What is Ketamine?

Ketamine is a dissociative anesthetic widely used by physicians and veterinarians in the United States. In addition to its anesthetic properties, ketamine also has a multitude of other psychological and pharmacological properties, which include analgesic, sedative, neuroprotective, anxiolytic, antidepressant, stimulant, euphoriant, and dissociative effects.

Ketamine belongs to the arylcyclohexylamines that were originally developed as anesthetics by Parke-Davis. Unlike all other anesthetic agents, the arylcyclohexylamines do not generally extinguish consciousness, but instead appear to “dissociate” mind from body (thus the name of “dissociative anesthetic”). The arylcyclohexylamines predominantly block the N-methyl-D-aspartate (NMDA) receptor, a target for the neurotransmitter glutamate in the brain, and prevent the NMDA receptor from being activated by glutamate. In addition to NMDA antagonism, the arylcyclohexylamines produce µ opioid receptor agonism and cause dopamine reuptake inhibition. Some of the arylcyclohexylamines also produce σ receptor agonistic, nACh receptor antagonistic and D2 receptor agonistic actions.

Antagonism of the NMDA receptor generates dissociative (hallucinogenic), anesthetic, neuroprotective and anticonvulsant effects; stimulation of the σ and D2 receptors contributes to hallucinogenic (psychomimetic) effects; activation of the μ-opioid receptor causes analgesic and anxiolytic effects; blockade of the dopamine transporter mediates stimulant and euphoriant effects (as well as adding to psychomimetic effects in higher doses); the combination of the two last qualities confers a strong antidepressant effect; and the combination of all the above pharmacological properties make the arylcyclohexylamines powerful psychedelic drugs.

Ketamine hydrochloride, a phencyclidine derivative, was originally invented in 1962 by the American organic chemist Calvin Stevens. Ketamine, like all the arylcyclohexylamines, predominantly targets the neurotransmitter glutamate, which is an excitatory messenger that turns on the brain cells and triggers an electrical impulse. Ketamine opposes this action by blocking the N-methyl-D-aspartate (NMDA) receptor. It prevents the NMDA receptor from being activated by glutamate. Ketamine also has direct and/or indirect effects on the mu opioid, dopamine, serotonin, acetylcholine, GABA, cannabinoid, nitric oxide and sigma systems.

Ketamine hydrochloride may be administered via a variety of routes including oral, sublingual, rectal, intranasal, intramuscular, and intravenous routes. Ketamine is a highly lipid soluble chemical and, as a result, its clinical effects present within 45 to 50 seconds of administration when given intravenously, within 3 to 4 minutes when given intramuscularly, within 5 to 10 minutes when given intranasally, and within 20 to 30 minutes when given orally. Ketamine use is usually devoid of life-threatening side-effects and several instances of unintentional administration of overdoses of ketamine of up to ten times that usually required for surgical anesthesia have been followed by prolonged but complete recovery.

Ketamine is on the World Health Organization’s list of essential medicines. More than 10,000 published reports describe ketamine’s high level of effectiveness and its confirmed biological safety in most cases, as it has a very low frequency of adverse effects in doses used for conscious sedation and analgesia. Clinical studies have generally detected no long-term impairment of behavior or personality functioning as a result of repeated ketamine use. Ketamine performs as a superior fast-acting analgesic and anxiolytic in low doses (0.2 – 0.3 mg/kg IV, 0.5 – 1 mg/kg IM and intranasal, and 1 – 2 mg/kg sublingual and oral), as an effective reliable sedative in medium doses (0.5 – 0.75 mg/kg IV, 1.5 – 4 mg/kg IM), and a safe short-acting anesthetic in high doses (1 – 4.5 mg/kg IV and 6.5 to 13 mg/kg IM). Ketamine has neuroprotective properties and, subsequently, it has been used as a neuroprotective agent to prevent brain damage from head trauma, strokes, heart attacks, epileptic seizures, low oxygen levels, and low blood-sugar levels.

Ketamine has been used in the USA since 1964 and, in 1970, the FDA approved the use of ketamine anesthesia with children, adults, and the elderly. Since that time, ketamine has been widely used in hospitals and for office procedures due to its rapid onset, short duration of action, and superior safety. Ketamine has now been in clinical practice for more than half a century and has been continually used as a usually very safe anesthetic to evoke general anesthesia, a first line agent to induce procedural conscious sedation, a potent non-opiate analgesic to control both acute and chronic pain, a unique neuroprotective agent to prevent brain damage, a superior anxiolytic to control preoperative and end-of-life anxiety, a rapid-onset antidepressant to treat chronic depression and other treatment-resistant psychiatric conditions, and the only legally-available (i.e., through a physician’s off-label prescription) hallucinogenic substance within the United States that can reliably produce mind-expanding experiences and be used to conduct psychedelic psychotherapy.

How does Ketamine work?

Ketamine is well-known to have both pharmacological effects on the human brain and psychological effects on the human mind.

Ketamine has several direct and indirect pharmacological effects on the human brain that may immediately relieve anxiety and improve the subject’s mood. These effects are multifactorial. In addition to affecting the glutamate system (similarly to alcohol), ketamine affects the dopamine system (similarly to Wellbutrin, Ritalin and Adderall), GABA system (similarly to Xanax, Ativan and Valium), serotonin system (similarly to Prozac, Celexa and Lexapro), mu opioid system (similarly to Hydrocodone, Oxycodone and Morphine), cannabinoid system (similarly to Cannabis, more commonly referred to as ), and nitric system (similarly to Nitrous Oxide, more commonly referred to as laughing gas). All of the above compounds have been shown to rapidly produce anti-anxiety and anti-depressant effects.

Ketamine also predictably generates very specific psychological effects, dubbed “dissociative states,” which are, in fact, non-ordinary states of consciousness (NOSOC) during which the individual’s awareness and perception are dramatically changed and radically refocused. There are four distinct ketamine-induced dissociative states that depend on three major factors (as is the case with all other classical psychedelic substances): the dose of ketamine, the physical “setting” of the ketamine administration, and the mindset (often just referred to as “set”) of the person prior to the ketamine administration. These different states of consciousness may be partly distinguished by: a) the degree of a dissociation of the mind from the body, and b) the degree of ego dissolution. All four NOSOC can be very transformative in some people and induce a resolution of the person’s psychological problems, addictive illnesses and personality disorders. These experiences can also generate a dramatic improvement in moral character and positive changes in spiritual development and worldview.

What are the features of ketamine-induced dissociative states?

State Features Typical Ketamine Dose Duration
Mild Dissociative State, or Empathogenic Experience Awareness of body; comfort and relaxation; reduced ego defenses; empathy, compassion, and warmth; love and peace; euphoria; mind is dreamy with non-specific colorful visual effects. Low sub-psychedelic dose similar to that used for anxiolysis and/or analgesia (0.25 mg/kg – 0.5 mg/kg IM, or 25 mg – 50 mg IM). 45 – 120 minutes
Moderate Dissociative State, or Out-of-Body Experience (OOBE) Complete separation from one’s body; significantly diminished ego defenses; visits to mythological realms of consciousness; encounters with non-terrestrial beings; emotionally intense visions (e.g., deceased relatives, spirits); vivid dreams of past and future incarnations; re-experiencing the birth process. Medium psychedelic dose such as that used for mild conscious dissociative sedation (0.75 mg/kg – 1.5 mg/kg IM, or 75 mg – 125 mg IM) 45 – 60 minutes
Strong Dissociative State, or Near-Death Experience (NDE) Departure from one’s body; complete ego dissolution/loss of identity; experience physical (body) and psychological (mind) death; experience being a single point of consciousness simply aware of itself; reliving one’s life; aware of how actions have affected others, with moral judgment of self. High psychedelic dose such as that used for moderate to severe conscious dissociative sedation (2.0 mg/kg – 3.0 mg/kg IM, or 150 – 250 mg IM) 45 – 60 minutes
Profound Dissociative State, or Ego-dissolving Transcendental Experience (EDT) Ecstatic state of the dissolution of boundaries between the self and external reality; complete dissolution of one’s body and self (soul); transcending normal mass/time/space continuum; collective consciousness; unity with Nature/Universe; sacredness. Rare in low doses (0.25 mg/kg – 0.5 mg/kg IM, or 25 – 50 mg IM), more common in high psychedelic doses (0.75 mg/kg – 2.0 mg/kg IM, or 75 – 200 mg IM) 45 – 60 minutes

What are the common side effects?

The most commonly reported side effects include blurred vision, double vision, jerky muscle movements, dizziness, drowsiness, nausea, vomiting and a temporary increase in blood pressure. These side effects occur following rapid intravenous administration of high doses of ketamine used for surgical anesthesia. When ketamine is administered in small doses that are used for pharmacotherapy of depression and anxiety, or in medium doses that are used for psychedelic psychotherapy of depression and anxiety, it has a very low frequency of adverse effects.

Is ketamine an addictive drug?

Ketamine is a very addictive drug, which generates very strong effects on mood (feelings), cognition (thinking), and perception (imagery) that make some people want to use it repeatedly. The 68th edition of the Physicians’ Desk Reference specifically warns physicians that prolonged use of ketamine may lead to tolerance and drug dependence.

Ketamine has been available to hospital staff since late 1960s and persons working in this context were among the first to personally test the drug’s empathogenic and psychedelic effects. The street use of ketamine solutions was first noted in San Francisco and Los Angeles circa 1971, while other forms of ketamine (powder and tablets) were first noticed on the street in 1974. Ketamine went under a variety of street names, including Special K and Vitamin K.

Ketamine was popularized during the 1970s by John Lilly and Marcia Moore, who wrote books on the subject of self-use of ketamine. Lilly published the book entitled The Scientist and Moore (together with her husband, Dr. Alltounian) published the book called Journeys into the Bright World. Both books documented the unusual phenomenology of ketamine intoxication and prompted others to experiment with ketamine. Subsequently, many ketamine users in the “first wave” preferred ketamine for its psychedelic properties and administered it via IM self-injections.

The ketamine scene began changing during the late 1980s – early 1990s when lower doses of ketamine, in pill and powder form for intransal use, became more prevalent due to its empathogenic and stimulant effects at lower doses. Ketamine began appearing on the club, underground party and raves scenes, being used together with or instead of “Ecstasy” (MDMA), cocaine, and amphetamine. By the mid-1990s, ketamine had entered mainstream dance culture and it remains a popular dance drug today.

Eventually, the U.S. Drug Enforcement Agency (DEA) became alarmed by this development and changed ketamine’s schedule in August of 1999, making it a controlled substance and moving the drug to Schedule III of the Controlled Substances Act of 1970. Other countries have also done so, most recently India which had been a major source for the European market.

The Russian government moved ketamine from Schedule III into Schedule II in 2002 after ketamine became popular with Muscovite teenagers. In 2005, Canada re-classified ketamine as a Schedule I narcotic. The United Kingdom has moved ketamine from Class C to Class B in June of 2014, and controls were also tightened in New Zealand.

Ketamine’s use as a recreational drug has been rising over the last 30 years. In 2005 Travis reported that ketamine was one of the six most common drugs for sale in United Kingdom cities. The 2006 National Survey on Drug Use and Health (NSDUH) reported that in the United States an estimated 2,300,000 persons aged 12 and older had used ketamine in their lifetime.

The medical literature has documented ketamine dependence and the number of case studies is mounting. The ketamine recurrent binges can be sustained for many days and even several weeks. The evidence from animal studies indicates that ketamine can form a dependence syndrome. The multiple problems related to dependence on ketamine, including education, relationships, employment, finances, and involvement in crime, have also been documented. Therefore, Ketamine should never be used except under the direct supervision of a licensed physician.

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