Ketamine Therapy For Depression – How It Works

If you’re interested in ketamine therapy for depression — you’re in the right place.

This in-depth article covers everything you need to know about the benefits of ketamine for depression, including how it works, how it’s used, all about the treatment as well as legality.  

In this article, you’ll learn: 

  1. What is ketamine? 
  2. How it works and helps severe depression
  3. Why do antidepressants fail? 
  4. How does ketamine work as an antidepressant? 
  5. What is the process to receive ketamine treatment for depression?
  6. Dosage and length of treatment
  7. Cost of treatment
  8. Differences between ketamine infusion and nasal spray
  9. Risks and side-effects
  10. Legality
  11. FAQs

What’s it like to get ketamine therapy for treatment-resistant depression?

To people who have battled severe depression unsuccessfully for years, it feels like the heaviness that consumed their lives has been lifted. Before treatment, they could barely get out of bed. After treatment, they have their life back. 

In the U.S., over 17 million people (7% of adults) are dealing with this condition. While most receive some sort of treatment, about 35% of people who suffered a major depressive episode don’t. 

Patients with major depressive disorder see ketamine as their rescue drug the last glimmer of hope that can pull them out of the darkness of depression. Research reveals that his drug rapidly improves mood and reduces suicidality compared to placebo or antidepressants. 

What is ketamine? 

Ketamine is traditionally known as an anesthetic with dissociative properties. A dissociative is a drug that causes a trans-like state or mind and body “separation.” 

Doctors use it religiously in the emergency room. If a patient comes in with an injury like a dislocated shoulder they give him ketamine. Aside from its analgesic effects, this medicine causes brief memory loss. That way, the patient won’t remember when his shoulder popped back into place. The World Health Organization approved ketamine as one of the safest and most efficient anesthetic drugs. 

On ketamine, the user experiences visions and altered physical sensations, which is why it’s often used recreationally. 

The antidepressant effects of this medicine started getting the attention of both psychiatrists and patients two decades ago. A 2000 study published in Biological Psychiatry was the first one to assess the treatment effects of a single dose of ketamine on patients with depression [1]. 

Today, a growing body of researchers and psychiatrists recommends ketamine for treatment-resistant depression, off label. “Off label” means that your psychiatrist can’t prescribe you this medicine for depression yet, because it’s not FDA approved for this condition. So, its current lawful use in ketamine clinics is “off label.” 

How ketamine works and helps severe depression? 

Until more research is done, ketamine is recommended and used on patients with diagnosed treatment-resistant depression. There are several definitions of depression resistant to treatment. But the general consensus is that patients are diagnosed with it when: 

  • They’ve tried at least two trials with antidepressants from different pharmacologic classes.
  • Both trials were adequate in dose, duration, and compliance. 
  • Both failed to produce a significant clinical improvement like remission or at least 50% improvement in mood. 
  • The psychiatrist has reassessed the patient to reinforce the diagnosis.  

The treatment options for patients diagnosed with treatment-resistant depression are limited to psychotherapy, medication therapy, and electroconvulsive therapy. The issue with these traditional treatments is that they take too long for the patient to respond to them (if they respond at all) or come with a set of side effects. 

Ketamine is different. As an experimental drug, it has shown one of the fastest prevention of suicidal thoughts in severely depressed patients. Suicide is a major public health concern and a leading cause of death in the U.S., causing more deaths than breast cancer annually.  

One 2006 study looked at the effects of ketamine on 18 patients with treatment-resistant depression. The study performed by the National Institute of Mental Health revealed that ketamine improved depression symptoms in 71% of patients within one day. Twenty-nine percent (29%) of patients saw a complete reduction of symptoms [2]. 

A new study on this drug for depression published in the June 2020 issue of Translational Psychiatry confirmed what doctors already were seeing in patients. Ketamine works extremely quickly and benefits patients with major depressive disorder, even in low doses [3]. 

In the study, researchers used brain scans of 30 participants with a major depressive disorder who have tried antidepressant treatment. After a low dose of ketamine 0.5mg per kg the scans showed an increased number of serotonin receptors within 24 to 72 hours. Serotonin is a chemical that contributes to mood regulation and feelings of wellbeing. Such quick results were seen in 72% of participants. 

Its fast-acting qualities make ketamine potentially the first “anti-suicide” drug [4].

Why do antidepressant treatments fail? 

To understand what stands behind the effectiveness of ketamine for treatment-resistant depression, researchers are on a quest to find what actually causes depression. More importantly, what changes in the brain of a depressed person.

To get a better understanding of how this drug works in the brain, we’ll compare it to two traditional types of antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs).  

As the name suggests, SSRIs and SNRIs are two different types of antidepressants that act on different neurotransmitters. Neurotransmitters are chemicals in the brain that help carry nerve signals between neurons. 

The main theory of antidepressants is that they change the levels of the monoamines (a particular group of neurotransmitters) in the brain. The main monoamines are dopamine, norepinephrine, and serotonin.

While serotonin can have both excitatory and inhibitory roles, norepinephrine is a strictly excitatory neurotransmitter (meaning it facilitates happiness).  

Antidepressants prevent the reuptake of these neurotransmitters in the brain. The term reuptake indicates the process of reabsorption of the neurotransmitter by the cell that originally produced it.

The process of reuptake reduces the availability of a neurotransmitter because the brain absorbs it. So, by blocking the reuptake process, antidepressants increase the availability of these neurotransmitters. 

Serotonin helps the body regulate mood. So, when this neurotransmitter is too high or too low, the person may become depressed. Antidepressants increase serotonin levels in the brain, helping the person cope with the symptoms. 

Norepinephrine also regulates mood, as well as sleep, attention, and memory. Low norepinephrine causes poor concentration and potential symptoms of attention deficit hyperactivity disorder (ADHD).

While SSRIs work on the serotonin in the brain, SNRIs work on both serotonin and norepinephrine.

In conclusion, antidepressants work on the monoamine (serotonin, norepinephrine, dopamine) neurotransmitter system. But, here’s the issue. 

Researchers now believe that depression is more than a brain chemical imbalance. 

They’ve found that more important parts of the brain like nerve cell connections, nerve cell growth, and nerve circuits have a major impact on depression. Although they don’t know the whole ordeal yet, they are exploring the potential connection between sluggish production of new neurons in the hippocampus (a complex brain structure that plays a major role in learning and memory) and low moods.

A significant fact that supports this new theory is that antidepressants boost concentration of neurotransmitters (chemical messengers in the brain) immediately, but it takes several weeks for people to start feeling better. Up to two-thirds of patients with major depression do not respond to the first medication prescribed.

Experts have wondered why people don’t feel better as soon as the levels of neurotransmitters (serotonin, dopamine) increase. The new theory is that mood improves as nerves grow and form new connections this is a process that takes weeks. 

Animal studies show that antidepressants do spur growth and connection of new cells. So, their real value might be in creating new neurons and improving the exchange of information between nerve circuits, known as neurogenesis. If that’s the case, antidepressants should be developed in a way that promotes neurogenesis.

Researchers theorize that this potential process of new brain cell growth has already been happening with ketamine. 

Antidepressant effects of ketamine

Researchers are still investigating the effects of this substance on the brain. The leading theory is that this drug stimulates the regrowth of synapses (connections between neurons) and rewires the brain. An extremely different function compared to antidepressants, because it doesn’t only affect one “monoamine” neurotransmitter like dopamine and serotonin, but acts on an entirely different pathway known as glutamate. 

Glutamate is the most common chemical messenger in the brain and plays a huge role in learning and memory. And this is why researchers believe neuroplasticity — the brain’s lifelong capacity to change and rewire itself in response to the stimulation of learning and experience — to be central to the antidepressant effects of this molecule.

Too much glutamate activity in the brain results in over-excitation (toxicity) of nerve cells. Also known as a glutamate storm, this eventually leads to cell death. In people with depression and other mental health diseases, there is a dysfunction in the glutamate system. Several studies have found decreased glutamate levels in the prefrontal cortex in chronic major depressive disorder compared to healthy individuals. 

Researchers still don’t know how ketamine forms stronger neural circuits. But, they have a hypothesis that suggests that ketamine, a “dirty drug” that may bind to different molecular targets in the brain, causes a short-term explosion of neuronal activity. This activity triggers various biochemical reactions that create stronger brain cell connections [5]. 

In the beginning, researchers believed that ketamine blocked the NMDA receptor in the brain. This receptor is a ketamine-binding receptor that causes neurons to release glutamate. 

But, there’s recent evidence that that’s not entirely true. Researchers now believe that ketamine acts through a different receptor that binds glutamate, known as AMPA. Knowing the receptor this drug acts on will bring them a step closer to developing another drug that acts on that receptor, but with fewer side effects [6].  

Ketamine Therapy for Treatment-Resistant Depression

Wondering if you’re eligible for ketamine infusion therapy? Here are the most important things you need to know if you are interested in getting or suggesting this treatment to your doctor. 

Ketamine is not a first-line treatment. This means that it’s only given to adults age 18 and older who are diagnosed with moderate to severe depression. These patients have not had success with antidepressants and are diagnosed with treatment-resistant depression. If that’s the case with you, contact your therapist or a reliable ketamine clinic for a consult. 

Ketamine doesn’t cure treatment-resistant depression. It provides immediate relief that can last for a few weeks, but its effects wear off afterward. Some patients use the quick “boost” to continue with therapy and other treatments for depression. Others get ketamine muscle injection “boosters” once in a while to keep them going. 

Even in low doses, ketamine can cause vivid hallucinations. During treatment, you may feel extremely relaxed, have an out of body experience, see sensational colors and visuals, and simply appreciate life. Some people compare the effects of the treatment with taking a few glasses of wine. 

What is the process to receive ketamine treatment for depression? 

To get ketamine treatment, you will first go through a comprehensive evaluation. A psychiatrist performs the evaluation by looking at the medical history and basic lab results to ensure this treatment is safe. It’s recommended to choose a clinic with an anesthesiologist on board because they are experts in ketamine.

  1. Free consultation. Most ketamine clinics offer a free phone consultation with their specialists. The initial consultation should be about scheduling an evaluation, not scheduling the actual treatment. Please beware of clinics that do not evaluate your mental and physical state before suggesting therapy, this is a huge red flag. 
  1. Psychiatric evaluation. Reliable clinics provide a 60-90-minute evaluation by a psychiatrist that specializes in treatment-resistant depression. The psychiatrist will determine if ketamine therapy is right for you or you should move in another direction. 
  1. Evaluation of basic lab results. The clinic should also evaluate the basic lab results to ensure this treatment is safe for you.

Dosage and length of treatment

If you get the green light from the experts, you will soon start your ketamine treatment. 

They will determine the dosage and length of therapy. The typical dosage is 0.5mg per kg, as used in most research trials. Some clinics recommend doing six (6) infusions over the course of two weeks, while others recommend 8-12 treatments over 4-6 weeks. With the latter option, patients get two treatments a week within the course of two (2) weeks, with the rest being follow-up “boosters” recommended by a psychiatrist. 

The effects of ketamine are felt immediately after finishing the treatment. But, they start to wear off in a few weeks or months after the last treatment. 

An expensive treatment

Because it’s an experimental treatment, ketamine is not covered by insurance. This treatment can cost anything from $300 to $750 per infusion, which is very expensive, and not everyone can afford to stay on it. As this therapy becomes more accepted, insurance companies are slowly getting interested in it. 

Can I do one infusion? You can, but for better results, you should do at least three. Keep in mind that around 20-30 percent of patients with treatment-resistant depression don’t respond to this medicine. So, if you don’t feel the relief after a few treatments, consider the thought that it may not work for you. 

According to studies, if ketamine doesn’t work after two treatments, it won’t work for the patient. If effective, the patient experiences a significant improvement in symptoms within the first day. Researchers are now trying to find out how long the follow-up periods should last for responsive patients [7]. 

Does it matter if ketamine is administered via IV or nasal spray (esketamine)? 

Yes. An IV infusion always delivers a more precise dose than a nasal spray. Things can get complicated if a person has a cold or their nasal mucosa is damaged. If that’s the case, the nasal spray won’t deliver the same dose as an infusion. The nasal delivery and absorption of a drug depends on the type of drug used, its concentration, dose, and volume. An IV drug administration results in fast delivery of the dosage to the brain and rapid onset of drug effects. 

The most important difference between ketamine and the nasal spray (brand name: Spravato) is that they are not the same. Esketamine (S-ketamine) is the left-facing enantiomer in the ketamine molecule (R-ketamine being the right-facing one). As such, it possesses some of ketamine’s beneficial properties, but not nearly all. 

Esketamine is an FDA-approved form of ketamine for treatment-resistant depression that can be used via a nasal spray. The spray was approved in 2019 and must be administered in a certified doctor’s office or clinic. Why? Experts worry that esketamine is as much habit-forming as regular ketamine. It can be hard for a patient dealing with treatment-resistant depression to control the dosage and may end up over using it. After taking the dosage, patients should be monitored for up to two hours. Legally, patients are not allowed to take the spray at home. 

Despite their differences, both can bring relief to those who suffer from depression. 

In one four-week clinical study, a group of subjects was given Spravato for four weeks vs. an oral antidepressant. Another group took placebo and an oral depressant. The results showed improvement in depression symptoms in the first group, especially within the first 24 hours [8]. 

Is there a price difference between ketamine infusion and esketamine (Spravato) nasal spray?

Yes. Esketamine is generally advertised as less expensive than ketamine infusion. But unless it’s covered by insurance, you’d be surprised to learn that esketamine is actually more expensive. This is because most clinics charge the service of administering the drug in their offices. In some clinics, the cost of the service of administering the medicine can go up to $650. This equals the cost of a single ketamine infusion. 

This doesn’t include the cost of the actual drug, which, again, may be covered by insurance. The cost for Spravato nasal spray two 28mg sprayers is around $240 per beginning dose of 56mg. If the dose is increased to 84mg, the patient needs to buy 3 sprayers instead of 2. The patient should get a dose of 84mg twice a week for 4 weeks, which adds up to over $5 000 per course of therapy [9].   

If the medicine is covered by insurance, and you’re administering it at a doctor’s office, it shouldn’t cost you more than $200 for the service per course of therapy. 

Risks and side-effects

Ketamine treatment for depression is administered in low doses, which makes it a safe and effective medicine. You can (and is recommended) to use antidepressants while receiving your therapy. 

There is a risk that the drug will change your blood pressure and heart rate, monitored closely in the clinic. One 2017 JAMA Psychiatry analysis revealed that long term use of ketamine in people who abuse it repeatedly, over long periods, causes memory loss and severe bladder damage [10]. 

You should not mix ketamine with heart meds, alcohol, opioids, or other drugs that depress breathing. 

Common side effects

  • Increased blood pressure
  • Increased heart rate
  • Anxiety (especially in people with underlying psychosis)
  • Urinary retention
  • Urge to pee more frequently
  • Dizziness
  • Dissociation
  • Confusion
  • Lightheadedness
  • Loss of coordination
  • Bad flashbacks
  • Tremors or shaking

Some of these side-effects happen immediately after treatment but wear off pretty quickly. Most patients describe them as insignificant compared to the beneficial effects of ketamine. Ketamine reverses depression in 30% of people with severe depression who don’t respond to other treatments. 

One of the most significant concerns about using ketamine for depression is whether it causes neural damage in the long run. Animal studies show that long-term use may cause neurodegeneration or progressive loss of structure or function of neurons. That’s why medical professionals advise against taking ketamine and microdosing at home without supervision [11]. 

Large doses of ketamine are addictive because this drug can bind to opioid receptors. This raises the alarm that even low doses can lead to dependence if used long term. But, long term use may be the key to maintaining these diseases at bay. Maintenance, length of treatment, and dosage are just a few things that experts don’t know about ketamine therapy for depression. 

Ketamine is NOT recommended for patients who have had or may have psychosis. The effects of this drug (even in low doses) are similar to those of schizophrenia. Ketamine is a strong dissociative anesthetic that causes the person to hallucinate, experience unusual thoughts, and emotional withdrawal. It has shown to exacerbate psychotic symptoms in such patients and may trigger the disorder to come back. 

Are ketamine clinics legal?

Yes, they are! Ketamine clinics operate lawfully by using ketamine for depression off label. What is an off label use of a drug? It’s a very common practice when the doctor prescribes a drug for a medical condition other than the original FDA-approved use. 

For example, Prazosin (Minipress) is approved for hypertension but is also used off label to treat PTSD triggered nightmares. Clonidine (Catapres) is approved for hypertension treatment, but it’s used off label for ADHD, hot sweats, nicotine dependence, migraine headaches, etc. Research shows that about 12% to 38% of all prescriptions are off label. 

Ketamine is a Schedule III drug under the Federal Controlled Substances Acted from 1999. As a Schedule III drug, it shows a “moderate to low potential for physical and psychological dependence.” 

So, if a doctor judges that a patient with treatment-resistant depression should undergo ketamine infusion therapy, they can prescribe it off label. Ketamine clinics must receive a DEA license and consider both state and local laws before opening. 

Find a legal ketamine clinic in your state:



Bottom Line

Major depressive disorder is one of the most disabling mental health conditions. Researchers are on a quest for new therapeutic approaches to treat or delay the onset of this disorder. Ketamine is, so far, proving to be the most effective drug for treatment-resistant depression. This therapy works quickly, in some patients in just a few hours, and delivers significant relief. The most impressive thing about this drug is that it works in patients who have “tried everything” and found no relief.

Ketamine Infusion Therapy For Depression FAQ

Are ketamine infusions for depression safe?

Yes. Ketamine infusions are a low dose of ketamine for depression and are very safe and effective. 

What are the possible side effects of ketamine?

Possible side effects include high blood pressure, nausea and vomiting, dissociation, time appears to speed or slow down, loss of coordination, tremors or shaking.

Does ketamine make you psychotic?

No. Ketamine is a dissociative anesthetic, meaning, it may cause hallucinations. In a person without underlying psychosis, after these effects wear off, everything is back to normal.

Is ketamine addictive?

A person can become dependent on ketamine. This drug is not as addictive as cocaine or heroin, but in high doses may cause addiction. In patients with depression, ketamine hasn’t caused addiction.

What’s the safest way to take ketamine?

Both IV infusions and injections are safe if performed in a controlled medical setting.

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