Ketamine is a medication used widely to induce and maintain anesthesia. While known in medicine for its sedative properties and on the streets for the vivid hallucinations it causes, it can also protect the brain, reduce depression, and alleviate the symptoms of PTSD. Read more to learn about the uses, mechanisms, and side effects of this drug.
Disclaimer: By writing this post, we are not recommending this drug. Some of our readers who were already taking the drug requested that we commission a post on it, and we are simply providing information that is available in the clinical and scientific literature. Please discuss your medications with your doctor.
What is Ketamine?
Ketamine, also known as Ketalar or Ketaject, is a drug that initiates and maintains anesthesia .
The original drug was first discovered in the early 1960s and approved for use in the United States in 1970. Now it is considered by the World Health Organization (WHO) as one of the safest and most essential drugs in a health system .
Ketamine is considered a Schedule III controlled substance, which means that it requires a written, oral, or electronic prescription to possess or buy the drug.
Even so, many people use ketamine as a recreational drug to experience the hallucinations and “high” or pleasurable feeling it causes. For this reason, ketamine has a definite potential for addiction [3, 4].
On the streets, it is known by many names, including K, special K, kit-kat, keets, super acid, super K, and jet .
Ketamine is a dissociative drug, which means that it alters the senses, leading to hallucinations and feelings of detachment from the environment and oneself .
Ketamine Mechanism of Action
Ketamine blocks NMDA receptors, which reduces signaling activity in the brain. This accounts for the general anesthesia, hallucinations, dissociation (at lower doses), and memory loss (at higher doses) associated with ketamine [11, 12].
Although the precise mechanisms of ketamine are currently unclear, it is also believed to work by:
Increasing glutamate levels, which:
- Causes psychosis, or a loss of contact with reality .
- Causes antidepressant effects by increasing BDNF levels .
Increasing dopamine and possibly reducing nicotinic acetylcholine levels, which may cause feelings of delirium .
Reducing opioid receptor responsiveness (in chronic pain patients), which reduces opioid tolerance and pain .
Increasing amine levels, which:
Inhibiting enzymes that make nitric oxide, which reduces pain .
Binding to acetylcholine sites on NMDA receptors, which reduces acetylcholine levels, leading to slower breathing and disrupted sleep .
Blocking sodium channels, which results in local anesthesia .
Ketamine exists as R and S enantiomers, which means that it exists as a pair of molecules that are mirror images of each other. The S isomer is 3 times more potent than the R isomer and results in faster recovery of brain and motor (movement) function post-anesthesia. Regardless, the racemic form (a mixture of the two) is currently used as its interaction with the body is comparable to that of the S isomer [21, 22].
Uses of Ketamine
1) Aids in Treating Depression
Ketamine may also be effective in reducing symptoms in patients with treatment-resistant depression (TRD). In a review, it was found that a single dose of ketamine (in the vein) can produce a strong and rapid antidepressant effect lasting for 1 week in patients with TRD .
Additionally, depressive symptoms improved just 40 minutes after ketamine use in a 14-day study (double-blind randomized controlled trial) of 18 treatment-resistant bipolar depression patients .
In a study (randomized controlled trial) of 73 patients over 24 hours, patients who used ketamine had greater improvement in their scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), a test psychiatrists use to measure the severity of depression, compared to midazolam (a benzodiazepine) .
While much is known about the immediate antidepressant effects of ketamine, there is minimal information regarding ketamine ’s long-term effects. In one study of 24 TRD patients over 83 days, patients experienced over 2 weeks of sustained improvement of their symptoms after 6 repeated ketamine doses .
However, in a review, it was found that ketamine’s antidepressant effects are only short-term .
Another review found that while ketamine can act as an effective antidepressant (likely by blocking NMDA receptors), it may have dissociative side effects (disconnecting from one’s sense of identity) .
One study found that ketamine in combination with the electroconvulsive therapy (commonly used to treat depression) was more effective in improving depression symptoms than another anesthetic, propofol, in a year-long study of 31 inpatients .
In a 4-week study (double-blind randomized controlled trial), 42 depression patients were given an initial dose of ketamine followed by a dose of riluzole (a drug that increases glutamate). About a fourth of the patients did not experience a depression relapse by the end of the trial. However, riluzole did not potentiate the antidepressant effects of ketamine .
Similar to ketamine, esketamine (the S(+) enantiomer of ketamine) is a rapid-acting antidepressant. However, in a review comparing the individual effects of ketamine isomers, it was found that arketamine (the R(-) enantiomer form of ketamine) was a more effective and safe antidepressant compared to esketamine [31, 32, 33].
2) Reduces Pain
Ketamine is a well-known general anesthetic.
It reduces chronic pain. In a study of 12 male volunteers, low doses of ketamine activated portions of the brain that are involved in the inhibition of pain (e.g., frontal cortex and brainstem) .
Normally, chronic pain patients have a defect in accessing these portions of their brains, which prevents them from reducing pain.
In an 11-week study (double-blind randomized controlled trial) of 60 female patients with Complex Regional Pain Syndrome (CRPS), a chronic pain condition, a 100-hour infusion (in the vein) of ketamine relieved pain lasting up to 3 months following treatment .
Additionally, in a study of 12 cancer patients with severe cancer pain, patients required 50% less morphine to reduce their pain after prolonged use of ketamine .
It also enhanced the effectiveness of intrathecal (into spinal cord) morphine treatment in a study of 20 cancer pain patients (double-blind randomized controlled trial) .
Ketamine completely reduced phantom limb pain (pain felt after amputation) in a 31-year-old male with a 5-month history of pain .
Ketamine is also effective in reducing pain when combined with other drugs. A combination of ketamine and a local anesthetic (bupivacaine) reduced pain following operation in a study (double-blind randomized controlled trial) of 53 amputee patients compared to placebo .
When used as a local anesthetic with diazepam (a benzodiazepine), meperidine (Demerol – a narcotic pain killer), and nitrous oxide (in the mouth) ketamine reduced pain, discomfort, and anxiety in a study of 40 healthy adults undergoing oral surgery .
Ketamine has also successfully worked as an anesthetic in cats .
3) Promotes Sleep
Ketamine can also be used as a sedative. When ketamine was administered through the veins in 30 children, all patients experienced sedation within 2 minutes .
In another study of 431 children, ketamine was administered through the muscles. In this study, 98% of patients experienced sedation .
4) Reduces Seizures
Ketamine decreased the duration of seizures in 10 patients during electroconvulsive therapy .
In rats, ketamine effectively controlled seizures in all animals 1 hour after seizure stimulation .
Another study in rats found that ketamine stopped seizure activity in 3 rats 30 minutes after administration .
5) May Protect the Brain
Ketamine can protect the brain from damage caused by seizures.
Ketamine reduced unhealthy brain pressure in traumatic brain injury patients during propofol sedation in a study of 8 male patients .
Similarly, ketamine significantly protected 22 out of 24 regions of the rat brain after induced seizures .
Systematic dosing of ketamine also prevented the decay of brain neurons caused by persistent seizures in rats .
In the lab, ketamine increased brain cell viability and preserved brain cell shape during harmful conditions (i.e., lack of oxygen) .
6) May Reduce Symptoms of PTSD
Ketamine quickly and effectively reduced the symptoms of PTSD compared to midazolam (a benzodiazepine) 24 hours after administration in a study (double-blind randomized controlled trial) of 41 patients with chronic PTSD .
7) May Improve Asthma Symptoms
Ketamine improved the breathing of 11 patients with severe asthma 2 hours after administration when therapy and assisted breathing failed .
Similarly, 2 patients with severe asthma resumed normal breathing after ketamine was administered via IV (at a rate of 0.15 mg/kg/hr) .
8) May Help with Obsessive Compulsive Disorder (OCD)
In a 1-week study (double-blind randomized controlled trial) of 15 drug-free OCD adults, ketamine significantly improved obsessive symptoms compared to placebo .
In a study of 10 treatment-resistant OCD patients, 35% of patients reported improvement in their symptoms after 3 days of ketamine treatment .
Side Effects of Ketamine
Normally, ketamine is known to have a variety of side effects, including :
- Disorientation or confusion after anesthesia
- Nausea and/or vomiting
- Increased heart rate
- Elevated blood pressure
- Increased salivation
- Muscle spasms
- Temporary rash
Ketamine also causes apoptosis in the brain, or programmed cell death in lab studies .
Hallucinations or delirium can be reduced by taking benzodiazepines with a lower dose of ketamine (10 mg) .
Users can also experience extreme dissociation from their environment (known as the “K-hole”) when taking high doses (over 150 mg) of ketamine .
Long-term use of ketamine may also cause brain damage. In young rhesus monkeys, a single 24-hour episode of ketamine-induced anesthesia triggered brain cell death .
Contraindications of Ketamine
They include :
Those that have shown past hypersensitivity reactions to ketamine or any of its components.
Chronic alcoholics or anyone that is acutely intoxicated.
Patients with cardiovascular-related conditions such as aortic dissection, uncontrolled hypertension, myocardial infarction or aneurysms.
Ketamine Use During Pregnancy and Breastfeeding
Ketamine should not be used during pregnancy or while breastfeeding as its effects in pregnancy have not been evaluated and it is unknown whether the drug is present in breast milk .
Drug Interactions of Ketamine
Ketamine is often taken with other drugs that enhance its effects and limit its side effects.
Side effects of ketamine such as delirium and hallucinations are reduced when taken with benzodiazepines .
Vomiting caused by ketamine decreased in children when taken with midazolam, another anesthetic (a benzodiazepine). However, this combination reduced oxygen levels in the blood and had no effect on post-anesthesia anxiety [62, 63].
Sufficient anesthesia with a smooth, negative hallucination-free recovery can be induced and maintained by combining ketamine with methohexitone (a barbiturate derivative), diazepam (Valium – a benzodiazepine), and alcuronium (a muscle relaxant) .
When taken with halothane, another anesthetic, ketamine remained in the brain tissue longer than when taken alone in rats .
When the painkilling opioid tramadol was taken with ketamine in mice, pain reduction was increased .
Ketamine also enhances the effects of morphine in pain relief after surgery .
Additionally, ketamine’s sedative effects were more effective when administered with propofol .
Ketamine can also be taken with anti-seizure medications. When combined with diazepam and the anti-seizure drugs carbamazepine (also known as Tegretol) and phenytoin (Dilantin), ketamine reduced brain damage caused by the seizures in rats .
Ketamine concentrations can also be affected by some antibiotics. When taken with the antibiotic rifampicin, ketamine concentrations were reduced in healthy volunteers .
Ketamine increases the amount of fluid pressure in the brain and spine, which can damage these organs. Taking diazepam with ketamine reduces these effects .
Ketamine is often combined with other recreationally abused drugs, such as MDMA (ecstasy), LSD, GHB, and flunitrazepam (Rohypnol). These combinations can have negative effects. For example, one user reported that while he normally had no problems taking ketamine, the combination of ketamine and LSD made him feel “unpleasant” and “unsettled” [74, 75].
In mice, ketamine combined with MDMA (ecstasy) increased the number of toxic substances made by dopamine in the brain. This inhibits cellular respiration, the set of metabolic processes that create usable energy in the body [76, 77].
When administered professionally, Rohypnol and ketamine taken together have beneficial effects. In a study done on 140 women undergoing an abortion, a ketamine-Rohypnol combination reduced restlessness and confusion after the surgery. Dreams were also less frequent .
While ketamine is generally thought to cause severe adrenaline-related problems when combined with monoamine oxidase (MAO) inhibitors, one case found that ketamine had no negative effects in a 42-year-old woman when taken with tranylcypromine, a monoamine oxidase (MAO) inhibitor .
This is just one case, however, and more research must be conducted to support this data.
Ketamine may also be taken in combination with sleep aids. This has anecdotally been reported to increase drowsiness. In a study (double-blind randomized controlled trial) of 73 patients with treatment-resistant major depression, no adverse effects were observed when the sleep aid zolpidem (Ambien) was taken prior to ketamine .
Interestingly, ketamine concentrations increase when ingested with grapefruit juice. Dose reduction should be considered when taken with this fruit .
Forms and Dosage of Ketamine
Ketamine is available as a white powder and is taken through the nose, mouth, the veins, the muscles, or under the tongue. It is administered by medical professionals through the muscles or the veins; any other methods of use are highly ill-advised.
Generally, doses vary from person to person and are based on the method of ketamine use. For example, an adult low-dose of ketamine is 0.5 mg/kg through the veins or an epidural route, and less than 2 mg/kg through the muscles .
For children, the dosage is usually 3 to 10 mg/kg orally or 2 to 4 mg/kg through the muscles. It is also effective when combined with local anesthesia in a dose of 0.5 to 1 mg/kg .
When ketamine is taken improperly or very large amounts, overdose can occur. The exact amount of ketamine resulting in overdose varies from person to person.
Ketamine overdose can happen by accident, especially in children .
There is also a high possibility of permanent brain damage during overdose .
While ketamine has many benefits, it is a volatile and unpredictable drug and should not be taken without medical supervision.
Limitations and Caveats
Clinical studies on ketamine’s effects in high doses are limited .
Also, there are few reliable studies supporting the use of the drug in adults to treat traumatic brain injury or eye injury .
There is also a lack of clinical trials that determine the durability, long-term safety, tolerability, and effectiveness of ketamine .
There are also mixed results as to whether ketamine reduces recovery time in patients undergoing electroconvulsive therapy (ECT) for depression .