苯丙胺
 | 此条目可参照英语维基百科相应条目来扩充，此条目在对应语言版为高品质条目。 |
 | 此条目翻译品质不佳，原文在en:Amphetamine。 |
“安非他命”重定向至此。关于其他用法，请见“安非他命 (消歧义)”。此条目介绍的是中文通称“苯丙胺”的管制药物1-苯基丙-2-胺。关于ACD软件索引名（ACD/Index Name）为“苯丙胺”（Benzenepropanamine）的化合物3-苯基丙-1-胺（C₆H₅CH₂CH₂CH₂NH₂），请见“3-苯丙胺”。“苯异丙胺”重定向至此。关于其他用法，请见“苯异丙胺 (消歧义)”。 | |
 | |
| 临床资料 | |
|---|---|
| 读音 |  i/æmˈfɛtəmiːn/ |
| 其他名称 | α-甲基苯乙胺 |
| AHFS/Drugs.com | amphetamine |
| 依赖性 | 生理依赖: 无 心理依赖: 中等 |
| 成瘾性 | 中等 |
| 给药途径 | 医用：口服给药、鼻腔给药、静脉注射[1] 非医疗用（Recreational）： 口服给药、鼻腔给药, 吹入剂、栓剂、静脉注射 |
| ATC码 | |
| 法律规范状态 | |
| 法律规范 |
|
| 药物动力学数据 | |
| 生物利用度 | 口服 75–100%[2] |
| 血浆蛋白结合率 | 15–40%[3] |
| 药物代谢 | Amphetamine only: CYP2D6,[4]Dopamine β-hydroxylase,[14][15][16]含黄素的单加氧酶[14][17][18] |
| 代谢产物 | 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-羟基苯基丙酮, 苯甲酸, 马尿酸, 苯丙醇胺, 苯基丙酮[4][5][6] |
| 药效起始时间 | 短效型（IR 立即释放药物） 使用后（dosing）：30–60 ；分钟内[7] 长效型 （XR 缓缓释放药物） 使用后（dosing）：1.5–2 ；小时内[8][9][10] |
| 生物半衰期 | D-amph：9–11 ；小时[4][11] L-amph：11–14 ；小时[4][11] 视PH值而定：8–31 ；小时[12] |
| 作用时间 | 短效型（IR 立即释放药物） 使用后（dosing）：3–7 小时内[8][13] 长效型（XR 缓缓释放药物） 使用后(dosing): 12 ；小时内[8][10][13] |
| 排泄途径 | 主要透过肾脏; 视PH值而定 范围：1–75%[4] |
| 识别信息 | |
| |
| CAS号 | 300-62-9  |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| NIAID ChemDB | |
| PDB配体ID | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.005.543 |
| 化学信息 | |
| 化学式 | C9H13N |
| 摩尔质量 | 135.20622 g/mol[19] |
| 3D模型（JSmol） | |
| 密度 | 0.9±0.1 g/cm3 at 25 °C[20] |
| 熔点 | 11.3 °C（52.3 °F） (预测)[22] |
| 沸点 | 203 °C（397 °F） 为 760 毫米汞柱[21] |
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安非他明（英语：amphetamine, alpha-methylphenethylamine）（化学式：C₆H₅CH₂CH(CH₃)NH₂，为中枢神经刺激剂，用来治疗注意力不足过动症、嗜睡症、和肥胖症。英语源通称“安非他明”撷取自α-甲基苯乙胺的英文读法“alpha‑methylphenethylamine”之缩读。安非他明是在1887年发现的，以两种对映异构体的形式存在[I]，分别是左旋安非他明和右旋安非他明。准确来说，安非他明指的是特定的化学物质，是外消旋的纯胺类型态[24][25]，这个物质等同于安非他明的两个对映异构体：左旋安非他明和右旋安非他明等量之纯胺类型态。不过，安非他明一词已用来表示任何比例安非他明对映异构体的组合，或是任一种异构体[26][25][27]。
以往曾用安非他明来治疗鼻塞和抑郁。在非医疗用途上，安非他明也有用作体能增强药物、益智药、春药及欣快药物。安非他明在许多国家为合法的处方药。然而，私自散布和囤积安非他明被视为非法行为，因为安非他明被用于非医疗用途的助兴可能性极高，而且有明显健康上的危害[25][28][24]。
首个药用安非他明的药品名称为Benzedrine。当今药用安非他明[参 1]以下列几种形式存在：外消旋安非他明[参 2]、阿得拉尔 [II]、右旋安非他明，或前驱药物甲磺酸赖氨酸安非他明。安非他明借着自身作用于儿茶酚胺神经传导元素：正肾上腺素及多巴胺的特点来活化痕量胺受体，进而增加单胺类神经递质和神经递质在脑内的活动。[1][11][30]
在医疗用的剂量范围内，安非他明能带来情绪以及执行功能的变化，例如：欣快感的增强、性欲的改变、清醒度的提升、大脑执行功能的进化。安非他明所改变的生理反应包含：减少反应时间、降低疲劳、以及肌耐力的增强。若摄取剂量远超过医疗用的剂量范围，将会导致大脑执行功能受损以及横纹肌溶解症，摄取过分超越医疗用剂量范围的安非他明可引发严重的药物成瘾，服用远超医疗用剂量范围的安非他明会引起精神疾病（例如：妄想、偏执）。然而长期摄取医疗剂量范围的安非他明并不会引起上述疾病。那些为享乐而摄入的安非他明通常会远超过医疗用剂量范围，且伴随着非常严重甚至致命的副作用。[11][31][32][33]。
安非他明属于苯乙胺衍生物。安非他明的衍生物也归在同一分类中[参 3]的分类中[III]，比如说：安非他酮[参 4]、卡西酮、MDMA、和甲基苯丙胺[参 5]。安非他明也与人体内可自然生成的两个属于痕量胺的神经传导物质——特别是苯乙胺和N-甲基苯乙胺——有关。苯乙胺只比安非他明少了一个甲基，而N-甲基苯乙胺则是安非他明的结构异构（差异只在于甲基位置的不同）。[34][35][36]
用途
[编辑]医疗
[编辑]安非他明可以治疗注意力不足过动症（ADHD）、嗜睡症（一种睡眠疾病）、和肥胖症。有时候安非他明会以仿单标示外使用的方式处方来治疗顽固性忧郁症和顽固性强迫症[1][11][37][38]。在动物试验中，已知非常高剂量的安非他明会造成某些动物的多巴胺系统和神经系统的受损。[39][40]但是，在人体试验中，注意力不足过动症患者在接受安非他明的治疗后，则发现安非他明可促进大脑的发育及神经的成长。[41][42][43]
回顾许多核磁共振照影（英语：Nuclear Magnetic Resonance Imaging）的研究后发现，长期以安非他明治疗注意力不足过动症患者能显著降低患者大脑结构及大脑执行功能上的异常。并且改善大脑中数个部位，例如：基底神经节的右尾状核[41][42][43]。
众多临床研究的系统性及统合性回顾已确立长期使用安非他明治疗注意力不足过动症的疗效及安全。[44][45][46][47]
持续长达两年的随机对照试验[参 6][a]结果显示：长期使用安非他明治疗注意力不足过动症，是有效且安全的[44][47]。
两个系统性/统合性回顾的结果显示长期且持续地使用中枢神经兴奋剂治疗注意力不足过动症能有效地减少注意力不足过动症的核心症状（核心症状即为：过动、冲动和分心/无法专心）、增进生活品质、提升学业成就、广泛地强化大脑的执行功能。[IV]这些执行功能分别与下列项目有关：学业、反社会行为、驾驶习惯、药物滥用、肥胖、职业、日常活动、自尊心、服务使用（例如：学习、职业、健康、财金、和法律等）、社交功能[45][47]。
一篇系统性／统合性回顾标志了一个重要发现：一个为期九个月的随机双盲试验中，持续以安非他明治疗的ADHD患者，其智力商数平均增加4.5单位[注 1]，且在专注力、冲动、过动的改善皆呈现持续进步的态势。[44]另一篇系统性／统合性回顾则指出：根据迄今为止为时最长的数个临床追踪研究[参 7]，可以得到一个结论：即便从儿童时期开始以中枢神经兴奋剂治疗直到老年，中枢神经兴奋剂都能持续有效地控制ADHD的症状并且减少物质滥用的风险。[47] 研究表明，ADHD与大脑的执行功能受损有关。而这些受损的执行功能分别与大脑中部分的神经传导系统有关[参 8][48]；又此部分受损的神经传导系统和中脑皮质激素-多巴胺[参 9]的传导及蓝斑核[参 10]和前额叶[参 11]中的正肾上腺素[参 12]的传导相关。[48]
中枢神经兴奋剂，例如：methylphenidate和安非他明对于治疗ADHD都是有效的，因为中枢神经兴奋剂刺激了上述神经系统中的神经传导物质活动。[31][48][49]
至少超过80%的ADHD患者在使用中枢神经兴奋剂治疗后，其ADHD的症状可以获得改善。[50]
使用中枢神经兴奋剂治疗的ADHD患者相较之下，普遍与同侪及家庭成员的关系较佳并且在学校拥有较好的表现。兴奋剂能使ADHD患者较不易分心、冲动、且拥有较长的专注力时间和范围。[51][52]
根据考科蓝协作组织[参 13]所提供的文献回顾结果[V]指出：使用中枢神经兴奋剂治疗的ADHD患者即便其症状改善，相较于使用非中枢神经兴奋剂，仍因副作用而有较高的停药率。[54][55]
回顾结果也发现，中枢神经兴奋剂并不会恶化抽动综合症的症状，例如：妥瑞氏症，除非服用dextroamphetamine[b]的剂量过高才有可能在部分妥瑞氏症合并注意力不足过动症患者身上观察到抽动综合症的症状恶化。[56]
中枢神经兴奋剂只要依照医师指示用药，都是相当安全的。[57][58][59][59][60]中枢神经兴奋剂，例如：利他林与专思达，可能导致：心悸、头痛、胃痛、丧失食欲、失眠、因相对专注而变得冷淡（面无表情）等副作用，因此6岁以下的儿童不适宜服用。（副作用产生与否因人而异）[61]
随着时间推进与各方的努力，中枢神经兴奋剂的相关副作用已可借由包括但不限于剂量调整、服药时间、饭前饭后服用、服药频率等服药模式之改变以及改变药物组合等方式获得相当程度的减少。[59][62][63][64][65]
提升表现
[编辑]- 认知方面
2015年，一篇系统综述[参 14]和一篇元分析/整合分析[参 15]回顾了数篇优秀的临床试验[参 16]报告后发现，低剂量（医疗用剂量）的安非他明能适度但不强烈地促进一个人的认知功能，包含工作记忆、长期的情节记忆、抑制控制以及在一些方面的注意力。[66] [67]安非他明强化认知功能的效果已知是部分透过间接活化在大脑前额叶的多巴胺受体D1和肾上腺素受体 α2。[31] [66]一篇2014年的系统综述发现，低剂量（医疗用剂量）的安非他明能促进和稳固记忆巩固的过程，进而提升一个人回忆的能力。[68]低剂量（医疗用剂量）的安非他明也可增加大脑皮层（质）区的效率，这能让一个人的工作记忆获得进步。[31][69]安非他明和其他用于治疗ADHD的中枢神经刺激剂能透过提升task saliency来增加一个人去做事情的动机、并强化一个人的警觉心（清醒度），因而能刺激一个人开始做“以目标为导向”的行为。[31][70][71]中枢神经兴奋剂（例如：安非他明）能提升一个人在困难且枯燥的任务中的表现。[31][71][72]超过医疗用剂量范围（包含其误差范围及容许最大上限）的安非他明剂量将不利于工作记忆和其他的认知功能。[31][71]
- 生理
虽然安非他明可以提升速度、耐力（延迟疲劳的发生）、肌耐力、身体素质和警觉心并减少心理反应时间。[32][73][74][75]然而，“非因医疗需求使用安非他明”在各种运动场合都是被严格禁止的。[76][77]
安非他明借由抑制多巴胺在中枢神经系统中的回收及外流来促进耐力和反应时间的提升。[74][75][78]安非他明和其他作用于多巴胺系统的药物一样，都能增加在固定施力（levels of perceived exertion）下的动力（能）输出。这是因为安非他明能夺取（override）体温的“安全开关”的控制权并将身体核心温度的上限提高以取得在体温安全上限提高前被身体保留的能量。[75][79][80]于医疗用剂量范围（包含其误差范围），安非他明的副作用不至于影响运动员的运动表现；[32][74]然而，当摄取的剂量过多时，安非他明可能会引起严重的后果，例如：横纹肌溶解症和高热(体温过高)。[33][81][74]
医疗上的禁忌
[编辑]根据国际化学品安全规划署（IPCS, International Programme on Chemical Safety）和美国食品药物管理局(USFDA)，[VI]安非他明不建议处方给有药物滥用、心血管疾病、对于各种刺激严重反应过度、和严重焦虑历史的人。[VII][83][84]安非他明也不被建议处方给正经历动脉血管硬化（血管硬化）、中度到重度高血压、青光眼（眼压过高）、或甲状腺机能亢进（身体在体内制造出过量的甲状腺贺尔蒙/激素）的人。[83][84][85]曾对中枢神经刺激剂有药物过敏的人以及正在服用单胺氧化酶抑制剂(MAOI)或单胺氧化酶抑制剂类药物(MAOIs)，可能不适合使用安非他明。即便曾有合并使用安非他明和单胺氧化酶抑制剂后仍一切平安的案例。[83][84][86][87]
IPCS和美国食品药物管理局也同意患有神经性厌食症、双极性情感疾患、忧郁、高血压、狂躁、精神分裂症、雷诺氏综合症、癫痫发作、抽动综合症、妥瑞氏症、和有甲状腺问题、肝肾问题的人在使用安非他明时应密切追踪上述疾病的变化。[83][84]
人体试验证明，医疗用剂量下的安非他明并不会导致胎儿或新生儿畸形。然而超越医疗用剂量甚多的安非他明确实会增加胎儿或新生儿畸形的机会。[84]
研究观察发现，安非他明会进入母亲的母乳中，因此建议母亲不要在使用安非他明药物的期间内授乳。[83][84]
由于安非他明可能影响食欲继而导致可反转的身高及体重的成长迟缓，[VIII]，因此建议儿童或青少年在用药期间定期测量自己的身高及体重。[83]
副作用
[编辑]安非他明的副作用以及其发生率和严重度大致上与使用的剂量呈正相关。[33][89][73]成分为安非他明的药品，诸如：阿得拉尔、Dexedrine、和安非他明的等价物质（generic equivalents）目前皆已获得美国食品药物管理署许可用于长期性的治疗。[89][29]
摄取大幅超出医疗剂量的安非他明将大幅增加严重副作用出现的风险。[73]
生理
[编辑]在治疗剂量下，生理副作用会因年龄或个人情况而有所不同[89]。心血管方面的副作用包含：迷走-血管反射导致的高血压或是低血压、雷诺氏症（因小动脉收缩而导致流往手脚的血流减少）、以及心搏过速（tachycardia）。[89][73][88]
男性性方面而言，副作用可能包含：勃起障碍、频繁勃起、或是勃起时间过长。[89]
消化方面的副作用可能包含：腹痛、丧失胃口、反胃以及体重降低。[89][90]其他潜在的副作用包含：视力模糊、口干、磨牙、流鼻血、多汗症、药物性鼻炎（药物导致的鼻塞）、癫痫阈值/触发门槛降低，以及抽搐[来源组 1]。在一般的治疗剂量下鲜少发生危险副作用[73]。
安非他明刺激延脑的呼吸中枢，使得呼吸变得较快速且较深。[73]正常人在治疗剂量下，此作用通常难以察觉；然而，此作用在呼吸已经受损的病人身上有可能变得明显。[73]
安非他明会使膀胱括约肌收缩，而导致解尿困难[73]。此效果可以应用在遗尿或是失去膀胱控制能力的病人身上。[73]
安非它命在胃肠道的作用是难以预测的[73]。安非他明可能会减少胃肠活动力（内容物通过肠胃道的速率）[73]；然而，安非他明亦可能在胃肠道的平滑肌处于松弛状态时，增加其活动力。[73]
安非他明有轻微的止痛作用且可以增强鸦片类物质的止痛作用。[73]
美国食药署2011年委任的研究发现：不论是小孩或是成人，“安非他明（于医疗情境下使用）”和“其他用于治疗ADHD的中枢神经兴奋剂”均和重大的心血管疾病（猝死、心脏病发、中风）无关[来源组 2]；然而，当病患已有心血管方面的疾病时，禁用此药。[来源组 3]
心理
[编辑]在医疗用剂量范围，最常见的副作用为：警觉心的增强、（对未来或即将发生的不愉快之事的）忧虑/担心/恐惧、理解力提升、专注力的提升、主动性/自主决断行事的能力的提升、自信心的提升、社交能力的提升；情绪阴晴不定、失眠或清醒、和疲劳感的减退。[89][73]
比较少见的副作用包括焦虑、性欲改变、应激性、重复性的或强迫性的行为（repetitive or obsessive behaviors）、静不下来;[来源组 4]。副作用出现与否因人而异，端视用药者的个性及精神状态（mental state）。
安非他明所引起的精神疾病，例如：妄想和偏执，可能出现在重度的使用者身上。[33][89][98]长期摄取医疗剂量的安非他明虽然有可能引起上一段文中所述的疾病，但这是非常罕见的。[33][89][99]根据美国食品药物管理局所提供的资讯，“目前没有证据显示‘中枢神经刺激剂’会导致‘攻击性的行为（aggressive behavior）’或‘敌意（hostility）’”。[89]
使用医疗剂量的用药者可能会培养出习惯在某个特定地方用药的偏好。[54][100][100][101]
法律
[编辑]安非他明在中华民国受毒品危害防制条例管制，若无处方笺，在司法上视为第二级管制药品，持有、运输、贩卖皆为违法行为。[102]
严重过量
[编辑]安非他明过量使用会引起许多症状，然而在适当的医疗照护下，不至于死亡。[84][103]
药物过量症状的严重度与剂量成正比；与身体对安非他明的药物耐受性成反比。[73][84]已知每天摄取达到5公克的安非他明（每天最大摄取量的五十倍）会导致身体对安非他明产生药物耐受性。[84]严重过量的安非他明摄取所致的症状列于下方；安非他明中毒一旦到达出现全身抽搐和昏迷则必须立刻急救以避免死亡。[33][73]在2013年，安非他明、甲基安非他明和其他列于ICD-10 第五章：精神和行为障碍§使用化学药物、物质或酒精引起的精神和行为障碍中的安非他明相关物质的过量使用在世界上共导致3788人死亡。(3,425–4,145人死亡、95%信赖区间）。[IX][104]
被过度活化达到病态程度的中脑边缘回路（一个连接腹侧被盖区和伏隔核的多巴胺通道），在安非他明的成瘾中扮演着主要的角色。[105][106]
当一个人经常服用严重过量的安非他明，将伴随安非他明成瘾的高度风险，因为持续过量的安非他明会逐渐增加伏隔核的ΔFosB（“成瘾”与否的分子开关和主控蛋白）的档次。[107][108][109]一旦伏隔核的ΔFosB过度表达，这个人的“成瘾性行为”[注 2]（例如：出现试图取得安非他明的冲动行为）将开始随之增加。[107][110]虽然目前没有治疗安非他明成瘾的有效药物，但规律的且每次都有持续一定时间的有氧运动能降低安非他明的成瘾风险也是治疗安非他明成瘾的天然疗法。[111][112][来源组 5]运动能提升临床治疗的预后，且可能与认知行为治疗（目前已知最有效的安非他明成瘾的临床治疗法）相搭配为联合疗法。[111][113][114]
| 生物系统 | 轻度、中度过量[33][73][84] | 过量[来源组 6] |
|---|---|---|
| 心脏血管系统 | ||
| 中枢神经系统 | ||
| 肌肉骨骼系统 |
| |
| 呼吸系统 |
|
|
| 生殖泌尿系统 | ||
| 其他 |
成瘾
[编辑]| “成瘾及生理、心理依赖”的相关术语词汇表[101][108][117][118] | |
|---|---|
| |
长期服用远超医疗用剂量范围的安非他明会导致安非他明成瘾。然而长期摄取医疗剂量范围的安非他明并不会引起上述问题。[119][120][121]安非他明滥用（例如：长期摄取严重过量的安非他明）会导致大脑对于该剂量产生药物耐受性。渐渐地，滥用者必须服用更大量的安非他明以换取同样的效果。[122][123]
分子生物机转
[编辑]当前关于“长期安非他明滥用所致的成瘾”的模型中，已知会改变一些脑部的结构（特别是伏隔核）[124][125][126]。造成脑部结构改变的最重要的转录因子（transcription factor）为：ΔFosB、cAMP反应元件结合蛋白(CREB)、和核因子κB(NF-κB)。[X][125]ΔFosB在药物成瘾的发展过程中扮演着至关重要的角色，主要的原因在于其在伏隔核中D1-type中型多棘神经元的过度表达，为“成瘾”及“成瘾衍生的行为”及“神经元为了适应新常态所做的调适”的充分且必要条件。[XI][107][108][125]
一旦ΔFosB充分过度表达（sufficiently overexpressed），将诱发越来越严重的成瘾状态并伴随ΔFosB值的持续创新高。[107][108]ΔFosB已被证明与酒精成瘾、大麻成瘾、古柯碱成瘾、派醋甲酯成瘾、尼古丁成瘾、鸦片成瘾、phencyclidine成瘾、异丙酚、和安非他明的替代性物质成瘾、及其他成瘾有关。[来源组 7]ΔJunD为一个转录因子；而G9a为组织蛋白甲基转移酶的一种。ΔJunD和G9a直接与伏隔核中的ΔFosB值的升高成反比。[108][125][130]
利用载体让伏隔核中的ΔJunD充分过度表达，可以使由长期药物滥用所致的渐进式神经元和行为改变完全停止。（比如说：ΔFosB所致的改变）。[125]ΔFosB也在人们于天然酬赏（natural rewards）中的行为反应调节上扮演重要的脚色。天然酬赏包含：美味的食物、性爱、运动......。[110][125][131]因为天然酬赏以及成瘾性药物皆会激发ΔFosB（这些酬赏让大脑刺激ΔFosB的增加），长期过度地从事上述行为将可能导致类似的成瘾之病理生理（pathological）。[110][125]
ΔFosB是导致“安非他明成瘾”、“安非他明引起的性成瘾”中最关键的致瘾因素。“安非他明引起的性成瘾”为“安非他明使用”加上“过度的性活动”所引发的“冲动之下的性行为”。[110][132][133]这类的性成瘾与多巴胺失调综合症相关，有时此症会出现在正在服用作用于多巴胺的药物的人身上。[110][131]
安非他明基因调控（gene regulation）的效果端视剂量与通路（dose- and route-dependent）而定。[126]绝大多数主题为“基因调节（gene regulation）”和“成瘾”的研究都是透过动物试验以及利用静脉注射的方式对实验动物注射超高剂量的安非他明来进行。[126]少数几个透过人体试验（依照体重来决定医疗用剂量）来进行的研究表明，口服医疗用剂量的安非他明并不会影响基因调控，即便有，也是极为轻微的。这表示安非他明用作医疗用途是十分安全的。[126]
药物治疗
[编辑]截至2014年5月[update]并没有能够有效治疗安非他明成瘾的药理疗法[134][135][136]。2015年到2016年间的论文回顾结果指出：选择性TAAR1促进剂有非常大的可能在将来被用来治疗中枢神经兴奋剂的成瘾；[137][138]然而，截至2016年2月[update]，已知可作为选择性TAAR1促进剂的物质都属于试验性药物。[137][138]安非他明成瘾与伏隔核中的多巴胺接收器们以及位置相同（co-localized）的NMDA 接受器们的活化高度相关；[XII][106]镁离子借由封锁一个接受器-钙离子通道，来阻断 NMDA接受器们。[106][139]一篇论文回顾做成结论：根据动物试验，因成瘾而使用中枢神经刺激剂的人，可以发现过量的中枢神经兴奋剂显著降低脑细胞内部的镁离子活动。[106]利用镁元素补充剂，能降低安非他明使用者自我服用[c]的机会。然而这不被认为是有效治疗安非他明成瘾的单一疗法（mono-therapy）。[XIII][106]
行为治疗
[编辑]认知行为治疗是当前治疗中枢神经刺激剂成瘾的疗法。[114]除此之外，运动在生物神经元产生的效果的研究中表明维持每天从事有氧运动（例如：跑步等）的习惯，能避免药物成瘾缠身；本身也是一个对于治疗安非他明成瘾的有效附加疗法。[来源组 5]运动能让所有疾病的预后都更加乐观，特别是对于中枢神经刺激剂成瘾。[111][113][140]值得一提的是，有氧运动能降低擅自服用中枢神经兴奋剂的欲望，降低再次擅自服用中枢神经兴奋剂的几率（reinstatment）(i.e., relapse)、降低“试图取得药物所做出的举动（drug-seeking behavior）”、降低多巴胺受体D2在纹状体中的密度。[110][140]它在病生理学中的脚色是相对于“兴奋剂的使用”和“兴奋剂的效果”，它会引起纹状体中DRD2密度的减少。[110]一篇论文回顾提到，借由改变纹状体（striatum）中的ΔFosB、c-Fos immunoreactivity或部分的脑内回馈系统来避免药物成瘾在一个人身上的发展。[112]
| 神经可塑性和行为可塑性的形式 | 增强物的种类 | 来源 | |||||
|---|---|---|---|---|---|---|---|
| 鸦片类 | 中枢神经刺激剂 | 高脂肪或高糖食物 | 性交 | 运动与神经元关系 | 环境丰富化 | ||
| 伏隔核中D1-type中的ΔFosB表现 | ↑ | ↑ | ↑ | ↑ | ↑ | ↑ | [110] |
| 行为可塑性 | |||||||
| 摄取量的增加 | 有 | 有 | 有 | [110] | |||
| 中枢神经刺激剂跨越-敏化作用 | 有 | 不适用 | 有 | 有 | 削减 | 削减 | [110] |
| 未经过处方而自行私下摄取中枢神经刺激剂 | ↑ | ↑ | ↓ | ↓ | ↓ | [110] | |
| 强化“在特定地点摄取兴奋剂的习惯” | ↑ | ↑ | ↓ | ↑ | ↓ | ↑ | [110] |
| 强化“试图取得该致瘾药物的行为” | ↑ | ↑ | ↓ | ↓ | [110] | ||
| 神经化学物质的可塑性 | |||||||
| 伏隔核中CREB磷酸化 | ↓ | ↓ | ↓ | ↓ | ↓ | [110] | |
| 伏隔核中对于多巴胺的过敏反应 | 没有 | 有 | 没有 | 有 | [110] | ||
| 经过变动的纹状体多巴胺接收器的讯号发送 | ↓DRD2 , ↑DRD3 | ↑DRD1, ↓DRD2 , ↑DRD3 | ↑DRD1, ↓DRD2, ↑DRD3 | ↑DRD2 | ↑DRD2 | [110] | |
| 经过变动的纹状体鸦片样肽受体的讯号发送 | 未改变，或 ↑μ-鸦片接收器 |
↑μ-鸦片接收器 ↑κ-鸦片接收器 |
↑μ-鸦片接收器 | ↑μ-鸦片接收器 | 未改变 | 未改变 | [110] |
| 发生于纹状体鸦片肽的改变 | ↑强啡肽 脑啡肽未改变 |
↑强啡肽 | ↓脑啡肽 | ↑强啡肽 | ↑强啡肽 | [110] | |
| 多巴胺通道的神经突触的可塑性 | |||||||
| 伏隔核中树突的数量 | ↓ | ↑ | ↑ | [110] | |||
| 伏隔核中树突棘的密度 | ↓ | ↑ | ↑ | [110] | |||
注解：DRD2 = 多巴胺受体D2；↑ = 上升；↓ = 下降
依赖和戒断症状
[编辑]根据另一篇由考科蓝协作组织所做的一篇论文回顾指出当一个长期严重摄取安非他明或甲基安非他明的药物成瘾者某天突然停止摄取安非他明或甲基安非他明，那么根据许多成瘾个案的报告显示，具有时效性（time-limited）的戒断症状将在他们上一次摄取安非他明后的24小时内出现。 在成瘾患者停用安非他明后，安非他明的戒断症状的出现率接近九成。这九成都出现至少六个定义在“《精神疾病诊断与统计手册》安非他明戒断症状”中的症状。年纪与剂量和戒断症状的严重度呈正相关。安非他明的戒断症状共有两个阶段且总共可能历时三周或更多。第一阶段（撞墙期marked "crush" phase）约持续一周。[141]安非他明的戒断症状可能包含：对于各种刺激极度敏感、躁动不安（irritability）、焦虑、对于安非他明有难以抑制的渴求、烦躁、疲倦、多食症、过动或行动迟缓、缺乏动机、嗜睡、和清醒梦。[141][142]
这些特征及症状必须非由其他疾病（包含心理疾病）引起，且无法归因于其他物质的滥用。满足上述条件，才符合“安非他明戒断症状”综合症的诊断标准。[141][143]
通过美国食品药物管理局严格审核的安非他明药品说明书上并未提到任何安非他明在医疗用剂量下突然停用会导致任何安非他明戒断症状的出现。[85][144][145][146]
DSM中，安非他明中毒及戒断症状之标准
[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明类的物质、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）长期的安非他明类物质、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。
安非他明戒断症状的频率列表
[编辑]| 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% |
| 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 |
| - | 自我尝试戒毒（Self detoxication） | 被迫戒毒（Enforced detoxication） |
|---|---|---|
| 服用更多其他药物 | - | - |
| 大麻（Cannabis） | 22(27%) | 10(59%) |
| 替马西泮（Temazepam） | 21(26%) | - |
| 酒精 | 17(21%) | 2(12%) |
| 鸦片类物质（Opiates） | 12(15%) | 1(6%) |
| 地西泮（Diazepam） | 4(5%) | - |
| 巴比妥类药物（Barbiturates） | 3(4%) | 1(6%) |
| 心理学技巧 | - | - |
| 转移注意力（例如：工作、看电视） | 35(21%) | 1(6%) |
| 不再与药物成瘾的朋友来往 | 31(19%) | - |
| 获得人们的支持（家庭、社会中的支持团体） | 11(7%) | - |
| 把药物及针头丢掉 | 5(3%) | - |
中毒与致病
[编辑]中毒
[编辑]在啮齿动物（rodents）和灵长类动物（primates）的药物试验发现到，够高的安非他明剂量会导致多巴胺神经中毒甚或致使多巴胺末梢神经受损退化并降低转运体和接收器的功能。[148][149]目前并无证据显示安非他明会直接荼毒人类的神经。[150][151]然而，超高剂量（large doses）的安非他明摄取量可能会产生高热（体温过高）的现象并间接导致：多巴胺的神经性中毒（dopaminergic neurotoxicity）、过多的活性氧类（reactive oxygen species）生成、自然氧化（autoxidation）增加。[来源组 8]从高剂量的安非他明摄取量引起的神经中毒的生物模式中发现，人体核心体温高于40°C是“高剂量的安非他明摄取量”是否引起神经中毒的“必要条件”。[149]在动物试验中，若动物的脑温长期超过40°C，容易因过多的活性氧类生成、受干扰的细胞蛋白功能和短暂的血脑屏障标准放宽而促使安非他明性的神经中毒发生。[149]
致病
[编辑]严重的安非他明过量可能造成“中枢神经刺激剂过量所引发的精神异常（stimulant psychosis）”，症状包含但不限于幻觉（delusion）和被害妄想、疑神疑鬼、妄想、偏执等。[98]此机制用于精神分裂症研究时诱发精神病发作的药物。[154]一篇由考科蓝协作组织所做的论文回顾及统整发现在所有因摄取严重过量的“安非他明、dextro-安非他明、及甲基安非他明”而导致精神异常的患者中，有5%-15%的患者即便经过治疗，仍无法完全康复。[98][155]
根据同一篇由考科蓝协作组织所做的论文回顾及统整，至少一个实验（trial）显示抗精神病药物（antipsychotic）能有效解决因严重过量的安非他明所致的急性精神异常症状。 [98]另外，稳定在服用抗精神病药物的人使用安非他明后心跳血压等生理变化也较一般人来的少。[154]
“摄取医疗剂量的安非他明所致的急性精神异常”是非常罕见的（very rare）。
（非常罕见 very rare： < 1/10000 ；罕见 rare：>= 1/10000 & <1/1000）[99][83]
交互作用
[编辑]目前已知许多种物质都会和安非他明发生药物相互作用，导致安非他明或参与作用的另一物质的药效或代谢过程发生改变。[4][156]用于分解安非他明的酶的抑制剂（如CYP2D6、FMO3）都会延长其半衰期，这意味着药效会更持久。[17][156]安非他明也会和MAOIs产生交互作用，特别是MAOI类中的monoamine oxidase A抑制剂（monoamine oxidase A inhibitors）。
因为MAOIs和安非他明两者都会增加儿茶酚胺（i.e.,正肾上腺素和多巴胺）在血浆中的浓度[156]；因此MAOIs与安非他明合并使用是危险的[156]。
安非他明会调节几乎所有作用于中枢神经的药物的活动。特别需要注意的是，安非他明可能会降低镇静剂和中枢神经抑制剂）的效果，并增加其他中枢神经刺激剂和抗忧郁药的效果。[156]
安非他明也可能降低抗高血压药和抗精神病药（anti-psychotics）的药效，这是因为安非他明本身对于血压及多巴胺系统的作用。[156]
锌的补充剂可能会降低安非他明用于治疗注意力不足过动症时的最小有效剂量（minimum effective dose）。[XIV][160]
整体来说，安非他明并不会与日常生活中常见的食物起任何重大的交互作用，但安非他明的吸收和排泄会分别受到肠胃内容物（gastrointestinal content）的pH值和尿液的酸碱值影响。[156] 酸性物质会减少安非他明的吸收并增加尿液的排泄；碱性物质则相反。
由于pH值在安非他明的吸收这件事上具有影响力，所以安非他明也会和 氢离子泵阻断剂（PPI, proton pump inhibitors）和H2受体阻抗剂（H2 antihistamines）等中和胃酸的制酸剂产生交互作用。[156]
药学
[编辑]药物代谢动力学
[编辑]安非他明的口服生物体可利用率[参 17]与肠胃的pH值连动；[156]安非他明非常容易在肠道被吸收，右旋苯丙胺的生体可利用率在多数的情况下高于75%。[2]安非他明呈弱碱性，其pKa值介于9–10之间;[4]因此，当pH值呈碱性时，多数的安非他明会以其易溶于脂类的纯胺类型态形式存在。在此情况下，身体会通过肠道上皮组织富含脂类的细胞膜[参 18]来吸收安非他明。[4][156]相反地，酸性的pH值表示安非他明主要以易溶于水的离子（盐）形式存在，因此较少能被吸收。[4]大约15–40%循环于血管中的安非他明与血浆蛋白[参 19]相连接。[3]安非他明的对映异构体的半衰期会随着尿液的pH值而有所不同。[4]当尿液的酸碱值落在正常范围中，右旋苯丙胺和左旋苯丙胺的半衰期分别为9–11小时及11–14小时。[4]酸性饮食会导致安非他明的对映异构体的半衰期降低至8–11小时；碱性饮食则会使安非他明的对映异构体的半衰期增加到16–31小时。[5][12]
成分为安非他明或其衍生物的短效药品大约在口服后三小时在体内达到最高血浆浓度；而成分为安非他明或其衍生物的长效药品则在口服后大约七小时在体内达到最高血浆浓度。[4]
安非他明主要透过肾脏来代谢，大约30–40%的药物以药物本身原始的型态从酸碱度正常的尿液中排出。[4] 尿液是碱性时，安非他明倾向以其纯胺类型态存在，因此较少被排泄。[4]
当尿液的pH值失常时，各种安非他明的分解物在尿液中重新结合的程度将从最低1%到最高75%。该程度的高低大多取决于于尿液的酸碱值，尿液越酸，结合率越高；尿液愈碱，结合率越低。[4]安非他明通常于口服后两天内自体内完全代谢完毕。[5]安非他明确切的半衰期及药效作用期随着（小于两天的）重复服用导致的血浆内安非他明浓度（plasma concentration of amphetamine）的增加而延长。[161]
对人体无药效的前药（prodrug）：赖氨酸安非他明并不若安非他明一样容易受肠胃道环境的pH值影响；[162]赖氨酸安非他明在肠道被吸收进入血管的血液后很快就会透过水解的方式转化为右旋安非他明。而参与这水解反应的酶与红血球有关。[162]
Lisdexamfetamine的半衰期通常小于一个小时。[162]
细胞色素 P450 2D6（Cytochrome P450 2D6、或CYP2D6）、多巴胺β羟化酶（Dopamine β-hydroxylase、或DBH）、flavin-containing monooxygenase 3、butyrate-CoA ligase、和glycine N-acyltransferase为已知在人体中参与[注 3]“安非他明”及“安非他明代谢后之产物”的代谢反应的酶。[来源组 9]
“安非他明代谢后之产物”包含：4-hydroxyamphetamine、4-hydroxynorephedrine、4-羟基苯基丙酮、苯甲酸、马尿酸、苯丙醇胺、苯基丙酮[注 4][4][5][6]。
在这些“安非他明代谢后之产物”之中，有实际药效的产物（sympathomimetics）为：4‑hydroxyamphetamine[166]、4‑hydroxynorephedrine[6]、和norephedrine[167]。 [166]4‑hydroxynorephedrine,[168]and norephedrine.[167]
安非他明的主要代谢途径包含：芳香对羟基化、脂肪族α-、β-羟基化、N-氧化、N-脱烷基、和脱氨基。[4][5]
下图为已知的“安非他明”代谢途径和“安非他明代谢后之产物”：[4][17][6]
苯丙胺的代谢途径
 从酸碱度正常的尿液中可发现，大约30–40%的“安非他明”以本身原始的型态排出；大约50%的安非他明以不具药效的“安非他明代谢后之产物”（即为图片中最下列的产物）的型态排出。 [4] 剩下的10–20%则为“安非他明代谢后之产物”之中，有实际药效的产物。 [4] 苯甲酸（Benzoic acid）被butyrate-CoA连接酶（butyrate-CoA ligase）代谢后成为一个中介物质/中间产物（intermediate product）：benzoyl-CoA [164] 随后透过glycine N-acyltransferase代谢并转化为马尿酸（hippuric acid）。[165] |
药物效应动力学
[编辑]关于安非他明作用机制的一个更简单且比较非技术性的解释，请见“阿得拉尔 § Mechanism of action”。苯丙胺在多巴胺能神经元的药物效应动力学
|
安非他明借由将单胺类神经递质在脑中（主要于脑中那酬赏与执行功能路径上的儿茶酚胺的神经元）的用途改变为神经讯号来产生疗效。[30][49]
安非他明作用于monoamine transporter上的效应使得犒赏系统和管控功能中的主要神经传导物质（多巴胺、正肾上腺素）依安非他明的剂量，成比例的迅速上升。[30][49][169]
服用安非他明所带来的增强和促进motivational salience的效果起因于中脑边缘通路中的多巴胺活动变得更加活跃之故。[31]
安非他明带给使用者的欣快感和运动协调激励之效果和安非他明刺激纹状体的神经突触之多巴胺和正肾上腺素浓度增加的速度和规模成正比[1]。
安非他明已经被确认为trace amine-associated receptor 1(TAAR1)[注 5]的强刺激剂（potent full agonist）。[30][170]
TAAR1受额外刺激后会借由活化腺苷酸环化酶和抑制单胺转运蛋白的功能而增加cAMP的生成。[30][171]
单胺的自身受体（例如：D2 short、presynaptic α2、和presynaptic 5-HT1A)）具有与TAAR1相反的效果，而这些受体形成了一个对于单胺的管理系统。[30][137]
值得注意的是，安非他明和痕量胺拥有对TAAR1相当高的连结亲缘性（连结吸引力），但对于单胺之autoreceptors则不然。[30][137]
神经造影研究表示，安非他明和痕量胺对单胺类神经递质的再回收抑制作用具有位置上的针对性，进一步来说，就是针对那些相关且有TAAR1同时存在的单胺类神经递质神经元。[30]
截至2010年[update]，TAAR1和多巴胺转运体的“共同位置化”co-localization现象已可在恒河猴身上透过视觉化的方式观察到，但【带有去甲肾上腺素转运体(NET)的TAAR1】和【血清素转运体(SERT)】的共同位置化现象迄今只能透过信使核糖核酸(mRNA)的表现（expression）来证明。[30]
已隐藏部分未翻译内容，欢迎参与翻译。
In addition to the neuronal monoamine transporters, amphetamine also inhibits both vesicular monoamine transporters, VMAT1 and VMAT2, as well as SLC1A1, SLC22A3, and SLC22A5.[来源组 10] SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.[来源组 10]Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[3][178]a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[3][179][180]The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR.[180][181]Amphetamine also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines.[19][182]In humans, the only post-synaptic receptor at which amphetamine is known to bind is the 5-HT1A receptor, where it acts as an agonist with micromolar affinity.[183][184]
The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine,[30]serotonin,[30]norepinephrine,[30]epinephrine,[169]histamine,[169]CART peptides,[3][178]endogenous opioids,[185][186][187]adrenocorticotropic hormone,[188][189]corticosteroids,[188][189]and glutamate,[172][174]which it effects through interactions with CART, 5-HT1A, EAAT3, TAAR1, VMAT1, VMAT2, and possibly other biological targets.[来源组 11]
Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[190]Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[73][190]
历史、社会与文化
[编辑]成药
[编辑]目前几种安非他明的处方药配方含有两种对映异构体，包括阿得拉尔，Dyanavel XR和Evekeo，其中最后一种是外消旋的安非他明硫酸盐。[1][37][90]目前的一些品牌及其通用等同物如下。
| 药物商品名称 | United States Adopted Name |
(D:L) ratio | 药剂型 Dosage form |
上市日期Marketing start date |
来源 |
|---|---|---|---|---|---|
| Adderall | – | 3:1 (salts) | 锭剂 tablet |
1996 | [1][29] |
| Adderall XR | – | 3:1 (salts) | 胶囊 capsule |
2001 | [1][29] |
| Adzenys XR | amphetamine | 3:1 (base) | ODT | 2016 | [191][192] |
| Dyanavel XR | amphetamine | 3.2:1 (base) | suspension | 2015 | [90][193] |
| Evekeo | amphetamine sulfate | 1:1 (salts) | tablet | 2012 | [37][194] |
| Dexedrine | dextroamphetamine sulfate | 1:0 (salts) | capsule | 1976 | [1][29] |
| ProCentra | dextroamphetamine sulfate | 1:0 (salts) | liquid | 2010 | [29] |
| Zenzedi | dextroamphetamine sulfate | 1:0 (salts) | tablet | 2013 | [29] |
| Vyvanse | lisdexamfetamine dimesylate | 1:0 (prodrug) | capsule | 2007 | [1][162] |
| tablet |
| 药物 | 化学式 | 分子量[XV] | amphetamine base [XVI] |
amphetamine base in equal doses |
doses with equal base content[XVII] | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| (g/mol) | (percent) | (30 mg dose) | ||||||||
| total | base | total | dextro- | levo- | dextro- | levo- | ||||
| dextroamphetamine sulfate[196][197] | (C9H13N)2•H2SO4 | |||||||||
| amphetamine sulfate[198] | (C9H13N)2•H2SO4 | |||||||||
| Adderall | ||||||||||
| 25% | dextroamphetamine sulfate[196][197] | (C9H13N)2•H2SO4 | ||||||||
| 25% | amphetamine sulfate[198] | (C9H13N)2•H2SO4 | ||||||||
| 25% | dextroamphetamine saccharate[199] | (C9H13N)2•C6H10O8 | ||||||||
| 25% | amphetamine aspartate monohydrate[200] | (C9H13N)•C4H7NO4•H2O | ||||||||
| lisdexamfetamine dimesylate[201] | C15H25N3O•(CH4O3S)2 | |||||||||
| amphetamine base suspension[XVIII][90] | C9H13N | |||||||||
备注A
[编辑]- ^ 对映异构体指的是两个形状相同但方向相反的两个分子，二个分子互为镜像。[23]Levoamphetamine 和 dextroamphetamine 分别被简称为 L-amph 或 levamfetamine (INN) 和 D-amph 或 dexamfetamine (INN) [19]
- ^ "阿得拉尔"是一个品牌名称而非公有领域的称呼。但因为以下几个安非他明的异构体的名称及其英文名称 ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate") 太长了，因此本文将以此品牌名称来表示此种安非他明的混合物。[29])
- ^ “安非他明”一词也意指一个化学分类，但与“安非他明衍生物”这个化学分类不同的是，“安非他明”类在学术上并无标准的定义。[14][25]
有一个“安非他明”类的定义严格限定分类中仅有：安非他明的racemate and enantiomers和甲基安非他明methamphetamine的racemate and enantiomers。[25]
大多数“安非他明”类的定义为那些在药理学上以及结构上与安非他明相关的化合物。[25]
为避免读者混淆，本条目中仅会使用amphetamine、amphetamines来表示racemic amphetamine, levoamphetamine, and dextroamphetamine；安非他明衍生物（substituted amphetamines）来表示安非他明的结构分类。 - ^ 研究证实，长期以中枢神经兴奋剂治疗ADHD能在下列这些方面产生大幅的进步：学业、驾驶、降低药物滥用、降低肥胖、自尊、和社交功能等。[45]
在上述领域中，最为突出的领域为： 学业（例如：GPA分数、成果测验分数、受教育的时间长度、和教育程度）、自尊（例如：自尊心测验分数、尝试自杀的次数、自杀率等）和社交功能（例如：peer nomination scores、社交技巧、家庭关系、同侪关系、和浪漫关系/情侣关系）[45]
长期以“药物治疗合并行为治疗”的模式来治疗ADHD，能够比单独以药物治疗，产生更全面且更长足的进步。 [45] - ^ 考科蓝协作组织对于历年众多的“随机对照试验”的系统综述、数据统整分析后所得出的总结，基本上都是非常有水准且深具参考价值的。 [53]
- ^ 美国食品药物管理局核准的药品使用指引及医疗上的禁忌（放在药盒中的仿单/说明书）并非为了限制医师的决策而是为了避免药商恣意宣称药物的作用。医师可以此为参考，并依照每位病人的实际情况做出独立的判断。 [82]
- ^ 然而根据一篇回顾性论文，安非他明可以处方给曾有药物滥用历史的人，不过需要有对患者适度的药品控管，例如：每天由医护人员配给处方剂量。[1]
- ^ 曾受此副作用的用药者，身高及体重在在短暂停药后恢复至应有水准是可以被预期的。[44][47][88] 根据追踪，持续三年过程不停歇的安非他明治疗（没有合并任何积极减少安非他明副作用的疗法的情况下）平均会减少 2公分的最终身高。 [88]
- ^ “95% 信赖区间”指的是：有95%的几率，真实的死亡人数介于3,425 和 4,145 之间。
- ^ 转录因子是一种可以增加或降低一个特定基因的基因表现的蛋白。[127]
- ^ 简单来说，这里的“充分且必要（necessary and sufficient）”关系指的是“ΔFosB在伏隔核中的过度表达（over-expression）”与“成瘾衍生的行为”及“神经元为了适应新常态所做的调适”永远都是一起发生。
- ^ NMDA接受器们为与电压相关的ligand-gated ion channels。ligand-gated ion channels这个通道需要glutamate 以及一个共同促进剂（co-agonist ）：(D-serine 或 大豆属glycine)的同时连接才能被开启。
[139] - ^ 该篇回顾表示magnesium L-aspartate 及 氯化镁能大幅改善成瘾行为。
- ^ The human dopamine transporter contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro.[157][158][159]The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[159]
- ^ For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[195] and were within 0.01g/mol of published pharmaceutical values.
- ^ Amphetamine base percentage=molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
- ^ (1 / amphetamine base percentage) × scaling factor = (molecular masstotal / molecular massbase) × scaling factor. The values in this column were scaled to a 30 mg dose of dextroamphetamine sulfate. Due to pharmacological differences between these medications (e.g., differences in the release, absorption, conversion, concentration, differing effects of enantiomers, half-life, etc.), the listed values should not be considered equipotent doses.
- ^ This product (Dyanavel XR) is an oral suspension (i.e., a drug that is suspended in a liquid and taken by mouth) that contains 2.5 mg/mL of amphetamine base.[90] The product uses an ion exchange resin to achieve extended release of the amphetamine base.[90]
备注B
[编辑]- ^ 智力测验结果与专注力有关，详见注意力不足过动症#智力
- ^ 因成瘾所致的行为
- ^ 酶做为反应的催化剂catalyst，并不实际参与反应。
- ^ 不是苯丙酮
- ^ a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.
备注C
[编辑]注释
[编辑]英文名称对照
[编辑]- ^ 英文名称为：Pharmaceutical amphetamine
- ^ 英文名称为：racemic amphetamine
- ^ 英文名称为：substituted amphetamine
- ^ 英文名称为：Bupropion
- ^ 英文名称为：meth-amphetamine
- ^ 英文名称为：Randomized controlled trials
- ^ 英文名称为：follow-up studies
- ^ 英文名称为：neurotransmitter systems
- ^ 英文名称为：dopamine
- ^ 英文名称为：locus coeruleus
- ^ 英文名称为：prefrontal cortex
- ^ 英文名称为：nor-epinephrine或nor-adrenaline
- ^ 英文名称为：Cochrane Collaboration
- ^ 英文名称为：systematic review
- ^ 英文名称为：meta-analysis
- ^ 英文名称为：clinical trial
- ^ 英文名称为：bioavailability
- ^ 英文名称为：cell membrane
- ^ 英文名称为：plasma protein
引用
[编辑]- ^ [89][73][88][90][91]
- ^ [92][93][94][95]
- ^ [83][84][92][94]
- ^ [96][89][73][97]
- ^ 5.0 5.1 [110][111][112][113][140]
- ^ [115][33][73][103][116]
- ^ [107][110][125][128][129]
- ^ [149][152][153]
- ^ [4][14][163][16][17][18][164][165]
- ^ 10.0 10.1 [169][172][173][174][175][176][177]
- ^ [30][169][173][174][178][183]
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. PMID 23539642. doi:10.1177/0269881113482532. The intravenous use of d-amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice. Some of this intravenous abuse is derived from the diversion of ampoules of d-amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation. ... For these reasons, observations of dependence and abuse of prescription d-amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place (Jasinski and Krishnan, 2009b).
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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]
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|archiveurl=需要含有|url=(帮助).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%.
|section-url=被忽略 (帮助);|section=被忽略 (帮助); - ^ 13.0 13.1 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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The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
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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.
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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.
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One of a pair of molecular entities which are mirror images of each other and non-superposable.
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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).
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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.
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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. - ^ 32.0 32.1 32.2
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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
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Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). ... Beyond (1R,2S)-ephedrine and (1S,2S)-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. ... For example, (S)-amphetamine (Figure 4b), a key ingredient in Adderall® and Dexedrine®, is used to treat attention deficit hyperactivity disorder (ADHD) [79]. ...
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Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.
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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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The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes.
Figure 3: Treatment benefit by treatment type and outcome group （页面存档备份，存于互联网档案馆） - ^ Arnold, L. Eugene; Hodgkins, Paul; Caci, Hervé; Kahle, Jennifer; Young, Susan. Effect of Treatment Modality on Long-Term Outcomes in Attention-Deficit/Hyperactivity Disorder: A Systematic Review. PLoS ONE. [2017-05-15]. PMID 25714373. doi:10.1371/journal.pone.0116407. （原始内容存档于2020-11-09）.
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Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
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Only one paper53 examining outcomes beyond 36 months met the review criteria. ... There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term.
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"Three studies to be published in the August 2016 issue of the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) report that combining two standard medications could lead to greater clinical improvements for children with attention-deficit/hyperactivity disorder (ADHD) than either ADHD therapy alone.", August, 2016
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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). ... 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.
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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.
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In 1980, Chandler and Blair47 showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.
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In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. ... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is ‘off-limits’ in a normal (placebo) situation.
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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.
- ^
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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This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the “safety switch” or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.
- ^ 引用错误：没有为名为
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statements on package inserts are not intended to limit medical practice. Rather they are intended to limit claims by pharmaceutical companies. ... the FDA asserts explicitly, and the courts have upheld that clinical decisions are to be made by physicians and patients in individual situations.
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Table 2. Decongestants Causing Rhinitis Medicamentosa
– Nasal decongestants:
– Sympathomimetic:
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A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
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. - ^ 99.0 99.1 Greydanus D. Stimulant Misuse: Strategies to Manage a Growing Problem (PDF). American College Health Association (Review Article). ACHA Professional Development Program: 20. [2013-11-02]. （原始内容 (PDF)存档于2013-11-03）.
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This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.
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Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.
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Amphetamine use disorders ... 3,788 (3,425–4,145)
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ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
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ΔFosB serves as one of the master control proteins governing this structural plasticity.
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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).
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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.
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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.
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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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Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.
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Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
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When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.
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Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.
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To date, no pharmacological treatment has been approved for [addiction], and psychotherapy remains the mainstay of treatment. ... Results of this review do not support the use of psychostimulant medications at the tested doses as a replacement therapy
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When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse.
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Physical Exercise
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. - ^ 141.0 141.1 141.2 Shoptaw SJ, Kao U, Heinzerling K, Ling W. Shoptaw SJ , 编. Treatment for amphetamine withdrawal. Cochrane Database Syst. Rev. April 2009, (2): CD003021. PMID 19370579. doi:10.1002/14651858.CD003021.pub2.
The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005) ...
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Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. ... The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. ... In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus.
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Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.
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Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.
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Zinc binds at ... extracellular sites of the DAT [103], serving as a DAT inhibitor. In this context, controlled double-blind studies in children are of interest, which showed positive effects of zinc [supplementation] on symptoms of ADHD [105,106]. It should be stated that at this time [supplementation] with zinc is not integrated in any ADHD treatment algorithm.
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They did not confirm the predicted straightforward relationship between uptake and release, but rather that some compounds including AMPH were better releasers than substrates for uptake. Zinc, moreover, stimulates efflux of intracellular [3H]DA despite its concomitant inhibition of uptake (Scholze et al., 2002).
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The human dopamine transporter (hDAT) contains an endogenous high affinity Zn2+ binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396). ... Although Zn2+ inhibited uptake, Zn2+ facilitated [3H]MPP+ release induced by amphetamine, MPP+, or K+-induced depolarization specifically at hDAT but not at the human serotonin and the norepinephrine transporter (hNET).
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With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30 mg/day of zinc were safe for at least 8 weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30 mg per day of zinc.110
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VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC). ... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.
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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
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Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons. ... internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission.
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The physiological importance of CART was further substantiated in numerous human studies demonstrating a role of CART in both feeding and psychostimulant addiction. ... Colocalization studies also support a role for CART in the actions of psychostimulants. ... CART and DA receptor transcripts colocalize (Beaudry et al., 2004). Second, dopaminergic nerve terminals in the NAc synapse on CART-containing neurons (Koylu et al., 1999), hence providing the proximity required for neurotransmitter signaling. These studies suggest that DA plays a role in regulating CART gene expression possibly via the activation of CREB.
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Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. ... The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART
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Several studies on CART (cocaine- and amphetamine-regulated transcript)-peptide-induced cell signalling have demonstrated that CART peptides activate at least three signalling mechanisms. First, CART 55–102 inhibited voltage-gated L-type Ca2+ channels ...
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More recently, Colasanti and colleagues reported that a pharmacologically induced elevation in endogenous opioid release reduced [11C]carfentanil binding in several regions of the human brain, including the basal ganglia, frontal cortex, and thalamus (Colasanti et al. 2012). Oral administration of d-amphetamine, 0.5 mg/kg, 3 h before [11C]carfentanil injection, reduced BPND values by 2–10 %. The results were confirmed in another group of subjects (Mick et al. 2014). However, Guterstam and colleagues observed no change in [11C]carfentanil binding when d-amphetamine, 0.3 mg/kg, was administered intravenously directly before injection of [11C]carfentanil (Guterstam et al. 2013). It has been hypothesized that this discrepancy may be related to delayed increases in extracellular opioid peptide concentrations following amphetamine-evoked monoamine release (Colasanti et al. 2012; Mick et al. 2014).
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Similar MOR activation patterns were reported during positive mood induced by an amusing video clip (Koepp et al., 2009) and following amphetamine administration in humans (Colasanti et al., 2012).
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ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.
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参见
[编辑]外部链接
[编辑]
维基共享资源上的相关多媒体资源：Category:Amphetamine
- CID 3007 from PubChem – Amphetamine
- CID 5826 from PubChem – Dextroamphetamine
- CID 32893 from PubChem – Levoamphetamine
- Comparative Toxicogenomics Database entry: Amphetamine （页面存档备份，存于互联网档案馆）
- Comparative Toxicogenomics Database entry: CARTPT（页面存档备份，存于互联网档案馆）
- YouTube上的Drug abuse and drug addictions
- YouTube上的Mechanism of Drug Addiction in the Brain, Animation.
- YouTube上的Drug dependence
毒品危害防制条例-全国法规数据库 （页面存档备份，存于互联网档案馆）