Ketamine to enhance methadone treatment retention in patients with opioid use disorder and co-morbid depression
P. Manza, Annabelle M. Belcher, Heather Fitzsimons, Max Spaderna, Aaron D. Greenblatt, Hannah C. Smith, M. Derenoncourt, Donald S. Gann, Umer Farooq, Mark D Kvarta, Bethany DiPaula, Sarah Merritt, I. Mitić, Carlos A. Zarate, Todd D Gould, Eric Weintraub, S. Kattakuzhy
The American Journal of Drug and Alcohol Abuse August 22, 2025 DOI: 10.1080/00952990.2025.2541212 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Case series (single-arm open-label feasibility trial) Randomized Case report Peer reviewed |
|---|---|
| Sample size | 3 |
| Population | Patients diagnosed with opioid use disorder initiating methadone treatment and reporting depression symptoms at an opioid treatment program in Baltimore, Maryland |
| Interventions | Ketamine methadone |
| Dose | 0.5 mg/kg infusion over 40 min, three times per week for 2 weeks |
| Duration | 2-week ketamine regimen; 10-day follow-up post-infusions; 3-month timepoint |
| Topics | Addiction Depression Esketamine Ketamine |
| Registration | NCT05051449 |
| Key findings | In three patients with opioid use disorder beginning methadone treatment, a two-week course of ketamine infusions was safe and generally well tolerated, with mostly favorable acceptability ratings. All three stayed in treatment through three months with strong adherence, and self-reported depression symptoms improved: severe to mild/moderate in two patients and moderate to remission in the third. The authors conclude that randomized controlled trials are warranted to test ketamine as an adjunctive treatment in this population. |
Abstract
ABSTRACT
Background: Opioid use disorder (OUD) is a chronic relapsing condition with a high mortality rate. While medications such as methadone are valuable first-line therapies, retention is poor, with the highest dropout rates early in a treatment attempt. Poor outcomes are due in part to the very high rates of co-morbid depression in people with OUD, as depression can drive opioid use. Therefore, administering a rapid-acting antidepressant such as ketamine early in a treatment attempt may be an effective strategy to improve outcomes.
Objectives: Here, we describe a case series of three patients (two males, one female) diagnosed with OUD initiating methadone treatment and endorsing symptoms of depression, who met criteria for a single-arm open-label feasibility trial (NCT05051449) at an opioid treatment program in Baltimore, Maryland.
Methods: Participants underwent a 2-week ketamine regimen (0.5 mg/kg infusion over 40 min, three times per week for 2 weeks).
Results: Ketamine was safe and generally well-tolerated. At 10-day follow-up post-ketamine infusions, participant acceptability ratings were mostly favorable. All three patients remained in treatment through the 3-month timepoint with strong treatment adherence. With treatment, self-reported depression symptoms decreased from severe to mild/moderate in two patients, and from moderate to remission in the third.
Conclusions: Randomized controlled trials are warranted to test whether ketamine may be a feasible and safe adjunctive treatment for OUD in patients initiating methadone treatment.
Comparable studies
Other non-randomized and open-label trials on ketamine for addiction, most cited first.