For individuals grappling with severe depression that has resisted all other forms of treatment, ketamine therapy is emerging as a powerful and rapid-acting intervention, fundamentally shifting the landscape of psychiatric care. Administered in controlled clinical settings, this anesthetic-turned-antidepressant works on a completely different neural pathway than traditional medications, often providing relief from debilitating symptoms within hours or days, rather than weeks or months. Its primary use is for patients with treatment-resistant depression (TRD), offering a lifeline to those who have found little to no success with standard antidepressants and psychotherapy, by directly stimulating the growth of new connections in the brain.
How Ketamine Works Differently in the Brain
For decades, the primary approach to treating depression with medication has centered on neurotransmitters like serotonin and norepinephrine. Selective serotonin reuptake inhibitors (SSRIs), the most common class of antidepressants, work by increasing the amount of available serotonin in the brain. While effective for many, these medications can take a long time to work and are ineffective for a significant portion of patients.
Ketamine breaks from this model entirely. It is a powerful antagonist of the N-methyl-D-aspartate (NMDA) receptor, which means it blocks the action of glutamate, the most abundant excitatory neurotransmitter in the brain. This initial blockade triggers a cascade of downstream effects, leading to a surge in glutamate activity in other areas. This surge is what scientists believe produces ketamine’s rapid antidepressant effects.
This process stimulates what is known as synaptogenesis—the formation of new synapses, or connections, between neurons. In brains affected by chronic stress and depression, these crucial connections can atrophy and wither away. Ketamine appears to not only halt this process but actively reverse it, effectively “rewiring” brain circuits associated with mood and cognition. This neuroplasticity is the biological foundation for its remarkable speed and efficacy.
Who Is a Candidate for Ketamine Therapy?
Ketamine therapy is not a first-line treatment for depression. Its use is typically reserved for individuals who have a confirmed diagnosis of treatment-resistant depression. Clinically, this is defined as major depressive disorder that has not responded adequately to at least two different trials of traditional antidepressant medications at a sufficient dose and duration.
Beyond TRD, it is also being used and studied for other challenging conditions. The FDA-approved nasal spray, esketamine, is also indicated for major depressive disorder with acute suicidal ideation or behavior. Researchers are also actively investigating its potential benefits for post-traumatic stress disorder (PTSD), certain anxiety disorders, and obsessive-compulsive disorder (OCD).
However, not everyone is a suitable candidate. A thorough medical and psychiatric evaluation is essential to rule out contraindications. Individuals with uncontrolled high blood pressure, a history of psychosis (like schizophrenia), or certain severe cardiovascular or respiratory conditions may not be eligible due to the drug’s physiological effects. A history of substance use disorder requires careful consideration, as ketamine has a known potential for abuse.
Types of Ketamine Administration
The method by which ketamine is administered is a critical factor in its safety, efficacy, and cost. Several different formulations are currently in use, both on-label and off-label.
Intravenous (IV) Infusion
The most widely studied method is intravenous (IV) infusion of racemic ketamine (a mix of its two mirror-image molecules). During this procedure, a low, sub-anesthetic dose is administered slowly over approximately 40 minutes in a medical clinic. This method provides 100% bioavailability, meaning the entire dose enters the bloodstream, allowing for precise and predictable control.
A typical treatment course begins with an induction phase of several infusions over a few weeks, followed by maintenance infusions at decreasing frequency—perhaps once a month or less—to sustain the antidepressant effects.
Esketamine (Spravato) Nasal Spray
In 2019, the U.S. Food and Drug Administration (FDA) approved Spravato, a nasal spray whose active ingredient is esketamine, one of the molecules found in racemic ketamine. Spravato is specifically approved for adults with TRD and those with major depressive disorder experiencing active suicidal thoughts. It must be administered by the patient under the supervision of a healthcare provider in a certified clinic.
After using the spray, patients are required to remain at the clinic for at least two hours for monitoring of potential side effects, such as sedation and increased blood pressure. Spravato is always prescribed in conjunction with a traditional oral antidepressant.
Other Formulations (Intramuscular and Oral)
Less common but still utilized are intramuscular (IM) injections, which offer high bioavailability but can be harder to titrate in real-time compared to an IV drip. There are also compounded ketamine formulations, such as oral lozenges or troches, which are prescribed for at-home use. While more convenient, these methods have much lower and more variable bioavailability and raise significant safety concerns due to the lack of direct medical supervision during administration.
The Patient Experience: What to Expect During a Session
Undergoing ketamine therapy is an active process that involves more than just receiving a drug. The experience itself, and how it is integrated, is considered a key part of the therapeutic process.
Preparation
Before the first session, patients undergo a comprehensive screening. Many clinics also encourage patients to work with a therapist to set intentions for the treatment. This involves thinking about what they hope to achieve, what personal challenges they want to address, and adopting a mindset of openness to the experience. Practical preparations include fasting for several hours beforehand and arranging for transportation home, as driving is not permitted on the day of treatment.
During the Infusion
The treatment itself takes place in a calm, private, and comfortable setting. Patients typically recline in a chair, and vital signs like heart rate and blood pressure are monitored throughout. Many choose to use eye masks and listen to calming music to facilitate an internal focus.
As the ketamine takes effect, most people experience a temporary state of dissociation. This can feel like a dream-like state, a sense of detachment from one’s body or immediate surroundings, altered perceptions of time and space, and sometimes vivid imagery or profound insights. While some find this experience deeply meaningful, it can be disorienting for others. Having a trusted medical professional present is crucial for ensuring safety and providing reassurance.
After the Session
Immediately following the infusion, patients may feel groggy, tired, or lightheaded, effects that typically subside within an hour or two. The most critical part of the therapy often happens in the days and weeks that follow. The period after a ketamine treatment is thought to be a time of enhanced neuroplasticity—a “window of opportunity” where the brain is more receptive to change. This is why most experts strongly recommend that ketamine treatment be paired with psychotherapy. Therapy during this period can help patients process insights from the experience and translate the new neural connections into lasting changes in thinking patterns and behaviors.
Risks, Side Effects, and Long-Term Concerns
While ketamine offers significant promise, it is not without risks. It is a powerful substance that requires respect and careful medical oversight.
Short-Term Side Effects
The most common side effects are temporary and occur during or shortly after the infusion. These include nausea, dizziness, confusion, and a transient increase in blood pressure and heart rate, which is why medical monitoring is mandatory. The dissociative, or psychedelic, experience can itself be psychologically challenging for some individuals if they are not properly prepared.
Long-Term Risks
The long-term effects of repeated ketamine use for depression are still being studied. There are concerns about the potential for psychological dependence or abuse, given its history as a recreational drug. Chronic, high-dose recreational use is associated with significant health problems, including severe bladder inflammation (cystitis) and cognitive impairment. While these issues are not typically seen with the low, infrequent doses used in clinical settings, they underscore the importance of adhering to medically supervised protocols.
The Future of Ketamine and Psychedelic-Assisted Therapy
Ketamine’s success has cracked the door open for a new era in psychiatry. It has served as a proof-of-concept for fast-acting, neuroplasticity-promoting treatments and has paved the way for clinical research into other psychedelic compounds, such as psilocybin (from mushrooms) and MDMA, for treating mental health disorders.
This represents a paradigm shift away from the model of daily medication for symptom management toward one of targeted, acute interventions that can catalyze lasting psychological change. The future of this field lies in understanding not just the drug’s effect, but how to best harness it within a supportive therapeutic framework to produce profound and durable healing.
In conclusion, ketamine therapy stands as one of the most significant breakthroughs in the treatment of severe depression in the last half-century. By acting rapidly on the brain’s glutamate system to repair and build neural connections, it offers hope where there was none for many. It is a specialized tool, not a cure-all, that requires careful screening, medical supervision, and a commitment to concurrent psychotherapy to maximize its benefits. For those who qualify, it can be a transformative intervention that re-opens the door to recovery and a fuller life.
