用户:It's gonna be awesome/amphetamine
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| 临床资料 | |
|---|---|
| 读音 |  i/æmˈfɛtəmiːn/ |
| 其他名称 | α-methylphenethylamine |
| AHFS/Drugs.com | amphetamine |
| 核准状况 |
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| 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, Insufflation (medicine), 栓剂, 静脉注射 |
| ATC码 | |
| 法律规范状态 | |
| 法律规范 |
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| 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,[13][14][15] Flavin-containing monooxygenase[13][16][17] |
| 代谢产物 | 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, 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] |
| 生物半衰期 | D-amph:9–11 小时[4][10] L-amph:11–14 小时[4][10] 视PH值而定: 8–31 小时[11] |
| 作用时间 | 短效型 ( IR 立即释放药物) 使用后(dosing): 3–7 小时内[8][12] 长效型 (XR 缓缓释放药物) 使用后(dosing): 12 小时内[8][9] [12] |
| 排泄途径 | 主要透过肾脏; 视PH值而定 范围：1–75%[4] |
| 识别信息 | |
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| CAS号 | 300-62-9  |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| NIAID ChemDB | |
| PDB配体ID | |
| 化学信息 | |
| 化学式 | C9H13N |
| 摩尔质量 | 135.20622 g/mol[18] |
| 3D模型（JSmol） | |
| 密度 | 0.9±0.1 g/cm3 |
| 熔点 | 11.3 °C（52.3 °F） (预测)[20] |
| 沸点 | 203 °C（397 °F） 为 760 毫米汞柱[19] |
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安非他命（英文名称：Amphetamine[note 1]为一种中枢神经兴奋剂，用来治疗注意力不足过动症、嗜睡症、和肥胖症。“Amphetamine”一名撷取自alpha‑methylphenethylamine。
安非他命是在公元1887年发现的，以两种对映异构体的形式存在[note 2] ，分别是左旋安非他命和右旋安非他命。
准确来说，安非他命指的是特定的化学物质-外消旋纯胺类型态[24][25]，这个物质等同于安非他命的的两个对映异构体：左旋安非他命和右旋安非他命的等比化合物之纯胺类型态。 然而，实际上安非他命一词已被广泛的用来表示任何由安非他命对映异构体构成的物质或安非他命对映异构体本身。[21][26][25]
安非他命是一种中枢神经兴奋剂，适度适量地使用能提升整体抑制控制能力[27][28]。在医疗用的剂量范围内，安非他命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。安非他命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。然而，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命可引发严重的药物成瘾。然而长期摄取医疗剂量范围的安非他命并不会产生上瘾的风险。
此外，服用远超医疗用剂量范围的安非他命会引起精神疾病（例如：妄想[参 1]、偏执[参 2]）。然而长期摄取医疗剂量范围的安非他命并不会引起上述疾病。
那些为享乐而摄入的安非他命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。 [sources 1]
安非他命也被用来提升表现、促进大脑的认知功能及在助兴时（非医疗用途情况下）被作为增强性欲[a]和欣快感促进剂。
安非他命在许多国家为合法的处方药。然而，私自散布和囤积安非他命被视为非法行为，因为安非他命被用于非医疗用途的助兴可能性极高。[sources 2]
首个药用安非他命的药品名称为Benzedrine。当今药用安非他命[参 3]以下列几种形式存在：外消旋安非他命[参 4]、Adderall [note 3]、右旋安非他命，或对人体无药效的前驱药物甲磺酸赖氨酸安非他命。
安非他命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。[sources 3]
安非他命属于替代性苯乙胺类的物质。由安非他命衍伸出的物质被归纳在替代性苯乙胺[参 5]的分类中[note 4]，比如说：安非他酮[参 6]、 cathinone、 MDMA、 和 甲基苯丙胺[参 7]。安非他命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-Methylphenethylamine——有关。
Phenethylamine 是安非他命的原始化合物，而N-methylphenethylamine则是安非他命的位置异构体（只有在甲基族中才会区分出此位置异构体）。[sources 4]
用途
医疗
安非他命是用来治疗注意力不足过动症（ADHD）、嗜睡症（一种睡眠疾病）、和肥胖症。有时候安非他命会以仿单标示外使用的方式处方来治疗顽固性忧郁症及顽固性强迫症[1][10] [43] [50]。 在动物试验中，已知非常高剂量的安非他命会造成某些动物的多巴胺系统和神经系统的受损。[51][52] 但是，在人体试验中，注意力不足过动症患者在接受安非他命的治疗后，则发现安非他命可促进大脑的发育及神经的成长。[53][54][55]
回顾许多核磁共振照影（MRI）的研究后发现，长期以安非他命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。并且优化大脑中数个部位，例如：基底神经节的右尾状核。[53][54][55]
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命治疗注意力不足过动症的疗效及安全。[56][57][58][59]
持续长达两年的随机对照试验[参 8][b]结果显示：长期使用安非他命治疗注意力不足过动症，是有效且安全的。[56][59]
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。[note 5] 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。[57][59]
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，持续以安非他命治疗的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。[56] 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 9]，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。[59] 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 10]。[60] ；又此部分受损的神经传导系统和中脑皮质激素-多巴胺[参 11]的传导及蓝斑核[参 12]和前额叶[参 13]中的正肾上腺素[参 14]的传导相关。[60]
中枢神经兴奋剂，例如：methylphenidate和安非他命对于治疗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。[29][60] [61]
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。[62]
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。[63] [64]
根据考科蓝协作组织[参 15]所提供的文献回顾结果[note 6]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。[66] [67]
回顾结果也发现，中枢神经兴奋剂并不会恶化抽动综合征的症状，例如：妥瑞氏症，除非服用dextroamphetamine[c]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征的症状恶化。[68]
中枢神经兴奋剂只要依照医师指示用药，都是相当安全的。[69][70][71][71][72]
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）
[73]
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。[74] [75] [76] [71] [77]
提升表现
- 认知方面
公元2015年中，一篇系统综述[参 16]和一篇元分析/整合分析[参 17]回顾了数篇优秀的临床试验[参 18]报告后发现， 低剂量（医疗用剂量）的安非他命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。 [78] [79] 安非他命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。 [29] [78] 一篇2014年的系统综述发现低剂量（医疗用剂量）的安非他命能促进和稳固记忆的形成以及记忆品质，进而提升一个人的回忆的能力。[80] 低剂量（医疗用剂量）的安非他命也可增加大脑皮层（质）区的效率，这能让一个人的工作记忆获得进步。 [29] [81] 安非他命和其他用于治疗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。 [29] [82] [83] 中枢神经兴奋剂（例如：安非他命）能提升一个人在困难且枯燥的任务中的表现。 [29] [83] [84] 超过医疗用剂量范围（包含其误差范围及容许最大上限）的安非他命剂量将不利于工作记忆和其他的认知功能。 [29][83]
- 生理
虽然安非他命可以提升速度、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。[30][34] [30] [85] [86] 然而，“非因医疗需求使用安非他命”在各种运动场合都是被严格禁止的。[87] [88]
安非他命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。 [85][86] [89] 安非他命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。这是因为安非他命能夺取（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。[86] [90] [91] 于医疗用剂量范围（包含其误差范围），安非他命的副作用不至于影响运动员的运动表现； [30][85] 然而，当摄取的剂量过多时，安非他命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)。 [31][33] [85]
医疗上的禁忌
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)， [note 7] 安非他命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。 [note 8][93][94] 安非他命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。 [93][94][95] 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命。即便曾有合并使用安非他命和单胺氧化酶抑制剂后仍一切平安的案例。 [93][94][96][97]
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、雷诺氏综合征、癫痫发作、抽动综合征、妥瑞氏症、和有甲状腺问题、肝肾问题的人在使用安非他命时应密切追踪上述疾病的变化。[93][94]
人体试验证明，医疗用剂量下的安非他命并不会导致胎儿或新生儿畸形(i.e., it is not a human teratogen)。然而超越医疗用剂量甚多的安非他命确实会增加胎儿或新生儿畸形的机会。[94]
研究观察发现，安非他命会进入母亲的母乳中，因此建议母亲不要在使用安非他命药物的期间内授乳。[93][94]
由于安非他命可能影响食欲继而导致可反转的身高及体重的成长迟缓，[note 9] ，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。[93]
副作用
安非他命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。[31][33][34] 成分为安非他命的药品，诸如：Adderall、 Dexedrine、和安非他命的等价物质（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。 [44][33]
摄取大幅超出医疗剂量的安非他命将大幅增加严重副作用出现的风险。[34]
生理
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[33]。 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）。[33][34][98]
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。 [33]
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。[33][99] 其他潜在的副作用包含：视觉模糊、口干、磨牙、流鼻血、多汗、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[sources 5]。在一般的治疗剂量下鲜少发生危险副作用[34]。
安非他命刺激延脑的呼吸中枢，使得呼吸变得较快速且较深。[34] 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。[34]
安非他命会使膀胱括约肌收缩，而导致解尿困难[34]。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。[34]
安非它命在胃肠道的作用是难以预测的[34]。安非他命可能会减少胃肠活动力（内容物通过肠胃道的速率）[34]；然而，安非他命亦可能在胃肠道的平滑肌处于松弛状态时，增加其活动力。[34]
安非他命有轻微的止痛作用且可以增强鸦片类物质的止痛作用。[34]
美国食药署2011年委任的研究发现：不论是小孩或是成人，“安非他命（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[sources 6]；然而，当病患已有心血管方面的疾病时，禁用此药。[sources 7]
心理
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。 [33][34]
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;[sources 8] 。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）。
安非他命所引起的精神疾病，例如：妄想 和 偏执，可能出现在重度的使用者身上。[31][33][35] 长期摄取医疗剂量的安非他命虽然有可能引起上一段文中所述的疾病，但这是非常罕见（very rare）的。[31][33][36] 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）’”。[33]
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。[66][106][106][107]
严重过量
安非他命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。[94][108]
药物过量症状的严重度与剂量成正比；与身体对安非他命的药物耐受性成反比。[34][94] 已知每天摄取达到5公克的安非他命（每天最大摄取量的五十倍）会导致身体对安非他命产生药物耐受性。[94] 严重过量的安非他命摄取所致的症状列于下方；安非他命中毒一旦到达出现全身抽蓄（convulsion）和昏迷（coma）则必须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命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)。 [note 10][109]
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），在安非他命的成瘾中扮演着主要的脚色。 [110] [111]
当一个人经常服用严重过量的安非他命，将伴随安非他命成瘾的高度风险， 因为持续过量的安非他命会逐渐增加伏隔核的ΔFosB（“成瘾”与否的分子开关和主控蛋白 原文：a "molecular switch" and "master control protein" for addiction.）的档次。 [112][113][114] 一旦伏隔核的ΔFosB过度表达（over-expressed），这个人的“成瘾性行为”[注 2]（例如：出现试图取得安非他命的冲动行为）将开始随之增加。 [112][115] 虽然目前没有治疗安非他命成瘾的有效药物，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命的成瘾风险也是治疗安非他命成瘾的天然疗法。[116][117] [sources 9] 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命成瘾的临床治疗法）相搭配为联合疗法（combination therapy）。 [116][118][119]
| 生物系统 | 轻度、中度过量[31][34][94] | 过量[sources 10] |
|---|---|---|
| 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
| “成瘾及生理、心理依赖”的相关术语词汇表[107][113][121][122] | |
|---|---|
| |
| “成瘾及生理、心理依赖”的相关术语词汇表[107][113][121][122] | |
|---|---|
| |
长期服用远超医疗用剂量范围的安非他命会导致安非他命成瘾。然而长期摄取医疗剂量范围的安非他命并不会引起上述问题。 [37][38][39] 安非他命滥用（例如：长期摄取严重过量的安非他命）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命以换取同样的效果。 [123][124]
分子生物机转
当前关于“长期安非他命滥用所致的成瘾”的模型中，已知会改变一些脑部的结构（特别是伏隔核） [125][126][127]。 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)。[note 11] [126] 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。 [note 12] [112][113][126]
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。 [112][113] 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、和安非他命的替代性物质成瘾、及其他成瘾有关。 [sources 11] 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。 [113][126][131]
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）。 [126] 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（palatable food）、性爱、运动、......。 [115][126][132] 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。原文：i.e., they cause the brain to produce more of it），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）。 [115][126]
ΔFosB是导致“安非他命成瘾”、“安非他命引起的性成瘾”中最关键的致瘾因素。“安非他命引起的性成瘾”为“安非他命使用”加上“过度的性活动”所引发的“冲动之下的性行为”。 [115][133][134] 这类的性成瘾与多巴胺失调综合征相关，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。 [115][132]
安非他命基因调控（gene regulation）的效果端视剂量与通路（dose- and route-dependent）而定。 [127] 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命来进行。 [127] 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命并不会影响基因调控，即便有，也是极为轻微的。这表示安非他命用作医疗用途是十分安全的。 [127][127]
药物治疗
截至2014年5月[update]并没有能够有效治疗安非他命成瘾的药理疗法 [135][136][137] 。 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； [46][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。 [46][138] 安非他命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； [note 13] [111] 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。 [111][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。 [注 3][111] 利用镁元素补充剂，能降低安非他命使用者自我服用[d]的机会。然而这不被认为是有效治疗安非他命成瘾的单一疗法（mono-therapy）。 [note 14][111]
行为治疗
认知行为治疗是当前治疗中枢神经刺激剂成瘾的疗法。 [119] 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命成瘾的有效附加疗法。 [sources 9] 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。 [116][118][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[e]，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）”、降低多巴胺接收器 D2在纹状体中的密度。 [115][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。 [115] 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。 [117]
| 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 | ↑ | ↑ | ↑ | ↑ | ↑ | ↑ | [115] |
| 行为可塑性 | |||||||
| 摄取量的增加 | 有 | 有 | 有 | [115] | |||
| 中枢神经刺激剂跨越-敏化作用 | 有 | 不适用 | 有 | 有 | 削减 | 削减 | [115] |
| 未经过处方而自行私下摄取中枢神经刺激剂 | ↑ | ↑ | ↓ | ↓ | ↓ | [115] | |
| 强化“在特定地点摄取兴奋剂的习惯” | ↑ | ↑ | ↓ | ↑ | ↓ | ↑ | [115] |
| 强化“试图取得该致瘾药物的行为” | ↑ | ↑ | ↓ | ↓ | [115] | ||
| 神经化学物质的可塑性 | |||||||
| 伏隔核中CREB磷酸化 | ↓ | ↓ | ↓ | ↓ | ↓ | [115] | |
| 伏隔核中对于多巴胺的过敏反应 | 没有 | 有 | 没有 | 有 | [115] | ||
| 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 | [115] | |
| 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 | [115] |
| 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 | [115] | |
| 多巴胺通道的神经突触的可塑性 | |||||||
| 伏隔核中树突的数量 | ↓ | ↑ | ↑ | [115] | |||
| 伏隔核中树突棘的密度 | ↓ | ↑ | ↑ | [115] | |||
注解：DRD2 = 多巴胺受体D2；↑ = 上升；↓ = 下降
依赖和戒断症状
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命或甲基安非他命的药物成瘾者某天突然停止摄取安非他命或甲基安非他命，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命后的24小时内出现。 在成瘾患者停用安非他命后，安非他命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》安非他命戒断症状”中的症状。年纪与剂量和戒断症状的严重度呈正相关。安非他命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] [141] 安非他命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、对于安非他命有难以抑制的渴求、烦躁、疲倦、食欲放大、过动或行动迟缓、缺乏动机、嗜睡、和清醒梦。 [142] [141]
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“安非他命戒断症状”综合征的诊断标准。 [143] [141]
通过美国食品药物管理局严格审核的安非他命药品说明书上并未提到任何安非他命在医疗用剂量下突然停用会导致任何安非他命戒断症状的出现。[95][144][145][146]
DSM中，安非他命中毒及戒断症状之标准
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
| 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（Increased consumption of other drugs ） | - | - |
| 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 （Psychosocial techniques） |
- | - |
| 转移注意力（例如：工作、看电视） 〔Keeping occupied with other things (working, watching television)〕 |
35 (21%) | 1 (6%) |
| 不再与药物成瘾的朋友来往 （Cutting off contact with drug-using friends） |
31 (19%) | - |
| 获得人们的支持（家庭、社会中的支持团体） Gaining support from others (friends giving up, family, support groups) |
11 (7%) | - |
| 把药物及针头丢掉 （Throwing away drugs and needles） |
5 (3%) | - |
中毒与致病
中毒
在啮齿动物（rodents）和灵长类动物（primates）的药物试验发现到，够高的安非他命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命会直接荼毒人类的神经。[150][151] 然而，超高剂量（large doses）的安非他命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。 [sources 12] 从高剂量的安非他命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“高剂量的安非他命摄取量”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命性的神经中毒发生。[149]
致病
严重的安非他命过量可能造成“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。 [35] 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“安非他命、dextro-安非他命、及甲基安非他命”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。 [35][154]
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命所致的急性精神异常症状。 [35]
“摄取医疗剂量的安非他命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）
[36][93]
交互作用
参见：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或分解过程发生改变。[4][155]用于分解安非他命的酶的抑制剂（如CYP2D6、FMO3）都会延长其半衰期，这意味着药效会更持久。[16][155] 安非他命也会和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和安非他命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[155]；因此MAOIs与安非他命合并使用是危险的[155]。
安非他命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，安非他命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。[155]
安非他命也可能降低抗高血压药和抗精神病药（anti-psychotics）的药效，这是因为安非他命本身对于血压及多巴胺系统的作用。 [155]
锌的补充剂 可能会将低安非他命用于治疗注意力不足过动症时的最小有效剂量（minimum effective dose）。 [note 15][159]
整体来说，安非他命并不会与日常生活中常见的食物起任何重大的交互作用，但安非他命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。[155] 酸性物质会减少安非他命的吸收并增加尿液的排泄；碱性物质正好做相反的事。
由于pH值在安非他命的吸收这件事上具有影响力，所以安非他命也会和 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。 [155]
药学
药效动力学
苯丙胺在多巴胺能神经元的药物效应动力学
 |
Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways of the brain.[45][61] The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine due to its effects on monoamine transporters.[45][61][160] The reinforcing and motivational salience-promoting effects of amphetamine are mostly due to enhanced dopaminergic activity in the 中脑边缘通路.[29] The euphoric and locomotor-stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum.[1]
Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.[45][161] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function.[45][162] Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[45][46] Notably, amphetamine and trace amines bind to TAAR1, but not monoamine autoreceptors.[45][46] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons.[45] 截至2010年[update] co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.[45]
In addition to the neuronal monoamine transporters, amphetamine also inhibits both vesicular monoamine transporters, VMAT1 and VMAT2, as well as SLC1A1, SLC22A3, and SLC22A5.[sources 13] 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.[sources 13] Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[169][170] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[170][171][172] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR.[172][173] Amphetamine also inhibits monoamine oxidase at very high doses, resulting in less dopamine and phenethylamine metabolism and consequently higher concentrations of synaptic monoamines.[18][174] 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.[175][176]
The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine,[45] serotonin,[45] norepinephrine,[45] epinephrine,[160] histamine,[160] CART peptides,[169][170] endogenous opioids,[177][178][179] adrenocorticotropic hormone,[180][181] corticosteroids,[180][181] and glutamate,[163][165] which it effects through interactions with CART, 5-HT1A, EAAT3, TAAR1, VMAT1, VMAT2, and possibly other biological targets.[sources 14]
Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[182] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[34][182]
多巴胺
In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[45] Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[45] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[45] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[45] Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces the reversal of dopamine transport through DAT (i.e., dopamine efflux).[45][183] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux.[161][163][184] Through direct activation of G protein-coupled inwardly-rectifying potassium channels, TAAR1 reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state.[185][186][187]
Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[160][188] Following amphetamine uptake at VMAT2, amphetamine induces the collapse of the vesicular pH gradient, which results in the release of dopamine molecules from synaptic vesicles into the cytosol via dopamine efflux through VMAT2.[160][188] Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT.[45][160][188]
去甲肾上腺素
Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[47][61] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[45][160][183] In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.[45][160]
血清素
Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[45][61] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[45][160] Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.[175][176]
其他的中枢神经递质、肽、和激素 Other neurotransmitters, peptides, and hormones
Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system.[177][178][179] Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine.[163] This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons.[163][165] Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2.[160] Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis.[43][180][181]
药物代谢动力学
安非他命的口服生物体可利用率[参 19]与肠胃的pH值连动； [155] 安非他命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] 安非他命呈弱碱性，其pKa值介于9–10之间;[4] 因此，当pH值呈碱性时，多数的安非他命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 20]来吸收安非他命。 [4] [155] 相反地，酸性的pH值表示安非他命主要以易溶于水的离子[参 21]（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命与血浆蛋白[参 22]相连接。 [3] 安非他命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命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命的对映异构体的半衰期增加到16–31 小时。 [5][11]
成分为安非他命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；而成分为安非他命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]
安非他命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] 当尿液是碱性时，安非他命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，各种安非他命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] 安非他命通常于口服后两天内自体内完全代谢完毕。 [5] 安非他命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命浓度（plasma concentration of amphetamine）的增加而延长。[189]
对人体无药效的前药（prodrug）：赖氨酸安非他命并不若安非他命一样容易受肠胃道环境的pH值影响； [190] 赖氨酸安非他命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命。而参与这水解反应的酶与红血球有关。 [190]
Lisdexamfetamine的半衰期通常小于一个小时。 [190]
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 4]“安非他命”及“安非他命代谢后之产物”的代谢反应的酶。 [sources 15]
“安非他命代谢后之产物”包含：4-hydroxyamphetamine、4-hydroxynorephedrine、4-hydroxyphenylacetone、苯甲酸（benzoic acid）、马尿酸、苯丙醇胺（norephedrine）、苯基丙酮（phenylacetone）[注 5] [4] [5] [6]。
在这些“安非他命代谢后之产物”之中，有实际药效的产物（sympathomimetics）为：4‑hydroxyamphetamine[193]、4‑hydroxynorephedrine[194]、和norephedrine[195]。 [193] 4‑hydroxynorephedrine,[194] and norephedrine.[195]
安非他命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“安非他命”代谢途径和“安非他命代谢后之产物”：[4][16][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“安非他命”以本身原始的型态排出；大约50%的安非他命以不具药效的“安非他命代谢后之产物”（即为图片中最下列的产物）的型态排出。 [4] 剩下的10–20%则为“安非他命代谢后之产物”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 [191] 随后透过glycine N-acyltransferase代谢并转化为马尿酸（hippuric acid）。[192] |
相关的内内源性化合物/混和物
化学 Chemistry
Racemic amphetamine
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Phenyl-2-nitropropene (right cups)
Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula C9H13N. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomeric mirror images.[21] This racemic mixture can be separated into its optical isomers:[note 16] levoamphetamine and dextroamphetamine.[21] At room temperature, the pure free base of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste.[19] Frequently prepared solid salts of amphetamine include amphetamine aspartate,[31] hydrochloride,[196] phosphate,[197] saccharate,[31] and sulfate,[31] the last of which is the most common amphetamine salt.[48] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[13][21] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[198]
Substituted derivatives
The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone";[13][49][199] specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents.[13][49][200] The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.[13][49][199]
Synthesis
Since the first preparation was reported in 1887,[201] numerous synthetic routes to amphetamine have been developed.[202][203] The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 1).[48][204] In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields N-formylamphetamine. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.[204][205]
A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[202] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[206] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[207] In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure (R)-1-phenyl-ethanamine is condensed with phenylacetone to yield a chiral Schiff base. In the key step, this intermediate is reduced by catalytic hydrogenation with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the benzylic amine bond by hydrogenation yields optically pure dextroamphetamine.[207]
A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions.[202][203] One example is the Friedel–Crafts alkylation of benzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 2).[208] Another example employs the Ritter reaction (method 3). In this route, allylbenzene is reacted acetonitrile in sulfuric acid to yield an organosulfate which in turn is treated with sodium hydroxide to give amphetamine via an acetamide intermediate.[209][210] A third route starts with ethyl 3-oxobutanoate which through a double alkylation with methyl iodide followed by benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 4).[211]
A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime or other nitrogen-containing functional groups.[203] In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields phenyl-2-nitropropene. The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride (method 5).[204][212] Another method is the reaction of phenylacetone with ammonia, producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 6).[204]
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Detection in body fluids
Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics.[sources 16] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[216] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[217] Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., selegiline), over-the-counter drug products that contain levomethamphetamine,[note 17] or illicitly obtained substituted amphetamines.[217][220][221] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[1][222][223] These compounds may produce positive results for amphetamine on drug tests.[222][223] Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for two to four days.[216]
For the assays, a study noted that an enzyme multiplied immunoassay technique (EMIT) assay for amphetamine and methamphetamine may produce more false positives than liquid chromatography–tandem mass spectrometry.[220] Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine.[217] GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher's acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine.[217] Hence, the latter method may be used on samples that test positive using other methods to help distinguish between the various sources of the drug.[217]
历史、社会与文化
| 种类 | 最佳估计 | 低估值 | 高估值 |
|---|---|---|---|
| 苯丙胺类兴奋剂 | 33.90 | 13.87 | 53.81 |
| 大麻 | 181.79 | 128.48 | 232.07 |
| 可卡因 | 17.04 | 13.80 | 20.73 |
| Ecstasy | 18.79 | 9.34 | 28.39 |
| 天然鸦片 | 16.53 | 12.92 | 20.46 |
| 鸦片类药物 | 32.42 | 27.99 | 37.56 |
安非他命在1887年由罗马尼亚化学家首次在德国合成 Lazăr Edeleanu 并起名为 phenylisopropylamine;[201][225][226] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[226] Amphetamine had no pharmacological use until 1934, when Smith, Kline and French began selling it as an inhaler under the trade name Benzedrine as a decongestant.[40] Benzedrine sulfate was introduced three years later and found a wide variety of medical applications, including narcolepsy.[40][227] During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[201][228][229]随着药物的上瘾性逐渐被人所知，各国政府开始严格控制苯丙胺类销售。[201] 例如，在70年代初在美国，安非他明就成了一个二级管制药物 在 受控物质条例.[230] 尽管政府严格管制，但安非他明已被各种背景的人士合法或非法使用，包括作家,[231] 音乐家,[232] mathematicians,[233] 和运动员.[30]
安非他明今天仍然被非法合成在秘密实验室 and sold on the black market, 尤其在欧洲国家.[234] Among European Union (EU) member states, 1.2 million young adults used illicit amphetamine or methamphetamine in 2013.[235] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[235] the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period.[235] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[234]
合法状态与条件
As a result of the United Nations 1971 Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all (183) state parties.[41] Consequently, it is heavily regulated in most countries.[236][237] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[238][239] In other nations, such as Canada (schedule I drug),[240] the Netherlands (List I drug),[241] the United States (schedule II drug),[31] Australia (schedule 8),[242] Thailand (category 1 narcotic),[243] and United Kingdom (class B drug),[244] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[234][42]
成药
目前几种安非他命的处方药配方含有两种对映异构体，包括Adderall，Dyanavel XR和Evekeo，其中最后一种是外消旋的安非他命硫酸盐。[1][43][99] Amphetamine is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively.[44][190] Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.[190] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[1] Levoamphetamine was previously available as Cydril.[1] Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[1][44][48] However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016.[99][245][246] 目前的一些品牌及其通用等同物如下.
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| 药物 | 化学式 | 分子量[I] | amphetamine base [II] |
amphetamine base in equal doses |
doses with equal base content[III] | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| (g/mol) | (percent) | (30 mg dose) | ||||||||
| total | base | total | dextro- | levo- | dextro- | levo- | ||||
| dextroamphetamine sulfate[250][251] | (C9H13N)2•H2SO4 | |||||||||
| amphetamine sulfate[252] | (C9H13N)2•H2SO4 | |||||||||
| Adderall | ||||||||||
| 25% | dextroamphetamine sulfate[250][251] | (C9H13N)2•H2SO4 | ||||||||
| 25% | amphetamine sulfate[252] | (C9H13N)2•H2SO4 | ||||||||
| 25% | dextroamphetamine saccharate[253] | (C9H13N)2•C6H10O8 | ||||||||
| 25% | amphetamine aspartate monohydrate[254] | (C9H13N)•C4H7NO4•H2O | ||||||||
| lisdexamfetamine dimesylate[255] | C15H25N3O•(CH4O3S)2 | |||||||||
| amphetamine base suspension[IV][99] | C9H13N | |||||||||
备注A
- ^ 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]
- ^ 对映异构体指的是两个形状相同但方向相反的两个分子，他们又称为彼此的镜中影像。[23] Levoamphetamine 和 dextroamphetamine 分别被简称为 L-amph 或 levamfetamine (INN) 和 D-amph 或 dexamfetamine (INN) [18]
- ^
"Adderall"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命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命的混合物。
[44]) - ^
“安非他命”一词也意指一个化学分类，但与“替代性安非他命”这个化学分类不同的是，“安非他命”类在学术上并无标准的定义。[13][25]
有一个“安非他命”类的定义严格限定分类中仅有：安非他命的racemate and enantiomers和甲基安非他命methamphetamine的racemate and enantiomers。[25]
大多数“安非他命”类的定义为那些在药理学上以及结构上与安非他命相关的化合物。[25]
为避免让amphetamine 和 amphetamines 把读者给弄糊涂了，本条目中仅会使用amphetamine、amphetamines来表示racemic amphetamine, levoamphetamine, and dextroamphetamine；‘替代性安非他命（substituted amphetamines）’来表示安非他命的结构分类。 - ^
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。
[57]
在上述领域中，最为突出的领域为： 学业（例如：GPA分数 grade point average、成果测验分数 achievement test scores、受教育的时间长度 length of education、和教育程度 education level）、自尊（例如：自尊心测验分数 self-esteem questionnaire assessments、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 quality of family、同侪关系 quality of peer、和浪漫关系/情侣关系 romantic relationships） [57]
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。 [57] - ^ 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。 [65]
- ^ 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。 [92]
- ^ 然而根据一篇回顾性论文，安非他命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。[56][59][98] 根据追踪，持续三年过程不停歇的安非他命治疗（没有合并任何积极减少安非他命副作用的疗法的情况下）平均会减少 2公分的最终身高。 [98]
- ^ “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。[128]
- ^ 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（magnesium chloride）能大幅改善成瘾行为。
原文： The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[111] other forms of magnesium were not mentioned. - ^ 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.[156][157][158] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[158]
- ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[23]
- ^ The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.[218][219]
备注B
备注C
注释
英文名称对照
- ^ 英文名称为：delusions
- ^ 英文名称为：paranoia
- ^ 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：cation
- ^ 英文名称为：plasma protein
引用
- ^ [10][29][30][31][32][33][34][35][36][37][38][39]
- ^ [1][25] [29] [30] [31] [40] [41] [42] [32] [26] [24][43]
- ^ [1] [10] [29] [40] [43] [45] [46]
- ^ [47] [48] [49]
- ^ [33][34][98][99][100]
- ^ [101][102][103][104]
- ^ [93][94][101][103]
- ^ [32][33][34][105]
- ^ 9.0 9.1 [115][116][117][118][140]
- ^ [22][31][34][108][120]
- ^ [112][115][126][129][130]
- ^ [51][149][152][153]
- ^ 13.0 13.1 [160][163][164][165][166][167][168]
- ^ [45][160][164][165][169][175]
- ^ [4][13] [14] [15] [16] [17] [191] [192]
- ^ [30][213][214][215]
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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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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%.
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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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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.
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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.
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"Table 5: N-containing drugs and xenobiotics oxygenated by FMO" - ^ 17.0 17.1 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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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.
- ^ 24.0 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).
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Yoshida T. Chapter 1: Use and Misuse of Amphetamines: An International Overview. Klee H (编). 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.
- ^ 26.0 26.1 Amphetamine. Medical Subject Headings. United States National Library of Medicine. [2013-12-16].
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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). 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.
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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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Malenka RC, Nestler EJ, Hyman SE. Chapter 13: Higher Cognitive Function and Behavioral Control. Sydor A, Brown RY (编). 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. - ^ 30.0 30.1 30.2 30.3 30.4 30.5 30.6
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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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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) ...
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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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Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile) ...
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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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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.
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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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Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
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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.
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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.
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Table 2. Decongestants Causing Rhinitis Medicamentosa
– Nasal decongestants:
– Sympathomimetic:
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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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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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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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Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction.
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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. - ^ 141.0 141.1 141.2 141.3 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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|section-url=被忽略 (帮助);|section=被忽略 (帮助); - ^ Zhang M, Han L, Xu Y. Roles of cocaine- and amphetamine-regulated transcript in the central nervous system. Clin. Exp. Pharmacol. Physiol. June 2012, 39 (6): 586–592. PMID 22077697. doi:10.1111/j.1440-1681.2011.05642.x.
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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Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.
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参见
外部链接
- CID 3007 from PubChem – Amphetamine
- CID 5826 from PubChem – Dextroamphetamine
- CID 32893 from PubChem – Levoamphetamine
- Comparative Toxicogenomics Database entry: Amphetamine
- Comparative Toxicogenomics Database entry: CARTPT
- YouTube上的Drug abuse and drug addictions
- YouTube上的Mechanism of Drug Addiction in the Brain, Animation.
- YouTube上的Drug dependence
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