How Ketamine Affects Your Brain

Ketamine is trending as a promising new treatment for anxiety and depression. Let’s dive into how ketamine affects the brain and how these effects help to deliver therapeutic outcomes.

woman laying down eye mask ketamine treatment

There’s been a lot of buzz lately about ketamine, a powerful new player in the field of psychiatric care that’s showing exciting promise as an effective, fast-acting treatment for mental health conditions like depression and anxiety.

Ketamine reflects a completely new approach in the treatment of these disorders, with effects on the brain that are completely different from those of traditional treatments.

But in a field of tremendous unmet need (some studies report that up to 50% of patients don’t respond to SSRIs, a class of medications that has been considered the gold standard of treatment for depression and anxiety for decades), ketamine’s novel mechanism offers a beacon of hope.

Let’s dive into what exactly ketamine does within the brain and how these effects are helping us better understand mental health conditions and how to treat them.

What is Ketamine?

Originally synthesized in the 1960s by chemists in search of the ideal anesthetic agent, ketamine received FDA approval for clinical use in anesthesia in 1970 and has been used widely in hospitals since.

Medical professionals began noticing and studying ketamine’s ability to rapidly alleviate depression and suicidal thoughts around 2000, and over the last two decades, a growing number of studies are showing ketamine could be a promising treatment for a broad range of psychiatric conditions.

Today, more and more physicians are prescribing ketamine off-label to patients with depression and anxiety. Off-label prescribing refers to the practice wherein an FDA-approved drug is prescribed by a physician for a different condition than what the medication is officially approved for. Off-label prescribing is extremely common- about one in five prescriptions written today are for an off-label use.

Mechanism of Action of Ketamine

Ketamine’s principal mechanism of action within the brain is as an antagonist for a class of receptors known as N-methyl-D-aspartate receptors (NMDARs). NMDARs are a type of receptor for a molecule known as glutamate, the most common excitatory neurotransmitter in the central nervous system.

Ketamine’s interactions with this receptor type and subsequent effects on glutamate signaling result in an enhancement of neuroplasticity, which refers to the brain’s capacity to continually grow, change, and reorganize itself throughout the lifespan. The antidepressant and anxiolytic effects of ketamine are hypothesized to stem primarily from the medication’s ability to support and promote processes related to neuroplasticity in the brain.

Through the modulation of glutamate, ketamine triggers a complex array of downstream processes that ultimately lead to an enhancement of neural plasticity within the brain. These cascading effects include increasing levels of a protein known as brain-derived neurotrophic factor (BDNF), a growth factor that supports healthy neuron functioning. Often referred to as “Miracle-Gro for the brain,” BDNF plays an important role in a variety of processes related to neuroplasticity, including dendritic spine growth, synapse formation, and adult neurogenesis.

Ketamine also increases activation of a protein complex known as the mechanistic target of rapamycin complex (mTORC1), which plays an important role in synaptic plasticity and in regulating neurogenesis, dendritic spine growth, and synthesis of various proteins.

Therapeutic Effects of Neuroplasticity Changes

Through modifications to the brain’s structure, functioning, and connectivity, neuroplasticity has a powerful ability to alter thought patterns and other cognitive processes, and this process is crucial to healthy brain functioning.

Neuroplasticity is a powerful component of ketamine treatment because it provides an opportunity to create lasting, meaningful changes in the brain by forming new neural pathways using insights from their treatment session.

By enhancing the neural plastic capabilities of the brain, ketamine enables patients to strengthen brain circuits that drive beneficial thought patterns and behaviors, as well as more easily weaken circuits that may be potentiating detrimental thoughts and behaviors.

The increased neuroplasticity induced by treatment with ketamine also offers a window of opportunity during which a patient can more readily prime their mind to respond more positively to stimuli that may otherwise trigger negative emotions and thought patterns.

By initiating a period of increased openness to change in the days and weeks following treatment, ketamine creates an optimal state for “rewiring” the brain to function in a healthier way. This is a prime time to incorporate daily holistic practices such as meditation, breathwork, and journaling.

Alterations in Higher-Order Functional Networks in the Brain

In addition to impacting the brain’s organization through local changes to neural pathways and circuits, ketamine also impacts the connectivity of the brain at the macro level by altering the functioning of higher-order cognitive networks.

One such network, referred to as the default mode network, or the DMN, is a system of connected brain regions that are most active when the brain is not focused on the outside world and is instead engaged in introspective thought.

Alterations to the normal functioning of the DMN have been linked to the pathologies of both depression and anxiety. In individuals suffering from these disorders, the resting, default brain state is often dominated by incessant worrying, catastrophizing, ruminating, and other negative cognitive patterns. Studies have found that the brains of patients with depression or anxiety commonly exhibit abnormal increases in DMN functioning, suggesting a connection between this brain network and the physiology of these mental health conditions.

Research has found that the administration of ketamine reduces this dysfunctional increase in DMN activity. In other words, ketamine essentially “turns down the volume” on this overactive stream of negative thoughts, helping the brain break out of these maladaptive cognitive patterns that depression and anxiety can drive a patient to automatically revert to.

Does Ketamine Cause You to Hallucinate?

Ketamine is often classified as a psychedelic, a group of psychoactive substances that includes the likes of psilocybin, MDMA, ayahuasca, and LSD. Psychedelics induce an altered state of consciousness characterized by changes to how an individual ordinarily thinks and feels.

Because of ketamine’s categorization as a psychedelic, one commonly raised question surrounding this substance is whether patients will experience hallucinations during a treatment session.

While the subjective experience produced by ketamine shares certain similarities with the experience produced by other psychedelics, it also shows key differences. For example, ketamine can induce closed-eye visuals and visions, but it will not cause the open-eye, visual hallucinations (such as morphing of stagnant items) that can occur with the use of “classical,” serotonergic psychedelic agents.

Also important to note is the direct relationship between dosage and the extent to which ketamine elicits perceptual distortions. At lower doses, the psychoactive effects of ketamine are generally fairly mild.

During a treatment session, many patients experience a state of deep relaxation and often describe a sense of floatiness or lightness that feels “dream-like.” Patients also may experience changes in their perceptions of time, sounds, and colors for the duration of their session.

Is Ketamine Safe?

With a history of clinical use that spans back over fifty years, ketamine has an extensive track record of safety.

While some patients can experience mild, but unpleasant side effects during ketamine treatment (dissociative symptoms, dizziness, nausea, and headache are some of the most commonly reported), these effects are temporary and will resolve on their own shortly after the treatment session.

The risk for the occurrence of more serious adverse effects in response to ketamine treatment is minimal. In one study investigating the safety of repeated administration of ketamine for the treatment of depression, only 0.7% of patients experienced adverse effects that required them to discontinue treatment.

Fact Checking
Lila Jones is the Research and Data Science Lead at Wondermed. She graduated with a B.S. in health promotion and disease prevention from the University of Southern California, where she also studied the science and management of biomedical therapeutics and completed a curriculum of requisites necessary for pre-medical undergraduate studies. Lila has over four years of experience in STEM journalism working as a content writer for the USC Viterbi School of Engineering.

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External References

Scientific Articles and Clinical Trials

Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide

Ketamine: A Paradigm Shift for Depression Research and Treatment

Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site, randomized controlled trial

Small-Dose Ketamine Improves the Postoperative State of Depressed Patients

A Randomized Trial of an N-methyl-d-aspartate Antagonist in Treatment-Resistant Major Depression

Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression

Ketamine: 50 Years of Modulating the Mind

Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial

Ketamine enhances structural plasticity in human dopaminergic neurons: possible relevance for treatment-resistant depression

Safety of Repeated Administration of Parenteral Ketamine for Depression

Ketamine in the News

Ketamine: A Promising Novel Therapy for Anxiety and PTSD
Ketamine was originally approved by the FDA as an anesthetic, but is increasingly being used to treat mood disorders such as treatment-resistant depression, anxiety disorders, and PTSD.
Researchers Are Closer to Explaining How Ketamine Treats Depression
A recent study sheds light on why ketamine may trigger antidepressant effects.
Mayo Clinic Minute: How esketamine can help severe depression - Mayo Clinic News Network
Millions of people struggle with clinical depression. The Food and Drug Administration recently approved a medication to help those suffering with this serious mental health issue. Unlike other antidepressants, Dr. Jennifer Vande Voort, a Mayo Clinic psychiatrist, says it can work very quickly to re…
Ketamine monotherapy reduces suicidal ideation in adults with depression
In adults with treatment-resistant depression, ketamine monotherapy significantly reduced suicidal ideation compared with adjunctive ketamine, according to a retrospective study in Journal of Psychiatric Research.