Does Ketamine Work for Depression? Or Are Its Risks Too High?

Although antidepressants are such a commonly prescribed group of medications, studies show that a large percentage of patients with depression do not get an adequate level of relief from using these drugs. Even patients who try several different types of antidepressants over the course of years are unlikely to experience significant improvements in their depression symptoms.

Currently, most approved medications for depression have similar mechanisms of actions and roughly the same limited efficacy — however, a drug called ketamine (or esketamine), which has been around since the 1970s but is now being used in new ways, may change the way depression is treated forever. In a May 2018 Business Insider report, it said “Ketamine is emerging as a potential new drug for depression — the first of its kind in 35 years.”

In the U.S., as of early March, 2019, the Food and Drug Administration (FDA) approved ketamine as a prescription treatment intended to help treat depression. Ketamine has been called “the first major depression treatment to reach the U.S in decades.” Researchers have also found evidence in mice that ketamine can induce changes in the brain that are responsible for maintaining remission of depression. These effects are believed to carry over to humans, promoting lasting remission among people who previously experienced relapses.

That being said, there’s still concern over how ketamine may be used “off label.” Not only is ketamine used legally as an anesthetic during surgery and now as an anti-depressive, but more recently it’s gained popularity as a party/club/street drug, having earned a reputation as providing users with an “out-of-body experience.”

What Is Ketamine?

Ketamine is an FDA-approved anesthetic drug that has been used for nearly 50 years and, overall, has a very safe track record. It was developed in the 1960s and first FDA approved in 1970. In 2019, ketamine officially became approved for treating depression for the first time.

Ketamine has potent anesthetic effects, which is why it has been used for decades during surgery to provide pain relief and for various veterinary purposes. Ketamine is considered an NMDA receptor antagonist drug. It has been shown to produce minor hallucinogenic/psychotomimetic effects, meaning it results in not only pain relief but also a mild, short psychotic state. (1)

Is ketamine safe? The World Health Organization considers ketamine to be an “Essential Medicine,” and in the U.S., it’s widely administered to children, adults and pets prior to surgical procedures. (2) Ketamine is used around the world and is actually one of the only anesthetic agents available in most developing countries.

Ketamine Gains FDA Approval

Because ketamine has long had federal approval as an anesthesia agent, clinics have been legally able to administer the drug for patients for decades, although it’s been used “0ff-label” when given to patients for other conditions, including depression up until recently. It’s estimated that even before its approval, at least 100 clinics spanning the U.S. were administering ketamine infusion to patients with depression and pain-related conditions.

For example, Kalypso Wellness Centers is one organization that has promoted ketamine as a treatment for more than two dozen conditions, including: depression, chronic pain, migraines/headaches, anxiety, bipolar disorder, PTSD and inflammatory disorders. According to Kalypso’s website, their clinics (run by Board Certified Anesthesiologists and Pain Medicine Doctors) have over 50 years of experience and have administered more than 3,500 ketamine infusions. They claim that their ketamine treatments have a 91 percent success rate and only cause adverse reactions in about 5 percent of cases. (3)

Actify Neurotherapies is another network of clinics that offer the drug via intravenous injection. There’s been growing concern about clinics such as these that may be offering ketamine even though most providers at the clinics (such as nurses or physician assistant) aren’t qualified to provide mental health care on their own without more supervision.

Does Ketamine Work for Depression?

This has been the big question for years now. Esketamine only recently became indicated to treat depression, as it was historically used as an anesthetic agent to be used during surgical procedures, sometimes combined with muscle relaxant medications or other painkillers/anesthetic agents.

The analgesic effects of ketamine work by prevention of central sensitization in certain neurons as well as by the inhibition on the synthesis of nitric oxide. Ketamine can also cause cardiovascular changes and bronchodilation (dilation of the airways in the lungs due to the relaxation of surrounding smooth muscle).

There’s also promise that ketamine can help people sustaining recovery from depression after initial treatment. In April, 2019, the journal Science published findings from a study funded by the National Institute of Mental Health (NIMH) showing that ketamine-induced brain-related changes seem to be responsible for maintaining remission of behaviors related to depression in mice. These findings are expected to help researchers develop interventions that promote lasting remission of depression in humans. One finding from the study was that ketamine treatment rapidly helps restore connectivity and activity of neurons in the prefrontal cortex in the brains of mice, and increases dendritic spine formation that help neurons to communicate better, leading to an elimination of behaviors related to depression.

There are dozens of free-standing clinics across the U.S. that provide various “proprietary blends” of ketamine off-label to patients with mood-related conditions who are “desperate for an effective therapy and hopeful that ketamine can help,” according to an article published by STAT news. (4) Johnson & Johnson is one company who has actively pursued a nasal formulation of ketamine and has paid for several clinical trials in order to obtain approval.

One downside of using esketamine for depression or other mental health problems is its high cost. It’s commonly been administered via infusion, which can cost about $495–$570 (or sometimes more) per infusion, although some discount programs are now being offered.

Is ketamine covered by insurance? It hasn’t typically been when given for depression, but should be more often in the near future now that it’s gained FDA approval. When a drug is used “off-label,” most patients must pay for the treatments out of pocket, which can really add up if treatments last several months or longer. Approval should help many more patients obtain ketamine at reasonable costs. However right now many patients still pay for ketamine out of pocket, as the generic version of this anesthetic is not yet approved by the FDA.

How Ketamine Works

Ketamine for the use of treating depression has a different mechanism of action compared to standard antidepressants. Regarding how ketamine helps to combat depression, we still have more to learn, but we know that the drugs works in at least several ways:

• it inhibits serotoninergic pathways, which is one way it exerts antidepressive effects
• interacts with N-methyl-D-aspartate (NMDA) receptors, opioid receptors and monoaminergic receptors
• affects calcium ion channels (it does not interact with GABA receptors, unlike many other anesthesia drugs) (5)

According to Kalypso Wellness Clinics, “It functions by ‘re-setting’ nerves and triggers growth of nerve pathways. It is also a very powerful anti-inflammatory medicine, therefore, it helps with both of the main types of pain (nerve pain and inflammatory pain).”

What does the research to date tell us about ketamine’s effectiveness for depression?

• The drug typically acts quickly (sometimes within hours), can have powerful effects and even offers hope to patients who have not seen improvements with other antidepressants. Ketamine may also help individuals who experience severe depression and suicidal thoughts.
• Results from a clinical trial of the nasal-spray formulation of the drug suggest that the formula is well-tolerated by patients and linked with long-lasting improvements in depressive symptoms.
• In 2016, the FDA awarded the drug esketamine, an investigational antidepressant medication with the same effects as ketamine that is made by Janssen Pharmaceutical Companies of Johnson & Johnson, the status “Breakthrough Therapy Designation.” This was meant to highlight the drug’s potential as a treatment for patients with major depressive disorder who are at imminent risk for suicide. (7) The company’s 2016 press release stated that, “If approved by the FDA, esketamine would be one of the first new approaches to treat major depressive disorder available to patients in the last 50 years.” A major advantage that esketamine will have is that it’s taken as a nasal spray, eliminating the need for infusions.
• In 2019 Janssen’s product called Spravato, which contains ketamine molecules, officially became FDA approved.
• Data from Janssen’s ketamine clinical trials suggest that patients with one of the hardest to treat forms of depression (known as treatment-resistant depression) on average tolerate the drug well and experience sustained improvements in depressive symptoms over more than 11 months.
• Esketamine has also been shown to be valuable because it works within days, rather than the 4–8 weeks that most antidepressants usually take to kick in. (8)
• In each trial submitted by Janssen, all patients were started on a new antidepressant drug, and given a course of esketamine treatment or a placebo for one month. The patients taking esketamine performed better statistically than those on placebo when they completed a depression test measuring their symptoms. However in two others trials, the drug did not statistically outperform placebo treatment. The FDA still chose to approve esketamine and to focus on studying how it affects relapse in people with treatment-resistant depression who did well when taking the drug. One trial found that about one-quarter (25 percent) of subjects relapsed when taking esketamine, compared to 45 percent of subjects who received the placebo spray.

Ketamine Infusions

In the past ketamine has typically been given as an infusion, or intravenously via a needle. Infusions usually last about 45–60 minutes. Most patients receive 10 infusions over the course of about 10 weeks, with more frequent infusions administered during the first several weeks.

During a ketamine infusion, patients might feel symptoms including: disorientation, floating sensations, feelings of intoxication, seeing lights or colors more vividly, blurred vision, or tingling in the toes, lips and mouth. These symptoms usually start about 20 minutes into an infusion and diminish approximately 10–15 minutes after the infusion ends. Ketamine infusions are described as being relaxing and usually involve the patient laying down comfortably in a relaxed position that allows their body to unwind.

Prior to the nasal formula being approved, the fact that ketamine needed to be injected meant it was much harder to get and take regularly than a typical antidepressant pill. This, along with the high cost, have been major downsides to using ketamine on an ongoing basis for conditions like depression or pain management.

Ketamine Dosage

The “optimal dose” of ketamine is still under investigation. Currently, the goal is to find a dose for individual patients that provide antidepressive effects but do not cause addiction or adverse side effects.

• In studies, ketamine has been shown to help decrease depression symptoms even when used in small amounts, such as concentrations that are ten times lower than the amount that would be needed for anesthetic proposes.
• Ketamine is absorbed rapidly and highly bioavailable. It is eliminated relatively quickly through urine, bile and feces.
• The recommended course of the newly approved drug Spravato is twice a week, for four weeks, with boosters as needed, along with other commonly used oral antidepressants in some cases.
• The FDA’s approval requires that Spravato be taken in a doctor’s office or clinic, with patients monitored for at least two hours. Patients’ experience must be entered in a registry. Patients are also instructed not to drive on the day of treatment.

Reports show that there is currently inconsistencies in the dosage and frequency of ketamine infusions that are being recommended to patients, especially those with depression. Most clinics will recommend dosages that are very low and considered sub-anesthetic, meaning only a fraction of the dose a patient would get in the hospital for surgery is given to help manage depression. However, because there is no standard dose that has been established or approved by the FDA, there may be risks involved with meeting with an unexperienced practitioner who offers ketamine.

If a patient with depression is taking other medications (antidepressants) to manage their condition, ketamine might be given in addition to these medications, but does not necessarily take the place of them. It’s up to the individual patient and their doctor to determine if current medications are still needed.

Risks and Side Effects

In general, esketamine is widely used around the world, has been studied extensively since the 1960s, and is usually well-tolerated. However, ketamine side effects are still possible, especially when it’s taken illegally and in high doses.

Critics warn that ketamine has not been studied sufficiently for the use of depression and similar conditions. It also has a high cost that is a barrier for many patients. There’s also concern that off-label use of ketamine is not being properly monitored, and that we don’t know enough about the potential for addiction.

It’s possible that esketamine tolerance may develop, especially if it’s used very frequently or for long periods. It’s also important to point out that ketamine is not intended to become the sole source of mental health care for patients with depression; therapy and working with a professional is still recommended. If you do visit a clinic in hopes of receiving ketamine, it’s critical that you choose a clinic with qualified caregivers. Many working at these clinics have not been trained to handle patients at risk for behavioral problems and are not doctors, so do your research.

Ketamine may not be safe to take long-term. Studies related to the blocking of NMDA receptors have shown an increase in apoptosis (cell death) in the developing brain, which results in cognitive deficits when ketamine is used for longer than three hours.

Ketamine is also mood-altering; it’s a psychedelic drug that makes people mildly hallucinate, and some “bad trips” have been reported. While most people find ketamine to have a calming or even “spiritual effect,” some become anxious and feel very “out of touch” after using the drug. (6)

When used a street/party drug, esketamine has been used to commit sexual assaults due to its ability to sedate and incapacitate victims. Therefore, some consider ketamine to be a “date rape” drug and warn that its distribution should be more tightly-controlled. There have also been reports of ketamine side effects when used at high doses that include:

• Bloody pee
• Paleness
• Blurry vision
• Chest pain and shortness of breath
• Confusion
• Convulsions
• Problems with swallowing
• Dizziness and fainting
• Irregular heartbeats
• Hives, itching, rash
• Delusions
• Unusual tiredness or weakness
• and others

As of December 2015, the World Health Organization (WHO) recommends that ketamine should not be placed under international control, after concluding that ketamine abuse does not pose a global public health threat and that the medical benefits of ketamine far outweigh potential harm from recreational use.

The WHO states that ketamine is one of the only anaesthetics and painkillers available in large areas of the developing world and that “controlling ketamine internationally could limit access to essential and emergency surgery, which would constitute a public health crisis in countries where no affordable alternatives exist.”

Final Thoughts