研究设计的不同而产生差异[9]。

结论： 中等（存在多项 RCT 和荟萃分析，但在所提供的证据中，其对认知的改善作用并不一致）[10]。

Bacopa monnieri (bacosides)

一项评估 Bacopa 是否能提高人类认知的系统评价报告称，在各项研究中，Bacopa 改善了 17 项记忆自由回忆测试中的 9 项表现，但在其他认知领域几乎没有发现改善证据；在纳入的研究中，试验通常持续 12 周以上，提取物剂量为 300–450 mg/day[32]。一项对合格 RCT 受试者进行的荟萃分析报告称，在长期服用标准化提取物（≥12 周）后，认知得到改善，表现为 Trail B 测试耗时缩短，选择反应时间减少[2]。在另一项针对轻度认知障碍的 RCT 中，各组之间的睡眠质量总评分无统计学显著差异（所述剂量为 160 mg 提取物，持续 2 个月），这表明并非所有人群和结局指标都能显示出益处[7]。

结论： 强（特定认知指标具有荟萃分析 RCT 证据，具有领域特异性而非广谱效应）[2, 32]。

Ginkgo biloba (EGb 761)

针对痴呆症的系统评价/荟萃分析使用经过验证的认知、日常生活活动能力 (ADL) 和全局评估来评价 EGb 761[1]。在合并分析中，认知、ADL 和全局评分的变化分值显著倾向于 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），另一项荟萃分析则强调，获益主要与 240 mg/day 剂量的 EGb 761 且持续 22–24 周相关[1, 33, 34]。荟萃分析中的安全性结果报告称，没有重大的安全疑虑，且不良事件发生率与安慰剂组相似[1, 33, 35]。

结论： 强（多项 RCT 和荟萃分析显示出一致的痴呆相关终点改善，且耐受性可接受）[1, 33]。

猴头菇 (Hericium erinaceus)

文献综述描述了 Hericium erinaceus 在认知衰退/阿尔茨海默病和心理健康状况方面的测试情况，一项 RCT 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 pro-BDNF（循环 BDNF 无显著变化）[15, 36]。一项纳入了一项 RCT 和一项试点临床试验的综述报告称，干预组的 MMSE 评分合并加权均数增加了 1.17，但在其他总结中也指出了不同症状领域的混合结果[36, 37]。各综述中报告的副作用并不常见且通常较轻微（例如胃肠道不适），但也提到了头痛和过敏反应等潜在副作用[4, 37]。

结论： 中等（存在多项对照试验，且认知和情绪信号好坏参半；证据库仍然相对较小）[37]。

Huperzine A

荟萃分析总结报告称，在阿尔茨海默病人群中，与安慰剂相比，Huperzine A 在 8–16 周时改善了通过 MMSE 测量的认知功能，且在多个时间点上 ADL 结果也更倾向于 Huperzine A[38]。一项系统评价纳入了 20 项 RCT（n=1823），但指出大多数纳入的试验具有高偏倚风险，尽管有积极发现，但这限制了对效应评估值的信心[38]。安全性总结表明，不良事件大多属于胆碱能性质，且在荟萃分析摘要所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 RCT，但高偏倚风险降低了确定性）[38]。

Vinpocetine

一项针对痴呆症双盲随机试验（总 n=583）的 Cochrane 系统评价得出结论，关于 vinpocetine 获益的证据不确定，不支持临床应用，同时指出某些获益与 30 mg/day 和 60 mg/day 相关，但接受 ≥6 个月治疗的患者人数较少[40]。在系统评价引用的另一项合并分析中，vinpocetine 组的 MMSE 变化优于安慰剂组（合并 WMD 0.92，95% CI 0.02–1.82）[41]。痴呆症试验中对不良反应的报告不一致，且 Cochrane 总结中的任何试验均无法获得意向性治疗分析数据[40]。

结论： 中等（存在多项 RCT，但最高级别的痴呆症系统评价得出结论，证据仍不确定）[40]。

Souvenaid / Fortasyn Connect (医疗食品)

Souvenaid / Fortasyn Connect (医疗食品) 被描述为一种旨在支持阿尔茨海默病突触合成的医疗食品，其 Fortasyn Connect 配方包括用于神经元膜形成的前体和辅助因子（例如单磷酸尿苷、胆碱、磷脂、EPA/DHA、以及维生素和硒）[8]。在针对 527 名接受标准 AD 药物治疗的轻中度 AD 患者进行的 S-Connect 为期 24 周的双盲 RCT 中，两组通过 ADAS-cog 评估的认知水平均有所下降，且活性成分组与对照组之间无显著差异（相差 0.37 分；p=0.513）[8]。安全性报告指出，各组之间的不良事件发生率没有差异，且 Souvenaid 与 AD 药物联用时耐受性良好，在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 RCT 且结果不一；一项大型 RCT 显示在接受药物治疗的轻中度 AD 中对 ADAS-cog 无明显改善效果）[8]。

L-tyrosine

Tyrosine 被明确描述为多巴胺和去甲肾上腺素的前体，综述合成分析报告称，在认知负荷或极端天气等严苛条件下，摄入 tyrosine 可以急性对抗工作记忆和信息处理能力的下降[14]。单项 RCT 报告了警觉性/精神运动结果的改善（例如失误减少）和认知灵活性的改善（转换成本降低）[43, 44]。然而，一项系统评价也得出结论，现有证据不足以针对减轻压力对表现的影响做出确切的推荐，并强调了异质性和背景依赖性[45]。

结论： 中等（在压力环境下具有看似合理的急性效应的多项试验，但系统评价层面的不确定性依然存在）[14, 45]。

Centrophenoxine (meclofenoxate)

在阿尔茨海默型老年痴呆症患者中，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、IQ），据报告，含有 meclofenoxate 的神经代谢复合物显著优于单独使用 meclofenoxate[46]。在另一项针对老年人的双盲试验中，在接受剂量为 2 g/day 的 centrophenoxine 治疗 8 周后（如研究方案中所述），活性成分组中 48% 的受试者表现出记忆功能改善，而安慰剂组为 28%[5]。在慢性脑低灌注模型中的临床前研究结果报告称，口服 centrophenoxine 改善了记忆损伤并减少了氧化/炎性介质的变化，但这并不是人类机制或疗效的直接证据[47]。 结论： 有限（具有积极信号的小样本/较早期 RCT；所提供的文献中未显示当代高质量的重复试验）[5]。

Caffeine

在睡眠剥夺/受限的情况下，急性摄入 caffeine 显示出跨认知领域的荟萃分析层面的改善，包括改善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]。同样的一系列证据表明 caffeine 会损害睡眠，通常会延长睡眠潜伏期，并减少总睡眠时间/效率和慢波睡眠，且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 变体与焦虑/睡眠障碍相关联，并将 CYP1A2 变体与认知功能相关联[50]。 结论： 中等（确凿的急性表现证据，但被明确的睡眠干扰效应所抵消）[48, 49]。

Domain 2 — 抗压韧性、焦虑缓解与睡眠结构

Domain 2 的成分对应于当压力系统、抑制性神经传递和昼夜节律睡眠-觉醒调节向具有临床意义的方向转变时所表现出的脑功能结果，这体现在测量感知压力、焦虑严重程度、皮质醇、入睡/睡眠质量以及次日功能的试验中。因此，该领域的机制锚定于

HPA 轴和神经内分泌压力反应调节（例如，具有明确 HPA 轴讨论的 Rhodiola 等适应原，以及已阐明参与 HPA 轴调节的 magnesium）[51, 52]，
GABAergic 调节（例如，缬草对“……GABA 功能的调整”、啤酒花的 GABAA 受体调节，以及卡瓦胡椒与 GABA 相关的机制）[53–55]，
影响情绪和睡眠生物学的 serotonergic 前体（例如，作为 serotonin 前体的 tryptophan 和 5-HTP，以及 5-HTP 在大脑中向 serotonin 的转化）[56–58]，以及
通过与压力和睡眠表型相关的神经调节代谢物和炎症控制起作用的肠-脑轴干预（精神益生菌和益生元）[59]。

Rhodiola rosea (rosavins/salidroside)

从机制上讲，在所审查的文献中，Rhodiola 被描述为调节 HPA 轴和神经递质系统，并对抗氧化途径和线粒体功能进行了补充讨论[51]。在临床上，系统评价总结了安慰剂对照 RCTs 并得出结论，Rhodiola “可能缓解轻度至中度抑郁和轻度焦虑的症状”并改善情绪，同时也强调鉴于实验数据有限，研究结果“尚不明确”，且在至少一项纳入研究中存在高偏倚风险/报告缺陷的系统评价中，其疗效被描述为“矛盾的”[60, 61]。这些总结中的安全性信号通常较温和（“仅报告了少数轻度不良事件”）[62]。评估结论：中等。

Ashwagandha (Withania somnifera; KSM-66 / Sensoril)

在一项荟萃分析总结的人类睡眠试验中（5 个 RCTs；400 名受试者），ashwagandha 提取物对整体睡眠表现出微弱但显著的改善（SMD −0.59, 95% CI −0.75 至 −0.42），其中在诊断为失眠且剂量 ≥600 mg/day 且持续 ≥8 周的成年人中表现出更大的亚组效应；该综合报告还指出，清晨醒来时的精神警觉性和焦虑水平有所改善[63]。在针对压力/焦虑的荟萃分析中，与安慰剂相比，ashwagandha 制剂降低了感知压力（PSS MD −4.72）、汉密尔顿焦虑量表（MD −2.19）和血清皮质醇（MD −2.58），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 证据库中报告了“无严重副作用”[63]，但长期严重不良反应的数据被明确描述为有限。评估结论：中等。

L-theanine

在一项系统评价/荟萃分析中（纳入 18 项研究；N=897），L-theanine 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）和整体主观睡眠质量评分（SMD 0.43）[65]。另一项证据合成报告称，暴露于压力环境中的人群每日摄入 200–400 mg/day “可能有助于减轻压力和焦虑”[66]。在试验摘要报告的一项针对无重大精神疾病成年人的 RCT 中，与基线/安慰剂对照组相比，200 mg/day 持续 4 周降低了抑郁、焦虑和 PSQI 评分，并改善了言语流畅性和执行功能评分[67, 68]。评估结论：强。

Magnesium (glycinate / threonate / citrate)

Magnesium 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”，为各种制剂在压力和睡眠终点方面提供了与图谱一致的机制合理性[52]。针对失眠相关结局，一项系统评价/荟萃分析确定了三项 RCTs（151 名老年人），发现与安慰剂相比，合并入睡潜伏期缩短了 17.36 分钟，同时也指出存在中至高偏倚风险，且证据质量为低至极低[69]。具体针对 magnesium L-threonate，在有睡眠问题成年人中进行的 RCTs 报告称，与安慰剂相比，客观测量的深层和 REM 睡眠评分（Oura ring 指标）以及多项日间指标（精力、生产力、情绪、警觉性）均有所改善，并报告其安全且耐受性良好；另一项 RCT 报告称 Magtein® 改善了整体认知表现，对工作记忆和情景记忆的影响更大[70, 71]。评估结论：中等。

Glycine

Glycine 被描述为通过 NMDA 型谷氨酸受体和 glycine 受体在兴奋性和抑制性神经传递中发挥作用，且一篇综述提出核心体温的下降“可能是 glycine 对睡眠产生影响的潜在机制”[72]。然而，有一篇综述指出，虽然长期给予 glycine 改善了健康人群的睡眠，但这些研究的样本量较小且偏倚风险较高，从而限制了该数据集对睡眠适应症的置信度[73]。在另一个精神病学背景下，NMDA 受体共激动剂 glycine 和 D-serine 可有效减少精神分裂症的阴性症状（固定效应 SMD −0.66），而合并认知功能则未显示出显著效应（随机效应 WMD −2.79, p=0.11）[74]。评估结论：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 摄入对压力的益处证据“有限”，对睡眠的益处证据“非常有限”，同时还指出，在做出推论之前需要进行更多研究[75]。纳入研究集中的单个试验报告了特定领域的信号，例如在第 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，以及在为期 90 天的补充剂研究中改善了习惯性睡眠效率（降低 PSQI），该研究还观察到 HRV 增加，这与更强的副交感神经优势一致[76–78]。评估结论：有限。

Taurine

在一项评估认知功能的 RCTs 系统评价/荟萃分析中，taurine（单独使用或结合运动训练）未对认知评分显示出显著影响，作者得出结论，目前证据不足以支持其增强认知功能的功效[79]。随后的一项系统评价总结了急性 taurine 给药研究，结果显示其对认知功能的改善充其量是微弱且不一致的（通常为 1–3 g，最高约为 ~50 mg/kg）[80]。评估结论：中等（多项 RCTs，在现有的综合分析中对认知功能基本无显著效果）。

领域 3 — 细胞能量、线粒体功能与身体耐力

领域 3 的成分是根据机制图谱进行筛选的，因为大脑的表现受到细胞能量供应（ATP 生成）、底物灵活性以及线粒体氧化还原平衡的严格限制，这些因素可继而影响认知、疲劳、情绪和压力耐受性。所包含的成分对应于

生物能量辅因子和电子传递/氧化还原系统（例如，CoQ10 被描述为“密切参与能量产生”并能预防过氧化损伤）[81]，
NAD+-前体策略（NR、NMN 和烟酰胺作为 NAD+ 相关途径）[82, 83]，
磷酸肌酸缓冲（肌酸作为脑生物能量学的重要组成部分）[84]，以及
替代燃料策略（MCTs、caprylic triglycerides 和外源性酮体，用以在葡萄糖利用受损时提高酮体水平）[85, 86]。

Acetyl-L-carnitine (ALCAR)

Acetyl-L-carnitine (ALCAR) 被置于领域 3 中，因为作为乙酰基供体，并能促进 beta-oxidation 期间脂肪酸向线粒体的转移，它“在中间代谢中发挥着至关重要作用”，且据报道其对脑能量/磷脂代谢和突触传递具有额外的神经调节作用[87, 88]。与这种以能量为中心的理论基础一致，对随机试验进行的荟萃分析在以下方面报告了临床信号：(a) 抑郁症（汇总 9 个 RCTs，与安慰剂/无干预相比，ALC 减轻了抑郁症状，SMD = -1.10）[89]，以及 (b) MCI/轻度 Alzheimer’s disease（在综合临床/心理测量结果和临床医生全局变化方面较安慰剂具有显著优势，其益处在 3 个月时显现并随时间推移而增加）[90]。MCI/轻度 AD 证据库中的剂量在 1.5–3.0 g/day 之间变化，且在该荟萃分析的所有研究中，耐受性均被描述为良好[90]。结论：中等。（多项 RCTs 且有荟萃分析支持情绪和 MCI/轻度 AD 结局。）[89, 90]。

Axona (caprylic triglyceride 医疗食品)

Axona (caprylic triglyceride 医疗食品) 通过替代燃料策略针对领域 3：它不侧重于改善葡萄糖利用，而是旨在提供能够穿过血脑屏障的酮体，并在葡萄糖利用受损时提供替代能量来源[86, 91]。在大型双盲 RCT (NOURISH AD；26 weeks；413 名患者根据 APOE 基因型分层) 中，AC-1204 (caprylic triglyceride) 并未改善主要认知终点 (ADAS-Cog11)，且次要终点“未能检测到任何药物效应”[92]。较小的研究报告了矛盾的结果，包括一个总体上的否定陈述（“未改善认知功能”），以及在基线 MMSE ≥ 14 的某些 ApoE4-negative 患者中的亚组信号[93]。实际考虑因素是胃肠道耐受性，在一次临床干预中其被描述为“良好，无严重胃肠道不良反应”，并采用 10 to 40 g/day 的剂量滴定以减少胃肠道不良反应（其中 40 g 粉末含有 20 g caprylic triglycerides）[93]。结论：中等（在最大的 RCT 中，认知方面的结果好坏参半/多为阴性）[92, 93]。

Coenzyme Q10 (ubiquinol / ubiquinone)

Coenzyme Q10 (ubiquinol / ubiquinone) 被纳入领域 3，因为其被描述为具有“生物能量和抗氧化活性”，且“密切参与能量产生”并能预防膜磷脂的过氧化损伤[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 RCTs，474 名参与者；SMD = -0.68），而基于仅有的两项试验，未显示出对疲劳具有统计学意义的显著益处[94]。另外的荟萃分析生物标志物证据表明，CoQ10 提高了总抗氧化能力和 SOD，并降低了 malondialdehyde，这与符合领域 3 氧化还原防御节点的系统性抗氧化信号相一致[95]。结论：中等。（多项 RCTs 具有荟萃分析证据支持抑郁症状改善和抗氧化生物标志物变化。）[94, 95]。

领域 4 — 汇聚节点（跨领域主调控因子）

领域 4 的成分被优先考虑，因为它们针对“汇聚节点”，这些节点极有可能同时影响多个与大脑相关的结局——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供应）以及单碳/甲基化途径（可影响单胺类神经递质的合成及相关的抑郁症状）。这种跨领域逻辑与人参（ginseng）等植物药的多途径机制描述相一致（神经炎症、抗氧化能力、线粒体代谢、突触可塑性），并与将营养保健品与认知终点（例如，再认记忆）和系统性炎症标志物（例如，CRP、TNF-α）联系起来的人类研究文献相一致[96–99]。

Panax ginseng

从机制上讲，人参被描述为通过与汇聚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、改善线粒体代谢和调节突触可塑性；在情绪调节方面，它还被描述为可以调节 HPA/HPG-轴信号传导、神经递质和 BDNF–TrkB 途径[96]。临床上，一项纳入 15 项 RCT（分析样本量 n=671）的荟萃分析报告了记忆力的改善微小但在统计学上显著（总体 SMD=0.19, 95% CI 0.02–0.36），在“高剂量”亚组分析中显示出更大的效应量（SMD=0.33, 95% CI 0.04–0.61），但对于整体认知、注意力或执行功能结局，未发现积极的合并效应[100]。另一项系统评价确定了 9 项符合纳入标准的随机、双盲、安慰剂对照试验，表明虽然存在多项 RCT，但其研究终点和结果存在差异[101]。其中一项 RCT 示例每日给予 3 g/day Panax ginseng 粉末，持续 6 months，且未报告严重不良事件；跨试验的更广泛安全性汇总同样发现“无严重不良事件”，但同时也指出大多数研究中的偏倚风险尚不明确[102, 103]。 证据等级判定：中等。

厚朴皮 (honokiol / magnolol)

所提供文献中的现有证据仅限于机制和临床前研究：honokiol 和 magnolol 抑制了神经元中 NMDA 刺激的超氧化物产生（该途径涉及 NADPH oxidase），并通过 p‑ERK 依赖性途径抑制了小胶质细胞中 IFNγ±LPS 诱导的 iNOS 表达、一氧化氮和 ROS 的产生[104]。一项综述明确指出，需要进行更多研究以提高生物利用度并在临床研究中验证这些化合物，这进一步印证了本证据包中缺乏严格的人体疗效证据[105]。 证据等级判定：仅限机制。

Resveratrol (trans-resveratrol)

针对不同认知结局的人体证据好坏参半。一项针对干预性试验的系统评价报告显示，在纳入的 10 项研究中，部分研究发现有所改善，部分研究结果好坏参半，其他研究则显示无效果；而合并分析显示，其对延迟再认（合并 SMD=0.39, 95% CI 0.08–0.70；n=3 项研究，n=166 名参与者） and 负面情绪（合并 SMD=-0.18, 95% CI −0.31 to −0.05；n=3 项研究，n=163 名参与者）具有统计学上显著的益处[97]。相比之下，另一项荟萃分析报告称，对于通过听觉词语学习测试评估的记忆 and 认知表现，未发现显著影响，这支持了终点特异性的不一致性[106]。更长期的血管-认知证据包括一项在 125 名绝经后女性中开展、为期 24‑month 的随机、安慰剂对照交叉试验。该试验中，受试者每日两次服用 75 mg trans-resveratrol，结果显示与安慰剂相比，“整体认知表现显著改善了 33%”，且脑血管测量指标（静息平均 CBFV 和 CVR）也有所改善[107]。补充 resveratrol 后，系统性炎症标志物（CRP 和 TNF-α）呈荟萃分析显示的下降趋势，这支持了其作为汇聚节点的作用合理性，尽管其中一项分析指出在该特定数据集中，可能存在 CRP 降低但 IL‑6 和 TNF-α 未发生一致性改变的情况[98, 99]。 证据等级判定：中等。

讨论

这篇基于机制的综述对用于改善脑功能的膳食补充剂和医学食品进行了结构化评估。结果显示出清晰的证据分级，部分成分在特定结局上拥有强有力的临床数据支持，而许多其他成分则仅基于临床前理论依据，或存在不一致的人体临床试验结果。

跨领域最佳证据推荐

基于结果部分综合的证据，可针对四个领域中的每一个确定一个“最佳证据推荐”，代表在相关脑功能结局上拥有最一致且高质量人体临床数据的成分：

领域 1（认知）： Ginkgo biloba extract EGb 761 展现出强有力的证据，多项 RCTs 的单项及荟萃分析表明其在改善痴呆患者的认知、日常生活活动能力和总体临床评级方面具有一致的益处，且安全性记录详实[1]。
领域 2（压力/睡眠）： Melatonin 脱颖而出，其拥有来自众多 RCTs 和荟萃分析的广泛证据库，证实了其在缩短不同人群的入睡潜伏期和延长总睡眠时间方面的有效性，且耐受性良好[108]。
领域 3（能量/线粒体）： Creatine monohydrate 获得了来自 RCTs 荟萃分析的强有力支持，显示出对记忆能力的显著积极作用（尤其是在老年人中），这与其在脑生物能量学中的作用相一致[84, 109]。
领域 4（融合）： Folate / L-methylfolate (5-MTHF) 拥有来自多项 RCTs 和荟萃分析的强有力证据，支持其作为辅助治疗手段，可显著减轻抑郁症状、提高治疗反应率并提升缓解率[110]。

机制融合

几种成分通过同时作用于多个调节节点，体现了“机制融合”的原理。例如，omega-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），并且可能影响神经营养因子信号传导，如 BDNF（领域 4）[9]。同样，creatine 不仅通过磷酸肌酸系统支持大脑能量（领域 3），还因其神经保护特性而受到研究[84]。B-vitamins (Folate, B6, B12) 在甲基化循环（领域 4）中处于核心地位，而该循环对于多种神经递质的合成（领域 1）、同型半胱氨酸（血管与神经健康的标志物）的调节以及 SAMe 的产生至关重要[111, 112]。这些多靶点作用可能解释了为什么某些补充剂似乎在不同的功能领域都具有益处。

截至目前尚无证据的成分

本综述的一个关键发现是，在所提供的文献来源中，许多热门成分都缺乏针对脑部特异性终点的严谨人体临床证据。对于这些成分，其对认知或情绪益处的宣称尚未得到高质量临床试验的证实。有必要明确指出：截至目前尚无确证证据。示例如下：

口服 GABA 补充剂：虽然在机制上合理，但系统性综述得出的结论是，口服时其对睡眠或压力的功效证据非常有限[75]。
Spermidine：针对认知的人体 RCTs 结果并不一致，部分研究显示有益，而其他研究则发现对记忆没有显著影响[113]。

Uridine monophosphate, Pterostilbene, Palmitoylethanolamide (PEA)：对于这些成分，在初始证据库中未检索到支持其脑部相关功效宣称的严谨人体临床试验。

安全性考量与监管现状

安全性是首要考量，其中几种成分存在显着的安全警示。Kava 虽然在抗焦虑方面显示出中等强度的证据，但存在肝毒性风险，监管机构建议谨慎使用、进行常规肝功能检测并避免饮酒[55]。作为一种乙酰胆碱酯酶抑制剂，Huperzine A 可能会引起胆碱能副作用，其使用需保持谨慎，特别是对于正在服用其他胆碱能药物的患者[39]。这些实例突显了不仅要评估疗效，还要评估潜在不良反应和药物相互作用的重要性，而这一评估过程在补充剂中往往不如药品那样严格。

局限性

本综述存在若干局限性。初步的广泛检索和筛选基于标题和摘要，这可能导致排除了部分相关研究。现有证据基础在成分配方（例如，不同的 Ashwagandha 或 Curcumin 提取物）、剂量、治疗周期以及研究人群方面具有显著的异质性，导致难以进行直接比较。倾向于阳性结果的发表偏倚可能对现有文献产生了影响。最后，本综述未进行全新的 Meta 分析，而是依赖于现有系统综述中报告的数据和质量评估。由于大多数成分缺乏头对头试验，因此无法确定其相对疗效。

研究重点

机制锚定图谱揭示了若干尚缺乏深入研究成分的节点。例如，胶质淋巴清除系统的直接调节剂（如靶向 Aquaporin-4）代表了一个现有干预手段有限的前沿领域。同样，虽然许多成分声称具有抗氧化功效，但在人体认知试验中，很少有成分经过严格测试，以验证其通过 Nrf2/Keap1 通路等靶点特异性调节神经元氧化还原信号传导的能力。未来的研究应优先针对这些探索较少但在生物学上具有重要意义的靶点测试新型或现有化合物，以填补证据图谱中的关键空白。

结论

本文将用于改善大脑功能的食品补充剂和医学食品这一复杂领域，整合至一个基于作用机制的、连贯的系统性框架中。这种方法超越了模棱两可的市场营销分类，转而根据成分的特定生物学靶点和相应临床证据的力度对其进行评估。

结果表明，证据质量存在显著差异。少数成分（包括用于痴呆症的 Ginkgo biloba (EGb 761)、用于睡眠的 melatonin、用于记忆的 creatine 以及用于抑郁症辅助治疗的 L-methylfolate）得到了多项 RCTs 和荟萃分析的大量证据支持。更多成分则显示出中等或有限的证据，其结果虽有前景但并不一致，需要进行更深入、更严格的研究。关键是，许多广泛销售的成分并无坚实的人体临床试验数据支持其在脑健康相关结局中的应用。

通过将成分与其作用机制及相应证据进行关联，本综述为临床医生、研究人员和消费者提供了一个宝贵的工具。它有助于更明智、更安全地使用这些产品，突出了在特定应用中拥有最强科学支持的化合物。同时，它也阐明了现有文献中的重大空白，为未来研究提供了明确指引，以期通过营养手段，为增强和保护大脑功能构建更完整、更可靠的证据基础。

附录 A

附录 A：主证据表（交叉引用表 1 —— 单独提供）

注：主证据表是一个详尽的附录，针对本手稿分析的 70+ 种成分中的每一种，逐行提供了详细的数据。该表作为本文档的独立补充文件单独提供。

附录 A — 补充证据表

集成的补充来源： Appendix A — Master Evidence Table Brain-Function Ingredients.xlsx

成分	领域	机制靶点	主要临床结局	证据级别	最佳证据总结	典型剂量	安全注意事项
Citicoline (CDP-choline)	领域 1 认知与神经塑性[1, 2]	Phosphatidylcholine/结构磷脂膜合成（CDP-choline 前体）[3, 4]；支持乙酰胆碱生物合成[5]；文献综述显示可增加脑代谢并影响神经递质水平[4]。	认知功能/认知状态和记忆/行为结局[1, 3]；创伤性脑损伤后的功能独立性（Glasgow Outcome Scale）。[2, 6]	强：荟萃分析 + 多项 RCT[2, 1]	针对急性 TBI 的系统评价/荟萃分析（11 项临床研究；n=2771）发现，与对照组相比，使用 citicoline 具有更高的独立率（RR 1.18，95% CI 1.05–1.33）。[2]	500–2,000 mg/day（临床试验中报道的有效剂量范围）。[7]	针对急性 TBI 的荟萃分析未报告安全问题[2]；Cochrane 系统评价中指出 citicoline “耐受性良好”。[8]
Bacopa monnieri (bacosides)	领域 1 认知与神经塑性[9]	来源未提及。	记忆自由回忆（跨研究的 9/17 项测试中有所改善）[9]；荟萃分析中的注意力/速度（Trail B；选择反应时间）[10]；在一项 RCT 中评估了睡眠质量，但无显著差异。[11]	强：荟萃分析 + 多项 RCT[10]	荟萃分析（9 项研究；518 名受试者）报告，长期（≥12 weeks）补充 Bacopa 提取物可改善认知，包括缩短 Trail B 时间和减少选择反应时间。[10]	常用 RCT 提取物剂量：~12 weeks 期间为 300–450 mg/day。[9]	来源未提及。
Ginkgo biloba (EGb 761)	领域 1 认知与神经塑性[12]	来源未提及。	痴呆结局：认知、日常生活活动能力和全局评估[12]；神经精神症状（例如 NPI 综合评分）和认知测试（例如 SKT）。[13]	强：荟萃分析 + 多项 RCT[12, 14, 15]	针对痴呆门诊患者的系统评价/荟萃分析发现，在认知、ADLs 和全局评分方面，EGb 761 优于安慰剂；与治疗相关的副反应风险与安慰剂相比无明显差异。[12]	120–240 mg/day（在汇总试验中通常为 240 mg/day）。[12, 14, 15]	荟萃分析未发现重要的安全问题，且不良事件发生率与安慰剂相似。[14, 16, 12]
Citicoline + other (note: separate ingredient row preserved)	来源未提及。	来源未提及。	来源未提及。	目前尚无证据 — 所提供来源中未发现严格的人体临床证据。	目前尚无证据 — 所提供来源中未发现严格的人体临床证据。	来源未提及。	来源未提及。
Alpha-GPC	领域 1 认知与神经塑性[17]	含胆碱的磷脂，用作乙酰胆碱生物合成的前体，并被探讨为神经保护信号通路的调节剂。[18]	认知（例如 ADAS-cog）。[19] 此外还有成人发病认知障碍研究中的功能和行为结局。[17]	中等：多项 RCT[17, 19]	一项针对轻度认知障碍的为期 12-week 多中心 RCT（n=100；600 mg αGPC）报告，与安慰剂相比，ADAS-cog 降幅更大（−2.34 分），且无严重不良事件。[19]	12-week RCT 中为 600 mg/day αGPC；在交叉设计中，急性补充方案使用 315–630 mg。[19, 20]	在一项为期 12-week 的 MCI RCT 中，未发生严重 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，报告 AE 的比例为 2.14%，常见主诉包括胃灼热、恶心/呕吐、失眠/兴奋和头痛。[21]
Phosphatidylserine	领域 1 认知与神经塑性（也研究了压力/睡眠结局）[22]	来源未提及。	年龄相关性认知衰退/记忆[22]；在某些试验中的情绪/压力（POMS 上的恐慌评分）和睡眠质量（PSQI）。[23]	中等：多项 RCT + 系统评价/荟萃分析[22, 24]	系统评价/荟萃分析（9 项研究；5 项 RCT）得出结论，phosphatidylserine 对伴有认知衰退的老年人的记忆力有积极作用，且未报告不良反应。[22]	老年人认知衰退研究中为 100–300 mg/day；PS-DHA 试验中为 300 mg/day PS；在短期压力/睡眠研究中为 400–800 mg/day。[22, 24, 23]	在 15 weeks 内服用 300 mg/day PS-DHA（或在 30 weeks 内服用 100 mg/day）被报告为安全/耐受性良好，且对测试参数无负面影响。[24]
Choline (bitartrate / chloride)	领域 1 认知与神经塑性；也与甲基供体通路相关（领域 4）。[25]	acetylcholine 和 betaine（甲基供体）的前体。[25, 26] 1 g/day 可增加循环中的游离 choline 和 betaine，可能增强 tHcy 再甲基化（BHMT 通路）。[26]	成人认知（被描述为缺乏高质量干预数据）[25]；对孕期补充以改善儿童认知结局进行了系统评价[27]；生化结局（血浆 choline/betaine/tHcy）。[26]	有限：单项 RCT 或小型研究（认知 RCT 证据被描述为缺乏）。[25, 26]	《Nutrition Reviews》的合成分析得出结论，成人认知获益是有可能的，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，使用 1 g/day choline（作为 choline bitartrate）；孕期试验在妊娠晚期的剂量为 480–930 mg/day。[26, 28]	系统评价指出潜在的有害心血管代谢效应需要仔细评估。[25] 在一项 1 g/day 的 RCT 中，血浆脂质未受影响。[26]
Omega-3 EPA/DHA (fish oil)	领域 1 认知与神经塑性[29]	DHA/EPA 被描述为对大脑发育和认知表现很重要[29]；DHA 影响神经递质和脑功能（机制描述）。[30]	认知结局（RCT 中的多个参数）；一项针对孕期/哺乳期的荟萃分析未发现与儿童认知参数有显著关联。[29]	中等：多项 RCT（证据在系统评价/荟萃分析中进行了总结；结果好坏参半）。[29, 30]	系统评价/荟萃分析（11 项试验）报告，孕妇补充 DHA/EPA 与评估的儿童认知参数之间无显著关联。[29]	来源未提及。	来源未提及。
Phosphatidylcholine	领域 1 认知与神经塑性[31]	acetylcholine 生物合成的前体和完整的神经元膜成分（脑部疾病试验的依据）。[31]	母亲补充后的婴儿神经发育结局（视觉空间记忆、情景记忆、语言/全局发育）；未报告显著差异。[32]	有限：单项 RCT 或小型研究[32]	从妊娠 18 weeks 至产后 90 days 母亲补充 phosphatidylcholine 750 mg/day，与安慰剂相比，在 10–12 months 时婴儿的全局发育、语言或记忆结局无显著差异。[32]	从妊娠 18 weeks 至产后 90 days 补充 750 mg/day。[32]	来源未提及。
Panax ginseng	领域 1 认知与神经塑性（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、调节突触塑性[33]；通过 HPA/HPG 轴调节、神经递质平衡和 BDNF–TrkB 通路激活进行情绪调节。[33]	记忆结局在荟萃分析中有所改善；汇总分析未显示对整体认知、注意力或执行功能有积极作用。[34]	中等：多项 RCT（系统评价/荟萃分析包括 15 项 RCT）。[34]	对 15 项 RCT（671 名患者）的荟萃分析发现记忆力有显著改善（SMD 0.19），但对整体认知、注意力或执行功能无积极作用。[34]	在一项 RCT 中，使用 3 g/day Panax ginseng 粉，持续 6 months。[35]	系统评价未报告严重不良事件，但大多数研究的偏倚风险尚不明确。[36]
Lion's Mane (Hericium erinaceus)	领域 1 认知与神经塑性；也研究了情绪/睡眠结局。[37, 38]	在一项试验中发现循环中的 pro-BDNF 增加[38]；文献综述中提出了神经营养作用（增强 pro-BDNF/BDNF 和海马神经发生）[39]；一项研究报告了可能通过增加微生物群多样性实现脑肠轴机制。[40]	认知测试结局（例如 RCT/PCT 中的 MMSE 综合效应）[39]；在一项研究中，8 weeks 后情绪/睡眠障碍有所减少。[38]	中等：多项 RCT（系统评价包括数项 RCT）。[37, 39]	口服 H. erinaceus 补充剂 8-week 可减少抑郁、焦虑和睡眠障碍，并增加循环中的 pro-BDNF（试验发现）。[38]	来源未提及。	潜在的副作用包括胃部不适、头痛和过敏反应；在一项系统评价中，不良反应罕见且通常为轻度胃肠道不适。[39, 40]
Huperzine A	领域 1 认知与神经塑性[41]	在提供的摘要中未完全指明；文献综述提及 NMDA 拮抗作用、增加 NGF、抗氧化和抗淀粉样变性作用。[42]	阿尔茨海默病患者的认知和功能结局（在某些分析中包括 MMSE、ADL、ADAS-Cog/HDS）。[41, 43]	中等：多项 RCT（包括 20 项 RCT；指出偏倚风险较高）。[41]	系统评价/荟萃分析（20 项 RCT；n=1823）发现，在多个时间点，与安慰剂相比，认知（MMSE）有所改善，但大多数试验的偏倚风险较高。[41]	来源未提及。	在一项荟萃分析中，大多数不良事件属于胆碱能性质，且未发生严重不良事件；另一项系统评价报告无严重不良事件。[43, 41]
Vinpocetine	领域 1 认知与神经塑性[44]	来源未提及。	痴呆/认知障碍患者的认知结局（例如 MMSE、ADAS-Cog）。[45, 46]	中等：多项 RCT（系统评价包括 3 项痴呆 RCT；还报告了其他安慰剂对照 RCT）。[44, 45]	针对痴呆试验的 Cochrane 系统评价（3 项研究；n=583）得出结论，vinpocetine 获益的证据尚无定论，不支持临床使用。[44]	痴呆研究中报告的口服剂量为 30–60 mg/day。[44]	在痴呆试验中，不良反应的报告不一致，且无法获得意向性治疗数据；系统评价作者呼吁在常规使用前开展针对卒中的更大规模且设计良好的 RCT。[44, 45]
Centrophenoxine (meclofenoxate)	领域 1 认知与神经塑性（老年痴呆试验；还有临床前记忆效应）。[47, 48]	来源未提及。	老年痴呆/记忆结局（在一项试验中报告了与安慰剂相比，记忆功能有所改善）。[48]	有限：单项 RCT 或小型研究[47, 48, 49]	在一项针对伴有痴呆/记忆损害的老年人的双盲随机试验中，与安慰剂相比，使用 centrophenoxine 治疗与更高比例的记忆改善相关（48% 对比 28%）。[48]	在一项试验中为 2 g/day 持续 8 weeks；在安慰剂对照交叉研究中为 600 mg 每日两次，持续 12 weeks。[48, 49]	来源未提及。
Caffeine	领域 1 认知与神经塑性和领域 2 睡眠（睡眠中断）。[50]	在来源中未作为受体水平的机制提及；系统评价强调了腺苷相关通路中的基因变异会影响睡眠中断敏感性，以及 CYP1A2/ADORA2A 与认知/焦虑/睡眠障碍的关联。[50, 51]	在睡眠剥夺背景下，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（睡眠潜伏期、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 RCT[50, 52]	针对睡眠剥夺/受限人群的荟萃分析（45 篇文献；327 个效应量估计）发现，与安慰剂/对照组相比，caffeine 改善了注意力反应时间和准确性，并改善了执行功能。[52]	来源未提及。	Caffeine 通常会延长睡眠潜伏期，并减少总睡眠时间/睡眠效率；慢波睡眠通常会减少（取决于剂量和使用时间）。[50]
Ergothioneine	领域 1 认知与神经塑性（也评估了睡眠结局）。[54]	通过 OCTN1/SLC22A4 转运体被大脑摄取[55]；机制合成分析中提出了抗氧化/抗炎特性。[56]	综合记忆（主要结局）和次要认知领域、主观记忆以及睡眠质量结局。[54]	有限：单项 RCT 或小型研究[54]	在 55–79 岁有主观记忆主诉的成人中进行的为期 16-week 的随机、双盲、安慰剂对照试验测试了 10 mg/day 和 25 mg/day ergothioneine 对比安慰剂的效果（主要终点：综合记忆）。[54]	16-week RCT 中为 10–25 mg/day。[54]	在试验人群中，报告补充 ergothioneine 是安全且耐受性良好的。[54]
Cocoa flavanols	领域 1 认知与神经塑性（急性认知需求表现）。[57]	提出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]	认知需求测试量表任务（Serial Threes/Sevens、RVIP）和精神疲劳评分。[57]	有限：单项 RCT 或小型研究（即时作用的证据被描述为有限/无定论）。[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 mg 和 994 mg）改善了 Serial Threes 的表现，且 520 mg 减轻了自我报告的精神疲劳。[57, 59]	交叉研究中急性补充 520–994 mg 可可黄烷醇；另一项 RCT 中每日补充 250 mg 可可，持续四 weeks。[57, 59]	来源未提及。
Souvenaid / Fortasyn Connect (medical food)	领域 1 认知与神经塑性[60]	旨在利用前体/辅助因子（uridine monophosphate；choline；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 和其他记忆/认知测试（例如，神经心理学综合 z 评分；亚组中的延迟言语回忆）评估认知。[60, 61]	中等：多项 RCT + 系统评价/荟萃分析（3 项研究；总 n=1011）。[61]	S-Connect 24-week RCT（n=527，接受药物治疗的轻中度 AD）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]	S-Connect 试验中为 125 mL/day（125 kcal），持续 24 weeks。[60]	在不良事件发生率或临床相关的血液安全参数方面无组间差异；被描述为与 AD 药物合用时耐受性良好。[60]
Uridine monophosphate	来源未提及。	来源未提及。	来源未提及。	目前尚无证据 — 所提供来源中未发现严格的人体临床证据。	目前尚无证据 — 所提供来源中未发现严格的人体临床证据。	来源未提及。	来源未提及。
Ashwagandha (Withania somnifera; KSM-66 / Sensoril)	领域 2 压力/焦虑缓解/睡眠[62, 63]	来源未提及。	睡眠量/质量（主要结局）和精神警觉度/焦虑/QoL（次要结局）。[62] 在荟萃分析中也报告了压力/焦虑和皮质醇结局（PSS、HAS、血清皮质醇）。[63]	中等：多项 RCT（系统评价/荟萃分析）。[62, 63, 64]	对 5 项 RCT（400 名参与者）的荟萃分析发现，与安慰剂相比，服用 ashwagandha 后整体睡眠有小幅但显著的改善（SMD −0.59；95% CI −0.75 至 −0.42）。[62]	在失眠亚组中，当剂量 ≥600 mg/day 且持续时间 ≥8 weeks 时，睡眠益处更为突出；一项 RCT 使用 600 mg/day 持续 8 weeks。[62, 65]	在睡眠 RCT 中未报告严重副作用，但长期使用的严重不良反应数据有限；一些研究报告了轻度至中度的 AE。[62, 63]
L-theanine	领域 2 压力/焦虑缓解/睡眠[66, 67]	来源未提及。	荟萃分析显示睡眠改善（主观睡眠潜伏期、白天功能障碍、整体睡眠质量）[66]；在一项 RCT 中，语言流利度和执行功能等认知结局有所改善。[68]	强：荟萃分析 + 多项 RCT[66, 69]	荟萃分析报告，L-theanine 改善了主观睡眠潜伏期（SMD 0.15；95% CI 0.01–0.29；p=0.04）。[66]	针对睡眠结局的研究测试了 50–900 mg/day；RCT 中使用 200 mg/day；证据合成分析建议在压力/焦虑背景下使用 200–400 mg/day。[70, 68, 67]	来源未提及。
Magnesium (glycinate / threonate / citrate)	领域 2 压力/焦虑缓解/睡眠（也通过睡眠/情绪研究了认知）。[71]	镁参与神经递质传递、HPA 轴调节和睡眠-觉醒控制。[72]	失眠/睡眠质量（包括睡眠潜伏期）[73]；使用 MgT 的日间功能（精力/工作效率）[71]；在一项 RCT 中，使用 MgT 的认知（NIH 综合认知总分、工作/情景记忆）。[74]	中等：多项 RCT（睡眠）+ 系统评价/荟萃分析[73, 75]	对 3 项 RCT（151 名伴有失眠的老年人）的系统评价/荟萃分析发现，与安慰剂相比，补充镁可使睡眠潜伏期缩短 17.36 分钟（95% CI −27.27 至 −7.44；p=0.0006）。[73]	在有睡眠问题的成人中，使用 MgT 1 g/day 持续 21 days[71]；在另一项睡眠 RCT 中使用 MgT 2 g/day[74]；在一项为期 4-week 的 RCT 中，使用甘氨酸镁（magnesium bisglycinate）以提供每日 250 mg 的元素镁。[76]	RCT 中报告 MgT 安全且耐受性良好。[71, 74] 一项针对失眠的荟萃分析指出证据质量存在局限性（偏倚风险为中到高；确定性为低到极低）。[73]
Glycine	领域 2 压力/焦虑缓解/睡眠[77]	通过兴奋性/抑制性神经递质传递（NMDA 受体和 glycine 受体）发挥作用。[78]	健康人群中的睡眠结局（证据总结为规模小/偏倚风险高）[77]；在荟萃分析中，精神分裂症的阴性症状通过 NMDA 共激动剂（glycine/D-serine）得到改善。[79]	有限：小型研究；睡眠证据总结为规模小/偏倚风险高。[77]	系统评价的合成分析报告称，长期补充 glycine 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]	在一项针对急性缺血性卒中的 RCT 中，glycine 剂量在 5 days 内为 0.5–2.0 g/day。[80]	在急性卒中试验中，4.5% 的患者出现轻度镇静，未出现其他明显的不良事件。[80]
GABA (exogenous)	领域 2 压力/焦虑缓解/睡眠[81]	来源未提及。	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]	交叉研究中报告的 EEG 睡眠阶段变化。[83]	中等：多项 RCT（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 摄入在压力方面的益处有限，而在睡眠方面的益处非常有限；需要更多研究。[81]	例如：一项 RCT 中为 100 mg/day，持续 12 weeks[82]；交叉睡眠研究中睡前服用 100 mg[83]；90-day 试验中为 200 mg/day；交叉认知试验中急性服用 800 mg。[84, 85]
Taurine	领域 2 压力/焦虑缓解/睡眠（认知证据混杂/无活性）。[86]	来源未提及。	认知评分（荟萃分析报告无显著效果）。[86]	中等：多项 RCT（荟萃分析包括 7 项 RCT）。[86]	对 RCT（7 项 RCT；402 名受试者）的荟萃分析报告，taurine 未对认知评分表现出显著影响。[86]	在认知试验中，急性剂量通常为 1–3 g（最高达 ~50 mg/kg）（系统评价总结）。[87]	来源未提及。
Melatonin	领域 2 压力/焦虑缓解/睡眠[88]	来源未提及。	伴有 MCI/痴呆的老年人的睡眠结局（睡眠潜伏期、总睡眠时间）和 MMSE。[89, 88]	强：荟萃分析 + 多项 RCT[89, 88]	针对伴有 MCI/痴呆的 ≥65 岁成人的 10 项 RCT（n=516）的荟萃分析发现，melatonin 增加了总睡眠时间（+12.4 min）并改善了 MMSE（+1.8 分）。[89]	来源未提及。	来源未提及。
5-HTP	领域 2 压力/焦虑缓解/睡眠（5-羟色胺前体）。[90, 91]	5-HTP 是 5-羟色胺生物合成的中间体[92]，并在脑内转化为 5-羟色胺；有报道补充后血清 5-羟色胺增加。[93, 90]	系统评价/荟萃分析中的情绪/抑郁结局[94]；在某些研究中睡眠质量成分有所改善。[91]	中等：含荟萃分析的多项 RCT（指出研究质量存在局限性）。[95, 94]	荟萃分析报告，13 项研究的抑郁缓解率为 0.65（95% CI 0.55–0.78）；由于安慰剂组较少，整体偏倚风险被评定为相对较弱。[94]	在一项为期 4-week 的交叉研究中为 50 mg/day[96]；在一项以睡眠为重点的研究中，老年人使用 100 mg/day，持续 12 weeks。[91]	系统评价讨论了与可能致命的嗜酸性粒细胞增多-肌痛综合征的潜在关联，该关联尚未阐明；证据质量不足以得出明确结论。[97]
L-tryptophan	领域 2 压力/焦虑缓解/睡眠（5-羟色胺/melatonin 前体）。[98, 99]	Tryptophan 是 5-羟色胺的前体；下游转化为 melatonin 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（在荟萃分析中有所改善）。[100]	RCT 系统评价中健康成人的情绪结局（对消极/快乐情绪的影响）。[98]	中等：多项 RCT（系统评价包括 11 项 RCT）。[100, 98]	双盲安慰剂对照交叉试验使用 1000 mg/day tryptophan，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]	在一项安慰剂对照交叉 RCT 中使用 1000 mg/day；系统评价总结显示跨 RCT 的范围为 0.14–3 g/day。[101, 98]

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]文献中未提及。抑郁（BDI；DASS-21）、焦虑（BAI）和睡眠质量（PSQI；睡眠质量评分）。[104, 105, 106]强：荟萃分析 + 多项 RCT[103, 104]荟萃分析（21 项试验）发现，与对照组相比，藏红花降低了 BDI（WMD −4.86）、BAI（WMD −5.29）和 PSQI（WMD −2.22）。[104]在情绪 RCT 和睡眠 RCT 中使用 Affron® 28 mg/day（睡前 1 小时服用）。[106, 107]RCT 报告称藏红花/affron® 耐受性良好，无显著不良反应；系统评价者指出，部分证据源自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]镇静作用归因于调节 CNS 中的 GABA 功能（其成分包括缬草烯酸和缬草三酯）。[110]随机安慰剂对照试验和荟萃分析中的睡眠质量/失眠结局。[109, 111]中等：多项 RCT（不同试验之间的结果不一致）。[109, 112, 113]系统评价/荟萃分析（16 项符合条件的研究；1093 例患者）发现，二分类睡眠质量结局有获益（改善睡眠的 RR = 1.8；95% CI 1.2–2.9），但存在发表偏倚证据。[109]文献中未提及。缬草通常被描述为安全且罕见不良事件；系统评价指出在 7–80 岁人群中未见严重不良事件。[113, 114]柠檬香蜂草 (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（影响睡眠质量）。[116] 体外胆碱能受体结合/置换实验表明，其可能与 AD 的认知缺陷具有潜在相关性。[117]荟萃分析显示焦虑和抑郁症状评分有所改善；RCT 中对睡眠质量进行了测定。[115, 118]中等：多项 RCT（荟萃分析和临床试验）。[115, 118]荟萃分析报告，与安慰剂相比，柠檬香蜂草改善了焦虑（SMD −0.98）和抑郁（SMD −0.47），且无严重副作用（由于异质性，需谨慎对待结果）。[115]一项临床试验中，采用 1.5 g/day 干燥叶粉治疗 7-day 可改善 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]荟萃分析报告无严重副作用，但强调了其异质性和试验数量有限。[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-羟色胺能通路介导（系统评价）。[121]多项试验显示焦虑减轻[119]；RCT 中多导睡眠图记录的总睡眠时间和主观睡眠质量有所改善。[120, 122]中等：多项 RCT（系统评价纳入了 9 项临床试验）。[119]双盲安慰剂对照失眠研究报告，与安慰剂相比，多导睡眠图记录的总睡眠时间增加（P=0.049）。[120]文献中未提及。系统评价报告无包括记忆丧失在内的不良反应；其他系统评价则提醒注意，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]文献中未提及。焦虑严重程度（HAMA）和睡眠质量（PSQI）。[124, 125]强：荟萃分析 + 多项 RCT[124]对 3 项随机安慰剂对照试验（697 例患者）的荟萃分析发现，在 10 周期内，与安慰剂相比，80 mg/day Silexan 降低了 HAMA 总分（均值差 3.83 分；95% CI 1.28–6.37）。[124]80 mg/day，持续 10 weeks（部分研究评估了 160 mg/day）。[124, 126]不良事件发生率与安慰剂相当（RR 1.06）；系统评价指出，可能会出现轻微的 GI 症状，但在 80–160 mg/day 剂量下没有镇静或戒断反应，也无药物相互作用。[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]；有体外结合 5-羟色胺/褪黑素受体的报告[129]；其睡眠效应归因于结合 GABA(A) 受体上的 GABA 位点并增强 δ-波睡眠。[130]在非器质性睡眠障碍患者中，入睡潜伏期和入睡后醒来时间减少，慢波睡眠增加；在缬草-啤酒花联合试验中，入睡潜伏期得到改善。[129, 131]有限：小型人体研究（通常为缬草-啤酒花联合用药）。[129]人体研究报告，入睡潜伏期和入睡后醒来时间减少，慢波睡眠延长；一项试验报告，与安慰剂相比，啤酒花（复方制剂）增加了临床疗效并缩短了延长的入睡潜伏期。[129, 131]文献中未提及。文献中未提及。α-s1 酪蛋白水解物 (Lactium)领域 2 压力/抗焦虑/睡眠[132]文献中未提及。睡眠质量和心理压力结局（ISI/GSDS/PSQI/ESS/HADS）以及多导睡眠图入睡潜伏期。[132]中等：多项 RCT[132]一项为期 4-week 的随机双盲安慰剂对照失眠试验（n=36）显示，与安慰剂相比，主观睡眠指标改善，PSG 入睡潜伏期缩短（p=0.012）。[132]在一项 RCT 中，初始剂量为 600 mg/day，随后两周减至 300 mg/day；其他试验在胶囊中使用了 150 mg（有时与 L-theanine 联用）。[132, 133]文献中未提及。洋甘菊 (Matricaria chamomilla)领域 2 压力/抗焦虑/睡眠[134, 135]文献中未提及。睡眠质量（PSQI；醒来次数；入睡潜伏期）和广泛性焦虑障碍结局（HAM-A）。[134, 135]中等：多项 RCT（系统评价/荟萃分析）。[134, 135]系统评价/荟萃分析（10 项研究；772 例受试者）发现洋甘菊降低了 PSQI 评分（WMD −1.88；95% CI −3.46 to −0.31）。[134]文献中未提及。部分试验报告了轻微不良事件；另一项系统评价报告无不良事件（被动监测）。[135, 134]卡瓦胡椒 (Piper methysticum)领域 2 压力/抗焦虑/睡眠（GAD）。[136]通过脂质膜效应和钠通道功能调节 GABA 活性；MAO-B 抑制作用；去甲肾上腺素/多巴胺再摄取抑制作用。[137]焦虑严重程度（HAM-A 及相关量表，如 STAI-state）。[138]中等：多项 RCT（Cochrane 分析中包含 12 项双盲 RCT）。[139]Cochrane 荟萃分析（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 weeks）服用 120–280 mg/day 卡瓦内酯。[136]应考虑安全性问题；指南建议使用传统的非脂溶性（水溶性）提取物、避免饮酒、在使用精神药物/驾车时保持谨慎，并对定期使用者进行常规肝功能检查。[137]红景天 (Rhodiola rosea) (rosavins/salidroside)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-axis 调节、神经递质系统效应和抗氧化通路；系统评价描述了线粒体功能改善和细胞能量产生增加（机制总结）。[141]自觉压力和疲劳、轻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（根据系统评价，在临床研究中有所报告）。[141, 140]中等：多项 RCT（一项系统评价中包含 11 项安慰剂对照 RCT）。[142]系统评价证据：共确定了 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]文献中未提及。系统评价仅报告了极少数轻微不良事件；由于纳入研究中存在高偏倚风险/报告缺陷，证据确定性有限。[142, 143, 140]维生素 D3 (cholecalciferol)领域 2 压力/抗焦虑/睡眠（睡眠质量结局）。[144]文献中未提及。干预性荟萃分析中的睡眠质量（PSQI）和抑郁症状（BDI）。[145, 146]强：荟萃分析 + 多项 RCT[144, 145]系统评价/荟萃分析发现，与安慰剂相比，补充维生素 D 显著降低了 PSQI（均值差 −2.33；95% CI −3.09 to −1.57；p<0.001；I²=0%）。[144]文献中未提及。荟萃分析报告，补充维生素 D 未引起副作用（在所纳入的研究中）。[145]乙酰-L-肉碱 (ALCAR)领域 3 能量与线粒体（也研究用于抑郁/认知）。[147]支持 β-氧化和 acetyl-CoA 维持[148]；调节脑能量/磷脂代谢以及突触形态/传递（多种神经递质）[148]；讨论了抗氧化、抗凋亡活性和对神经炎症的益处。[147]RCT 荟萃分析中的抑郁症状[149]；MCI/轻度 AD 荟萃分析中的临床总体变化和认知结局。[150]中等：多项 RCT（针对抑郁和 MCI/轻度 AD 的荟萃分析）。[149, 150]抑郁荟萃分析：合并 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 to −0.56）。[149]1.5–3.0 g/day（MCI/轻度 AD 试验的每日剂量范围）。[150]在与抗抑郁药对比的 RCT 中，ALC 的不良反应显著较低；在认知试验中，ALC 总体耐受性良好。[149, 150]辅酶 Q10 (ubiquinol / ubiquinone)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 荟萃分析中的抑郁症状和疲劳结局（抑郁得到改善；疲劳不显著）。[152]中等：多项 RCT（荟萃分析）。[152, 153]对 5 项 RCT（474 例受试者）的荟萃分析发现，与对照组相比，CoQ10 减轻了抑郁症状（SMD −0.68；95% CI −1.02 to −0.33；P<0.01）。[152]在一项分析中，低剂量 100–200 mg/day 持续 6–8 weeks 被描述为与抑郁症状改善相关。[153]文献中未提及。吡咯喹啉醌 (PQQ)领域 3 能量与线粒体（也研究用于压力/疲劳/睡眠）。[154]机制总结描述了激活 Nrf2/ARE 抗氧化通路、AMPK/PGC-1α 线粒体生物发生/功能，以及抑制 NF-κB 进行炎症调节。[154]一项开放标签试验中的压力/疲劳/生活质量（QoL）/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]一项为期 12-week 的随机、双盲、安慰剂对照 RCT 评估了 21.5 mg/day 的 PQQ 二钠盐在 64 例健康志愿者中的认知功能/表现结局。[156]开放标签试验中为 20 mg/day，持续 8 weeks；RCT 中为 21.5 mg/day（PQQ 二钠盐），持续 12 weeks。[155, 156]认知 RCT 中未报告不良事件；毒理学常规测试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 可用性/磷酸肌酸缓冲以支持线粒体功能（系统评价文献中的机制解释）。[158]荟萃分析中记忆结局有所改善；报告了注意力时间合处理速度结局；在一项荟萃分析中，总体认知/执行功能无显著改善。[159, 157]强：荟萃分析 + 多项 RCT[157, 159]系统评价/荟萃分析（16 项 RCT；492 例受试者）发现肌酸改善了记忆和处理速度，但未改善总体认知功能或执行功能。[159]示例：在一项 RCT 中为 5 g，每日四次，持续 7 days；在一项交叉研究中为 20 g/day 负荷量，持续 7 days。[160, 161]总体耐受性良好，但在一项精神医学评价中，2/17 的受试者出现了轻躁狂/躁狂；肾脏疾病患者或使用影响肾脏的药物时建议谨慎。[162, 163]MCT 油 (medium-chain triglycerides)领域 3 能量与线粒体（酮体/替代燃料）。[164, 165]诱导轻度酮症并可能改善 MCI/AD 患者的认知；当葡萄糖利用受阻时，提高 β-hydroxybutyrate 水平作为替代底物。[164, 165]MCI/AD 患者的认知表现（例如 ADAS-Cog 和 MMSE）以及记忆指标（强调工作记忆）。[164, 166]中等：多项 RCT（系统评价/荟萃分析；指出存在偏倚风险）。[164, 167]RCT 的荟萃分析（12 篇记录；422 例受试者）发现，MCT 增加了 β-hydroxybutyrate 并改善了综合认知结局（ADAS-Cog+MMSE SMD −0.289；95% CI −0.551 to −0.027）。[164]示例：在 MCI 中为 56 g/day，持续 24 weeks；健康年轻成人中为 12–18 g/day，持续 4 weeks；交叉试验中每日总脂肪剂量约为 17.3 g/day。[168, 169, 170]主要报告了胃肠道副作用；系统评价指出，由于方案具有异质性/设计较差以及存在利益冲突，证据存在局限性。[167]Beta-hydroxybutyrate (ketone esters/salts)领域 3 能量与线粒体（脑部替代燃料）。[171]外源性酮提高血液 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定；代谢结局包括血糖/β-OHB 变化。[173, 172]强：荟萃分析 + 多项 RCT[171]系统评价/荟萃分析（38 项研究/41 项方案；1,602 例受试者）发现，与安慰剂相比，补充外源性酮改善了认知表现（SMD 0.29；95% CI 0.16–0.41；p<0.001）。[171]文献中未提及。静脉注射 β-hydroxybutyrate 输注耐受性良好，且不良事件极少；血糖偶有降低，但仍保持在正常范围内。口服外源性酮会急性降低血糖（在有低血糖风险时可能需要进行监测）。[174, 172]Axona (caprylic triglyceride 医疗食品)领域 3 能量与线粒体（酮体替代燃料）。[165, 175]（通过 medium-chain triglycerides）提供酮体，以便在葡萄糖利用受损时提供替代葡萄糖的能量来源。[175, 165]通过 ADAS-Cog11 和 MMSE 测定的轻至中度阿尔茨海默病患者的认知功能；临床医生总体变化量表（C-GIC）。[176, 177]中等：多项 RCT（例如 26-week RCT；其他较小型的临床干预）。[176, 177]一项为期 26-week 的双盲安慰剂对照 RCT（AC-12-010；NOURISH AD）报告，在主要 ADAS-Cog11 结局（LS 均值差 −0.761；p=0.2458）上未检测到药物作用，次要结局也未能检测到药物作用。[176]示例方案：含有 20 g caprylic triglycerides 的 40 g/day 粉剂，持续 3 months，在 7 days 内滴定至 10→40 g/day。[177]据报告耐受性良好，无严重胃肠道不良反应；滴定减少了胃肠道不良反应。[177]D-ribose领域 3 能量与线粒体（所提供文献中的证据为临床前，并提示有认知损害）。[178]文献中未提及。临床前认知结局：动物模型中的平台穿梭和认知损伤；脑和血液中的 AGEs 增加。[178]仅机制/临床前[178]啮齿动物系统评价/荟萃分析得出结论，D-ribose 会导致认知功能障碍，且呈剂量相关性恶化，并增加脑和血液中的晚期糖基化终末产物（AGEs）。[178]文献中未提及。文献中未提及。Nicotinamide riboside (NR)领域 3 能量与线粒体（NAD+ 前体；神经保护依据）。[179, 180]NAD+ 前体支持线粒体/神经功能并减轻炎症（在试验背景中描述）；脑部 NAD+ 验证是 MCI/轻度 AD 试验设计中的既定目标。[180, 181]在一项为期 24-week 的长新冠 RCT 中的认知（ECog/RBANS/TMT-B）以及疲劳/抑郁/焦虑/睡眠质量结局；在叙述性系统评价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]一项为期 24-week 的双盲安慰剂对照 RCT（长新冠）显示，NR 提高了 NAD+ 水平（在 5–10 weeks 后增加 2.6–3.1-fold），但在认知结局（ECog/RBANS/TMT-B）上组间差异无显著性。[180]示例：一项为期 24-week 试验中的 NR 2000 mg/day；8-week 交叉试验中的 NR 1 g/day；老年男性 21-day 交叉试验中的 NR 1 g/day。[180, 182, 183]长新冠试验中报告的一例严重不良事件被认为与 NR 无关；系统评价将 NR 描述为具有生物可利用性且耐受性良好，在人体中的不良反应有限。[180, 184]Nicotinamide mononucleotide (NMN)领域 3 能量与线粒体（NAD+ 前体；睡眠和身体功能终点）。[185, 186]文献中未提及。随着血液 NAD+ 和代谢物的增加，睡眠质量终点（PSQI；在一项方案中为主要结局）和身体表现（例如 4-m 步行时间）。[186, 187]中等：多项 RCT（NAD+ 增加的证据；正在进行的睡眠 RCT/方案）。[188, 185]一项为期 12-week 的双盲安慰剂对照研究（n=60；NMN 250 mg/day）报告，与安慰剂相比，4-m 步行时间显著缩短，且血液 NAD+ 和代谢物水平更高。[187]RCT 中为 250 mg/day 持续 12 weeks；慢性失眠 RCT 方案中为 320 mg/day；一项系统评价的 RCT 中为 250–900 mg/day。[187, 186, 185]系统评价报告仅观察到轻微的不良反应，在纳入的研究中未观察到严重的不良反应。[185, 189]Nicotinamide / niacinamide (B3)领域 3 能量与线粒体（NAD+ 前体；人体认知子研究呈阴性结果）。[190]NAD+ 前体作用及讨论的机制，包括维持细胞能量和抑制 SIRT1（系统评价讨论）；在临床前 AD 模型中的神经保护作用涉及保留线粒体完整性和自噬（临床前）。[191, 192]在一项为期 12-month 的子研究（n=310）中，口服 nicotinamide 对认知功能或生活质量未显示出显著影响。[193]有限：小型临床研究/RCT 子研究；在所提供的文献中，临床前证据强于人体认知获益。[193]Phase III 子研究（n=310）发现，口服 nicotinamide 在 12-month 内对认知功能或生活质量无显著影响。[193]在 12-month 子研究中为 500 mg PO 每日两次；在一项 N-of-1 设计（焦虑试验）中为 3000 mg/day。[193, 194]在一项 N-of-1 试验中，在 3000 mg/day niacinamide 期间转氨酶保持正常；系统评价指出高水平可能会导致神经毒性（一般性警告）。[194, 191]Curcumin (Longvida / Theracurmin / Meriva)领域 4 会聚/多靶点（也在老年人中研究了认知结局）。[195, 196]Curcumin 增加了血清 BDNF（WMD ~1789 pg/mL；指出存在异质性）。[197] 临床前综合分析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 成人中的认知结局（记忆/注意力测试）[195]；RCT 荟萃分析显示抑郁/焦虑症状有所改善。[198]中等：多项 RCT（系统评价/荟萃分析；异质性/制剂变异性）。[195, 198]对 >50 成人进行的安慰剂对照 RCT 的系统评价报告，在某些研究中认知有所改善，包括一项使用 90 mg curcumin 每日两次的试验，在 18 months 内选择性回忆、视觉记忆和注意力得到改善。[195]示例：90 mg 每日两次（一项长期试验）；在另一项试验中为 1,500 mg/day（持续 52 weeks）。[195]GI 症状是认知 RCT 中最常见的不良事件（58 例 AEs；34 例 GI）。[195] 部分试验报告无 AEs；系统评价者因异质性和潜在发表偏倚而提醒需保持谨慎。[199, 198]Resveratrol (trans-resveratrol)领域 4 会聚/多靶点（认知/情绪证据不一）。[200]荟萃分析中报告了抗炎生物标志物（hs-CRP/TNF-α）的降低。[201]认知表现领域（例如延迟识别）和情绪/负面情绪；在的一项荟萃分析中，延迟识别和负面情绪的合并效应显著。[200]中等：多项 RCT（系统评价/荟萃分析；各终点之间不一致）。[200]系统评价/荟萃分析报告，延迟识别（SMD 0.39；n=166）和负面情绪（SMD −0.18；n=163）有合并获益，但总体文献被描述为不一致/有限。[200]文献中未提及。文献中未提及。Sulforaphane (from glucoraphanin)领域 4 会聚/多靶点（Keap1/Nrf2；表观遗传学效应）。[202]Keap1/Nrf2 轴和组蛋白去乙酰化酶抑制（表观遗传机制）。[202]自闭症谱系障碍的症状改善和精神分裂症的认知获益（系统评价总结）；在安慰剂对照试验中测试了健康成人的睡眠质量。[202, 203]有限：所提供文献中的人体证据包括针对睡眠的小型安慰剂对照研究以及针对大脑障碍的系统评价级综合分析。[203, 202]安慰剂对照试验：睡眠质量较差的成年人服用西兰花芽胶囊（30 mg glucoraphanin）持续 4 weeks（探索对睡眠质量的影响）。[203]30 mg glucoraphanin 每日，持续 4 weeks（西兰花芽胶囊）。[203]文献中未提及。S-adenosylmethionine (SAMe)领域 4 会聚/多靶点（甲基供体；重点针对抑郁）。[204, 205]在所提供的摘要中未完全指明；系统评价指出 SAMe 可能促进神经传递（与甲基化相关的依据）。[206]系统评价和 RCT 中的抑郁症状和可接受性。[207, 208]中等：多项 RCT/荟萃分析，但确定性各异。[207, 208]Cochrane 系统评价（8 项试验）发现，无强有力证据表明 SAMe 作为单药治疗在改善抑郁症状方面与安慰剂存在差异（SMD −0.54；95% CI −1.54 to 0.46；极低质量证据）。[208]各试验的每日剂量范围为 200–3200 mg/day；一项 RCT 测试了 800 mg/day，持续 8 weeks。[204, 205]在一项系统评价中，不良事件多为轻微/一过性 GI 紊乱；有躁狂/轻躁狂报告（441 例受试者中有 2 例报告），并指出了关于双相情感障碍患者出现躁狂的警告。[209, 208, 206]Folate / L-methylfolate (5-MTHF)领域 4 趋同/多靶点（单碳循环；抑郁症辅助治疗）。[210]L-methylfolate 是甲硫氨酸合成酶的甲基供体，可将同型半胱氨酸转化为甲硫氨酸[210]，从而支持 SAMe 的形成[210]以及通过 BH4 相关通路进行下游单胺类递质（dopamine、norepinephrine、serotonin）的合成。[210]用作抗抑郁药辅助治疗时的抑郁评分/应答/缓解。[211]强：荟萃分析 + 多项 RCT[211, 212]系统评价/荟萃分析（6 项 RCT）发现，与单用 SSRI/SNRI 相比，辅助使用 folate（L-methylfolate/叶酸）可降低 HAM-D（MD −2.16），并提高应答率（RR 1.36）和缓解率（RR 1.39）。[211]证据表明，当作为 SSRI 治疗的辅助手段且剂量限制在 folate <5 mg/day 或 methylfolate 15 mg/day 时，患者可获益。[213]潜在的担忧包括掩盖 B12 缺乏以及与癌症风险相关的争议；文献系统评价指出，相关试验未发现 folate 的安全性/可接受性问题。[210, 214]Vitamin B12 (methylcobalamin)领域 4 趋同/多靶点（在非缺乏人群中整体上无认知/抑郁获益）。[215]来源文献未提及。荟萃分析报告，在无明显缺乏/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（在非缺乏人群中，认知/抑郁的总体结果为阴性）。[215]系统评价/荟萃分析（16 项 RCT；n=6276）发现，在无明显 B12 缺乏/晚期神经系统疾病的患者中，没有证据表明单独使用 B12 或 B族维生素能改善认知子领域或抑郁指标。[215]一项针对认知障碍的 RCT 使用了 IM vitamin B12 500 mg/day ×7 days，随后使用 cobamamide 0.25 mg/day 联合 methylcobalamin 0.50 mg/day。[217]针对 ASD 的荟萃分析报告，轻度 AE（如多动、易怒、睡眠障碍）与安慰剂相比无显著差异；所提供的文献摘要中未提到更广泛的禁忌症。[218]Vitamin B6 (P5P)领域 4 趋同/多靶点（单碳代谢辅因子；未显示认知获益）。[219, 220]P5P 参与单碳代谢和神经递质生物合成；一项试验总结表明，补充剂增加了血浆 pyridoxal-5'-phosphate 浓度。[220, 221]健康老年人的认知和情绪结局（无显著获益）。[221]有限：小型 RCT（2 项试验；109 名健康老年人）。[221]Cochrane 系统评价发现，在 2 项安慰剂对照 RCT（n=109）中，尽管 vitamin B6 状态标志物有所改善，但 vitamin B6 对认知或情绪无显著改善作用。[221]老年女性 75 mg/day 持续 5 weeks；老年男性 20 mg/day 持续 12 weeks（pyridoxine HCl）。[221]纳入的试验中未报告不良反应。[221]Vitamin C (ascorbic acid)领域 4 趋同/多靶点（情绪/认知与 vitamin C 状态相关；RCT 结果不一）。[222]来源文献未提及。抑郁症状/情绪和心理困扰结局（荟萃分析总体结果为阴性）。[223]中等：多项 RCT + 荟萃分析（总体结果为阴性；存在亚组效应）。[223]对 10 项试验（n=836）的荟萃分析发现，情绪状态总体上无显著改善（Hedges’ g 0.09），但亚组分析表明，对于未开具抗抑郁药处方的亚临床抑郁受试者有益（Hedges’ g −0.18）。[223]住院患者每日两次，每次 500 mg（情绪/心理困扰试验）；学生补充剂试验中为 500 mg/day。[224, 225]来源文献未提及。Zinc领域 4 趋同/多靶点（认知证据不一；在 BDNF/炎症和抑郁方面证据较强）。[226, 227]在 RCT 荟萃分析中，补充 zinc 可增加循环 BDNF；在荟萃分析中，系统性炎症标志物（CRP、TNF-α）和 MDA 降低。[226, 228]儿童认知（在 6 项 RCT 中总体上无显著影响）[229]；在抑郁症患者的荟萃分析中，抑郁症状得到改善（WMD −4.15）。[227]中等：多项 RCT/荟萃分析（对认知的作用不一；对抑郁/BDNF 为阳性结果）。[229, 227]儿童认知荟萃分析（6 项 RCT）发现，zinc 对智力、执行功能或运动技能总体上无显著影响。[229]来源文献未提及。来源文献未提及。Selenium领域 4 趋同/多靶点（人类 RCT 证据包括脑卒中结局）。[230]来源文献未提及。RCT 荟萃分析中的脑卒中结局（1 month 后的格拉斯哥预后评分）和呼吸道感染结局。[230]中等：多项 RCT（系统评价/荟萃分析纳入了 5 项 RCT）。[230]对 5 项 RCT 的系统评价/荟萃分析发现，与安慰剂相比，selenium 在 1 month 时改善了格拉斯哥预后评分（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]来源文献未提及。来源文献未提及。Iron领域 4 趋同/多靶点（脑能量代谢、神经递质合成；认知和疲劳结局）。[231]Iron 支持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 合成和神经递质循环。[232]荟萃分析/RCT：疲劳、焦虑、身体健康、认知智力、短期记忆结局（在注意力和抑郁方面存在一些阴性发现）。[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，在非贫血人群中补充 iron 可改善焦虑、疲劳、认知智力和短期记忆。[231]来源文献未提及。来源文献未提及。Iodine领域 4 趋同/多靶点（轻度缺乏情况下的儿童认知结局）。[233]来源文献未提及。学龄儿童的认知结局（知觉推理；综合认知评分）以及妊娠期补充剂试验中的孕妇甲状腺结局（综述）。[234]中等：多项 RCT/系统评价（认知效应温和/不一）。[234, 235]在一项针对轻度缺碘儿童（10–13 y）的随机安慰剂对照试验中，报告使用 150 µg/day iodine 持续 28 weeks 后，其整体认知评分有所提高（+0.19 SD），且 4 个认知子测试中有 2 个得到改善。[233]儿童每日 150 µg/day iodine 片剂，持续 28 weeks。[233]来源文献未提及。Glutathione (liposomal / S-acetyl)领域 4 趋同/多靶点（GSH/氧化还原；通过 GlyNAC 前体补充获得的认知信号）。[236, 237]Glutathione 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]试点试验证据表明，补充 GlyNAC（glutathione 前体）后，老年人的认知得到改善，且多种与衰老相关的缺陷发生逆转；停止补充导致缺陷再次出现。[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]一项试点人体试验报告，24 weeks 的 GlyNAC 补充逆转了老年人的缺陷并改善了其认知；停用 12 weeks 后这些缺陷重新出现。[237]来源文献未提及。在 TB 背景下的系统评价报告称，对于 GSH/NAC 而言，不良反应大多温和/可控；综述指出，在 GSH/前体补充的背景下需要开展进一步的临床研究。[238, 236]N-acetylcysteine (NAC)领域 4 趋同/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 glutathione 前体；综述引用了其在氧化应激、线粒体功能障碍、神经炎症以及 glutamate/dopamine 失调中的作用。[240, 239]跨疾病的认知结局（系统评价）以及精神/神经疾病背景下的抑郁症状。[240]中等：多项 RCT（针对认知及更广泛精神/神经系统应用的系统评价证据）。[240]对 NAC 与人类认知的系统评价报告称，现有数据表明 NAC 治疗后认知有统计学意义上的显著改善，但由于缺乏针对 NAC 的专门研究，证据有限且难以解释。[240]纳入的研究中剂量为 1000–3000 mg/day；汇总试验中的治疗持续时间为 8–24 weeks。[241]总体而言，NAC 治疗似乎是安全且可耐受的（系统评价）。[239]Lactobacillus rhamnosus / Bifidobacterium longum (psychobiotics)领域 4 趋同/多靶点（肠-脑轴）。[242]精神益生菌（psychobiotics）菌株产生神经调节代谢产物（SCFAs，以及 GABA/serotonin 等神经递质），并能调节神经递质、肠道菌群组成和炎症反应。[242]在荟萃分析中，抑郁和焦虑症状得到改善；一项针对混合菌株的 RCT 改善了健康志愿者的抑郁心境和睡眠质量。[243, 244]中等：多项 RCT + 荟萃分析[243, 245]对 16 项 RCT（n=1,125）的荟萃分析报告，使用益生菌后抑郁症状（BDI MD −3.20）和焦虑（STAI MD −6.88）有所改善（确定性被评为中等/低，具体取决于结局）。[243]来源文献未提及。来源文献未提及。Prebiotic fibers (GOS / FOS / inulin)领域 4 趋同/多靶点（肠道-菌群-脑轴，影响情绪/嗜睡）。[246]益生元增加 Bifidobacterium 丰度并可能调节炎症通路（机制研究中报告了 TLR4–Myd88–NF-κB 下调）。[247, 248]在一项小型交叉试验中，受试者在睡眠限制/昼夜节律失调下的情绪/嗜睡和认知表现得到改善；一些试验发现，尽管发生了微生物组改变，但压力/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（结局不一）。[249, 250]一项随机双盲交叉试验（n=11）发现，在睡眠限制/昼夜节律失调下，与安慰剂相比，益生元饮食可减少嗜睡（KSS）并增加积极/平静的情绪（PANAS）；PVT 反应时间缩短，但一致的 Stroop 反应时间延长。[249]示例：在一项交叉试验中为 5 g/day FOS + 5 g/day GOS；在一项睡眠限制/昼夜节律失调研究中，polydextrose 和 GOS 各 7.5 g/day，持续 14 days；在肥胖 RCT 中为 16 g/day inulin，持续 3 months。[250, 249, 251]来源文献未提及。Lactoferrin领域 4 趋同/多靶点（免疫调节；及睡眠结局）。[252, 253]涉及 NF-κB 信号通路的免疫调节作用（荟萃分析的研究目的）。[253]在一项脂质体 lactoferrin 试验中，睡眠质量结局（起床时的嗜睡/疲劳；睡眠的启动/维持）得到改善；同时改善了情绪（POMS 抑郁-沮丧）。[252]有限：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-week 的随机安慰剂对照试验中，与安慰剂相比，脂质体 lactoferrin 270 mg/day 改善了睡眠评估量表领域（“起床时的嗜睡和疲劳”；“睡眠的启动和维持”）以及 POMS 抑郁-沮丧评分。[252]在一项试验中为 270 mg/day 脂质体 lactoferrin 持续 4 weeks；在一项儿科 RCT 中为 48 mg/day lactoferrin 强化配方奶粉。[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]Spermidine领域 4 趋同/多靶点（自噬/线粒体与认知结局的联系）。[256, 257]与增强自噬有关（机制原理），且在临床前模型中提示对线粒体功能有影响；假设认知获益取决于自噬/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]在一篇微型综述汇总的各项 RCT 中，结果不一：两项试验（Wirth 2018；Pekar 2021）显示在 3 months 后认知有所改善，而一项为期 12-month 的试验（Schwarz 2022）发现与安慰剂相比记忆力无显著变化。[256]纳入的 RCT 中剂量为 0.9–3.3 mg/day。[256]来源文献未提及。Alpha-lipoic acid (ALA / R-ALA)来源文献未提及。来源文献未提及。来源文献未提及。迄今尚无证据——在所提供的文献来源中未找到严格的人类证据。迄今尚无证据——在所提供的文献来源中未找到严格的人类证据。来源文献未提及。来源文献未提及。Vitamin E (mixed tocopherols / tocotrienols)来源文献未提及。来源文献未提及。来源文献未提及.迄今尚无证据——在所提供的文献来源中未找到严格的人类证据。迄今尚无证据——在所提供的文献来源中未找到严格的人类证据。来源文献未提及。来源文献未提及。Pterostilbene来源文献未提及。来源文献未提及。来源文献未提及。迄今尚无证据——在所提供的文献来源中未找到针对 pterostilbene 的严格人类证据。迄今尚无证据——在所提供的文献来源中未找到针对 pterostilbene 的严格人类证据。来源文献未提及。来源文献未提及。Palmitoylethanolamide (PEA)来源文献未提及。来源文献未提及。来源文献未提及。迄今尚无证据——在所提供的文献来源中未找到严格的人类证据。迄今尚无证据——在所提供的文献来源中未找到严格的人类证据。来源文献未提及。来源文献未提及。Green tea / EGCG领域 4 趋同/多靶点（情绪/认知信号；睡眠证据不一）。[259]EGCG 与 EEG alpha/beta/theta 活动增加有关（急性）。[260] 荟萃分析报告 theanine+caffeine 以及单用 theanine 可能对认知/情绪有益（茶叶成分证据）。[69]在文献综述中，有关于精神病理学症状（如焦虑）、认知（记忆/注意力）以及睡眠结局的证据不一。[259, 261]中等：多项 RCT + 系统评价/荟萃分析[262, 261]荟萃分析发现，在摄入后的最初 1–2 hours 内，与安慰剂相比，theanine+caffeine 在某些认知和情绪结局（如选择反应时间、数字警觉准确性、整体情绪）方面有轻度至中度的改善优势。[69]来源文献未提及。来源文献未提及。Anthocyanins (blueberry / Concord grape)领域 1 认知与神经塑性（由多项 RCT 荟萃分析支持）。[263, 264]来源文献未提及。在荟萃分析中，综合认知得到改善（SMD 0.46），并报告了特定领域的益处（注意力、处理速度、流畅性、情景和工作记忆）。[264]强：荟萃分析 + 多项 RCT[263, 265]荟萃分析报告，与对照组相比，anthocyanin 干预显著改善了综合认知（SMD 0.46；95% CI 0.30–0.63；I²=0%）。[264]来源文献未提及。来源文献未提及。Magnolia bark (honokiol / magnolol)来源文献未提及。来源文献未提及。来源文献未提及。迄今尚无证据——证据仅限于机制/临床前工作。[266]迄今尚无证据——呼吁开展临床研究：针对 magnolol/honokiol，“需要开展更多研究……以在临床研究中进行实验”。[266]来源文献未提及。来源文献未提及。

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Appendix A — Supplementary Evidence Table

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

Ingredient	Domain	Mechanism Targets	Primary Clinical Outcomes	Evidence Level	Best Proof Summary	Typical Dose	Safety 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-GPC	Domain 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]
Phosphatidylserine	Domain 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).
Phosphatidylcholine	Domain 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 ginseng	Domain 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 A	Domain 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]
Vinpocetine	Domain 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).
Caffeine	Domain 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]
Ergothioneine	Domain 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 flavanols	Domain 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 monophosphate	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).
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-theanine	Domain 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]
Glycine	Domain 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).
Taurine	Domain 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).
Melatonin	Domain 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-HTP	Domain 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-tryptophan	Domain 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 monohydrate	Domain 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-ribose	Domain 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).
Zinc	Domain 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).
Selenium	Domain 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).
Iron	Domain 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).
Iodine	Domain 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).
Lactoferrin	Domain 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]
Spermidine	Domain 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).
Pterostilbene	Not 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 / EGCG	Domain 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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摘要

背景：

目的：

方法：

结果：

结论：

关键词：

引言

方法

结果

领域 1 — 认知表现与神经塑性

Citicoline (CDP-choline)

Alpha-GPC

Choline (bitartrate / chloride)

Phosphatidylserine (PS)

Phosphatidylcholine (PC)

Omega-3 EPA/DHA (鱼油)

Bacopa monnieri (bacosides)

Ginkgo biloba (EGb 761)

猴头菇 (Hericium erinaceus)

Huperzine A

Vinpocetine

Souvenaid / Fortasyn Connect (医疗食品)

L-tyrosine

Centrophenoxine (meclofenoxate)

Caffeine

Domain 2 — 抗压韧性、焦虑缓解与睡眠结构

Rhodiola rosea (rosavins/salidroside)

Ashwagandha (Withania somnifera; KSM-66 / Sensoril)

L-theanine

Magnesium (glycinate / threonate / citrate)

Glycine

GABA (外源性)

Taurine

领域 3 — 细胞能量、线粒体功能与身体耐力

Acetyl-L-carnitine (ALCAR)

Axona (caprylic triglyceride 医疗食品)

Coenzyme Q10 (ubiquinol / ubiquinone)

领域 4 — 汇聚节点（跨领域主调控因子）

Panax ginseng

厚朴皮 (honokiol / magnolol)

Resveratrol (trans-resveratrol)

讨论

跨领域最佳证据推荐

机制融合

截至目前尚无证据的成分

安全性考量与监管现状

局限性

研究重点

结论

附录 A

附录 A：主证据表（交叉引用表 1 —— 单独提供）

附录 A — 补充证据表

参考文献

Appendix A — Supplementary Evidence Table

References

作者贡献

利益冲突

参考文献

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