TY - JOUR
T1 - N-acetylcysteine (NAC) for methamphetamine dependence
T2 - A randomised controlled trial
AU - McKetin, Rebecca
AU - Dean, Olivia M.
AU - Turner, Alyna
AU - Kelly, Peter J.
AU - Quinn, Brendan
AU - Lubman, Dan I.
AU - Dietze, Paul
AU - Carter, Gregory
AU - Higgs, Peter
AU - Sinclair, Barbara
AU - Reid, David
AU - Baker, Amanda L.
AU - Manning, Victoria
AU - Pas, Nina te
AU - Thomas, Tamsin
AU - Bathish, Ramez
AU - Raftery, Dayle K.
AU - Wrobel, Anna
AU - Saunders, Lucy
AU - Arunogiri, Shalini
AU - Cordaro, Frank
AU - Hill, Harry
AU - Hall, Scott
AU - Clare, Philip J.
AU - Mohebbi, Mohammadreza
AU - Berk, Michael
N1 - Funding Information:
OMD has received grant support from Lilly and ASBDD/Servier. She has also received in kind support from BioMedica Nutracuticals, NutritionCare and Bioceuticals. MB has received Grant/Research Support from the A2 milk company, Meat and Livestock Board, Woolworths, and Avant, has been a speaker for Abbott, Astra Zeneca, Janssen, Lundbeck, Merck, Otsuka, Milken Institute, Sandoz, Allori (for Eisai), Medplan Canada, Servier and Medisquire India, and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Janssen, Lundbeck Merck, Pfizer and Servier, and has licences with Allen and Unwin and Cambridge University Press. MB has received patents for agents that modulate physiological processes and diseases of the central nervous system and related processes, including xanthone-rich plant extracts. DL has provided consultancy advice to Lundbeck and Indivior and has received travel support and speaker honoraria from Astra Zeneca, Camurus, Indivior, Janssen, Lundbeck, Servier and Shire. PD has received investigator-initiated funding from Gilead Sciences, an untied educational grant from Indivior and was an unpaid member of an Advisory Board for Mundipharma for work unrelated to this study. PH has received investigator-driven research funding from Gilead Sciences and Abbvie for work on hepatitis C unrelated to this study. GC has received speaker fees from Otsuka (Australia), Servier, Lundbeck and Janssen, all unrelated to the current study. SA has received speaker honoraria from Gilead, Janssen and Camurus for work unrelated to this study. Other researchers have no interests to declare.
Funding Information:
RM was supported by a Curtin Senior Research Fellowship. OMD is supported by a R.D. Wright Biomedical NHMRC Career Development Fellowship (APP1145634). MB is supported by a NHMRC Senior Principal Research Fellowship (1059660 and 1156072). PD and AB are supported by NHMRC Research Fellowships (1136908, 1135901). DL is supported by a NHMRC Investigator grant (1196892). DKR was supported by an Australian Government Research Training Scholarship. Thanks go to members of our DSMB (Jason White, Matthew Spittal, Debra Kerr, Grant Sara, Juanita Koeijers), Wenbin Liang (WL) for development of the randomisation program, Long Nguyen (LN) for developing our online unblinding portal, Steven Shoptaw for advice on trial methods, staff at the Victorian Institute of Forensic Medicine (Linda Glowacki, Dimitri Gerostamoulos) for assisting with oral fluid collection protocols, pharmacy staff, trial staff (including Nicole Edwards, Margie Kent, Alcy Meehan, Davinia Rizzo, Bruno Agustini, Ellie Brown, Behrooz Maylie, Olalekan Ogunleye, and Vicky Phan), agencies and individuals who have assisted with recruitment efforts, and the trial participants.
Funding Information:
The funding source, the Australian National Health and Medical Research Council (NHMRC Project Grant No. 1128147) played no role in the design of the study or the collection, analysis, and interpretation of data, or in writing the manuscripts from the study.
Funding Information:
This research was funded by the Australian NHMRC (Project Grant No. 1128147). All authors contributed to writing and reviewing the final manuscript. RM drafted the original manuscript. RM OMD AT PK PH PD BQ DL GC AB MB BS and DR contributed to the conceptualisation, funding acquisition, methodology and supervision of the project. RM OMD AT PK BQ DL PD BS DR SH VM and SA contributed to project administration and supervision. HH FC and SA contributed to investigation. LS NtP DKR RB AW and TT contributed to project administration and data curation. PC and MM contributed to the formal analyses. All study investigators (RM OMD AT PK PH PD BQ DL GC) had to access the full dataset. RM, PC and MM accessed the full dataset for the purposes of analysing data for this paper. Anonymised data will be made available upon reasonable request, which must include a protocol and statistical analysis plan, be consistent with our data sharing policy (available on request from RM), involve collaboration with one of our project investigators, and not conflict with our prespecified publication plan. Requests for data sharing will be considered by RM and the trial investigator team and will require relevant ethics approval. RM was supported by a Curtin Senior Research Fellowship. OMD is supported by a R.D. Wright Biomedical NHMRC Career Development Fellowship (APP1145634). MB is supported by a NHMRC Senior Principal Research Fellowship (1059660 and 1156072). PD and AB are supported by NHMRC Research Fellowships (1136908, 1135901). DL is supported by a NHMRC Investigator grant (1196892). DKR was supported by an Australian Government Research Training Scholarship. Thanks go to members of our DSMB (Jason White, Matthew Spittal, Debra Kerr, Grant Sara, Juanita Koeijers), Wenbin Liang (WL) for development of the randomisation program, Long Nguyen (LN) for developing our online unblinding portal, Steven Shoptaw for advice on trial methods, staff at the Victorian Institute of Forensic Medicine (Linda Glowacki, Dimitri Gerostamoulos) for assisting with oral fluid collection protocols, pharmacy staff, trial staff (including Nicole Edwards, Margie Kent, Alcy Meehan, Davinia Rizzo, Bruno Agustini, Ellie Brown, Behrooz Maylie, Olalekan Ogunleye, and Vicky Phan), agencies and individuals who have assisted with recruitment efforts, and the trial participants.
Funding Information:
This research was funded by the Australian NHMRC (Project Grant No. 1128147 ).
Publisher Copyright:
© 2021
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - Background: 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. Methods: 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 p < 0.025 for primary outcomes and p < 0.01 for secondary outcomes. Adverse events were compared between groups by system organ class. The study was prospectively registered, ACTRN12618000366257. Results: Participants (N = 153; 59% male, mean [SD] age 38 [8]) were randomised to placebo (n = 77) or NAC (n = 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. Interpretation: 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.
AB - Background: 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. Methods: 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 p < 0.025 for primary outcomes and p < 0.01 for secondary outcomes. Adverse events were compared between groups by system organ class. The study was prospectively registered, ACTRN12618000366257. Results: Participants (N = 153; 59% male, mean [SD] age 38 [8]) were randomised to placebo (n = 77) or NAC (n = 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. Interpretation: 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.
KW - Glutamate
KW - Mental disorders
KW - Methamphetamine
KW - N-Acetylcysteine
KW - Neuroscience
KW - Psychiatry
KW - Randomised controlled trials
KW - Substance-related disorders
UR - http://www.scopus.com/inward/record.url?scp=85111100782&partnerID=8YFLogxK
U2 - 10.1016/j.eclinm.2021.101005
DO - 10.1016/j.eclinm.2021.101005
M3 - Article
C2 - 34308314
AN - SCOPUS:85111100782
SN - 2589-5370
VL - 38
JO - eClinicalMedicine
JF - eClinicalMedicine
M1 - 101005
ER -
