Addiction

Article information
Title: Mirtazapine for Methamphetamine Use Disorder: A Randomized Clinical Trial
Authors: McKetin R, Shoptaw S, Saunders L, et al.
Journal Citation: JAMA Psychiatry. 2026 Jun 1;83(6):581-589
PubMed Link: https://pubmed.ncbi.nlm.nih.gov/41920558/

Abstract:
Importance: Methamphetamine use disorder is a global health challenge for which there are no approved pharmacotherapies. The safety and effectiveness of mirtazapine, a promising candidate for methamphetamine use disorder, has not been established in routine clinical practice.

Objective: To determine the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder in routine clinical practice.

Design, setting, and participants: This phase 3, parallel-group, double-blind, placebo-controlled randomized clinical trial was conducted between November 16, 2022, and May 1, 2025, at 6 outpatient alcohol and other drug clinics in Australia among adults with moderate to severe methamphetamine use disorder. Data analysis was conducted from May to September 2025.

Intervention: Mirtazapine (30 mg daily for 12 weeks) or equivalent placebo.

Main outcomes and measures: The primary end point was the change in days of methamphetamine use in the past 28 days from baseline to week 12. Secondary end points were depression, insomnia, HIV risk behavior, quality of life, and methamphetamine-negative oral fluid samples.

Results: Of 344 participants randomized, 339 participants received the intervention (167 in the placebo group and 172 in the mirtazapine group). Mean (SD) age was 42.0 (8.6) years, 126 participants (37.2%) were female, and participants had used methamphetamine for a median (IQR) of 24 days (17-28) of the past 28 days at baseline. The mean reduction in days of methamphetamine use from baseline to week 12 was greater in the mirtazapine group (7.0 days of 28 days) than in the placebo group (4.8 days of 28 days; mean difference, 2.2 days; 95% CI, -4.2 to -0.2 days; P = .02). More participants in the mirtazapine group reported drowsiness (47% vs 33%) and weight gain (10% vs 3%). Forty participants (23%) discontinued mirtazapine due to adverse events compared to 25 participants (15%) in the placebo group. No significant effects of mirtazapine on secondary end points were found.

Conclusions and relevance: In this parallel-group randomized clinical trial, mirtazapine delivered in routine clinical practice reduced methamphetamine use in adults with methamphetamine use disorder. No unexpected safety concerns delivering mirtazapine in this setting were found; this finding has important clinical implications in the absence of any approved pharmacotherapies for methamphetamine use disorder.

Trial registration: anzctr.org.au Identifier: ACTRN12622000235707.

Annotation
The findings:
Methamphetamine use disorder remains a major global treatment gap, with no FDA-approved pharmacotherapy despite substantial morbidity related to psychosis, cardiovascular events, suicide, homicide, etc. In this phase 3, multisite, double-blind randomized clinical trial, McKetin and colleagues tested whether mirtazapine could reduce methamphetamine use when delivered in routine outpatient addiction treatment rather than in a narrowly controlled research setting. The study enrolled 344 adults with moderate to severe methamphetamine use disorder across 6 Australian clinics; 339 received mirtazapine 30 mg nightly or placebo for 12 weeks. Participants had long-standing, high-frequency use (mean age 42 years, 37% female, median 24 days of use in the prior 28 days). At week 12, mirtazapine led to a greater reduction in use than placebo (7.0 vs 4.8 fewer days per 28 days; difference 2.2 days), corresponding to about an 8% lower daily risk of use. Secondary outcomes including depression, insomnia, HIV risk behavior, and quality of life, did not differ overall, though insomnia improved among those with baseline depression. The safety profile was reassuring, with more drowsiness and weight gain in the mirtazapine group.

Strength and weaknesses:
The major strength of this study is the transition from smaller phase 2 studies to a larger, pragmatic phase 3 trial in routine care, with a broader population including women and those with depressive symptoms. The design was rigorous (randomized, double-blind, placebo-controlled, prospectively registered), and retention was strong (86% at week 12). Limitations include a modest effect size and reliance on self-reported use-days, though supported by oral-fluid testing. Adherence was moderate (median 52%), with 25% discontinuing medication. The trial excluded several groups common in C-L settings, such as patients on antidepressants, recent suicide attempts, pregnant or medically unstable patients, thereby limiting generalizability.

Relevance:
For C-L psychiatrists, this study is useful because it gives clinicians a practical off-label medication option to discuss when diagnosing moderate to severe methamphetamine use disorder in medical settings. The medication effect is not dramatic, but in a disorder with no approved pharmacotherapy, even a modest reduction in use may be clinically meaningful, particularly given the associated risks. The dosing is straightforward: the regimen tested, and therefore the evidence-based target, is mirtazapine 30 mg by mouth nightly for 12 weeks. A 15 mg rescue dose was permitted for tolerability, and participants received a 15 mg taper for 28 days after the treatment phase, but the efficacy signal should be attributed to the 30 mg nightly regimen rather than to lower-dose mirtazapine. In practice, this may be especially relevant when methamphetamine use disorder co-occurs with insomnia or depressive symptoms, while requiring counselling about sedation, increased appetite, and weight gain. For C-L psychiatrists working in EDs, inpatient medical units, addiction consult services, or discharge planning, the study supports framing mirtazapine as an off-label medication to help reduce use, not as a stand-alone cure or an abstinence-producing treatment.

Article information
Title: Short-Acting Opioid Dose and Patient-Directed Discharge in Hospitalized Patients with Opioid Use Disorder
Authors: Logan A, Baisey T, McCulloch CE, Bazazi AR, Martin M, Suen LW
Journal Citation: JAMA Netw Open. 2026 Jun 1;9(6):e2618698
PubMed Link: https://pubmed.ncbi.nlm.nih.gov/42301710/

Abstract:
Importance: Patient-directed discharge, common among hospitalized patients with opioid use disorder (OUD) experiencing opioid withdrawal, is associated with poor outcomes. Increasingly, hospital-based clinicians are using short-acting opioids alongside methadone and buprenorphine to treat opioid withdrawal. However, no published studies have examined the association between this practice and patient-directed discharge.

Objective: To examine associations between dosing of short-acting opioids and time to first dose of short-acting opioid with early patient-directed discharge (within 72 hours).

Design, setting, and participants: This retrospective cohort study included hospitalizations involving adults with OUD who were treated with short-acting opioids between February 7 and December 31, 2024, using an opioid withdrawal order set in the electronic health record at an urban safety-net hospital. Statistical analysis was conducted between October 2024 and October 2025.

Exposures: Total daily dose of short-acting opioids (oxycodone and hydromorphone) expressed in morphine milligram equivalents, and time from emergency department intake to first dose of short-acting opioid.

Main outcomes and measures: The primary outcome was early patient-directed discharge, adjusted for age, race and ethnicity, gender, other substance use disorder, receipt of medications for OUD, and addiction care team consultation.

Results: A total of 669 hospitalizations, representing 520 unique patients, were included. Patients were a mean (SD) age of 44.1 (12.2) years, with most identifying as male (531 of 669 [79.4%], with 122 of 669 female [18.2%] and 16 of 669 gender minority [2.4%]) and unhoused (555 of 669 [83.0%]). A total of 92 hospitalizations (13.8%) resulted in early patient-directed discharge. In the final adjusted model, each doubling of the patient's daily dose of short-acting opioids was associated with an 8% reduction in the hazard of early patient-directed discharge (adjusted hazard ratio, 0.92 [95% CI, 0.86-0.99]; P = .03). There was no statistically significant association between time to first dose of short-acting opioid and patient-directed discharge within 72 hours.

Conclusions and relevance: In this cohort study of hospitalized adults with OUD, treatment of opioid withdrawal with short-acting opioids exhibited a dose-dependent association with reduced hazard of early patient-directed discharge. These findings support the use of short-acting opioids alongside methadone and buprenorphine for inpatient treatment of opioid withdrawal.

Annotation
The findings:
In this article, Logan and colleagues examined whether short-acting opioid dosing for inpatient opioid withdrawal was associated with early patient-directed discharge among hospitalized adults with opioid use disorder (OUD). This retrospective cohort study included 669 hospitalizations, representing 520 unique patients, at an urban safety-net hospital using an electronic opioid withdrawal order set between February and December 2024. The cohort was medically and socially complex: 83% of hospitalizations involved unhoused patients, 58.9% received addiction care team consultation, and 76.2% received medications for OUD during hospitalization. Overall, 92 hospitalizations (13.8%) ended in patient-directed discharge within 72 hours. In adjusted Cox models, each doubling of the daily short-acting opioid dose was associated with an 8% lower hazard of early patient-directed discharge (adjusted HR 0.92, 95% CI 0.86-0.99). Time to first short-acting opioid dose was not significantly associated with early patient-directed discharge. The authors interpret these findings as supporting short-acting opioids, used alongside methadone or buprenorphine, as part of inpatient withdrawal management for patients with OUD.

Strength and weaknesses:
The study’s main strength is its pragmatic focus on a real inpatient problem: patients with OUD leaving the hospital early, often in the setting of undertreated withdrawal. The authors used a dedicated opioid withdrawal order set to identify hospitalizations in which short-acting opioids were being used specifically for withdrawal, cravings, or concurrent pain, rather than relying on OUD diagnosis codes alone. The time-varying Cox model is also a strength because it reduces bias from the fact that patients hospitalized longer have more opportunity to receive opioids. Still, this remains a single-site retrospective cohort study, not a causal trial. The authors could not adjust for several key confounders, including OUD severity, physiologic opioid tolerance, opioid withdrawal severity, acute illness severity, or clinician-level differences in care. Safety, tolerability, and downstream consequences of this practice were not directly assessed. Generalizability may also be limited because the study occurred at a safety-net hospital with an established addiction care team and clinician education around short-acting opioid use for withdrawal.

Relevance:
This article is highly relevant for C-L psychiatrists, particularly addiction consult teams, because it addresses one of the most common and consequential inpatient addiction scenarios: a hospitalized patient with OUD, high opioid tolerance, active withdrawal or cravings, and a high risk of patient-directed discharge before medical treatment is complete. The findings support a more assertive, symptom-responsive approach to opioid withdrawal management, using short-acting opioids as an adjunct to methadone or buprenorphine rather than viewing MOUD and short-acting opioids as mutually exclusive. Clinically, the paper reinforces the value of addiction consultation, standardized order sets, and education of frontline teams in safe titration. It also provides a useful framing for C-L psychiatrists: early discharge is not simply “non-adherence” or “poor judgment”; it may reflect inadequately treated withdrawal, craving, pain, stigma, boredom, or competing social demands. Treating withdrawal effectively is therefore both good addiction care and good hospital medicine.