A groundbreaking clinical trial led by researchers at the University of New South Wales (UNSW) and Monash University has demonstrated that mirtazapine, a widely used antidepressant, can significantly reduce methamphetamine use among individuals with dependence. This phase 3 study, known as the Tina Trial, marks a pivotal advancement in addressing one of Australia's most pressing public health challenges in the realm of substance use disorders.

Methamphetamine, commonly referred to as meth, ice, or crystal meth, is a potent central nervous system stimulant that leads to addiction through profound alterations in brain chemistry, particularly in dopamine pathways responsible for reward and motivation. In Australia, methamphetamine dependence affects a substantial portion of the population, with recent data indicating that approximately 1% of individuals aged 14 and over reported recent use in 2022–2023, translating to hundreds of thousands grappling with its consequences. The absence of approved pharmacotherapies has left treatment reliant on behavioral interventions, which often suffer from high dropout and relapse rates exceeding 50% within months.

🌡️ The Methamphetamine Crisis in Australia

Australia faces one of the highest per capita rates of methamphetamine dependence globally, with wastewater analysis revealing record-high consumption levels in 2025, particularly in regions like Western Australia and the Northern Territory. The drug contributes to severe health burdens, including psychosis, cardiovascular events, strokes, and increased mortality—meth-related deaths quadrupled over the past two decades. Economically, it imposes billions in healthcare and social costs annually, with treatment access limited by long waitlists and insufficient specialized services.

Current treatments emphasize psychosocial support, such as cognitive behavioral therapy (CBT) and contingency management, where incentives reward abstinence. However, these approaches demand intensive resources and show variable efficacy, with relapse common due to intense cravings and withdrawal symptoms like profound fatigue, depression, and insomnia. The Tina Trial's success highlights the urgent need for pharmacological options to complement existing strategies.

Understanding Mirtazapine: From Antidepressant to Addiction Aid

Mirtazapine (brand name Remeron), a tetracyclic antidepressant approved since the 1990s, primarily enhances noradrenergic and serotonergic neurotransmission by antagonizing central presynaptic α2-adrenergic autoreceptors and heteroreceptors. This boosts serotonin and norepinephrine release while blocking certain serotonin receptors (5-HT2 and 5-HT3), alleviating depression and improving sleep.

In the context of methamphetamine dependence, chronic use dysregulates these same α2-adrenergic receptors and depletes monoamines, fueling cravings. Mirtazapine's mechanism likely restores balance, reducing withdrawal severity and reward-seeking behavior independently of its antidepressant effects—as evidenced by benefits across depressed and non-depressed participants.

Unlike stimulants or opioids with abuse potential, mirtazapine's sedating profile and low addiction risk make it ideal for outpatient use. Generic availability keeps costs low, around AUD 0.50 per dose.

The Tina Trial: Design and Execution

Funded by the Medical Research Future Fund and led by UNSW's National Drug and Alcohol Research Centre (NDARC), the Tina Trial (ACTRN12622000235707) was a multicenter, double-blind, placebo-controlled phase 3 study spanning November 2022 to May 2025. Conducted at six outpatient addiction clinics across New South Wales, Victoria, Queensland, South Australia, and Western Australia, it enrolled 339 adults (aged 18-65) meeting DSM-5 criteria for moderate to severe methamphetamine use disorder, with recent positive urine screens.

Participants, averaging 22 days of use in the prior month at baseline, were randomized 1:1 to 30mg daily mirtazapine or matching placebo for 12 weeks, self-administered at home alongside standard counseling. Primary outcome: change in self-reported methamphetamine use days (Timeline Follow-Back method). Secondary measures included depression (PHQ-9), insomnia (Athens Insomnia Scale), HIV risk behaviors, and quality of life (EQ-5D).

Key Findings: Significant Reductions in Use

The trial's primary endpoint revealed a mean reduction of 7.0 days of methamphetamine use (out of 28) in the mirtazapine group versus 4.8 days for placebo—a statistically significant difference of 2.2 days (95% CI, -4.2 to -0.2; P=0.02). Incidence rate ratio indicated an 8-11% lower risk of use days (0.89; 95% CI, 0.80-0.98).

Benefits persisted across subgroups, including by sex and baseline depression status. While secondary outcomes like depression scores showed no significant group differences, trends favored mirtazapine, particularly for insomnia in depressed individuals. Full results are detailed in the JAMA Psychiatry publication.

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Safety Profile and Tolerability

No unexpected safety signals emerged, affirming mirtazapine's suitability for this population. Adverse events were higher in the treatment arm (drowsiness 47% vs 33%; weight gain 10% vs 3%), but discontinuation rates were comparable (23% vs 15%). This profile supports scalable, routine prescribing without intensive monitoring, a stark contrast to more complex regimens.

Implications for Australian Healthcare and Policy

This trial positions mirtazapine as the first evidence-based pharmacotherapy for methamphetamine use disorder, potentially filling a critical gap. Off-label prescribing is feasible per RANZCP guidelines, enabling immediate integration into services. Cost-effectiveness—due to generics and home dosing—could alleviate pressures on overburdened clinics.

Challenges remain: suboptimal adherence diluted effect sizes, and long-term outcomes require further study. Yet, even modest reductions translate to fewer harms, echoing contingency management's impact.

Expert Perspectives from UNSW and Monash

Lead investigator Associate Professor Rebecca McKetin (UNSW NDARC) stated, "Although this reduction is small, in the absence of any alternative medication this is an important step forward." Addiction psychiatrist Associate Professor Shalini Arunogiri (Monash) emphasized, "Mirtazapine's direct action on dysregulated brain pathways disrupted by meth offers hope beyond symptom management."

These insights underscore the collaborative prowess of UNSW and Monash, institutions renowned for addiction research. UNSW's NDARC has pioneered cohorts like MATES, tracking treatment outcomes, while Monash advances integrated mental health models.

Building on Prior Research

Phase 2 U.S. trials (n=60,120) in high-HIV-risk groups showed similar reductions, but exclusions limited generalizability. The Tina Trial's diverse cohort (including women, depressed individuals) confirms broader applicability. Ongoing UNSW-Monash studies explore co-use with opioids and novel interventions like lisdexamfetamine for withdrawal.

Future Directions and Research Outlook

Regulatory approval pathways loom, with phase 4 trials needed for abstinence and relapse prevention. Combination therapies, digital adherence tools, and equity-focused access (e.g., rural/remote) are priorities. UNSW and Monash's momentum—bolstered by NHMRC funding—promises sustained innovation, positioning Australia as a leader in stimulant use disorder research.

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This UNSW-Monash breakthrough heralds a new era for methamphetamine treatment, offering tangible hope amid entrenched challenges. By leveraging existing medications through rigorous university-led trials, Australian higher education continues to drive real-world health solutions.