Ketamine, a widely used anesthetic medication, is now being used to treat depression, suicidality, chronic pain, migraines, OCD and even some PTSD symptoms. For many, this breakthrough treatment represents a powerful opportunity to manage their mental health challenges. Those familiar with ketamine, however, are also aware of its reputation as a party drug, its dissociative characteristics, including “out-of-body” experiences, and its addictive qualities.

Here at Psychological Care & Healing Center (PCH), we believe in providing our community with a thorough understanding of available treatment modalities.

So how has ketamine, a drug that was previously used on battlefields and in operating rooms become a potential solution for treating depression and suicidality? How does it work, what effects does it have on the brain, and what, if any, risks are involved in its use?

The Uses of Ketamine: A Timeline

Ketamine is a medicine that was initially employed for anesthesia and analgesia (pain relief) and for minor surgery. It is not new. In fact, ketamine was first synthesized in 1962. Since then, it has had an interesting history. Ketamine was first patented for use as a human anesthetic in Belgium and Germany in 1963, followed by the United States in 1966. In 1970, the drug was approved by the U.S. Food and Drug Administration (FDA) and quickly became the most widely used battlefield anesthetic during the Vietnam War.

By the 1970s, ketamine was also popular in veterinary medicine and was added to the World Health Organization’s “Essential Medicine” list in 1985. It wasn’t until the 2000s, however, that researchers began exploring ketamine as a treatment for depression.

Unfortunately, as ketamine grew in popularity, people started to use it recreationally. Known popularly as “Special K,” “Kit-Kat,” “Super Acid,” “Jet” and “Cat Valium,” ketamine became popular as partygoers and others sought out its dissociative effects. Often used in clubs, users typically choose to snort ketamine, but it can also be injected or taken orally. The immediate effects of the drug, known on the street as being in the “K-hole,” are a sense of being “outside the body.” Side effects include reduced awareness of the environment, reduced pain perception, sedation, and hallucinations.

Ketamine Reconceptualized: From Party Drug to Depression Treatment

As psychologists and psychiatrists explored the challenges of depression, pioneering studies from Yale revealed that ketamine triggered the brain to produce glutamate, which stimulates new neural connections.

“It wasn’t just, ‘let’s try this drug and see what happens.’ There was increasing evidence suggesting that there was some abnormality within the glutamatergic system in the brains of people suffering from depression, and this prompted the idea of using a drug that targets this system,” researcher Dr. Gerard Sanacora explained to Yale Medicine.

Using intravenous doses of ketamine in controlled studies, they observed the results on patients with severe depression whose conditions had not improved with standard antidepressants. The results were statistically significant. In most studies, more than 50% of the participants exhibited a decrease in their depression symptoms just 24 hours after ketamine treatment.

On March 5, 2019, after nearly 20 years of research, the FDA approved Spravato (esketamine) nasal spray for adults suffering from treatment-resistant depression. Recognizing the potential for abuse and misuse of the drug, the prescription is only available through a strict distribution system.

Dr. John Krystal, chief psychiatrist at Yale Medicine and a leading ketamine researcher, said. ketamine is the “anti-medication” medication. He explains that “with most medications, like valium, the anti-anxiety effect you get only lasts when it is in your system. When the valium goes away, you can get rebound anxiety. When you take ketamine, it triggers reactions in your cortex that enable brain connections to regrow. It’s the reaction to ketamine, not the presence of ketamine in the body that constitutes the effect.”

Treatment Resistant Depression

Out of the estimated 16.1 million adults in America struggling with Major Depressive Disorder (MDD), 66% are not helped by their first antidepressant treatment and 33% remain depressed as they don’t respond to any treatment, despite several different attempts and types of medications.

“Although there is some disagreement as to how to define treatment-resistant depression,” neuroscientist Dr. Jaskaran Singh told Johnson and Johnson, “a patient is generally considered to have it if the individual hasn’t responded to adequate doses of two different antidepressants for a sufficient duration of time, which is usually six weeks.”

Interestingly, some patients with treatment resistant depression are finding help with ketamine; and preliminary research shows that about 60% of treatment resistant patients will respond favorably to ketamine infusions. This occurs because ketamine affects the brain differently from other antidepressants.

Ketamine & The Brain

While the majority of antidepressants target one of the “monoamine” neurotransmitters, such as serotonin, norepinephrine or dopamine, ketamine targets glutamate, the brain’s most common excitatory chemical messenger. Regulating the brain’s ability to process cognitive thoughts, emotions, and neuroplasticity, glutamate promotes and strengthens synaptic connections. It also plays a key role in how an individual learns, remembers, and responds to experiences.

Ketamine Rebalances Glutamate & GABA Levels

Another role glutamate plays in the brain is producing and balancing Gamma Aminobutyric Acid (GABA), a calming neurotransmitter. Overactive glutamate receptor genes can cause an imbalance with GABA resulting in changes in mental health. High levels of glutamate and low GABA can lead to anxiety, for example, while depleted glutamate and GABA can result in depression. Ketamine works to treat this imbalance in three different phases:

• Phase 1: Rapid Effects
  During this phase, ketamine activates the brain’s opiate receptors which can affect symptoms of depression. Patients generally feel relaxed, free from pain and in a sedated like-feeling during this stage.

• Phase 2: Sustained Effects
  In phase two, glutamate receptors are increased, which helps restore normal levels of glutamate and GABA. At this point, patients generally feel relaxed after treatment. Patients can experience feelings of invulnerability during this time.

• Phase 3: Return to Baseline
  After the levels are stabilized, the brain’s reaction to ketamine causes new neural receptors to grow which may “reset” the depressed brain. Ketamine may be particularly useful for patients whose depression involves suicidal thoughts.

Ketamine also reduces inflammation and increases stress resilience

Stress induces structural changes in the brain. Ketamine counterbalances these changes by promoting synaptic growth in affected areas of depressed brains such as the prefrontal cortex and the hippocampus, which regulate behavior, mood, personality development, and memory.

“Depression is linked to the build-up of proteins in the brain — ketamine can repair damage to the brain that is the result of long-term stress hormones,” Dr. Steven Levine told Psycom. “The body’s response to stress spills cortisol and other hormones in the brain and they can damage it in the process.”

Ketamine quiets abnormal activity in the lateral habenula

The lateral habenula is a center of emotional processing. It is also known as the brain’s “disappointment center.” Specifically, the lateral habenula focuses on emotions and feelings that are difficult. In 2017, a study revealed that the lateral habenula in depressed animals and humans functions abnormally and tends to “over fire” neurons, causing an overwhelming abundance of negative thoughts, feelings and essentially, a depressive episode. Increasing evidence indicates that the aberrant activity of the LHb is associated with depressive symptoms such as helplessness, anhedonia, and excessive negative focus. Ketamine is known to directly affect this area of the brain. and it may serve to “reset” the brain’s “disappointment center” and thus ease symptoms of depression and restore more normal processing of disappointment or emotional pain.

Long Term-Effects & Risks of Ketamine

While data clearly show that Ketamine is efficacious for some cases of treatment resistant depression and suicidality, the data on longterm effects are not as clear. At PCH Treatment Center, we believe that intravenous Ketamine infusions can be useful in certain cases of severe treatment resistant depression and/or suicidality, in conjunction with an immersive treatment plan and a contained supervised environment. Accordingly, at PCH, we offer daily psychotherapy and over 100 groups per week to help our clients with severe depression and/or suicidality establish longterm safety and wellness.

Despite ketamine’s positive effects on the brain, patients should also consider potential negative long-term effects and risks. Some of the long-term negative effects of intravenous ketamine infusion can include:

• High blood pressure
• Nausea and vomiting
• Bladder issues
• Blurry vision
• Disassociation
• Dizziness

Ketamine is also addictive and has qualities similar to opiates and Phencyclidine (PCP). In order to minimize risk, the FDA-approved esketamine only contains half the dose found in the commonly-used intraveous form of the drug. Esketamine is only prescribed for people with moderate to severe depression who have been unable to find help from at least two other medications.

Better Mental Health for All

If you or a loved one is struggling with depression, take the next step and find out if PCH is right for you.