Ketamine: Also called “Special K,” this animal tranquilizer is sometimes used as a recreational drug by attendees at dance raves and other events. The drug may also effectively combat the symptoms of depression.What to know about ketamine .
A 2012 study from the journal Science found that ketamine may help stimulate the growth of synapses in the brain, and beneficial effects of the drug on people with chronic depression can occur within hours. “The rapid therapeutic response of special K in treatment-resistant patients is the biggest breakthrough in depression research in a half century,” Ronald Duman, professor of psychiatry and neurobiology at Yale University, said in a statement.
Ketamine is a medication mainly used for starting and maintaining anesthesia. It induces a trance-like state while providing pain relief, sedation, and memory loss. Other uses include for chronic pain, sedation in intensive care, and depression. Heart function, breathing, and airway reflexes generally remain functional. Effects typically begin within five minutes when given by injection, and last up to about 25 minutes.
Common side effects include agitation, confusion, or hallucinations as the medication wears off. Elevated blood pressure and muscle tremors are relatively common.Spasms of the larynx may rarely occur. Ketamine is an NMDA receptor antagonist, but it may also have other actions.
Ketamine was discovered in 1962, first tested in humans in 1964, and was approved for use in the United States in 1970.It was extensively used for surgical anesthesia in the Vietnam War due to its safety. It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. The wholesale price in the developing world is between US$0.84 and US$3.22 per vial. Ketamine is also used as a recreational drug for its hallucinogenic and dissociative effects.
Medical uses What to know about ketamine .
Uses as an anesthetic:
- Anesthesia in children, as the sole anesthetic for minor procedures or as an induction agent followed by muscle relaxant and tracheal intubation
- Asthmatics or people with chronic obstructive airway disease
- As a sedative for physically painful procedures in emergency departments
- Emergency surgery in field conditions in war zones
- To supplement spinal or epidural anesthesia/analgesia using low doses
Since it suppresses breathing much less than most other available anesthetics, ketamine is used in medicine as an anesthetic; however, due to the hallucinations it may cause, it is not typically used as a primary anesthetic, although it is the anesthetic of choice when reliable ventilation equipment is not available.What to know about ketamine .
Ketamine is frequently used in severely injured people and appears to be safe in this group. A 2011 clinical practice guideline supports the use of ketamine as a dissociative sedative in emergency medicine. It is the drug of choice for people in traumatic shock who are at risk of hypotension. low blood pressure is harmful in people with severe head injury and ketamine is least likely to cause low blood pressure, often even able to prevent it.
The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. When used at anesthetic doses, it will usually stimulate rather than depress the circulatory system. It is sometimes possible to perform ketamine anesthesia without protective measures to the airways. Ketamine is considered relatively safe because protective airway reflexes are preserved.
Ketamine is used as a bronchodilator in the treatment of severe asthma.However, evidence of clinical benefit is limited.What to know about ketamine .
Pain management what to know about ketamine .
Ketamine may be used for postoperative pain management. Low doses of ketamine may reduce morphine use, nausea, and vomiting after surgery.
Ketamine has similar efficacy to opioids in a hospital emergency department setting for management of acute pain and for control of procedural pain.
It may also be used as an intravenous analgesic with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic. It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain. At these doses, the psychotropic side effects are less apparent and well managed with benzodiazepines. Ketamine is an analgesic that is most effective when used alongside a low-dose opioid; because, while it does have analgesic effects by itself, the doses required for adequate pain relief when it is used as the sole analgesic agent are considerably higher and far more likely to produce disorienting side effects. A review article in 2013 concluded, “despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain”.
Low-dose ketamine is sometimes used in the treatment of complex regional pain syndrome (CRPS). A 2013 systematic review found only low-quality evidence to support the use of ketamine for CRPS.
See also: Esketamine § Depression
Ketamine has been found to be a rapid-acting antidepressant in depression. It also may be effective in decreasing suicidal ideation, although based on lower quality evidence. The antidepressant effects of ketamine were first shown in small studies in 2000 and 2006. They have since been demonstrated and characterized in subsequent studies. A single low, sub-anesthetic dose of ketamine given via intravenous infusion may produce antidepressant effects within four hours in people with depression. These antidepressant effects may persist for up to several weeks following a single infusion. This is in contrast to conventional antidepressants like selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), which generally require at least several weeks for their benefits to occur and become maximal. Moreover, based on the available preliminary evidence, the magnitude of the antidepressant effects of ketamine appears to be more than double that of conventional antidepressants. On the basis of these findings, a 2017 review described ketamine as the single most important advance in the treatment of depression in over 50 years. It has sparked interest in NMDA receptor antagonists for depression, and has shifted the direction of antidepressant research and development.What to know about ketamine .
Ketamine has not been approved for use as an antidepressant, but its active enantiomer, esketamine, has been. Esketamine was developed as a nasal spray for treatment-resistant depression and is approved for use in the United States. While there is evidence to support the effectiveness of ketamine in treating depression, there is a lack of consensus on optimal dosing and the effects and safety of long-term therapy. Ketamine can produce euphoria and dissociative hallucinogen effects at higher doses, and thus has an abuse potential. Moreover, ketamine has been associated with cognitive deficits, urotoxicity, hepatotoxicity, and other complications in some individuals with long-term use. These undesirable effects may serve to limit the use of ketamine for depression. Dozens of “ketamine clinics” have opened across the United States, where intravenous ketamine is used off-label to treat people with depression. What to know about ketamine .
The use of ketamine is cautioned against in cases of:
- Conditions worsened by an increase in blood pressure or heart rate, such as angina, stroke, poorly controlled high blood pressure. Ketamine increases both heart rate and blood pressure.
- Psychiatric disorders: Ketamine can cause hallucinations, and therefore may exacerbate the symptoms of certain psychiatric disorders.
- Ketamine was once thought to cause increased intracranial pressure (IICP): as of 2014, this is believed not to be the case.
- Raised intraocular pressure (IOP): Ketamine can further increase IOP.
- Penetrating eye injury: Can increase risk of loss of eye contents, due to increased IOP.
- Acute porphyria: Ketamine is considered porphyrinogenic, that is, it may provoke an attack of acute porphyria, a disease of the nervous system, in susceptible people.
Side effects What to know about ketamine .
When administered by trained medical professionals, ketamine is generally safe for those people who are critically ill. Even in these cases, there are known side effects that include one or more of the following:
- Cardiovascular: abnormal heart rhythms, slow heart rate or fast heart rate, high blood pressure or low blood pressure
- Central nervous system: Ketamine is traditionally avoided in people with or at risk of intracranial hypertension (ICP) due to concerns about ketamine causing increased intracranial pressure. It does not increase ICP more than opioids.
- Dermatologic: Transient reddening of the skin, transient measles-like rash
- Gastrointestinal: reduced appetite, nausea, increased salivation, vomiting
- Local: Pain, eruptions or rashes at the injection site
- Neuromuscular and skeletal: Increased skeletal muscle tone (tonic-clonic movements)
- Ocular: Double vision, increased intraocular pressure, involuntary eye movements, tunnel vision
- Respiratory: Airway obstruction, cessation of breathing, increased bronchial secretions, reduced effort to breathe, spasm of the vocal cords (larynx)
- Other: Anaphylaxis, dependence, emergence reaction
At anesthetic doses, 10–20% of people experience adverse reactions that occur during emergence from anesthesia, reactions that can manifest as seriously as hallucinations and delirium. These reactions may be less common in some subpopulations, and when administered intramuscularly, and can occur up to 24 hours postoperatively; the chance of this occurring can be reduced by minimizing stimulation to the person during recovery and pretreating with a benzodiazepine, alongside a lower dose of ketamine. People who experience severe reactions may require treatment with a small dose of a short- or ultrashort-acting barbiturate.
Effects of ketamine on Zebrafish development. Green areas indicate neurons, and increasing doses of ketamine reduced growth of neurons from the spinal cord.
In 1989, psychiatry professor John Olney reported ketamine caused irreversible changes, known as Olney’s lesions, in two small areas of the rat brain. However, the rat brain has significant differences in metabolism from the human brain; therefore such changes may not occur in humans.
The first large-scale, longitudinal study of ketamine users found current frequent (averaging 20 days/month) ketamine users had increased depression and impaired memory by several measures, including verbal, short-term memory, and visual memory. Current infrequent (averaging 3.25 days/month) ketamine users and former ketamine users were not found to differ from controls in memory, attention, and psychological well-being tests. This suggests the infrequent use of ketamine does not cause cognitive deficits, and that any deficits that might occur may be reversible when ketamine use is discontinued. However, abstinent, frequent, and infrequent users all scored higher than controls on a test of delusional symptoms.
Short-term exposure of cultures of GABAergic neurons to ketamine at high concentrations led to a significant loss of differentiated cells in one study, and noncell-death-inducing concentrations of ketamine (10 μg/ml) may still initiate long-term alterations of dendritic arbor in differentiated neurons. The same study also demonstrated chronic (>24 h) administration of ketamine at concentrations as low as 0.01 μg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal maintenance and development.
More recent studies of ketamine-induced neurotoxicity have focused on primates in an attempt to use a more accurate model than rodents. One such study administered daily ketamine doses consistent with typical recreational doses (1 mg/kg IV) to adolescent cynomolgus monkeys for varying periods of time. Decreased locomotor activity and indicators of increased cell death in the prefrontal cortex were detected in monkeys given daily injections for six months, but not those given daily injections for one month. A study conducted on rhesus monkeys found a 24-hour intravenous infusion of ketamine caused signs of brain damage in five-day-old but not 35-day-old animals.
Some neonatal experts do not recommend the use of ketamine as an anesthetic agent in human neonates because of the potential adverse effects it may have on the developing brain. These neurodegenerative changes in early development have been seen with other drugs that share the same mechanism of action of NMDA receptor antagonism as ketamine.
The acute effects of ketamine cause cognitive impairment, including reductions in vigilance, verbal fluency, short-term memory, and executive function, as well as schizophrenia-like perceptual changes.
A 2011 systematic review examined 110 reports of irritative urinary tract symptoms from ketamine recreational use. Urinary tract symptoms have been collectively referred as “ketamine-induced ulcerative cystitis” or “ketamine-induced vesicopathy”, and they include urge incontinence, decreased bladder compliance, decreased bladder volume, detrusor overactivity, and painful blood in urine. Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases. The pathogenesis of papillary necrosis has been investigated in mice, and mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence has been suggested as a possible mechanism.What to know about ketamine .
The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use correspond linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5 g/day reported symptoms of the lower urinary tract. Urinary tract symptoms appear to be most common in daily ketamine users who have used the drug recreationally for an extended period of time. These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.
Management of these symptoms primarily involves ketamine cessation, for which compliance is low. Other treatments have been used, including antibiotics, NSAIDs, steroids, anticholinergics, and cystodistension. Both hyaluronic acid instillation and combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some people, but in the latter case, it is unclear whether relief resulted from ketamine cessation, administration of pentosan polysulfate, or both. Further follow-up is required to fully assess the efficacy of these treatments.
In case reports of three people treated with esketamine for relief of chronic pain, liver enzyme abnormalities occurred following repeat treatment with ketamine infusions, with the liver enzyme values returning below the upper reference limit of normal range on cessation of the drug. The result suggests liver enzymes must be monitored during such treatment.
Radar plot showing relative physical harm, social harm, and dependence of ketamine
Ketamine’s potential for dependence has been established in various operant conditioning paradigms, including conditioned place preference and self-administration; further, rats demonstrate locomotor sensitization following repeated exposure to ketamine. Increased subjective feelings of ‘high’ have been observed in healthy human volunteers exposed to ketamine. Additionally, the rapid onset of effects following smoking, insufflation, and/or intramuscular injection is thought to increase the drug’s recreational use potential. The short duration of effects promotes bingeing; tolerance can develop; and withdrawal symptoms, including anxiety, shaking, and palpitations, may be present in some daily users following cessation of use.What to know about ketamine .
Ketamine can cause a variety of urinary tract problems that are more likely to occur with heavier and/or higher dosed use, especially in those not watching for a healthy lifestyle, according to a UK study.