N-acetylcysteine as a Potential Treatment for Methamphetamine Dependence

描述（由申请方提供）：N-乙酰基-L-半胱氨酸（NAC）治疗与大鼠可卡因寻求行为恢复的易感性降低（Baker et al 2002）以及可卡因依赖性人类志愿者的线索诱导渴求降低（LaRowe et al 2006）相关。我们提出这些目标来评估NAC作为甲基苯丙胺（MA）依赖治疗的潜力：具体目标1：确定NAC治疗（安慰剂，每天1800和3600 mg）的效果，与安慰剂治疗相比，在非寻求治疗的MA依赖性人类志愿者中，提示和MA诱导的渴望和MA主观效应。我们假设，NAC治疗将减少暴露于MA线索后报告的MA渴求，并将减少MA非偶然给药（0 mg、9 mg和30 mg，IV）后报告的渴求和MA主观效应。具体目标二：通过测量非寻求治疗的MA依赖性人类志愿者的MA自我给药，确定NAC治疗（安慰剂，每日1800和3600 mg）与安慰剂治疗相比对MA强化作用的影响。我们假设，NAC治疗将减少在选择阶段对MA的选择数量。采用受试者内、双盲、安慰剂对照设计，15名受试者将在安慰剂、NAC 1800 mg和NAC 3600 mg治疗期间完成手术，每次治疗间隔至少2周。研究药物治疗2天后，将使用我们新开发的虚拟现实（VR）设备，在将参与者暴露于MA和中性线索之前和之后，使用视觉模拟评级量表评估线索诱导的渴望。然后，参与者将完成2个样本会话和2个选择会话，每个会话在单独的一天发生。在抽样阶段，他们将接受安慰剂、9 mg MA和30 mg MA，并将收集主观效应评级。在随后的2个选择环节中，参与者将在该环节中的金钱和可用药物（安慰剂或MA）之间做出一系列10个选择。与NAC治疗相关的MA强化作用的任何改变都将随着MA选择数量的变化而明显。停用研究药物后，受试者将出院，并在至少2周后返回，直至完成每次研究药物治疗期间的程序。公共卫生相关性：N-乙酰-L-半胱氨酸（NAC）治疗与大鼠可卡因寻求行为恢复的敏感性降低以及可卡因依赖性人类志愿者线索诱导的渴望降低相关。因此，我们提出了一项探索性/开发性临床研究，以评估NAC作为MA依赖性志愿者潜在治疗的潜力。这一提议具有相当大的公共卫生意义，因为它提供了一种有前途的化合物用于治疗MA依赖的治疗潜力的初步评估，MA依赖是一种目前没有有效药物治疗的疾病。

DESCRIPTION (provided by applicant): N-acetyl-l-cysteine (NAC) treatment is associated with reduced susceptibility to reinstatement of cocaine- seeking behavior in rats (Baker et al 2002) and with reduced cue-induced craving in cocaine-dependent human volunteers (LaRowe et al 2006). We propose these aims to evaluate the potential of NAC as a treatment for methamphetamine (MA) dependence: Specific Aim 1: To determine the effects of treatment with NAC (placebo, 1800 and 3600mg daily), compared to treatment with placebo, on cue- and MA-induced craving and MA subjective effects in non-treatment-seeking MA-dependent human volunteers. We hypothesize that treatment with NAC will reduce craving for MA reported following exposure to MA cues and will reduce craving and MA subjective effects reported following non-contingent administration of MA (0mg, 9mg, and 30 mg, IV). Specific Aim 2: To determine the effects of treatment with NAC (placebo, 1800 and 3600mg daily), compared to treatment with placebo, on the reinforcing effects of MA by measuring MA self-administration in non-treatment-seeking MA-dependent human volunteers. We hypothesize that treatment with NAC will reduce the number of choices made for MA during choice sessions. Fifteen participants will complete procedures during treatment with placebo, NAC 1800mg, and NAC 3600mg, using a within-subjects, double-blind, placebo-controlled design with at least 2 weeks separating each treatment episode. After 2 days of treatment with study medication, cue-induced craving will be assessed using visual analogue rating scales prior to and after exposing participants to MA and neutral cues using our newly developed virtual reality (VR) apparatus. Participants will then complete 2 sample sessions and 2 choice sessions, each occurring on a separate day. In sample sessions they will receive placebo, 9mg MA, and 30mg MA and subjective effects ratings will be collected. In 2 subsequent choice sessions participants will make a series of 10 choices between money and the drug available (placebo or MA) in that session. Any alterations in the reinforcing effects of MA associated with NAC treatment will be evident as changes in the number of choices made for MA. After discontinuation of study medication participants will be discharged, to return after at least 2 weeks until procedures have been completed during treatment with each dose of study medication. PUBLIC HEALTH RELEVANCE: N-acetyl-l-cysteine (NAC) treatment is associated with reduced susceptibility to reinstatement of cocaine-seeking behavior in rats and with reduced cue-induced craving in cocaine-dependent human volunteers. Therefore, we propose an exploratory/developmental clinical research study to evaluate the potential of NAC as a potential treatment in MA-dependent volunteers. This proposal is of considerable public health significance as it provides an initial evaluation of the therapeutic potential of a promising compound for the treatment of MA dependence, a disorder for which there no effective medication treatments currently exists.