A Controlled Trial of NAC for Cocaine Dependence

描述(申请人提供)：尽管经过二十多年的研究，目前尚无有效的可卡因依赖药物治疗方法。临床前研究已经阐明了伏核、腹侧被盖区和前额叶皮质之间谷氨酸和多巴胺能回路的重要性。这些研究表明，反复服用可卡因会减少突触谷氨酸。大多数突触谷氨酸来自非囊泡释放，特别是半胱氨酸/谷氨酸逆向转运体。这种交换器是一种质膜结合的钠依赖的阴离子氨基酸转运体，可以将细胞外的半胱氨酸交换为细胞内的谷氨酸。反复服用可卡因会损害半胱氨酸谷氨酸交换器，降低细胞外谷氨酸水平。半胱氨酸的反向透析可恢复伏隔核内基础谷氨酸水平。全身性给予半胱氨酸前体药物，如N-乙酰半胱氨酸(NAC)，也可以使细胞外谷氨酸正常化，并阻止可卡因的行为恢复。Mac是FDA批准用于治疗囊性纤维化和对乙酰氨基酚过量的药物。 我们研究了13名未寻求治疗的可卡因依赖者，他们每天两次口服600 mg NAC，并测量副作用、耐受性、自我报告的可卡因渴求、可卡因戒断症状和线索反应性的电生理指标。NAC和安慰剂之间的副作用数量没有差异(p=0.29)。渴望评级表明，当受试者接受NAC治疗时，渴望程度下降(p=0.05)，而安慰剂受试者的渴望程度并没有显著下降。根据可卡因严重程度评估(p&lt；0.05)，NAC显著减少了可卡因戒断症状。在线索反应范式中，受试者对可卡因和中性幻灯片的反应相似；在安慰剂条件下，受试者对可卡因的反应水平高于中性刺激(p=0.052)。 令人信服的临床前分子和行为研究支持使用NAC治疗可卡因依赖。我们有初步的人体实验室数据表明，NAC可以减少渴求、可卡因戒断症状，并可能减少皮肤电导线索的反应性。我们已经从FDA获得了IND，将进行NAC加认知行为疗法(CBT)治疗可卡因依赖的双盲II期试验。这项建议的主要目标包括：1)确定两种剂量(1200、2400毫克)的NAC口服CBT与安慰剂和CBT治疗可卡因依赖(N=282)的疗效，通过自我报告并经定量尿药筛查证实；2)确定NAC与安慰剂的安全性；以及3)研究服用NAC或安慰剂的受试者对可卡因的渴望/提示反应和戒断症状。

DESCRIPTION (provided by applicant): There is no effective pharmacological treatment for cocaine dependence despite over two decades of research. Pre-clinical studies have elucidated the importance of glutaminergic and dopaminergic circuits among the nucleus accumbens, ventral tegmental area, and prefrontal cortex. These studies have indicated that repeated cocaine administration reduces synaptic glutamate. Most synaptic glutamate arises from nonvesicular release, and specifically from the cysteine/glutamate antiporter. This exchanger is a plasma membrane-bound sodium dependent anionic amino acid transporter that exchanges extra cellular cystine for intra cellular glutamate. Repeated cocaine administration impairs the cystine glutamate exchanger, lowering extracellular glutamate levels. Reverse dialysis of cysteine restores diminished basal glutamate levels in the nucleus accumbens. Systemic administration of cysteine pro drugs such as N-acetylcysteine (NAC) also normalizes extracellular glutamate and blocks behavioral reinstatement by cocaine. MAC is FDA-approved for the treatment of cystic fibrosis and acetaminophen overdose. We studied 13 non-treatment seeking cocaine dependent subjects who were given 600 mg of NAC orally twice daily and measured side effects, tolerability, self-reported cocaine craving, cocaine withdrawal symptoms, and electrophysiologic measures of cue reactivity. Number of side effects did not differ between NAC and placebo (p=0.29). Craving ratings suggested that when subjects were treated with NAC, cravings dropped (p=0.05) while placebo subjects did not show a significant drop in craving. NAC significantly reduced cocaine withdrawal symptoms as measured by the Cocaine Severity Assessment (p<0.05). In the cue reactivity paradigm, subjects showed comparable responses to both cocaine and neutral slides; in the placebo condition, subjects showed a higher level of responding to cocaine relative to neutral stimuli (p=0.052). Convincing pre-clinical molecular and behavioral studies support the use of NAC to treat cocaine dependence. We have preliminary human laboratory data suggesting that NAC reduces craving, cocaine withdrawal symptoms, and possibly skin conductance cue reactivity. We have received an IND from the FDA to conduct a double blind, phase II trial of NAC plus cognitive-behavioral therapy (CBT) in the treatment of cocaine dependence. The primary objective to this proposal include: 1) to determine the efficacy of two doses (1200, 2400 mg) of NAC orally with CBT as compared to placebo and CBT in treating cocaine dependence (N=282) as measured by self-report and validated by quantitative urine drug screens; 2) to determine the safety of NAC vs. placebo; and 3) to study cocaine craving/cue reactivity and withdrawal symptoms in subjects taking NAC or placebo.