Contaminated Time Your likely not as busy as you say you are, your just wasting time.

Contaminated Time           see Phil Zimbardo.......

You’re Not As Busy As You Say You Are

Also, by talking about it so much, you’re wasting time.

by Hanna Rosin for Slate

Are you too busy? You should be, and you should let people know in a proud but exasperated tone.

 Like this, from an old colleague I recently asked for advice: “I would like to help but I can not. I am desperately trying to finish a screenplay and a talk I need to give in Milan. Once I get an assistant I will be happy to help!” 

Or this, from the website of a researcher I know:  “I work roughly 100 hours a week and am getting more and more behind as the years go by. I am simply unable to keep up with demands on my time let alone handle more requests. I feel extremely guilty about this, but it’s important that I push folks away so that I can continue to produce research and do the work that I do.”

The Art of Busyness

Desperate and need to give a talk in Milan. Unable to keep up and do the work that I do. 

The art of busyness is to convey genuine alarm at the pace of your life and a helpless resignation, as if someone else is setting the clock, and yet simultaneously make it clear that you are completely on top of your game. These are not exactly humble brags. They are more like fretful brags, and they are increasingly becoming the idiom of our age. 

In her new book, Overwhelmed: Work, Love, and Play When No One Has the Time, Washington Post reporter Brigid Schulte calls this cultural epidemic the “overwhelm,” and it will be immediately recognizable to most working adults. 

“Always behind and always late, with one more thing and one more thing and one more thing to do before rushing out the door.”

 Muting the phone during a conference call so no one can hear soccer practice drills in the background, stepping over mounds of unfolded laundry, waking up in a 2 a.m. panic to run over the to-do list, and then summing up your life to your friends—in the two seconds you dedicate to seeing your friends—as “crazy all the time” while they nod in agreement.

To be deep in the overwhelm requires not just doing too many things in one 24-hour period but doing so many different kinds of things that they all blend into each other and a day has no sense of distinct phases.
Researchers call it “contaminated time,” and apparently women are more susceptible to it than men, because they have a harder time shutting down the tape that runs in their heads about what needs to get done that day.
The only relief from the time pressure comes from cordoning off genuine stretches of free or leisure time, creating a sense of what Schulte calls “time serenity” or “flow.” But over the years, time use diaries show that women have become terrible at that, squeezing out any free time and instead, as Schulte puts it, resorting to “crappy bits of leisure time confetti.”

So if the time squeeze is so miserable, why do people brag about it?
This is the curious thing about  this particular disease—and the first clue to recovery.

For her book, Schulte interviews Ann Burnett, who studies how the language we use creates our reality.
Since the 1960s Burnett has been collecting hundreds of holiday letters, which serve as an excellent anthropological record of how families choose to present themselves. Burnett chronicles the rise of certain words and phrases—“hectic,” “whirlwind,” “consumed,” “crazy,” “hard to keep up with it all,” “on the run,” “way too fast.” Lately the cards have entered the meta-busy phase, where the busyness infects the style of the card itself.

 Like this one Burnett received recently:

I’m not sure whether writing a Christmas letter when I’m working at the speed of light is a good idea, but given the amount of time I have to devote to any single project, it’s the only choice I have, We start every day at 4:45 AM, launch ourselves through the day at breakneck speed (the experience is much like sticking your head in a blender), only to land in a crumpled heap at 8:30 PM, looking something like the Halloween witches impaled spread-eagled on front doors, wondering how we made it through the day.

It was after this letter that Burnett realized that busyness of a certain kind—meaning not the work-three-menial-jobs-and-put-your-kids-in-precarious-day-care-by-necessity kind—became a mark of social status, that somewhere in the drudgery of checklists and the crumpled heaps one could detect a hint of glamour.
“My God, people are competing about being busy,” Burnett realized.
“It’s about showing status.
That if you’re busy, you’re important. You’re leading a full and worthy life. … As if you don’t get to choose, busyness is just there.
I call it the nonchoice choice. Because people really do have a choice.”

Do people really have a choice? At some point in her journey through time, Schulte attaches herself to John Robinson, a sociologist known as Father Time because he was one of the first people to start collecting time use diaries, which became the basis for the American Time Use Surveys that tell us so much about how we live.

Although she doesn’t say it outright, Schulte seems suspicious of Robinson, and probably for good reason. He is divorced and lives alone and thus is free to spend his time however he wants. (He often just gets on the metro with an entertainment guide in his hand and no particular aim.) But Robinson seemed to me to have come up with the most convincing antidote to the “overwhelm.”

Robinson doesn’t ask us to meditate, or take more vacations, or breathe, or walk in nature, or do anything that will invariably feel like just another item on the to-do list. The answer to feeling oppressively busy, he says, is to stop telling yourself that you’re oppressively busy, because the truth is that we are all much less busy than we think we are.
And our consistent insistence that we are busy has created a host of personal and social ills which Schulte reports on in great detail in her book—unnecessary stress, exhaustion, bad decision-making, and, on a bigger level, a conviction that the ideal worker is one who is available at all times because he or she is grateful to be “busy,” and that we should all aspire to the insane schedules of a Silicon Valley entrepreneur.

“It’s very popular, the feeling that there are too many things going on, that people can’t get in control of their lives and the like,” Robinson says. “But when we look at peoples’ diaries there just doesn’t seem to be the evidence to back it up … It’s a paradox. When you tell people they have thirty or forty hours of free time every week, they don’t want to believe it.”

Busyness is a virtue, so people are terrified of hearing they may have empty time, as Tim Kreider wrote in “The ‘Busy’ Trap.”*
It’s the equivalent of being told that you’re redundant or obsolete. Robinson has Schulte keep a time use diary and shows her lots of free time she hadn’t counted as such—lying in bed aimlessly, exercising, playing backgammon on her computer, talking to a friend on the phone. Yet she still doesn’t believe that, as a working mother, she could possibly have any leisure time. In fact, she seems skeptical of Robinson’s whole premise that we are busy because we say we are.

As it happens, the day I had to write this review had all the ingredients for contaminated time.

 I had to record a podcast, hire an au pair because our nanny of 13 years is leaving, figure out what to do with a kid who had a half-day of school, let in the repairman coming to fix the washing machine, comfort a friend freaking out about her ailing mother, do pre-interviews for a TV appearance, fly to New York for the media interviews, see my parents, have drinks with a fellow editor, go to a hotel. (I skipped a long-scheduled doctor’s appointment.) And I am not even counting the normal stuff—email, work, breakfast, getting kids to school, checking on them in the afternoon.

All day, I tried to convince myself that I wasn’t that busy. The way I did this was by silently repeating, “You’re not that busy.” Doing this did actually stop the tape in my head of what had to get done that day.
 I just calmly did one thing after another. I believe that means I was being mindful, or maybe living in the moment or being present but I’m not sure. And I am not going to check because if I give it a name, then it will be just one more thing you feel obligated to do.

Instead just take one thing off your to-do list, which is telling everyone how busy you are.

Correction, March 24, 2014: This article previously misspelled the first name of author Tim Kreider.
Hanna Rosin is the founder of DoubleX and a writer for theAtlantic. She is also the author of The End of Men. Follow her on Twitter.

This article originally appeared in Slate.com.

Why Readers, Scientifically, Are The Best People To Fall In Love With

Why Readers, Scientifically, Are The Best People To Fall In Love With

Life • Lauren Martin • Jul 9, 2014 - 1:59pm

Like Us On Facebook  ( editors note, please don't use facebook)

 

Ever finished a book? I mean, truly finished one? Cover to cover. Closed the spine with that slow awakening that comes with reentering consciousness?

You take a breath, deep from the bottom of your lungs and sit there. Book in both hands, your head staring down at the cover, back page or wall in front of you.

You’re grateful, thoughtful, pensive. You feel like a piece of you was just gained and lost. You’ve just experienced something deep, something intimate. (Maybe, erotic?) You just had an intense and somewhat transient metamorphosis.

Like falling in love with a stranger you will never see again, you ache with the yearning and sadness of an ended affair, but at the same time, feel satisfied. Full from the experience, the connection, the richness that comes after digesting another soul. You feel fed, if only for a little while.

This type of reading, according to TIME magazine’s Annie Murphy Paul, is called “deep reading,” a practise that is soon to be extinct now that people are skimming more and reading less.

Readers, like voice mail leavers and card writers, are now a dying breed, their numbers decreasing with every GIF list and on line tabloid.

The worst part about this looming extinction is that readers are proven to be nicer and smarter than the average human, and maybe the only people worth falling in love with on this shallow hell on earth.

According to both 2006 and 2009 studies published by Raymond Mar, a psychologist at York University in Canada, and Keith Oatley, a professor of cognitive psychology at the University of Toronto, those who read fiction are capable of the most empathy and “theory of mind,” which is the ability to hold opinions, beliefs and interests apart from their own.
They can entertain other ideas, without rejecting them and still retain their own. While this is supposed to be an innate trait in all humans, it requires varying levels of social experiences to bring into fruition and probably the reason your last partner was such a narcissist.

Did you ever see your ex with a book? Did you ever talk about books? If you didn’t, maybe you should think about changing your type.

It’s no surprise that readers are better people. Having experienced someone else’s life through abstract eyes, they’ve learned what it’s like to leave their bodies and see the world through other frames of reference.

They have access to hundreds of souls, and the collected wisdom of all them. They have seen things you’ll never understand and have experienced deaths of people you’ll never know.

They’ve learned what it’s like to be a woman, and a man. They know what it’s like to watch someone suffer. They are wise beyond their years.

Another 2010 study by Mar reinforces this idea with results that prove the more stories children have read to them, the keener their “theory of mind.” So while everyone thinks their kids are the best, the ones who read have the edge as they truly are the wiser, more adaptable and understanding children.

Because reading is something that molds you and adds to your character. Each triumph, lesson and pivotal moment of the protagonist becomes your own.

Every ache, pain and harsh truth becomes yours to bear. You’ve travelled with authors and experienced the pain, sorrow and anguish they suffered while writing through it. You’ve lived a thousand lives and come back to learn from each of them.

If you’re still looking for someone to complete you, to fill the void of your singly-healed heart, look for the breed that’s dying out. You will find them in coffee shops, parks and subways.

You will see them with backpacks, shoulder bags and suitcases. They will be inquisitive and soulful, and you will know by the first few minutes of talking to them.

They Won’t Talk To You… They’ll Speak To ( with )You

They will write you letters and texts in verse. They are verbose, but not in the obnoxious way. They do not merely answer questions and give statements, but counter with deep thoughts and profound theories. They will enrapture you with their knowledge of words and ideas.

According to the study, “What Reading Does For The Mind” by Anne E. Cunningham of the University of California, Berkeley, reading provides a vocabulary lesson that children could never attain by schooling.

According to Cunningham, “the bulk of vocabulary growth during a child’s lifetime occurs indirectly through language exposure rather than through direct teaching.”

Do yourself a favor and date someone who really knows how to use their tongue.

See: New From The Health Sciences Lab

---

They Don’t Just Get You… They Understand You

You should only fall in love with someone who can see your soul. It should be someone who has reached inside you and holds those innermost parts of you no one could find before. It should be someone who doesn’t just know you, but wholly and completely understands you.
According to Psychologist David Comer Kidd, at the New School for Social Research, “What great writers do is to turn you into the writer. In literary fiction, the incompleteness of the characters turns your mind to trying to understand the minds of others.”

This is proved? over and over again, the more people take to reading. Their ability to connect with characters they haven’t met makes their understanding of the people around them much easier.

They have the capacity for empathy. They may not always agree with you, but they will try to see things from your point of view.

---

They’re Not Just Smart… They’re Wise

Being overly smart is obnoxious, being wise is a turn on. There’s something irresistible about someone you can learn from. The need for banter and witty conversation is more imperative than you may believe, and falling in love with a reader will enhance not just the conversation, but the level of it.

According to Cunningham, readers are more intelligent, due to their increased vocabulary and memory skills, along with their ability to spot patterns. They have higher cognitive functions than the average non-reader and can communicate more thoroughly and effectively.

Finding someone who reads is like dating a thousand souls. It’s gaining the experience they’ve gained from everything they’ve ever read and the wisdom that comes with those experiences. It’s like dating a professor, a romantic and an explorer.

If you date someone who reads, then you, too, will live a thousand different lives.
Photo Courtesy: We Heart It

Growing Doubt on Statin Drugs: The Problem of Drug-Lifestyle Interaction

Growing Doubt on Statin Drugs: The Problem of Drug-Lifestyle Interaction

 Medscape June 2014

 John Mandrola

 My mind is changing about statins. I'm growing increasingly worried about the irrational exuberance over these drugs, especially when used for prevention of heart disease that is yet to happen.

 An elderly patient called my office last week to tell me thank you . . . not for a successful procedure or surgery, but rather for helping with a problem that had dogged her for a decade. 

How did an electrophysiologist help a patient without doing a procedure? 

I stopped her statin. A few weeks later, the patient said, her muscle and joint pain were gone. "I thought it was arthritis. I'm walking now. I haven't felt this good in years. I've even lost five pounds." 

So why was this elderly patient on a statin?

 It was being used to lower cholesterol in the hopes that it would lower the risk of a future heart attack or stroke. This is called primary prevention. The patient had no vascular disease but had a high cholesterol level. The problem, of course, is that statins have not been well-studied in elderly women. Her doctor and the medical establishment writ large have extrapolated findings of clinical trials on younger, mostly male, patients to all patients with high cholesterol levels. This is a striking jump to make, given that low cholesterol levels in the elderly are associated with higher death rates. 

Anecdotes are not evidence, but this one moved me to review some of the statin evidence. And to think (again) about treating people vs disease. As always, let's start with the truth — absolute, not relative values. Then I will move on to some new revelations about statins, and then an interesting theory of why potent cholesterol-lowering drugs have such painfully small effects on overall cardiovascular outcomes. 

The Truths 

When statins are used in low-risk patients without heart disease (primary prevention) there is no mortality benefit.

 That's right. Your chances of dying are the same on or off the drug, regardless of how much the statin lowers the cholesterol level.

 When statins are used for primary prevention, there is a small lowering of future vascular events (stroke/heart attack) over five to 10 years.

 The absolute risk reduction is in the range of seven per 1000. That means you have to treat 140 patients with a statin (for five years) to prevent one event. Or this: for 99.3% of statin-treated patients, there is no benefit. I like to call this the PSR, or percent same result. 

There is also general agreement that statins increase the risk of developing diabetes, especially in women, and that risk is about the same as preventing a stroke or heart attack, approximately 1%.

 Another fact is that patient-level (raw) data from the industry-sponsored cholesterol trials have not been independently analyzed.

 Systematic reviews from the Cochrane group have analyzed only published data rather than the raw data. There is likely a difference [1]. 

There is great debate about the incidence of statin side effects, such as muscle pain, cognitive issues, decreased energy, sexual problems, and kidney and liver injury, among others. 

In the industry-sponsored randomized controlled clinical trials, discontinuation of statins was not significantly different from placebo.

 Observational data and the observations of any clinician provide a different picture[2]. New Revelations 

Individuals prescribed statin therapy consumed more calories and more fat than nonstatin users.

A study presented in April 2014 at the Society of General Internal Medicine meeting in San Diego showed that individuals prescribed statin therapy for high cholesterol consumed more calories and more fat than nonstatin users. And, not surprisingly, this increase in calories paralleled an increase in BMI in statin users. 

An analysis of a prospective cohort study of men (published in JAMA Internal Medicine) revealed that physical-activity levels were "modestly" lower among statin users compared with nonusers independent of other cardiac medications and of medical history.

Possible Connecting Theory: Drug-Lifestyle Interaction 

 

 These two recent studies are troublesome.

 As pointed out in the excellent coverage from heartwire journalist Michael O'Riordan, there may be an interaction between medication and lifestyle. 

Namely, if statin users consume more calories, gain weight, and exercise less, it becomes easy to see why cardiovascular benefits are so small. 

It's been really hard to explain why the striking reductions in LDL cholesterol—up to 30% to 50%—from statins haven't translated into significant future benefit. 

One possibility is that cholesterol levels are a lousy surrogate for outcomes. 

That surely seems true in the elderly, but what about in younger patients and those with familial high cholesterol? These patients are definitely at increased cardiovascular risk. So cholesterol levels are surely not unimportant. 

There are convincing data, for instance, that higher HDL levels are associated with lower CV risk. 
Another possibility for lack of statin benefit is analogous to AF rhythm control and high blood-pressure issues. 

As in, yes, it's better to be in regular sinus rhythm and have normal blood pressure, but getting to those goals with pills isn't the same as being there naturally. 

With rhythm-control and blood-pressure drugs, the achievement of the desired outcome is muted by side effects from the drugs. 

Perhaps it's the same with statin drugs? 

You don't have to posit malfeasance on the part of big pharma here.

 All you have to do is think past the disease-specific mind-set of modern-day medicine. 
We are much more than our cholesterol level.

 A statin drug, like so many drugs that block enzyme pathways far upstream in major cellular pathways, is going to have much more biologic action than just moving an easily measured cholesterol level. 

When you step back and look at medications as chemical modifiers of cellular processes in complex biologic systems like our body, it's easy to understand that health comes not from pills. 

Not even statins. 

Related Links 
• Reduced Activity Raises Cautions in Older Men Using Statins 
• Statin Users Eating More, Gaining Weight, Study Shows 

Heartwire

Reduced Activity Raises Cautions in Older Men Using Statins

Steve Stiles

June 10, 2014

 

 

CHICAGO, IL — Physical-activity levels were "modestly" lower among statin users compared with nonusers independently of other cardiac medications and of medical history, but activity wasn't further inhibited over time, in a prospective community-based cohort of men aged >65 followed for about seven years^[1].

Whereas activity levels declined similarly in prevalent statin users and statin nonusers, "new statin use was associated with a more rapid decline in physical activity than nonuse," according to the authors of the new analysis, led by Dr David SH Lee (Oregon State University, Portland).

The observational study suggests that in men like those in the cohort, "statins are associated with less physical activity for as long as statins are used." It wasn't possible to discern a cause-and-effect relationship, but "possible reasons for lower physical-activity levels in statin users may be general muscle pain caused by statins (a well-known adverse effect), exercise-endured myopathy, or muscular fatigue."

The group's report, based on participants in the Osteoporotic Fractures in Men Study (MrOS) enrolling from 2000 to 2002, was published June 9, 2014 in JAMA Internal Medicine.

The men self-reported activity levels at baseline and at two follow-up visits using the Physical Activity Scale for the Elderly (PASE). The second follow-up also included accelerometer-based measurements of metabolic equivalents (METs) and minutes of moderate activity, vigorous activity, or sedentary behavior.

Among the 4137 persons in the baseline analysis, 24% were statin users and 76% were statin nonusers. Statin users scored a mean of 5.8 points lower than nonusers (p=0.03) on the PASE assessment controlled for age, clinical site, MI, stroke, hypertension, diabetes, perceived health, body-mass index, and total-cholesterol levels.

Of the 3039 patients in the longitudinal analyses, 24% were already on statins, 48% did not take statins, and 28% initiated statins during follow-up. PASE scores fell an average of 2.5 per year in statin nonusers and 2.8 per year for the prevalent users, not a significant difference. They dropped a significant 0.9 points further for new users than for nonusers, according to the group. However, the overall adjusted difference in PASE score changes across the three groups wasn't significant (p=0.07).

Of note, statin users achieved a mean of 0.03 kcal/kg/h fewer METS (p<0.001), engaged in significantly less moderate and vigorous activity, and were more often sedentary compared with nonusers.

Statin User-to-Nonuser Ratios for Three Median Physical-Activity Levels* (minutes per day) by Accelerometer in an MrOS Cohort
 

Activity Level	Ratio	p
Moderate physical activity	0.91	0.003
Vigorous physical activity	0.92	0.01
Sedentary behavior	1.006	0.003

 

*Controlled for clinical site and season of the year, age, body-mass index, beta-blockers, ACE inhibitors or angiotensin-receptor blockers, total cholesterol, MI, stroke, hypertension, diabetes, and perceived health

 

The group proposed "two possible reasons" that prevalent statin use didn't seem to cause a more rapid fall in physical activity, as hypothesized: those most susceptible to muscle symptoms may have stopped their use during the study, or they may have gone off the drugs after a decline in health, they write. Indeed, 11% of statin users had gone off the drugs before the second follow-up visit.

"Some might imagine that reduced activity in new statin users should be managed by urging statin users to exercise more, but this approach is not without hazard," writes Dr Beatrice Alexandra Golomb (University of California San Diego, La Jolla) in an accompanying editorial^[2]. "Statins compromise muscle in part by marring cell energy (by mitochondrial and oxidative mechanisms). Adding exercise aggravates risk of energy shortfall relative to demand."

Activity and fitness have salutary effects on overall health, including but not limited to cardiovascular, metabolic, cognitive, functional, sleep-related, and healing-related benefits, she notes. In this light, statin-related activity reduction is "a reminder that all medications bear risks, and prescribing them involves trade-offs. When considering statin use in a given patient, effects on function and the spectrum of outcomes, not merely cause-specific ones, should be considered."

Golomb also pointed out that the current analysis is limited in not including women, "who have shown more statin-related muscle problems compared with men," and people with metabolic syndrome "or other risk factors for statin-related muscle problems."

The analysis was funded by a grant from the Medical Research Foundation of Oregon; neither Lee nor the other authors had disclosures, nor did Golomb.

Vitamin K; A Manic Depression Reset and Pain Modifier ?

 Ketamine; A Manic Depression Reset and Pain Modifier ?

From Wikipedia, the free encyclopedia and Medscape

Systematic (IUPAC) name
(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
Clinical data
AHFS/Drugs.com	Consumer Drug Information
Licence data	US FDA:link
Pregnancy cat.	B3 (AU) C (US)
Legal status	Controlled (S8) (AU) Schedule I (CA) CD (UK) Schedule III (US)
Dependence liability	Moderate
Routes	IV, IM, Insufflated, oral, topical
Pharmacokinetic data
Metabolism	Hepatic, primarily by CYP3A4[1]
Half-life	2.5–3 hours
Excretion	renal (>90%)

Ketamine is a drug used in human and veterinary medicine, mainly for starting and maintaining general anesthesia. Other uses include sedation in intensive care, as a pain killer (particularly in emergency medicine and patients with potentially compromised respiration and/or allergies to opiate and barbiturate analgesics), and treatment of bronchospasm. This drug is sometimes used recreationally.
 Like other drugs in its class , ketamine is classified as a dissociative agent.^[2] The state it induces is defined as "a trancelike cataleptic state characterized by profound analgesia and amnesia, with retention of protective airway reflexes, spontaneous respirations, and cardiopulmonary stability".^[3] 
Studies have shown that respiratory function is unchanged with the administration of ketamine.^[4] Though its impact on respiratory function is favorable, ketamine can still cause adverse effects which will be discussed below.
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a health system.^[6]

Ketamine tends to increase heart rate and blood pressure. Because it tends to increase or maintain cardiac output, it is sometimes used in anesthesia for emergency surgery when the patient's fluid volume status is unknown (e.g., from traffic accidents). Ketamine can be used in podiatry and other minor surgery, and occasionally for the treatment of migraine. Research is ongoing in France, the Netherlands, Russia, Australia and the US into the drug's usefulness in pain therapy, depression,^[13] and for the treatment of alcoholism^[14] and heroin addiction.^[15]
Ketamine may be used in small doses as a local anesthetic, particularly for the treatment of pain associated with movement and neuropathic pain.^[16] 

It may also be used as an intravenous coanalgesic with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic (pain due to vascular insufficiency or shingles are good examples). 
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.^[17] 
Ketamine is a coanalgesic, so is most effective when used alongside a low-dose opioid; while it does have analgesic effects by itself, the higher doses required can cause disorienting side effects.^[17] 
The combination of ketamine with an opioid may be useful for pain caused by cancer, as suggested in animal models.^[18] A review article in 2013 concluded that "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".^[19]

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.^[20] It is sometimes possible to perform ketamine anesthesia without protective measures to the airways. Ketamine is also a potent analgesic and can be used in subanesthetic doses to relieve acute pain; however, its psychotropic properties must be taken into account. Patients have reported vivid hallucinations, "going into other worlds" or "seeing God" while anesthetized, and these unwanted psychological side effects have reduced the use of ketamine in human medicine. They can, however, usually be avoided by concomitant application of a sedative such as a benzodiazepine.^[17]

Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS).^[21] Although low-dose ketamine therapy is established as a generally safe procedure, reported side effects in some patients have included hallucinations, dizziness, lightheadedness and nausea. Therefore, nurses administering ketamine to patients with CRPS should do so only in a setting where a trained physician is available if needed to assess potential adverse effects on patients.^[22]

In some neurological intensive care units, ketamine has been used in cases of prolonged seizures. Some evidence indicates the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.<sup>[23]

Pain Relieving Compounds</sup>

As part of a cream, gel, or liquid (only available from compounding pharmacies as it is not a branded product, specific formulation and ratios are specified by the prescribing physician) for topical application for nerve pain — the most common mixture is 10% ketoprofen, 5% lidocaine, and 10% ketamine.^{[citation needed]} 

Other ingredients found useful by pain specialists and their patients, as well as the compounding pharmacists who make the topical mixtures, include amitriptyline, cyclobenzaprine, clonidine, tramadol, gabapentin, baclofen, and mepivacaine and other longer-acting local anaesthetics (e.g. tetracaine, procaine).

Ketamine is a "core" medicine in the World Health Organization's "Essential Drugs List", a list of minimum medical needs for a basic healthcare system.^[24]

Pain

The dissociative anesthetic effects of ketamine have also been applied for postoperative pain management. Low doses of ketamine have been found to significantly reduce morphine consumption, as well as reports of nausea following abdominal surgery.^[25]

Oral ketamine

Ketamine can be started using the oral route, or people may be changed from a subcutaneous infusion once pain is controlled. Bioavailability of oral ketamine hydrochloride is approximately 20%

Converting from a 24-hour subcutaneous ketamine infusion to oral ketamine

• Oral ketamine is easily broken down by bile acids and thus has a low bioavailability (~20%). Oftentimes lozenges or "gummies" for sublingual or buccal absorption prepared by a compounding pharmacy are used to combat this issue.
• Some specialists stop the subcutaneous infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.^[26]

Recreational use

Main article: Recreational use of ketamine

Ketamine poured onto glass and left to dry.

Unlike the other well-known dissociatives PCP and DXM, ketamine is very short-acting. It takes effect within approximately 10 minutes,^[27] while its hallucinatory effects last 60 minutes when insufflated or injected and up to two hours when ingested orally. The total experience lasts no more than a few hours.^[28]

At subanesthetic doses, ketamine produces a dissociative state, characterised by a sense of detachment from one's physical body and the external world which is known as depersonalization and derealization.^[29] At sufficiently high doses, users may experience what is called the "K-hole", a state of extreme dissociation with visual and auditory hallucinations.^[30] 
John C. Lilly,^[31] Marcia Moore^[32] and D. M. Turner^[33] (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with, ketamine. Both Moore and Turner died prematurely in a way that has been indirectly linked to the sedative properties of ketamine.^[34]

Side effects

These include:^[35]

• Cardiovascular: Arrythmias, bradycardia or tachycardia, hyper or hypotension
• Central nervous system: Increased intracranial pressure
• Dermatologic: Transient erythema, transient morbilliform rash
• Gastrointestinal: Anorexia, nausea, increased salivation, vomiting
• Local: Pain or exanthema of the injection site
• Neuromuscular & skeletal: Increased skeletal muscle tone (tonic-clonic movements)
• Ocular: Diplopia, increased intraocular pressure, nystagmus
• Respiratory: Airway obstruction, apnea, increased bronchial secretions, respiratory depression, laryngospasm
• Other: Anaphylaxis, dependence, emergence reaction

Emergence reactions manifest as vivid dreams, hallucinations, and delirium and occur in 12 percent of patients. These reactions are much less common in patients less than 15 years old and greater than 65 years old and when administered intramuscularly. 
Emergence reactions can occur up to 24 hours postoperatively. The chance of this occurring can be reduced by minimizing stimulation to the patient during recovery and pretreating with a benzodiazepine. If given a benzodiazepine, a lower dose of ketamine than normal should be given. Patients who experience severe reactions may require treatment with a small dose of a short or ultra-short acting barbiturate.^[35]

Tonic-clonic movements are reported at higher anesthetic doses in greater than 10% of patients.^[36]

As discussed below, current research suggests that acute ketamine exposure does not cause significant neurotoxicity.

Long term

Because ketamine is not administered chronically in a typical clinical setting, long-term effects are primarily reported and investigated in recreational ketamine users and in animal models.^[37]

Neurological effects

In 1989, psychiatry professor John Olney reported ketamine caused irreversible changes in two small areas of the rat brain, which, however, has significant differences in metabolism from the human brain, so may not occur in humans.^{[38][39][40][41]} 

Indeed, a review published in 2009 found no evidence of ketamine-induced neuron death in humans.^[42]

The first large-scale, longitudinal study of ketamine users found that current frequent ketamine users (at least 4 days/week, averaging 20 days/month) had increased depression and impaired memory by several measures, including verbal, short-term memory and visual memory. However, current infrequent (1–4 days/month, 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.^[43]

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 non-cell-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.^[44][45]
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.^[46] 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.^[46] A study conducted on rhesus monkeys found that a 24-hour intravenous infusion of ketamine caused signs of brain damage in 5-day-old but not 35-day-old animals.^[47] Some neonatal experts do not recommend the use of ketamine as an anesthetic agent in human neonates because of the potential adverse effects that 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.^[48]

The acute effects of ketamine cause cognitive impairment including reduced vigilance, verbal fluency, short-term memory, and executive function, as well as schizophrenia-like perceptual changes.^[49]

Urinary tract effects

According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist.^[50] 
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 haematuria (blood in urine).
 Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases.^[37][50] 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.^[51]

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 corresponds linearly to the presentation of these symptoms.
 All reported cases where the user consumed greater than 5 grams per day reported symptoms of the lower urinary tract.^[50] Urinary tract symptoms appear to be most common in daily ketamine abusers who have abused the drug for an extended period of time.^[37] These symptoms have presented in only one case of medical use of ketamine. 
However, following dose reduction, the symptoms remitted.^[37]

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.^[50] Both hyaluronic acid instillation and combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some patients, 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.^[50]

Case reports of hepatotoxicity in chronic pain management

In case reports of three patients treated with (S)-(+)-ketamine 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.^[52]

Interactions

Other drugs which increase blood pressure may interact with ketamine in having an additive effect on blood pressure including: stimulants, SNRI anti-depressants, MAOIs. Increase blood pressure, increased heart rate, palpitations and arrhythmias may be potential effects. 


Ketamine alone additionally increases intracranial pressure (ICP)

Ketamine may increase the effects of other sedatives, including but not limited to: benzodiazepines, barbiturates, opiates/opioids, anesthetics, and alcoholic beverages.^{[citation needed]}

Mechanism of action

Central nervous system

Ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist. 
It appears to inhibit the receptor by binding both in the open channel and at an allosteric site.^[53] The S(+) and R(-) stereoisomers bind with different affinities: K_i = 3200 and 1100 nM, respectively.^[54] NMDAR antagonism results in analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamine's actions interfere with pain transmission in the spinal cord.^[36] 

Ketamine also inhibits nitric oxide synthase, inhibiting production of nitric oxide, a neurotransmitter involved in pain perception, and hence further contributing to analgesia.^[55] It also interacts with sigma and opioid receptors, but with lower affinity and without significantly contributing to analgesia.^[56]

Ketamine also interacts with a host of other receptors to effect analgesia. 
It blocks voltage-sensitive calcium channels and depresses sodium channels, attenuating hyperalgesia; it alters cholinergic neurotransmission, which is implicated in pain mechanisms; and it acts as a noradrenaline and serotonin uptake inhibitor, which are involved in descending antinociceptive pathways.^[36][57]

Peripheral systems

Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:^[55]

• Cardiovascular: Ketamine inhibits reuptake of catecholamines, stimulating the sympathetic nervous system, resulting in cardiovascular symptoms.
• Gastrointestinal: Inhibition of neuronal uptake and increased serotonergic activity are thought to underly nausea and vomiting.
• Respiratory: Induced catecholamine release and stimulation of β₂ adrenergic receptors causes bronchodilation.

• 

Chemical structure

Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in their enantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S.^[58]

Pharmacology

Pharmacokinetics

Ketamine is absorbable via intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubilities.^[59] 

 When administered orally, it undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) isoenzymes into norketamine (through N-demethylation) and finally dehydronorketamine.^[60] Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into 5-hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine.^[61] As the major metabolite of ketamine, norketamine is one-third to one-fifth as potent anesthetically, and plasma levels of this metabolite are three times higher than ketamine following oral administration.^[59][62] 

 Bioavailability through the oral route reaches 17–20%; bioavailability through other routes are as follows: 93% intramuscularly, 25–50% intranasally, 30% sublingually, and 30% rectally.^[36][60] Peak plasma concentrations are reached within a minute intravenously, 5–15 min intramuscularly, and 30 min orally.^[62] Ketamine's duration of action in a clinical setting is 30 min to 2 h intramuscularly and 4–6 h orally.^[36]

Plasma concentrations of ketamine are increased by diazepam and other CYP3A4 inhibitors.^[36]

History

Medical use

Ketamine vials

Ketamine was originally developed in 1962 as a derivative of phencyclidine (PCP), which was synthesized in 1926, a feat made possible by the discovery of a new organic Grignard reaction by Parke-Davis scientist Harold Maddox.^[69] Initially known as CI-581, ketamine was first synthesized by Parke-Davis scientist Calvin Stevens. Pharmacological investigations in human subjects began in 1964.^[69] 
These investigations demonstrated that ketamine's shorter duration of action and lesser psychotomimetic profile made it favorable over PCP as a "dissociative" anesthetic.^[70] 

Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.^[71]

Non-medical use

Main article: Recreational use of ketamine

Non-medical use of ketamine began on the West Coast of the United States in the early 1970s.^[71] Early use was documented in underground literature such as The Fabulous Furry Freak Brothers. 
It was used in psychiatric and other academic research through the 1970s, culminating in 1978 with the publishing of psychonaut John Lilly's The Scientist, and Marcia Moore and Howard Alltounian's Journeys into the Bright World, which documented the unusual phenomenology of ketamine intoxication.^[72] 
 The incidence of non-medical ketamine use increased through the end of the century, especially in the context of raves and other parties.^{[73][74][75][76][77]} 

However, its emergence as a club drug differs from other club drugs (e.g. MDMA) due to its anesthetic properties (e.g., slurred speech, immobilization) at higher doses;^[77] in addition, reports of ketamine being sold as "ecstasy" are common.^[78] 

 The use of ketamine as part of a "post-clubbing experience" has also been documented.^[79] Ketamine's rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.^[77] 
Related to its purported ability to cause confusion and amnesiac effects, ketamine can leave users vulnerable to drug-facilitated sexual assault.^[80]

Society and culture

Legal status

The increase in illicit use prompted ketamine's placement in Schedule III of the United States Controlled Substance Act in August 1999.^[81]

In the United Kingdom, it became labeled a Class C drug on 1 January 2006.^[61][82] On 10 December 2013 the UK ACMD recommended that the government reclassify ketamine to become a Class B drug,^[83] and on 12 February 2014 the Home Office announced they would follow this advice "in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage".^[84][85]

The UK Minister of State for Crime Prevention, Norman Baker, responding to the ACMD's advice said that the issue of its recheduling for medical and veterinary would be addressed "separately to allow for a period of consultation."^[84]

In Canada, ketamine is classified as a Schedule I narcotic, as of August 2005.^[86] In Hong Kong, as of 2000, ketamine is regulated under Schedule 1 of Hong Kong Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals, for university research purposes, or with a physician's prescription.^[87] By 2002, ketamine was classified as schedule III in Taiwan; given the recent rise in prevalence in East Asia, however, rescheduling into schedule I or II is being considered.^[61]

In December 2013 the government of India added ketamine to Schedule X of the Drug and Cosmetics Act, adding restrictions on who can buy or sell it.^[88]

Research

Antidepressant use

Animal studies

Some research in rodents has attributed the effects of ketamine to being an NMDA receptor antagonist,^[53] which increases the activity of the AMPA receptor, and this boost in AMPA activity may be crucial for ketamine’s rapid antidepressant actions.^[90] NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system is an emerging target for antidepressant drug discovery and development.^[91][92][93]

Acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. The increase of hippocampal BDNF protein levels induced by ketamine might also be necessary to produce a rapid onset of antidepressant action in rats.^[94]

Human studies

Research on the antidepressant effects of ketamine infusions at subanaesthetic doses has consistently shown rapid (4 to 72 hours) responses from single doses, with substantial improvement in mood in the majority of patients and remission in some. 

However, these effects are often short-lived, and attempts to prolong the antidepressant effect with repeated doses and extended ("maintenance") treatment have resulted in only modest success.^[95]

When treating patients suffering from complex regional pain syndrome (CRPS) with a low-dose (subanesthetic) ketamine infusion, some patients were observed in the early 2000s to make a significant recovery from depression. This recovery was not formally documented, as the primary concern was pain management and it was not possible to quantify to what degree depression recovery was secondary to the patient's recovery from CRPS.^[96] 

This led the investigators to conduct a study in two patients with severe depression, with the dose carefully monitored to prevent hallucinogenic side effects. The patients demonstrated significant, long-term improvement.^[96]

A randomized placebo-controlled study in 18 patients conducted at the US NIH and published in 2006, found ketamine significantly improved treatment-resistant major depression within hours of injection that lasted up to one week after the single dose.^[97]

  NIMH director Dr. Thomas Insel remarked:"To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose. These were very treatment-resistant patients."^[98]


A 2013 two-site randomized controlled clinical trial of ketamine in patients with treatment-resistant depression found that 64% of the patients responded after 24 hours according to the Montgomery–Åsberg Depression Rating Scale compared to 28% responding to midazolam.^[99] 

A 2014 study found that a series of three or six ketamine infusions had a rapid antidepressant effect in treatment-resistant depression (TRD). 29% of a small sample responded, in a period ranging from six hours to the third infusion; beneficial effects lasted from 25 to 168 days. Some test subjects suffered acute adverse reactions during the infusion (7%) or failure to benefit and increasing anxiety (18%). 
 Ketamine was not associated with memory impairment.^[100]


Kudoh et al. investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery.^[101] Depressed mood, suicidal tendencies, somatic anxiety, and hypochondriasis significantly decreased in the active group as compared with the control. The group receiving ketamine also had significantly lower postoperative pain.

Treatment of addiction

The Russian doctor Evgeny Krupitsky has claimed to have encouraging results by using ketamine as part of a treatment for alcohol addiction which combines psychedelic and aversive techniques.^[102][103] 
This method involved psychotherapy, controlled ketamine use, and group therapy, and resulted in 60 of the 86 alcoholic males selected for the study remaining fully abstinent through one year of treatment. 
For heroin addiction, the same researcher reached the conclusion that one ketamine-assisted psychotherapy session was significantly more effective than active placebo in promoting abstinence from heroin during one year without any adverse reactions. In a recently published study, 59 detoxified inpatients with heroin dependence received a ketamine-assisted psychotherapy (KPT) session prior to their discharge from an addiction treatment hospital, and were then randomized into two treatment groups.^{[citation needed]}

Participants in the first group received two addiction counseling sessions followed by two KPT sessions (with a single IM injection of 2 mg/kg ketamine), with sessions scheduled on a monthly interval (multiple KPT group). 
Participants in the second group received two addiction counseling sessions on a monthly interval, but no additional ketamine therapy sessions (single KPT group). 

At one-year follow-up, survival analysis demonstrated a significantly higher rate of abstinence in the multiple KPT group. Thirteen of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 of 27 subjects (22.2%) in the single KPT group (p < 0.05).

 No differences between groups were found in depression, anxiety, craving for heroin, or their understanding of the meaning of their lives. 

Three sessions of ketamine-assisted psychotherapy were found to be more effective than a single session for the treatment of heroin addiction.^[104][105]
Krupitsky and Kolp summarized their work to date in 2007.^[106]

Complex regional pain syndrome

Ketamine is being used as an experimental and controversial treatment for complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy (RSD). CRPS/RSD is a severe chronic pain condition characterized by sensory, autonomic, motor, and dystrophic signs and symptoms. 

The pain in CRPS is continuous, worsens over time, and is usually disproportionate to the severity and duration of the inciting event.
 The hypothesis is that ketamine manipulates NMDA receptors which might reboot aberrant brain activity. 
One treatment modality is a low-dose ketamine infusion of between 25 and 90 mg per day, over five days, either in hospital or as an outpatient, called the awake technique. Open label, prospective, pain journal evaluation of a 10-day infusion of intravenous ketamine (awake technique) in the CRPS patient concluded, "A four-hour ketamine infusion escalated from 40–80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation".^[107]

Case notes of 33 patients whose CRPS pain was treated by the inpatient administration of a continuous subanesthetic intravenous infusion of ketamine were reviewed at Mackay Base Hospital, Queensland, Australia. A total of 33 patients with diagnoses of CRPS who had undergone ketamine treatment at least once were identified.
 Due to relapse, 12 of 33 patients received a second course of therapy, and twoof 33 patients received a third. There was complete pain relief in 25 (76%), partial relief in six (18%), and no relief in two (6%) patients. The degree of relief obtained following repeat therapy (N=12) appeared even better, as all 12 patients who received second courses of treatment experienced complete relief of their CRPS pain. 

The duration of relief was also impressive, as was the difference between the duration of relief obtained after the first and after the second courses of therapy. In this respect, following the first course of therapy, 54% of 33 individuals remained pain-free for three months or more and 31% remained pain free for six months or more. 
After the second infusion, 58% of 12 patients experienced relief for a year or more, while almost 33% remained pain free for over three years. 

The most frequent side effect observed in patients receiving this treatment was a feeling of inebriation.
 Hallucinations occurred in six patients. Less-frequent side effects also included complaints of light-headedness, dizziness, and nausea. In four patients, an alteration in hepatic enzyme profile was noted; the infusion was terminated and the abnormality resolved thereafter. No long-term side effects were noted.^[107] 
This procedure has only recently been allowed in the United States for the treatment of CRPS.
A second treatment modality consists of putting the patient into a medically induced coma and giving an extremely high dosage of ketamine, typically between 600 and 900 mg.^[108] 


This version, previously done in Germany and Mexico, is now currently only preformed in the United States.^[109] 
According to Dr Schwartzman, 14 of 41 patients in the coma-induced ketamine experiments were completely cured. "We haven't cured the original injury", he says, "but we have cured the RSD or kept it in remission. 

The RSD pain is gone." He added, "No one ever cured it before... In 40 years, I have never seen anything like it. These are people who were disabled and in horrible pain. 

Most were completely incapacitated. They go back to work, back to school, and are doing everything they used to do. Most are on no medications at all. I have taken morphine pumps out of people. You turn off the pain and reset the whole system."^[108]

In Tuebingen, Germany, Dr Kiefer treated a patient who presented with a rapidly progressing contiguous spread of CRPS from a severe ligamentous wrist injury. 
Standard pharmacological and interventional therapy successively failed to halt the spread of CRPS from the wrist to the entire right arm. Her pain was unmanageable with all standard therapies. 
As a last treatment option, the patient was transferred to the intensive care unit and treated on a compassionate care basis with anesthetic doses of ketamine in gradually increasing (3–5 mg/kg·h) doses in conjunction with midazolam over a period of five days. 
On the second day, edema and discoloration began to resolve and increased spontaneous movement was noted. 
On day six, symptoms completely resolved and infusions were tapered. The patient emerged from anesthesia completely free of pain and associated CRPS signs and symptoms. 

The patient has maintained this complete remission from CRPS for eight years now. The psychiatric side effects of ketamine were successfully managed with the concomitant use of midazolam and resolved within a month of treatment.^[110]

Fear of harm

According to a recent report on NPR,^[111] Demitri Papolos uses ketamine to treat children with "fear of harm" profile, a condition characterized by: sleep disturbances including frequent and terrifying nightmares; an extreme reaction when anyone tries to control their behavior; and overheating, especially at night.

 Although "fear of harm" profile has been lumped in with bipolar disorder over the recent decades that understanding is emerging about these concerns, "fear of harm" may be related to an overly-sensitive "flight-or-fight" reaction, which classical bipolar disorder is not.

Veterinary medicine

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals.
It is an important part of the "rodent cocktail" a mixture of drugs used for anesthetizing rodents.^{[citation needed]} 
 Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant-rate infusion to help prevent pain wind-up. 

Ketamine is used to manage pain among large animals, though it has less effect on bovines.^{[citation needed]} It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.

Use in popular culture

Ketamine was referenced in several episodes of the television show House. It was first mentioned in the finale of the second season, "No Reason",^[112] and was responsible for temporarily relieving House's leg pain.^[113]

See also

Pharmacy and Pharmacology portal

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• Arylcyclohexylamine
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