Optimizing ketamine dosing strategies across diverse clinical applications: a comprehensive review

Abstract

Ketamine has emerged as a versatile therapeutic agent with applications spanning anesthesia, pain management, and psychiatric disorders. This review examines ketamine’s clinical utility across diverse administration routes, including intravenous, intramuscular, intranasal, and oral, emphasizing the need to individualize dosing regimens. We explore factors influencing ketamine dosing, such as patient characteristics (age, weight, comorbidities), concomitant medications, and desired clinical effects, while balancing efficacy and side effects. The impact of dose, infusion rate, and administration frequency on therapeutic outcomes is analyzed to provide a comprehensive understanding of its clinical implications. The review highlights the critical role of individualized dosing regimens tailored to patient-specific factors. The therapeutic effects of ketamine are dose-dependent, with infusion rate and administration frequency significantly influencing both efficacy and safety. Achieving a balance between clinical benefits and potential side effects remains paramount. There are gaps in knowledge, necessitating for further research into long-term effects, alternative administration routes, and personalized approaches informed by pharmacokinetic variability. Developing standardized, evidence-based protocols and exploring alternative strategies will improve ketamine’s therapeutic potential while addressing safety, misuse, and availability concerns.

Introduction

A pharmaceutical agent called ketamine was first used in medical practices 50 years ago. It is well known for its unique qualities and the vast range of therapeutic uses in several medical fields. Initially, ketamine was developed as an anesthetic. In 1966, Corssen and Domino proposed the concept of dissociative anesthesia and conducted the first clinical study of it^[1]. Patients under dissociative anesthesia appear awake and maintain their airway reflexes but are not sensitive to their surroundings^[1]. The utilization of ketamine has increased recently because of its quick onset of action, safety record, and ability to work for a variety of patient types. In anesthesia, ketamine is prized for its capacity to produce dissociative anesthesia while preserving circulatory stability, making it particularly helpful for high-risk patients^[2]. Beyond the original use of ketamine in anesthesia, it has shown great promise in several medical fields. Sub-anesthetic ketamine dosages have demonstrated analgesic effects in the treatment of acute and chronic pain, including neuropathic pain^[3]. Moreover, ketamine has attracted a lot of interest in the field of psychiatry because of its rapid antidepressant effects in depression, treatment-resistant depression (TRD), and post-traumatic stress disorder (PTSD), as well as its role in enhancing strategies for managing mood disorders^[4,5]. Ketamine increases the synaptic strength and neuroplasticity by promoting the release of neurotransmitters like glutamate. The therapeutic flexibility of ketamine is supported by its dual activity as a modulator of glutamatergic transmission and an antagonist of the N-methyl-d-aspartate (NMDA) receptor. Ketamine binds to the NMDA receptor and inhibits excitatory neurotransmission. As a result, ketamine not only induces dissociative effects but also enhances synaptic plasticity, which is significant in the management of depression^[2].

Despite the wide range of applications of ketamine, its dosing guidelines are still under study^[6]. The ideal dosage for optimizing therapeutic efficacy while reducing side effects varies greatly depending on patient characteristics and clinical setting^[7,8]. This review aims to explore the optimization of ketamine dosing strategies across diverse clinical applications, synthesizing the latest evidence to enhance patient outcomes while mitigating potential risks. It provides a comprehensive overview of ketamine’s evolving role in medicine and offers insights into how tailored dosing regimens can maximize its therapeutic potential.

Methods

A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and the Cochrane Library. The following keywords and Boolean operators were used: ([Ketamine] AND [Dosing OR Dose Optimization OR Dosage]) AND ([Anesthesia] OR [Pain Management] OR [Depression] OR [Psychiatric Disorders] OR [Chronic Pain]). The search focused on studies discussing ketamine administration routes, dosing strategies, pharmacokinetics, clinical outcomes, and safety profiles. Reference lists of relevant articles and reviews were also screened to identify additional sources. No filters were applied except for limiting to English-language studies involving human subjects, published between 2010 and 2025.

A cross-disciplinary approach to ketamine use

Clinical application of ketamine

Ketamine is extensively used for both anesthetic and non-anesthetic reasons^[1].

Anesthesia

The rapid onset of action, safety profile, and hemodynamic stability of ketamine contribute to its increased usage. It can be used for short-term procedural anesthesia, brief medical procedures that don’t require muscle relaxants, emergent intubation, and as a pre-anesthetic for the induction of general anesthesia. It is also used to enhance the efficacy of low-potent anesthesia, such as nitrous oxide (N₂O)^[9].

Various sedative and analgesic drugs, such as fentanyl, midazolam, atropine, etomidate, ketamine, and succinylcholine, may be used to ease tracheal intubation^[10]. A randomized clinical trial (RCT) done on 235 critically ill patients who needed emergent intubation in the emergency room (ER) reported that ketamine is a reliable and efficient substitute for etomidate in endotracheal intubation for critically ill patients^[11].

Traumatic head injury

Traumatic head injury can lead to bleeding in the brain and increase intracranial pressure, presenting with different neurological symptoms. A meta-analysis of RCTs analyzes the published data and found that ketamine doesn’t increase intracranial pressure in comparison with opioids but also provides good maintenance of hemodynamic status^[12].

Neurological diseases

Status epilepticus (SE) is an emergent condition that is diagnosed when a seizure persists for over 5 min or if multiple seizures occur without the individual regaining normal consciousness between episodes^[13]. SE without treatment can lead to resistant SE. A recent systematic review and meta-analysis of six studies involving 172 patients with resistant SE treated with ketamine found that a weighted maximum dose of 7.44 mg/kg/h provided evidence supporting using ketamine in managing SE and resistant SE in pediatrics^[14].

HIGHLIGHTS

• Children and elderly require adjusted dosing due to metabolism differences.

• Liver/kidney impairment affects ketamine clearance and requires dose modifications.

• CYP enzyme inhibitors (e.g., fluoxetine) may prolong ketamine effects.

• Lower doses (subanesthetic) are effective for depression and pain without significant psychotropic effects.

• Rapid infusions increase risk of psychotomimetic side effects.

In another systematic review encompassing 19 studies, a total of 336 patients ranging in age from 9 months to 86 years were reviewed. The dosing varied between adult and pediatric patients: adults received 0.5 mg/kg (bolus) and 0.2–15 mg/kg/h (maintenance), whereas pediatric patients received 1–3 mg/kg (bolus) and 0.5–3 mg/kg/h (maintenance). The results indicated that ketamine is safe and effective in managing resistant SE^[15].

Depression

The use of NMDA ketamine has been investigated as a new medical treatment for TRD^[1]. Early studies employed a conventional dosage of 0.5 mg/kg over 40 min given intravenously, which resulted in fast antidepressant effects. However, data shows that ketamine may have an “inverted U-shaped” dose–response curve, indicating that moderate subanesthetic doses are more effective than lower or higher ones^[16]. In larger controlled studies, a dosage of 0.5 mg/kg has been shown to have the most consistent antidepressant effects, although smaller doses (e.g., 0.2 mg/kg) are less beneficial for serious depression^[16]. Higher dosages have not been extensively investigated for effectiveness, although they may increase the possibility of side effects.

The effectiveness of racemic ketamine (a mix of R-ketamine and S-ketamine) and esketamine (pure S-ketamine) in treating depression has been evaluated through a systematic review and meta-analysis. Nine of the 36 studies used esketamine, and the other 27 used racemic ketamine. Response, remission, and depression severity improved with both types of ketamine^[17]. Moreover, one intravenous (IV) dosage of ketamine was administered to 120 participants with major depressive disorder (MDD) as part of the trial. The severity of depression was evaluated prior to the infusion, as well as 4 and 24 h post-infusion, using the Montgomery–Asberg Depression Rating Scale (MADRS)^[18]. Adverse effects were also recorded at these time points. The results demonstrated ketamine’s rapid efficacy, providing significant relief in acute suicidal crises within hours of administration. Statistically significant improvements in depression severity were observed at both 4 and 24 h post-infusion, further supporting ketamine’s rapid therapeutic effects^[18].

Some studies show that a single dosage of IV ketamine can give antidepressant benefits for up to 7 days, but repeated infusions result in higher response rates and more persistent antidepressant effects^[19]. For example, six injections over 2 weeks had a 70.8% response rate, with benefits lasting an average of 18 days^[20]. Furthermore, in another trial, thrice-weekly infusions over 2 weeks resulted in a substantial decrease in depression symptoms, alongside weekly maintenance treatments that helped maintain the benefits and prevent relapse^[19,21]. These data indicate that repeated and strategically spaced ketamine infusions can increase the amplitude and durability of its therapeutic effects.

Postoperative disorders

The perioperative use of IV esketamine to limit postoperative pain is challenging. A meta-analysis reviewed postoperative pain in adults following abdominal surgery. The findings indicated that the esketamine group experienced significantly lower pain-at-rest scores at 4 and 24 h after surgery compared to the control group. However, no significant difference in pain was observed between the two groups at 48 h. Additionally, esketamine lessened movement-related pain 24 h after surgery but not 48 h later. The two groups experienced identical postoperative problems, such as nausea, vomiting, and psychotomimetic symptoms. Notably, this study focused exclusively on abdominal surgery patients^[22].

Postoperative fatigue syndrome (POFS) after surgery is a common symptom that presents with fatigue, sleep problems, decreased attention, and other enduring symptoms^[23]. Many studies have reported that the administration of esketamine during the perioperative phase can improve recovery and postoperative rehabilitation^[24]. However, it is not entirely established. A recent RCT study using standardized anesthesia and esketamine versus standardized anesthesia only in the management of POFS found that the use of esketamine during the perioperative period can speed up the recovery of POFS after laparoscopic radical gastrectomy without unpleasurable effects^[25].

Another trial estimated the efficacy of esketamine in reducing postoperative sleep disturbance (PSD) in gynecological laparoscopy procedures and found that Esketamine infusion during surgery has shown to reduce the incidence of PSD in patients undergoing gynecological laparoscopic procedures. However, larger studies are needed to confirm its preventive benefits^[26].

Adjusting doses for optimal outcomes

Ketamine dosage differs depending on the intended outcome, patient age, and underlying medical conditions.

For analgesic and sedative effect

A study highlights the benefits of using ketamine for analgesia in the ER, administered at a low dose of 0.1–0.3 mg/kg via slow infusion over 15 min. This method has fewer adverse effects than rapid infusion over 1 min^[27]. A total of 500 mg of ketamine via the oral route in adults shows an analgesic impact within 30 min, extending for 4–6 h^[28].

The Food and Drug Administration (FDA) recommends an anesthetic induction dose of IV ketamine ranging from 1 to 4.5 mg/kg administered over 60 s for adults. A typical dose of 2 mg/kg is generally required to induce anesthesia or dissociative effects for about 5–10 min. The effects take impact within 10–30 s and persist for 5–15 min^[29]. The first IM dose of ketamine typically ranges from 6.5 to 13 mg/kg. A 10 mg/kg dose generally induces surgical anesthesia within 3–5 min, with the effects lasting for 12–30 min. For chronic pain, subcutaneous (SC) injections of ketamine at 0.1–1.2 mg/kg/h have shown optimal outcomes^[30].

The ketamine infusion rate does not appear to have a major influence on pain reduction effectiveness, as equivalent durations of alleviation were found at both high and low infusion rates^[31]. According to most studies, larger infusion rates delivered in ICU settings resulted in longer pain relief duration, while lower rates over a longer length of time had equivalent benefits in both inpatient and outpatient settings. Furthermore, infusion rate had no meaningful effect on side effect safety^[31].

For psychological disorders

A study reviewed 24 articles on the use of ketamine in the treatment of depression with suicidal ideation. It was found that the optimal dose is 0.5 mg/kg IV over 40 minutes. However, data on IM, intranasal (IN), and oral ketamine use are scarce and of lower quality. Research on these formulations shows inconsistent results in limiting suicidal ideation and self-injurious behavior^[18,32].

Moreover, another study shows that IV administration of 0.1–0.75 mg/kg over 45 min can show a reduction of depression symptoms. Still, it requires the administration of treatment twice every week for extended relief. So, remission can be achieved after six sessions^[33]. A low oral dose of 1 mg/kg thrice a week can be an adjunct to TRD^[34]. IM ketamine can also be used for depression at a small dose of 0.1 mg/kg^[35]. For SC injections, doses ranging from 0.1 to 0.5 mg/kg of racemic ketamine and 0.5 to 1 mg/kg of esketamine are effective for treating depression^[35,36].

Additionally, the effect of ketamine dose on treatment results varies based on the psychiatric disease being treated and the mode of administration. In TRD, subanesthetic ketamine is often given at a dose of 0.5 mg/kg over 40 min, which leads to considerable improvements in depression symptoms^[37].

Ketamine can also reduce opioid consumption due to its potential for addiction when administered at a low-dose continuous infusion rate of 0.06 to 0.30 mg/kg/h in management of chronic pain^[38]. A recent small-scale study involving 48 pediatric patients having scoliosis spine surgery revealed that administering a subanesthetic ketamine dose of 0.5 mg/kg, followed by an infusion at 0.12 mg/kg/h for 72 h, showed no significant difference from placebo regarding opioid consumption or pain levels^[39]. Another cohort study analyzed different ketamine doses based on opioid tolerance. Patients who were not opioid-tolerant received ketamine infusions of 0.05–0.4 mg/kg/h, while those who were opioid-tolerant received doses from 0.05 to 1 mg/kg/h^[40].

Dakar et al assessed the impact of various ketamine dosages on the course of treatment for cocaine-dependent patients. After receiving two doses of ketamine (0.41 mg/kg and 0.71 mg/kg), ketamine produced markedly stronger acute mystical-type effects (as measured by hood mystical experience scale [HMS]) compared to the active control lorazepam. The 0.71 mg/kg dose of ketamine was linked to significantly higher HMS scores than the 0.41 mg/kg dose^[41]. These mystical experiences showed a stronger desire to stop using cocaine than did the dissociative effects, suggesting a possible psychological mechanism underlying ketamine’s therapeutic benefits.

Therefore, ketamine administered in carefully regulated sub-anesthetic dosages under close observation can improve therapeutic results without producing long-term psychotropic adverse effects. Higher doses of ketamine produced more potent mystical experiences, although both doses were well tolerated and had no long-term negative consequences^[41].

Dose-limiting toxicity

Due to its wide range of action sites, ketamine toxicity can develop through various routes, including inappropriate dosages of IV or IN ketamine, or through abuse and misuse via IV, IM injection, nasal administration, oral consumption, or smoking^[42].

Symptoms of ketamine toxicity can be general, ranging from sedation and decreased consciousness to the affection of multiple systems without being specific to overdose. These symptoms include nystagmus, gastrointestinal upset, and cardiac issues like hypertension, tachycardia, palpitations, arrhythmias, chest pain. Additionally, patients may experience disorientation, anxiety, confusion, paranoia, dysarthria, and psychomotor disturbances^[43]. Other symptoms unique to a ketamine overdose, which may be fatal, include respiratory depression, apnea, hypotension, bradycardia, and myocardial infarction. Additionally, seizures, stupor, and coma can occur^[4].

While low-dose ketamine (e.g., 0.5 mg/kg) is beneficial in treating psychiatric disorders like depression, it also carries the risk of causing symptoms similar to schizophrenia^[44]. Research indicates that ketamine is linked to a greater rise in psychomimetic effects, such as hallucinations and emotional withdrawal. Careful dose and delivery methods are required to balance between safety and efficacy. The strength of these effects varies depending on the infusion technique used. In particular, compared to continuous infusion alone, the combination of a bolus and continuous infusion increases the likelihood of positive symptom induction^[44]. Therefore, slower infusion rates (40–60 min) without bolus administration are advised to decrease side effects, especially psychotic symptoms. By lowering the possibility of causing momentary psychotic symptoms, this method makes the drug safer to employ therapeutically for illnesses like depression.

The optimal dose must be applied according to guidelines to achieve the preferred effect and prevent toxicity^[45]. It is critical to titrate the dose to get the desired clinical impact while minimizing side effects. Different doses have proven to influence efficacy and safety: sub-anesthetic doses of ketamine are helpful for lowering pain and opioid requirements, particularly in acute and chronic pain treatment, and have fewer respiratory depressive effects than opioids^[28]. Higher doses, particularly when delivered fast, are linked with an increased risk of undesirable effects like psychotomimetic responses and respiratory depression. Low-dose techniques such as IV administration of less than 1.2 mg/kg/h, have been demonstrated to be useful in lowering postoperative pain, limiting opioid use, and limiting side effects such as hallucinations^[46]. While high-dose strategies such as quick bolus injections have been related to a higher prevalence of psychotomimetic symptoms and agitation, particularly with R-ketamine, which is less powerful but causes more auditory and visual disruptions^[28,46].

A summary of the effect of ketamine dose on therapeutic outcomes, including strategies to maximize efficacy while minimizing adverse effects, has been presented in Table 1.

Table 1.

Effect of ketamine dose strategy on therapeutic outcome^{[16,37,41,46]}

Dose strategy	Dosage (mg/kg)	Efficacy	Safety profile	Notes
Low-dose strategy	0.5	Enhanced early antidepressant response; minimal improvement overall.	Minimal risk of psychomimetic effects (e.g., hallucinations).	Good balance of efficacy and safety; safe for individuals with mood disorders.
High-dose strategy	0.7–2.8	Potential for greater efficacy but may not be sustained.	Higher risk of adverse effects (e.g., confusion, agitation).	Increased risk of side effects, particularly in bipolar disorder patients; careful monitoring is needed.
Intranasal route	0.25–4	Rapid onset of antidepressant effects; less invasive.	Risk of transient psychomimetic symptoms, lower than IV.	It may offer rapid symptom relief in urgent clinical situations.
Intravenous route	0.25–1 (analgesia)/1–2 (anesthesia)	Effective for sedation and analgesia; varying efficacy based on dose.	Higher doses are linked to significant side effects.	Considered safe when administered at lower doses, higher doses must be closely monitored.

The management of ketamine toxicity is primarily supportive, as there is no approved medical treatment for ketamine overdose. The effects of toxicity can extend from 15 minutes to several hours, based on factors such as dose, route of administration, individual sensitivity, and metabolic capacity^[47]. Activated charcoal can be administered at 1 mg/kg in very high ketamine doses or mixed drug ingestion^[48]. Benzodiazepines, such as lorazepam (2–4 mg IV) or diazepam (5–10 mg IM), can be used to reduce agitation, psychomotor disturbances, hypertension, and psychosis^[42]. Additionally, haloperidol can be given at a dose of 5–10 mg every 10–15 min till sedation is reached.

Routes of Administration

Ketamine can be given in different ways, with different bioavailabilities summarized in Table 2 ^{[28,33,49–55]}.

Table 2.

Ketamine administration methods and their bioavailability

Route	Bioavailability (%)	Key characteristics
Intravenous (IV)	100	Rapid onset, direct venous system delivery.
Intranasal (IN)	40–50	Efficient due to nasal vascularity, and fast brain access.
Intramuscular (IM)	93	High vascularity of muscles, effective absorption.
Subcutaneous (SC)	80–93	Effective absorption, and an alternative to IM.
Oral	20–30	First-pass metabolism reduces bioavailability.
Other routes	Varies	Includes spinal, intraosseous, and sublingual options.

Individualizing ketamine dosing regimens

Age and weight

Age and weight are important factors when it comes to ketamine dosage, especially in young and elderly patients. Because of developmental factors, the pharmacokinetics of ketamine differ significantly from those in adults. Since ketamine is metabolized more quickly in pediatric patients, higher weight-based dosages are required to produce adequate sedation and anesthesia^[56]. An RCT involving children aged 3–18 years evaluated the effects of IV ketamine at doses of 1, 1.5, and 2 mg/kg. The study demonstrated that the necessity for redosing was significantly higher in the 1 mg/kg group compared to the higher doses. The redosing required in 16%, 2.9%, and 5% of cases for the 1 mg/kg group, 1.5 mg/kg, and 2 mg/kg groups, respectively^[57]. This indicates that higher doses may enhance efficacy and reduce the frequency of redosing required to maintain adequate sedation. Moreover, a regression analysis of medical records from children who were successfully sedated with ketamine revealed that the required dose for induction increased with age, height, weight, and body surface area (BSA). The following formula was derived to calculate the appropriate dose: Dose (mg) = −1.62 + (0.7 × age in months) + (36.36 × BSA in m²)^[58]. In contrast, elderly patients tend to have reduced metabolic rates and altered pharmacokinetics, which necessitates lower ketamine doses to prevent prolonged sedation and potential adverse effects^[56](Fig. 1).

Figure 1.

Ketamine dosing based on age and weight.

Another significant factor affecting ketamine dosage is weight. Dosing has always been determined using total body weight (TBW), although this method may cause variations in plasma concentrations among people with different body compositions^[56]. A systematic review indicated that weight-to-scale doses are essential for efficient dosing techniques in pediatric and adult populations because they reduce age-dependent variability in plasma concentration^[58]. Weight-based dosage remains very important in pediatric populations since children’s body composition changes at a high rate as they grow^[56].

Comorbid conditions

Ketamine dosing techniques are significantly affected by comorbid conditions, including neurological diseases, liver and kidney disease, cardiovascular (CV) problems, and respiratory disorders. The pharmacokinetics of ketamine may change in people with CV illnesses, which could raise their risk of CV problems. As a result, in these populations, careful consideration and dosage adjustments are crucial^[59]. Szarmach et al found that after the second ketamine infusion, people with hypertension showed a notable increase in systolic blood pressure than people without hypertension. Furthermore, patients with diabetes mellitus exhibited a substantial increase in heart rate throughout several infusions, highlighting that comorbid diseases can significantly alter CV responses^[59].

Ketamine dosage in individuals with liver and kidney impairments must be carefully monitored as these conditions have a significant impact on drug metabolism and excretion. A meta-analysis study of 51 patients with ketamine-associated uropathy found that those with hydronephrosis had notably lower estimated glomerular filtration rates (eGFR) compared to those with ketamine cystitis, with 50% of hydronephrosis patients reaching endpoints of end-stage renal disease or a decline in eGFR more significant than 30% from baseline^[60]. Additionally, the elevated levels of gamma-glutamyl transferase and alkaline phosphatase are linked to renal failure. This highlights the need for dose modifications in patients with liver impairment to avoid possible toxicity from drug accumulation^[60].

In a study involving 30 patients with chronic obstructive pulmonary disease (COPD) having lobectomies, continuous ketamine infusion significantly improved arterial oxygenation (PaO₂/FiO₂) and reduced shunt fraction (Qs/Qt) during one-lung ventilation. Improvements were statistically significant 60 min after infusion^[61]. Furthermore, in a cohort of 100 patients with COPD on mechanical ventilation who were receiving continuous ketamine infusions at 24, 48, and 72 h following the initial stages, there were notable decreases in the need for opioids and benzodiazepines. Between 24 and 72 h, the median propofol requirements decreased from 54.7 mg/kg to 34.2 mg/kg. This highlights how effectively ketamine works in controlling sedation and lowering the danger of respiratory depression^[62].

Moreover, the way in which patients react to ketamine treatment may be affected by some mental comorbidities such as PTSD and generalized anxiety disorder. A clinical trial involving 158 veterans with PTSD who had not responded to prior antidepressant therapies found that the standard dose of IV ketamine (0.5 mg/kg) significantly improved depression symptoms as measured by the MADRS, but it did not significantly reduce PTSD symptoms as measured by the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (PCL-5) or the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)^[63]. Ketamine may have quick antidepressant effects, but its effectiveness for PTSD, in particular, is yet unknown and may differ depending on how severe the comorbid illnesses are.

Cancer patients represent a unique group where comorbid conditions such as depression are prevalent due to the emotional and physical toll of their diagnosis and treatment. A systematic review highlighted that ketamine has the potential to be a useful supplementary therapy since it can quickly alleviate depressed symptoms, especially in postoperative situations^[64]. However, a customized dose is necessary to maximize ketamine’s effectiveness and safety for this population. A customized strategy is required because of the variability in patient responses, which is impacted by variables such as cancer type, stage, treatments, and comorbidities. Azari et al administered ketamine based on body weight starting at 0.1 mg/kg/h and titrating up to a maximum of 20 mg/h to ensure that each patient received an appropriate dose^[64]. A more accurate balance between therapeutic effectiveness and safety was made possible by this weight-based dosing approach in conjunction with continuous evaluations to monitor side effects, which maximized the antidepressant effects in cancer patients. Healthcare professionals can increase the therapeutic advantages of ketamine for depressed cancer patients by using this individualized method.

Pregnancy and breastfeeding

Ketamine treatment during pregnancy needs to be carefully considered due to the potential risks to fetal development. The effects of a single low-dose ketamine infusion (0.5 mg/kg) on postpartum depression ratings were investigated in a pilot randomized trial involving 66 women with prenatal depressive symptoms^[65]. At 48 h postpartum, the median depression levels were 9 and 8, respectively. The ketamine and placebo groups did not differ significantly. Despite its absence of a statistically significant antidepressant effect, ketamine was associated with less pain for 4 h after surgery and less intraoperative nausea (0% vs. 21.2% in the placebo group)^[65]. The FDA advises against the use of ketamine in pregnancy and breastfeeding due to insufficient safety data^[65,66]. However, available clinical evidence indicates that ketamine and its metabolites are excreted in low levels in breast milk, and its poor oral bioavailability suggests a minimal risk to infants^[67]. Ketamine should only be administered to nursing mothers while a clinician closely monitors the newborn to reduce any potential adverse effects^[65,67]

Concomitant medications

Many patients with comorbid disorders are taking many different medications that may interact with ketamine by changing its effectiveness or raising the risk of side effects. As a result, polypharmacy is an important consideration when customizing the dose of ketamine. An RCT involving 47 veterans with PTSD found that 40% were taking concurrent benzodiazepines^[68]. This study demonstrated that patients on higher doses of benzodiazepines (greater than 8 mg diazepam equivalent) had a significantly lower response to ketamine treatment. Specifically, only 28% of these patients achieved a ≥50% reduction in MADRS within 1 week post-infusion. Receiver operating characteristic (ROC) analysis indicated that >8 mg threshold had an 80% sensitivity and 85% specificity for identifying nonresponders. Additionally, repeated measures ANOVA showed significantly worse outcomes for patients on higher benzodiazepine doses on Days 3 and 7 following treatment^[68].

Beyond benzodiazepines, other classes of medications can also impact the outcomes of ketamine treatment. Patients with TRD frequently use antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs). The rapid antidepressant benefits of ketamine may be considerably reduced by taking SSRIs at the same time. Riggs et al. found that following ketamine treatment, only 35% of patients taking SSRIs exhibited an improvement in their depression levels^[69]. In addition to SSRIs, SNRIs can also influence the effectiveness of ketamine. The presence of these medications may interfere with ketamine’s mechanism of action, which is primarily glutamatergic rather than serotonergic^[69].

Concomitant medications that affect the cytochrome P450 enzyme system can significantly alter the metabolism and efficacy of ketamine. In particular, CYP3A4 is the primary enzyme responsible for the N-demethylation of ketamine in human liver microsomes. It was found that CYP3A4 suppression significantly decreased ketamine metabolism, which affected its therapeutic effects^[70]. Although ketamine plasma levels were higher in patients on carbamazepine, their therapeutic benefits were decreased. This suggests that these drugs can alter the pharmacokinetics of ketamine and reduce its clinical effectiveness^[70].

Considerations and contraindications of ketamine

Ketamine is widely used, so caution should be considered when using especially in cardiac patients^[71] with hemodynamically unstable patients, as it can affect the heart rate, blood pressure, and cardiac index, so it should be avoided in any vital unstable patient or with any susceptibility to increasing blood pressure^[72].

According to the FDA, ketamine is contraindicated in obstetrics, pregnancy, or breastfeeding and any previous known allergy to ketamine^[73,74]. While ketamine is used in depression, it is not recommended to be used in schizophrenic patients as it may worsen the disease symptoms^[75].

Furthermore, multiple toxicities may also occur, as neurotoxicity mentioned by a study that was using ketamine for over 3 h in children ≤3 years may progress to a cognitive deficit caused by neuronal apoptosis by blocking NMDA receptors^[76,77]. Additionally, several case studies reported separate cases of sclerosing cholangitis and hepatotoxicity due to inflammation and irritation of the biliary tract, leading to an acute or chronic cholestatic liver injury^[78–81]. Ketamine was previously contraindicated in intracranial hypertension because cerebrospinal fluid pressure can rise as a result of its use, especially in individuals with elevated cerebrospinal fluid (CSF). However, recent studies show a few, no, or opposite effects^[12,82]. Ketamine affects the urinary tract, and the patient presents with many symptoms, such as cystitis, uropathy, and upper urinary tract dysfunction^[83–86].

Limitations

While this review provides a comprehensive analysis of ketamine dosing strategies across various clinical applications, several limitations should be acknowledged. The reviewed literature includes studies with varying methodologies, patient populations, and outcome measures, making direct comparisons challenging. Differences in dosing regimens, administration routes, and follow-up durations limit the ability to establish uniform dosing guidelines. Most studies focus on short-term outcomes, with insufficient data on the long-term safety, efficacy, and potential risks of repeated ketamine administration, particularly in chronic conditions like depression and pain management. Positive results are more likely to be published than negative or inconclusive findings, which may skew the perceived effectiveness of ketamine in certain applications. Individual differences in metabolism, comorbidities, and concomitant medications can significantly influence ketamine’s effects, making standardized dosing difficult. Additionally, many recommendations are based on small-scale studies, case reports, or observational data. Larger, well-designed RCTs are needed to validate optimal dosing strategies. While weight-based dosing is common, factors such as body composition, age, and organ function (e.g., hepatic/renal impairment) may necessitate alternative dosing approaches that are not yet well-defined. The potential for adverse effects (e.g., hallucinations, hypertension, and tachycardia) complicates dosing, particularly in vulnerable populations such as those with psychiatric or cardiovascular conditions. While IV ketamine is well-studied, data on IN, IM, and oral formulations remain limited, restricting broader clinical applicability. Ketamine’s abuse potential and regulatory restrictions in some regions may limit its widespread adoption and the availability of high-quality studies. Drug interactions (e.g., with benzodiazepines, SSRIs, or CYP3A4 inhibitors/inducers) can alter ketamine’s pharmacokinetics and efficacy, yet optimal adjustments remain understudied.

While, IV ketamine is FDA-approved for anesthesia, and esketamine is FDA-approved for TRD, many other indications – including the use of racemic ketamine for depression, chronic pain, and PTSD – remain off-label and are still awaiting more robust evidence and, in some cases, regulatory approval.

Future research directions

Potential future research paths for improving ketamine dose include investigating the impact of active metabolites like 2R and 6R-hydroxynorketamine, which may contribute to antidepressant properties^[87]. Furthermore, long-term trials with repeated doses are required to investigate the development of tolerance, as previous research has only involved single doses with large washout intervals^[87]. Elkomy et al investigated the application of AI and pharmacokinetic modeling to improve ketamine dose in pediatric patients and recommended weight-based dosing to reduce age-dependent variability. A dosing regimen of 2.25 mg/kg IV bolus followed by 0.1 mg/kg/min infusion efficiently induced anesthesia in 3 min and lasted up to 3 h^[56]. However, drawbacks include a limited sample size, a broad age range, and a lack of data on hepatic and renal function, all of which might impair a dose model’s accuracy^[56]. Additional clinical studies are necessary to verify these findings before widespread clinical use.

Additional research is necessary to refine ketamine dosing protocols for neuropathic pain. It is essential to conduct well-designed, prospective comparative efficacy studies that explore various ketamine infusion methods, including different dosages, durations, and the use of adjunctive medications^[31]. These studies should uncover characteristics that enhance outcomes for illnesses like complex regional pain syndrome and postherpetic neuralgia or long-term pain in shingles-affected areas, as present data is insufficient to offer conclusive recommendations^[31].

To increase accessibility and reduce clinical resource demands, less invasive forms of ketamine administration, such as IM and IN routes, should be explored. Research should also aim to ensure thorough access to ketamine therapies, particularly for low-income populations, and investigate potential associative benefits when combined with psychotherapy^[88].

Further research is needed to better define the long-term effects of subanesthetic doses of ketamine and to develop standard treatment guidelines, especially for IN administration, which has shown promise due to its simplicity and effectiveness. Further studies are also needed to assess the safety and efficacy profile of different ketamine induction frequencies across diverse patient groups^[19].

Conclusion

Tailored ketamine-dosing strategies are important for optimal clinical outcomes in its various clinical applications including anesthesia, analgesia, and psychiatric disorders. This review highlights the importance of individualized treatment plans to maximize therapeutic benefits while minimizing risks. Clinicians are encouraged to adopt a patient-centered approach, leveraging available evidence to tailor ketamine regimens that align with specific clinical objectives.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Funding

This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

A.M.K., A.S.E., R.S., and N.A.K: Validation of idea. A.M.K., R.S., A.S.E., and N.A.K.: Original draft preparation. N.S.J., E.A.H., and A.M.A.: Writing. A.S.E. and N.A.K.: Supervision. R.S. and A.S.E.: Writing – Reviewing and Editing.

Conflicts of interest disclosure

The authors declare no competing interest.

Guarantor

Reem Sayad.

Research registration unique identifying number (UIN)

Not required.

Provenance and peer review

Not invited.

Data availability

Not applicable.