Ketamine Shows Promise in the Treatment of Depression

THE ESSENTIAL GUIDE TO

KETAMINE

(K, Ket, Special K, Vitamin K, Lady K)

 

(±)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
C13H16ClNO

TABLE OF CONTENTS

1. Overview | 2. History & Stats | 3. Pharmacology | 4. Effects | 5. Myths | 6. Therapeutic Use |
7. Personal Growth | 8. Legality | 9. FAQ | 10. Footnotes

 

Disclaimer: Ketamine is a potentially illegal substance, and we do not encourage or condone the use of this substance where it is against the law. However, we accept that illegal drug use occurs, and believe that offering responsible harm reduction information is imperative to keeping people safe. For that reason, this guide is designed to ensure the safety of those who decide to use the substance.

1. OVERVIEW

Ketamine is a general anesthetic with powerful dissociative and psychedelic effects. Although more widely used on animals since its development in the1960s, ketamine has long been used on humans as well—especially in patients with respiratory or circulatory problems. More recently, the drug has been hailed as a breakthrough therapy for depression.

Recreationally, ketamine is either insufflated (snorted) or injected. The drug is most famously associated with the ‘K-hole’ effect, a depersonalized state that many find therapeutic.

Despite its benefits, ketamine remains a controlled substance in the United States and many other countries.

2. HISTORY & STATS

Ketamine was developed in 1962 as an anesthetic to replace PCP (phencyclidine).[1] It was first synthesized by Calvin Stevens of Parke-Davis, Michigan—once the largest pharmaceutical company in the US. Initially known as CI-581, the drug was tested on human prisoners in 1964 and the term “dissociative anesthetic” was coined to describe its effects[2]

Recreational use began around 1965 and became internationally prevalent by the mid-1970s. During this period, psychedelic researchers such as John C. Lilly, Marcia Moore, Stanislav Grof, and D. M. Turner were exploring ketamine’s psychotherapeutic potential. It was also being used by Vietnam veterans with PTSD, having been the field anesthetic of choice during the war. Lilly referred to the drug as “Vitamin K” and once took it for 100 days straight[3]; Grof found it useful and integrative for therapy with LSD.[4]

In the 1980s, ketamine’s popularity shifted to the rave culture of Ibiza and Goa. It was often encountered as a cheaper alternative to another up-and-coming “club drug,” MDMA.

In 1981, the DEA filed a notice of intention to place ketamine in Schedule III of the Controlled Substances Act,, but evidence of actual abuse was too scarce to support the designation. In 1995, the drug was added to the agency’s “emerging drugs list” and finally labeled Schedule III in 1999, making it illegal to possess without a prescription. As a result, it was commonly stolen from hospitals or smuggled from overseas.[1]

CURRENT USAGE

In 2016, ketamine was among the top ten illicit drugs used worldwide, with a global past-year prevalence of 6.72% (compared with 11.75% for psilocybin and 12.89% for LSD).[5]

In 2006, people between the ages of 18 and 25 comprised the age group most likely to use ketamine in the US, at a rate comparable to PCP. An estimated 2.3 million people aged 12 or older had used ketamine at least once in their lifetimes, and around 203,000 had used it in the past year.[6] Between 2000 and 2011, the rate of ketamine use among US high school students steadily declined, never reaching more than 2.6%.[7]

Ketamine is reported to be around five times more prevalent in the UK[8], where 2013 statistics highlight a similar age bracket—20-24-year-olds—as the most likely group to use it. It has also been identified as one of the most likely drugs to be used in combination, with around 50% of UK users mixing it—often with alcohol.[9]

In China, one of the drug’s major manufacturing centers, ketamine has seen a dramatic rise in popularity. In part, this is due to its low production cost.[10]

3. PHARMACOLOGY

Ketamine is a water-soluble PCP derivative. As a chiral molecule, it has two enantiomers: an S(+) isomer, or “esketamine,” and an R(-) isomer, or “arketamine.”[11]

RECEPTOR BINDING

Ketamine antagonistically binds to, or blocks, NMDA (N-methyl-D-aspartate) receptors.[12]This interaction prevents signals passing between the brain and spinal column and is responsible for the molecule’s analgesic effect. Ketamine also interacts with opioid receptors and the monoamine, cholinergic, purinergic, and adrenoreceptor systems.[11]

SAFETY AND TOXICITY

Ketamine appears to be relatively safe for occasional users. However, frequent use carries the potential long-term risk of neurodegeneration. Prolonged intravenous exposure to the drug (over nine or 24 hours) has led to brain cell death in rhesus monkeys.[13] A similar effect has been seen in neonatal rats.[14] In the monkeys’ case, however, continual exposure to ketamine over a shorter period of three hours had no adverse effects. Likewise, frequent human users have been found to exhibit signs of cognitive impairment affecting thought and memory[15], while occasional users (i.e. those who take ketamine once or twice a month) have not.[16]

 Schizotypal symptoms, including delusions, superstitious thinking, dissociation, and flashbacks, have also been observed in frequent users. Symptoms may persist for some time after ketamine use ceases.[17][18]

Bladder pain is another common complaint among frequent users[19], often accompanied in the long term by reduced bladder volume, incontinence, passing blood in urine, and cystitis.[20]More research is needed to fully determine the relationship between ketamine and urological problems, but in some cases it has been necessary to surgically remove the bladder.[21]

In 2009, there were 529 ketamine-related emergency department visits in the US—compared to 36,719 for PCP and a total of 973,591 for any illicit drug.[22] Only 12 ketamine-related deaths were recorded worldwide between 1987 and 2000, and only three of these involved ketamine alone. The cause of death in each case was an overdose by injection.[23] More often, ketamine-related deaths are caused by interactions with other drugs, leading to respiratory depression and cardiac arrest.[24]

4. EFFECTS

Ketamine is active at 10-15 mg when insufflated or injected into a muscle, while more common doses range between 30 and 75 mg. Effects are usually felt within the first five minutes, but they may take up to 15 minutes after insufflation. Injection has a faster, more intense onset.

Ketamine may also be swallowed by mixing the powder with a little hot water and orange juice. The threshold oral dose is 40-50 mg, but 75-300 mg is more common.[25]

WHAT TO EXPECT

At lower doses, ketamine may cause numbness, a tingling body-high (especially in the hands, feet, and head), jerky movements, rapid breathing, and dizziness. These effects are often accompanied by euphoria, relaxation, a feeling of weightlessness, mild visuals, and blurred or roving vision. Users may also experience introspective thoughts and enhanced appreciation for music. At higher doses, visual, auditory, and even gustatory (taste-oriented) hallucinations are common, with some reporting a metallic flavor in the mouth. Hallucinations may be extremely realistic, including conversations with friends who aren’t there. [26][27][28]

At high-end “K-hole” doses, awareness of the physical environment and body dissolves. Out-of-body or near-death experiences are common, as are vivid internal realities and a distorted sense of time. The K-hole dosage is approximately 0.75 mg/lb injected or 1 mg/lb insufflated.

Some negative effects include paranoia, nausea, amnesia, and depersonalization—some of which may persist after frequent use.

PRECAUTIONS

A sitter is a good idea with ketamine, as it’s important to ensure a safe, comfortable environment. If alone, there should be no lit cigarettes or candles to be dropped or knocked over when bodily control is lost. Physical movement may become impossible, so it’s crucial not to take ketamine while driving, or anywhere near water. Numerous people have drowned in baths after losing physical control—including D. M. Turner[29] and John C. Lilly.[30]

Ketamine should also be taken on an empty stomach to avoid vomiting, which can lead to choking.[31]

5. MYTHS

“KETAMINE IS A CAT OR HORSE TRANQUILIZER AND NOT SUITABLE FOR HUMAN CONSUMPTION”

A common misrepresentation by the media, this myth gives the impression that ketamine use in humans is somehow deviant. But despite its wider use in veterinary medicine, ketamine was originally devised for and tested on humans.[1] Nowadays, it’s perhaps the most effective therapy for treatment-resistant depression, while remaining one of our most reliable anesthetics. In fact, it’s one of only two injected general anesthetics listed on the World Health Organization’s Model List of Essential Medicines—a core list of “the most efficacious, safe and cost-effective medicines for priority conditions.”[32]

6. THERAPEUTIC USE

Because it doesn’t disrupt breathing or circulation to the extent of traditional anesthetics, ketamine is well suited to patients with respiratory problems or heart disease. For the same reason it’s also useful when supplementary oxygen is scarce, making it ideal for the military.

Ketamine has been used, either topically or intravenously, to treat chronic pain like fibromyalgia and migraine (the latter of which John C. Lilly used the drug for). Since there’s no cross-tolerance between ketamine and opioids, it’s also given to patients who build up a tolerance to other anesthetics. The dissociative effects of ketamine make it especially useful for sedating patients after traumatic emergency procedures such as amputation.[11]

As an antidepressant, ketamine’s S-enantiomer, or “esketamine,” has twice been designated a “breakthrough therapy” by the FDA. In August 2016, it was fast-tracked for development as a viable medication.[33] One of its most promising features, and one that sets it apart from traditional antidepressants, is an extremely rapid onset. Depressive symptoms tend to improve within just 4-72 hours—a revolutionary improvement on the 6-12 week waiting period of other medications.[34]

While it doesn’t work for everyone, ketamine’s success rate of 85% is almost double that of traditional antidepressants (45%).[35] It’s also highly effective in patients with treatment-resistant depression, even if their symptoms have persisted for decades without relief.[36]Furthermore, it shows great promise in quickly and reliably eliminating suicidal thoughts, essentially making ketamine the first emergency “anti-suicide” drug.[37] When administered as an intranasal spray, ketamine’s antidepressant effects may last up to 30 days from a single dose.[38]

While some researchers hope for a non-hallucinogenic analogue to ketamine[39][40], others consider its unique psychedelic effects to be crucial for treatment. Ketamine psychedelic therapy (KPT), for instance, takes advantage of the highly suggestible dissociative state to address the underlying psychology of addiction. Specifically, Evgeny Krupitsky and others have been able to imprint drug addicts and alcoholics with new beliefs and memories about substance abuse, effectively creating a strong inner taboo to prevent relapse. One year after treatment, 66% of alcoholic KPT patients remained sober, while 69% of a non-KPT control group returned to drinking.[26]

Recent studies have linked this effect to ketamine’s antagonism of NMDA receptors, destabilizing and even erasing memories that reinforce drinking.[41][42]

KPT has also helped heroin addicts abstain following release from rehab. Those given regular KPT sessions were far less likely to use heroin again than those who received counseling alone.[43] Importantly, it’s the hallucinogenic doses that have the effect; sub-psychedelic doses of 0.2 mg/kg are found to be ineffective.[44]

Other psychotherapeutic applications of ketamine’s dissociative effect include regression, ego-dissolution, and group healing ceremonies.[4]

7. PERSONAL GROWTH

The “near-death experience,” or ego-dissolution, of ketamine can have profoundly transformative effects on an individual’s worldview. Concurrent with the neuroplasticity effect observed in animal and human studies, many have reported shifts in their awareness or perspective and the fading away of otherwise fixed habits and behaviors.[45]

John C. Lilly was enthusiastic about what he called the “emergent state” on ketamine, more commonly known as the “K-hole.” In this state, he said, time slows to the point of becoming meaningless; and events that shape one’s life, along with the causal relationships between them, become readily available for analysis. Dissociated from personal involvement, one may objectively examine one’s ego, behavior, and motivations. Lilly recommended experimentation with different personality traits, or self “programs” while in the emergent state. He advised “trying them on” to see their consequences before deciding to adopt them for good. He called this “metaprogramming.”[46]

Ketamine has also been found to increase compassion and sensitivity to others, reduce fear of death, and increase joy in living.[47]

8. LEGALITY

Ketamine was designated a Schedule III non-narcotic substance under the Federal Controlled Substances Act in August 1999.[48] This places it in the same category as anabolic steroids, immediate-acting barbiturates, and LSA (d-lysergic acid amide, or ergine).[49] It is illegal to possess ketamine in the US without a prescription[50] and first offenses may be subject to federal fines of up to $250,000 and/or three years in prison—although possession in small amounts for personal use is more likely to be prosecuted at the state level.

In the UK, ketamine is a Class B substance, the same category as cannabis, codeine, and most amphetamines. Possession is punishable by up to five years in prison.[51]

Ketamine is also illegal in Canada, Australia, and New Zealand. Most countries, including Brazil, restrict the drug to veterinary use, while others permit it for humans on prescription. Very few countries allow it to be sold over-the-counter.[52]

9. FAQ

CAN IT BE DETECTED IN A DRUG TEST?

Ketamine isn’t usually tested for, but it may be included in some extended screens. Because of its chemical similarities to PCP, it may also trigger a false positive. It’s usually detectable in urine for 2-4 days, but tests looking for ketamine specifically will detect norketamine (the major metabolite) in blood and urine for up to 14 days, or longer in frequent users.[53]

WILL KETAMINE MAKE ME CRAZY?

Frequent users may notice long-term cognitive impairments but occasional users tend not to. In any case, symptoms like perceptual distortion, memory loss, and delusional thinking are likely to fade over time. Nonetheless, it’s easy to feel “crazy” in the dissociative state itself. As with any psychedelic, set and setting are important.

ARE THERE RISKS?

While overdose fatalities are rare, there are certainly risks involved. As a general anesthetic, ketamine heavily impairs physical movement and people have been known drown or otherwise injure themselves as a result. Serious injuries may go unnoticed and therefore untreated because of the analgesic effect. Long-term health risks are associated with frequent use.

WHAT IS THE SAFEST WAY TO TAKE KETAMINE?

Some users prefer intramuscular injection because snorting can lead to blocked nostrils and watery eyes. Injection tends to be more intense, which is a plus for some users but a minus for others. Muscle pain is also common when injecting, especially with lower gauge needles. Intravenous injection is rare among recreational users, as is oral use, perhaps because of the unpleasant taste.

CAN I USE KETAMINE TO MICRODOSE?

A mood enhancement effect has been noticed, particularly among sufferers of depression, with sub-perceptual doses of up to 0.2 mg/kg. However, ketamine is not considered safe for microdosing at the same rate as LSD or psilocybin.

Further information on microdosing with ketamine can be found here.

DOES KETAMINE PRODUCE TOLERANCE?

Tolerance builds up slowly, often over a period of weeks with regular use. It can easily be habit-forming if it’s readily available. Although there’s no risk of physical addiction, it’s a good idea to set personal limits to avoid habituation.

CAN I MIX IT WITH OTHER DRUGS?

Ketamine should never be mixed with drugs that depress breathing. These include alcohol, GHB/GBL, opioids, and tramadol. Doing so increases the risk of unconsciousness and choking (e.g. on vomit). Benzodiazepenes, MAOIs, amphetamines, and cocaine are also risky in combination with ketamine. While the drug appears to be safe with LSD, MDMA, and cannabis, among others, combinations are generally advised against. Find out more here.

10. FOOTNOTES

[1] Jansen, K. L. R. (2001). A review of the non-medical use of ketamine: use, users and consequences. Journal of Psychoactive Drugs, 32(4), 419-33.

[2] Domino, E. F., Chodoff, P., Corssen, G. (1965). Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clinical Pharmacology & Therapeutics, 6, 279-91.

[3] Hooper, J. (1983). John Lilly: Altered States. Omni Magazine.

[4] Browne-Miller, A. (Ed.). (2009). The Praeger International Collection on Addictions. Westport, CT: Praeger Publishers.

[5] Global Drug Survey. (2016). What we learned from GDS2016: An overview of our key findings.

[6] SAMHSA. (2008). The NSDUH Report -Use of Specific Hallucinogens: 2006.

[7] The University of Michigan. (2011). Monitoring the Future.

[8] Daly, M. (2016). Why Do the British Love Ketamine So Much? Vice.

[9] ACMD. (2013). Ketamine: a review of use and harm.

[10] Hatton, C. (2015). The Ketamine Connection. BBC News.

[11] Kurdi, M. S., Theerth, K. A., Deva, R. S. (2014). Ketamine: Current applications in anesthesia, pain, and critical care. Anesthesia Essays and Researches, 8(3), 283-290.

[12] Mion, G., Villevieille, T. (2013). Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neuroscience & Therapeutics, 19(6), 370-80.

[13] Zou, X. et al. (2009). Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain. International Journal of Developmental Neuroscience, 27(7), 727-731.

[14] Yan, J., Huang, Y., Chen, J., Jiang, H. (2014). Repeated administration of ketamine can induce hippocampal neurodegeneration and long-term cognitive impairment via the ROS/HIF-1α pathway in developing rats. International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, 33(6), 1715-32.

[15] Morgan, C. J.,