The Science

What Is Ketamine?

Ketamine was first used in the 60s as an anesthetic. It was unique in that it was able to anesthetize patients without decreasing respiratory function. It became a popular choice for treating wounded soldiers in the field, which led to a breakthrough discovery. Those treated with ketamine showed reduced rates of PTSD, as well as better pain management. This correlation between ketamine treatment and mental health has led to numerous studies over the past 50 years to find out just how effective it is for a range of mental and physical health conditions.
‍
While ketamine is still not FDA-approved for mental health disorders, studies show positive outcomes in those with depression, anxiety, PTSD, and chronic stress, as well as those suffering from chronic pain conditions. In fact, the National Institute of Mental Health and the American Psychiatric Association consider ketamine to be the fastest-acting medication available for depression. Ketamine has also been lauded as an essential medicine for mental and physical health by the World Health Organization since 1985.

The Rise of Ketamine Therapy in Mental Health Care

More and more people seeking treatment for mental health conditions are dissatisfied with the traditional pharmaceutical methods available. These medications, while FDA-approved, have relatively low success rates and come with side effects ranging from mild to severe.

As interest in psychedelic therapy grows among individuals seeking alternatives to traditional treatments, the question arises: what is ketamine therapy? This therapy offers a new pathway for those disillusioned by conventional pharmaceutical options, which often have limited effectiveness and a range of side effects. Ketamine therapy utilizes low doses of ketamine, a drug originally used as an anesthetic, to target the brain's NMDA receptors, which influence mood and thought processes. This approach has been found to quickly alleviate symptoms of depression, anxiety, and PTSD in many patients who have not responded to other treatments, making it a compelling option for those exploring new avenues for relief from mental health conditions.
‍
So, what is ketamine therapy and what makes ketamine such an effective treatment for mental illness and chronic pain? To truly understand how ketamine works, you must first understand the science behind it.

How Ketamine Works to Heal the Brain

A leading researcher in the neuroscience of ketamine, who conducts research at the Neurological Institute at Cleveland Clinics reveals that chronic stress (which can happen from PTSD, anxiety, OCD, and other conditions) and depression result in neuronal changes that reduce prefrontal and hippocampal connections in the brain. These changes negatively affect mental wellness over time.
‍
Ketamine shows to rapidly resolve these abnormalities and lead to a normalization in the connectivity pattern. The extent of connectivity changes after ketamine also appears to be proportional to the clinical response to the treatment.
‍
Basically, ketamine-assisted psychotherapy can create a cascade of positive changes, starting with your brain’s neuronal network.

Understanding How the Brain Works

In the most highly developed area of the brain, the cerebral cortex, there are between 14 and 16 billion neurons. And that’s only one section. There are trillions upon trillions of neurons throughout your entire brain and body. Every millisecond, they make connections and send signals that help with speech, learning, movement, and everything else.
‍
Neurons are the building blocks of the brain. Also called nerve cells, neurons are electrically excitable cells that communicate with other cells using special connections called synapses. They are responsible for receiving sensory input, for sending commands to our muscles, and for transforming and relaying electrical signals. A typical neuron comprises a cell body (soma), a nucleus that stores DNA, and dendrites and a single axon (both are nerve fibers that extend out). Among other things, the cell body also contains ribosomes, which are needed to make neurotransmitters (a type of protein).
‍
Axon terminals are found at the farthest tip of an axon. This terminal allows each neuron to transmit a signal across the synapse to another cell. Most neurons receive signals using the dendrites and soma and send out signals down the axon. Signals cross from the axon of one neuron to a dendrite of another. But they don’t actually touch. This is where neurotransmitters come into play.

Neurotransmitters and Their Role in Mental Health

Though neurons pass impulses to each other between axons and dendrites, the junction where they meet creates a gap called a synaptic cleft. Neurotransmitters have the important job of carrying the nerve impulse over this gap. Essentially, neurotransmitters are messengers. They reside within tiny sacs at the tips of axons, waiting for an impulse to arrive so they can get to work.
‍
There are different types of neurotransmitters, and each one connects to a specific receptor within a cell membrane. They are like keys that fit into specific locks, opening a pathway into the cell so a message can be sent and received. First, a nerve impulse travels down the axon to the end, opening calcium channels so positively charged calcium ions can flow in. Neurotransmitters then move into the synaptic cleft, cross the gap, and bind to matching receptors in the opposing neuron (where a message needs to be sent). This connection opens more channels so sodium, magnesium, calcium, and other ions can flow in.
‍
This flow of ions changes the polarity of the cell membrane, making the cell’s charge less negative. Once the polarity changes enough, the impulse (message) is transmitted into the receiving cell. From there, this process continues and the message can flow from neuron to neuron, down an extensive network of neurons that are all linked together.

Once the neurotransmitters have done their job, reuptake receptors capture them and carry them back into their originating cell, so they can be ‘repackaged’ and wait for their next message to arrive. Once they are reabsorbed, the synapse turns off. This entire process takes about seven milliseconds, so it happens almost instantly inside your brain every moment of the day.

Understanding this process of how neurons relay impulses to each other is key to understanding mental health wellness and why ketamine therapy is so effective. Before we dive into how ketamine works in the brain, let’s go over one more important aspect of neurotransmitters.

Different Neurotransmitters and Chronic Stress

Not all neurotransmitters are the same. There are both inhibitory and excitatory neurotransmitters and they influence neurons in unique ways. As their names suggest, inhibitory transmitters inhibit (or slow) the neuron, decreasing its ability to fire impulses. Excitatory transmitters do the opposite: they excite neurons so they are more likely to fire impulses. While many neurotransmitters are only one type, some (like dopamine) can be both excitatory and inhibitory. It all depends on which receptors are present. Two excitatory neurotransmitters are glutamate and dopamine. Examples of inhibitory neurotransmitters are serotonin, GABA (gamma-amino-butyric acid), and dopamine (sometimes).
‍
Maintaining balance in the body is extremely important because too much or too little of something can create ill health. If there is too much of one type of neurotransmitter versus another, balance is disrupted, which leads to struggles with mental wellness. One example of this is glutamate. It’s the most common excitatory neurotransmitter in the brain. Glutamate is crucial for neuroplasticity (the brain’s ability to create new neural connections and synapses), and it is important for learning and forming memories. When the brain has slightly increased levels of glutamate, neurons can become hyper-excited. If the imbalance is severe, with way too much glutamate in the brain, neurons can become damaged or even die.
‍
Research within the past two decades has focused on stress and how long-lasting stress can negatively affect the body. Not only does chronic stress create an imbalance of cortisol in your system (which can cause neurons to shrivel and shrink), intense stress can change glutamate signaling. This change can cause neurons to respond less and fail at making connections with other neurons. Brain imaging has proven that depressed individuals have a smaller prefrontal cortex, which affects decision-making, memory, emotions, and attention.
‍
Glutamate-related neuronal changes are key influencers in conditions like depression and anxiety. Thankfully, ketamine works by targeting glutamate and creating a healthy balance in the brain so neurons can thrive.

Why Ketamine Therapy Can Be So Effective

Since its approval as an anesthetic in the 1960s, researchers have known the effectiveness of ketamine lies in its ability to trigger a glutamate release into the synapses of the brain, however it took many years to understand its full potential due to the high doses that were being used. Ketamine’s effect on glutamate and its receptors is significant to understanding the link between ketamine and mental health.
‍
The medical community has understood the connection between glutamate and depression since the 90s, yet there were no drugs that made a significant impact on this area of the brain. Once anecdotal evidence started to spread about ketamine’s positive impact on PTSD and pain response in veterans, Yale University researchers began a research study in which depressed people were treated with ketamine. As researchers modified and reduced the dosage, they unlocked the true potential of ketamine in regards to mental health. This research provided great insights into both ketamine as a potential treatment for mental health conditions, as well as the conditions themselves.
‍
When normal brain patterns are disrupted; whether from stress, a traumatic incident, or something else, an imbalance is created between the brain’s receptors and synapses. This means the brain isn’t sending or receiving the necessary information. In order to reprogram the brain, synapses must be restored or repaired and binding sites must be activated and regulated to receive the proper impulses.
‍
Ketamine specifically targets the NMDA (N-methyl-D-aspartate) and the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. These receptors rely on glutamate to activate and regulate their ion channels so messages between synapses are sent and received. When glutamate production is disrupted, a person’s mental health is affected.
‍
That’s where ketamine comes in. Ketamine triggers the NMDA receptor to release glutamate, which repairs damaged synapses. It then shifts the glutamate to the AMPA receptor, increasing activation and restoring balance between the two receptors. From here, ketamine boosts the brain’s neuroplasticity by triggering the release of BDNF (brain-derived neurotrophic factor), and mTOR (mammalian target of rapamycin). BDNF acts like a fertilizer for your brain, encouraging the growth of healthy neurons, while mTOR supports long-term memory. When these two proteins are stimulated, damaged neurons are repaired, synaptic damage is reversed (particularly in the prefrontal cortex and hippocampus), and the neural network is able to reset itself.

Ketamine Therapy’s Potential Benefits & Contraindications

Once this process is underway, patients can see results quickly. Their negative thought patterns may decrease or disappear completely. Healthy behavior patterns are learned more easily, and trauma is processed with a more open mind and a greater sense of self. As the nervous system continues to regulate itself, symptoms will continue to improve and normal function should return.

While many patients experience significant benefits , it's crucial to understand who is not a good candidate for ketamine therapy. Individuals with certain medical conditions, such as uncontrolled high blood pressure, a history of psychosis, or those with a significant history of substance misuse, may not be suitable for this treatment. Additionally, those who are pregnant or have severe liver disease should avoid ketamine therapy due to potential risks. Patients need to undergo a thorough evaluation by a healthcare professional to determine their suitability for ketamine therapy, ensuring the safety and effectiveness of the treatment for each individual.

There is still more testing that needs to be done before the FDA will approve ketamine as a treatment for mental health conditions, chronic pain, nerve pain, and other ailments. There must be clear answers to questions about long term side effects, who is and who is not a good candidate for ketamine therapy, methods of administration and more. In the meantime, Esketamine has been granted FDA approval for treatment resistant depression. You can learn more about getting started with ketamine therapy by reading our blog or contacting us.

In Conclusion: The Four Ways Ketamine Works

After years of research and thousands of patients whose lives have changed for the better because of ketamine therapy, it’s clear that using ketamine for anxiety, chronic pain, depression, and other mental health conditions may create positive, long-lasting outcomes. The reasons are simple: ketamine works in four ways simultaneously to jumpstart healing, so patients can live healthier, fuller lives.
‍
First, ketamine works biologically by changing glutamate activity and increasing BDNF (fertilizer for your brain). This improves neuroplasticity to achieve a greater balance in neuronal activity while restoring synaptic strength. The brain is restored and reset.
‍
Second, ketamine works functionally by stifling negative thought patterns. Imaging has shown that the Default Mode Network (DMN) of the brain gets suppressed by ketamine, giving individuals relief from constant worry and doubt. This break allows greater personal insights to arise, leading to personal growth.
‍
Third, Ketamine works psychologically by creating a mild dissociative state that allows patients to access the unconscious. Memories and repressed emotions can be explored and traumatic events can be processed and released. This state of mind isn’t scary. It allows a patient to gain a different perspective on their life, encouraging self love and compassion.
‍
Fourth, ketamine works spiritually for some. Individuals on ketamine therapy with spiritual beliefs may experience feelings of greater connection with life around them. This experience is ineffable, but those who experience it say it is something that offered them great relief, peace, and hope.
‍
Whether ketamine therapy is delivered through an IV or taken orally, years of science and research prove this safe and effective treatment promotes positive mental health and may enhance the lives of those who use it.

References

Abdallah, C. G., Dutta, A., Averill, C. L., McKie, S., Akiki, T. J., Averill, L. A., & Deakin, J. (2018). Ketamine, but not the NMDAR antagonist lanicemine, increases prefrontal global connectivity in depressed patients. Chronic stress (Thousand Oaks, Calif.), 2.

Andrade, C. Oral Ketamine for Depression, 1. The Journal of Clinical Psychiatry 80, (2019)

Berman, R.M., Cappiello, A., Anand, A., Oren, D.A., Heninger, G.R., Charney, D.S. and Krystal, J.H., 2000. Antidepressant effects of ketamine in depressed patients. Biological psychiatry, 47(4), pp.351-354.

Duman, R.S. and Aghajanian, G.K., 2012. Synaptic dysfunction in depression: potential therapeutic targets. Science, 338(6103), pp.68-72.

Fava, M., Freeman, M.P., Flynn, M., Judge, H., Hoeppner, B.B., Cusin, C., Ionescu, D.F., Mathew, S.J., Chang, L.C., Iosifescu, D.V. and Murrough, J., 2018. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Molecular psychiatry,

p.1.Lester, H. A., Miwa, J. M., & Srinivasan, R. (2012). Psychiatric drugs bind to classical targets within early exocytotic pathways: therapeutic effects. Biological psychiatry, 72(11), 907–915. doi:10.1016/j.biopsych.2012.05.020

Li, N., Lee, B., Liu, R.J., Banasr, M., Dwyer, J.M., Iwata, M., Li, X.Y., Aghajanian, G. and Duman, R.S., 2010. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science, 329(5994), pp.959-964.

Luckenbaugh, D.A., Niciu, M.J., Ionescu, D.F., Nolan, N.M., Richards, E.M., Brutsche, N.E., Guevara, S. and Zarate, C.A., 2014. Do the dissociative side effects of ketamine mediate its antidepressant effects?. Journal of affective disorders, 159, pp.56-61.

Murrough, J.W., Perez, A.M., Pillemer, S., Stern, J., Parides, M.K., aan het Rot, M., Collins, K.A., Mathew, S.J., Charney, D.S. & Iosifescu, D.V. (2013). Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biological psychiatry, 74(4), pp.250-256.

Newport DJ, CarpenterLL,McDonaldWM, Potash JB, Tohen M, Nemeroff CB; APA Council of Research Task Force on Novel Biomarkers and Treatments. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015; 172(10):950-966.

Perry EB Jr, Krystal JH; Yale Ketamine Study Group, et al. Psychiatric safety of ketaminein psychopharmacology research. Psychopharmacology (Berl). 2007 Jun;192(2):253-60.

Schenberg, E. E. Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development. Frontiers in Pharmacology 9, (2018).

Sanacora, G. et al. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry 74, 399 (2017).
Important Safety Information‍