In Search of a Remedy for Use Disorder of Amphetamines: How Close Are We?

Amphetamine use disorder is emerging as a silent public health problem claiming more lives in 2020s than ever before in Canada and the US. According to the results of the Global Burden of Disease (GBD) 2021 study (1), the age-standardized mortality rates have skyrocketed in the past 20 years (0.15 per 100,000 in 2000 vs 1.12 per 100,000 in 2020) in the high-income North American countries (Figure). This alarming trend underscores the urgent need for effective harm-reduction strategies and pharmacological treatments to complement existing psychosocial interventions. There’s currently no widely accepted pharmacological treatment for amphetamine use disorder. Out of hundreds of clinical trials over the past 30 years, some medications, such as psychostimulants and bupropion, have shown modest size signals of efficacy. However, no medication has still consistently demonstrated robust efficacy to be integrated into the care of people living with amphetamine use disorder.

A recent study (ADAPT-2) published in the New England Journal of Medicine in 2021 (2) provided us with concrete evidence of the efficacy and safety of the combination of bupropion (a stimulant-like anti-depressant) and extended-release injectable naltrexone (an opioid antagonist) for the treatment of amphetamine use disorder. This combination therapy brought hope showing that it can be associated with a short-term decrease of methamphetamine use and craving. Although these encouraging findings can change the evidence-based recommendations, the results were for only two 6-week study phases without providing the signals for the long-term efficacy of this treatment. Additionally, the ADAPT-2 study did not include separate groups for bupropion and naltrexone alone. This makes it difficult to determine the individual contributions of each medication to the observed benefits. A meta-analysis by Bakouni et al. (3) confirmed the results of the ADAPT-2 study even including the bupropion-only studies. This suggests that bupropion may be effective in treating amphetamine use disorder. Another meta-analysis (an accepted manuscript) by Bastien et al. (4) on the naltrexone-only intervention didn’t support a standalone naltrexone regimen as an effective treatment. While the results of the ADAPT-2 study evolved our insight into the management of amphetamine use disorder, more clinical trials of these medications are needed to help with the establishment of a compelling evidence-based treatment.

The prescription psychostimulants such as methylphenidate and dextroamphetamine are another group of medications that have been widely studied for the treatment of amphetamine use disorder. These studies also ended up finding a modest size for the effect of prescription psychostimulants on mostly abstinence-based outcomes. A meta-analysis by Sharafi et al. (5) emphasized the utility of prescription psychostimulants to reduce methamphetamine use and craving. Furthermore, this meta-analysis found evidence to suggest that increasing the dosage of stimulant therapy or extending the duration of treatment may improve outcomes. While this looks promising, the reliability of this evidence is limited by the number of studies included in the data pooling. The implementation of prescription psychostimulants as stimulant agonist therapy has been criticized because of their abuse potential, their modest effect size on the target outcome measures, long-term safety and their cost-effectiveness (5, 6). Currently, two groups are studying the efficacy and safety of high-dose lisdexamfetamine, a prodrug of dextroamphetamine that provides a longer duration of action and a lower risk of abuse. The LiMA (7) and the ASCME (8) studies can contribute to the proposal of a high-dose stimulant agonist therapy framework. Findings from these studies are highly anticipated by the scientific and medical community, given their potential to transform the interventions dispensed to this population.

Recently, The American Society of Addiction Medicine (ASAM) and the American Academy of Addiction Psychiatry (AAAP) recommended pharmacological interventions for the management of amphetamine use disorder in their evidence-based Clinical Practice Guideline on the Management of Stimulant Use Disorder (9). The recommendations for the prescription of bupropion, bupropion/naltrexone, topiramate, mirtazapine, and methylphenidate come with moderate to low certainty and conditional strength. This means we need more high-quality clinical trials and knowledge synthesis strategies such as meta-analyses. In this regard, a network meta-analysis investigating the effect of pharmacological, psychosocial and harm reduction interventions for the treatment of amphetamine use disorder has been just recently published (10). The efficacy signals were mostly observed in favour of the formulations with only one study result such as quetiapine and riluzole than for the medications studied frequently such as bupropion, modafinil, and naltrexone. These results may implicate new candidates for more trials to replicate the results in large and diverse study populations. There are more similar network meta-analyses on the way including one on pharmacological interventions (CRD42023473768) and another one on psychosocial interventions (CRD42023450375). The results of these secondary studies can contribute to our knowledge and understanding of the available modalities for the treatment of amphetamine use disorder and inform the researchers about the research gap and capacity.

Some of the strategies that can be used to care for people with amphetamine use disorder include the management of concomitant disorders such as psychosis and depression. To address this end, the Centre d’Expertise et de Collaboration en Troubles Concomitants (CECTC) recently published a scientific opinion, formulating pieces of advice on the good practices related to the assessment and management of people living with psychosis and stimulant use disorder in emergency room settings (accessible here). This initiative, along with many others from academia and the medical community, shows how the field is evolving toward providing innovative and contemporary effective treatment options to people living with amphetamine use disorder. Robust and evidence-based treatment modalities tailored-made for this specific population are just around the corner, fingers crossed!

References

1. Global Burden of Disease (GBD) 2021 study [Internet]. 2021 [cited 2024-10-09]. Available from: https://vizhub.healthdata.org/gbd-results/.
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3. Bakouni H, Sharafi H, Bahremand A, Drouin S, Ziegler D, Bach P, et al. Bupropion for treatment of amphetamine-type stimulant use disorder: A systematic review and meta-analysis of placebo-controlled randomized clinical trials. Drug Alcohol Depend. 2023;253:111018.
4. Bastien G, McAnulty C, Sharafi H, Amani M, Elkrief L, Ziegler D, et al. Is naltrexone effective and safe for treating amphetamine-type stimulant use disorder? A systematic review and meta-analysis. Journal of Addiction Medicine. 2024; Accepted manuscript.
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7. Ezard N, Dunlop A, Hall M, Ali R, McKetin R, Bruno R, et al. LiMA: a study protocol for a randomised, double-blind, placebo controlled trial of lisdexamfetamine for the treatment of methamphetamine dependence. BMJ Open. 2018;8(7):e020723.
8. Clinical Trial of High Dose Lisdexamfetamine and Contingency Management in MA Users [Internet]. National library of medicine. 2024 [cited 2024-10-09]. Available from: https://clinicaltrials.gov/study/NCT05854667.
9. The ASAM/AAAP Clinical Practice Guideline on the Management of Stimulant Use Disorder. Journal of Addiction Medicine. 2024;18(1S):1-56.
10. Khalili M, Sadeghirad B, Bach P, Crabtree A, Javadi S, Sadeghi E, et al. Management of Amphetamine and Methamphetamine Use Disorders: A Systematic Review and Network Meta-analysis of Randomized Trials. International Journal of Mental Health and Addiction. 2024.