Naltrexone-Bupropion Shows Promise for Methamphetamine Use Disorder with Depression
Want the latest research insights delivered straight to your inbox?
Published: July 30, 2025, in The Journal of Clinical Psychiatry
Study: Early Change in Depressive Symptom Severity With Naltrexone-Bupropion Combination and Its Association With Reduction in Methamphetamine Use in ADAPT-2 Trial (J Clin Psychiatry 2025;86(3):25m15825)
Methamphetamine use disorder is a challenging condition with no FDA-approved pharmacological treatments. Many patients also present with comorbid depressive symptoms, which can worsen prognosis and complicate recovery efforts.
The ADAPT-2 trial (Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder) previously demonstrated that naltrexone-bupropion can significantly reduce methamphetamine use. This secondary analysis explores whether early improvements in depression also play a role in treatment success.
🧐 Study Objectives:
To determine:
🗓️ Whether naltrexone-bupropion improves depressive symptoms early in treatment (first 4 weeks) compared to placebo.
💉 Whether early depression improvement predicts subsequent reductions in methamphetamine use.
🔬 Methods:
Design: Secondary analysis of the ADAPT-2 trial (May 2017–July 2019)
Population: 326 adults with moderate/severe methamphetamine use disorder and baseline PHQ-9 ≥5
Intervention: Extended-release naltrexone + bupropion vs placebo
Depression Outcomes:
Response: ≥50% PHQ-9 reduction
Remission: PHQ-9 ≤4
Methamphetamine Response: ≥3 of 4 negative urine drug screens in weeks 5–6
📚 Key Findings:
1. Depression Symptom Reduction
Greater PHQ-9 decrease at week 4 with naltrexone-bupropion vs placebo (estimate = −2.52; SE = 0.81)
Higher odds of depression response: OR = 2.54 (95% CI, 1.42–4.55)
Higher odds of depression remission: OR = 3.04 (95% CI, 1.57–5.87)
2. Depression Improvement & Methamphetamine Response
Greater PHQ-9 improvement between baseline and week 4 was linked to higher likelihood of methamphetamine response: OR = 3.74 (95% CI, 1.28–10.93)
Early depression change explained ~25% of the treatment effect on methamphetamine use
🚀 Comparison to Previous Studies
- Earlier pharmacotherapy studies for methamphetamine use disorder, including those evaluating bupropion alone or mirtazapine, have shown modest or inconsistent effects on both drug use and mood symptoms.
- The original ADAPT-2 trial was the first large RCT to show significant reductions in methamphetamine use with a combination pharmacotherapy approach.
- This secondary analysis strengthens the case by showing that mood improvements are not just a parallel benefit—they are partially mediating treatment success.
🎓 Clinical Takeaway
- For patients with methamphetamine use disorder and depressive symptoms, naltrexone-bupropion not only improves mood early in treatment but may also boost the likelihood of reducing methamphetamine use.
- Early mood improvement could serve as an important clinical signal for predicting and enhancing long-term recovery outcomes.
FOR ACADEMY MEMBERS:
490th CHAPTER ADDED TO our ACADEMY:
This chapter will be summarized in the following sections:
- First Line Treatment (Add to Contingency Management When Available)
- Reasonable Second-Line Options.
- Which ones are generally Not Recommended (Negative or Insufficient RCT Efficacy)
Methamphetamine Use Disorder: Pharmacological Treatment Options
Want the latest research insights delivered straight to your inbox?
We continue to review and summarize clinically relevant research to support your daily practice.
INTERESTED IN ACCESS TO THIS & OTHER CLINICALLY RELEVANT LECTURE SERIES?
JOIN ACADEMY MEMBERSHIP:
This is a closed membership for medical professionals only.
- 400+ Clinically Relevant Chapters: Each chapter within these sections is of direct clinical relevance for your daily practice. (Table of Content)
- Journal Club: we will post the most recently published psychiatry articles relevant to your daily clinical practice. (Read Content)
- Clinical Case Discussion: Dr. Singh (Psychiatry) and Dr. Kaur (Family Medicine) discuss clinical cases to integrate the clinical cases from Psychiatry and Medicine. (Read Content)
- Monthly Insights: Gain access to our monthly sessions featuring the latest on recent publications, new medication approvals, FDA updates, and more. (Monthly Insights)
- Discussion Forum & Community: Connect with other medical professionals and discuss your difficult-to-treat clinical cases. (Academy Network)
- Goal: is to have all important clinically relevant topics in one place for ease of access.
DISCOUNTS AVAILABLE FOR: Residents & Students ONLY.
Email us your student information (program information and way to confirm your student status) to: [email protected]
© 2025 All Rights Reserved.
