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苯丙胺

(重定向自安非他命

安非他命(英文名稱:Amphetamine[note 1]为一种中樞神經興奮劑,用來治療注意力不足過動症嗜睡症、和肥胖症。“Amphetamine”一名擷取自 alphamethylphenethylamine

安非他命(Amfetamine) (INN)
An image of the amphetamine compound
A 3d image of the D-amphetamine compound
系统(IUPAC)命名名称
(RS)-1-phenylpropan-2-amine
临床数据
读音 聆聽i/æmˈfɛtəmn/
Drugs.com amphetamine
医疗法规
妊娠分级
  • US: C (不排除有风险的可能)
依赖性 生理依賴: 無
心理依賴: 中等
成瘾性 中等
给药途径 醫用: 口服给药, 鼻腔給藥, 靜脈注射[1]
非醫療用(Recreational): 口服给药, 鼻腔給藥, Insufflation (medicine)英语Insufflation (medicine), 栓剂, 靜脈注射
合法狀態
合法状态
药代动力学数据
生物利用度 口服 75–100%[2]
蛋白结合度 15–40%[3]
代谢 Amphetamine only:
CYP2D6,[4] Dopamine β-hydroxylase,[5][6][7] Flavin-containing monooxygenase英语Flavin-containing monooxygenase[5][8][9]
代谢产物 4-hydroxyamphetamine英语4-hydroxyamphetamine, 4-hydroxynorephedrine英语4-hydroxynorephedrine, 4-hydroxyphenylacetone英语4-hydroxyphenylacetone, 苯甲酸, 馬尿酸, 苯丙醇胺, 苯基丙酮[4][10][11]
起效

IR dosing: 30–60 minutes[12]
XR dosing: 1.5–2 hours[13]

[14]
生物半衰期 D-amph:9–11 hours[4][15]
L-amph:11–14 hours[4][15]
PH值-dependent: 8–31 hours[16]
作用时间

IR dosing: 3–7 hours[13][17]
XR dosing: 12 hours[13] [14]

[17]
排泄 Primarily ;
PH值-dependent range: 1–75%[4]
识别信息
CAS注册号 300-62-9 ✓
ATC代码 N06BA01
PubChem CID 3007
IUPHAR/BPS英语IUPHAR/BPS 4804
DrugBank DB00182 ✓
ChemSpider 13852819 ✓
UNII CK833KGX7E ✓
KEGG D07445 ✓
ChEBI CHEBI:2679 ✓
ChEMBL英语ChEMBL CHEMBL405 ✓
NIAID ChemDB英语NIAID ChemDB 018564
其他名称 α-methylphenethylamine
PDB配体ID FRD (PDBe, RCSB PDB)
化学信息
化学式 C9H13N
摩尔质量 135.20622 g/mol[18]
物理性质
密度 0.9±0.1 g/cm3
熔点 11.3 °C(52.3 °F) (predicted)[19]
沸点 203 °C(397 °F) at 760 毫米汞柱[20]
  (verify)

安非他命於西元1887年被發現,以兩種對映異構體的形式存在[note 2] ,分別是左旋安非他命右旋安非他命

准确来说,安非他命指的是特定的化學物質-外消旋純胺類型態英语free base[24][25],這個物質等同於安非他命的的兩個對映異構體:左旋安非他命右旋安非他命的等比化合物之純胺類型態。 然而,實際上安非他命一詞已被廣泛的用來表示任何由安非他命對映異構體構成的物質或安非他命對映異構體本身。[21][26][25]

安非他命是一种中樞神經興奮劑,適度適量地使用能提升整體抑制控制能力[27][28]。在醫療用的劑量範圍內,安非他命能帶來情緒以及執行功能的變化,例如:欣快感的增强、性欲的改變、清醒度的提升、大腦執行功能的進化。安非他命所改變的生理反應包含:減少反應時間、降低疲勞、以及肌耐力的增強。然而,若攝取劑量远超过醫療用的劑量範圍,將會導致大腦執行功能受損以及橫紋肌溶解症。 攝取過份超越醫療用劑量範圍的安非他命可引发嚴重的藥物成癮。然而長期攝取醫療劑量範圍的安非他命並不會產生上癮的風險。

此外,服用远超醫療用劑量範圍的安非他命會引起精神疾病(例如:妄想[參 1]、偏執[參 2])。然而長期攝取醫療劑量範圍的安非他命並不會引起上述疾病。

那些为享乐而摄入的安非他命通常会遠超過醫療用劑量範圍,且伴隨著非常嚴重甚至致命的副作用。 [sources 1]

历史上,安非他命也曾被用來治療鼻塞nasal congestion)和抑鬱

安非他命也被用來提升表現英语performance-enhancing substance促進大腦的認知功能及在助興時(非醫療用途情況下)被作為增強性慾[a]、和欣快感促進劑

安非他命在許多國家為合法的處方藥[參 3]。然而,私自散布和囤積安非他命被視為非法行為,因為安非他命被用於非醫療用途的助興可能性極高。[sources 2]

首個藥用安非他命的藥品名稱為Benzedrine。當今藥用安非他命英语#Pharmaceutical products[參 4]以下列幾種形式存在:外消旋安非他命[參 5]Adderall英语Adderall [note 3]。 、dextroamphetamine、或對人體無藥效的前驅藥物體[參 6]lisdexamfetamine

安非他命藉著自身作用於兒茶酚胺神經傳導元素:正腎上腺素多巴胺的特點來活化trace amine receptor英语TAAR1 ,進而增加单胺类神经递质神经递质(excitatory neurotransmitter)在腦內的活動。[sources 3]

安非他命屬於替代性苯乙胺英语substituted phenethylamine類的物質。由安非他命衍伸出的物質被歸納在替代性苯乙胺英语substituted phenethylamine[參 7]的分類中[note 4],比如說:安非他酮[參 8]cathinone英语cathinoneMDMA、 和 甲基苯丙胺[參 9]。安非他命也與人體內可自然生成的兩個屬於痕量胺的神經傳導物質--特別是 苯乙胺(phenethylamine) 和 N-Methylphenethylamine英语N-Methylphenethylamine--有關。 Phenethylamine 是安非他命的原始化合物,而N-methylphenethylamine則是安非他命的位置異構體(只有在甲基族中才會區分出此位置異構體)。[sources 4]

目录

用途编辑

醫療编辑

安非他命是用來治療注意力不足過動症(ADHD)、嗜睡症(一種睡眠疾病)、和肥胖症。有時候安非他命會以仿單標示外使用英语off-label use的方式處方來治療頑固性憂鬱症英语treatment-resistant depression頑固性強迫症[1][15] [43] [50]。 在動物試驗中,已知非常高劑量的安非他命會造成某些動物的多巴胺系統英语dopamine receptor和神經系統的受損。[51][52] 但是,在人體試驗中,注意力不足過動症患者在接受安非他命的治療後,則發現安非他命可促進大腦的發育及神經的成長。[53][54][55]

回顧許多核磁共振照影(MRI)的研究後發現,長期以安非他命治療注意力不足過動症患者能顯著降低患者大腦結構及大腦執行功能上的異常。並且優化大腦中數個部位,例如:基底神經節的右尾狀核[53][54][55]


眾多臨床研究的系統性及統合性回顧已確立長期使用安非他命治療注意力不足過動症的療效及安全。[56][57][58][59]

持續長達兩年的隨機對照試驗[參 10][b]結果顯示:長期使用安非他命治療注意力不足過動症,是有效且安全的。[56][59]

兩個系統性/統合性回顧的結果顯示長期且持續地使用中樞神經興奮劑治療注意力不足過動症能有效地減少注意力不足過動症的核心症狀(核心症狀即為:過動、衝動和分心/無法專心)、增進生活品質、提升學業成就、廣泛地強化大腦的執行功能。[note 5] 這些執行功能分別與下列項目有關:學業、反社會行為、駕駛習慣、藥物濫用、肥胖、職業、日常活動、自尊心、服務使用(例如:學習、職業、健康、財金、和法律等)、社交功能。[57][59]

一篇系統性/統合性回顧標誌了一個重要發現:一個為期九個月的隨機雙盲試驗中,持續以安非他命治療的ADHD患者,其智力商數平均增加4.5單位[註 1],且在專注力、衝動、過動的改善皆呈現持續進步的態勢。[56] 另一篇系統性/統合性回顧則指出:根據迄今為止為時最長的數個臨床追蹤研究[參 11],可以得到一個結論:即便從兒童時期開始以中樞神經興奮劑治療直到老年,中樞神經興奮劑都能持續有效地控制ADHD的症狀並且減少物質濫用的風險。[59] 研究表明,ADHD與大腦的執行功能受損有關。而這些受損的執行功能分別與大腦中部分的神經傳導系統英语neurostransmitter systems有關[參 12][60] ;又此部分受損的神經傳導系統和中腦皮質激素英语mesocorticolimbic projection-多巴胺[參 13]的傳導及藍斑核[參 14]前額葉[參 15]中的正腎上腺素[參 16]的傳導相關。[60]

中樞神經興奮劑,例如:methylphenidate和安非他命對於治療ADHD都是有效的,因為中樞神經興奮劑刺激了上述神經系統中的神經傳導物質活動。[29][60] [61]

至少超過80%的ADHD患者在使用中樞神經興奮劑治療後,其ADHD的症狀可以獲得改善。[62]

使用中樞神經興奮劑治療的ADHD患者相較之下,普遍與同儕及家庭成員的關係較佳並且在學校擁有較好的表現。興奮劑能使ADHD患者較不易分心、衝動、且擁有較長的專注力時間和範圍。[63] [64]

根據考科藍協作組織[參 17]所提供的文獻回顧結果[note 6]指出:使用中樞神經興奮劑治療的ADHD患者即便其症狀改善,相較於使用非中樞神經興奮劑,仍因副作用而有較高的停藥率。[66] [67]

回顧結果也發現,中樞神經興奮劑並不會惡化抽動綜合症的症狀,例如:妥瑞氏症,除非服用dextroamphetamine[c]的劑量過高才有可能在部分妥瑞氏症合併注意力不足過動症患者身上觀察到抽動綜合症的症狀惡化。[68]

中樞神經興奮劑只要依照醫師指示用藥,都是相當安全的。[69][70][70][71] 中樞神經興奮劑,例如:利他能與專思達,可能導致:心悸、頭痛、胃痛、喪失食慾、失眠、因相對專注而變得冷淡(面無表情)等副作用,因此6歲以下的兒童不適宜服用。(副作用產生與否因人而異) [72]

隨著時間推進與各方的努力,中樞神經興奮劑的相關副作用已可藉由包括但不限於劑量調整、服藥時間、飯前飯後服用、服藥頻率等服藥模式之改變以及改變藥物組合等方式獲得相當程度的減少。[73] [74] [75] [70] [76]

提昇表現编辑

認知方面(Cognitive)

西元2015年中,一篇系統性回顧[參 18]和一篇元分析/整合分析[參 19]回顧了數篇優秀的臨床試驗[參 20]報告後發現, 低劑量(醫療用劑量)的安非他命能適度但不強烈地促進一個人的認知功能,包含工作記憶(working memory)、長期的情節記憶(episodic memory)、抑制控制以及在一些方面的注意力(attention)。 [77] [78] 安非他命強化認知功能的效果已知是部分透過間接活化英语indirect agonist在大腦前額葉(prefrontal cortex)的dopamine receptor D1英语dopamine receptor D1adrenoceptor α2英语Alpha-2 adrenergic receptor[29] [77] 一篇2014年的系統性回顧發現低劑量(醫療用劑量)的安非他命能促進和穩固記憶的形成以及記憶品質英语memory consolidation(memory consolidation),進而提升一個人的回憶(recall of information)的能力。 [79] 低劑量(醫療用劑量)的安非他命也可增加大腦皮層(質)區的效率,這能讓一個人的工作記憶(working memory)獲得進步。 [29] [80] 安非他命和其他用於治療ADHD的中樞神經刺激劑能透過提升task saliency英语Incentive salience來增加一個人去做事情的動機、並強化一個人的警覺心(清醒度),因而能刺激一個人開始做「以目標為導向」的行為。 [29] [81] [82] 中樞神經興奮劑(例如:安非他命)能提升一個人在困難且枯燥的任務中的表現。 [29] [82] [83] 超過醫療用劑量範圍(包含其誤差範圍及容許最大上限)的安非他命劑量將不利於工作記憶(working memory)和其他的認知功能。 [29][82]

生理(physical)

雖然安非他命可以提升速度、耐力(延遲疲勞的發生)、肌耐力、身體素質和警覺心並減少心理反應時間[30][34] [30] [84] [85] 然而,「非因醫療需求使用安非他命」在各種運動場合都是被嚴格禁止的。[86] [87]

安非他命藉由抑制多巴胺在中樞神經系統中的回收及外流來促進耐力和反應時間的提升。 [84][85] [88] 安非他命和其他作用於多巴胺系統的藥物一樣,都能增加在固定施力(levels of perceived exertion英语rating of perceived exertion)下的動力(能)輸出。這是因為安非他命能奪取(override)體溫的「安全開關」的控制權並將身體核心溫度(core temperature limit)的上限提高以取得在體溫安全上限提高前被身體保留的能量。 [85] [89] [90] 於醫療用劑量範圍(包含其誤差範圍),安非他命的副作用不至於影響運動員的運動表現; [30][84] 然而,當攝取的劑量過多時,安非他命可能會引起嚴重的後果,例如:橫紋肌溶解症體溫過高英语hyperthermia(hyperthermia)。 [31][33] [84]

醫療上的禁忌编辑

根據國際化學品安全規劃署(IPCS, International Programme on Chemical Safety)和美國食品藥物管理局 (USFDA), [note 7] 安非他命不建議處方給有藥物濫用心血管疾病、對於各種刺激嚴重反應過度、和嚴重焦慮歷史的人。 [note 8][92][93] 安非他命也不被建議處方給正經歷動脈血管硬化(血管硬化)、中度到重度高血壓青光眼(眼壓過高)、或甲狀腺機能亢進(身體在體內製造出過量的甲狀腺 賀爾蒙/激素)的人。 [92][93][94] 曾對中樞神經刺激劑藥物過敏的人以及正在服用單胺氧化酶抑制劑 (MAOI)或單胺氧化酶抑制劑類藥物 (MAOIs),可能不適合使用安非他命。即便曾有合併使用安非他命和單胺氧化酶抑制劑後仍一切平安的案例。 [92][93] [95][96]

IPCS和美國食品藥物管理局也同意患有神經性厭食症(anorexia nervosa)、雙極性情感疾患(bipolar disorder)、憂鬱高血壓狂躁(mania)、思覺失調症Raynaud's phenomenon英语Raynaud's phenomenon心臟病發(seizures)、抽動綜合症(tics)、妥瑞氏症(Tourette's disease)、和有甲狀腺問題、問題的人在使用安非他命時應密切追蹤上述疾病的變化。 [92][93]

人體試驗證明,醫療用劑量下的安非他命並不會導致胎兒或新生兒畸形(i.e., it is not a human teratogen)。然而超越醫療用劑量甚多的安非他命確實會增加胎兒或新生兒畸形的機會。 [93]

研究觀察發現,安非他命會進入母親的母乳中,因此建議母親不要在使用安非他命藥物的期間內授乳。 [92][93]

由於安非他命可能影響食慾繼而導致可反轉的身高及體重的成長遲緩, [note 9] ,因此建議兒童或青少年在用藥期間定期測量自己的身高及體重。 [92]

副作用编辑

安非他命的副作用以及其發生率和嚴重度大致上與使用的劑量呈正相關。[34] [31][33][34] 成分為安非他命的藥品,諸如:Adderall英语Adderall、 Dexedrine、和安非他命的等價英语equivalent物質(generic equivalents)目前皆已獲得美國食品藥物管理署(USFDA)許可用於長期性的治療。 [44][33]

攝取大幅超出醫療劑量的安非他命將大幅增加嚴重副作用出現的風險。[34]

{{#ifeq:Side effects|Side effects|

生理编辑

在治療劑量下,生理副作用會因年齡或個人情況而有所不同[33]心血管方面的副作用包含:迷走-血管反射英语vasovagal response導致的高血壓或是低血壓雷諾氏症英语Raynaud's phenomenon(Raynaud's phenomenon)(因小動脈收縮而導致流往手腳的血流減少)、以及心搏過速(tachycardia)。[33][34][97]

男性性方面而言,副作用可能包含:勃起障礙、頻繁勃起、或是勃起時間過長英语prolonged erections(prolonged erections)。 [33]

消化方面的副作用可能包含:腹痛喪失胃口(appetite loss)、反胃(nausea)以及體重降低(weight loss)。[33][98] 其他潛在的副作用包含:視覺模糊(blurred vision)、口乾(dry mouth)、磨牙(excessive grinding of the teeth)、流鼻血(nosebleed)、多汗(profuse sweating)、藥物性鼻炎(rhinitis medicamentosa,藥物導致的鼻塞)、癲癇閾值/觸發門檻降低(seizure threshold),以及抽搐(tics)[sources 5]。在一般的治療劑量下鮮少發生危險副作用[34]

安非他命刺激延腦的呼吸中樞英语Respiratory center(medullary respiratory centers),使得呼吸變得較快速且較深。[34] 正常人在治療劑量下,此作用通常難以察覺;然而,此作用在呼吸已經受損的病人身上有可能變得明顯。[34]

安非他命會使膀胱括約肌收縮(bladder sphincter,控制排尿的肌肉之一)收縮(contraction),而導致解尿困難[34]。此效果可以應用在夜尿英语enuresis(bed wetting)或是失去膀胱控制能力的病人身上。[34]

安非它命在胃腸道的作用是難以預測的[34]。安非他命可能會減少胃腸活動力英语gastrointestinal motility(內容物通過腸胃道的速率)[34];然而,安非他命亦可能在胃腸道的平滑肌(smooth muscle)處於鬆弛狀態時,增加其活動力。[34]

安非他命有輕微的止痛作用(analgesic effect)且可以增強鴉片類物質的止痛作用。[34]

美國食藥署2011年委任的研究發現:不論是小孩或是成人,「安非他命(於醫療情境下使用)」和「其他用於治療ADHD的中樞神經興奮劑」均和重大的心血管疾病(猝死心臟病發中風)無關[sources 6];然而,當病患已有心血管方面的疾病時,禁用此藥。[sources 7]

心理编辑

嚴重過量编辑

安非他命過量使用會引起許多症狀,然而在適當的醫療照護下,不至於死亡。 [93][104]

藥物過量症狀的嚴重度與劑量成正比;與身體對安非他命的藥物耐受性成反比。 [34][93] 已知每天攝取達到5公克的安非他命(每天最大攝取量的五十倍)會導致身體對安非他命產生藥物耐受性。 [93] 嚴重過量的安非他命攝取所致的症狀列於下方;安非他命中毒一旦到達出現全身抽蓄(convulsion)和昏厥(coma)則必須立刻急救以避免死亡。 [31][34] 在2013年,安非他命、甲基安非他命和其他列於ICD-10 第五章:精神和行為障礙§使用化學藥物、物質或酒精引起的精神和行為障礙中的安非他命相關物質的過量使用在世界上共導致3788人死亡。(3,425–4,145 人死亡、  95% 信賴區間)。 [note 10][105]

被過度活化達到病態程度的mesolimbic pathway英语mesolimbic pathway(一個連接腹側被蓋區(ventral tegmental area)和伏隔核(nucleus accumbens)的多巴胺通道英语dopamine pathway),在安非他命的成癮中扮演著主要的腳色。 [106] [107]

當一個人經常服用嚴重過量的安非他命,將伴隨安非他命成癮的高度風險, 因為持續過量的安非他命會逐漸增加伏隔核ΔFosB(「成癮」與否的分子開關和主控蛋白 原文:a "molecular switch" and "master control protein" for addiction.)的檔次。 [108][109][110] 一旦伏隔核的ΔFosB破表(over-expressed),這個人的「成癮性行為」[註 2](例如:出現試圖取得安非他命的衝動行為)將開始隨之增加。 [108][111] 雖然目前沒有治療安非他命成癮的有效藥物,但規律的且每次都有持續一定時間的有氧運動能降低安非他命的成癮風險也是治療安非他命成癮的天然療法。 [112][113] [sources 8] 運動能提升臨床治療英语clinical therapy預後,且可能與認知行為治療(目前已知最有效的安非他命成癮的臨床治療法)相搭配為联合疗法(combination therapy)。 [112][114][115]

嚴重過量的安非他命劑量所致的症狀(依照體內生物系統分類)Overdose symptoms by system
生物系統 輕度、中度過量[31][34][93] 重度過量[sources 9]
心臟血管系統
中樞神經系統
肌肉骨骼系统
呼吸系統
  • 呼吸過速
生殖泌尿系統
(Urogenital system)
其他(Other)

成癮编辑

「成癮及生理、心理依賴」的相關術語詞彙表[117][109][118][119]
成瘾(addiction):腦部失調英语brain disorder的情形,特徵是會強迫性的接觸犒赏刺激英语Stimulus (psychology),不去考慮其帶來的負面結果。
成瘾行为英语addictive behavior(addictive behavior):具有犒赏性及正向增強效應的行為
成瘾药物(addictive drug):具有犒赏性及正向增強效應的藥物
依赖性(dependence):之前曾頻繁接觸刺激源(例如藥物攝取),中斷接觸後出現戒斷症狀的情形
药物敏化(drug sensitization)或逆耐药性(reverse tolerance):在固定藥物劑量的情形下重複給藥,而相同劑量的藥物效果增強的情形
藥物戒斷(drug withdrawal):在重複藥物使用後停藥,出現的症狀
生理依赖(physical dependence):出現持續生理戒斷症狀(例如疲勞及震顫性譫妄)的依赖性
精神依赖(psychological dependence):出現情緒或是精神戒斷症狀(例如煩躁失乐)的依赖性
增强刺激(reinforcing stimuli):特定類型的刺激,接觸後會增加再接觸此刺激的可能性
犒赏刺激(rewarding stimuli):特定類型的刺激,大腦會認為此刺激是正向的,會想再進行的
敏化作用(sensitization):重複接受某一刺激後產生的刺激增強性反應
物質使用疾患 (substance use disorder):使用特定物質,而且造成臨床上或是功能上的損傷或是困境的情形
藥物耐受性(drug tolerance):重複接受某一藥物後產生的藥物降低性反應
 ·  ·  ·
造成安非他命成癮的位於伏隔核中的訊息傳遞
·
 
Note: colored text contains article links.
AMPAR英语AMPA receptor
Gs英语Gs alpha subunit
Gi/o英语Gi alpha subunit
ΔFosB英语ΔFosB
JunD英语JunD
c-Fos英语c-Fos
SIRT1英语Sirtuin 1
本圖表描繪(depicts)在Mesolimbic pathway英语Mesolimbic pathway中由於「長期攝取超高劑量的中樞神經刺激劑(例如:安非他命甲基苯丙胺、和苯乙胺.)使得多巴胺的神經突觸的濃度增加」的微觀示意圖。[d]

註:專業內容暫時保留原文

Following presynaptic dopamine and glutamate co-release英语cotransmission by such psychostimulants,[120][121] postsynaptic receptors英语Neurotransmitter receptor for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway英语cAMP-dependent pathway and a calcium-dependent pathway英语Calcium signaling that ultimately result in increased CREB phosphorylation.[120][122][123] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressor英语corepressors;[120][124][125] c-Fos repression英语gene repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[126] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[124][125] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[124][125]  

長期服用遠超醫療用劑量範圍的安非他命會導致安非他命成癮(Addiction)。然而長期攝取醫療劑量範圍的安非他命並不會引起上述問題。 [37][38][39] 安非他命濫用(例如:長期攝取嚴重過量的安非他命)會導致大腦對於該劑量產生藥物耐受性。漸漸地,濫用者必須服用更大量的安非他命以換取同樣的效果。 [127][128]

分子生物機轉(Biomolecular mechanisms)编辑

當前關於「長期安非他命濫用所致的成癮」的模型(model)中,已知會改變一些腦部的結構(特別是伏隔核[129][130][131]。 造成腦部結構改變的最重要的轉錄因子(transcription factor)為:ΔFosBcAMP response element binding protein (CREB英语cAMP response element binding protein)、和 nuclear factor kappa B (NF-κB)。 [note 11] [130] ΔFosB 在藥物成癮的發展過程中扮演著至關重要的角色,主要的原因在於其在伏隔核中D1-type英语D1-type medium spiny neuron英语medium spiny neuron的破表(over-expression),為「成癮」及「成癮衍生的行為」及「神經元為了適應新常態所做的調適」的充分且必要條件[note 12] [108][109][130]

一旦ΔFosB充分破表(sufficiently overexpressed),將誘發越來越嚴重的成癮狀態並伴隨ΔFosB值的持續創新高。 [108][109] ΔFosB已被證明與酒精成癮大麻成癮古柯鹼成癮、派醋甲酯成癮、尼古丁成癮、鴉片成癮、phencyclidine英语phencyclidine成癮、異丙酚、和安非他命的替代性物質英语substituted amphetamines成癮、及其他成癮有關。 [sources 10] ΔJunD英语ΔJunD為一個轉錄因子;而G9a英语EHMT2組織蛋白甲基轉移酶的一種。ΔJunD英语ΔJunDG9a英语EHMT2直接與伏隔核中的ΔFosB值的升高成反比。 [109][130][135]

利用載體讓伏隔核中的ΔJunD充分破表,可以使由長期藥物濫用所致的漸進式神經元和行為改變完全停止。(比如說:ΔFosB所致的改變)。 [130] ΔFosB也在人們於天然酬賞英语natural reward(natural reward)中的行為反應調節上扮演重要的腳色。天然酬賞(natural rewards)包含:美味的食物(palatable food)、性愛(sex)、運動(exercise)、......。 [111][130][136] 因為天然酬賞以及成癮性藥物皆會激發英语inducible geneΔFosB(這些酬賞讓大腦刺激ΔFosB的增加。原文:i.e., they cause the brain to produce more of it),長期過度地從事上述行為將可能導致類似的成癮之病理生理(pathological)。 [111][130]

ΔFosB是導致「安非他命成癮」、「安非他命引起的性成癮」中最關鍵的致癮因素。「安非他命引起的性成癮」為「安非他命使用」加上「過度的性活動」所引發的「衝動之下的性行為」。 [註 5][111][137][138] 這類的性成癮與多巴胺失調症候群英语dopamine dysregulation syndrome相關,有時此症會出現在正在服用作用於多巴胺的藥物英语dopaminergic#Supplements and drugs的人身上。 [註 6][111][136]

安非他命調節基因(gene regulation)的效果端視劑量與路徑(dose- and route-dependent)而定。 [131] 絕大多數主題為「基因調節(gene regulation)」和「成癮(addiction)」的研究都是透過動物試驗以及利用靜脈注射的方式對實驗動物注射超高劑量的安非他命來進行。 [131] 少數幾個透過人體試驗(依照體重來決定醫療用劑量)來進行的研究表明,口服醫療用劑量的安非他命並不會影響基因調節,即便有,也是極為輕微的。這表示安非他命用作醫療用途是十分安全的。 [131][131]

藥物治療(Pharmacological treatments)编辑

截至2014年5月 (2014-05)並沒有能夠有效治療安非他命成癮的藥理療法 [139][140][141] 。 2015年到2016年間的論文回顧結果指出:選擇性TAAR1英语TAAR1促進劑有非常大的可能在將來被用來治療中樞神經興奮劑的成癮; [46][142] 然而,截至2016年2月 (2016-02),已知可作為選擇性TAAR1英语TAAR1促進劑的物質都屬於試驗性藥物英语experimental drug[46][142] 安非他命成癮與伏隔核中的多巴胺接收器英语dopamine receptor們以及位置相同(co-localized)的NMDA 接受器們的活化高度相關; [note 13] [107] 鎂離子藉由封鎖一個接受器-鈣離子通道,來阻斷 NMDA接受器們。 [107][143] 一篇論文回顧做成結論:根據動物試驗,因成癮而使用中樞神經刺激劑的人,可以發現過量的中樞神經興奮劑顯著降低腦細胞內部的鎂離子活動。 [註 7][107] 利用元素補充劑,能降低安非他命使用者自我服用英语self-administration[e]的機會。然而這不被認為是有效治療安非他命成癮的單一療法(mono-therapy)。 [note 14][107]

行為治療(Behavioral treatments)编辑

認知行為治療是當前治療中樞神經刺激劑成癮的療法。 [115] 除此之外,運動在生物神經元產生的效果英语neurobiological effects of physical exercise的研究中表明維持每天從事有氧運動(例如:跑步等)的習慣,能避免藥物成癮纏身;本身也是一個對於治療安非他命成癮的有效附加療法英语adjunct theraot[sources 8] 運動能讓所有疾病的預後都更加樂觀,特別是對於中樞神經刺激劑成癮。 [112][114][144] 值得一提的是,有氧運動能降低擅自服用中樞神經興奮劑的慾望[f],降低再次擅自服用中樞神經興奮劑的機率英语reinstatment(reinstatment)(i.e., relapse)、降低「試圖取得藥物所做出的舉動(drug-seeking behavior)」、降低多巴胺接收器 D2紋狀體英语striatum中的密度。 [111][144] 它在病生理學中的腳色是相對於「興奮劑的使用」和「興奮劑的效果」,它會引起紋狀體中DRD2密度的減少。 [111] 一篇論文回顧提到,藉由改變紋狀體(striatum)中的ΔFosB、c-Fos英语c-Fos immunoreactivity英语immunoreactivity或部份的腦內回饋系統(reward system)來避免藥物成癮在一個人身上的發展。 [113]


Summary of addiction-related plasticity
神經可塑性行為可塑性英语行為可塑性的形式
( Form of neuroplasticity
or behavioral plasticity英语behavioral plasticity
增強物的種類
Type of reinforcer
來源
Sources
鴉片類 Opiates 中樞神經刺激劑 Psychostimulants 高脂肪或高糖食物
High fat or sugar food
性交
Sexual intercourse
運動與神經元關係 環境豐富化
Environmental enrichment
伏隔核中D1-type中的ΔFosB表現
ΔFosB expression in
nucleus accumbens D1-type英语D1-type MSNs
[111]
行為可塑性
Behavioral plasticity
攝取量的增加
(Escalation of intake)
Yes Yes Yes [111]
中樞神經刺激劑跨越-敏化作用
( Psychostimulant cross-sensitization
Yes 不適用
Not applicable
Yes Yes 削減
Attenuated
Attenuated [111]
未經過處方而自行撕下攝取中樞神經刺激劑
(Psychostimulant self-administration英语self-administration
[111]
強化「在特定地點攝取興奮劑的習慣」 Psychostimulant
conditioned place preference英语conditioned place preference
[111]
強化「試圖取得該致癮藥物的行為」
Reinstatement of drug-seeking behavior英语Reinstatement of drug-seeking behavior
[111]
神經化學物質的可塑性
Neurochemical plasticity
伏隔核中 CREB 磷酸化
CREB phosphorylation
in the nucleus accumbens
[111]
伏隔核中對於多巴胺的過敏反應
( Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [111]
經過變動的紋狀體多巴胺接收器的訊號發送
( Altered striatal英语striatum dopamine signaling英语dopamine receptor
DRD2 , ↑DRD3英语DRD3 DRD1英语DRD1, ↓DRD2 , ↑DRD3英语DRD3 DRD1英语DRD1, ↓DRD2, ↑DRD3英语DRD3 DRD2 DRD2 [111]
經過變動的紋狀體鴉片样肽受体的訊號發送
(Altered striatal opioid signaling
No change or
μ-opioid receptor英语μ-opioid receptors
μ-opioid receptor英语μ-opioid receptors
κ-opioid receptor英语κ-opioid receptors
μ-opioid receptor英语μ-opioid receptors μ-opioid receptor英语μ-opioid receptors 未改變
No change
未改變
No change
[111]
發生於紋狀體鴉片肽的改變
(Changes in striatal opioid peptide英语opioid peptides)
dynorphin英语dynorphin
No change: enkephalin英语enkephalin
dynorphin英语dynorphin enkephalin英语enkephalin dynorphin英语dynorphin dynorphin英语dynorphin [111]
多巴胺通道的神經突觸的可塑性
Mesocorticolimbic英语Dopaminergic pathways#Pathways synaptic plasticity
伏隔核树突的數量
(Number of dendrites in the nucleus accumbens
[111]
伏隔核中Dendritic spine的密度
Dendritic spine英语Dendritic spine density in
the nucleus accumbens
[111]

註解:Not applicable(N/A)=不適用;No change = 沒有改變;DRD2 = 多巴胺受體D2;Attenuated = 削減;↑ = 上升;↓ = 下降;enkephalin = 腦啡肽;dynorphin = 強啡肽;opioid receptor = 鴉片接收器。


依賴和戒斷症狀 Dependence and withdrawal编辑

根據另一篇由考科藍協作組織所做的一篇論文回顧指出當一個長期嚴重攝取安非他命或甲基安非他命的藥物成癮者某天突然停止攝取安非他命或甲基安非他命,那麼根據許多成癮個案的報告顯示,具有時效性(time-limited)的戒斷症狀將在他們上一次攝取安非他命後的24小時內出現。 在成癮患者停用安非他命後,安非他命的戒斷症狀的出現率接近九成。這九成都出現至少六個定義在「《精神疾病診斷與統計手冊》安非他命戒斷症狀」中的症狀。年紀與劑量和戒斷症狀的嚴重度呈正相關。安非他命的戒斷症狀共有兩個階段且總共可能歷時三周或更多。第一階段(撞牆期 marked "crush" phase)約持續一周。 [145] [145] 安非他命的戒斷症狀可能包含:對於各種刺激極度敏感、躁動不安(irritability)焦慮對於安非他命有難以抑制的渴求英语Craving (withdrawal)煩躁疲倦食慾放大英语herperphagia、過動或行動遲緩英语decreased movement、缺乏動機、嗜睡、和清醒夢(lucid dreams)。 [146] [145]

這些特徵及症狀必須非由其他疾病(包含心理疾病)引起,且無法歸因於其他物質的濫用。滿足上述條件,才符合「安非他命戒斷症狀」症候群的診斷標準。 [147] [145]

通過美國食品藥物管理局嚴格審核的安非他命藥品說明書上並未提到任何安非他命在醫療用劑量下突然停用會導致任何安非他命戒斷症狀的出現。 [94][148][149][150]

DSM中,安非他命中毒及戒斷症狀之標準(DSM criteria for intoxication and withdrawal)编辑

DSM-5中关于兴奋剂中毒的标准如下:

A.最近曾经服用过安非他命类的物质、可卡因或其他兴奋剂

B. 在服用兴奋剂时(或者服用后很快表现出)临床表现出显著问题行为或心理变化(如:欣快症或感情迟钝;群性、社交性的改变;过于警觉;人际交往敏感;焦虑、紧张或者恼怒;刻板行为;判断力受损)。

C.在服用兴奋剂时或服用后即刻表现出以下任意两种(或以上)症状:

  • 心动过速或心动过缓
  • 瞳孔扩散
  • 血压升高或降低
  • 出汗或发冷
  • 感到恶心或呕吐
  • 体重降低
  • 精神运动性焦躁或精神运动性迟滞
  • 肌肉无力、呼吸抑制、胸口疼痛或心律失常
  • 精神错乱、癫痫、运动困难、肌张力障碍或昏迷

包括其他物质中毒的情况在内,其他身体情况不可能出现该发病迹象、症状,并且也无法理解为其他的精神问题。

DSM-5中关于兴奋剂戒断症状的标准如下:

A. 停止服用(或减少服用)长期的安非他命类物质、可卡因或其他兴奋剂。

B. 在A的情况发生后的几小时至几天内,出现烦躁的情绪并伴有以下任意两种(或以上)的心理变化:

  • 疲劳
  • 生动而不愉快的梦
  • 失眠或嗜睡
  • 食欲增大
  • 精神运动性焦躁或精神运动性迟滞

B中的症状或迹象导致了临床显著的压力,或者在社会、工作等重要方面功能出现受损。

安非他命戒断症状的频率列表(Table of symptoms of amphetamine withdrawal by frequency)编辑

停止服用硫酸安非他命后,个人报告的戒断症状的百分比
症状 频率
无症状 14%
易怒 78%
疼痛和痛苦 58%
感到沮丧 50%
社交能力受损 46%
发抖、出冷汗 36%
难以入睡 32%
虚脱 22%
恶心、呕吐 16%
头痛 14%
难以保持清醒 12%
食欲增大 12%
便秘 10%
食欲缩小 8%
腹泻 6%

[151]

个人尝试戒毒和接受医学指导戒毒的原因与百分比
原因 个人尝试戒毒 医学指导戒毒
对生活整体现状(犯罪、无聊、金钱)不满 42(89%) 6(37%)
对心理健康感到担忧(偏执、忧虑、依赖) 25(53%) 3(19%)
家庭原因(父母或配偶的压力,子女出生) 24(51%) 5(31%)
身体健康(动脉注射、血管萎陷、感染) 17(36%) 4(25%)
避免入狱 0 2 (12%)
其他原因 2(4%) 0

[151]

用來協助戒毒的方法(Methods used to assist detoxication)
- 自我嘗試戒毒(Self detoxication) 被迫戒毒(Enforced detoxication)
服用更多其他药物(Increased consumption of other drugs ) - -
大麻(Cannabis) 22 (27%) 10 (59%)
Temazepam 21 (26%) -
酒精(Alcohol) 17 (21%) 2 (12%)
鴉片類物質(Opiates) 12 (15%) 1 (6%)
Diazepam 4 (5%) -
巴比妥類藥物(Barbiturates) 3 (4%) 1 (6%)
心理學技巧
(Psychosocial techniques)
- -
轉移注意力(例如:工作、看電視)
〔Keeping occupied with other things (working, watching television)〕
35 (21%) 1 (6%)
不再與藥物成癮的朋友來往
(Cutting off contact with drug-using friends)
31 (19%) -
獲得人們的支持(家庭、社會中的支持團體)
Gaining support from others (friends giving up, family, support groups)
11 (7%) -
把藥物及針頭丟掉
(Throwing away drugs and needles)
5 (3%) -

[151]

中毒與致病(Toxicity and psychosis)编辑

中毒编辑

在囓齒動物(rodents)和靈長類動物(primates)的藥物試驗發現到,夠高的安非他命劑量會導致多巴胺神經中毒英语neurotoxicity甚或致使多巴胺末梢神經英语axon terminal受損退化並降低轉運體接收器的功能。 [152][153] 目前並無證據顯示安非他命會直接荼毒人類的神經。[註 8] [154][155] 然而,超高劑量(large doses)的安非他命攝取量可能會產生體溫過高的現象並間接導致:多巴胺的神經性中毒(dopaminergic neurotoxicity)、過多的活性氧类(reactive oxygen species)生成、自然氧化(autoxidation)增加。 [sources 11] 從高劑量的安非他命攝取量引起的神經中毒的生物模式中發現,人體核心體溫高於40 °C是「高劑量的安非他命攝取量」是否引起神經中毒的「必要條件」。 [153] 在動物試驗中,若動物的腦溫長期超過40 °C,容易因過多的活性氧类(reactive oxygen species)生成、受干擾的細胞蛋白功能和短暫的血腦屏障(blood–brain barrier)標準放寬而促使安非他命性的神經中毒發生。 [153]

致病编辑

嚴重的安非他命過量可能造成「中樞神經刺激劑過量所引發的精神異常(stimulant psychosis)」,症狀包含但不限於幻覺(delusion)和被害妄想、疑神疑鬼、妄想、偏執 (paranoia)等。 [35] 一篇由考科藍協作組織所做的論文回顧及統整發現在所有因攝取嚴重過量的「安非他命、dextro-安非他命、及甲基安非他命」而導致精神異常的患者中,有5%-15%的患者即便經過治療,仍無法完全康復。 [35][158]

根據同一篇由考科藍協作組織所做的論文回顧及統整,至少一個實驗(trial)顯示抗精神病藥物(antipsychotic)能有效解決因嚴重過量的安非他命所致的急性精神異常症狀。 [35]

「攝取醫療劑量的安非他命所致的急性精神異常」是非常罕見的(very rare)。
(非常罕見 very rare: < 1/1000 ;罕見 rare:1/101~1/1000) [36][92]

交互作用(Interactions)编辑

      參見:Amphetamine § Contraindications

目前已知许多种物质都会和安非他命发生药物相互作用,导致安非他命或参与作用的另一物质的药效英语drug action分解过程英语Drug metabolism发生改变。[4][159]用于分解安非他命的酶的抑制剂(如CYP2D6FMO3英语Flavin-containing monooxygenase 3#Ligands)都会延长其半衰期,这意味着药效会更持久。[8][159] 安非他命也會和MAOIs產生交互作用,特別是MAOI類中的monoamine oxidase A英语monoamine oxidase A抑制劑(monoamine oxidase A inhibitors)。 <--inhibitors, -->

因為MAOIs和安非他命兩者都會增加兒茶酚胺(i.e., 正腎上腺素 和 多巴胺)在血漿中的濃度[159];因此MAOIs與安非他命合併使用是危險的[159]。 安非他命會調節幾乎所有作用於中樞神經的藥物的活動。特別需要注意的是,安非他命可能會降低鎮靜劑(sedative)和中樞神經抑制劑英语depressants(depressant)的效果,並增加其他中樞神經刺激劑(stimulant)和抗憂鬱藥(anti-depressants)的效果。 [159]

安非他命也可能降低抗高血壓藥(anti-hypertensives)和抗精神病藥(anti-psychotics)的藥效,這是因為安非他命本身對於血壓及多巴胺系統的作用。 [159]

鋅的補充劑 可能會將低安非他命用於治療注意力不足過動症時的最小有效劑量(minimum effective dose)。 [note 15][163]

整體來說,安非他命並不會與日常生活中常見的食物起任何重大的交互作用,但安非他命的吸收和排泄會分別受到腸胃內容物(gastrointestinal content)的pH值和尿液的酸鹼值影響。[g][159] 酸性物質會減少安非他命的吸收並增加尿液的排泄;鹼性物質正好相反。 [h][159]

由於pH值在安非他命的吸收這件事上具有影響力,所以安非他命也會和 氫離子幫浦阻斷劑(PPI, proton pump inhibitors)和 H2 受体阻抗剂(H2 antihistamines)等中和胃酸的制酸劑產生交互作用。 [159]

藥學(Pharmacology)编辑

藥物代謝動力學编辑

安非他命的口服生物體可利用率[參 21]與腸胃的pH值連動; [159] 安非他命非常容易在腸道被吸收,dextroampetamine的生體可利用率在多數的情況下高於75%。 [2] 安非他命呈弱鹼性,其pKa值介於9–10之間;[4] 因此,當pH值呈鹼性時,多數的安非他命會以其易溶於脂類純胺類型態英语free base形式存在。在此情況下,身體會通過腸道上皮組織富含脂類的細胞膜[參 22]來吸收安非他命。 [4] [159] 相反地,酸性的pH值表示安非他命主要以易溶於水的離子[參 23](鹽)形式存在,因此較少能被吸收。 [4] 大約15–40%循環於血管中的安非他命與血漿蛋白[參 24]相連接。 [3] 安非他命的對映異構物的半衰期會隨著尿液的pH值而有所不同。 [4] 當尿液的酸鹼值落在正常範圍中,dextroamphetamine和levoamphetamine的半衰期分別為9–11 小時及 11–14 小時。 [4] 酸性飲食會導致安非他命的對映異構物的半衰期降低至8–11 小時;鹼性飲食則會使安非他命的對映異構物的半衰期增加到16–31 小時。 [10][16]

成分為安非他命或其衍生物的短效藥品大約在口服後三小時在體內達到最高血漿濃度英语plasma concentration;而成分為安非他命或其衍生物的長效藥品則在口服後大約七小時在體內達到最高血漿濃度。 [4]

安非他命主要透過腎臟來代謝,大約30–40%的藥物以藥物本身原始的型態從酸鹼度正常的尿液中排出。 [4] 當尿液是鹼性時,安非他命傾向以其純胺類型態存在,因此較少被排泄。 [4]

當尿液的pH值失常時,各種安非他命的分解物在尿液中重新結合的程度將從最低1%到最高75%。該程度的高低大多取決於於尿液的酸鹼值,尿液越酸,結合率越高;尿液愈鹼,結合率越低。 [4] 安非他命通常於口服後兩天內自體內完全代謝完畢。 [10] 安非他命確切的半衰期及藥效作用期隨著(小於兩天的)重複服用導致的血漿內安非他命濃度(plasma concentration of amphetamine)的增加而延長。[193]

對人體無藥效的前驅藥物體(prodrug):lisdexamfetamine並不若安非他命一樣容易受腸胃道環境的pH值影響; [194] lisdexamfetamine在腸道被吸收進入血管的血液後很快就會透過水解(hydrolysis)的方式轉化為dextroamphetamine。而參與這水解反應的酶(enzymes)與紅血球有關。 [194]

Lisdexamfetamine的半衰期通常小於一個小時。 [194]

細胞色素 P450 2D6(Cytochrome P450 2D6、或CYP2D6)、多巴胺β羥化酶(Dopamine β-hydroxylase、或DBH)、flavin-containing monooxygenase 3英语flavin-containing monooxygenase 3butyrate-CoA ligase英语butyrate-CoA ligase、和 glycine N-acyltransferase英语glycine N-acyltransferase為已知在人體中參與[註 9]「安非他命」及「安非他命代謝後之產物」的代謝反應的(enzyme)。 [sources 14]

「安非他命代謝後之產物」包含:4-hydroxyamphetamine英语4-hydroxyamphetamine4-hydroxynorephedrine英语4-hydroxynorephedrine4-hydroxyphenylacetone英语4-hydroxyphenylacetone苯甲酸(benzoic acid)、馬尿酸(hippuric acid)、苯丙醇胺(norephedrine)、苯基丙酮(phenylacetone)[註 10] [4] [10] [11]

在這些「安非他命代謝後之產物」之中,有實際藥效的產物(sympathomimetics)為:4‑hydroxyamphetamine[197]4‑hydroxynorephedrine[198]、和norephedrine[199]

安非他命的主要代謝途徑包含:aromatic para-hydroxylation、aliphatic alpha- 、beta-hydroxylation、N-oxidation、N-dealkylation、和 deamination。 [4][10]

下圖為已知的「安非他命」代謝途徑和「安非他命代謝後之產物」: [4][8][11]

苯丙胺的代謝途徑
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
Glycine
Conjugation
在這些「安非他命代謝後之產物」之中,主要的且有實際藥效的產物為:4-hydroxyamphetamine去甲麻黃鹼(norephedrine)[11]

從酸鹼度正常的尿液中可發現,大約30–40%的「安非他命」以本身原始的型態排出;大約50%的安非他命以不具藥效的「安非他命代謝後之產物」(即為圖片中最下列的產物)的型態排出。 [4]

剩下的10–20%則為「安非他命代謝後之產物」之中,有實際藥效的產物。 [4]

苯甲酸(Benzoic acid)被butyrate-CoA連接酶(butyrate-CoA ligase)代謝後成為一個中介物質/中間產物(intermediate product):benzoyl-CoA英语benzoyl-CoA [195]

隨後透過glycine N-acyltransferase代謝並轉化為馬尿酸(hippuric acid)。[196]

相關的內部生成化合物/混和物(endogenous compound)编辑

歷史、社會與文化编辑

合法狀態與條件编辑

藥品编辑

備註A编辑

  1. ^ 别名有:1-phenylpropan-2-amine (IUPAC name), α-methylbenzeneethanamine, α-methylphenethylamine, amfetamine (International Nonproprietary Name [INN]), β-phenylisopropylamine, desoxynorephedrine, and speed.[18][21][22]
  2. ^ 對映異構體指的是兩個形狀相同但方向相反的兩個分子,他們又稱為彼此的鏡中影像。[23] Levoamphetamine 和 dextroamphetamine 分別被簡稱為 L-amph 或 levamfetamine (INN) 和 D-amph 或 dexamfetamine (INN) [18]
  3. ^ "Adderall"是一個品牌名稱。因為以下幾個安非他命的異構物的英文名稱太長了:("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate"),因此本文單獨以此名稱來表示此安非他命的此種混合物。
    原文對照:"Adderall" is a brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate" [44]) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.
  4. ^ 「安非他命」一詞也意指一個化學分類,但與「替代性安非他命」這個化學分類不同的是,「安非他命」類在學術上並無標準的定義。 [5][25] 有一個「安非他命」類的定義嚴格限定分類中僅有:安非他命的racemate and enantiomers 和 甲基安非他命methamphetamine的racemate and enantiomers。 [25] 大多數「安非他命」類的定義為那些在藥理學上以及結構上與安非他命相關的化合物。 [25]
    為避免讓amphetamine 和 amphetamines 把讀者給弄糊塗了,本條目中僅會使用amphetamine、amphetamines來表示racemic amphetamine, levoamphetamine, and dextroamphetamine;‘替代性安非他命(substituted amphetamines)’來表示安非他命的結構分類。
    原文對照: Due to confusion that may arise from use of the plural form, this article will only use the terms "amphetamine" and "amphetamines" to refer to racemic amphetamine, levoamphetamine, and dextroamphetamine and reserve the term "substituted amphetamines" for its structural class.
  5. ^ 研究證實,長期以中樞神經興奮劑治療ADHD能在下列這些方面產生大幅的進步:學業、駕駛、降低藥物濫用、降低肥胖、自尊、和社交功能等。 [57]

    在上述領域中,最為突出的領域為: 學業(例如:GPA分數 grade point average、成果測驗分數 achievement test scores、受教育的時間長度 length of education、和教育程度 education level) 、自尊(例如:自尊心測驗分數 self-esteem questionnaire assessments、嘗試自殺的次數、自殺率等) 和社交功能(例如:peer nomination scores、社交技巧、家庭關係 quality of family、同儕關係 quality of peer、和浪漫關係/情侶關係 romantic relationships) [57]

    長期以「藥物治療合併行為治療」的模式來治療ADHD,能夠比單獨以藥物治療,產生更全面且更長足的進步。 [57]
  6. ^ 考科藍協作組織對於歷年眾多的「隨機對照試驗」的系統性回顧數據統整分析後所得出的總結,基本上都是非常有水準且深具參考價值的。 [65]
  7. ^ 美國食品藥物管理局核准的藥品使用指引及醫療上的禁忌(放在藥盒中的仿單/說明書)並非為了限制醫師的決策而是為了避免藥商恣意宣稱藥物的作用。醫師可以此為參考,並依照每位病人的實際情況做出獨立的判斷。 [91]
  8. ^ 然而根據一篇回顧性論文,安非他命可以處方給曾有藥物濫用歷史的人,不過需要有對患者適度的藥品控管,例如:每天由醫護人員配給處方劑量。[1]
  9. ^ 曾受此副作用的用藥者,身高及體重在在短暫停藥後恢復至應有水準是可以被預期的。[56][59][97] 根據追蹤,持續三年過程不停歇的安非他命治療(沒有合併任何積極減少安非他命副作用的療法的情況下)平均會減少 2公分的最終身高。 [97]
  10. ^ 「95% 信賴區間」指的是:有95%的機率,真實的死亡人數介於3,425 和 4,145 之間。
  11. ^ 轉錄因子是一種可以增加或降低一個特定基因的基因表現的蛋白。
    原文:Transcription factors are proteins that increase or decrease the expression of specific genes.[132]
  12. ^ 簡單來說,這裡的「充分且必要(necessary and sufficient)」關係指的是「ΔFosB在伏隔核中的破表(over-expression)」與「成癮衍生的行為」及「神經元為了適應新常態所做的調適」永遠都是一起發生。
  13. ^ NMDA接受器們為與電壓相關的ligand-gated ion channels英语ligand-gated ion channelsligand-gated ion channels英语ligand-gated ion channels這個通道需要glutamate 以及一個共同促進劑(co-agonist ):(D-serine大豆屬glycine)的同時連接才能被開啟。
    原文: NMDA receptors are voltage-dependent ligand-gated ion channels英语ligand-gated ion channels that requires simultaneous binding of glutamate and a co-agonist (D-serine or glycine) to open the ion channel.[143]
  14. ^ 該篇回顧表示magnesium L-aspartate英语magnesium aspartate氯化鎂(magnesium chloride)能大幅改善成癮行為。
    原文: The review indicated that magnesium L-aspartate英语magnesium aspartate and magnesium chloride produce significant changes in addictive behavior;[107] other forms of magnesium were not mentioned.
  15. ^ The human dopamine transporter contains a high affinity extracellular zinc binding site英语binding site which, upon zinc binding, inhibits dopamine reuptake英语reuptake and amplifies amphetamine-induced dopamine efflux英语neurotransmitter efflux in vitro.[160][161][162] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[162]

備註B编辑

  1. ^ 智力測驗結果與專注力有關,詳見注意力不足過動症#智力
  2. ^ 因成癮所致的行為
  3. ^ 妄想的英文名稱為:delusion
  4. ^ 偏執的英文名稱為:paranoia
  5. ^ 原文:Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.
  6. ^ 原文:These sex addictions are associated with a 多巴胺失調症候群英语dopamine dysregulation syndrome which occurs in some patients taking 作用於多巴胺的藥物英语dopaminergic#Supplements and drugs.
  7. ^ 原文:One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.
  8. ^ Original texts: There is no evidence that amphetamine is directly neurotoxic in humans.
  9. ^ 酶做為反應的催化劑catalyst,並不實際參與反應。
  10. ^ 不是苯丙酮

備註C编辑

  1. ^
      (Text color) 转录因子

注释编辑

  1. ^ 安非他命是一种春药
  2. ^ 又稱為「隨機分配且包含控制組的臨床試驗」,是臨床試驗的一種
  3. ^ 中樞神經興奮劑的一種
  4. ^ 原文: This diagram depicts the signaling events in the Mesolimbic pathway英语Mesolimbic pathway that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like 安非他命, 甲基苯丙胺, and 苯乙胺.
  5. ^ (self-administration,i.e., doses given to oneself)
  6. ^ 原文:aerobic exercise decreases psychostimulant self-administration
  7. ^ 原文:In general, there is no significant interaction when consuming amphetamine with food, but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively.
  8. ^ 原文:Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.

英文名稱對照编辑

  1. ^ 英文名稱為:delusions
  2. ^ 英文名稱為:paranoia
  3. ^ 英文名稱為:Prescription drug
  4. ^ 英文名稱為:Pharmaceutical amphetamine
  5. ^ 英文名稱為:racemic amphetamine
  6. ^ 英文名稱為:Prodrug
  7. ^ 英文名稱為:substituted amphetamine
  8. ^ 英文名稱為:Bupropion
  9. ^ 英文名稱為:meth-amphetamine
  10. ^ 英文名稱為:Randomized controlled trials
  11. ^ 英文名稱為:follow-up studies
  12. ^ 英文名稱為:neurotransmitter systems
  13. ^ 英文名稱為:dopamine
  14. ^ 英文名稱為:locus coeruleus
  15. ^ 英文名稱為:prefrontal cortex
  16. ^ 英文名稱為:nor-epinephrine或nor-adrenaline
  17. ^ 英文名稱為:Cochrane Collaboration
  18. ^ 英文名稱為:systematic review
  19. ^ 英文名稱為:meta-analysis
  20. ^ 英文名稱為:臨床試驗
  21. ^ 英文名稱為:bioavailability
  22. ^ 英文名稱為:cell membrane
  23. ^ 英文名稱為:cation
  24. ^ 英文名稱為:plasma protein

引用编辑

來源编辑

  1. ^ 1.0 1.1 1.2 1.3 1.4 1.5 引用错误:没有为名为Amph_Uses的参考文献提供内容
  2. ^ 2.0 2.1 Pharmacology. Dextroamphetamine. DrugBank. University of Alberta. 2013-02-08 [2013-11-05]. 
  3. ^ 3.0 3.1 Pharmacology. Amphetamine. DrugBank. University of Alberta. 2013-02-08 [2013-11-05]. 
  4. ^ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 Adderall XR Prescribing Information (PDF). United States Food and Drug Administration. Shire US Inc: 12–13. December 2013 [2013-12-30]. 
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  6. ^ 6.0 6.1 Taylor KB. Dopamine-beta-hydroxylase. Stereochemical course of the reaction (PDF). J. Biol. Chem. January 1974, 249 (2): 454–458 [2014-11-06]. PMID 4809526. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine. 
  7. ^ 7.0 7.1 Horwitz D, Alexander RW, Lovenberg W, Keiser HR. Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity. Circ. Res. May 1973, 32 (5): 594–599. PMID 4713201. doi:10.1161/01.RES.32.5.594. Subjects with exceptionally low levels of serum dopamine-β-hydroxylase activity showed normal cardiovascular function and normal β-hydroxylation of an administered synthetic substrate, hydroxyamphetamine. 
  8. ^ 8.0 8.1 8.2 8.3 Krueger SK, Williams DE. Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol. Ther. June 2005, 106 (3): 357–387. PMC 1828602. PMID 15922018. doi:10.1016/j.pharmthera.2005.01.001. 
    "Table 5: N-containing drugs and xenobiotics oxygenated by FMO"
  9. ^ 9.0 9.1 Cashman JR, Xiong YN, Xu L, Janowsky A. N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication. J. Pharmacol. Exp. Ther. March 1999, 288 (3): 1251–1260. PMID 10027866. 
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  12. ^ Pharmacology. amphetamine/dextroamphetamine. Medscape. WebMD. [2016-01-21]. Onset of action: 30–60 min 
  13. ^ 13.0 13.1 13.2 Millichap JG. Chapter 9: Medications for ADHD. (编) Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD 2nd. New York, USA: Springer. 2010: 112. ISBN 9781441913968.
    Table 9.2 Dextroamphetamine formulations of stimulant medication
    Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
    Adderall [Peak:2–3 h] [Duration:5–7 h]
    Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
    Adderall XR [Peak:7–8 h] [Duration:12 h]
    Vyvanse [Peak:3–4 h] [Duration:12 h]
     
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  16. ^ 16.0 16.1 Biological Half-Life. AMPHETAMINE. United States National Library of Medicine – Toxnet. Hazardous Substances Data Bank. [2014-01-05]. Concentrations of (14)C-amphetamine declined less rapidly in the plasma of human subjects maintained on an alkaline diet (urinary pH > 7.5) than those on an acid diet (urinary pH < 6). Plasma half-lives of amphetamine ranged between 16-31 hr & 8-11 hr, respectively, & the excretion of (14)C in 24 hr urine was 45 & 70%. 
  17. ^ 17.0 17.1 Mignot EJ. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics. October 2012, 9 (4): 739–752. PMC 3480574. PMID 23065655. doi:10.1007/s13311-012-0150-9. 
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  19. ^ Properties: Predicted – EP|Suite. Amphetamine. Chemspider. [2013-11-06]. 
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  23. ^ Enantiomer. IUPAC Goldbook. International Union of Pure and Applied Chemistry. [2014-03-14]. doi:10.1351/goldbook.E02069. (原始内容存档于2013-03-17). One of a pair of molecular entities which are mirror images of each other and non-superposable. 
  24. ^ 24.0 24.1 Guidelines on the Use of International Nonproprietary Names (INNS) for Pharmaceutical Substances. World Health Organization. 1997 [2014-12-01]. In principle, INNs are selected only for the active part of the molecule which is usually the base, acid or alcohol. In some cases, however, the active molecules need to be expanded for various reasons, such as formulation purposes, bioavailability or absorption rate. In 1975 the experts designated for the selection of INN decided to adopt a new policy for naming such molecules. In future, names for different salts or esters of the same active substance should differ only with regard to the inactive moiety of the molecule. ... The latter are called modified INNs (INNMs). 
  25. ^ 25.0 25.1 25.2 25.3 25.4 25.5 Yoshida T. Chapter 1: Use and Misuse of Amphetamines: An International Overview. (编) Klee H. Amphetamine Misuse: International Perspectives on Current Trends. Amsterdam, Netherlands: Harwood Academic Publishers. 1997: 2 [2014-12-01]. ISBN 9789057020810. Amphetamine, in the singular form, properly applies to the racemate of 2-amino-1-phenylpropane. ... In its broadest context, however, the term [amphetamines] can even embrace a large number of structurally and pharmacologically related substances. 
  26. ^ 26.0 26.1 Amphetamine. Medical Subject Headings. United States National Library of Medicine. [2013-12-16]. 
  27. ^ Spencer RC, Devilbiss DM, Berridge CW. The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex. Biol. Psychiatry. June 2015, 77 (11): 940–950. PMID 25499957. doi:10.1016/j.biopsych.2014.09.013. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation. ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses. 
  28. ^ Ilieva IP, Hook CJ, Farah MJ. Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis. J. Cogn. Neurosci. January 2015: 1–21. PMID 25591060. doi:10.1162/jocn_a_00776. Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ... The results of this meta-analysis ... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size. 
  29. ^ 29.0 29.1 29.2 29.3 29.4 29.5 29.6 29.7 29.8 29.9 Malenka RC, Nestler EJ, Hyman SE. Chapter 13: Higher Cognitive Function and Behavioral Control. (编) Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience 2nd. New York, USA: McGraw-Hill Medical. 2009: 318, 321. ISBN 9780071481274. Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors. ...
    Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.
     
  30. ^ 30.0 30.1 30.2 30.3 30.4 Liddle DG, Connor DJ. Nutritional supplements and ergogenic AIDS. Prim. Care. June 2013, 40 (2): 487–505. PMID 23668655. doi:10.1016/j.pop.2013.02.009. Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
    Physiologic and performance effects
     · Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
     · Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
     · Improved reaction time
     · Increased muscle strength and delayed muscle fatigue
     · Increased acceleration
     · Increased alertness and attention to task
     
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  33. ^ 33.0 33.1 33.2 33.3 33.4 33.5 33.6 33.7 33.8 引用错误:没有为名为FDA_Effects的参考文献提供内容
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    About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
    Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
     
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  56. ^ 56.0 56.1 56.2 56.3 Millichap JG. Chapter 9: Medications for ADHD. (编) Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD 2nd. New York, USA: Springer. 2010: 121–123, 125–127. ISBN 9781441913968. Ongoing research has provided answers to many of the parents’ concerns, and has confirmed the effectiveness and safety of the long-term use of medication. 
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    Figure 3: Treatment benefit by treatment type and outcome group
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  88. ^ Parker KL, Lamichhane D, Caetano MS, Narayanan NS. Executive dysfunction in Parkinson's disease and timing deficits. Front. Integr. Neurosci. October 2013, 7: 75. PMC 3813949. PMID 24198770. doi:10.3389/fnint.2013.00075. Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or “clock,” activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing. 
  89. ^ Rattray B, Argus C, Martin K, Northey J, Driller M. Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance?. Front. Physiol. March 2015, 6: 79. PMC 4362407. PMID 25852568. doi:10.3389/fphys.2015.00079. Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). ... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008) 
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    DOSAGE FORMS AND STRENGTHS
    Extended-release oral suspension contains 2.5 mg amphetamine base per mL.
     
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       • Amphetamine
     
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  111. ^ 111.00 111.01 111.02 111.03 111.04 111.05 111.06 111.07 111.08 111.09 111.10 111.11 111.12 111.13 111.14 111.15 111.16 111.17 111.18 111.19 111.20 111.21 Olsen CM. Natural rewards, neuroplasticity, and non-drug addictions. Neuropharmacology. December 2011, 61 (7): 1109–1122. PMC 3139704. PMID 21459101. doi:10.1016/j.neuropharm.2011.03.010. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008). 
  112. ^ 112.0 112.1 112.2 112.3 Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA. Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis. Neurosci. Biobehav. Rev. September 2013, 37 (8): 1622–1644. PMC 3788047. PMID 23806439. doi:10.1016/j.neubiorev.2013.06.011. These findings suggest that exercise may “magnitude”-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes. 
  113. ^ 113.0 113.1 113.2 Zhou Y, Zhao M, Zhou C, Li R. Sex differences in drug addiction and response to exercise intervention: From human to animal studies. Front. Neuroendocrinol. July 2015, 40: 24–41. PMID 26182835. doi:10.1016/j.yfrne.2015.07.001. Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use. ... The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation. 
  114. ^ 114.0 114.1 114.2 Linke SE, Ussher M. Exercise-based treatments for substance use disorders: evidence, theory, and practicality. Am. J. Drug Alcohol Abuse. January 2015, 41 (1): 7–15. PMC 4831948. PMID 25397661. doi:10.3109/00952990.2014.976708. The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects. 
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  117. ^ Malenka RC, Nestler EJ, Hyman SE. Chapter 15: Reinforcement and Addictive Disorders. (编) Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience 2nd. New York: McGraw-Hill Medical. 2009: 364–375. ISBN 9780071481274. 
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    Figure 2: Psychostimulant-induced signaling events
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  122. ^ Kanehisa Laboratories. Amphetamine – Homo sapiens (human). KEGG Pathway. 10 October 2014 [31 October 2014]. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain. 
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  124. ^ 124.0 124.1 124.2 Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat. Rev. Neurosci. November 2011, 12 (11): 623–637. PMC 3272277. PMID 21989194. doi:10.1038/nrn3111. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression. 
    Figure 4: Epigenetic basis of drug regulation of gene expression
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  126. ^ Nestler EJ. Review. Transcriptional mechanisms of addiction: role of DeltaFosB. Philos. Trans. R. Soc. Lond., B, Biol. Sci. October 2008, 363 (1507): 3245–3255. PMC 2607320. PMID 18640924. doi:10.1098/rstb.2008.0067. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure 
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    There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.
     
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  167. ^ 167.0 167.1 167.2 167.3 167.4 Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG. Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons. Neuron. July 2014, 83 (2): 404–416. PMC 4159050. PMID 25033183. doi:10.1016/j.neuron.2014.05.043. AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH 
  168. ^ 168.0 168.1 SLC18 family of vesicular amine transporters. IUPHAR database. International Union of Basic and Clinical Pharmacology. [2015-11-13]. 
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  172. ^ Inazu M, Takeda H, Matsumiya T. [The role of glial monoamine transporters in the central nervous system]. Nihon Shinkei Seishin Yakurigaku Zasshi. August 2003, 23 (4): 171–178. PMID 13677912 (Japanese). 
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  191. ^ Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC. TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc. Natl. Acad. Sci. U.S.A. May 2011, 108 (20): 8485–8490. PMC 3101002. PMID 21525407. doi:10.1073/pnas.1103029108. 
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  197. ^ 引用错误:没有为名为sympathomimetics的参考文献提供内容
  198. ^ 引用错误:没有为名为metabolites的参考文献提供内容
  199. ^ 引用错误:没有为名为norephedrine的参考文献提供内容

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