Transforming treatment-resistant depression care in Norway: Public health reimbursement for off-label intravenous ketamine

One of the most consequential developments in psychiatry around the turn of the millennium was the discovery that racemic ketamine—an established and widely used generic anesthetic—produced both a rapid and robust antidepressant effect (Berman et al., 2000; Zarate et al., 2006). This effect was demonstrated to appear within hours to days, compared to weeks to months for conventional antidepressants. Nevertheless, due to the lack of economic incentives to seek regulatory approval for a generic off-patent medicine, patient access to and reimbursement for this treatment has been very limited. In most countries where the treatment is currently available such as the United States, Canada, Germany and France, ketamine treatment is rarely used within the public health services, only regionally accessible, costly in outpatient private clinics with limited or no private insurance coverage and not universally reimbursed within public health care systems. A major development occurred in August of 2025, when Norway became the first country to approve nationwide public reimbursement for off-label racemic ketamine for treatment-resistant depression (TRD). In this article, we review the historical advances in ketamine research and clinical practice that culminated in this recent policy decision in Norway.

Ketamine, primarily an N-methyl-D-aspartate (NMDA) receptor antagonist, was synthesized in 1962 and FDA approved for use in anesthesia in the United States in 1970. It gained early prominence for battlefield analgesia during the Vietnam War and has since become one of the most widely used anesthetic agents, earning a place on the World Health Organizatiońs list of essential medicines in 1985. Its ability to produce dissociation and anesthesia without compromising airway reflexes, respiration, or blood pressure makes it uniquely useful across age groups and in medically complex patients with comorbidities. At subanesthetic dosing, where the patient remains consciousness, ketamine induces profound alterations in the conscious state including distortions in perception, cognition, affect, sense of space and time, and an experience of disconnection with the body and sense of self, leading to its initial classification as a “dissociative” anesthetic. Due to the diversity and variability of subjective effects of ketamine in addition to dissociation at the subanesthetic doses, other classifications based on its pharmacology have also been proposed for use in psychiatry, such as rapidly acting antidepressant (RAAD) or glutamatergic psychedelic (Nutt et al., 2025).

The potentially psychotherapeutic value of the dreamlike subjective properties of ketamine was reported shortly after approval (Collier, 1972) and the earliest published psychiatric use of ketamine occurred in Iran in 1973 (Khorramzadeh and Lofty, 1973). As classic psychedelic research and use in psychiatry was curtailed globally following United Nation restrictions, psychiatrists in Iran and the former Soviet Union explored ketamine for a variety of indications as a psychotherapeutic catalyst, utilizing its unique psychoactive properties to promote abreaction and positive psychological change (Krupitsky and Grinenko, 1997).

In the United States, a separate historically more biomedical paradigm emerged. Dissatisfaction with the real-world effectiveness of monoaminergic antidepressants, coupled with growing work on glutamatergic mechanisms in depression, led to preclinical investigations of NMDA antagonists as potential antidepressants. The first randomized controlled trial on ketamine for major depressive disorder was conducted at Yale in 2000, demonstrating a striking antidepressant effect within hours—dramatically faster than traditional pharmacotherapies (Berman et al., 2000). Subsequent research at the National Institute of Mental Health (NIMH) and elsewhere expanded the evidence base over the following decades (Zarate et al., 2006, Diazgranados et al., 2010; Zarate et al., 2012). With the absence of industry financial support for large trials due to ketamine's generic status, it took many years to accumulate the necessary confirmatory data. Numerous meta-analyses of both controlled trials and real-world data have been done over the last 25 years overwhelmingly supporting ketamine's rapid antidepressant and anti-suicidal effects for unipolar and bipolar depression with an acceptable safety profile (Alnefeesi et al., 2022; Bahji et al., 2022; Smith-Apeldoorn et al., 2022; Nikolin et al., 2023; Shen et al., 2024; Saelens et al., 2025; Shi et al., 2025). Nevertheless, many questions remain regarding long-term outcomes, optimal maintenance dosing strategies, and complimentary methods to prolong the antidepressant response (McMullen et al., 2021; Smith-Apeldoorn et al., 2022; Al-Garni et al. 2026). A range of mechanistic pathways have been proposed, including enhanced neuroplasticity, normalization of dysregulated neural networks, anti-inflammatory actions, modulation of negative reward processing, and psychotherapeutic effects linked to the subjective experience itself (Zanos and Gould, 2018; Garel et al., 2023; Lullau et al., 2023; Krystal et al., 2024). Emerging trial and real-world data suggest that pairing ketamine with psychotherapy may augment therapeutic outcomes and extend durability of benefit (Kew et al., 2023; Al-Garni et al., 2026).

The American Psychiatric Association endorsed the use of ketamine for TRD in 2017 (Sanacora et al., 2017). Since then, multiple international academic associations including the Canadian Network for Mood and Anxiety Treatments (Swainson et al., 2021), and more recently the UK Royal College of Psychiatrists (2025), have issued similar supportive consensus reports.

Ketamine's entry into Norwegian psychiatric practice occurred long after the treatment was widely used in the USA, but before many other European countries. An early effort to introduce the treatment into the Norwegian public system as a pilot project proved slow to materialize and was followed by the opening of private clinics in Oslo in 2018 (Lien and Clausen, 2025). The Norwegian Psychiatric Association requested a review of this practice by the medical board, and in 2019 the board concluded that using ketamine for TRD constituted a professionally sound off-label treatment based on currently available scientific evidence (Mølmen et al., 2023). The same year, Johnson and Johnson’s Spravato (a patented nasal administration of esketamine—the (S) enantiomer of ketamine) received European Medicines Agency (EMA) approval for TRD. But priced at up to 7800 NOK (around 650 Euro) per effective dose, more than 100 times the cost of racemic ketamine, Spravato has not yet secured approval for public reimbursement in Norway. This is consistent with health economic assessments conducted by the National Institute for Health and Care Excellence (NICE) in the UK and those of several other European states (National Institute for Health and Care Excellence, 2022; Gründer et al., 2026). Of note, in 2025 the Australian Pharmaceutical Benefits Scheme (PBS) added Spravato to the list of publicly subsidized medicines to increase patient accessibility, which highlights the potential additional cost savings to the health system had they chosen national reimbursement for generic racemic ketamine (Department of Health and Aged Care, 2025).

In 2020, Scandinavia's first dedicated ketamine unit for depression and acute suicidality was opened at Østfold Hospital and approximately 400 patients in total have since been treated (Sykehuset Østfold, 2021). This public healthcare unit treats patients with moderate to severe depression inadequately responsive to two prior pharmacotherapies, with an induction series of six treatments over 3 weeks followed by monthly maintenance over 6 months (Berthold-Losleben et al., 2025). The treatment model also incorporates nonpharmacologic components of set and setting such as preparation, eyeshades and music, and concurrent psychotherapy as a mandatory prerequisite for admission into the program. This is a relatively unique feature of the Norwegian protocol compared to the practice of most other public hospital settings in Europe. This integrated Norwegian approach is very similar to the biomedical-psychedelic approach described as the Montreal model by Garel et al. in 2023. The requirement that enrolled patients engage in concurrent psychotherapy is an element intended to increase the likelihood of more sustained psychological and behavioral change and to enhance safety outcomes with additional longer-term psychotherapeutic support. While this was a component intentionally integrated into the protocol, it should be noted that many empirical questions remain and there is a paucity of research data regarding the type, quantity, and overall necessity of concurrent psychotherapy with ketamine treatment for short- and longer-term outcomes (Veraart et al., 2026; Simpson and Juruena, 2026).

Despite a population of primarily chronic, severely depressed patients, most have demonstrated significant clinical improvement, with few adverse events. A large observational study is underway to share data from the public unit; but preliminary analyses indicate response rates (≥50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS)) of roughly 60% and remission rates (MADRS ≤12) near 40% (Berthold-Losleben et al., unpublished data). A summary of initial experience from the public unit, including public online access to the standardized policies and procedures used at Østfold Hospital, was recently published (Berthold-Losleben et al., 2025). This has allowed other psychiatric units throughout the country to incorporate the practice into their hospitals in a safe, structured, and comprehensive manner, without having to build their own protocols from ground up. Examples have included the new ketamine units at Oslo University Hospital, Stavanger University Hospital, and Innlandet Hospital.

To support both coordinated national research and translational clinical development, the Norwegian Rapid Acting Antidepressant Network (NORAAD) was created in 2023, bringing together leading psychiatrists from all regional health authorities (Sykehuset Østfold, 2024). The group organized Norway's first national meeting on ketamine in psychiatry in 2024, and NORAAD secured public funding for a multisite (11 regional psychiatric units from every geographical region in Norway) randomized controlled trial including approximately 230 participants to address questions around initial dosing during induction and optimization of maintenance strategies. Training for the trial has been completed, several sites have already begun clinical treatment outside the trial, and recruitment is expected to begin in early 2026. While the study will indeed fill an important knowledge gap in the literature, perhaps even more importantly, preparation for the trial required putting in place all of the physical and personnel infrastructure which is also necessary for the clinical treatment of patients outside of clinical trials. This ensured more rapid adoption of ketamine treatment for those who could benefit, as implementation of the novel practice has a higher learning curve and institutional challenges than simply prescribing a new oral antidepressant.

The development of public healthcare ketamine units in Norway had the additional effect of catalyzing both professional interest and institutional support for publicly funded research on other psychedelic medicines currently being investigated for the treatment of mental health disorders. The research unit PsykForsk (the Center for Innovative Clinical Research) of the Østfold Hospital Trust, recently completed the world's first trial on MDMA-assisted therapy for the treatment of major depressive disorder, funded primarily by the regional health authorities (Kvam et al., 2025a; Kvam et al., 2025b). They are preparing another study on MDMA-assisted therapy for chronic treatment-resistant depression in young adults and have done population research on other psychedelics with the University of Oslo (Jacobsen et al., 2021; Kvam et al., 2023). Several psilocybin trials are currently in preparation, and the first graduate training program for health professionals in psychedelic assisted psychotherapy is underway at the University of Inland Norway.

Because generic racemic ketamine remains an off-label therapy for depression, its personnel and infrastructure costs fall on local mental health units, despite the low cost of the medication itself. In 2022, a request was filed for a formal health technology assessment (HTA) to determine eligibility for public reimbursement. The mandate was to assess the efficacy of ketamine for TRD and to perform a health economic evaluation. The Norwegian agency responsible for HTAs, the Bestillerforum for Nye Metoder, commissioned the assessment in 2024. It was sent to the Norwegian Medicines Agency (NoMA), and in June 2025 NoMA released its final report (Ohm et al., 2025). NoMA concluded that ketamine is generally well tolerated in TRD and delivers superior response and remission rates, as well as greater improvements in depressive symptoms, when compared with saline, midazolam, and ECT—at substantially lower cost.

Subsequently, in August of 2025, the Beslutningsforum for Nye Metoder endorsed the NoMA report, effective immediately, making Norway the first country in the world to implement nationwide publicly funded off-label ketamine treatment for TRD (Nye Metoder, 2025). All Norwegians suffering from TRD will now be able to access this additional treatment tool without personal cost. As the ruling on this indication did not go through the traditional regulatory process in the medicines agency, use for TRD still remains “off-label,” which in Norway requires a strict compliance with formal documentation of informed consent. The decision is set for reevaluation before the end of 2028, with a focus on long-term safety and durability of effect (Nye Metoder, 2025). The decision for reimbursement dictates that the treatment occurs within the specialist mental health services and that patient data is to be collected either in clinical registries or ongoing clinical studies. This requirement is a tremendous opportunity for the accumulation of invaluable data on ketamine treatment from potentially thousands of patients over the next few years. In contrast to the fragmented and heavily private health system in the USA—where many pioneering trials have been done over the years—Norway has a strong and coordinated public health service, enabling shared data registries, simplified patient consent for biobank, and treatment data to be accessible for large multisite research studies. The national Norwegian program also provides a potential model contrasting with the relatively poorly monitored widespread use of off-label ketamine that has emerged in the USA, with a wide diversity of treatment protocols in use inconsistently aligned with evidence-based practices.

Despite almost a century of modern evidence-based medicine, today there continues to exist a global deficit in rapid and effective treatment modalities for one of the most prevalent health care challenges we face from a global health perspective. Despite relatively high measures of societal well-being in the Nordic region, the prevalence of depression and TRD remains comparable to other countries, and no clear change in this trend is seen on the horizon. The discovery of ketamine's rapid and significant antidepressant effect, even for patients who do not respond to traditional oral antidepressants, has the potential to have an impact on the lives of millions of people, their families, and our societies. New pharmacotherapies usually come with an unfortunate significant opportunity cost, an obstacle to implementation and universal access. The majority of new treatments emerge from the pharmaceutical industry pipeline, with the annual median cost of a new patented drug currently surpassing $180,000 USD (Rome et al., 2022). This story of the repurposing of cheap and widely accessible generic ketamine, an old anesthetic with a half century safety record, as a novel antidepressant, is an uncommon but welcome example of “interventional pharmacoeconomics” leading to the development of not only effective but also cost-effective therapies for society (Kerdemelidis, 2024). Norway's adoption of generic ketamine also reflects a distinctive commitment to health equity: prioritizing value-based decisions over default alignment with traditional pharmaceutical industry regulatory pathways. As ketamine treatment services expand across all health regions in Norway over the next year, we expect to see a profound impact for many more people who do not respond adequately to existing standard psychiatric treatment options. We hope that other countries might be able to use the pioneering Norwegian experience as a practical model for public health systems to help more people in need, with more effective treatments, at a lower cost to our communities.