A Controlled Trial of NAC for Cocaine Dependence

描述（由申请人提供）：尽管有超过二十年的研究，可卡因依赖没有有效的药物治疗。临床前研究已经阐明了谷氨酰胺和多巴胺能回路在伏隔核、腹侧被盖区和前额皮质中的重要性。这些研究表明，反复服用可卡因可减少突触谷氨酸。大多数突触谷氨酸产生于非囊泡释放，特别是半胱氨酸/谷氨酸反转运蛋白。这种交换剂是一种质膜结合的钠依赖的阴离子氨基酸转运体，它将细胞外的胱氨酸交换为细胞内的谷氨酸。反复服用可卡因会损害胱氨酸谷氨酸交换器，降低细胞外谷氨酸水平。半胱氨酸反透析可恢复伏隔核降低的基础谷氨酸水平。半胱氨酸前体药物如n -乙酰半胱氨酸（NAC）的全身管理也能使细胞外谷氨酸正常化，并阻断可卡因的行为恢复。MAC是fda批准的治疗囊性纤维化和对乙酰氨基酚过量的药物。

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.