{"id":6456,"date":"2021-06-04T10:01:10","date_gmt":"2021-06-04T17:01:10","guid":{"rendered":"https:\/\/wou.edu\/chemistry\/?page_id=6456"},"modified":"2021-06-04T10:08:37","modified_gmt":"2021-06-04T17:08:37","slug":"ketamine","status":"publish","type":"page","link":"https:\/\/wou.edu\/chemistry\/chemistry-degree\/student-activities-2\/chemistry-corner\/ketamine\/","title":{"rendered":"Ketamine &#8211; Special K"},"content":{"rendered":"<h2><span style=\"color: #e01616\"><strong>Special K and the Special Ways It Affects Society<\/strong><\/span><\/h2>\n<p><span style=\"color: #000000\">By: Tiffany Homewood<\/span><\/p>\n<p><a href=\"https:\/\/wou.edu\/chemistry\/files\/2021\/06\/PDF-Downloadable-Verion.pdf\">PDF Downloadable Version<\/a><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/lh3.googleusercontent.com\/9K8DiM4Fvt-DR_hnpz7MF_Ghd1W-h8XuNAWNtD5V0K5ExsgZ8-dKmjguWeitWfqmg_LJ8BgCnKhvtw6nALx1Vkn2ImI5HZVvO30U-WRW6lrJeWx3fvNqli9FSd4fP43Vv6vClQVe\" width=\"595\" height=\"446\" class=\"\" \/><\/p>\n<p><em><span style=\"font-weight: 400\">Bottles of ketamine. Reprinted from Wikimedia Commons (2006). Copyright Wikimedia Commons 2006<sup>1<\/sup><\/span><\/em><\/p>\n<h3><strong><span style=\"color: #000000\">Introduction<\/span><\/strong><\/h3>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">For years, medical professionals used phencyclidine as an anesthetic. However, they noticed many patients waking up from the anesthesia would experience a psychosis eerily similar to schizophrenia and began research into a suitable alternative. In 1962 ketamine, a derivative of phencyclidine, was first synthesized by Calvin Stevens<\/span><span style=\"font-weight: 400\">. After several trial tests on live prisoners, ketamine was found to have much milder side effects than phencyclidine and was approved for use as a battlefield anesthetic.<\/span><sup><span style=\"font-weight: 400\">2 <\/span><\/sup><span style=\"font-weight: 400\">It soon after replaced phencyclidine as the go-to anesthetic for medical procedures<\/span><span style=\"font-weight: 400\">.\u00a0<\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">However, this replacement would not last. Because ketamine is still able to induce psychosis and because abuse of the drug became more prevalent, ketamine was discontinued as an anesthetic for most procedures<\/span><span style=\"font-weight: 400\">.<sup>2<\/sup> Typically, it is relegated to use in veterinary medicine as a sedative and a calming agent for agitated animals. Though its importance faded for some time, ketamine has seen a resurgence in popularity. In <\/span><span style=\"font-weight: 400\">recent years, ketamine has seen many uses. Aside from being used recreationally and nefariously, ketamine is also a chemical restraint utilized by police and a potential tool in the treatment of depression.<\/span><span style=\"font-weight: 400\"><\/span><\/span><\/p>\n<h3><span style=\"color: #000000\"><b>Illicit uses<\/b><\/span><\/h3>\n<p><span style=\"font-weight: 400;color: #000000\">Given its anesthetic properties, ketamine is ripe for abuse. As an illicit substance, it is typically used recreationally due to the euphoric feelings and out of body experiences associated with it. Not surprising considering people like to feel good. But there is a much more horrific use for ketamine. Sometimes the drug is used to facilitate sexual assault. At anesthetic doses, ketamine can render the victim physically helpless. The dissociative effect and possible amnesia can also make identifying the perpetrator extremely difficult. Sexual assault cases are often difficult to prosecute to begin with. Date rape drugs provide a much bigger hurdle to overcome. So how do we prove they were drugged? How do we know ketamine was used? To answer this, we must first understand the metabolic pathway of ketamine.<\/span><span style=\"font-weight: 400;color: #000000\"><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">Ketamine&#8217;s metabolic pathway begins in the liver where the process is facilitated by various cytochrome P450 enzymes<\/span><span style=\"font-weight: 400\">,<\/span><span style=\"font-weight: 400\">. Most commonly, ketamine undergoes N-demethylation<\/span><span style=\"font-weight: 400\">.<sup>3,4<\/sup> This means the nitrogen atom loses a methyl group which is then replaced with a hydrogen. The process turns ketamine into its primary metabolite, norketamine, which is still biologically active<\/span><span style=\"font-weight: 400\">.<sup>3,4<\/sup> From there, norketamine can then be hydroxylated on one of several locations on the cyclohexane ring by CYP2B6 and CYP2A6 to form hydroxynorketamine<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> Hydroxynorketamine can further metabolize by shedding a water molecule non-enzymatically, creating dehydronorketamine<\/span><span style=\"font-weight: 400\">.<sup>3 <\/sup>Other metabolic pathways are facilitated by various enzymes as shown in <\/span><b>Figure 1<\/b><span style=\"font-weight: 400\">. Metabolism of ketamine occurs quite quickly with the elimination half life being around 2 to 4 hours<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> About 90% of ketamine leaves the body through urine as either norketamine or dehydronorketamine while 2-4% leaves unchanged<\/span><span style=\"font-weight: 400\">4<\/span><span style=\"font-weight: 400\">. Some of the drug becomes attached to hair as it passes through the bloodstream, allowing for some interesting analytical techniques.<\/span><\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/lh6.googleusercontent.com\/89ozg48nOuZlLiawQ49SHkUG8zMcQ3nP3RZ9PMgrueHUj2-VN3uGPSNFwrIx-Pgh9piP5ctcD89EUCtFciJQZFL1gD5B99_7NhIcyFoK20e7L6ZyffduVc_WdEFAL4quw2CCQUKY\" width=\"699\" height=\"608\" class=\"\" \/><\/p>\n<p><span style=\"color: #000000\"><b>Figure 1.<\/b><span style=\"font-weight: 400\"> The metabolic pathways of ketamine. Reprinted from Yartsev. (2020). Copyright 2020 Alex Yartsev<\/span><span style=\"font-weight: 400\">.<sup>3<\/sup><\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">Currently, possession and use of ketamine outside of a medical environment is illegal. Obviously when police come across ketamine, there is no way to tell what it is just by looking. Luckily, there are chemical presumptive tests that can be used to distinguish ketamine from other substances. Reagents like gold (III) bromide and Mandelin\u2019s reagent will change color upon contact with ketamine<\/span><span style=\"font-weight: 400\">,<\/span><span style=\"font-weight: 400\">. Mandelin\u2019s reagent is the more commonly used between the two and will change to a reddish color upon reacting with ketamine as shown in <\/span><b>Figure <span style=\"color: #000000\">2<\/span><\/b><span style=\"font-weight: 400\">. Unfortunately, these reagents can react with other chemicals, potentially giving a false positive. One recently developed chemical test, a modified Scott\u2019s test, has so far shown to be relatively specific to <\/span><span style=\"font-weight: 400\">ketamine<\/span><span style=\"font-weight: 400\">.<sup>5<\/sup> A typical Scott\u2019s test uses cobalt (II) thiocyanate to test for cocaine and gives a blue color upon a positive result. A modified test converts the reagent to cobalt (II) tetrathiocyanate and adds potassium hydroxide to prevent reactions with cocaine as shown in <\/span><b>Figure 3<\/b><span style=\"font-weight: 400\">. When reacted with ketamine, the test gives a pinkish-purple precipitate<\/span><span style=\"font-weight: 400\">.<sup>5 <\/sup>A negative test will result in either no color change, or a blue solution<\/span><span style=\"font-weight: 400\">.<sup>5<\/sup> Though the test is highly specific to ketamine, there is always a chance for false positives. For this reason, presumptive tests are not admissible in court. This is where confirmatory tests play a role.<\/span><\/span><\/p>\n<p><img decoding=\"async\" src=\"https:\/\/lh5.googleusercontent.com\/DRofAMzC-qJvuUwoHo2ucswBG8g5Fu5w6cLN1nyovJJdUpiojZYjgHSIl-g1464pxTSwcjlWWK2c48QCINDvzSE-WV9xmEvS43OEDmQ2P7J_b25CWizkgIJYfHG9GxoIRiipSjqk\" \/><\/p>\n<p><span style=\"color: #000000\"><b>Figure 2.<\/b><span style=\"font-weight: 400\"> Chart of Mandelin reagent with various drugs. Reprinted from Agro (2015). Copyright CSSDP 2015<\/span><span style=\"font-weight: 400\">.<sup>6<\/sup><\/span><\/span><\/p>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/lh3.googleusercontent.com\/oMF1Psvb2Pbhu-_BhcmozkCE1Mm6NcBYg_3EVxd8Owf4PZSGj5oXO-SVCmOa-WZqDhEcUVj16oXpbpuEUTM7HfjkOKxtpKY79V51oRSO\" width=\"612\" height=\"122\" class=\"\" \/><\/p>\n<p><span style=\"color: #000000\"><b>Figure 3.<\/b><span style=\"font-weight: 400\"> The chemical equation of tetrathiocyanate synthesis and a modified Scott\u2019s test reaction. Reprinted from Dubey et al. (2013). Copyright 2013 Taylor &amp; Francis Group<\/span><span style=\"font-weight: 400\">.<sup>5<\/sup><\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">Confirmatory tests are conducted through instrumentation such as gas chromatography, liquid chromatography, and infrared spectroscopy. By analyzing a drug or biological sample, these instruments can determine the composition of a mixture and identify illicit substances. Liquid and gas chromatography work by separating complex samples into their components so they can be analyzed by a mass spectrometer which measures the mass to charge ratio of molecules as shown in <\/span><b>Figure 4<\/b><span style=\"font-weight: 400\">. In gas chromatography, the mobile phase is a gas and separation is based on the boiling points of the solute<\/span><span style=\"font-weight: 400\">.<sup>7<\/sup> In liquid chromatography , a liquid mobile phase is used and separation is based on the interactions of the solute with the medium<\/span><span style=\"font-weight: 400\">.<sup>8<\/sup> Another instrument that\u2019s commonly used is infrared spectroscopy. This technique works by shining beams of light with different combinations of frequencies at a sample. Once the raw data is collected, it is put through an algorithm called a Fourier Transformation to create a spectrum shown in <\/span><b>Figure 5<\/b><span style=\"font-weight: 400\"> that can be used to determine what functional groups are present.<\/span><\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/lh6.googleusercontent.com\/VDnJ1fpdESae_aLVy5JBP1Ejab6Zy1ziXqC5ycsrQTppfyd8Y4oWoK0LnrjsIOwdsCYOyXwqoRo062OEVfIrsoeSUuDAULxhTOWWmXjb\" width=\"638\" height=\"386\" class=\"\" \/><\/p>\n<p><span style=\"color: #000000\"><b>Figure 4.<\/b><span style=\"font-weight: 400\"> A mass spectrum of ketamine. Reprinted from Scientific Working Group (2005). Copyright Scientific Working Group 2005<\/span><span style=\"font-weight: 400\">.<sup>9<\/sup><\/span><\/span><\/p>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/lh3.googleusercontent.com\/kq2pLQLUmqWZffxQToBmOEzlsxKSesXAqDKpGUKWvRRHIU7whT2X09YEsTKz4b5_gEat7CqETGyTNVitukMcs74THhOYY9TJ1rPdgrDn\" width=\"640\" height=\"410\" class=\"\" \/><\/p>\n<p><span style=\"color: #000000\"><b>Figure 5.<\/b><span style=\"font-weight: 400\"> Ketamine FTIR spectra. Reprinted from Dubey et al. (2013). Copyright 2013 Taylor &amp; Francis Group<\/span><span style=\"font-weight: 400\">.<sup>5<\/sup><\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">A more recent and fascinating instrumentation technique involves using molecular imprinting to separate ketamine from hair samples before it is analyzed through liquid chromatography. Molecular imprinting works by building a template polymer<\/span><span style=\"font-weight: 400\">.<sup>8<\/sup> This polymer is totally synthetic and is designed to bind to molecules with certain structures and constituents<\/span><span style=\"font-weight: 400\">.<sup>8<\/sup> Once the polymer is imprinted to the specific shape, it is able to bind to target molecules and others that share similar structures<\/span><span style=\"font-weight: 400\">.<sup>8<\/sup> For example, an experiment was able to use molecular imprinting to pull ketamine and its metabolite, norketamine from hair<\/span><span style=\"font-weight: 400\">.<sup>8 <\/sup><\/span><b>Figure 6<\/b><span style=\"font-weight: 400\"> shows a generic example of the process. This technique can also be refined so it is highly specific to the target molecule.<\/span><\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/lh3.googleusercontent.com\/6_qe-bQqWFhSr-Izq5bLwcQUkrv9PYIt6_6FFb9DMkDUOVujG4QIaAKRV_uB7kXZyj4nrPt43N2VIXROUzDhPO88SFBLABCpxw4LEDH1\" width=\"620\" height=\"367\" class=\"\" \/><\/p>\n<p><span style=\"color: #000000\"><b>Figure 6.<\/b><span style=\"font-weight: 400\"> The process of molecular imprinting. Reprinted from Saylan et al. (2019). Copyright MDPI 2019<\/span><span style=\"font-weight: 400\">.<sup>10<\/sup><\/span><\/span><\/p>\n<h3><span style=\"color: #000000\"><b>Uses in law enforcement<\/b><\/span><\/h3>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">As ironic as it sounds, ketamine is sometimes used by law enforcement. In certain states, a law enforcement officer can mandate an EMT to administer ketamine to chemically restrain a suspect when they are declared to be in a &#8220;state of excited delirium&#8221;. What is worrisome is that the definition of this condition is about as vague as the name. To this day, there is no universal definition of Excited Delirium nor is there a standard list of symptoms required to diagnose someone with the syndrome<\/span><span style=\"font-weight: 400\">. The general consensus is that the patient must be in a state of agitation and aggression coupled with unexpected strength and they must pose a danger to themselves or others<\/span><span style=\"font-weight: 400\">.<sup>11<\/sup> Typically this syndrome is considered to be a result of drug abuse or a mental health crisis. As it stands, Excited Delirium is a bit of a controversial topic. At least half of well-known medical organizations, including the World Health Organization, do not consider Excited Delirium to be real<\/span><span style=\"font-weight: 400\">.<sup>11<\/sup> Another point of contention is the potential for law enforcement to abuse the diagnosis to justify excessive force. The story of Elijah McClain justifies this concern.<\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">Elijah McClain (<\/span><b>Figure 7<\/b><span style=\"font-weight: 400\">) was just 23 years old on the fateful night of his death. McClain was returning home from a convenience store on August 24, 2019 when police <\/span><span style=\"font-weight: 400\">confronted him after receiving a report of someone who looked suspicious<\/span><span style=\"font-weight: 400\">.<sup>12,13<\/sup> After a brief altercation where he was rendered unconscious through a carotid chokehold, McClain was injected with ketamine by EMS while physically restrained<\/span><span style=\"font-weight: 400\">.<sup>12 <\/sup>McClain went into cardiac arrest soon after and had to be intubated. He was ultimately declared brain dead and unfortunately died a few days later<\/span><span style=\"font-weight: 400\">.<sup>12 <\/sup>Follow up medical examiner reports declared they could not determine whether the ketamine injection caused McClain&#8217;s death, but they could also not rule out the possibility<\/span><span style=\"font-weight: 400\">.<sup>12 <\/sup>This tragic incident, and others like it, raised a vital question about ketamine sedation and chemical restraints in general: Are they truly that safe?<\/span><\/span><\/p>\n<p><img decoding=\"async\" src=\"https:\/\/lh4.googleusercontent.com\/q5PvnxZmnpP8C7l9CMjsrg4f_DD_Bhy0iomLgjsjbEUIWAhpvM1mydWfcwlrdvvE7ArPj_BLkwO53Ziqf7fZaxOnybx1SEPZ1AvYbBx0\" \/><\/p>\n<p><span style=\"color: #000000\"><b>Figure 7.<\/b><span style=\"font-weight: 400\"> A photograph of Elijah McClain. Reprinted from Tompkins, L. (2019). Copyright New York Times 2019<\/span><span style=\"font-weight: 400\">.<sup>14<\/sup><\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">Though ketamine sedation is considered relatively safe in a hospital setting, there are inherent risks involved during police encounters. Some of the more immediate effects of ketamine include increased heart rate and laryngospasms<\/span><span style=\"font-weight: 400\">.<sup>15<\/sup>\u00a0A study conducted in Minneapolis found that 49% of patients given ketamine in a prehospital setting experienced severe side effects that required immediate attention<\/span><span style=\"font-weight: 400\">.<sup>16<\/sup>\u00a0Naturally, this is extremely dangerous in cases where a patient has pre existing medical conditions involving the heart or lungs. It has also been noted that fatal ketamine toxicity overwhelmingly occurs when other drugs, particularly depressants, are present<\/span><span style=\"font-weight: 400\">.<sup>17<\/sup>\u00a0Because of these factors, ketamine sedation poses a dangerous threat in situations that involve police when medical histories are typically unknown and the presence of other drugs is likely. It should also be mentioned that the FDA has not approved the use of ketamine as a chemical restraint<\/span><span style=\"font-weight: 400\">.<sup>16<\/sup>\u00a0Not surprisingly, the risks of ketamine toxicity increase greatly when given at higher doses and when given rapidly. Now how much is a safe dose?<\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">Studies have recommended a sedation dose of 4 mg\/kg<\/span><span style=\"font-weight: 400\">.<sup>15 <\/sup>Others have noted that any dose beyond that greatly increases the risk of complications with the likelihood of intubation increasing by 20%<\/span><span style=\"font-weight: 400\">.<sup>15 <\/sup>Respiratory depression appears to be common at high doses. In the United States, in the states where it is legal, the standard dose of ketamine is 5 mg\/kg<\/span><span style=\"font-weight: 400\">.<sup>15<\/sup>\u00a0There does not appear to be an official reason for the higher dose. One possible reason is to get the sedative effect much quicker. Now looking back at the Elijah McClain case, it seems very unlikely that ketamine sedation had no role in his death. For reasons unknown, McClain was estimated to be around 90 kg while in reality, he weighed about 63 kg at the time of his death<\/span><span style=\"font-weight: 400\">12<\/span><span style=\"font-weight: 400\">. Because of this estimation, he was given 500 mg of ketamine. After doing the math, this means he was given a dose of 7.95 mg\/kg, almost twice the amount of the scientifically determined safe dose. Given that McClain had several pre existing conditions like asthma and anemia, and combined with how roughly he was handled by police, it is unlikely he would have ever left that situation unscathed.<\/span><\/span><\/p>\n<h3><span style=\"color: #000000\"><b>Medicinal uses<\/b><\/span><\/h3>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">Despite some questionable uses, ketamine can actually be quite helpful. While it is no longer administered during most procedures, ketamine is still used in veterinary <\/span><span style=\"font-weight: 400\">and occasionally pediatric medicine<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup>\u00a0As has been mentioned plenty of times, ketamine functions primarily as an anesthetic due to its dissociative properties<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup>\u00a0Ketamine also makes a good analgesic, or painkiller, even at subanesthetic levels<\/span><span style=\"font-weight: 400\">.<sup>19<\/sup>\u00a0When given ketamine, a patient essentially is dissociated physically and mentally from the pain. Obviously these two functions are extremely important when performing any kind of surgery. Any good doctor would not want his patients to feel pain during an operation. But there are more properties that make ketamine a bit more ideal for surgical procedures. Ketamine has anti-inflammatory properties<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup>\u00a0This is ideal for surgeries because it reduces over exaggerated inflammatory responses<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup>\u00a0Oftentimes, these responses can cause hyperalgesia or send the patient into shock<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup>\u00a0Another advantage is that, unlike other anesthetics, ketamine renders the patient unconscious while allowing them to breathe autonomously<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup>\u00a0The patient\u2019s airway is still able to respond to outside stimuli. This means that surgeons don\u2019t have to be as concerned about airway collapses during the surgery. There is a tradeoff, however. Ketamine maintains the airway by inducing muscle tone<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup>\u00a0This makes surgeries that require muscle relaxation extremely difficult without the use of benzodiazepines<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup><\/span><span style=\"font-weight: 400\"><\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">Ketamine\u2019s primary mechanism of function is through its action on NMDA receptors<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup>\u00a0It can non-competitively bind to a channel blocker site within the ion channel such as in <\/span><b>Figure 8<\/b><span style=\"font-weight: 400\">. During normal functions, cations like sodium and calcium flow through the channel to allow for the activation of cell signalling pathways.<\/span><span style=\"font-weight: 400\"><sup>.4,18<\/sup> Ketamine blocks the flow of these cations which prevents depolarization of the neuronal membrane and stops the activation of different pathways<\/span><span style=\"font-weight: 400\">.<sup>.4,18<\/sup> One of these pathways is neuronal activation which is needed to remain conscious. This antagonism of the NMDA receptors is also heavily linked to ketamine\u2019s psychomimetic effects<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup><\/span><\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/lh3.googleusercontent.com\/K7oEOrE7QD454wh04iGeSbSSpwY3mWfEq-BUeJvx99tHFQp6uvRaHhTSX-1AkjVBTToashIfdKjFHq465EXtOcSQznTj4vyNWo7aJ5nAyudFOgqMFPxTNwc2t1VBVqWDIhqIWVX4\" width=\"707\" height=\"563\" class=\"\" \/><\/p>\n<p><span style=\"color: #000000\"><b>Figure 8.<\/b><span style=\"font-weight: 400\"> Ketamine blocking an NMDA receptor. Reprinted from Das (2020). Copyright 2020 ACS Publications<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup><\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">There are a variety of other receptors that ketamine can bind to. Some of these, like the opioid receptors and non-opioid sigma receptors, are believed to be the cause of ketamine\u2019s analgesic effect<\/span><span style=\"font-weight: 400\">.<sup>19<\/sup> Though it can bind to opioid receptors, ketamine\u2019s mechanism of action on them is still a bit of a mystery since naloxone, a known opioid receptor antagonist, has so far shown no effect on ketamine<\/span><span style=\"font-weight: 400\">19<\/span><span style=\"font-weight: 400\">. To reduce inflammation, ketamine reduces the excess of proinflammatory cytokines<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup>\u00a0This is done by inhibiting the protein nuclear kappa B, the protein responsible for producing the cytokines<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup><\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">Now by far the most fascinating use for ketamine is its potential as an antidepressant. Right now, there are many issues with current antidepressants. Mainly, traditional antidepressants can take weeks to months for effects to be felt<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> Depending on the patient, the effects may not even be felt at all. Additionally, side effects from these antidepressants can vary greatly from person to person. Sometimes these side effects actually worsen the depression symptoms<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup> During clinical trials for ketamine, patients were able to start feeling the antidepressant effects in about 2 hours after the first treatment was finished<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> This effect often lasted up to about a week per dose<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup><\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">Unfortunately, the mechanism of action behind the antidepressant effects of ketamine is still mostly a mystery. What we do know is that ketamine primarily inhibits NMDA receptors, but it can also bind to several other receptors with less selectivity. A few possible mechanisms that have been proposed based on NMDA receptor inhibition are shown in <\/span><b>Figure 9<\/b><span style=\"font-weight: 400\">. The first one hypothesizes that ketamine inhibits NMDA receptors on GABAergic interneurons<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> From there, the presynaptic glutamate nerve terminal is activated, releasing glutamate so it can bind to AMPA receptors on the postsynaptic nerve terminal<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> Binding of AMPA receptors would then trigger TrkB and the rapamycin complex 1 to synthesize proteins that restore synaptic connectivity<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> Another proposed mechanism is that ketamine causes direct intracellular changes on postsynaptic nerve terminals that activate AKT and ERK\/MAPK pathways that suppress eukaryotic elongation factor 2<\/span><span style=\"font-weight: 400\">4<\/span><span style=\"font-weight: 400\">. This would then increase the release of brain-derived neurotrophic factors. These neurotrophic factors produce proteins that are able to repair the degenerated synapses associated with depression<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> If this mechanism is correct, it may be possible to actually reverse the neuro degeneracy that causes depression.<\/span><\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/lh5.googleusercontent.com\/SYOPbQGMd77kD4ddD528hT7YSxJXENjoQEXz1cxvvBkpKLISGDOFYdu1ow1koYfPdLZJ6rC5eqgwSpy2ulG6xSn09lOe9Bqtz007N5ngOHmRLFvNIPWF3p-cKP1ugKP0dh87qgWN\" width=\"700\" height=\"827\" class=\"\" \/><\/p>\n<p><span style=\"color: #000000\"><b>Figure 9.<\/b><span style=\"font-weight: 400\"> Proposed mechanisms of ketamine antidepressant effects. Reprinted from Das (2020). Copyright 2020 ACS Publications<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup><\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">It also turns out that the configuration of ketamine determines its potency. <\/span><b>Figure 10<\/b><span style=\"font-weight: 400\"> shows the two enantiomers of ketamine. Studies found that R ketamine is 4 times more potent as an antidepressant while S ketamine is three times more potent as an analgesic in rat models<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup> S ketamine was also found to be the enantiomer that causes more of the unwanted side effects<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup> As with other chiral drugs, this difference in effects happens because biological systems are also chiral making them more favorable to certain configurations<\/span><span style=\"font-weight: 400\">.<sup>18<\/sup>\u00a0This could be extremely useful in getting more potent antidepressant effects and studying biosystems responsible for causing depression.<\/span><\/span><\/p>\n<p>&nbsp;<\/p>\n<p><img decoding=\"async\" src=\"https:\/\/lh4.googleusercontent.com\/tIq-bRekzQBJaDDfSL-4OwBMkZpZcSh5qrQJV7ueboVuOQeFHpS7RIrj798j1aWMMUUgL7fMO8D0p0yNTQSG5jOPdbdAUr7hwkVB2wsn\" \/><\/p>\n<p><span style=\"color: #000000\"><b>Figure 10.<\/b><span style=\"font-weight: 400\"> Ketamine\u2019s enantiomers. Reprinted from Das (2020). Copyright 2020 ACS Publications<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup><\/span><\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">When comparing ketamine to traditional antidepressants, you can really see the potential. From what researchers can tell, ketamine works by binding certain receptors rather than trying to increase the amount of monoamine neurotransmitters through blocking their reuptake transporters<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> Ketamine also works significantly quicker than traditional medicine and has more predictable side effects that can resolve on their own<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> Another advantage that ketamine has is that patients experience a much lower rate of suicidal thoughts than they do with other antidepressants<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> This is because conventional antidepressants can induce mood swings<\/span><span style=\"font-weight: 400\">. They can also marginally elevate the mood of someone who is severely depressed to the point where they have no motivation<\/span><span style=\"font-weight: 400\">. This margin is often just enough that the patient regains their motivation, but not enough to stop the hopeless feeling. Because they are no longer immobilized by feeling helpless, suicidal thoughts and actions may actually increase<\/span><span style=\"font-weight: 400\">.<sup>21 <\/sup>With ketamine, the antidepressant effect is significantly stronger and is usually enough to decrease both the helpless and hopeless feeling<\/span><span style=\"font-weight: 400\">.<sup>4<\/sup> Right now, ketamine is available as a treatment in humans though it is not covered by any insurance. There also isn\u2019t any information on whether these lower doses of ketamine will have any significant long term effects or not. But with more research into ketamine, we may have safer and more effective treatments for depression.<\/span><\/span><\/p>\n<h3><span style=\"color: #000000\"><b>Conclusions<\/b><\/span><\/h3>\n<p><span style=\"font-weight: 400;color: #000000\">Regardless of why it\u2019s used, there are many reasons to care about how ketamine affects us and there are just as many concerns we should have. In terms of illegal uses, our focus should not be on whether recreational use is moral. The main concern in this case is the potential for abuse as a date rape drug. Currently, ketamine is illegal to possess outside of a medical setting and therapeutic use is restricted to medical facilities. Because it\u2019s a common date rape drug, ketamine should only be legal to possess as a medicine, similar to other prescription drugs.<\/span><\/p>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">In terms of law enforcement, to call ketamine sedation concerning would be an understatement. As we saw in the Elijah McClain incident, not everyone who\u2019s forcefully given ketamine needs it. Currently, Colorado, Minnesota, and New York allow paramedics to assist officers through ketamine injections. Ketamine injections in these situations are dangerous enough on their own, but the potential for abuse and excessive force is way too high. An internal affairs report in Minneapolis reviewed body cam footage of incidents involving ketamine and the results were horrific. In many cases, suspects were compliant and officers pressured paramedics into administering ketamine<\/span><span style=\"font-weight: 400\">.<sup>16<\/sup> With today\u2019s political climate and the frequency of the blatant police brutality we\u2019re seeing, we should be asking ourselves if this is the standard we want to set.<\/span><\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">In terms of medicine, the possibilities extend beyond just how ketamine can be directly used. While it has been shown to be a powerful antidepressant, there are side effects. These side effects can be dangerous enough to prevent people with certain pre-existing conditions from getting the treatment they need. But if we use ketamine to help research and map out the mechanisms of depression, we could theoretically build a safer molecule. This could lead to significantly safer and effective treatments than what we currently have. And these treatments could be available even to people with high risk health conditions. We could even extend the research and treatments to other mental illnesses. NMDA receptor antagonism is linked to psychosis and memory loss. Ketamine could be used to model these conditions so we can research medicine to treat diseases such as Huntington\u2019s and schizophrenia. There is so much untapped potential that can come from exploring the possibilities of ketamine in the medical field.\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">Ultimately, ketamine on its own isn\u2019t super scary. Depending on who\u2019s using it, it can be a helpful medicine or a nightmarish tool. With that being said, hopefully you learned something from this. And hopefully now you too can teach others about Special K and the special ways it affects society.<\/span><\/p>\n<h3><span style=\"color: #000000\"><strong>References<\/strong><\/span><\/h3>\n<p><span style=\"color: #000000\"><span style=\"font-weight: 400\">[1] <\/span><span style=\"font-weight: 400\">File:Ketamine 10ml bottle.jpg https:\/\/commons.wikimedia.org\/wiki\/File:Ketamine_10ml_bottle.jpg (accessed Jun 4, 2021).<\/span><\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[2] Restorative health &#8211; history of Ketamine https:\/\/www.restorativehealthprimarycare.com\/about\/published-articles\/history-of-ketamine (accessed Apr 16, 2021).<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[3] Yartsev, A. Ketamine https:\/\/derangedphysiology.com\/main\/cicm-primary-exam\/required-reading\/nervous-system\/Chapter%20802\/ketamine (accessed Apr 14, 2021).<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[4] Das, J. Repurposing of Drugs-the Ketamine Story. J. Med. Chem. 2020, 63 (22), 13514\u201313525.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[5] Dubey, P.; Shukla, S. K.; Gupta, K. C. Modified Scott\u2019s Test for Ketamine Hydrochloride. Aust. J. Forensic Sci. 2013, 45 (2), 165\u2013171.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[6] Agro, H. Test it before you ingest it https:\/\/cssdp.org\/test-it-before-you-ingest-it\/ (accessed Jun 2, 2021).<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[7] Matey, J. M.; Moreno de Simon, M. D.; Garc\u00eda-Ruiz, C.; Montalvo, G. A Validated GC-MS Method for Ketamine and Norketamine in Hair and Its Use in Authentic Cases. Forensic Sci. Int. 2019, 301, 447\u2013454.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[8] Harun, N.; Anderson, R. A.; Cormack, P. A. G. Analysis of Ketamine and Norketamine in Hair Samples Using Molecularly Imprinted Solid-Phase Extraction (MISPE) and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS\/MS). Anal. Bioanal. Chem. 2010, 396 (7), 2449\u20132459.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[9] Scientific Working Group. Ketamine, 2005.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[10] Saylan, Y.; Akg\u00f6n\u00fcll\u00fc, S.; Yavuz, H.; \u00dcnal, S.; Denizli, A. Molecularly Imprinted Polymer Based Sensors for Medical Applications. Sensors (Basel) 2019, 19 (6), 1279.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[11] Gonin, P.; Beysard, N.; Yersin, B.; Carron, P.-N. Excited Delirium: A Systematic Review. Acad. Emerg. Med. 2018, 25 (5), 552\u2013565.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[12] Ortiz, E. Elijah McClain was injected with ketamine while handcuffed. Some medical experts worry about its use during police calls https:\/\/www.nbcnews.com\/news\/us-news\/elijah-mcclain-was-injected-ketamine-while-handcuffed-some-medical-experts-n1232697 (accessed Apr 14, 2021).<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[13] Young, R.; McMahon, S. Some states allow authorities to use ketamine to subdue suspects in the field. But is it safe? https:\/\/www.wbur.org\/hereandnow\/2020\/09\/08\/ketamine-police-safety-elijah-mcclain (accessed Apr 14, 2021).<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[14] Tompkins, L. Here\u2019s What You Need to Know about Elijah McClain\u2019s Death. The New York times. The New York Times February 23, 2021.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[15] Bernard, S.; Roggenkamp, R.; Delorenzo, A.; Stephenson, M.; Smith, K.; Ketamine in Severely Agitated Patients Study Investigators. Use of Intramuscular Ketamine by Paramedics in the Management of Severely Agitated Patients. Emerg. Med. Australas. 2021, No. 1742-6723.13755. https:\/\/doi.org\/10.1111\/1742-6723.13755.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[16] Zaret, A.; Obasogie, O. Medical Professionals, Excessive Force, and the Fourth Amendment. California Law Review 2021. https:\/\/doi.org\/10.15779\/Z38NK3658H.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[17] Darke, S.; Duflou, J.; Farrell, M.; Peacock, A.; Lappin, J. Characteristics and Circumstances of Death Related to the Self-Administration of Ketamine. Addiction 2021, 116 (2), 339\u2013345.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[18] Zanos, P.; Moaddel, R.; Morris, P. J.; Riggs, L. M.; Highland, J. N.; Georgiou, P.; Pereira, E. F. R.; Albuquerque, E. X.; Thomas, C. J.; Zarate, C. A., Jr; Gould, T. D. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol. Rev. 2018, 70 (3), 621\u2013660.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[19] Rasc\u00f3n-Mart\u00ednez, D. M.; Carrillo-Torres, O.; Ramos-Nataren, R. G.; Rend\u00f3n-Jaramillo, L. Advantages of Ketamine as a Perioperative Analgesic. Rev. m\u00e9dica Hosp. Gen. M\u00e9x. 2016. https:\/\/doi.org\/10.1016\/j.hgmx.2016.10.007.<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[20] Suicide and antidepressants &#8211; increased anxiety, related suicides https:\/\/www.drugwatch.com\/ssri\/suicide\/ (accessed Jun 2, 2021).<\/span><\/p>\n<p><span style=\"font-weight: 400;color: #000000\">[21] AACAP. Do antidepressants increase the risk of suicide in children and adolescents? https:\/\/www.aacap.org\/aacap\/medical_students_and_residents\/mentorship_matters\/developmentor\/Do_Antidepressants_Increase_the_Risk_of_Suicide_in_Children_and_Adolescents.aspx (accessed Jun 2, 2021).<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Special K and the Special Ways It Affects Society By: Tiffany Homewood PDF Downloadable Version Bottles of ketamine. Reprinted from Wikimedia Commons (2006). Copyright Wikimedia Commons 20061 Introduction For years, medical professionals used phencyclidine as an anesthetic. However, they noticed many patients waking up from the anesthesia would experience a psychosis eerily similar to schizophrenia [&hellip;]<\/p>\n","protected":false},"author":280,"featured_media":0,"parent":4577,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","_lmt_disableupdate":"","_lmt_disable":"","_et_pb_use_builder":"","_et_pb_old_content":"","_et_gb_content_width":"","footnotes":"","_links_to":"","_links_to_target":""},"class_list":["post-6456","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/wou.edu\/chemistry\/wp-json\/wp\/v2\/pages\/6456","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/wou.edu\/chemistry\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/wou.edu\/chemistry\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/wou.edu\/chemistry\/wp-json\/wp\/v2\/users\/280"}],"replies":[{"embeddable":true,"href":"https:\/\/wou.edu\/chemistry\/wp-json\/wp\/v2\/comments?post=6456"}],"version-history":[{"count":0,"href":"https:\/\/wou.edu\/chemistry\/wp-json\/wp\/v2\/pages\/6456\/revisions"}],"up":[{"embeddable":true,"href":"https:\/\/wou.edu\/chemistry\/wp-json\/wp\/v2\/pages\/4577"}],"wp:attachment":[{"href":"https:\/\/wou.edu\/chemistry\/wp-json\/wp\/v2\/media?parent=6456"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}