Ketamine is a dissociative anesthetic and analgesic that is a derivative of the drug PCP. It is commonly used as anesthesia during surgery, most commonly in veterinary medicine, but also in humans. It is an effective option when full sedation is not required, such as setting a broken bone or thoroughly cleaning a burn. More recently it has also seen application as a painkiller for specific types of chronic pain, such as neuropathic pain conditions or hyperalgesia. The way ketamine works is quite unique among anesthetics and depressants, and it can selectively suppress certain functions while leaving others almost completely unaltered. Ketamine also produces dose-dependent effects, with smaller doses producing depressant effects and larger doses producing hallucinogenic effects. The exact way these hallucinogenic effects are produced is unclear, as ketamine interacts in fairly complex ways with a wide range of neurotransmitters in the brain.
The main mechanism of action through which ketamine produces its anesthetic and analgesic effects is through interaction with the glutamate neurotransmitter system. Glutamate is a major excitatory neurotransmitter in the brain that is responsible for maintaining a wide range of processes. Specifically, ketamine acts as an antagonist at NMDA glutamate receptors and acts to blockade these receptors which prevent them from being activated as they normally would. This leads to a reduced ability for signals to travel between certain parts of the brain, so while pain signals may reach the brain, they do not make it to a center of awareness, therefore are not perceived.
In addition to glutamate interactions, ketamine also interacts with the opioid system; more specifically it acts as an agonist (activator) at μ-opioid receptors and possibly δ-opioid receptors as well. These receptors are responsible for the perception of pain and interactions with these receptors are the main way that opiate drugs like heroin suppress pain. In addition, ketamine can produce interactions with the dopamine and serotonin neurotransmitter systems, although these interactions are not well understood. These neurotransmitters can produce pleasure and feelings of reward in the case of dopamine, and act as a mood regulator and elevator in the case of serotonin. Very recently, ketamine has been proposed as a treatment for refractory depression, although research into its effectiveness and safety is ongoing. 1, 2, 3, 4, 5, 6, 7, 13
Through continued ketamine use, both the glutamate and opioid neurotransmitter systems can undergo a process known as upregulation (for NMDA glutamate receptors) and downregulation (for the opioid receptors). For glutamate, since ketamine blocks activation of the receptors, the brain will increase its sensitivity to glutamate in an effort to compensate. A similar process can occur with the opioid system, although it is the reverse. Since ketamine activates the opioid receptors, the brain will reduce sensitivity at these receptors to maintain balance. This can occur in a fairly short time, often just a few weeks of regular or heavy use. Once downregulation has occurred, ketamine withdrawal symptoms will emerge when someone goes too long without using the drug.
The symptoms of ketamine withdrawal may vary greatly between individuals and this is due to multiple factors. Individual metabolism plays a large role as does liver health and function. Genetics may also play a role regarding certain genes and their relationship to metabolic capacity.9 Additionally, the quality of ketamine is a large factor as well, as pharmaceutical grade ketamine is often of high quality, but illicitly produced ketamine can vary greatly in purity. This has to do with the fact that ketamine exists in two unique forms, (R) levo-ketamine and (S) dextro-ketamine, and these enantiomers have slightly different effects. These two forms are present in a roughly 50-50 ratio in pharmaceutical-grade ketamine but illicitly produced ketamine can have wildly varying ratios. The exact ratio of these different forms can greatly impact the potency of ketamine, thus the withdrawal symptoms may be more or less intense, and different symptoms may be present or absent depending on the ratio of these two distinct forms of ketamine. 10, 11, 12, 14
Ketamine addiction is quite rare compared to many other drugs of abuse, so there have not been many studies done regarding the symptoms of ketamine withdrawal. That being said, due to the mechanisms that ketamine utilizes to produce its effects, drugs with similar mechanisms of action as well as anecdotal evidence in the form of case reports8 may give us a general and broad overview.
Some of the symptoms of ketamine withdrawal include:
These symptoms are rarely dangerous in average, otherwise healthy ketamine users, but in the cases of heavy users or those with pre-existing health conditions, there may be an increased risk during withdrawal. Of particular note is the increased risk of dangerous complications with people who have pre-existing heart conditions. The sometimes sharp increase in heart rate can easily lead to dangerous and potentially fatal complications such as stroke and cardiac arrest if medical help is not provided. Another aspect to consider is the presence of mood swings and increased aggression. While this may pose indirect risks they could potentially be severe, both to the one experiencing these symptoms, and others nearby.
Ketamine is a powerful depressant, and a hallucinogen depending on the dose, that can produce profound physical effects fairly soon after the last time someone used the drug.
With a very short half-life of ~3 hours, someone will begin experiencing the effects of ketamine detox within 6 hours of the last use. The physical effects may be dangerous in those with underlying health issues, but for most people, they are merely uncomfortable.
Some of the physical effects of ketamine detox include disruptions to a number of physical processes and systems. Let’s take an in-depth look at some of the physical systems most heavily affected:
The motor effects of ketamine detox are often the most noticeable signs. These effects include shaking and tremor, myoclonic muscle jerks, and possibly convulsions. Glutamate is one of the major excitatory neurotransmitters in the brain and it has very powerful effects all throughout the body. Through ketamine use and the upregulation that occurs to glutamate receptors, once someone stops using the drug, the brain is both more sensitive to glutamate as well as open to glutamate signals now that ketamine is not blocking the receptors. This can result in profound hyperactivity in brain signaling and motor neurons that can produce both resting tremor and intention tremor. Myoclonic muscle spasms are common as well, with random and unexpected jerks or large twitches being commonplace during ketamine detox.
In the case of heavy or long-term users, seizures are also a very real possibility. While seizures are a neurological phenomenon, they can often result in physical convulsions and other complications that may result in physical injury, brain damage, or death. These could be due to the seizure itself, or the result of an injury sustained secondary to the seizure.
Even in the absence of seizures or hyperactive signaling, there can still be structural issues that arise from neurological remodeling that occurs subsequent to glutamate upregulation. Some of the most obvious effects of this that arise during ketamine detox are ataxia and nystagmus. These are movement issues, and in the case of ataxia, it is most commonly manifest as an ataxic gait and dysarthria. Ataxic gait is when someone will have trouble walking due to abnormal or uncoordinated movements. Dysarthria is speech troubles that arise from uncoordinated or irregular control of the muscles used to make certain sounds. These issues can sometimes persist for many months after ketamine detox, although they often improve with time.
Both the glutamate and the opioid system play a role in heart function, with glutamate being more of a contributor than the opioid system. Glutamate has a direct impact on heart rate and even blood pressure, and during detox from ketamine, the increased impact of glutamate can lead to hyperactive cardiovascular function. The opioid system also contributes to heart function, although it’s contribution is more indirect. Through opioid downregulation and subsequent ketamine detox, levels of the neurotransmitter norepinephrine can increase. This neurotransmitter is a critical component of the fight-or-flight system and is a major mediator of epinephrine (aka adrenaline) levels. When norepinephrine levels are high, blood pressure increases as does heart rate, and blood sugar levels can spike. While normally not dangerous, this can lead to problems if someone were diabetic and can increase the risks of diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic syndrome (HHNS). 13
Aside from the physical impact of glutamate, it also plays an enormous role in cognition and emotions. Additionally, ketamine has interactions with the serotonin neurotransmitter system, which is a major contributor to mood elevation and regulation. Due to the upregulation of glutamate receptors and the downregulation of serotonin receptors and subsequent ketamine detox, the psychological effects can be severe and sometimes persist for quite a long time.
While hallucinations are an effect of ketamine use, they are also fairly common in heavy users while they are undergoing ketamine detox. While the exact mechanism is not understood, the emergence of hallucinations seems to be related to both glutamate upregulation and structural changes performed in the brain as a result of chronic glutamate upregulation. Known as remodeling, this process is the brain’s attempt to reorganize so that it can better operate in a glutamate-upregulated environment. Those who used larger amounts of ketamine are more likely to experience hallucinations as an effect of ketamine detox, and these can be auditory, visual, tactile, or a combination of all three. 15, 16, 17
Anxiety is an extremely common effect of ketamine detox, and it may persist to some degree for some time after the last time someone used ketamine. While it often reduces in intensity over time, the first week or two may exhibit severe levels of anxiety. This is mainly due to glutamate upregulation that increases the brain’s sensitivity to this excitatory neurotransmitter, and the sudden lack of ketamine to balance out this increased sensitivity. Glutamate acts as an exciter and stimulator of neurological processes and can lead to states of hyperactivity that manifest signs both physical and psychological. Essentially, the anxiety system in the brain is put into overdrive during ketamine detox, and it will take several days for the brain to substantially perform glutamate downregulation for these often severe levels of anxiety to resolve.
The short answer: in most cases. While ketamine detox may not often be particularly dangerous in a direct and physical manner, the psychological symptoms can pose significant, although secondary, risks. Aside from the risks, detoxing from ketamine is oftentimes very uncomfortable. Entering a detox can not only minimize the risks, both direct and indirect, but these facilities can also reduce the discomfort of the experience.
Through the use of medications, medical supervision, and behavioral therapies these programs can offer support and care for both the physical and psychological symptoms. Medications and medical supervision can reduce the discomfort of the experience and the risks of dangerous complications. Behavioral therapies can help someone deal with the psychological stress and discomfort while also helping them to break old, unhealthy habits and to build newer, healthier ones.
Some situations where entering a ketamine detox center is especially recommended includes:
If someone has a history of withdrawal seizures or has a seizure condition such as epilepsy, then the likelihood of them experiencing a ketamine withdrawal seizure is greatly increased. Seizures may not seem potentially fatal, but even minor convulsive seizures can result in injury or death. For example, if someone had a seizure while standing, or even laying in bed, they may hit their head. Even more dangerous could be having a seizure while on a staircase or driving a car. Additionally, there is a certain seizure state known as status epilepticus that is considered a medical emergency and this can result in brain damage or death.
If someone has a history with ketamine abuse treatment or any drug treatment for that matter, then it is highly recommended for them to enter a ketamine detox center. Past history of periods of sobriety and relapse indicates that help may be needed. Ketamine detox centers can not only make the detox process more safe and comfortable, but they can also act as a liaison to further treatment and care after detox is complete. Entering one of these facilities is often an important step on the journey of recovery, and the wealth of resources they provide can be extremely beneficial to someone’s chances of long-term recovery.
Ketamine addiction is a very serious and powerful affliction, and it often requires help to overcome. Life without ketamine is not only possible, but it can often be better than anyone in active addiction could ever imagine. Yes, it may be scary and yes it may be hard, but with the help of professionals and those who have taken this journey before, hope, guidance, and helping hands can make recovery possible. Recovery doesn’t have to wait, find a detox center today.
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