Ketamine addiction

Ketamine is a medication originally used as an anesthetic and pain reliever, but it also has psychoactive properties and can cause a variety of effects when used unintentionally, including altered consciousness and perception. It is important to note that unauthorized use of ketamine can be dangerous and can lead to serious side effects or even death. Here are some of the effects and symptoms associated with ketamine use:

Psychological effects:

• Changes in perception: distortion of sounds, colors and shapes, and a feeling of separation of consciousness from the body (dissociation or "leaving the body").
• Euphoria: a feeling of happiness and bliss.
• Hallucinations: visual and auditory hallucinations.
• Anxiolytic effects: decreased feelings of anxiety.
• Confusion and disorientation: difficulty perceiving time, space and self-identity.
• Paranoia and fear: can cause feelings of fear orparanoid thoughts in some people.

Physical effects:

• Reducing pain sensitivity: ketamine is a powerful anesthetic.
• Increase in blood pressure and heart rate: short-term increase after ingestion.
• Coordination disorders and ataxia: difficulty maintaining balance and coordinating movements.
• Nystagmus: involuntary eye movements.
• Weakness and lethargy: after disappearance of the initial stimulation effect.
• Vomiting and nausea: especially at high doses.

Long-term effects:

• Damage to the urinary tract: can cause bladder and kidney problems with frequent use.
• Psychological dependence: the potential for addiction and mental health problems.
• Cognitive impairment: memory and concentration difficulties with long-term use.

Ketamine use outside of a medical context carries serious health risks and can lead to unpredictable and dangerous consequences.

Mechanism of action of ketamine

Ketamine is a powerful dissociative anesthetic agent that is often used in medicine and veterinary medicine. It also has antidepressant properties and can be used to treat severe forms of depression for which traditional antidepressants have proven ineffective. The mechanism of action of ketamine is multidimensional and differs from that of most other anesthetics and antidepressants. [1] Here are the main aspects of its mechanism of action:

1. NMDA receptors: Ketamine acts primarily as a non-competitive antagonist of NMDA receptors in the central nervous system. These receptors are a subtype of glutamate receptors that play a key role in the excitation and plasticity processes of the nervous system. Blocking of NMDA receptors by ketamine leads to a decrease in the excitatory action of glutamate, which may explain its anesthetic, antidepressant, and psychomimetic effects.
2. Dopaminergic and noradrenergic systems: Ketamine also affects the dopaminergic and noradrenergic systems of the brain, which may contribute to its antidepressant effects. It can enhance the release of these neurotransmitters, which improves mood and overall well-being.
3. mTOR pathway: Ketamine has been shown to activate a molecular pathway known as mammalian target of rapamycin (mTOR), which plays an important role in the regulation of protein synthesis and neuroplasticity. This activation may contribute to the rapid antidepressant action of ketamine by stimulating the growth and development of new synapses in the brain.
4. Anti-inflammatoryeffects: Ketamine demonstrates anti-inflammatory properties by reducing levels of inflammatory cytokines. This may be involved in its antidepressant and analgesic effects, as inflammation is considered one of the pathophysiologic mechanisms of depression and chronic pain.
5. Effects on other receptors: In addition to its effects on NMDA receptors, ketamine may interact with a number of other molecular targets, including opioid receptors and gamma-aminobutyric acid (GABA)-sensitive receptors. These additional mechanisms may also contribute to its complex pharmacological profile.

Ketamine's primary site of action is as a non-competitive antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor, although it has effects at numerous other receptors. It acts as an antagonist of muscarinic and nicotinic acetylcholine receptors, blocks sodium and potassium channels, activates high-affinity dopamine D2 receptors and L-type potential-dependent calcium channels, and promotes inhibition of gamma-aminobutyric acid (GABA). Ketamine can also increase levels of neurotransmitters such as norepinephrine, dopamine, and serotonin in the brain. [2] When ketamine is used as a drug that stimulates the sympathetic nervous system, tachycardia and hypertension often occur, masking its direct cardiac depressant effect. However, in ICU patients with catecholamine depletion, the use of ketamine may result in hypotension. Although ketamine binds to mu and other opioid receptors, naloxone does not block its analgesic effects. [3]

Research into ketamine's mechanisms of action is ongoing, and more aspects of its effects on the central nervous system may be revealed as new data become available.

Side effects

Studies show that ketamine, used in anesthesia and to treat a variety of chronic pain syndromes, can cause a number of side effects. The main ones include:

1. Respiratory problems: From mild hypoventilation to prolonged central apnea. Ketamine can increase systemic and pulmonary vascular resistance, which can lead to increased pulmonary artery pressure (Greene, Gillette, & Fyfe, 1991).
2. Psychotomimetic side effects and dissociative states: Including hallucinations, changes in the perception of time and space, and feelings of alienation from oneself and the world around. These effects may be related to the antidepressant effects of ketamine, but also limit its clinical use due to the difficulty in managing these symptoms (Sanacora et al., 2013).
3. Neurotoxicity: Animal studies have shown that ketamine can causeneuronal damage when administered at high doses or with prolonged use, especially in the developing brain (Zou et al., 2009).
4. Urinary tract injury: Ketamine abuse is associated with serious functional impairment of the urinary tract, including cystitis, bladder dysfunction, and renal failure (Mason et al., 2010).
5. Cardiovascular Reactions: Ketamine may cause an increase in blood pressure and heart rate, requiring caution in its use in patients with cardiovascular disease.

These data emphasize the importance of careful monitoring of patients when using ketamine, especially with prolonged use or at high doses, and the need for further studies to fully understand all potential risks.

Mechanism of development of ketamine dependence

The development of ketamine dependence, like dependence on other psychoactive substances, involves a complex interplay of biological, psychological and social factors. Ketamine acts on the central nervous system, causing changes in perception, mood and consciousness. Its main mechanism of action is blocking NMDA receptors (N-methyl-D-aspartate receptors), which leads to changes in the neurotransmission of glutamate, the main excitatory neurotransmitter in the brain.

Mechanisms of addiction development:

1. Effects on NMDA receptors: Ketamine is an NMDA receptor antagonist and its action leads to a decrease in the excitatory activity of glutamate. This change in glutamatergic neurotransmission may contribute to the development of tolerance and dependence as the body attempts to compensate for the decreased glutamate activity by increasing its release or receptor sensitivity.
2. Changes in the brain's reward system: Although ketamine does not act directly on the dopamine receptor system, which plays a key role in pleasure and reward mechanisms, changes in the glutamatergic system can indirectly affect dopaminergic pathways. This may lead to altered perception of pleasure and contribute to the development of psychological dependence.
3. Tolerance: With regular use of ketamine, tolerance develops when higher and higher doses of the substance are required to achieve the initial effect. This can lead to an increase in the frequency and amount of ketamine used.
4. Psychological dependence: The effects of ketamine, such as feelings of dissociation, euphoria or altered perception, can become a means of coping with psychological discomfort, stress or depression. This may contribute to the development of psychological dependence. [4]
5. Physical dependence and withdrawal: Although ketamine causes less withdrawal than other substances such as opioids or alcohol, long-term use can lead to physical dependence. Withdrawal symptoms may include anxiety, depression, sleep disturbances, fatigue, and cognitive impairment.

Understanding the mechanism of ketamine dependence requires more research, especially with regard to the long-term effects of ketamine use on brain structure and function. It is important to seek medical attention at the first sign of ketamine dependence or abuse.

Epidemiology

The World Drug Report in 2015 categorized ketamine as a recreational drug worldwide, with 58 countries reporting illicit use.

Symptoms of the ketamine addiction

Ketamine addiction, like any other drug, can have serious consequences for a person's physical and mental health. The symptoms of ketamine dependence can vary depending on the duration of use, dosage and individual body characteristics. Like its chemical relative phencyclidine, ketamine's psychomimetic effects have made it a popular recreational drug. At low doses, it produces euphoric and dissociative effects, while at high doses it produces immobilizing and hallucinogenic effects. [5], [6] Here are some of the most common symptoms:

Physical Symptoms:

• Apersistent desire to use ketamine, even in spite of awareness of its harms.
• Tolerance to the drug, which makes it necessary to take larger and larger doses to achieve the desired effect.
• Withdrawal symptoms when trying to stop using, including anxiety, depression, irritability, insomnia, sweating, and tremors.
• Problems with memory and concentration.
• Physical exhaustion, deterioration of general health.
• Problems with the urinary system, including abdominal pain, difficulty urinating, and in some cases blood in the urine.

Psychological symptoms:

• Changes in mood, including depression, apathy, and irritability.
• Hallucinations and psychosis, especially with high doses or prolonged use.
• Loss of interest in previously enjoyable activities and hobbies.
• Problems with social interactions and relationships, isolation from friends and family.
• Increased risk of suicidal thoughts and behaviors.

Behavioral symptoms:

• Ketamine use becomes a priority, overriding the importance of work, school and family commitments.
• Continued use despite awareness of its negative impact on health, social and financial status.
• Concealing or lying about ketamine use.
• Financial hardship due to spending on the drug.
• Legal problems related to drug use or possession.

Ketamine toxicity can cause a variety of neurological, cardiovascular, psychiatric, urogenital and abdominal symptoms that are dose-dependent and depend on whether the administration of ketamine was iatrogenic or illicit. For example, some experts have linked the higher incidence of ulcerative cystitis in recreational users to the impurities with which the drug is mixed. Emergency providers should be aware of the various mechanisms for managing ketamine toxicity and preventing acute complications such as rhabdomyolysis, seizures, and chronic complications such as psychiatric disorders and ulcerative cystitis.

Developing an addiction to ketamine requires professional treatment and support. If you or someone you love is experiencing these symptoms, it is important to seek help from addiction treatment professionals. [7]

Complications and consequences

Research on the effects of ketamine addiction indicates serious mental and physical risks. Key findings from the studies reviewed include:

• Cognitive impairment: Ketamine use can lead to significant cognitive impairment, including problems with memory, attention and executive function. These effects may persist even after discontinuation of use.
• Psychiatric disorders: There is an association between ketamine use and an increased risk of developing psychiatric disorders such as depression, anxiety, and psychosis.
• Physical effects: Prolonged use of ketamine can lead to serious physical effects, including damage to the kidneys and urinary tract, which can manifest as abdominal pain, frequent and painful urination, and blood in the urine.
• Dependence and withdrawal: Ketamine can cause mental and physical dependence. Withdrawal symptoms include depression, anxiety, irritability and sleep disturbances.

Unfortunately, ketamine has now become a drug of abuse in many parts of the world, and its chronic and long-term use has resulted in multi-organ damage in experimental animals (Yeung et al., 2009 [8]; Chan et al., 2011 [9]; Tan et al., 2011a). [10]; Wai et al., 2012 [11]; Wong et al., 2012 [12]). Nervous system damage included neuronal loss, synaptic changes, changes in functional magnetic resonance imaging (fMRI) activity, and formation of mutated tau protein in neurons, as described in rodent and monkey models (Yeung et al., 2010a; Sun et al., 2011 [13]; Yu et al., 2012 [14]). [15]

Conclusion: Ketamine dependence can lead to serious and long-lasting mental and physical health consequences. It is important to provide access to information and support for those suffering from this addiction, and to conduct further research to understand and treat the effects of ketamine addiction.

Diagnostics of the ketamine addiction

Diagnosis of ketamine dependence, as with other substance dependence, is based on a comprehensive approach that includes clinical examination, history taking and, if necessary, laboratory tests. A detailed history of substance use is important, including frequency of ketamine use, dosage, duration of use, and the presence of tolerance and withdrawal symptoms.

Clinical diagnostic criteria

Diagnosis is usually based on clinical criteria such as the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) or ICD-10 (International Classification of Diseases, 10th revision) criteria. These criteria include:

• Failed attempts to reduce or control ketamine use.
• Significant amount of time spent on activities associated with ketamine use.
• A desire to use ketamine or a strong craving for the substance.
• Continued use of ketamine despite awareness of health or social problems caused or exacerbated by its use.
• Withdrawal from or reduction in social, occupational, or leisure activities due to ketamine use.
• Development of tolerance to the effects of ketamine.
• The occurrence of withdrawal symptoms when ketamine use is discontinued or reduced.

Laboratory tests

Laboratory tests such as urine or blood drug tests can be used to confirm ketamine use. However, it should be remembered that standard drug screening panels do not always include ketamine, so a specific request may be required.

Instrumental methods

Although specific instrumental methods are not used to diagnose ketamine dependence, they can be used to assess the consequences of substance abuse, including possible effects on the urinary system (e.g. Renal and bladder ultrasound) or on neuropsychological status.

Psychological assessment

Psychological assessments can also be helpful in identifying co-occurring mental health disorders that often accompany substance dependence, such as depression or anxiety disorders.

Diagnosis of ketamine addiction requires a comprehensive approach and should be carried out by qualified specialists. It is important to seek help at the first signs of addiction to start timely treatment and minimize possible complications.

Treatment of the ketamine addiction

Treatment for ketamine dependence, like treatment for other types of drug dependence, requires a comprehensive approach that includes both medical and psychosocial components. It is important to seek professional medical help, as withdrawal from drug use and subsequent recovery requires supervision and support from professionals. The following are key aspects of ketamine addiction treatment:

Detoxification

The first step in addiction treatment is detoxification, which aims to safely remove ketamine from the body and manage withdrawal symptoms. This process may require inpatient treatment, especially if the addiction is accompanied by severe physical or psychological symptoms.

Usually, patients with ketamine toxicity require only maintenance therapy. The effects of ketamine intoxication usually last from 15 minutes to several hours, depending on the dose, route of administration (e.g., orally rather than intravenously), metabolic capacity, and intrinsic sensitivity to the effects of the drug, which depends on genetics and a number of other factors. Factors. Factors. [16] Patients who are asymptomatic at the time of referral but report recent ketamine use should be monitored for six hours. Patients who show relief of symptoms after intoxication should be monitored continuously for one to two hours after the last symptom has disappeared.

Monitoring includes monitoring the patient's airway, breathing and circulation, as ketamine has the potential to cause cardiopulmonary failure, especially when administered in combination with other medications. If the patient is vomiting, the patient should be positioned so that he or she is leaning forward or lying on the left side with head down to avoid compromising airway patency and aspiration. Ketamine has been shown to induce bronchodilation and provide airway protection better than other anesthetics used for sedation, although aspiration has been reported. [17] If airway obstruction occurs, intubation can provide respiratory support. The patient's vital signs, especially temperature, should also be monitored for other symptoms, especially hyperthermia. If the patient develops severe symptoms or complications, he or she should be placed under monitor and hospitalized for observation.

If ketamine has been swallowed, especially in large quantities or together with other medications, activated charcoal may be used to decontaminate the gastrointestinal tract. Activated charcoal is usually administered at a dose of 1 g/kg with a maximum oral dose of 50 g/ng. Activated charcoal should be avoided in patients with unprotected airways or no peristaltic murmurs. [18] Administration of activated charcoal for a sufficiently short period of time may obviate the need for gastric lavage. Hemoperfusion and dialysis are generally ineffective because of the large volume of distribution of ketamine.

Pharmacotherapy

The U.S. Food and Drug Administration has not approved medications to treat ketamine overdose, but the drugs may help manage agitation and psychosis, according to the Toxicology Data Network. Benzodiazepines such as lorazepam and diazepam can relieve agitation, psychomimetic effects, hypertension, hyperthermia and seizures. Lorazepam is usually administered 2 to 4 mg intravenously or intramuscularly, and the diazepam dose is usually 5 to 10 mg intravenously. Butyrophenones, including haloperidol, have been used to treat psychotic episodes and agitation. Haloperidol is usually administered in doses of 5 to 10 mg intramuscularly and can be administered every 10 to 15 minutes until adequate sedation is achieved. However, clinicians should exercise caution when using haloperidol because decreased seizure threshold, prolongation of the QT interval, and flutter-fibrillation correlate with prolonged use of haloperidol. Unnecessary stimulation should be avoided, and the patient's room should be dark and quiet. If necessary, the medical team can provide physical restraints to initiate intravenous access and ensure patient safety. If sedation does not adequately manage hyperthermia, evaporative cooling may reduce heat production.

Other medications may manage other symptoms. Alpha-2 agonists such as clonidine may treat or prevent the psychomimetic side effects of ketamine, increase hemodynamic stability by lowering blood pressure, and provide synergism with the analgesic action of ketamine. [19], [20], [21] Clonidine is usually administered at a dose of 2.5-5 mcg/kg orally, although patches can be used for prolonged steady-state infusions, and intravenous clonidine can be used for acute symptoms. Atropine or glycopyrrolate may prevent and treat excessive salivation associated with ketamine use, and physostigmine may help resolve nystagmus and blurred vision. Hydration with crystalloids may improve dehydration.

Psychotherapy

Psychotherapeutic interventions play a key role in the treatment of ketamine dependence. These include:

• Cognitive Behavioral Therapy (CBT): helps change negative patterns of thinking and behavior associated with drug use.
• Motivational counseling: aims to increase motivation to change and develop coping strategies for drug use problems.
• Group therapy and self-help programs: provide support and share experiences with others facing similar problems.

Social support and rehabilitation

Rehabilitation programs and social support can help with recovery and return to normal life. Including family and friends in the treatment program can strengthen social support and promote successful recovery.

Ongoing monitoring and relapse prevention

After completing the main course of treatment, it is important to continue to monitor the patient's condition and implement measures to prevent relapse. This may include regular meetings with a therapist, participation in support groups and the development of individualized strategies for coping with stress and avoiding situations that may encourage relapse.

Ketamine addiction treatment is a complex and multi-step process that requires an individualized approach and the active participation of the patient, his or her family and medical professionals.

Forecast

Because ketamine overdose is relatively rare and its concomitant administration often complicates severe cases, information on survival is limited. Cases of ketamine dependence are relatively rare, and statistics on relapse rates and prognosis are scarce. Nevertheless, ketamine remains one of the few psychoactive drugs with a serious complication rate of less than 1%. [22], [23]

According to several studies, the risk of accidental death in ketamine poisoning is associated with the highest mortality rate. In a longitudinal study, two ketamine users died within one year: one from drowning in a bathtub and the other from hypothermia. [24]

Ketamine in the background of other cardiovascular diseases can lead to catastrophic consequences. Ketamine stimulates the sympathetic nervous system, resulting in increased heart rate, cardiac output, and blood pressure. Consequently, intoxicated patients with severe cardiovascular disease or hypertension may be at increased risk for stroke, myocardial ischemia, or increased intracranial pressure. The guidelines for the administration of ketamine for chronic pain note several case reports of ketamine inducing unstable angina and arrhythmias.

Acute administration of ketamine may rarely cause encephalopathy, seizures or coma. Acute kidney injury, electrolyte disturbances, hepatic failure and rhabdomyolysis may also occur.

Chronic ketamine abuse is associated with ulcerative cystitis [25], which can reduce bladder capacity and ureter size and contribute to hydronephrosis. Symptomatically, urologic complications of chronic ketamine abuse can cause abdominal pain, pelvic pain, hematuria, dysuria, increased frequency, urges, and urinary incontinence. Chronic ketamine use may also be associated with liver abnormalities, as evidenced by LFT or biliary tract abnormalities, or diagnosed by imaging studies including CT and ERCPH. [26] The genitourinary and hepatic effects of ketamine appear to be dose dependent.

Some psychiatric effects of ketamine, including hallucinations and vivid dreams, may recur days or weeks after ketamine use, although these effects are usually temporary. [27] However, chronic ketamine use causes more long-term psychiatric effects such as depression, memory and concentration problems. Ketamine dependence can occur, as chronic users of PCP or ketamine report psychiatric symptoms including anxiety, irritability, depression, and changes in sleep patterns and energy throughout the day after discontinuing ketamine use. [28] However, there is no definitive evidence of physical dependence in the form of withdrawal syndrome. Ironically, an intranasal form of ketamine has recently been approved for the treatment of depression [29] and has attracted attention as a treatment for persistent PTSD. The drug is also being actively investigated as a means of reducing alcohol, cocaine or opioid dependence. [30]

List of studies related to the study of ketamine addiction

1. Decreased Blood Levels of Oxytocin in Ketamine-Dependent Patients During Early Abstinence

   • Authors: Ming-Chyi Huang, Lian-Yu Chen, Hu-Ming Chang, X. Liang, Chih-Ken Chen, Wan-Ju Cheng, Ke Xu
   • Year of release: 2018
   • Journal: Frontiers in Psychiatry

2. Use of naltrexone in ketamine dependence

   • Authors: Amit X Garg, P. Sinha, Pankaj Kumar, O. Prakash
   • Year of release: 2014
   • Journal: Addictive behaviors

3. Alterations in regional homogeneity of resting-state brain activity in ketamine addicts

   • Authors: Y. Liao, Jinsong Tang, A. Fornito, Tieqiao Liu, Xiaogang Chen, Hong-xian Chen, Xiaojun Xiang, Xu-yi Wang, W. Hao
   • Year of release: 2012
   • Journal: Neuroscience Letters

4. Chronic effects of ketamine on gene expression changes in neurotransmitter receptors and regulators-A PCR-array study

   • Authors: Sijie Tan, Ju Zou, Mei-xiang Li, D. Yew
   • Year of release: 2015
   • Journal: Molecular & Cellular Toxicology

5. The Nonmedical Use of Ketamlne, Part Two: A Review of Problent Use and Dependence

   • Authors: K. Jansen, Rachael Darracot-Cankovic
   • Year of release: 2001
   • Journal: Journal of Psychoactive Drugs

6. Family History of Alcohol Dependence and Initial Antidepressant Response to an N-methyl-D-aspartate Antagonist

   • Authors: Laura E. Phelps, N. Brutsche, J. R. Moral, D. Luckenbaugh, H. Manji, C. Zarate
   • Year of release: 2009
   • Journal: Biological Psychiatry

Literature

1. Ivanets, N. N. Narcology. National manual. Brief edition / ed. By N. N. Ivanets, M. A. Vinnikova. - Moscow : GEOTAR-Media, 2020.
2. Maya Rokhlina: Addictions. Toxicomanias. Mental and behavioral disorders. LitTerra, 2010.