褪黑素：作为人体自身分泌的激素，未检测到 LD50

研究表明，褪黑素分泌减少是衰老的主要原因；因为，褪黑素能够刺激细胞和神经细胞再生，刺激NK细胞和CD4+细胞的产生，恢复疾病或衰老损伤的神经系统；修复疾病或衰老损伤的免疫系统；修复坐骨神经损伤，恢复肾衰竭干细胞，修复糖尿病神经损伤，治疗退行性疾病，治愈阿尔茨海默病，促进伤口愈合，预防和治疗癌症；调节生理活动；调节睡眠、情绪、学习和记忆、生育能力和生殖能力，促进解毒并保护线粒体，褪黑激素对肝脏有活性,褪黑激素在改善血脂组成方面效果更佳。褪黑激素可降低肝脏胆固醇，降低血浆胆固醇,褪黑激素降低氧化应激，改善血脂异常。等等。褪黑素对所有研究的疾病都有治疗作用，缺乏褪黑素会导致身体问题和疾病。

褪黑素 发现 药理 研究进展

https://en.wikipedia.org/wiki/Melatonin

褪黑素是一种吲哚胺类化合物，由包括细菌和真核生物在内的多种生物体产生。[1] 1958年，Aaron B. Lerner及其同事从牛的松果体中分离出一种能使普通青蛙皮肤变白的物质，由此发现了褪黑素。后来，这种化合物被确认为一种夜间在大脑中分泌的激素，在调节脊椎动物的睡眠-觉醒周期（也称为昼夜节律）中发挥着至关重要的作用。[2][3]

在脊椎动物中，褪黑素的功能包括同步睡眠-觉醒周期（涵盖睡眠-觉醒时间和血压调节），以及控制季节性节律（周年周期），包括繁殖、增肥、换毛和冬眠。[4] 褪黑素的作用是通过激活褪黑素受体和发挥其抗氧化作用来实现的。[5][6][7]在植物和细菌中，褪黑素主要作为一种防御机制来对抗氧化应激，这表明其具有重要的进化意义。[8] 线粒体是细胞内的关键细胞器，也是抗氧化剂褪黑素的主要生产者，[9] 这凸显了该分子的“古老起源”及其在保护早期细胞免受活性氧侵害方面发挥的根本作用。[10][11]

除了作为激素和抗氧化剂的内源性功能外，褪黑素还可作为膳食补充剂和药物外源性服用。褪黑素在医学上主要用于治疗睡眠相关问题：例如，缓释褪黑素（Circadin）已在多个国家获准用于短期治疗55岁以上人群的失眠症。[12] 它用于治疗睡眠障碍，包括失眠和各种昼夜节律睡眠障碍。

生物活性

在人体内，褪黑素主要作为两种褪黑素受体的强效完全激动剂发挥作用：褪黑素受体1（皮摩尔级结合亲和力）和褪黑素受体2（纳摩尔级结合亲和力）。这两种受体均属于G蛋白偶联受体（GPCR）家族，具体而言是Gi/o α亚基GPCR家族[13][14]，尽管褪黑素受体1也与Gq α亚基偶联[13]。

此外，褪黑素在细胞线粒体内发挥着高效抗氧化剂或自由基清除剂的作用，在对抗细胞氧化应激方面发挥着双重作用。首先，它直接中和自由基；其次，它促进必需抗氧化酶的基因表达，例如超氧化物歧化酶、谷胱甘肽过氧化物酶、谷胱甘肽还原酶和过氧化氢酶。抗氧化酶表达的增加是通过褪黑素与其受体结合激活的信号转导通路介导的。通过这些机制，褪黑素以两种方式保护细胞免受氧化应激，凸显了其在调节睡眠-觉醒周期之外对人类健康的益处。[15][13][16][17][18][19]

生物学功能

可见光进入眼睛后，可能引发哺乳动物大脑神经元结构中一系列正负信号通路：当眼睛暴露于阳光下时，松果体褪黑素的产生受到抑制，导致分泌促进觉醒的激素。相反，在没有光线的情况下，松果体持续合成褪黑素，导致困倦感并促进睡眠。

昼夜节律

在哺乳动物中，褪黑激素对调节睡眠-觉醒周期（即昼夜节律）至关重要。[20] 人类婴儿体内褪黑激素水平的规律性建立大约在出生后第三个月，其峰值浓度出现在午夜至早上 8:00 之间。[21] 已有文献记载，褪黑激素的产生会随着年龄的增长而减少。[22] 此外，在青春期，褪黑激素的分泌时间也会发生变化，导致睡眠和觉醒时间延迟，从而增加他们在此期间患睡眠时相延迟障碍的风险。[23]

褪黑激素的抗氧化特性最早于 1993 年被发现。[24] 体外研究表明，褪黑激素可以直接中和多种活性氧，包括羟基自由基 (OH•)、超氧阴离子 (O2−•) 和活性氮，例如一氧化氮 (NO•)。[25][26]在植物中，褪黑素与其他抗氧化剂协同作用，增强每种抗氧化剂的整体功效。[26] 研究发现，褪黑素清除过氧自由基的能力是维生素E（一种已知的强效亲脂性抗氧化剂）的两倍。[27] 褪黑素受体触发的信号转导通路可促进抗氧化酶（如超氧化物歧化酶、谷胱甘肽过氧化物酶、谷胱甘肽还原酶和过氧化氢酶）的表达。[13][15]

褪黑素在细胞线粒体基质中的浓度显著高于血浆中的浓度，[16][17][18] 这凸显了其在细胞线粒体中的作用，而不仅仅是在细胞线粒体基质中的作用。

褪黑素不仅能直接清除自由基，还能调节抗氧化酶的表达并维持线粒体的完整性。这种多方面的作用表明褪黑素作为线粒体抗氧化剂具有重要的生理意义，这一观点得到了众多学者的支持。[15][16][17][18][19]

此外，褪黑素与活性氧和活性氮的相互作用会生成能够还原自由基的代谢物。[13][19] 这些代谢物，包括环状3-羟基褪黑素、N1-乙酰基-N2-甲酰基-5-甲氧基犬尿胺（AFMK）和N1-乙酰基-5-甲氧基犬尿胺（AMK），通过与自由基的进一步氧化还原反应，增强褪黑素的抗氧化作用。[13][19]

免疫系统

褪黑素与免疫系统的相互作用已被人们所认识，但这些相互作用的具体机制仍未得到充分阐明。[28][29][30][31] 抗炎作用似乎是最显著的作用。[30][31] 褪黑素在疾病治疗中的疗效研究有限，现有数据大多来自小规模的初步研究。有观点认为，任何有益的免疫学影响都归因于褪黑素对免疫活性细胞上存在的高亲和力受体（MT1 和 MT2）的作用。临床前研究表明，褪黑素可能增强细胞因子生成并促进 T 细胞扩增，[32][33] 从而可能减轻获得性免疫缺陷。[34]

体重调节

褪黑素调节体重增加的潜力被认为与其对瘦素的抑制作用有关。瘦素是一种长期反映身体能量状态的激素。[35][36] 瘦素通过发出饱腹信号和减少食物摄入来调节能量平衡和体重。褪黑素通过调节清醒时间以外的瘦素活性，可能有助于恢复白天的瘦素敏感性，从而对抗瘦素抵抗。

生物化学

生物合成

褪黑素生物合成

动物体内褪黑素的生物合成涉及一系列酶促反应，起始于L-色氨酸。L-色氨酸可以通过莽草酸途径由植物中的莽草酸合成，也可以通过蛋白质分解代谢获得。褪黑素生物合成途径的第一步是色氨酸羟化酶催化L-色氨酸吲哚环的羟基化，生成5-羟色氨酸（5-HTP）。随后，5-HTP在磷酸吡哆醛和5-羟色氨酸脱羧酶的催化下脱羧，生成血清素。[37]

血清素是一种重要的神经递质，在乙酰辅酶A的作用下，经血清素N-乙酰转移酶进一步转化为N-乙酰血清素。[38] 该途径的最后一步是羟基吲哚O-甲基转移酶以S-腺苷甲硫氨酸为甲基供体，对N-乙酰血清素的羟基进行甲基化，生成褪黑素。[38]

在细菌、原生生物、真菌和植物中，褪黑素的合成也以色氨酸为中间体，但其来源并非直接来自莽草酸途径。该途径起始于D-赤藓糖-4-磷酸和磷酸烯醇式丙酮酸，在光合细胞中，还需二氧化碳参与。尽管后续的生物合成反应与动物中的反应相似，但在最后阶段涉及的酶略有不同。[39][40]

褪黑素合成发生在线粒体和叶绿体中的假说表明，褪黑素在细胞能量代谢和抗氧化应激防御机制中具有重要的进化和功能意义，反映了该分子的古老起源及其在不同生命领域中的多重作用。[41]

机制

褪黑素生物合成机制

褪黑素的生物合成机制始于L-色氨酸的羟基化，该过程需要辅因子四氢生物蝶呤 (THB) 与氧气和色氨酸羟化酶的活性位点铁反应。尽管完整的机制尚未完全阐明，但目前提出了两种主要机制：

第一种机制涉及THB向分子氧 (O₂) 缓慢转移一个电子，可能产生超氧阴离子 (O₂⁻)。该超氧阴离子随后可能与THB自由基重新结合形成4α-过氧蝶呤。4α-过氧蝶呤可能与活性位点铁(II)反应生成铁-过氧蝶呤中间体，或者直接将一个氧原子转移给铁，从而促进L-色氨酸的羟基化。

另一种机制是，氧气首先与活性位点铁(II)相互作用，形成铁(III)超氧阴离子。该分子随后可与THB反应生成铁-过氧蝶呤中间体。

铁-过氧蝶呤中间体生成氧化铁(IV)后，该氧化物选择性地攻击双键。

吲哚环C5位上的碳正离子与氢键结合。随后，氢发生1,2-位移，失去C5位上的两个氢原子中的一个，从而恢复芳香性，生成5-羟基-L-色氨酸。[42]

5-羟基-L-色氨酸脱羧生成5-羟色胺的过程由脱羧酶催化，该酶以磷酸吡哆醛（PLP）为辅因子。[43] PLP与氨基酸衍生物形成亚胺，促进碳-碳键断裂并释放二氧化碳。色氨酸衍生的胺质子化后恢复吡啶环的芳香性，最终生成5-羟色胺和PLP。[44]

血清素N-乙酰转移酶（其组氨酸残基为His122）被认为能够使5-羟色胺的伯胺去质子化。这种去质子化使得胺上的孤对电子能够攻击乙酰辅酶A，形成四面体中间体。随后，辅酶A中的巯基作为离去基团，在一般碱的攻击下生成N-乙酰血清素。[45]

褪黑素生物合成的最后一步是S-腺苷甲硫氨酸（SAM）对N-乙酰血清素羟基进行甲基化，生成S-腺苷高半胱氨酸（SAH）和褪黑素。[44][46]

调控

在脊椎动物中，褪黑素的分泌受去甲肾上腺素激活β1肾上腺素能受体的调控。[47]去甲肾上腺素通过β-肾上腺素能受体增加细胞内cAMP的浓度，进而激活cAMP依赖性蛋白激酶A（PKA）。PKA随后磷酸化芳烷基胺N-乙酰转移酶（AANAT），AANAT是褪黑素合成途径中的倒数第二个酶。当暴露于日光下时，去甲肾上腺素能刺激停止，导致蛋白质立即被蛋白酶体降解。[48] 褪黑素的产生在傍晚重新开始，这一阶段被称为弱光褪黑素起始期。

蓝光，尤其是波长在460-480纳米范围内的蓝光，会抑制褪黑素的生物合成，[49] 抑制程度与光照强度和持续时间成正比。历史上，温带地区的人们在冬季接触蓝光的机会有限，主要接收来自以黄光为主的光源（例如火）的光照。[50] 20世纪广泛使用的白炽灯泡发出的蓝光含量相对较低。[51] 研究发现，在强光条件下，波长大于530纳米的光不会抑制褪黑素的分泌。[52] 睡前几小时佩戴防蓝光眼镜可以减轻褪黑素的抑制作用。[53] 此外，对于需要调整作息时间的人，建议在睡前几小时佩戴防蓝光护目镜，因为褪黑素有助于入睡。[54]

代谢

褪黑素的代谢半衰期为20至50分钟。[55][2][56] 其主要代谢途径是将褪黑素转化为6-羟基褪黑素，后者与硫酸盐结合，并作为代谢废物随尿液排出体外。[57]褪黑素主要由肝酶 CYP1A2 代谢，其次由 CYP1A1、CYP2C19 和 CYP1B1 代谢。[57]

测量

无论是用于研究还是临床，人体内的褪黑素水平都可以通过唾液或血浆分析来测定。[58]

作为药物和补充剂的用途[编辑]

主条目：褪黑素作为药物和补充剂

失眠

一种缓释型褪黑素制剂以商品名 Circadin 获批用于治疗某些人群（例如 55 岁以上人群）的失眠症。[59][60][61][62] 该药物已在欧盟、以色列、澳大利亚以及亚洲和世界其他地区的国家获得批准，但未在美国获得批准（该药物已在美国完成 III 期临床试验，但未获批准）。[61][62]该药物自 2007 年起获得许可。[61][62]

2023 年欧洲失眠指南建议，对于 55 岁及以上人群，使用缓释褪黑素治疗失眠，疗程最长可达 3 个月。[63] 该指南不建议使用速释或非处方褪黑素治疗失眠。[63] 这些建议基于 2022 年和 2023 年发表的多项荟萃分析。[63]

美国睡眠医学会 2017 年临床实践指南不建议使用褪黑素治疗失眠，因为其疗效不佳且证据质量极低。[64][65]

昼夜节律睡眠障碍

褪黑素可能有助于治疗睡眠时相延迟综合征。[66]

已知褪黑素可以减轻时差反应，尤其是在向东旅行时。然而，如果服用时间不当，反而会延缓适应过程。[67]

褪黑素对某些人群的睡眠问题似乎作用有限。

轮班工作。[68]初步证据表明，它可以延长人们的睡眠时间。[68]

2005年至2017年间发表的荟萃分析似乎对褪黑素是否对昼夜节律睡眠障碍有效得出了不同的结果。[69][70][71][72]一些研究发现它有效，[69][70][72]而另一些研究则未发现其有效性。[71]针对睡眠时相延迟综合征的褪黑素荟萃分析发现其有效，并报告称它可以将入睡时间缩短约40分钟（0.67小时），并将内源性褪黑素分泌的起始时间提前约1.2小时（72分钟）。[70][72]一项荟萃分析发现，褪黑素在改善睡眠相位延迟综合征患者的入睡潜伏期方面，比在改善失眠患者方面更为有效（分别改善39分钟和7分钟）。[72] 另一项荟萃分析发现，褪黑素可能对时差综合征有效。[73]

在治疗睡眠周期紊乱方面，低剂量褪黑素可能优于高剂量。[74]

快速眼动睡眠行为障碍

在治疗快速眼动睡眠行为障碍（一种与帕金森病和路易体痴呆等突触核蛋白病相关的疾病）方面，褪黑素比氯硝西泮更安全。[75][76][77] 然而，氯硝西泮可能更有效。[78] 无论如何，这两种疗法的证据质量都很低，尚不清楚哪一种疗法确实有效。[78]

痴呆症

2020 年的一项 Cochrane 系统评价发现，没有证据表明褪黑素能帮助中度至重度阿尔茨海默病患者的睡眠问题。[79] 2019 年的一项评价发现，虽然褪黑素可能改善轻度认知障碍患者的睡眠，但在阿尔茨海默病发病后，其效果甚微或无效。[80] 然而，褪黑素可能有助于缓解痴呆症患者的黄昏综合征（夜间意识混乱和躁动加剧）。[81]

可用剂型

一瓶褪黑素片剂。褪黑素也有缓释剂型和液体剂型。

一种名为 Circadin 的 2 毫克缓释口服褪黑素制剂已获准在欧盟用于短期治疗 55 岁及以上人群的失眠症。[59][60][82]

褪黑素在许多国家也作为非处方膳食补充剂出售。它有速释型和缓释型（缓释型较少见）两种剂型。补充剂中的褪黑素剂量范围从 0.3 毫克到 10 毫克或更高。也可以按重量购买褪黑素粉末。[83] 速释型褪黑素制剂可使血液中褪黑素浓度在大约一小时内达到峰值。这种激素可以口服，剂型包括胶囊、软糖、片剂、口腔膜或液体。[84] 它也可用于舌下含服或透皮贴剂。[85] 市面上有多种吸入式褪黑素产品，剂量范围很广，但其安全性仍有待评估。[84]

美国睡眠医学会 (AASM) 指出，未经监管（没有 USP 认证标志）的补充剂中的褪黑素含量可能与标示含量存在很大差异；一项研究发现，褪黑素含量是标示剂量的二分之一到四倍。[86]

历史

发现

褪黑素的发现与对某些两栖动物和爬行动物皮肤颜色变化的研究有关，这种现象最初是通过施用松果体提取物观察到的。[87][88] 1917年，凯里·普拉特·麦考德和弗洛伊德·P·艾伦发现，喂食牛的松果体提取物会导致蝌蚪的皮肤颜色变浅，这是由于深色表皮黑色素细胞收缩所致。[89][90]

褪黑激素于1958年由耶鲁大学皮肤病学教授亚伦·B·勒纳及其团队分离出来。出于对松果体分泌物可能有助于治疗皮肤疾病的设想，他们从牛松果体提取物中提取并鉴定了褪黑素。[91] 20世纪70年代中期，林奇等人开展的后续研究表明，人类松果体中褪黑素的分泌遵循昼夜节律。[92]

1995年，麻省理工学院的理查德·沃特曼获得了首个将褪黑素作为低剂量助眠剂用于治疗的专利。[93]

词源

褪黑素的词源源于其美白功效。正如他们在《美国化学会志》上发表的文章[94]中详述的那样，勒纳及其同事提出了褪黑素（melatonin）这个名称，源自希腊语melas（意为“黑色”或“深色”）和tonos（意为“劳动”[95]、“颜色”[96]或“抑制”[97]）。这一命名规则与血清素（serotonin）的命名规则相同，血清素是另一种影响肤色的物质，于1948年被发现，是一种血管张力调节剂，其名称也源于其血清血管收缩作用[98]。

因此，褪黑素的命名恰如其分地反映了它在防止皮肤变黑方面的作用，凸显了生物化学和语言学在科学发现中的交叉融合。[94]

分布

动物和人类

在脊椎动物中，褪黑素由松果体在黑暗中产生，因此通常在夜间产生。松果体是一个位于大脑中心、血脑屏障之外的小型内分泌腺。[99] 光/暗信息通过视网膜感光神经节细胞传递到视交叉上核[100][101]，而不是通过褪黑素信号（正如曾经假设的那样）。褪黑素被称为“黑暗激素”，它在黄昏时分开始分泌，促进夜行性动物的活动，并促进包括人类在内的昼行性动物的睡眠。[102]

人体每日产生约30微克褪黑激素，其中80%的总量在夜间产生。夜间血浆褪黑激素浓度峰值为80–120 pg/mL，而白天浓度则在10–20 pg/mL之间。[103][104]

许多动物和人类利用每日褪黑激素分泌持续时间的变化作为季节性生物钟。[105] 在包括人类在内的动物中，[106] 夏季和冬季夜晚时长的变化会影响褪黑激素的合成和分泌模式。因此，分泌持续时间的变化可以作为一种生物信号，用于调控依赖于日照长度（光周期）的季节性功能，例如季节性动物的繁殖、行为、毛发生长和伪装色。[106]对于妊娠期较短且交配时间较长的季节性繁殖动物而言，褪黑激素信号控制着其性生理的季节性变化。外源性褪黑激素也能在包括八哥[107]和仓鼠[108]在内的动物中诱导类似的生理效应。褪黑激素可通过抑制垂体前叶分泌黄体生成素和卵泡刺激素来抑制性欲，尤其是在繁殖季节日照时间较长的哺乳动物中。褪黑激素抑制长日照繁殖动物的繁殖，并刺激短日照繁殖动物的繁殖。在绵羊中，褪黑激素的给药还显示出对产前受胁迫的幼崽具有抗氧化和免疫调节作用，帮助它们度过生命最初的关键时期[109]。

夜间，褪黑激素调节瘦素水平，降低其分泌。

鲸类动物已经失去了所有合成褪黑素的基因以及褪黑素受体的基因。[110] 这被认为与它们的单侧半球睡眠模式（一次只使用一个大脑半球）有关。海牛类动物也发现了类似的趋势。[110]

植物

在1987年于植物中发现褪黑素之前，几十年来人们一直认为它主要是一种动物神经激素。20世纪70年代，当人们在咖啡提取物中发现褪黑素时，它被认为是提取过程的副产品。然而，随后在所有研究过的植物中都发现了褪黑素。它存在于植物的各个部分，包括叶、茎、根、果实和种子，含量各不相同。[8][111]褪黑素浓度不仅因植物种类而异，即使是同一物种的不同品种，其浓度也会因农艺生长条件的不同而有所差异，从皮克级到微克级不等。[40][112] 值得注意的是，在咖啡、茶、葡萄酒和啤酒等常见饮品以及玉米、大米、小麦、大麦和燕麦等农作物中，都检测到了较高的褪黑素浓度。[8] 在一些常见的食物和饮料中，例如咖啡[8]和核桃[113]，褪黑素的浓度估计或测量结果显示，其浓度足以使血液中褪黑素的水平高于白天的基线值。

尽管褪黑素作为植物激素的作用尚未完全明确，但它参与生长和光合作用等过程已得到充分证实。目前仅有少量证据表明某些植物物种存在内源性褪黑素昼夜节律，而且尚未发现与动物体内已知的膜结合受体类似的受体。褪黑素并非植物的直接代谢产物，它在植物中发挥着重要的生长调节和环境胁迫保护作用。当植物暴露于生物胁迫（例如真菌感染）和非生物胁迫（例如极端温度、毒素、土壤盐碱化、干旱等）时，都会合成褪黑素。[40][114][115]

在体内实验中，高褪黑素转基因水稻能够减轻除草剂引起的氧化胁迫。[116][117][118] 对盐碱土壤条件下生长的莴苣进行的研究表明，施用褪黑素能够显著减轻盐胁迫的有害影响。叶面喷施褪黑素可以增加叶片数量、叶片表面积、鲜重以及叶绿素a和叶绿素b的含量。

与未用褪黑素处理的植物相比，经褪黑素处理的植物类胡萝卜素含量更高。[118]

抗真菌病害是褪黑素的另一作用。添加褪黑素可提高小叶苹果（Malus prunifolia）对苹果双孢菌（Diplocarpon mali）的抗性。[117][119] 褪黑素还能抑制多种真菌病原体的生长，包括链格孢属（Alternaria）、灰霉病属（Botrytis）和镰刀菌属（Fusarium spp.）。褪黑素还能降低感染速度。作为种子处理剂，褪黑素可保护白羽扇豆（Lupinus albus）免受真菌侵害。褪黑素还能显著减缓丁香假单胞菌番茄DC3000（Pseudomonas syringae tomato DC3000）对拟南芥（Arabidopsis thaliana）和本氏烟草（Nicotiana benthamiana）的感染。[119]

真菌

在植物-病原体系统中，褪黑素已被观察到会降低致病疫霉（Phytophthora infestans）的胁迫耐受性。[120]丹麦制药公司诺和诺德（Novo Nordisk）利用基因改造的酵母（酿酒酵母，Saccharomyces cerevisiae）生产褪黑素。[121]

细菌

α-变形菌和光合蓝细菌都能产生褪黑素。目前尚无古菌中存在褪黑素的报道，这表明褪黑素起源于细菌[11]，很可能是为了保护早期细胞免受原始地球大气中氧气的损害。[10]

诺和诺德（Novo Nordisk）利用基因改造的大肠杆菌（Escherichia coli）生产褪黑素。[122][123]

古菌

2022年，在古菌火山热原体（Thermoplasma volcanium）中发现了血清素N-乙酰转移酶（SNAT）——褪黑素生物合成途径中的倒数第二个限速酶[124]，这确凿地表明褪黑素的生物合成存在于生命的三大域中，其历史可追溯到约40亿年前[125]。

食品

据报道，天然存在的褪黑素存在于多种食物中，包括酸樱桃（含量约为0.17–13.46 ng/g）[126]、香蕉、李子、葡萄、大米、谷物、香草[127]、橄榄油、葡萄酒[128]和啤酒[129]。食用牛奶和酸樱桃可能有助于改善睡眠质量[130]。当鸟类摄入富含褪黑素的植物饲料（如大米）时，褪黑素会与它们大脑中的褪黑素受体结合。[131] 当人类食用富含褪黑素的食物（如香蕉、菠萝和橙子）时，血液中的褪黑素水平会显著升高。[132]

Melatonin,

https://en.wikipedia.org/wiki/Melatonin

It is an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes.^[1] Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cows that could induce skin lightening in common frogs. This compound was later identified as a hormone secreted in the brain during the night, playing a crucial role in regulating the sleep-wake cycle, also known as the circadian rhythm, in vertebrates.^[2][3]

In vertebrates, melatonin's functions extend to synchronizing sleep-wake cycles, encompassing sleep-wake timing and blood pressure regulation, as well as controlling seasonal rhythmicity (circannual cycle), which includes reproduction, fattening, molting, and hibernation.^[4] Its effects are mediated through the activation of melatonin receptors and its role as an antioxidant.^[5][6][7] In plants and bacteria, melatonin primarily serves as a defense mechanism against oxidative stress, indicating its evolutionary significance.^[8] The mitochondria, key organelles within cells, are the main producers of antioxidant melatonin,^[9] underscoring the molecule's "ancient origins" and its fundamental role in protecting the earliest cells from reactive oxygen species.^[10][11]

In addition to its endogenous functions as a hormone and antioxidant, melatonin is also administered exogenously as a dietary supplement and medication. Melatonin is used medically primarily for sleep-related problems: for example, prolonged-release melatonin (Circadin) is approved in several countries for short-term treatment of insomnia in people over 55.^[12] It is used in the treatment of sleep disorders, including insomnia and various circadian rhythm sleep disorders.

In humans, melatonin primarily acts as a potent full agonist of two types of melatonin receptors: melatonin receptor 1, with picomolar binding affinity, and melatonin receptor 2, with nanomolar binding affinity. Both receptors are part of the G-protein coupled receptors (GPCRs) family, specifically the G_i/o alpha subunit GPCRs,^[13][14] although melatonin receptor 1 also exhibits coupling with G_q alpha subunit.^[13]

Furthermore, melatonin functions as a high-capacity antioxidant, or free radical scavenger, within mitochondria, playing a dual role in combating cellular oxidative stress. First, it directly neutralizes free radicals, and second, it promotes the gene expression of essential antioxidant enzymes, such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. This increase in antioxidant enzyme expression is mediated through signal transduction pathways activated by the binding of melatonin to its receptors. Through these mechanisms, melatonin protects the cell against oxidative stress in two ways, highlighting how it serves human health beyond regulating the sleep-wake cycle.^{[15][13][16][17][18][19]}

In mammals, melatonin is critical for the regulation of sleep–wake cycles, or circadian rhythms.^[20] The establishment of regular melatonin levels in human infants occurs around the third month after birth, with peak concentrations observed between midnight and 8:00 am.^[21] It has been documented that melatonin production diminishes as a person ages.^[22] Additionally, a shift in the timing of melatonin secretion is observed during adolescence, resulting in delayed sleep and wake times, increasing their risk for delayed sleep phase disorder during this period.^[23]

The antioxidant properties of melatonin were first recognized in 1993.^[24] In vitro studies reveal that melatonin directly neutralizes various reactive oxygen species, including hydroxyl (OH•), superoxide (O2−•), and reactive nitrogen species such as nitric oxide (NO•).^[25][26] In plants, melatonin works synergistically with other antioxidants, enhancing the overall effectiveness of each antioxidant.^[26] This compound has been found to be twice as efficacious as vitamin E, a known potent lipophilic antioxidant, at scavenging peroxyl radicals.^[27] The promotion of antioxidant enzyme expression, such as superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase, is mediated through melatonin receptor-triggered signal transduction pathways.^[13][15]

Melatonin's concentration in the mitochondrial matrix is significantly higher than that found in the blood plasma,^[16][17][18] emphasizing its role not only in direct free radical scavenging but also in modulating the expression of antioxidant enzymes and maintaining mitochondrial integrity. This multifaceted role shows the physiological significance of melatonin as a mitochondrial antioxidant, a notion supported by numerous scholars.^{[15][16][17][18][19]}

Furthermore, the interaction of melatonin with reactive oxygen and nitrogen species results in the formation of metabolites capable of reducing free radicals.^[13][19] These metabolites, including cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK), contribute to the broader antioxidative effects of melatonin through further redox reactions with free radicals.^[13][19]

Melatonin's interaction with the immune system is recognized, yet the specifics of these interactions remain inadequately defined.^{[28][29][30][31]} An anti-inflammatory effect appears to be the most significant.^[30][31] The efficacy of melatonin in disease treatment has been the subject of limited trials, with most available data deriving from small-scale, preliminary studies. It is posited that any beneficial immunological impact is attributable to melatonin's action on high-affinity receptors (MT1 and MT2), which are present on immunocompetent cells. Preclinical investigations suggest that melatonin may augment cytokine production and promote the expansion of T cells,^[32][33] thereby potentially mitigating acquired immunodeficiencies.^[34]

Melatonin's potential to regulate weight gain is posited to involve its inhibitory effect on leptin, a hormone that serves as a long-term indicator of the body's energy status.^[35][36] Leptin is important for regulating energy balance and body weight by signaling satiety and reducing food intake. Melatonin, by modulating leptin's actions outside of waking hours, may contribute to the restoration of leptin sensitivity during daytime, thereby counteracting leptin resistance.

The biosynthesis of melatonin in animals involves a sequence of enzymatic reactions starting with L-tryptophan, which can be synthesized through the shikimate pathway from chorismate, found in plants, or obtained from protein catabolism. The initial step in the melatonin biosynthesis pathway is the hydroxylation of L-tryptophan's indole ring by the enzyme tryptophan hydroxylase, resulting in the formation of 5-hydroxytryptophan (5-HTP). Subsequently, 5-HTP undergoes decarboxylation, facilitated by pyridoxal phosphate and the enzyme 5-hydroxytryptophan decarboxylase, yielding serotonin.^[37]

Serotonin, an essential neurotransmitter, is further converted into N-acetylserotonin by the action of serotonin N-acetyltransferase, using acetyl-CoA.^[38] The final step in the pathway involves the methylation of N-acetylserotonin's hydroxyl group by hydroxyindole O-methyltransferase, with S-adenosyl methionine as the methyl donor, to produce melatonin.^[38]

In bacteria, protists, fungi, and plants, the synthesis of melatonin also involves tryptophan as an intermediate but originates indirectly from the shikimate pathway. The pathway commences with D-erythrose 4-phosphate and phosphoenolpyruvate, and in photosynthetic cells, additionally involves carbon dioxide. While the subsequent biosynthetic reactions share similarities with those in animals, there are slight variations in the enzymes involved in the final stages.^[39][40]

The hypothesis that melatonin synthesis occurs within mitochondria and chloroplasts suggests an evolutionary and functional significance of melatonin in cellular energy metabolism and defense mechanisms against oxidative stress, reflecting the molecule's ancient origins and its multifaceted roles across different domains of life.^[41]

The mechanism of melatonin biosynthesis initiates with the hydroxylation of L-tryptophan, a process that requires the cofactor tetrahydrobiopterin (THB) to react with oxygen and the active site iron of tryptophan hydroxylase. Although the complete mechanism is not entirely understood, two main mechanisms have been proposed:

The first mechanism involves a slow transfer of one electron from THB to molecular oxygen (O₂), potentially producing a superoxide (O−2). This superoxide could then recombine with the THB radical to form 4a-peroxypterin. 4a-peroxypterin may either react with the active site iron (II) to create an iron-peroxypterin intermediate or directly transfer an oxygen atom to the iron, facilitating the hydroxylation of L-tryptophan.

Alternatively, the second mechanism proposes that oxygen interacts with the active site iron (II) first, forming iron (III) superoxide. This molecule could then react with THB to form an iron-peroxypterin intermediate.

Following the formation of iron (IV) oxide from the iron-peroxypterin intermediate, this oxide selectively attacks a double bond to yield a carbocation at the C5 position of the indole ring. A subsequent 1,2-shift of the hydrogen and the loss of one of the two hydrogen atoms on C5 would restore aromaticity, producing 5-hydroxy-L-tryptophan.^[42]

The decarboxylation of 5-hydroxy-L-tryptophan to produce 5-hydroxytryptamine is then facilitated by a decarboxylase enzyme with pyridoxal phosphate (PLP) as a cofactor.^[43] PLP forms an imine with the amino acid derivative, facilitating the breaking of the carbon–carbon bond and release of carbon dioxide. The protonation of the amine derived from tryptophan restores the aromaticity of the pyridine ring, leading to the production of 5-hydroxytryptamine and PLP.^[44]

Serotonin N-acetyltransferase, with histidine residue His122, is hypothesized to deprotonate the primary amine of 5-hydroxytryptamine. This deprotonation allows the lone pair on the amine to attack acetyl-CoA, forming a tetrahedral intermediate. The thiol from coenzyme A then acts as a leaving group when attacked by a general base, producing N-acetylserotonin.^[45]

The final step in the biosynthesis of melatonin involves the methylation of N-acetylserotonin at the hydroxyl position by SAM, resulting in the production of S-adenosyl homocysteine (SAH) and melatonin.^[44][46]

In vertebrates, the secretion of melatonin is regulated through the activation of the beta-1 adrenergic receptor by the hormone norepinephrine.^[47] Norepinephrine increases the concentration of intracellular cAMP via beta-adrenergic receptors, which in turn activates the cAMP-dependent protein kinase A (PKA). PKA then phosphorylates arylalkylamine N-acetyltransferase (AANAT), the penultimate enzyme in the melatonin synthesis pathway. When exposed to daylight, noradrenergic stimulation ceases, leading to the immediate degradation of the protein by proteasomal proteolysis.^[48] The production of melatonin recommences in the evening, a phase known as the dim-light melatonin onset.

Blue light, especially within the 460–480 nm range, inhibits the biosynthesis of melatonin,^[49] with the degree of suppression being directly proportional to the intensity and duration of light exposure. Historically, humans in temperate climates experienced limited exposure to blue daylight during winter months, primarily receiving light from sources that emitted predominantly yellow light, such as fires.^[50] The incandescent light bulbs used extensively throughout the 20th century emitted relatively low levels of blue light.^[51] It has been found that light containing only wavelengths greater than 530 nm does not suppress melatonin under bright-light conditions.^[52] The use of glasses that block blue light in the hours preceding bedtime can mitigate melatonin suppression.^[53] Additionally, wearing blue-blocking goggles during the last hours before bedtime is recommended for individuals needing to adjust to an earlier bedtime since melatonin facilitates the onset of sleep.^[54]

Melatonin is metabolized with an elimination half-life ranging from 20 to 50 minutes.^[55][2][56] The primary metabolic pathway transforms melatonin into 6-hydroxymelatonin, which is then conjugated with sulfate and excreted in urine as a waste product.^[57] It is primarily metabolized by the liver enzyme CYP1A2 and to a lesser extent by CYP1A1, CYP2C19, and CYP1B1.^[57]

For both research and clinical purposes, melatonin levels in humans can be determined through saliva or blood plasma analysis.^[58]

An extended-release pharmaceutical formulation of melatonin is approved under the brand name Circadin for the treatment of insomnia in certain settings, such as in people over 55 years of age.^{[59][60][61][62]} It is approved in the European Union, Israel, Australia, and countries in Asia and elsewhere in the world, but not in the United States (where it reached phase 3 trials but was not approved).^[61][62] The medication has been licensed since 2007.^[61][62]

The 2023 European Insomnia Guideline recommended use of prolonged-release melatonin for treatment of insomnia in people age 55 or older for up to 3 months.^[63] It recommended against fast-release or over-the-counter melatonin for treatment of insomnia.^[63] These recommendations were based on several meta-analyses published in 2022 and 2023.^[63]

The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended against the use of melatonin in the treatment of insomnia due to poor effectiveness and very low quality of evidence.^[64][65]

Melatonin may be useful in the treatment of delayed sleep phase syndrome.^[66]

Melatonin is known to reduce jet lag, especially in eastward travel. However, if it is not taken at the correct time, it can instead delay adaptation.^[67]

Melatonin appears to have limited use against the sleep problems of people who work shift work.^[68] Tentative evidence suggests that it increases the length of time people are able to sleep.^[68]

Meta-analyses, published between 2005 and 2017, appear to show different results as to whether melatonin is effective for circadian rhythm sleep disorders or not.^{[69][70][71][72]} Some found that it was effective,^[69][70][72] while others found no evidence of effectiveness.^[71] Meta-analyses of melatonin for delayed sleep phase syndrome that found it effective have reported that it improves time to sleep onset by about 40 minutes (0.67 hours) and advances onset of endogenous melatonin secretion by about 1.2 hours (72 minutes).^[70][72] One meta-analysis found that melatonin was notably more effective in improving sleep onset latency in people with delayed sleep phase syndrome than in people with insomnia (improvement of 39 minutes vs. 7 minutes, respectively).^[72] One meta-analysis found that melatonin was probably effective for jet lag syndrome.^[73]

Low doses of melatonin may be advantageous to high doses in the treatment of sleep-cycle disorders.^[74]

Melatonin is a safer alternative than clonazepam in the treatment of REM sleep behavior disorder – a condition associated with the synucleinopathies like Parkinson's disease and dementia with Lewy bodies.^[75][76][77] However, clonazepam may be more effective.^[78] In any case, the quality of evidence for both treatments is very low and it is unclear whether either is definitely effective.^[78]

A 2020 Cochrane review found no evidence that melatonin helped sleep problems in people with moderate to severe dementia due to Alzheimer's disease.^[79] A 2019 review found that while melatonin may improve sleep in minimal cognitive impairment, after the onset of Alzheimer's disease it has little to no effect.^[80] Melatonin may, however, help with sundowning (increased confusion and restlessness at night) in people with dementia.^[81]

A prolonged-release 2 mg oral formulation of melatonin sold under the brand name Circadin is approved for use in the European Union in the short-term treatment of insomnia in people age 55 and older.^[59][60][82]

Melatonin is also available as an over-the-counter dietary supplement in many countries. It is available in both immediate-release and less commonly prolonged-release forms. The compound is available in supplements at doses ranging from 0.3 mg to 10 mg or more. It is also possible to buy raw melatonin powder by weight.^[83] Immediate-release formulations of melatonin cause blood levels of melatonin to reach their peak in about an hour. The hormone may be administered orally, as capsules, gummies, tablets, oral films, or as a liquid.^[84] It is also available for use sublingually, or as transdermal patches.^[85] Several inhalation-based melatonin products with a wide range of doses are available but their safety remains to be evaluated.^[84]

The American Academy of Sleep Medicine (AASM) says that the melatonin content in unregulated (without a USP verified mark) supplements can diverge widely from the claimed amount; a study found that the melatonin content ranged from one half to four times the stated dose.^[86]

Melatonin's discovery is linked to the study of skin color changes in some amphibians and reptiles, a phenomenon initially observed through the administration of pineal gland extracts.^[87][88] In 1917, Carey Pratt McCord and Floyd P. Allen found that feeding extracts from the pineal glands of cows caused the skin of tadpoles to lighten by contracting the dark epidermal melanophores.^[89][90]

The hormone melatonin was isolated in 1958 by Aaron B. Lerner, a dermatology professor, and his team at Yale University. Motivated by the possibility that a substance from the pineal gland could be beneficial in treating skin diseases, they extracted and identified melatonin from bovine pineal gland extracts.^[91] Subsequent research in the mid-1970s by Lynch and others demonstrated that melatonin production follows a circadian rhythm in human pineal glands.^[92]

The first patent for the therapeutic use of melatonin as a low-dose sleep aid was awarded to Richard Wurtman at the Massachusetts Institute of Technology in 1995.^[93]

The etymology of melatonin stems from its skin-lightening properties. As detailed in their publication in the Journal of the American Chemical Society,^[94] Lerner and his colleagues proposed the name melatonin, derived from the Greek words melas, meaning 'black' or 'dark', and tonos, meaning 'labour',^[95] 'colour'^[96] or 'suppress'.^[97] This naming convention follows that of serotonin, another agent affecting skin color, discovered in 1948 as a modulator of vascular tone, which influenced its name based on its serum vasoconstrictor effect.^[98] Melatonin was thus aptly named to reflect its role in preventing the darkening of the skin, highlighting the intersection of biochemistry and linguistics in scientific discovery.^[94]

In vertebrates, melatonin is produced in darkness, thus usually at night, by the pineal gland, a small endocrine gland^[99] located in the center of the brain but outside the blood–brain barrier. Light/dark information reaches the suprachiasmatic nuclei from retinal photosensitive ganglion cells of the eyes^[100][101] rather than the melatonin signal (as was once postulated). Known as "the hormone of darkness", the onset of melatonin at dusk promotes activity in nocturnal (night-active) animals and sleep in diurnal ones including humans.^[102]

In humans, ~30 μg of melatonin is produced daily and 80% of the total amount is produced in the night (W). The plasma maximum concentration of melatonin at night are 80–120 pg/mL and the concentrations during the day are between 10–20 pg/mL.^[103][104]

Many animals and humans use the variation in duration of melatonin production each day as a seasonal clock.^[105] In animals including humans,^[106] the profile of melatonin synthesis and secretion is affected by the variable duration of night in summer as compared to winter. The change in duration of secretion thus serves as a biological signal for the organization of daylength-dependent (photoperiodic) seasonal functions such as reproduction, behavior, coat growth, and camouflage coloring in seasonal animals.^[106] In seasonal breeders that do not have long gestation periods and that mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds^[107] and hamsters.^[108] Melatonin can suppress libido by inhibiting secretion of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin. In sheep, melatonin administration has also shown antioxidant and immune-modulatory regime in prenatally stressed offspring helping them survive the crucial first days of their lives.^[109]

During the night, melatonin regulates leptin, lowering its levels.

Cetaceans have lost all the genes for melatonin synthesis as well as those for melatonin receptors.^[110] This is thought to be related to their unihemispheric sleep pattern (one brain hemisphere at a time). Similar trends have been found in sirenians.^[110]

Until its identification in plants in 1987, melatonin was for decades thought to be primarily an animal neurohormone. When melatonin was identified in coffee extracts in the 1970s, it was believed to be a byproduct of the extraction process. Subsequently, however, melatonin has been found in all plants that have been investigated. It is present in all the different parts of plants, including leaves, stems, roots, fruits, and seeds, in varying proportions.^[8][111] Melatonin concentrations differ not only among plant species, but also between varieties of the same species depending on the agronomic growing conditions, varying from picograms to several micrograms per gram.^[40][112] Notably high melatonin concentrations have been measured in popular beverages such as coffee, tea, wine, and beer, and crops including corn, rice, wheat, barley, and oats.^[8] In some common foods and beverages, including coffee^[8] and walnuts,^[113] the concentration of melatonin has been estimated or measured to be sufficiently high to raise the blood level of melatonin above daytime baseline values.

Although a role for melatonin as a plant hormone has not been clearly established, its involvement in processes such as growth and photosynthesis is well established. Only limited evidence of endogenous circadian rhythms in melatonin levels has been demonstrated in some plant species and no membrane-bound receptors analogous to those known in animals have been described. Rather, melatonin performs important roles in plants as a growth regulator, as well as environmental stress protector. It is synthesized in plants when they are exposed to both biological stresses, for example, fungal infection, and nonbiological stresses such as extremes of temperature, toxins, increased soil salinity, drought, etc.^{[40][114][115]}

Herbicide-induced oxidative stress has been experimentally mitigated in vivo in a high-melatonin transgenic rice.^{[116][117][118]} Studies conducted on lettuce grown in saline soil conditions have shown that the application of melatonin significantly mitigates the harmful effects of salinity. Foliar application increases the number of leaves, their surface area, increases fresh weight and the content of chlorophyll a and chlorophyll b, and the content of carotenoids compared to plants not treated with melatonin.^[118]

Fungal disease resistance is another role. Added melatonin increases resistance in Malus prunifolia against Diplocarpon mali.^[117][119] Also acts as a growth inhibitor on fungal pathogens including Alternaria, Botrytis, and Fusarium spp. Decreases the speed of infection. As a seed treatment, protects Lupinus albus from fungi. Dramatically slows Pseudomonas syringae tomato DC3000 infecting Arabidopsis thaliana and infecting Nicotiana benthamiana.^[119]

Melatonin has been observed to reduce stress tolerance in Phytophthora infestans in plant-pathogen systems.^[120] Danish pharmaceutical company Novo Nordisk have used genetically modified yeast (Saccharomyces cerevisiae) to produce melatonin.^[121]

Melatonin is produced by α-proteobacteria and photosynthetic cyanobacteria. There is no report of its occurrence in archaea which indicates that melatonin originated in bacteria^[11] most likely to prevent the first cells from the damaging effects of oxygen in the primitive Earth's atmosphere.^[10]

Novo Nordisk have used genetically modified Escherichia coli to produce melatonin.^[122][123]

In 2022, the discovery of serotonin N-acetyltransferase (SNAT)—the penultimate, rate-limiting enzyme in the melatonin biosynthetic pathway—in the archaeon Thermoplasma volcanium^[124] firmly places melatonin biosynthesis in all three major domains of life, dating back to ~4 Gya.^[125]

Naturally occurring melatonin has been reported in foods including tart cherries to about 0.17–13.46 ng/g,^[126] bananas, plums, grapes, rice, cereals, herbs,^[127] olive oil, wine,^[128] and beer.^[129] The consumption of milk and sour cherries may improve sleep quality.^[130] When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains.^[131] When humans consume foods rich in melatonin, such as banana, pineapple, and orange, the blood levels of melatonin increase significantly.^[132]