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 symptoms.
Currently, most approved medications for depression have similar mechanisms of actions and roughly the same limited efficacy — however, a drug called ketamine, which has been around since the 1970s but is now being used in new ways, may change the way depression is treated forever.
Not only is ketamine used legally as an anesthetic during surgery, 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.” Recently, studies have also focused on the potential use of ketamine as a therapeutic tool for the management of depression. 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.”
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 FDA approved in 1970. 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 and 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.
Because ketamine has federal approval as an anesthesia agent, clinics are legally able to administer the drug for patients, although it’s used “0ff-label” when given to patients for conditions like depression. It’s estimated that around 100 clinics spanning the U.S. now administer ketamine infusion to patients with depression and pain-related conditions.
Kalypso Wellness Centers is one organization that promotes 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 is the big question. Ketamine is only currently indicated as an anesthetic agent that is intended 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 are now dozens of free-standing clinics across the U.S. that provide various “proprietary blends” of ketamine off-label to patients with depression 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 is actively pursuing a nasal formulation of ketamine and is awaiting results from advanced clinical trials in order to widen distribution.
One downside of using ketamine for depression or other mental health problems is that it needs to be injected and comes at a high cost: ketamine can cost about $495–$570 (or sometimes more) per infusion, although some discount programs are now being offered. It ketamine covered by insurance? Not usually. 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.
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?
- A 2015 report published in The Lancet explains that so far, findings suggest that ketamine can lead to sustained improvements in depressive symptoms that last a year or more. (6)
- 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.
- Early results of 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 press release states 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.
- Data that is available so far from the esketamine clinical study suggests 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.
- Ketamine/esketamine are also valuable because they seem to work within days, rather than the 4–8 weeks that most antidepressants usually take to kick in. (8)
Ketamine is typically 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.
The fact that ketamine needs to be injected means it is much harder to get and take regularly than a typical antidepressant pill. This, along with the high cost, is a major downside to using ketamine on an ongoing basis for conditions like depression or pain management.
The optimal dose of ketamine is still under investigation. Currently, the goal is to find a dose that provides antidepressive effects but does 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.
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.
Precautions & Side Effects of Ketamine
In general, ketamine 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 ketamine 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, ketamine 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
- Blurry vision
- Chest pain and shortness of breath
- Problems with swallowing
- Dizziness and fainting
- Irregular heartbeats
- Hives, itching, rash
- Unusual tiredness or weakness
- and others
Ad 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.” (2)
Final Thoughts on Ketamine
- Ketamine is an FDA approved anesthetic drug that has been used for nearly 50 years. Recently, studies have also focused on the potential use of ketamine as a therapeutic tool for the management of depression and suicidal thoughts.
- Findings from studies conducted thus far seem hopeful regarding the use of ketamine for depression, but we still need more research to confirm its efficacy and safety. There is not yet an established ketamine dosage for treating depression since it’s considered “off label” when used for any purpose besides as an anesthesia agent.
- Overall ketamine seems to be well-tolerated and safe, but ketamine side effects can occur during infusions that usually diminish when the infusion ends. Side effects can include: feeling out of touch, anxiety, disorientation, floating sensations, feelings of intoxication, seeing lights or colors more vividly, blurred vision, or tingling in the toes, lips and mouth.
- There are some risks to be aware of regarding ketamine, such as the potential to experience a “bad trip” and for the illegal use of ketamine that can result in hallucinations and even sexual assault.
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