Uses and Side Effects of Ketamine: A Comprehensive Guide

It’s been more than 60 years since ketamine was discovered, and since then, it’s come to be widely used for general anesthesia. In recent years, it’s also drawn significant interest as a treatment for depression.

At the same time, ketamine can have potentially serious side effects. Its risks are amplified when it is misused, taken as a recreational drug, or administered without cautious monitoring.

Given the potency of ketamine, it’s important for both providers and patients to be informed about its benefits and risks and how to maximize its safety and effectiveness.

What Is Ketamine?

Ketamine hydrochloride, often known simply as ketamine, was initially identified as an anesthetic. It is a substance with sedative and dissociative properties, affecting a person’s sensations and their perceptions of reality and their environment.

First synthesized in 1962, ketamine is a combination of two molecules, arketamine (R-ketamine) and esketamine (S-ketamine). In medical care, doctors may use either ketamine or esketamine, depending on the situation.

Ketamine is typically administered through an IV or an injection into a muscle. Esketamine has been formulated as a nasal spray in a medicine known as Spravato. This drug was approved by the U.S. Food and Drug Administration (FDA) in 2019.

Ketamine has also been used illicitly for sedation and to induce hallucinations. Chemically, ketamine is related to the street drug PCP. Ketamine is classified as a Schedule III drug under the Controlled Substances Act, which reflects a low-to-moderate risk of abuse. When used recreationally, ketamine may be in a powder or liquid form. Street names include K, vitamin K, and special K.

Another concern about illicit ketamine use is its potential role in sexual assault. Some forms of ketamine can be given without someone knowing, such as by putting it in a drink, making them vulnerable by inducing unconsciousness and loss of memory.

Ketamine is a drug that can cause you to see and hear things that aren’t there. It can make you feel disconnected from reality and not in control. It’s used as a short-acting anesthetic for both people and animals. It’s called a “dissociative anesthetic” because it makes you feel separated from your pain and surroundings.

Medical Uses of Ketamine

Ketamine has been used in multiple ways in the practice of medicine. Ketamine and esketamine have only limited approved uses, but they are sometimes prescribed off-label for different health conditions.

Ketamine in Anesthesia

Ketamine was first approved by the FDA in 1970 as an intravenous or intramuscular anesthetic, and it continues to be used for surgery and medical procedures. In this context, ketamine is usually given to patients via an IV, and it can be used alone or with other anesthetics.

Benefits of ketamine as an anesthetic include its pain-relieving effect and the fact that it does not reduce heart rate or blood pressure. However, a downside is its potential to cause hallucinations or other changes in perception and feeling.

Ketamine and Esketamine as Treatments for Depression

Ketamine’s potential as a therapy for depression was first reported in 2000. This kicked off significant interest in its antidepressant effects, especially for the roughly 3 million people in the U.S. with treatment-resistant depression.

For depression, a healthcare provider can prescribe ketamine itself or esketamine, which is one of ketamine’s component molecules.

• Ketamine has not been approved as a treatment for depression, but it may be prescribed as an off-label therapy.
• Esketamine — formulated as a nasal spray known by the product name Spravato — was approved by the FDA in 2019 as a medication for treatment-resistant depression.

One of the things that makes these drugs compelling is that they take effect within hours, which stands in stark contrast to many oral antidepressants that take weeks to affect mood.

The mechanism behind ketamine and esketamine’s effects on depression is not fully understood, but results from various studies suggest that it acts on multiple different receptors in the brain involved in regulating feelings and mental states.

In our practice, we believe in both the psychological and biological benefits of ketamine. Ketamine lifts mood and also raises levels of BDNF — brain-derived neurotrophic factor — which is like “miracle-grow,” for neurons. BDNF increases neuroplasticity, the brain’s ability to change or to see things from a new perspective. Neuroplasticity can be helpful to almost everyone but is especially beneficial for people stuck in low moods or ineffective modes of thinking.

Building on this, we emphasize and incorporate therapy around each ketamine experience, setting intention prior, and debriefing or integration afterward. Put another way, if you think of your brain as chocolate — ketamine softens the chocolate, and therapy around it is the new form that it can “melt” into.

Of course, your brain won’t melt! Ketamine may actually be protective of brain cells. However, it might make it easier to see things in a new way, which can be a huge boost to people with depression. We believe this is a significant advantage to in-office ketamine sessions with mental health experts (versus at home treatment) – the supportive environment and close guidance has been tremendously helpful to our patients.

The following two sections provide more specific information about how both ketamine and esketamine may be used in treating depression.

Ketamine and Depression

A number of research studies have found that an IV infusion of ketamine can have a fast-acting effect on many people with treatment-resistant depression. It may moderate the severity of depression and reduce suicidal thoughts and behavior. Though primarily studied in people with major depressive disorder, some evidence suggests it may be effective for people with bipolar disorder during depressive episodes. An initial test dose may be 0.5mg of ketamine per kilogram of body weight; however, this will often be adjusted based on response.

Many studies have investigated only a single infusion or other short-term use of ketamine. While the effect is rapid, it can wear off within days to weeks. As a result, providers may recommend repeated infusions, but more research is needed to understand the effectiveness and optimal dosage and frequency of ketamine over a longer period of time.

As a treatment for depression, ketamine can be administered not only intravenously but also orally, under the tongue, as a nasal spray, or as an injection under the skin or into the muscles. Unfortunately, there is a lack of evidence comparing these different methods of taking ketamine. The primary difference between these various modes of administering ketamine is in its bio-availability, which is how much ketamine actually makes it into the bloodstream and brain. Below is an outline of these differences:

• Oral (swallowed) – 16-24%
• Oral (sublingual) – 30%
• Nasal spray – 50%
• Intramuscular injection – 93%
• Intravenous injection – 100%

In many cases, ketamine is taken alongside other antidepressants. However, there may be interactions with some medicines, so a doctor needs to review all of a person’s medications before beginning treatment with ketamine.

Esketamine and Depression

Spravato (esketamine) is a nasal spray approved for use in people who are already taking an oral antidepressant but have persistent symptoms of depression. For many people, it provides rapid relief for depressive thinking and thoughts of self-harm.

This drug is given in a medical setting, and after inhaling the spray through the nose, individuals are monitored for two hours in case there are any serious adverse effects.

It is normal for Spravato to be given once or twice per week for a period of months, usually with a schedule intended to taper off the drug gradually. Beneficial effects may last for an extended period after the final treatment.

Other Off-Label Uses of Ketamine

Beyond depression, ketamine has been proposed as an off-label treatment for other conditions. For these uses, evidence from clinical trials is limited. This makes it difficult to evaluate ketamine’s ability to help with these conditions relative to other medications.

That said, some of the potential off-label uses of ketamine include:

• Minimizing pain during medical procedures without the need for general anesthesia
• Addressing symptoms of post-traumatic stress disorder (PTSD)
• Stopping a seizure that lasts for five minutes or longer
• Managing chronic pain, such as from nerve damage (neuropathy)
• Reducing severe agitation, including in individuals who are receiving mechanical ventilation in an intensive care unit (ICU)

Side Effects of Ketamine

When administered at an appropriate dose by a trained health professional, ketamine is generally considered to be safe for adults. However, there is a range of potential side effects and reactions, some of which can be severe.

Some of the most common side effects of ketamine and esketamine include:

• Disassociation: Ketamine can cause a person to experience a state of detachment in which they don’t feel connected to their body or their identity. This is sometimes called a “k-hole,” and it can trigger different responses, including confusion, anxiety, fear, and delirium.
• Distorted perception: Alterations to perception may continue after taking ketamine with the potential to cause hallucinations, flashbacks, lack of attention, and memory loss.
• Other neurological effects: Some people who take ketamine go through bouts of nausea, dizziness, double vision, insomnia, and lethargy.
• Cardiovascular effects: Ketamine can lead to an increase in heart rate and blood pressure.
• Urinary effects: In more than one study, people taking ketamine were more likely to have problems affecting the bladder and urinary tract, including infections and pain when passing urine.

Although it’s possible for side effects to persist, they often go away quickly after stopping ketamine use. 

Potential Risks and Complications of Ketamine

Ketamine use can cause significant and even life-threatening complications. Some of the most concerning potential risks of ketamine use include:

• Addiction and abuse: Ongoing use of ketamine can cause dependence on the drug. Regular users can build up a tolerance, requiring an increasing amount of ketamine to achieve the same effect. Stopping use can trigger withdrawal, heightening the potential for addiction.
• Psychiatric instability: The powerful effects of ketamine on the mind may worsen mental health in some individuals. It can provoke anxiety and may incite suicidal ideation in young people. Some research has found a greater risk of schizophrenia in long-term users of ketamine.
• Overdose: Excess intake can lead to ketamine poisoning, which may cause coma or death. Overdosage is much more common with poorly monitored or illicit use, and poison control centers have reported significant increases in ketamine overdoses in recent years.
• Trouble breathing: Ketamine can cause slowed and distressed breathing. Dramatic reductions in breathing are known as respiratory depression.
• Muscle changes: It is possible for people taking ketamine to experience seizures or other events marked by a loss of muscle control.

Although these severe reactions are uncommon, trained health care providers are aware of them and carefully monitor patients to react quickly if problems arise. The dangers of ketamine use are higher when the drug is given by inexperienced providers or used recreationally and without medical oversight.

Precautions and Contraindications

Taking precautions can make the difference between safe and unsafe ketamine use. This drug should only be used under the guidance and advice of a healthcare provider who can control the dosage and watch for signs of an adverse reaction.

Ketamine is generally not given to children or teenagers. It may also be inappropriate for people of older age who have certain coexisting health conditions.

Ketamine can have effects on a fetus during pregnancy and on an infant when breastfeeding. However, untreated depression can also be harmful for fetal or infant health, so the benefits and risks of ketamine in these situations should always be discussed with a doctor.

Ketamine can cause drowsiness and slower reflexes, raising the risk of all types of accidents. When taking ketamine, people should avoid driving and other activities where drowsiness or delayed reaction time can pose a risk to themselves and others.

The dangers of ketamine are greater in people who are frequent users of alcohol. Adverse reactions are more common when ketamine is used by people who are also under the influence of mind-altering drugs like cocaine, LSD, marijuana, tobacco, and opioids.

Certain prescription drugs can also have interactions with ketamine. These include some asthma medicines like aminophylline and other theophylline-derived drugs. Ketamine can enhance the effects of drugs that are sedatives or central nervous system depressants like benzodiazepines and some sleeping pills.

Dosage and Administration of Ketamine

Ketamine should only be given after carefully selecting the dose for a specific patient and their condition. There are no universal guidelines for dosage, which can vary based on a person’s weight.

Healthcare providers should also consider whether a person has preexisting health conditions, such as kidney or liver injury, that could influence their reaction to ketamine.

Doses of ketamine are often scheduled to gradually taper down, which can decrease the risk of withdrawal, addiction, and future misuse.

Safe Use of Ketamine

The safety of ketamine can depend on the setting in which it is provided. Ketamine should only be prescribed and administered by experienced health professionals who can ensure the purity of ketamine products, follow standard terms of use, and incorporate ketamine within an overall plan for patient care.

In recent years, a growing number of standalone ketamine clinics have sprung up in the United States. These clinics often advertise the use of ketamine for a long list of health problems, but the providers may not be trained in psychiatry or mental health care.

If you or a loved one is considering going to one of these clinics, make sure to ask questions about their experience and training related to ketamine and mental health care. Ask for information about the function of the clinic, including whether they simply provide ketamine or integrate the drug into multi-faceted care for depression.

You can also ask about how they monitor patients to reduce the chances of adverse effects, their typical dosage schedule, and steps they take to reduce the risk of addiction and abuse.

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