Ketamine For Depression: A Starting Guide

Ketamine For Depression: A Starting Guide

According to the World Health Organization, depression is the leading cause of disability worldwide. A quarter of a billion people suffer its effects, from children to senior citizens. It can be extremely debilitating in its severe forms and may lead to a range of associated problems, from lack of productivity at work to suicide. 

While modern medications and various forms of talk therapy have proven invaluable in addressing the depression epidemic, some patients are resistant to conventional treatment. Given the severity of the effects of the disease, this is no small problem. And now using ketamine for depression is becoming a more popular and accepted therapy.

In recent years, an unexpected but highly promising new form of treatment has emerged: ketamine assisted psychotherapy.

According to Sam Mandel, co-founder and COO of Ketamine Clinics of Los Angeles, “While intravenous infusions of ketamine for depression and other mood disorders can produce dramatic results in a matter of hours, it is more typical for patients to require 2-3 infusions and several days before seeing improvement. This is still extremely rapid when compared to the 4-6 weeks that many antidepressant medications take to work, and also not the instant change some patients have come to expect from ketamine after hearing of its reputation of rapid relief.”

RELATED: The One Thing You Should Do Before Starting Ketamine Therapy

Origins of Using Ketamine For Depression

In 1964, ketamine was first trialed on human prisoners. It was found to have high effectiveness in reducing pain and in rendering patients unconscious for surgical procedures. Side effects dissipated rapidly upon emergence from anesthesia. 

These findings led to its approval as an anesthetic in 1970 and from that point, it came into wide use. It was particularly important during the Vietnam War. Its fast action and relatively few side effects made it essential in treating injured soldiers on the battlefield. 

Ketamine remains a popular anesthetic in emergency settings, as it increases heart rate and blood pressure, which helps with blood loss. It also doesn’t lower the breathing rate. This makes it one of the safest anesthetics available. Other anesthetics lower heart rate, blood pressure, and breathing rate, making them unsuitable in certain medical emergencies and procedures.

Soon after its introduction as an anesthetic, some began to use it as a recreational drug due to its pleasant side effects. (In fact, this tendency has resulted in a spate of veterinary clinic burglaries executed by criminals in search of ketamine.) 

Ketamine ingestion may produce visual and other sensory distortions. It is more strictly a dissociative drug (producing a feeling of detachment from your body, self, and the world). However, its effects can be similar to those of psychedelics. In clinical settings, ketamine is safe. However, without physician supervision, various street formulations — sometimes adulterated with other drugs — have resulted in death due to overdose. Ketamine was made a schedule III illegal drug in the United States in 1999.

Beginning in the early 2000s, researchers began to investigate the use of ketamine in treating resistant forms of depression.

Mechanism Of Action

Most drugs that help treat depression fall under the category of selective serotonin reuptake inhibitors (SSRIs). These drugs prevent the reuptake or reabsorption of the neurotransmitter serotonin. Serotonin is responsible for the regulation of mood and plays a part in many other brain functions, notably cognition and memory.

While the efficacy of SSRIs in a portion of depressed patients has been demonstrated, several other neurotransmitters also play a role in regulating mood and a sense of well-being. In fact, GABA is present in 20-50% of all synapses in the brain while for glutamate this figure rises to approximately 80%. These neurotransmitters are, along with serotonin, responsible for brain plasticity and mood regulation, among other functions. SSRIs do not affect these.

Further, SSRIs do not affect the number of serotonin receptors in the brain. Depressed patients may have fewer serotonin receptors in the first place — or they may have an excess of certain types of serotonin receptors. In the former case, damage to the cells that contain the receptors may occur, due to high levels of stress hormones such as cortisol.

Interestingly, it seems that ketamine may facilitate the repair of the cells involved in serotonin reception. By increasing the number of these receptors, the brain may be able to process serotonin more normally. However, further research is necessary.

RELATED: Study Finds Ketamine Telehealth Is A Safe And Effective Treatment For Anxiety And Depression

Ketamine’s Impact On The Brain

Ketamine may actually prompt the brain to produce more glutamate. It may also block the uptake of glutamate by NMDA receptors and thus reduce the firing of certain neurons. In doing so, it may reactivate the reward centers of the brain, leading to the alleviation of depression by allowing the brain to react to positive stimuli in a healthy way.

Glutamate may also induce the formation of new connections between neurons. These new connections serve to make the brain more adaptable to negative events and stress, thus alleviating depression. In combination with cognitive behavioral therapy and other modalities, the treatment thus has the potential to break some of the patterns that lead to depression, though this has not been conclusively proven.

One key way that ketamine could help depression is by increasing the number of synapses in the prefrontal cortex.

This is an area of the brain responsible for regulating emotions and it has been shown to shrink in patients with depression. The prefrontal cortex is like a control center. People who have depression also have overactive amygdalas, the brain region that processes emotions, such as fear and anxiety. 

Having an underactive prefrontal cortex and overactive amygdala means you are more likely to get stuck in patterns of negative thoughts and emotions. It has been proposed that ketamine can normalize activity in these brain regions by increasing the synapses in the prefrontal cortex. This allows this area to strengthen connections with the amygdala and then regain control over it. When this happens, many people will find that the negative emotional bias of depression goes away.

Ketamine may also affect the processing of other neurotransmitters in the brain on short- and long-term scales. For example, some research has found that ketamine may also alleviate depression through its action on serotonin 1B receptors (which increases dopamine), as well as opioid receptors

Ketamine’s effects on dopamine may be crucial. After all, anhedonia (the inability to feel pleasure) and a lack of motivation are characteristics of depression. And these symptoms are associated with a deficit in dopamine. By boosting dopamine, ketamine could improve depressive-like behaviors.


Many major cities in the United States now have ketamine therapy clinics that offer treatment for patients with depression. It is typically provided in one of two ways.

  • Intravenous (IV) or intramuscular (IM) injection. Administering ketamine often comes in a tapered fashion, with six doses or more in the course of three weeks to a month. They may then receive booster infusions once a month or as needed.
  • Intranasally. Esketamine, a new form of ketamine as a nasal spray, gained approval by the FDA in 2019. Patients still need to go into a doctor’s office to receive the treatment. Typically prescribed in conjunction with a conventional oral antidepressant, it may enhance the effect of these drugs. Administering it comes in tapered doses, with twice-weekly doses to start and decreasing to once every several weeks for maintenance.

Please note that treatment protocols differ based on the practitioner in question and are likely to change as new research emerges. Here’s how to find the best ketamine therapy clinic near you.

RELATED: Is Ketamine Therapy For Depression Safe?


Some studies have shown that ketamine may begin acting upon depressive symptoms as soon as two hours after treatment. Patients have reported improved mood in addition to increased alertness, motivation, and mental clarity in the wake of their initial ketamine treatments. 

KCLA’s Sam Mendel adds, “Results can be near-instant, but patients should not expect them to be. At Ketamine Clinics Los Angeles, most patients experience some improvement 1-2 days after their 3rd infusion. However, it’s important to note that there are some slow responders who may not see notable improvement until after they have completed their full series of six infusions over 2-3 weeks, which is one reason we encourage all patients to complete a full series.”

There have also been reports of reduced suicidal ideation following treatment. These improvements compare positively to the effects of SSRIs, which some patients have stated as having a “smoothing” effect on their negative emotions without necessarily alleviating the mental fogginess that often manifests in depression. Many patients experience this as a numbing or blunting of emotions generally. So while the intensity of negative emotions is reduced, the same may apply to positive emotions. 

Ketamine, in contrast, allows many people to experience the full range of emotional responses, without becoming overwhelmed by negative emotions.

SSRIs also typically take 6-8 weeks or longer to take effect. Ketamine differs in that the antidepressant and antisuicidal effects are rapid, experienced within two hours post-infusion.

These early improvements are by no means the rule for ketamine treatment. And they typically only last a week at most, underscoring the need for repeated administrations. Some patients may require multiple doses of ketamine before they see even minor improvement in their depressive symptoms. And some may not respond at all.

Side Effects And Risks When Using Ketamine For Depression

Even when a clinic is administering ketamine, like most drugs, it may cause side effects. In addition to psychedelic-like sensory distortions caused by its dissociative properties, ketamine may also have a number of negative physiological side effects.

  • Dizziness
  • Increased heart rate and blood pressure
  • Lethargy
  • Nausea
  • Sedation
  • Vertigo
  • Bladder problems

Researchers have also highlighted that ketamine treatment for depression can, even in a clinical setting, have an addiction risk. As one paper published in Neurobiology of Stress states, “Although more studies are needed, some clinical and preclinical reports indicated that repeated infusions of low doses of ketamine may have addictive properties, and suggested that adolescent and adult female subjects may be more sensitive to ketamine’s addictive effects.” If you are someone who struggles – or has struggled with substance abuse and addiction – it’s important to discuss this with a ketamine provider before proceeding with treatment.

Ketamine for depression remains a promising treatment modality, as well as a number of other mental health problems such as PTSD and bipolar disorder. It is also effective in the treatment of chronic pain.

RELATED: What, Exactly, Is Psychedelic Therapy?

If an ongoing condition might benefit from ketamine therapy, talk to a licensed physician who can help assess your options.

Interested in Trying Psychedelic Therapy? Check out these Healing Maps Clinic Spotlights:

Ketamine Center of Connecticut Guilford

Ketamine Health Centers – Coral Gables, Florida

South Florida Ketamine Centers – South Miami, Florida

Bristol Hospital, Bristol Connecticut

Sun Valley Ketamine Clinic – Ketchum, Idaho

Ketamine Health Centers – West Palm Beach, Florida

Treasure Coast Ketamine Wellness and IV Nutrition Center – Vero Beach, Florida

Silo Wellness Renew, Restore, Revitalize – Jamaica

Serenity Mental Health – Gilbert, Arizona

Advanced Pain Relief Institute – Beeville, Texas

Arthur T Davidson MD – New York, New York

Sam Woolfe

Sam Woolfe

View all posts by Sam Woolfe

Sam Woolfe is a freelance writer based in London. His main areas of interest include mental health, mystical experiences, the history of psychedelics, and the philosophy of psychedelics. He first became fascinated by psychedelics after reading Aldous Huxley's description of the mescaline experience in The Doors of Perception. Since then, he has researched and written about psychedelics for various publications, covering the legality of psychedelics, drug policy reform, and psychedelic science.

Dr. Ben Medrano

This post was medically approved by Dr. Ben Medrano

Dr. Ben Medrano is a board certified psychiatrist specializing in Integrative Psychiatry, Ketamine Assisted Therapy and Psychedelic Harm Reduction and Integration. He received his MD from the University of Colorado School of Medicine with additional training in the Urban Underserved Track (CU-UNITE). Dr. Medrano is most known for his work with ketamine assisted therapy and is the former Senior Vice President and US Medical Director of Field Trip Health - the largest in-office ketamine assisted therapy practice to date. He continues to sponsor Field Trip clinics as a local medical director at multiple sites on the East Coast allowing him to further the field of psychedelic assisted therapy and research.

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