McKetin Rebecca, Dean Olivia M, Turner Alyna, Kelly Peter J, Quinn Brendan, Lubman Dan I, Dietze Paul, Carter Gregory, Higgs Peter, Sinclair Barbara, Reid David, Baker Amanda L, Manning Victoria, Pas Nina Te, Thomas Tamsin, Bathish Ramez, Raftery Dayle K, Wrobel Anna, Saunders Lucy, Arunogiri Shalini, Cordaro Frank, Hill Harry, Hall Scott, Clare Philip J, Mohebbi Mohammadreza, Berk Michael
National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW 2052, Australia.
Deakin University, School of Medicine, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, Geelong, Australia.
EClinicalMedicine. 2021 Jul 13;38:101005. doi: 10.1016/j.eclinm.2021.101005. eCollection 2021 Aug.
Methamphetamine dependence is a significant global health concern for which there are no approved medications. The cysteine prodrug, N-acetylcysteine (NAC), has been found to ameliorate glutamate dysregulation in addiction, and to reduce craving for methamphetamine and other drugs. We evaluated the efficacy and safety of NAC as a pharmacotherapy for methamphetamine dependence.
A parallel double-blind randomised placebo-controlled trial of people dependent on methamphetamine recruited from Geelong, Melbourne and Wollongong, Australia, between July 2018 and December 2019. Participants were randomised to receive either 12 weeks of oral NAC (2400 mg/day) or matched placebo, delivered as a take-home medication. The primary outcome was methamphetamine use, measured in two ways: (a) change in days of use in the past 4 weeks from baseline to weeks 4, 8 and 12, assessed using the Timeline Followback; and (b) methamphetamine-positive oral fluid samples taken weekly. Analyses were intention-to-treat and based on imputed data. Secondary outcomes were craving, severity of dependence, withdrawal severity and psychiatric symptoms (depression, suicidality, hostility and psychotic symptoms). Significance levels were < 0.025 for primary outcomes and < 0.01 for secondary outcomes. Adverse events were compared between groups by system organ class. The study was prospectively registered, ACTRN12618000366257.
Participants ( = 153; 59% male, mean [SD] age 38 [8]) were randomised to placebo ( = 77) or NAC ( = 76). Both groups had a median (IQR) of 24 (15-28) days of methamphetamine use in the 4 weeks prior to baseline. Both groups significantly reduced methamphetamine use (mean [SE] reduction of 7.3 [1.2]) days for placebo, 6.8 [1.2] for NAC) but NAC did not reduce days of methamphetamine use more than placebo (group difference of 0.5 days, 97.5% CI -3.4-4.3). There was no significant effect of NAC on methamphetamine-positive oral fluid samples (placebo 79%, NAC 76%; mean difference -2.6, 97.5% CI -12.6-7.4). NAC did not significantly reduce craving, severity of dependence, withdrawal, suicidality, depression, hostility or psychotic symptoms relative to placebo. Adverse events did not differ significantly between placebo and NAC groups.
These findings suggest that take-home oral NAC has no significant effect on methamphetamine use or most clinically related outcomes amongst people who are dependent on the drug.
甲基苯丙胺成瘾是一个重大的全球健康问题，目前尚无获批的治疗药物。半胱氨酸前体药物N-乙酰半胱氨酸（NAC）已被发现可改善成瘾中谷氨酸调节异常，并减少对甲基苯丙胺和其他药物的渴望。我们评估了NAC作为甲基苯丙胺成瘾药物治疗的疗效和安全性。
2018年7月至2019年12月在澳大利亚吉朗、墨尔本和卧龙岗招募了甲基苯丙胺成瘾者进行一项平行双盲随机安慰剂对照试验。参与者被随机分配接受为期12周的口服NAC（2400毫克/天）或匹配的安慰剂，作为家庭用药。主要结局是甲基苯丙胺使用情况，通过两种方式测量：（a）从基线到第4、8和12周过去4周内使用天数的变化，使用时间线追溯法评估；（b）每周采集的甲基苯丙胺阳性口腔液样本。分析采用意向性分析并基于插补数据。次要结局包括渴望、成瘾严重程度、戒断严重程度和精神症状（抑郁、自杀倾向、敌意和精神病性症状）。主要结局的显著性水平<0.025，次要结局的显著性水平<0.01。通过系统器官类别比较两组间的不良事件。该研究已进行前瞻性注册，注册号为ACTRN12618000366257。
参与者（n = 153；59%为男性，平均[标准差]年龄38 [8]岁）被随机分配至安慰剂组（n = 77）或NAC组（n = 76）。两组在基线前4周内甲基苯丙胺使用天数的中位数（四分位间距）均为24（15 - 28）天。两组甲基苯丙胺使用量均显著减少（安慰剂组平均[标准误]减少7.3 [1.2]天，NAC组减少6.8 [1.2]天），但NAC组减少甲基苯丙胺使用天数并不比安慰剂组更多（组间差异为0.5天，97.5%可信区间为 - 3.4 - 4.3）。NAC对甲基苯丙胺阳性口腔液样本无显著影响（安慰剂组为79%，NAC组为76%；平均差异为 - 2.6，97.5%可信区间为 - 12.6 - 7.4）。与安慰剂相比，NAC在减少渴望、成瘾严重程度、戒断、自杀倾向、抑郁、敌意或精神病性症状方面无显著作用。安慰剂组和NAC组之间的不良事件无显著差异。
这些发现表明，对于甲基苯丙胺成瘾者，家庭口服NAC对甲基苯丙胺使用或大多数临床相关结局无显著影响。
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