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Caffeine
CaffeineCaffeine
一般
系統名稱 1,3,7-三甲基-1H-嘌呤-2,6(3H,7H)-二酮
其他名稱 1,3,7-三甲基黃嘌呤, 三甲基黃嘌呤,
咖啡鹼，茶毒, 馬黛因, 瓜拉納因子,
甲基可可鹼
分子式 C8H10N4O2
SMILES O=C1C2=C(N=CN2C)N(C(=O)N1C)C
摩爾質量 194.19 g mol−1
外觀 無嗅，白色針狀或粉狀固體
CAS號 [58-08-2]
性質
密度和相態 1.2 g/cm³, 固體
水中溶解性 微溶
其他溶劑 乙酸乙酯、氯仿、嘧啶、吡咯、四氫呋喃中可溶；酒精和丙酮中一般可溶；石油醚、醚及苯中微溶
熔點 237 °C
沸點 178 °C (升華)
酸度係數 (pKa) 10.4 (40 °C)
危險性
化學物質安全性表 外部連結
主要危害 吸入、吞咽及皮膚吸收均可能致命。
NFPA 704
0
0
0
 
閃點 N/A
RTECS號 EV6475000
若非註明，所有數據都依從國際單位制和來自標準溫度和壓力條件下。

參考和免責條款

咖啡因是一個黃嘌呤生物鹼化合物，在人體中是一種興奮劑。存在於瓜拉納（guarana）中的咖啡因有時也被稱為瓜拉納因子（guaranine），而存在於瑪黛茶中的被稱為馬黛因（mateine），在茶中的則被稱為茶毒（theine）。它存在於咖啡樹、茶樹、巴拉圭冬青及瓜拿納的果實及葉片裡，少量的咖啡因也存在於可可樹、可樂樹果實及代茶冬青樹。總體上來說，作為一種自然殺蟲劑，在超過60種植物的果實、葉片和種子中能夠發現咖啡因，它能使以這些植物為食的昆蟲麻痹因而達到殺蟲的效果。

咖啡因是一種中樞神經興奮劑，能夠臨時的驅走睡意並恢復精力。有咖啡因成分的咖啡、茶、軟飲料及能量飲料十分暢銷，因此，咖啡因也是世界上最普遍被使用的精神藥品。在北美，90%成年人每天都使用咖啡因.[1] 。

很多咖啡因的自然來源也含有多種其他的黃嘌呤生物鹼，包括強心劑茶鹼和可可鹼以及其他物質例如單寧酸。

來源 編輯

 
烘焙咖啡豆，世界咖啡因的最初來源
常見食品藥品的咖啡因含量[2][3]
產品 計量單位 每單位咖啡因含量 (毫克)
咖啡因片劑 (Vivarin) 1片 200
Excedrin片劑 1片 65
咖啡，釀製 240 mL (8 US fl oz) 135*
咖啡，脫咖啡因 240 mL (8 US fl oz) 5*
咖啡，濃咖啡 57 mL (2 US fl oz) 100*
巧克力，黑 (Hershey's Special Dark) 1條 (43 g; 1.5 oz) 31
巧克力，牛奶 (Hershey Bar) 1條 (43 g; 1.5 oz) 10
紅牛 240 mL (8.2 US fl oz) 80
Bawls瓜拿納 296 mL (10 US fl oz) 67
軟飲料，經典可口可樂 355 mL (12 US fl oz) 34
Atomic Rush 255 mL (7 US fl oz) 100
茶，綠茶 240 mL (8 US fl oz) 15
茶，葉或袋 240 mL (8 US fl oz) 50
* Estimated average caffeine content per serving. Actual content varies according to preparation.

咖啡因是一種植物生物鹼，在許多植物中都能夠被發現。作為自然殺蟲劑，它能使以植物為食的昆蟲麻痹[4]。人類最常使用的含咖啡因的植物包括咖啡、茶及一些可可。其他不經常使用的包括一般被用來制茶或能量飲料的巴拉圭冬青[5]和瓜拿納樹。兩個咖啡因的別名：馬黛因(mateine)[6]和瓜拿納因子(guaranine)[7]就是從這兩種植物演化而來。

世界上最主要的咖啡因來源是咖啡豆（咖啡樹的種子），同時咖啡豆也是咖啡的原料。咖啡中的咖啡因含量極大程度上依賴於咖啡豆的品種和咖啡的製作方法;[8]，甚至同一棵樹上的咖啡豆中的咖啡因含量都有很大的區別。一般來說一杯咖啡中咖啡因的含量從阿拉伯濃縮咖啡中的40毫克到濃咖啡中的100毫克。深焙咖啡一般比淺焙咖啡的咖啡因含量少，因為烘焙能減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鹼，但不含可可鹼。

茶是另外一個咖啡因的重要來源，每杯茶的咖啡因含量一般只有每杯咖啡的一半，決定於制茶的強度。特定品種的茶，例如紅茶和烏龍茶，比其他茶的咖啡因含量高。茶含有少量的可可鹼以及比咖啡略高的茶鹼。茶的製作對於茶有很大影響，但是茶的顏色幾乎不能指示咖啡因的含量.[9]。日本綠茶的咖啡因含量就遠遠高於許多紅茶，例如正山小種茶，幾乎不含咖啡因。

由可可粉制的巧克力也含有少量的咖啡因。巧克力是一種很弱的興奮劑，主要歸因於其中含有的可可鹼和茶鹼.[10]。一條典型的28克牛奶巧克力與脫咖啡因咖啡的咖啡因含量差不多。

咖啡因也是軟飲料中的常見成分，例如可樂，最初就是由可樂樹製得。一瓶軟飲料中一般含有10毫克至50毫克的咖啡因。能量飲料，例如紅牛，每瓶含有80毫克咖啡因。這些飲料中的咖啡因來源於它們所用的原始成分或由脫咖啡因咖啡所得的添加劑，也有是通過化學合成的。瓜拿納，很多能量飲料的基本成分，含有大量的咖啡因及少量的可可鹼。自然存在的緩釋賦形劑中含有少量茶鹼[11]。

歷史 編輯

 
一個為巴勒斯坦的咖啡屋, 大約1900年

早在石器時代[12] ，人類已經開始使用咖啡因。早期的人們發現咀嚼特定植物的種子、樹皮或樹葉有減輕疲勞和提神的功效。直到很多年以後，人們才發現使用熱水泡這些植物能夠增加咖啡因的效用。許多文化都有關於遠古時期的人們發現這些植物的神話。

根據一個古老的蒙古神話，大約公元前3000年的中國皇帝神農氏，在一次偶然的機會下，發現當有的樹葉飄進沸水中會產生一種芳香且提神的飲品[13] 。一本古老的關於茶的著作陸羽《茶經》中也提到了神農氏的名字[14]。

咖啡早期的歷史十分朦朧，不過一個流傳廣泛的神話能讓我們回溯到阿拉伯咖啡的發源地埃塞俄比亞。根據這個神話，一個名叫卡迪的牧羊人發現，當山羊食用了咖啡灌木上的漿果時會變得興奮異常並且在夜裡失眠，山羊也會不斷地再次食用該漿果，體驗相同的活力。最早的有關咖啡的書面記載可能是9世紀波斯醫師al-Razi所著的Bunchum。1587年，Malaye Jaziri匯編了一本追溯咖啡歷史及合法性爭議的書，名叫《Umdat al safwa fi hill al-qahwa》。在這本書中，Jaziri記錄了一個亞丁的伊斯蘭教長Jamal-al-Din al-Dhabhani是首先於1454年飲用咖啡的人，15世紀後，也門的蘇菲派穆斯林開始有規律的飲用咖啡來保持祈禱時的清醒。16世紀快要結束的時候，在埃及的歐洲居民們記錄了咖啡的使用，大概這個時候，咖啡開始在近東廣泛使用。咖啡最為一種飲料在17世紀流傳到歐洲，最初被稱為阿拉伯酒。這段時間，咖啡屋開始增多，最初的咖啡屋是在君士坦丁堡和威尼斯。在英國，第一家咖啡屋開業於1652年，在倫敦Cornhill街聖邁克爾巷。很快咖啡開始在西歐流行並在17和18世紀社會交流中扮演了重要的角色[15]。

就像咖啡漿果和茶葉一樣，可樂樹堅果也有很古老的起源。很多西非的文明通過單獨或群體的咀嚼可樂樹堅果來恢復精力和減輕飢餓。1911年，當美國政府沒收了40大桶和20小桶可口可樂時，可樂成了第一個有記錄的關於健康的恐慌焦點[16]。當年3月13日，美國政府開始了美國對40大桶和20小桶可口可樂，希望通過誇大的宣傳迫使可口可樂將咖啡因從其配方中移除，比如宣傳在一個女子學校，過多的飲用可口可樂導致「夜間荒誕行為，違背學院規則和女性的禮節，甚至不道德。[17] 」儘管法官最後支持了可口可樂，1912年仍然有兩個旨在修正純粹食品與藥品法案的議案被提交眾議院，把咖啡因添加進「上癮」和「有害」的物質清單，必須在產品標籤中列出。

使用可可的最早的證據是從公元前８世紀古瑪雅文明時期的罐中發現的殘渣。在新世界裡，巧克力被混入一種叫Xocoatl得苦辣飲品之中使用，也常伴有香草、辣椒和胭脂。xocoatl被廣泛認為能夠抗疲勞，這大概歸功於其中可可鹼和咖啡因成分。巧克力在哥倫布發現美洲大陸以前的中美洲是一種奢侈品，可可豆也曾被用來作為貨幣。

巧克力在1700年由西班牙人引進歐洲，他們也將可可樹引入了西印度群島和菲律賓。它們被用於鍊金術，叫做黑豆。

1819年，德國化學家Friedrich Ferdinand Runge第一次分離得到純的咖啡因。根據一個傳說，他之所以這樣做是聽了歌德的吩咐[18]。

現在，每年咖啡因的國際銷量已達到120000噸[19]，這個數字相當於每天每個人消耗一份咖啡飲品，這也使它成為了世界最流行的影響精神的物質。在北美，90%的成年人每天消耗一定量的咖啡因。

影響 編輯

 
咖啡因對蜘蛛有很顯著的影響，從蜘蛛網的結構可以反映出來

咖啡因是一個中樞神經系統興奮劑，[20]也是一個新陳代謝的刺激劑。咖啡因既被作為飲品，也被作為藥品，其作用都是提神及解除疲勞。咖啡因能使中樞神經系統興奮，因此能夠增加警覺度，使人警醒，有快速而清晰的思維，增加注意力和保持較好的身體狀態。[21]每個人所需要的能夠產生效果的咖啡因精確劑量並不相同，主要取決於體型和咖啡因耐受度。咖啡因在不到一個小時的時間內就可以開始在身體裡發揮作用，對於一個溫和劑量的咖啡因攝取，在3到4個小時內作用消失[21]。食用咖啡因並不能減少所需睡眠時間，它只能臨時的減弱困的感覺。

因為這些影響，咖啡因是一個機能增進劑：提升大腦和身體的能力。一項在1979年的研究表明，與對照組相比，攝取了咖啡因之後的運動員在長距離自行車項目中的表現增加7%[22]。其他的研究獲得了更加顯著的結果：一個對經過訓練的跑步運動員的實驗表明，在攝取一劑9毫克每千克體重的咖啡因之後，運動員的直線跑耐久性增加44%，環形跑耐久力增加55%。[23] 如此顯著的提升並不是孤立的偶然情況，一些後續的研究也得到相似的結果。另外一個研究表明，在攝取了5.5毫克每千克體重咖啡因之後，在自行車項目中，能夠提升29%的持續時間[24]。

咖啡因有時也與其他藥物混合提高它們的功效。咖啡因能夠使減輕頭痛的藥的功效提高40%，並能使身體更快的吸收這些藥品縮短起作用的時間[25]。因此，很多非處方治療頭痛的藥品中包含有咖啡因。咖啡因也與麥角胺一起使用，治療偏頭痛和集束性頭痛，也能克服由抗組胺劑帶來的困意。

早產嬰兒的呼吸問題，有時也使用檸檬酸咖啡因治療。使用檸檬酸咖啡因療法後，早產嬰兒的支氣管發育不良明顯減少。此療法的唯一缺點是在治療中暫時性的體重增長變慢.[26]。檸檬酸咖啡因在很多國家只能通過處方獲得.[27]。

對人類而言，咖啡因是安全的，但是咖啡因對某些動物而言確是有毒性的，例如狗，馬和鸚鵡，因為這些動物分解咖啡因的能力比人類弱很多。咖啡因對蜘蛛有顯著的影響，遠遠高於其他藥物[28]。


過度使用 編輯

 
在短時間內過多的咖啡因可以導致上癮和一系列的身體與心理的不良反應

在長期攝取的情況下，大劑量的咖啡因是一種毒品，能夠導致「咖啡因中毒」。咖啡因中毒包括上癮和一系列的身體與心理的不良反應，比如神經過敏，易怒，焦慮，震顫，肌肉抽搐（反射亢進），失眠和心悸[29] （在嚴格的上癮的定義下，只有逐漸增高用量才是上癮，用咖啡因依賴描述更為恰當一些，但是在一個被廣泛接受的定義下，所有慢性的很難擺脫的行為都叫做上癮，所以也可以用咖啡因上癮來描述。）另外，由於咖啡因能使胃酸增多，持續的高劑量攝入會導致消化性潰瘍，糜爛性食道炎和胃食管反流病[30]。然而，因為無論是正常的咖啡還是脫咖啡因咖啡，都會刺激胃粘膜，增加胃酸分泌，所以咖啡因可能不是咖啡唯一的成分[31]。

四個被精神疾病診斷與統計手冊（第四版）所驗證的有咖啡因引起的精神紊亂包括咖啡因過度輕奮、咖啡因焦慮症、咖啡因睡眠失調及其他咖啡因相關紊亂。

咖啡因過度輕奮 編輯

一個急劇的過量咖啡因，通常超過250毫克（相當於2-3杯煮咖啡）就能夠導致中樞神經系統過度興奮，也就是咖啡因過度輕奮。咖啡因過度輕奮的症狀包括：煩躁，神經過敏，興奮，失眠，臉紅，尿液增加，胃腸紊亂，肌肉抽搐，思維渙散，心跳不規則或過快以及躁動[29][32][33]。

攝取極大劑量的咖啡因會導致死亡[34] 。對於實驗鼠，咖啡因的半數致死量為192毫克每千克體重。咖啡因半數致死量取決於體重和個人敏感程度，大概是150至200毫克每千克體重，大約是一個普通成年人在一個有限的時間內攝取140至180杯咖啡，時間取決於生物半衰期。儘管飲用普通咖啡幾乎不可能致死，但有由於過度服用咖啡因藥丸致死的報告[35][36][37][38]。

對於咖啡因過度輕奮的治療通常是輔助性的，即對個別的症狀進行相應的治療。但是如果患者的血清咖啡因濃度過高，則有可能採取腹膜透析、血液透析和血液濾過等方法。

咖啡因焦慮症及睡眠失調 編輯

長期的過度攝取咖啡因會引起一系列的精神紊亂。其中兩種被美國精神病學協會驗證的是咖啡因焦慮症和咖啡因睡眠失調。

咖啡因睡眠失調是指由一個個體有規律的攝取高劑量的咖啡因所導致的他或她的睡眠紊亂，並且能被臨床診斷所發現[39]。

對某些個體而言，大劑量的咖啡飲所導致的焦慮足夠被臨床診斷發現。咖啡因焦慮症會以不同的形式出現，一般性焦慮失調，恐慌發作，強迫症甚至是恐怖症[39]。因為這些症狀容易與基本神經失調混淆，比如恐慌失調，一般性焦慮失調，躁鬱症或甚至是精神分裂症，所以一些醫務工作者認為部分咖啡因攝入過量的人被誤診並給予了不必要的治療，他們認為咖啡因誘發的精神疾病可以通過切斷咖啡因來源而很簡單的控制[40] 。一個由不列顛上癮期刊（British Journal of Addiction）所作的調查表明，雖然很少被診斷出，咖啡因慢性中毒至少困擾了十分之一的總人口[41]。


藥理學 編輯

新陳代謝 編輯

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

咖啡因在45分鐘內，在胃和小腸中被完全消化。攝取後，咖啡因分散於全身所有的組織之中，最終按一級反應速率排除。[42]

咖啡因的生物半衰期是指身體消除攝入咖啡因總量一半所需要用的時間，這個時間隨着個體的變化而大幅的變化，主要因素有年齡、肝功能、懷孕與否、同時攝入的藥物以及肝中咖啡因代謝所需的酶的數量。對於一個健康的成年人來說，咖啡因的半衰期大概是3-4個小時。對於服用口服避孕藥的女性，這個時間會增加至5-10個小時。[43]對於懷孕的女性，咖啡因的生物半衰期則為9-11個小時。[44]咖啡因能夠在有着嚴重肝臟疾病的人體內積聚，半衰期能夠達到96個小時。[45]在嬰兒和小孩的體內，其生物半衰期比在成年人體內長；在新生因而體內甚至能夠達到30個小時。其他的因素例如吸煙能夠縮短咖啡因的半衰期。[46]

咖啡因的新陳代謝發生在肝臟，由P450細胞色素氧化酶系統將其代謝為三個代謝產物黃嘌呤，[47] 它們對於身體有着不同的影響：

這些代謝產物還會經過最終的代謝，最後通過尿液排出體外。

作用機理 編輯

 
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 編輯

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 編輯

主條目：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 編輯

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 編輯

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 編輯

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 編輯

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 編輯

 
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 編輯

 
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 編輯

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[誰？] 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 編輯

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 編輯

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 編輯

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.引用錯誤：沒有找到與<ref>對應的</ref>標籤[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 編輯

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 編輯

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 編輯

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 編輯

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 編輯

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 編輯

主條目：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 編輯

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 編輯

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 編輯

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 編輯

  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]. 
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  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]
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  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
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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]. 
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  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. 
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  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. 
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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. 
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  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. 
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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. 
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  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. 
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External links 編輯

 
查看維基詞典中的詞條「test」。

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Appendix 編輯

Relative content: comparison of different sources 編輯

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（濃至淡）
小果咖啡產地
咖啡主題
化學物質
烘豆咖啡加工
發酵
  • 傳統（綠咖啡豆）
  • 貓屎
炒制
研磨
烘豆咖啡沖泡
沖泡咖啡器械
咖啡飲料列表（英語：List of coffee beverages）
咖啡替代品
咖啡與生活

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