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Hurdles of Ketamine Therapy: Off-Label, Non-FDA Approved, and High-Cost. The Journey from Breakthrough to Accessibility

It has been more than two decades since we first became aware of the robust and nearly instantaneous antidepressant effects of ketamine (Berman et al., 2000). Since then, numerous trials have replicated these initial findings, consistently demonstrating the effectiveness of ketamine for treatment-resistant depression and other depressive disorders. However, the journey to make generic ketamine (used for intravenous and intramuscular administration) widely accessible, has been sluggish, in stark contrast to the patented and FDA-approved nasal form known as esketamine, under the brand name Spravato®.

Despite the well-established evidence that generic ketamine has been shown to be highly effective, if not more effective than the nasal alternative, this delay persists. In fact, UpToDate, the most widely read medical reference globally, (which physicians and medical professionals rely on for the latest evidence-based best practices) now recommends generic ketamine over electroconvulsive therapy (ECT) and nasal Spravato for the treatment of resistant depression. This recommendation is founded on considerations of efficacy, safety, and adverse effects. Moreover, one recent study (Singh et al., 2023) found that the number of treatments administered to achieve remission was much lower in the intravenous (IV) ketamine group compared to the nasal alternative.

In our society, where depression persists as a widespread global health issue affecting every individual on the planet either directly or through their connections with someone grappling with this disorder, I am eager to discuss and explore the reasons behind the limitations in accessing the best available tools for mental healthcare. Let's delve into some of the hurdles surrounding ketamine therapy—its off-label status, FDA approval, as well as the challenges related to cost and accessibility.

The Roadblocks to Access: FDA-Approval

The classification of ketamine as a generic drug has rendered it less attractive for pharmaceutical industry investment, leading to primarily small-scale, publicly funded studies. While numerous clinical trials demonstrate positive outcomes for ketamine, sample size matters. In contrast, Spravato® has navigated the regulatory landscape more smoothly, gaining FDA approval in 2019 as a nasal spray thanks partly to industry funding that allowed for much larger studies.

The FDA may be cautious about approving treatments without a comprehensive understanding of efficacy and potential risks. Another reason for the FDA's trepidation in approval likely stems from the variability in the administration of IV ketamine treatments, which can vary widely in terms of dosage, frequency, and duration. Regulatory boards may find this variability in the practice of ketamine therapy less appealing. However, most ketamine providers, much like myself, embrace it, understanding that patients are treated as individuals in this approach, with unique treatment plans specific to their diagnosis, prior experiences, and physical characteristics (i.e., body weight).

The Tall Hurtles for Ketamine: Cost & Insurance

Spravato, patented by Janssen Pharmaceuticals and now known as Johnson & Johnson, has swiftly navigated the regulatory process, propelled by industry funding. However, this success comes at a considerable expense to the medical system. The cost per nasal spray dose is nearly $800, and although insurance may cover it depending on strict criteria, the financial impact on the healthcare sector is substantial.

The eligibility criteria for insurance coverage include having a diagnosis of Treatment-Resistant Depression (TRD) with no meaningful improvement after trying at least two antidepressants from different classes for a minimum of four weeks each. Alternatively, individuals may qualify if diagnosed with Major Depressive Disorder (MDD) and experiencing acute suicidal ideation or behavior, in addition to depressive symptoms.

While insurance may offset the cost of Spravato, the financial burden it imposes on the healthcare system is a growing concern in our nation. This contributes to rising insurance premiums and an overall expensive, often unaffordable healthcare landscape for many.

Generic ketamine, which costs significantly less than Spravato, is not covered by insurance primarily due to the lack of financial backing for large-scale clinical trials and FDA approval as a treatment for depression. Consequently, ketamine remains "off-label." Yet, it is important to understand that this designation does not imply a lack of safety or effectiveness.

chart with examples of off-label drugs
Example of commonly used and highly effective drugs considered “off-label” include: Propranolol (Inderal) for Performance Anxiety, Sildenafil (Viagra) for Female Sexual Arousal Disorder, Colchicine (Colcrys) for Pericarditis, Quetiapine (Seroquel) for Insomnia

What Lies Ahead? The Future of Ketamine Therapy

I recently attended the American Society of Ketamine Physicians conference and was pleased to observe numerous discussions focused on enhancing access and affordability. The main barrier for individuals considering ketamine therapy at my clinic is the cost. It is disheartening to turn down a prospective patient who could benefit greatly from ketamine due to financial constraints.

Ketamine practitioners, much like myself, are actively seeking solutions to address this issue through various means. These include offering ketamine in group settings and collaborating with companies, such as Enthea, which after an extensive provider credentialing process to ensure adherence to strict practice guidelines allows the provision of Ketamine-Assisted Psychotherapy (KAP) as an employee health benefit.

I anticipate witnessing more creative approaches to increase access and affordability in the future. As a growing body of research demonstrates the safety and efficiency of ketamine, insurance companies will likely be compelled to step up and cover costs. This increasing evidence makes it progressively challenging for them to ignore the potential benefits of ketamine therapy.


The delayed and arduous journey for the acceptance of generic IV ketamine's antidepressant promise reflects broader challenges in the pharmaceutical industry and the healthcare system. It is imperative to nurture a future healthcare model that prioritizes breakthrough treatments while ensuring accessibility for everyone. Through united efforts in addressing systemic issues obstructing the availability of cost-effective treatments, we can shape a more equitable and affordable future. Cultivating collaboration among policymakers, healthcare professionals, pharmaceutical companies, and the public empowers us to actively contribute to an effective healthcare system. The choice lies with us: to passively observe the evolution of healthcare, or to actively participate in building a system that prioritizes patient access and affordability alongside medical breakthroughs.

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