Treating Depression Early in Treatment May Improve Methamphetamine Use Disorder Outcomes

2 days ago
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Methamphetamine use disorder (MUD) continues to pose a growing public health challenge in the United States. Despite rising rates of use and overdose deaths, there are currently no FDA-approved medications for treating MUD.

Prior studies have shown that naltrexone (used to treat opioid and alcohol use disorders) and bupropion (an antidepressant) have independently been effective in MUD treatment. In a 2021 landmark clinical trial (ADAPT-2), researchers found that combining the two medications (naltrexone-bupropion) in the treatment regimen can significantly reduce methamphetamine use (Trivedi et al., 2021).

Building on those findings, the researchers conducted a secondary analysis to examine whether early improvements in depressive symptoms could help explain reductions in methamphetamine use among individuals with MUD receiving naltrexone-bupropion. Depression is highly prevalent among individuals with MUD and is strongly associated with poorer long-term outcomes and continued heavy use of methamphetamines.

The Study

This secondary analysis used data from the ADAPT-2 randomized controlled trial, which included 326 adults with moderate to severe MUD and at least mild depressive symptoms at baseline (Jha et al., 2026). During the initial study, participants were randomly assigned to receive either the naltrexone-bupropion combination or a placebo.

Researchers assessed changes in depressive symptoms during the first four weeks of treatment using the Patient Health Questionnaire (PHQ-9) and examined whether early improvements in mood were associated with reductions in methamphetamine use later in treatment, based on regular drug screenings.

Key Findings

Participants receiving naltrexone-bupropion experienced significantly greater reductions in depressive symptoms within the first 4 weeks compared to those in the placebo group.
By week 4, participants were more than twice as likely to show major improvement in depression and were also more likely to have minimal symptoms of depression than those on placebo.
Participants who showed improvement in depression by week 3 were significantly less likely to have a positive drug test at week 4, indicating that early improvements in depressive symptoms were associated with a higher likelihood of reducing methamphetamine use later in treatment.
Improvements in depressive symptoms accounted for approximately 25% of the medication’s overall effect on reducing methamphetamine use, suggesting that changes in mood may represent a key mechanism underlying the treatment’s efficacy.

These findings suggest that improvement in depressive symptoms may be an important mechanism through which naltrexone-bupropion reduces methamphetamine use. In addition, addressing co-occurring depression early in treatment may enhance outcomes and underscores the importance of integrated approaches that target both substance use and mental health.

While the findings are promising, additional research is needed to confirm these results and clarify causal pathways. The naltrexone-bupropion combination is also not yet FDA-approved for MUD, though evidence supporting its use continues to grow.

Article

Jha, M. K., Ghitza, U. E., Shoptaw, S., Minhajuddin, A., Kuruvila, S., Wakhlu, S., Nunes, E. V., Schmitz, J., Coffin, P. O., Bart, G., Carmody, T., & Trivedi, M. H. (2025). Early Change in Depressive Symptom Severity With Naltrexone-Bupropion Combination and Its Association With Reduction in Methamphetamine Use in ADAPT-2 Trial. The Journal of clinical psychiatry, 86(3), 25m15825. https://doi.org/10.4088/JCP.25m15825

Reference:

Trivedi, M. H., Walker, R., Ling, W., Dela Cruz, A., Sharma, G., Carmody, T., Ghitza, U. E., Wahle, A., Kim, M., Shores-Wilson, K., Sparenborg, S., Coffin, P., Schmitz, J., Wiest, K., Bart, G., Sonne, S. C., Wakhlu, S., Rush, A. J., Nunes, E. V., & Shoptaw, S. (2021). Bupropion and Naltrexone in Methamphetamine Use Disorder. The New England journal of medicine, 384(2), 140–153. https://doi.org/10.1056/NEJMoa2020214