N-acetylcysteine for methamphetamine dependence

NAC has the potential to be a much-needed and affordable pharmacological option for harm minimisation related to not only methamphetamine dependence, but also of other drugs of addiction.

Methamphetamine use has decreased among the general population (2.1% in 2013 vs 1.4% in 2016),¹ but deaths involving methamphetamine and other stimulants are increasing in Australia.

According to the 8th National Wastewater Drug Monitoring Program in 2019,² methamphetamine was the highest-consumed illicit drug monitored by the program. Therefore, it remains a significant public health concern due to its impact on causing persistent and serious psychiatric, cognitive and neurological dysfunction.

Unfortunately, there are few options for managing methamphetamine dependence.³ Intensive psychological therapies in clinical trial settings have seen small to moderate reductions in methamphetamine use, but benefits are not translated to clinical practice.³

Community-based treatments such as residential rehabilitation are costly and produce only short-term benefits as relapse rates are high.³ There are no approved pharmacological management options for methamphetamine dependence due to lack of evidence to support efficacy and/or safety in options which have been trialed,³ e.g. sertraline, mirtazapine, bupropion, modafinil, ondansetron, risperidone, aripiprazole, naltrexone, baclofen and gabapentin. Many trials have reportedly also focused on agonist therapies that aim to substitute methamphetamine with similar acting drugs, e.g. off-label dexamphetamine (up to 80 mg oral daily dose) or similar-acting agonists, to normalise brain function and reduce cravings. These therapies, however, have failed to significantly reduce methamphetamine use compared to a placebo.³

Recent improvements in the understanding of addiction has identified the role of glutamatergic abnormalities. Elevated glutamate levels in the nucleus accumbens in response to drug intake appears to be important for drug seeking and relapse. Similarly, withdrawal from stimulant drugs causes a reduction in basal levels of extrasynaptic glutamate in the nucleus accumbens. Targeting changes to restore glutamate homeostasis is promising.

One such agent is N-acetylcysteine (NAC), most well-known in paracetamol overdose in people deemed to be at risk of hepatotoxicity. For this purpose, NAC acts as a precursor for glutathione synthesis. Glutathione and NAC bind to the reactive metabolite of paracetamol, and repletion of glutathione directly reduces oxidative cell injury. NAC may also improve hepatic perfusion in established liver injury due to paracetamol.

In modulating glutamate function and addiction, NAC stimulates inhibitory metabotropic glutamate receptors to reduce the release of glutamate from the synapsis. Additionally, boosting cysteine levels (administration of cysteine, or its pro-drug NAC) in animals withdrawn from chronic cocaine administration restored extracellular glutamate levels, blocking the reinstatement of drug seeking usually seen in chronically drug-exposed animals.

Several small trials looking at NAC as potential pharmacotherapy for cocaine, cannabis, or nicotine addiction have been conducted. Each varied in design quality and/or produced mixed results. A recent trial in Iran looked at the effectiveness of NAC as a single agent to reduce methamphetamine cravings.⁵ This was a small randomised placebo-controlled crossover trial (n = 23). NAC was dosed daily for 4 weeks with a 3-day washout period, starting at 600 mg daily for one week, then increased to 1,200 mg daily. The authors used the cocaine craving questionnaire-brief to gather data about participants’ cravings and concluded NAC showed good efficacy in suppressing cravings. The craving score (mean ± standard deviation) in groups A and B were 3.38 ± 1.16 and 5.96 ± 1.03 respectively at the end of the first four weeks, and 4.57 ± 1.88 and 3.2 ± 0.86 respectively at the end of the second four weeks (p<0.001). The overall rate of reported side effects (nausea, abdominal cramping, blunting, diarrhoea, constipation, mild headache and dry mouth) was not statistically significant (p = 0.353).

Clearly more research and insights into the clinical utility and effectiveness of NAC for methamphetamine dependence is needed, e.g. doses, other outcome measures such as abstinence symptoms, rates of relapse, and when its use would be most beneficial. There is a larger scale randomised placebo-controlled trial now underway in Australia, looking at larger doses (2,400 mg daily), for a longer period (12 weeks) and measuring more outcomes.⁶

TABLE 1 – NAC (oral) dosing information

Reference: Australian Medicines handbook⁵
* NAC does not have an indication for this condition – dose provided is indicative only

References

1. Australian Institute of Health and Welfare. Alcohol, tobacco & other drugs in Australia. Canberra: AIHW; 2019. At: aihw.gov.au/reports/alcohol/alcohol-tobacco-other-drugs-australia/contents/drug-types/meth/amphetamine-and-other-stimulants
2. National Wastewater Drug Monitoring Program – Eighth report. Canberra: Australian Criminal Intelligence Commission; 2019 August. At: www.acic.gov.au/publications/reports/national-wastewater-drug-monitoring-program-eighth-report
3. McKetin R, Dean OM, Baker AL, et al. A potential role for N-acetylcysteine in the management of methamphetamine dependence. Drug Alcohol Rev 2017;36(2):153–159. At: www.ncbi.nlm.nih.gov/pubmed/27241765
4. Rossi S, ed. Australian medicines handbook. Adelaide: Australian Medicines Handbook; 2019. At: amhonline.amh.net.au/
5. Mousavi SG, Sharbafchi MR, Salehi M, et al. The efficacy of N-acetylcysteine in the treatment of methamphetamine dependence: a double-blind controlled, crossover study. Arch Iran Med 2015;18(1):28–33. At: www.ncbi.nlm.nih.gov/pubmed/25556383
6. McKetin R, Dean OM, Turner A et al. A study protocol for the N-ICE trial: A randomised double-blind placebo-controlled study of the safety and efficacy of N-acetyl-cysteine (NAC) as a pharmacotherapy for methamphetamine (“ice”) dependence. Trials 2019;20(1):325. At: trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3450-0