It has been widely used to induce narcosis, because of the preservation of cardiovascular and respiratory functions, and in the context of an emergency, because it allows the preservation of pharyngeal and laryngeal reflexes. Recently, several experimental studies have raised the possibility of neurotoxic effects in the developing brain 145. Animal studies suggest that neurodegeneration, with possible cognitive sequelae, is a potential long‐term risk of anesthetics in neonatal and young pediatric patients.

A wealth of evidence indicates the value of ketamine in treating severe pain, including conditions such as trauma, fractures, abdominal and flank pain, low back pain, and extremity pain. When used for pain management, sub-dissociative dosing, otherwise known as low-dose ketamine (LDK), is used either alone or as an adjunct to other pain relief medications. It is safe and effective to use in combination with injectable nonsteroidal pain medications as well as opioids. As concerns about opioid use have grown, it has become more widely accepted.12 The dosage determines the application and resulting effects of the drug, leading to variations in the prescribing protocol.

• Ongoing research explores the potential applications of ketamine in psychiatry across all isomeric forms.
• An interprofessional approach is crucial for maximizing the drug’s effectiveness, ensuring that healthcare providers are well-versed in patient eligibility, intravenous (IV) ketamine administration, and potential post-treatment reactions.
• Cytochromes, belonging to the cytochromes P450 system and responsible for ketamine metabolism, are not totally identified 12, but in humans, several microsomal enzymes are responsible for norketamine demethylation.
• The antagonism of NMDA receptor is responsible for the specific ketamine properties (amnesic and psychosensory effects, analgesia, and neuroprotection).
• Strict adherence to guidelines is essential to mitigate risks like psychological effects, cardiovascular issues, and dependency.

The clinical toxicology of ketamine

• Butyrophenones, including haloperidol, have been used to treat psychotic episodes and agitation.8 Haloperidol is typically given in doses of 5 mg to 10 mg IM and can be administered every 10 to 15 minutes until adequate sedation is achieved.
• From a pharmacological point of view, there is an alteration 60, also a possible hypofunction 61 of NMDA receptors, with a hyperglutamatergic state 62.
• The site of the proton detector is unknown, but it is assumed that it is ane area near ABD domain.
• The adoption of protocols that emphasize SAD usage and robust monitoring can significantly improve patient outcomes59,60.
• Four case reports, describing 4 male participants, reported on 3 unique pharmacological interventions to promote relapse prevention or the treatment of craving in the context of successful withdrawal.

The national survey-based ‘Monitoring the Future Study’ in the United States reported that ketamine use decreased between 2012 and 2002, from 2.5% to 1.5%, and from 1.3% to 0.4%, among 12th graders and college students, respectively. In the United Kingdom, where ketamine has been classified as a Class C drug since 2006,9 ketamine misuse has also decreased during the 21st century. According to the World Health Organization fact file on ketamine, the percentage of adults and young adults in the United Kingdom who used ketamine decreased from 0.6% to 0.4% and from 1.8% to 0.8%, respectively, between 2011 and 2013. We implemented robust methods to conduct the review, using a broad search strategy and a predefined protocol to capture evidence from studies of any design. Three-quarters of published studies were case reports, and as such, meta-analysis could not be performed.

Patients may be unable to provide a relevant history, and clinicians should seek pertinent clinical information from witnesses. No studies reported on any safety outcomes, nor did they describe any concerns with regard to pharmacological intervention tolerability. Four case reports, describing 4 male participants, reported on 3 unique pharmacological interventions to promote relapse prevention or the treatment of craving in the context of successful withdrawal. We do not know precisely the location of the proton detector, but it is known that protons act by stabilizing the closed state of the channel, independently of membrane polarization. Thus, tissue acidosis that accompanies ischemia or epileptic discharges reduces damage to neurons 99.

Safety considerations and risk mitigation strategies for ketamine use: a comprehensive review

Ketamine provides a totally different state of anesthesia compared with other anesthetic drugs (barbiturates, propofol, benzodiazepines, halogenated volatile anesthetics, etc.), the so‐called “dissociative anesthesia” 2. This is a cataleptic state in which the eyes stay open, with a typical nystagmus and conservation of laryngeal, corneal, and papillary reflexes. The anesthesia depth is compatible with the performance of a surgical procedure, with the absence of motor reaction orientated toward the nociceptive stimulus 28. Injection site reactions, erythema, localized pain, and morbilliform rash are dermatological responses of ketamine administration19. Ketamine intoxication can present similarly to PCP, methoxetamine, and dextromethorphan intoxication, all of which bind to the N-methyl-D-aspartate receptor.

Importance of provider training

Two studies reported on pharmacological treatments for ketamine intoxication, 6 for withdrawal, and 4 for craving or relapse prevention. All studies reported only descriptive outcomes, and as such, meta-analysis was not possible. All results are thus reported narratively, and a summary of all included studies, with outcomes described verbatim, is available in Table 1.

Figure

The medication is preferred for patients with bronchospasm because of its bronchodilatory properties. Ketamine is used for procedures that require short-term sedation or anesthesia and can be safely used in a wide age range, starting from 3 months. The World Drug Report in 2015 categorized ketamine as a worldwide recreational drug, with 58 countries reporting illicit use. However, ketamine misuse occurs on a relatively small scale, and PCP derivatives constituted only 1% of “new psychoactive substances” reported to the United Nations Office of Drugs and Crime in 2014 (fact file on ketamine). Ketamine misuse often occurs in combination with other substances, including alcohol, amphetamines, MDMA, cocaine, and caffeine.

Glutamate‐Dependant Mechanisms

Patients who experience symptom relief after intoxication should have continuous monitoring for 1 to 2 hours after their last symptom resolves. In the United States, where ketamine classifies as a C-III controlled substance since 1999, ketamine misuse has increased since the 1980s.9 However, compared to the surges in opioid and illicit cannabis misuse, ketamine misuse has occurred on a relatively small scale. Ketamine was involved in 0.033% of the United States Emergency Department visits involving illicit drugs in 2005, with this proportion increasing slightly to 0.12% in 2011 (Drug Abuse Warning Network, 2011). Ketamine-related emergency department visits often involved other drugs, with 71.5% of ketamine-related visits in the United States in 2011 involving alcohol (Drug Abuse Warning Network, 2011).

Used as a chlorhydrate in a slightly acid (pH 3.5–5.5) aqueous solution, ketamine sometimes includes benzethonium chloride or chlorobutanol as preservatives. Ketalar® is the racemic mixture (optically inactive) of 2 enantiomers of equal quantity (isomers that diverge light in opposite ways). The active enantiomer is S(+)‐ketamine (“S” spatial structure, light diverged to the right), two times stronger than the racemic form, and four times than the ketamine toxicity statpearls ncbi bookshelf R(−)‐ketamine isomer.

Kinetics and Metabolism’s Modification Due to Other Drugs

Structured clinical guidelines provide a framework for standardized ketamine use, particularly for TRD, emphasizing the importance of specific dosing protocols tailored to individual patient needs52. Initial dosing typically starts at 0.5 mg/kg administered over 40 minutes, with adjustments made based on patient tolerance and weight46,85. When considering possible intervention, patients and professionals need to understand that the current evidence base available for pharmacological treatment in ketamine use disorder is limited and of very low quality. Although this review demonstrates a clear need to investigate novel compounds in the management of ketamine use disorder, there are some promising avenues for future potential research based on the published literature.

In animal studies, however, the safety ratio (defined as the proportion of the usual recreational dose to a fetal or lethal dose) has been used to evaluate the acute risk observed with ketamine. Five case reports, describing 6 male participants, and 1 retrospective case series in 104 participants reported on different pharmacological strategies to treat ketamine withdrawal. Because of an increase of intracellular calcium, the NMDA receptor stimulation by glutamate liberated in the nociceptive afferents leads to the activation of a neuronal NO‐synthase (NO‐s) and the production of NO from L‐arginine 106. NO stimulates the synthesis of cyclic guanosine monophosphate 3′5′ (c‐GMP), which plays a role in the central transmission of pain messages (“nitroxidergic” transmission) 107.

If sedation does not adequately manage hyperthermia, evaporative cooling can decrease heat production. We searched MEDLINE, EMBASE, PsychINFO, and CENTRAL (Cochrane Central Register of Controlled Trials) from database inception to November 14, 2023, for studies of any design that reported on any pharmacological intervention in the management of ketamine use disorder. We extracted any reported measure of efficacy or tolerability and assessed outcome quality using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. We planned to combine outcomes using random-effects meta-analysis, where this was not possible results were reported narratively. NMDA receptor is implicated in depression state, which is strongly related to the glutamatergic system as recently demonstrated 63.

Difficulty in abstract thinking was correlated with pronounced activations in prefrontal as well as in anterior cingulate regions, whereas hyperactivations in the left superior temporal gyrus were found in association with a lack of spontaneity and flow of conversation. In the absence of behavioral impairments during verbal fluency, NMDAR blockade evoked psychopathological symptoms and cortical activations in regions previously reported in schizophrenia patients 55. Ketamine’s pharmacological benefits span various medical fields, but its safety profile necessitates careful use.