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Caffeine
CaffeineCaffeine
一般
系统名称 1,3,7-三甲基-1H-嘌呤-2,6(3H,7H)-二酮
其他名称 1,3,7-三甲基黄嘌呤, 三甲基黄嘌呤,
咖啡碱，茶毒, 马黛因, 瓜拉纳因子,
甲基可可碱
分子式 C8H10N4O2
SMILES O=C1C2=C(N=CN2C)N(C(=O)N1C)C
摩尔质量 194.19 g mol−1
外观 无嗅，白色针状或粉状固体
CAS号 [58-08-2]
性质
密度和相态 1.2 g/cm³, 固体
水中溶解性 微溶
其他溶剂 乙酸乙酯、氯仿、嘧啶、吡咯、四氢呋喃中可溶；酒精和丙酮中一般可溶；石油醚、醚及苯中微溶
熔点 237 °C
沸点 178 °C (升华)
酸度系数 (pKa) 10.4 (40 °C)
危险性
化学物质安全性表 外部链接
主要危害 吸入、吞咽及皮肤吸收均可能致命。
NFPA 704
0
0
0
 
闪点 N/A
RTECS号 EV6475000
若非注明，所有数据都依從国际单位制和来自标准温度和压力条件下。

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咖啡因是一个黄嘌呤生物碱化合物，在人体中是一种兴奋剂。存在于瓜拉纳（guarana）中的咖啡因有时也被称为瓜拉纳因子（guaranine），而存在于玛黛茶中的被称为马黛因（mateine），在茶中的则被称为茶毒（theine）。它存在于咖啡树、茶树、巴拉圭冬青及瓜拿纳的果实及叶片里，少量的咖啡因也存在于可可树、可乐树果实及代茶冬青树。总体上来说，作为一种自然杀虫剂，在超过60种植物的果实、叶片和种子中能够发现咖啡因，它能使以这些植物为食的昆虫麻痹因而达到杀虫的效果。

咖啡因是一种中枢神经兴奋剂，能够临时的驱走睡意并恢复精力。有咖啡因成分的咖啡、茶、软饮料及能量饮料十分畅销，因此，咖啡因也是世界上最普遍被使用的精神药品。在北美，90%成年人每天都使用咖啡因.[1] 。

很多咖啡因的自然来源也含有多种其他的黄嘌呤生物碱，包括强心剂茶碱和可可碱以及其他物质例如单宁酸。

来源 编辑

 
烘焙咖啡豆，世界咖啡因的最初来源
常见食品药品的咖啡因含量[2][3]
产品 计量单位 每单位咖啡因含量 (毫克)
咖啡因片剂 (Vivarin) 1片 200
Excedrin片剂 1片 65
咖啡，酿制 240 mL (8 US fl oz) 135*
咖啡，脱咖啡因 240 mL (8 US fl oz) 5*
咖啡，浓咖啡 57 mL (2 US fl oz) 100*
巧克力，黑 (Hershey's Special Dark) 1条 (43 g; 1.5 oz) 31
巧克力，牛奶 (Hershey Bar) 1条 (43 g; 1.5 oz) 10
红牛 240 mL (8.2 US fl oz) 80
Bawls瓜拿纳 296 mL (10 US fl oz) 67
软饮料，经典可口可乐 355 mL (12 US fl oz) 34
Atomic Rush 255 mL (7 US fl oz) 100
茶，绿茶 240 mL (8 US fl oz) 15
茶，叶或袋 240 mL (8 US fl oz) 50
* Estimated average caffeine content per serving. Actual content varies according to preparation.

咖啡因是一种植物生物碱，在许多植物中都能够被发现。作为自然杀虫剂，它能使以植物为食的昆虫麻痹[4]。人类最常使用的含咖啡因的植物包括咖啡、茶及一些可可。其他不经常使用的包括一般被用来制茶或能量饮料的巴拉圭冬青[5]和瓜拿纳树。两个咖啡因的别名：马黛因(mateine)[6]和瓜拿纳因子(guaranine)[7]就是从这两种植物演化而来。

世界上最主要的咖啡因来源是咖啡豆（咖啡树的种子），同时咖啡豆也是咖啡的原料。咖啡中的咖啡因含量极大程度上依赖于咖啡豆的品种和咖啡的制作方法;[8]，甚至同一棵树上的咖啡豆中的咖啡因含量都有很大的区别。一般来说一杯咖啡中咖啡因的含量从阿拉伯浓缩咖啡中的40毫克到浓咖啡中的100毫克。深焙咖啡一般比浅焙咖啡的咖啡因含量少，因为烘焙能减少咖啡豆里的咖啡因含量。阿拉伯咖啡的咖啡因含量通常比中果咖啡低.[8]。 咖啡也含有痕量的茶碱，但不含可可碱。

茶是另外一个咖啡因的重要来源，每杯茶的咖啡因含量一般只有每杯咖啡的一半，决定于制茶的强度。特定品种的茶，例如红茶和乌龙茶，比其他茶的咖啡因含量高。茶含有少量的可可碱以及比咖啡略高的茶碱。茶的制作对于茶有很大影响，但是茶的颜色几乎不能指示咖啡因的含量.[9]。日本绿茶的咖啡因含量就远远高于许多红茶，例如正山小种茶，几乎不含咖啡因。

由可可粉制的巧克力也含有少量的咖啡因。巧克力是一种很弱的兴奋剂，主要归因于其中含有的可可碱和茶碱.[10]。一条典型的28克牛奶巧克力与脱咖啡因咖啡的咖啡因含量差不多。

咖啡因也是软饮料中的常见成分，例如可乐，最初就是由可乐树制得。一瓶软饮料中一般含有10毫克至50毫克的咖啡因。能量饮料，例如红牛，每瓶含有80毫克咖啡因。这些饮料中的咖啡因来源于它们所用的原始成分或由脱咖啡因咖啡所得的添加剂，也有是通过化学合成的。瓜拿纳，很多能量饮料的基本成分，含有大量的咖啡因及少量的可可碱。自然存在的缓释赋形剂中含有少量茶碱[11]。

历史 编辑

 
一个为巴勒斯坦的咖啡屋, 大约1900年

早在石器时代[12] ，人类已经开始使用咖啡因。早期的人们发现咀嚼特定植物的种子、树皮或树叶有减轻疲劳和提神的功效。直到很多年以后，人们才发现使用热水泡这些植物能够增加咖啡因的效用。许多文化都有关于远古时期的人们发现这些植物的神话。

根据一个古老的蒙古神话，大约公元前3000年的中国皇帝神农氏，在一次偶然的机会下，发现当有的树叶飘进沸水中会产生一种芳香且提神的饮品[13] 。一本古老的关于茶的著作陆羽《茶经》中也提到了神农氏的名字[14]。

咖啡早期的历史十分朦胧，不过一个流传广泛的神话能让我们回溯到阿拉伯咖啡的发源地埃塞俄比亚。根据这个神话，一个名叫卡迪的牧羊人发现，当山羊食用了咖啡灌木上的浆果时会变得兴奋异常并且在夜里失眠，山羊也会不断地再次食用该浆果，体验相同的活力。最早的有关咖啡的书面记载可能是9世纪波斯医师al-Razi所著的Bunchum。1587年，Malaye Jaziri汇编了一本追溯咖啡历史及合法性争议的书，名叫《Umdat al safwa fi hill al-qahwa》。在这本书中，Jaziri记录了一个亚丁的伊斯兰教长Jamal-al-Din al-Dhabhani是首先于1454年饮用咖啡的人，15世纪后，也门的苏菲派穆斯林开始有规律的饮用咖啡来保持祈祷时的清醒。16世纪快要结束的时候，在埃及的欧洲居民们记录了咖啡的使用，大概这个时候，咖啡开始在近东广泛使用。咖啡最为一种饮料在17世纪流传到欧洲，最初被称为阿拉伯酒。这段时间，咖啡屋开始增多，最初的咖啡屋是在君士坦丁堡和威尼斯。在英国，第一家咖啡屋开业于1652年，在伦敦Cornhill街圣迈克尔巷。很快咖啡开始在西欧流行并在17和18世纪社会交流中扮演了重要的角色[15]。

就像咖啡浆果和茶叶一样，可乐树坚果也有很古老的起源。很多西非的文明通过单独或群体的咀嚼可乐树坚果来恢复精力和减轻饥饿。1911年，当美国政府没收了40大桶和20小桶可口可乐时，可乐成了第一个有记录的关于健康的恐慌焦点[16]。当年3月13日，美国政府开始了美国对40大桶和20小桶可口可乐，希望通过夸大的宣传迫使可口可乐将咖啡因从其配方中移除，比如宣传在一个女子学校，过多的饮用可口可乐导致“夜间荒诞行为，违背学院规则和女性的礼节，甚至不道德。[17] ”尽管法官最后支持了可口可乐，1912年仍然有两个旨在修正纯粹食品与药品法案的议案被提交众议院，把咖啡因添加进“上瘾”和“有害”的物质清单，必须在产品标签中列出。

使用可可的最早的证据是从公元前８世纪古玛雅文明时期的罐中发现的残渣。在新世界里，巧克力被混入一种叫Xocoatl得苦辣饮品之中使用，也常伴有香草、辣椒和胭脂。xocoatl被广泛认为能够抗疲劳，这大概归功于其中可可碱和咖啡因成分。巧克力在哥伦布发现美洲大陆以前的中美洲是一种奢侈品，可可豆也曾被用来作为货币。

巧克力在1700年由西班牙人引进欧洲，他们也将可可树引入了西印度群岛和菲律宾。它们被用于炼金术，叫做黑豆。

1819年，德国化学家Friedrich Ferdinand Runge第一次分离得到纯的咖啡因。根据一个传说，他之所以这样做是听了歌德的吩咐[18]。

现在，每年咖啡因的国际销量已达到120000吨[19]，这个数字相当于每天每个人消耗一份咖啡饮品，这也使它成为了世界最流行的影响精神的物质。在北美，90%的成年人每天消耗一定量的咖啡因。

影响 编辑

 
咖啡因对蜘蛛有很显著的影响，从蜘蛛网的结构可以反映出来

咖啡因是一个中枢神经系统兴奋剂，[20]也是一个新陈代谢的刺激剂。咖啡因既被作为饮品，也被作为药品，其作用都是提神及解除疲劳。咖啡因能使中枢神经系统兴奋，因此能够增加警觉度，使人警醒，有快速而清晰的思维，增加注意力和保持较好的身体状态。[21]每个人所需要的能够产生效果的咖啡因精确剂量并不相同，主要取决于体型和咖啡因耐受度。咖啡因在不到一个小时的时间内就可以开始在身体里发挥作用，对于一个温和剂量的咖啡因摄取，在3到4个小时内作用消失[21]。食用咖啡因并不能减少所需睡眠时间，它只能临时的减弱困的感觉。

因为这些影响，咖啡因是一个机能增进剂：提升大脑和身体的能力。一项在1979年的研究表明，与对照组相比，摄取了咖啡因之后的运动员在长距离自行车项目中的表现增加7%[22]。其他的研究获得了更加显著的结果：一个对经过训练的跑步运动员的实验表明，在摄取一剂9毫克每千克体重的咖啡因之后，运动员的直线跑耐久性增加44%，环形跑耐久力增加55%。[23] 如此显著的提升并不是孤立的偶然情况，一些后续的研究也得到相似的结果。另外一个研究表明，在摄取了5.5毫克每千克体重咖啡因之后，在自行车项目中，能够提升29%的持续时间[24]。

咖啡因有时也与其他药物混合提高它们的功效。咖啡因能够使减轻头痛的药的功效提高40%，并能使身体更快的吸收这些药品缩短起作用的时间[25]。因此，很多非处方治疗头痛的药品中包含有咖啡因。咖啡因也与麦角胺一起使用，治疗偏头痛和集束性头痛，也能克服由抗组胺剂带来的困意。

早产婴儿的呼吸问题，有时也使用柠檬酸咖啡因治疗。使用柠檬酸咖啡因疗法后，早产婴儿的支气管发育不良明显减少。此疗法的唯一缺点是在治疗中暂时性的体重增长变慢.[26]。柠檬酸咖啡因在很多国家只能通过处方获得.[27]。

对人类而言，咖啡因是安全的，但是咖啡因对某些动物而言确是有毒性的，例如狗，马和鹦鹉，因为这些动物分解咖啡因的能力比人类弱很多。咖啡因对蜘蛛有显著的影响，远远高于其他药物[28]。


过度使用 编辑

 
在短时间内过多的咖啡因可以导致上瘾和一系列的身体与心理的不良反应

在长期摄取的情况下，大剂量的咖啡因是一种毒品，能够导致“咖啡因中毒”。咖啡因中毒包括上瘾和一系列的身体与心理的不良反应，比如神经过敏，易怒，焦虑，震颤，肌肉抽搐（反射亢进），失眠和心悸[29] （在严格的上瘾的定义下，只有逐渐增高用量才是上瘾，用咖啡因依赖描述更为恰当一些，但是在一个被广泛接受的定义下，所有慢性的很难摆脱的行为都叫做上瘾，所以也可以用咖啡因上瘾来描述。）另外，由于咖啡因能使胃酸增多，持续的高剂量摄入会导致消化性溃疡，糜烂性食道炎和胃食管反流病[30]。然而，因为无论是正常的咖啡还是脱咖啡因咖啡，都会刺激胃粘膜，增加胃酸分泌，所以咖啡因可能不是咖啡唯一的成分[31]。

四个被精神疾病诊断与统计手册（第四版）所验证的有咖啡因引起的精神紊乱包括咖啡因过度轻奋、咖啡因焦虑症、咖啡因睡眠失调及其他咖啡因相关紊乱。

咖啡因过度轻奋 编辑

一个急剧的过量咖啡因，通常超过250毫克（相当于2-3杯煮咖啡）就能够导致中枢神经系统过度兴奋，也就是咖啡因过度轻奋。咖啡因过度轻奋的症状包括：烦躁，神经过敏，兴奋，失眠，脸红，尿液增加，胃肠紊乱，肌肉抽搐，思维涣散，心跳不规则或过快以及躁动[29][32][33]。

摄取极大剂量的咖啡因会导致死亡[34] 。对于实验鼠，咖啡因的半数致死量为192毫克每千克体重。咖啡因半数致死量取决于体重和个人敏感程度，大概是150至200毫克每千克体重，大约是一个普通成年人在一个有限的时间内摄取140至180杯咖啡，时间取决于生物半衰期。尽管饮用普通咖啡几乎不可能致死，但有由于过度服用咖啡因药丸致死的报告[35][36][37][38]。

对于咖啡因过度轻奋的治疗通常是辅助性的，即对个别的症状进行相应的治疗。但是如果患者的血清咖啡因浓度过高，则有可能采取腹膜透析、血液透析和血液滤过等方法。

咖啡因焦虑症及睡眠失调 编辑

长期的过度摄取咖啡因会引起一系列的精神紊乱。其中两种被美国精神病学协会验证的是咖啡因焦虑症和咖啡因睡眠失调。

咖啡因睡眠失调是指由一个个体有规律的摄取高剂量的咖啡因所导致的他或她的睡眠紊乱，并且能被临床诊断所发现[39]。

对某些个体而言，大剂量的咖啡饮所导致的焦虑足够被临床诊断发现。咖啡因焦虑症会以不同的形式出现，一般性焦虑失调，恐慌发作，强迫症甚至是恐怖症[39]。因为这些症状容易与基本神经失调混淆，比如恐慌失调，一般性焦虑失调，躁郁症或甚至是精神分裂症，所以一些医务工作者认为部分咖啡因摄入过量的人被误诊并给予了不必要的治疗，他们认为咖啡因诱发的精神疾病可以通过切断咖啡因来源而很简单的控制[40] 。一个由不列颠上瘾期刊（British Journal of Addiction）所作的调查表明，虽然很少被诊断出，咖啡因慢性中毒至少困扰了十分之一的总人口[41]。


药理学 编辑

新陈代谢 编辑

 
Caffeine is metabolized in the liver into three primary metabolites: paraxanthine (84%), theobromine (12%), and theophylline (4%)

咖啡因在45分钟内，在胃和小肠中被完全消化。摄取后，咖啡因分散于全身所有的组织之中，最终按一级反应速率排除。[42]

咖啡因的生物半衰期是指身体消除摄入咖啡因总量一半所需要用的时间，这个时间随着个体的变化而大幅的变化，主要因素有年龄、肝功能、怀孕与否、同时摄入的药物以及肝中咖啡因代谢所需的酶的数量。对于一个健康的成年人来说，咖啡因的半衰期大概是3-4个小时。对于服用口服避孕药的女性，这个时间会增加至5-10个小时。[43]对于怀孕的女性，咖啡因的生物半衰期则为9-11个小时。[44]咖啡因能够在有着严重肝脏疾病的人体内积聚，半衰期能够达到96个小时。[45]在婴儿和小孩的体内，其生物半衰期比在成年人体内长；在新生因而体内甚至能够达到30个小时。其他的因素例如吸烟能够缩短咖啡因的半衰期。[46]

咖啡因的新陈代谢发生在肝脏，由P450细胞色素氧化酶系统将其代谢为三个代谢产物黄嘌呤，[47] 它们对于身体有着不同的影响：

这些代谢产物还会经过最终的代谢，最后通过尿液排出体外。

作用机理 编辑

 
Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain. They are presented here side by side for comparison.


Caffeine acts through multiple mechanisms involving both cell membrane level direct action on receptors and channels, as well as intracellular action on Calcium and cAMP pathways.

The principal mode of action of caffeine is as an antagonist of adenosine receptors in the brain.[48] The caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of cells without activating them (a "false transmitter" method of antagonism). The reduction in adenosine activity results in increased activity of the neurotransmitter dopamine, largely accounting for the stimulatory effects of caffeine. Caffeine can also increase levels of epinephrine/adrenaline,[49] possibly via a different mechanism. Acute usage of caffeine also increases levels of serotonin, causing positive changes in mood.

The inhibition of adenosine may be relevant in its diuretic properties. Because adenosine is known to constrict preferentially the afferent arterioles of the glomerulus, its inhibition may cause vasodilation, with an increase in renal blood flow (RBF) and glomerular filtration rate (GFR). This effect, called competitive inhibition, interrupts a pathway that normally serves to regulate nerve conduction by suppressing post-synaptic potentials. The result is an increase in the levels of epinephrine and norepinephrine/noradrenaline released via the hypothalamic-pituitary-adrenal axis.[50] Epinephrine, the natural endocrine response to a perceived threat, stimulates the sympathetic nervous system, leading to an increased heart rate, blood pressure and blood flow to muscles, a decreased blood flow to the skin and inner organs and a release of glucose by the liver.

Caffeine is also a known competitive inhibitor of the enzyme cAMP-phosphodiesterase (cAMP-PDE), which converts cyclic AMP (cAMP) in cells to its noncyclic form, allowing cAMP to build up in cells. Cyclic AMP participates in the messaging cascade produced by cells in response to stimulation by epinephrine, so by blocking its removal caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such as amphetamine, methamphetamine, or methylphenidate. Increased concentrations of cAMP in parietal cells causes an increased activation of protein kinase A (PKA) which in turn increases activation of H+/K+ ATPase, resulting finally in increased gastric acid secretion by the cell.

Caffeine (and theophylline) can freely diffuse into cells and causes intracellular calcium release (independent of extracellular calcium) from the calcium stores in the Endoplasmic Reticulum(ER). This release is only partially blocked by Ryanodine receptor blockade with ryanodine, dantrolene, ruthenium red, and procaine (thus may involve ryanodine receptor and probably some additional calcium channels), but completely abolished after calcium depletion of ER by SERCA inhibitors like Thapsigargin (TG) or cyclopiazonic acid (CPA). [51]. The action of caffeine on the ryanodine receptor may depend on both cytosolic and the luminal ER concentrations of Ca2+. At low millimolar concentration of caffeine, the RyR channel open probability (Po) is significantly increased mostly due to a shortening of the lifetime of the closed state. At concentrations >5 mM, caffeine opens RyRs even at picomolar cytosolic Ca2+ and dramatically increases the open time of the channel so that the calcium release is stronger than even an action potential can generate.

Caffeine amy also directly inhibit delayed rectifier and A-type K+ currents and activate plasmalemmal Ca2+ influx in certain vertebrate and invertebrate neurons.

The metabolites of caffeine contribute to caffeine's effects. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline, the second of the three primary metabolites, acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and efficiency. The third metabolic derivative, paraxanthine, is responsible for an increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used as a source of fuel by the muscles.[52]

Tolerance and withdrawal 编辑

Because caffeine is primarily an antagonist of the central nervous system's receptors for the neurotransmitter adenosine, the bodies of individuals who regularly consume caffeine adapt to the continual presence of the drug by substantially increasing the number of adenosine receptors in the central nervous system. This increase in the number of the adenosine receptors makes the body much more sensitive to adenosine, with two primary consequences.[53] First, the stimulatory effects of caffeine are substantially reduced, a phenomenon known as a tolerance adaptation. Second, because these adaptive responses to caffeine make individuals much more sensitive to adenosine, a reduction in caffeine intake will effectively increase the normal physiological effects of adenosine, resulting in unwelcome withdrawal symptoms in tolerant users.[53]

Because adenosine, in part, serves to regulate blood pressure by causing vasodilation, the increased effects of adenosine cause the blood vessels of the head to dilate, leading to an excess of blood in the head and causing a headache and nausea. Reduced catecholamine activity may cause feelings of fatigue and drowsiness. A reduction in serotonin levels when caffeine use is stopped can cause anxiety, irritability, inability to concentrate and diminished motivation to initiate or to complete daily tasks; in extreme cases it may cause mild depression.

Withdrawal symptoms — possibly including headache, irritability, and an inability to concentrate — may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from one to five days - representing the time required for the number of adenosine receptors in the brain to revert to "normal" levels, uninfluenced by caffeine consumption. Analgesics, such as aspirin, can relieve the pain symptoms, as can a small dose of caffeine.[54] Most effective is a combination of both an analgesic and a small amount of caffeine.

Currently caffeine withdrawal is recognized as meriting further study by the Diagnostic and Statistical Manual of Mental Disorders for DSM-IV, although research demonstrating its clinical significance means that it will likely be included as an Axis-1 disorder in the DSM-V.[55]

Extraction of pure caffeine 编辑

主条目：Decaffeination
 
Anhydrous (dry) USP-grade caffeine

Caffeine extraction is an important industrial process and can be performed using a number of different solvents. Benzene, chloroform, trichloroethylene and dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost and flavor, they have been superseded by the following main methods:

Water extraction 编辑

Coffee beans are soaked in water. The water, which contains not only caffeine but also many other compounds which contribute to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with a good flavor.[56] Coffee manufacturers recover the caffeine and resell it for use in soft drinks and medicines.

Supercritical carbon dioxide extraction 编辑

Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine (as well as many other organic compounds), and is safer than the organic solvents that are used for caffeine extraction. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, CO2 is in a "supercritical" state: it has gaslike properties which allow it to penetrate deep into the beans but also liquid-like properties which dissolve 97-99% of the caffeine. The caffeine-laden CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.[56]

Extraction by nonhazardous organic solvents 编辑

Organic solvents such as ethyl acetate present much less health and environmental hazard than previously used chlorinated and aromatic solvents. The hydrolysis products of ethyl acetate are ethanol and acetic acid, both nonhazardous in small quantities. Another method is to use triglyceride oils obtained from spent coffee grounds.


Pharmacology 编辑

Caffeine is a central nervous system and metabolic stimulant,[57] and is used both recreationally and medically to reduce physical fatigue and restore mental alertness when unusual weakness or drowsiness occurs. Caffeine stimulates the central nervous system first at the higher levels, resulting in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination, and later at the spinal cord level at higher doses.[21] Once inside the body, it has a complex chemistry, and acts through several mechanisms as described below.

Metabolism 编辑

 
Caffeine is metabolized in the liver into three primary metabolites: paraxanthine (84%), theobromine (12%), and theophylline (4%)

Caffeine is completely absorbed by the stomach and small intestine within 45 minutes of ingestion. After ingestion it is distributed throughout all tissues of the body and is eliminated by first-order kinetics.[58]

The half-life of caffeine—the time required for the body to eliminate one-half of the total amount of caffeine consumed at a given time—varies widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. In healthy adults, caffeine's half-life is approximately 3–4 hours. In women taking oral contraceptives this is increased to 5–10 hours,[59] and in pregnant women the half-life is roughly 9–11 hours.[60] Caffeine can accumulate in individuals with severe liver disease when its half-life can increase to 96 hours.[61] In infants and young children, the half-life may be longer than in adults; half-life in a newborn baby may be as long as 30 hours. Other factors such as smoking can shorten caffeine's half-life.[62]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (specifically, the 1A2 isozyme) into three metabolic dimethylxanthines,[63] which each have their own effects on the body:

Each of these metabolites is further metabolized and then excreted in the urine.

Mechanism of action 编辑

 
Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain. They are presented here side by side for comparison.

Caffeine acts through multiple mechanisms involving both action on receptors and channels on the cell membrane, as well as intracellular action on calcium and cAMP pathways. By virtue of its purine structure it can act on some of the same targets as adenosine related nucleosides and nucleotides, like the cell surface P1 GPCRs for adenosine, as well as the intracellular Ryanodine receptor which is the physiological target of cADPR (cyclic ADP ribose), and cAMP-phosphodiesterase (cAMP-PDE). Although the action is agonistic in some cases, it is antagonistic in others. Physiologically, however, caffeine action is unlikely due to increased RyR opening, as it requires plasma concentration above lethal dosage. The action is most likely through adenosine receptors.

Like alcohol, nicotine, and antidepressants, caffeine readily crosses the blood brain barrier. Once in the brain, the principal mode of action of caffeine is as an antagonist of adenosine receptors found in the brain.[64] The caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of cells without activating them (an "antagonist" mechanism of action). Therefore, caffeine acts as a competitive inhibitor. The reduction in adenosine activity results in increased activity of the neurotransmitter dopamine, largely accounting for the stimulatory effects of caffeine. Caffeine can also increase levels of epinephrine/adrenaline,[65] possibly via a different mechanism. Acute usage of caffeine also increases levels of serotonin, causing positive changes in mood.

The inhibition of adenosine may be relevant in its diuretic properties. Because adenosine is known to constrict preferentially the afferent arterioles of the glomerulus, its inhibition may cause vasodilation, with an increase in renal blood flow (RBF) and glomerular filtration rate (GFR). This effect, called competitive inhibition, interrupts a pathway that normally serves to regulate nerve conduction by suppressing post-synaptic potentials. The result is an increase in the levels of epinephrine and norepinephrine/noradrenaline released via the hypothalamic-pituitary-adrenal axis.[66] Epinephrine, the natural endocrine response to a perceived threat, stimulates the sympathetic nervous system, leading to an increased heart rate, blood pressure and blood flow to muscles, a decreased blood flow to the skin and inner organs. Biochemically, it stimulates glycogenolysis, inhibits glycolysis, and stimulates gluconeogenesis to produce more glucose in the muscles and release of glucose into the blood stream from the liver.

Caffeine is also a known competitive inhibitor of the enzyme cAMP-phosphodiesterase (cAMP-PDE), which converts cyclic AMP (cAMP) in cells to its noncyclic form, allowing cAMP to build up in cells. Cyclic AMP participates in activation of Protein Kinase A (PKA) to begin the phosphorylation of specific enzymes used in glucose synthesis. By blocking its removal caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such as amphetamine, methamphetamine, or methylphenidate. Increased concentrations of cAMP in parietal cells causes an increased activation of protein kinase A (PKA) which in turn increases activation of H+/K+ ATPase, resulting finally in increased gastric acid secretion by the cell.

Caffeine (and theophylline) can freely diffuse into cells and causes intracellular calcium release (independent of extracellular calcium) from the calcium stores in the Endoplasmic Reticulum(ER). This release is only partially blocked by Ryanodine receptor blockade with ryanodine, dantrolene, ruthenium red, and procaine (thus may involve ryanodine receptor and probably some additional calcium channels), but completely abolished after calcium depletion of ER by SERCA inhibitors like Thapsigargin (TG) or cyclopiazonic acid (CPA).[67] The action of caffeine on the ryanodine receptor may depend on both cytosolic and the luminal ER concentrations of Ca2+. At low millimolar concentration of caffeine, the RyR channel open probability (Po) is significantly increased mostly due to a shortening of the lifetime of the closed state. At concentrations >5 mM, caffeine opens RyRs even at picomolar cytosolic Ca2+ and dramatically increases the open time of the channel so that the calcium release is stronger than even an action potential can generate. This mode of action of caffeine is probably due to mimicking the action of the physiologic metabolite of NAD called cADPR (cyclic ADP ribose) which has a similar potentiating action on Ryanodine receptors.

Caffeine may also directly inhibit delayed rectifier and A-type K+ currents and activate plasmalemmal Ca2+ influx in certain vertebrate and invertebrate neurons.

The metabolites of caffeine contribute to caffeine's effects. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline, the second of the three primary metabolites, acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and efficiency. The third metabolic derivative, paraxanthine, is responsible for an increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used as a source of fuel by the muscles.[68]

 
Caffeine has a significant effect on spiders, which is reflected in their web construction

Effects when taken in moderation 编辑

The precise amount of caffeine necessary to produce effects varies from person to person depending on body size and degree of tolerance to caffeine. It takes less than an hour for caffeine to begin affecting the body and a mild dose wears off in three to four hours.[21] Consumption of caffeine does not eliminate the need for sleep: it only temporarily reduces the sensation of being tired.

With these effects, caffeine is an ergogenic: increasing the capacity for mental or physical labor. A study conducted in 1979 showed a 7% increase in distance cycled over a period of two hours in subjects who consumed caffeine compared to control tests.[69] Other studies attained much more dramatic results; one particular study of trained runners showed a 44% increase in "race-pace" endurance, as well as a 51% increase in cycling endurance, after a dosage of 9 milligrams of caffeine per kilogram of body weight.[70] The extensive boost shown in the runners is not an isolated case; additional studies have reported similar effects. Another study found 5.5 milligrams of caffeine per kilogram of body mass resulted in subjects cycling 29% longer during high intensity circuits.[71]

Breathing problems in premature infants, apnea of prematurity, are sometimes treated with citrated caffeine, which is available only by prescription in many countries.[72] A reduction in bronchopulmonary dysplasia has been exhibited in premature infants treated with caffeine citrate therapy regimens. The only short term risk associated with this treatment is a temporary reduction in weight gain during the therapy.[73] It is speculated[谁？] that this reduction in bronchopulmonary dysplasia is tied to a reduction in exposure to positive airway pressure.

While relatively safe for humans, caffeine is considerably more toxic to some other animals such as dogs, horses and parrots due to a much poorer ability to metabolize this compound. Caffeine has a much more significant effect on spiders, for example, than most other drugs do.[74] Another substance toxic to dogs, for the same reasons, is theobromine (chocolate).

Tolerance and withdrawal 编辑

Caffeine content of select common food and drugs[75][76]
Product Serving size Caffeine per serving (mg)
Caffeine tablet (regular strength) 1 tablet 100
Caffeine tablet (extra strength) 1 tablet 200
Excedrin tablet 1 tablet 65
Coffee, brewed 240 mL (8 U.S. fl oz) 135*
Coffee, decaffeinated 240 mL (8 U.S. fl oz) 5*
Coffee, espresso 57 mL (2 U.S. fl oz) 100*
Chocolate, Dark (Hershey's Special Dark) 1 bar (43 g; 1.5 oz) 31
Shock-A-Lots (Candy-Coated Chocolate-Covered Coffee Beans) 1 oz. pack 300
Chocolate, Milk (Hershey Bar) 1 bar (43 g; 1.5 oz) 10
Red Bull 250 mL (8.2 U.S. fl oz) 80
Powershot 30 mL (1 U.S. fl oz) 100
Cocaine Energy Drink 250 mL (8.4 U.S. fl oz) 280
Rockstar Energy Drink 473 mL (16 U.S. fl oz) 160
Full Throttle 473 mL (16 U.S. fl oz) 141
Jolt Cola 694 mL (23.5 U.S. fl oz) 150
Bawls Guarana 296 mL (10 U.S. fl oz) 67
Soft drink, Mountain Dew "Dew Fuel" 355 mL (12 U.S. fl oz) 54.5
Soft drink, Coca-Cola Classic 355 mL (12 U.S. fl oz) 34
Alcoholic drink, Buckfast Tonic Wine 750ml (24.6 U.S. fl oz) 281.25
Tea, green 240 mL (8 U.S. fl oz) 15*
Tea, leaf or bag 240 mL (8 U.S. fl oz) 50*
* Estimated average caffeine content per serving. Actual content varies according to preparation.

Because caffeine is primarily an antagonist of the central nervous system's receptors for the neurotransmitter adenosine, the bodies of individuals who regularly consume caffeine adapt to the continual presence of the drug by substantially increasing the number of adenosine receptors in the central nervous system. This increase in the number of the adenosine receptors makes the body much more sensitive to adenosine, with two primary consequences.[53] First, the stimulatory effects of caffeine are substantially reduced, a phenomenon known as a tolerance adaptation. Second, because these adaptive responses to caffeine make individuals much more sensitive to adenosine, a reduction in caffeine intake will effectively increase the normal physiological effects of adenosine, resulting in unwelcome withdrawal symptoms in tolerant users.[53]

Caffeine tolerance develops very quickly, especially among heavy coffee drinkers. Complete tolerance to sleep disruption effects of caffeine develops after consuming 400 mg of caffeine 3 times a day for 7 days. Complete tolerance to subjective effects of caffeine was observed to develop after consuming 300 mg 3 times per day for 18 days, and possibly even earlier.[77] Partial tolerance to caffeine has been observed in all other areas, studies with mice indicate that after a long period of caffeine exposure the learning benefits of caffeine observed earlier cannot be found to any significant level. Considering that 80% to 90% of American adults consume caffeine daily, and their mean daily caffeine intake exceeds 200 mg/day,[78] it can be surmised that a large fraction of the U.S. adult population is completely tolerant to most of the effects of caffeine.

Because adenosine, in part, serves to regulate blood pressure by causing vasodilation, the increased effects of adenosine due to caffeine withdrawal cause the blood vessels of the head to dilate, leading to an excess of blood in the head and causing a headache and nausea. Reduced catecholamine activity may cause feelings of fatigue and drowsiness. A reduction in serotonin levels when caffeine use is stopped can cause anxiety, irritability, inability to concentrate and diminished motivation to initiate or to complete daily tasks; in extreme cases it may cause mild depression. Together, these effects have come to be known as a "crash".[來源請求]

Withdrawal symptoms—possibly including headache, irritability, an inability to concentrate, and stomach aches[79]—may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from one to five days, representing the time required for the number of adenosine receptors in the brain to revert to "normal" levels, uninfluenced by caffeine consumption. Caffeine causes excess release of stomach acids during ingestion.[80] When in withdrawal the stomach acid levels decrease substantially and can cause some stomach aches in certain people.[來源請求] The aches normally last between 24–48 hours and can be confused with constipation.[來源請求] Analgesics, such as aspirin, can relieve the pain symptoms, as can a small dose of caffeine.[81] Most effective is a combination of both an analgesic and a small amount of caffeine.

This is not the only case where caffeine increases the effectiveness of a drug. Caffeine makes pain relievers 40% more effective in relieving headaches and helps the body absorb headache medications more quickly, bringing faster relief.[82] For this reason, many over-the-counter headache drugs include caffeine in their formula. It is also used with ergotamine in the treatment of migraine and cluster headaches as well as to overcome the drowsiness caused by antihistamines.

Overuse 编辑

In large amounts, and especially over extended periods of time, caffeine can lead to a condition known as "caffeinism." Caffeinism usually combines "caffeine dependency" with a wide range of unpleasant physical and mental conditions including nervousness, irritability, anxiety, tremulousness, muscle twitching (hyperreflexia), insomnia, headaches, respiratory alkalosis[83] and heart palpitations.[29] Furthermore, because caffeine increases the production of stomach acid, high usage over time can lead to peptic ulcers, erosive esophagitis, and gastroesophageal reflux disease.[84] However, since both "regular" and decaffeinated coffees have been shown to stimulate the gastric mucosa and increase stomach acid secretion, caffeine is probably not the sole component of coffee responsible.[85]

There are four caffeine-induced psychiatric disorders recognized by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorder not otherwise specified (NOS).

Other side effects of caffeine overuse include: dizziness, tachycardia, blurred vision, drowsiness, dry mouth, flushed dry skin, diuresis, loss of appetite, nausea and stomachaches.[86]

Caffeine intoxication 编辑

An acute overdose of caffeine, usually in excess of 400 milligrams (more than 3–4 cups of brewed coffee), can result in a state of central nervous system overstimulation called caffeine intoxication. Some people seeking caffeine intoxication resort to insufflation (snorting) of caffeine powder, usually finely crushed caffeine tablets. This induces a faster and more intense reaction. The symptoms of caffeine intoxication may include restlessness, nervousness, excitement, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation.引证错误：没有找到与<ref>对应的</ref>标签[87]

In cases of extreme overdose, death can result. The median lethal dose (LD50) of caffeine is 192 milligrams per kilogram in rats.[88] The LD50 of caffeine in humans is dependent on weight and individual sensitivity and estimated to be about 150 to 200 milligrams per kilogram of body mass, roughly 80 to 100 cups of coffee for an average adult taken within a limited timeframe that is dependent on half-life. Though achieving lethal dose with caffeine would be exceptionally difficult with regular coffee, there have been reported deaths from overdosing on caffeine pills, with serious symptoms of overdose requiring hospitalization occurring from as little as 2 grams of caffeine.[89][90][91][92] Death typically occurs due to ventricular fibrillation brought about by effects of caffeine on the cardiovascular system.

Treatment of severe caffeine intoxication is generally supportive, providing treatment of the immediate symptoms, but if the patient has very high serum levels of caffeine then peritoneal dialysis, hemodialysis, or hemofiltration may be required.

Anxiety and sleep disorders 编辑

Long-term overuse of caffeine can elicit a number of psychiatric disturbances. Two such disorders recognized by the American Psychiatric Association (APA) are caffeine-induced sleep disorder and caffeine-induced anxiety disorder.

In the case of caffeine-induced sleep disorder, an individual regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention.[39]

In some individuals, the large amounts of caffeine can induce anxiety severe enough to necessitate clinical attention. This caffeine-induced anxiety disorder can take many forms, from generalized anxiety to panic attacks, obsessive-compulsive symptoms, or even phobic symptoms.[39] Because this condition can mimic organic mental disorders, such as panic disorder, generalized anxiety disorder, bipolar disorder, or even schizophrenia, a number of medical professionals believe caffeine-intoxicated people are routinely misdiagnosed and unnecessarily medicated when the treatment for caffeine-induced psychosis would simply be to withhold further caffeine.[93] A study in the British Journal of Addiction concluded that caffeinism, although infrequently diagnosed, may afflict as many as one person in ten of the population.[94]

Parkinson's disease 编辑

Several large studies have shown that caffeine intake is associated with a reduced risk of developing Parkinson's disease (PD) in men, but studies in women have been inconclusive. The mechanism by which caffeine affects PD remains a mystery. In animal models, researchers have shown that caffeine can prevent the loss of dopamine-producing nerve cells seen in PD, but researchers still do not know how this occurs.[95]

Effects on memory and learning 编辑

An array of studies found that caffeine could induce certain changes in memory and learning. In one study, caffeine was added to rat neurons in vitro. The dendritic spines (a part of the brain cell used in forming connections between neurons) taken from the hippocampus (a part of the brain associated with memory), grew by 33% and new spines formed. After an hour or two, however, these cells returned to their original shape.[96]

Another study showed that subjects — after receiving 100 milligrams of caffeine — had increased activity in brain regions located in the frontal lobe, where a part of the working memory network is located, and the anterior cingulum, a part of the brain that controls attention. The caffeinated subjects also performed better on the memory tasks.[97]

However, a different study showed that caffeine could impair short term memory and increase the likelihood of the tip-of-the-tongue phenomenon. The study allowed the researchers to suggest that caffeine could aid short-term memory when the information to be recalled is related to the current train of thought, but also to hypothesize that caffeine hinders short-term memory when the train of thought is unrelated.[98] In essence, focused thought coupled with caffeine consumption increases mental performance.

Effects on the heart 编辑

Caffeine increases the levels of cAMP in the heart cells, mimicking the effects of epinephrine. cAMP diffuses through the cell and acts as a "secondary messenger," activating protein kinase A (PKA; cAMP- dependent Protein Kinase). This increased PKA activity increases the responsiveness of cardiomyocytes to the calcium currents that control beating.[來源請求]

According to one study, caffeine, in the form of coffee, significantly reduces the risk of heart disease in epidemiological studies. However, the protective effect was found only in participants who were not severely hypertensive (i.e. patients that are not suffering from a very high blood pressure). Furthermore, no significant protective effect was found in participants aged less than 65 years or in cerebrovascular disease mortality for those aged equal or more than 65 years.[99]

Effects on children 编辑

It is commonly believed that caffeine consumption causes stunted growth in children, but this is not supported by scientific research.[100] However, just as with adults, there is legitimate reason to limit the amount consumed by children.[101]

Extraction of pure caffeine 编辑

主条目：Decaffeination
 
Anhydrous (dry) USP-grade caffeine

Pure caffeine is a white powder, and can be extracted from a variety of natural sources. Caffeine extraction is an important industrial process and can be performed using a number of different solvents. Benzene, chloroform, trichloroethylene and dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost and flavor, they have been superseded by the following main methods:

Water extraction 编辑

Coffee beans are soaked in water. The water, which contains not only caffeine but also many other compounds which contribute to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with a good flavor.[56] Coffee manufacturers recover the caffeine and resell it for use in soft drinks and medicines like No-doz.

Supercritical carbon dioxide extraction 编辑

Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine (as well as many other organic compounds), and is safer than the organic solvents that are used for caffeine extraction. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, CO2 is in a "supercritical" state: it has gaslike properties which allow it to penetrate deep into the beans but also liquid-like properties which dissolve 97–99% of the caffeine. The caffeine-laden CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.[56]

Extraction by nonhazardous organic solvents 编辑

Organic solvents such as ethyl acetate present much less health and environmental hazard than previously used chlorinated and aromatic solvents. The hydrolysis products of ethyl acetate are ethanol and acetic acid, both nonhazardous in small quantities. Another method is to use triglyceride oils obtained from spent coffee grounds.



References 编辑

  1. ^ Lovett, Richard. Coffee: The demon drink? (PDF). New Scientist. 24 September 2005, (2518). 
  2. ^ Caffeine Content of Food and Drugs. Nutrition Action Health Newsletter. Center For Science in the Public Interest. December 1996 [2006-08-22]. 
  3. ^ Erowid. Caffeine Content of Beverages, Foods, & Medications. The Vaults of Erowid. July 7 2006 [2006-08-22]. 
  4. ^ Nathanson, JA. Caffeine and related methylxanthines: possible naturally occurring pesticides. Science. 12 October 1984, 226 (4671): 184–7. PMID 6207592. 
  5. ^ Erowid. Does Yerba Maté Contain Caffeine or Mateine?. The Vaults of Erowid. Dec 2003 [2006-08-16]. 
  6. ^ PubChem: mateina. National Library of Medicine. [2006-08-16]. . Generally translated as mateine in articles written in English
  7. ^ PubChem: guaranine. National Library of Medicine. [2006-08-16]. 
  8. ^ 8.0 8.1 Caffeine. International Coffee Organization. [2006-08-21]. 
  9. ^ Caffeine in tea vs. steeping time. September 1996 [2006-08-12]. 
  10. ^ Smit, HJ; Gaffan EA, Rogers PJ. Methylxanthines are the psycho-pharmacologically active constituents of chocolate. Psychopharmacology. 2004 Nov, 176 (3-4): 412–9. 
  11. ^ Haskell, CF; Kennedy D, Wesnes KA, Milne AL, Scholey AB. A double-blind, placebo-controlled, multi-dose evaluation of the acute behavioural effects of guarana in humans. J Psychopharmacol. 13 March 2006, 0 (0): 0–0. PMID 16533867.  ; [Epub ahead of print]
  12. ^ Escohotado, Antonio; Ken Symington. A Brief History of Drugs: From the Stone Age to the Stoned Age. Park Street Press. May 1999. ISBN 978-0-89281-826-6. 
  13. ^ Chow p. 19-20 (Czech edition); also Arcimovicova p. 9, Evans p. 2 and others
  14. ^ Yu, Lu. The Classic of Tea: Origins & Rituals. Ecco Pr; Reissue edition. October 1995. ISBN 978-0-88001-416-8. 
  15. ^ Coffee. Encyclopædia Britannica. 1911. 
  16. ^ Benjamin, LT Jr; Rogers AM, Rosenbaum A. Coca-Cola, caffeine, and mental deficiency: Harry Hollingworth and the Chattanooga trial of 1911. J Hist Behav Sci. 1991 Jan, 27 (1): 42–55. PMID 2010614. 
  17. ^ Jarvis, Gail. The Rise and Fall of Cocaine Cola. May 21 2002 [2006-08-19]. 
  18. ^ Weinberg, BA; BK Bealer. The World of Caffeine. Routledge. January 2001. ISBN 978-0-415-92722-2. 
  19. ^ Whats your poison: caffeine. Australian Broadcasting Corporation. 1997 [2006-08-20]. 
  20. ^ Nehlig, A; Daval JL, Debry G. Caffeine and the central nervous system: Mechanisms of action, biochemical, metabolic, and psychostimulant effects. Brain Res Brain Res Rev. 1992 May-Aug, 17 (2): 139–70. PMID 1356551. 
  21. ^ 21.0 21.1 21.2 21.3 Bolton, Ph.D., Sanford; Gary Null, M.S. Caffeine: Psychological Effects, Use and Abuse. Orthomolecular Psychiatry. 1981, 10 (3): 202–211 [2006-08-12].  引证错误：带有name属性“effects”的<ref>标签用不同内容定义了多次
  22. ^ Ivy, JL; Costill DL, Fink WJ, Lower RW. Influence of caffeine and carbohydrate feedings on endurance performance. Med Sci Sports. 1979 Spring, 11 (1): 6–11. PMID 481158. 
  23. ^ Graham, TE; Spriet, LL. Performance and metabolic responses to a high caffeine dose during prolonged exercise. J Appl Physiol. 1991 Dec, 71 (6): 2292–8. PMID 1778925. 
  24. ^ Trice, I; Haymes, EM. Effects of caffeine ingestion on exercise-induced changes during high-intensity, intermittent exercise. Int J Sport Nutr. Mar 1995, 5 (1): 37–44. PMID 7749424. 
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  50. ^ Fredholm B, Bättig K, Holmén J, Nehlig A, Zvartau E. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use.. Pharmacol Rev. 1999, 51 (1): 83–133. PMID 10049999. Full text
  51. ^ Alexei Verkhratsky Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons Physiol. Rev. 85: 201-279, 2005. doi:10.1152/physrev.00004.2004
  52. ^ Dews, P.B. (1984). "Caffeine: Perspectives from Recent Research". Berlin: Springer-Valerag
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  56. ^ 56.0 56.1 56.2 56.3 Senese, Fred. How is coffee decaffeinated?. General Chemistry Online. 2005-09-20 [2006-08-21]. 
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  58. ^ Newton, R; Broughton LJ, Lind MJ, Morrison PJ, Rogers HJ, Bradbrook ID. Plasma and salivary pharmacokinetics of caffeine in man. European Journal of Clinical Pharmacology. 1981, 21 (1): 45–52. PMID 7333346. 
  59. ^ Meyer, FP; Canzler E, Giers H, Walther H. Time course of inhibition of caffeine elimination in response to the oral depot contraceptive agent Deposiston. Hormonal contraceptives and caffeine elimination. Zentralbl Gynakol. 1991, 113 (6): 297–302. PMID 2058339. 
  60. ^ Ortweiler, W; Simon HU, Splinter FK, Peiker G, Siegert C, Traeger A. Determination of caffeine and metamizole elimination in pregnancy and after delivery as an in vivo method for characterization of various cytochrome p-450 dependent biotransformation reactions. Biomed Biochim Acta. 1985, 44 (7–8): 1189–99. PMID 4084271. 
  61. ^ Bolton, Ph.D., Sanford; Gary Null, M.S. Caffeine: Psychological Effects, Use and Abuse. Orthomolecular Psychiatry. 1981, 10 (3): 202–211 [2006-08-14]. 
  62. ^ Springhouse. Physician's Drug Handbook; 11th edition. Lippincott Williams & Wilkins. January 1 2005. ISBN 978-1-58255-396-2. 
  63. ^ Caffeine. The Pharmacogenetics and Pharmacogenomics Knowledge Base. [2006-08-14]. 
  64. ^ Fisone G, G; Borgkvist A, Usiello A. Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004 Apr, 61 (7–8): 857–72. PMID 15095008. 
  65. ^ Graham T, Rush J, van Soeren M. Caffeine and exercise: metabolism and performance.. Can J Appl Physiol. 1994, 19 (2): 111–38. PMID 8081318. 
  66. ^ Fredholm B, Bättig K, Holmén J, Nehlig A, Zvartau E. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use.. Pharmacol Rev. 1999, 51 (1): 83–133. PMID 10049999. Full text
  67. ^ Verkhratsky A. Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons. Physiol. Rev. 2005, 85 (1): 201–279. doi:10.1152/physrev.00004.2004. 
  68. ^ Dews, P.B. Caffeine: Perspectives from Recent Research. Berlin: Springer-Valerag. 1984. ISBN 978-0387135328. 
  69. ^ Ivy, JL; Costill DL, Fink WJ, Lower RW. Influence of caffeine and carbohydrate feedings on endurance performance. Med Sci Sports. 1979 Spring, 11 (1): 6–11. PMID 481158. 
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  71. ^ Trice, I; Haymes, EM. Effects of caffeine ingestion on exercise-induced changes during high-intensity, intermittent exercise. Int J Sport Nutr. Mar 1995, 5 (1): 37–44. PMID 7749424. 
  72. ^ Caffeine (Systemic). MedlinePlus. 05/25/2000 [2006-08-12]. 
  73. ^ Schmidt, B; Roberts, RS, Davis, P, Doyle, LW, et al. Caffeine therapy for apnea of prematurity. N Engl J Med. May 18 2006, 354 (20): 2112–21. 
  74. ^ Noever, R., J. Cronise, and R. A. Relwani. 1995. Using spider-web patterns to determine toxicity. NASA Tech Briefs 19(4):82. Published in New Scientist magazine, 27 April 1995.
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  89. ^ Kerrigan, S; Lindsey T. Fatal caffeine overdose: two case reports. Forensic Sci Int. 2005, 153 (1): 67–9. 
  90. ^ Holmgren, P; Norden-Pettersson L, Ahlner J. Caffeine fatalities — four case reports. Forensic Sci Int. 2004, 139 (1): 71–3. 
  91. ^ Walsh, I; Wasserman GS, Mestad P, Lanman RC. Near-fatal caffeine intoxication treated with peritoneal dialysis. Pediatr Emerg Care. Dec 1987, 3 (4): 244–9. PMID 3324064. 
  92. ^ Mrvos, RM; Reilly PE, Dean BS, Krenzelok EP. Massive caffeine ingestion resulting in death. Vet Hum Toxicol. Dec 1989, 31 (6): 571–2. PMID 2617841. 
  93. ^ Shannon, MW; Haddad LM, Winchester JF. Clinical Management of Poisoning and Drug Overdose, 3rd ed.. 1998. ISBN 978-0-7216-6409-5. 
  94. ^ James, JE; KP Stirling. Caffeine: A summary of some of the known and suspected deleterious effects of habitual use. British Journal of Addiction. September 1983, 78 (3): 251–8. PMID 6354232. 
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External links 编辑

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Appendix 编辑

Relative content: comparison of different sources 编辑

Caffeine equivalents
In general, each of the following contains approximately 200 milligrams of caffeine:
  • One 200 milligram caffeine pill
  • One and one quarter 16 fluid ounce cans of Monster Energy (590 millilitres)
  • One and a half pounds of milk chocolate (680 grams)
  • Two 8 fluid ounce containers of regular coffee (470 millilitres)
  • Two and a half 10 oz. bottles of Bawls caffeinated drink (740 millilitres)
  • Three standard Excedrin pills
  • Three 8 fluid ounce cups of Red Bull energy drink (710 millilitres)
  • Four 8 fluid ounce cups of Vault energy drink (1.0 litre)
  • Five 1 fluid ounce shots of espresso from robusta beans (150 millilitres)
  • Five 8 fluid ounce cups of black tea (1.2 litres)
  • Five 8 fluid ounce cups of Mountain Dew (1.2 litres)
  • Five 12 fluid ounce cans of typical soda pop (1.8 litres) (variable)
  • Eight and a half 8 fluid ounce cups of Coca-Cola Classic (2.0 litres)
  • Ten 8 fluid ounce cups of green tea (2.4 litres)
  • Fifty 8 fluid ounce cups of decaffeinated coffee (12 litres)
物種（浓至淡）
小果咖啡产地
咖啡主題
化學物質
烘豆咖啡加工
发酵
  • 传统（绿咖啡豆）
  • 猫屎
炒制
研磨
烘豆咖啡冲泡
冲泡咖啡器械
咖啡飲料列表（英语：List of coffee beverages）
咖啡替代品
咖啡與生活

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