Clinical Trials That Showed Ketamine Could Help Mental Health

ketamine trials
By Brian Lissak

Ketamine has become a first-line defense against depression. Thanks to its rapid-acting nature and higher efficacy rates when compared to SSRIs, ketamine received FDA approval on March 5, 2019. Hailed by researchers a decade ago as “the biggest breakthrough in depression research” in 50 years, ketamine trials offer hope to those suffering as well as new insights into mental health.

What is Ketamine?

Ketamine is an anesthetic first synthesized in 1956 from phencyclidine. Used as a field anesthetic for medical emergencies, it saw much use by medics during the Vietnam War. It is still used for some extremely painful procedures and to manage chronic pain. Veterinarians also favor it as an anesthetic. After rising in popularity as a club and party drug, ketamine today is best known for its antidepressant qualities.

The First Randomized, Double Blind Study

The year 2000 saw the first randomized, double-blind ketamine trials for depression. The study took place in light of the growing body of clinical research implicating the glutamate system in depression. Glutamate is the major excitatory neurotransmitter in the nervous system. It plays a significant role in regulating and enabling “excitatory” emotions generally associated with a positive and healthy disposition. Research shows that people suffering from depression have an impaired glutamate system. This means that the brain lacks the ability to effectively create the neural connections required to experience happiness, excitement, etc. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, which means it interacts with the glutamate system.

This study involved patients with major depressive symptoms and randomly assigned them ketamine hydrochloride or a saline solution placebo. The dosing was sub-psychedelic (the patients did not experience a “trip”) and administered intravenously. The results showed unequivocal improvement in depressive symptoms, with higher immediacy than any other available treatment of depression. All other medical interventions for depression take on average weeks to months to kick in. The rapid improvement of depression symptoms was a major breakthrough and has led to many additional studies.

A New Way of Understanding Depression

Up until now, the medical establishment understood depression as a chemical/hormonal imbalance largely due to serotonin. This theory came about by accident. Researchers observed that drugs (for non-mental health illnesses) interacting with the neurotransmitter serotonin affect mood. Drugs that lowered serotonin sometimes created depression-like symptoms. Drugs that raised serotonin sometimes created euphoric feelings, even in patients with depression. This led to the development of selective serotonin reuptake inhibitors (SSRIs) which have been the standard treatment for depression since. However, this theory does not fully explain depression. Besides the fact that SSRIs are completely ineffective in over one third of patients, serotonin only accounts for less than 20% of neurotransmitters. The other 80% are glutamate and GABA.

Stress is often a major factor in depression, as well as other mental health illnesses. One effect stress has on the brain is to inhibit glutamate signaling, impairing neural communication and adaptability. Basically, stress impairs your brain’s ability to communicate with itself. This becomes a destructive self-feeding cycle. The research has led to a new way of understanding what depression is and explains why ketamine works so well.

Lessons Learned From Depressed Mice

In March 2013, researchers published a report on ketamine and depressive behaviors in mice. They learned that depression actually leaves a very tangible footprint, especially neurologically. These researchers administered substances to the mice to activate depressive-like synapses (or lack thereof) in the brain. This again has to do with the glutamate system and mood regulation. The effects of depression go well beyond mood, however. They influence energy levels, appetite, immune response, digestion, and a host of other physically observable and measurable responses. These researchers experimented with different doses and timing of ketamine relative to the depression-activating substances. There was also a placebo group that received a saline solution. The results, again, were unequivocal: ketamine relieves depressive symptoms. Now, however, there is a broader window into the how and why.

Ketamine affects the brain in the exact opposite way that stress and other depression instigators do. Where stress impairs neuroactivity, ketamine increases GABA and glutamate neurotransmitter activity and encourages neurogenesis. Ketamine reverses the damage done by chronic stress and thereby relieves depression symptoms. This has led to a new theory on depression, whereby neural stagnation and degeneration, often caused by prolonged stress, is the cause of depressive symptoms.

Ketamine is also unique in depression treatment in that it continues to work after the substance has left the body. SSRIs and other antidepressants are typically only effective while they’re present in the body. Because ketamine reestablishes neuropathways, it sets off reactions in the brain that continue on their own. “It’s the reaction to ketamine, not the presence of ketamine in the body that constitutes its effects,” says Dr. John Krystal of Yale.

What Does Ketamine Treatment Look Like?

Since 2000, when ketamine trials first began, there have been many studies exploring proper dosing. Two similar studies found that patients who show positive responses to a single dose will benefit more from multiple doses. This may sound obvious, but in the mental health world, more is not always better. The established standard practice is for patients to receive multiple subanesthetic doses spaced over several weeks to months. In many ways, ketamine diverges from the psychedelic-assisted psychotherapy model. Whereas psychedelic substances are used as an aid to therapy, ketamine has been viewed from a strictly pharmacological understanding. This means patients are often administered ketamine without therapeutic guidance. The experience they have while on ketamine has been largely ignored. However, in light of the paradigm-shattering advancements in psychedelic-assisted psychotherapy, another aspect is being added to ketamine treatment.

Psychedelic-assisted psychotherapy capitalizes on the neuroplasticity and neurogenesis engendered by the psychedelic substance. While the brain is in a regenerative state, therapists help patients to create new, healthy neural pathways. These healthy neural pathways change baseline thinking and remain in place after the therapeutic session. Even though ketamine as a strictly pharmacological treatment (without therapy) is very effective, it can be even more so. While we are still some ways away from seeing classic psychedelics – psilocybin, LSD, and MDMA – legalized for therapy, ketamine trials and treatments have largely avoided the political gauntlet. Recognizing the potential, many ketamine clinics are currently in operation all over North America, giving much-needed healing to those suffering from depression.